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Brenner Glomerular disease in rheumatology

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Secondary Glomerular
Disease
33
Gerald B. Appel | Jai Radhakrishnan | Vivette D’Agati
CHAPTER OUTLINE
SYSTEMIC LUPUS ERYTHEMATOSUS, 1092
Epidemiology, 1092
Pathogenesis of Systemic Lupus Erythematosus
and Lupus Nephritis, 1093
Pathology of Lupus Nephritis, 1094
Tubulointerstitial Disease, Vascular Lesions,
and Lupus Podocytopathy, 1097
Clinical Manifestations, 1098
Serologic Tests, 1098
Monitoring Clinical Disease, 1099
Drug-Induced Lupus, 1099
Pregnancy and Systemic Lupus
Erythematosus, 1100
Dialysis and Transplantation, 1100
Course and Prognosis of Lupus
Nephritis, 1100
Treatment of Lupus Nephritis, 1102
ANTIPHOSPHOLIPID SYNDROME, 1106
Treatment, 1107
MIXED CONNECTIVE TISSUE DISEASE, 1108
SMALL VESSEL VASCULITIS, 1109
Granulomatosis with Polyangiitis, 1109
Microscopic Polyangiitis, 1114
Eosinophilic Granulomatosis with
Polyangiitis, 1116
GLOMERULAR INVOLVEMENT IN OTHER
VASCULITIDES, 1118
Polyarteritis Nodosa (Classic Macroscopic
Polyarteritis Nodosa), 1118
Temporal Arteritis (Giant Cell Arteritis), 1120
Takayasu Arteritis, 1120
HENOCH-SCHÖNLEIN PURPURA, 1121
Clinical Findings, 1121
Laboratory Features, 1121
Pathology, 1122
Pathogenesis, 1123
Course, Prognosis, and Treatment, 1123
ANTI–GLOMERULAR BASEMENT
MEMBRANE DISEASE AND GOODPASTURE’S
SYNDROME, 1124
Pathogenesis, 1124
Clinical Features, 1125
Laboratory Findings, 1125
Pathology, 1125
Course, Treatment, and Prognosis, 1126
SJÖGREN’S SYNDROME, 1127
SARCOIDOSIS, 1127
AMYLOIDOSIS, 1128
AL and AA Amyloidosis, 1128
End-Stage Kidney Disease in
Amyloidosis, 1132
FIBRILLARY GLOMERULONEPHRITIS AND
IMMUNOTACTOID
GLOMERULONEPHRITIS, 1132
MONOCLONAL IMMUNOGLOBULIN
DEPOSITION DISEASE, 1134
OTHER GLOMERULAR DISEASES AND
DYSPROTEINEMIA, 1136
WALDENSTRÖM’S
MACROGLOBULINEMIA, 1136
MIXED CRYOGLOBULINEMIA, 1137
HEREDITARY NEPHRITIS, INCLUDING
ALPORT’S SYNDROME, 1138
Clinical Features, 1138
Pathology, 1139
Pathogenesis and Genetics, 1140
Course and Treatment, 1141
THIN BASEMENT MEMBRANE
NEPHROPATHY, 1141
Clinical Features, 1141
Pathology, 1142
Pathogenesis, 1142
Differential Diagnosis of Familial
Hematurias, 1142
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SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
NAIL-PATELLA SYNDROME (HEREDITARY
OSTEO-ONYCHODYSPLASIA), 1142
Clinical Features, 1142
Pathology, 1143
Pathogenesis, 1143
Treatment, 1143
FABRY’S DISEASE (ANGIOKERATOMA
CORPORIS DIFFUSUM UNIVERSALE), 1143
Clinical Features, 1143
Pathology, 1144
Pathogenesis, 1144
Diagnosis, 1144
Treatment, 1145
SICKLE CELL NEPHROPATHY, 1145
Clinical Features, 1145
Pathology, 1145
Pathogenesis, 1146
Treatment, 1146
LIPODYSTROPHY, 1146
LECITHIN-CHOLESTEROL ACYLTRANSFERASE
DEFICIENCY, 1147
Clinical Features, 1147
Pathology, 1147
Pathogenesis, 1148
Diagnosis, 1148
Treatment, 1148
LIPOPROTEIN GLOMERULOPATHY, 1148
GLOMERULAR INVOLVEMENT WITH
BACTERIAL INFECTIONS, 1148
Infectious Endocarditis, 1148
Shunt Nephritis, 1149
Visceral Infection, 1149
Other Bacterial Infections and Fungal
Infections, 1149
SYSTEMIC LUPUS ERYTHEMATOSUS
Lupus nephritis (LN) is a frequent and potentially serious
complication of systemic lupus erythematosus (SLE).1-6
Kidney disease influences morbidity and mortality both
directly and indirectly through complications of therapy.
Recent studies have more clearly defined the spectrum of
clinical, prognostic, and renal histopathologic findings in
SLE. Controlled randomized trials of induction therapy for
severe LN have focused on achieving remissions of renal
disease while minimizing adverse reactions to therapy. Maintenance trials have compared the efficacy of therapeutic
agents in preventing renal flares and the progression of
renal disease over several years. For patients who fail to
respond to current treatment regimens, a number of newer
GLOMERULAR INVOLVEMENT WITH
PARASITIC DISEASES, 1150
Malaria, 1150
Schistosomiasis, 1150
Leishmaniasis, Trypanosomiasis, and
Filariasis, 1150
Other Parasitic Diseases, 1151
GLOMERULAR INVOLVEMENT WITH VIRAL
INFECTIONS, 1151
HIV-Related Glomerulopathies, 1151
HIV-Associated Nephropathy, 1151
Other Glomerular Lesions in Patients with HIV
Infection, 1153
GLOMERULAR MANIFESTATIONS OF LIVER
DISEASE, 1154
Hepatitis B, 1154
Hepatitis C, 1155
Autoimmune Chronic Active Hepatitis, 1156
Liver Cirrhosis, 1156
GLOMERULAR LESIONS ASSOCIATED WITH
NEOPLASIA, 1157
Clinical and Pathologic Features, 1157
GLOMERULAR DISEASE ASSOCIATED WITH
DRUGS, 1157
Heroin Nephropathy, 1157
Nonsteroidal Antiinflammatory Drug–Induced
Nephropathy, 1158
Anti–Rheumatoid Arthritis Therapy–Induced
Glomerulopathy, 1158
Other Medications, 1159
MISCELLANEOUS DISEASES ASSOCIATED
WITH GLOMERULAR LESIONS, 1159
immunomodulatory agents are being studied in resistant or
relapsing disease.
EPIDEMIOLOGY
The incidence and prevalence of SLE depend on the age,
gender, geographic locale, and ethnicity of the population
studied as well as the diagnostic criteria for defining SLE.1,6-9
Females outnumber males by about 10 to 1. However, males
with SLE have the same incidence of renal disease as females.
The onset of disease peaks between 15 and 45 years of age
and more than 85% of patients are younger than 55 years
of age. SLE is more often associated with severe nephritis in
children and in males and is milder in older adults.1,3,7,8 SLE
and LN are more common and are associated with more
severe renal involvement in African American, Asian, and
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CHAPTER 33 — Secondary Glomerular Disease
Hispanic populations although the precise roles of biologicgenetic versus socioeconomic factors have not been clearly
defined.1,10-12 The overall incidence of SLE ranges from 1.8
to 7.6 cases per 100,000 with a prevalence of from 40 to 200
cases per 100,000.1,6,7 The incidence of renal involvement
varies depending on the populations studied, the diagnostic
criteria for kidney disease, and whether involvement is
defined by renal biopsy or clinical findings. Approximately
25% to 50% of unselected lupus patients will have clinical
renal disease at onset while as many as 60% of adults with
SLE will develop renal disease during their course.1,2,5,7,8
A number of genetic, hormonal, and environmental
factors clearly influence the course and severity of SLE.1,2,6-9
A multiplicity of genes are involved in both SLE and LN. A
genetic predisposition is supported by a higher concordance rate in monozygotic twins (25%) than fraternal twins
(<5%), the greater risk of relatives of SLE patients developing SLE or other autoimmune disease, the association with
certain HLA genotypes (e.g., HLA-B8, HLA-DR2, and HLADR3), inherited deficiencies in complement components
(e.g., homozygous C1q, C2, and C4 deficiencies), and Fc
receptor polymorphisms.1,13 Genome-wide analyses have
identified approximately 20 different genetic loci associated
with an increased risk of SLE. These candidate susceptibility
genes regulate diverse immune functions such as T cell
activation, B cell signaling, Toll-like receptors, signal transduction, neutrophil function, and interferon (IFN) production.1,8 Inbred spontaneous genetic murine models of SLE
and LN include the NZB B/W F1 hybrid, the BXSB, and the
MRL/lpr mouse. SLE is inducible in some murine strains
through injection of autoantibodies against DNA or by
injection of Smith antigen peptides. Evidence for the role
of hormonal factors includes the strong predominance of
SLE in females of childbearing age and the increased incidence of lupus flares during or shortly after pregnancy.1,2,6,9-14
In the F1 NZB/NZW mice, females have more severe disease
than males and disease severity is ameliorated by oophorectomy or androgen therapy. Environmental factors other
than estrogens also modulate disease expression; these
factors include immune responses to viral or bacterial antigens, exposure to sunlight and ultraviolet radiation, and
certain medications.1,6,9,14,15
For study purposes, the diagnosis of SLE is established by
the presence of certain clinical and laboratory criteria
defined by the American College of Rheumatology (ACR).1,5
Development of any 4 of the 11 criteria over a lifetime gives
a 96% sensitivity and specificity for SLE. These criteria
include malar rash, discoid rash, photosensitivity, oral ulcerations, nondeforming arthritis, serositis (including pleuritis
or pericarditis), central nervous system disorder (such
as seizures or psychoses), renal involvement, hematologic
disorder (including hemolytic anemia, leukopenia, lymphopenia, or thrombocytopenia), immunologic disorder
(including anti-DNA antibody, anti-Sm antibody, lupus anticoagulant, or antiphospholipid antibody), and antinuclear
antibody (ANA). The criterion of renal involvement is
defined by persistent proteinuria exceeding 500 mg/dL/
day (or 3+ on the dipstick) or the presence of cellular
urinary casts. Because some patients, especially those with
mesangial or membranous LN, will present with clinical
renal disease before they have fulfilled 4 of the 11 criteria,
the diagnosis of SLE remains a clinical diagnosis with
1093
histopathologic findings supporting or confirming the presumed diagnosis.1
PATHOGENESIS OF SYSTEMIC LUPUS
ERYTHEMATOSUS AND LUPUS NEPHRITIS
In patients with SLE, abnormalities of immune regulation
lead to a loss of self-tolerance, autoimmune responses, and
the production of a variety of autoantibodies and immune
complexes.1,2,14-20 SLE is associated with defective regulation
of T cells with decreased numbers of cytotoxic and suppressor T cells, increased helper (CD4+) T cells, dysfunctional
T cell signaling, and abnormal TH1, TH2, and TH17 cytokine
production.1,6,16-21 There is also polyclonal activation of B
cells and defective B cell tolerance. The failure of apoptotic
mechanisms to delete autoreactive B cell and T cell clones
may promote their expansion and may trigger immune
responses through interactions with Toll-like receptors with
subsequent autoantibody production. The result of this loss
of tolerance is the production of a wide range of autoantibodies, including those directed against nucleic acids,
nucleosomes (double-stranded DNA in association with a
core of positively charged histones), chromatin antigens,
and nuclear and cytoplasmic ribonuclear proteins.1,6,15,20,22
Viral or bacterial peptides containing sequences similar to
native antigens may lead to “antigen mimicry” and stimulate
autoantibody production.
In SLE, autoantibodies combine with self antigens to
produce circulating immune complexes that deposit in the
glomeruli, activate complement, and incite an inflammatory
response. Immune complexes are also detectable in the skin
at the dermal-epidermal junction, in the choroid plexus,
pericardium, and pleural spaces. Renal involvement in SLE
has been considered a human prototype of classic experimental chronic immune complex–induced glomerulonephritis.23 The chronic deposition of circulating immune
complexes plays a major role in the mesangial and the
endocapillary proliferative patterns of LN. Immune complex
size, charge, avidity, local hemodynamic factors, and the
clearing ability of the mesangium influence the localization
of circulating immune complexes within the glomerulus.2,6,17,23 In diffuse proliferative LN, the deposited complexes consist of nuclear antigens (e.g., DNA) and
high-affinity complement-fixing immunoglobulin G (IgG)
antibodies.1,2,23 In some SLE patients, the initiating event
may be the local binding of cationic nuclear antigens such
as histones to the subepithelial region of the glomerular
capillary wall, followed by in situ immune complex formation. Once glomerular immune deposits form, the complement cascade is activated, leading to complement-mediated
damage, activation of procoagulant factors, leukocyte Fc
receptor activation with leukocyte infiltration, release of
proteolytic enzymes, and production of various cytokines
regulating glomerular cellular proliferation and matrix
synthesis.
Neutrophils undergoing cell death may release chromatin meshworks (called neutrophil extracellular traps
[NETs]). These NETs, which are detectable in LN biopsies,
are not degraded properly in patients with lupus and are a
source of autoantigen presentation and induction of IFN-α
by plasmacytoid dendritic cells.24 There is also evidence for
intrarenal autoantibody production in patients with LN.25
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SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
Glomerular damage may be potentiated by mechanisms
distinct from immune complex deposition, such as hypertension and coagulation abnormalities. Some lupus
patients with associated antineutrophil cytoplasmic antibodies (ANCAs) have documented focal segmental necrotizing
glomerular lesions without significant immune complex
deposition, resembling a “pauci-immune” glomerulonephritis.26,27 The presence of antiphospholipid antibodies, with
their attendant alterations in endothelial and platelet function (including reduced production of prostacyclin and
other endothelial anticoagulant factors, activation of plasminogen, inhibition of protein C or S, and enhanced platelet aggregation), can also potentiate glomerular and vascular
lesions.27
PATHOLOGY OF LUPUS NEPHRITIS
1-4,23
The histopathology of LN is pleomorphic.
This diversity
is evident when comparing biopsy findings from different
patients or even adjacent glomeruli in a single biopsy. Moreover, the lesions have the capacity to transform from one
pattern to another spontaneously or following treatment.
Early classifications of LN simply divided glomerular changes
into mild and severe forms.2,23 The World Health Organization (WHO) classification system, used for almost 30
years,28,29 classified LN by combining glomerular light microscopic, immunofluorescence, and electron microscopic
findings. The 2003 International Society of Nephrology/
Renal Pathology Society (ISN/RPS) classification of LN
addressed limitations of the WHO classification system and
is now widely accepted by nephrologists, pathologists, and
rheumatologists30 (Table 33.1). It has proven more reproducible and provides more standardized definitions for
precise clinical pathologic correlations.31,32
ISN/RPS class I denotes normal-appearing glomeruli by
light microscopy but with mesangial immune deposits
by immunofluorescence and electron microscopy. Even
patients without clinical renal disease often have mesangial
immune deposits when studied carefully by the more sensitive techniques of immunofluorescence and electron
microscopy.30
ISN/RPS class II is defined on light microscopy by mesangial hypercellularity, with mesangial immune deposits on
immunofluorescence and electron microscopy (Figures
33.1, 33.2, and 33.3).30 Mesangial hypercellularity is defined
as more than three cells in mesangial regions distant from
the vascular pole in 3-µm–thick sections. There may be rare
minute subendothelial or subepithelial deposits visible by
immunofluorescence or electron microscopy but not by
light microscopy.
ISN/RPS class III, focal LN, is defined as focal segmental
and/or global endocapillary and/or extracapillary glomerulonephritis affecting less than 50% of the total glomeruli
sampled. Both active and chronic lesions are taken into
account when determining the percentage of total glomeruli involved. There is typically focal segmental endocapillary proliferation, including mesangial cells and endothelial
cells, with infiltrating mononuclear and polymorphonuclear
leukocytes (Figures 33.4, 33.5, and 33.6).30 Class III biopsies
are classified as A (active, proliferative), C (inactive, chronic
sclerosing), or A/C (active and inactive lesions). Active
lesions may display cellular crescents, fibrinoid necrosis,
Table 33.1 International Society of Nephrology/
Renal Pathology Society (2003)
Classification of Lupus Nephritis (LN)
Class
Description
I
II
III
Minimal mesangial LN
Mesangial proliferative LN
Focal LN* (<50% of glomeruli)
Active lesions
Active and chronic lesions
Chronic lesions
Diffuse LN† (≥50% of glomeruli)
Diffuse segmental (IV-S) or global (IV-G) LN
Active lesions
Active and chronic lesions
Chronic lesions
Membranous LN
Advanced sclerosing LN
(≥90% globally sclerosed glomeruli without
residual activity)
III (A)
III (A/C)
III (C)
IV
IV (A)
IV (A/C)
IV (C)
V‡
VI
*Indicate the proportion of glomeruli with active and with sclerotic
lesions.
†
Indicate the proportion of glomeruli with fibrinoid necrosis and
with cellular crescents.
‡
Class V may occur in combination with III or IV, in which case
both will be diagnosed.
Figure 33.1 Lupus nephritis class II. There is mild global mesangial
hypercellularity. (Periodic acid–Schiff stain, ×400.)
nuclear pyknosis or karyorrhexis, and rupture of the glomerular basement membrane (GBM). Hematoxylin bodies,
swollen basophilic nuclear material resulting from binding
to ambient ANAs, are occasionally found within the necrotizing lesions. Subendothelial immune deposits may be
visible by light microscopy as “wire loop” thickenings of the
glomerular capillary walls or large intraluminal masses
known as “hyaline thrombi.” Chronic glomerular lesions
consist of segmental and/or global glomerular sclerosis
owing to scarred glomerulonephritis with or without fibrous
crescents.30 In class III biopsies, glomeruli adjacent to those
with severe histologic changes may show only mesangial
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CHAPTER 33 — Secondary Glomerular Disease
1095
Figure 33.5 Lupus nephritis class III. The glomerular endocapillary
proliferation is discretely segmental with necrotizing features and an
early cellular crescent. (Jones’ methenamine silver stain, ×400.)
Figure 33.2 Lupus nephritis class II. Immunofluorescence photomicrograph showing deposits of C3 restricted to the glomerular mesangium. (×400.)
Figure 33.6 Lupus nephritis class III. Electron micrograph showing
deposits in the mesangium as well as involving the peripheral capillary
wall in subendothelial (double arrow) and subepithelial (single arrows)
locations. (×4900.)
Figure 33.3 Lupus nephritis class II. Electron micrograph showing
abundant mesangial electron-dense deposits (×12,000.)
Figure 33.4 Lupus nephritis class III. There is focal segmental endocapillary proliferation. (Jones’ methenamine silver stain, ×100.)
abnormalities by light microscopy. In class III, diffuse mesangial and focal and segmental subendothelial immune deposits are typically identified by immunofluorescence and
electron microscopy. The segmental subendothelial deposits are usually present in the distribution of the segmental
endocapillary proliferative lesions.
ISN/RPS class IV, diffuse LN, has qualitatively similar
glomerular endocapillary and/or extracapillary lesions as
class III but involves more than 50% of the total glomeruli
sampled (Figures 33.7, 33.8, and 33.9).28,30,33,34 Again, both
active (proliferative) and chronic (sclerosing) lesions are
included when determining the percentage of glomeruli
affected. Class IV is subdivided into diffuse segmental proliferation, class IV-S, in which more than 50% of affected
glomeruli have segmental lesions, and diffuse global proliferation, class IV-G, in which more than 50% of affected
glomeruli have global lesions. All the active features
described earlier for class III (including fibrinoid necrosis,
leukocyte infiltration, wire loop deposits, hyaline thrombi,
hematoxylin bodies, and crescents) may be encountered in
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SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
Figure 33.7 Lupus nephritis class IV. There is global endocapillary
proliferation with infiltrating neutrophils and segmental wire loop
deposits. (Hematoxylin and eosin stain, ×320.)
Figure 33.10 Lupus nephritis class V. There is diffuse uniform thickening of glomerular basement membranes accompanied by mild
segmental mesangial hypercellularity. (Hematoxylin and eosin stain,
×320.)
Figure 33.8 Lupus nephritis class IV. Immunofluorescence photomicrograph showing global deposits of IgG in the mesangial regions
and outlining the subendothelial aspect of the peripheral glomerular
capillary walls. (×600.)
Figure 33.11 Lupus nephritis class V. Silver stain highlights glomerular basement membrane (GBM) spikes projecting outward from
the GBMs toward the urinary space. (Jones’ methenamine silver
stain, ×800.)
Figure 33.9 Lupus nephritis class IV. Electron micrograph showing
a large subendothelial electron-dense deposit as well as a few small
subepithelial deposits (arrow). (×1200.)
class IV LN. In general, there is more extensive peripheral
capillary wall subendothelial immune deposition, and
extracapillary proliferation in the form of crescents is not
uncommon. Class IV lesions may have features similar to
those of primary membranoproliferative glomerulonephritis (MPGN; also known as mesangiocapillary glomerulonephritis) with mesangial interposition along the peripheral
capillary walls and double contours of the GBMs. Some class
III and IV biopsies will have focal necrotizing and crescentic
lesions akin to those seen in small vessel vasculitides. Some
of these patients have had circulating ANCAs.26,35
ISN/RPS class V is defined by regular subepithelial
immune deposits producing a membranous pattern (Figures
33.10, 33.11, and 33.12).30,36-38 The coexistence of mesangial
immune deposits and mesangial hypercellularity in most
cases helps to distinguish membranous LN from primary
membranous glomerulopathy.39 Early membranous LN class
V may have no identifiable abnormalities by light microscopy, but subepithelial deposits are detectable by immunofluorescence and electron microscopy. In well-developed
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CHAPTER 33 — Secondary Glomerular Disease
1097
intracellular branching tubular structures measuring 24 nm
in diameter located within dilated cisternae of the endoplasmic reticulum of glomerular and vascular endothelial cells,
are commonly observed in SLE biopsies.2,4,23 Tubuloreticular inclusions are inducible on exposure to IFN-α (so-called
interferon footprints) and are also present in biopsies of
patients infected with human immunodeficiency virus
(HIV) and those with some other viral infections.40
Figure 33.12 Lupus nephritis class V. Electron micrograph showing
numerous subepithelial electron-dense deposits as well as mesangial
deposits. (×5000.)
membranous lesions, there is typically thickening of the
glomerular capillary walls and “spike” formation between
the subepithelial deposits. Because sparse subepithelial
deposits may also be encountered in other classes (III or IV)
of LN, a diagnosis of pure lupus membranous LN should
be reserved only for those cases in which the membranous
pattern predominates. When the membranous alterations
involve more than 50% of the total glomerular capillaries
and are accompanied by focal or diffuse endocapillary proliferative lesions and subendothelial immune complex
deposition, they are classified as class V + III or class V + IV,
respectively.
ISN/RPS class VI, advanced sclerosing LN or end-stage
LN, is reserved for biopsies with more than 90% of the
glomeruli sclerotic and no residual activity.30 In such cases,
it may be difficult even to establish the diagnosis of LN
without the identification of residual glomerular immune
deposits by immunofluorescence and electron microscopy
or a biopsy history of prior active LN.
IMMUNOFLUORESCENCE
In LN, immune deposits can be found in the glomeruli,
tubules, interstitium, and blood vessels.2-4,23,39 IgG is almost
universal, with co-deposits of IgM, IgA, C3, and C1q
common.2,23,30 The presence of all three immunoglobulins
(IgG, IgA, and IgM) along with the two complement components (C1q and C3) is known as “full house” staining and
is highly suggestive of LN. Staining for fibrin-fibrinogen is
common in crescents and segmental necrotizing lesions.
The “tissue ANA”39 (i.e., nuclear staining of renal epithelial
cells in sections stained with fluoresceinated antisera to
human IgG) is a frequent finding in any LN class. It results
from the binding of patient’s own ANA to nuclei exposed
in the course of cryostat sectioning.
ELECTRON MICROSCOPY
The distribution of glomerular, tubulointerstitial, and vascular deposits seen by electron microscopy correlates closely
with that observed by immunofluorescence microscopy.2,6,23
Deposits are typically electron dense and granular.
Some exhibit focal organization with a “fingerprint” substructure composed of curvilinear parallel arrays measuring
10 to 15 nm in diameter.2,23 Tubuloreticular inclusions,
ACTIVITY AND CHRONICITY
Some investigators grade biopsies for features of activity
(potentially reversible lesions) and chronicity (irreversible
lesions). In the widely used National Institutes of Health
(NIH) system, activity index is calculated by grading the
biopsy on a scale of 0 to 3+ for each of six histologic features;
these features are endocapillary proliferation, glomerular
leukocyte infiltration, wire loop deposits, fibrinoid necrosis
and karyorrhexis, cellular crescents, and interstitial inflammation.41 The severe lesions of crescents and fibrinoid
necrosis are assigned double weight. The sum of the individual components yields a total histologic activity index
score of from 0 to 24. Likewise, a chronicity index of 0 to
12 is derived from the sum of glomerulosclerosis, fibrous
crescents, tubular atrophy, and interstitial fibrosis, each
graded on a scale of 0 to 3+. Studies at the NIH correlated
both a high activity index (>12) and especially a high chronicity index (>4) with a poor 10-year renal survival rate.41
However, in several other large studies, neither the activity
index nor the chronicity index correlated well with longterm prognosis.28,42,43 Other NIH studies concluded that a
combination of an elevated activity index (>7) and an elevated chronicity index (>3) predicts a poor long-term
outcome.41 A major value of calculating the activity and
chronicity indices is in the comparison of sequential biopsies in individual patients. This provides useful information
about the efficacy of therapy and the relative degree of
reversible versus irreversible lesions.2-4,23,44,45
TUBULOINTERSTITIAL DISEASE, VASCULAR
LESIONS, AND LUPUS PODOCYTOPATHY
Some SLE patients have major changes in the tubulointerstitial compartment.46-49 Active tubulointerstitial lesions
include edema and inflammatory infiltrates, including T
lymphocytes (both CD4+ and CD8+ cells), monocytes, and
plasma cells.49 Tubulointerstitial immune deposits of immunoglobulin and/or complement may be present along the
basement membranes of tubules and interstitial capillaries.
