european urology 51 (2007) 1534–1541 available at www.sciencedirect.com journal homepage: www.europeanurology.com Review – Female Urology – Incontinence Hyaluronic Acid: An Effective Alternative Treatment of Interstitial Cystitis, Recurrent Urinary Tract Infections, and Hemorrhagic Cystitis? Christos Iavazzo a, Stavros Athanasiou a,b, Eleni Pitsouni a, Matthew E. Falagas a,c,* a Alfa Institute of Biomedical Sciences (AIBS), Athens, Greece 1st Department of Obstetrics and Gynecology, Athens University School of Medicine, Athens, Greece c Department of Medicine, Tufts University School of Medicine, Boston, MA, USA b Article info Abstract Article history: Accepted March 9, 2007 Published online ahead of print on March 20, 2007 Objectives: Hyaluronic acid is a protective barrier of the urothelium. A damaged glycosaminoglycan layer may increase the possibility of bacterial adherence and infection. This damage is proposed to be a causative factor in the development of interstitial cystitis, common urinary tract infections, and hemorrhagic cystitis due to posthematopoietic stem cell transplantation. The aim of this article was to review the available data regarding the use of hyaluronic acid as an alternative treatment of the above-mentioned conditions. Methods: Articles relevant to our review that were archived by September 2006 were retrieved from PubMed. Results: Nine relevant studies were identified and evaluated. Hyaluronic acid was administered intravesically at a dose of 40 mg every week for 4–6 wk; patients with noted improvement received two additional monthly doses. Short-term responses of patients with interstitial cystitis, hemorrhagic cystitis, and recurrent urinary tract infections were 30–73% (7 studies), 71% (1 study), and 100% (1 study), respectively. The treatment was well tolerated except for occasional development of bacterial cystitis. The cost of each intravesical installation of hyaluronic acid is 120 UK pounds (excluding the cost of the urinary catheterization). Conclusions: The available clinical data regarding the effectiveness of hyaluronic acid as a potential treatment of patients with interstitial cystitis, recurrent urinary tract infections, and hemorrhagic cystitis are limited. There is need for randomized controlled trials for further investigation of this important therapeutics question; these clinical trials should be disease-specific, blinded, and controlled, and of a sufficient number of patients. Until such studies are available, intravesical instillation of hyaluronic acid cannot be unquestionably endorsed for use for the aforementioned diseases. Keywords: Hyaluronate Glycosaminoglycan replacement treatment Intravesical administration Cystitis # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Alfa Institute of Biomedical Sciences (AIBS), 9 Neapoleos Street, 151 23 Marousi, Greece. Tel. +30 694 611 0000; Fax: +30 210 683 9605. E-mail address: [email protected] (M.E. Falagas). 0302-2838/$ – see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2007.03.020 european urology 51 (2007) 1534–1541 1. Introduction Hyaluronic acid is a major mucopolysaccharide found widely in the connective, epithelial, and neural tissues. It is one of the main components of the extracellular matrix that contributes significantly to cell proliferation and migration, and may also be involved in the progression and migration of some malignant tumors [1]. Hyaluronic acid in the urothelium constitutes a protective barrier [2,3]. It exhibits a variety of properties that may contribute to its prophylactic mechanism [4–10]. Among them are (1) inhibition of adherence of immune complexes to polymorphonuclear cells; (2) marked inhibition of leukocyte migration and aggregation, depending on viscosity; (3) regulation of fibroblast and endothelial cell proliferation; and (4) enhancement of connective tissue healing. A damaged glycosaminoglycan layer may lead to direct exposure of epithelial cells to components of urine; for this reason the possibility of bacterial adherence and infection increases [8–10]. This damage is proposed to be a causative factor in the development of interstitial cystitis [11], common urinary tract infections (UTIs) [12], and hemorrhagic cystitis due to posthematopoietic stem cell transplantation [2]. Hyaluronic acid is used in clinical practice in the treatment of patients with osteoarthritis (by intraarticular injections) [13] or asthma [14]; in certain ophthalmologic [15] and otologic [16] operations; in cosmetic regeneration and reconstruction tissue [17]; and in cystitis [2,3] and vesicoureteral reflux [18]. The aim of this article is to critically review the available evidence regarding the use of hyaluronic acid as an alternative treatment of interstitial cystitis, recurrent urinary tract infections, and hemorrhagic cystitis. 2. 1535 microorganisms, and toxic molecules, to the bladder urothelium [25,26], and urinary hyaluronic acid levels correlate with interstitial cystitis [27]. There is no specific treatment for interstitial cystitis because of its uncertain cause and pathogenesis. Tricyclic antidepressants, anti-inflammatory drugs, and a wide range of epithelial-coating techniques including the use of heparin, sodium pentosan polysulfate, and hyaluronic acid have been used [20,22,26,28–31]. Hyaluronic acid is considered a good candidate for glycosaminoglycan substitution. In addition, heparin and dimethyl sulfoxide are often used in patients with interstitial cystitis. These agents’ actions are not quite clear, but they supposedly act via their anti-inflammatory effects. Other agents for intravesical treatment are Bacillus Calmette-Guerin vaccine and botulinum toxin, and some recent studies have pointed to resiniferatoxin and RDP58 [32]. 3. Urinary tract infections UTI is a very common type of bacterial infection, especially in women. Not every patient with UTI has symptoms. When symptoms are present, patients feel urgency, frequency, nocturition with small voidal volume, bladder or utethra pain during urination, suprapubic discomfort, and sometimes fullness in the rectum. Presence of fever, pain in the back or side below the ribs, nausea, and vomiting indicates kidney infection [33]. Management of UTIs involves administration of antibiotics, but a high percentage of recurrent infections still occur [12]. Contemporary treatment options could also be estrogen replacement therapy [12], use of cranberry juice [34] or probiotics [35], as well as glycosaminoglycan substitution by using heparin, sodium pentosan polysulfate, or hyaluronic acid [12]. Interstitial cystitis Interstitial cystitis is a chronic disease characterized by urinary frequency, bladder pain, nocturia, and urgency. It usually affects women [19]. The prevalence of interstitial cystitis ranges from 10 up to 510 cases per 100,000 population [20,21]. Interstitial cystitis is frequently a diagnosis of exclusion. Many etiologic factors [20,22–24] have been suggested for this condition, including autoimmune response, mast cell activation, neuropathic changes, occult infection, toxic substances in the urine, and a primary defect in the glycosaminoglycan layer of the bladder mucosa. It has been suggested that a defect in the glycosaminoglycan layer allows access of different components of urine, such as ions, 4. Hemorrhagic cystitis Hemorrhagic cystitis is a relatively common (incidence: 7–68%) and potentially severe complication of high-dose chemoradiotherapy, especially in conjunction with hematopoietic stem cell transplantation. There is no established effective treatment for this type of cystitis [2]. 5. Literature search Using the online PubMed database, we searched for articles relevant to our study that were archived by Year No. of patients Miodosky et al [2] 2006 7 Daha et al [19]* 2005 48 32/48 patients with a Cmax of <350 cc (group 1) 16/48 patients with a Cmax of >350 cc (group 2) Gupta et al [22]* 2005 38 Kallestrup et al [20] 2005 20 Age (yr) Mean: 54 (range: 22–82) 34–80 Treatment of Treatment scheme Results Hemorrhagic cystitis after HSCT 4 weekly doses plus monthly doses 5/7 complete response at a median of 12 d (range: 7–23) 1/7 partial response 1/7 no response (death from septic shock) No local or systemic side effects Interstitial cystitis (but a bladder capacity of >350 cc on a 0.9% NaCl cystometry was accepted) 10 weekly doses 41/48 improvement 27/32 (84%) in group 1 Interstitial cystitis 6 weekly doses and choice of continuing monthly in responders 20/36 improvement (55%) after 6 doses (74% of PST-positive patients and 23% of PST-negative patients) 3 patients referred pain 3 patients developed UTI Current cost: UK 120 pounds, excluding nursing and day-surgical unit costs Inconvenience of weekly visits Loss of working time and earnings Interstitial cystitis 4 weekly doses plus 2 monthly doses plus choice of continuing monthly in responders 40% decrease in nocturia 30% decrease in pain Decrease in analgesic use 13/20 responders (65%) 6/20 lack of response 1/20 withdrawn due to cystectomy Well tolerated by all patients 5/20 bacterial cystitis due to repeated catheterisation No correlation between efficacy and time of retained solution in the bladder After 3 yr: 4/13 complete responders, 7/13 partial responders 2/13 other diseases during follow-up Follow-up 6 mo (3–16 mo) 14/16 (87%) in group 2 3 yr european urology 51 (2007) 1534–1541 Author 1536 Table 1 – The role of intravesical use of hyaluronic acid in cystitis 2004 40 Mean: 35 (range: 18–45) Recurrent UTIs 4 weekly doses plus 4 monthly doses 40/40: recurrence free during 5 mo 28/40 (70%): recurrence free during follow-up Median time of recurrence 498 d (compared with 96 d before treatment) Excellent tolerability 9/40 mild bladder irritation 40/40 compliance 12.4 mo Leppilahti et al [38] 2002 11 Mean: 64.5 (range: 51–76) Interstitial cystitis 4 weekly doses 8/11 responders 3/8 long-term responders 5/8 short-term responders Responders: 75% decrease in pain Long-term responders: 40% decrease in frequency Short-term responders: 26% % decrease in frequency 1 yr Nordling et al [26] 2001 20 Interstitial cystitis 4 weekly doses plus monthly doses for 2 mo 1/20 7/19 6/19 4/19 2/19 3 yr Morales et al [3] 1997 25 Interstitial cystitis 4 weekly doses plus monthly doses for 1 yr responders 16% complete response by week 4 25% complete response by week 24 56% response (complete or partial) for week 4 71% response (complete or partial) by week 12 71% response (complete or partial) till week 20 Decrease beyond rate 24 weeks No significant toxicity 1/25 withdrew because of exacerbation of bladder irritability 6 mo Porru et al [39]* 1997 10 Interstitial cystitis 6 weekly doses plus monthly doses 30% response in 6 weeks 30% response in 24 weeks No significant local or general side effects Well tolerated 6 mo withdrawn due to cystectomy responders nonresponders recovered during treatment stopped before follow-up european urology 51 (2007) 1534–1541 Constantinides et al [12] HSCT = hematopoietic stem cell transplant; Cmax = maximum plasma concentration; PST = potassium sensitivity test; UK = United Kingdom; UTI = urinary tract infection. These three studies were randomised controlled trials. The studies by Gupta et al and Porru et al were double-blinded, placebo-controlled trials. Porru et al did not report the method used for double-blinding, while Gupta et al reported that the pharmacy supplied the medications in bottles labeled A and B to ensure double-blinding. * 1537 1538 european urology 51 (2007) 1534–1541 September 2006. The key words we used in our literature searches were hyaluronic acid, hyaluronate, cystitis. 6. Study selection and evaluation The focus of our study was in articles that described the role of hyaluronic acid in the prevention or treatment of different types of cystitis. Only English language studies were included in this review. We identified a total of 27 potentially relevant articles. From these, 15 were excluded because they did not focus on the topic of our study. In addition, 3 articles were excluded because they were animal studies. As a result 9 studies remained that met the inclusion criteria of our review. Relevant data were extracted from each study and tabulated. The information retrieved included the number of patients, the route of hyaluronic acid administration, the results (positive or negative), and the follow-up of each study. 