Volume 16 • Number 4 • November 2017 NephSAP ® Nephrology Self-Assessment Program Transplantation Co-Editors: John P. Vella, MD Alexander C. Wiseman, MD Co-Directors: Gerald Hladik, MD Jerry Yee, MD CO-DIRECTOR, NephSAP Gerald A. Hladik, MD University of North Carolina at Chapel Hill Chapel Hill, NC CO-DIRECTOR, NephSAP Jerry Yee, MD, FASN Henry Ford Hospital Detroit, MI MANAGING EDITOR Gisela Deuter, BSN, MSA Washington, DC ASSOCIATE EDITORS Debbie L. Cohen, MD University of Pennsylvania School of Medicine Philadelphia, PA Richard J. Glassock, MD Professor Emeritus, The David Geffen School of Medicine at the University of California Los Angeles, CA Stanley Goldfarb, MD University of Pennsylvania School of Medicine Philadelphia, PA Karen A. Griffin, MD, FASN Loyola University Medical Center Maywood, IL Jay L. Koyner, MD University of Chicago Chicago, IL Holly J. Kramer, MD Loyola University Medical Center Maywood, IL Ruediger W. Lehrich, MD Duke University Durham, NC Kevin J. Martin, MBBCh St. Louis University School of Medicine St. Louis, MO John P. Middleton, MD Duke University Durham, NC Sankar D. Navaneethan, MD, MPH Baylor College of Medicine Houston, TX Preface NephSAPÒ is one of the premiere educational activities of the American Society of Nephrology (ASN). Its primary goals are self-assessment, education, and the provision of Continuing Medical Education (CME) credits and Maintenance of Certification (MOC) points for individuals certified by the American Board of Internal Medicine. Members of the ASN receive NephSAP electronically through the ASN website by clicking on the NephSAP link under “Education and Meetings” tab. EDUCATION: Medical and nephrologic information continually accrues at a rapid pace. Bombarded from all sides with demands on their time, busy practitioners, academicians, and trainees at all levels are increasingly challenged to review and understand new and evolving evidence. Each bimonthly issue of NephSAP is dedicated to a specific theme, i.e., to a specific area of clinical nephrology, hypertension, dialysis, and transplantation, and consists of an editorial, a syllabus, and self-assessment questions, to serve as a self-study device. Over the course of 24 months, all clinically relevant and key elements of nephrology will be reviewed and updated. The authors of each issue digest, assimilate, and interpret key studies published since the release of the previous issues and integrate this new material with the body of existing information. Occasionally a special edition is produced to cover an area not ordinarily addressed by core issues of NephSAP. SELF-ASSESSMENT: Thirty, single-best-answer questions will follow the 80 to 100 pages of syllabus text. The examination is available online with immediate feedback. Those answering 75% correctly will receive MOC and CME credit, and receive the answers to all the questions along with brief discussions and an updated bibliography. Members will find a new area reviewed every 2 months, and they will be able to test their understanding with our quiz. This format will help readers stay up to date in developing areas of clinical nephrology, hypertension, dialysis, and transplantation, and the review and update will support those taking certification and recertification examinations. CONTINUING MEDICAL EDUCATION: Most state and local medical agencies as well as hospitals are demanding documentation of requisite CME credits for licensure and for staff appointments. A maximum of 50 credits annually can be obtained by successfully completing the NephSAP examinations. In addition, individuals enrolled in Maintenance of Certification (MOC) through the American Board of Internal Medicine may obtain points toward MOC by successfully completing the self-assessment examination of NephSAP. This paper meets the requirements of ANSI/NISO Z39.48-1921 (Permanence of Paper), effective with July 2002, Vol. 1, No. 1. Asghar Rastegar, MD Yale School of Medicine New Haven, CT Brad H. Rovin, MD Ohio State University Medical Center Columbus, OH Manoocher Soleimani, MD University of Cincinnati Cincinnati, OH Charuhas V. Thakar, MD University of Cincinnati Cincinnati, OH John P. Vella, MD Maine Medical Center Portland, ME Alexander C. Wiseman, MD University of Colorado at Denver Denver, CO FOUNDING EDITORS Richard J. Glassock, MD Editor-in-Chief Emeritus Robert G. Narins, MD NephSAPÒ Ó2017 by The American Society of Nephrology Volume 16, Number 4, November 2017 273 Editorial 295 Recipient Factors Modern Hepatitis C Virus Therapy and Its Effect on Transplantation 295 Delayed Graft Function and Rejection Risk Andrew F. Malone, Daniel C. Brennan Syllabus 280 NephSAP, Volume 16, Number 4, November 2017— Transplantation John P. Vella, Alexander C. Wiseman 280 Learning Objectives 280 Access to Transplantation and Outcomes 280 Patient and Graft Survival 282 Ethnicity 283 Physical Frailty 283 Cardiovascular Outcomes 284 Obesity 284 Immunosuppression 296 Induction Therapy 298 Maintenance Therapy 298 Tacrolimus 300 Pharmacokinetics 301 Extended Release Tacrolimus 301 Antimetabolite Therapy 302 Belatacept 302 Steroid Therapy 303 Mammalian Target of Rapamycin Inhibitor Therapy 305 Discarded Kidneys 286 Deceased Donor Hypothermia 286 Use of Hepatitis C Virus–Seropositive Kidneys 286 Prior Living Donors in Need of Transplantation 287 Public Health Service Increased Risk Donors Rejection 307 Temporal Dynamics 307 Transfusion 307 Novel Rejection Mediators 308 Adherence 308 Gene Activation 308 Subclinical Rejection 309 Antibody-Mediated Rejection 310 Immunoglobulin Subtypes 311 Histoincompatibility Strategies Deceased Donor Kidney Allocation 285 288 296 Living Kidney Donation 288 Kidney Paired Donation 289 Living Donor Kidney Function Assessment 289 Medically Complex Living Donors 290 Surgery Complications 290 Pregnancy Risk 315 291 Kidney Failure Risk 316 Clinical Tolerance Induction 291 Prior Living Donors and Kidney Transplantation 317 Biomarkers 292 APOL1 319 292 Other Complications 319 Proteinuria in the Post-Transplant Setting 320 Glomerular Disease: Post-Transplant Outcomes 293 Delayed Graft Function 312 ABO-Incompatible Transplantation 314 HLA Antibody Desensitization 314 Novel Desensitization Strategies Clinical Tolerance Glomerular Injury Post-Transplant 293 Premortem AKI 320 Focal and Segmental Glomerulosclerosis 294 Predonation Interventions 321 Membranous Nephropathy 294 Procedure Times 321 APOL1 and Kidney Transplantation Volume 16, Number 4, November 2017 321 323 Complement-Mediated Glomerular Disease Infection after Transplant Interventions and Outcomes 340 342 Bone and Mineral Disorders 324 Cytomegalovirus 342 Hyperparathyroidism 324 BK Virus 343 Osteoporosis 325 HIV 345 327 Hepatitis C Virus 345 Simultaneous Pancreas-Kidney Transplantation 328 Hepatitis B Virus 346 Simultaneous Liver-Kidney Transplantation 328 Epstein Barr Virus 347 Multiorgan Transplantation: Utility Considerations 329 Malignancy and Kidney Transplantation 330 Risk Factors for Malignancy in the Transplant Recipient 333 Transplant Candidate Cancer Screening 334 Recipient Screening for Malignancy 335 Cancer Management in the Transplant Recipient 336 Cardiovascular Disease Multiorgan Transplant 347 Pregnancy 349 Acid-Base and Electrolyte Disorders after Transplant CME Self-Assessment Questions 350 NephSAP, Volume 16, Number 4, November 2017— Transplantation Upcoming Issues Hypertension 336 Pretransplant Screening 337 Hypertension 338 Post-Transplant Diabetes Mellitus 338 Hyperlipidemia 339 Obesity June 2018 339 Nontraditional and Novel Cardiovascular Risk Factors under Investigation Interventional Nephrology and Dialysis Access 339 Structural Parameters 339 Biochemical Markers 340 Clinical Features Debbie L. Cohen, MD and Karen A. Griffin, MD March 2018 Primary and Secondary Glomerular Diseases Richard J. Glassock, MD and Brad H. Rovin, MD Anil Agarwal, MD, Lalathaksha Kumbar, MD and Vandana Dua Niyyar, MD July 2018 Disorders of Divalent Ions, Renal Bone Disease, and Nephrolithiasis Stanley Goldfarb, MD and Kevin J. Martin, MBBCh September 2018 Volume 16, Number 4, November 2017 The Editorial Board of NephSAP and KSAP extends its sincere appreciation to the following reviewers. Their efforts and insights help improve the quality of these postgraduate education offerings. NephSAP Review Panel Mustafa Ahmad, MD, FASN King Fahad Medical City Riyadh, Saudi Arabia Chokchai Chareandee, MD, FASN University of Minnesota Minneapolis, MN Pedram Fatehi, MD Stanford Medicine Palo Alto, CA Nasimul Ahsan, MD, FASN University of Florida and Oscar G. Johnson Veteran Affairs Medical Center Iron Mountain, MI Joline L. Chen, MD Long Beach Veteran Affairs Healthcare System Orange, CA William H. Fissell, MD Vanderbilt University Medical Center Nashville, TN Jafar Al-Said, MD, FASN Bahrain Specialist Hospital Manama, Bahrain Carmichael Angeles, MD, FASN John T. Mather Memorial Hospital Stony Brook, NY Kisra Anis, MBBS Jacobi Medical Center/ Albert Einstein College of Medicine Bronx, NY Naheed Ansari, MD, FASN Jacobi Medical Center/Albert Einstein College of Medicine Bronx, NY Karen Ching, MD Hawaii Permanente Medical Group Honolulu. HI W. James Chon, MD University of Arkansas for Medical Sciences Little Rock, AR Lynda A. Frassetto, MD, FASN University of California at San Francisco San Francisco, CA Jason Cobb, MD Emory University School of Medicine Atlanta, GA Tibor Fulop, MD University of Mississippi Medical Center Jackson, MS Armando Coca, MD, PhD Hospital Clínico Universitario Valladolid, Spain Scott D. Cohen, MD, FASN George Washington University Washington, DC Nabeel Aslam, MD, FASN Mayo Clinic Florida Jacksonville, FL Beatrice Concepcion, MD Vanderbilt University Medical Center Nashville, TN Nisha Bansal, MD University of Washington Seattle, WA Gabriel Contreras, MD University of Miami Miami, FL Krishna M. Baradhi, MD University of Oklahoma Tulsa, OK Patrick Cunningham, MD University of Chicago Chicago, IL Emmy Bell, MD, MSPH University of Alabama at Birmingham Birmingham, AL Kevin A. Curran, MD Kevin A. Curran, MD, PA Canton, TX Bruce E. Berger, MD Case Western Reserve University Cleveland, OH Rajiv Dhamija, MD Rancho Los Amigos National Rehabilitation Center Downey, CA Mona B. Brake, MD Robert J. Dole Veteran Affairs Medical Center Wichita, KS D. Kevin Flood, MD Mike O’Callaghan Federal Medical Center Nellis AFB, NV Alejandro Diez, MD The Ohio State University Columbus, OH Pooja Budhiraja, MBBS University of Kansas Medical Center Kansas City, KS John J. Doran, MD Emory School of Medicine Atlanta, GA Ruth C. Campbell, MD Medical University of South Carolina Charleston, SC Randa A. El Husseini, MD, FASN HealthPartners Medical Group St. Paul, MN Chia-Ter Chao, MD National Taiwan University Hospital Taipei, Taiwan Mahmoud El-Khatib, MD University of Cincinnati Cincinnati, OH Maurizio Gallieni, MD, FASN University of Milano Milano, Italy Duvuru Geetha, MD, FASN Johns Hopkins University Baltimore, MD Ilya Glezerman, MD Memorial Sloan Kettering Cancer Center New York, NY Carl S. Goldstein, MD, FASN Rutgers University New Brunswick, NJ Basu Gopal, MBBS, FASN Royal Adelaide Hospital Adelaide, Australia Steven Gorbatkin, MD, PhD Emory University and Atlanta Veteran Affairs Medical Center Decatur, GA Aditi Gupta, MD University of Kansas Medical Center Kansas City, KS Susan Hedayati, MD University of Texas Southwestern Dallas, TX Marie C. Hogan, MBBCh, PhD Mayo Clinic Rochester, MN Susie Hu, MD Warren Alpert Medical School of Brown University, Rhode Island Hospital Providence, RI Edmund Huang, MD University of California at Los Angeles School of Medicine Los Angeles, CA Ekambaram Ilamathi, MD, FASN Northwell Health, Southside Hospital Bayshore, NY Joshua M. Kaplan, MD Rutgers New Jersey Medical School Newark, NJ Amir Kazory, MD University of Florida Gainesville, FL Quresh T. Khairullah, MD St. Clair Nephrology Roseville, MI Apurv Khanna, MD State University of New York Upstate Medical University Syracuse, NY Yong-Lim Kim, MD, PhD Kyungpook National University Hospital Daegu, South Korea Nitin V. Kolhe, MD, FASN Derby Teaching Hospital NHS Trust Derby, Derbyshire, UK Farrukh M. Koraishy, MD, PhD St. Louis University St. Louis, MO Eugene C. Kovalik, MD Duke University Medical Center Durham, NC Steven Kraft, MD Western Nephrology Lafayette, CO Tingting Li, MD Washington University in St. Louis St. Louis, MO Todd Pesavento, MD Ohio State University Columbus, OH Orfeas Liangos, MD, FASN Klinikum Coburg Coburg, Bayern, Germany Phuong-Thu Pham, MD David Geffen School of Medicine at UCLA Los Angeles, CA Michael Lioudis, MD Cleveland Clinic Nephrology Cleveland, OH Pairach Pintavorn, MD, FASN East Georgia Kidney and Hypertension Augusta, GA Ajit Mahapatra, MD The Permanente Medical Group Santa Clara, CA A. Bilal Malik, MBBS University of Washington Seattle, WA Jolanta Malyszko, MD, PhD Medical University Bialystok, Poland Ernest Mandel, MD Brigham and Women’s Hospital Boston, MA Naveed N. Masani, MD Winthrop University Hospital Mineola, NY Teri Jo Mauch, MD, PhD University of Nebraska College of Medicine Omaha, NE James M. Pritsiolas, MD, FASN CarePoint Health - Bayonne Medical Center Bayonne, NJ Paul H. Pronovost, MD, FASN Yale University School of Medicine Waterbury, CT Mohammad A. Quasem, MD, FASN State University of New York Medical University Binghamton, NY Wajeh Y. Qunibi, MD University of Texas Health Science Center San Antonio, TX Hanna W. Mawad, MD, FASN University of Kentucky Lexington, KY Pawan K. Rao, MD, FASN St. Joseph’s Hospital and Health Center Syracuse, NY Ellen T. McCarthy, MD University of Kansas Medical Center, Kidney Institute Kansas City, KS Hernan Rincon-Choles, MD Cleveland Clinic Foundation Cleveland, OH Vineeta Kumar, MD University of Alabama at Birmingham Birmingham, AL Kirtida Mistry, MBBCh Children’s National Medical Center Washington, DC Sarat Kuppachi, MD University of Iowa Iowa City, IA Lawrence S. Moffatt, MD Carolinas Medical Center Charlotte, NC Norbert H. Lameire, MD, PhD University Hospital Gent, East Flanders, Belgium David B. Mount, MD Brigham and Women’s Hospital, Harvard Medical School Boston, MA Sheron Latcha, MD Memorial Sloan Kettering Cancer Center New York, NY Roberto Pisoni, MD Medical University of South Carolina Charleston, SC Dario Roccatello, MD San Giovanni Hospital and University of Torino Torino, Italy Helbert Rondon-Berrios, MD, FASN University of Pittsburgh School of Medicine Pittsburgh, PA Ehab R. Saad, MD, FASN Medical College of Wisconsin Milwaukee, WI Thangamani Muthukumar, MD Weill Cornell Medicine New York, NY Vincent Weng Seng Lee, MBBS, PhD Westmead Hospital Sydney, NSW Australia Mark C. Saddler, MBChB Mercy Regional Medical Center Durango, CO Mohanram Narayanan, MD Baylor Scott & White Health Temple, TX Neil Sanghani, MD Vanderbilt University Nashville, TN Paolo Lentini, MD, PhD St. Bortolo Hospital Bassano del Grappa, Italy Macaulay A. Onuigbo, MD Mayo Clinic Rochester, MN Mohammad N. Saqib, MD Lehigh Valley Hospital Allentown, PA Oliver Lenz, MD University of Miami Health System Miami, FL Rosemary Ouseph, MD St. Louis University Webster Groves, MO Hitesh H. Shah, MD Hofstra Northwell School of Medicine Great Neck, NY Michiko Shimada, MD, PhD Hirosaki University Hirosaki, Japan Hung-Bin Tsai, MD National Taiwan University Hospital Taipei, Taiwan Nand K. Wadhwa, MD Stony Brook University Stony Brook, NY Shayan Shirazian, MD Winthrop-University Hospital State University of New York at Stony Brook Mineola, NY Katherine Twombley, MD Medical University of South Carolina Charleston, SC Connie Wang, MD Hennepin County Medical Center Minneapolis, MN Kausik Umanath, MD Henry Ford Hospital Detroit, MI Maura A. Watson, DO Walter Reed National Military Medical Center Bethesda, MD Puchimada M. Uthappa, MBBS, FASN Columbia Asia Hospital Mysore, Karnataka, India Dawn Wolfgram, MD Medical College of Wisconsin Milwaukee, WI Anthony M. Valeri, MD Columbia University Medical Center New York, NY Sri Yarlagadda, MBBS University of Kansas Medical Center Kansas City, KS Allen W. Vander, MD, FASN Kidney Center of South Louisiana Thibodaux, LA Brian Young, MD Santa Clara Valley Medical Center San Jose, CA Arif Showkat, MD, FASN University of Tennessee Memphis, TN Stephen M. Sozio, MD Johns Hopkins University School of Medicine Baltimore, MD Ignatius Yun-Sang Tang, MD, FASN University of Illinois at Chicago Chicago, IL Ahmad R. Tarakji, MD King Saud University, King Khalid University Hospital Riyadh, Saudi Arabia Jon R. Von Visger, MD, PhD The Ohio State University Columbus, OH Mario Javier Zarama, MD Kidney Specialists of Minnesota, PA Saint Paul, MN Volume 16, Number 4, November 2017 Program Mission and Objectives The Nephrology Self-Assessment Program (NephSAP) provides a learning vehicle for clinical nephrologists to renew and refresh their clinical knowledge, diagnostic, and therapeutic skills. This enduring material provides nephrologists challenging, clinically oriented questions based on case vignettes, a detailed syllabus that reviews recent publications, and an editorial on an important and evolving topic. This combination of materials enables clinicians to rigorously assess their strengths and weaknesses in the broad domain of nephrology. Accreditation Statement The American Society of Nephrology (ASN) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. AMA Credit Designation Statement The ASN designates this enduring material for a maximum of 10 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Original Release Date November 2017 CME Credit Termination Date October 31, 2019 Examination Available Online On or before Wednesday, November 15, 2017 Estimated Time for Completion 10 hours Answers with Explanations Provided with a passing score after the first and/or after the second attempt November 2019: posted on the ASN website when the issue is archived. • • Target Audience Nephrology certification and recertification candidates Practicing nephrologists Internists • • • Method of Participation Read the syllabus that is supplemented by original articles in the reference lists. Complete the online self-assessment examination. Each participant is allowed two attempts to pass the examination (.75% correct) for CME credit. Upon completion, review your score and incorrect answers and print your certificate. Answers and explanations are provided with a passing score or after the second attempt. • • • • • Volume 16, Number 4, November 2017 Activity Evaluation and CME Credit Instructions Go to www.asn-online.org/cme, and enter your ASN login on the right. Click the ASN CME Center. Locate the activity name and click the corresponding ENTER ACTIVITY button. Read all front matter information. On the left-hand side, click and complete the Demographics & General Evaluations. Complete and pass the examination for CME credit. Upon completion, click Claim Your CME Credits, check the Attestation Statement box, and enter the number of CME credits commensurate with the extent of your participation in the activity. If you need a certificate, Print Your Certificate on the left. • • • • • • • • For your complete ASN transcript, click the ASN CME Center banner, and click View/Print Transcript on the left. Instructions to obtain American Board of Internal Medicine (ABIM) Maintenance of Certification (MOC) Points Each issue of NephSAP provides 10 MOC points. Respondents must meet the following criteria: Be certified by ABIM in internal medicine and/or nephrology and enrolled in the ABIM–MOC program Enroll for MOC via the ABIM website (www.abim.org). Enter your (ABIM) Candidate Number and Date of Birth prior to completing the examination. Take the self-assessment examination within the timeframe specified in this issue of NephSAP. Upon completion, click Claim Your MOC points, the MOC points submitted will match your CME credits claimed, check the Attestation Statement box and submit. ABIM will notify you when MOC points have been added to your record. • • • • • • Maintenance of Certification Statement Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 10 MOC points in the American Board of Internal Medicine’s (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider’s responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. MOC points will be applied to only those ABIM candidates who have enrolled in the MOC program. It is your responsibility to complete the ABIM MOC enrollment process. System Requirements Compatible Browser and Software The ASN website (asn-online.org) has been formatted for cross-browser functionality, and should display correctly in all modern web browsers. To view the interactive version of NephSAP, your browser must have Adobe Flash Player installed or have HTML5 capabilities. NephSAP is also available in Portable Document Format (PDF), which requires Adobe Reader or comparable PDF viewing software. Monitor Settings The ASN website was designed to be viewed in a 1024 · 768 or higher resolution. Medium or Combination of Media Used The media used include an electronic syllabus and online evaluation and examination. Technical Support If you have difficulty viewing any of the pages, please refer to the ASN technical support page for possible solutions. If you continue having problems, contact ASN at [email protected]. Volume 16, Number 4, November 2017 Disclosure Information The ASN is responsible for identifying and resolving all conflicts of interest prior to presenting any educational activity to learners to ensure that ASN CME activities promote quality and safety, are effective in improving medical practice, are based on valid content, and are independent of the control from commercial interests and free of bias. All faculty are instructed to provide balanced, scientifically rigorous and evidence-based presentations. In accordance with the disclosure policies of the Accreditation Council for Continuing Medical Education (ACCME), individuals who are in a position to control the content of an educational activity are required to disclose relationships with a commercial interest if (a) the relation is financial and occurred within the past 12 months; and (b) the individual had the opportunity to affect the content of continuing medical education with regard to that commercial interest. For this purpose, ASN consider the relationships of the person involved in the CME activity to include financial relationships of a spouse or partner. Peer reviewers are asked to abstain from reviewing topics if they have a conflict of interest. Disclosure information is made available to learners prior to the start of any ASN educational activity. EDITORIAL BOARD for this Issue: Gerald A. Hladik, MD, FASN—Current Employer: University of North Carolina at Chapel Hill; Honoraria: Renal Research Institute; Scientific Advisor/Membership: ASN Co-Director, NephSAP; Board Member, Renal Research Institute Ruediger W. Lehrich, MD—Current Employer: Duke University Medical Center Manoocher Soleimani, MD—Current Employer: University of Cincinnati; Scientific Advisor/Membership: Editorial Board: American Journal of Kidney Disease John P. Vella, MD, FASN—Current Employer: Maine Nephrology Associates PA; Research Funding: Bristol-Myers Squibb, Astellas; Scientific Advisor/Membership: UpToDate Alexander C. Wiseman, MD—Current Employer: University of Colorado at Denver and Health Sciences Center; Research Funding: Novartis, Alexion, Bristol-Myers Squibb, Oxford Immunotec, Quark, Astellas; Scientific Advisor/Membership: American Society of Transplantation, American Journal of Transplantation Jerry Yee, MD, FASN—Current Employer: Henry Ford Hospital; Consultancy: OptumHealth, Merck, Vasc-Alert, Akebia, Mallinckrodt, CV-RX, Keryx, DynaMed/Ebsco, Abbvie; Ownership Interest: Merck, Gilead, Vasc-Alert; Honoraria: Washington University of St. Louis, National Kidney Foundation; Patents/Inventions: Vasc-Alert, Henry Ford Hospital; Scientific Advisor/Membership: NKF: Editor-in-Chief of Advances in CKD (journal); Editorial Board: American Journal of Nephrology, American Journal of Hypertension, CJASN, Heart Failure Journal; Section Editor: EBSCO DynaMed, ASN Co-Director, NephSAP; Other Interests: Elsevier and NKF, Editor-in-Chief, Advances in CKD EDITORIAL AUTHORS: Daniel C. Brennan, MD—Current Employer: Washington University in St. Louis; Consultancy: Alexion, CareDx, Immucor, Sanofi, Veloxis; Research Funding: Alexion, Astellas, Bristol-Myers Squib, CareDx, Oxford Immunotec, Shire, Veloxis; Honoraria: Alexion, Sanofi, Veloxis; Scientific Advisor/Membership: Editorial Board: Transplantation, UpToDate; Speakers Bureau: Alexion, Astellas, Novartis, Sanofi, Veloxis Andrew F. Malone, MBChB—Current Employer: Washington University in St. Louis; Ownership Interests: Gilead ASN STAFF: Gisela A. Deuter, BSN, MSA—Nothing to disclose Commercial Support There is no commercial support for this issue. Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 Editorial Modern Hepatitis C Virus Therapy and Its Effect on Transplantation Andrew F. Malone, MB, BCh, MRCPI, and Daniel C. Brennan, MD, FACP Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri anti–HCV-positive serology at the time of referral for transplant (compared with anti–HCV-negative serology patients) had a relative risk of death from all causes of 1.41 (95% confidence interval [95% CI], 1.01 to 1.97) and had a relative risk of death due to liver disease or infection of 2.39 (95% CI, 1.28 to 4.48). For those HCV-positive patients who went on to get transplanted (compared with those who remained on dialysis), the relative risks of death from all causes were 4.75 (95% CI, 2.76 to 8.17) between 0 and 3 months, 1.76 (95% CI, 0.75 to 4.13) between 3 and 6 months, 0.31 (95% CI, 0.18 to 0.54) between 3 months and 4 years, and 0.84 (95% CI, 0.51 to 1.37) after 4 years (3). Other more recent studies (but still 10 years old) have confirmed this increased risk in dialysis patients with HCV. A significant proportion of this risk was due to an excess of cardiovascular-associated mortality and liver disease–related risk (4–6). The hepatitis C virus (HCV) is a small, enveloped, single-stranded RNA virus from the family Flaviviridae. This virus is transmitted by contact with small amounts of blood and can also be transmitted sexually and from mother to baby; it is estimated that 71 million persons worldwide are infected with HCV, and it is most prevalent in eastern European regions. Between 15% and 45% of infected persons spontaneously clear the virus within 6 months of infection without any treatment. The remaining 55%–85% will develop chronic HCV infection. The risk of cirrhosis of the liver in those with chronic HCV infection is between 15% and 30% within 20 years (1). Infection is commonly occult, and nearly 80% of those who become infected do not have any symptoms. This observation renders screening for HCV important among at-risk groups and in areas of high prevalence. HCV and ESRD HCV is a significant issue among patients with ESRD. Patients on hemodialysis are at risk of infection due to exposure at hemodialysis units, and there is currently no vaccination for HCV in contrast to hepatitis B virus. The prevalence of HCV likely varies between different dialysis units due to patient behaviors and intravenous drug use in the surrounding community. Seroconversion rates also vary between dialysis units and likely reflect facility protocols and practices. The Dialysis Outcomes and Practice Patterns Study examined HCV infection in dialysis units by country (2). The unadjusted prevalence of HCV in United States centers was estimated at over 14%, with a seroconversion rate of three per 100 patient-years (between 1997 and 2001). Prevalence also increased with time on dialysis, rising to over 20% after 10 years. Perhaps the increased mortality and morbidity associated with HCV infection are more important. A nearly 20-year-old study using New England Organ Bank samples and data showed that waitlisted patients with HCV Infection in the Post-Transplant Patient There are complications in the post-transplant period related to HCV infection. There is an increase in secondary infections in patients with HCV posttransplant, and this is the second most common cause of death after cardiovascular disease among these patients (7–11). Extrahepatic malignancies, such as post-transplant lymphoproliferative disorder and myeloma, have been associated with HCV infection post-transplantation (12–14). Furthermore, there is a direct effect of HCV on lymphoid carcinogenesis, and regression of Hodgkin lymphoma with treatment of HCV has been shown (15,16). Patients with HCV are at increased risk of post-transplant diabetes mellitus, and post-transplant diabetes mellitus is an independent risk factor for death and graft loss (17). From the renal aspect, recurrence or de novo glomerular disease is also a concern, and post-transplant HCV infection, membranoproliferative GN (cryoglobulinemic and noncryoglobulinemic), membranous glomerulopathy, 273 274 anticardiolipin-associated glomerulopathy, and acute and chronic transplant glomerulopathy have all been described. Whether there is an increased risk of allograft rejection in patients with HCV infection is debated, but in general, HCV infection likely confers an increased degree of immunosuppression due to reduced number and responsiveness of T-helper lymphocytes (18). Finally, HCV infection increases the risk of hepatocellular carcinoma and liver cirrhosis (19). Despite the concerns for these complications, a clear survival advantage exists with kidney transplantation compared with remaining on dialysis with HCV. Ingsathit et al. (20) performed a meta-analysis of data reporting outcomes of HCV-positive patients who were transplanted compared with those who were not transplanted. This study used a random effects model and reported a pooled risk ratio (RR) for death at 5 years of 2.19 (95% CI, 1.50 to 3.20) for those remaining on the waiting list compared with those transplanted. These results and the advantage of transplantation existed before the modern era of direct-acting antiviral (DAA) therapy treatment of HCV infection posttransplantation. Before the advent of DAA drugs, treatment was rarely successful, and the use of IFN alfa is associated with increased risk of rejection and graft loss. Thus, treatment options were limited to ribavirin monotherapy; however, this strategy was controversial: improvement in liver histology was variable, and therapy was limited by a dose-dependent hemolytic anemia (21). Using HCV-Positive Donor Kidneys in the Pre-DAA Era There is no doubt that, even in the pre-DAA therapy era, ESRD patients with HCV infection benefited from kidney transplantation. However, whether this benefit remained when kidneys from donors with HCV were transplanted into HCV-positive recipients has always been controversial, and this practice varies widely. Decisions as to whether to use a kidney from an HCV-positive donor are center specific. It is known that transmission of HCV infection from donor to recipient is almost 100%. Therefore, only transplantation of HCV-positive donors to known HCV-positive recipients has occurred in routine practice to date (22). HCVpositive patients receiving an HCV-positive kidney transplant have worse outcomes compared with HCVpositive patients receiving an HCV-negative kidney (23). These issues led to the questions of for whom Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 (among HCV-positive recipients) and when we should use HCV-positive kidneys. Kucirka et al. (24) explored the use of HCV kidneys in HCV recipients and found that African Americans (RR, 1.56; 95% CI, 1.39 to 1.75), patients with diabetes (RR, 1.29; 95% CI, 1.18 to 1.40), and those at a center with long wait times (RR, 1.19 per quartile of waiting time; 95% CI, 1.06 to 1.33, P50.002) were more likely to receive an HCV-positive kidney. However, those who received HCV-positive kidneys waited 310 days less on the waitlist, and the authors suggested that this likely offsets the higher patient and graft loss associated with HCV-positive kidneys (24). Modern Era of HCV Treatment: DAAs A paradigm shift in the approach to HCV management due to the recent introduction of DAAs is likely to make such issues outlined above irrelevant soon. In 2011, the first generation DAAs for treatment of HCV were approved by the US Food and Drug Administration: telaprevir and boceprevir. Efficacy of these oral protease inhibitors was tested in two trials: A New Direction in HCV Care: A Study of Treatment-Naive Hepatitis C Patients with Telaprevir and Serine Protease Inhibitor Therapy 2 Study (25,26). When added to dual therapy of pegylated IFN (peg-IFN) and ribavirin for the treatment of HCV genotype 1 infections, these agents enhanced sustained virologic response (SVR) rates to about 70% but at the expense of increased toxicities. Since 2013, there has been explosive proliferation of new oral DAAs in the clinical arena with better tolerability, side effect profiles, and SVR rates (27– 39); also, treatment regimens are typically only 12 weeks in duration. DAAs for HCV are NS5A inhibitors, NS5B inhibitors, and NS3/4A protease inhibitors. Current therapies are combinations of two or more of these drug classes. These viral proteins are HCVencoded nonstructural proteins that constitute the HCV RNA replication machinery. NS5B is an RNAdependent RNA polymerase, NS5A is responsible for the assembly of the membrane-bound replication complex, and NS3/4A is a serine protease, an enzyme involved in post-translational processing and replication of HCV (40). Sofosbuvir is an NS5B inhibitor and currently, the most commonly prescribed DAA in combination therapy. This utilization pattern is largely attributable to the success of the Sofosbuvir/Velpatasvir Fixed Dose Combination for 12 Weeks in Adults With Chronic HCV Infection (ASTRAL-1) Trial, and the 275 x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x Any Over 30 ml/min Any; ESRD not studied Over 30 ml/min Over 30 ml/min Over 30 ml/min Reduce dose; ESRD not studied Listed are the most common DAA combinations available currently. Columns 3–13 represent HCV genotypes 1–6 and subgenotypes (1a and 1b). Each genotype is further divided into indications for C2 and C1 patients. DAA combinations with activity are marked x. Column 2 refers to FDA-recommended GFR limitations of use. FDA, Food and Drug Administration; C2, noncirrhotic; C1, cirrhotic. HCV has been successfully treated with modern DAA regimens in the postkidney transplant population. Elbasvir/grazaprevir Ledipasvir/sofosbuvir Paritaprevir/ritonavir/ ombitasvir/dasabuvir Simeprevir/sofosbuvir Sofosbuvir/velpatasvir Daclatasvir/sofosbuvir Paritaprevir/ritonavir/ ombitasvir/ribavirin DAAs and HCV Treatment Post-Transplantation 1a, C2 From the renal point of view, sofosbuvir’s hepatic metabolite is renally eliminated by 80%; however, renal elimination is not significant for all other DAAs. All currently licensed DAA regimens can be used in patients with a GFR.30 ml/min per 1.73 m2. Two studies have examined the use of DAA regimens in CKD patients with lower GFRs. In the RUBY-1 Trial, 12 weeks of paritaprevir/ritonavir/ ombitasvir/dasabuvir combination therapy were used in 20 noncirrhotic patients with drug-naı̈ve genotype 1 and GFR,30 ml/min per 1.73 m2 or on dialysis (41). Genotype 1a patients also received IFN. The 12week post-treatment SVR was reported in 90% of patients. In the C-SURFER Trial, 116 patients with CKD stage 4/5 or ESRD on maintenance dialysis were treated for 12 weeks with elbasvir/grazaprevir. These patients had genotype 1 HCV, and most were treatment naı̈ve and noncirrhotic. With this combination, 99% experienced an SVR at 12 weeks post-treatment (42). DAAs were well tolerated in both trials, except for ribavirin-treated patients, in whom anemia was common. The HCV-Therapeutic Registry and Research Network Trial is an observational trial following patients with renal disease on sofosbuvir-based regimens. Some regimens included ribavirin, and 12.3% of regimens included peg-IFN. SVR among the 73 patients with GFR,45 ml/min per 1.73 m2 was 83%. Anemia, worsening renal function, and serious side effects were more common in those with reduced GFR. The efficacy of lower doses of sofosbuvir in patients with low GFR was assessed by Bhamidimarri et al. (43). This group used 200 mg daily or 400 mg on alternate days with a standard dose of simeprevir in genotype 1 patients with GFRs,30 ml/min per 1.73 m2 or on dialysis (most had cirrhosis as well). SVRs were 75%– 100%, with best responses in noncirrhotic genotype 1a patients who were not on dialysis and were treated with sofosbuvir at 200 mg daily (43). Table 1. Spectrum of activity of direct-acting antiviral therapy DAAs and CKD FDA Label GFR DAA Combination Recommendation American Association for the Study of Liver Diseases guidelines state that sofosbuvir/velpatasvir is the only combination DAA therapy currently recommended for use in all genotypes, regardless of the presence of compensated cirrhosis (Table 1) (34,35). 1a, C1 1b, C2 1b, C1 2, C2 2, C1 3, C2 3, C1 4, C2 4, C1 5/6, C2/1 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 276 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 This was first reported in 2016 in the United States and European cohorts. In the United States study, 20 patients, primarily of genotype 1 (88%; genotype 2 was also treated) and most without cirrhosis (n516 of 20), received DAA drug therapy at a median of 888 days post-transplant. Maintenance immunosuppression was calcineurin inhibitors, antimetabolite agents, and prednisone. Serum creatinine levels at the initiation of treatment ranged from 0.86 to 2.18 mg/dl. All received a sofosbuvir-based regime (primarily treatment with sofosbuvir/simeprevir or sofosbuvir/ledipasvir), and three patients also received ribavirin. All patients cleared the virus and had an SVR at 12 weeks post-treatment (44). The French group treated 25 patients for posttransplant HCV infection. Genotypes 1a, 1b, 2, 3, and 4 were all represented, but genotype 1b was most common (n515). The median time from transplant to the start of DAA treatment was 146 months. All received sofosbuvirbased regimens (simeprevir/sofosbuvir or ledipasvir/ sofosbuvir), with two patients receiving a ribavirin-based regimen and one receiving sofosbuvir/ribavirin/peg-IFN. All drugs except ribavirin were not dose reduced for GFR. All patients had GFRs.30 ml/min per 1.73 m2 at the start of therapy. The SVR at 12 weeks post-treatment was 100% (45). In both studies, the average tacrolimus trough levels were lower post-therapy compared with the levels at the start of and during therapy. In both studies, drugs were well tolerated, with no significant side effects noted, and no rejection episodes occurred. It is important to understand the pharmacokinetics of DAAs in the setting of transplantation so that appropriate monitoring and dose adjustments can be made during and after therapy. Daclatasvir and sofosbuvir are not substrates of the cytochrome P450 isoenzymes 3A4/5 or the drug transporter P-glycoprotein. Therefore, no clinically significant interactions with common transplant immunosuppression drugs are expected. All DAAs in use today as single agents or in combination, except for sofosbuvir alone, have drugdrug interactions that need to be monitored (Table 2). In two previous trials of post-transplant HCV treatment, tacrolimus trough levels were decreased posttreatment by approximately 45%, despite no dose reductions. This decrease was postulated to result from improved hepatic enzyme function post-HCV viral clearance. The optimal treatment regime in post-transplant patients is dependent on GFR and genotype, with close monitoring of immunosuppression drug levels required. The ideal regimen has an SVR of 100%, is not cleared by the kidneys, treats all genotypes, and is easily available from a cost and regulation standpoint. No such combination currently exists. However, treatment efficacy in the post-transplant patient with available drugs is excellent. Given the huge disparity between the waitlist population and number of patients transplanted each year, new ways to increase the donor pool are always welcome. According to the Centers for Disease Control and Prevention, 3.4 million people in the United States are living with HCV infection (46). Using Organ Procurement Transplant Network donor registration data from 2012, 2.4% of deceased donors used were HCV serology positive (47). Approximately 50% of HCV-positive kidneys are discarded, and about 500 of these are highquality kidneys (48,49). Among nonextended criteria donor organs, HCV infection is the most likely reason for an organ to be discarded (24). Table 2. Direct-acting antiviral therapy and immunosuppression drug interactions Paritaprevira /Ritonavir/ Immunosuppressive Sofosbuvir/ Ledipasvir/ Elbasvir/ Ombitasvir/ Agent Velpatasvir Sofosbuvir Grazoprevira Dasabuvir Simeprevira Sofosbuvir Daclatasvir Tac Ciclo Myf Aza Everol Sirol A A A A C A A A A A C A C D A A C C C C C A C C C D A A C C A A A A A A A A A A C A According to www.hep-druginteractions.org (University of Liverpool). Tac, tacrolimus; A, no interactions; C, potential interactions; Ciclo, ciclosporin; D, do not administer; Myf, myfortic/cellcept; Aza, azathioprine; Everol, everolimus; Sirol, sirolimus. a NS3/4A protease inhibitors (most Cyp 3A inhibition). 277 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 Can We and Should We Use HCV-Positive Donor Kidneys in the HCV-Negative Recipient? Recent studies have examined the feasibility of transplanting HCV-positive kidneys into HCV-negative donors followed by immediate treatment with DAA regimens. The Zepatier for Treatment of Hepatitis C– Negative Patients Who Receive Kidney Transplants from Hepatitis C–Positive Donors (THINKER) Trial is a single-center, open-label trial of the use of HCVpositive kidneys in HCV-negative recipients (50). Early results have been reported, and the trial is still ongoing. This trial determined the safety and efficacy of using kidneys from HCV genotype 1 viremic donors followed by elbasvir/grazoprevir treatment. Recipients with any liver disease, HIV, hepatitis B virus, or HCV infection were excluded. HCV viremia post-transplant and genotype were confirmed in study subjects posttransplantation and before initiation of DAA therapy. Initiation of therapy on day 3 post-transplant was established because of the delay in confirming viremia and HCV genotype. Elbasvir/grazoprevir is only licensed for use in genotype 1 and 4 patients. Therefore, the investigators limited the THINKER Trial to genotype 1 patients. Ten patients were studied, and all patients cleared HCV and had an SVR at 12 weeks post-treatment. Median 6-month creatinine levels and GFRs were 1.1 mg/ dl and 62.8 ml/min per 1.73 m2, respectively. One patient had delayed graft function, two patients had transient transaminitis, and one patient developed transient class I de novo donor-specific antibodies. Before using HCV-positive kidneys in HCVnegative recipients, informed consent is required. However, most recipients who are HCV negative have little knowledge of their illness. One study determined how willing an HCV-negative recipient would be to accept an HCV-positive kidney. This study questioned 185 patients and found that 29% of patients would accept under any conditions and that over 50% would accept under certain conditions (51). Use of HCVpositive kidneys in HCV-negative patients is also cost effective on the basis of the assumption that cure rates remain .97% (52). The cost benefit of using HCVpositive kidneys is also suggested by a United Kingdom study (53). The elbasvir/grazoprevir combination was likely chosen in the THINKER Trial for its nonrenal elimination. Notably, this drug combination is not active against genotypes 2, 3, 5, and 6. Pangenotypic treatments that include sofosbuvir have not been studied in the immediate post-transplant period. This may represent a significant limitation in certain regions, and 50%–70% of donors in United States cohorts (the THINKER Trial, National Health and Nutrition Examination Survey, and Kaiser Permanente) are genotype 1a or 1b (54). Many insurance companies and some Medicaid programs will only approve the use of DAA therapy for patients with advanced biopsy-proven liver cirrhosis (Metavir fibrosis stages 2–4). This is likely due to the current high cost of DAAs and the opinions expressed by some professional societies. Namely, those with the greatest need should be treated first (55,56). Treatment of HCV post-transplantation will continue to be a challenge until payers make DAAs available to all HCV-infected patients. 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N Engl J Med 373: 303–305, 2015 PubMed Goldberg DS, Blumberg E, McCauley M, Abt P, Levine M: improving organ utilization to help overcome the tragedies of the opioid epidemic. Am J Transplant 16: 2836–2841, 2016 PubMed Goldberg DS, Abt PL, Blumberg EA, Van Deerlin VM, Levine M, Reddy KR, Bloom RD, Nazarian SM, Sawinski D, Porrett P, Naji A, Hasz R, Suplee L, Trofe-Clark J, Sicilia A, McCauley M, Farooqi M, Gentile C, Smith J, Reese PP: Trial of transplantation of HCVinfected kidneys into uninfected recipients. N Engl J Med 376: 2394– 2395, 2017 PubMed Reese PP, Goldberg D, Mussell A, McCauley M, Sawinski D, Molina N, Tomlin R, Doshi S, Abt P, Blumberg E, Thiessen C, Kulkarni S, Esnaola G: Willingness of end-stage renal disease patients (ESRD) without Hepatitis C (HCV) to accept a HCV1 kidney [Abstract]. Am J Transplant 17[Suppl 3], 2017. Available at: http://atcmeetingabstracts. com/abstract/willingness-of-end-stage-renal-disease-patients-esrd-withouthepatitis-c-hcv-to-accept-a-hcv-kidney/. Accessed June 6, 2017. Kiberd B, Doucette K, Tennankore K: Use of hepatitis c infected organs for kidney transplantation: A cost-effective analysis [Abstract]. Am J Transplant 17[Suppl 3], 2017. Available at: http://atcmeetingabstracts. com/abstract/use-of-hepatitis-c-infected-organs-for-kidney-transplantationa-cost-effective-analysis/ Accessed June 6, 2017. Trotter P, Robb M, Ushiro-Lumb I, Powell J, Watson C, Bradley J, Neuberger J: Transplantation of organs from donors with hepatitis C: The potential to substantially increase transplant activity. [Abstract]. Am J Transplant 17[Suppl 3], 2017. Available at: http://atcmeetingabstracts. com/abstract/transplantation-of-organs-from-donors-with-hepatitis-c-thepotential-to-substantially-increase-transplant-activity/ Accessed June 6, 2017. Goldberg D, Van V, Farooqi M, Sicilia A, Hasz R, Bloom R, Blumberg E, Gentile C, Abt P, Reese P: Hepatitis C genotypes among deceased organ donors in the United States [Abstract]. Am J Transplant 17[Suppl 3], 2017. Available at: http://atcmeetingabstracts.com/abstract/hepatitis-cgenotypes-among-deceased-organ-donors-in-the-united-states/ Accessed June 6, 2017. Reau N, Fried MW, Nelson DR, Brown RS Jr., Everson GT, Gordon SC, Jacobson IM, Lim JK, Pockros PJ, Reddy KR, Sherman KE: HCV Council–critical appraisal of data: Recommendations for clinical practice in a rapidly evolving therapeutic landscape. Liver Int 36: 488–502, 2016 PubMed Ooka K, Connolly JJ, Lim JK: Medicaid reimbursement for oral direct antiviral agents for the treatment of chronic hepatitis C. Am J Gastroenterol 112: 828–832, 2017 PubMed Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 Syllabus NephSAP, Volume 16, Number 4, November 2017—Transplantation John P. Vella, MD, FASN, FAST* and Alexander C. Wiseman, MD, FASTy *Division of Nephrology and Transplantation, Maine Medical Center and Tufts University School of Medicine, Portland, Maine; and yDivision of Renal Diseases and Hypertension, Transplant Center, University of Colorado Denver, Aurora, Colorado (1) Implementation of the new Kidney Allocation System on December 4, 2014 led to an increase in deceased donor kidney transplants among black candidates and those with calculated panel reactive antibodies 98%–100% but a decrease among candidates ages 65 years old or older. (2) There are positive trends in graft and patient survival for deceased and living donor kidney transplants, but the challenge of limited kidney supply persists. (3) The total number of patients on the waiting list decreased for the first time in a decade due to fewer waiting list additions, an increased number of removals due to medical deterioration, and an increase in the total number of transplants. (4) Waiting list deaths remain stable, presumably from the removal of inactive candidates too sick for transplantation. Learning Objectives 1. Describe current transplant outcomes, including delayed graft function, rejection, graft, and patient survival, and living donor outcomes 2. Discuss early outcomes associated with the 2014 changes to the Kidney Allocation System 3. Examine the spectrum of complications that occur after transplantation, including infection, malignancy, and cardiovascular disease, and accompanying individual diagnostic and therapeutic strategies 4. Review the status of immunosuppression, incompatible transplantation, and efforts to achieve immunologic tolerance This syllabus reviews the major clinical studies published between January of 2015 and January of 2017 in pertinent journals with the highest impact factors. The authors have focused on randomized trials, case series, and registry data whenever possible. In the interest of brevity, case reports, basic science studies, preclinical studies, and data published only in abstract form have been, in general, excluded. Smith et al. (2) reported that the new allocation policy is associated with increased quality-associated life-years at lower cost compared with the old policy, thereby yielding net benefits to the US Medicare system totaling $271 million United States dollars in the first year and $55 million United States dollars yearly after. Patient and Graft Survival The total number of kidney transplant recipients alive with a functioning graft exceeded 200,000 within the United States as of June of 2015, more than doubling since 2000 (1). Although allograft function and survival remained better for living than for deceased donor transplants, long-term outcomes continued to improve for both. All-cause and death-censored graft failure at 1, 3, 5, and 10 years continued to decline for living and deceased donor transplants. For deceased donor transplants, 10-year graft failure for transplants in 2005 was 52.8%, which decreased from 59.2% in 1995 (Figures 1 and 2). Similarly, 10-year graft Access to Transplantation and Outcomes The Scientific Registry of Transplant Recipients (SRTR) evaluates the clinical and scientific status of organ transplantation in the United States in close collaboration with the Organ Procurement and Transplantation Network, which is administered by the United Network for Organ Sharing under contract with the Health Resources and Services Administration. Each year, the SRTR reports on the state of transplantation in the United States (1). Important findings include the following. 280 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 Figure 1. Adult deceased donor transplant recipient deathcensored graft failure rates are improving over time. Deathcensored graft failure among adult deceased donor kidney transplant recipients. Estimates are unadjusted and computed using Kaplan–Meier competing risk methods. Recipients are followed to the earliest of kidney graft failure; kidney retransplant; return to dialysis; death; or 6 months or 1, 3, 5, or 10 years post-transplant. Death-censored graft failure is defined as a return to dialysis, reported graft failure, or kidney retransplant. OPTN, Organ Procurement and Transplantation Network. Reprinted with permission from Hart A, Smith JM, Skeans MA, Gustafson SK, Stewart DE, Cherikh WS, Wainright JL, Kucheryavaya A, Woodbury M, Snyder JJ, Kasiske BL, Israni AK: OPTN/SRTR 2015 Annual Data Report: Kidney. Am J Transplant 17[Suppl 1]: 21–116, 2017. failure for living donor transplants in 2005 was 37.3%, down from 44.8% in 1995 (Figures 3 and 4). Death with a functioning graft remained essentially constant for living and deceased donor transplants. Five-year deceased Figure 2. Adult deceased donor transplant recipient death with function rates are stable over time. Death with function among adult deceased donor kidney transplant recipients. Estimates are unadjusted and computed using Kaplan–Meier competing risk methods. Recipients are followed to the earliest of kidney graft failure; kidney retransplant; return to dialysis; death; or 6 months or 1, 3, 5, or 10 years post-transplant. Death with function is defined as death without prior graft failure, return to dialysis, or retransplant. OPTN, Organ Procurement and Transplantation Network. Reprinted with permission from Hart A, Smith JM, Skeans MA, Gustafson SK, Stewart DE, Cherikh WS, Wainright JL, Kucheryavaya A, Woodbury M, Snyder JJ, Kasiske BL, Israni AK: OPTN/SRTR 2015 Annual Data Report: Kidney. Am J Transplant 17[Suppl 1]: 21–116, 2017. 