Severe acute interstitial changes and tubulointerstitial
immune deposits are most commonly found in patients with
active proliferative class III and IV LN. The degree of interstitial inflammation does not correlate well with the presence or quantity of tubulointerstitial immune deposits.46,47
Interstitial fibrosis, tubular atrophy, or both are commonly
encountered in the more chronic phases of LN. One study
documented a strong inverse correlation between the
degree of tubular damage and renal survival.47 In addition,
the renal survival rate was higher for patients with less
expression on their renal biopsy of the intercellular adhesion molecule-1 (ICAM-1).48
Vascular lesions are not included in either the ISN/RPS
classification or in the NIH activity and chronicity indices
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SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
despite their frequent occurrence and clinical significance.27,50-52 The most frequent vascular lesion is simple vascular immune deposition, most common in patients with
active class III and IV biopsies. Vessels may be normal by
light microscopy, but by immunofluorescence and electron
microscopy there are granular immune deposits in the
media and intima of small arteries and arterioles. Noninflammatory necrotizing vasculopathy, most common in arterioles in active class IV LN, is a fibrinoid necrotizing lesion
without leukocyte infiltration that severely narrows or
occludes the arteriolar lumen. True inflammatory vasculitis
resembling polyangiitis is extremely rare in SLE patients.
It may be renal limited or part of a more generalized
systemic vasculitis.27,51,52 Thrombotic microangiopathy
involving vessels and glomeruli may be associated with
anticardiolipin/antiphospholipid antibody or a hemolytic
uremic/thrombotic thrombocytopenic purpura (HUS/
TTP)–like syndrome.27,51,52
A number of other renal diseases have been documented
on biopsy in SLE patients, including podocytopathies with
features of minimal change disease, focal segmental glomerulosclerosis (FSGS), or collapsing glomerulopathy.53-55
In some, the relationship between SLE and the podocytopathy suggests this is not a coincidental occurrence but perhaps
related to SLE-induced cytokine effects on podocyte function. A collapsing pattern of focal sclerosis in SLE patients
of African descent has been associated with APOL1 risk
alleles.56
CLINICAL MANIFESTATIONS
Although SLE predominantly affects young females, the
clinical manifestations are similar in both sexes and in
adults and children.5-8 Organ systems commonly affected
include the kidneys, joints, serosal surfaces (including
pleura and pericardium), central nervous system, and skin.
In addition, cardiac, hepatic, pulmonary, hematopoietic,
and gastrointestinal involvement is not infrequent.
Renal involvement often develops concurrently or shortly
after the onset of SLE and may follow a protracted course
with periods of remissions and exacerbations. Clinical renal
involvement usually correlates well with the degree of glomerular involvement. However, some patients may have disproportionately severe vascular or tubulointerstitial lesions
that dominate the clinical course.27,46,52
Patients with ISN/RPS class I biopsies often have little
evidence of clinical renal disease. Likewise, most patients
with mesangial lesions (ISN/RPS class II) have mild or
minimal clinical renal findings.1-4,21,28 They may have active
lupus serology (a high anti-DNA antibody titer and low
serum complement), but the urinary sediment is inactive,
hypertension is infrequent, proteinuria is usually less than
1 g/day, and the serum creatinine concentration and glomerular filtration rate (GFR) are usually normal. Nephroticrange proteinuria is extremely rare unless there is a
superimposed podocytopathy.53,54
Class III, focal proliferative LN, is often associated with
active lupus serologies, although the degree of serologic
activity does not necessarily correlate with the histologic
severity.28,33 Hypertension and active urinary sediment are
common. Proteinuria is often more than 1 g/day, and one
quarter to one third of patients with focal LN have nephrotic
syndrome at presentation. Many patients have an elevated
serum creatinine concentration at presentation. Patients
with less extensive glomerular proliferation, fewer necrotizing features, and no crescents are more likely to be normotensive and have preserved renal function.
Patients with ISN/RPS class IV, diffuse proliferative LN,
typically present with the most active clinical features. They
often have high anti-DNA antibody titers, low serum complement levels, and very active urinary sediment, with erythrocytes, and cellular casts on urinalysis.1-4,28,30,32,34 Virtually all
have proteinuria and as many as 50% of the patients will
have nephrotic syndrome. Hypertension and renal dysfunction are typical. Even when the serum creatinine level is in
the “normal range,” the GFR is usually depressed.
Patients with membranous LN, ISN/RPS class V, typically
present with proteinuria, edema, and other manifestations
of nephrotic syndrome.1-4,28,30,36-38 However, as many as 40%
will have proteinuria of less than 3 g/day, and 16% to 20%
less than 1 g/day. Only about 60% of membranous LN
patients have a low serum complement concentration and
an elevated anti-DNA antibody titer at presentation.28
However, hypertension and renal dysfunction may occur
without superimposed proliferative lesions. Patients with
membranous LN may present with nephrotic syndrome
before developing other clinical and laboratory manifestations of SLE.28,36-38 In addition, they are predisposed to
thrombotic complications such as renal vein thrombosis and
pulmonary emboli.27,51 Patients with mixed membranous
and proliferative biopsies have clinical features that reflect
both disease components.
End-stage LN, ISN/RPS class VI, is usually the result of
“burned-out” LN of long duration.30 Some renal histologic
damage may represent nonimmunologic progression of
sclerosis mediated by hyperfiltration in remnant nephrons.
Although the lesions are sclerosing and inactive, class VI
patients may still have microhematuria and proteinuria. Virtually all have hypertension and a decreased GFR. Levels of
anti-DNA antibodies and serum complement levels often
normalize at this late stage of disease.
“Silent LN”1,22,57 has been described in patients without
clinical evidence of renal involvement despite biopsy evidence of active proliferative LN. Some define silent LN as
active biopsy lesions without active urinary sediment, proteinuria, or a depressed GFR, whereas others require negative lupus serologies as well. Although silent LN is well
described in some studies, others have been unable to find
even isolated examples.1,21 It appears to be uncommon, and
it is highly likely that even patients with true “silent disease”
will manifest clinical renal involvement when followed into
their course.
SEROLOGIC TESTS
The presence of antibodies directed against nuclear antigens (ANAs) and especially against DNA (anti-DNA) antibodies are included in the ACR criteria for SLE and are
commonly used to monitor the disease course.1,6,15 ANAs are
a highly sensitive screen for SLE, being found in more than
90% of untreated patients, but they are not specific for SLE
and occur in many other rheumatologic and nonrheumatologic conditions.1,6,15,23 Neither the particular
pattern of ANA fluorescence (homogeneous, speckled,
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CHAPTER 33 — Secondary Glomerular Disease
nucleolar, or rim) nor the titer correlates well with the presence or the severity of renal involvement in SLE.
Autoantibodies directed against double-stranded DNA
(anti-dsDNA) are a more specific but less sensitive marker
of SLE and are found in almost three fourths of untreated
active SLE patients.1,6,15 Anti-dsDNA IgG antibodies of high
avidity that fix complement have correlated best with the
presence of renal disease,1,6,15 and such anti-dsDNA antibodies have been found in the glomerular immune deposits of
murine and human LN.1,15,58,59 High anti-dsDNA antibody
titers correlate well with clinical activity.1,6,15 Anti–singlestranded DNA antibodies (anti-ssDNA), commonly found in
SLE and other collagen vascular diseases, do not correlate
with clinical lupus activity.
Autoantibodies directed against ribonuclear antigens are
commonly present in lupus patients and include antiSm and anti-nRNP against extractable nuclear antigen
(ENA).1,6,15,20 Anti-Sm antibodies, although very specific for
SLE, are found in only about 25% of lupus patients and are
of unclear prognostic value. Anti-nRNP antibodies, found
in over one third of SLE patients, are also present in many
other rheumatologic diseases, particularly mixed connective
tissue disease.15,20,60 Anti-Ro/SSA antibodies are directed
against the protein complex of a cytoplasmic RNA and are
present in 25% to 30% of SLE patients. Anti-La/SSB autoantibodies, directed against a nuclear RNP antigen, are
present in from 5% to 15% of lupus patients. Neither of the
latter two antibodies is specific for SLE and both are found
in other collagen vascular diseases, especially Sjögren’s syndrome. Maternal anti-Ro antibodies are important in the
pathogenesis of neonatal lupus and the development of
cardiac conduction abnormalities in the newborn.61 Anti-Ro
antibodies are also associated with a unique dermal psoriasiform type of lupus, with SLE patients who are homozygous C2 deficient, and with a vasculitic disease associated
with central nervous system involvement and cutaneous
ulcers.62,63 In addition, lupus patients may develop antibodies directed against histones, endothelial cells, phospholipids, the N-methyl-d-aspartate receptor (associated with
central nervous system disease in SLE) and neutrophil cytoplasmic antigens (ANCAs).64-66
Levels of total hemolytic complement (CH50) and complement components are usually decreased during active
SLE and especially active LN.1,4,6 Levels of C4 and C3 often
decline before a clinical flare of SLE. Serial monitoring of
complement levels, with a decline in levels predicting a
flare, is considered more useful clinically than an isolated
depressed C3 or C4 value.4 Likewise, normalization of
depressed serum complement levels is often associated with
improved renal outcome.67 Levels of total complement and
C3 may be decreased in the absence of active systemic or
renal disease in patients with extensive dermatologic involvement by SLE. Several heritable complement deficiency
states (including C1r, C1s, C2, C4, C5, and C8) have been
associated with SLE, and such patients may have depressed
total complement levels despite inactive disease.68
Other immunologic test results commonly found in lupus
patients include elevated levels of circulating immune complexes, a positive lupus band test, and the presence of cryoglobulins. None correlates well with SLE or LN activity.69-71
In both SLE and isolated discoid lupus, immune complex
deposits containing IgG antibody and complement are
1099
found along the dermal-epidermal junction of involved skin
lesions.8,70 The presence of granular deposits in clinically
unaffected skin (the lupus band test) is usually found only
in patients with systemic disease. However, the specificity
and sensitivity of this test is debated, and it requires immunofluorescence microscopy of the dermal biopsy.1 Patients
with SLE commonly have a false-positive Venereal Disease
Research Laboratory (VDRL) test result due to the presence
of antiphospholipid antibodies.1
MONITORING CLINICAL DISEASE
It is important to be able to predict systemic and renal
relapses and prevent their occurrence through the judicious
use of immunosuppressive agents. Serial measurements of
many serologic tests (including complement components,
autoantibodies, erythrocyte sedimentation rate [ESR],
C-reactive protein [CRP], circulating immune complexes,
and, recently, levels of cytokines and interleukins) have
been used to predict lupus flares. Although there is controversy regarding the value of serum C3 and C4 levels and
anti-DNA antibody titers in predicting clinical flares of SLE
or LN, these have yet to be replaced by new biomarkers.3,6,71
Serum levels of anti-dsDNA typically rise and serum complement levels typically fall as the clinical activity of SLE
increases, often preceding clinical renal deterioration. In
patients with active renal involvement, the urinalysis frequently reveals dysmorphic erythrocytes, red blood cell
casts, and other formed elements. An increase in proteinuria from levels of less than 1 g/day to more than this
amount, and certainly from low levels to nephrotic levels, is
a clear indication of either increased activity or a change in
renal histologic class.3,28
DRUG-INDUCED LUPUS
A variety of medications may induce a lupus-like syndrome
or exacerbate an underlying predisposition to SLE. Those
medications metabolized by acetylation, such as procainamide and hydralazine, have been common causes.72,73
This occurs more commonly in patients who are slow acetylators due to a genetic decrease in hepatic N-acyltransferase.
Diltiazem, minocycline, penicillamine, isoniazid, methyldopa, chlorpromazine, and practolol are other potential
causes of drug-induced lupus.72-75 Other drugs that
have been associated less frequently with this syndrome
include phenytoin, quinidine, propylthiouracil, sulfonamides, lithium, β-blockers, nitrofurantoin, PAS, captopril,
glyburide, hydrochlorothiazide, interferon alfa, carbamazepine, sulfasalazine, rifampin, and TNF-α blockers.72,76,77
Clinical manifestations of drug-induced lupus include
fever, rash, myalgias, arthralgias and arthritis, and serositis.
Central nervous system and renal involvement are relatively
uncommon.72,78,79 While elevated anti-DNA antibodies
and depressed serum complement levels are less common
in drug-induced lupus, antihistone autoantibodies are
present in more than 95% of patients.72 These are usually
formed against a complex of the histone dimer H2A-H2B
and DNA and other histone components.72,80 Antihistone
antibodies are also present in the vast majority of idiopathic,
non–drug-related SLE patients, but they are directed primarily against different histone antigens (H1 and H2B).72
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SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
The presence of antihistone antibodies in the absence of
anti-DNA antibodies and other serologic markers for SLE is
also indicative of drug-induced disease. The diagnosis of
drug-induced lupus depends on documenting the offending agent and achieving a remission following withdrawal of
the drug. The primary treatment consists of discontinuing
the offending drug.
PREGNANCY AND SYSTEMIC LUPUS
ERYTHEMATOSUS
Because SLE occurs so commonly in women of childbearing
age, the issue of pregnancy arises often in the care of this
population. Independent but related issues are the health
of the mother (in terms of both flares of lupus activity and
progression of renal disease) and the fate of the fetus. It is
unclear whether flares of lupus activity occur more commonly during pregnancy or shortly after delivery.81-84
Some controlled studies found no increase in lupus flares
in pregnant patients versus nonpregnant lupus controls.81,83,84 Patients with quiescent lupus at the time of pregnancy are less likely to experience an exacerbation of SLE.
However, in two small retrospective studies, flares of lupus
activity including renal involvement occurred in more than
50% of the pregnancies.81,84 This was significantly greater
than the rate of flare after delivery and in nonpregnant
lupus patients.
Pregnancy in patients with preexisting LN has also been
associated with worsening of renal function.85,86 This is less
likely to occur in patients who have been in remission for
at least 6 months. Patients with hypertension are likely to
develop higher blood pressure levels, and those with proteinuria are likely to have increased levels during pregnancy.
Patients with elevated serum creatinine levels are most likely
to suffer worsening of renal function and to be at highest
risk for fetal loss. Although high-dose corticosteroids, cyclosporine, tacrolimus, and azathioprine have all been used in
pregnant lupus patients, their safety is unclear. Cyclophosphamide is contraindicated due to its teratogenicity, and
newer agents such as mycophenolate and rituximab are not
recommended, thus making the treatment of severe LN
difficult.
The rate of fetal loss in all SLE patients in most series is
20% to 40% and may approach 50% in some series.81,83,85,86
While fetal mortality is increased in SLE patients with renal
disease, it may be decreasing in the modern treatment
era.85-88 Patients with anticardiolipin or antiphospholipid
antibodies, hypertension, or heavy proteinuria are at higher
risk for fetal loss.84 One review of 10 studies in more than
550 women with SLE found fetal death occurred in 38% to
59% of all pregnant SLE patients with antiphospholipid
antibodies compared to 16% to 20% of those without these
antibodies.89
DIALYSIS AND TRANSPLANTATION
The percentage of patients with severe LN who progress to
dialysis or transplantation varies from 5% to 50% depending
on the population studied, the length of follow-up, and the
response to therapy.1,4,6,28,90-93 Many with slow progressive
renal failure have a resolution of their extrarenal disease
manifestations and serologic activity.94,95 With more
prolonged time on dialysis, the incidence of clinically active
patients declines further, decreasing in one study from 55%
at the onset of dialysis to less than 10% by the fifth year and
0% by the tenth year of dialysis.95 Patients with end-stage
kidney disease (ESKD) due to LN have increased mortality
during the early months of dialysis due to infectious complications of immunosuppressive therapy.94,95 Long-term
survival of SLE patients on chronic hemodialysis or continuous ambulatory peritoneal dialysis is similar to that of nonlupus patients, with the most common cause of death being
cardiovascular.94-96
Most renal transplant programs suggest that patients with
active SLE undergo a period of dialysis for from 3 to 12
months to allow clinical and serologic disease activity to
become quiescent before transplantation.95 Allograft survival rates in patients with LN are comparable to the rest of
the transplant population.1,4,96-100 The rate of recurrent SLE
in the allograft has been low, less than 4% in most series,96-100
although in several recent reports a higher recurrence rate
has been noted.98 The prevalence of recurrent LN was only
2.44% in a 20-year study of nearly 7000 lupus transplant
recipients and was more common in black, female, and
younger patients.99 When surveillance biopsies were used,
however, recurrences could be detected in as many as 54%
of a small cohort of lupus transplant recipients, although
this was mostly subclinical mild mesangial LN.100 The low
rate of clinically important recurrence may be due, in part,
to the immune suppressant action of the renal failure prior
to transplantation and, in part, to the immunosuppressive
regimens used following transplantation. Lupus patients
with an antiphospholipid antibody may benefit from anticoagulation therapy during the posttransplant period.101,102
COURSE AND PROGNOSIS OF LUPUS NEPHRITIS
The course of patients with LN is extremely varied, with
from less than 5% to more than 60% of patients developing
progressive renal failure.1,2,4,28,33,44,90-93,103 This course is
defined by the initial pattern and severity of renal involvement as modified by therapy, exacerbations of the disease,
and complications of treatment. The prognosis has clearly
improved in recent decades with wider and more judicious
use of new immunosuppressive medications. Most studies
have found additional prognostic value of renal biopsy over
clinical data in patients with LN.33,104-106
Patients with lesions limited to the renal mesangium generally have an excellent course and prognosis.1-4,23 Patients
with lesions that do not transform into other patterns are
unlikely to develop progressive renal failure, and mortality
is due to extrarenal manifestations and complications of
therapy. Patients with focal proliferative disease have an
extremely varied course. Those with mild proliferation
involving a small percentage of glomeruli respond well to
therapy and less than 5% progress to renal failure over 5
years.1-4,28,106,107 Patients with more proliferation, necrotizing
features, and/or crescent formation have a prognosis more
akin to patients with class IV diffuse LN. Class III patients
may transform into class IV over time. Some patients with
very active segmental proliferative and necrotizing lesions
resembling ANCA-associated small vessel vasculitis have a
worse renal prognosis than other patients with focal proliferative lesions.26,35,108
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CHAPTER 33 — Secondary Glomerular Disease
Patients with diffuse proliferative disease have the
least favorable prognosis in most older series.1-4,23,28,33,34 Nevertheless, the prognosis for this group has markedly
improved, with renal survival rates now exceeding 90%
in some series of patients treated with modern immunosuppressive agents.4,34,107,109 In trials from NIH, the risk of doubling the serum creatinine concentration, a surrogate
marker for progressive renal disease, at 5 years in patients
with diffuse proliferative lupus treated with cyclophosphamide-containing regimens ranged from 35% to less than
5%.91,92,109 In an Italian study of diffuse proliferative LN,
survival was 77% at 10 years and more than 90% if extrarenal deaths were excluded.34 In a U.S. study of 89 patients
with diffuse proliferative LN, renal survival was 89% at 1 year
and 71% at 5 years.110 It is unclear whether the improved
survival rates in these recent series are largely due to
improved immunosuppression or better supportive care
and clinical use of these medications.
In the past, some studies have found age, gender, and
race to be as important prognostic variables as clinical features in patient and renal survival in SLE.1,3,10-12,41,105,110-113
However, a consistent finding is that African Americans
have a greater frequency of LN and a worse renal and
overall prognosis.1,3,11,12,41,110-114 This worse prognosis appears
to relate to both biologic/genetic and socioeconomic
factors.11,12 In a study from NIH of 65 patients with severe
LN, clinical features at study entry associated with progressive renal failure included age, black race, hematocrit less
than 26%, and serum creatinine concentration greater than
2.4 mg/dL.41 Patients with combined activity index (>7)
plus chronicity index (>3) on renal biopsy, as well as those
with the combination of cellular crescents and interstitial
fibrosis also had a worse prognosis. In another U.S. study of
89 patients with diffuse proliferative LN, none of the following features affected renal survival: age, gender, SLE duration, uncontrolled hypertension, or any individual histologic
variable.110 Entry serum creatinine level higher than 3.0 mg/
dL, combined activity and chronicity indices on biopsy, and
black race predicted a poor outcome. Five-year renal survival rate was 95% for the Caucasian patients but only 58%
for the black patients. In a study of more than 125 LN
patients with WHO class III or IV from New York, both racial
and socioeconomic factors were associated with the worse
outcomes in African Americans and Hispanics.11 An evaluation of 203 patients from the Miami area confirmed worse
renal outcomes in African Americans and Hispanics related
to both biologic and economic factors.12
More rapid and more complete renal remissions are associated with improved long-term prognosis.115,116 Renal flares
during the course of SLE also may predict a poor renal
outcome.103,117,118 Relapses of severe LN over 5 to 10 years
of follow-up occur in up to 50% of patients and usually
respond less well and more slowly to repeated course of
therapy.3,103,119-121 A retrospective analysis of 70 Italian
patients in which more than half had diffuse proliferative
disease found excellent patient survival (100% at 10 years
and 86% at 20 years) as well as preserved renal function with
probability of not doubling the serum creatinine concentration to be 85% at 10 years and 72% at 20 years.103 Most
patients in this study were Caucasian, which likely influenced the excellent long-term prognosis. Multivariate analysis in the Italian study showed males, those more anemic
1101
and especially those with flare-ups of disease, to have a worse
outcome. Patients with renal flares of any type had 7 times
the risk of renal failure, and those with rapid rises in creatinine had 27 times the chance of doubling their serum creatinine concentration. Another Italian study of 91 patients
with diffuse proliferative LN showed more than 50% having
a renal flare, which correlated with a younger age at biopsy
(<30 years old), higher activity index, and karyorrhexis on
biopsy.117 The number of flares, nephritic flares, and flares
with increased proteinuria correlated with a doubling of the
serum creatinine. The role of relapses in predicting progressive disease has been documented by others as well, although
relapse does not invariably predict a bad outcome.122
While an elevated anti-DNA antibody titer and low serum
complement levels may correlate with active renal involvement, they do not correlate with long-term renal prognosis.1,28,90,103,110 In several studies anemia has been a poor
prognostic finding regardless of the underlying cause.41,103
Severe hypertension has also been related to renal prognosis in some studies but not others.28 Renal dysfunction, as
noted by an elevated serum creatinine or decreased GFR
or by heavy proteinuria, and nephrotic syndrome are
indicative of a poor renal prognosis in the vast majority of
series.1-4,6,33 However, not all studies have found an elevation
of the initial serum creatinine to predict a poor long-term
prognosis, and in some the initial serum creatinine only
predicted short-term renal survival.110 Other renal features,
such as duration of nephritis and rate of decline of GFR,
may also predict prognosis.90,107
Finally, histologic features such as the class, the degree of
activity and chronicity, and the severity of tubulointerstitial
damage have also predicted prognosis. In a number of
studies, the pattern of renal involvement, especially when
using the ISN/RPS or older WHO classification, has been a
useful guide to prognosis.1,2,28,31,32 In NIH trials, patients with
severe proliferative LN with a higher activity index or chronicity index were more likely to have progressive renal
failure.107 Other studies with different referral populations
could not confirm this.2,3,23,28,43 Regardless, the contribution
of chronic renal scarring to a poor long-term outcome has
been confirmed by many studies.48,90,117,122,123 Some studies
have found the initial renal biopsy to have little predictive
value; rather, certain features on a repeat biopsy at 6 months
proved to be a strong predictor of doubling the serum creatinine or progression to renal failure.47,124 These include
ongoing inflammation with cellular crescents, macrophages
in the tubular lumens, persistent immune deposits (especially C3) on immunofluorescence microscopy, and persistent subendothelial and mesangial deposits. Other studies
suggest that reversal of interstitial fibrosis and glomerular
segmental scarring along with remission of initial inflammation and immune deposition is an important favorable prognostic finding on the 6-month biopsy.122 Thus, chronic
changes on biopsy are not always cumulative or immutable,
and their reversal may be crucial in preventing ultimate
renal failure when new acute lesions develop.