7. is from 30% [39] up to 73% [38], and the long-term (3 yr) response of such patients could reach 55% [20]. Miodosky et al [1] reported that the total response to the treatment in patients with hemorrhagic cystitis is 71%. Constantinides et al [12] found that, in patients with recurrent UTIs, intravesical treatment with hyaluronic acid was associated with absence of recurrence in 100% and 70% of patients during 5-mo and 1-yr follow-up, respectively. 8. Adverse events The use of hyaluronic acid is usually well tolerated [2,12,19,20,22,26,36–39]; for this reason high compliance with the treatment was achieved in the reviewed studies and is also expected in clinical practice. No serious local or systemic adverse events were mentioned in the reviewed studies, except mild bladder irritation. A reported adverse event was bacterial cystitis that was most likely related to the repeated urinary catheterization rather than the therapeutic agent itself. Critical review of the available evidence From our literature search we found seven studies [19,20,22,26,36–39] that investigated the role of hyaluronic acid in the treatment of patients with interstitial cystitis (total number of patients: 172), one study [12] regarding the treatment of patients with recurrent UTIs (total number of patients: 40), and one study [2] regarding the treatment of patients with hemorrhagic cystitis (total number of patients: 7). In Table 1 we present the data extracted from the relevant reviewed studies. Patients received four to six weekly intravesical installations of hyaluronic acid at a dose of 40 mg in a volume of 50 ml of phosphate-buffered saline. Responders then received monthly doses. The intravesical installation was performed with the use of a catheter, under sterile conditions, after removal of residual urine. The patients retained the intravesical hyaluronic acid for a minimum time of 30 min [2,12,19,20,22,26,36–39]. Kallestrup et al [20] found no correlation between the retention time in the bladder (range: 28–155 min) and the effectiveness of hyaluronic acid. Gupta et al [21,37] and Daha et al [19] proposed the use of a positive potassium sensitivity test before the use of hyaluronic acid to identify patients with predominant epithelial dysfunction, who are thought to be better responders to this treatment. The available data suggest that the total shortterm response of patients with interstitial cystitis 9. Cost The cost of each intravesical installation of hyaluronic acid is 120 UK pounds. This figure does not include the cost of the urinary catheterization, the cost of the services of the health care personnel, and the loss of working time and earnings due to the need for intravesical administration of the drug [22]. For these reasons, we believe that cost-effectiveness analyses regarding the use of hyaluronic acid in patients with the examined diseases should be performed. 10. Limitations in the interpretation of the available evidence The major issue in interpreting the available evidence regarding the effectiveness and safety of hyaluronic acid for the examined diseases is that there are only limited relevant published data. Thus, one cannot make definitive statements on the reviewed topics. In addition, an important limitation of the evaluated studies is the fact that only three of the nine reviewed studies were randomized controlled trials. It should be mentioned that, in two of these three trials, hyaluronic acid was compared with placebo, while in one of these three trials women were stratified by bladder capacity or european urology 51 (2007) 1534–1541 potassium chloride test, and pre- and protreatment analyses were done. While this methodology has several advantages, we should emphasize that this new therapeutic modality was not compared with other commonly used therapeutic options in patients with the examined diseases. In addition, the statistical significance and the cut-off of significance were reported in only six of the reviewed articles, the number of dropouts from the study and the reason that led participants to dropout were reported in three articles, and specific information regarding adverse events of intravesical treatment with hyaluronic acid in were reported in six articles. Finally, it should be emphasized that intravesical hyaluronic acid is not an approved treatment for the examined indications in the United States and United Kingdom at the time of writing of this article (November 2006). 