281 Figure 3. Adult live donor transplant recipient death with function rates are stable or marginally improving over time. Graft failure among adult living donor kidney transplant recipients. Estimates are unadjusted and computed using Kaplan–Meier competing risk methods. Recipients are followed to the earliest of kidney graft failure; kidney retransplant; return to dialysis; death; or 6 months or 1, 3, 5, or 10 years post-transplant. All-cause graft failure is defined as any of the prior outcomes before 6 months or 1, 3, 5, or 10 years. OPTN, Organ Procurement and Transplantation Network. Reprinted with permission from Hart A, Smith JM, Skeans MA, Gustafson SK, Stewart DE, Cherikh WS, Wainright JL, Kucheryavaya A, Woodbury M, Snyder JJ, Kasiske BL, Israni AK: OPTN/SRTR 2015 Annual Data Report: Kidney. Am J Transplant 17[Suppl 1]: 21–116, 2017. donor graft survival was lowest for patients with diabetes or hypertension as a cause of kidney failure: 70.4% and 71.8%, respectively. As previously reported, the overall outcomes of donation after brain and cardiac death transplants continue to be identical, which is reassuring (Figure 5). Such observations should not lead to complacency. Lim et al. (3), studying donation after cardiac death outcomes, examined the association between delayed graft function (DGF) and graft and patient outcomes. A greater proportion of recipients with DGF had experienced overall graft loss and death-censored graft loss at 3 years compared with those without DGF (14% versus 4%; P50.04 and 11% versus 0%, P,0.01, respectively). Compared with recipients without DGF, the adjusted hazard ratio (HR) for overall graft loss at 3 years for recipients with DGF was 4.31 (95% confidence interval [95% CI], 1.13 to 16.44). The kidney donor profile index (KDPI) is a numeric score that has been developed to assess deceased donor kidney quality, and it is an integral part of the Kidney Allocation System. Factors include donor age, height, weight, creatinine, diabetes, hypertension, cause of death, hepatitis C status, and donation after cardiac death, and they are incorporated into a calculator (https://optn.transplant. hrsa.gov/resources/allocation-calculators/kdpi-calculator/). 282 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 Ethnicity Figure 4. Adult live donor transplant recipient death censored graft failure rates are improving improving over time. Death-censored graft failure among adult living donor kidney transplant recipients. Estimates are unadjusted and computed using Kaplan–Meier competing risk methods. Recipients are followed to the earliest of kidney graft failure; kidney retransplant; return to dialysis; death; or 6 months or 1, 3, 5, or 10 years post-transplant. Death-censored graft failure is defined as a return to dialysis, reported graft failure, or kidney retransplant. OPTN, Organ Procurement and Transplantation Network. Reprinted with permission from Hart A, Smith JM, Skeans MA, Gustafson SK, Stewart DE, Cherikh WS, Wainright JL, Kucheryavaya A, Woodbury M, Snyder JJ, Kasiske BL, Israni AK: OPTN/SRTR 2015 Annual Data Report: Kidney. Am J Transplant 17[Suppl 1]: 21–116, 2017. Lower scores are better. Not surprisingly, there continues to be a marked graft survival outcome discrepancy between the highest KDPI kidneys (.85%) compared with lower KDPI kidneys (,85%) (Figure 5). Figure 5. Graft survival among adult deceased donor kidney transplant recipients associates with graft quality as measured by the Kidney Donor Profile Index (KDPI) (lower is better). Those who receive kidneys with a KDPI .85% have the worse long term graft survival rates. Graft survival among adult deceased donor kidney transplant recipients in 2010 by KDPI. Graft survival was estimated using unadjusted Kaplan–Meier methods. The reference population for the KDRI to KDPI conversion is all deceased donor kidneys recovered for transplant in the United States in 2015. OPTN, Organ Procurement and Transplantation Network. Reprinted with permission from Hart A, Smith JM, Skeans MA, Gustafson SK, Stewart DE, Cherikh WS, Wainright JL, Kucheryavaya A, Woodbury M, Snyder JJ, Kasiske BL, Israni AK: OPTN/SRTR 2015 Annual Data Report: Kidney. Am J Transplant 17[Suppl 1]: 21–116, 2017. Taber et al. (4) examined the outcomes of black kidney transplant recipients, a group known to experience higher rates of graft loss for the last 40 years. They studied 3306 non-Hispanic whites (67%) compared with 1612 non-Hispanic blacks (33%) with 6 years of follow-up. In the unadjusted analysis, black recipients were significantly more likely to have overall graft loss (HR, 1.19; 95% CI, 1.07 to 1.33) and death-censored graft loss (HR, 1.67; 95% CI, 1.45 to 1.92) but had lower mortality (HR, 0.83; 95% CI, 0.72 to 0.96). In fully adjusted models, only death-censored graft loss remained significant (HR, 1.38; 95% CI, 1.12 to 1.71). The authors concluded that non-Hispanic black kidney transplant recipients experience a substantial disparity in graft loss but not mortality. Recognition that susceptibility to kidney disease has a genetic component has been evaluated by candidate gene studies identifying alterations in a variety of genes as reviewed in a prior Nephrology Self-Assessment Program on transplantation (5). Chief among them are two risk variants of the apolipoprotein L1 gene (APOL1) in association with nondiabetic nephropathy in blacks. Freedman et al. (6) evaluated the impact of APOL1 positivity in black kidney donors with data from 478 newly analyzed deceased donor recipients reported to the SRTR. Shorter renal allograft survival in recipients of APOL1 kidneys was confirmed (HR, 2.00; 95% confidence interval [95% CI], 1.39 to 3.02, P50.03). Combined analysis of 1153 deceased donor kidney transplants from black donors revealed that donor APOL1 highrisk genotype (HR, 2.05), older donor age (HR, 1.18; 95% CI, 1.00 to 1.40), and younger recipient age (HR, 0.70) significantly impacted allograft survival adversely. Although prolonged allograft survival was seen in many recipients of APOL1 kidneys, follow-up serum creatinine concentrations were higher than those in recipients without APOL1 renal risk variant kidneys. A competing risk analysis revealed that APOL1 impacted renal allograft survival but not recipient survival. Arce et al. (7) reported that risks for graft failure and mortality (HR, 0.69; 95% CI, 0.65 to 0.73) and allcause graft failure (HR, 0.79; 95% CI, 0.75 to 0.83) are lower in Hispanics compared with non-Hispanic transplant recipients. Furthermore, the association between Hispanic ethnicity and graft failure excluding death was significantly modified by age. Compared with non-Hispanic whites, graft failure, excluding death with a functioning Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 graft, did not differ in Hispanics ages 18–39 years old (HR, 0.96; 95% CI, 0.89 to 1.05) or 40–59 years old (HR, 1.08; 95% CI, 1.00 to1.16) but was 13% lower in those ages $60 years old (HR, 0.87; 95% CI, 0.78 to 0.98). Adler et al. (8) analyzed socioeconomic status (SES) and racial/ethnic gradients between donors and recipients. In a retrospective cohort study, traditional demographic and socioeconomic factors as well as an SES index were compared in 56,697 deceased kidney donor and recipient pairs transplanted between 2007 and 2012. Kidneys were more likely to be transplanted in recipients of the same racial/ethnic group as the donor (P,0.001). Kidneys tended to go to recipients of lower SES index (50.5% of the time; P,0.001), a relationship that remained after adjusting for other available markers of donor organ quality and SES (P,0.001). Physical Frailty Frailty is associated with inferior survival and increased resource requirements among kidney transplant candidates. Lynch et al. (9) examined US Renal Data System data from 51,111 adult ESRD patients waitlisted for transplant from 2000 to 2011. Frequently admitted patients had higher subsequent resource requirements, increased waitlist mortality, and decreased likelihood of transplant (death after listing: 1–7 days: HR, 1.24; 95% CI, 1.20 to 1.28; 8–14 days: HR, 1.49; 95% CI, 1.42 to 1.56; $15 days: HR, 2.07, 95% CI; 1.99 to 2.15 versus 0 days). Graft and recipient survival was inferior, with higher admissions, although survival benefit was preserved. A model, including waitlist admissions alone, performed better in predicting postlisting mortality than estimated post-transplant survival. Similarly, McAdamsDeMarco et al. (10) studied the association between prospectively assessed physical frailty and postkidney transplantation mortality and found that frailty was independently associated with a 2.17-fold higher risk of death (95% CI, 1.01 to 4.65; P50.05). Physical frailty is associated with decreased likelihood of transplantation and inferior survival after kidney transplantation. Cardiovascular Outcomes Cardiovascular death remains the leading cause of mortality in kidney transplant recipients. Lim et al. (3) 283 conducted a retrospective study using health care databases in Ontario, Canada to determine whether the incidence of cardiovascular events after kidney transplantation has changed over time. Recipients (n54954) were older and had more baseline comorbidity in recent years. A total of 445 recipients (9.0%) died or experienced a major cardiovascular event within 3 years of transplantation. There was no significant change in the incidence of the composite outcome or death-censored cardiovascular events over time (P50.41 and P50.92, respectively). After adjusting for age, sex, and comorbidities, the risk of death or major cardiovascular event steadily declined across the years of transplant (2006– 2009 adjusted HR, 0.70; P,0.01; referent, 1994–1997). When recipients were matched for age, sex, and date of cohort entry to members of the general population and to the CKD population, the risk was lowest in the general population and highest in the CKD population. Shin et al. (11) analyzed 2684 primary kidney transplant recipients who had a functioning graft at 6 months after transplantation to assess the association of renin-angiotensin system (RAS) blockade with patient and graft survival. RAS blockade was associated with an adjusted HR of 0.63 (95% CI, 0.53 to 0.75) for total graft loss, an adjusted HR of 0.69 (95% CI, 0.55 to 0.86) for death, and an adjusted HR of 0.62 (95% CI, 0.49 to 0.78) for death-censored graft failure. The associations of RAS blockade with a lower risk of total graft loss and mortality were stronger with more severe proteinuria. The RAS blockade was associated with a twofold higher risk of hyperkalemia. By comparison, Dad et al. (12) analyzed the Folic Acid for Vascular Outcome Reduction in Transplantation Trial database and reported that aspirin use did not associate with reduced risk for incident cardiovascular disease, allcause mortality, or kidney failure in stable kidney transplant recipients without a history of cardiovascular disease. Pihlstrøm et al. (13) investigated the association between baseline parathyroid hormone (PTH) levels and major cardiovascular events, renal graft loss, and all-cause mortality. Significant associations between PTH and all three outcomes were found in univariate analyses. When adjusting for a range of plausible confounders, including measures of renal function and serum mineral levels, PTH remained significantly associated with all-cause mortality (4% increased risk per 10 U; P50.004) and graft loss (6% increased risk per 10 U; P,0.001) but not major cardiovascular events. 284 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 Obesity The impact of pretransplant body mass index (BMI) on long-term allograft outcomes after kidney transplantation remains controversial. Naik et al. (14) studied 108,654 transplant recipients and determined that increasing BMI level was associated with increased risk of long-term allograft failure. In an adjusted model with BMI of 18.5 to ,25 kg/m2 as referent, the subhazard ratios (SHRs) for BMI were ,18.5 kg/m2: SHR, 0.96; P50.41; 25 to ,30 kg/m2: SHR, 1.05; P50.01; 30 to ,35 kg/m2: SHR, 1.15; P#0.001; 35 to ,40 kg/m2: SHR, 1.21; P,0.001; and .40 kg/m2: SHR, 1.13; P50.002. Mechanistically, it has been suggested that obesity is often associated with the development of an adiposity-induced inflammatory state that induces metabolic dysfunction that increases the risk for developing type 2 diabetes (15). References 1. Hart A, Smith JM, Skeans MA, Gustafson SK, Stewart DE, Cherikh WS, Wainright JL, Kucheryavaya A, Woodbury M, Snyder JJ, Kasiske BL, Israni AK: OPTN/SRTR 2015 Annual Data Report: Kidney. Am J Transplant 17[Suppl 1]: 21–116, 2017 PubMed 2. Smith JM, Schnitzler MA, Gustafson SK, Salkowski NJ, Snyder JJ, Kasiske BL, Israni AK: Cost implications of new national allocation policy for deceased donor kidneys in the United States. Transplantation 100: 879–885, 2016 PubMed 3. Lim WH, McDonald SP, Russ GR, Chapman JR, Ma MK, Pleass H, Jaques B, Wong G: Association between delayed graft function and graft loss in donation after cardiac death kidney transplants - a paired kidney registry analysis [published online ahead of print July 29, 2016]. TransplantationPubMed 4. Taber DJ, Gebregziabher M, Payne EH, Srinivas T, Baliga PK, Egede LE: Overall graft loss versus death-censored graft loss: Unmasking the magnitude of racial disparities in outcomes among US kidney transplant recipients. Transplantation 101: 402–410, 2017 PubMed 5. Vella JP, Wiseman A: Nephrol Self Assess Program 14: 375–439, 2015 6. Freedman BI, Pastan SO, Israni AK, Schladt D, Julian BA, Gautreaux MD, Hauptfeld V, Bray RA, Gebel HM, Kirk AD, Gaston RS, Rogers J, Farney AC, Orlando G, Stratta RJ, Mohan S, Ma L, Langefeld CD, Bowden DW, Hicks PJ, Palmer ND, Palanisamy A, Reeves-Daniel AM, Brown WM, Divers J: APOL1 genotype and kidney transplantation outcomes from deceased African American donors. Transplantation 100: 194–202, 2016 PubMed 7. Arce CM, Lenihan CR, Montez-Rath ME, Winkelmayer WC: Comparison of longer-term outcomes after kidney transplantation between Hispanic and non-Hispanic whites in the United States. Am J Transplant 15: 499–507, 2015 PubMed 8. Adler JT, Hyder JA, Elias N, Nguyen LL, Markmann JF, Delmonico FL, Yeh H: Socioeconomic status and ethnicity of deceased donor kidney recipients compared to their donors. Am J Transplant 15: 1061– 1067, 2015 PubMed 9. Lynch RJ, Zhang R, Patzer RE, Larsen CP, Adams AB: First-year waitlist hospitalization and subsequent waitlist and transplant outcome. Am J Transplant 17: 1031–1041, 2017 PubMed 10. McAdams-DeMarco MA, Law A, King E, Orandi B, Salter M, Gupta N, Chow E, Alachkar N, Desai N, Varadhan R, Walston J, Segev DL: Frailty and mortality in kidney transplant recipients. Am J Transplant 15: 149–154, 2015 PubMed 11. Shin JI, Palta M, Djamali A, Kaufman DB, Astor BC: The association between renin-angiotensin system blockade and long-term outcomes in 12. 13. 14. 15. renal transplant recipients: The Wisconsin Allograft Recipient Database (WisARD). Transplantation 100: 1541–1549, 2016 PubMed Dad T, Tighiouart H, Joseph A, Bostom A, Carpenter M, Hunsicker L, Kusek JW, Pfeffer M, Levey AS, Weiner DE: Aspirin use and incident cardiovascular disease, kidney failure, and death in stable kidney transplant recipients: A post hoc analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial. Am J Kidney Dis 68: 277–286, 2016 PubMed Pihlstrøm H, Dahle DO, Mjøen G, Pilz S, März W, Abedini S, Holme I, Fellström B, Jardine AG, Holdaas H: Increased risk of all-cause mortality and renal graft loss in stable renal transplant recipients with hyperparathyroidism. Transplantation 99: 351–359, 2015 PubMed Naik AS, Sakhuja A, Cibrik DM, Ojo AO, Samaniego-Picota MD, Lentine KL: The impact of obesity on allograft failure after kidney transplantation: A competing risks analysis. Transplantation 100: 1963–1969, 2016 PubMed Wu D, Dawson NA, Levings MK: Obesity-associated adipose tissue inflammation and transplantation. Am J Transplant 16: 743–750, 2016 PubMed Deceased Donor Kidney Allocation The Kidney Allocation System (KAS), a major change to deceased donor kidney allocation implemented by the United Network for Organ Sharing (UNOS) in December of 2014, incorporated specific goals, which included directing the highest quality organs to younger, healthier recipients; increasing access to deceased donor kidney transplantation for highly sensitized patients, racial/ethnic minorities, and those with an extended duration on dialysis while mitigating regional variability. To assess the impact of this major change in allocation policy, Stewart et al.(1) compared Organ Procurement and Transplantation Network data 1 year before and 1 year after implementation of the KAS. Transplants in which the donor and recipient ages differed by .30 years declined by 23%. Initial sharp increases in transplants were observed for calculated panel reactive antibody 99%–100% recipients and recipients with at least 10 years on dialysis, with a subsequent tapering of transplants to these groups, suggesting a bolus effect. It was noted that kidneys were more often being shipped over long distances, leading to longer cold ischemic times and higher delayed graft function (DGF) rates. Importantly, 6-month graft survival rates had not changed significantly. Building on the prior observations, Massie et al.(2) compared kidney distribution, transplant rates for waitlist registrants, and recipients for the 2 years preand post-KAS. Some of their key findings included an increase in regional imports from 8.8% pre-KAS to 12.5% post-KAS and an increase in national imports from 12.7% pre-KAS to 19.1% post-KAS (P,0.001). The proportion of recipients .30 years older than their Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 donor decreased from 19.4% to 15.0% (P,0.001). The proportion of recipients with calculated panel reactive antibody 100% increased from 1.0% to 10.3% (P,0.001). This latter observation is truly remarkable, because such patients previously had low transplant rates with markedly prolonged waiting times. The overall deceased donor transplant rate did not change. However, rates increased for blacks (incidence ratio [IR], 1.19; 95% confidence interval [95% CI], 1.13 to 1.25), Hispanics (IR, 1.13; 95% CI, 1.05 to 1.20), and candidates ages 18–40 years old (IR, 1.47; 95% CI, 1.38 to 1.57) but declined for candidates ages .50 years old (IR, 0.93; 95% CI, 0.87 to 0.98), those 51–60 years old (IR, 0.90; 95% CI, 0.85 to 0.96), and those ages .70 years old. Of some concern, the DGF rate increased from 24.8% pre-KAS to 29.9% post-KAS (P,0.001). In summary, KAS has been associated with improved access to transplantation for minorities, younger candidates, and highly sensitized patients but declines for older candidates as projected by preimplementation modeling. DGF increased substantially. This is of concern due to the association of DGF with inferior long-term outcomes (discussed below). Changes in United States national kidney allocation implemented in December of 2014 have improved transplantation access for minorities, younger candidates, and those who are highly sensitized. This is at the expense of reduced access for older patients and higher delayed graft function rates. Discarded Kidneys One of the central features of the new system was the development of the kidney donor profile index (KDPI), a numeric score on the basis of ten clinical criteria that describe organ quality implemented pre-KAS in 2012 (lower score is better; calculator is available online:https:// optn.transplant.hrsa.gov/resources/allocation-calculators/ kdpi-calculator/). It is known that allograft prognosis is inferior when the KDPI exceeds 85%, which includes a group of donor kidneys that approximates the previous designation of expanded criteria donors (ECDs). Bae et al. (3) studied the discard rates of the kidneys recovered for transplantation from the ECD era with those of the KDPI era. There was no significant change in discard rate from the ECD era (18.1%) to the KDPI era (18.3%) among the 285 entire population (adjusted odds ratio [aOR], 0.97; 95% CI, 1.04 to 1.10; P=0.30) or in any KDPI stratum. However, among kidneys in which ECD and KDPI indicators were discordant, high-risk standard criteria donor (SCD) kidneys (with KDPI.0.85) were at increased risk of discard in the KDPI era (aOR, 1.07; 95% CI, 1.42 to 1.89; P=0.02). However, recipients of these kidneys were at much lower risk of death (adjusted risk ratio, 0.56; 95% CI, 0.77 to 0.94 at 2 years post-transplant) compared with those remaining on dialysis and waiting for low-KDPI kidneys. The authors suggested that there might be an unexpected harmful labeling effect of reporting a high KDPI for SCD kidneys without the expected advantage of providing a more granular risk index. Such concerns warrant ongoing vigilance. Stewart et al.(4) also evaluated trends in donor characteristics with specific reference to discard kidneys. They reported that most of the kidney discard rate rise was explained by the broadening donor pool. However, the presence of an unexplained residual increase suggests that behavioral factors, such as programmatic risk aversion or allocation inefficiencies, may also play a role. Snyder et al. (5) examined whether accepting high-risk kidneys (KDPI$0.85) is associated with transplant programs receiving inferior evaluations. Despite a clear relationship between KDPI, graft failure, and mortality, there was no relationship between a program’s use of high-KDPI kidneys and subsequently receiving a poor performance evaluation after risk adjustment. Excluding high-KDPI donor transplants did not alter the programs identified as underperforming, because in every case, underperforming programs also had worse than expected outcomes among lower-risk donor transplants. The authors concluded that there is no evidence that programs that accept higher-KDPI kidneys are at greater risk for poor performance evaluations, and risk aversion may limit access to transplant for candidates while providing no measurable benefit to program evaluations. Therefore, do we have predictors of kidney discard? Marrero et al.(6) performed an analysis of the Organ Procurement and Transplantation Network database from 2000 to 2012 of all solid organ donors. Perhaps as expected, predictors of increased discard included age older than 50 years old, performance of a kidney biopsy, cytomegalovirus seropositive status, donation after cardiac death, hepatitis B and C seropositive status, cigarette use, diabetes, hypertension, terminal creatinine .1.5 mg/dl, and blood type AB. Does timing of kidney procurement impact the discard rate? Indeed, the answer is yes given a recent 286 report by Mohan et al.(7) that studied the impact of the day of the week of the procurement and subsequent utilization or discard of deceased donor kidneys in the United States. Compared with weekday kidneys, organs procured on weekends were significantly more likely to be discarded than transplanted (OR, 1.16; 95% CI, 1.13 to 1.19), even after adjusting for organ quality (aOR, 1.13; 95% CI, 1.10 to 1.17). Weekend discards were of a significantly higher quality than weekday discards, although the effect was small (KDPI: 76.5% versus 77.3%). Considerable geographic variation was also noted in the proportion of transplants that occurred over the weekend (Figure 6). Deceased Donor Hypothermia DGF, which is reported in up to 50% of kidney transplant recipients, is associated with increased costs and inferior prognosis (see below). Targeting mild hypothermia in organ donors before organ recovery may impact DGF risk. Niemann et al.(8) enrolled organ donors (after declaration of death by neurologic criteria) from two large donation service areas and randomly assigned them to one of two targeted temperature ranges: 34C to 35C (hypothermia) or 36.5C to 37.5C (normothermia). The study was terminated early on the recommendation of an independent data and safety monitoring board after the interim analysis showed efficacy of hypothermia. DGF developed in 79 recipients of kidneys from donors in the hypothermia Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 group (28%) and 112 recipients of kidneys from donors in the normothermia group (39%; odds ratio, 0.62; 95% CI, 0.43 to 0.92; P=0.02). The authors concluded that mild hypothermia compared with normothermia in organ donors after declaration of death per neurologic criteria significantly reduced the rate of DGF among recipients. It is now up to organ procurement organizations to either repeat the study or implement the protocols for deceased donors. Use of Hepatitis C Virus–Seropositive Kidneys The impact of transplanting hepatitis C virus (HCV)–seropositive deceased donor kidneys was studied by Scalea et al.(9), who analyzed 1679 adult allografts between 2000 and 2012. Of these, 195 hepatitis C virus–seropositive recipients (R+) received kidneys from hepatitis C virus–seropositive donors (D+) in contrast to 1418 HCV-negative recipients who received grafts from hepatitis C virus–negative donors (D–) and 66 R+ patients who received D– kidneys. Death-censored graft survival in the D+/R+ population was better than graft survival for D–/R+ patients, despite D+/R+ patients having higher rates of hypertension and black ethnicity. Waitlist times for patients accepting HCV-seropositive grafts were 318 days (for D+/R+ patients) versus 613 days (D–/HCV-negative recipients) or 570 days (D–/R+). The authors reasonably concluded that HCV D+/R+ patients spent less time on the transplant waitlist, which contributed to improved death-censored graft survival compared with D–/R+ patients. Prior Living Donors in Need of Transplantation Figure 6. There is marked geographic variation in the proportion of deceased donor transplants that are performed over the weekend. Geographic variation in the proportion of deceased donor kidney transplants performed over the weekend by state, 2000–2013. Reprinted with permission from Mohan S, Foley K, Chiles MC, Dube GK, Patzer RE, Pastan SO, Crew RJ, Cohen DJ, Ratner LE: The weekend effect alters the procurement and discard rates of deceased donor kidneys in the United States. Kidney Int90: 157–163, 2016. The incidence of ESRD in prior living kidney donors (PLDs) has been estimated at 30 in 10,000, higher than four in 10,000 in the general population (reviewed in prior issues of the Nephrology SelfAssessment Program on transplantation). Wainright et al.(10) investigated the early effects of the KAS on the access of PLDs to deceased donor kidney transplants. Using the Organ Procurement and Transplantation Network data, this group compared prevalent and incident cohorts of PLDs in the 1-year periods before and after KAS implementation. Importantly, transplant rates were not statistically different before or after KAS implementation for either prevalent (2.37 versus 2.29; relative risk [RR], 0.96; 95% CI, 0.62 to 1.49) or incident (4.76 versus 4.36; RR, 0.92; 95% CI, 0.53 to 1.60) candidates. Median waiting time to deceased Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 donor kidney transplant for prevalent PLDs in the postKAS cohort was 102.6 days compared with 82.3 days in the pre-KAS cohort (P=0.98). The median KDPI for PLD recipients was 31% with KAS versus 23% before KAS (P=0.02). Despite a sharp decrease in the waiting time for highly prioritized candidates with calculated panel reactive antibodies of 98%–100% (from .7000 to 1164 days), PLDs still had much shorter waiting times (mean of 102.6 days). The incidence of ESRD in prior living donors is 30 in 10,000, which is higher than that in nondonors (four in 10,000). This risk is mitigated to an extent in that prior donors have ready access to transplantation. Public Health Service Increased Risk Donors The US Public Health Service redefined donors previously classified by the Centers for Disease Control as being at high risk for transmission of hepatitis B, HCV, and HIV. These categories include the following. (1) People who have had sex with a person known or suspected to have HIV, hepatitis B, or HCV infection within the previous year. (2) Men who have had sex with men within the previous year. (3) Women who have had sex with a man with a history of having sex with men within the previous year. (4) People who have had sex for money or drugs within the previous year. (5) People who have had sex with a person who had sex in exchange for money or drugs within the previous year. (6) People using nonmedical injection of drugs within the previous year. (7) People who have sex with a person who used nonmedical injection of drugs within the previous year. (8) People who have been in lockup, jail, prison, or juvenile correctional facility for .72 consecutive hours. (9) Persons who have been newly diagnosed with or treated for syphilis, gonorrhea, Chlamydia, or genital ulcers in the preceding 12 months. 287 (10) Deceased donors whose medical/behavioral history cannot be determined. (11) Deceased donors whose blood specimen has been hemodiluted. The UNOS regulations specify that such donors be screened for hepatitis B virus, HCV, and HIV by both serology and nucleic acid testing (NAT). These kidneys can only be offered as Public Health Service Increased Risk Donor if hepatitis B virus, HCV, and HIV testing is negative. It should be understood that there is still risk of a false negative result should such a donor remain within the window period after infection but before viral nucleic acid has sufficiently amplified to yield a positive result. Such kidneys are only offered to recipients who have been informed of the risks and consented to receive such a kidney. Kidneys that test positive for HCV or hepatitis B virus can be offered to recipients who are HCV seropositive or hepatitis B virus positive, respectively. Kidneys from HIV-positive donors can now be transplanted into HIV-positive recipients under experimental protocols since the HIV Organ Policy Equity Act was enacted in 2013. Importantly, the number of such deceased donors has increased markedly over the last decade driven by the epidemic of opiate addiction within the United States. Kucirka et al.(11) quantified the impact of the new guidelines and found that 19.5% of donors were labeled increased risk donors (IRD) compared with 10.4%, 12.2%, and 12.3% in the 3 most recent years under the old guidelines (incidence rate ratio, 1.45; P,0.001). Increases were consistent across organ procurement organizations: 44 of 59 had an increase in the percentage of donors labeled as being at increased risk, and 14 organ procurement organizations labeled 25% of their donors as being at increased risk under the new guidelines (versus five organ procurement organizations under the old guidelines). Blacks were 52% more likely to be labeled IRD under the new guidelines (RR, 1.52; P=0.01). The risk of transmission of disease using the prior Centers for Disease Control and Prevention guidelines was previously reviewed by Kucirka et al.(12). They found that increased risk organs are discarded at higher rates than SCD kidneys. Their estimated risk of undetected window period HIV infection varies by IRD behavior category (range, 0.035–4.9 per 10,000 donors when NAT is used), and HCV risk is higher (range, 0.027–32.4 per 10,000). Recipients who receive such kidneys are tested at time 0 and again at defined time 288 points until the end of the first post-transplant year by NAT. Information about recipients who test positive needs to be shared with the UNOS Disease Transmission Advisory Committee. Updated information on actual disease transmission on the basis of the new criteria is eagerly awaited. Deceased donor kidneys procured from individuals who meet the US Public Health Service definitions of increased risk now make up approximately 20% of the entire donor pool. These donors are tested for viral infections by both serology and NAT. Organs from these donors can be offered for transplantation when the testing is negative. Point estimates of risk for transmission of HIV, HCV, and hepatitis B virus are all <1%. These kidneys tend to be from young donors with low KDPIs and may be associated with reduced waiting time for transplantation. References 1. Stewart DE, Kucheryavaya AY, Klassen DK, Turgeon NA, Formica RN, Aeder MI:Changes in deceased donor kidney transplantation one year after KAS implementation.Am J Transplant 16:1834–1847,2016 PubMed 2. Massie AB, Luo X, Lonze BE, Desai NM, Bingaman AW, Cooper M, Segev DL:Early changes in kidney distribution under the new allocation system.J Am Soc Nephrol 27:2495–2501,2016 PubMed 3. Bae S, Massie AB, Luo X, Anjum S, Desai NM, Segev DL:Changes in discard rate after the introduction of the kidney donor profile index (KDPI).Am J Transplant 16:2202–2207,2016 PubMed 4. Stewart DE, Garcia VC, Rosendale JD, Klassen DK, Carrico BJ: Diagnosing the decades-long rise in the deceased donor kidney discard rate in the United States.Transplantation 101:575–587,2017 PubMed 5. Snyder JJ, Salkowski N, Wey A, Israni AK, Schold JD, Segev DL, Kasiske BL:Effects of high-risk kidneys on Scientific Registry of Transplant Recipients Program Quality Reports.Am J Transplant 16:2646– 2653,2016 PubMed 6. Marrero WJ, Naik AS, Friedewald JJ, Xu Y, Hutton DW, Lavieri MS, Parikh ND:Predictors of deceased donor kidney discard in the United States.Transplantation 101:1690–1697,2017 PubMed 7. Mohan S, Foley K, Chiles MC, Dube GK, Patzer RE, Pastan SO, Crew RJ, Cohen DJ, Ratner LE:The weekend effect alters the procurement and discard rates of deceased donor kidneys in the United States.Kidney Int 90:157–163,2016 PubMed 8. Niemann CU, Feiner J, Swain S, Bunting S, Friedman M, Crutchfield M, Broglio K, Hirose R, Roberts JP, Malinoski D:Therapeutic hypothermia in deceased organ donors and kidney-graft function.N Engl J Med 373:405–414,2015 PubMed 9. Scalea JR, Redfield RR, Arpali E, Leverson GE, Bennett RJ, Anderson ME, Kaufman DB, Fernandez LA, D’Alessandro AM, Foley DP, Mezrich JD:Does DCD donor time-to-death affect recipient outcomes? Implications of time-to-death at a high-volume center in the United States.Am J Transplant 17:191–200,2017 PubMed 10. Wainright JL, Kucheryavaya AY, Klassen DK, Stewart DE:The impact of the new kidney allocation system on prior living kidney donors’ Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 access to deceased donor kidney transplants: An early look.Am J Transplant 17:1103–1111,2017 PubMed 11. Kucirka LM, Bowring MG, Massie AB, Luo X, Nicholas LH, Segev DL:Landscape of deceased donors labeled increased risk for disease transmission under new guidelines.Am J Transplant 15:3215–3223, 2015 PubMed 12. Kucirka LM, Singer AL, Segev DL:High infectious risk donors: what are the risks and when are they too high?Curr Opin Organ Transplant 16:256–261,2011 PubMed Living Kidney Donation In 2015, 5626 living donor transplants were performed, an increase from 5539 in 2014 but a decrease from the peak of 6647 in 2004 (Figure 7) (1). This decline is due to a decrease in related kidney donations, because unrelated donations have been stable. Although the number of paired donations has increased, this is not enough to offset the overall decline in related donations. Women made up 63.5% of living donors, an increase from 59.2% in 2005. The proportion of black donors has continued to decline over 10 years from 13.4% to 9.6%. Laparoscopic nephrectomy made up .97% of procedures in 2015. Readmissions after living donation, although infrequent, are not rare, with rates of 2.5% at 6 weeks, 3.9% at 6 months, and 5.2% at 1 year. Overall, complications postnephrectomy occured in 5.3% of living donors at 6 weeks, 7.2% of living donors at 6 months, and 8.8% of living donors at 12 months. The distribution of body mass index (BMI) remained relatively stable over 10 years, with a slight decrease in the proportion of donors with BMI.35 kg/m2 (from 4.6% to 2.6%) and an increase in the proportion with BMI530–35 kg/m2 (from 16.1% to 19.5%). From 2011 to 2015, 17 deaths within 1 year of donation were reported to the Organ Procurement and Transplantation Network (OPTN). The most common causes of death were medical (including donation related) in seven and accident/homicide in five living donors. The number of living donors has declined in the United States, despite increasing kidney paired donation (KPD). Kidney Paired Donation Approximately 30% of living donors are incompatible with their intended recipients due to either preformed ABO or donor-specific antibodies. KPD is the 289 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 facilitated 47 transplants, and thus far, eight of their paired recipients have received a kidney within a mean of 178 (range, 10–562) days. Fumo et al. (3) studied potential swaps that failed and found three primary reasons that could be prevented by changes in protocol or software: positive laboratory crossmatch (28%), transplant center declined donor (17%), and pair transplanted outside the APD (14%). Making such changes allowed their group to improve the success rate and the number of transplants performed annually. Living Donor Kidney Function Assessment Figure 7. The relationship between living donors and their intended recipients has evolved over time with an overall decline in those that are biologically related. Kidney paired donation is a growing trend however still makes up a small proportion of live donor transplants. Kidney transplants from living donors by donor relation. Numbers of living donor donations and characteristics recorded on the OPTN living donor registration form. Reprinted with permission from Hart A, Smith JM, Skeans MA, Gustafson SK, Stewart DE, Cherikh WS, Wainright JL, Boyle G, Snyder JJ, Kasiske BL, Israni AK: Kidney. Am J Transplant 16[Suppl 2]: 11–46, 2016. most exciting novel approach gaining traction that addresses incompatibility, while avoiding the financial costs, adverse events, and inferior outcomes associated with desensitization. Numerous programs have been created to promote KPD, including those managed by the United Network for Organ Sharing (UNOS), the National Kidney Registry, the Alliance for Paired Donation, and other regional or single-center initiatives. At core, these programs promote the search for compatible living donors when candidate recipients have living donors who are incompatible. The concept of an open chain, often triggered by an altruistic donor, frequently garners interest by the popular press. The practice of shipping live donor kidneys is now firmly established, eliminating some of the logistic barriers previously encountered. Flechner et al. (2) described an interesting twist on the general concept of KPD in the description of their Advanced Donation Program (ADP) that permits a donor who desires to donate by a specific date but does not yet have a matched donor to effectively “pay it forward.” After obtaining informed consent from donor and paired recipient, ten KPD chains were constructed using an ADP donor. These ten ADP donors have Per UNOS regulations, all living kidney donor candidates undergo evaluation of GFR. Guidelines recommend measured GFR (mGFR) via an endogenous filtration marker or creatinine clearance rather than eGFR by any methodology. However, measurement methods are challenging, time consuming, and costly, and they can yield variable results. Huang et al. (4) investigated whether GFR estimated from serum creatinine with or without sequential cystatin C was sufficiently accurate to identify donor candidates with high probability that mGFR is above or below thresholds for clinical decision making. They combined the pretest probability for mGFR thresholds ,60, ,70, $80, and $90 ml/min per 1.73 m2 on the basis of demographic characteristics from the National Health and Nutrition Examination Survey with test performance of eGFR (Chronic Kidney Disease Epidemiology Collaboration) to compute post-test probabilities. Using data from the Scientific Registry of Transplant Recipients, 53% of recent living donors had predonation GFR estimated from serum creatinine levels sufficiently high to ensure $95% probability that predonation mGFR was $90 ml/min per 1.73 m2, suggesting that mGFR may not be necessary in a large proportion of donor candidates. They developed a web-based application (http:// ckdepi.org/equations/donor-candidate-gfr-calculator/) to compute the probability on the basis of eGFR that mGFR for a donor candidate is above or below a range of thresholds useful in living donor evaluation and selection. Although intriguing, such methodology does not currently meet UNOS regulatory requirements. Medically Complex Living Donors Living donation has been deemed the chief weapon in the fight to redistribute the gap between supply and demand for kidneys given the continued expansion of the national waiting list. Ahmadi et al. (5) 290 reviewed current guidelines pertaining to the selection of medically complex donors with regard to older age, obesity, hypertension, vascular anomalies/multiplicity, nulliparous women, and minors as donors. Their summary conclusions included the following statements: live kidney donation in older donors (up to 70 years of age) seems to be safe when outcome is compared with that of younger donors; obese donors have comparable outcomes to lean donors, at least in short- and midterm follow-up; given the paucity of data pertaining to hypertensive donor safety, caution is advised; vascular multiplicity poses no direct danger to the donor; women of childbearing age can be safely included as donors; and minors should only be considered as kidney donors if no other options exist. To facilitate decision making when a transplant candidate has multiple living donors, Massie et al. (6) developed a living kidney donor profile index (LKDPI) using the same scale as the deceased donor kidney donor profile index. Multivariate analysis indicated that donor age over 50 years old (hazard ratio [HR] per 10 years, 1.15; 95% confidence interval [95% CI], 1.24 to 1.33), elevated BMI (HR per 10 U, 1.01; 95% CI, 1.09 to 1.16), black race (HR, 1.15; 95% CI, 1.25 to 1.37), and cigarette use (HR, 1.09; 95% CI, 1.16 to 1.23) as well as ABO incompatibility (HR, 1.03; 95% CI, 1.27 to 1.58), HLA B mismatches (HR, 1.03; 95% CI, 1.08 to 1.14), and DR mismatches (HR, 1.04; 95% CI, 1.09 to 1.15) were associated with greater risk of graft loss after living donor transplantation (all P,0.05). The median LKDPI score was 13 (1–27); 24.2% of donors had LKDPI,0 (less risk than any deceased donor kidney), and 4.4% of donors had LKDPI.50 (more risk than the median deceased donor kidney). An online calculator is available http://www.transplantmodels.com/lkdpi/. Muzaale et al. (7) questioned whether it was possible that living kidney donors had undetected, subclinical, preexisting kidney disease that subsequently contributed to risk of ESRD. To test this theory, the authors compared a cohort of 257 recipients whose donors subsequently developed ESRD with a matched cohort whose donors remained ESRD free. The median follow-up time from transplantation was 12.5 years (interquartile range, 7.4–17.9; maximum 520 years). Recipients of allografts from donors who developed ESRD had increased death-censored graft loss (74% versus 56% at 20 years; adjusted HR, 1.7; 95% CI, 1.5 to 2.0; P,0.001) and mortality (61% versus 46% at 20 years; adjusted HR, 1.5; 95% CI, 1.2 to 1.8; P,0.001) compared with matched recipients of allografts from Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 donors who did not develop ESRD. This association was similar among related, spousal, and unrelated nonspousal donors. Surgery Complications Lentine et al. (8) studied perioperative complications associated with living kidney donation. Nephrectomies were predominantly laparoscopic (94%). Overall, 16.8% of donors experienced a perioperative complication, most commonly gastrointestinal (4.4%), bleeding (3.0%), respiratory (2.5%), surgical/anesthesia-related injuries (2.4%), and other complications (6.6%). Major Clavien Classification of Surgical Complications grade IV (life threatening, organ dysfunction) or grade V (death) affected 2.5% of donors. After adjustment for demographic, clinical (including comorbidities), procedure, and center factors, blacks had increased risk of any complication (adjusted odds ratio [aOR], 1.26; P50.001) as well as Clavien grade II (requiring pharmacologic treatment or transfusion) or higher (aOR, 1.39; P,0.001), grade III (requiring anesthesia/surgery) or higher (aOR, 1.56, P,0.001), and grade IV or higher (aOR, 1.56; P50.004) events. Other significant correlates of Clavien grade IV or higher events included obesity (aOR, 1.55; P,0.001), predonation hematologic (such as thrombocytopenia; aOR, 2.78; P,0.001) and psychiatric (aOR, 1.45; P50.04) conditions, and robotic nephrectomy (aOR, 2.07; P50.002), whereas an annual center volume .50 transplants (aOR, 0.55; P,0.001) was associated with lower risk. The same group found that predonation narcotic analgesia use was independently associated with readmission after donor nephrectomy (9). Postnephrectomy surgical complications occur in approximately 17% of donors and are more common in blacks and those with obesity or hematologic or psychiatric conditions. The risk of more serious complications (Clavien grade IV or higher) is 2.5%. Pregnancy Risk Garg et al. (10) recently reported that gestational hypertension or preeclampsia was more common among living kidney donors than among nondonors (occurring in 15 of 131 pregnancies [11%] versus 38 of 788 pregnancies [5%]). The odds ratio (OR) for donors Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 was 2.4 (95% CI, 1.2 to 5.0; P50.01). Each component of the primary outcome was also more common among donors (OR, 2.5 for gestational hypertension and OR, 2.4 for preeclampsia). On a positive note, there were no significant differences between donors and nondonors with respect to rates of preterm birth (8% and 7%, respectively) or low birth weight (6% and 4%, respectively). There were no reports of maternal death, stillbirth, or neonatal death among donors. Most women had uncomplicated pregnancies after donation. Gestational hypertension and preeclampsia are more common in living donors than nondonors. Kidney Failure Risk There have been few prospective, controlled studies of kidney donors. Kasiske et al. (11) posited that understanding the pathophysiologic effects of kidney donation may be important for judging donor safety and improving our understanding of the consequences of reduced kidney function in CKD. In their prospective, controlled, observational cohort study, this group reported that GFR measured by plasma iohexol clearance declined 0.3667.55 ml/min per year in 194 controls but increased 1.4765.02 ml/min per year in 198 donors (P,0.01) between 6 and 36 months. BP was not different between donors and controls at any visit. Urinary protein-to-creatinine and albumin-tocreatinine ratios were not increased in donors compared with controls. From 6 to 36 months postdonation, serum parathyroid hormone, uric acid, homocysteine, and potassium levels were higher, whereas hemoglobin levels were lower in donors compared with controls. The authors concluded that kidney donors manifest several of the findings of mild CKD. However, at 36 months after donation, kidney function continues to improve in donors (presumably because of hyperfiltration), whereas controls have expected age-related declines in function. Previous reports on the risk of ESRD in prior living kidney donors (PLDs) have been variously criticized due to small sample size, inappropriate comparators, short follow-up time, and incomplete data acquisition. Grams et al. (12) studied data from almost 5 million nondonors studied for up to 16 years compared with 52,998 living kidney donors in the United States. For a 40-year-old 291 person with health characteristics that were like those of age-matched kidney donors, the 15-year projections of the risk of ESRD in the absence of donation varied according to race and sex; the risk was 0.24% among black men, 0.15% among black women, 0.06% among white men, and 0.04% among white women. Risk projections were higher in the presence of lower eGFR, higher albuminuria, hypertension, current or former smoking, diabetes, and obesity. The risk of ESRD was highest among persons in the youngest age group, particularly among young blacks. The 15-year observed risks after donation among kidney donors in the United States were 3.5–5.3 times as high as the projected risks in the absence of donation. Looking at this question another way, Ross (13) reported that .325 living kidney donors have developed ESRD and have been listed on the OPTN/UNOS deceased donor kidney waitlist. Unfortunately, because of lack of standardized data collection, the denominator is unknown. Anjum et al. (14) studied the causes of ESRD among PLDs. Overall, 125,427 donors were observed for a median of 11.0 years. The cumulative incidence of ESRD increased from ten events per 10,000 at 10 years postdonation to 85 events per 10,000 at 25 years postdonation (late versus early ESRD adjusted for age, race, and sex: incidence rate ratio, 1.3; 95% CI, 1.7 to 2.3). Early postdonation ESRD was predominantly reported as GN; however, late postdonation ESRD was more frequently reported as diabetes and hypertension. Living kidney donors have a small but significantly increased risk of ESRD compared with nondonors. This is driven early postdonation by GN and late postdonation by diabetes and hypertension. Prior Living Donors and Kidney Transplantation The impact of the new Kidney Allocation System (KAS) on the access of PLDs to deceased donor kidney transplants was studied by Wainright et al. (15). Using data from the OPTN, the numbers of PLDs registered for transplantation before and after KAS were examined (pre-KAS group: December 4, 2013 to December 3, 2014 [n550, newly listed PLDs]; postKAS group: December 4, 2014 to December 3, 2015 [n539]). Transplant rates were similar before and after 292 KAS implementation for both prevalent (2.37 versus 2.29; relative risk, 0.96; 95% CI, 0.62 to 1.49) and incident (4.76 versus 4.36; relative risk, 0.92; 95% CI, 0.53 to 1.60) candidates. Median waiting time to deceased donor kidney transplantation for prevalent PLDs in the post-KAS cohort was 102.6 days compared with 82.3 days in the pre-KAS cohort (P50.98). The median kidney donor profile index for PLD recipients was 31% with KAS versus 23% before KAS (P50.02). Despite a sharp decrease in the waiting times for highly prioritized candidates with calculated panel reactive antibodies of 98%–100% (from .7000 to 1164 days), PLDs still had much shorter waiting times (102.6 days). In conclusion, the new system continues to provide PLDs with quick access to highquality kidneys for transplantation. APOL1 Individuals of black ancestry who express two variant copies of the gene encoding apo1 (APOL1), an HDL that binds to apoA-1, make up 13% of the black population and are at increased risk of ESRD (16). Limited studies suggest that the survival of allografts from donors expressing two APOL1 risk alleles is inferior to that of allografts with zero or one risk allele. In living kidney donation, two case reports describe donors expressing two APOL1 risk alleles who developed ESRD (17). Given the potential impact of APOL1 variants on the utility and safety of kidney transplantation and living kidney donation, the American Society of Transplantation convened a meeting with the goals of summarizing the current state of knowledge with respect to transplantation and APOL1, identifying knowledge gaps and studies to address these gaps, and considering approaches to integrating APOL1 into clinical practice (16). Other Complications Lam et al. (18) reported an increased risk of gout in donors compared with nondonors. They studied 1988 donors and 19,880 matched nondonors who were followed for a median of 8.4 years. Donors compared with nondonors were more likely to be given a diagnosis of gout (3.4% versus 2.0%; 3.5 versus 2.1 events per 1000 person-years, respectively; HR, 1.6; 95% CI, 1.2 to 2.1; P,0.001). Similarly, donors compared with nondonors were more likely to receive a prescription for allopurinol or colchicine (3.8% versus 1.3%; OR, 3.2; 95% CI, 1.5 to 6.7; P50.002). Results were consistent in Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 multiple additional analyses. From a cohort of 1333 living donors with 5332 matched controls, Lin et al. (19) reported that the overall incidence of peptic ulcer disease was 1.74-fold higher in the living donor cohort than in the nonliving donor cohort (2.14 versus 1.48 per 1000 person-years). This finding persisted after adjustment for age, sex, monthly income, and comorbidities. References 1. Hart A, Smith JM, Skeans MA, Gustafson SK, Stewart DE, Cherikh WS, Wainright JL, Boyle G, Snyder JJ, Kasiske BL, Israni AK: Kidney. Am J Transplant 16[Suppl 2]: 11–46, 2016 PubMed 2. Flechner SM, Leeser D, Pelletier R, Morgievich M, Miller K, Thompson L, McGuire S, Sinacore J, Hil G: The incorporation of an advanced donation program into kidney paired exchange: Initial experience of the national kidney registry. Am J Transplant 15: 2712–2717, 2015 PubMed 3. Fumo DE, Kapoor V, Reece LJ, Stepkowski SM, Kopke JE, Rees SE, Smith C, Roth AE, Leichtman AB, Rees MA: Historical matching strategies in kidney paired donation: The 7-year evolution of a web-based virtual matching