The natural history of membranous LN is less clear. In
early studies, its course appeared far better than that for
active proliferative disease.21 Subsequent studies with longer
follow-up suggested a worse outcome for membranous LN
with persistent nephrotic syndrome.28 Retrospective analyses show 5-year renal survival rates largely depend on
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SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
whether patients have pure membranous lesions (class V)
or superimposed proliferative lesions in a focal (class III +
V) or diffuse (IV + V) distribution.37,38 One U.S. study found
the 10-year survival rate was 72% for patients with pure
membranous lesions but only 20% to 48% for those with
superimposed proliferative lesions.37 Black race, elevated
serum creatinine, higher degrees of proteinuria, hypertension, and transformation to another WHO pattern all portended a worse outcome.1,3 The poor survival in blacks with
membranous LN may explain the excellent results in retrospective Italian studies, which follow largely Caucasian
cohorts. One such Italian study found the 10-year survival
rate of membranous LN patients to be 93%.38 Even in this
Italian population, survival for pure membranous LN was
far better than in patients with superimposed proliferative
lesions. Thus, at least in part, the variability of prognosis in
older studies can be explained by the differences in racial
background, histology, and therapy.
TREATMENT OF LUPUS NEPHRITIS
The treatment of severe LN remains controversial.1,3,6
Although recent controlled studies have better defined the
course and therapy for this group, the most effective and
least toxic regimen for any given patient is often less clear.
While cyclophosphamide has been effective therapy for
many patients with severe LN, newer regimens have been
developed in the hope of attaining equal or greater efficacy
with less toxicity. The concept of more vigorous initial
therapy during an “induction” treatment phase followed by
more prolonged lower dose therapy during a “maintenance
phase” is now widely accepted.1,2,125,126
Patients with ISN/RPS class I and II biopsies have an
excellent renal prognosis and need no therapy directed to
the kidney. Transformation to another histologic class is
usually heralded by increasing proteinuria and activity of
the urinary sediment. At this point, repeat renal biopsy may
serve as a guide to therapy.1 ISN/RPS class III patients with
only few mild proliferative lesions and no necrotizing features or crescent formation have a good prognosis and will
often respond to a short course of high-dose corticosteroid
therapy or a brief course of other immunosuppressive
agents. Patients with greater numbers of affected glomeruli
and those with necrotizing features and crescents usually
require more vigorous therapy similar to therapy for patients
with diffuse proliferative LN.
Patients with diffuse proliferative disease, ISN/RPS class
IV lesions, require aggressive treatment to avoid irreversible
renal damage and progression to ESKD.1,2,6,107,109,115 The
ideal immunosuppressive regimen should be individualized
and based on the patient’s prior therapy, risk and concern
over potential side effects, compliance, and tolerability.
Initial regimens may include combinations of the following:
oral or intravenous corticosteroids, oral or intravenous
cyclophosphamide, mycophenolate mofetil, cyclosporine,
tacrolimus, and/or rituximab. A number of other treatments are currently being studied for resistant or relapsing
disease and for maintenance therapy.
Prednisone, despite the lack of controlled trials, is
included in most treatment regimens for LN. In retrospective studies, higher initial doses of corticosteroids appeared
more effective than lower dose therapy (<30 mg prednisone
daily).1,3,4,6 Initial use of high-dose corticosteroid treatment
alone is still used by some clinicians for limited focal proliferative disease. However, for severe proliferative LN, either
class III or class IV, corticosteroids along with other immunosuppressive agents are required.4 Common regimens use
1 mg/kg/day of prednisone, tapering after 4 to 6 weeks of
treatment so that patients are on 30 mg/day or less by the
end of 3 months of therapy. Other clinicians start with daily
pulses of IV methylprednisolone for 1 to 3 days followed by
the oral corticosteroids.
Despite initial favorable results with pulse methylprednisolone followed by oral corticosteroids in treating severe
LN, there have been few randomized trials using this
regimen versus other immunosuppressive therapy.1,91,92 Two
NIH trials have found pulse corticosteroids to be less effective than intravenous cyclophosphamide in preventing progressive renal failure.91,92 In one trial, 48% of the pulse
steroid–treated patients doubled their serum creatinine at
5 years compared to only 25% of the cyclophosphamidetreated group.92
Controlled randomized trials at the NIH and elsewhere
have helped establish the role of cyclophosphamide in the
treatment of severe LN.44,91,92,109,125-127 In one seminal trial,
patients were randomly assigned to regimens of high-dose
corticosteroids for 6 months or oral cyclophosphamide, oral
azathioprine, combined oral azathioprine plus cyclophosphamide, or intravenous cyclophosphamide every third
month, all given with low-dose corticosteroids.109 Evaluation
at 120 months showed superior renal survival in the intravenous cyclophosphamide group versus the steroid group.
At longer follow-up to 200 months, the renal survival of the
azathioprine group was statistically no better than that of
the corticosteroid group.109 A subsequent Dutch collaborative trial found remission rates comparable between oral
azathioprine and cyclophosphamide, but more relapses and
worse long-term outcome with azathioprine.128 Thus, for a
number of years, cyclophosphamide was the most effective
immunosuppressive agent for LN. Since side effects in the
NIH trial appeared least severe when cyclophosphamide was
used intravenously, subsequent NIH protocols utilized the
drug in this manner given once monthly. Other trials at NIH
and elsewhere have also used monthly pulses of intravenous
cyclophosphamide for 6 consecutive months as opposed to
the original every third month regimen.119,125-127
These studies and others have confirmed the benefits and
response rate of intravenous cyclophosphamide regimens in
severe LN.44,110,119 In most patients treated with intravenous
cyclophosphamide, side effects such as hemorrhagic
cystitis, alopecia, and neoplasms have been infrequent.1,6
Exceptions are menstrual irregularities and premature
menopause, which are most common in women older than
25 years of age who have received intravenous cyclophosphamide for more than 6 months.129 The dose of intravenous cyclophosphamide must be reduced for significant
renal impairment and adjusted for some removal by hemodialysis. The cytoprotective agent Mesna has been used successfully by some to reduce bladder complications from
cyclophosphamide.
A three-armed controlled randomized trial at NIH of 1
year of monthly doses of intravenous methylprednisolone,
versus monthly intravenous cyclophosphamide for 6 months
and then every third month, versus the combination of both
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CHAPTER 33 — Secondary Glomerular Disease
therapies found the remission rate was highest with the
combined treatment regimen (85%) as opposed to cyclophosphamide alone (62%) and methylprednisolone
alone (29%).91 Mortality was low and similar in all groups.
Long follow-up indicated drug toxicity was not different
between the cyclophosphamide group and the combined
cyclophosphamide-methylprednisolone group.127 It is likely
that through higher sustained remissions and fewer relapses,
fewer patients required repeated treatments in the combined cyclophosphamide-steroid–treated group. Moreover,
the long-term efficacy, especially in terms of renal outcomes,
was greatest for the combination therapy group. Thus, combined treatment with intravenous methylprednisolone
pulses and intravenous cyclophosphamide pulses became a
standard therapy for severe LN. However, it should be noted
that some groups have achieved equal efficacy and few side
effects using short courses of oral cyclophosphamide followed by other immunosuppressive medications.130
Studies showing that oral maintenance immunosuppressive agents other than cyclophosphamide were more effective and safer than cyclophosphamide have led the search
for equally effective but safer regimens as induction therapy.
One approach to obtain efficacy with less toxicity uses lower
induction doses of the cytotoxic agent. The Euro Lupus
Nephritis Trial, a multicenter prospective trial of 90 patients
with severe LN, compared low-dose versus “conventional”
high-dose intravenous cyclophosphamide.131 Patients were
randomized to either 6-monthly intravenous pulses of 0.5 to
1 g/m2 cyclophosphamide followed by two quarterly pulses
or only 500 mg intravenously every 2 weeks for a total of six
doses, both followed by oral azathioprine as maintenance
therapy. At 40 months, follow-up, there were no statistically
significant differences in treatment failures, renal remissions, or renal flares, but twice as many infections occurred
in the high-dose group. Although this trial may have
included some patients with milder renal disease (mean
creatinine, 1 to 1.3 mg/dL; mean proteinuria, 2.5 to 3.5 g/
day for both groups) and a predominantly Caucasian patient
population, it supported the use of shorter duration and
lower total dose cyclophosphamide for induction therapy.
Longer follow-up of this population confirms these data and
suggests that early response to therapy is predictive of a
good long-term outcome and that the long-term results are
excellent.115 A recent trial of this regimen as standard care
in both arms of an investigational study of Abatacept in
patients with severe LN confirms that this regimen is effective in black as well as Caucasian populations.
Mycophenolate mofetil (MMF) has proven to be an
effective immunosuppressive in transplant patients and a
variety of other immunologic renal diseases.132 It is a
reversible inhibitor of inosine monophosphate dehydrogenase required for purine synthesis and blocks B and T cell
proliferation, inhibits antibody formation, and decreases
expression of adhesion molecules, among other effects.
MMF is effective in treating murine LN.132 MMF was shown
to have good efficacy and reduced complications when compared to standard treatment regimens in a number of
uncontrolled trials in LN.132 In one 6-month Chinese trial
of patients randomized to either MMF or intravenous pulse
cyclophosphamide for induction therapy of severe LN,133
proteinuria and microhematuria decreased more in the
MMF-treated patients than in the cytotoxic group, with
1103
renal impairment before and after therapy, activity index on
biopsy before and after therapy, and serologic improvement
equivalent. MMF was better tolerated with fewer gastrointestinal side effects and fewer infections. In another randomized controlled trial of patients given either a regimen of
prednisone plus oral MMF or a regimen of prednisone plus
cyclophosphamide orally for 6 months followed by oral azathioprine for another 6 months, both regimens proved
similar in efficacy.134 Of the MMF group 81% achieved
complete and 14% partial remission versus 76% complete
and 14% partial remission for the cyclophosphamideprednisone group. Treatment failures, relapses following
therapy, discontinuations of therapy, mortality, and time to
remission were similar. Longer follow-up at 4 years with the
addition of more patients showed MMF to have comparable
efficacy to cyclophosphamide with no significant difference
in complete or partial remissions, doubling of baseline creatinine, or relapses. Significantly fewer MMF-treated patients
developed severe infections, leukopenia, or amenorrhea,
and all deaths and renal failure were in the cyclophosphamide group.135
A multicenter U.S. study comparing induction therapy in
140 patients with severe class III and class IV LN included
more than 50% blacks, most with heavy proteinuria and
active urinary sediment.136 Patients were randomized to
monthly pulses of intravenous cyclophosphamide 0.5 to
1 g/m2 or oral MMF 2 to 3 g/day, both with tapering corticosteroid doses for 6 months. Although designed as an
equivalency study, MMF proved superior in attaining both
complete remissions and complete and partial remissions.
The side effect profile also appeared better with MMF. At
the 3-year follow-up, there was a trend to less renal failure
and mortality with MMF. Thus, in a patient population at
high risk for poor renal outcomes, MMF proved superior to
intravenous cyclophosphamide. A subsequent international
multicenter randomized controlled trial compared similar
regimens of MMF to intravenous cyclophosphamide for
induction therapy in 370 LN patients with ISN/RPS classes
III, IV, or V.10 This study found virtually identical rates of
complete and partial remission (over 50%), improvement
of renal function and proteinuria, and mortality rates
between the two regimens. Diarrhea and gastrointestinal
side effects were most common in the MMF group, whereas
nausea, vomiting, and alopecia were more common in the
cyclophosphamide group. In the small group of about 30
patients with a greatly reduced GFR (<30 mL/min), MMF
proved at least as effective if not more so than intravenous
cyclophosphamide.137 In an analysis of different geographic
and ethnic backgrounds, MMF proved uniformly more
effective across different groups.138 In another study of 52
patients with crescentic LN (>50% crescents on biopsy) randomized to induction therapy with MMF or intravenous
cyclophosphamide, the MMF group had a higher remission
rate and a lower relapse rate.139 Thus, taken together, these
two large, randomized controlled trials and a variety of
other analyses support the use of MMF as a first-line treatment of severe LN. Both ACR and Kidney Disease: Improving Global Outcomes (KDIGO) guidelines support either a
cyclophosphamide- or a mycophenolate-based regimen as
first-line therapy for severe LN.140 For patients who fail to
achieve remission with either initial regimen at 6 months of
therapy, use of the other regimen is recommended.
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SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
A number of studies have focused on the optimal maintenance therapy for LN with the goal of avoiding relapse
and flares while minimizing the long-term immunosuppressive toxicity. One randomized controlled trial examined LN
patients who had successfully completed induction of remission with 4 to 7 monthly pulses of intravenous cyclophosphamide and were then randomized to either continue with
intravenous cyclophosphamide every third month, oral azathioprine, or oral MMF.1,2,141 The 54 LN patients randomized were largely composed of blacks (50%) and Hispanics
and included many patients with nephrotic syndrome
(64%), reduced GFR, and severe proliferative LN. Fewer
patients in the azathioprine and the MMF groups reached
the primary end points of death and chronic renal failure
compared to the group that continued to receive cyclophosphamide. The cumulative probability of remaining relapse
free was higher with MMF (78%) and azathioprine (58%)
compared with cyclophosphamide (43%), and there was
increased mortality in patients given continued cyclophosphamide. Complications of therapy were also reduced in
the MMF and azathioprine groups, including days of hospitalization, amenorrhea, and infections. Thus, maintenance
therapy with either oral MMF or azathioprine was superior
to intravenous cyclophosphamide and had less toxicity.
The results of two large randomized trials further delineate the role of these oral agents in the maintenance of
patients with proliferative LN.142,143 In the European MAINTAIN trial, 105 patients were randomized to either azathioprine or MMF for at least 3 years of maintenance (mean, 53
months).142 There was no difference between these medications in the time to renal flares or to renal remission. In the
worldwide Aspreva Lupus Management Study (ALMS)
maintenance trial, 227 patients who achieved remission
after induction therapy with either intravenous cyclophosphamide or MMF were re-randomized in double-blind
fashion to either MMF or azathioprine maintenance for 3
years.143 MMF proved superior to azathioprine with respect
to the primary end point of time to treatment failure (death,
ESKD, doubling of serum creatinine, LN flare, or requirement for rescue therapy).143 Differences between the two
studies likely explain the differing results. The MAINTAIN
trial was prerandomized from day 1, included smaller
numbers of patients who were largely Caucasian, and used
the end point of renal flare since few patients in this population progress to renal failure. Even so, there were 26% flares
in the azathioprine group compared to only 19% in the
MMF group, although this difference was not statistically
significant. The ALMS maintenance trial included only
those patients who achieved remission after induction; was
international, including multiracial and diverse populations; and used harder end points for response (doubling
creatinine, ESKD, etc.). At present, both the ACR and
KDIGO recommend either agent, azathioprine or MMF, as
maintenance therapy.
The calcineurin inhibitors cyclosporine and tacrolimus
have been proven to increase the induction remission rate
in a number of uncontrolled and controlled trials.1 Tacrolimus has been successful in increasing remissions as part of
a multidrug regimen for severe LN patients with combined
ISN/RPS class IV and V lesions.144 Intravenous cyclophosphamide resulted in complete remission in 5% and partial
remissions in 40% at 6 months versus a “multitargeted
regimen” of tacrolimus, MMF, and corticosteroids, which
led to a 50% complete and a 40% partial remission rate in
this time period. A recent large multicenter trial from China
of more than 350 patients showed equally good results with
this multitargeted therapy.
Rituximab, a chimeric monoclonal antibody targeting
CD20 B cells, depletes them through multiple mechanisms, including complement-dependent cell lysis; FcRγdependent, antibody-dependent, cell-mediated cytotoxicity;
and induction of apoptosis. Rituximab, which is approved
by the U.S. Food and Drug Administration (FDA) for the
treatment of rheumatoid arthritis, granulomatosis with polyangiitis (formerly designated Wegener’s granulomatosis),
and microscopic polyangiitis, has been utilized with varying
success in many other immunologic and autoimmune diseases, including a variety of primary glomerular diseases.140
In LN it has been used in more than 300 patients, mostly in
case reports and open-label uncontrolled trials.1,4 However,
two large randomized controlled trials have given disappointing results.1,4,145,146 In one trial of 257 SLE patients
without severe renal disease, patients were randomized to
receive rituximab or placebo.145 Although subgroup analyses suggested a beneficial effect in the African American and
Hispanic subgroups, there were no significant differences
between the placebo and the rituximab arms of therapy. In
the Lupus Nephritis Assessment with Rituximab (LUNAR)
trial, 140 patients with class III and IV LN were randomized
to rituximab or placebo in addition to an induction regimen
of MMF (goal 3 g/day) and tapering corticosteroids.146
Although the rituximab group had a greater fall in antiDNA antibody titers and rise in serum complement levels,
there was no statistically significant difference in the primary
renal response between treatment groups at 1 year.147 At
present, rituximab is not a first-line agent for induction
therapy of most patients with severe LN. It continues to be
used in patients resistant to other treatments and in those
who do not tolerate conventional treatment.148,149 A recent
study of the use of rituximab and MMF in 50 LN patients
without use of oral corticosteroids has given excellent
complete and partial remission results.150 A large multicenter controlled randomized trial of the use of rituximab
as a steroid-sparing agent for the induction of LN is now
under way.
Other monoclonal antibodies directed at B cells have
been or are being studied. Ocrelizumab, a fully humanized
anti-CD20 monoclonal antibody had the advantages of
avoiding first-dose infusion reactions and the development
of human antichimeric antibodies (HACAs) that were
potential problems with rituximab therapy.140 A controlled
randomized trial using this agent in patients with LN was
terminated early due to adverse events. Atacicept, a soluble
fully humanized recombinant fusion protein that inhibits B
cell stimulating factor (BLISS) and a proliferation-inducing
ligand (APRIL), also failed in initial trials with patients with
LN.151 Epratuzumab, a humanized monoclonal antibody
against CD22, a marker of mature B cells but not plasma
cells, is currently being studied.152
T lymphocyte activation requires two signals.140,153 The
first occurs when the antigen is presented to the T cell
receptor in the context of MHC class II molecules on
antigen-presenting cells and the second by the interaction
of costimulatory molecules on T lymphocytes and
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CHAPTER 33 — Secondary Glomerular Disease
antigen-presenting cells. Disruption of costimulatory signals
interrupts the (auto)immune response. Two clinical trials
using different humanized anti-CD40L monoclonal antibodies in LN patients to block B and T cell costimulation
have not been successful.154,155 Another costimulatory
pathway is mediated through the interaction of
CD28CD80/86.1 CTLA-4 Ig, Abatacept, a fusion molecule
that combines the extracellular domain of human CTLA4
with the constant region (Fc) of the human IgG1 heavy
chain, interrupts the CD28CD80/86 interaction. It is FDA
approved for the treatment of rheumatoid arthritis. Two
major randomized controlled trials in patients with severe
LN treated with intravenous cyclophosphamide and steroids
have now given negative results.1,156,157 Recently belimumab,
a humanized monoclonal antibody against BLys (B lymphocyte stimulator), has been FDA approved for the treatment
of lupus based on two trials.158,159 Although some patients
with renal disease were included in these trials, few patients
had true severe LN.160 An ongoing trial is testing the use of
this agent in LN.
Other therapies studied in controlled trials in LN have
included plasmapheresis and intravenous γ-globulin administration. Plasmapheresis was studied in a multicenter controlled trial of 86 patients with severe LN.161 This study
found no benefit in terms of clinical remission, progression
to renal failure, or patient survival beyond a more rapid
lowering of anti-DNA antibody titers. Likewise, plasmapheresis synchronized to intravenous cyclophosphamide pulse
therapy has not proven effective.162 At present, plasmapheresis should be reserved for only certain LN patients (e.g.,
those with severe pulmonary hemorrhage, those with a TTPlike syndrome, and those with antiphospholipid antibodies
and a clotting episode who cannot be anticoagulated due
to hemorrhage, etc.).
Intravenous immune globulin has been used successfully
in a number of SLE patients to treat thrombocytopenia as
well as LN, leading to clinical and histologic improvement
in some patients.163,164 One controlled trial included only 14
patients but showed stabilization of the plasma creatinine,
creatinine clearance, and proteinuria when intravenous
immune globulin was used as maintenance therapy
after successful induction of remission with intravenous
cyclophosphamide.165
Other therapies that have been studied in small numbers
of LN patients include the proteasome inhibitor bortezomib, adrenocorticotropic hormone (ACTH), total lymphoid
irradiation, bone marrow ablation with stem cell rescue,
laquinimod therapy, and use of tolerance molecules.4,93,165-168
All are still experimental since none has yet undergone
large successful controlled clinical trials. Immunoablative
therapy with high-dose cyclophosphamide with and without
stem cell transplantation has been used successfully in a
limited number of SLE patients with only a short period of
follow-up and relatively high risks. One new tolerance molecule, Abetimus, despite efficacy in animal models and
encouraging early trials, failed to prevent flares of LN in the
largest controlled randomized trial.168
For patients with class V membranous LN, there have
been conflicting data regarding the course, prognosis, and
response to treatment.1,4 The degree of superimposed proliferative lesions greatly influences outcome in class V
patients, and it is unclear if older trials included only pure
1105
membranous LN patients. Thus, early trials reported low
and inconsistent response rates with oral corticosteroids.36
Excellent long-term results with intensive immunosuppressive regimens from Italian studies and others raise questions
of whether the results are related to the therapeutic intervention or to the population studied and better supportive
treatments.38 A retrospective Italian trial found better
remission with a regimen of chlorambucil and methylprednisolone than with corticosteroids alone.169 In a small nonrandomized trial of cyclosporine in membranous LN, there
was an excellent remission rate of nephrotic syndrome with
mean proteinuria decreasing from 6 to 1 or 2 g/day by 6
months.45 At long-term follow-up and re-biopsy, there was
no evidence of cyclosporine-induced renal damage, but two
patients had developed superimposed proliferative lesions
over time. An NIH trial of 42 nephrotic patients with membranous LN compared cyclosporine, prednisone, and intravenous cyclophosphamide and found superior remission
rates for the cyclosporine and cyclophosphamide regimens
but a trend toward more relapses when the cyclosporine was
withdrawn.170 Tacrolimus has also been used for class V LN
with good results. A study of 38 patients with pure membranous LN evaluated long-term treatment with prednisone
plus azathioprine.133 At 12 months 67% of the patients had
experienced a complete remission and 22% a partial remission. At 3 years only 12% had relapsed, at 5 years only 16%,
and at 90 months only 19% had relapsed. At the end of
follow-up, no patient had doubled serum creatinine. Clearly
in this population a regimen of steroids plus azathioprine
was highly effective. The response of patients with membranous LN to MMF has been varied.171-173 There were 84
patients with pure ISN class V membranous LN among the
510 patients enrolled in two similarly designed randomized
controlled trials comparing MMF and intravenous cyclophosphamide induction therapy.173 Rates of remissions,
relapse, and course were similar in both treatment groups.
Thus, MMF can also be considered a first-line therapy for
certain patients with membranous LN.
Given limited data, the treatment of membranous LN
should be individualized.1,4 Patients with pure membranous
LN and a good renal prognosis (subnephrotic levels of proteinuria and preserved GFR) may benefit from a short
course of cyclosporine with low-dose corticosteroids along
with inhibitors of the renin angiotensin aldosterone system
and statins. For those at higher risk of progressive disease
(African Americans, those fully nephrotic), options include
cyclosporine, monthly intravenous pulses of cyclophosphamide, MMF, or azathioprine plus corticosteroids. Patients
with mixed membranous and proliferative LN are treated
in the same way as those with proliferative disease alone.
As effective and safer therapies for LN have evolved,
greater attention has been directed to other causes of morbidity and mortality in the SLE population. Lupus patients
have accelerated atherogenesis and a disproportionate rate
of coronary vascular disease, leading to a high mortality
rate.174 The high cardiovascular risk rate has been attributed
to concurrent hypertension, hyperlipidemia, nephrotic syndrome, prolonged corticosteroid use, antiphospholipid syndrome, and, in some, the added vascular risks of chronic
kidney disease (CKD).175,176 Despite limited data on therapeutic interventions in this population, aggressive management of modifiable cardiovascular risk factors may alter the
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SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
morbidity and mortality of this population. Extrapolating
from other proteinuric CKD populations, closely monitored
blood pressure control (<130/80), the use of angiotensinconverting enzyme inhibitors (ACEIs) and/or angiotensin
receptor blockers (ARBs), and correction of dyslipidemia
with statins are all reasonable in LN patients. In addition, use
of calcium, vitamin D supplements, and bisphosphonates to
prevent glucocorticoid-induced osteoporosis may be useful.
Some form of antiphospholipid antibodies is present in
40% to 75% of lupus patients.177-179 Since most do not experience thrombotic complications, they require no special
treatment. However, some would recommend low-dose
aspirin and hydroxychloroquine for prophylaxis of asymptomatic patients with antiphospholipid antibodies. In
patients with evidence of a clinical thrombotic event, most
investigators use chronic anticoagulation with warfarin as
long as the antibody persists. While the standard practice
has been not to anticoagulate other patients, in one recent
series of more than 100 SLE patients, over one fourth had
antiphospholipid antibodies, of whom almost 80% had a
thrombotic event. The antibody-positive patients also had a
greater incidence of chronic renal failure than the antibodynegative patients.179 (See discussion of anticardiolipin antibodies and glomerulonephritis in the following section.)