11. Conclusions There is a scarcity of data regarding the mode of action of hyaluronic acid as well as its effectiveness for the examined diseases in this article. The limited available evidence from the reviewed studies suggests that hyaluronic acid may be considered for further studies, including randomized controlled trials with adequate power. These clinical trials should be disease-specific, blinded, and controlled, and include a sufficient number of patients to answer the important relevant study questions. Until such studies are available, the effectiveness of intravesical instillation of hyaluronic acid as a potential alternative treatment of interstitial cystitis, recurrent UTIs, and hemorrhagic cystitis remains unknown. Conflicts of interest There are no financial or other relationships that might lead to a conflict of interest. Funding: None. References [1] Available at: http://wikipedia.org/wiki/Cochrane_Collaboration. [2] Miodosky M, Abdul-Hai A, Tsirigotis P, et al. Treatment of post-hematopoietic stem cell transplantation hemorrhagic cystitis with intravesicular sodium hyaluronate. Bone Marrow Transplant 2006;38:507–11. [3] Morales A, Emerson L, Nickel JC. Intravesical hyaluronic acid in the treatment of refractory interstitial cystitis. Urology 1997;49(5A suppl):111–3. 1539 [4] Sato H, Takahashi T, Ide H. Antioxidant activity of synovial fluid, hyaluronic acid and two sub-components of hyaluronic acid. Synovial fluid scavenging effect is enhanced in rheumatoid arthritis patients. Arch Rheum 1988;31:63–7. [5] Goldberg RL, Toole BP. Hyaluronate inhibition of cell proliferation. Arth Rheum 1987;30:769–73. [6] Abatangelo G, Martelli M, Vecchia P. 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Do cystometric findings predict the results of intravesical hyaluronic acid in women with interstitial cystitis? Eur Urol 2005; 47:393–7. [20] Kallestrup EB, Jorgensen SS, Nordling J, et al. Treatment of interstitial cystitis with Cystistat: a hyaluronic acid product. Scand J Urol Nephrol 2005;39:143–7. [21] Temml C, Wehrberger C, Riedl C, et al. Prevalence and correlates for interstitial cystitis symptoms in women participating in a health screening project. Eur Urol 2007;51:803–9. 1540 european urology 51 (2007) 1534–1541 [22] Gupta SK, Pidcock L, Parr NJ. The potassium sensitivity test: a predictor of treatment response in interstitial cystitis. BJU Int 2005;96:1063–6. [23] Parsons CL, Stein PC, Bidair M, et al. Abnormal sensitivity to intravesical potassium in interstitial cystitis and radiation cystitis. Neurourol Urodyn 1994;13:515–20. [24] Moldwin RM, Sant GR. Interstitial cystitis: a pathophysiology and treatment update. Clin Obstet Gynecol 2002;45: 259–72. [25] Morales A, Emerson L, Nickel JC. Treatment of refractory interstitial cystitis. Int Urogynecol J Pelvic Floor Dysfunct 1996;7:215–20. [26] Nordling J, Jorgensen S, Kallestrup E. Cystistat for the treatment of interstitial cystitis: a 3-year follow-up study. Urology 2001;57(6 suppl 1):123. [27] Lokeshwar VB, Selzer MG, Unwala DJ, et al. Uronate peaks and urinary hyaluronic acid levels correlate with interstitial cystitis severity. J Urol 2006;176:1001–7. [28] Ruggieri MR, Chelsky MJ, Rosen SI, et al. Current findings and future research avenues in the study of interstitial cystitis. Urol Clin North Am 1994;21:163–76. [29] Parsons C. Current strategies for managing interstitial cystitis. Expert Opin Pharmacother 2004;5:287–93. [30] Parsons CL, Housley T, Schmidt JD, et al. Treatment of interstitial cystitis with intravesical heparin. Br J Urol 1994;73:504–7. [31] Parsons CL. Prevention of urinary tract infection by the exogenous glycosaminoglycan sodium pentosanpolysulfate. J Urol 1982;127:167–9. Editorial Comment on: Hyaluronic Acid: An Effective Alternative Treatment of Interstitial Cystitis, Recurrent Urinary Tract Infections, and Hemorrhagic Cystitis? Lindsay E. Nicolle Departments of Internal Medicine and Medical Microbiology, University of Manitoba, Winnipeg, MB R3A 1R9, Canada [email protected] In this issue, Iavazzo et al review studies evaluating the use of intravesical