system. Am J Transplant 15: 2646–2654, 2015 PubMed 4. Huang N, Foster MC, Lentine KL, Garg AX, Poggio ED, Kasiske BL, Inker LA, Levey AS: Estimated GFR for living kidney donor evaluation. Am J Transplant 16: 171–180, 2016 PubMed 5. Ahmadi AR, Lafranca JA, Claessens LA, Imamdi RM, IJzermans JN, Betjes MG, Dor FJ: Shifting paradigms in eligibility criteria for live kidney donation: a systematic review. Kidney Int 87: 31–45, 2015 PubMed 6. Massie AB, Leanza J, Fahmy LM, Chow EK, Desai NM, Luo X, King EA, Bowring MG, Segev DL: A risk index for living donor kidney transplantation. Am J Transplant 16: 2077–2084, 2016 PubMed 7. Muzaale AD, Massie AB, Anjum S, Liao C, Garg AX, Lentine KL, Segev DL: Recipient outcomes following transplantation of allografts from live kidney donors who subsequently developed end-stage renal disease. Am J Transplant 16: 3532–3539, 2016 PubMed 8. Lentine KL, Lam NN, Axelrod D, Schnitzler MA, Garg AX, Xiao H, Dzebisashvili N, Schold JD, Brennan DC, Randall H, King EA, Segev DL: Perioperative complications after living kidney donation: A national study. Am J Transplant 16: 1848–1857, 2016 PubMed 9. Lentine KL, Lam NN, Schnitzler MA, Hess GP, Kasiske BL, Xiao H, Axelrod D, Garg AX, Schold JD, Randall H, Dzebisashvili N, Brennan DC, Segev DL: Predonation prescription opioid use: A novel risk factor for readmission after living kidney donation. Am J Transplant 17: 744– 753, 2017 PubMed 10. Garg AX, Nevis IF, McArthur E, Sontrop JM, Koval JJ, Lam NN, Hildebrand AM, Reese PP, Storsley L, Gill JS, Segev DL, Habbous S, Bugeja A, Knoll GA, Dipchand C, Monroy-Cuadros M, Lentine KL; DONOR Network: Gestational hypertension and preeclampsia in living kidney donors. N Engl J Med 372: 124–133, 2015 PubMed 11. Kasiske BL, Anderson-Haag T, Israni AK, Kalil RS, Kimmel PL, Kraus ES, Kumar R, Posselt AA, Pesavento TE, Rabb H, Steffes MW, Snyder JJ, Weir MR: A prospective controlled study of living kidney donors: Three-year follow-up. Am J Kidney Dis 66: 114–124, 2015 PubMed 12. Grams ME, Sang Y, Levey AS, Matsushita K, Ballew S, Chang AR, Chow EK, Kasiske BL, Kovesdy CP, Nadkarni GN, Shalev V, Segev DL, Coresh J, Lentine KL, Garg AX; Chronic Kidney Disease Prognosis Consortium: Kidney-failure risk projection for the living kidney-donor candidate. N Engl J Med 374: 411–421, 2016 PubMed 13. Ross LF: Living kidney donors and ESRD. Am J Kidney Dis 66: 23–27, 2015 PubMed 14. Anjum S, Muzaale AD, Massie AB, Bae S, Luo X, Grams ME, Lentine KL, Garg AX, Segev DL: Patterns of end-stage renal disease caused by diabetes, hypertension, and glomerulonephritis in live kidney donors. Am J Transplant 16: 3540–3547, 2016 PubMed 293 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 15. Wainright JL, Kucheryavaya AY, Klassen DK, Stewart DE: The impact of the new kidney allocation system on prior living kidney donors’ access to deceased donor kidney transplants: An early look. Am J Transplant 17: 1103–1111, 2017 PubMed 16. Newell KA, Formica RN, Gill JS, Schold JD, Allan JS, Covington SH, Wiseman AC, Chandraker A: Integrating APOL1 gene variants into renal transplantation: Considerations arising from the American Society of Transplantation Expert Conference. Am J Transplant 17: 901–911, 2017 PubMed 17. Zwang NA, Shetty A, Sustento-Reodica N, Gordon EJ, Leventhal J, Gallon L, Friedewald JJ: APOL1-associated end-stage renal disease in a living kidney transplant donor. Am J Transplant 16: 3568–3572, 2016 PubMed 18. Lam NN, McArthur E, Kim SJ, Prasad GV, Lentine KL, Reese PP, Kasiske BL, Lok CE, Feldman LS, Garg AX; Donor Nephrectomy Outcomes Research (DONOR) Network; Donor Nephrectomy Outcomes Research DONOR Network: Gout after living kidney donation: A matched cohort study. Am J Kidney Dis 65: 925–932, 2015 PubMed 19. Lin SY, Lin CL, Liu YL, Hsu WH, Lin CC, Wang IK, Jeng LB, Kao CH: Peptic ulcer disease in living liver donors: A longitudinal populationbased study. Am J Transplant 16: 2925–2931, 2016 PubMed Delayed Graft Function Delayed graft function (DGF) after kidney transplantation is variably defined as the need for dialysis during the first postoperative week, anuria, or failure of prompt azotemia resolution. Importantly, DGF develops in up to 25%–30% of kidney transplant recipients and is associated with increased cost, length of stay, and inferior long-term graft survival. There has been concern that the Kidney Allocation System (KAS), a major change to organ sharing implemented by the United Network for Organ Sharing in December of 2014, may be associated with increased DGF rates. Goals of the KAS included directing the highest quality organs to younger/healthier recipients and increasing access to deceased donor kidney transplantation organs for highly sensitized patients and racial/ethnic minorities at the expense of increased cold ischemic time. Massie et al. (1), using national registry data, compared kidney distribution, transplant rates, and recipient characteristics between January 1, 2013 and December 3, 2014 (pre-KAS) with those between December 4, 2014 and August 31, 2015 (post-KAS). Regionally imported organs increased from 8.8% preKAS to 12.5% post-KAS; national imports increased from 12.7% pre-KAS to 19.1% post-KAS (P,0.001). In parallel, DGF increased from 24.8% pre-KAS to 29.9% post-KAS (P,0.001). The impact of this increase in DGF rates nationwide on outcomes remains to be determined. Donor, peritransplant, and recipient factors have been implicated in the pathogenesis of DGF. For example, Allen et al. (2) recently showed that donation after cardiac death kidneys have inferior survival when preprocurement hypotension persists (odds ratio [OR], 1.42; 95% confidence interval [95% CI], 1.06 to 1.90). Donor hypoxia during the first 10 minutes after extubation was also associated with graft failure (hazard ratio [HR], 1.30; 95% CI, 1.03 to 1.64), with 5-year graft survival of 70.0% (95% CI, 64.5% to 74.8%) for donors above the median versus 61.4% (95% CI, 55.5% to 66.7%) for those below the median. Patel et al. (3) described the impact of premortem donor hydroxyethyl starch (HES) use on allograft outcomes. Kidneys from donors who received HES had a higher crude rate of DGF (41% versus 31%; P,0.001). In this report, independent predictors of DGF included donor age (OR, 1.02; 95% CI, 1.01 to 1.04 per year), cold ischemia time (OR, 1.04; 95% CI, 1.02 to 1.06 per hour), creatinine elevation (OR, 1.5; 95% CI, 1.32 to 1.72 per mg/dl), and HES use (OR, 1.41; 95% CI, 1.02 to 1.95). The broader applicability of this remains unclear, because there are no published data on the use of HES in kidney donors. Donor, peritransplant, and recipient factors are implicated in the pathogenesis of delayed graft function after transplant, which in turn, impacts patient and graft survival. Premortem AKI What about the use of kidneys from deceased donors with premortem AKI? Heilman et al. (4) described the outcome and phenotype of kidneys with and without donor AKI. DGF was more common in the AKI group, but eGFR, graft survival at 1 year, and fibrosis scores at 12 months were similar for the two groups. At 1 month, there were 898 differentially expressed genes in the AKI group (P,0.01), but at 4 months, there were no differences. The authors concluded that transplanting selected kidneys from deceased donors with AKI is safe and associates with excellent outcomes. Batra et al. (5) added to this literature by studying the clinical and histologic outcomes related to 61 transplanted kidneys from deceased donors with glomerular fibrin thrombi (GFT) consequent on disseminated intravascular coagulation before organ procurement. DGF occurred in 49% of the GFT group and 39% of the control group (P50.14). Serum creatinine values at 1, 4, and 12 months and eGFR at 12 months were similar in the two groups. Estimated 1-year graft survival was 93.2% in the GFT group and 95.1% in 294 the control group (P50.22 by log rank test). The authors concluded that GFT resolves rapidly after transplantation and that transplanting selected kidneys from deceased donors with GFT is a safe practice. Despite these observations, deceased donor kidneys with AKI are often discarded due to fear of poor outcomes. Hall et al. (6) performed a multicenter study to determine associations of AKI with kidney discard, DGF, and 6-month eGFRs. In 1632 donors, the kidney discard risk increased for AKI stages 1, 2, and 3 compared with no AKI, with adjusted relative risks (aRRs) of 1.28 (95% CI, 1.08 to 1.52), 1.82 (95% CI, 1.45 to 2.30), and 2.74 (95% CI, 2.0 to 3.75), respectively. The aRRs for DGF also increased by donor AKI stage: aRR, 1.27; 95% CI, 1.09 to 1.49; aRR, 1.70; 95% CI, 1.37 to 2.12; and aRR, 2.25; 95% CI, 1.74 to 2.91, respectively. The 6-month eGFRs were similar across AKI categories but lower for recipients with DGF: 48 (interquartile range, 31–61) ml/min per 1.73 m2 versus 58 (interquartile range, 45–75) ml/min per 1.73 m2 for no DGF (P,0.001). What about the use of postprocurement biopsy on outcomes? Wang et al. (7) carried out a systematic review of the medical literature on the utility of procurement and implantation biopsies for predicting post-transplant outcomes. Between 1994 and 2014, 47 studies were reviewed that examined the association between pretransplant donor biopsy findings and post-transplant graft failure, DGF, or graft function. In general, study quality was poor. All of them were retrospective or did not indicate if they were prospective. Results were heterogeneous, with authors as often as not concluding that biopsy results did not predict post-transplant outcomes. The percentage glomerular sclerosis was the most often examined parameter, and it failed to predict graft failure in seven of 14 studies. Of 15 proposed semiquantitative scoring systems, none consistently predicted post-transplant outcomes across studies. In summary, it seems that the routine use of biopsies to help determine whether to transplant a kidney is of little value in predicting outcomes. Predonation Interventions Preprocurement interventions to mitigate deceased donor recipient DGF risk have yielded inconsistent results to date. For example, preliminary reports that donor remote ischemic preconditioning reduced DGF have not been reproduced (8). Provocatively, Niemann et al. (9) recently targeted mild hypothermia in organ donors before organ recovery. Organ donors (after declaration of death per neurologic criteria) from two large Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 donation service areas were randomly assigned to one of two targeted temperature ranges: 34C to 35C (hypothermia) or 36.5C to 37.5 C (normothermia). The study was terminated early on the recommendation of an independent data safety monitoring board after the interim analysis showed efficacy of hypothermia. DGF developed in 79 recipients of kidneys from donors in the hypothermia group (28%) and 112 recipients of kidneys from donors in the normothermia group (39%; OR, 0.62; 95% CI, 0.43 to 0.92; P50.02). Feng (10), in an accompanying editorial, describes some of the barriers that exist in conducting research in deceased donors while issuing a cry to action: “The astonishing benefits of therapeutic hypothermia should inspire governmental regulatory and funding agencies, basic and clinical scientists, and the entire donation and transplantation communities to vigorously advocate for innovative research interventions in deceased donors to improve the quality and increase the quantity of organs available for transplantation” (10). Procedure Times Perhaps intuitively, prolonged ischemia during procurement, storage, and time to complete the vascular anastomoses has long been thought to impact DGF risk. Osband et al. (11) studied the extraction time of 576 kidneys beginning with aortic crossclamp and perfusion/cooling of the kidneys and ending with removal of the kidneys and placement on ice on the back table. This cohort was compared with Scientific Registry of Transplant Recipients (SRTR) data for outcomes. Extraction time ranged from 14 to 123 minutes, with a mean of 44.7 minutes. In SRTR-adjusted analyses, longer extraction times and DGF were statistically associated (OR, 1.19 per 5 minutes beyond 60 minutes; 95% CI, 1.02 to 1.39; P50.03). Up to 60 minutes of extraction time, DGF incidence was 27.8%; by 120 minutes, it doubled to nearly 60%. Primary nonfunction rate also rose dramatically to nearly 20% by 120 minutes of extraction time. Heylen et al. investigated the effect of anastomosis time on allograft outcome in 669 first single-kidney transplantations from brain-dead donors (12). Anastomosis time independently increased the risk of DGF (OR per minute, 1.05; 95% CI, 1.02 to 1.07; P,0.001) and impaired allograft function after transplantation (P,0.01). In a subgroup of transplant recipients, protocol-specified biopsies at 3 months, 1 year, and 2 years were blindly reviewed. Prolonged anastomosis time independently increased the risk of post-transplant interstitial fibrosis and tubular atrophy 295 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 of these protocol-specified biopsies (P,0.001). Tennankore et al. (13) similarly found that ischemia time is associated with adverse long-term patient and graft survival after kidney transplantation. Recipient Factors The prevalence of obesity is increasing globally and associates with CKD and premature mortality. However, the impact of recipient obesity on kidney transplant outcomes remains unclear. Hill et al. (14) investigated the association between recipient obesity (defined as body mass index .30 kg/m2) and mortality, death-censored graft loss, and DGF after kidney transplantation. A systematic review and meta-analysis, including 17 studies with a total of 138,081 patients, were analyzed. After adjustment, there was no significant difference in mortality risk in obese recipients (HR, 1.24; 95% CI, 0.90 to 1.70; studies 55; n583,416). However, obesity was associated with an increased risk of death-censored graft loss (HR, 1.06; 95% CI, 1.01 to 1.12; studies 55; n583,416) and an increased likelihood of DGF (OR, 1.68; 95% CI, 1.39 to 2.03; studies 54; n528,847). Peräsaari et al. (15) examined the association of donor-specific antibodies (DSAs) with DGF. Patients with DSAs had a higher incidence of DGF compared with nonsensitized patients (48% and 26%, respectively; P,0.001). Third-party antibodies (anti-HLA antibodies that are not donor specific) had no effect on DGF incidence. The relative risk of DGF for patients with DSAs in the multivariate analysis was 2.04 (95% CI, 1.25 to 3.34; P,0.01). Analyses of the cumulative mean fluorescent intensity (MFI) value of the DSAs revealed a rate of DGF more than two times higher in patients with cumulative values of 3000–5000 MFI compared with cumulative values of 1000–3000 MFI (65% versus 31%; P50.04). DSAs against any locus were associated with an elevated DGF incidence of 44%–69% compared with patients without DSA (27%), independent of rejection. Importantly, neither the use of antibody induction nor nonuse of such agents impact risk of DGF in allosensitized patients. Schold et al. (16), in a cohort of approximately 14,000 kidney retransplant recipients reported to the SRTR, disclosed DGF rates of approximately 22% for all groups noted above, except alemtuzumab (27%; P50.04). Patients with donor specific antibodies before transplant have twice the incidence of delayed graft function after transplantation. Delayed Graft Function and Rejection Risk DGF is commonly considered to be a risk factor for acute rejection, a biologically plausible association given upregulation of chemokines, cytokines, and MHC class II with AKI. However, this association has not been uniformly observed across all studies. In addition, the link between DGF and acute rejection may have changed over time due to advances in immunosuppression and medical management. Wu et al. (17) conducted a cohort study of 645 patients over 12 years to evaluate the association of DGF and biopsy-proven acute rejection (BPAR) in a modern cohort of kidney transplant recipients. The 1-, 3-, and 5-year cumulative probabilities of BPAR were 16.0%, 21.8%, and 22.6% in the DGF group, significantly different from 10.1%, 12.4%, and 15.7% in the non-DGF group. In a multivariable Cox proportional hazards model, the adjusted relative HR for BPAR in DGF (versus no DGF) was 1.55 (95% CI, 1.03 to 2.32). This association was generally robust to different definitions of DGF. The relative HR was also similarly elevated for T cell– or antibody-mediated BPAR (HR, 1.52; 95% CI, 0.92 to 2.51 and HR, 1.54; 95% CI, 0.85 to 2.77, respectively). Finally, the association was consistent across clinically relevant subgroups. Thus, DGF remains an important risk factor for BPAR in a contemporary cohort of kidney transplant recipients. Interventions to reduce the risk of DGF and/or its after effects remain of paramount importance to improve kidney transplant outcomes. Delayed graft function increases the risk of allograft rejection by 50% compared with prompt graft function. References 1. Massie AB, Luo X, Lonze BE, Desai NM, Bingaman AW, Cooper M, Segev DL: Early changes in kidney distribution under the new allocation system. J Am Soc Nephrol 27: 2495–2501, 2016 PubMed 2. Allen MB, Billig E, Reese PP, Shults J, Hasz R, West S, Abt PL: Donor hemodynamics as a predictor of outcomes after kidney transplantation from donors after cardiac death. Am J Transplant 16: 181–193, 2016 PubMed 3. Patel MS, Niemann CU, Sally MB, De La Cruz S, Zatarain J, Ewing T, Crutchfield M, Enestvedt CK, Malinoski DJ: The impact of hydroxyethyl starch use in deceased organ donors on the development of delayed graft function in kidney transplant recipients: A propensityadjusted analysis. Am J Transplant 15: 2152–2158, 2015 PubMed 4. Heilman RL, Smith ML, Kurian SM, Huskey J, Batra RK, Chakkera HA, Katariya NN, Khamash H, Moss A, Salomon DR, Reddy KS: Transplanting kidneys from deceased donors with severe acute kidney injury. Am J Transplant 15: 2143–2151, 2015 PubMed 5. Batra RK, Heilman RL, Smith ML, Thomas LF, Khamash HA, Katariya NN, Hewitt WR, Singer AL, Mathur AK, Huskey J, Chakkera HA, 296 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 Moss A, Reddy KS: Rapid resolution of donor-derived glomerular fibrin thrombi after deceased donor kidney transplantation. Am J Transplant 16: 1015–1020, 2016 PubMed Hall IE, Schröppel B, Doshi MD, Ficek J, Weng FL, Hasz RD, Thiessen-Philbrook H, Reese PP, Parikh CR: Associations of deceased donor kidney injury with kidney discard and function after transplantation. Am J Transplant 15: 1623–1631, 2015 PubMed Wang CJ, Wetmore JB, Crary GS, Kasiske BL: The donor kidney biopsy and its implications in predicting graft outcomes: A systematic review. Am J Transplant 15: 1903–1914, 2015 PubMed Krogstrup NV, Oltean M, Nieuwenhuijs-Moeke GJ, Dor FJ, Møldrup U, Krag SP, Bibby BM, Birn H, Jespersen B: Remote ischemic conditioning on recipients of deceased renal transplants does not improve early graft function: A multicenter randomized, controlled clinical trial. Am J Transplant 17: 1042–1049, 2017 PubMed Niemann CU, Feiner J, Swain S, Bunting S, Friedman M, Crutchfield M, Broglio K, Hirose R, Roberts JP, Malinoski D: Therapeutic hypothermia in deceased organ donors and kidney-graft function. N Engl J Med 373: 405–414, 2015 PubMed Feng S: Got it! Let’s cool it! But what’s next in organ donor research? Am J Transplant 16: 5–6, 2016 PubMed Osband AJ, James NT, Segev DL: Extraction time of kidneys from deceased donors and impact on outcomes. Am J Transplant 16: 700–703, 2016 PubMed Heylen L, Naesens M, Jochmans I, Monbaliu D, Lerut E, Claes K, Heye S, Verhamme P, Coosemans W, Bammens B, Evenepoel P, Meijers B, Kuypers D, Sprangers B, Pirenne J: The effect of anastomosis time on outcome in recipients of kidneys donated after brain death: a cohort study. Am J Transplant 15: 2900–2907, 2015 Tennankore KK, Kim SJ, Alwayn IP, Kiberd BA: Prolonged warm ischemia time is associated with graft failure and mortality after kidney transplantation. Kidney Int 89: 648–658, 2016 PubMed Hill CJ, Courtney AE, Cardwell CR, Maxwell AP, Lucarelli G, Veroux M, Furriel F, Cannon RM, Hoogeveen EK, Doshi M, McCaughan JA: Recipient obesity and outcomes after kidney transplantation: A systematic review and meta-analysis. Nephrol Dial Transplant 30: 1403– 1411, 2015 PubMed Peräsaari JP, Kyllönen LE, Salmela KT, Merenmies JM: Pre-transplant donor-specific anti-human leukocyte antigen antibodies are associated with high risk of delayed graft function after renal transplantation. Nephrol Dial Transplant 31: 672–678, 2016 PubMed Schold J, Poggio E, Goldfarb D, Kayler L, Flechner S: Clinical outcomes associated with induction regimens among retransplant kidney recipients in the United States. Transplantation 99: 1165–1171, 2015 PubMed Wu WK, Famure O, Li Y, Kim SJ: Delayed graft function and the risk of acute rejection in the modern era of kidney transplantation. Kidney Int 88: 851–858, 2015 PubMed Immunosuppression Induction Therapy Rabbit antithymocyte globulin (rATG)–induced lymphocyte depletion and basiliximab-induced IL-2 receptor blockade (IL2RA) are the induction strategies in general use within the United States (1). Alemtuzumab (AZ) use is dwindling due to restricted access by the manufacturer. Prior randomized trials revealed that rATG or IL2RA induction reduced early acute rejection, prompting recommendations by the Kidney Disease Improving Global Outcomes group that IL2RA induction be used routinely as first-line therapy after kidney transplantation, with lymphocyte-depleting induction reserved for high-risk cases. Despite this recommendation, most United States transplant recipients receive depleting induction therapy (Figure 8). It has been suggested that the older studies referenced by Kidney Disease Improving Global Outcomes mainly used outdated maintenance regimens, and specifically, no large randomized trial has examined the effect of IL2RA or rATG induction versus no induction in patients receiving tacrolimus (TAC), mycophenolic acid (MPA), and steroids (2). It has been suggested that, with this triple maintenance therapy, the addition of basiliximab induction may achieve an absolute risk reduction for acute rejection of only 1%–4% in standard risk patients without improving graft or patient survival compared with no induction. In contrast, rATG induction lowers the relative risk (RR) of acute rejection by almost 50% versus IL2RA in patients at higher immunologic risk. Tanriover et al. (3) evaluated the United Network for Organ Sharing data of transplant recipients maintained on TAC/mycophenolate (MPA) from 2000 to 2012 to compare outcomes of IL2RA and other induction agents. Acute rejection within the first year and overall graft failure within 5 years of transplantation were more common with no induction therapy (13.3%; P,0.001 and 28%; P50.01, respectively) with steroids and in the IL2RA category (11.1%; P50.16 and 27.4%; P,0.001, respectively) without steroids (Figure 8). Compared with IL2RA, analyses showed that outcomes in the steroid group were similar among induction categories, except that acute rejection was significantly lower with rATG (odds ratio [OR], 0.68; 95% confidence interval [95% CI], 0.62 to 0.74). In the no steroid group compared with IL2RA, the probabilities of acute rejection with rATG (OR, 0.80; 95% CI, 0.60 to 1.00) and AZ (OR, 0.68; 95% CI, 0.53 to 0.88) were lower. rATG was associated with better graft survival (hazard ratio [HR], 0.86; 95% CI, 0.75 to 0.99). The authors concluded that, in deceased donor transplantation, compared with IL2RA induction, no induction was associated with similar outcomes when TAC/MPA/ steroids were used. However, rATG seems to offer better graft survival over IL2RA in steroid avoidance protocols. The same authors reached similar conclusions when studying living donor transplant recipients (4). Rituximab is a monoclonal antibody that targets CD20 leading to B cell depletion. It is licensed for various non-transplant indications and has been studied off label both as an induction and rescue immunotherapeutic. The efficacy and safety of rituximab as Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 297 Figure 8. Allograft rejection rates within the first post transplant year are lowest for those who receive lymphocyte depletion (rabbit antithymocyte globulin [rATG] or alemtuzumab) compared with interleukin-2 receptor antibody [IL2r Ab] (basiliximab) induction therapy versus no induction therapy. Observed frequencies of outcomes by induction type with or without steroids at discharge. Reprinted with permission from Tanriover B, Jaikaransingh V, MacConmara MP, Parekh JR, Levea SL, Ariyamuthu VK, Zhang S, Gao A, Ayvaci MU, Sandikci B, Rajora N, Ahmed V, Lu CY, Mohan S, Vazquez MA: Acute rejection rates and graft outcomes according to induction regimen among recipients of kidneys from deceased donors treated with tacrolimus and mycophenolate. Clin J Am Soc Nephrol 11: 1650–1661, 2016. induction therapy in renal transplant patients were evaluated by van den Hoogen et al. (5). In a doubleblind, placebo-controlled study, 280 adult kidney transplant patients were randomized to either a single dose of rituximab (375 mg/m2) or placebo. Maintenance immunosuppression consisted of TAC, mycophenolate mofetil (MMF), and steroids. The incidence of rejection was comparable between rituximab- (23 of 138; 16.7%) and placebo-treated (30 of 142; 21.2%; P50.25) patients. Immunologically high-risk patients (panel reactive antibody .6% or retransplant) not receiving rituximab had a significantly higher incidence of rejection (13 of 34; 38.2%) compared with other treatment groups (rituximabtreated immunologically high-risk patients and rituximabor placebo-treated immunologically low-risk [panel reactive antibody #6% or first transplant] patients: 17.9%, 16.4%, and 15.7%, respectively; P50.004). Neutropenia (,1.53109/L) occurred more frequently in rituximab-treated patients (24.3% versus 2.2%; P,0.001). After 24 months, the cumulative incidence of infections and malignancies was comparable. The authors concluded that a single dose of rituximab was safe as induction therapy but did not reduce the overall incidence of biopsy-proven acute rejection, and it could benefit immunologically high-risk patients. Treatment with rituximab was deemed safe. AZ is a humanized anti-CD52 mAb that is infrequently used as induction therapy due to access restrictions imposed by the manufacturer (Bayer, Wayne, NJ). Serrano et al. (6) reported a retrospective cohort study of primary kidney transplant recipients receiving induction with AZ (n55521) or antithymocyte globulin (n58504) and maintenance immunosuppression as TAC and MMF with early steroid withdrawal. The transplant eras were subcategorized. AZ was significantly associated with inferior death-censored graft survival in the earliest 2003–2005 era (adjusted hazard ratio [aHR], 2.21; 95% CI, 1.72 to 2.84). However, these findings were no longer significant more recently. Patient survival and acute rejection with AZ were comparable with antithymocyte globulin in the most recent era. The effect of such findings is moot given the lack of general 298 availability of AZ. However, it may be distributed under research protocols by the manufacturer with institutional review board approval. Maintenance Therapy Although maintenance immunosuppression management in kidney transplantation has evolved to include a diverse repertoire of agents, TAC, mycophenolate, and prednisone continue to represent the most commonly used therapies (Figure 9) (1). Despite this, the choice of immunosuppression regimen varies across transplant programs. Using a database integrating national transplant registry and pharmacy fill records, immunosuppression use after transplant was evaluated for 22,453 patients transplanted in 249 United States programs between 2005 and 2010 by Axelrod et al. (7). Use of triple immunosuppression composed of TAC, MPA, or azathioprine (AZA), and steroids varied widely (0%–100% of patients per program), as did use of steroid-sparing regimens (0%– 77%), sirolimus-based regimens (0%–100%), and cyclosporine-based regimens (0%–78%) (Figure 10). Use of triple therapy was more common in highly sensitized patients, women, and recipients with dialysis duration .5 years. TAC has largely replaced cyclosporine due to improved efficacy in preventing rejection, although registry data indicate that patient and graft survival rates are equivalent when a calcineurin inhibitor (CNI) is utilized. Sirolimus use has decreased Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 substantially with time. Patient and donor characteristics explained only a limited amount of the observed variation in regimen use, whereas center choice explained 30%–46% of the use of nontriple-therapy immunosuppression. The authors suggest that substantial variation in center practice exists beyond that explained by differences in patient and donor characteristics. Regardless of regimen, medication nonadherence increases the risk for kidney transplant loss after transplantation. Reese et al. (8) studied the utility of electronic reminders to enhance adherence in real time using wireless-enabled pill bottles. Mean participant age was 50 years old; 60% were men, and 40% were black. Mean adherence rates were 78%, 88%, and 55% in groups with reminders, reminders plus notification, or neither (control), respectively (P,0.001 for comparison of each intervention with control). Interestingly, mean TAC levels were not significantly different between groups. Tacrolimus Long-term transplant outcomes are clearly limited, at least in part, by adverse effects of immunosuppressive therapies, which have led to the search for minimization or withdrawal strategies. Many have been reported, and although some result in improved renal function, this is often at increased risk of rejection (9). Dugast et al. (10) conducted a prospective, randomized, multicenter, doubleblind, placebo-controlled clinical study to analyze the Figure 9. Immunosuppression in adult kidney transplant recipients. First post transplant year immunosuppression trends in US transplant recipients reveals in (A) most patients receive lymphocyte depleting induction therapy (rATG or alemtuzumab), (B) Tacrolimus has almost completely replaced cyclosporine as the calcineurin inhibitor of choice, (C) Mycophenolate has almost completely replaced Azathioprine as the antimetabolite of choice, (D) the use of mTOR inhibitors was never widespread and has dwindled to almost zero, and in (E) most patients continue to receive corticosteroids. One-year post-transplant data are limited to patients alive with graft function at 1 year post-transplant. Mycophenolate includes MMF and mycophenolate sodium. Reprinted with permission from Hart A, Smith JM, Skeans MA, Gustafson SK, Stewart DE, Cherikh WS, Wainright JL, Boyle G, Snyder JJ, Kasiske BL, Israni AK: Kidney. Am J Transplant 16[Suppl 2]: 11–46, 2016. Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 299 Figure 10. While most patients continue to receive the combination of tacrolimus (Tac)/mycophenolate mofetil (MMF)/ Prednisone, a degree of intercenter and regional variability exists regarding the specific alternate combinations that are in use. The graphic represents the proportion of patients who receive one of six mutually exclusive immunosuppression (ISx) regimens during months 6–12 after transplant. Each horizontal bar represents an individual center within United States regions ordered by the proportion of patients who received triple ISx (TAC 1 mycophenolic acid (MPA)/azathioprine (AZA) 1 prednisone [Pred]; orange). Overall percentages of regimen use at patient level across centers: TAC 1 MPA/AZA 1 Pred, 33.8%; TAC 1 MPA/AZA (no Pred), 25.8%; TAC without MPA/AZA, 11.3%; sirolimus (SRL) based, 9.9%; cyclosporine (CSA) based, 7.8%; and other regimens (including CSA withdrawal or other trial medications), 11.6%. Proportion of patients receiving one of six mutually 300 impact of TAC withdrawal on patients .4 years posttransplantation with baseline normal histology, stable graft function, and no anti-HLA immunization. Only ten of 52 eligible patients were randomized. Five patients were assigned to the placebo arm, and five were assigned to the TAC maintenance arm. In the TAC maintenance arm, all patients maintained stable graft function, and no immunologic events occurred. By contrast, all five patients in the placebo arm had to reintroduce TAC, because three presented with an acute rejection episode (one humoral, one mixed, and one borderline) and two showed anti-HLA antibodies without histologic lesion (one with donor-specific antibodies [DSAs] and one non-DSA). The authors concluded that TAC withdrawal must be avoided long-term, even in highly selected stable kidney recipients. Another nail in the TAC elimination coffin was provided by Hricik et al. (11), who reported the results of the Clinical Trials in Organ Transplantation09 Trial. This was a randomized, prospective study of nonsensitized primary recipients of living donor kidney transplants. Subjects received rATG, TAC, MMF, and prednisone. Six months post-transplantation, subjects without de novo DSAs, acute rejection, or inflammation at protocol biopsy were randomized to wean off or remain on TAC. The study was terminated prematurely because of unacceptable rates of acute rejection (four of 14) and/or de novo DSAs (five of 14) in the TAC withdrawal arm. Gatault et al. (12) took a different approach and sought to determine the efficacy and safety of two different doses of extended release tacrolimus (LCPT) in steroid-free kidney transplant recipients. More rejection episodes occurred in the lower target TAC–level group (50% dose reduction at 6 months with target level .3 ng/ml; group A) than the higher target-level group B (continued full-dose therapy with target level of 7– 12 ng/ml; 11 versus three; P50.02): subclinical inflammation (21.4% versus 8.8%; P50.05) and DSAs (six versus zero patients; P,0.01). The authors concluded that TAC levels should be maintained .7 mg/L during the first year after transplantation in low-immunologic risk, Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 steroid-free kidney transplant recipients receiving a moderate dose of MPA. Tacrolimus remains the single most effective immunosuppressive agent available to prevent acute allograft rejection. Prospective elimination studies in low risk kidney allograft recipients have yielded unacceptable results. Maintenance of therapeutic levels remains of critical importance for all transplant recipients. Pharmacokinetics TAC blood-level variability associates with inferior graft survival (13). TAC trough blood concentrations for black kidney allograft recipients are lower than those observed in white patients. This finding can be associated with increased rejection and graft failure risks (14). Oetting et al. (14) identified two CYP3A5 variants uniquely found in black recipients that independently associated with TAC troughs: CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343). These variants and various clinical factors accounted for 53.9% of the observed variance in trough levels, with 19.8% of the variance originating from demographic and clinical factors (14). It has been suggested that pretransplantation adaptation of the daily dose of TAC to cytochrome genotype may be associated with improved achievement of target trough levels. CYP3A4*22 is an allelic variant of the cytochrome P450 3A4 that associates with decreased enzymatic degradatory activity, leading to reduced dosing. Pallet et al. (15) tested this concept in a population of 186 kidney transplants, of whom 9.3% (18 patients) were heterozygous for the CYP3A4*22 genotype and none were homozygous (allele frequency, 4.8%). Ten days after transplantation, 11% of the CYP3A4*22 carriers were within the target range, whereas among the CYP3A4*1/*1 carriers, 40% were exclusive immunosuppression (ISx) regimens during months 6–12 after transplant. Each horizontal bar represents an individual center within United States regions ordered by the proportion of patients who received triple ISx (TAC 1 MPA/AZA 1 prednisone [Pred]; orange). Overall percentages of regimen use at patient level across centers: TAC 1 MPA/AZA 1 Pred, 33.8%; TAC 1 MPA/AZA (no Pred), 25.8%; TAC without MPA/AZA, 11.3%; SRL based, 9.9%; cyclosporine (CSA) based, 7.8%; and other regimens (including CSA withdrawal or other trial medications), 11.6%. Reprinted with permission from Axelrod DA, Naik AS, Schnitzler MA, Segev DL, Dharnidharka VR, Brennan DC, Bae S, Chen J, Massie A, Lentine KL: National variation in use of immunosuppression for kidney transplantation: A call for evidence-based regimen selection. Am J Transplant 16: 2453–2462, 2016. 301 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 within the target range (P50.02). The authors concluded that the CYP3A4*22 allelic variant is associated with a significantly altered TAC metabolism, and carriers of this polymorphism often reach supratherapeutic concentrations. The same group evaluated the long-term clinical impact of the adaptation of initial TAC dosing according to the cytochrome genotype (16). The outcomes of 236 kidney transplant recipients included in the Tactique Study were retrospectively investigated over a period of 5 years. These patients were randomly assigned to receive TAC at either a fixed dosage or one determined by genotype. The incidence rates of biopsy-proven acute rejection and graft survival were similar between the control and the adapted TAC dose groups. Patient deaths, cancer, cardiovascular events, and infections were also similar, and renal function did not change. The authors concluded that optimization of initial TAC dose using pharmacogenetic testing did not improve clinical outcomes. Shuker et al. (17) similarly studied 244 living donor kidney transplant recipients. They concluded that pharmacogenetic adaptation of the TAC starting dose did not increase the number of patients having therapeutic TAC exposure early after transplantation and did not lead to improved clinical outcome in a low-immunologic risk population. Pharmacogenetic testing is not associated with improved outcomes after kidney transplantation. Extended Release Tacrolimus The safety and efficacy of LCPT (Envarsus XR; Veloxis Pharmaceuticals, Edison, NJ) compared with immediate release tacrolimus (IR-Tac) twice daily after kidney transplantation were studied by Rostaing et al. (18). This group carried out a 2-year, double-blind, multicenter, noninferiority design, phase 3 trial involving 543 de novo kidney recipients. Patients were randomly assigned to LCPT (n5268) or IR-Tac (n5275), and 507 (93.4%) completed the 24-month study. LCPT tablets were administered at 0.17 mg/kg daily, and IR-Tac was administered twice daily at 0.1 mg/kg per day to maintain target trough ranges (first 30 days, 6–11 ng/ml; thereafter, 4–11 ng/ml). There were no differences in efficacy failure or adverse effects between groups, including tremor and new-onset diabetes mellitus. Similar reports were previously reviewed in the Nephrology Self-Assessment Program (NephSAP) transplantation issue regarding other LCPT preparations. Antimetabolite Therapy Mycophenolate (either MMF or enteric-coated MPA/mycophenolate) has largely supplanted AZA as a first-line agent in primary immunosuppression. Wagner et al. (19) performed a Cochrane review of randomized, controlled trials to evaluate the benefits and risks of MPA versus AZA as primary immunotherapy after kidney transplantation. Data from 23 studies involving 3301 participants were included. MMF reduced the risk for graft loss, including death (RR, 0.82; 95% CI, 0.67 to 1.0), and death-censored graft loss (RR, 0.78; 95% CI, 0.62 to 0.99; P,0.05). No statistically significant difference for MMF versus AZA treatment was found for all-cause mortality (16 studies, 2987 participants: RR, 0.95; 95% CI, 0.70 to 1.29). The risks for any acute rejection (22 studies, 3301 participants: RR, 0.65; 95% CI, 0.57 to 0.73; P,0.01), biopsy-proven acute rejection (12 studies, 2696 participants: RR, 0.59; 95% CI, 0.52 to 0.68), and antibody-treated acute rejection (15 studies, 2914 participants: RR, 0.48; 95% CI, 0.36 to 0.65; P,0.01) were reduced in MMF-treated patients. Metaregression analysis suggested that the magnitude of risk reduction of acute rejection may be dependent on the control rejection rate (relative risk reduction [RRR], 0.34; 95% CI, 0.10 to 1.09; P50.08), AZA dose (RRR, 1.01; 95% CI, 1.00 to 1.01; P50.10), and use of cyclosporine A microemulsion (RRR, 1.27; 95% CI, 0.98 to 1.65; P50.07). Pooled analyses failed to show a significant and meaningful difference between MMF and AZA in kidney function measures. The risk for cytomegalovirus (CMV) viremia in 13 studies with 2880 participants was not statistically significantly different between MMF- and AZA-treated patients (RR, 1.06; 95% CI, 0.85 to 1.32). The likelihood of tissue-invasive CMV disease was greater with MMF therapy in seven studies with 1510 participants (RR, 1.70; 95% CI, 1.10 to 2.61). Adverse event profiles varied. Gastrointestinal symptoms were more likely in MMF-treated patients. Thrombocytopenia and elevated liver enzymes were more common during AZA therapy. Adverse MMF-related effects often prompt dose reduction or discontinuation, which can lead to rejection and possibly, graft loss. McAdams-DeMarco et al. (20) reported on risk factors for MMF dose reduction. Frailty measures assessed included sarcopenia, weakness, exhaustion, low physical activity, and slowed walking 302 speed along with other patient and donor characteristics, including longitudinal MMF doses, and graft loss in 525 kidney transplantation recipients. Frail recipients were 1.29 times (95% CI, 1.01 to 1.66; P50.04) more likely to experience MMF dose reduction, as were deceased donor recipients (aHR, 1.92; 95% CI, 1.44 to 2.54; P,0.001) and older adults (age $65 versus ,65 years old: aHR, 1.47; 95% CI, 1.10 to 1.96; P50.01). Importantly, MMF dose reduction was independently associated with a substantially increased risk of death-censored graft loss (aHR, 5.24; 95% CI, 1.97 to 13.98; P50.001). MMF dose reduction after kidney transplantation occurs more frequently in older and frailer individuals and deceased donor allograft recipients. MMF dose reduction significantly associates with increased risk of graft loss. Belatacept Belatacept is a cytotoxic T lymphocyte–associated antigen-4 fusion protein that inhibits costimulation that was Food and Drug Administration–approved for prevention of kidney allograft rejection in 2011 on the basis of the Belatacept Evaluation of Nephroprotection and Efficacy as First-Line Immunosuppression Trial and the Belatacept Evaluation of Nephroprotection and Efficacy as First-Line Immunosuppression Trial Extended Criteria Donors Trial previously discussed in prior NephSAP transplantation issues. The impact of belatacept in a real clinical setting has been recently reported. Wen et al. (21) performed a retrospective cohort study using registry data comparing clinical outcomes between belataceptand TAC-treated adult kidney transplant recipients from January 6, 2011 to January 12, 2014. Of 50,244 total participants, 417 received belatacept plus TAC, 458 received belatacept alone, and 49,369 received TAC alone at discharge. Belatacept alone was associated with a higher risk of 1-year acute rejection, with the highest rates associated with nonlymphocyte-depleting induction (aHR, 2.65; 95% CI, 1.90 to 3.70; P,0.001). There were no significant differences in rejection rates between belatacept plus TAC and TAC alone. In expanded criteria donor allograft recipients, 1-year kidney function was higher with belatacept plus TAC and belatacept alone versus TAC alone (mean eGFRs 565.6, 60.4, and 54.3 ml/min per 1.73 m2, respectively; P,0.001). The incidence of new- Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 onset diabetes after transplantation was significantly lower with belatacept plus TAC and belatacept alone versus TAC alone (1.7%, 2.2%, and 3.8%, respectively; P50.01). The authors suggested the addition of short-term TAC in the first year after transplant and lymphocytedepleting induction may be advisable when using belatacept. Similarly, Cohen et al. (22) performed a cohort study of adult kidney transplant recipients transplanted between May 1, 2001 and December 31, 2015 using national transplant registry data to compare patient and allograft survival in patients discharged on belatacept versus TAC-based regimens. They found that belatacept was not associated with a significant difference in risk of patient death (HR, 0.84; 95% CI, 0.61 to 1.15; P50.28) or allograft loss (HR, 0.83; 95% CI, 0.62 to 1.11; P50.20), despite an increased risk of acute rejection in the first year post-transplant (OR, 3.12; 95% CI, 2.13 to 4.57; P,0.001). These findings were confirmed in additional sensitivity analyses that accounted for use of belatacept in combination with TAC, transplant center effects, and differing approaches to matching. Because of the increased incidence of rejection seen with belatacept compared with CNI therapy, Xu et al. (23) combined belatacept with AZ and rapamycin. Compared with conventional immunosuppression, lymphocyte depletion evoked substantial homeostatic lymphocyte activation balanced by regulatory T and B cell phenotypes. The reconstituted T cell repertoire was enriched for CD281 naı̈ve cells, notably diminished in belatacept-resistant CD282 memory subsets, and depleted of polyfunctional donor-specific T cells. Importantly, the latter cells could respond to third party and latent herpes viruses. B cell responses were similarly favorable without alloantibody development and a reduction in memory subsets, changes not seen in conventionally treated patients. The combined belatacept with AZ and rapamycin regimen uniquely altered the immune profile, producing a repertoire enriched for CD281 T cells, hyporesponsive to donor alloantigen, and competent in its protective immune capabilities. The resulting repertoire was permissive for control of rejection with belatacept monotherapy. The broader applicability of such an approach remains to be determined. Steroid Therapy Haller et al. (24) performed a Cochrane review to evaluate the benefits and harms of steroid withdrawal or avoidance for kidney transplant recipients. Forty-eight studies (224 reports) that involved 7803 randomized Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 participants were included. These studies evaluated three different comparisons: steroid avoidance or withdrawal compared with steroid maintenance and steroid avoidance compared with steroid withdrawal. For adult studies, there was no significant difference in patient mortality in either studies comparing steroid withdrawal with steroid maintenance (ten studies, 1913 participants, death at 1 year post-transplantation: RR, 0.68; 95% CI, 0.36 to 1.30) or studies comparing steroid avoidance with steroid maintenance (ten studies, 1462 participants, death at 1 year post-transplantation: RR, 0.96; 95% CI, 0.52 to 1.80). Similarly, no significant difference in graft loss was found comparing steroid withdrawal with steroid maintenance (eight studies, 1817 participants) or graft loss (excluding death with functioning graft at 1 year after transplantation: RR, 1.17; 95% CI, 0.72 to 1.92) and comparing steroid avoidance with steroid maintenance (seven studies, 1211 participants, graft loss excluding death with functioning graft at 1 year after transplantation: RR, 1.09; 95% CI, 0.64 to 1.86). The risk of acute rejection significantly increased in patients treated with steroids for ,14 days post-transplantation (seven studies, 835 participants: RR, 1.58; 95% CI, 1.08 to 2.30) and patients withdrawn from steroids later post-transplantation (ten studies, 1913 participants; RR, 1.77; 95% CI, 1.20 to 2.61). There was no evidence to suggest a difference in harmful events, such as infection and malignancy, in adult kidney transplant recipients. The effect of steroid withdrawal in children is unclear. The authors concluded that steroid avoidance and withdrawal after kidney transplantation significantly increase the risk of acute rejection. Steroid avoidance and withdrawal after kidney transplantation significantly increase the risk of acute rejection. Mammalian Target of Rapamycin Inhibitor Therapy The use of mammalian target of rapamycin inhibitor (mTORi) therapy, sirolimus and everolimus, continues to decline due to inferior outcomes compared with conventional immunotherapy. In parallel, new reports of the use of such therapy are dwindling. One of the potential complications of mTORi therapy is proteinuria from nephrin inhibition that associates with FSGS. Mandelbrot et al. (25) reported on a prospective, 303 randomized, double-blind, placebo-controlled study protocol that evaluated the impact of ramipril on urinary protein excretion in renal transplant patients converted to sirolimus from CNI treatment. Patients received ramipril or placebo for up to 6 weeks before conversion and 52 weeks afterward. Doses were increased if patients developed proteinuria (urine protein-to-creatinine ratio $0.5); losartan was given as rescue therapy for persistent proteinuria. The primary end point was time to losartan initiation. Of 295 patients randomized, 264 met the criteria for sirolimus conversion (ramipril, n5138; placebo, n5126). At 52 weeks, the cumulative rate of losartan initiation was significantly lower with ramipril (6.2%) versus placebo (23.2%; P,0.001). No significant differences were observed between ramipril and placebo for change in GFR or rejection. Treatmentemergent adverse events were consistent with the known safety profile of sirolimus and were not potentiated by ramipril coadministration. Ramipril was deemed effective in reducing the incidence of proteinuria for up to 1 year after conversion to sirolimus in maintenance renal transplant patients. Sirolimus has antineoplastic properties compared with CNI therapy. Yanik et al. (26) investigated sirolimus effects on cancer incidence among kidney recipients. Overall, the incidence was not significantly lowered by sirolimus use (HR, 0.88; 95% CI, 0.70 to 1.11). However, the frequency of prostate cancer was greater during sirolimus use (HR, 1.86; 95% CI, 1.15 to 3.02). Incidence of other cancers was similar or lower with sirolimus use, with a 26% decrease overall (HR, 0.74; 95% CI, 0.57 to 0.96; excluding prostate cancer). Results were similar after adjustment for demographic and clinical characteristics. Despite such properties, mortality rates for patients with cancer treated with mTORi are higher than for similar patients maintained on CNI therapy as discussed in a prior transplantation NephSAP. There are occasional reports of the utility of everolimus in combination with cyclosporine. Oh et al. (27) performed an open label study to compare the efficacy and tolerability of everolimus and reduced exposure to cyclosporine (investigational group) with enteric-coated mycophenolate sodium and standard exposure cyclosporine (control group) in combination with basiliximab and steroids. Rejection rates were similar between groups (7.5% [investigational group] versus 11.1% [control group]; P50.57). The mean eGFRs of the investigational group at 12 months after transplantation were significantly higher (68.1616.8 304 ml/min per 1.73 m2) than those of the control group (60.6615.8 ml/min per 1.73 m2; P50.02). There were no significant differences (P.0.05) in the frequency of discontinuations or serious adverse events between groups. Tedesco-Silva et al. (28) studied the incidence of CMV infection/disease in de novo kidney transplant recipients receiving everolimus or mycophenolate with no CMV pharmacologic prophylaxis. Patients were randomized to receive rATG/TAC/everolimus/prednisone (group 1), basiliximab/TAC/everolimus/prednisone (group 2), or basiliximab/TAC/mycophenolate/prednisone (group 3). Patients in group 1 had a 90% proportional reduction in the incidence of CMV infection (4.7% versus 37.6%; HR, 0.10; 95% CI, 0.04 to 0.29; P,0.001). Group 2 had a 75% proportional reduction in frequency of CMV infection/ disease compared with the control group (10.8% versus 37.6%; HR, 0.25; 95% CI, 0.13 to 0.48; P,0.001). No differences were observed in the frequencies of acute rejection, wound-healing complications, delayed graft function, or proteinuria. The salutary effect of mTORi therapy on GFR compared with CNI therapy has been well described. Rostaing et al. (29) provide a cautionary note. They report the results of a randomized, open label, 12-month trial, in which de novo kidney transplant patients received cyclosporine, enteric-coated mycophenolate sodium, and steroids. Patients were stratified by an epithelial-mesenchymal transition profile based on their month 3 biopsies and then randomized to start everolimus with half-dose entericcoated mycophenolate sodium (EC1; 720 mg/d) and cyclosporine withdrawal (CNI2) or continue cyclosporine with standard enteric-coated mycophenolate sodium (CNI). The primary end point was progression of graft fibrosis that developed in 46.2% (12 of 26) of CNI2/EC1 patients versus 51.6% (16 of 31) of CNI/EC1 patients (P50.68). Biopsy-proven acute rejection and subclinical events occurred in 25.0% and 5.1% of CNI2 and CNI patients, respectively (P,0.001). The authors concluded that early CNI withdrawal with everolimus initiation does not prevent interstitial fibrosis. The use of the mTOR inhibitors, sirolimus and everolimus, continues to decline due to unfavorable efficacy, adverse event and outcome measures compared with calcineurin inhibition. Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 References 1. 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Axelrod DA, Naik AS, Schnitzler MA, Segev DL, Dharnidharka VR, Brennan DC, Bae S, Chen J, Massie A, Lentine KL: National variation in use of immunosuppression for kidney transplantation: A call for evidencebased regimen selection. Am J Transplant 16: 2453–2462, 2016 PubMed 8. Reese PP, Bloom RD, Trofe-Clark J, Mussell A, Leidy D, Levsky S, Zhu J, Yang L, Wang W, Troxel A, Feldman HI, Volpp K: Automated reminders and physician notification to promote immunosuppression adherence among kidney transplant recipients: A randomized trial. Am J Kidney Dis 69: 400–409, 2017 PubMed 9. Sawinski D, Trofe-Clark J, Leas B, Uhl S, Tuteja S, Kaczmarek JL, French B, Umscheid CA: Calcineurin inhibitor minimization, conversion, withdrawal, and avoidance strategies in renal transplantation: A systematic review and meta-analysis. Am J Transplant 16: 2117–2138, 2016 PubMed 10. Dugast E, Soulillou JP, Foucher Y, Papuchon E, Guerif P, Paul C, Riochet D, Chesneau M, Cesbron A, Renaudin K, Dantal J, Giral M, Brouard S: Failure of calcineurin inhibitor (tacrolimus) weaning randomized trial in long-term stable kidney transplant recipients. Am J Transplant 16: 3255–3261, 2016 PubMed 11. Hricik DE, Formica RN, Nickerson P, Rush D, Fairchild RL, Poggio ED, Gibson IW, Wiebe C, Tinckam K, Bunnapradist S, Samaniego-Picota M, Brennan DC, Schröppel B, Gaber O, Armstrong B, Ikle D, Diop H, Bridges ND, Heeger PS; Clinical Trials in Organ Transplantation-09 Consortium: Adverse outcomes of tacrolimus withdrawal in immune-quiescent kidney transplant recipients. J Am Soc Nephrol 26: 3114–3122, 2015 PubMed 12. Gatault P, Kamar N, Büchler M, Colosio C, Bertrand D, Durrbach A, Albano L, Rivalan J, Le Meur Y, Essig M, Bouvier N, Legendre C, Moulin B, Heng AE, Weestel PF, Sayegh J, Charpentier B, Rostaing L, Thervet E, Lebranchu Y: Reduction of extended-release tacrolimus dose in low-immunological-risk kidney transplant recipients increases risk of rejection and appearance of donor-specific antibodies: A randomized study. Am J Transplant 17: 1370–1379, 2017 PubMed 13. Rozen-Zvi B, Schneider S, Lichtenberg S, Green H, Cohen O, Gafter U, Chagnac A, Mor E, Rahamimov R: Association of the combination of time-weighted variability of tacrolimus blood level and exposure to low drug levels with graft survival after kidney transplantation. Nephrol Dial Transplant 32: 393–399, 2017 PubMed 14. 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Am J Transplant 15: 800–805, 2015 PubMed Pallet N, Etienne I, Buchler M, Bailly E, Hurault de Ligny B, Choukroun G, Colosio C, Thierry A, Vigneau C, Moulin B, Le Meur Y, Heng AE, Legendre C, Beaune P, Loriot MA, Thervet E: Long-term clinical impact of adaptation of initial tacrolimus dosing to CYP3A5 genotype. Am J Transplant 16: 2670–2675, 2016 PubMed Shuker N, Bouamar R, van Schaik RH, Clahsen-van Groningen MC, Damman J, Baan CC, van de Wetering J, Rowshani AT, Weimar W, van Gelder T, Hesselink DA: A randomized controlled trial comparing the efficacy of Cyp3a5 genotype-based with body-weight-based tacrolimus dosing after living donor kidney transplantation. Am J Transplant 16: 2085–2096, 2016 PubMed Rostaing L, Bunnapradist S, Grinyó JM, Ciechanowski K, Denny JE, Silva HT Jr., Budde K; Envarsus Study Group: Novel once-daily extended-release tacrolimus versus twice-daily tacrolimus in de novo kidney transplant recipients: Two-year results of phase 3, double-blind, randomized trial. Am J Kidney Dis 67: 648–659, 2016 PubMed Wagner M, Earley AK, Webster AC, Schmid CH, Balk EM, Uhlig K: Mycophenolic acid versus azathioprine as primary immunosuppression for kidney transplant recipients. Cochrane Database Syst Rev 12: CD007746, 2015 PubMed McAdams-DeMarco MA, Law A, Tan J, Delp C, King EA, Orandi B, Salter M, Alachkar N, Desai N, Grams M, Walston J, Segev DL: Frailty, mycophenolate reduction, and graft loss in kidney transplant recipients. Transplantation 99: 805–810, 2015 PubMed Wen X, Casey MJ, Santos AH, Hartzema A, Womer KL: Comparison of utilization and clinical outcomes for belatacept- and tacrolimus-based immunosuppression in renal transplant recipients. Am J Transplant 16: 3202–3211, 2016 PubMed Cohen JB, Eddinger KC, Forde KA, Abt PL, Sawinski D: Belatacept compared to tacrolimus for kidney transplantation: A propensity score matched cohort study [published online ahead of print December 8, 2016]. Transplantation PubMed Xu H, Samy KP, Guasch A, Mead SI, Ghali A, Mehta A, Stempora L, Kirk AD: Postdepletion lymphocyte reconstitution during belatacept and rapamycin treatment in kidney transplant recipients. Am J Transplant 16: 550–564, 2016 PubMed Haller MC, Royuela A, Nagler EV, Pascual J, Webster AC: Steroid avoidance or withdrawal for kidney transplant recipients. Cochrane Database Syst Rev 8: CD005632, 2016 PubMed Mandelbrot DA, Alberú J, Barama A, Marder BA, Silva HT Jr., Flechner SM, Flynn A, Healy C, Li H, Tortorici MA, Schulman SL: Effect of ramipril on urinary protein excretion in maintenance renal transplant patients converted to sirolimus. Am J Transplant 15: 3174– 3184, 2015 PubMed Yanik EL, Gustafson SK, Kasiske BL, Israni AK, Snyder JJ, Hess GP, Engels EA, Segev DL: Sirolimus use and cancer incidence among US kidney transplant recipients. Am J Transplant 15: 129–136, 2015 PubMed Oh CK, Huh KH, Ha J, Kim YH, Kim YL, Kim YS: Safety and efficacy of the early introduction of everolimus with reduced-exposure cyclosporine a in de novo kidney recipients. Transplantation 99: 180–186, 2015 PubMed Tedesco-Silva H, Felipe C, Ferreira A, Cristelli M, Oliveira N, SandesFreitas T, Aguiar W, Campos E, Gerbase-DeLima M, Franco M, Medina-Pestana J: Reduced incidence of cytomegalovirus infection in kidney transplant recipients receiving everolimus and reduced tacrolimus doses. Am J Transplant 15: 2655–2664, 2015 PubMed 29. Rostaing L, Hertig A, Albano L, Anglicheau D, Durrbach A, Vuiblet V, Moulin B, Merville P, Hazzan M, Lang P, Touchard G, Hurault deLigny B, Quéré S, Di Giambattista F, Dubois YC, Rondeau E; CERTITEM Study Group: Fibrosis progression according to epithelial-mesenchymal transition profile: A randomized trial of everolimus versus CsA. Am J Transplant 15: 1303–1312, 2015 PubMed Rejection The incidence of acute rejection within the first year post-transplant decreased for living and deceased donor transplant recipients (Figure 11) from 10% during 2009 and 2010 to 7.9% during 2013 and 2014 (1). The Banff consortium that classifies allograft rejection recently reported the outcomes of the 12th Banff Conference on Allograft Pathology (2). Some of the key issues discussed and reported at this meeting included C4d2 antibody-mediated rejection (AMR), the relationships of donor-specific antibody (DSA) tests with transplant histopathology, molecular transplant diagnostics, and transcriptome gene sets to supplement the diagnosis and classification of rejection. Newly introduced concepts include the inflammation within areas of Interstitial Fibrosis and Tubular Atrophy (i-IFTA) score that describes inflammation within areas of interstitial fibrosis and tubular atrophy and acceptance of transplant arteriolopathy within the descriptions of chronic active Figure 11. Allograft rejection rates within the first post transplant year are steadily declining for both deceased and living donor transplant recipients. Incidence of acute rejection by 1 year post-transplant among adult kidney transplant recipients by donor type. Acute rejection is defined as a record of acute or hyperacute rejection as reported on the Organ Procurement and Transplantation Network (OPTN) Transplant Recipient Registration or Transplant Recipient Follow-Up Form. Only the first rejection event is counted. Cumulative incidence is estimated using the Kaplan–Meier competing risk method. SRTR, Scientific Registry of Transplant Recipients. Reprinted with permission from Hart A, Smith JM, Skeans MA, Gustafson SK, Stewart DE, Cherikh WS, Wainright JL, Boyle G, Snyder JJ, Kasiske BL, Israni AK: Kidney. Am J Transplant 16[Suppl 2]: 11–46, 2016. 306 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 Table 1. Updated Banff classification categories Updated Banff Classification Categories Category 1: Normal biopsy or nonspecific changes Category 2: Antibody-mediated changes Acute/active ABMR: Three features required Histologic evidence of acute tissue injury (inflammation, TMA, ATN) Linear C4d staining Serologic evidence of DSA Chronic active ABMR: Three features required Histologic evidence of chronic tissue injury (interstitial fibrosis and tubular atrophy/TG, arterial sclerosis) Linear C4d staining Serologic evidence of DSA C4d staining without evidence of rejection Category 3: Borderline changes Category 4: TCMR Acute TCMR: Grades IA. Significant interstitial inflammation (.25% of nonsclerotic cortical parenchyma, i2 or i3) and foci of moderate tubulitis (t2) IB. Significant interstitial inflammation (.25% of nonsclerotic cortical parenchyma, i2 or i3) and foci of severe tubulitis (t3) IIA. Mild to moderate intimal arteritis IIB. Severe intimal arteritis III. Transmural arteritis Chronic TCMR Chronic allograft arteriopathy Category 5: Interstitial fibrosis and tubular atrophy Grades I. Mild interstitial fibrosis and tubular atrophy (#25% of cortical area) II. Moderate interstitial fibrosis and tubular atrophy (26%–50% of cortical area) III. Severe interstitial fibrosis and tubular atrophy (.50% of cortical area) Category 6: Other changes not considered to be rejection BK virus nephropathy Post-transplant lymphoproliferative disorders Calcineurin inhibitor nephrotoxicity Acute tubular injury Recurrent disease De novo glomerulopathy (other than transplant glomerulopathy) Pyelonephritis Drug-induced interstitial nephritis ABMR, antibody mediated rejection; TMA, thrombotic microangiopathy; ATN, acute tubular necrosis; TG, transplant glomerulopathy; i2 and i3, scores that represent increasing degrees of inflammatory cell infiltrate in the interstitium; t2 and t3, scores that represent increasing degrees of inflammatory cell infiltrate in the tubules. Modified from Loupy A, Haas M, Solez K, Racusen L, Glotz D, Seron D, Nankivell BJ, Colvin RB, Afrouzian M, Akalin E, Alachkar N, Bagnasco S, Becker JU, Cornell L, Drachenberg C, Dragun D, de Kort H, Gibson IW, Kraus ES, Lefaucheur C, Legendre C, Liapis H, Muthukumar T, Nickeleit V, Orandi B, Park W, Rabant M, Randhawa P, Reed EF, Roufosse C, Seshan SV, Sis B, Singh HK, Schinstock C, Tambur A, Zeevi A, Mengel M: The Banff 2015 Kidney Meeting Report: Current challenges in rejection classification and prospects for adopting molecular pathology. Am J Transplant 17: 28–41, 2017. T cell–mediated rejection (TCMR) or chronic AMR. A mixed pattern of TCMR and AMR was increasingly recognized. The current iteration of the classification system follows (Table 1). Although the Banff consortium initially convened to standardize renal histology definitions for research, the classification is now broadly clinically utilized. To evaluate adherence with the system, Becker et al. (3) conducted a worldwide survey among members of the Renal Pathology Society. A web-based survey was sent out to all 503 current members with 153 responses. Among the 139 nephropathologists using the borderline category, 67% use the Banff 1997 definition. Thirty-seven percent admitted to sometimes exaggerating Banff in the presence of tubulitis to reach a diagnosis of borderline. Forty-eight percent 307 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 were dissatisfied with the definition of borderline. Most of the influential manuscripts used the 1997 definition, contrary to the current one. The authors concluded that there is considerable dissatisfaction with the borderline category and that practice is variable. It is unclear whether the more recent update described above addresses these issues. Halloran et al. (4) used microarray-derived molecular AMR scores as a histology-independent estimate of AMR in 703 biopsies to re-evaluate AMR criteria and determine the relative importance of various lesions. They confirmed that the important features for AMR diagnosis were peritubular capillaritis (PTC), glomerulitis, glomerular double contours, DSA, and C4d staining. The group questioned some features, including arterial fibrosis, vasculitis, and acute tubular injury. The incidence of acute renal allograft rejection declined from 10% in 2009 and 2010 to 7.9% in 2013 and 2014. Temporal Dynamics Halloran et al. (5) used microarrays and conventional methods to study rejection in 703 unselected biopsies taken between 3 days and 35 years posttransplant. Rejection was conventionally diagnosed in 205 biopsy specimens (28%): 67 pure TCMR, 110 pure AMR, and 28 mixed (89 designated borderline). Using microarrays, rejection was diagnosed in 228 biopsy specimens (32%): 76 pure TCMR, 124 pure AMR, and 28 mixed. Molecular assessment confirmed most conventional diagnoses (agreement was 90% for TCMR and 83% for AMR), but it revealed some variation, particularly in mixed rejection, and improved prediction of graft failure. AMR was strongly associated with increased graft loss, but TCMR was not. AMR became common in biopsy specimens obtained .1 year posttransplant and continued to appear in all subsequent intervals. TCMR was common early but progressively disappeared over time. Provocatively, TCMR defined by molecular and conventional features was never observed after 10 years in this cohort. Transfusion The purported benefits of blood transfusion pretransplantation (the so-called transfusion effect) have long been overshadowed by the risk of allosensitization, with adverse impact on both access to transplantation and outcomes; thus, the current practice is transfusion avoidance for transplants candidates. However, little is known about the impact of post-transplant blood transfusion on the sensitization of anti-HLA antibodies and the formation of DSAs. Ferrandiz et al. (6) determined the 1-year incidence of DSAs and AMR in kidney transplant patients who had or had not received a blood transfusion during the first year post-transplantation. There were 390 non–HLA-sensitized patients who had received an ABO-compatible kidney transplant and had not previously or simultaneously received a nonrenal organ transplant. A surprisingly high proportion of patients, 64%, received a red blood cell transfusion within the first year after transplantation, most within the first month. Importantly, the overall 1-year incidence of DSAs was significantly higher in patients who had undergone transfusion (7.2% versus 0.7% in patients with no transfusion; P,0.001). More importantly, AMR also occurred more often in the transfusion group (n515; 6%) compared with the nontransfusion group (n52; 1.4%; P50.04). Blood transfusion was an independent predictive factor for de novo donor-specific antibody (dnDSA) formation but not for AMR. Patients who had a transfusion and developed DSAs were more often treated with cyclosporine (n510; 55.5%) rather than tacrolimus (n545; 19.4%; P,0.001). The authors concluded that post-transplant blood transfusion may increase immunologic risk, especially in underimmunosuppressed patients. Although this finding is indeed cautionary, the generalizability of the observation is less clear, because most transplant recipients are treated with tacrolimus and are not transfused. Transfusion post-transplantation may be associated with new-onset donor specific antibodies and increased risk of antibodymediated rejection. Novel Rejection Mediators Allocation algorithms for deceased donor kidney transplantation often incorporate HLA mismatches at the HLA A, B8, and DR loci but not HLA mismatches at other loci, including HLA-DQ. Lim et al. (7) studied the impact of HLA-DQ mismatches on renal allograft outcomes. Seven hundred eighty-eight recipients who 308 received zero, one, or two HLA-DQ mismatched kidneys were followed for a median of 2.8 years. Compared with no HLA-DQ mismatched allograft recipients, those who had received one or two HLADQ mismatched kidneys experienced more rejection (50 of 321 [15.6%] versus 117 of 467 [25%]; P,0.01), late rejections (occurring .6 months post-transplant; eight of 321 [2.4%] versus 27 of 467 [5.8%]; P50.03), and AMRs (12 of 321 [3.7%] versus 38 of 467 [8.1%]; P50.01). Compared with recipients of zero HLA-DQ mismatched kidneys, the adjusted hazard ratios [HRs] for any and late rejections in recipients who had received one or two HLA-DQ mismatched kidneys were 1.54 (95% confidence interval [95% CI], 1.08 to 2.19) and 2.85 (95% CI, 1.05 to 7.75), respectively. Bachelet et al. (8) similarly reported that preformed anti–HLA-Cw and anti–HLA-DP DSAs are as deleterious as anti–HLA-A/B/DR/DQ DSAs. Jackson et al. (9) suggested a pathogenic role for non-HLA antiendothelial cell antibodies (AECAs) in allograft rejection. High-density protein arrays that identified AECA target antigens were developed, and four antigenic targets expressed on endothelial cells were identified: endoglin; fms-like tyrosine kinase-3 ligand; EGF-like repeats, discoidin I-like domains 3; and intercellular adhesion molecule 4. These AECAs were detected in 24% of pretransplant sera by ELISA, and they were associated with post-transplant donor-specific HLA antibodies, AMR, and early transplant glomerulopathy. The role of the lectin pathway of complement activation and its recognition molecules in acute rejection and outcome after transplantation was studied by Golshayan et al. (10). Polymorphisms and serum levels of lectin pathway components in 710 consecutive kidney transplant recipients together with all biopsyproven rejection episodes and 1-year outcomes were studied. Low mannose binding lectin levels were associated with a higher incidence of acute cellular rejection during the first year, especially in recipients of deceased donor kidneys. This association remained significant (HR, 1.75; 95% CI, 1.18 to 2.60) in a Cox regression model after adjustment for relevant covariates. In contrast, there were no significant associations with rates of AMR, patient death, early graft dysfunction, or loss. Such studies underscore the multiplicity of molecules, pathways, and potential biomarkers that continue to be elucidated. However, these scientific observations have not yet achieved clinical applicability. Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 Adherence Nonadherence and HLA mismatch have been independently associated with poorer long-term outcomes post-transplantation. Wiebe et al. (11) prospectively correlated HLA mismatching with medication adherence measurement via electronic monitors in medication vial caps. Recipients were grouped by medication adherence and high- or low-epitope mismatch load. They found that the combination of higher epitope mismatch and poor adherence acted synergistically to determine the risk of rejection or graft loss. For example, nonadherent recipients with an HLA-DR epitope mismatch experienced increased graft loss (35% versus 8%; P,0.01) compared with adherent recipients with low epitope mismatch. Nonadherent patients are at increased risk for rejection as HLA mismatches increase. Gene Activation Acute kidney rejection is a major risk factor for chronic allograft dysfunction and long-term graft failure. Ghisdal et al. (12) performed a genome-wide study to detect loci associated with acute, biopsy-proven TCMR occurring within the first year after kidney transplantation. In a discovery cohort of 4127 European renal allograft recipients, Ghisdal et al. (12) utilized a DNA pooling approach that reduced the cost of large-scale association studies to compare an initial cohort of cases and controls before utilizing an independent replication cohort of 2765 allograft recipients. Two loci were consistently and significantly associated with acute rejection in univariate and multivariate analyses. One locus encompassed protein tyrosine phosphatase, receptor type O, which encodes a receptor-type tyrosine kinase essential for B cell receptor signaling. The other locus involved a ciliary gene coiled-coil domain containing 67. The clinical implications of these findings remain to be determined Subclinical Rejection The use of protocol biopsies is generally restricted to patients undergoing experimental immunosuppressive protocols, because the incidence of subclinical rejection in patients treated with tacrolimus, mycophenolate mofetil, and steroids is extremely low as discussed in a previous Nephrology Self-Assessment Program transplantation issue. That said, the impact of subclinical rejection in Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 patients taking lower-intensity immunotherapy has remained unclear. Loupy et al. (13) studied whether early recognition of subclinical rejection impacted long-term consequences for kidney allograft survival. Participants underwent prospective screening biopsies at 1 year posttransplant, with concurrent evaluations of graft complement deposition and circulating anti-HLA antibodies. Three distinct groups of patients were identified at the 1-year screening: 727 (73%) patients without rejection, 132 (13%) patients with subclinical TCMR, and 142 (14%) patients with subclinical AMR. Patients with subclinical AMR had the poorest graft survival 8 years post-transplant (56%) compared with subclinical TCMR (88%) and nonrejection (90%) groups (P,0.001). In a multivariate Cox model, subclinical AMR at 1 year was independently associated with a 3.5fold increase in graft loss (95% CI, 2.1 to 5.7) along with eGFR and proteinuria (P,0.001). Subclinical AMR was associated with more rapid progression to transplant glomerulopathy. Of patients with subclinical TCMR at 1 year, only those who subsequently developed dnDSAs and transplant glomerulopathy had a greater risk of graft loss compared with patients without rejection. Antibody-Mediated Rejection Schinstock et al. (14) retrospectively studied adult conventional solitary kidney transplant recipients to define histologic features associated with new-onset dnDSA (defined by mean fluorescent intensity [MFI] .1000). The incidence of dnDSA was 7.0% (54 of 771) over a mean follow-up of 4.261.9 years. Patients with dnDSA had reduced death-censored allograft survival (87.0% versus 97.0% no dnDSA; P,0.01). AMR was present in 25.0% and 52.9% of patients at dnDSA detection and 1 year. Patients with both classes I and II dnDSAs had the highest rates of allograft loss. Antibody levels correlated with the incidence of AMR. The authors concluded that patients with dnDSA without AMR at time of detection may benefit from a follow-up biopsy within 1 year, because AMR can be missed initially. Similarly, Wiebe et al. (15) studied a consecutive cohort of 508 renal transplant recipients, of whom 64 developed dnDSA. Recipients without dnDSA or allograft dysfunction had an eGFR decline of 20.65 ml/min per 1.73 m2 per year. In recipients with dnDSA, the rate of eGFR decline was significantly increased before dnDSA onset (22.89 versus 20.65 ml/min per 1.73 m2 per year; P,0.001) and accelerated 309 post-dnDSA (23.63 versus 22.89 ml/min per 1.73 m2 per year; P,0.001), suggesting that dnDSA is a marker and contributor to ongoing alloimmunity. Time to 50% post-dnDSA graft loss was greater in recipients with subclinical versus clinical dnDSA phenotype (8.3 versus 3.3 years; P,0.001). Analysis of 1091 allograft biopsies found that dnDSA and time independently predicted chronic glomerulopathy but not interstitial fibrosis and tubular atrophy. The diagnosis of AMR in the absence of peritubular capillary C4d staining has recently been incorporated into the Banff classification system. Ono et al. (16) quantified allograft loss risk in patients with C4d2 AMR compared with C4d1 AMR patients and AMRfree controls. C4d2 AMR patients were not different from C4d1 AMR patients regarding baseline characteristics, including immunologic risk factors (panel reactive antibody, prior transplant, HLA mismatch, donor type, DSA class, and anti-HLA/ABO incompatibility). C4d1 AMR patients were more likely to have a clinical presentation (85.3% versus 54.9%; P,0.001), and those patients presented substantially earlier posttransplantation (median, 14 days; interquartile range, 8–32 days versus median, 46; interquartile range, 20–191 days; P,0.001) and were three times more common (7.8% versus 2.5%); 1- and 2-year post–AMR-defining biopsy graft survival rates in C4d2 AMR patients were 93.4% and 90.2%, respectively, versus 86.8% and 82.6%, respectively, in C4d1 AMR patients (P50.40). C4d2 AMR was associated with a 2.56-fold (95% CI, 1.08 to 6.05; P50.03) increased risk of graft loss compared with AMRfree matched controls. No clinical characteristics reliably distinguished C4d2 from C4d1 AMR. However, both phenotypes are associated with increased graft loss. The impact of subclinical AMR was recently studied by Orandi et al. (17). This group compared 219 patients with AMR (77 subclinical; 142 clinical) with controls matched on HLA/ABO compatibility, donor type, prior transplant, panel reactive antibody, and age; 1- and 5-year graft survival rates in subclinical AMR were 95.9% and 75.7%, respectively, compared with 96.8% and 88.4%, respectively, in matched controls (P50.01). Subclinical AMR was independently associated with a 2.15-fold increased risk of graft loss (95% CI, 1.19 to 3.91; P50.01) compared with matched controls but was not different from clinical AMR (defined as AKI with DSA demonstration and pathologic evidence of tissue injury and C4d deposition; P50.13). Most subclinical AMR patients were treated 310 with plasmapheresis within 3 days of their AMRdefining biopsy. The impact of AMR on graft loss was heterogeneous when stratified by compatible deceased donor (HR, 4.73; 95% CI, 1.57 to 14.26; P,0.01), HLA-incompatible deceased donor (HR, 2.39; 95% CI, 1.10 to 5.19; P50.03), compatible live donor (no AMR patients experienced graft loss), ABO-incompatible live donor (HR, 6.13; 95% CI, 0.55 to 67.70; P50.14), and HLA-incompatible live donor (HR, 6.29; 95% CI, 3.81 to 10.39; P,0.001) transplant. The authors concluded that subclinical AMR substantially increases graft loss, and treatment seems warranted. Underscoring the refractory nature of some AMR cases, the Johns Hopkins investigators reported the utility of splenic irradiation for refractory AMR in two patients. The generalizability of this approach remains unknown (18). The impact of microvascular inflammation and extent of PTC has also been recently reported. Gupta et al. (19) classified kidney allograft biopsies into groups based on microvascular inflammation scores of zero, one, two, or more. Gene expression profiles were also assessed. The incidence of donor-specific anti-HLA antibodies increased from 25% in group 1 to 36% in group 2 and 54% in group 3. Acute and chronic AMRs were significantly more frequent in group 3 (15% and 35%, respectively) compared with group 2 (3% and 15%, respectively) and group 1 (0% and 5%, respectively). Gene expression profiling revealed more immune activation in the third group as well. Kozakowski et al. (20) studied the degree of PTC with allograft loss rates. They found that a score of three (HR, 2.57; 95% CI, 1.25 to 5.28) and diffuse PTC (HR, 1.67; 95% CI, 1.1 to 2.54) were significant impartial risk factors for allograft loss. The development of donor specific antibody and antibody mediated rejection, whether clinical or subclinical, impacts graft survival adversely. Immunoglobulin Subtypes Antibodies may have different pathogenicities per IgG subclass. Lefaucheur et al. (21) investigated the association between anti-human HLA antibodies IgG subclasses and rejection. This group studied 125 of 635 patients with donor-specific anti-human HLA antibodies (DSAs) detected in the first year post-transplant; 51 (40.8%) patients had acute AMR, 36 (28.8%) patients had subclinical AMR, and 38 (30.4%) patients were AMR free. The MFI of the immunodominant donor-specific antibody (iDSA; the DSA with the highest MFI level) was 67246464, and 41.6% of patients had Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 iDSA with C1q positivity. The distributions of iDSA IgG1, -2, -3, and -4 subclasses among the population were 75.2%, 44.0%, 28.0%, and 26.4%, respectively. AMR was mainly driven by IgG3 iDSA, whereas subclinical AMR was driven by IgG4 iDSA. IgG3 iDSA was associated with a shorter time to rejection (P,0.001), increased microcirculation injury (P50.002), and C4d capillary deposition (P,0.001). IgG4 iDSA was associated with later allograft injury, with increased allograft glomerulopathy and interstitial fibrosis/tubular atrophy lesions (P,0.001 for all comparisons). IgG3 iDSA and C1q binding iDSA were strongly and independently associated with allograft failure. The C1q complex is a complement protein involved in the innate immune system. C1q binds to IgM and IgG/antigen complexes, leading to activation of the classical complement pathway. Calp-Inal et al. (22) reported that the incidence of acute AMR was higher in C1q1/DSA1 patients compared with C1q2/DSA1 and Cq12/DSA2 patients. In two different temporal cohorts, the frequency of chronic AMR ranged from 36% to 51% in C1q1/DSA1 patients. In contrast, chronic AMR ranged from 5% to 25% in C1q2/DSA1 patients and from 2% to 6% of DSA2 patients (P,0.001). The authors concluded that the C1q2/DSA1 phenotype was associated with acute and chronic AMR. References 1. Hart A, Smith JM, Skeans MA, Gustafson SK, Stewart DE, Cherikh WS, Wainright JL, Boyle G, Snyder JJ, Kasiske BL, Israni AK: Kidney. Am J Transplant 16[Suppl 2]: 11–46, 2016 PubMed 2. Loupy A, Haas M, Solez K, Racusen L, Glotz D, Seron D, Nankivell BJ, Colvin RB, Afrouzian M, Akalin E, Alachkar N, Bagnasco S, Becker JU, Cornell L, Drachenberg C, Dragun D, de Kort H, Gibson IW, Kraus ES, Lefaucheur C, Legendre C, Liapis H, Muthukumar T, Nickeleit V, Orandi B, Park W, Rabant M, Randhawa P, Reed EF, Roufosse C, Seshan SV, Sis B, Singh HK, Schinstock C, Tambur A, Zeevi A, Mengel M: The Banff 2015 Kidney Meeting Report: Current challenges in rejection classification and prospects for adopting molecular pathology. Am J Transplant 17: 28–41, 2017 PubMed 3. Becker JU, Chang A, Nickeleit V, Randhawa P, Roufosse C: Banff borderline changes suspicious for acute T cell-mediated rejection: Where do we stand? Am J Transplant 16: 2654–2660, 2016 PubMed 4. Halloran PF, Famulski KS, Chang J: A probabilistic approach to histologic diagnosis of antibody-mediated rejection in kidney transplant biopsies. Am J Transplant 17: 129–139, 2017 PubMed 5. Halloran PF, Chang J, Famulski K, Hidalgo LG, Salazar ID, Merino Lopez M, Matas A, Picton M, de Freitas D, Bromberg J, Serón D, Sellarés J, Einecke G, Reeve J: Disappearance of T cell-mediated rejection despite continued antibody-mediated rejection in late kidney transplant recipients. J Am Soc Nephrol 26: 1711–1720, 2015 PubMed 6. Ferrandiz I, Congy-Jolivet N, Del Bello A, Debiol B, Trébern-Launay K, Esposito L, Milongo D, Dörr G, Rostaing L, Kamar N: Impact of early blood transfusion after kidney transplantation on the incidence of donor-specific anti-HLA antibodies. Am J Transplant 16: 2661–2669, 2016 PubMed 311 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 7. Lim WH, Chapman JR, Coates PT, Lewis JR, Russ GR, Watson N, Holdsworth R, Wong G: HLA-DQ mismatches and rejection in kidney transplant recipients. Clin J Am Soc Nephrol 11: 875–883, 2016 PubMed 8. Bachelet T, Martinez C, Del Bello A, Couzi L, Kejji S, Guidicelli G, Lepreux S, Visentin J, Congy-Jolivet N, Rostaing L, Taupin JL, Kamar N, Merville P: Deleterious impact of donor-specific anti-HLA antibodies toward HLA-Cw and HLA-DP in kidney transplantation. Transplantation 100: 159–166, 2016 PubMed 9. Jackson AM, Sigdel TK, Delville M, Hsieh SC, Dai H, Bagnasco S, Montgomery RA, Sarwal MM: Endothelial cell antibodies associated with novel targets and increased rejection. J Am Soc Nephrol 26: 1161– 1171, 2015 PubMed 10. Golshayan D, Wójtowicz A, Bibert S, Pyndiah N, Manuel O, Binet I, Buhler LH, Huynh-Do U, Mueller T, Steiger J, Pascual M, Meylan P, Bochud PY; Swiss Transplant Cohort Study: Polymorphisms in the lectin pathway of complement activation influence the incidence of acute rejection and graft outcome after kidney transplantation. Kidney Int 89: 927–938, 2016 PubMed 11. Wiebe C, Nevins TE, Robiner WN, Thomas W, Matas AJ, Nickerson PW: The synergistic effect of class II HLA epitope-mismatch and nonadherence on acute rejection and graft survival. Am J Transplant 15: 2197–2202, 2015 PubMed 12. Ghisdal L, Baron C, Lebranchu Y, Viklický O, Konarikova A, Naesens M, Kuypers D, Dinic M, Alamartine E, Touchard G, Antoine T, Essig M, Rerolle JP, Merville P, Taupin JL, Le Meur Y, Grall-Jezequel A, Glowacki F, Noël C, Legendre C, Anglicheau D, Broeders N, Coppieters W, Docampo E, Georges M, Ajarchouh Z, Massart A, Racapé J, Abramowicz D, Abramowicz M: Genome-wide association study of acute renal graft rejection. Am J Transplant 17: 201–209, 2017 PubMed 13. Loupy A, Vernerey D, Tinel C, Aubert O, Duong van Huyen JP, Rabant M, Verine J, Nochy D, Empana JP, Martinez F, Glotz D, Jouven X, Legendre C, Lefaucheur C: Subclinical rejection phenotypes at 1 year post-transplant and outcome of kidney allografts. J Am Soc Nephrol 26: 1721–1731, 2015 PubMed 14. Schinstock CA, Cosio F, Cheungpasitporn W, Dadhania DM, Everly MJ, Samaniego-Picota MD, Cornell L, Stegall MD: The value of protocol biopsies to identify patients with de novo donor-specific antibody at high risk for allograft loss. Am J Transplant 17: 1574–1584, 2017 PubMed 15. Wiebe C, Gibson IW, Blydt-Hansen TD, Pochinco D, Birk PE, Ho J, Karpinski M, Goldberg A, Storsley L, Rush DN, Nickerson PW: Rates and determinants of progression to graft failure in kidney allograft recipients with de novo donor-specific antibody. Am J Transplant 15: 2921–2930, 2015 PubMed 16. Ono E, Dos Santos AM, Viana PO, Dinelli MI, Sass N, De Oliveira L, Goulart AL, de Moraes-Pinto MI: Immunophenotypic profile and increased risk of hospital admission for infection in infants born to female kidney transplant recipients. Am J Transplant 15: 1654–1665, 2015 PubMed 17. Orandi BJ, Chow EH, Hsu A, Gupta N, Van Arendonk KJ, GaronzikWang JM, Montgomery JR, Wickliffe C, Lonze BE, Bagnasco SM, Alachkar N, Kraus ES, Jackson AM, Montgomery RA, Segev DL: Quantifying renal allograft loss following early antibody-mediated rejection. Am J Transplant 15: 489–498, 2015 PubMed 18. Orandi BJ, Lonze BE, Jackson A, Terezakis S, Kraus ES, Alachkar N, Bagnasco SM, Segev DL, Orens JB, Montgomery RA: Splenic irradiation for the treatment of severe antibody-mediated rejection. Am J Transplant 16: 3041–3045, 2016 PubMed 19. Gupta A, Broin PO, Bao Y, Pullman J, Kamal L, Ajaimy M, Lubetzky M, Colovai A, Schwartz D, de Boccardo G, Golden A, Akalin E: Clinical and molecular significance of microvascular inflammation in transplant kidney biopsies. Kidney Int 89: 217–225, 2016 PubMed 20. Kozakowski N, Herkner H, Böhmig GA, Regele H, Kornauth C, Bond G, Kikić Ž: The diffuse extent of peritubular capillaritis in renal allograft rejection is an independent risk factor for graft loss. Kidney Int 88: 332– 340, 2015 PubMed 21. Lefaucheur C, Viglietti D, Bentlejewski C, Duong van Huyen JP, Vernerey D, Aubert O, Verine J, Jouven X, Legendre C, Glotz D, Loupy A, Zeevi A: IgG donor-specific anti-human HLA antibody subclasses and kidney allograft antibody-mediated injury. J Am Soc Nephrol 27: 293–304, 2016 PubMed 22. Calp-Inal S, Ajaimy M, Melamed ML, Savchik C, Masiakos P, Colovai A, Akalin E: The prevalence and clinical significance of C1q-binding donor-specific anti-HLA antibodies early and late after kidney transplantation. Kidney Int 89: 209–216, 2016 PubMed Histoincompatibility Strategies Approximately 30% of medically suitable living donor candidates are incompatible with their intended recipients due to preformed ABO or HLA antibodies. Historically, such candidate recipients had little option other than waiting for a suitable deceased donor offer. Consequentially, those with highest levels of HLA antibodies often incurred long waiting times with reduced access to transplantation. To alleviate such problems, three strategies have emerged: • Change in kidney allocation to prioritize highly sensitized patients, • Kidney paired donation (KPD), and • Desensitization to either ABO or HLA antibodies. These approaches are not necessarily mutually exclusive. For candidates with an incompatible donor, KPD can improve the prospects of finding a compatible living donor, but for many highly sensitized patients, the probability of finding a match in the relatively small pools of donors in such programs remains limited. Keith and Vranic (1) suggest that desensitization of a living donor/recipient pair with low levels of incompatibility is another reasonable approach. Note that desensitization has never been a large-volume endeavor and may decline due to the prior changes in deceased donor allocation and KPD. An unexpectedly positive impact of the new Kidney Allocation System (KAS), implemented December 4, 2014, is the degree of increase in allograft recipients with the highest calculated panel reactive antibody (cPRA) levels (2). Historically, such candidates have had extremely low transplant rates and are consistently under-represented among transplant recipients relative to their prevalence on the waiting list. Priority point allocations for cPRAs changed significantly from a flat four-point allocation for cPRAs#80% to a sliding scale that progressively increases priority with cPRA elevations. Transplants among patients with cPRAs of 99%–100% increased from 2.2% pre-KAS, 312 peaked at 13.3% in the first quarter of 2015, and tapered off to 10.1% by the end of 2015. In summary, these data represent a 366% increase, slightly above these candidates’ waitlist prevalence of 8.1% (Figure 12). Transplants among candidates with cPRAs of 98% also doubled from 1.2% pre-KAS to 2.4% post-KAS, with no appreciable bolus effect. The greater than anticipated effect of the KAS on high-cPRA transplants may be explained by an underestimate of the acceptance of highquality regional and national offers for these highly sensitized candidates. In some regions, the proportion of such patients awaiting transplantation has declined by .50%. ABO-Incompatible Transplantation ABO-incompatible (ABOi) living kidney transplantation is a low-volume endeavor internationally that includes a preconditioning regimen that variously involves combinations of plasmapheresis, immunoadsorption (IA), intravenous Ig (IVIg), rituximab (RTX), conventional immunosuppression, and less commonly, splenectomy. Lo et al. (3) performed a meta-analysis of 83 published reports involving 4810 ABOi transplant recipients. During a mean follow-up time of 28 months, the overall graft survival rates for recipients who received either IA or apheresis were 94.1% (95% confidence interval [95% CI], 88.2% to 97.1%) and 88.0% (95% CI, 82.6% to 91.8%), respectively. For Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 those who received RTX or underwent splenectomy, the overall graft survival rates were 94.5% (95% CI, 91.6% to 96.5%) and 79.7% (95% CI, 72.9% to 85.1%), respectively. Data on other longer-term outcomes, including malignancy, were sparse. The authors concluded that RTX and IA were potentially promising preconditioning strategies before ABOi kidney transplantation. However, the overall quality of evidence and the confidence in the observed treatment effects are low. Note that IA is not readily available in the United States, although it has been used successfully in Europe (see below). Okumi et al. (4) studied changes in outcomes of ABOi transplants during the last 25 years. Patients were divided into four groups by transplantation era and ABO compatibility. In the past decade, ABOi live donor transplant and ABO-compatible (ABOc) recipients yielded almost equivalent outcomes with respect to 9-year graft survival rates: 86.9% and 92.0%, respectively (hazard ratio [HR], 1.38; 95% CI, 0.59 to 3.22; P50.46). The graft survival rate for ABO-incompatible living kidney transplants (ABO-ILKTs) conducted between 2005 and 2013 was superior compared with that of ABO-ILKTs conducted between 1998 and 2004 (HR, 0.30; 95% CI, 0.13 to 0.72; P,0.01). ABO-ILKT recipients showed substantial improvements in graft survival rate over time. Graft survival was almost identical over the past decade, regardless of ABO Figure 12. There has been a marked increase in the number of deceased donor transplant recipients in the most highly allosensitized recipients (defined as cPRA.98%) since implementation of KAS 12/4/14. There was an initial bolus effect that is now declining. This has been at the expense of a small reduction in proportion of kidneys allocated to non sensitized individuals. Distribution of kidney transplants by cPRA. Kidney-alone transplant recipients from January 1, 2013 to December 31, 2015. KAS was implemented December 4, 2014. OPTN, Organ Procurement and Transplantation Network; SRTR, Scientific Registry of Transplant Recipients. Reprinted with permission from Hart A, Gustafson SK, Skeans MA, Stock P, Stewart D, Kasiske BL, Israni AK: OPTN/SRTR 2015 Annual Data Report: Early effects of the new kidney allocation system. Am J Transplant 17 [Suppl 1]: 543–564, 2017. Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 compatibility. Similarly, Zschiedrich et al. (5) reported excellent graft survival rates equivalent to ABOc kidney transplantation outcome in Germany. Patient and graft survival rates for ABO compatible and preconditioned ABO incompatible transplantation are generally equivalent. It has been suggested that the infrequent use of ABOi kidney transplantation in the United States may reflect concern about the costs of necessary preconditioning and post-transplant care (6). Axelrod et al. (6) studied Medicare data for 26,500 live donor kidney transplant recipients (2000 to March of 2011), including 271 ABOi and 62 A2-incompatible (A2i) recipients, and these data were analyzed to assess the impact of pretransplant, peritransplant, and 3-year posttransplant costs. Compared with ABOc transplantation, 3-year rates of patient (93.2% versus 88.15%; P,0.001) and death-censored graft survival (85.4% versus 76.1%; P,0.05) were lower after ABOi transplant. Excluding the cost of organ acquisition, the average overall cost of the transplant episode was significantly higher for ABOi ($65,080) compared with blood type A2i ($36,752) and ABOc ($32,039) transplantation (P,0.001); ABOi transplant was associated with high adjusted post-transplant spending (marginal costs compared with ABOc: year 1, $25,044; year 2, $10,496; year 3, $7307; P,0.01). The authors concluded that ABOi transplantation provides a clinically effective method to expand access to transplantation, albeit with the risks of greater cost and inferior, if acceptable, outcomes. RTX, an mAb that targets B cell CD20, induces lymphodepletion and is frequently a part of the ABOi conditioning regimen. Lee et al. (7) provide a note of caution regarding the safety of this approach after analyzing 213 recipients (n5118 ABOc kidney transplants and n595 ABOi kidney transplants) who underwent living donor transplantation. The effect of RTX dose on infectious complications in ABOi kidney transplantation was studied; ABOi kidney transplant patients were categorized by RTX dose: standard dose (n576; 375 mg/m2) versus reduced RTX dose (n519; 200 mg). All participants received basiliximab induction for nondepleting IL-2 receptor blockade and were maintained on conventional triple immunosuppression. 313 The rates of overall infectious complications among the three groups were comparable. However, serious infections developed in 13 of the ABOc kidney transplants (11.0%), 20 from the standard RTX group (26.3%), and two from the reduced RTX group (10.5%; P50.02). Standard dose RTX was found to be an independent risk factor for serious infections (HR, 2.59; 95% CI, 1.33 to 5.07; P,0.01). There were no significant differences in rejection, renal function, graft survival, and patient survival between standard and reduced RTX groups. IA was previously reviewed in prior editions of the Nephrology Self-Assessment Program on transplantation and continues to be reported outside of the United States. Becker et al. (8) compared the clinical outcomes of 34 ABOi living donor kidney recipients who were transplanted using this protocol with those of 68 matched ABOc patients. Before desensitization, the median titer of 34 ABOi patients was 1:64. Patients received a median of seven preoperative IA treatments. Twenty-four patients had a median of two additional plasmapheresis treatments to reach the preoperative target isoagglutinin titer of 1:8 or less. After a median postoperative follow-up of 22 months, overall graft survival in the ABOi group was not significantly different from that in ABOc patients (log rank P50.20), whereas patient survival tended to be lower (log rank P50.05). The incidence of rejection episodes was 15% in both groups. The ABOi recipients had a higher incidence of BK virus replication (P50.04) and nephropathy (P50.01) and showed colonization with multidrug-resistant bacteria (P50.02) more frequently. In comparison with blood group antigen–specific IA, nonantigen-specific IA showed equal efficacy but was associated with cost reduction. The histologic findings and incidence of antibodymediated rejection (AMR) after ABOi preconditioning remain unclear. Masutani et al. (9) reviewed the histologic findings at 3 and 12 months after ABOc and ABOi transplantation. Subclinical acute rejection occurred in 6.9% and 9.9% of patients in the ABOc and ABOi groups, respectively, at 3 months (P50.40) and 12.4% and 10.1%, respectively, at 12 months (P50.50). The cumulative incidence rates of acute rejection were 20.5% and 19.6%, respectively (P50.80). The degrees of microvascular inflammation (MVI) and interstitial fibrosis/tubular atrophy were comparable. Polyomavirus BK nephropathy was found in 2.7% and 3.0% of patients in the ABOc and ABOi groups, respectively (P.0.99). The incidence of other infections and the 314 graft/patient survival rates were not different. It has been reported that C4d deposition is common after ABOi transplantation, although the prognostic significance remains unclear. Ishihara et al. (10) investigated MVI scores greater than or equal to two within 1 year after ABOi transplantation as a predictor of graft outcome. They determined that 5-year graft survival was significantly lower (P50.01) in MVI patients (89.8%) than in non-MVI patients. Graft function, characterized by serum eGFR, was also significantly worse for patients with MVI than it was for patients without MVI from 3 months to 10 years post-transplantation (P50.05). Multivariate analysis indicated that HLA class II mismatch (P,0.01) was an independent marker of MVI. The authors concluded that MVI score greater than or equal to two is significantly associated with poor graft outcome after ABOi kidney transplantation. HLA Antibody Desensitization Preconditioning regimens to permit HLA-incompatible transplantation generally follow protocols similar in principle to those for ABOi regimens. However, these protocols are associated with inferior outcomes; even intense immunomodulation may not completely abrogate HLA AMR. Schwaiger et al. (11) evaluated transplant outcomes in 101 donor-specific antibody–positive (DSA1) deceased donor kidney transplant recipients with a median followup of 24 months who were subjected to IA-based desensitization. Treatment included a single pretransplant IA session followed by antilymphocyte antibody and serial post-transplant IA. Three-year death-censored graft survival in DSA1 patients was significantly worse than that in 513 DSA2 recipients transplanted during the same period (79% versus 88%; P,0.01). Thirty-three DSA1 recipients (33%) had AMR. Vo et al. (12) described their updated results of IVIg and RTX in 226 highly sensitized patients who received transplants after desensitization. Most received alemtuzumab induction and standard immunosuppression. Significant risks for AMR included previous transplants and pregnancies as sensitizing events, DSA relative intensity scores, presence of both classes I and II DSAs at transplant, and time on the waitlist. Banff pathology characteristics for AMR patients with or without graft loss did not differ. C4d1 versus C4d2 AMR did not predict graft loss (P50.09); however, thrombotic microangiopathy (TMA) significantly predicted graft failure (P50.05). Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 AMR episodes were treated with IVIg/RTX (n525) or in more severe AMR, the addition of plasma exchange (n520). Graft survival for patients treated with IVIg plus RTX was superior (P50.03). Increased mortality was seen in AMR patients experiencing graft loss after AMR treatment (P50.004). Plasmapheresis and eculizumab improved graft survival for TMA patients (P50.04). The authors concluded that patients desensitized with IVIg plus RTX who remained AMR free experienced long-term graft and patient survival. However, AMR patients had significantly reduced graft survival and GFRs at 5 years, especially after development of TMA. Jackson et al. (13) studied 256 post-transplant HLA antibody levels in 25 recipients desensitized with and 25 without RTX induction to determine the impact of B cell depletion. They found significantly less HLA antibody rebound in the RTX-treated patients (7% of DSAs and 33% of non-DSAs) compared with in a control cohort desensitized and transplanted without RTX (32% DSAs and 55% non-DSAs). Importantly, although RTX induction in HLA-incompatible recipients reduced the incidence and magnitude of HLA antibody rebound, it did not affect DSA elimination, AMR, or 5-year allograft survival compared with recipients desensitized and transplanted without RTX. Desensitization to permit HLA-incompatible transplantation continues to be associated with antibody-mediated rejection and inferior outcomes compared with either HLAcompatible or ABO incompatible transplants. Novel Desensitization Strategies The limitations of existing desensitization strategies continue to drive the search for alternate options. Bortezomib (BTZ), a proteasome inhibitor that causes plasma cell depletion, has been studied in this regard. Moreno Gonzalez et al. (14) studied the safety and efficacy of 32 doses of BTZ (1.3 mg/m body surface area) in ten highly sensitized kidney transplant candidates with alloantibodies against their intended living donor. Dose reduction was needed in two patients, and two others completely discontinued therapy for adverse events. Anti-HLA antibody mean fluorescence intensity (MFI) values were stable before BTZ administration (P50.96) but decreased after therapy (mean decrease, 1916; SEM5425 MFI; P,0.01). No patients 315 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 developed a negative crossmatch against their original intended donor, and the cPRAs based on MFIs of 2000, 4000, and 8000 were unchanged in all patients. The authors concluded that 32 doses of BTZ monotherapy were not well tolerated and resulted in only a modest reduction in anti-HLA antibodies. By way of contrast, Woodle et al. (15) performed a prospective iterative trial of proteasome inhibitor–based therapy for reducing HLA antibody. Nineteen of 44 patients (43.2%) were transplanted with low acute rejection rates (18.8%) and de novo DSA formation (12.5%). Although the authors concluded that proteasome inhibition–based desensitization consistently and durably reduced HLA antibody levels and provided an alternative to IVIg-based desensitization, most patients were still not transplanted. IL-6 may also be an attractive target, because it promotes B cell differentiation to plasma cells, is important for Ig production, and induces Th17 cells, a subset of proinflammatory T helper cells defined by their production of IL-17 that is related to T regulatory cells. Tocilizumab (TCZ) is an anti–IL-6 receptor antibody undergoing investigation as a potential treatment for AMR. Vo et al. (16) performed a phase I/II pilot study using TCZ with IVIg to assess safety and limited efficacy for clinical AMR. Ten patients, unresponsive to desensitization with IVIg 1 RTX, were treated with IVIg 1 TCZ. No differences in baseline characteristics were seen in patients not transplanted versus transplanted. Two patients in each group developed serious adverse events: not transplanted, pulmonary congestion with status epilepticus; transplanted, infectious colitis with colonic perforation and Bell palsy. Five of ten patients were transplanted. Six-month protocol biopsies showed no AMR. DSA strength and number were reduced by TCZ treatment. Renal function at 12 months was 60625 ml/min. The authors concluded that TCZ and IVIg seem safe; however, larger controlled studies are required. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. References 1. Keith DS, Vranic GM: Approach to the highly sensitized kidney transplant candidate. Clin J Am Soc Nephrol 11: 684–693, 2016 PubMed 2. Hart A, Gustafson SK, Skeans MA, Stock P, Stewart D, Kasiske BL, Israni AK: OPTN/SRTR 2015 Annual Data Report: Early effects of the new kidney allocation system. Am J Transplant 17[Suppl 1]: 543–564, 2017 PubMed 3. Lo P, Sharma A, Craig JC, Wyburn K, Lim W, Chapman JR, Palmer SC, Strippoli GF, Wong G: Preconditioning therapy in ABO-incompatible living kidney transplantation: A systematic review and meta-analysis. Transplantation 100: 933–942, 2016 PubMed 4. Okumi M, Toki D, Nozaki T, Shimizu T, Shirakawa H, Omoto K, Inui M, Ishida H, Tanabe K: ABO-incompatible living kidney transplants: Evolution of outcomes and immunosuppressive management. Am J Transplant 16: 886–896, 2016 PubMed Zschiedrich S, Kramer-Zucker A, Jänigen B, Seidl M, Emmerich F, Pisarski P, Huber TB: An update on ABO-incompatible kidney transplantation. Transpl Int 28: 387–397, 2015 PubMed Axelrod D, Segev DL, Xiao H, Schnitzler MA, Brennan DC, Dharnidharka VR, Orandi BJ, Naik AS, Randall H, Tuttle-Newhall JE, Lentine KL: Economic impacts of ABO-incompatible live donor kidney transplantation: A national study of medicare-insured recipients. Am J Transplant 16: 1465–1473, 2016 PubMed Lee J, Lee JG, Kim S, Song SH, Kim BS, Kim HO, Kim MS, Kim SI, Kim YS, Huh KH: The effect of rituximab dose on infectious complications in ABO-incompatible kidney transplantation. Nephrol Dial Transplant 31: 1013–1021, 2016 PubMed Becker LE, Siebert D, Süsal C, Opelz G, Leo A, Waldherr R, MacherGoeppinger S, Schemmer P, Schaefer SM, Klein K, Beimler J, Zeier M, Schwenger V, Morath C: Outcomes following ABO-incompatible kidney transplantation performed after desensitization by nonantigen-specific immunoadsorption. Transplantation 99: 2364–2371, 2015 PubMed Masutani K, Tsuchimoto A, Kurihara K, Okabe Y, Kitada H, Okumi M, Tanabe K, Nakamura M, Kitazono T, Tsuruya K; Japan Academic Consortium of Kidney Transplantation (JACK) investigators: Histological analysis in ABO-compatible and ABO-incompatible kidney transplantation by performance of 3- and 12-month protocol biopsies. Transplantation 101: 1416–1422, 2017 PubMed Ishihara H, Ishida H, Unagami K, Hirai T, Okumi M, Omoto K, Shimizu T, Tanabe K: Evaluation of microvascular inflammation in ABO-incompatible kidney transplantation. Transplantation 101: 1423– 1432, 2017 PubMed Schwaiger E, Eskandary F, Kozakowski N, Bond G, Kikić Ž, Yoo D, Rasoul-Rockenschaub S, Oberbauer R, Böhmig GA: Deceased donor kidney transplantation across donor-specific antibody barriers: Predictors of antibody-mediated rejection. Nephrol Dial Transplant 31: 1342– 1351, 2016 PubMed Vo AA, Sinha A, Haas M, Choi J, Mirocha J, Kahwaji J, Peng A, Villicana R, Jordan SC: Factors predicting risk for antibody-mediated rejection and graft loss in highly human leukocyte antigen sensitized patients transplanted after desensitization. Transplantation 99: 1423– 1430, 2015 PubMed Jackson AM, Kraus ES, Orandi BJ, Segev DL, Montgomery RA, Zachary AA: A closer look at rituximab induction on HLA antibody rebound following HLA-incompatible kidney transplantation. Kidney Int 87: 409–416, 2015 PubMed Moreno Gonzales MA, Gandhi MJ, Schinstock CA, Moore NA, Smith BH, Braaten NY, Stegall MD: 32 Doses of bortezomib for desensitization is not well tolerated and is associated with only modest reductions in antiHLA antibody. Transplantation 101: 1222–1227, 2017 PubMed Woodle ES, Shields AR, Ejaz NS, Sadaka B, Girnita A, Walsh RC, Alloway RR, Brailey P, Cardi MA, Abu Jawdeh BG, Roy-Chaudhury P, Govil A, Mogilishetty G: Prospective iterative trial of proteasome inhibitorbased desensitization. Am J Transplant 15: 101–118, 2015 PubMed Vo AA, Choi J, Kim I, Louie S, Cisneros K, Kahwaji J, Toyoda M, Ge S, Haas M, Puliyanda D, Reinsmoen N, Peng A, Villicana R, Jordan SC: A phase I/II trial of the interleukin-6 receptor-specific humanized monoclonal (tocilizumab) 1 intravenous immunoglobulin in difficult to desensitize patients. Transplantation 99: 2356–2363, 2015 PubMed Clinical Tolerance The overwhelming majority of conventionally immunosuppressed allograft recipients who stop therapy develop symptomatic rejection and premature allograft 316 failure. However, the occasional fortunate patient who conducts this experiment fails to undergo rejection, having developed operational tolerance. Furthermore, it is possible that there are more such patients who may forego immunosuppression (IS) who never take the risk with ongoing implications for cost and adverse effects. The reader is reminded that the clinical trials of calcineurin inhibitor withdrawal in low-immunologic risk allograft recipients discussed above revealed significant rejection risk, underscoring the importance of ongoing adherence for most patients. For all of these reasons, the cellular and immunologic events that underlie tolerance events are of interest, because prospective identification could potentially identify that subset of individuals who may undergo immunotherapy reduction or withdrawal. Baron et al. (1) collected samples and clinical data from 96 tolerant patients from five different centers with specific reference to measurable transcription patterns. Common gene signatures and discriminating biomarkers for tolerance after kidney transplantation were identified. A robust gene signature involving proliferation of B and CD41 T cells with inhibition of CD14 monocyte functions was confirmed and crossvalidated with almost 92% accuracy. The data also indicated participation of other cell subsets in tolerance. The authors concluded that the use of the top 20 biomarkers, mostly centered on B cells, may provide a standardized tool toward personalized medicine for monitoring of tolerant or low-risk patients among kidney allotransplant recipients. Chesneau et al. (2) analyzed the role of B cells from 12 operationally tolerant patients compared with healthy volunteers and stable kidney transplant recipients on IS. Proliferation, apoptosis, and type I proinflammatory cytokine production by effector CD41CD25– T cells were measured. They reported that B cells inhibit the CD41CD25– effector T cell response in a dose-dependent manner. This effect required B cells to interact with T cell targets and was achieved through a granzyme B–dependent pathway. Tolerant recipients harbored a higher number of B cells expressing granzyme B and displayed a particular plasma cell phenotype. The investigators concluded that these data provide insights into the characterization of B cell–mediated immunoregulation in clinical tolerance. The role of Foxp31 regulatory T cells (Tregs) in operational tolerance was studied by Braza et al. (3). They observed a higher proportion of CD41 T cells with demethylated Foxp3 and a specific expansion of CD41CD45RA– Foxp3(hi) memory Tregs exclusively Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 in tolerant patients. Taken together, the data show that operationally tolerant patients mobilize an array of potentially suppressive cells, including regulatory B cells and Tregs. Clinical Tolerance Induction It has been lightheartedly suggested that clinical tolerance is the “holy grail” of transplantation and always will be. This viewpoint has been challenged by reports from three centers in the United States with proof of concept data that are described in greater detail below. Note that tolerance induction is deemed experimental and has met with varying degrees of success. Rejections and graft losses, although infrequent, have occurred using regimens that generally rely on induction of either transient or persistent donor chimerism. This comment is made to refocus the readers’ attention on the experimental nature of these regimens in evolution, not to undermine the importance of such work. The three protocols below share common themes that include the use of lymphocyte depletion, cellular therapy with either donor bone marrow or CD34positive stem cells, and various combinations of conventional immunotherapy that are subsequently tapered off with time. A more recent clinical trial planned to evaluate administration of Tregs to harness the immune response has recently been initiated in eight European and American centers. (4). Leventhal and coworkers (5–7) described results of a nonchimeric, operational tolerance protocol in HLA-identical living donor renal transplants. Recipients given alemtuzumab and tacrolimus/mycopenolic acid with early sirolimus conversion were repeatedly infused with donor hematopoietic CD341 stem cells. IS was withdrawn by 24 months. Twelve months later, operational tolerance was confirmed by rejection-free transplant biopsies. Five of the first eight enrollees were initially tolerant 1 year off IS. Biopsies of three others after total withdrawal showed Banff 1A acute cellular rejection without allograft dysfunction. At 5 years posttransplantation, four of five tolerant recipients remained rejection free, whereas one developed Banff 1A rejection without allograft dysfunction. Significant timedependent increases of circulating Tregs were seen in a more recent cohort of tolerant versus nontolerant subjects (P,0.001). Gene expression signatures, developed using global RNA expression, were highly associated with operational tolerance as early as 1 year post-transplant. 317 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 Kawai et al. (8) previously reported the long-term results of HLA-mismatched kidney transplantation without maintenance IS in ten subjects after combined kidney and bone marrow transplantation. All subjects were treated with nonmyeloablative conditioning and an 8- to 14-month course of calcineurin inhibitor with or without rituximab. All ten subjects developed transient chimerism, and in seven of these, IS was successfully discontinued for 4 or more years. At the time of publication, four subjects remained IS free for periods of 4.5–11.4 years, whereas three required reinstitution of IS after 5–8 years due to recurrence of original disease or chronic antibody-mediated rejection (AMR). Of the ten renal allografts, three failed due to thrombotic microangiopathy or rejection. In collaboration with the Massachusetts General Hospital group, Newell et al. (9) theorized that biomarkers of transplant tolerance could enhance the safety and feasibility of clinical tolerance trials and potentially facilitate management of patients receiving IS. To this end, blood from spontaneously tolerant renal transplant recipients and patients enrolled in two interventional tolerance trials using flow cytometry and gene expression profiling was examined. They found that tolerance was associated with increased expression of B cell–associated genes relative to immunosuppressed patients. Moreover, serial measurements of gene expression showed that this pattern persisted over several years, although patients receiving IS also displayed an increase in the two most dominant tolerance-related B cell genes, IGKV1D-13 and IGLL-1, over time. Importantly, patients rendered tolerant via induction of transient mixed chimerism and those weaned to minimal IS showed similar increases in IGKV1D-13 as did spontaneously tolerant individuals. Collectively, these findings support the notion that alterations in B cells may be a common theme for tolerant kidney transplant recipients. Scandling et al. (10) have provided iterative reports, the most recent of which describes 38 HLAmatched and -mismatched living kidney donor recipients enrolled in tolerance protocols using post-transplant conditioning with total lymphoid irradiation, enriched CD341 hematopoietic cell, and antithymocyte globulin. Persistent chimerism for at least 6 months was associated with successful complete withdrawal of immunosuppressive drugs in 16 of 22 matched patients without rejection episodes or kidney disease recurrence with up to 5 years follow-up. Persistent mixed chimerism was achieved in some haplotype-matched patients for at least 12 months by increasing the dose of T cells and CD341 cells infused compared with matched recipients in a dose escalation study. Success of drug withdrawal in chimericmismatched patients remains to be determined. None of the 38 patients had kidney graft loss or graft versus host disease in up to 14 years of observation. The authors concluded that complete immunosuppressive drug withdrawal could be achieved with the tolerance induction regimen in HLA-matched patients with uniform, long-term graft survival in all patients. In a subsequent publication, Scandling and coworkers (11) contended that, although tolerance conditioning is expensive, the negation of the IS requirement may be less costly long term. This group estimated costs for a hypothetical 40-year-old two-haplotype match living donor kidney transplant recipient. The standard IS therapy cost is $179,000 over a patient’s lifetime, whereas the tolerance induction cost is $88,000, yielding an expected lifetime savings of $92,000. If all 5170 two-haplotype match living donor kidney transplant recipients in the United States from 2003 to 2012 had received tolerance induction, this would have potentially yielded approximately $350 million United States dollars in aggregate lifetime savings. Regarding tolerance induction, kidney allografts behave differently from heart allografts, which behave differently from lung allografts for reasons that remain unclear. Madariaga et al. (12) remind us that inducing tolerance in experimental recipients of heart and lung allografts has proven more challenging than for kidney allografts. Experimental tolerance induction utilizing transient or persistent donor chimerism has led to durable, IS-free engraftment for a limited number of human transplant recipients. Biomarkers Despite almost 20 years of research, the use of individual biomarkers (e.g., granzyme B, perforin, kidney injury molecule-1, and neutrophil gelatinase–associated lipocalin) to noninvasively ascertain allograft stability or differentiate among different causes of kidney injury has failed to transition from the laboratory to the clinic due to cost, availability, reproducibility, and performance characteristics. The clinical nephrologist still utilizes 318 more conventional allograft markers, including serum creatinine, urine protein-to-creatinine ratio, BK virus nucleic acid testing, donor-specific antibody testing for surveillance, and the allograft biopsy for definitive diagnostics, with all of their associated limitations. Overall, the increasing availability of sophisticated and complex genomic and proteomic testing provides novel avenues of investigation. Sigdel et al. (13) aimed to map changes in the urine proteome after kidney transplantation by comparing urine and biopsy changes in 396 transplant recipients. Blinded histologic data were used to classify urine samples into diagnostic categories of acute rejection (AR), chronic allograft nephropathy, BK virus nephritis, and stable graft function. Ultimately, a minimal set of 35 proteins was identified for its ability to segregate the three major transplant injury clinical groups, making up the final panel of 11 urinary peptides for AR (93% area under the curve [AUC]), 12 urinary peptides for chronic allograft nephropathy (99% AUC), and 12 urinary peptides for BK virus nephritis (83% AUC). Thus, urinary proteome discovery and targeted validation may identify peptidomes that provide rapid, noninvasive differentiation of causes of kidney transplant injury without an invasive kidney biopsy. Modena et al. (14) examined gene expression profiles of 234 graft biopsy samples matched with their clinical and outcome data to study interstitial fibrosis and tubular atrophy (IFTA). The biopsies were divided into subphenotypes by degree of histologic inflammation: IFTA with AR, IFTA with inflammation, and IFTA without inflammation. A novel analysis using gene coexpression networks revealed that all IFTA phenotypes were strongly enriched for dysregulated gene pathways that were shared with the biopsy profiles of AR, including IFTA samples without histologic evidence of inflammation. Thus, by molecular profiling, most IFTA samples have ongoing immune-mediated injury or chronic rejection more sensitively detected by gene expression profiling. Venner et al. (15) used microarray analysis of kidney transplant biopsies to identify changes of pure AMR. In a set of 703 biopsies, 2603 transcripts were significantly changed (P,0.05) in AMR versus all other biopsies. In cultured cells, the transcripts strongly associated with AMR were expressed in endothelial cells. Pathway analysis of AMR transcripts identified angiogenesis, with roles for angiopoietin and vascular endothelial growth factors, leukocyte-endothelial interactions, and natural killer signaling, including evidence for CD16a Fc receptor–signaling elements shared with T cells. These data support a model of AMR involving Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 injury repair in the microcirculation induced by cognate recognition between antibody and CD16a that triggers IFN-g release and antibody-dependent natural killer cell–mediated cytotoxicity. O’Connell et al. (16) studied gene sets to predict renal allografts at risk of progressive injury due to fibrosis. They prospectively collected biopsies from renal allograft recipients (n5204) with stable renal function 3 months after transplantation. The group identified a set of 13 genes independently predictive for the development of fibrosis at 1 year. The gene set had high predictive capacity (AUC, 0.967), which was superior to that of baseline clinical variables (AUC, 0.706) and clinical and pathologic variables (AUC, 0.806). Furthermore, routine pathologic variables were unable to identify which histologically normal allografts would progress to fibrosis (AUC, 0.754), whereas the predictive gene set accurately discriminated between transplants at high and low risk of progression (AUC, 0.916). The 13 genes also accurately predicted early allograft loss (AUC, 0.842 at 2 years and AUC, 0.844 at 3 years). The predictive value of this gene set was established in an independent cohort. The authors concluded that this set of 13 genes could be used to identify kidney transplant recipients at risk of allograft loss before the onset of irreversible damage, potentially allowing therapy to be modified to prevent progression to fibrosis. Oetting et al. (17) provide a cautionary note about using such technology for prognostic purposes, warning about the requirement for validation beyond the initial dataset. One goal of a genome-wide association study was to associate the allele(s) of a single-nucleotide polymorphism with phenotype. Although there have been many successful associations documented, there have been many more genome-wide association study–based results that were later deemed false positives. As an example, Pihlstrøm et al. (18) were unable to reproduce prior study data suggesting that two single-nucleotide polymorphisms (rs3811321 and rs6565887) associated with serum creatinine and clinical outcome. Allograft biomarkers have not impacted clinical practice to date. Novel genomic and proteomic analyses are elucidating molecular events underlying allograft injury and tolerance. However, broader clinical applicability remains to be determined. 319 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 References 1. Baron D, Ramstein G, Chesneau M, Echasseriau Y, Pallier A, Paul C, Degauque N, Hernandez-Fuentes MP, Sanchez-Fueyo A, Newell KA, Giral M, Soulillou JP, Houlgatte R, Brouard S: A common gene signature across multiple studies relate biomarkers and functional regulation in tolerance to renal allograft. Kidney Int 87: 984–995, 2015 PubMed 2. Chesneau M, Michel L, Dugast E, Chenouard A, Baron D, Pallier A, Durand J, Braza F, Guerif P, Laplaud DA, Soulillou JP, Giral M, Degauque N, Chiffoleau E, Brouard S: Tolerant kidney transplant patients produce B cells with regulatory properties. J Am Soc Nephrol 26: 2588–2598, 2015 PubMed 3. Braza F, Dugast E, Panov I, Paul C, Vogt K, Pallier A, Chesneau M, Baron D, Guerif P, Lei H, Laplaud DA, Volk HD, Degauque N, Giral M, Soulillou JP, Sawitzki B, Brouard S: Central role of CD45RAFoxp3hi memory regulatory T cells in clinical kidney transplantation tolerance. J Am Soc Nephrol 26: 1795–1805, 2015 PubMed 4. Elias N, Cosimi AB, Kawai T: Clinical trials for induction of renal allograft tolerance. Curr Opin Organ Transplant 20: 406–411, 2015 PubMed 5. Leventhal JR, Mathew JM, Salomon DR, Kurian SM, Friedewald JJ, Gallon L, Konieczna I, Tambur AR, Charette J, Levitsky J, Jie C, Kanwar YS, Abecassis MM, Miller J: Nonchimeric HLA-identical renal transplant tolerance: Regulatory immunophenotypic/genomic biomarkers. Am J Transplant 16: 221–234, 2016 PubMed 6. Yolcu ES, Leventhal JR, Ildstad ST: Facilitating cells in tolerance induction for kidney transplantation. Curr Opin Organ Transplant 20: 57–63, 2015 PubMed 7. Leventhal JR, Elliott MJ, Yolcu ES, Bozulic LD, Tollerud DJ, Mathew JM, Konieczna I, Ison MG, Galvin J, Mehta J, Badder MD, Abecassis MM, Miller J, Gallon L, Ildstad ST: Immune reconstitution/immunocompetence in recipients of kidney plus hematopoietic stem/facilitating cell transplants. Transplantation 99: 288–298, 2015 PubMed 8. Kawai T, Sachs DH, Sprangers B, Spitzer TR, Saidman SL, Zorn E, Tolkoff-Rubin N, Preffer F, Crisalli K, Gao B, Wong W, Morris H, LoCascio SA, Sayre P, Shonts B, Williams WW Jr., Smith RN, Colvin RB, Sykes M, Cosimi AB: Long-term results in recipients of combined HLAmismatched kidney and bone marrow transplantation without maintenance immunosuppression. Am J Transplant 14: 1599–1611, 2014 PubMed 9. Newell KA, Asare A, Sanz I, Wei C, Rosenberg A, Gao Z, Kanaparthi S, Asare S, Lim N, Stahly M, Howell M, Knechtle S, Kirk A, Marks WH, Kawai T, Spitzer T, Tolkoff-Rubin N, Sykes M, Sachs DH, Cosimi AB, Burlingham WJ, Phippard D, Turka LA: Longitudinal studies of a B cell-derived signature of tolerance in renal transplant recipients. Am J Transplant 15: 2908–2920, 2015 PubMed 10. Scandling JD, Busque S, Shizuru JA, Lowsky R, Hoppe R, DejbakhshJones S, Jensen K, Shori A, Strober JA, Lavori P, Turnbull BB, Engleman EG, Strober S: Chimerism, graft survival, and withdrawal of immunosuppressive drugs in HLA matched and mismatched patients after living donor kidney and hematopoietic cell transplantation. Am J Transplant 15: 695–704, 2015 PubMed 11. Erickson KF, Winkelmayer WC, Busque S, Lowsky R, Scandling JD, Strober S: A cost analysis of tolerance induction for two-haplotype match kidney transplant recipients. Am J Transplant 16: 371–373, 2016 PubMed 12. Madariaga ML, Kreisel D, Madsen JC: Organ-specific differences in achieving tolerance. Curr Opin Organ Transplant 20: 392–399, 2015 PubMed 13. Sigdel TK, Gao Y, He J, Wang A, Nicora CD, Fillmore TL, Shi T, Webb-Robertson BJ, Smith RD, Qian WJ, Salvatierra O, Camp DG 2nd, Sarwal MM: Mining the human urine proteome for monitoring renal transplant injury. Kidney Int 89: 1244–1252, 2016 PubMed 14. Modena BD, Kurian SM, Gaber LW, Waalen J, Su AI, Gelbart T, Mondala TS, Head SR, Papp S, Heilman R, Friedewald JJ, Flechner SM, Marsh CL, Sung RS, Shidban H, Chan L, Abecassis MM, Salomon DR: Gene expression in biopsies of acute rejection and interstitial fibrosis/tubular atrophy reveals highly shared mechanisms that correlate with worse longterm outcomes. Am J Transplant 16: 1982–1998, 2016 PubMed 15. Venner JM, Hidalgo LG, Famulski KS, Chang J, Halloran PF: The molecular landscape of antibody-mediated kidney transplant rejection: Evidence for NK involvement through CD16a Fc receptors. Am J Transplant 15: 1336–1348, 2015 PubMed 16. O’Connell PJ, Zhang W, Menon MC, Yi Z, Schröppel B, Gallon L, Luan Y, Rosales IA, Ge Y, Losic B, Xi C, Woytovich C, Keung KL, Wei C, Greene I, Overbey J, Bagiella E, Najafian N, Samaniego M, Djamali A, Alexander SI, Nankivell BJ, Chapman JR, Smith RN, Colvin R, Murphy B: Biopsy transcriptome expression profiling to identify kidney transplants at risk of chronic injury: A multicentre, prospective study. Lancet 388: 983–993, 2016 PubMed 17. Oetting WS, Jacobson PA, Israni AK: Validation is critical for genomewide association study-based associations. Am J Transplant 17: 318– 319, 2017 PubMed 18. Pihlstrøm HK, Mjøen G, Mucha S, Haraldsen G, Franke A, Jardine A, Fellström B, Holdaas H, Melum E: Single nucleotide polymorphisms and long-term clinical outcome in renal transplant patients: A validation study. Am J Transplant 17: 528–533, 2017 PubMed Glomerular Injury Post-Transplant Proteinuria in the Post-Transplant Setting Measures of proteinuria post-transplant may signal de novo or recurrent glomerular disease or a manifestation of alloantibody-mediated injury, also referred to as transplant glomerulopathy (see above). A recent study showed the predictive value of proteinuria (measured 3 months and 1, 2, 5, and 10 years post-transplantation and at the time of renal allograft biopsy) for graft failure in 1518 patients followed for over 7 years posttransplant. Protocol biopsies correlated proteinuria with graft histology (1). Although proteinuria of 300–1000 mg/d was associated with a twofold increased risk of graft loss, proteinuria of 1–3 g/d was associated with a threefold increased risk of graft loss, independent of GFR and histology. The predictive value, in terms of sensitivity, specificity, and negative and positive predictive values of proteinuria, was relatively low for abnormal glomerular histology or graft loss. The best predictor for biopsy findings of transplant glomerulopathy, glomerular disease, and/or microcirculatory inflammation was proteinuria .1 g/d measured 3 months post-transplant. The positive predictive value of this parameter was 58.2%, whereas the negative predictive value was 78.7%. The research group suggested that kidney biopsy was indicated when a proteinuria threshold of $1 g/d was achieved to better characterize the nature of glomerular injury. Beyond these modestly predictive findings, a separate retrospective study of 805 kidney transplant recipients concluded that the resolution of low-grade proteinuria (from 0.15–1000 mg/d to ,0.15 g/d from years 1 and 2 to years 2 and 3 post-transplant) was associated with a higher graft survival rate compared with those with persistent proteinuria, independent of BP (2). The combination of persistent low-grade proteinuria and systolic BP .140 320 mmHg during the first 3 years was associated with inferior patient survival and death-censored graft survival (60.2% and 87.6%, respectively) compared with in normotensive patients without proteinuria (87.9% and 97.0% with P,0.001 and P,0.01, respectively). One potential contributor to the development of proteinuria is mammalian target of rapamycin inhibitor (mTORi). Prevention of proteinuria related to mTORi may be reasonably achieved using reninangiotensin system blockade. A prospective, randomized, double-blind, placebo-controlled study of 264 renal transplant patients converted from a calcineurin inhibitor to sirolimus compared ramipril with placebo in primary prevention of proteinuria (defined as urinary protein-to-creatinine ratio $0.5) (3). Losartan was administered if proteinuria was not controlled, despite uptitration of ramipril. At 52 weeks, the cumulative rate of losartan initiation was significantly lower in the ramipril arm (6.2%) than placebo (23.2%; P,0.001), with no difference between study arms with respect to changes in eGFR over the study period. A recent review provides the reader with greater depth of the topic of proteinuria in the post-transplant setting (4). Glomerular Disease: Post-Transplant Outcomes Patients with GN tend to have excellent outcomes after kidney transplantation when assessed as a grouped cohort. However, there is variation within individual subtypes. A United States registry analysis of outcomes in 32,131 patients with one of six GN subtypes showed highest graft survival in IgA nephropathy and lowest graft survival in vasculitis, the latter driven entirely due to death as an end point rather than graft loss (5). Regarding the hazard for death-censored graft loss, the IgA nephropathy and vasculitis subgroups were similar (hazard ratio [HR], 0.94; P value not significant) and superior to FSGS (HR, 1.20; 95% CI, 1.12 to 1.28), membranous nephropathy (MN; HR, 1.27; 95% CI, 1.14 to 1.41), membranoproliferative GN (MPGN; HR, 1.50; 95% CI, 1.36 to 1.66), and lupus nephritis (HR, 1.11; 95% CI, 1.02 to 1.20), with all HRs statistically significant, compared with IgA as reference. A European registry analysis of 41,383 patients with GN showed similar findings of highest death-censored graft survival in the IgA subtype and lowest survival in the MPGN subtypes (6). Addressing the potential concern of using living donors for individuals with primary GNs, all subtypes had superior graft survival with living versus deceased donor kidney transplant (e.g., IgA: HR, 0.74; 95% confidence interval [95% CI], 0.59 to 0.92; FSGS: HR, 0.69; 95% CI, 0.45 to 1.06), except MPGN type I (HR, 1.08; 95% CI, 0.73 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 to 1.60) and type II (HR, 0.90; 95% CI, 0.32 to 2.52). The authors concluded that living donation should be not be discouraged across all GN subtypes, with informed decision making in cases involving MPGN. Focal and Segmental Glomerulosclerosis The risk for recurrent of FSGS post-transplant is substantial and frequently leads to early graft loss. In an Australian and New Zealand Dialysis and Transplant Registry analysis of 666 adults and 70 pediatric kidney transplant recipients with ESRD eventuating from biopsy-proven FSGS, the disorder recurred in 10.3% of cases, with a 52% 5-year graft survival versus 83% in those without recurrent disease (P,0.001) (7). Risk factors for recurrence included younger age, nonwhite ethnicity, and living donor versus deceased donor transplant. Overall, median graft survival was still superior with living donor transplant than deceased donor transplant (14.8 versus 12.1 years; P,0.01), again suggesting that living donor transplant should not be avoided in this cohort. Recurrence rates strongly depend on etiology of FSGS. In pediatric patients with known or suspected genetic causes of FSGS, the post-transplant recurrence rate is low. For example, only one of 25 patients in a National Israeli Kidney Registry Study developed recurrent FSGS versus 17 of 22 patients (64%), in whom FSGS was considered “primary/nongenetic” (8). Treatment for recurrent post-transplant FSGS remains a challenge. A review and meta-analysis of the role of plasma exchange (PLEX) as a primary intervention pooled 34 case reports and 43 case series totaling 423 patients (9). Defining remission as ,3.5 g/d (partial) or ,0.5 g/d (complete), the overall remission rate was 71%. Neither age nor donor type were associated with remission. Proteinuria .7 g/d was inversely associated with remission, whereas men and early treatment within 2 weeks of recurrence were associated with higher rates of remission. Rituximab (RTX) administration to individuals who failed or could not be weaned from PLEX and high-dose calcineurin inhibitors was reported in a series of 19 patients. Ten patients underwent RTX readministration after failure to respond to PLEX (10): five achieved partial (n54) or complete (n51) remission, and eight developed serious infections within 1 year, suggesting that adding RTX to achieve control of FSGS must be done with close monitoring and expectation for infectious complications. Finally, initial optimism regarding targeted B7-1 (putative role in aberrant podocyte integrity) treatment with the costimulation blockers, abatacept or belatacept, has been tempered by 321 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 a recent report of nine patients with recurrent, post-transplant FSGS. All failed to respond to this therapy, despite combination with other therapies that included PLEX and/ or immunoadsorption in all patients and RTX in most (11). Membranous Nephropathy Membranous Nephropathy (MN) often recurs posttransplant but typically, with a far less aggressive course than FSGS. In the largest and most comprehensive case series to date, 63 recipients with biopsy-proven primary MN pretransplant were followed for a median of 77 months post-transplant. Recurrent disease developed in 30 of 63 (48%) cases, and 16 were diagnosed by protocol biopsy. In 17 of the 30 cases, there was progressive proteinuria (12). Progressors were treated with RTX, with complete or partial remission in 14 (82%) cases. Importantly, graft and patient survival rates were not different among those who developed recurrence versus those who did not, similar to a concurrently transplanted autosomal dominant polycystic kidney disease cohort. The degree of pretransplant proteinuria was associated with recurrence (approximately 50% recurrence rate for proteinuria of 5–10 g/d; approximately 80% for .10 g/d). The presence of pretransplant antiphopholipase A2 receptor antibodies (anti-PLA2R Abs) was also associated with recurrence (HR, 3.76; 95% CI, 1.64 to 8.65; P50.002). In a separate study, the positive predictive value of pretransplant anti-PLA2R for recurrence was 83%, and negative predictive value was 42%, suggesting a role in screening for anti-PLA2R Ab to risk stratify recurrence. Namely, a positive value may indicate a need for heightened surveillance, whereas a negative value does not necessarily rule out the possibility of recurrent disease (13). This finding was corroborated by another single-center analysis of 16 patients (14). A more detailed review of the value of anti-PLA2R Ab screening and monitoring in pre- and post-transplant settings has been recently published (15). APOL1 and Kidney Transplantation APOL1 gene polymorphisms (risk variants) are enriched in blacks due to the trypanolytic effects conferred by these ApoL1 proteins. Individuals with two APOL1 risk variants (10%–15% of the black population) are more likely to develop glomerular diseases, including FSGS, HIV-associated nephropathy, lupus nephritis, and hypertensive nephrosclerosis, in the nontransplant setting (16). In the transplant setting, recent clinical observations suggest that kidneys from donors with two APOL1 risk variants may confer risk of decreased allograft survival in the recipient. In a twocenter report of 675 kidneys transplanted, the presence of two donor risk variants was associated with graft loss (HR, 2.26; P50.001) (17). In an extension of this study including an additional 478 deceased donor kidney transplants, in whom APOL1 genotyping was performed, donor APOL1 high-risk genotype was associated with inferior allograft survival (Figure 13) (HR, 2.05; 95% 95% CI 1.39 to 3.02; P,0.001) (18). Despite this risk, most recipients maintained excellent function (72.6% of grafts functioning for .5 years and 56.9% of those functioning .10 years). It is possible that the risk conferred by APOL1 risk variant donors is only loosely approximated by the inclusion of black race in the calculation of the deceased donor risk index that determines the donor profile index for deceased donor kidney allocation. A recent assessment of the impact of substituting APOL1 status for race described the potential for refinement of risk for graft loss and may more precisely classify the impact of black race as a donor risk factor (19). Current understanding of the role and value of testing for APOL1 risk variants is rapidly evolving and includes consideration for not only recipients but also, potential living donors. These concepts were recently summarized in proceedings from an American Society of Transplantation Expert Conference (20). The presence of two APOL1 renal risk variants in deceased donors is associated with a 1.5- to twofold increased risk of graft loss. APOL1 renal risk variants may explain the disparity in allograft outcomes from black kidney donors. Complement-Mediated Glomerular Disease Complement-mediated diseases, including atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathies, have high recurrence rates in renal allografts and substantially impact graft survival. Despite this, a recent registry analysis reported the persistence of survival benefit of transplant in adult patients with a diagnosis of hemolytic uremic syndrome (not explicitly defined as aHUS) compared with those remaining on the waiting list (5-year mortality risk with living donor: HR, 0.27; 95% CI, 0.11 to 0.65; with deceased donor: HR, 0.52; 95% CI, 0.29 to 0.94) (21). In general, data are 322 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 Figure 13. Adjusted Kaplan–Meier survival plots (full model) in 1153 deceased donor kidney transplantations from black donors based on donor APOL1 genotypes. Plots compare survival of kidneys from donors with two renal risk variants with that for kidneys from donors with fewer than two renal risk variants. The numbers within the parentheses below the curves reflect the following: (number of functioning allografts at the start of each year, number of allograft failures within that year). Reprinted with permission from Freedman BI, Pastan SO, Israni AK, Schladt D, Julian BA, Gautreaux MD, Hauptfeld V, Bray RA, Gebel HM, Kirk AD, Gaston RS, Rogers J, Farney AC, Orlando G, Stratta RJ, Mohan S, Ma L, Langefeld CD, Bowden DW, Hicks PJ, Palmer ND, Palanisamy A, Reeves-Daniel AM, Brown WM, Divers J: APOL1 genotype and kidney transplantation outcomes from deceased African American donors. Transplantation 100: 194–202, 2016. sparse for the management of patient with complementmediated injury, but examples can be gleaned from the nontransplant population. In a recent open label trial of 41 patients treated with eculizumab for aHUS, 73% had a complete thrombotic microangiopathic response, with 15 of 19 patients dialysis dependent at initiation of therapy discontinuing dialysis (22). Of the overall cohort, nine patients had a history of prior kidney post-transplant (three on dialysis); data were not reported for this small cohort. A recent review describes current considerations for diagnosis and management of these rare diseases in the transplant setting (23). Pertinent recommendations include careful consideration of C3 glomerulopathy in any renal transplant candidate whose original disease was reported as MPGN, mesangial proliferative GN, or endocapillary proliferative GN. If C3 glomerulopathy can be verified, detailed complement testing can be performed to identify and predict the risk of recur- rence. These recommendations may help in prediction, but in practice, they may unfortunately not change management. For example, when a high-risk complement mutation is identified, therapy may be considered to prevent or treat recurrence; however, expense may limit access to therapies, such as eculizumab, except in cases where clinical diagnosis of aHUS has been established. References 1. Naesens M, Lerut E, Emonds MP, Herelixka A, Evenepoel P, Claes K, Bammens B, Sprangers B, Meijers B, Jochmans I, Monbaliu D, Pirenne J, Kuypers DR: Proteinuria as a noninvasive marker for renal allograft histology and failure: An observational cohort study. J Am Soc Nephrol 27: 281–292, 2016 PubMed 2. Cherukuri A, Tattersall JE, Lewington AJ, Newstead CG, Baker RJ: Resolution of low-grade proteinuria is associated with improved outcomes after renal transplantation-a retrospective longitudinal study. Am J Transplant 15: 741–753, 2015 PubMed 3. Mandelbrot DA, Alberú J, Barama A, Marder BA, Silva HT Jr., Flechner SM, Flynn A, Healy C, Li H, Tortorici MA, Schulman SL: Effect of ramipril on urinary protein excretion in maintenance renal 323 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. transplant patients converted to sirolimus. Am J Transplant 15: 3174– 3184, 2015 PubMed Tsampalieros A, Knoll GA, Molnar AO, Fergusson N, Fergusson DA: Corticosteroid use and growth after pediatric solid organ transplantation: A systematic review and meta-analysis. Transplantation 101: 694– 703, 2017 PubMed O’Shaughnessy MM, Liu S, Montez-Rath ME, Lenihan CR, Lafayette RA, Winkelmayer WC: Kidney transplantation outcomes across GN subtypes in the United States. J Am Soc Nephrol 28: 632–644, 2017 PubMed Pippias M, Stel VS, Aresté-Fosalba N, Couchoud C, FernandezFresnedo G, Finne P, Heaf JG, Hoitsma A, De Meester J, Pálsson R, Ravani P, Segelmark M, Traynor JP, Reis×ter AV, Caskey FJ, Jager KJ: Long-term kidney transplant outcomes in primary glomerulonephritis: Analysis from the ERA-EDTA Registry. Transplantation 100: 1955– 1962, 2016 PubMed Francis A, Trnka P, McTaggart SJ: Long-term outcome of kidney transplantation in recipients with focal segmental glomerulosclerosis. Clin J Am Soc Nephrol 11: 2041–2046, 2016 PubMed Cleper R, Krause I, Bar Nathan N, Mor M, Dagan A, Weissman I, Frishberg Y, Rachamimov R, Mor E, Davidovits M: Focal segmental glomerulosclerosis in pediatric kidney transplantation: 30 Years’ experience. Clin Transplant 30: 1324–1331, 2016 PubMed Kashgary A, Sontrop JM, Li L, Al-Jaishi AA, Habibullah ZN, Alsolaimani R, Clark WF: The role of plasma exchange in treating post-transplant focal segmental glomerulosclerosis: A systematic review and meta-analysis of 77 case-reports and case-series. BMC Nephrol 17: 104, 2016 PubMed Garrouste C, Canaud G, Büchler M, Rivalan J, Colosio C, Martinez F, Aniort J, Dudreuilh C, Pereira B, Caillard S, Philipponnet C, Anglicheau D, Heng AE: Rituximab for recurrence of primary focal segmental glomerulosclerosis after kidney transplantation: Clinical outcomes. Transplantation 101: 649–656, 2017 PubMed Delville M, Baye E, Durrbach A, Audard V, Kofman T, Braun L, Olagne J, Nguyen C, Deschênes G, Moulin B, Delahousse M, KeslerRoussey G, Beaudreuil S, Martinez F, Rabant M, Grimbert P, Gallazzini M, Terzi F, Legendre C, Canaud G: B7-1 blockade does not improve post-transplant nephrotic syndrome caused by recurrent FSGS. J Am Soc Nephrol 27: 2520–2527, 2016 PubMed Grupper A, Cornell LD, Fervenza FC, Beck LH Jr., Lorenz E, Cosio FG: Recurrent membranous nephropathy after kidney transplantation: Treatment and long-term implications [published online ahead of print December 30, 2015]. Transplantation PubMed Kattah A, Ayalon R, Beck LH Jr., Sethi S, Sandor DG, Cosio FG, Gandhi MJ, Lorenz EC, Salant DJ, Fervenza FC: Anti-phospholipase A2 receptor antibodies in recurrent membranous nephropathy. Am J Transplant 15: 1349–1359, 2015 PubMed Gupta G, Fattah H, Ayalon R, Kidd J, Gehr T, Quintana LF, Kimball P, Sadruddin S, Massey HD, Kumar D, King AL, Beck LH Jr.: Pretransplant phospholipase A2 receptor autoantibody concentration is associated with clinically significant recurrence of membranous nephropathy post-kidney transplantation. Clin Transplant 30: 461–469, 2016 PubMed De Vriese AS, Glassock RJ, Nath KA, Sethi S, Fervenza FC: A proposal for a serology-based approach to membranous nephropathy. J Am Soc Nephrol 28: 421–430, 2017 PubMed Riella LV, Sheridan AM: Testing for high-risk APOL1 alleles in potential living kidney donors. Am J Kidney Dis 66: 396–401, 2015 PubMed Freedman BI, Julian BA, Pastan SO, Israni AK, Schladt D, Gautreaux MD, Hauptfeld V, Bray RA, Gebel HM, Kirk AD, Gaston RS, Rogers J, Farney AC, Orlando G, Stratta RJ, Mohan S, Ma L, Langefeld CD, Hicks PJ, Palmer ND, Adams PL, Palanisamy A, Reeves-Daniel AM, Divers J: Apolipoprotein L1 gene variants in deceased organ donors are associated with renal allograft failure. Am J Transplant 15: 1615–1622, 2015 PubMed 18. Freedman BI, Pastan SO, Israni AK, Schladt D, Julian BA, Gautreaux MD, Hauptfeld V, Bray RA, Gebel HM, Kirk AD, Gaston RS, Rogers J, Farney AC, Orlando G, Stratta RJ, Mohan S, Ma L, Langefeld CD, Bowden DW, Hicks PJ, Palmer ND, Palanisamy A, Reeves-Daniel AM, Brown WM, Divers J: APOL1 genotype and kidney transplantation outcomes from deceased African American donors. Transplantation 100: 194–202, 2016 PubMed 19. Julian BA, Gaston RS, Brown WM, Reeves-Daniel AM, Israni AK, Schladt DP, Pastan SO, Mohan S, Freedman BI, Divers J: Effect of replacing race with apolipoprotein L1 genotype in calculation of kidney donor risk index. Am J Transplant 17: 1540–1548, 2017 PubMed 20. Newell KA, Formica RN, Gill JS, Schold JD, Allan JS, Covington SH, Wiseman AC, Chandraker A: Integrating APOL1 gene variants into renal transplantation: Considerations arising from the American Society of Transplantation Expert Conference. Am J Transplant 17: 901–911, 2017 PubMed 21. Santos AH Jr., Casey MJ, Wen X, Zendejas I, Rehman S, Womer KL, Andreoni KA: Survival with dialysis versus kidney transplantation in adult hemolytic uremic syndrome patients: A fifteen-year study of the waiting list. Transplantation 99: 2608–2616, 2015 PubMed 22. Fakhouri F, Hourmant M, Campistol JM, Cataland SR, Espinosa M, Gaber AO, Menne J, Minetti EE, Provôt F, Rondeau E, Ruggenenti P, Weekers LE, Ogawa M, Bedrosian CL, Legendre CM: Terminal complement inhibitor eculizumab in adult patients with atypical hemolytic uremic syndrome: A single-arm, open-label trial. Am J Kidney Dis 68: 84–93, 2016 PubMed 23. Barbour S, Gill JS: Advances in the understanding of complement mediated glomerular disease: Implications for recurrence in the transplant setting. Am J Transplant 15: 312–319, 2015 PubMed Infection after Transplant Infectious complications after transplant are a major cause of morbidity and mortality and may interpose allograft injury and graft loss (1). Newer infections, such as Zika virus, are incompletely understood in the transplant population (2). Only a small case series from Brazil described the courses of two kidney and two liver transplant recipients. All cases were identified concurrent with confounding bacterial infections that do not permit greater understanding of the impact of Zika infection per se (3). Preventing common infections, such as influenza and common urinary tract infections (UTIs), are worthy goals but have limitations. After an outbreak of influenza A in one inpatient transplant unit, 23 kidney transplant patients were identified as at risk: 17 had adequate seasonal influenza vaccination, of whom two tested positive without clinical consequences. Of six unvaccinated recipients, five developed influenza, and three died from severe respiratory failure (4). In a study of 60 patients after influenza vaccination, adequate seroconversion to at least one of the three influenza antigens occurred in 63% without an increase in HLA alloantibody titers (5). In conclusion, vaccination is less efficacious in ESRD 324 and kidney transplant populations than the general population but is still considered valuable. The same utility cannot be ascribed to screening for and treating asymptomatic bacteriuria to prevent UTI. In 112 kidney transplant recipients with at least one episode of asymptomatic bacteriuria after the second month, post-transplant routine screening was conducted, with subsequent randomization in 1:1 fashion to antimicrobial therapy or no therapy. No difference in the acute pyelonephritis rate at 24 months was found (7.5% versus 8.4%). There was no difference in lower UTI frequency, allograft function, or mortality (6). Cytomegalovirus To prevent cytomegalovirus (CMV) infection/ disease, most transplant centers in the United States use a CMV prophylaxis strategy using valganciclovir for 3–6 months post-transplant. High-dose valacyclovir has also been recommended. A randomized trial of 119 patients receiving either valganciclovir 900 mg daily or valacyclovir 2 g four times daily showed similar efficacy in prevention of CMV viremia at 12 months (31% versus 43%; P50.36). Notably, the valganciclovir group had a lower incidence of acute rejection (17% versus 31%; P50.03) and higher BK virus (BKV) viremia rates (36% versus 18%; P50.04), supporting an additive immunosuppressive effect of valganciclovir (7). Conversely, immunosuppressive medications (specifically, sirolimus and everolimus) may have additive antiviral effects. In the absence of CMV prophylaxis, 288 kidney transplant recipients were randomized to receive tacrolimus (TAC), prednisone, and everolimus (n5102 with antithymocyte globulin induction, n585 with basiliximab induction) or mycophenolate (n5101 with basiliximab induction) (8). Rates of CMV infection/disease at 12 months were 4.7%, 10.8%, and 37.6%, respectively (P,0.001 for each everolimus versus mycophenolate group). This finding was corroborated in a multicenter registry analysis of 311 pediatric kidney transplant recipients that revealed an 83% lower risk of CMV replication overall and a lower CMV disease rate in high-risk (CMV IgG1 donor/CMV IgG2 recipient) recipients when prescribed immunosuppression consisting of cyclosporine (CsA)/everolimus versus CsA or TAC in combination with mycophenolate (9). These findings support experimental data that document inhibition of CMV replication by mammalian target of rapamycin inhibition. Monitoring for CMV infection may be warranted even after prophylaxis in certain high-risk circumstances. Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 Forty-eight high-risk (CMV IgG1 donor/CMV IgG– recipient) recipients who received thymoglobulin induction and 6 months of valganciclovir underwent CMV PCR monitoring during prophylaxis and for 3 additional months of surveillance (10). Nineteen (40%) developed CMV infection: nine occurred during prophylaxis (five were associated with suboptimal valganciclovir dosing); six occurred during the surveillance period post-transplant, and four occurred during the 3-month postsurveillance period. The authors suggest that identification of viremia can ideally permit immunosuppression adjustment and reduce morbidity and hospitalizations. Beyond CMV PCR monitoring, a number of other markers that may identify CMV-specific immunity are under study, including T cell subsets (11), chemokine (C-C motif) ligand 8 (CCL8) (12), and single-nucleotide polymorphisms in genes involved in CMV immune response (13). These references are provided for the interested reader (11–13). BK Virus Control of BK virus (BKV) reactivation from the transplanted kidney remains an important challenge in optimizing graft survival. Recent advances in the understanding of the mechanisms that contribute to viral reactivation include measures of BKV-specific immunity, viral relationship to specific immunosuppressive agents, and contribution of donor versus recipient pretransplant BKV exposure. In a study comparing BKV-specific and alloreactive T cells from 24 kidney transplant patients who developed BKV viremia with those from 127 patients without BKV (sampled pretransplant and 1, 2, and 3 months posttransplant), changes in BKV-specific T cells from the pre- to post-transplant period were associated with risk for subsequent BKV replication (14). Another study of cytokine profiles from T cell subsets from individuals who cleared BKV versus those who did not revealed an increase in a specific polyfunctional T cell subset that secreted multiple cytokines only in the former group (15). Thus, measures of T cell functionality may be predictive of risk for BKV infection, and the likelihood of clearance after replication has been established. Mammalian target of rapamycin inhibitors (mTORis) may not only preserve BKV-specific T cell immunity but may also inhibit BKV replication in renal tubular epithelial cells more than calcineurin inhibitors. The former hypothesis was supported by a study showing reductions in cytotoxic T cell function using CsA but not mTORi (16), 325 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 whereas the latter hypothesis was shown in an in vitro study, in which sirolimus exerted inhibitory effects on BKV replication in renal tubular epithelial cells (17). TAC increased BKV replication and counteracted sirolimus inhibition when the two medications were combined. This suggests a possible advantage of mTORi compared with TAC for prevention of BKV infection. The measurement of pretransplant anti-BKV serostatus from the donor and recipient has been proposed as a measure to determine risk of post-transplant BKV infection, analogous to measuring CMV IgG status in donors and recipients pretransplant to define CMV risk. Recent studies increasingly support this concept as a potential risk stratification tool. In 407 living kidney donor-recipient pairs, donor but not recipient BKV seroreactivity was strongly associated with BKV viremia within 1 year post-transplant. Coupling donors with high seroreactivity with recipients of low seroreactivity was associated with a tenfold increased risk of BKV viremia (18). Another study of 116 donor/recipient pairs reported that kidneys from donors with significant serum neutralizing activity (donor positive) had a fivefold elevated risk for BKV viremia, regardless of recipient serostatus (donor positive versus donor negative: odds ratio, 5.0; 95% confidence interval [95% CI], 1.9 to 12.7; P,0.001), and those donor-recipient pairs with donor-positive/recipient-negative neutralizing serostatus had the greatest risk for BKV viremia (odds ratio, 4.9; 95% CI, 1.7 to 14.6; P50.004) (19). These data together with another study that described a correlation of specific donor-derived BKV subtypes with post-transplant BKV infection (20) implicate donor source and immunity as important risk factors for clinically significant BKV infection post-transplant. Transplant recipients who are seronegative for BK virus who receive seropositive grafts (BK D1/R-) are at increased risk of BK viremia. Other possible risk factors for BKV susceptibility were clarified in a registry analysis using a paired kidney analysis that identified recipient pairs receiving kidneys from the same deceased donor. By stratifying those cases where one of two recipients were treated for BKV (discordant treatment) from those cases where both recipients were treated for BKV (concordant treatment), associations could be made to determine risk invoked by the donor (concordant treatment) versus the recipient (discordant treatment) (21). Recipient factors that were associated with increased risk for treated BKV infection included age ,18 or $60 years old, men, four or more HLA mismatches, acute rejection, and antibody-depleting induction therapy. Factors associated with reduced risk included recipient diabetes and sirolimus use. The rate of BKV infection in paired transplanted kidneys was threefold higher than expected, implying that donor factors, such as serostatus, are of greater importance in BKV risk. Allograft biopsy findings and other recipient antibodies during BKV infection and BKV may elicit enhanced understanding of the subsequent clinical course. Associations of de novo donor-specific antibodies (DSAs) with persistent BKV viremia (22) and increased risk of rejection with antibodies to selfantigens fibronectin and collagen type IV with BKV viremia (23) have recently been reported. Regarding the risk (or association) of BKV viremia and de novo DSA formation, in a large, single-center study, 785 patients were screened for BKV viremia, of which 132 (17%) developed BKV viremia. BKV viremia that persisted .140 days despite immunosuppression dose reduction was not associated with inferior graft or patient survival. However, de novo HLA DSAs were identified in 30% with persistent viremia compared with 23% in those who rapidly cleared the virus and 15% in those without BKV viremia (on multivariate analysis: hazard ratio [HR], 2.53; 95% CI, 1.40 to 4.59; P,0.01 for the development of de novo DSA with persistent BKV viremia). Development of de novo DSAs generally occurred after BKV viremia had been identified (median 344 days post-transplant versus 137 days posttransplant, respectively). Beyond serologic assessment, other studies have examined biopsies of BKV nephropathy and found a higher frequency of allospecific T cell clones rather than BKV-specific clones (24). These findings highlight the interplay between BKV-related inflammation/viral immunity and rejection/alloimmunity and make the clinical strategy immunosuppression dose reduction for BKV viremia a more complex decision than previously understood. HIV Although kidney transplantation for HIV1 candidates is associated with generally good outcomes, there is an increased risk of acute rejection along with other donor and recipient risk factors that may contribute to inferior graft and patient survival compared with in the HIV– recipient. In a recent analysis of 499 HIV1 recipients, improvements in graft survival and mortality were noted over time (2008–2011 versus 2004–2007). Encouragingly, center experience (performance of less than 326 Figure 14. Three-year allograft survival was higher in the HIV monoinfected (81%) and uninfected groups (86%) than in the HCV monoinfected (78%) and HIV/HCV coinfected patients (60%; P,0.001). Reprinted with permission from Sawinski D, Forde KA, Eddinger K, Troxel AB, Blumberg E, Tebas P, Abt PL, Bloom RD: Superior outcomes in HIVpositive kidney transplant patients compared with HCVinfected or HIV/HCV-coinfected recipients. Kidney Int 88: 341–349, 2015. or more than six HIV1 transplants) was not associated with outcomes, a point that should encourage further expansion to a greater number of centers (25). In other registry studies, factors that were predictive of acute rejection included short duration of viral suppression pretransplant (greater than twofold risk in those with HIV RNA suppression for 6 months; 2 years versus .2 years) (26) and nonuse of antithymocyte globulin (27). In the latter study, antithymocyte globulin use was associated with a 31% reduction in risk for rejection (95% CI, 0.35 to 0.99) (27). Antithymocyte globulin induction was also associated with a reduction in delayed graft function and graft loss and a trend to lower mortality without an increase in risk of infection. Such data support the relative safety and efficacy of the counterintuitive strategy of T cell–depleting therapy in the HIV1 recipient. However, a word of caution is offered by a single-center series that reported that, in 38 HIV1 recipients treated with antithymocyte globulin induction, pretransplant CD4 counts of 200–349 versus $350 cells per 1 mm3 were associated with severe lymphopenia (,200 cells per mm3) at 4 weeks post-transplant (75% versus 30%; relative risk, 2.6; 95% CI, 1.3 to 5.1). The lymphopenia was associated with a more than twofold greater rate of severe infection during the first 6 months (28). TAC versus CsA seems to be the preferred calcineurin inhibitor in HIV1 kidney transplant recip- Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 ients. In a national cohort study in the United Kingdom composed of 78 patients (31 treated with CsA and 47 treated with TAC), 1-year acute rejection rates were 58% versus 21%, respectively (HR for acute rejection with TAC versus CsA, 0.25; 95% CI, 0.11 to 0.57; P50.001) (29). Beyond immunosuppression, a major factor that strongly contributes to inferior outcomes in HIV1 recipients is coinfection with HCV. Two recent studies highlighted that monoinfected HIV1 transplant recipients have similar graft and patient survival compared with HIV– reference groups (30, 31). However, coinfection with hepatitis C virus (HCV; HIV1 /HCV1) is associated with marked reductions in graft and patient survival (Figure 14). An updated analysis not only examined the relationship of HCV coinfection on outcomes but also, focused on other factors that may contribute to inferior graft loss compared with HIV– recipients (32). In total, 526 HIV1 kidney transplant recipients were compared with 82,236 HIV– recipients in a registry analysis of the era from 2001 to 2013. Two primary risk factors, HCV coinfection and more than three HLA mismatches, were identified as risk amplifiers when examining risk factors for graft loss (adjusted HR, 3.86; 95% CI, 2.37 to 6.30; P,0.001). Transplant recipients co-infected with HIV and HCV have markedly inferior graft survival rates compared with either monoinfected or non-infected individuals. With the passage of the HIV Organ Policy Equity Act, HIV1 recipients may now consent in clinical trials to receive organs from deceased donors who were HIV1. The precedent for this originated from experiences in South Africa, where an updated report of 27 HIV1 recipients of kidneys from HIV1 donors was recently published (33). Death-censored graft survival rates were 93%, 84%, and 84% at 1, 3, and 5 years (median follow-up, 2.4 years). Updated reviews on medication interactions and considerations for drug resistance, opportunistic infection, and HIV-associated kidney dysfunction are available (34, 35). Although any increase in organ donation is of benefit, an estimate of the impact on the organ shortage in the greater Philadelphia area by examination of the medical records of HIV-infected patients dying in care at six HIV clinics implies a small impact locally 327 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 Table 2. Main characteristics of the approved direct-acting antivirals that are currently used for the treatment of HCV Direct-Acting Antiviral (Commercial Name), Dose Sofosbuvir (Sovaldi), tablet 400 mg, once daily Simeprevir (Olysio), tablet 150 mg, once daily with food Daclatasvir (Daklinza), tablet 60 mg, once daily Ledipasvir/sofosbuvir (Harvoni), tablet 90/400 mg, once daily Category Dose Adjustment in Renal Impairment Antiviral Activity Nucleotide analogue NS5B polymerase inhibitor NS3/4A protease inhibitor Contraindicated in patients with GFR,30 ml/min No change in renal impairment NS5A inhibitor No change in renal impairment Contraindicated in patients with GFR,30 ml/min NS5A inhibitor 1 nucleotide analogue NS5B polymerase inhibitor Ombitasvir/paritaprevir/ NS5A inhibitor 1 NS3/4A No change in renal ritonavir (Viekirax), protease inhibitor dysfunction tablet 12.5/75/50 mg, boosted by ritonavir two once daily with food boosted Dasabuvir (Exviera), tablet Non-nucleos(t)ide No change in renal 250 mg, every 12 h analogue NS5B dysfunction polymerase inhibitor Elbasvir/grazoprevir NS5A inhibitor 1 NS3/4A No change in renal (Zepatier), tablet inhibitor dysfunction 100/50 mg, once daily Velpatasvir/sofosbuvir/ NS5A inhibitor 1 Contraindicated in (Epclusa), tablet 100/ nucleotide analogue patients with 400 mg, once daily NS5B polymerase GFR,30 ml/min inhibitor CNIs Coadministration Genotypes 1-6 High genetic barrier No change Genotypes 1 and 4 Low genetic barrier Contraindicated with CsA Genotypes 1–4 No change Low genetic barrier Genotypes 1 and 4–6 No change High genetic barrier Genotypes 1 and 4 Genetic barrier depending on HCV genotype Genotype 1 Low genetic barrier CsA: 20% of pretreatment total daily dose; TAC: 0.2 mg/72 h or 0.5 mg once weekly Genotypes 1 and 4 Coadministration increases TAC concentrations No change Genotypes 1–6 CNI, calcineurin inhibitor. Modified from Cholongitas E, Pipili C, Papatheodoridis GV: Interferon-free regimens in patients with hepatitis C infection and renal dysfunction or kidney transplantation. World J Hepatol 9: 180–190, 2017. (four to five organ donors annually). When extrapolated nationally, the authors estimated an additional 192 kidneys transplanted annually (36). Hepatitis C Virus As described above, HCV1 recipients have inferior kidney graft and patient survival compared with non–HCV-infected recipients. With the new generation direct-acting antiviral (DAA) agents, cure for HCV is achievable. However, until recently, there were no data supporting their use in advanced CKD or after kidney transplantation. In CKD, a large, multicenter, doubleblind, randomized trial (the C-SURFER Trial) using a 12-week course of elbasvir-grazoprevir in 235 patients with creatinine clearances ,30 ml/min (n5179, dialysis dependent) achieved viral eradication in 94% of patients with an excellent safety profile. There were no discontinuations due to adverse events (37). After transplant, a number of case series are now available that show efficacy similar to that in the general population with a number of different DAA regimens that include all six HCV genotypes (38, 39). One small case series describes successful clearance of HCV in six HIV/HCV-coinfected recipients, a population that had been excluded from study in the C-SURFER Trial (40). The American Association for the Study of Liver Diseases continues to update its recommendations for use of DAA in HCV (41). A recent review of literature for DAA in CKD and after kidney transplant forms a good reference (Table 2) (42). In patients with CKD, drug-drug interactions between calcineurin inhibitors and DAAs should always be considered and reviewed (43). These data have encouraged the expansion of use of HCV1 organ donors for not only HCV1 recipients, thereby shortening the waiting time to transplant, but also, the possibility of using HCV1 donors for HCV– 328 recipients who have no living donors and are expected to fare poorly on dialysis and/or have an excessively long expected waiting time for transplant when considering the candidate’s comorbidities (44). Pilot studies in this regard are underway. Direct-acting antiviral agents can effectively clear HCV pre- or post-transplantation. Before treating a potential transplant candidate, carefully consider the patient’s expected waiting time and willingness to accept a kidney from an HCV1 deceased donor. Hepatitis B Virus Similar to efforts to utilize HIV1 and HCV1 deceased donors in a thoughtful manner and expand organ utilization, recent guidelines have been published that clarify the risk of transmission from organ donors with serologic evidence of hepatitis B virus infection (45). This guideline specifically reviews considerations when using kidneys from deceased donors who are hepatitis B surface antigen positive or hepatitis B core antibody positive. In general, kidneys from an hepatitis B surface antigen positive donor can be considered in hepatitis B virus–vaccinated recipients with high hepatitis B surface antibody (HbSAb) titers, provided that lifelong chronic antiviral therapy is administered. Additionally, hepatitis B surface antigen positive donor kidneys can be considered for recipients with low/ absent HbSAb titer with a combination of hepatitis B immune globulin administration and continuation of chronic antiviral therapy. Conversely, kidneys from an hepatitis B core antibody positive donor pose negligible risks and should be considered for all recipients, with recommendations for a period of antiviral prophylaxis for up to 1 year only for the recipient with low HbSAb titer. Epstein Barr Virus Issues related to Epstein Barr virus infection are discussed below. References 1. Martin-Gandul C, Mueller NJ, Pascual M, Manuel O: The impact of infection on chronic allograft dysfunction and allograft survival after solid organ transplantation. Am J Transplant 15: 3024–3040, 2015 PubMed 2. Blumberg EA, Fishman JA: Zika virus in transplantation: Emerging infection and opportunities. Am J Transplant 17: 599–600, 2017 PubMed Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 3. Nogueira ML, Estofolete CF, Terzian AC, Mascarin do Vale EP, da Silva RC, da Silva RF, Ramalho HJ, Fernandes Charpiot IM, Vasilakis N, Abbud-Filho M: Zika virus infection and solid organ transplantation: A new challenge. Am J Transplant 17: 791–795, 2017 PubMed 4. Helanterä I, Anttila VJ, Lappalainen M, Lempinen M, Isoniemi H: Outbreak of influenza A(H1N1) in a kidney transplant unit-protective effect of vaccination. Am J Transplant 15: 2470–2474, 2015 PubMed 5. Kumar D, Campbell P, Hoschler K, Hidalgo L, Al-Dabbagh M, Wilson L, Humar A: Randomized controlled trial of adjuvanted versus nonadjuvanted influenza vaccine in kidney transplant recipients. Transplantation 100: 662–669, 2016 PubMed 6. Origüen J, López-Medrano F, Fernández-Ruiz M, Polanco N, Gutiérrez E, González E, Mérida E, Ruiz-Merlo T, Morales-Cartagena A, PérezJacoiste Asín MA, García-Reyne A, San Juan R, Orellana MA, Andrés A, Aguado JM: Should asymptomatic bacteriuria be systematically treated in kidney transplant recipients? Results from a randomized controlled trial. Am J Transplant 16: 2943–2953, 2016 PubMed 7. Reischig T, Kacer M, Jindra P, Hes O, Lysak D, Bouda M: Randomized trial of valganciclovir versus valacyclovir prophylaxis for prevention of cytomegalovirus in renal transplantation. Clin J Am Soc Nephrol 10: 294–304, 2015 PubMed 8. Tedesco-Silva H, Felipe C, Ferreira A, Cristelli M, Oliveira N, SandesFreitas T, Aguiar W, Campos E, Gerbase-DeLima M, Franco M, Medina-Pestana J: Reduced incidence of cytomegalovirus infection in kidney transplant recipients receiving everolimus and reduced tacrolimus doses. Am J Transplant 15: 2655–2664, 2015 PubMed 9. Höcker B, Zencke S, Pape L, Krupka K, Köster L, Fichtner A, Dello Strologo L, Guzzo I, Topaloglu R, Kranz B, König J, Bald M, Webb NJ, Noyan A, Dursun H, Marks S, Ozcakar ZB, Thiel F, Billing H, Pohl M, Fehrenbach H, Schnitzler P, Bruckner T, Ahlenstiel-Grunow T, Tönshoff B: Impact of everolimus and low-dose cyclosporin on cytomegalovirus replication and disease in pediatric renal transplantation. Am J Transplant 16: 921–929, 2016 PubMed 10. Puttarajappa C, Bhattarai M, Mour G, Shen C, Sood P, Mehta R, Shah N, Tevar AD, Humar A, Wu C, Hariharan S: Cytomegalovirus infection in high-risk kidney transplant recipients receiving thymoglobulin induction-a single-center experience. Clin Transplant 30: 1159–1164, 2016 PubMed 11. Kaminski H, Garrigue I, Couzi L, Taton B, Bachelet T, Moreau JF, Déchanet-Merville J, Thiébaut R, Merville P: Surveillance of gd T cells predicts cytomegalovirus infection resolution in kidney transplants. J Am Soc Nephrol 27: 637–645, 2016 PubMed 12. Lisboa LF, Egli A, Fairbanks J, O’Shea D, Manuel O, Husain S, Kumar D, Humar A: CCL8 and the immune control of cytomegalovirus in organ transplant recipients. Am J Transplant 15: 1882–1892, 2015 PubMed 13. Fernández-Ruiz M, Corrales I, Arias M, Campistol JM, Giménez E, Crespo J, López-Oliva MO, Beneyto I, Martín-Moreno PL, LlamasFuente F, Gutiérrez A, García-Álvarez T, Guerra-Rodríguez R, Calvo N, Fernández-Rodríguez A, Tabernero-Romo JM, Navarro MD, Ramos-Verde A, Aguado JM, Navarro D; OPERA Study Group: Association between individual and combined SNPs in genes related to innate immunity and incidence of CMV infection in seropositive kidney transplant recipients. Am J Transplant 15: 1323–1335, 2015 PubMed 14. Schachtner T, Stein M, Babel N, Reinke P: The loss of BKV-specific immunity from pretransplantation to posttransplantation identifies kidney transplant recipients at increased risk of bkv replication. Am J Transplant 15: 2159–2169, 2015 PubMed 15. Schaenman JM, Korin Y, Sidwell T, Kandarian F, Harre N, Gjertson D, Lum EL, Reddy U, Huang E, Pham PT, Bunnapradist S, Danovitch GM, Veale J, Gritsch HA, Reed EF: Increased frequency of BK virus-specific polyfunctional CD81 T cells predict successful control of BK viremia after kidney transplantation. Transplantation 101: 1479–1487, 2017 PubMed 16. Weist BJ, Wehler P, El Ahmad L, Schmueck-Henneresse M, Millward JM, Nienen M, Neumann AU, Reinke P, Babel N: A revised strategy for monitoring BKV-specific cellular immunity in kidney transplant patients. Kidney Int 88: 1293–1303, 2015 PubMed 329 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 17. Hirsch HH, Yakhontova K, Lu M, Manzetti J: BK polyomavirus replication in renal tubular epithelial cells is inhibited by sirolimus, but activated by tacrolimus through a pathway involving FKBP-12. Am J Transplant 16: 821–832, 2016 PubMed 18. Wunderink HF, van der Meijden E, van der Blij-de Brouwer CS, Mallat MJ, Haasnoot GW, van Zwet EW, Claas EC, de Fijter JW, Kroes AC, Arnold F, Touzé A, Claas FH, Rotmans JI, Feltkamp MC: Pretransplantation donor-recipient pair seroreactivity against BK polyomavirus predicts viremia and nephropathy after kidney transplantation. Am J Transplant 17: 161–172, 2017 PubMed 19. Abend JR, Changala M, Sathe A, Casey F, Kistler A, Chandran S, Howard A, Wojciechowski D: Correlation of BK virus neutralizing serostatus with the incidence of BK viremia in kidney transplant recipients. Transplantation 101: 1495–1505, 2017 PubMed 20. Schwarz A, Linnenweber-Held S, Heim A, Framke T, Haller H, Schmitt C: Viral origin, clinical course, and renal outcomes in patients with BK virus infection after living-donor renal transplantation. Transplantation 100: 844–853, 2016 PubMed 21. Thangaraju S, Gill J, Wright A, Dong J, Rose C, Gill J: Risk factors for BK polyoma virus treatment and association of treatment with kidney transplant failure: Insights from a paired kidney analysis. Transplantation 100: 854–861, 2016 PubMed 22. Sawinski D, Forde KA, Trofe-Clark J, Patel P, Olivera B, Goral S, Bloom RD: Persistent BK viremia does not increase intermediate-term graft loss but is associated with de novo donor-specific antibodies. J Am Soc Nephrol 26: 966–975, 2015 PubMed 23. Seifert ME, Gunasekaran M, Horwedel TA, Daloul R, Storch GA, Mohanakumar T, Brennan DC: Polyomavirus reactivation and immune responses to kidney-specific self-antigens in transplantation. J Am Soc Nephrol 28: 1314–1325, 2017 PubMed 24. Zeng G, Huang Y, Huang Y, Lyu Z, Lesniak D, Randhawa P: Antigenspecificity of T cell infiltrates in biopsies with t cell-mediated rejection and BK polyomavirus viremia: Analysis by next generation sequencing. Am J Transplant 16: 3131–3138, 2016 PubMed 25. Locke JE, Reed RD, Mehta SG, Durand C, Mannon RB, MacLennan P, Shelton B, Martin MY, Qu H, Shewchuk R, Segev DL: Center-level experience and kidney transplant outcomes in HIV-infected recipients. Am J Transplant 15: 2096–2104, 2015 PubMed 26. Husson J, Stafford K, Bromberg J, Haririan A, Sparkes T, Davis C, Redfield R, Amoroso A: Association between duration of human immunodeficiency virus (HIV)-1 viral suppression prior to renal transplantation and acute cellular rejection. Am J Transplant 17: 551–556, 2017 PubMed 27. Kucirka LM, Durand CM, Bae S, Avery RK, Locke JE, Orandi BJ, McAdams-DeMarco M, Grams ME, Segev DL: Induction immunosuppression and clinical outcomes in kidney transplant recipients infected with human immunodeficiency virus. Am J Transplant 16: 2368–2376, 2016 PubMed 28. Suarez JF, Rosa R, Lorio MA, Morris MI, Abbo LM, Simkins J, Guerra G, Roth D, Kupin WL, Mattiazzi A, Ciancio G, Chen LJ, Burke GW, Goldstein MJ, Ruiz P, Camargo JF: Pretransplant CD4 count influences immune reconstitution and risk of infectious complications in human immunodeficiency virus-infected kidney allograft recipients. Am J Transplant 16: 2463–2472, 2016 PubMed 29. Gathogo E, Harber M, Bhagani S, Levy J, Jones R, Hilton R, Davies G, Post FA; UK HIV Kidney Transplantation Study Group: Impact of tacrolimus compared with cyclosporin on the incidence of acute allograft rejection in human immunodeficiency virus-positive kidney transplant recipients. Transplantation 100: 871–878, 2016 PubMed 30. Sawinski D, Forde KA, Eddinger K, Troxel AB, Blumberg E, Tebas P, Abt PL, Bloom RD: Superior outcomes in HIV-positive kidney transplant patients compared with HCV-infected or HIV/HCV-coinfected recipients. Kidney Int 88: 341–349, 2015 PubMed 31. Locke JE, Mehta S, Reed RD, MacLennan P, Massie A, Nellore A, Durand C, Segev DL: A national study of outcomes among HIVinfected kidney transplant recipients. J Am Soc Nephrol 26: 2222–2229, 2015 PubMed 32. Locke JE, Shelton BA, Reed RD, MacLennan PA, Mehta S, Sawinski D, Segev DL: Identification of optimal donor-recipient combinations among human immunodeficiency virus (HIV)-positive kidney transplant recipients. Am J Transplant 16: 2377–2383, 2016 PubMed 33. Muller E, Barday Z, Mendelson M, Kahn D: HIV-positive-to-HIVpositive kidney transplantation–results at 3 to 5 years. N Engl J Med 372: 613–620, 2015 PubMed 34. Patel SJ, Kuten SA, Musick WL, Gaber AO, Monsour HP, Knight RJ: Combination drug products for HIV-a word of caution for the transplant clinician. Am J Transplant 16: 2479–2482, 2016 PubMed 35. Boyarsky BJ, Durand CM, Palella FJ Jr., Segev DL: Challenges and clinical decision-making in HIV-to-HIV transplantation: Insights from the HIV literature. Am J Transplant 15: 2023–2030, 2015 PubMed 36. Richterman A, Sawinski D, Reese PP, Lee DH, Clauss H, Hasz RD, Thomasson A, Goldberg DS, Abt PL, Forde KA, Bloom RD, Doll SL, Brady KA, Blumberg EA: An assessment of HIV-infected patients dying in care for deceased organ donation in a United States urban center. Am J Transplant 15: 2105–2116, 2015 PubMed 37. Roth D, Nelson DR, Bruchfeld A, Liapakis A, Silva M, Monsour H Jr., Martin P, Pol S, Londoño MC, Hassanein T, Zamor PJ, Zuckerman E, Wan S, Jackson B, Nguyen BY, Robertson M, Barr E, Wahl J, Greaves W: Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): A combination phase 3 study. Lancet 386: 1537–1545, 2015 PubMed 38. Kamar N, Marion O, Rostaing L, Cointault O, Ribes D, Lavayssière L, Esposito L, Del Bello A, Métivier S, Barange K, Izopet J, Alric L: Efficacy and safety of sofosbuvir-based antiviral therapy to treat hepatitis c virus infection after kidney transplantation. Am J Transplant 16: 1474–1479, 2016 PubMed 39. Sawinski D, Kaur N, Ajeti A, Trofe-Clark J, Lim M, Bleicher M, Goral S, Forde KA, Bloom RD: Successful treatment of hepatitis C in renal transplant recipients with direct-acting antiviral agents. Am J Transplant 16: 1588–1595, 2016 PubMed 40. Sawinski D, Lee DH, Doyle AM, Blumberg EA: Successful posttransplant treatment of hepatitis C with ledipasvir-sofosbuvir in HIV1 kidney transplant recipients. Transplantation 101: 974–979, 2017 PubMed 41. Panel AIHG; AASLD/IDSA HCV Guidance Panel: Hepatitis C guidance: AASLD-IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus. Hepatology 62: 932–954, 2015 PubMed 42. Cholongitas E, Pipili C, Papatheodoridis GV: Interferon-free regimens in patients with hepatitis C infection and renal dysfunction or kidney transplantation. World J Hepatol 9: 180–190, 2017 PubMed 43. Badri P, Dutta S, Coakley E, Cohen D, Ding B, Podsadecki T, Bernstein B, Awni W, Menon R: Pharmacokinetics and dose recommendations for cyclosporine and tacrolimus when coadministered with ABT-450, ombitasvir, and dasabuvir. Am J Transplant 15: 1313–1322, 2015 PubMed 44. Reese PP, Abt PL, Blumberg EA, Goldberg DS: Transplanting hepatitis C-positive kidneys. N Engl J Med 373: 303–305, 2015 PubMed 45. Huprikar S, Danziger-Isakov L, Ahn J, Naugler S, Blumberg E, Avery RK, Koval C, Lease ED, Pillai A, Doucette KE, Levitsky J, Morris MI, Lu K, McDermott JK, Mone T, Orlowski JP, Dadhania DM, Abbott K, Horslen S, Laskin BL, Mougdil A, Venkat VL, Korenblat K, Kumar V, Grossi P, Bloom RD, Brown K, Kotton CN, Kumar D: Solid organ transplantation from hepatitis B virus-positive donors: Consensus guidelines for recipient management. Am J Transplant 15: 1162– 1172, 2015 PubMed Malignancy and Kidney Transplantation There is an increased risk of certain malignancies after kidney transplant compared with in the general 330 Figure 15. Observed cumulative incidence of lung cancer during the first 10 years after renal transplantation. All between-group comparisons were significant by pairwise log rank test (P,0.001). Reprinted with permission from Opelz G, Döhler B: Influence of current and previous smoking on cancer and mortality after kidney transplantation. Transplantation 100: 227–232, 2016. population. Quantifying the excess risk of malignancy specifically due to kidney transplantation and attendant immunosuppression has been challenging. One issue is the difficulty of accurate reporting. When comparing malignancy rates of the Scientific Registry of Transplant Recipients (SRTR) with those of 15 linked cancer registries, only 36.8% of cancers were identified in both sources, with 47.5% additional cases documented only in cancer registries and 15.7% only identified in the SRTR (1). Thus, malignancy data solely utilizing the SRTR are likely an underestimate of the magnitude of the difference. When using linked data, certain malignancies have a clear relationship with transplantation: Kaposi sarcoma, non-Hodgkin lymphoma (NHL), lip cancer, and nonepithelial skin cancer. Others are linked more strongly with renal failure itself (kidney cancer and thyroid cancer) (2). The risk of cancer in retransplanted recipients compared with primary kidney transplant recipients, again using linked databases, is similar, except for renal cell carcinoma (RCC) of the native kidneys (twofold increased risk; adjusted incidence risk ratio [aIRR], 2.03; 95% confidence interval [95% CI], 1.45 to 2.77), perhaps due to increased kidney disease exposure or dialysis time (3). The incidence, clinical consequences, and economic costs of malignancy after transplantation are significant. When segregating malignancies into three types, nonmelanoma skin cancer, viral linked, and other cancers, in 67,157 recipients from Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 2000 to 2011, the incidence of nonmelanoma skin cancer was diagnosed in 5.7%, viral-linked cancer was diagnosed in 1.9%, and other cancers were diagnosed in 6.3%. The mortality risk was more than three times higher in those with viral-linked malignancy compared with individuals who were malignancy free by 3 years. Overall, malignancy accounted for 3%–5.5% of total inpatient Medicare expenditures and 1.5%–3.3% of outpatient expenditures in the first 3 years after transplant (4). A separate analysis described a twofold increased risk of death in transplant recipients after they were diagnosed with de novo cancer compared with in the general population, despite the competing risk of death that transplant recipients face otherwise (5). These data help define the magnitude of the ongoing problem of cancer in the transplant population and support ongoing screening of CKD patients as they pass from phases of ESRD to transplant and back to ESRD. Risk Factors for Malignancy in the Transplant Recipient To define appropriate surveillance strategies, one must first be able to identify potential risk factors in addition to common malignancy patterns. Perhaps the most compelling recent analysis regarding risk factor identification and management comes from a large registry study addressing the risk of smoking and the benefits of smoking cessation. In 45,548 kidney transplant recipients from 1995 to 2012, smoking cessation before transplant led to a significant reduction in frequency of many malignancies, most prominently lung cancer (Figure 15 and Table 3) (6). Persistent smoking was associated with 50% increase in all-cause graft loss, with similar findings for death and death-censored graft loss (P,0.001), whereas those who stopped smoking before transplant had only a modest 10% increase in all-cause graft loss compared with nonsmokers. Thus, smoking cessation should be strongly recommended at the time of transplant evaluation and while on the waiting list. Smoking cessation before transplant is associated with a significant reduction in risk for lung cancer and other virus-associated malignancies after transplant. A history of malignancy or specific types of cancer before transplant may compel heightened screening after Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 331 Table 3. The standardized incidence ratio (SIR; the ratio of the incidence of malignancy in the kidney transplant population to the incidence in the general population) of various malignancy subtypes during the first 10 years after renal transplantation by smoking status ICD10, International statistical classification of diseases and related health problems, 10th revision; CNS, central nervous system. Reprinted with permission from Opelz G, Döhler B: Influence of current and previous smoking on cancer and mortality after kidney transplantation. Transplantation 100: 227–232, 2016. transplant. A recent United States registry analysis showed that pretransplant skin cancer was associated with post-transplant malignancy (PTM) for not only skin cancer (subhazard ratio [SHR], 2.92; 95% CI, 2.52 to 3.39) but also, solid tumors (SHR, 1.44; 95% CI, 1.04 to 1.99) and post-transplant lymphoproliferative disease (PTLD; SHR, 1.93; 95% CI, 1.01 to 3.66) (7). The 5year cumulative incidence of any malignancy in those with pretransplant skin cancer was 31.6% versus 7.4% (P,0.001) in those with no such history. Conversely, an Australian and New Zealand Dialysis and Transplant Registry analysis of prior malignancy history (excluding melanocytic skin cancers) failed to find an association between pretransplant malignancy history and posttransplant recurrence or a second primary malignancy (8). A systematic meta-analysis of solid organ transplant recipients reported an association of pretransplant malignancy (of any type) with all-cause mortality (ten studies, 1.5-fold increased risk), cancer-specific mortality (three studies, threefold increased risk), and post-transplant de novo malignancy (seven studies, twofold increased risk) (9). Perhaps the Australian/New Zealand data are distinctly different from the other analyses due to differences in transplant eligibility criteria or differences in point prevalence of nonmelanoma skin cancer. Regarding risk factors for specific types of PTM, the risk of RCC was specifically studied in a linked registry analysis of kidney transplant recipients from 1987 to 2010 (10). There was a more than fivefold increased risk (standardized incidence ratio, 5.68; 95% CI, 5.27 to 6.13) of RCC, particularly of the papillary subtype, compared with in the general population. Additive risk was noted with blacks, men, increasing dialysis time, and the use of induction therapy but was not noted with specific maintenance immunosuppression regimen. Interestingly, for colon cancer, an increased risk was present in kidney transplant patients treated with cyclosporine and azathioprine but not in those treated with tacrolimus and mycophenolate, suggesting differential effects of immunosuppression on different types of solid tumors (11). The question of which immunosuppression regimen confers the greatest risk (or the least risk) for development of PTM is an ongoing subject of study. Two recent studies implicate azathioprine as a primary offender in the development of skin cancer, but one provocatively acquits mycophenolate use as a risk factor. In a meta-analysis of 27 studies that evaluated the risk of skin cancer in relation to azathioprine treatment, there was a significant risk of squamous cell carcinoma (SCC; hazard ratio [HR], 1.56; 95% CI, 1.11 to 2.18) but not of other types of skin cancers (12). In a second report of solid organ transplant recipients (not limited to kidney transplant), a matched 332 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 Table 4. Association between induction therapy and incident virus–related cancers Malignancy Type NHL No induction Polyclonal Muromonab-CD3 Alemtuzumab Anti-IL2R Non-NHL VRCs No induction Polyclonal Muromonab-CD3 Alemtuzumab Anti-IL2R All VRCs No induction Polyclonal Muromonab-CD3 Alemtuzumab Anti-IL2R P Value Cancers, N Incidencea 377 125 80 15 96 142.1 131.6 210.9 216.2 114.9 0.96 1.37 1.79 0.82 Reference (0.77 to 1.20) (1.06 to 1.76) (1.02 to 3.14) (0.65 to 1.05) 0.70 0.02 0.04 0.10 164 56 25 4 53 61.8 60.0 65.9 57.6 63.5 1.11 1.02 2.05 1.09 Reference (0.82 to 1.53) (0.65 to 1.58) (0.66 to 6.33) (0.78 to 1.51) 0.50 0.90 0.20 0.60 541 181 104 19 149 203.9 190.6 276.8 273.8 178.4 1.01 1.26 1.84 0.90 Reference (0.84 to 1.21) (1.01 to 1.57) (1.11 to 3.03) (0.74 to 1.10) 0.90 0.04 0.02 0.30 aIRR (95% CI) aIRRs for VRCs after kidney transplantation. The number of cancers diagnosed in each stratum is shown (N). VRCs included NHL, Hodgkin lymphoma, human papillomavirusrelated cancers (cancers of the cervix, vagina, vulva, anus, penis, oropharynx, and tonsil), Kaposi sarcoma, and liver cancer. All models were adjusted for recipient age, sex, race, retransplantation, zero HLA mismatch status, receipt of living donor kidney, and year of transplant. Only transplants completed in years with at least 20 recipients receiving the induction therapy of interest were included: polyclonal: 1987–2009; muromonab-CD3: 1987–2003; alemtuzumab: 2001–2009; and anti-IL2R: 1995–2009. Anti-IL2R, anti–IL-2 receptor (daclizumab and basiliximab); VRC, virus-related cancer. Modified from Hall EC, Engels EA, Pfeiffer RM, Segev DL: Association of antibody induction immunosuppression with cancer after kidney transplantation. Transplantation 99: 1051–1057, 2015. a Per 100,000 person-years. control study of 170 affected patients and 324 controls, azathioprine use again was associated with increased risk of SCC (odds ratio, 2.67; 95% CI; 1.23 to 5.76), whereas an inverse relationship was noted with mycophenolate use with or without concomitant use of tacrolimus (approximately 50% reduction in odds ratio) (13). The authors concluded that the excess risk of SCC historically noted with azathioprine is substantially reduced using modern immunosuppressive regimens. Beyond azathioprine use, the association of induction therapy and malignancy risk has remained a question. Using linked registry analyses, aIRRs of NHL, melanoma, and the solid tumors lung, colorectal, kidney, and thyroid cancers were calculated based on use of different types of induction therapy (14). Nondepleting induction agents (IL-2 receptor antagonists) were not associated with a higher aIRR of any malignancy compared with kidney transplant recipients who did not receive induction. Conversely, muromonab-CD3 (OKT3) and alemtuzumab were associated with an increased risk of NHL (aIRR, 1.37; 95% CI, 1.06 to 1.76 and aIRR, 1.79; 95% CI, 1.02 to 3.14, respectively). Polyclonal induction therapies, such as antithymocyte globulin preparations, were associated with an increased risk of melanoma (aIRR, 1.50; 95% CI, 1.06 to 2.14) (Tables 4 and 5). Both thyroid and colorectal cancer, incidence risk ratios were also higher in the cohort treated with alemtuzumab. In general, these data point to the safety of IL-2 receptor antagonists, the lack of increased risk of NHL with polyclonal depleting therapy, and the need for tailored monitoring for other malignancies based on the specific induction agent. Finally, the question of the effects on PTM of mammalian target of rapamycin inhibitors (mTORis) has been further clarified. A large linked registry analysis of cancer registries and national pharmacy claims examined cancer incidence in 32,604 kidney transplant recipients. Non-melanoma skin cancers were excluded from this analysis (15). Overall, cancer incidence was modestly and nonsignificantly lower with sirolimus use (HR, 0.88; 95% CI, 0.70 to 1.11). A second analysis that included skin cancer data from a single-registry analysis from the Collaborative Transplant Study of 78,146 primary deceased donor kidney transplant recipients from 1999 to 2013 showed only a reduction in the incidence of basal cell carcinoma with mTORi (HR, 0.56; P50.004), with no reduction in incidence or risk of any other type of tumor, including 333 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 Table 5. Associations of induction agents with nonvirus-related cancers Malignancy Type P Value Cancers, N Incidencea 297 127 46 7 77 111.9 133.7 121.3 100.9 92.2 1.14 1.03 0.93 0.73 Reference (0.91 to 1.43) (0.75 to 1.41) (0.42 to 2.07) (0.56 to 0.95) 0.20 0.80 0.90 0.02 261 121 34 11 102 98.4 127.4 89.6 158.5 122.1 1.08 0.93 1.20 1.03 Reference (0.85 to 1.38) (0.65 to 1.34) (0.63 to 2.30) (0.81 to 1.32) 0.50 0.70 0.60 0.80 164 60 20 7 47 61.8 63.2 52.7 100.9 56.3 1.14 0.77 2.46 0.88 Reference (0.82 to 1.58) (0.48 to 1.24) (1.03 to 5.91) (0.62 to 1.25) 0.40 0.30 0.04 0.50 103 26 5 10 27 38.8 27.4 131.8 144.1 32.3 0.65 0.32 3.37 0.81 Reference (0.40 to 1.04) (0.12 to 0.80) (1.55 to 7.33) (0.51 to 1.29) 0.07 0.01 0.002 0.40 107 56 11 3 38 68.7 103.4 51.1 81.1 88.1 1.50 0.77 1.14 1.15 Reference (1.06 to 2.14) (0.41 to 1.45) (0.33 to 3.95) (0.77 to 1.72) 0.02 0.40 0.80 0.50 Lung cancer No induction Polyclonal Muromonab-CD3 Alemtuzumab Anti-IL2R Kidney cancer No induction Polyclonal Muromonab-CD3 Alemtuzumab Anti-IL2R Colorectal cancer No induction Polyclonal Muromonab-CD3 Alemtuzumab Anti-IL2R Thyroid cancer No induction Polyclonal Muromonab-CD3 Alemtuzumab Anti-IL2R Melanomab No induction Polyclonal Muromonab-CD3 Alemtuzumab Anti-IL2R aIRR (95% CI) aIRRs for nonvirus-related cancers after kidney transplantation. The number of cancers diagnosed in each stratum is shown (N). All models were adjusted for recipient age, sex, race, retransplantation, zero HLA mismatch status, receipt of living donor kidney, and year of transplant. Only transplants completed in years with at least 20 recipients receiving the induction therapy of interest were included: polyclonal: 1987–2009; muromonab-CD3: 1987–2003; alemtuzumab: 2001–2009; and anti-IL2R: 1995–2009. Anti-IL2R, anti–IL2 receptor (daclizumab and basiliximab). Modified from Hall EC, Engels EA, Pfeiffer RM, Segev DL: Association of antibody induction immunosuppression with cancer after kidney transplantation. Transplantation 99: 1051–1057, 2015. a Per 100,000 person-years. b Among non-Hispanic white kidney recipients. SCC (16). A final large, longitudinal analysis from Australia and New Zealand, where utilization of mTORi has been higher due to its hypothesized potential impact on skin cancer, showed a higher risk of all-cause mortality with mTORi use during a median follow-up of 7 years (17). Taken collectively, the application of mTORi, specifically for its antineoplastic properties in the prevention of PTM, is not supported by existing data. Transplant Candidate Cancer Screening In general, there have been few studies specific to the transplant candidate population to guide whether screening practices for malignancies should be substan- tially different from those used in the general population. For prostate cancer screening, prostate-specific antigen (PSA)–based screening per American Urological Association screening guidelines of 3782 men undergoing transplant evaluation did not lead to improved patient survival after transplant but did increase the time to listing for those with a positive test result (18). Furthermore, those screened had a reduced likelihood of receiving a transplant, regardless of PSA value. Thus, routine PSA screening should be discouraged, because it may create an unnecessary barrier to transplantation. For colon cancer, the findings of 70 patients with ESRD undergoing colonoscopy as a function of 334 kidney transplant evaluation were compared with those from 70 non-ESRD controls matched for age, sex, and endoscopist (19). Adenomatous polyps were present in 54.3% of ESRD subjects versus 32.9% of controls (P,0.01), supporting the practice of colonoscopy screening in the candidate transplant evaluation similar to the general population. Regarding the use of mammography for breast cancer screening, a study of 541 women $40 years old undergoing kidney transplant evaluation from 2006 to 2012 showed that patients ages 40–49 and $50 years old had similar biopsy rates and breast malignancy (20). Although not a cost-effectiveness analysis, these data generally support the American Cancer Society recommendations to start annual mammogram at age 40 years old in transplant candidates rather than the US Preventative Services Task Force recommendation of biennial mammogram beginning at age 50 years old. In cases where breast cancer is identified, genomic profiling may be increasingly possible to identify low-risk cancers and shorten the “disease-free inactive status” that is often 2–5 years long without this information (21). Regarding dermatology clearance in individuals who have had a prior skin cancer, there has been a consensus report from the International Transplant Skin Cancer Collaborative that describes a waiting time construct for each skin cancer subtype based on its staging (22). Using a 60% 5-year post-transplant survival as a threshold for acceptable expected survival post-transplant, the International Transplant Skin Cancer Collaborative advocates for a 2-year waiting time for SCC that is high risk (.2 cm, high-risk location [e.g., ear, lip, scalp, or temple], recurrent lesion, or poorly differentiated), and waiting times of 2 years for melanoma stage Ia, 5 years for stage Ib, and 5–10 years for stages IIa, IIb, and IIIa; patients with stages IIc, IIIb, IIIc, and IV would not be candidates for transplant. Finally, the question of screening for RCC via ultrasound remains controversial. There is clearly an increased risk of RCC in patients with ESRD as described previously. In a surveillance study of 2642 transplant candidates who underwent renal ultrasound at the time of evaluation followed by annual screening (23) 71 RCCs were identified (52 on initial screening), with independent associations with men and black race. Whether this 2%–3% detection rate warrants such a monitoring strategy remains unanswered, and no firm consensus has been adopted across the transplant community. Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 Recipient Screening for Malignancy As in the setting of transplant candidate malignancy screening, perhaps even less has been published specific to screening practices after transplant. A systematic review of the literature identified 13 relevant clinical practice guidelines for all organ transplants, of which eight were specific to kidney transplant recipients (24). The reviewers noted specifically that “there is a lack of direct evidence to support cancer screening recommendations” (24). Recommendations were based primarily on the authors’ interpretations of risk in the context of general population risk rather than evidence in a transplant population, without input from oncology specialists, primary care providers, and public health experts. Despite these limitations, the relationship of immunosuppression and virus-mediated cancers is strong. The appropriate screening for Epstein Barr virus (EBV)–related cancer remains an area of active research. Routine screening for EBV by PCR has been generally ineffective in the prediction of risk for PTLD in the adult kidney transplant population: a positive EBV PCR is insensitive and nonspecific, hindered by the lack of standardized assay or source (i.e., whole blood or plasma) (reviewed in ref. 25). An additional confounder is the increase in the number of cases of EBV-related PTLD over time (from 10% during the period 1990–1995 to 48% of cases during the period 2008–2013 in one large series) (26). Parenthetically, remission rates and survival were found to be similar whether PTLD was EBV1 or EBV–. Although the data supporting EBV PCR screening for PTLD risk have been inconsistent, a positive test may generally predict an overimmunosuppressed state that is associated with a higher malignancy risk in general. In 669 patients screened annually with EBV PCR from whole blood (if positive, repeated on each routine visit), 147 patients had a persistently high EBV viral load (27). Persistent EBV replication was associated with a 70% increase in the risk of post-transplant cancer (of all types) during a mean follow-up of 94 months, with an incidence of cancer of 26.7% in 45 recipients with a persistent PCR of .10,000 copies per 1 ml. These findings are provocative, and a standard of care regarding EBV PCR screening remains undefined. In the absence of screening, prophylactic antiviral treatment of those at high risk (EBV-seronegative recipients of organs from seropositive donors) has been considered a strategy in minimizing risk for PTLD. Unfortunately, a meta-analysis of 31 335 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 studies found no effect of this strategy on the prediction or the incidence of PTLD (28). Cancer Management in the Transplant Recipient A common question in the transplant patient with malignancy is whether altering immunosuppression is safe and/or effective. Regarding the safety of immunosuppression withdrawal during chemotherapy for PTLD, a study of 24 patients investigated immunosuppression cessation during chemotherapy and resumption at lower dose (calcineurin inhibitor at 50%, prednisolone #10 mg daily, no third agent) approximately 6 weeks after chemotherapy (29). Compared with 83 matched controls, no difference was noted in time to $25% increase in serum creatinine. Only one patient with PTLD experienced a $25% increase in serum creatinine within 6 months of withdrawal, which was associated with progressive PTLD and death. This provides some comfort in eliminating immunosuppression for short intervals during periods of aggressive chemotherapy. There are no recent publications addressing immunosuppression reduction/ withdrawal/transition during treatment for solid tumors. Novel therapeutic targets for control of a variety of malignancies include the programmed cell death pathway (programmed cell death protein 1 [PD-1] ligand and its receptor PD-1) and the cytotoxic T lymphocyte–associated antigen-4 (CTLA-4) pathway (CTLA-4 binding to its ligand B7-1/2) (30). PD-1 is expressed on T cells (as well as B cells, and natural killer cells) and binds PD-1 ligand expressed by tumor cells. This ligand binding leads to T cell exhaustion, creating a state of immunosuppression. Like the PD-1 pathway, CTLA-4 is expressed on T cells, and ligand binding leads to T cell exhaustion. Two mAbs to PD-1, nivolumab and pembrolizumab, inhibit T cell exhaustion and increase tumor surveillance. These agents have shown efficacy in advanced melanoma and nonsmall cell lung cancer, and they are under investigation in multiple other tumor types. In transplant recipients (kidney and other organs), these agents have been associated with a near-universal incidence of rejection, often leading to dialysis dependence in the kidney transplant setting (31, 32). The mAb ipilimumab binds and inhibits this CTLA4–induced T cell suppression. Although effective in preventing tumor progression in metastatic disease, rejection has not been reported in solid organ transplant recipients treated with ipilimumab. A recent review of case reports was published describing 15 cases (in kidney and liver transplants) using ipilimumab, nivolumab, and pembrolizumab, with no allograft rejection with ipilimumab (but potentially lesser antitumor effect [33] than the PD-1 mAbs [34]). Checkpoint inhibitors targeting PD-1 (nivolumab and pembrolizumab) and CTLA4 (ipilimumab) are used to treat metastatic malignancies. These agents restore T cell function; PD-1 inhibition can place the transplant at very high risk for rejection. References 1. Yanik EL, Nogueira LM, Koch L, Copeland G, Lynch CF, Pawlish KS, Finch JL, Kahn AR, Hernandez BY, Segev DL, Pfeiffer RM, Snyder JJ, Kasiske BL, Engels EA: Comparison of cancer diagnoses between the US solid organ transplant registry and linked central cancer registries. Am J Transplant 16: 2986–2993, 2016 PubMed 2. Yanik EL, Clarke CA, Snyder JJ, Pfeiffer RM, Engels EA: Variation in cancer incidence among patients with ESRD during kidney function and nonfunction intervals. J Am Soc Nephrol 27: 1495–1504, 2016 PubMed 3. Kalil RS, Lynch CF, Engels EA: Risk of cancer in retransplants compared to primary kidney transplants in the United States. Clin Transplant 29: 944–950, 2015 PubMed 4. Dharnidharka VR, Naik AS, Axelrod D, Schnitzler MA, Xiao H, Brennan DC, Segev DL, Randall H, Chen J, Kasiske B, Lentine KL: Clinical and economic consequences of early cancer after kidney transplantation in contemporary practice. Transplantation 101: 858– 866, 2017 PubMed 5. Acuna SA, Fernandes KA, Daly C, Hicks LK, Sutradhar R, Kim SJ, Baxter NN: Cancer mortality among recipients of solid-organ transplantation in Ontario, Canada. JAMA Oncol 2: 463–469, 2016 PubMed 6. Opelz G, Döhler B: Influence of current and previous smoking on cancer and mortality after kidney transplantation. Transplantation 100: 227–232, 2016 PubMed 7. Kang W, Sampaio MS, Huang E, Bunnapradist S: Association of pretransplant skin cancer with posttransplant malignancy, graft failure and death in kidney transplant recipients. Transplantation 101: 1303– 1309, 2017 PubMed 8. Viecelli AK, Lim WH, Macaskill P, Chapman JR, Craig JC, Clayton P, Cohney S, Carroll R, Wong G: Cancer-specific and all-cause mortality in kidney transplant recipients with and without previous cancer. Transplantation 99: 2586–2592, 2015 PubMed 9. Acuna SA, Huang JW, Daly C, Shah PS, Kim SJ, Baxter NN: Outcomes of solid organ transplant recipients with preexisting malignancies in remission: A systematic review and meta-analysis. Transplantation 101: 471–481, 2017 PubMed 10. Karami S, Yanik EL, Moore LE, Pfeiffer RM, Copeland G, Gonsalves L, Hernandez BY, Lynch CF, Pawlish K, Engels EA: Risk of renal cell carcinoma among kidney transplant recipients in the United States. Am J Transplant 16: 3479–3489, 2016 PubMed 11. Safaeian M, Robbins HA, Berndt SI, Lynch CF, Fraumeni JF Jr., Engels EA: Risk of colorectal cancer after solid organ transplantation in the United States. Am J Transplant 16: 960–967, 2016 PubMed 12. Jiyad Z, Olsen CM, Burke MT, Isbel NM, Green AC: Azathioprine and risk of skin cancer in organ transplant recipients: Systematic review and meta-analysis. Am J Transplant 16: 3490–3503, 2016 PubMed 13. Coghill AE, Johnson LG, Berg D, Resler AJ, Leca N, Madeleine MM: Immunosuppressive medications and squamous cell skin carcinoma: 336 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 Nested case-control study within the Skin Cancer after Organ Transplant (SCOT) Cohort. Am J Transplant 16: 565–573, 2016 PubMed Hall EC, Engels EA, Pfeiffer RM, Segev DL: Association of antibody induction immunosuppression with cancer after kidney transplantation. Transplantation 99: 1051–1057, 2015 PubMed Yanik EL, Gustafson SK, Kasiske BL, Israni AK, Snyder JJ, Hess GP, Engels EA, Segev DL: Sirolimus use and cancer incidence among US kidney transplant recipients. Am J Transplant 15: 129–136, 2015 PubMed Opelz G, Unterrainer C, Süsal C, Döhler B: Immunosuppression with mammalian target of rapamycin inhibitor and incidence of post-transplant cancer in kidney transplant recipients. Nephrol Dial Transplant 31: 1360– 1367, 2016 PubMed Badve SV, Pascoe EM, Burke M, Clayton PA, Campbell SB, Hawley CM, Lim WH, McDonald SP, Wong G, Johnson DW: Mammalian target of rapamycin inhibitors and clinical outcomes in adult kidney transplant recipients. Clin J Am Soc Nephrol 11: 1845– 1855, 2016 PubMed Vitiello GA, Sayed BA, Wardenburg M, Perez SD, Keith CG, Canter DJ, Ogan K, Pearson TC, Turgeon N: Utility of prostate cancer screening in kidney transplant candidates. J Am Soc Nephrol 27: 2157–2163, 2016 PubMed Saumoy M, Jesudian AB, Aden B, Serur D, Sundararajan S, Sivananthan G, Gambarin-Gelwan M: High prevalence of colon adenomas in endstage kidney disease patients on hemodialysis undergoing renal transplant evaluation. Clin Transplant 30: 256–262, 2016 PubMed Stoecker JB, Cote DR, Augustine JJ, Sarabu N, Schulak JA, Sanchez EQ, Humphreville VR, Ammori JB, Woodside KJ: Utility of mammography for chronic kidney disease patients undergoing kidney transplant evaluation. Clin Transplant 30: 445–451, 2016 PubMed Mukhtar RA, Piper ML, Freise C, Van’t Veer LJ, Baehner FL, Esserman LJ: The novel application of genomic profiling assays to shorten inactive status for potential kidney transplant recipients with breast cancer. Am J Transplant 17: 292–295, 2017 PubMed Zwald F, Leitenberger J, Zeitouni N, Soon S, Brewer J, Arron S, Bordeaux J, Chung C, Abdelmalek M, Billingsley E, Vidimos A, Stasko T: Recommendations for solid organ transplantation for transplant candidates with a pretransplant diagnosis of cutaneous squamous cell carcinoma, merkel cell carcinoma and melanoma: A consensus opinion from the International Transplant Skin Cancer Collaborative (ITSCC). Am J Transplant 16: 407–413, 2016 PubMed Klein JA, Gonzalez SA, Fischbach BV, Yango AF, Rajagopal A, Rice KM, Saim M, Barri YM, Melton LB, Klintmalm GB, Chandrakantan A: Routine ultrasonography surveillance of native kidneys for renal cell carcinoma in kidney transplant candidates. Clin Transplant 30: 946– 953, 2016 PubMed Acuna SA, Huang JW, Scott AL, Micic S, Daly C, Brezden-Masley C, Kim SJ, Baxter NN: Cancer screening recommendations for solid organ transplant recipients: A systematic review of clinical practice guidelines. Am J Transplant 17: 103–114, 2017 PubMed Dharnidharka VR: Peripheral blood epstein-barr viral nucleic acid surveillance as a marker for posttransplant cancer risk. Am J Transplant 17: 611–616, 2017 PubMed Luskin MR, Heil DS, Tan KS, Choi S, Stadtmauer EA, Schuster SJ, Porter DL, Vonderheide RH, Bagg A, Heitjan DF, Tsai DE, Reshef R: The impact of EBV status on characteristics and outcomes of posttransplantation lymphoproliferative disorder. Am J Transplant 15: 2665–2673, 2015 PubMed Bamoulid J, Courivaud C, Coaquette A, Crépin T, Carron C, Gaiffe E, Roubiou C, Rebibou JM, Ducloux D: Late persistent positive EBV viral load and risk of solid cancer in kidney transplant patients. Transplantation 101: 1473–1478, 2017 PubMed AlDabbagh MA, Gitman MR, Kumar D, Humar A, Rotstein C, Husain S: The role of antiviral prophylaxis for the prevention of epstein-barr virus-associated posttransplant lymphoproliferative disease in solid 29. 