ANTIPHOSPHOLIPID SYNDROME
Antiphospholipid syndrome (APS) may be associated with
glomerular disease, small and large vessel renal involvement, as well as coagulation problems in dialysis and renal
transplant patients.177-180 Patients with APS have autoantibodies directed against plasma proteins bound to phospholipids. They may include IgG and/or IgM anticardiolipin
antibodies, antibodies to β2-glycoprotein I of IgG or IgM
isotype, or lupus anticoagulant activity.181-183 In some studies
the presence of specific β2-glycoprotein I antibodies has
been correlated with an increased risk of thrombotic events
in patients with APS.184 Antiphospholipid antibodies may
cause a false-positive VDRL. In addition to having one of
these autoantibodies, patients with APS must have one or
more episodes of venous, arterial, or small vessel thrombosis, or fetal morbidity. Thrombocytopenia and prolonged
partial thromboplastin time are frequent laboratory findings. The presence of antiphospholipid antibodies should
be documented on two or more occasions at least 12 weeks
apart and within 5 years of clinical manifestations.
The pathogenesis of the APS remains unclear.185-191 Susceptible individuals may develop antiphospholipid antibodies after exposure to infectious or other noxious agents.
Among SLE patients there may be a genetic predisposition
associated with HLA-DRB1 loci.192 However, despite the
presence of antiphospholipid antibodies, a “second hit”
(such as pregnancy, contraceptive use, nephrotic syndrome,
or hyperlipidemia) may be necessary for them to produce
thrombotic events and the APS. The mechanism(s) of the
procoagulant effect is likely to be multifactorial. Antiphospholipid antibodies exert procoagulant effects at multiple
sites in the clotting cascade, including prothrombin, protein
C, annexin V, coagulation factors VII and XII, platelets,
serum proteases, and tissue factor procoagulant. They may
also impair fibrinolysis through inhibition of such factors as
tissue type plasminogen activator. The result is endothelial
damage and intravascular coagulation.
Among patients with antiphospholipid antibodies, 30%
to 50% have the primary APS in which there is no associated
autoimmune disease.177-179,181-183 Antiphospholipid antibodies are found in from 25% to 75% of SLE patients, although
most patients never experience clinical features of the
APS.177-179,181-183 In an analysis of 29 published series with
more than 1000 SLE patients, 34% were positive for the
lupus anticoagulant and 44% for anticardiolipin antibodies.189 Most studies have found a higher incidence of thrombotic events in SLE patients positive for antiphospholipid
antibodies.190,193-195 A European study of almost 575 SLE
patients found the prevalence of IgG anticardiolipin antibodies to be 23% and of IgM 14%.196 Patients with IgG
antibodies had a clear association with thrombocytopenia
and thromboses. A multicenter European analysis of 1000
SLE patients found thromboses in 7% of patients over 5
years. Patients with IgG anticardiolipin antibodies again had
a higher incidence of thromboses, as did those with a lupus
anticoagulant.197 Antiphospholipid antibodies are also
found in up to 2% of normal individuals and in those with
a variety of infections (commonly in patients with HIV or
hepatitis C virus [HCV]) and drug reactions, but these are
not usually associated with the clinical features of the
APS.198-200
The clinical features of APS relate to thrombotic events
and consequent ischemia. Among 1000 APS patients the
most common features were deep vein thrombosis (32%),
thrombocytopenia (22%), livedo reticularis (20%), stroke
(13%), pulmonary embolism (9%), and fetal loss (9%).197
Patients may also experience pulmonary hypertension,
cardiac involvement, memory impairment and other neurologic manifestations, fever, malaise, and constitutional
symptoms.177-180,194 Patients who test positive for all three
diagnostic tests (lupus anticoagulant, anticardiolipin antibodies, and β2-glycoprotein antibodies) are at higher risk
for thromboembolic events. Catastrophic APS, a rare event
(occurring in 0.8% of APS patients), is associated with rapid
thromboses in multiple organ systems and has a high fatality
rate.201,202
Renal involvement, so-called antiphospholipid nephropathy, occurs in as many as 25% of patients with primary APS
and is characterized by thrombosis of blood vessels ranging
from the glomerular capillaries to the main renal artery and
vein.177,180,203,204 Lesions involving the arteries and arterioles
often have both a thrombotic component and a reactive or
proliferative one with intimal mucoid thickening, subendothelial fibrosis, and medial hyperplasia (Figure 33.13).204,205
Interstitial fibrosis and cortical atrophy may occur due to
tissue ischemia. Glomerular lesions include glomerular capillary thrombosis with associated mesangiolysis, mesangial
interposition and duplication of GBMs, and subendothelial
accumulation of electron-lucent, flocculent material, resembling the changes in other forms of glomerular thrombotic
microangiopathy such as HUS and TTP.
A retrospective renal biopsy study found antiphospholipid
nephropathy in almost 40% of antiphospholipid-positive
patients versus only 4% of patients without antiphospholipid
antibody. When antiphospholipid nephropathy was present,
it was associated with both lupus anticoagulant and anticardiolipin antibodies.206 Among antiphospholipid-positive SLE
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CHAPTER 33 — Secondary Glomerular Disease
Figure 33.13 Antiphospholipid syndrome. Organizing recanalized
thrombi narrow the lumens of two interlobular arteries. The adjacent
glomerulus displays ischemic-type retraction of its tuft. (Hematoxylin
and eosin stain, ×200.)
patients, antiphospholipid nephropathy was found in two
thirds of those with APS and in one third of those without
APS. Although patients with antiphospholipid nephropathy
had a higher frequency of hypertension and elevated serum
creatinine levels at biopsy in this series, they did not have a
higher frequency of progressive renal insufficiency, ESKD, or
death at follow-up.207 This is in contrast to another series of
more than 100 SLE patients which found the presence of
antiphospholipid antibodies to be associated with both
thrombotic events and a greater progression to renal
failure.179 In patients with antiphospholipid nephropathy,
renal biopsies with thrombotic microangiopathy may be misclassified as FSGS, membranous nephropathy, and MPGN.208
However, a recent study reports that some patients with APS
may develop a number of other glomerular histologic
patterns on light microscopic examination, including
membranous nephropathy, minimal change/focal sclerosis,
mesangial proliferative glomerulonephritis, and pauciimmune rapidly progressive glomerulonephritis (RPGN).209
The most frequent clinical renal findings are proteinuria, at times in the nephrotic range, active urinary
sediment, hypertension, and progressive renal dysfunction.177,178,203,205,206,208,209 Some patients present with an acute
deterioration in renal function.208 With major renal arterial
involvement there may be renal infarction, and renal vein
thrombosis may be silent or present with sudden flank pain
and a decrease in renal function. Renal artery stenosis has
been reported with and without malignant hypertension.210-212
About 10% of biopsied lupus patients have glomerular
microthromboses as the major histopathologic finding.
Therapy of this glomerular lesion clearly differs from that
of immune complex–mediated glomerulonephritis.51 One
study of 114 biopsied SLE patients found vaso occlusive
lesions in one third of biopsies, which correlated with both
hypertension and an increased serum creatinine level.213 In
SLE, features that correlate well with high titers of IgG
antiphospholipid antibodies are thrombocytopenia, the
presence of a false-positive VDRL for syphilis (FTA negative), and a prolonged activated partial thromboplastin
time.177,178,213 Neither the titer of anti-DNA antibodies nor
the serum complement levels correlate well with the
antiphospholipid antibody levels. In SLE, high titers of IgG
anticardiolipin antibody usually correlate well with the risk
1107
of thrombosis. However, in one study of 114 biopsied SLE
patients, renal thrombi were related to lupus anticoagulant
but not anticardiolipin antibodies.213 The clinical features
of APS in SLE patients are identical to those of primary APS.
An important study documents the prevalence of antiphospholipid antibodies in 26% of 111 LN patients followed for
a mean of 173 months.179 Of the antiphospholipid antibody–
positive patients, 79% developed a thrombotic event or fetal
loss, and the presence of antibodies was strongly correlated
with the development of progressive CKD.
There is a high prevalence of antiphospholipid antibodies
(10% to 30%) in hemodialysis patients irrespective of patient
age, gender, or duration of the dialysis.214,215 In contrast,
patients with renal insufficiency and those on peritoneal
dialysis have a much lower incidence of antiphospholipid
antibodies.177 One hemodialysis study found more patients
with arteriovenous (AV) grafts than native fistulas to have a
raised titer of IgG anticardiolipin antibody.215,216 There was a
significant increase in the odds of having two or more episodes of AV graft thrombosis in patients with raised anticardiolipin titer. Whether AV grafts induce anticardiolipin
antibodies or whether patients with anticardiolipin antibodies require AV grafts remains unclear.177 In another study, of
230 hemodialysis patients, titers of IgG anticardiolipin antibodies were elevated in 26% of the patients as opposed to
elevated titers of IgM antibodies in only 4%.216 The mean
time to AV graft failure was significantly shorter in the group
with elevated IgG antibodies, and the use of warfarin
increased graft survival in these patients.
In several studies 20% to 60% of SLE patients with
antiphospholipid antibodies who received renal transplants had problems related to APS, such as venous
thromboses, pulmonary emboli, or persistent thrombocytopenia.101,102,217,218 In one large study of non-SLE patients,
28% of 178 transplant patients had antiphospholipid antibodies which were associated with a three- to fourfold
increased risk of arterial and venous thromboses.217 However,
another study of 337 renal transplant recipients found the
18% who were IgG or IgM anticardiolipin antibody positive
had no greater allograft loss or reduction in GFR than did
patients who were anticardiolipin antibody negative.219
Although most patients with antiphospholipid antibodies
who have tested positive for HCV do not have evidence of
increased thromboses and APS, when they receive a transplant, they appear to have a higher risk of allograft thrombotic microangiopathy.220 In many of these transplant
studies, treatment with anticoagulation has proven successful in preventing recurrent thromboses and graft loss.101,102,218
TREATMENT
The optimal treatment of patients with antiphospholipid
antibodies and APS remains to be defined.177,178,221 Many
patients with antiphospholipid antibodies do not experience thrombotic events. In asymptomatic patients with
antiphospholipid antibodies but no evidence of thrombotic
events or APS, low-dose aspirin may be beneficial based on
limited data.222
Since patients with higher titers of IgG antiphospholipid
antibody have a greater incidence of thrombotic events,
they may benefit from anticoagulation.196,197 In patients with
full APS, anticoagulation with heparin followed by warfarin
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1108
SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
has proven more effective than no therapy, aspirin, or lowdose anticoagulation in preventing recurrent thrombosis.177,180,221 A retrospective analysis of 147 APS patients
(including 62 primary disease, 66 SLE, and 19 lupus-like
syndrome) reported 186 recurrent thrombotic events in
69% of the patients.221 The median time between the initial
thrombosis and the first recurrence was 12 months but with
a broad range (0.5 to 144 months). Treatment with higher
dose warfarin (international normalized ratio [INR] > 3)
was more effective than treatment with low-dose warfarin
(INR < 3) or treatment with aspirin. The highest rate of
thrombosis (1.3 per patient-year) occurred in patients
within 6 months after discontinuing anticoagulation. Bleeding complications occurred in 29 of the 147 patients but
were severe in only 7 patients. The role of immunosuppression has been uncertain in APS.177,178,198 In SLE patients the
anti-DNA antibody titer and the serum complement may
normalize with immunosuppression without a significant
change in a high titer of IgG antiphospholipid antibody.177
In pregnant patients with APS, heparin and low-dose aspirin
have been successful, whereas prednisone therapy has
not.223,224 In rare patients who cannot tolerate anticoagulation due to recent bleeding, who have thromboembolic
events despite adequate anticoagulation, or who have catastrophic APS, plasmapheresis with corticosteroids and other
immunosuppressives have been used with some success.224,225
It is uncertain whether hydroxychloroquine, used mostly in
SLE patients, can prevent thromboembolic events in
APS.222,226,227 There is insufficient and conflicting data
whether newer agents such as rituximab lower the levels of
antiphospholipids or decrease the risk of thromboembolism.228,229 The use of other treatments, such as eculizumab,
intravenous γ-globulin, and stem cell transplant are only
reported in isolated patients.230,231
MIXED CONNECTIVE TISSUE DISEASE
Mixed connective tissue disease (MCTD) is defined by
a combination of clinical and serologic features.60,232,233
Patients share overlapping features of SLE, scleroderma,
and polymyositis.232-234 They also typically have distinct serologic findings with a very high ANA titer, often with a speckled pattern, and antibodies directed against a specific
ribonuclease-sensitive ENA, U1RNP.233,234 MCTD has a low
incidence and prevalence, a high female-to-male sex ratio,
and linkage to HLA-DR4 and DR2 genotypes.235,236 Not all
patients with clinical features of MCTD have a positive ENA,
and not all ENA-positive patients have the clinical features
of MCTD.234 Since over time some patients fulfill diagnostic
criteria for other connective tissue diseases, investigators
have questioned whether MCTD is a distinct syndrome and
have developed specific criteria to categorize patients as
having MCTD.237 The term undifferentiated autoimmune rheumatic and connective tissue disorder or overlap syndrome has also
been used.234,235 One study of 161 MCTD patients followed
for 8 years found 60% with unclassified MCTD, 17% systemic sclerosis, 9% SLE, 2.5% rheumatoid arthritis, and
11.5% with undifferentiated connective tissue disease.237 A
positive anti-DNA antibody predicted the development of
SLE while hypomotility of the esophagus or sclerodactyly
predicted the development of systemic sclerosis.
In early stages of MCTD, patients usually manifest nonspecific symptoms such as malaise, fatigue, myalgias, arthralgias, and low-grade fever. Over time features similar to other
rheumatologic connective tissue diseases appear, including
arthralgias, deforming arthritis, myalgias and myositis, Raynaud’s phenomenon, swollen hands and fingers, restrictive
pulmonary disease and pulmonary hypertension, esophageal dysmotility, pericarditis and myocarditis, serositis, oral
and nasal ulcers, digital ulcers and gangrene, discoid lupuslike lesions, malar rash, alopecia, photosensitivity, and
lymphadenopathy.233,234,238 However, patients with MCTD,
especially those documented to have anti-U1RNP antibodies, infrequently have major central nervous system disease
or severe proliferative glomerulonephritis.233,234,238 Lowgrade anemia, lymphocytopenia, and hypergammaglobulinemia are all common in MCTD.
The most widely used serologic test to confirm a diagnosis
of MCTD is the ENA with anti-U1RNP antibodies.234,239 The
diagnosis of MCTD is even firmer in those patients with IgG
antibodies against an antigenic component of U1RNP, the
68kD protein.239,240 Antibodies to other nuclear antigens
have been found in MCTD and some correlate better with
some clinical features of specific rheumatologic diseases.233
Antibodies against dsDNA, Sm antigen, and Ro are infrequently positive in MCTD, but up to 70% of patients will
have a positive rheumatoid factor.
The incidence of renal involvement has varied from 10%
to 26% of adults and from 33% to 50% of children with
MCTD.234,240 Many patients have mild clinical manifestations
with only microhematuria and less than 500 mg proteinuria
daily. However, heavier proteinuria, severe hypertension,
and acute kidney injury (AKI) reminiscent of “scleroderma
renal crisis” may occur.238,241,242 Although the titer of anti-RNP
does not correlate with renal involvement, the presence of
serologic markers of active SLE (e.g., high anti-dsDNA antibody titers, anti-Sm antibody) are more common with renal
disease.234 Low serum complement levels have not always correlated with the presence of renal involvement.238 Children
with MCTD more often have glomerular involvement with
few clinical or urinary findings.243
The pathology of MCTD is diverse with the glomerular
lesions resembling the spectrum found in SLE and the vascular lesions resembling those in scleroderma. Glomerular
disease is most common and is usually superimposed on a
background of mesangial deposits and hypercellularity as in
SLE.238,241,243-246 Up to 30% of biopsied patients have mesangial deposits of IgG and C3. Other patients have focal proliferative glomerulonephritis with both mesangial and
subendothelial deposits, but fibrinoid necrosis and crescents are rare. The most common pattern of glomerular
involvement is membranous nephropathy, reported in up
to 35% of cases,241,243-245 with typical peripheral capillary wall
granular immunofluorescence staining for IgG, C3, and, at
times, IgA and IgM. Some patients will have a mixed pattern
of membranous plus mesangial proliferative glomerulonephritis.243 Renal biopsy findings may transform over time
from one pattern of glomerular involvement to another,
similar to SLE patients. By ultrastructure analysis, lupus-like
findings have been reported, including endothelial tubuloreticular inclusions, deposits with “fingerprint” substructure, and tubular basement membrane deposits.238 In a
review of 100 biopsied patients with MCTD, 12% had normal
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CHAPTER 33 — Secondary Glomerular Disease
biopsies, 35% mesangial lesions, 10% proliferative glomerular lesions, and 36% membranous nephropathy.247 In addition, 15% to 25% of patients had interstitial disease and
vascular lesions. In autopsy series, in which two thirds of
patients had clinical renal disease, a similar distribution of
glomerular lesions was found.246 Other renal pathology findings in MCTD include secondary renal amyloidosis,248 vascular sclerosis ranging from intimal sclerosis to medial
hyperplasia, and vascular lesions resembling those in scleroderma kidney with involvement of the interlobular arteries
by intimal mucoid edema and fibrous sclerosis.238
Therapy of MCTD with corticosteroids is effective in treating the inflammatory features of joint disease and serositis.234,238 Steroids are less effective in treating sclerodermatous
features such as cutaneous disease, esophageal involvement,
and especially pulmonary hypertension. Intravenous immunoglobulin has been used to treat thrombocytopenia and
hemolytic anemia.249 Treatment of the glomerular lesions is
similar to that for LN.
Originally MCTD was felt to have a good prognosis with
low mortality and few patients developing other distinct
connective tissue disorders. The longer patients with MCTD
are followed, the greater the percentage who evolve more
clearly into a specific connective tissue disorder.234 In some
series, almost half of the patients with a short duration of
follow-up were still felt to have true MCTD, but in those with
longer follow-up the percentage had dropped to 15% or
less.234,238 Most patients evolve toward a picture of either SLE
or systemic sclerosis, but some develop features of rheumatoid arthritis.237,238 Mortality rates have been found to range
from 15% to 30% at 10 to 12 years with patients with more
clinical features of scleroderma and polymyositis faring
worse.234,238 The presence of anticardiolipin antibodies and
anti–β2-glycoprotein antibodies increases the mortality risk.
In a recent study, 5-, 10-, and 15-year survival rates were 98%,
96%, and 88%.250 The leading causes of mortality in MCTD
are pulmonary hypertension and cardiovascular disease.234,250
Other causes include vascular lesions of the coronary and
other vessels, hypertensive scleroderma crisis, and chronic
renal failure. Clearly MCTD is not a benign disorder but
rather a disease with significant morbidity and mortality.
1109
the upper and lower respiratory tracts and by glomerulonephritis.252 Subsequent descriptions of “limited” upper respiratory tract disease, of multiorgan system involvement,
and of the nature and pathogenesis of the serologic
marker, ANCA, have enhanced our understanding of this
disease.253-257 Even in the pre-ANCA era these clinical criteria
yielded a sensitivity of 88% and a specificity of 92% for the
diagnosis of GPA. Adding ANCA to the diagnostic criteria
increases these percentages.258-260
GPA has a slight male predominance and a peak incidence in the fourth to sixth decade of life.252,255,262,263 Pauciimmune RPGN (including GPA and MPA) are the most
common forms of crescentic glomerulonephritis at all ages,
and especially in older adults.259,260 Most patients have been
Caucasian, although with use of ANCA screening, patients
of all races are being diagnosed.262 The occurrence of GPA
in more than one family member has rarely been noted.263
Certain HLA frequencies such as HLA-DR2, HLA-B7, and
HLA-DR1 and DR1-DQW1 have been reported more
commonly.263,264
PATHOLOGY
The classic histopathologic finding in GPA is a focal segmental necrotizing and crescentic glomerulonephritis (Figure
33.14).256 Although the percentage of affected glomeruli
can vary widely, the necrotizing changes are usually segmental in distribution.256,265 Unaffected glomeruli typically
appear normal. Global proliferation and necrotizing glomerular tuft involvement are more common in the more
severe cases. The earliest lesions are “intracapillary thrombosis” with deposition of eosinophilic “fibrinoid” material
associated with endothelial cell swelling, infiltration by
polymorphonuclear leukocytes, and pyknosis or karyorrhexis.256,265 In areas of active necrotizing glomerular lesions,
there are ruptures in the GBM and formation of overlying
cellular crescents that range from segmental to circumferential. Crescents are frequently associated with breaks in or
broad destruction of Bowman’s capsule.266 Granulomatous
crescents containing epithelioid histiocytes and giant cells
SMALL VESSEL VASCULITIS
Granulomatosis with polyangiitis (GPA; formerly designated
Wegener’s granulomatosis), microscopic polyangiitis (MPA),
and eosinophilic granulomatosis with polyangiitis (EGPA;
formerly designated Churg-Strauss syndrome or ChurgStrauss vasculitis) are usually classified together as three
small vessel vasculitides.125,251-260 All may affect the arterioles,
capillaries, and venules. There is considerable overlap in the
clinical, histologic, and laboratory features of these entities.
Moreover, all may be associated with a positive serologic test
for ANCA. However, genetic analyses are defining differences between these entities, and differences in the course
and response to therapy are being noted.261
GRANULOMATOSIS WITH POLYANGIITIS
GPA has been traditionally defined by the triad of vasculitis
associated with necrotizing, granulomatous inflammation of
Figure 33.14 Granulomatosis with polyangiitis. A representative
glomerulus displays segmental fibrinoid necrosis with rupture of glomerular basement membrane, fibrin extravasation into the urinary
space, and an overlying segmental cellular crescent. (Jones’ methenamine silver stain, ×500.)
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1110
SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
Figure 33.15 Granulomatosis with polyangiitis. An interlobular
artery displays necrotizing vasculitis with intimal fibrin deposition and
transmural inflammation by neutrophils and lymphocytes. (Hematoxylin and eosin stain, ×375.)
may involve from less than 15% to more than 50% of cases,
and the finding of large numbers of them is more typical of
GPA and cytoplasmic ANCA (C-ANCA) positivity than other
vasculitides. Chronic segmental or global glomerulosclerosis with fibrous crescents often occur side by side with more
active glomerular lesions. Although there is much overlap
in the histologic findings between MPA and GPA, some differences have been noted. Patients with MPA and those who
have anti-myeloperoxidase (anti-MPO) ANCA are more
likely to have a greater degree and severity of glomerulosclerosis, interstitial fibrosis, and tubular atrophy on initial
biopsy.267
The true vasculitis in GPA may affect small- and mediumsized renal arteries, veins, and capillaries.256,265 It is focal in
nature and has been reported in 5% to 10% of GPA biopsies.252,255,256 It is more commonly found at autopsy with availability of larger tissue sampling and when serial sectioning
and a directed search for the lesions have been performed.
The necrotizing arteritis consists of endothelial cell swelling
and denudation, intimal fibrin deposition, and mononuclear and polymorphonuclear leukocyte infiltration of the
vessel wall with mural necrosis (Figure 33.15). In some cases,
the arteritis displays granulomatous features. Tubules show
focal degenerative and regenerative changes, and cortical
infarcts may occur.252,256 Interstitial inflammatory infiltrates
of lymphocytes, monocytes, plasma cells, and polymorphonuclear leukocytes are common. Granulomas containing
giant cells may form in the interstitium of the cortex and
medulla in 3% to 20% of cases. Some of these cortical
granulomas represent foci of glomerular destruction by
granulomatous crescents. Papillary necrosis, often bilateral
and affecting most papillae, has been reported, usually in
those with necrotizing interstitial capillaritis of the vasa
recta. Biopsy of extrarenal tissue may show necrotizing and
granulomatous inflammation or evidence of vasculitis.255,256
There is no specific glomerular or vascular immune
staining in most cases of GPA. Low-level staining for immunoglobulins and complement likely represents nonimmunologic trapping in areas of necrosis and sclerosis. This
negative or only focal low-intensity immunofluorescence
staining pattern is referred to as “pauci-immune.”252-256
Positivity for fibrin/fibrinogen is common in the distribution of the necrotizing glomerular lesions, crescents, and
vasculitic lesions. By electron microscopy the glomeruli
affected by necrotizing lesions often show areas of intraluminal and subendothelial fibrin deposition associated with
endothelial necrosis and gaps in the GBM through which
fibrin and leukocytes extravasate into Bowman’s space.252-256
There may be sub­endothelial accumulation of electronlucent flocculent material associated with intravascular
coagulation. True electron-dense immune-type deposits are
not usually identified and, when present, are sparse and illdefined.252-256 Electron microscopy of the vessels in GPA may
show swelling and denudation of endothelial cells, and subendothelial accumulation of fibrin, platelets, and amorphous electron-dense material, but no typical immune-type
electron-dense deposits.
PATHOGENESIS
The pathogenesis of GPA remains unknown with abnormalities of both humoral and cell-mediated immunity
described.253,255,256 A recent genome wide association study
found that GPA and MPA are genetically distinct diseases
with the genetic markers strongly associated with the antigenic specificity of the ANCA rather than the clinical syndrome.261 In vitro and animal experiments strongly support
a role for ANCA in the pathogenesis of the disease.268-271
ANCA production may relate to infectious, genetic, environmental, and other risk factors.268 Both molecular mimicry to
infectious pathogens and formation of antibody to antisense
peptide have been proposed in the development of ANCA.