instillation of hyaluronic acid, a glucosaminoglycan replacement therapy, for management of interstitial cystitis, recurrent urinary tract infection, or hemorrhagic cystitis [1]. The hyaluronic acid solution is instilled directly into the bladder, and repeated instillations are necessary. An effective treatment for any of these clinical entities could be enthusiastically embraced. However, these syndromes are characterized by remission and relapse and the short-term course for any given patient cannot be predicted. Unfortunately, as the review concludes, available studies are limited in number and quality. The authors identified only nine studies: one involving [32] Toft BR, Nordling J. Recent developments of intravesical therapy of painful bladder syndrome/interstitial cystitis: a review. Curr Opin Urol 2006;16:268–72. [33] Falagas ME, Gorbach SL. Urinary tract infections: practice guidelines. Infect Dis Clin Practice 1995;4: 241–57. [34] Sobota AE. Inhibition of bacterial adherence by cranberry juice; potential use for the treatment of urinary tract infections. J Urol 1984;131:1013–6. [35] Falagas ME, Betsi GI, Tokas T, et al. Probiotics for prevention of recurrent urinary tract infections in women: a review of the evidence from microbiological and clinical studies. Drugs 2006;66:1253–61. [36] Riedl CR, Daha LK, Pfluger H, et al. Intravesical hyaluronic acid for the treatment of interstitial cystitis. J Urol 2003;169(Suppl A):265. [37] Gupta SK. Re: Daha LK, Riedl CR, Lazar D, Hohlbrugger G, Pflüger H. Do cystometric findings predict the results of intravesical hyaluronic acid in women with interstitial cystitis? Eur Urol 2005;47:393–7. Eur Urol 2005;48:534. [38] Leppilahti M, Hellstrom P, Tammela TL. Effect of diagnostic hydrodistension and four intravesical hyaluronic acid instillations on bladder ICAM-1 intensity and association of ICAM-1 intensity with clinical response in patients with interstitial cystitis. Urology 2002;60: 46–51. [39] Porru D, Tinelli C, Gerardini M, et al. Results of treatment of refractory interstitial cystitis with intravesical hyaluronic acid. Urol Int 1997;59:26–9. 40 patients with urinary infection, one examining 5 patients with hemorrhagic cystitis, and seven studies on interstitial cystitis. They identify flaws, including statistical methodology and reporting of adverse effects. Only three studies were randomized trials, one of which used two different regimens of hyaluronic acid. Although the authors suggest two studies were double-blind and placebo-controlled, both of these, on inspection, are uncontrolled ‘‘before and after’’ studies [2,3]. Thus, the knowledge base is insufficient to support any conclusion about the role of hyaluronic acid bladder instillations. Placebo-controlled trials are essential to assess the efficacy of any therapy for chronic diseases without an accepted optimal treatment and with an unpredictable clinical course. For interstitial cystitis and recurrent urinary tract infection, prospective, randomized, placebo-controlled trials of potential therapies have repeatedly been published; such studies are certainly feasible. It is unfortunate that any potentially effective therapy has not been evaluated in appropriate clinical trials and unfair to promote interventions to patients who suffer from distressing illnesses before efficacy is european urology 51 (2007) 1534–1541 documented. We await, with interest, publication of well-conducted, randomized, placebo-controlled trials evaluating the use of intravesical hyaluronic acid for any urologic syndrome. References [1] Iavazzo C, Athanasiou S, Pitsouni E, Falagas ME. Hyaluronic acid: an effective alternative treatment of inter- 1541 stitial cystitis, recurrent urinary tract infections, and hemorrhagic cystitis? Eur Urol 2007;51:1534–41. [2] Gupta SK, Pidcock L, Parr NJ. The potassium sensitivity test: a predictor of treatment response in interstitial cystitis. BJU Int 2005;96:1063–6. [3] Porra D, Tinelli C, Gerardini M, et al. Results of treatment of refractory interstitial cystitis with intravesical hyaluronic acid. Urol Int 1997;59:26–9. DOI: 10.1016/j.eururo.2007.03.021 DOI of original article: 10.1016/j.eururo.2007.03.020