30. 31. 32. 33. 34. organ transplant recipients: A systematic review. Am J Transplant 17: 770–781, 2017 PubMed Taylor E, Jones M, Hourigan MJ, Johnson DW, Gill DS, Isbel N, Hawley CM, Marlton P, Gandhi MK, Campbell SB, Mollee P: Cessation of immunosuppression during chemotherapy for post-transplant lymphoproliferative disorders in renal transplant patients. Nephrol Dial Transplant 30: 1774–1779, 2015 PubMed Postow MA, Callahan MK, Wolchok JD: Immune checkpoint blockade in cancer therapy. J Clin Oncol 33: 1974–1982, 2015 PubMed Lipson EJ, Bagnasco SM, Moore J Jr., Jang S, Patel MJ, Zachary AA, Pardoll DM, Taube JM, Drake CG: Tumor regression and allograft rejection after administration of anti-PD-1. N Engl J Med 374: 896–898, 2016 PubMed Boils CL, Aljadir DN, Cantafio AW: Use of the PD-1 pathway inhibitor nivolumab in a renal transplant patient with malignancy. Am J Transplant 16: 2496–2497, 2016 PubMed Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators: Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 372: 2521–2532, 2015 PubMed Maggiore U, Pascual J: The bad and the good news on cancer immunotherapy: Implications for organ transplant recipients. Adv Chronic Kidney Dis 23: 312–316, 2016 PubMed Cardiovascular Disease Pretransplant Screening There is ongoing debate regarding the utility of testing for ischemic heart disease for risk stratification purposes in potential kidney transplant candidates. An updated meta-analysis of a total of 52 cohort and randomized, controlled studies that included 7401 participants evaluated major adverse cardiac events and cardiovascular and all-cause mortality after transplant after undergoing a preoperative cardiac screening test (1). Cardiac screening tests were either noninvasive (segregated by dobutamine stress echocardiography or myocardial perfusion scintigraphy) or invasive (angiography). The authors determined that the prognostic value of an abnormal noninvasive test was similar to that of abnormal coronary angiography for predicting cardiovascular mortality and major adverse cardiac events, with a trend suggesting lower all-cause mortality in the cohort screened by angiography. Based on these findings, the authors suggested that initial investigation using coronary angiography is not indicated in the absence of a conventional indication, and they did not find superiority of one noninvasive test over another. Disappointingly, even in large meta-analyses, such as this one, large numbers of patients with negative test results still have adverse cardiac outcomes, and large numbers of patients with abnormal test results do not have adverse cardiac outcomes; thus, the answer to the Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 question of whether any testing should be routinely performed remains unanswered. Regarding this latter point, the reader is referred to a review of the evidence for screening for cardiovascular disease in kidney transplant candidates (2). Despite this ongoing debate, it is heartening to note that, even with increasing rates of transplant of higher-risk candidates (older with more cardiovascular events before transplant), one regional Canadian study described that the risk of death or major cardiovascular event post-transplant has remained stable over time when comparing 3-year outcomes in a recent era (2006–2009) with those from a prior era (1994–1997) (3). Hypertension Although renin-angiotensin-aldosterone system (RAAS) blockade is a cornerstone of antihypertensive management in the CKD population, the nephroprotective benefits have not been shown in the kidney transplant population. Recently, a large, single-center series; a multicenter, randomized clinical trial; and a meta-analysis have been published that frame the issues surrounding RAAS use after kidney transplantation. In the single-center series, 2684 primary kidney transplant recipients from 1994 to 2010 with a functioning graft at 6 months were retrospectively evaluated for RAAS agent use or nonuse in a time-dependent analysis, and the outcomes of mortality and graft loss were assessed (4). A total of 638 graft failures occurred at a mean of 5.4 years post-transplant. RAAS blockade was associated with a statistically significant 37% reduction in hazard for overall graft loss (adjusted hazard ratio [aHR], 0.63; 95% CI, 0.53 to 0.75), a 31% reduction in hazard for death (aHR, 0.69; 95% CI, 0.55 to 0.86), and a 38% reduction in death-censored graft failure (aHR, 0.62; 95% CI, 0.49 to 0.78). Conversely, a double-blind, placebo-controlled, randomized trial (the first in kidney transplant recipients to investigate RAAS blockade) was conducted at 14 centers and enrolled 213 patients .3 months post-transplant who had eGFR$20 ml/min per 1.73 m2 and proteinuria $200 mg/24 h in a 1:1 ratio to receive placebo versus ramipril 5 mg twice daily (5). Ramipril did not reduce the primary end point, a composite of doubling serum creatinine, ESRD, or death. Despite .4 years of follow-up, the absolute difference between the groups was only 0.5% (Figure 16). Finally, a meta-analysis of eight randomized, controlled trials (1502 participants) with .1 year of follow-up failed to show reductions in risk of death (risk ratio [RR], 0.96; 95% CI, 0.62 to 337 1.51), transplant failure (RR, 0.76; 95% CI, 0.49 to 1.18), or creatinine level doubling (RR, 0.84; 95% CI, 0.51 to 1.39) compared with in the control group, with a more than twofold greater risk of hyperkalemia using RAAS agents (6). The small n in the case of the randomized trial, the uncontrolled nature of the single-center trial, and the meta-analysis inclusion of studies with generally short follow-up summarize the difficulties in proving (or disproving) benefit of RAAS agents in kidney transplant recipients. It has been estimated that it would require a study of over 10,000 subjects to determine if graft failure was impacted by RAAS inhibition, a very unlikely circumstance. A thoughtful editorial of the Lancet Trial concludes that, although RAAS blockade is unlikely to show a benefit in hard end points, there are no data to suggest avoiding RAAS inhibitors (7). A recently published expert review also concludes that no specific antihypertensive medication has been proven to be more efficacious than others in reducing mortality or preventing graft loss (8). As an aside, sodium restriction remains important in the efficacy of RAAS blockade in transplant recipients as shown in a series of 22 subjects treated with RAAS blockers whose systolic BP declined from a mean of 140614 to 129612 mmHg and diastolic BP declined from 8668 to 7968 mmHg Figure 16. Ramipril versus placebo after kidney transplantation. Time to the primary outcome of doubling serum creatinine, ESRD, or death during the extension phase of the study. Reprinted with permission from Knoll GA, Fergusson D, Chassé M, Hebert P, Wells G, Tibbles LA, Treleaven D, Holland D, White C, Muirhead N, Cantarovich M, Paquet M, Kiberd B, Gourishankar S, Shapiro J, Prasad R, Cole E, Pilmore H, Cronin V, Hogan D, Ramsay T, Gill J: Ramipril versus placebo in kidney transplant patients with proteinuria: A multicentre, double-blind, randomised controlled trial. Lancet Diabetes Endocrinol 4: 318–326, 2016. 338 after initiation of a low-sodium diet (total daily sodium intake change from164650 mmol/24 h during the regular sodium diet to 87655 mmol/24 h) (9). Post-Transplant Diabetes Mellitus Post-transplant diabetes mellitus (PTDM) remains an often-encountered clinical syndrome with strong associations for patient and graft survival. Multiple definitions and multiple risk factors clearly play a role in the frequency of diagnosis of PTDM. Regarding the incidence of PTDM, perhaps the best point of reference is a randomized, controlled trial of 1083 patients using the most objective definitions of diabetes (the American Diabetes Association definitions of hemoglobin A1c $6.5%, fasting blood glucose $7.0 mmol/L ($126 mg/dl), 2-hour plasma glucose $11.1 mmol/L ($200 mg/dl) during an oral glucose tolerance test, or symptomatic hyperglycemia and a random plasma glucose $11.1 mmol/L) and examining a low-risk population using tacrolimus-containing regimens (rapid corticosteroid withdrawal [CSWD], predominantly white, and mean body mass index [BMI] of 25 kg/m2) that reported an incidence of PTDM of approximately 17% 24 weeks post-transplant (10). Identification of risk factors for PTDM may facilitate mitigation of its development and/or severity. In a single-center study of 672 patients without preexisting diabetes, 32% developed PTDM (11). A bimodal incidence (#3 months and .3 months post-transplant) was identified, in which 31% of early PTDM reverted, and a normal oral glucose tolerance test and normal hemoglobin A1c at 3 months predicted a low risk (4% incidence) of later-onset PTDM. Obesity was strongly associated with PTDM, but tacrolimus levels were not. In a separate series of 150 patients, visceral adipose tissue content measured via dual energy X-ray absorptiometry scans was the strongest predictor of PTDM 1 year after transplant (12). In another series in which 102 of 481 (22.5%) patients developed PTDM, with mean follow-up of 57 months post-transplant, obesity (BMI$25 kg/m2) was the strongest predictor of PTDM followed by planned maintenance with sirolimus, nonwhite recipient status, and older recipient age (13). A novel risk factor for PTDM, hypomagnesemia, was reported in a retrospective series of 948 recipients (14). A serum magnesium of ,0.74 mmol/L at 1 month post-transplant (1.8 mg/dl) was significantly associated with increased risk of PTDM (hazard ratio [HR], 1.58; 95% CI, 1.07 to 2.34; P50.02) and also associated with PTDM using Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 a time-varying model (HR, 1.78; 95% CI, 1.29 to 2.45; P,0.001) and a rolling average model (HR, 1.83; 95% CI, 1.30 to 2.57; P50.001). The authors conjecture that the risk of PTDM imparted by hypomagnesemia is due to alterations in cellular transport of glucose and/or reduced b cell secretion of insulin. Interventional trials are needed to determine if this association can be remedied with magnesium supplementation. Finally, an ongoing concern is the role of chronic corticosteroids in the development of PTDM. In a recent report stemming from a 5-year double-blind study comparing early CSWD with corticosteroid maintenance tapered to 5 mg/d (CCS) from 6 months onward, no difference in PTDM rates was noted: 36.3% of CCS patients versus 35.9% of CSWD patients were diagnosed with PTDM by 5 years. Notably, insulin therapy was more prevalent in the CCS cohort versus CSWD (11.6% versus 3.7%; P50.05) (15). Thus, traditional risk factors (obesity) and nontraditional risk factors (hypomagnesemia) may help predict PTDM, whereas immunosuppression-related risk factors (lowdose corticosteroids and tacrolimus dose/trough concentrations) may be less valuable. Hyperlipidemia As reviewed in the last Nephrology Self-Assessment Program, the Kidney Disease Improving Global Outcomes Clinical Practice Guideline for Lipid Management in CKD states that “in adult kidney transplant recipients, we suggest treatment with a statin,” implying that all kidney transplant patients may derive benefit from therapy, regardless of lipid profile (grade 2B evidence) (16, 17). A recent provocative study evaluated HDL cholesterol (HDL-C) function and its association with cardiovascular and graft outcomes. HDL-C is thought to protect from the development of atherosclerosis in part due to its role in removal of cholesterol from macrophage foam cells (cholesterol efflux) (18). In a prospective study, 495 stable kidney transplant recipients underwent assessment of macrophage cholesterol efflux capacity and were followed for a mean of 7.0 years. When examined by tertile, cholesterol efflux capacity was independently associated with increased long-term kidney allograft survival. Interestingly, it was not associated with cardiovascular outcomes or mortality. The association with graft survival was independent of serum HDL-C levels, suggesting a novel potential therapeutic target for the prevention of graft failure may be to increase HDL-C function rather than quantity. Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 Obesity Although obesity is not a traditional cardiovascular risk factor, its association with PTDM, and its frequent consideration for transplant candidacy justifies discussion as a separate cardiovascular risk factor in kidney transplantation. Recently published trials continue to show the survival advantage of transplantation versus remaining on dialysis in obese candidates but with greater clarity regarding risks. Using the United Kingdom renal and transplant registry data from 2004 to 2010, 1- and 5-year survival rates after transplant were superior to those of waitlisted candidates in all BMI subgroups, including BMI535–40 and .40 kg/m2 (19). Further comparisons of obese with nonobese transplant recipients (BMI518.5–25 kg/m2) showed no differences in mortality with increasing BMI. However, conclusions regarding the latter subgroups are difficult to extrapolate, because only 540 of the 13,526 total patients available for analysis had BMI.35 kg/m2. Using statistical methodology to control for the competing risk of death, a United States registry analysis of 108,654 primary kidney transplant recipients from 2001–2009 showed worse graft survival with increasing BMI (20). With BMI518.5–25 kg/m2 as the reference, the sub-HRs were 1.15 for 30–35 kg/m2 (P,0.001), 1.21 for 35–40 kg/m2 (P,0.001), and 1.13 for .40 kg/m2 (P50.002). A meta-analysis that did not account for the competing risk of death similarly found an increased risk of death-censored graft loss (HR, 1.06; 95% CI, 1.01 to 1.12), an increased likelihood of delayed graft function (DGF; odds ratio, 1.68; 95% CI, 1.39 to 2.03), and no significant difference in mortality risk in obese recipients (defined as BMI$30 kg/m2; HR, 1.24; 95% CI, 0.90 to 1.70) (21). Taken together, kidney transplant can be considered effective therapy from the obese patient’s perspective compared with dialysis, but there are higher risks of morbidity (DGF and graft loss) than in nonobese transplant recipients that transplant programs must reconcile. This additive risk noted in obese patients has prompted transplant centers to explore surgical options to optimize outcomes. In one series, laparoscopic sleeve gastrectomy was performed in 52 renal transplant candidates with a mean BMI of 43.0 kg/m2 (range, 35.8– 67.7 kg/m2), with 29 achieving goal BMI of ,35 kg/m2 at a mean of 92 days (range, 13–420 days) and six undergoing successful transplant (22). A single-center series used minimally invasive robotic surgery in 67 living donor kidney transplants for patients with BMI$40 kg/m2 339 to minimize the substantial risk of wound complications known to occur in this patient segment (23). There were no graft losses due to graft thrombosis or infection. The authors compared their outcomes with registry data (a total of 612 living donor transplants in recipients with BMI$40 kg/m2 were performed during the period 2009–2014) and found similar rates of DGF and equivalent graft function and patient survival. However, 2% of morbidly obese recipients who underwent the open technique had graft loss due to infection or graft thrombosis. Perhaps expansion of these surgical approaches will lead to a greater comfort in evaluating and transplanting the obese transplant candidate. Nontraditional and Novel Cardiovascular Risk Factors under Investigation Structural Parameters. Left ventricular (LV) hypertrophy has been described as a risk factor for poor cardiovascular and renal outcomes in patients with stages 2–5 native CKD (24). After transplant, LV mass index and left atrial volume index often improve coincident with improvement in LV ejection fraction (25). In a long-term follow-up study of 100 patients from two randomized, controlled trials (mean of 8.4 years of follow-up), LV hypertrophy regression was significantly associated with reduction in risk for cardiovascular events and mortality, and it was associated with higher GFR (26). Beyond echocardiographic parameters, aortic stiffness has also been proposed as a cardiovascular risk predictor. A recent study of 1497 kidney transplant recipients evaluated aortic stiffness measured by carotid-femoral pulse wave velocity (PWV) 8 weeks after transplant, with median follow-up of 4.2 years (27). For every 1-m/s increase in PWV up to 12 m/s, an increase in mortality risk was identified (HR, 1.36; 95% CI, 1.14 to 1.62; P50.001). Each interquartile range increase was similar in magnitude for risk of death as an age increase of 20 years. Thus, structural assessments of LV hypertrophy and PWV may provide greater opportunity for post-transplant risk stratification, and intervention strategies with LV hypertrophy and PWV regression as surrogate or primary end points should be considered. Biochemical Markers. Substudies of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial have examined serum and urinary markers as potential indicators of cardiovascular outcomes. In a population of 1131 participants enriched for adverse events from the overall cohort of 4110 340 participants, combined elevations of B-type natriuretic peptide and cardiac troponin I exceeding clinical cutoffs were associated with future cardiovascular adverse events (HR, 6.3; 95% CI, 2.7 to 15.0). For kidney graft loss, the HR was 8.8 (95% CI, 3.4 to 23.1) (28). A separate post hoc study evaluated urine neutrophil gelatinase–associated lipocalin, kidney injury molecule1, IL-18, and liver-type fatty acid binding protein as potential biomarkers for adverse events (29). The urine neutrophil gelatinase–associated lipocalin-to-creatinine ratio was strongly and independently associated with all three end points of mortality, graft loss, and cardiovascular events. Urine kidney injury molecule-1–to-creatinine and IL-18–to-creatinine ratios were only independently associated with greater mortality risk. Beyond these exploratory biomarkers, another novel serum assay predictive of cardiovascular end points was recently reported, a measure of vascular calcification propensity referred to as T50. T50 represents the time point of the half-maximal generation of secondary calciprotein particles from primary calciprotein particles, and is a reflection of the capacity of serum to inhibit the amorphousto-crystalline transformation of calcium phosphate. In 1455 kidney transplant recipients, T50 measured at 10 weeks post-transplant was associated with all-cause mortality, with low (faster) versus high (slower) T50 quartile (HR, 1.60; 95% CI, 1.00 to 2.57) and cardiac mortality (HR, 3.60; 95% CI, 1.10 to 11.83) (30). These findings were replicated in a longitudinal cohort of 699 patients with a median follow-up of 3.1 years, in which lower T50 values were independently associated with increased all-cause mortality and increased cardiovascular mortality, independent of age, sex, eGFR, or other Framingham risk factors (31). Standardization of test characteristics and replication of these findings are warranted in the future. Clinical Features. Clinical assessments of BP at the extremes in the transplant candidate may predict kidney allograft outcomes. Midodrine, often used for symptomatic hypotension in the chronic dialysis setting, was evaluated as a risk factor for post-transplant outcomes by linking prescription use 1 year before transplant to 3-month and 1-year outcomes post-transplant (32). DGF was much more common in the midodrine cohort (32% versus 19%; P,0.05). More remarkably, at 3 months, graft failure (5% versus 2%), death (4% versus 1%), and acute myocardial infarction and cardiac arrest (all P,0.05) were more common in the midodrine cohort. In the latter, the 3-month death-censored graft failure aHR was 2.0 (95% Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 CI, 1.18 to 3.39), and the death aHR was 3.49 (95% CI, 1.95 to 6.24). These differential rates of mortality and graft loss persisted at 1 year and are clinically meaningful given modern transplant success rates (Figure 17). Conversely, severe hypertension before transplant may not associate with poor transplant outcomes. In a single-center study comparing recipients with severe preoperative hypertension, defined as systolic BP .180 mmHg or diastolic BP .110 mmHg (n5111), with those without severe hypertension (n598), there were no differences in cardiac events, patient or graft survival, or postoperative complications, such as DGF, length of stay, or nadir of serum creatinine (33). Midodrine use before transplant was recently identified as a risk factor for delayed graft function, early graft loss, and death after transplant. Interventions and Outcomes Applying cardioprotective principles garnered from the general and high-risk populations to the transplant population has been a challenge. For example, aspirin use as primary cardiovascular prevention in kidney transplant recipients with hyperhomocysteinemia was assessed in a post hoc analysis of 981 aspirin users versus a matched cohort of 981 nonusers in the FAVORIT Trial (34). After 4 years of follow-up, no differences in risk for cardiovascular disease events, all-cause mortality, kidney failure, composite of kidney failure or mortality, or composite of primary cardiovascular disease events or mortality were noted with aspirin use. Thus, there is no evidence that supports its use in primary prevention. Conversely, the survival advantage of drug-eluting stents (DESs) versus bare metal stents (BMS) for percutaneous coronary intervention in the high-risk general population was mirrored in a retrospective study of kidney transplant recipients (35). Using propensity score– matched registry data, 3245 kidney transplant recipients underwent percutaneous coronary intervention, in whom a 20% lower risk of death and 14% lower risk of death, myocardial infarction, or repeat revascularization at 3 years of follow-up were noted with DES versus BMS. Similarly, patency after endovascular intervention of transplant renal artery stenosis was 341 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 9. 10. Figure 17. Incidence of complications at 3 and 12 months posttransplant according to pretransplant midodrine use. AMI, acute myocardial infarction. Reprinted with permission from Alhamad T, Brennan DC, Brifkani Z, Xiao H, Schnitzler MA, Dharnidharka VR, Axelrod D, Segev DL, Lentine KL: Pretransplant midodrine use: A newly identified risk marker for complications after kidney transplantation. Transplantation 100: 1086–1093, 2016. 11. 12. shown to be superior with DES versus BMS, and both were superior to percutaneous transluminal angioplasty alone in a trial of 45 patients who underwent a total of 50 primary endovascular interventions (DES, 18; BMS, 26; percutaneous transluminal angioplasty, six) (36). 13. 14. References 1. Wang LW, Masson P, Turner RM, Lord SW, Baines LA, Craig JC, Webster AC: Prognostic value of cardiac tests in potential kidney transplant recipients: A systematic review. Transplantation 99: 731– 745, 2015 PubMed 2. Hart A, Weir MR, Kasiske BL: Cardiovascular risk assessment in kidney transplantation. Kidney Int 87: 527–534, 2015 PubMed 3. Lam NN, Kim SJ, Knoll GA, McArthur E, Lentine KL, Naylor KL, Li AH, Shariff SZ, Ribic CM, Garg AX: The risk of cardiovascular disease is not increasing over time despite aging and higher comorbidity burden of kidney transplant recipients. Transplantation 101: 588–596, 2017 PubMed 4. Shin JI, Palta M, Djamali A, Kaufman DB, Astor BC: The association between renin-angiotensin system blockade and long-term outcomes in renal transplant recipients: The Wisconsin Allograft Recipient Database (WisARD). Transplantation 100: 1541–1549, 2016 PubMed 5. Knoll GA, Fergusson D, Chassé M, Hebert P, Wells G, Tibbles LA, Treleaven D, Holland D, White C, Muirhead N, Cantarovich M, Paquet M, Kiberd B, Gourishankar S, Shapiro J, Prasad R, Cole E, Pilmore H, Cronin V, Hogan D, Ramsay T, Gill J: Ramipril versus placebo in kidney transplant patients with proteinuria: A multicentre, double-blind, randomised controlled trial. Lancet Diabetes Endocrinol 4: 318–326, 2016 PubMed 6. Hiremath S, Fergusson DA, Fergusson N, Bennett A, Knoll GA: Reninangiotensin system blockade and long-term clinical outcomes in kidney transplant recipients: A meta-analysis of randomized controlled trials. Am J Kidney Dis 69: 78–86, 2017 PubMed 7. Cross NB, Webster AC: Angiotensin-converting enzyme inhibitorsbeneficial effects seen in many patient groups may not extend to kidney transplant recipients. Transplantation 100: 472–473, 2016 PubMed 8. Weir MR, Burgess ED, Cooper JE, Fenves AZ, Goldsmith D, McKay D, Mehrotra A, Mitsnefes MM, Sica DA, Taler SJ: Assessment and 15. 16. 17. 18. 19. 20. 21. management of hypertension in transplant patients. J Am Soc Nephrol 26: 1248–1260, 2015 PubMed de Vries LV, Dobrowolski LC, van den Bosch JJ, Riphagen IJ, Krediet CT, Bemelman FJ, Bakker SJ, Navis G: Effects of dietary sodium restriction in kidney transplant recipients treated with renin-angiotensinaldosterone system blockade: A randomized clinical trial. Am J Kidney Dis 67: 936–944, 2016 PubMed Mourad G, Glyda M, Albano L, Viklický O, Merville P, Tydén G, Mourad M, Lõhmus A, Witzke O, Christiaans MHL, Brown MW, Undre N, Kazeem G, Kuypers DRJ; Advagraf-based immunosuppression regimen examining new onset diabetes mellitus in kidney transplant recipients (ADVANCE) study investigators: Investigators, Advagraf-based immunosuppression regimen examining new onset diabetes mellitus in kidney transplant recipients study: Incidence of posttransplantation diabetes mellitus in de novo kidney transplant recipients receiving prolonged-release tacrolimus-based immunosuppression with 2 different corticosteroid minimization strategies: ADVANCE, a randomized controlled trial. Transplantation 101: 1924–1934, 2017 PubMed Porrini EL, Díaz JM, Moreso F, Delgado Mallén PI, Silva Torres I, Ibernon M, Bayés-Genís B, Benitez-Ruiz R, Lampreabe I, Lauzurrica R, Osorio JM, Osuna A, Domínguez-Rollán R, Ruiz JC, Jiménez-Sosa A, González-Rinne A, Marrero-Miranda D, Macía M, García J, Torres A: Clinical evolution of post-transplant diabetes mellitus. Nephrol Dial Transplant 31: 495–505, 2016 PubMed von Düring ME, Jenssen T, Bollerslev J, Åsberg A, Godang K, Hartmann A: Visceral fat is strongly associated with post-transplant diabetes mellitus and glucose metabolism 1 year after kidney transplantation. Clin Transplant 31: e12869, 2017 PubMed Gaynor JJ, Ciancio G, Guerra G, Sageshima J, Hanson L, Roth D, Goldstein MJ, Chen L, Kupin W, Mattiazzi A, Tueros L, Flores S, Barba LJ, Lopez A, Rivas J, Ruiz P, Vianna R, Burke GW 3rd: Multivariable risk of developing new onset diabetes after transplantresults from a single-center study of 481 adult, primary kidney transplant recipients. Clin Transplant 29: 301–310, 2015 PubMed Huang JW, Famure O, Li Y, Kim SJ: Hypomagnesemia and the risk of new-onset diabetes mellitus after kidney transplantation. J Am Soc Nephrol 27: 1793–1800, 2016 PubMed Pirsch JD, Henning AK, First MR, Fitzsimmons W, Gaber AO, Reisfield R, Shihab F, Woodle ES: New-onset diabetes after transplantation: Results from a double-blind early corticosteroid withdrawal trial. Am J Transplant 15: 1982–1990, 2015 PubMed Kidney Disease: Improving Global Outcomes Transplant Work Group: KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 9[Suppl 3]: S1–S155, 2009 PubMed Wanner C, Tonelli M; Kidney Disease: Improving Global Outcomes Lipid Guideline Development Work Group Members: KDIGO Clinical Practice Guideline for Lipid Management in CKD: Summary of recommendation statements and clinical approach to the patient. Kidney Int 85: 1303–1309, 2014 PubMed Annema W, Dikkers A, de Boer JF, Dullaart RP, Sanders JS, Bakker SJ, Tietge UJ: HDL cholesterol efflux predicts graft failure in renal transplant recipients. J Am Soc Nephrol 27: 595–603, 2016 PubMed Krishnan N, Higgins R, Short A, Zehnder D, Pitcher D, Hudson A, Raymond NT: Kidney transplantation significantly improves patient and graft survival irrespective of BMI: A cohort study. Am J Transplant 15: 2378–2386, 2015 PubMed Naik AS, Sakhuja A, Cibrik DM, Ojo AO, Samaniego-Picota MD, Lentine KL: The impact of obesity on allograft failure after kidney transplantation: A competing risks analysis. Transplantation 100: 1963–1969, 2016 PubMed Hill CJ, Courtney AE, Cardwell CR, Maxwell AP, Lucarelli G, Veroux M, Furriel F, Cannon RM, Hoogeveen EK, Doshi M, McCaughan JA: Recipient obesity and outcomes after kidney transplantation: A systematic review and meta-analysis. Nephrol Dial Transplant 30: 1403– 1411, 2015 PubMed 342 22. Freeman CM, Woodle ES, Shi J, Alexander JW, Leggett PL, Shah SA, Paterno F, Cuffy MC, Govil A, Mogilishetty G, Alloway RR, Hanseman D, Cardi M, Diwan TS: Addressing morbid obesity as a barrier to renal transplantation with laparoscopic sleeve gastrectomy. Am J Transplant 15: 1360–1368, 2015 PubMed 23. Garcia-Roca R, Garcia-Aroz S, Tzvetanov I, Jeon H, Oberholzer J, Benedetti E: Single center experience with robotic kidney transplantation for recipients with BMI of 40 kg/m2 or greater: A comparison with the UNOS registry. Transplantation 101: 191–196, 2017 PubMed 24. Paoletti E, De Nicola L, Gabbai FB, Chiodini P, Ravera M, Pieracci L, Marre S, Cassottana P, Lucà S, Vettoretti S, Borrelli S, Conte G, Minutolo R: Associations of left ventricular hypertrophy and geometry with adverse outcomes in patients with CKD and hypertension. Clin J Am Soc Nephrol 11: 271–279, 2016 PubMed 25. Kensinger C, Hernandez A, Bian A, Fairchild M, Chen G, Lipworth L, Ikizler TA, Birdwell KA: Longitudinal assessment of cardiac morphology and function following kidney transplantation [published online ahead of print January, 2017]. Clin Transplant doi:10.1111/ctr. 12864PubMed 26. Paoletti E, Bellino D, Signori A, Pieracci L, Marsano L, Russo R, Massarino F, Ravera M, Fontana I, Carta A, Cassottana P, Garibotto G: Regression of asymptomatic cardiomyopathy and clinical outcome of renal transplant recipients: A long-term prospective cohort study. Nephrol Dial Transplant 31: 1168–1174, 2016 PubMed 27. Dahle DO, Eide IA, Åsberg A, Leivestad T, Holdaas H, Jenssen TG, Fagerland MW, Pihlstrøm H, Mjøen G, Hartmann A: Aortic stiffness in a mortality risk calculator for kidney transplant recipients. Transplantation 99: 1730–1737, 2015 PubMed 28. Jarolim P, Claggett BL, Conrad MJ, Carpenter MA, Ivanova A, Bostom AG, Kusek JW, Hunsicker LG, Jacques PF, Gravens-Mueller L, Finn P, Solomon SD, Weiner DE, Levey AS, Pfeffer MA: B-type natriuretic peptide and cardiac troponin I are associated with adverse outcomes in stable kidney transplant recipients. Transplantation 101: 182–190, 2017 PubMed 29. Bansal N, Carpenter MA, Weiner DE, Levey AS, Pfeffer M, Kusek JW, Cai J, Hunsicker LG, Park M, Bennett M, Liu KD, Hsu CY: Urine injury biomarkers and risk of adverse outcomes in recipients of prevalent kidney transplants: The Folic Acid for Vascular Outcome Reduction in Transplantation Trial. J Am Soc Nephrol 27: 2109–2121, 2016 PubMed 30. Dahle DO, Åsberg A, Hartmann A, Holdaas H, Bachtler M, Jenssen TG, Dionisi M, Pasch A: Serum calcification propensity is a strong and independent determinant of cardiac and all-cause mortality in kidney transplant recipients. Am J Transplant 16: 204–212, 2016 PubMed 31. Keyzer CA, de Borst MH, van den Berg E, Jahnen-Dechent W, Arampatzis S, Farese S, Bergmann IP, Floege J, Navis G, Bakker SJ, van Goor H, Eisenberger U, Pasch A: Calcification propensity and survival among renal transplant recipients. J Am Soc Nephrol 27: 239– 248, 2016 PubMed 32. Alhamad T, Brennan DC, Brifkani Z, Xiao H, Schnitzler MA, Dharnidharka VR, Axelrod D, Segev DL, Lentine KL: Pretransplant midodrine use: A newly identified risk marker for complications after kidney transplantation. Transplantation 100: 1086–1093, 2016 PubMed 33. Ajaimy M, Lubetzky M, Kamal L, Gupta A, Dunn C, de Boccardo G, Akalin E, Kayler L: Kidney transplantation in patients with severe preoperative hypertension. Clin Transplant 29: 781–785, 2015 PubMed 34. Dad T, Tighiouart H, Joseph A, Bostom A, Carpenter M, Hunsicker L, Kusek JW, Pfeffer M, Levey AS, Weiner DE: Aspirin use and incident cardiovascular disease, kidney failure, and death in stable kidney transplant recipients: A post hoc analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial. Am J Kidney Dis 68: 277–286, 2016 PubMed 35. Lenihan CR, Montez-Rath ME, Winkelmayer WC, Chang TI: Drugeluting stents versus bare metal stents for percutaneous coronary intervention in kidney transplant recipients. Transplantation 101: 851–857, 2017 PubMed Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 36. Biederman DM, Fischman AM, Titano JJ, Kim E, Patel RS, Nowakowski FS, Florman S, Lookstein RA: Tailoring the endovascular management of transplant renal artery stenosis. Am J Transplant 15: 1039–1049, 2015 PubMed Bone and Mineral Disorders Hyperparathyroidism Hyperparathyroidism is commonly recognized after transplant, but the natural history of disease, response to therapy, and long-term ramifications are less well understood. To shed light on the severity and natural history of disordered mineral metabolism after transplant, a multicenter, prospective study cohort of 246 recipients with parathyroid hormone (PTH) levels .65 pg/ml was intensively monitored in the first year post-transplant (1). In those untreated, 86.2% had persistent hyperparathyroidism .65 pg/ml, and 40% had PTH.130 pg/ml at 1 year. In those with persistent hyperparathyroidism, hypercalcemia rates (albumincorrected serum calcium .10.2 mg/dl) peaked at week 8 (48%), decreasing to 25% at 1 year. Similarly, hypophosphatemia (,2.5 mg/dl) rates peaked at week 2 post-transplant (54%) and improved progressively over 1 year. Fibroblast growth factor 23 reached a nadir by the third month post-transplant. This study together with another longitudinal study of 1237 children, in whom hyperparathyroidism was observed in 41% of recipients (2), provide perspectives on the need for and timing of potential interventions in the post-transplant setting. Potential interventions include medical (cinacalcet and paricalcitol) and surgical (subtotal parathyroidectomy) options. A recent randomized, controlled trial compared cinacalcet with parathyroidectomy for 30 patients with hypercalcemia and hyperparathyroidism 6 months or more from time of transplantation (mean, 3.7 years) (3). After 1 year, ten of 15 patients treated with cinacalcet had normal serum calcium levels versus 15 of 15 in the parathyroidectomy arm. The latter group had lower PTH levels and significant increases in femoral neck bone mineral density (BMD). In a separate singlecenter, crossover trial of 43 patients that examined the effect of a 6-month treatment with paricalcitol (1 mg/d for 3 months and uptitrated to 2 mg/d if tolerated), PTH declined during paricalcitol treatment from a mean of 115.6 to 63.3 pg/ml, with vertebral mineral bone density increasing and bone turnover markers decreasing with therapy for 6 months (4). Both a reduction in proteinuria and an increase of serum creatinine were detected during Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 therapy. The latter observation was hypothesized to result from decreased tubular secretion or increased generation of creatinine rather than a true change in GFR. In a separate 3-month study, paricalcitol increased serum fibroblast growth factor 23 levels and slightly increased serum KLOTHO levels, raising the possibility of longer-term benefits from this active vitamin D receptor analogue. This latter point is highlighted by a follow-up study of 1840 transplant recipients recruited in the Lescol in Renal Transplantation Trial with 6–7 years of follow-up (5). Persistent elevation in PTH.65 pg/ml was associated with a 46% (P,0.01) higher risk of death and an 85% higher risk of graft loss (P,0.001). Stepwise PTH elevations were associated with all-cause mortality and graft loss in multivariate analysis. Taken together, these findings support more aggressive monitoring and management of hyperparathyroidism and its effect on mineral metabolism. Osteoporosis The measure of bone integrity in CKD and after transplant often involves noninvasive markers as surrogates for hard end points, such as fracture or bone biopsy data. Although dual energy X-ray absorptiometry is commonly used to determine BMD, other novel methods include the trabecular bone score and the in vivo microindentation measurement that evaluates trabecular microarchitecture and the mechanical properties of bone to predict fracture risk. In 40 kidney transplant recipients, all three modalities were compared with those in 94 healthy controls (6). BMD by dual energy X-ray absorptiometry was lower compared with in controls. Trabecular bone score and bone strength did not differ from controls, despite longstanding kidney transplant status of .10 years. This observation suggests that declines in bone health may not necessarily be a forgone conclusion after transplant. That bone disease is less severe in the current transplantation era compared with prior eras is further supported by three recent studies from different geographic regions. A database analysis examining 21,769 patients transplanted between 2001 and 2013 disclosed a 3.8% incidence of hip fracture: a rate of 1.54/1000 patient-years for hip fracture and a rate of 9.99/1000 patient-years for any fracture. On balance, these contemporary rates are approximately one half of prior reports from earlier eras (7). A Canadian analysis of fracture rates from 4821 kidney transplant recipients from 1994 to 2008 showed a similar 10-year cumulative incidence of hip fracture of 1.7% (8). Additional 343 findings included a 3-year cumulative incidence of nonvertebral fracture of 1.6% (95% confidence interval [95% CI], 1.3% to 2.0%), a rate higher than that in the general population of 0.5% (95% CI, 0.4% to 0.6%; P,0.001), which is only slightly higher than that in the nondialysis CKD population (1.1%; 95% CI, 0.9% to 1.2%; P50.03). This may be due to changes over time in patient management as suggested by a single-center study from France comparing patients transplanted from 2004 to 2006 with a group transplanted from 2009 to 2011 (9). Cinacalcet, vitamin D, and bisphosphonates were used more frequently. Median PTH levels were lower, and vitamin D deficiency declined from 64% to 20%, whereas fracture incidence decreased from 9.1% to 3.1% (P50.05). The incidence of bone fracture post transplantation has declined over time concurrent with increasing use of prophylaxis. Prevention of osteoporosis post-transplant remains an active area of study. A recent meta-analysis of 12 studies evaluating the efficacy of bisphosphonates included 621 patients and described improvements in BMD of 6.0% at the femoral neck and 7.4% at the lumbar spine in those taking bisphosphonates compared with those not taking bisphosphonate. However, this was not associated with a difference in fracture incidence between groups (10). In the general population, treatment of low bone mineral density becomes cost effective when the 10-year probability of hip fracture reaches approximately 3% as assessed by the Fracture Risk Assessment Tool (11). In the post-transplant setting, it is reasonable to consider treatment with bisphosphonates in individuals with suspected osteoporosis when the 10-year probability of hip fracture reaches this threshold in the absence of other contributing factors in the first 12 months after transplant when the eGFR is .30 ml/min per 1.73 m2 (12). Another potential treatment for the prevention of osteoporosis and fractures post-transplant is the receptor activator of NF-kB ligand inhibitor denosumab. An open label, prospective, randomized trial of 90 patients compared two denosumab doses of 60 mg at 2 weeks and 6 months after transplant with no treatment (13). At 12 months, lumbar spine BMD increased by 4.6% in the denosumab group and decreased by 20.5% in the control group (between-group difference, 5.1%; 95% CI, 3.1% to 7.0%; P,0.001), and total 344 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 Table 6. Mean lifetimes up to 10 years for SPK and KA and their differences based on graft loss and death for recipients with ages at transplants from 18 to 55, from 18 to 39, and from 40 to 55 years old Graft loss Age group, Age group, Age group, Death Age group, Age group, Age group, SPK KA Difference between SPK and KA P Value 18–55 y 18–39 y 40–55 y 8.00 (0.05) 7.99 (0.07) 8.00 (0.08) 7.82 (0.09) 7.68 (0.11) 7.93 (0.10) 0.18 (0.09) 0.30 (0.13) 0.08 (0.12) 0.05 0.02 0.52 18–55 y 18–39 y 40–55 y 8.68 (0.04) 8.77 (0.06) 8.59 (0.06) 8.51 (0.07) 8.59 (0.10) 8.40 (0.09) 0.17 (0.08) 0.18 (0.11) 0.19 (0.11) 0.03 0.10 0.08 Numbers in parentheses are SEMs. Modified from Sung RS, Zhang M, Schaubel DE, Shu X, Magee JC: A Reassessment of the Survival Advantage of Simultaneous KidneyPancreas Versus Kidney-Alone Transplantation. Transplantation 99: 1900–1906, 2015. hip BMD increased by 1.9% (95% CI, 0.1% to 3.7%; P50.04) compared with in the control group. Other biochemical measures of bone turnover all significantly decreased with denosumab. The safety of denosumab within this trial was reported separately, with more infections in the denosumab group (n5146) compared with in the control group (n599), primarily driven by a higher incidence of urinary tract infection/cystitis (51 versus 25 episodes in 24 denosumab-treated versus 11 control patients; P,0.01). The frequencies of opportunistic viral infections, pyelonephritis, and urosepsis were not more common (14). The use of bisphosphonates after transplant is associated with improvements in BMD but has not been associated with reduction in risk for fracture. Finally, another potential contributor to the risk for hip fracture after transplant is the frequent use of proton pump inhibitors (PPIs). This specific risk has been described in the general population but until recently, was not reported in the transplant population. A case-control study compared 231 kidney transplant patients with a first hip fracture with 15,575 kidney transplant controls using registry data matched for age, sex, race, and transplant year (15). PPI use and persistence of use in the year before fracture (the index date) were greater in the hip fracture cohort. After multivariable adjustment, the odds ratio of hip fracture with PPI use was 1.39 (95% CI, 1.04 to 1.84), consistent with but not higher than the risk of PPI and fracture noted in the general population (16). References 1. Wolf M, Weir MR, Kopyt N, Mannon RB, Von Visger J, Deng H, Yue S, Vincenti F: A prospective cohort study of mineral metabolism after kidney transplantation. Transplantation 100: 184–193, 2016 PubMed 2. Bonthuis M, Busutti M, van Stralen KJ, Jager KJ, Baiko S, Bakkaloğlu S, Battelino N, Gaydarova M, Gianoglio B, Parvex P, Gomes C, Heaf JG, Podracka L, Kuzmanovska D, Molchanova MS, Pankratenko TE, Papachristou F, Reusz G, Sanahuja MJ, Shroff R, Groothoff JW, Schaefer F, Verrina E: Mineral metabolism in European children living with a renal transplant: A European Society for Paediatric Nephrology/European Renal Association-European Dialysis and Transplant Association Registry Study. Clin J Am Soc Nephrol 10: 767–775, 2015 PubMed 3. Cruzado JM, Moreno P, Torregrosa JV, Taco O, Mast R, Gómez-Vaquero C, Polo C, Revuelta I, Francos J, Torras J, García-Barrasa A, Bestard O, Grinyó JM: A randomized study comparing parathyroidectomy with cinacalcet for treating hypercalcemia in kidney allograft recipients with hyperparathyroidism. J Am Soc Nephrol 27: 2487–2494, 2016 PubMed 4. Trillini M, Cortinovis M, Ruggenenti P, Reyes Loaeza J, Courville K, Ferrer-Siles C, Prandini S, Gaspari F, Cannata A, Villa A, Perna A, Gotti E, Caruso MR, Martinetti D, Remuzzi G, Perico N: Paricalcitol for secondary hyperparathyroidism in renal transplantation. J Am Soc Nephrol 26: 1205–1214, 2015 PubMed 5. Pihlstrøm H, Dahle DO, Mjøen G, Pilz S, März W, Abedini S, Holme I, Fellström B, Jardine AG, Holdaas H: Increased risk of all-cause mortality and renal graft loss in stable renal transplant recipients with hyperparathyroidism. Transplantation 99: 351–359, 2015 PubMed 6. Pérez-Sáez MJ, Herrera S, Prieto-Alhambra D, Nogués X, Vera M, Redondo-Pachón D, Mir M, Güerri R, Crespo M, Díez-Pérez A, Pascual J: Bone density, microarchitecture and tissue quality long-term after kidney transplant. Transplantation 101: 1290–1294, 2017 PubMed 7. Ferro CJ, Arnold J, Bagnall D, Ray D, Sharif A: Fracture risk and mortality post-kidney transplantation. Clin Transplant 29: 1004–1012, 2015 PubMed 8. Naylor KL, Jamal SA, Zou G, McArthur E, Lam NN, Leslie WD, Hodsman AB, Kim SJ, Knoll GA, Fraser LA, Adachi JD, Garg AX: fracture incidence in adult kidney transplant recipients. Transplantation 100: 167–175, 2016 PubMed 9. Perrin P, Kiener C, Javier RM, Braun L, Cognard N, Gautier-Vargas G, Heibel F, Muller C, Olagne J, Moulin B, Ohlmann S: Recent changes in chronic kidney disease-mineral and bone disorders and associated fractures after kidney transplantation. Transplantation 101: 1897–1905, 2017 PubMed 10. Toth-Manikowski SM, Francis JM, Gautam A, Gordon CE: Outcomes of bisphosphonate therapy in kidney transplant recipients: A systematic review and meta-analysis. Clin Transplant 30: 1090–1096, 2016 PubMed 11. Tosteson AN, Melton LJ 3rd, Dawson-Hughes B, Baim S, Favus MJ, Khosla S, Lindsay RL: National Osteoporosis Foundation Guide Committee: Cost-effective osteoporosis treatment thresholds: the United States perspective. Osteoporos Int 19: 437–447, 2008 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 12. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group: KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl 7: 39–40, 2017 PubMed 13. Bonani M, Frey D, Brockmann J, Fehr T, Mueller TF, Saleh L, von Eckardstein A, Graf N, Wüthrich RP: Effect of twice-yearly denosumab on prevention of bone mineral density loss in de novo kidney transplant recipients: A randomized controlled trial. Am J Transplant 16: 1882–1891, 2016 PubMed 14. Bonani M, Frey D, de Rougemont O, Mueller NJ, Mueller TF, Graf N, Wüthrich RP: Infections in de novo kidney transplant recipients treated with the RANKL inhibitor denosumab [published online ahead of print October 28, 2016]. TransplantationPubMed 15. Lenihan CR, Sukumaran Nair S, Vangala C, Ramanathan V, Montez-Rath ME, Winkelmayer WC: Proton pump inhibitor use and risk of hip fracture in kidney transplant recipients. Am J Kidney Dis 69: 595–601, 2017 PubMed 16. Kwok CS, Yeong JK, Loke YK: Meta-analysis: Risk of fractures with acid-suppressing medication. Bone 48: 768–776, 2011 PubMed Multiorgan Transplant Simultaneous Pancreas-Kidney Transplantation Simultaneous pancreas-kidney transplantation (SPK) rates have remained stable over the past 2 years after falling significantly from 2004 to 2013. The number of active new patients on the waiting list fell over 50% from 2004 to 2013 as transplant rates fell 25% during the same period. This decline stabilized with 1160 patients added to the waiting list and 719 SPK transplants performed in 2015 (1). The waiting time to transplant remains significantly shorter for SPK transplants than for deceased donor transplants, with an average estimated waiting time of slightly over 18 months versus .7 years for deceased donor transplant (2). Five-year survival was 89.6% for SPK recipients transplanted in 2010, a steady improvement over time. An ongoing question is the relative advantage of SPK over kidney transplant alone (KA). A recent analysis of 7308 SPK and 4653 KA adult patients with type 1 diabetes transplanted in 1998–2009 simulated a randomized, controlled trial by using propensity score matching and transplant center volume to compare survival rates of SPK versus KA (3). There was a marginal advantage in patient survival (0.17 years) and graft survival (0.18 years) with SPK, findings contrary to previous comparisons (Table 6). The KA cohort was not stratified by donor type (deceased versus living donor), suggesting that the marginal benefit of SPK may disappear if limited to comparison with living donor KA. Benefits of pancreas transplant beyond survival rates have also been explored in smaller exploratory studies. Patients with type 1 diabetes who received SPK (n525) or living donor KA (n517) underwent angiography, echocardiography, and computed tomography for 345 measures of coronary calcification at the time of evaluation and again .7 years (median, 10.1 years) after transplant (4). Coronary artery disease progression, calcification, and systolic function were no different between groups, suggesting that the addition of the pancreas transplant did not impact these parameters, despite differences in hemoglobin A1c levels (mean, 5.5% versus 8.3%) between groups. In another single-center study, health-related quality of life was assessed in 126 SPK recipients pre- and post-transplant (mean, 5 years) (5). On multiple measures, including gastrointestinal quality of life, psychological status, social function, and burden of medical treatment, these measures improved with transplant but did not improve in those with only one organ functioning (15.9% of patients). In 2015, 9.7% of SPK transplants were for indications of type 2 diabetes mellitus (1). This reflects recent clarifications in eligibility criteria for SPK: (1) renal insufficiency with an eGFR,20 ml/min, (2) requirement for insulin for treatment of diabetes, and (3) C peptide ,2 ng/ml or C peptide .2 ng/ml with body mass index cutoff #30 kg/m2. Patient survival in SPK recipients with type 1 diabetes mellitus was higher than in patients with type 2 diabetes mellitus in the most recent registry analysis (90% versus 86.4% at 5 years) (1), likely due to older age and comorbidity in the type 2 diabetes mellitus cohort. Using these eligibility criteria, with the additional criterion of pretransplant insulin use ,1 U/kg per day, a comparison of glucose homeostasis in seven type 2 diabetes mellitus SPK recipients with that in nine type 1 diabetes mellitus SPK recipients within 1 year of transplant determined no differences in measures of insulin resistance and secretion (6). Recurrent autoimmunity was recently shown to contribute to pancreas allograft failure. In a cohort of 223 SPK recipients with a history of type 1 diabetes mellitus, antibodies to the autoantigens GAD65, IA-2, and ZnT8 were measured yearly (7). Biopsy-confirmed type 1 diabetes mellitus recurrence (insulitis and absence of insulin staining) was found in 5.8% over a mean follow-up of 6.264.1 years, and it strongly associated with autoantibody conversion but not with autoantibody persistence. Recurrent autoimmunity was not correlated with the type or degree of immunosuppression. Finally, for patients who experience pancreas graft failure, outcomes of a repeat pancreas transplant are encouraging. A recent comparison of 18 pancreas retransplant recipients with 78 primary pancreas after kidney transplant recipients found comparable 3-year pancreas graft survival rates: 85.1% in both groups (8). 