Patients with proteinase 3 (PR3)–positive ANCA have been
shown to have antibodies to complementary PR3, a protein
encoded by the antisense RNA of the PR3 gene, and CD4+
TH1 memory cells responsive to the complementary PR3
peptide.269 In Rag-2 mice, transfer of anti-MPO IgG causes
glomerulonephritis with necrosis and crescent formation
that appears identical to human ANCA-associated glomerulonephritis by light microscopy and immunofluorescence.271
This can occur in the absence of antigen-specific T lymphocytes strongly suggesting a pathogenetic role for the antibodies themselves. In humans, neonatal MPA with pulmonary
hemorrhage and renal disease has occurred secondary to
the transfer of maternal MPO-ANCA.272 One study has
found a unique subgroup of ANCA directed against lysosomal associated membrane protein 2 (LAMP2) as opposed
to MPO or PR3, to be present in more than 90% of ANCApositive pauci-immune necrotizing glomerulonephritis.273
Others have not been able to confirm a high incidence of
anti-LAMP2 antibodies in this population.274
Cell-mediated mechanisms of tissue injury in GPA are
supported by a predominance of CD4+ T lymphocytes and
monocytes in the inflammatory respiratory tract infiltrates,
high levels of TH1 cytokines, defects in delayed hypersensitivity, a rise in soluble markers of T cell activation as soluble
interleukin-2 (IL-2) receptor and CD30, impaired lymphocyte blastogenesis, and T cell response to PR3.257,275-277
Despite prominent respiratory tract involvement, no inhaled
pathogen or environmental allergen has been identified as
the initiator of the disease process. However, respiratory
infections may allow the release of cytokines such as tumor
necrosis factor (TNF) from cells that can “prime” neutrophils to express PR3 and other antigens on their cell
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CHAPTER 33 — Secondary Glomerular Disease
surfaces. The expression of granule proteins on the surface
of neutrophils and monocytes allows for the interaction with
circulating ANCA, leading to a respiratory burst in the cell,
degranulation and local release of damaging proteases and
reactive oxygen species, release of chemoattractant products, and neutrophil apoptosis.255-257,278-280 Endothelial injury,
fibrinoid necrosis, and inflammation ensue. In the presence
of ANCA, neutrophils exhibit exaggerated adhesion and
transmigration through endothelium.280
A spectrum of glomerular and vascular disease reaction
is seen depending on antigen expression, host leukocyte
activation, circulating and local cytokines and chemokines,
the condition of the endothelium, and the nature of T and
B cell interactions.255-257,278-280 The membranes of leukocytes
from GPA patients may be primed to express PR3 molecules
on their surfaces, making them ripe for activation of the
disease process.257,279,281,282 This priming phenomenon might
explain the exacerbations of disease activity associated with
respiratory infections as well as the potential benefits of
prophylaxis with trimethoprim-sulfamethoxazole.282,283
CLINICAL AND LABORATORY FEATURES
Patients with GPA may present with an indolent, slowly progressive involvement of the respiratory tract and mild renal
findings or with fulminant acute glomerulonephritis.
Despite greater awareness of the disease, more extensive use
of renal biopsy, and the widespread availability of ANCA
serologic testing, diagnosis is still often delayed. Most
patients will have constitutional symptoms, including fever,
weakness, and malaise at presentation.252-255,284,285 From 70%
to 80% of patients have upper respiratory findings at presentation and more than 90% eventually develop upper
respiratory problems over time.252-255,284,285 There may be rhinitis, purulent or bloody nasal discharge and crusting, and
sinusitis, typically involving the maxillary sinus and less commonly the sphenoid, ethmoid, and frontal sinuses.252-255,284,285
Radiographs show sinus opacification, air-fluid levels, mass
lesions, or rarely bony erosions. Upper respiratory tract
involvement can also be manifest by tinnitus and hearing
loss, otic discharge, earache, perforation of the tympanic
membrane, and hoarseness and throat pain.252-255 Chronic
sequelae include deafness, chronic sinusitis, and nasal septal
collapse with saddle nose deformity.254
Lower respiratory tract disease, found at presentation in
up to 75% of patients and eventually in 85%, leads to symptoms of cough (often with sputum production), dyspnea on
exertion and shortness of breath, alveolar hemorrhage and
hemoptysis, and pleuritic pain.252-256,286 Chest radiographs
and computed tomographic scans may reveal single or multiple nodules, some with areas of cavitation, alveolar infiltrates, and interstitial changes, and less commonly small
pleural effusions and atelectatic areas.
GPA is a multisystem disease with many organs involved
by the vasculitic process and its sequelae.252-256 Cutaneous
involvement, present in 15% to 50% of patients, occurs with
a variety of macular lesions, papules, nodules, or purpura,
usually on the lower extremities. Patients with rheumatologic involvement have arthralgias of large and small joints
as well as nondeforming arthritis of the knees and ankles
or, more rarely, a myopathy or myositis. Up to 65% of
patients have ophthalmologic disease with conjunctivitis,
episcleritis and uveitis, optic nerve vasculitis, or proptosis
1111
due to retro-orbital inflammation. Nervous system involvement is most typically manifested as a mononeuritis multiplex but may involve cranial nerves or the central nervous
system. Other organs involved include the liver, parotids,
thyroid, gallbladder, and the heart.252-256 Recent reports have
emphasized the risks of thromboembolism, especially
during active disease, perhaps related to endothelial injury
and hypercoagulability induced by the vasculitis and its
treatment.287
Abnormal laboratory tests in GPA include a normochromic, normocytic anemia and a mild leukocytosis and thrombocytosis.252,256 Nonspecific markers of an inflammatory
disease process such as elevated ESR and CRP levels, and
rheumatoid factor tests are often positive and correlate with
the general disease activity. Other serologic test results,
including those for ANA, serum complement levels, and
cryoglobulins, are normal or negative.252
ANCA has been detected in from 85% to more than 95%
of GPA patients.253-255,257,288 Patients with granulomatous
lesions are more likely to be C-ANCA positive with antibody
directed against PR3, a 228–amino acid serine proteinase
found in the azurophilic granules of neutrophils and the
lysosomes of monocytes.251,253-255,288 However, many patients
fitting the clinical and histologic definition of GPA will be
perinuclear ANCA (P-ANCA) positive with antibodies
directed against MPO, a highly cationic 140-kDa dimer
located in a similar cellular distribution to PR3.251,253-255,257
ANCA may also be directed to other antigens (e.g., lactoferrin, cathepsin, elastase, etc.), but these antibodies are not
usually associated with vasculitis and are usually found in
other immune-mediated diseases. In a study of 89 patients
from China who fulfilled clinical and histopathologic criteria for GPA, 61% were MPO-ANCA positive and only 38%
PR3-ANCA positive.262 Although the specificity of C-ANCA
for GPA has been as high as 98% to 99% by different assays,
the sensitivity may be low in certain populations with inactive or limited disease.289 Some patients with pauci-immune
crescentic glomerulonephritis will be ANCA negative and
may have a somewhat distinct disease from the more
common ANCA-positive patients.290 In a series of 141
Chinese patients with RPGN, 27% were ANCA negative and
had more upper airway disease than the ANCA-positive
group.290 However, they had no difference in other clinical
manifestations. Other patients with crescentic glomerulonephritis will be positive for both ANCA and anti-GBM antibodies (see “Anti–Glomerular Basement Membrane Disease
and Goodpasture’s Syndrome” section). “False-positive”
C-ANCA tests have been reported in patients with certain
infections (e.g., HIV, tuberculosis, subacute bacterial endocarditis) and neoplastic diseases. A number of medications
have also been associated with ANCA, usually anti-MPO, and
at very high titers. The strongest association is with the antithyroid drugs, including propylthiouracil, methimazole,
and carbimazole. Hydralazine, minocycline, penicillamine,
allopurinol, clozapine, rifampin, cefotaxime, isoniazid, and
a number of other drugs have also been associated with
ANCA-positive vasculitis.291 Levamisole as an adulterant in
cocaine has been associated with unique ANCA positivity,
often with a positive P-ANCA and PR3-ANCA but negative
MPO-ANCA.292 While there has been debate whether the
ANCA levels parallel the clinical and histologic activity in
GPA, many patients will normalize their ANCA titer during
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1112
SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
periods of quiescence.259,289,293-297 A subsequent rise in ANCA
titer from low titer has been suggested to be predictive of
renal and systemic flares.293-297 Most clinicians prefer to use
the ANCA level in the context of other clinical findings and
often with other markers of active inflammation such as ESR
and CRP. At times, renal biopsy is the only way to be certain
of the clinical significance of a change in ANCA titer.
RENAL FINDINGS
Renal findings in GPA are extremely variable and usually
occur together with other systemic manifestations.252-256,285
The degree of renal involvement in ANCA-associated vasculitis is highly predictive of patient survival. Patients with
active urinary sediment but normal GFR have a twofold
increased risk of death, while those with impaired renal
function have a fivefold greater risk of dying.298 A number
of studies confirm that severe renal disease is a negative
prognostic feature. Many patients have some evidence of
renal disease at presentation, and from 50% to 95% eventually develop clinical renal involvement. Proteinuria and
urinary sediment abnormalities, including microscopic
hematuria and red cell casts, are common. Patients with
more severe glomerular involvement have a decrease in
GFR and greater levels of proteinuria, but nephrotic syndrome is uncommon. The level of proteinuria may be
higher in those with less severe renal insufficiency and may
actually increase during therapy as the GFR improves.285
The degree of renal failure and serum creatinine do not
always correlate well with the percentage of glomerular necrotizing lesions, the percentage of glomerular crescent formation, or the presence of interstitial granulomas or
vasculitis. The incidence of both acute oliguric renal failure
and significant hypertension varies among reports but is
higher in reports from renal centers. Intravenous pyelograms are typically normal, and by angiography vascular
aneurysms are not usually present.
Other renal conditions found in GPA include pyelonephritis and hydronephrosis due to vasculitis, causing ureteral stenosis, papillary necrosis, perirenal hematoma from
arterial aneurysm rupture, and lymphoid malignancies with
neoplastic infiltration of the renal parenchyma in patients
treated with immunosuppression.299
COURSE AND TREATMENT
The course of the active glomerulonephritis in GPA is
typical of RPGN with progression to renal failure over days
to months.252-256 Patients with severe necrotizing, granulomatous glomerulonephritis are more likely to develop renal
failure, and patients with more global glomerulosclerosis
are more likely to develop ESKD. Greater degrees of glomerulosclerosis and interstitial fibrosis predict a poor renal
outcome.300 Even with immunosuppressive therapy, a significant number of patients will eventually progress over the
long term to renal failure.
The introduction of effective cytotoxic immunosuppressive therapy dramatically changed the course of GPA.
Initial studies of untreated or corticosteroid-treated patients
documented survivals of only 20% to 60% at 1 year.252,256
Both renal and extrarenal lesions may progress during corticosteroid therapy.252 Long-term survival with cyclophosphamide-based regimens ranges from 87% at 8 years to
64% at 10 years.252-256,301,302 Using a regimen of combined
cyclophosphamide (1.5 to 2 mg/kg/day) and corticosteroids, remissions were achieved in 85% to 90% of 133 GPA
patients.252 Although many patients eventually relapsed,
others remained in long-term remission off immunosuppression. Other studies have confirmed these results.254-257,301
Complete remissions of renal and extrarenal symptoms,
including severe pulmonary disease and renal failure requiring dialysis, have been described. More than 50% of dialysisdependent patients will be able to discontinue dialysis and
remain stable for years. Although resistance to therapy is
well documented, some patients do not benefit from treatment for reasons of noncompliance, intercurrent infection
requiring decreased treatment, or inadequate duration of
therapy.
The optimal dose, duration of treatment, route of administration, and concomitant therapy to be given with cyclophosphamide is still debated for patients with ANCA-positive
small vessel vasculitis.254-257 Many recent trials have included
both GPA and MPA patients. Cyclophosphamide is usually
administered with corticosteroids initially, with the dose of
the steroids tapered or changed to alternate-day therapy.
Some regimens include intravenous high-dose “pulse” corticosteroids initially, and others have used plasmapheresis in
critically ill patients. A typical regimen for induction therapy
of severe GPA or MPA RPGN might include intravenous
pulse methylprednisolone (7 mg/kg, to a maximum dose of
500 mg to 1000 mg) for 3 consecutive days followed by oral
prednisone 1 mg/kg/day (to a maximum of 60 to 80 mg/
day) for the first month, with subsequent tapering of the
dose along with either intravenous or oral cyclophosphamide given for approximately 6 months.253-256 Doses are
adjusted for leukopenia and other side effects as well as for
treatment response. Several studies have evaluated the role
of pulse intravenous cyclophosphamide versus oral cyclophosphamide in ANCA-positive small vessel vasculitis.303-306
In one study of 50 GPA patients randomly assigned to either
2 years of intravenous or oral cyclophosphamide, remissions
at 6 months occurred in 89% of the intravenous group
versus 78% of the oral group.303 At the end of the study,
remissions had occurred in 67% of the intravenous group
and 57% of the oral group, but relapses were more common
in the intravenous group (60% versus 13%). In a metaanalysis of 11 nonrandomized studies including more than
200 ANCA-associated vasculitis patients, complete remissions occurred in more than 60% of patients and partial
remissions in another 15%.304 Intravenous pulse cyclophosphamide was more likely to induce remission and less likely
to cause infection than oral cyclophosphamide. However,
relapses may be more frequent with intravenous use of the
drug. This is clarified by a recent large multicenter trial that
randomized 149 ANCA-positive vasculitis patients to either
Solu-Medrol plus pulsed intravenous cyclophosphamide
(15 mg/kg every 2 to 3 weeks) or plus oral cyclophosphamide (2 mg/kg/day).304 There was no difference in time to
remission or percentage of patients who achieved remission
by 9 months (88% of both groups) and no difference in
improvement of GFR over time. Although there were more
relapses in the intravenous group, this was not statistically
significant. The total dose of cyclophosphamide was approximately half as much in the intravenous group versus the
oral group, and infections were more common with oral
cyclophosphamide. Thus both regimens are effective,
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CHAPTER 33 — Secondary Glomerular Disease
relapses appear more common with intravenous therapy,
but total dose and adverse effects of the cytotoxic agent are
reduced by intravenous usage. It is unclear how frequent
the initial intravenous “pulses” of cyclophosphamide should
be given; some investigators use monthly doses and others
start with smaller doses every 2 to 3 weeks. It is clear
that early application of an intensive immunosuppressive
regimen helps prevent long-term morbidity and end-organ
damage. Since the total dose of the cyclophosphamide is far
less in patients receiving pulsed intravenous therapy, many
prefer to use it as a less toxic regimen and try to enhance
maintenance therapy to avoid relapse.
Methotrexate has been used for both induction and
maintenance therapy in patients with GPA and other ANCAassociated vasculitides.305-308 The largest trial, the NORAM
trial, compared methotrexate (20 to 25 mg/wk orally) to
oral cyclophosphamide (2 mg/kg/day), both for 1 year with
corticosteroids in 95 ANCA-positive vasculitis patients (89
GPA, 6 MPA).305 Although an equal percentage of both
groups achieved remission, the time to remission was longer
in the methotrexate group and the relapse rate much higher
(70% vs. 47%). Given these data, methotrexate is rarely used
for induction therapy in ANCA-positive vasculitis unless the
disease is very mild and rapidly controllable.
The addition of plasmapheresis to therapy for GPA
appears to benefit patients with severe renal failure, those
with pulmonary hemorrhage, those with coexistent antiGBM antibodies, and those failing all other therapeutic
agents.300,309 In one study of 20 ANCA-positive small vessel
vasculitis patients with massive pulmonary hemorrhage
treated with methylprednisolone, intravenous cyclophosphamide, and plasmapheresis, all 20 patients had resolution
of pulmonary hemorrhage.309 A trial of 137 patients with
ANCA-positive glomerulonephritis, the Methylprednisolone
versus Plasma Exchange (MEPEX) trial, evaluated patients
with a marked elevation of the serum creatinine (higher
than 500 µmol/L or 5.7 mg/dL) treated with induction
therapy with either plasma exchange or intravenous pulsed
methylprednisolone, both with oral corticosteroids and
cyclophosphamide.310 While both groups had an equal and
high 1-year mortality rate, the plasma exchange group had
an improved short-term patient survival and a greater likelihood of not reaching renal failure at 1 year (19% vs. 43%).
The addition of etanercept, a TNF-α blocker, to a standard
induction regimen for GPA was evaluated in 174 patients
and provided no additional benefit in terms of sustained
remissions or time to achieve remission.311 Disease flares and
adverse events were common in both treatment groups, and
solid tumors developed in six of the etanercept group. The
use of infliximab, another TNF-α blocker, in four uncontrolled trials was associated with an 80% remission rate but a
high rate of infectious complications.312 Likewise, a study of
alemtuzumab, an anti-CD52 monoclonal antibody, in 70
patients gave a remission rate of 83% but was associated with
high rates of relapse, infection, and mortality.313
Small uncontrolled trials initially found a role for
rituximab in ANCA-positive vasculitis, with sustained remissions in many of the patients studied.314,315 Two controlled
randomized studies support the use of rituximab as a firstline therapy comparable in efficacy to cyclophosphamide
for the treatment of ANCA-associated vasculitis.316,317 In the
RITUXIVAS study, 44 patients (mean age, 68 years old) were
1113
randomized with two thirds receiving four doses of intravenous rituximab and only two doses of intravenous cyclophosphamide and one of intravenous pulse Solu-Medrol
versus the remaining one third of patients receiving 6 to 10
pulses of intravenous cyclophosphamide.316 Both received
steroids in tapering doses. The number of remissions, time
to remission, and side effects were similar in the two groups.
Mortality and morbidity were high in both groups due to
the age of the patients and their renal dysfunction. In the
Rituximab in ANCA Associated Vasculitis (RAVE) trial, 197
patients with severe ANCA-associated vasculitis (75% GPA)
were randomized to steroids plus either four weekly doses
(375 mg/m2) of rituximab or oral cyclophosphamide
(2 mg/kg/day) with replacement by azathioprine maintenance only in the cyclophosphamide group.317 Among those
in the rituximab group, 64% reached remission, whereas
only 53% of the cyclophosphamide group did. More patients
in the rituximab arm had resolution of active vasculitis by
activity scores. Adverse events were similar in both arms of
the study. The subgroups with renal involvement and pulmonary hemorrhage also fared the same. Those with relapsing disease had a significantly higher remission rate with
rituximab compared with cyclophosphamide therapy.
Recent long-term follow-up of this population confirms the
equivalency of a steroid plus rituximab regimen to that of
steroids plus cyclophosphamide followed by azathioprine
maintenance in leading to a complete remission in ANCAassociated vascultitis.318 There was no difference in adverse
events in terms of infections or malignancies between the
groups. While this does not mean rituximab will replace
cyclophosphamide as standard treatment for ANCA-positive
vasculitis, it does allow it to be used as an initial treatment
option for many patients.319
Relapse rates from 20% to 50% have been reported often
when infectious complications have led to a discontinuation
of immunosuppressive therapy.293,296,301,320 Predictors of
relapse in a cohort of 350 patients with ANCA-positive vasculitis included C-ANCA or PR3 positivity, lung involvement,
and upper respiratory involvement, as opposed to factors
not predicting relapse, such as age, gender, race, and a clinical diagnosis of GPA rather than MPA or renal-limited vasculitis.315,320 Most patients respond to another course of
cyclophosphamide therapy.301 In patients whose ANCA level
has declined during remission, a major rise in titer may
predict a relapse, although ANCA levels and clinical disease
activity do not always correlate.293-297
Because of the potential for severe complications with
cyclophosphamide therapy (infections, infertility, hemorrhagic cystitis, and an increased risk of long-term malignancy), once an initial remission has been achieved, patients
have usually been switched to less toxic immunosuppressives
such as azathioprine, low-dose methotrexate, or MMF.320-323
A study of 155 patients with ANCA-positive vasculitis treated
patients with cyclophosphamide and steroids to induce a
remission and then randomized patients to either oral azathioprine or continued cyclophosphamide maintenance
therapy.323 Of the 155 patients, 144 entered remission and
were randomized. There was no difference in the relapse
rate in the two groups or in the adverse event rate. Relapse
rates were lower in patients with MPA than in the GPA
group. A controlled randomized trial of MMF versus azathioprine for remission maintenance found more relapses
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1114
SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
with MMF.324 Rituximab, timed to prevent B cell repopulation and rise in the ANCA titer, and cyclosporine have also
been used successfully for maintenance therapy.325,326 Since
respiratory infections, perhaps through priming of neutrophils or activation of ANCA, may be associated with
flares of disease activity, prophylactic use of trimethoprimsulfamethoxazole has been advocated.327 Methotrexate has
also been used as maintenance therapy in GPA.307 Supportive measures for GPA patients such as sinus drainage procedures, hearing aids, and corrective surgery for nasal septal
collapse may be helpful in individuals with chronic sequelae
of upper respiratory involvement.252-256 Attention to cardiovascular risks is important since patients with ANCAassociated vasculitis and renal disease have more than a
twofold increased risk of cardiovascular events when compared to matched controls with CKD.328
ESKD occurs in about 25% of patients at 3 to 4 years after
presentation. Dialysis and transplantation have been performed in increasing numbers of ANCA-associated vasculitis
patients.329-334 Many patients’ disease activity diminishes with
onset of renal failure, and relapses are significantly less
frequent for patients who reach ESKD.332 However, some
patients still require intensive immunosuppression, and
relapses have been reported well after onset of ESKD. Fatality rates may be high in some ESKD populations due to slow
recognition of relapses of the vasculitic process or, more
often, infectious complications. Most patients receiving
allografts have been maintained on prednisone and cyclosporine or tacrolimus with or without mycophenolate with
very good patient and allograft survival rates.329-334 Patients
should not receive a transplant until after a prolonged
period of remission.335,336 Recurrent active glomerulonephritis in the allograft occurs in 15% to 37% of patients and
may respond to cyclophosphamide or rituximab therapy or
other more intensive therapies.329-334 There is no evidence
that regimens including MMF or tacrolimus have advantages over older immunosuppressive regimens in preventing recurrences of ANCA-associated vasculitis.333 There is
only limited experience with sirolimus and other newer
transplant immunosuppressives.337
MICROSCOPIC POLYANGIITIS
The incidence of renal disease associated with this ANCApositive small vessel vasculitis appears to be increasing.253-256
While this may be due to wider use of ANCA testing and
renal biopsy, many investigators feel the absolute incidence
has increased. In one large series ANCA-associated crescentic glomerulonephritis made up almost 10% of all glomerular diseases diagnosed by renal biopsy in a 2-year period. In
very old adults this was the most common etiologic diagnosis.258 Vasculitis and glomerulonephritis similar to those seen
in MPA have been noted in relapsing polychondritis338 and
ANCA-positive polyangiitis induced by use of a number of
medications, most notably the antithyroid medication
propylthiouracil.339
PATHOLOGY
Light Microscopy
The most typical histologic finding is focal segmental necrotizing glomerulonephritis with crescents affecting from
Figure 33.16 Microscopic polyangiitis. There are diffuse crescents
with focal segmental necrosis of the glomerular tuft. (Jones’ methenamine silver stain, ×125.)
few to many glomeruli (Figure 33.16).253-257,340 There is segmental rupture of the GBM associated with polymorphonuclear infiltration, karyorrhexis, and fibrin deposition
within the glomerular tuft and the adjacent Bowman’s
space. Crescents characteristically overlie areas of segmental
tuft necrosis and may be segmental or circumferential. Cellular and fibrous crescents often coexist. Some crescents are
voluminous with a “sunburst” appearance due to massive
circumferential destruction of Bowman’s capsule. Uninvolved glomeruli are typically normocellular. In the chronic
or healing phase of the disease there is segmental and
global glomerulosclerosis with focal fibrocellular and fibrous
crescents. While there are many similarities, one study documents biopsy differences between MPA and GPA patients.
Biopsies from patients with MPA and patients who are MPOANCA positive were more likely to show glomerulosclerosis,
interstitial fibrosis, and tubular atrophy.267 This suggests a
more prolonged, less fulminant course in patients with MPA
compared to GPA. An international classification differentiates glomerular lesions depending on whether they are
focal, crescentic, mixed, or sclerotic and found correlates
with clinical outcome.341
Patients with MPA infrequently have a true arteritis identified on renal biopsy. The frequency ranges from 11% to
22% with predominant involvement of interlobular arteries
and arterioles.340 Involvement is circumferential, lesions are
generally of the same age, and aneurysm formation is rare.
The acute vasculitis is usually necrotizing with fibrinoid
necrosis of the vessel wall and infiltration by neutrophils and
mononuclear leukocytes. Vasculitis with granulomatous
features is uncommon. In later stages of the disease there
may be narrowing of the lumens of small arteries due to
concentric intimal fibroplasia and elastic reduplication, but
medial scarring is less frequent and severe than in classic
polyarteritis nodosa (PAN). In MPA there is often a diffuse
interstitial inflammatory cell infiltrate with plasma cells,
lymphocytes, polymorphonuclear leukocytes, and sometimes eosinophils especially around glomeruli and vessels.
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CHAPTER 33 — Secondary Glomerular Disease
Interstitial inflammatory cells may penetrate the tubular
basement membrane causing tubulitis.340 In more chronic
stages there is patchy tubular atrophy with interstitial fibrosis that parallels the distribution of the glomerular and vascular damage.
Immunofluorescence and Electron
Microscopic Findings
1115
whether the patients are P-ANCA or C-ANCA positive.253-256,342
Since MPA is a multisystem disease with various organs
involved, many of the clinical findings are similar to those
of ANCA-positive GPA, including the development of cutaneous disease, rheumatologic involvement, and neurologic
disease. Pulmonary disease is common and presents with
shortness of breath, dyspnea, cough, and wheezing.253-256
In most cases the glomeruli show no or only weak immunofluorescence staining consistent with the designation “pauciimmune” glomerulonephritis.340,341 A review of a number of
large series reported positivity for one or another immunoglobulin in 3% to 35% of cases with great heterogeneity and
variability of intensity.340 Fibrin/fibrinogen was the most
common and intensely staining reactant identified in the
glomeruli, followed by C3 with relatively sparse and weak
IgG and Clq.340,341 The pattern is thought to be consistent
with “nonspecific trapping” rather than immune complex
deposition. Vascular staining is similar.
By electron microscopy, the glomeruli in most patients
with MPA have no or rarely sparse irregular, glomerular
electron-dense deposits.340,341 Glomeruli may show endothelial swelling, subendothelial accumulation of “fluffy” electronlucent material, and subendothelial and intracapillary fibrin
deposition. Through gaps in the GBM, fibrin tactoids and
neutrophils exude into Bowman’s space associated with
epithelial crescents. Vascular changes have included swelling and focal degeneration of the endothelium; separation
of the endothelium from its basement membrane with subendothelial fibrin deposition; and, with severe damage,
intraluminal and intramural fibrin deposition, edema, and
inflammatory infiltration of the intima and media by leukocytes.340,341 No discrete electron-dense deposits are found in
the vessels. In vessels with chronic changes, there may be
expansion of the intima by concentric layers of fibrous or
fibroelastic tissue, with focal scarring of the media.
LABORATORY TESTS
Abnormal laboratory tests may include a normochromic,
normocytic anemia, thrombocytopenia, and a mild leukocytosis, at times with eosinophilia.253-257 Nonspecific inflammatory markers such as the ESR and CRP are often elevated.
ANA, serum complement levels, and cryoglobulins are
normal or negative.
The widespread use of accurate assays for ANCA has facilitated the clinical diagnosis of MPA.253-257 There is considerable clinical overlap between patients with MPA, GPA, and
EGPA, and all may have high rates of ANCA positivity.
Although C-ANCA–positive patients are more likely to have
biopsy-proven necrotizing vasculitis or granulomatous
inflammation of the sinuses or lower respiratory tract, there
is a large overlap in the clinical manifestations between
C-ANCA–positive and P-ANCA–positive patients. For
example, in a recent clinical trial of 198 patients with ANCApositive disease, 75% of patients were clinically GPA, but
only 67% were anti-PR3 positive.317 Likewise, 25% of patients
were clinically MPA, but 33% were anti-MPO positive. ANCA
titers vary considerably among patients with similar clinical
manifestation, and the role of the titer in predicting flares
of the disease is not fully defined (see the “Granulomatosis
with Polyangiitis” section under “Small Vessel Vasculitis”).
Some patients will retain high ANCA levels despite clinical
remission, and some patients are positive for anti-GBM antibodies as well as ANCA (see “Anti–Glomerular Basement
Membrane Disease and Goodpasture’s Syndrome” section).
PATHOGENESIS
ANCA is felt to play a pathogenetic role in ANCA-associated
MPA and glomerulonephritis in a manner similar to
GPA268,270,271 (see “Anti–Glomerular Basement Membrane
Disease and Goodpasture’s Syndrome” section). There is
initial priming of the neutrophil with cytokines and other
mediators of inflammation, perhaps in response to infection, leading to expression of MPO-ANCA antigens on the
surface of the neutrophil. These exposed antigens are then
poised to react with circulating ANCAs. Neutrophils become
activated and undergo a respiratory burst, with degranulation and release of reactive oxygen species onto endothelial
surfaces. In drug-induced MPA, although ANCAs develop
in relation to many different antigens (elastase, cathepsin
G, lactoferrin, etc.), only patients with high titers of high
avidity and complement-binding specific anti-MPO antibodies develop the disease.339
RENAL FINDINGS
Most MPA patients will have laboratory evidence of renal
involvement at presentation with urinary sediment changes
of microscopic hematuria and erythrocyte casts.253-257 Proteinuria is common but nephrotic syndrome is not. A
decreased GFR is common in unselected series, and even
more common in those selected for renal involvement.
Severe renal insufficiency may be found at presentation.
These renal findings are similar in patients with ANCApositive RPGN, whether or not it is associated with systemic
involvement.253-257,267,343 In MPA the severity of the clinical
renal findings generally correlates with the degree of glomerular involvement, similar to patients with GPA. Patients
with normal serum creatinines or normal creatinine clearances are likely to have greater numbers of normal glomeruli on biopsy, while patients with reduced or deteriorating
renal function are more likely to exhibit more glomeruli
with severe segmental necrotizing glomerulonephritis or
diffuse proliferative features.343,344 Extensive crescent formation correlates with oliguria, severe renal failure, and a
residual decrease in GFR after therapy.
CLINICAL FEATURES
Patients with ANCA-negative pauci-immune focal segmental
necrotizing glomerulonephritis and ANCA-positive RPGN
have similar clinical findings and presentations regardless
of whether vasculitis has been documented on renal
biopsy.253-256 Likewise, the extrarenal findings in many
patients with ANCA-positive RPGN have been similar
PROGNOSIS AND TREATMENT
Standard treatment for MPA has included cyclophosphamide and corticosteroids in a fashion similar to the treatment
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SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
of GPA (see the “Granulomatosis with Polyangiitis” section
under “Small Vessel Vasculitis”). Controlled trials of the use
of intravenous versus oral cyclophosphamide, anti–TNF-α
agents, methotrexate, and rituximab have all been examined
in populations of ANCA-positive vasculitis patients, including
those with GPA and MPA.304,305,309,310,312,316-319,323 These regimens are discussed extensively in the section on GPA. In most
studies both MPO- and PR3-ANCA–positive patients have
responded equally. Likewise, the presence or absence of systemic symptoms has not dictated the response. However,
even patients with a good initial response to therapy may
suffer residual glomerular damage and progress to ESKD.344
Thus, aggressive, vigorous early therapy to turn off the disease
process is thought to be crucial in preventing residual organ
damage. Therapeutic intervention in addition to immunosuppressive therapy includes measures to prevent nonimmunologic glomerular disease progression such as the use of
renin angiotensin aldosterone blockade, hyperlipidemia
control, and low-protein diets in some patients.
EOSINOPHILIC GRANULOMATOSIS
WITH POLYANGIITIS
EGPA (formerly designated Churg-Strauss syndrome or
allergic granulomatosis and angiitis) is an uncommon multisystemic disease characterized by vasculitis, asthma, allergic rhinitis, organ infiltration by eosinophils, and peripheral
eosinophilia.345-348 Although there may be some overlap with
other vasculitic and allergic processes such as GPA, MPA,
polyarteritis nodosa, Loeffler’s syndrome, and chronic
eosinophilic pneumonitis, the clinical and pathologic features of EGPA are distinct.345-348
EGPA is the least frequent of the ANCA-positive small
vessel vascultitides.345-358 In a review of almost 185,000
asthmatic patients taking medications, only 21 cases of
EGPA were identified.349 The low incidence may reflect, in
part, underrecognition. There is no gender predominance
in EGPA, and the mean age at diagnosis is around 40
years.345-351 Clinical renal involvement is clearly less prevalent
than morphologic renal involvement. In autopsy series, the
kidney is affected in more than 50% of patients, while clinical renal disease has been described in 25% to more than
90% of patients.346-351
A number of studies describe the rare occurrence of EGPA
in steroid-dependent asthmatic patients taking leukotriene
receptor antagonists (such as montelukast, zafirlukast, pranlukast) especially during reduction of the steroid therapy.352355
While not all investigators have been able to document
this association, analysis of published reports does support
it.356,357 This may occur via unmasking of the vasculitic syndrome as the leukotriene receptor antagonist permits the
steroid withdrawal. Similar cases have been reported in asthmatic patients following a change from oral to inhaled steroids. Rarely, substitution of a leukotriene receptor antagonist
for inhaled steroids has also led to EGPA.355-357
PATHOLOGY
Histologic findings suggestive of EGPA in any organ include
a number of the following features: eosinophilic infiltrates,
areas of necrosis, an eosinophilic giant cell vasculitis of small
arteries and veins, and interstitial and perivascular granulomas. Renal biopsies in EGPA vary from normal kidney tissue
Figure 33.17 Eosinophilic granulomatosis with polyangiitis. Granulomatous vasculitis involves an arcuate artery. There is granulomatous transmural inflammation with focal giant cells and superimposed
luminal thrombosis. (Hematoxylin and eosin stain, ×125.)
to severe glomerulonephritis, vasculitis, and interstitial
inflammation.339,345,346,358 There may be a focal segmental
necrotizing glomerulonephritis, sometimes with small crescents. In most cases the glomerulonephritis is mild, affects
only a minority of glomeruli, and involves the tuft segmentally. The glomerulonephritis rarely may be diffuse and
global with severe necrotizing features and crescents. In
some cases, there is only mesangial hypercellularity without
endocapillary proliferation or necrosis.
In the original autopsy studies by Churg and Strauss,
vasculitis was found in the kidney in more than one half of
cases, and it has been noted on renal biopsy as well.340 It
may involve any level of the renal arterial tree from arterioles to large arcuate or interlobar arteries and may vary
from fibrinoid necrotizing to granulomatous. Although
resembling other forms of vasculitis, the arteritis is characterized by eosinophilic granulocytes within the arterial wall
and in the surrounding connective tissue (Figure 33.17).
Vascular lesions may display destruction of elastic membrane, aneurysms, and luminal thrombosis with recanalization, as well as epithelioid cells and multinucleated giant
cells in the media, adventitia, and perivascular connective
tissue. Active and healed lesions may coexist. Less commonly, venules and small veins of interlobular size are
affected, typically with granulomatous features. The tubulointerstitial region is involved by an inflammatory infiltrate
containing many eosinophils and some lymphocytes, plasma
cells, and polymorphonuclear leukocytes in association with
interstitial edema.340 In some cases there are interstitial
granulomas composed of a core of eosinophilic or basophilic necrotic material surrounded by a rim of radially
oriented macrophages, giant cells of the Langhans type, and
numerous eosinophils. Interstitial nephritis may be present
without glomerular pathology.
By immunofluorescence, areas of segmental necrosis in
the glomeruli may contain IgM, C3, and fibrinogen.347 The
presence of IgE in renal or other tissues has not been adequately investigated.359 Electron microscopy of the glomeruli, pulmonary granulomas, venules, and capillaries reveals
no electron-dense deposits.340,346-348
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CHAPTER 33 — Secondary Glomerular Disease
PATHOGENESIS
Although the pathogenesis of EGPA remains unclear, allergic or hypersensitivity mechanisms are supported by the
presence of asthma, hypereosinophilia, and elevated plasma
levels of IgE.345-348,357,359 Eosinophils in patients with EGPA
have prolonged survival due to inhibition of CD95-mediated
apoptosis and T cell secretion of eosinophil-activating cytokines. Human eosinophil cationic proteins (ECPs), which
are capable of tissue destruction in a variety of hypereosinophilic syndromes, have been found in granulomatous tissue
from patients with EGPA.360,361 Higher serum levels of ECP,
soluble IL-2 receptor, and soluble thrombomodulin levels
have been associated with disease activity.362,363 The number
of peripheral T regulatory cells producing IL-10 is reduced
in EGPA and the number increases during clinical remission.364 Hypocomplementemia and circulating immune
complexes have rarely been observed, and the negative
immunofluorescence and electron microscopy findings do
not support an immune complex mechanism. Cell-mediated
immunity is likely involved, and high helper-to-suppressor
ratios in the peripheral blood during active disease, as well
as a preponderance of helper T cells in the granulomas of
skin biopsies, have been reported.346 In those patients with
positive ANCA, the ANCA antibody likely plays a pathogenic
role akin to GPA and MPA.278,279,282
CLINICAL AND LABORATORY FEATURES
Patients may have initial constitutional symptoms such as
weight loss, fatigue, malaise, and fever.345-348 Characteristic
extrarenal features include asthma (present in more than
95% of cases), an allergic diathesis, allergic rhinitis, and
peripheral eosinophilia.345-347,351 Asthmatic disease typically
precedes the onset of the vasculitis by years, but it may occur
simultaneously. The severity of the asthma does not necessarily parallel the severity of the vasculitis. Many patients
subsequently develop eosinophilia in the blood along with
eosinophilic infiltrates in multiple organs. Disease often
involves the heart, with pericarditis, heart failure, and/or
ischemic disease; the gastrointestinal tract, with abdominal
pain, ulceration, diarrhea, or bowel perforation; and the
skin, with subcutaneous nodules, petechiae, and/or purpuric lesions.345-347,364,365 Peripheral neuropathy with mononeuritis multiplex is common, but migrating polyarthralgias
and/or arthritis occur less frequently.366 The eye, prostate,
and genitourinary tract may be involved. Some patients with
EGPA have overlapping features with PAN- or other ANCApositive vasculitides.347,345-348
Laboratory evaluation may reveal anemia, leukocytosis,
hypergammaglobulinemia, and elevated ESR and CRP
levels.345-348,350,351 Eosinophilia is universally present and may
reach 50% of the total peripheral leukocyte count. The
degree of eosinophilia and the ESR may correlate with
disease activity as may the level of ECP, soluble IL-2 receptor,
and soluble thrombomodulin levels.362 Rheumatoid factor
is often positive, but serum complement, hepatitis markers,
circulating immune complexes, ANAs, and cryoglobulins
are usually negative or normal.345-347,350,351 Elevated serum
IgE levels and IgE-containing circulating immune complexes are frequently found.345-347,362 Chest radiography may
show patchy infiltrates, nodules, diffuse interstitial disease,
and pleural effusion.345-347,367 Pleural effusions may be
1117
exudative and contain large numbers of eosinophils.367 On
angiography visceral aneurysms may be present in patients
with both PAN overlap syndromes and classic EGPA.
ANCA levels are elevated in 40% to 60% of EGPA
patients.345-348,363,368,369 Most are P-ANCA and anti-MPO positive, but some are C-ANCA and anti-PR3 positive. In one
analysis of almost 100 patients 35% were ANCA positive by
indirect immunofluorescence with a perinuclear pattern
and anti-MPO specificity in about three quarters.363 Patients
with clinically active vasculitis and those with active glomerulonephritis are likely to be ANCA positive.358 Some investigators have found a good correlation between ANCA positivity
or ANCA titers and clinical activity, whereas others have
not.363,364 Clearly in some, ANCA titers may remain positive
despite clinical remissions. In EGPA, ANCA positivity has
often correlated with active glomerulonephritis, pulmonary
hemorrhage, neuropathy, and the presence of small vessel
vasculitis.345-348,368,369
Clinical renal involvement in EGPA is quite variable. In
one series of 383 patients with EGPA, renal involvement was
found in 22%.370 In another series of 116 patients, many
patients had isolated urinary findings and approximately
half had AKI.358 Microscopic hematuria and mild proteinuria are common, but nephrotic-range proteinuria is infrequent. Hypertension is found in 10% to 30% of patients. In
one study of patients undergoing renal biopsy, almost 70%
had a necrotizing crescentic glomerulonephritis while
others had an interstitial eosinophilic nephritis.358 ANCA
was positive in 75% of the patients with nephropathy as
opposed to 25% of patients without nephropathy.
PROGNOSIS, COURSE, AND TREATMENT
Patients may have several phases of the syndrome over many
years.345-347,350,351,370 There may be a prodromal phase of
asthma or allergic rhinitis followed by a phase of peripheral
blood and tissue eosinophilia that is remitting and relapsing
over months to years before the development of systemic
vasculitis. A shorter duration of asthma prior to the onset
of vasculitis has been associated with a worse prognosis. The
correlation between ANCA levels and disease activity has
been variable. In general, renal disease is mild, with only
7% of patients in one large literature review having renal
failure as a cause of death, even including untreated
patients.347 However, cases progressing to severe renal failure
and dialysis have certainly been reported.351 Most patients
surviving the initial insult fare well with survival rates in
treated patients of approximately 90% at 1 year and 70% at
5 years.345-347,350,351,370 Patients with significant cardiac, central
nervous system, and gastrointestinal involvement, and those
with greater degrees of renal damage have a poorer longterm survival.
Corticosteroid therapy is the primary treatment for many
patients with EGPA with mild disease and those with interstitial disease.345-347,350,351,370 Patients may respond rapidly to
high daily oral prednisone therapy, and even relapses
respond to re-treatment. Extrarenal disease often responds
as well. In patients with multisystem disease, with necrotizing glomerulonephritis, and other signs of severe organ
involvement, or for those with resistant or relapsing disease,
other immunosuppression has been used together with corticosteroids.371 Other agents have included cyclophosphamide, azathioprine, methotrexate, MMF, rituximab, or
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SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
plasma exchange.345-347,350,351,370,372,373 Intravenous immunoglobulin, interferon alfa, TNF blocking agents, mepolizumab (a humanized monoclonal antibody to IL-5), and
omalizumab (a monoclonal anti-IgE) have also been used
successfully in a few resistant patients.374,375 Although the
prognosis for recovery is good, some patients progress to
dialysis and others relapse or have chronic sequelae such as
permanent peripheral neuropathy, chronic pulmonary
changes, and hypertension.
GLOMERULAR INVOLVEMENT
IN OTHER VASCULITIDES
POLYARTERITIS NODOSA (CLASSIC
MACROSCOPIC POLYARTERITIS NODOSA)
PAN, also called periarteritis nodosa, was first described in
the mid-19th century.376 Classic PAN is a systemic necrotizing
vasculitis primarily affecting medium-sized, muscular arteries, often at branch points, producing lesions of varying ages
with focal aneurysm formation.288 A second, “microscopic”
form was originally described as manifesting necrotizing
inflammation of small arteries, veins, and capillaries associated with glomerulonephritis. The microscopic form is now
understood to represent ANCA-positive MPA and should
clearly be considered as part of the spectrum of ANCAassociated small vessel vasculitides (see the “Microscopic
Polyangiitis” section under “Small Vessel Vasculitis”).288 This
section will discuss only “classic” macroscopic PAN.
PAN is more common in males than females and occurs
most often in the fifth and sixth decades of life. Incidence
studies and prevalence studies show that PAN is uncommon
and has a major regional variation.377 Reduced rates have
been noted in parallel to the reduction of hepatitis B viral
(HBV) infections.378 Clinically, the prevalence of renal
disease in patients with PAN varies from 64% to 76% in
unselected series and virtually 100% in nephrology-based
series.378-381 The prevalence of pathologic renal involvement
exceeds that of clinically evident disease. True idiopathic
PAN is a primary vasculitis. Classic polyarteritis has also been
associated with abuse of amphetamines and other illicit
drugs, but it is unclear how many of these patients had
associated viral infectious hepatitis.382 The most common
associated illness found in patients with classic PAN is HBV
infection. The incidence ranges from 0 to 55% in different
series but is probably less than 10% of all cases.378 PAN associated with HBV has similar clinical features to idiopathic
PAN and often occurs early in the course of HBV infection.
It is unclear how many of these patients have had concomitant HCV infection. In one series of 1200 patients with systemic autoimmune disorders who tested positive for HCV,
78 had PAN.383 Hairy cell leukemia has also been reported
in association with PAN.
PATHOLOGY
In classic PAN the glomeruli are usually unaffected. Some
glomeruli may show ischemic retraction of the tuft and
sclerosis of Bowman’s capsule. Rarely, patients with large
vessel vasculitis may also have a focal necrotizing glomerulonephritis akin to that seen in MPA.288,340,381 The vasculitis
in classic PAN affects the medium-sized to large arteries (i.e.,
those of subarcuate, arcuate, and interlobar caliber) in a
segmental distribution, often producing lesions of different
ages, including acute, healing, and chronic lesions.288,381
Segments of arterial involvement are interspersed with
normal areas producing “skip lesions,” and even the involved
portions of the vessel wall have eccentric inflammation. In
areas of active vasculitis there is inflammation of the vessel
wall by infiltrates of lymphocytes, polymorphonuclear leukocytes, monocytes, and occasionally eosinophils, which
may involve the intima alone, the intima and media, or all
three layers of the vessel wall. Lesions are often necrotizing
with mural fibrin deposition and rupture of the elastic membranes. Areas of necrosis may lead to aneurysm formation
particularly in larger arteries (i.e., arcuate, interlobar),
which can be associated with rupture and hemorrhage into
the renal parenchyma. Superimposed thrombosis with
luminal occlusion is not uncommon. In the healing phase,
inflammation subsides and the vessel wall is thickened by
concentric cellular proliferation of myointimal cells separated by a loose ground substance. Localized destruction of
elastic lamellae is demonstrable with elastic stains. Eventually the media is replaced by areas of broad fibrous scars.
There may be almost total occlusion of the vessel lumen by
intimal fibroplasia with areas of concentric reduplication
and discontinuity of the internal elastic membrane. Wedgeshaped, macroscopic cortical infarcts are common and are
usually caused by thrombotic occlusion of the vasculitic
lesions.381 In more chronic phases, tubular atrophy and
interstitial fibrosis develop.
Autopsy studies in PAN describe the kidneys as being
the most commonly affected organ (65%), followed by the
liver (54%), periadrenal tissue (41%), pancreas (39%), and,
less commonly, muscle and brain.379-381 Other tissues giving
high yields when biopsied for diagnostic vasculitic lesions
include the testes, sural nerve, skin, rectum, and skeletal
muscle.
PATHOGENESIS
PAN patients are typically ANCA negative; therefore, this
form of vasculitis is not thought to be mediated by ANCA.
The vasculitis of PAN may involve diverse pathogenetic
factors, including humoral vascular immune deposits, cellular immunity, and endothelial cytopathic factors. An
immune complex pathogenesis of vasculitis is suggested by
experiments of acute serum sickness in which an acute glomerulonephritis is produced alongside a systemic vasculitis
resembling PAN.381 The vasculitis can be largely prevented
by complement or neutrophil depletion. The experimental
Arthus reaction can also induce a vasculitis resulting from
in situ vascular immune complex formation with vessel
injury preventable by neutrophil or complement depletion.384 MRL1 mice develop an immune complex glomerulonephritis with necrotizing vasculitis similar to PAN in
association with high levels of circulating immune complexes, predominantly with autoantibodies containing antiDNA.385 Viral infection of the muscle cells of the vessel
media by murine leukemia virus is also associated with a
necrotizing vasculitis and lupus-like syndrome with vascular
deposits of immunoglobulin and complement.386 However,
glomerular and vascular immune deposits are rarely found
in human PAN despite significant levels of circulating
immune complexes.
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CHAPTER 33 — Secondary Glomerular Disease
Two models of cell-mediated vasculitis have been produced experimentally in mice.387 There is no evidence in
these models for vascular immune deposits, and some have
a granulomatous form of vasculitis similar to that of PAN in
multiple organs. In Kawasaki’s vasculitis, IgM antiendothelial antibodies directed against endothelial surface antigens
inducible by cytokines have been found.388 Likewise, several
viral infections in humans are capable of inducing direct
cytopathic injury to arterial endothelium.381
CLINICAL FEATURES
The clinical features of PAN are quite variable. In classic
PAN, patients are ANCA negative and typically have findings
related to visceral organ infarction and ischemia, including
abdominal, cardiac, renal, and neurologic involvement. The
most common clinical features relate to constitutional symptoms of fever, weight loss, and malaise. Gastrointestinal
involvement may include nausea, vomiting, abdominal pain,
gastrointestinal bleeding, bowel infarcts, and perforations.381,389,390 Liver involvement may be associated with HBV
or HCV, and vasculitis of the mesenteric vessels, hepatic
arteries, and of the gallbladder leading to cholecystitis have
all been found.378,390 Patients may develop heart failure,
coronary artery ischemia with angina or myocardial infarction, and, less commonly, pericarditis and conduction
abnormalities. Disease of the nervous system may be central,
with seizures and cerebrovascular accidents, or related to
peripheral nerves, with mononeuritis multiplex and peripheral neuropathies.391-393 Patients may develop muscle weakness, myalgias or myositis, and arthralgias, but frank arthritis
is uncommon.381,394 Other clinical findings relate to disease
in the gonads, salivary glands, pancreas, adrenals, ureter,
breast, and eyes. In general, with the exception of liver
manifestations and arthralgias, there is little difference
between the clinical findings of patients who are HBV positive or negative. Cutaneous disease may present with “palpable purpura” owing to leukocytoclastic angiitis, or with
petechiae, nodules, papules, livedo reticularis, and skin
ulcerations.
LABORATORY TESTS
No laboratory test is diagnostic of PAN. Abnormal
laboratory tests commonly include an elevated ESR, anemia,
leukocytosis at times with eosinophilia, and thrombocytosis.343,378,381 Patients with classic PAN are usually ANCA negative, and the finding of a positive ANCA should suggest the
diagnosis of small vessel vasculitis such as MPA, GPA, or
EGPA.378 ANA testing is negative, and patients have normal
serum complement values. Tests for rheumatoid factor are
often positive. Although cryoglobulins have often been
reported to be positive, it is unclear what percentage of
cases have had associated viral hepatitis.381 The incidence of
hepatitis B antigenemia has ranged from 0 to 40% of PAN
patients, as opposed to less than 10% of unselected
patients.347,378
RENAL FINDINGS
The renal manifestations in classic PAN reflect renal
ischemia and infarction due to predominant involvement
of the larger vessels. Hypertension, which may be mild
or severe, is found initially in up to one half of patients
and can develop at any time during the course of the
1119
disease.336,378-380,389,395 Presenting renal symptoms are uncommon in PAN but may include hemorrhage from a renal
artery aneurysm, flank pain, and gross hematuria. Although
mild proteinuria and microhematuria may be found, signs
of glomerulonephritis such as erythrocyte casts and nephritic
syndrome are absent.