346 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 Simultaneous Liver-Kidney Transplantation In 2016, eligibility criteria for simultaneous liverkidney transplants (SLKs) were developed and approved by the Organ Procurement and Transplantation Network, and they are in the process of implementation (Table 7). This policy was in response to the increase in SLK transplants performed over time (626 in 2015 compared with 362 in 2009). A summary of the rationale has been recently published (9). Some of the more controversial aspects include the definition of CKD (,30 ml/min on one occasion with a history of GFR,60 for 90 days) and the duration of AKI (.6 weeks, GFR,25 ml/min, or dialysis dependence) that permit eligibility. In the meantime, many singlecenter reports and registry analyses have described the difficulties in defining the best utility of kidneys transplanted to either the kidney waiting list or the more morbid cohort of liver transplant candidates with renal disease (10, 11). Perhaps the analysis most reflective of clinical practice is one that compared 1884 SLK recipients with 31,882 liver transplant alone (LTA) recipients transplanted from 2002 to 2009. Patients were compared based on propensity score matching and included matching for dialysis needs and serum creatinine $2.0 mg/dl pretransplant (12). A small survival benefit of 3.7 months at 5 years was noted in patients with pretransplant CKD (no dialysis) who had an SLK versus an LTA. In those requiring dialysis (acute and chronic; unspecified duration), there was no benefit to SLK over LTA at 5 years post-transplant. Given the difficulties in predicting who truly requires a kidney transplant at the time of liver transplant, a recent report described the use of native renal biopsy before liver transplant to determine if a concurrent kidney transplant should be performed (13). In 59 liver transplant candidates with renal impairment of unclear etiology, SLK transplant was recommended for patients with .40% global glomerular sclerosis, with interstitial fibrosis .30%, or requiring hemodialysis for .2 months. Based on these criteria, 70% of patients listed for transplant did not undergo SLK: 23 ultimately underwent LTA and ten underwent SLK. Renal function and survival were comparable at 1 year post-transplant. Importantly, biopsy-related complications were uncommon (n52). Thus, biopsy may provide useful information to minimize unnecessary use of kidneys for SLK. Table 7. Medical eligibility criteria for adult simultaneous liver-kidney transplantation If the Candidate’s Transplant Nephrologist Confirms a Diagnosis of CKD with a measured or calculated GFR#60 ml/min for .90 consecutive d Sustained AKI Metabolic disease Then the Transplant Program Must Report in the UNOS Computer System and Document in the Candidate’s Medical Record At least one of the following That the candidate has begun regularly administered dialysis as an ESRD patient in a hospital-based, independent nonhospital-based, or home setting At the time of registration on the kidney waiting list, that the candidate’s most recent measured or calculated CrCl or GFR is #30 ml/min On a date after registration on the kidney waiting list, that the candidate’s measured or calculated CrCl or GFR is #30 ml/min At least one of the following or a combination of both of the following for the last 6 wk That the candidate has been on dialysis at least once every 7 d That the candidate has a measured or calculated CrCl or GFR that is #25 ml/min at least once every 7 d If the candidate’s eligibility is not confirmed at least once every 7 d for the last 6 wk, the candidate is not eligible to receive a liver and a kidney from the same donor A diagnosis of at least one of the following Hyperoxaluria Atypical HUS from mutations in factor H or factor I Familial non-neuropathic systemic amyloidosis Methylmalonic aciduria For the adult SLK candidate to be prioritized ahead of all KA candidates at the time of their liver offer, the candidate must meet one of the criteria related to kidney function. UNOS, United Network for Organ Sharing; CrCl, creatinine clearance; HUS, hemolytic uremic syndrome. Modified from https://optn.transplant.hrsa.gov/media/1240/05_slk_allocation.pdf. 347 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 Parenthetically, the most common renal diagnoses from these biopsies were membranoproliferative GN (23%), IgA nephropathy (19%), and acute tubular necrosis (19%). Finally, the question of whether the liver is immunoprotective for the kidney in the SLK transplant setting has been asked. In a relatively large, single-center cohort of 68 SLK recipients, 14 with pretransplant donor-specific antibodies (DSAs), protocol post-transplant renal biopsies were performed (14). Compared with a control group of patients who had undergone KA (n5136), 28 KA individuals with pretransplant DSAs experienced higher incidence rates of antibody-mediated rejection (46.4% versus 7.1%) and chronic transplant glomerulopathy (53.6% versus 0%). KA patients without DSAs had higher frequencies of T cell–mediated rejection (30.6% versus 7.4%) and decline in renal function, whereas the SLK cohort had stable GFRs. A concurrent liver transplant was strongly associated with lower cellular- and antibody-mediated rejection and stable GFR, suggesting that the liver may indeed protect against chronic immunologic injury. Multiorgan Transplantation: Utility Considerations Although kidney transplant coupled with a second organ may lead to improved outcomes for other organ transplant cohorts, this diminishes use of kidneys for the kidney transplant candidate. A recent paired kidney analysis evaluated kidney transplant outcomes where a kidney was transplanted to one recipient (KA) and the contralateral kidney was transplanted to an SLK (n51998) or simultaneous heart-kidney (SHK; n5276) recipient (15). The 5-year survival was higher in the KA cohort (81% versus 66% in SLK; P,0.001; 84% versus 75% in SHK; P50.02). Graft survival was significantly higher in KA versus SLK but not SHK. The authors suggest that these outcomes are contrary to allocation policies that are meant to optimize survival overall but instead, favor multiorgan transplantation. For greater details regarding allocation issues and outcomes in multiorgan transplant, the reader is referred to a recent review (16). References 1. Kandaswamy R, Stock PG, Gustafson SK, Skeans MA, Curry MA, Prentice MA, Israni AK, Snyder JJ, Kasiske BL: OPTN/SRTR 2015 Annual Data Report: Pancreas. Am J Transplant 17[Suppl 1]: 117–173, 2017 PubMed 2. Hart A, Smith JM, Skeans MA, Gustafson SK, Stewart DE, Cherikh WS, Wainright JL, Kucheryavaya A, Woodbury M, Snyder JJ, Kasiske BL, Israni AK: OPTN/SRTR 2015 Annual Data Report: Kidney. Am J Transplant 17[Suppl 1]: 21–116, 2017 PubMed 3. Sung RS, Zhang M, Schaubel DE, Shu X, Magee JC: A reassessment of the survival advantage of simultaneous kidney-pancreas versus kidneyalone transplantation. Transplantation 99: 1900–1906, 2015 PubMed 4. Lindahl JP, Massey RJ, Hartmann A, Aakhus S, Endresen K, Günther A, Midtvedt K, Holdaas H, Leivestad T, Horneland R, Øyen O, Jenssen T: Cardiac assessment of patients with type 1 diabetes median 10 years after successful simultaneous pancreas and kidney transplantation compared with living donor kidney transplantation. Transplantation 101: 1261–1267, 2017 PubMed 5. Martins LS, Outerelo C, Malheiro J, Fonseca IM, Henriques AC, Dias LS, Rodrigues AS, Cabrita AM, Noronha IL: Health-related quality of life may improve after transplantation in pancreas-kidney recipients. Clin Transplant 29: 242–251, 2015 PubMed 6. Chakkera HA, Kudva YC, Chang YH, Heilman RL, Singer AL, Mathur AK, Hewitt WR, Khamash HA, Huskey JL, Katariya NN, Moss AA, Behmen S, Reddy KS: Glucose homeostasis after simultaneous pancreas and kidney transplantation: A comparison of subjects with Cpeptide-positive non-type 1 diabetes mellitus and type 1 diabetes mellitus. Clin Transplant 30: 52–59, 2016 PubMed 7. Vendrame F, Hopfner YY, Diamantopoulos S, Virdi SK, Allende G, Snowhite IV, Reijonen HK, Chen L, Ruiz P, Ciancio G, Hutton JC, Messinger S, Burke GW 3rd, Pugliese A: Risk factors for type 1 diabetes recurrence in immunosuppressed recipients of simultaneous pancreaskidney transplants. Am J Transplant 16: 235–245, 2016 PubMed 8. Seal J, Selzner M, Laurence J, Marquez M, Bazerbachi F, McGilvray I, Schiff J, Norgate A, Cattral MS: Outcomes of pancreas retransplantation after simultaneous kidney-pancreas transplantation are comparable to pancreas after kidney transplantation alone. Transplantation 99: 623–628, 2015 PubMed 9. Formica RN, Aeder M, Boyle G, Kucheryavaya A, Stewart D, Hirose R, Mulligan D: Simultaneous liver-kidney allocation policy: A proposal to optimize appropriate utilization of scarce resources. Am J Transplant 16: 758–766, 2016 PubMed 10. Brennan TV, Lunsford KE, Vagefi PA, Bostrom A, Ma M, Feng S: Renal outcomes of simultaneous liver-kidney transplantation compared to liver transplant alone for candidates with renal dysfunction. Clin Transplant 29: 34–43, 2015 PubMed 11. Hmoud B, Kuo YF, Wiesner RH, Singal AK: Outcomes of liver transplantation alone after listing for simultaneous kidney: Comparison to simultaneous liver kidney transplantation. Transplantation 99: 823– 828, 2015 PubMed 12. Sharma P, Shu X, Schaubel DE, Sung RS, Magee JC: Propensity scorebased survival benefit of simultaneous liver-kidney transplant over liver transplant alone for recipients with pretransplant renal dysfunction. Liver Transpl 22: 71–79, 2016 PubMed 13. Pichler RH, Huskey J, Kowalewska J, Moiz A, Perkins J, Davis CL, Leca N: Kidney biopsies may help predict renal function after liver transplantation. Transplantation 100: 2122–2128, 2016 PubMed 14. Taner T, Heimbach JK, Rosen CB, Nyberg SL, Park WD, Stegall MD: Decreased chronic cellular and antibody-mediated injury in the kidney following simultaneous liver-kidney transplantation. Kidney Int 89: 909–917, 2016 PubMed 15. Choudhury RA, Reese PP, Goldberg DS, Bloom RD, Sawinski DL, Abt PL: A paired kidney analysis of multiorgan transplantation: Implications for allograft survival. Transplantation 101: 368–376, 2017 PubMed 16. Stites E, Wiseman AC: Multiorgan transplantation. Transplant Rev (Orlando) 30: 253–260, 2016 PubMed Pregnancy A greater understanding of the risks of pregnancy for the kidney transplant recipient and fetus has been advanced by recent large, single-center experiences, voluntary registry analyses, and patient surveys. In a single-center experience of 138 pregnancies in 89 renal 348 transplant patients from 1973 to 2013, 74% resulted in live births (1). Of these, 61% births were premature, 52% had low birth weight, and 14% were associated with preeclampsia. Long-term graft function (eGFR at 1, 5, and 10 years) and 10-year patient survival were no different compared with those in a paired, nonpregnant control group. Thus, although obstetric complications were common, most pregnancies were successful, with no overt risk to transplant function. A similar registry report from Italy in 1978–2013 compared 222 successful pregnancies with 1418 low-risk controls, with general findings of higher rates of preterm delivery (57.3% versus 6.3%; P,0.001) and babies small for gestational age (14.0% versus 4.5%; P,0.001) (2). In a subset of this cohort, 121 successful pregnancies from 2000 to 2014 were compared with the same control group (n51418) and an additional control group of 610 births in mothers with CKD, risk for preterm delivery was similar in the CKD and transplant cohorts, suggesting that degree of CKD rather than transplant status was the primary determinant for maternal-fetal outcomes (3). Greater insight into the appropriate timing posttransplant to pursue pregnancy for the health of the transplant was provided by a registry analysis of 21,814 women ages 15–45 years old transplanted from 1990 to 2010 with 729 pregnancies occurring within 3 years of transplant (4). When examining risk of death-censored graft loss after pregnancy in years 1–3 post-transplant, an increased risk was noted in those with pregnancies during the first post-transplant year (hazard ratio, 1.25; 95% confidence interval [95% CI], 1.04 to 1.50) and year 2 (hazard ratio, 1.26; 95% CI, 1.06 to 1.50) but not in year 3. Thus, current recommendations to wait at least 1 year post-transplant before pursuing pregnancy (5) perhaps should be tempered with the understanding that increased risk persists into the second year post-transplant. Beyond timing of pregnancy, the type and degree of immunosuppression are also an important consideration for individuals who plan to conceive or become pregnant. Mycophenolate (MPA) is teratogenic and carries a US Food and Drug Administration advisory to discontinue this agent when planning for pregnancy. A recent analysis of 382 pregnancies in patients with a history of MPA use from the National Transplantation Pregnancy Registry reported that birth defects and miscarriages were similar among kidney transplant recipients who discontinued MPA.6 versus ,6 weeks before pregnancy and during the first trimester, whereas the risks of were significantly increased when MPA was continued or discontinued after Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 the first trimester (6). Rather than interpret this as safe to continue MPA during the first trimester, a more appropriate interpretation is that MPA should be discontinued as soon as awareness of pregnancy (or planning) is present. A general guideline is that mycophenolate should be transitioned to azathioprine .6 weeks prior to conception. An editorial on this manuscript, which includes reference to a separate National Transplantation Pregnancy Registry analysis, describes pregnancy outcomes in 302 recipients who discontinued MPA before conception and 142 who took MPA in the first trimester. Higher incidences of miscarriages (20% versus 48%; P,0.001) and birth defects (5.7% versus 11.6%; P50.10) were noted in the latter group (7). With respect to other immunosuppressive agents, a recent study of changes in calcineurin inhibitor dose and blood trough concentrations highlighted changes that occur in pregnancy (8). In 75 women (88 deliveries), cyclosporine (n560) and tacrolimus (n528) trough concentrations fell by the second trimester compared with 12 months before delivery. These declines necessitated an increase in calcineurin inhibitor dose of 20%–25%, a reasonable rule of thumb to expect during pregnancy. When considering risk factors for untoward outcomes during pregnancy, one concern is that highly sensitized patients may be more susceptible to rejection, posing a greater risk to graft outcomes. In a retrospective, single-center study of 11 pregnant patients, eight had detectable panel reactive antibody levels (.0%) (9). Two of the eight had second trimester miscarriages, one had a stillbirth, and after a median follow-up of 2.3 years after delivery, three of the eight developed antibody-mediated rejection leading to graft loss. Although impossible to control for the many risk factors for rejection, this small report raises concern for fetal and allograft outcomes in sensitized patients. Lastly, whether organ transplant immunosuppression in the father impacts pregnancy outcomes was recently explored. A Norwegian registry analysis identified 2463 men who fathered babies of 4614 deliveries before and 474 deliveries after solid organ transplantation (396 after kidney transplant) from 1967 to 2009 and compared these cohorts with the general population of 2,511,506 births (10). They found no increased risk of congenital malformations or other fetal or maternal outcomes compared with in the general population. Higher rates of preeclampsia (adjusted odd ratio, 7.4; 95% CI, 1.1 to 51.4) occurred in pregnancies posttransplant compared with pretransplant. Given the wide 95% CI, this finding should be interpreted with caution. 349 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 References 1. Stoumpos S, McNeill SH, Gorrie M, Mark PB, Brennand JE, Geddes CC, Deighan CJ: Obstetric and long-term kidney outcomes in renal transplant recipients: A 40-yr single-center study. Clin Transplant 30: 673–681, 2016 PubMed 2. Piccoli GB, Cabiddu G, Attini R, Gerbino M, Todeschini P, Perrino ML, Manzione AM, Piredda GB, Gnappi E, Caputo F, Montagnino G, Bellizzi V, Di Loreto P, Martino F, Montanaro D, Rossini M, Castellino S, Biolcati M, Fassio F, Loi V, Parisi S, Versino E, Pani A, Todros T; Italian Study Group on Kidney and Pregnancy of the Italian Society of Nephrology: Pregnancy outcomes after kidney graft in Italy: Are the changes over time the result of different therapies or of different policies? A nationwide survey (1978-2013). Nephrol Dial Transplant 31: 1957–1965, 2016 PubMed 3. Piccoli GB, Cabiddu G, Attini R, Gerbino M, Todeschini P, Perrino ML, Manzione AM, Piredda GB, Gnappi E, Caputo F, Montagnino G, Bellizzi V, Di Loreto P, Martino F, Montanaro D, Rossini M, Castellino S, Biolcati M, Fassio F, Loi V, Parisi S, Versino E, Pani A, Todros T; Italian Study group on Kidney and Pregnancy of the Italian Society of Nephrology: Outcomes of pregnancies after kidney transplantation: lessons learned from CKD. A comparison of transplanted, nontransplanted chronic kidney disease low-risk pregnancies: A multicenter nationwide analysis [published online ahead of print January 21, 2017]. Transplantation doi:10.1097/TP.0000000000001645 4. Rose C, Gill J, Zalunardo N, Johnston O, Mehrotra A, Gill JS: Timing of pregnancy after kidney transplantation and risk of allograft failure. Am J Transplant 16: 2360–2367, 2016 PubMed 5. Kidney Disease: Improving Global Outcomes Transplant Work Group: KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 9[Suppl 3]: S1–S155, 2009 PubMed 6. King RW, Baca MJ, Armenti VT, Kaplan B: Pregnancy outcomes related to mycophenolate exposure in female kidney transplant recipients. Am J Transplant 17: 151–160, 2017 PubMed 7. Moritz MJ, Constantinescu S, Coscia LA, Armenti D: Mycophenolate and pregnancy: Teratology principles and national transplantation pregnancy registry experience. Am J Transplant 17: 581–582, 2017 PubMed 8. Kim H, Jeong JC, Yang J, Yang WS, Ahn C, Han DJ, Park JS, Park SK: The optimal therapy of calcineurin inhibitors for pregnancy in kidney transplantation. Clin Transplant 29: 142–148, 2015 PubMed 9. Ajaimy M, Lubetzky M, Jones T, Kamal L, Colovai A, de Boccardo G, Akalin E: Pregnancy in sensitized kidney transplant recipients: A single-center experience. Clin Transplant 30: 791–795, 2016 PubMed 10. Morken NH, Diaz-Garcia C, Reisaeter AV, Foss A, Leivestad T, Geiran O, Hervás D, Brännström M: Obstetric and neonatal outcome of pregnancies fathered by males on immunosuppression after solid organ transplantation. Am J Transplant 15: 1666–1673, 2015 PubMed Acid-Base and Electrolyte Disorders after Transplant A few recent studies were published on acid-base and electrolyte metabolism in transplantation during 2015 and 2016. A summary of key studies includes (1) metabolic acidosis and transplant outcomes, (2) fluid management post-kidney transplant, and (3) a novel analysis of the interplay of uric acid and allograft outcomes. In a multicenter, retrospective cohort of 2318 kidney transplant recipients from 1997 to 2015, the relationship of serum bicarbonate (total CO2 concentration) and outcomes was described (1) After multivariable adjustment, total CO2 ,22 mmol/L at 3 months post-transplant was associated with increased risk of death-censored graft failure (hazard ratio [HR], 1.66; 95% confidence interval [95% CI], 1.14 to 2.42), and time-varying concentration of total CO2 ,22 mmol/L was also associated with death-censored graft loss (HR, 3.17; 95% CI, 2.12 to 4.73) and death (HR, 3.16; 95% CI, 1.77 to 5.62), even after controlling for eGFR. Whether intervention reduces this risk is yet unproven. Further research in this area is required (2). Normal saline is commonly and liberally administered in the perioperative period after kidney transplantation. A theoretical concern is that this practice may provoke hyperchloremic metabolic acidosis and the risk of hyperkalemia with need for dialysis. A meta-analysis of lower-chloride solutions versus normal saline identified six randomized trials with 477 patients (3). No difference in risk of hyperkalemia or delayed graft function was noted, and there were no significant differences in rejection or graft loss. The use of balanced electrolyte solutions was associated with higher pH, higher bicarbonate, and lower serum chloride concentrations. A strong case cannot be made for the use of one solution versus the other. The ongoing question of whether elevated uric acid is a marker for or contributor to progressive CKD and graft loss was addressed in a novel retrospective analysis of 1170 transplants from 2000 to 2010 (4). Using time-dependent marginal structural Cox proportional hazards models that controlled for kidney function, with eGFR as a time-varying confounder, uric acid was not associated with graft failure (HR, 0.90; 95% CI, 0.85 to 0.94 for every 10-mmol/L increase in uric acid), death-censored graft loss, or death. This supports the concept that hyperuricemia is not an independent risk factor for progressive renal dysfunction post-transplant but rather, is a marker for lower eGFR. References 1. Park S, Kang E, Park S, Kim YC, Han SS, Ha J, Kim DK, Kim S, Park SK, Han DJ, Lim CS, Kim YS, Lee JP, Kim YH: Metabolic acidosis and long-term clinical outcomes in kidney transplant recipients. J Am Soc Nephrol 28: 1886–1897, 2017 PubMed 2. Messa PG, Alfieri C, Vettoretti S: Metabolic acidosis in renal transplantation: Neglected but of potential clinical relevance. Nephrol Dial Transplant 31: 730–736, 2016 PubMed 3. Wan S, Roberts MA, Mount P: Normal saline versus lower-chloride solutions for kidney transplantation. Cochrane Database Syst Rev 8: CD010741, 2016 PubMed 4. Kim ED, Famure O, Li Y, Kim SJ: Uric acid and the risk of graft failure in kidney transplant recipients: A re-assessment. Am J Transplant 15: 482–488, 2015 PubMed Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 Transplantation Claiming Credits and Evaluation Process Accreditation Statement The American Society of Nephrology (ASN) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. AMA Credit Designation Statement The ASN designates this enduring material for a maximum of 10 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Original Release Date: November 2017 CME Credit Termination Date: October 31, 2019 Examination Available Online: On or before Wednesday, November 15, 2017 Estimated Time for Completion: 10 hours Answers with Explanations Provided with a passing score after the first and/or after the second attempt November 2019: posted on the ASN website when the issue is archived. • • Method of Participation Read the syllabus that is supplemented by original articles in the reference lists. Complete the online self-assessment examination. Each participant is allowed two attempts to pass the examination (.75% correct) for CME credit. Upon completion, review your score and incorrect answers and print your certificate. Answers and explanations are provided with a passing score or after the second attempt. • • • • • Activity Evaluation and CME Credit Instructions Go to www.asn-online.org/cme, and enter your ASN login on the right. Click the ASN CME Center. Locate the activity name and click the corresponding ENTER ACTIVITY button. Read all front matter information. On the left-hand side, click and complete the Demographics & General Evaluations. Complete and pass the examination for CME credit. Upon completion, click Claim Your CME Credits, check the Attestation Statement box, and enter the number of CME credits commensurate with the extent of your participation in the activity. If you need a certificate, Print Your Certificate on the left. • • • • • • • • For your complete ASN transcript, click the ASN CME Center banner, and click View/Print Transcript on the left. Instructions to obtain American Board of Internal Medicine (ABIM) Maintenance of Certification (MOC) Points Each issue of NephSAP provides 10 MOC points. Respondents must meet the following criteria: Be certified by ABIM in internal medicine and/or nephrology and enrolled in the ABIM–MOC program Enroll for MOC via the ABIM website (www.abim.org). Enter your (ABIM) Candidate Number and Date of Birth prior to completing the examination. Take the self-assessment examination within the timeframe specified in this issue of NephSAP. Upon completion, click Claim Your MOC points, the MOC points submitted will match your CME credits claimed, check the Attestation Statement box and submit. ABIM will notify you when MOC points have been added to your record. • • • • • • Maintenance of Certification Statement Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 10 MOC points in the American Board of Internal Medicine’s (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider’s responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. MOC points will be applied to only those ABIM candidates who have enrolled in the MOC program. It is your responsibility to complete the ABIM MOC enrollment process. 350 Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 NephSAP, Volume 16, Number 4, November 2017—Transplantation transplant. You begin a discussion about the benefits and risks of a Public Health Service Increased Risk Donor (PHS-IRD) kidney. He is ambivalent about receiving a kidney from an intravenous drug user and concerned about the risk of acquiring an infection from the procedure. Which ONE of the following should you tell him about PHS-IRD kidneys? A. Transplantation of PHS-IRD kidneys is associated with an increased waiting time B. Kidneys from individuals with increased risk behaviors currently make up ,10% of all deceased donors C. Kidneys from intravenous drug users are never used for transplantation D. His risk of contracting HIV, hepatitis C virus (HCV), or hepatitis B virus from a PHS-IRD donor is ,1% 4. A 59-year-old woman with stage 5 CKD is referred for transplantation. She donated a kidney to her sister 18 years ago and now has advanced CKD complicating diabetes mellitus and hypertension. She has had multiple pregnancies and received several blood transfusions after a recent gastrointestinal bleed. Her blood type is A, and her cPRA is 9%. She is concerned about the effect of the new KAS on her chances of receiving a kidney. A discussion ensues about kidney transplantation options. Which ONE of the following should you tell her regarding her options for kidney transplantation? A. The quality of decreased donor kidneys has deteriorated since implementation of Kidney Allocation System (KAS), with a median kidney donor risk index of .80% B. Prior living donors have improved access to transplantation since implementation of KAS C. Her projected waiting time for a deceased donor kidney is likely to be ,4 months D. She can be listed for transplantation only after initiation of dialysis 5. A 63-year-old man with ESRD and HCV infection (genotype 1) as a consequence of a remote history 1. A 68-year-old black man with ESRD is waitlisted for deceased donor kidney transplantation. His blood type is A, and he has a calculated panel reactive antibody (cPRA) level of 80%. Since implementation of the new Kidney Allocation System (KAS) by the United Network for Organ Sharing on December 4, 2014, which ONE of the following factors now associates with him having an INCREASED likelihood of receiving a deceased donor kidney compared with the prior allocation system? A. His race B. His cPRA C. His age D. His blood type 2. A 66-year-old man is referred for kidney transplantation. He has stage 5 CKD due to membranous nephropathy (MN), and he has been maintained on hemodialysis for 3 months. He uses a walker and needs help to get dressed each day. His examination shows a slow walking speed and difficulty standing from a sitting position. He asks about his prognosis regarding kidney transplantation. Which ONE of the following should you tell him about the effect of his physical function on his transplantation outcomes? A. It will not affect his graft survival after kidney transplantation B. It is associated with increased waitlist mortality C. It is associated with a decreased risk for readmissions after transplantation D. Physical therapy can mitigate the effects of frailty on his transplant outcomes 3. A 56-year-old man with ESRD due to IgA nephropathy returns for his routine yearly re-evaluation visit with your local transplant program. He has been listed for deceased donor transplantation for 4 years. His blood type is B. No living donors have been identified. He previously was listed for an expanded criteria donor kidney, and he asks whether there are any other options to increase his chances of receiving a deceased donor kidney 351 352 of intravenous drug use is listed for kidney transplantation. He is HCV treatment naı̈ve. He asks whether it would be better to opt for an HCV-positive kidney compared with a standard criteria HCVnegative kidney. His HCV viral load is persistently high at .450,000 IU/ml. Which ONE of the following statements should you tell him regarding the expected outcomes of receiving an HCV-positive kidney and management of HCV infection? A. Consent to receive an HCV-positive kidney may dramatically reduce his waiting time B. Receipt of an HCV-positive donor kidney is associated with worse allograft survival compared with waiting for an HCV-negative donor kidney C. Consent to receive an HCV-positive donor kidney is not recommended in order to avoid infection with a virus of different genotype D. HCV infection should be treated before transplantation because direct-acting antiviral agents are contraindicated in transplant recipients receiving calcineurin inhibitors 6. Your transplant surgeon informs you that a deceased donor kidney with premortem AKI has been offered to a dialysis patient from an affiliated practice. The donor was 28 years old. The terminal serum creatinine level is 2.5 mg/dl. The preimplantation allograft biopsy shows fibrin thrombi. Glomerulosclerosis is not present. Your nephrology colleague asks you about the expected posttransplant prognosis. Which ONE of the following should you tell your colleague about the expected prognosis of transplanting this kidney? A. The risk of delayed graft function (DGF) is equivalent to receiving a deceased donor kidney without AKI B. This donor’s preimplantation kidney biopsy predicts that DGF is certain C. The finding of fibrin thrombi on biopsy is associated with .10% lower allograft survival at 1 year D. AKI in the donor kidney does not affect allograft function at 1 year 7. A 59-year-old woman with ESRD due to polycystic kidney disease is admitted for transplantation. She is asymptomatic. Her physical examination shows a body mass index (BMI) of 37 kg/m2. She has Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 a low-level donor-specific antibody targeting HLAA2 (mean fluorescence intensity of 1582). The flow cytometry crossmatch is negative. She receives the deceased donor kidney after 28 hours of cold ischemia time. The preimplantation biopsy shows no fibrin thrombi. Postoperatively, her urine output is 3 L over the initial 24 hours. However, the serum creatinine level rises from 5 mg/dl on postoperative day 1 to a peak of 6.2 mg/dl on postoperative day 7. She does not require dialysis, and the serum creatinine subsequently begins to decline to 1.4 mg/dl over the next 2 weeks. Which ONE of the following statements about this patient’s delayed graft function (DGF) is CORRECT? A. The presence of the donor-specific antibody increases her risk of DGF B. Her BMI does not influence her risk of DGF C. Her DGF only affects allograft prognosis when fibrin thrombi are seen on preimplantation biopsy D. Her DGF only affects long-term allograft function if she develops rejection 8. A 29-year-old woman is seen in consultation to assess her candidacy to donate a kidney to her father. She is planning to have a family within the next 3 years. All of her donor testing is normal. She is ABO compatible and has a negative crossmatch with her father. They are a one-haplotype match. Which ONE of the following should you tell her about her pregnancy risk after live donor nephrectomy? A. Pregnancy after kidney donation is more likely to be complicated by low-birth weight infants B. Pregnancy after kidney donation is more likely to be complicated by preterm births C. Pregnancy after kidney donation is associated with an increased risk of gestational hypertension and preeclampsia D. The risk of neonatal mortality is higher among kidney donors compared with nondonors 9. A 23-year-old white man has been accepted as an altruistic living donor. He is completely healthy and does not smoke. On physical examination, his BP is 110/80 mmHg. His creatinine clearance is 106 ml/min. He asks about his future risk of developing kidney failure. Which ONE of the following should you tell him about his risk of ESRD after kidney donation? Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 A. It is higher compared with black donors B. It is no higher than that of nondonors in the general population C. It is three to five times higher than nondonors in the general population D. It may be lower than that of older donors 10. A 32-year-old woman with ESRD due to reflux nephropathy is seen in follow-up 6 weeks after receiving a 6/6-antigen mismatch kidney transplant from a living unrelated donor. She received induction therapy with antithymocyte globulin and is now maintained on tacrolimus, mycophenolic acid (MPA), and prednisone 15 mg daily, with a plan to taper prednisone to 5 mg daily by week 10. Her serum creatinine concentration is 1.2 mg/dl. She wishes to taper entirely off prednisone because of weight gain and onset of glucose intolerance. Which ONE of the following should you advise her about the risks of steroid elimination after transplantation? A. It is associated with an increased risk of mortality B. It will lower her risk of infection C. It will lower her risk of developing diabetes mellitus D. It will lower her risk of malignancy E. It is associated with an increased risk of acute rejection 11. Which ONE of the following statements about antibody induction therapy for kidney transplantation is CORRECT? A. Basiliximab therapy associates with marked reduction in rejection risk in tacrolimus/ mycophenolate/steroid-treated nonsensitized patients B. Rituximab induction reduces rejection risk in nonsensitized allograft recipients C. An alemtuzumab/prednisone-free regimen is becoming the most widely used strategy in the United States D. Induction therapy associates with approximately 50% rejection risk reduction compared with no induction therapy 12. Which ONE of the following statements about use of mycophenolate after kidney transplantation is CORRECT? A. Dose reductions stemming from adverse effects are associated with an increased risk of rejection and graft failure 353 B. The risk of cytomegalovirus (CMV) viremia is greater with azathioprine compared with mycophenolate C. Mycophenolate is associated with a reduced risk of mortality compared with azathioprine D. Physical frailty does not affect the frequency of mycophenolate adverse events E. Dose-limiting adverse effects are more commonly seen in living compared with deceased donor allograft recipients 13. A 38-year-old kidney transplant recipient is admitted for management of an upper gastrointestinal bleed. She is found to have a bleeding gastric ulcer that is cauterized endoscopically. She is fatigued but otherwise asymptomatic. Her allograft function has been excellent since transplantation 4 months ago, and her serum creatinine has been stable at 1.3 mg/dl. Her medications include cyclosporine, mycophenolate mofetil, prednisone, and valganciclovir. Her hemoglobin stabilizes at 6.7–6.9 g/dl. Her internist recommends transfusion with 1 U packed red blood cells. You discuss the benefits and risks of transfusion as well as transfusion methods with her internist. Which ONE of the following statements should you advise about the risks and methods of transfusion in this patient? A. There is no risk of allosensitization, because she is immunosuppressed B. Blood transfusion may induce donor-specific antibody and an increased risk of rejection C. Leukocyte filtration will eliminate the risk of allosensitization D. If she receives blood, it should be CMV negative E. If she receives blood, it should be irradiated 14. A 48-year-old woman with ESRD due to lupus nephritis is evaluated during her annual visit while waitlisted for transplantation. Her cPRA is 99% as a result of prior pregnancies and remote transfusions. She has been on the waitlist for 3 years. Her sister is her only potential living donor. However, their complement-dependent cytotoxicity crossmatch is positive. Her nephrologist consults you about her candidacy for desensitization. She has already been listed for kidney paired donation nationally. Which ONE of the following should you advise about HLA antibody desensitization? 354 A. HLA antibody desensitization using plasmapheresis and intravenous Ig is associated with the same excellent outcomes as desensitization to permit ABO-incompatible transplantation B. Treatment of subclinical rejection detected by protocol biopsy abrogates the risk of allograft failure after HLA antibody desensitization C. The addition of rituximab to her regimen will increase the risk of infection and malignancies at 2 years D. HLA antibody desensitization is associated with inferior patient and graft survival compared with HLA-compatible transplantation E. Thrombotic microangiopathy after desensitization is mitigated by plasmapheresis and does not affect allograft outcome 15. A 68-year-old woman with polycystic kidney disease receives a kidney donor profile index .86% deceased donor kidney. Her achieved serum creatinine level is 1.8 mg/dl. She is tolerating maintenance immunosuppression with tacrolimus and mycophenolate well. In addition to serum creatinine levels, which ONE of the following biomarkers should be used to best monitor her allograft stability? A. Kidney injury marker-1 B. Neutrophil gelatinase–associated lipocalin C. Perforin D. Granzyme B E. Urine protein-to-creatinine ratio and/or urine albumin-to-creatinine ratio 16. A 54-year-old woman with a history of reflux nephropathy and recurrent urinary tract infection is seen six months after living donor kidney transplantation. She had prompt function of the allograft, and her serum creatinine level has been stable at 1.2 mg/dl for the last six weeks. She is concerned about her bone health because her 10-year probability of a hip fracture is estimated to be 3.2% based on the Fracture Risk Assessment Tool (FRAXÒ). Her immunosuppression includes tacrolimus, mycophenolate mofetil, and prednisone. The serum creatinine level is 1.2 mg/dl (eGFR .60 ml/min per 1.73 m2), the parathyroid hormone (PTH) level is 116 pg/ml (reference range, 12 - 88 pg/ml), the serum calcium is 9.1 mg/dl, the phosphorus is 2.6 mg/dl, the serum alkaline phosphatase is normal, the 25-hydroxyvitamin D level is 30 ng/ml (reference range 5 30– 50 ng/ml), and the 1,25-dihydroxy-vitamin D level is 32 pg/ml (reference range 5 25–65 pg/ml). Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 Which ONE of the following is the MOST appropriate management strategy for this woman? A. No further treatment B. Denosumab C. A bisphosphonate D. Teriparatide 17. A 56-year-old man has hypercalcemia and hyperparathyroidism 18 months after a second deceased donor kidney transplant. Laboratory studies show a serum creatinine of 1.0 mg/dl, a PTH of 1208 pg/ml (reference range 512–88 pg/ml), a serum calcium of 10.6–11.2 mg/dl, a serum albumin of 4.2 g/dl, a serum phosphorus of 1.4 mg/dl, and a serum 25-hydroxyvitamin D level of 35 ng/ml. A dual energy x-ray absorptiometry scan shows a Z score of 22.1 and a T score of 22.7, which was a significant decrease of 7.1% compared with a previous measurement 1 year ago. Parathyroid scintigraphy shows four enlarged glands. Which ONE of the following is the MOST appropriate next step in treatment? A. Subtotal parathyroidectomy B. Cinacalcet 30 mg daily and titrate until the serum PTH level is normalized C. Paricalcitol 1 mg/d titrated to 2 mg/d as tolerated D. Denosumab 60 mg administered every 6 months 18. A 31-year-old woman is seen for preconception counseling 5 years after successful kidney transplantation. She is maintained on stable doses of tacrolimus, mycophenolate mofetil (MMF), and prednisone. She had one episode of mild acute cellular rejection 3 months after transplantation that responded to pulse methylprednisolone. Her serum creatinine level has been stable in the 1.4- to 1.6mg/dl range over the past year, and the urine proteinto-creatinine ratio has averaged 400 mg/d. A biopsy 2 years ago showed mild to moderate transplant glomerulopathy with no active inflammation. At that time, a donor-specific antibody to HLA-DQ7 was detected with a mean fluorescence intensity of 7000. Which ONE of the following is the MOST appropriate management of her immunosuppression in preparation for and during pregnancy? A. Transition MMF to azathioprine .6 weeks prior to attempts to conceive and plan to increase tacrolimus about 20%–25% during the second trimester to maintain therapeutic levels B. Wait until the first trimester to discontinue mycophenolate mofetil Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 C. Transition mycophenolate mofetil to sirolimus now D. Discontinue tacrolimus after pregnancy is confirmed 19. A 54-year-old man with type 2 diabetes mellitus is evaluated for persistent hypertension 2 years after a living related kidney transplant. He has no prior cardiovascular history. His medications are tacrolimus, sirolimus (implemented because of gastrointestinal intolerance to mycophenolate), prednisone, amlodipine 10 mg daily, and hydrochlorothiazide 25 mg daily. The systolic BP has consistently been in the 150- to 159-mmHg range using home BP monitoring. On physical examination, the BP is 158/90 mmHg. There is no lower extremity edema. Laboratory studies show a serum creatinine level of 0.9 mg/dl, potassium of 4.3 mEq/L, and a urine protein-tocreatinine ratio of 200 mg/g. Which ONE of the following is the MOST appropriate agent to add for BP control? A. Furosemide B. Hydralazine C. Labetalol D. Lisinopril 20. A 62-year-old man with ESRD due to type 2 diabetes mellitus currently maintained on hemodialysis for 1 year is seen in consultation to evaluate his candidacy for kidney transplantation. His past medical history is significant for stable coronary artery disease that required placement of a drugeluting stent in the left circumflex artery 3 years ago. His BMI is 36.5 kg/m2. Which ONE of the following is the MOST appropriate statement regarding his expected transplant outcome? A. His risk of graft loss (death censored) is similar to that of nonobese transplant recipients B. His mortality risk is higher than nonobese transplant recipients C. His risk of DGF is higher than nonobese transplant recipients D. His mortality risk with transplant is higher than his nonobese waitlisted counterparts 21. A 64-year-old woman with ESRD due to chronic GN and a remote history of a transient ischemia attack and peptic ulcer disease has been on hemodialysis for 6 years. She is active on the kidney waitlist. She suffers from hypotension during dialysis and requires regular use of midodrine during 355 dialysis to maintain systolic BP .90 mmHg. Her systolic BP on nondialysis days is 90–100 mmHg. Her medications include omeprazole, aspirin, sevelamer carbonate, magnesium oxide, and methoxy polyethylene glycol epoetin-b. She had a normal exercise stress test within the past year. An echocardiogram shows severe left ventricular hypertrophy. Her laboratory studies are significant for a low serum magnesium of 1.3 mg/dl. In considering her clinical risk factors, which ONE of the following clinical features is MOST highly associated with graft loss after transplant? A. Midodrine use B. Hypomagnesemia C. Proton pump inhibitor use D. Aspirin use 22. A 44-year-old man with HIV-associated nephropathy has been on dialysis for 4 years. His HIV viral load is undetectable on highly active antiretroviral therapy, with a recent CD4 count of 480/ml and no opportunistic infections. He wishes to pursue kidney transplantation. When considering his transplant referral and management, which ONE of the following is the MOST appropriate management? A. Use of cyclosporine rather than tacrolimus for maintenance immunosuppression B. Use of thymoglobulin induction therapy C. Referral to a transplant center with extensive prior experience in HIV-positive transplantation D. Avoidance of HIV-positive deceased donors 23. A 62-year-old man was found to have BK virus (BKV) viremia (16,240 copies/ml) 6 months after deceased donor transplant while on tacrolimus, MPA, and prednisone. A biopsy of the allograft 6 months after transplantation showed no evidence of rejection or BKV nephropathy. His tacrolimus and MPA doses were initially reduced by 25%. MPA was further reduced by an additional 50% over the subsequent 3 months due to persistent viremia. Over the next 3 months, BKV viremia remained present at very low levels (1000–2000 copies/ml). Renal allograft function remained stable throughout the 6-month period, with serum creatinine of 1.2 mg/dl. Compared with individuals who never developed BKV viremia, which ONE of the following is the MOST likely clinical outcome? 356 A. Development of de novo donor-specific antibodies B. Graft loss due to BKV nephropathy C. Development of a second viral infection D. Increased mortality 24. A 55-year-old man with ESRD secondary to type 2 diabetes mellitus is evaluated for future kidney transplantation. He has been on dialysis for 6 months, and he has a potential living donor, his wife, who is otherwise healthy. He is a nonsmoker. He has a history of squamous cell skin cancer on his scalp that was diagnosed and successfully resected with clear margins 1 year ago. The lesion was 2.1 cm in size. He had a 1-cm tubular adenomatous polyp resected 2 years ago during screening colonoscopy. He has no symptoms of urinary frequency, urgency, or hesitancy. He does not have hematuria and has not worked in aluminum smelting, rubber manufacture, or leather industries. There is no family history of colon cancer or prostate cancer. Regarding his risk for malignancy after transplant, which ONE of the following is the MOST appropriate management recommendation? A. An additional 1-year waiting time (total waiting time 52 years) on the basis of prior skin cancer history B. Repeat colonoscopy now before proceeding with a living donor transplant C. Check a screening serum prostate-specific antigen level D. Refer him for screening cystoscopy 25. A 55-year-old man with ESRD secondary to membranous nephropathy (MN) is seen to assess his candidacy for kidney transplantation. He still produces urine and has persistent proteinuria (6 g/d). An antiphospholipase A2 receptor autoantibody level drawn at the time of evaluation is negative. He is scheduled to receive a living unrelated kidney transplant from a friend. Which ONE of the following is the MOST accurate regarding his risk for recurrent MN after transplant? A. He has a high (.80%) likelihood of developing recurrent MN B. The absence of anti-phospholipase A2 receptor (anti-PLA2R) antibody indicates a low risk (,20%) of recurrent MN C. Graft survival is significantly lower in those who develop recurrent MN than the general transplant population Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 D. Recurrent MN with progressive proteinuria typically responds to rituximab 26. A 49-year-old woman with type 2 diabetes mellitus and stage 5 CKD undergoes an evaluation for kidney transplantation. She has no identified living donors. She has had insulin-requiring diabetes mellitus for 18 years. Her BMI is 28 kg/m2. Laboratory studies show an eGFR of 14 ml/min per 1.73 m2, a C-peptide level of 3.2 ng/ml, and a hemoglobin A1c of 6.8%. She wishes to discuss pancreas transplantation. Which ONE of the following is the MOST accurate when discussing simultaneous pancreaskidney (SPK) transplantation with her? A. She is an eligible candidate for SPK transplantation B. SPK transplant in type 2 diabetes mellitus recipients is associated with a higher risk of rejection compared with in type 1 diabetes mellitus recipients C. SPK transplant in type 2 diabetes mellitus recipients is associated with an increased risk of primary nonfunction compared with in type 1 diabetes mellitus recipients D. SPK transplant in type 2 diabetes mellitus recipients is associated with worse pancreas graft survival compared with in type 1 diabetes mellitus recipients 27. A 55-year-old woman with type 1 diabetes and ESRD for 6 months is evaluated for kidney transplantation. She has consistently achieved a hemoglobin A1c level of about 7.2 %–7.8% using an insulin pump. Her BMI is 31 kg/m2. She has not had emergency care or third party assistance for hypoglycemia. She does not have symptomatic cardiovascular disease. She has no potential living kidney donors and wishes to consider pancreas transplantation. Her C peptide is ,2 ng/ml. Which ONE of the following should you tell her about SPK transplantation? A. She is not a candidate for SPK transplantation B. SPK transplant is associated with substantial improvements in health-related quality of life, even in the setting of early pancreas transplant failure C. SPK transplant is associated with substantial improvements in long-term survival compared with kidney transplant alone D. SPK transplant waiting time is substantially shorter than for deceased donor kidney transplant alone Nephrology Self-Assessment Program - Vol 16, No 4, November 2017 28. In 2016, eligibility criteria for simultaneous liverkidney transplant were developed and approved by the Organ Procurement and Transplantation Network. Which ONE of the following liver transplant candidates is NOT eligible for simultaneous liver-kidney transplantation? A. A 64-year-old man with stage 3 CKD (eGFR545–50 ml/min per 1.73 m2) documented for 4 months and a recent fall in eGFR during a period of hypovolemia to 25 ml/min per 1.73 m2 B. A 19-year-old woman with primary hyperoxaluria, nephrocalcinosis, and stage 5 CKD C. A 54-year-old man with HCV infection, type 2 diabetes mellitus, an eGFR of 35–40 ml/min per 1.73 m2, and proteinuria of 1 g/d D. A patient with type 2 hepatorenal syndrome with an eGFR of 15–25 ml/min per 1.73 m2 over the past 6 weeks 29. A 62-year-old man with chronic GN is to undergo living unrelated kidney transplant. He has a history of squamous cell carcinoma successfully treated 5 years ago. He is CMV naı̈ve (serum IgG for CMV is negative), whereas his prospective donor is CMV IgG positive. Other past medical history includes chronic idiopathic diarrhea two to three times daily. An extensive evaluation of the diarrhea was unrevealing. The transplant center is considering use of 357 tacrolimus combined with the mammalian target of rapamycin inhibitor everolimus and prednisone as initial maintenance immunosuppression. Compared with tacrolimus/mycophenolatebased immunosuppression, which ONE of the following is the MOST likely clinical outcome of using tacrolimus/everolimus/prednisone in the absence of CMV prophylaxis? A. Lower incidence of CMV viremia B. Lower incidence of acute rejection C. Lower incidence of mortality D. Lower incidence of nonskin malignancy 30. A 62-year-old man with chronic GN is to undergo living unrelated kidney transplant. His calculated panel reactive antibody score is 0%, and the HLA mismatch with the donor is four out of six. In addition to tacrolimus/mycophenolate-based immunosuppression with prednisone, the transplant center is planning use of rabbit antithymocyte globulin for induction therapy. Compared with induction therapy with an IL-2 receptor antagonist, which ONE of the following is the MOST likely clinical outcome of using rabbit antithymocyte globulin for induction therapy? A. A lower incidence of acute rejection B. A lower incidence of graft loss C. A lower incidence of mortality D. A lower incidence of malignancy