Angiographic examination of the vasculature in PAN
often reveals evidence of vasculitis and wedge-shaped areas
of ischemia. Angiograms demonstrate multiple rounded,
saccular aneurysms of medium-sized vessels in about 70% of
cases, as well as thromboses, stenoses, and other luminal
irregularities.389,397 Aneurysms most commonly involve the
hepatic, splanchnic, and renal vessels, are usually bilateral,
multiple, and vary in size from 1 to 12 mm.397 There is no
way to clinically predict the presence of aneurysms. Vasculitic changes and even aneurysms can heal over time as
documented by angiography, usually correlating with the
clinical response of the patient.395,397 Similar aneurysms have
been documented in GPA, SLE, TTP, bacterial endocarditis,
and EGPA.381
PROGNOSIS AND TREATMENT
In older studies, untreated patients with PAN had a dismal
survival rate.381 Many patients had a fulminant course with
a high early mortality due to acute vasculitis leading to renal
failure, gastrointestinal hemorrhage, or acute cardiovascular events. Late mortality has been attributed to chronic
vascular changes with chronic renal failure and congestive
heart failure.379,398 In one series of more than 300 PAN
patients, there were 20 deaths in the first year among the
109 HBV-positive patients and only 18 deaths among 200
non–HBV-positive PAN patients.399 Risk factors for early
mortality included older age, renal involvement, central
nervous system disease, and gastrointestinal involvement.
Treatment had no effect on this early mortality, which was
due to vasculitis and infection.
Corticosteroid use improved the survival rate of PAN
patients significantly, with a 5-year survival rate of approximately 50%.379 Nevertheless, some patients achieved only
partial remissions with long-term morbidity and mortality.
Even recent attempts to use corticosteroids alone only in
patients with mild disease have led to high relapse rates.400
The use of cytotoxic immunosuppression in idiopathic PAN
has improved the 5-year survival rate to well over
80%.344,378,397,401,402 While a number of immunosuppressive
medications have been used, cyclophosphamide is widely
accepted as the most effective agent.344,397,401,402 Initial therapy
of idiopathic PAN usually consists of high doses of cyclophosphamide (e.g., 2 mg/kg/day), commonly given along
with high doses of corticosteroids (e.g., prednisone, 1 mg/
kg/day), which are then tapered over time. Many use
another less toxic immunosuppressive (e.g., azathioprine)
for maintenance therapy. Successful treatment can lead to
complete inactivity of the vasculitic process and even reversal of severe renal failure. For PAN associated with HBV the
following regimen has been effective. A short 2-week course
of corticosteroids with or without plasma exchange followed
by antiviral agents has been used in the treatment of
PAN associated with HBV and hairy cell leukemia leading
to reduced rates of relapse and mortality.378 Hypertension control is an important part of therapy. For those
patients with ESKD, immunosuppressive therapy should be
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SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
continued for 6 to 12 months after the disease appears inactive. Transplantation has been performed in only a limited
number of patients with PAN.
TEMPORAL ARTERITIS (GIANT CELL ARTERITIS)
Temporal arteritis, or giant cell arteritis, is a systemic vasculitis with giant cell involvement targeting medium-sized and
large arteries.403-406 It is characterized by segmental transmural inflammation of medium-sized and large elastic arteries
by a mixed infiltrate of lymphocytes, monocytes, polymorphonuclear leukocytes, scattered eosinophils, and giant
cells.403-405
The disease is the most common form of arteritis in
Western countries.403-405,407,408 Temporal arteritis is primarily
a disease of older adults, the average age being 72 years,
with more than 95% of patients exceeding 50 years of
age.407,408 Extracranial vascular involvement occurs in 10%
to 15% of patients with giant cell arteritis.403-405 Temporal
arteritis should be suspected in older individuals who
present with persistent headaches, abrupt visual disturbances, jaw claudication, symptoms of polymyalgia rheumatica, or unexplained fevers and malaise along with
anemia and elevated levels of ESR and CRP. Temporal artery
biopsy is the definitive diagnostic test and other techniques
such as temporal artery ultrasonography are not sensitive.409
Renal manifestations are rare and generally mild, although
significant renal involvement has been reported.403-405,408,410
Some patients may have positive serology for P-ANCA or
less commonly C-ANCA. The renal pathology has been
described as a focal segmental necrotizing glomerulonephritis with focal crescents and vasculitis, primarily affecting
small arteries and arterioles. Rarely visceral aneurysms are
demonstrable angiographically. Whether these cases represent true manifestations of temporal arteritis or forms of
“overlap” with small vessel vasculitis is not clear. There are
also reports of LN, membranous nephropathy, and renal
amyloidosis in patients with temporal arteritis.410,411
The most common renal manifestations of mild proteinuria and microhematuria are present in less than 10% of
patients. Renal insufficiency is uncommon. Hypertension is
infrequent and most often mild to moderate when present.
Rare cases of renal failure have been attributed to renal
arteritis affecting the main renal artery or its major intraparenchymal branches.410 In some cases the pathology has
been inadequate to diagnose the precise cause of the renal
failure. Nephrotic syndrome has been reported in a patient
with temporal arteritis and membranous nephropathy, with
steroid therapy producing a reduction in proteinuria.410
The treatment of temporal arteritis with corticosteroids
usually causes rapid and dramatic improvement in general
well-being, specific symptomatology, and laboratory abnormalities.403-405,408 Use of intravenous pulse steroids and a
number of corticosteroid-sparing and secondary immunosuppressives have been used successfully.408,412-415 There are
conflicting results as to whether any agent such as methotrexate is equivalent to corticosteroids in efficacy, and some
agents such as infliximab do not appear useful.404,405,408,414
Some, such as cyclophosphamide, have led to good efficacy
in steroid-dependent patients.415,416 Recent studies have
found tocilizumab to be effective.417,418 With corticosteroid
use, abnormalities of the urinary sediment disappear, and
there is resolution of extracranial large vessel involvement.
However, once established, visual loss is often permanent,
despite resolution of the active disease process. Exacerbation of systemic vasculitis may occur if corticosteroids are
tapered too rapidly.
TAKAYASU’S ARTERITIS
Takayasu’s arteritis is a rare giant cell arteritis of unknown
pathogenesis characterized by inflammation and stenosis of
medium-sized and large arteries, with a predilection for the
aortic arch and its branches.419 The disease most commonly
affects young women between the ages of 10 and 40, and
Asians are much more commonly affected. Although findings are typically confined to the aortic arch (including the
subclavian, carotid, and pulmonary arteries), the abdominal
aorta and its branches may be affected. The histopathologic
findings of the vessels include arteritis with transmural infiltration by lymphocytes, monocytes, polymorphonuclear leukocytes, and multinucleated giant cells. In the chronic
phase of the disease, intimal fibroplasia and medial scarring
may result in severe vascular stenoses or total luminal
obliteration.
Although in the past, renal disease was thought to be
uncommon, it is now reported more frequently.420-422 This is
usually due to an obliterative arteritis of the main renal
artery or narrowing of the renal ostia by abdominal aortitis
leading to renovascular hypertension. Arteriography is
useful to diagnose Takayasu’s arteritis although computerized tomography, MRI, and PET scan imaging also have
been used.423-425 Laboratory abnormalities reveal mild
anemia, elevated ESR, increased levels of CRP, and elevated
γ-globulin levels, but other serologic tests such as ANA,
VDRL, anti--streptolysin O (ASLO), and serum complement
levels are normal. Some patients have antiendothelial cell
antibodies and others have elevated levels of pentraxin 3, a
product of immune and vascular cells produced in response
to inflammation.421,426 Hypertension, which may be severe,
occurs in 40% to 60% of patients and has been attributed
to decreased elasticity of the aorta, increased renin secretion due to stenosis of major renal arteries, and other mechanisms.427,428 Although mild proteinuria and hematuria are
found in some patients, nephrotic-range proteinuria is
uncommon.429 The serum creatinine is usually normal but
may be mildly elevated or associated with a high BUN-tocreatinine ratio suggestive of “prerenal” azotemia. Progressive renal failure is uncommon.419
A mild mesangial proliferative glomerulonephritis
may occur in patients with Takayasu arteritis.420-422 Mesangial
deposits of IgG, IgM, IgA, C3, and C4 have been reported
and mesangial electron-dense deposits are found. Most
patients have normal renal function and only mild hematuria and proteinuria. Some patients have had glomerular
involvement typical of IgA nephropathy.419,420 Whether
this is coincidental or part of the disease process is
unclear. One series of patients with Takayasu’s arteritis
had unusual glomerular histopathology with mesangial sclerosis and nodules, as well as mesangiolysis and glomerular microaneurysms resembling a chronic thrombotic
microangiopathy or diabetic glomerulosclerosis.420 Immunofluorescence and electron microscopy in these cases
of “centrolobular mesangiopathy” did not support an
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CHAPTER 33 — Secondary Glomerular Disease
immune pathogenesis. There are also reports of renal amyloidosis, MPGN, crescentic glomerulonephritis, and proliferative glomerulonephritis.430,431
TREATMENT
In the majority of patients, corticosteroids are effective
therapy for the vasculitis and systemic symptoms.429,432 Other
medications, including azathioprine, methotrexate, leflunomide, cyclophosphamide, and MMF, and anti-TNF therapy
have also been used successfully in some individuals, as have
anticoagulants, vasodilators, and acetylsalicylic acid.433-436
Recent reports of the use of tocilizumab, a monoclonal
antibody against the Il-6 receptor, have been promising.417,418
Residual morbidity and mortality may result from the progressive fibrosis and stenosis of previously inflamed
arteries.437
HENOCH-SCHÖNLEIN PURPURA
Henoch-Schönlein purpura (HSP), also called IgA vasculitis, is a systemic vasculitic syndrome with involvement of the
skin, gastrointestinal tract, and joints in association with a
characteristic glomerulonephritis.288,438-440 In HSP, IgAcontaining immune complexes deposit in association with
an inflammatory reaction of the vessels. In the skin this
leads to a leukocytoclastic angiitis with petechiae and
purpura. In the gastrointestinal tract, there may be ulcerations, pain, and bleeding. In the kidney an immune
complex–mediated glomerulonephritis is found.438-440
Males are slightly more commonly affected with HSP than
are females, and children are far more frequently affected
than are adults.438,439,441-446 HSP is the most common vasculitis of childhood. The peak age of patients with HSP is
approximately 5 years old as opposed to IgA nephropathy,
which has a broad age distribution.438,439,441-444 HSP may
account for up to 15% of all glomerulonephritis in young
children. More severe renal disease occurs in older children
and adults.445,447 HSP is uncommon in blacks. Familial occurrence has rarely been reported, and the frequency of HLABw35 is increased in some series.439-442 About one fourth of
patients will have a history of allergy, but exacerbations
related to a specific allergen are rare. Relapses of the syndrome have occurred after exposure to allergens or the
cold, and seasonal variations show peak occurrence in the
winter months.
HSP may be mistaken for systemic illnesses such as SLE
and MPA, with ongoing infections such as meningococcemia, gonococcemia, and Yersinia enterocolitis, with certain
medications and vaccination-related hypersensitivity, and
with some postinfectious glomerulonephritides associated
with systemic manifestations. Although an upper respiratory
infection precedes HSP in 30% to 50% of patients, serologic
evidence of streptococcal infection is often lacking.
CLINICAL FINDINGS
The classic tetrad of findings in HSP is dermal involvement,
gastrointestinal disease, joint involvement, and glomerulonephritis, but not all patients will have clinical involvement
of all organ systems.438-440,448 Constitutional symptoms may
include fever, malaise, fatigue, and weakness. Skin lesions
1121
are almost universal with HSP and are commonly found on
the lower and upper extremities but may also be on the
buttocks or elsewhere.438-440,447 They are characterized by
urticarial macular and papular reddish-violaceous lesions
that do not blanch. Lesions may be discrete or may coalesce
into palpable purpura associated with lower extremity
edema. New crops of lesions may recur over weeks or
months. On skin biopsy there is a leukocytoclastic angiitis
with evidence of IgA-containing immune complexes along
with IgG, C3, properdin but not C4 or C1q. Gastrointestinal
manifestations are present in from 25% to 90% of patients
and may include colicky pain, nausea and vomiting, melena,
and hematochezia.438-440,447-450 Abdominal pains may be mistaken for appendicitis, cholecystitis, or surgical emergencies, leading to exploratory laparotomy. One study of more
than 260 patients found that 58% had abdominal pain and
18% evidence of gastrointestinal bleeding.450 Endoscopy
may reveal purpuric lesions, and rarely patients may develop
areas of intussusception or perforation. Rheumatologic
disease involves the larger joints, usually the ankles and
knees, and less commonly the elbows and wrists. There may
be arthralgias or frank arthritis with painful, tender effusions, but patients do not develop joint deformities or
erosive arthritis.438-440 Rarely patients will have evidence of
involvement of other organs (e.g., lungs, central nervous
system, or ureters).438-440,447
Renal involvement at presentation varies from 20% to
50% of patients with HSP.438-440,447 Renal disease is more
frequent and of greater severity in older children and
adults.446,447,451 In studies routinely examining the urine,
renal involvement ranges from 40% to 60% of patients. The
onset of active renal disease usually follows within days to
weeks after the onset of the systemic manifestations and is
characterized by microscopic hematuria, active urinary sediment, and proteinuria.438,440,447,452 In one series of more than
200 children, HSP nephritis occurred in 46% of patients at
a mean of 14 days and within 1 month in the majority.452 In
a series of 250 adults with HSP, 32% had renal insufficiency,
usually with proteinuria (97%) and hematuria (93%).447
Some patients will develop nephrotic syndrome and some
will have a nephritic picture. There is no relationship
between the severity of extrarenal organ involvement and
the severity of the renal lesions.
LABORATORY FEATURES
In HSP, platelet counts and serum complement levels and
other serologic tests are all usually normal.438,440,448 Serum
albumin may be low due to renal or gastrointestinal losses.448
Serum IgA levels are elevated in up to one half of patients
during active illness but do not correlate well with the
severity of clinical manifestations or the course of the
disease.438-440,453 Patients with both IgA nephropathy and
HSP have high levels of galactose-deficient IgA in their
circulation.454,455 A number of abnormal IgA antibodies
have been noted, including IgA rheumatoid factor, circulating immune complexes with IgA and IgG, IgA anticardiolipin antibodies, IgA fibronectin aggregates, IgA
anti–α-galactosyl antibodies, and IgA ANCA.453,456-459 The
relationship of these to active renal or systemic disease
remains unclear, although concentrations of IgA and IgG
immune complexes, IgA rheumatoid factor, and IgG and
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SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
Figure 33.18 Henoch-Schönlein purpura nephritis. An example
with global mesangial proliferation and focal infiltrating neutrophils.
(Hematoxylin and eosin stain, ×500.)
Figure 33.19 Henoch-Schönlein purpura nephritis. There is segmental endocapillary proliferation with an overlying segmental cellular
crescent. (Periodic acid–Schiff, ×475.)
IgA anti-galactosyl antibodies have been correlated with
clinical renal disease manifestations.453,458,460 Recent studies
suggest IgG and IgA autoantibodies against galactosedeficient IgA correlate with clinical outcome.458
PATHOLOGY
The renal biopsy findings of HSP overlap with those of IgA
nephropathy. The typical glomerular pathology of HSP is a
mesangial and endocapillary proliferative glomerulonephritis with variable crescent formation.438-440,461 The mesangial
changes include both increased mesangial cellularity and
matrix expansion that may be focal or diffuse (Figure 33.18).
In severe cases, polymorphonuclear cells and mononuclear
cells also infiltrate the glomerular tufts in areas of endocapillary proliferation, often accompanied by fibrinoid necrosis.
Increased numbers of monocyte/macrophages and CD4
and CD8 T cells are found.462,463 Some cases have a welldeveloped membranoproliferative pattern with double contours of the GBM. Crescents are common and vary from
segmental to circumferential, with evolution from cellular to
fibrous crescents over time (Figure 33.19). Tubulointerstitial
changes of atrophy and interstitial fibrosis are consistent
Figure 33.20 Henoch-Schönlein purpura nephritis. Immunofluorescence photomicrograph showing intense deposits of IgA distributed
throughout the mesangium and also extending into a few peripheral
glomerular capillary walls. (×600.)
with the degree of glomerular damage. In general, endocapillary and extracapillary proliferation as well as glomerular
fibrin deposition are more frequent and severe in HSP than
in IgA nephropathy. The histopathologic classification
system proposed by the International Study of Kidney
Disease of Childhood correlates the glomerular lesions with
clinical manifestations as well as prognosis.464 These categories include class I, with minimal glomerular alterations;
class II, with mesangial proliferation only; class III, with
either focal (a) or diffuse (b) mesangial proliferation but
less than 50% of glomeruli containing crescents or segmental lesions of thrombosis, necrosis, or sclerosis; class IV, with
similar mesangial proliferation as classes IIIa and IIIb but
50% to 75% of glomeruli with crescents; class V, with similar
changes and more than 75% crescents; and class VI, a
“pseudo” membranoproliferative pattern. While hematuria
is common to all groups, and proteinuria of some degree
may be found in all, nephrotic syndrome is present in only
25% of groups I, II, and III. Likewise, groups IIIb, IV, and V
tend to have a more progressive course toward renal failure.465
Even by light microscopy, deposits may be seen in the mesangial regions and rarely along the capillary walls. It is unusual
to find the presence of vasculitis on renal biopsy.
By immunofluorescence, IgA is the dominant or codominant immunoglobulin. Co-deposits of IgG and IgM, C3, and
properdin are common. Deposits are typically found in the
mesangium, especially involving the paramesangial regions,
and often extend segmentally into the subendothelial areas
(Figure 33.20).438-440 Some cases may have more abundant
peripheral capillary wall than mesangial deposits. Early classical complement components of C1q and C4 are rarely
present. These findings contrast with LN in which IgG
usually predominates and C1q is almost always present. The
deposited IgA is usually IgA1 subclass and may have the
J-chain indicating its polymeric nature, but secretory piece
is not found.438-440,466,467 Fibrin-related antigens are also commonly present. IgA may be deposited along with C3 and C5
in both involved and uninvolved skin in the small vessels
similar to the findings in IgA nephropathy.468,469 Similar IgA
deposits may also occur in the skin in dermatitis herpetiformis and in SLE along with early and late complement
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CHAPTER 33 — Secondary Glomerular Disease
components. IgA is also found in vasculitic lesions in the
intestinal tract.449,450
By electron microscopy, characteristic immune-type
electron-dense deposits are found predominantly in the
mesangial regions, accompanied by increase in mesangial
cellularity and matrix.438-440,464 In some capillaries, the deposits extend subendothelially from the adjacent mesangial
regions. Occasionally, scattered subepithelial deposits are
also present and may resemble the humps of poststreptococcal disease. Evidence of coagulation with fibrin and platelet
thrombi may be found in capillary lumens. In cases with
severe crescent involvement there may be focal rupture of
the GBM. Immunoelectron microscopy has confirmed the
predominance of IgA in association with some C3 and IgG
in the deposits.461
PATHOGENESIS
The pathogenesis of HSP remains unknown. Patients with
HSP and their blood relatives, like those with IgA nephropathy, have high circulating levels of galactose-deficient
IgA.454,455 HSP is clearly a systemic immune complex disease
with IgA-containing deposits that are associated with small
vessel vasculitis and capillary damage. The deposits contain
polymeric IgA of the IgA1 subclass and late-acting complement components. This composition suggests alternate
pathway complement activation. Patients with IgA nephropathy have increased levels of IgG and IgA antibodies directed
against galactose-deficient IgA molecules.458 They also have
evidence of oxidative stress on proteins in their circulation
along with the high levels of galactose-deficient IgA.465 This
combination may trigger autoantibody and immune
complex formation. It is unclear whether IgA immune complexes trigger complement activation and what the ultimate
role of complement participation is. The presence of circulating polymeric IgA complexes, the deposition of IgA in
the kidney as well as the skin, intestines, and other organs,
and recurrence of disease in the allograft point to the systemic nature of the disease process. The precise mechanism(s)
whereby IgA deposition causes tissue injury is unclear
because IgA is deposited in some diseases such as celiac
disease and chronic liver disease without causing major
clinical glomerular damage.470 Complement activation,
platelet activation and coagulation, vasoactive prostanoids,
cytokines, and growth factors are thought to play a role.
Impaired T cell activity has also been implicated in the
pathogenesis of HSP.471 HSP has also been reported in rare
patients with IgA monoclonal gammopathy.472
The relationship of HSP to IgA nephropathy is obscure
with some investigators considering the diseases separate
entities and most describing them as opposite ends of a
pathogenetic spectrum.444 Similar renal histologic findings
and similar immunologic abnormalities such as elevated
circulating galactose-deficient IgA levels, IgA fibronectin
aggregates, and antimesangial cell antibodies suggest a
common mechanism of renal injury. IgG autoantibodies
against mesangial cells parallel the course of the renal
disease. Both IgA nephropathy and HSP have occurred in
different members of the same families and in monozygotic
twins after adenovirus infection.444 Infectious agents associated with the occurrence of HSP have included varicella,
measles, adenovirus, HBV and/or HCV, Yersinia spp.,
1123
Shigella spp., Mycoplasma, HIV infection, and staphylococci
including methicillin-resistant organisms, but none has
been proven to be a causal agent.439,473-475 Likewise, HSP has
been reported to occur in association with vaccinations,
insect bites, cold exposure and trauma, although causal
relation is unproven.476
COURSE, PROGNOSIS, AND TREATMENT
In most patients HSP is a self-limited disease with a good
long-term outcome.438,439,447-449 Patients may have recurrences
of the rash, joint symptoms, and gastrointestinal symptoms
for months or years, but most patients have a benign shortterm and long-term renal course. In general there is a good
correlation between the clinical renal presentation and the
ultimate prognosis.438-440,449 Patients with focal mesangial
involvement and only hematuria and mild proteinuria tend
to have an excellent prognosis. In one recent large pediatric
study, renal survival was 100%.452 In another series of 150
patients with 50% renal involvement, only 2 patients had
residual hematuria and no patients had abnormal renal
function at 2.5 years.438 In most series at several years from
presentation, more than 50% of the patients had no renal
abnormalities, less than 25% had urinary sediment abnormalities or proteinuria, and only 10% had decreased GFR.
Less than 10% of patients with severe clinical renal involvement at onset had persistent hypertension or declining GFR
over the long term. A review of more than 50 patients followed over 24 years after childhood-onset HSP found 7 of 20
with severe HSP at onset with residual renal impairment as
adults as opposed to only 2 of 27 patients with mild initial
renal disease.477 In a long-term follow-up of more than 1100
children with HSP in a retrospective review of published
series, no patients with a normal urinalysis developed renal
impairment.478 Renal impairment developed in less than 2%
of patients with isolated urinary abnormalities and in 20% of
those with full nephritic or nephrotic syndrome. Long-term
renal function is not as good in adults with HSP.447,460,477,479,480
In a series of more than 250 adults with HSP followed almost
15 years, 11% developed ESKD, 13% severe renal impairment with a clearance less than 30 mL/min, and 15% moderate renal insufficiency.447 A poor renal prognosis is
predicted by an acute nephritic presentation, older age, and
especially by larger amounts of proteinuria and more severe
nephrotic syndrome.460,479-481 In one retrospective analysis of
219 patients with HSP and nephritis, no data at diagnosis
were predictive of ultimate functional decline, but higher
proteinuria levels at follow-up did correlate with this
decline.460 On renal biopsy, a poor prognosis is predicted by
IgA deposits extending from the mesangium into the peripheral capillary walls, increased interstitial fibrosis, glomerular
fibrinoid necrosis, and especially the presence of greater
percentage of crescents.447,460,480 In one study of more than
150 children with HSP, those with greater than 50% of glomeruli containing crescents had progression to ESKD in more
than one third of cases and chronic renal insufficiency developed in another 18%. Repeat biopsies in patients with HSP
who have clinically improved show decreased mesangial
deposits and hypercellularity. Markers of oxidative stress
on plasma proteins, circulating levels of galactose-deficient
IgA, and the level of IgG and IgA antibodies directed
against galactose-deficient IgA have correlated with renal
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SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
prognosis.455,458,469 While complete clinical recovery occurs in
95% of affected children and many adults with HSP have a
lower recovery rate, those with nephritic syndrome, renal
insufficiency, hypertension, a large percentage of glomeruli
with crescents, and tubulointerstitial fibrosis are likely to
have progressive disease.460,480 More than one third of HSP
patients who become pregnant have associated hypertension
or proteinuria. Mortality in HSP is less than 10% at 10 years.
Therapy for the majority of patients with HSP has been
mostly supportive.438-440 Most fare well despite the lack of any
immunosuppressive intervention. The use of corticosteroids
is controversial, and although they are associated with
decreased abdominal and rheumatologic symptoms, they
have not clearly been proven to ameliorate the renal lesions
in any controlled fashion.448,482-484 On the other hand, several
controlled randomized trials have shown benefit in terms of
reductions of proteinuria and preservation of renal function after a short course of corticosteroids in patients with
IgA nephropathy.485,486 Since the renal pathology is the
same, one might extrapolate to HSP patients. HSP patients
with more severe clinical features, and especially those with
nephrotic syndrome or more crescents on biopsy, have also
been treated with anticoagulants, azathioprine, cyclophosphamide, chlorambucil, other immunosuppressives, and
even plasma exchange.487-489 Although these reports have
shown anecdotal success in reversing the renal progression,
controlled trials have not yet shown benefits of using cytotoxic immunosuppressive therapy.481 For example, in one
controlled trial of 54 adults with HSP, proliferative glomerulonephritis, and severe systemic manifestations, the addition
of cyclophosphamide added no benefit over steroids
alone in terms of remissions, renal outcome, or mortality.490
Cyclosporine has been used successfully in a number of
patients to control severe proteinuria.491 Intravenous
immune globulin has been used in several patients with
nephrotic syndrome and decreased GFR in an uncontrolled
nonrandomized but apparently successful fashion.492
ESKD occurs in 10% to 30% of adults with HSP at 15 years
of follow-up.445,447 Renal disease due to HSP may recur in
the renal allograft.493-495 As in IgA nephropathy, histologic
recurrence is far more common than clinical recurrence.
However, graft recurrence may lead to allograft loss in as
many as 8% to 14% of patients.494,495 This may be more
common in patients who are transplanted either with living
related donors or while still active clinically within the first
few years of developing ESKD. Although the severity of
original disease is not correlated with recurrent disease
outcome, many would suggest waiting before transplanting
a patient with active disease who has reached ESKD. Patient
survival after renal transplantation is excellent and reaches
95% at 15 years.494 Overall 5- and 10-year graft survival is
similar to that of patients with IgA nephropathy and other
disease leading to transplantation.493-495
ANTI–GLOMERULAR BASEMENT
MEMBRANE DISEASE AND
GOODPASTURE’S SYNDROME
Anti-GBM disease is caused by circulating antibodies
directed against an antigenic site on type IV collagen in the
GBM.496-498 Although the original description of pulmonary
hemorrhage and glomerulonephritis long antedated the
discovery of the pathogenesis of anti-GBM disease, true
Goodpasture’s syndrome should consist of the triad of (1)
proliferative, usually crescentic, glomerulonephritis; (2)
pulmonary hemorrhage; and (3) the presence of anti-GBM
antibodies.496-499 In anti-GBM disease the pulmonary hemorrhage may precede, occur concurrently with, or follow
the glomerular involvement.498,500 Some patients with antiGBM antibodies and glomerulonephritis and hence “antiGBM” disease never experience pulmonary involvement
and thus do not have true Goodpasture’s syndrome. Documentation of anti-GBM antibody–induced disease may
be via renal biopsy, or by establishing the presence of circulating anti-GBM antibodies.496,498,500 Indirect immunofluorescence, although highly specific for diagnosis, requires an
experienced pathologist.501,502 Radioimmunoassay, enzymelinked immunosorbent assay, and immunoblotting for the
antibodies are highly specific and sensitive and readily
available.496,502
PATHOGENESIS
Anti-GBM autoantibodies, produced in response to an
unknown inciting stimulus, react with epitopes on the noncollagenous domain of the α3- and α5-chains of type IV
collagen.496-499 The antigenic epitope has been localized
between amino acids 198 and 237 of the terminal region of
the α3-chain.496,497,500,503 The α3-chain of type IV collagen is
found predominantly in the GBM and alveolar capillary
basement membranes, which correlates with the limited distribution of disease involvement in Goodpasture’s syndrome.496,497,499 Goodpasture’s syndrome is now considered
an autoimmune “conformeropathy” involving perturbation
of the quaternary structure of the α345 NC1 hexamer of
type IV collagen.496,497,503 In Goodpasture’s disease autoantibodies to both the α3 NC1 and the α5 NC1 domains bind
to the kidneys and lungs. These autoantibodies bind to
epitopes encompassing the Ea region in the α5 NC1 domain
and the Ea and Eb region of the α3 NC1 domain, but they
do not bind to non-denatured native cross-linked α345 NC1
hexamers.503 The epitope is identical in the glomeruli and
the alveolar basement membranes and may require partial
denaturation for full autoantigen exposure. Eluates of
antibody from lung and kidney of patients with Goodpasture’s syndrome cross-react with GBM and the alveolar
basement membrane and can produce disease in animal
models.496,498-500 Antibody reacting with autoantigen(s) and
perhaps aided by autoreactive T cells leads to an inflammatory response, the formation of proliferative glomerulonephritis, breaks in the GBM, and the subsequent extracapillary
proliferation with exuberant crescent formation.496,499 A role
for T cells in Goodpasture’s syndrome is supported by the
T cell infiltrates on biopsy, patient T cell proliferation in
vitro in response to α3 (IV) NC1 domain, the correlation of
autoreactive T cells with disease activity, the role of
CD4+CD25+ regulatory cells controlling the autoreactive T
cell response, and a role for T cell epitope mimicry in
disease induction.496,504 An initial insult to the pulmonary
vascular integrity may be required to produce damage to
the basement membranes of the pulmonary capillaries,
since alveolar capillaries are not normally permeable to
passage of anti-GBM antibodies.498,505-507 Exacerbations of
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CHAPTER 33 — Secondary Glomerular Disease
disease and especially pulmonary disease with hemoptysis
have been related to exposure to hydrocarbon fumes, cigarette smoking, hair dyes, metallic dust, D-penicillamine, and
cocaine inhalation.507-509 Although smokers with anti-GBM
disease have a higher incidence of pulmonary hemorrhage,
circulating anti-GBM antibody levels are no higher than in
nonsmokers with the disease.507,508 Goodpasture’s syndrome
has occasionally been reported in more than one family
member. Certain HLA alleles may predispose to the syndrome and perhaps more severe disease.510 Influenza A2
infection may be associated with Goodpasture’s syndrome.
Anti-GBM disease can also occur in patients with typical
membranous nephropathy and in 5% to 10% of patients
with Alport’s syndrome receiving allografts.511 However, in
Alport’s syndrome patients post transplantation, the alloantibodies, in contrast to those in anti-GBM disease, bind to the
Ea region of the α5 NC1 domain of the intact α345 NC1
hexamer (rather than to denatured hexamer)499 (see “Hereditary Nephritis, Including Alport’s Syndrome” section).
CLINICAL FEATURES
Anti-GBM disease is rare.496,498-500 Although some studies suggested occurrences as high as 3% to 5% of all glomerular
diseases, most reduce this to 1% to 2%. The disease has two
peaks of occurrence, the first in younger males, often associated with pulmonary hemorrhage, and the second in older
females, often with isolated glomerulonephritis. Despite
these trends, anti-GBM disease can occur at any age and in
either gender.496,498,499,507,512 Anti-GBM disease limited to the
kidney may be more common in older patients. Goodpasture’s syndrome is less common in blacks, perhaps due to
less frequent occurrence of certain predisposing HLA antigens in this population. An upper respiratory infection precedes the onset of disease in 20% to 60% of cases.496,498,499,507
The most common extrarenal findings are pulmonary,
including cough, dyspnea, and shortness of breath, and
hemoptysis, which may vary from trivial amounts to lifethreatening amounts associated with exsanguination and
suffocation.288,498,507,512 In almost three fourths of cases pulmonary hemorrhage precedes or is coincident with the
glomerular disease.496,498,507 Patients infrequently have constitutional symptoms of weakness, fatigue, weight loss, chills,
and fevers. Others may have skin rash, hepatosplenomegaly,
nausea and vomiting, and arthralgias at onset.498
The clinical renal presentation is usually an acute
nephritic picture with hypertension, edema, hematuria and
active urinary sediment, and reduced renal function.
However, only 20% of patients are hypertensive at onset and
in some series 15% to 35% have normal urinary sediment
and GFR.496,498,500,512 Renal function is usually already reduced
at presentation and may deteriorate from normal to requiring dialysis in a matter of days to weeks.496,498,512-514 There is
a good correlation between the serum creatinine level and
the percentage of glomeruli involved by severe crescent
formation.
LABORATORY FINDINGS
Laboratory evaluation typically shows active urinary sediment with red cells and red cell casts.498 Proteinuria, although
common, is usually not in the nephrotic range. Serologic
1125
tests such as ASLO, ANA, serum complement levels, rheumatoid factor, and cryoglobulins are all either negative or
normal.498,507,512-514 Circulating anti-GBM antibodies are
present in more than 90% of patients although the antibody
titer does not always correlate well with the manifestations or
course of either the pulmonary or renal disease.499 From
registry samples of plasma, anti-GBM antibodies have been
found in the plasma of patients who eventually develop antiGBM disease prior to the presentation of clinical disease.515
Most patients have a decrease in serum antibody titer with
time. From 10% to 38% of patients will have both positive
anti-GBM antibodies and ANCA usually directed against
MPO, but occasionally against PR3.498,499,515,516 The anti-GBM
antibodies in patients who are ANCA positive have the same
antigenic specificity as in patients who are ANCA negative.517
Some studies suggest that the course of patients double positive for anti-GBM antibodies and ANCA parallels that of
patients with anti-GBM antibody disease, such that these
patients are more likely to develop severe renal failure than
those with purely ANCA-positive vasculitis.516,518 Some
patients have a clinical systemic vasculitis with purpura and
arthralgias and arthritis, findings rarely seen in isolated
Goodpasture’s syndrome without coexistent ANCA.516,517 In
Goodpasture’s syndrome a microcytic, hypochromic anemia
is common even without overt pulmonary hemorrhage.
Other patients may have leukocytosis. Iron deposition in the
lungs may be documented by Fe59 scanning, bronchopulmonary lavage, or expectorated sputum showing hemosiderin-laden macrophages.512 In patients with pulmonary
involvement the chest radiograph is abnormal in more than
75% and typically shows infiltrates corresponding to areas of
pulmonary hemorrhage. It may also demonstrate atelectasis,
pulmonary edema, and areas of coexistent pneumonia.498,500,512 Lung function discloses restrictive ventilatory
defects and hypoxemia, and an increased arterial alveolar
gradient is present in severe cases.498,500,512,514
PATHOLOGY
By light microscopy, patients with mild clinical involvement
often have a focal, segmental proliferative glomerulonephritis associated with areas of segmental necrosis and overlying
small crescents.498,499,514 However, the most common biopsy
picture is diffuse crescentic glomerulonephritis involving
more than 50% of glomeruli, with exuberant, predominantly circumferential crescents (Figure 33.21).266,500 The
underlying tuft is compressed but displays focal necrotizing
features. Disruption and destruction of large portions of the
GBM and the basal lamina of Bowman’s capsule may be seen
on silver stain.266 Early crescents are formed by proliferating
glomerular epithelial cells and infiltrating T lymphocytes,
monocytes, and polymorphonuclear leukocytes, while older
ones are composed predominantly of spindled fibroblastlike cells, with few if any infiltrating leukocytes.266 An associated tubulointerstitial nephritis with inflammatory cells and
edema is common. Multinucleated giant cells may be
present in the crescents or tubulointerstitial regions. Some
patients, especially those who are ANCA positive, have necrotizing vasculitis of small arteries and arterioles. In biopsies
taken later in the disease, there is progressive global and
segmental glomerulosclerosis and interstitial fibrosis. Pulmonary histology reveals intraalveolar hemorrhage with
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1126
SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
glomerulopathy with typical findings by light microscopy,
immunofluorescence, and electron microscopy.
COURSE, TREATMENT, AND PROGNOSIS
Figure 33.21 Anti-GBM disease (Goodpasture’s syndrome). There
is diffuse crescentic glomerulonephritis with large circumferential cellular crescents and severe compression of the glomerular tuft. (Periodic acid–Schiff stain, ×80.)
Figure 33.22 Anti-GBM disease (Goodpasture’s syndrome). Immunofluorescence photomicrograph showing linear glomerular basement membrane (GBM) deposits of IgG. Some of the GBMs are
discontinuous, indicating sites of rupture. (×800.)
widening and disruption of the alveolar septa and accumulations of hemosiderin-laden macrophages.498,500
The immunofluorescence findings define the disease
process in Goodpasture’s syndrome and differentiate it
from both pauci-immune—and immune complex–mediated
forms of crescentic glomerulonephritis. The diagnostic
finding is an intense and diffuse linear staining for IgG,
especially IgG1 and IgG4, involving the GBMs (Figure
33.22).519,520 Rarely has IgM or IgA been identified in a linear
distribution. C3 deposits are found in a more finely granular
GBM distribution in many patients. C1q is typically absent.
Linear immunofluorescence staining for IgG may also be
found along some tubular basement membranes, particularly distal tubules. Fibrin-related antigens are commonly
present within the crescents and segmental necrotizing
lesions. In the lungs, similar linear deposition of IgG occurs
along the alveolar capillary walls.
Electron microscopic findings typically do not reveal
immune-type electron-dense deposits. There may be widening of the subendothelial space by fibrin-like material, and
gaps in the GBM and in Bowman’s capsule are commonly
present.266 Rare patients have coexistent membranous
The course of untreated Goodpasture’s syndrome is one of
progressive renal dysfunction leading to uremia.499,500,516 In
early studies almost all patients died from either pulmonary
hemorrhage or progressive renal failure. In recent studies
mortality is less than 10%, probably related to improved
supportive care and more rapid diagnosis and treatment.498,521 Once the disease is quiescent, relapses are rare
in anti-GBM disease as opposed to GPA-, MPA-, and other
ANCA-positive vasculitides. Spontaneous remission of the
renal disease is rare, although with therapy many patients
will have a stable course and some dramatic improvement.498,521,522 If treatment is started early, patients may
regain considerable kidney function. The plasma creatinine
correlates fairly well with the degree of crescentic involvement, and if the plasma creatinine is markedly elevated and
the patient requires dialysis, most such cases will develop
ESKD.498,499 A recent study from China in more than 100
patients with anti-GBM antibodies noted a poorer prognosis
in patients with creatinine levels higher than 600 µmol/L,
oligo-anuria at presentation, more than 85% crescents on
biopsy, and renal involvement before pulmonary hemorrhage.520 Anti-GBM autoantibodies against different target
antigens may influence the disease severity.
There are no large randomized studies defining the benefits of any therapy for anti-GBM disease. While pulmonary
hemorrhage and even renal disease have abated in some
patients with high-dose oral or intravenous corticosteroids,
combination therapy with steroids, cyclophosphamide, and
plasmapheresis is now standard.498,522 A typical treatment
regimen might include a combination of oral prednisone
(1 mg/kg/day) or intravenous pulse methylprednisolone
(30 mg/kg/day up to 1000 mg/day) for several days followed by high-dose oral corticosteroid therapy along with
cyclophosphamide (2 mg/kg/day) and plasmapheresis.
Plasmapheresis may have a dramatic effect in reversing pulmonary hemorrhage and renal disease when used early
in the course in combination with immunosuppressive
agents.498,518 Plasmapheresis removes the circulating antiGBM antibodies while immunosuppressive therapy prevents
new antibody formation and controls the ongoing inflammatory response. One uncontrolled study found that 40%
of patients had stabilized or improved renal function with
plasmapheresis.522 Patients with severe renal failure who are
already on dialysis or who have serum creatinine levels
greater than 5 to 8 mg/dL are less likely to respond to
therapy, but some have recovered. In one series, patients
who were positive for both anti-GBM antibodies and ANCA
behaved similarly to those with anti-GBM antibodies alone
with a 1-year renal survival rate of 73% in those with a
plasma creatinine concentration of less than 500 µmol/L
and 0% in those on dialysis.522 In other series dialysisdependent patients who are both anti-GBM antibody and
ANCA positive are still more likely to recover than patients
who are dialysis dependent with only anti-GBM antibody
positivity.516 Although daily plasmapheresis is often maintained for weeks, its frequency can be determined by the
rapidity of clinical response. Exacerbations of disease may
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CHAPTER 33 — Secondary Glomerular Disease
occur with intercurrent infections. Immunosuppressive
therapy is usually continued for 6 months with a tapering
regimen to allow spontaneous cessation of autoantibody
production. Some patients with early disappearance of circulating anti-GBM antibodies may respond to shorter
therapy or tolerate change to less toxic maintenance immunosuppression such as azathioprine. There are limited data
on other immunosuppressive regimens in Goodpasture’s
syndrome.522-525 Rituximab has been used successfully in a
small number of patients.525 Immunoadsorption has also
been used to remove the anti-GBM antibodies in Goodpasture’s syndrome.526 Even in patients with initial improvement of renal function, some with severe crescentic
glomerular involvement will progress to renal failure over
time, perhaps related to nonimmunologic progression of
disease. The incidence of ESKD in patients with significant
glomerular involvement is more than 50%, and the renal
outcome is usually progressively downhill unless vigorous
prompt therapy is instituted.
Anti-GBM–mediated renal disease may rarely recur in the
renal allograft.527-529 De novo anti-GBM disease may appear
in patients with hereditary nephritis (see “Hereditary
Nephritis, Including Alport’s Syndrome” section). As with a
number of other forms of glomerulonephritis, evidence of
histologic recurrence (i.e., linear staining for IgG along
GBMs) is far higher than clinical involvement and may be
as high as 50%. The low recurrence rate recently reported
in transplants probably reflects a combination of waiting
sufficient time to document the absence of anti-GBM antibodies, the use of immunosuppressive medications and plasmapheresis to remove current antibody, and the “one-shot”
nature of the disease.528-530 Graft loss secondary to recurrent
disease is rare. Patients should not be transplanted during
the acute phase of their illness when autoantibody levels are
high, and prophylactic pretransplant immunosuppression
has been recommended for those receiving allografts from
living related donors. Although patients with resolving pulmonary disease may have residual diminished gas exchange,
most pulmonary function tests return to normal and do not
limit the renal transplant process.530
SJÖGREN’S SYNDROME
Sjögren’s syndrome is characterized by a chronic inflammatory cell infiltration of the exocrine salivary and lacrimal
glands and is associated with the “sicca complex” of xerostomia and xerophthalmia.531-533 Some patients may have involvement by a systemic inflammatory disease of the kidneys,
lungs, esophagus, thyroid, stomach, and pancreas.531-533
Others have manifestations of a connective tissue disease,
most commonly rheumatoid arthritis, and less frequently
SLE, scleroderma, polymyositis, or MCTD. Still other patients
have different immunologic disorders such as chronic
active hepatitis, primary biliary cirrhosis, Crohn’s disease,
and fibrosing alveolitis or develop lymphoma or Waldenström’s macroglobulinemia. Serologic abnormalities in
Sjögren’s syndrome include hypergammaglobulinemia,
rheumatoid factor, cryoglobulins, a homogeneous or speckled pattern ANA, anti-Ro/SSA and anti-La/SSB, but serum
complement levels are generally normal unless the patient
has associated SLE.531-533
1127
The major clinical renal manifestations of patients with
Sjögren’s syndrome usually relate to tubulointerstitial
involvement of the kidneys with tubular defects such as a
distal renal tubular acidosis, impaired concentrating ability,
hypercalciuria, and, less frequently, proximal tubular
defects.531-535 Most patients have no evidence of glomerular
disease. In an analysis of more than 470 patients with
primary Sjögren’s syndrome followed for a mean of 10 years,
only 20 patients (4%) developed overt renal disease.532 Ten
patients had interstitial nephritis, eight patients had glomerular lesions, and two had both interstitial nephritis and
lesions. In those infrequent patients with glomerular lesions,
hematuria, proteinuria, nephrotic syndrome, and renal
insufficiency are found. Others may develop renal vasculitis
with hypertension and renal insufficiency.
In most cases the renal pathology shows a chronic active
interstitial inflammation by a predominantly lymphocytic
infiltrate admixed with plasma cells, with variable interstitial
fibrosis and tubular atrophy.531-533,535 A nonspecific glomerulosclerosis with mesangial sclerosis and GBM thickening and
wrinkling is found in those with chronic and severe tubulointerstitial damage. Infrequent patients will have immune
complex–mediated glomerular involvement.57,532-539 In one
series of biopsied patients with primary Sjögren’s syndrome,
patients had either mesangial proliferative glomerulonephritis or MPGN.532 Other series have had SLE features with
the similar spectrum of glomerular involvement ranging
from mesangial proliferative to focal proliferative, diffuse
proliferative, and membranous glomerulonephritis.57,536-539
A membranoproliferative pattern of glomerulonephritis has
been reported in patients with associated cryoglobulinemia.532,537-539 By immunofluorescence and electron microscopy, immune deposits have been localized in the various
patterns to the mesangial region or the subendothelial or
subepithelial aspect of the GBM. Some patients with
Sjögren’s syndrome have a necrotizing arteritis of the kidney
occasionally with extrarenal involvement.540 Most Sjögren’s
patients with tubulointerstitial disease respond to treatment
with corticosteroids.531-533,535 Patients with immune complex
glomerulonephritis and Sjögren’s syndrome are generally
treated in a similar fashion to those with SLE, and those with
vasculitis generally receive cytotoxic therapy similar to other
necrotizing vasculitides.535
SARCOIDOSIS
Most manifestations of sarcoidosis are not related to the
kidney.541 The most common renal findings are granulomatous interstitial nephritis, nephrolithiasis, and tubular functional abnormalities.542,543 Glomerular disease is infrequent
and may be coincidental. Glomerular lesions described
include minimal change disease, FSGS, membranous
nephropathy, IgA nephropathy, MPGN, and proliferative
and crescentic glomerulonephritis with and without a positive ANCA serology.542-550 The immunofluorescence and
electron microscopy features conform to the various histologic patterns. Some patients have granulomatous renal
interstitial nephritis in addition to the glomerular lesions.
Glomerular disease in sarcoidosis presents with proteinuria,
active urinary sediment at times, and most commonly
nephrotic syndrome. Some degree of proteinuria, usually
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SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
0.5 to 1 g/day is common in sarcoid patients with tubulointerstitial disease and no evidence of glomerular lesions.551
Sarcoid patients have been treated with various forms of
immunosuppression, including steroids, depending on
their glomerular lesions.544-550
AMYLOIDOSIS
Amyloidosis comprises a diverse group of systemic and local
diseases characterized by the extracellular deposition of
fibrils in various organs.552-555 Although more than 25 different proteins can produce amyloid fibrils, all share an antiparallel β-pleated sheet configuration on x-ray diffraction,
leading to their amyloidogenic properties. All amyloid
fibrils bind Congo red (leading to diagnostic apple green
birefringence under polarized light) and thioflavin T, and
have a characteristic ultrastructural appearance with randomly oriented 8- to 12-nm nonbranching fibrils. All amyloids also contain a 25-kDa glycoprotein, serum amyloid P
component (SAP), a member of the pentraxin family.
Amyloid deposits may also contain restricted sulfated glycosaminoglycans and proteoglycans noncovalently linked to
the amyloid fibrils.552-555 Only some amyloid proteins deposit
in the kidney. Most renal amyloidoses are due to either AL
amyloidosis or AA amyloidosis. In one recent series from a
referral center for amyloidosis 1.3% of 21,500 renal biopsies
over an 8.5-year period were found to have amyloidosis with
86% AL amyloid, 7% AA amyloid, and the remainder being
a variety of types of “hereditary” amyloids.556 In another
single center series of 474 amyloidosis patients evaluated
from 2007 to 2011, 85% were AL amyloid, 7% AA amyloid,
and 4% hereditary amyloid.552 In AL amyloidosis, the deposited fibrils are derived from the variable portion of immunoglobulin light chains produced by a clonal population of
plasma cells or plasmacytic B cells. AA amyloid results from
the deposition of serum amyloid A (SAA) protein in chronic
inflammatory states.552,553,557 A small fraction of renal amyloidoses are due to rare hereditary forms of amyloidosis, such
as those caused by inherited gene mutations encoding transthyretin (ATTR), fibrinogen A α-chain (AFib), apolipoprotein A-I (apo A-I) or A-II (apo A-II), lysozyme (ALys),
gelsolin (A Gel), and leukocyte chemotactic factor 2
(LECT2) peptide.554,556,558-560 Laser microdissection and mass
spectrometry were necessary to determine the origin of
some of these unusual amyloid subtypes.552,556,561,562 Difficulty
in immunofluorescence diagnosis of AL amyloid occurs in
as many as 14% to 35% of cases.552,561,562
It is unclear what factors confer the propensity for amyloidogenic proteins to fold into amyloid fibrils.563-566 Cofactors such as amyloid P component may have an important
role in the pathogenesis of tissue deposition. These may act
by promoting fibrillogenesis, stabilization of the fibrils,
binding to matrix proteins, or inhibiting denaturation and
proteolysis. It is also possible that stabilizing co-factors are
deposited after fibrillogenesis.554,557,563-566 Amyloid fibrils generally resist biodegradation and accumulate in the tissues,
resulting in organ dysfunction. However, amyloid deposits
do exist in a dynamic state and have been shown to regress
by radiolabeled SAP scintigraphy.567 It is clear a critical mass
of an abnormal protein is necessary to produce clinically
significant amyloid of any type.568 In SAA amyloid the SAA
concentration has correlated with amyloid burden and
reduction in circulating SAA with regression of amyloid
deposits. Patients with AA amyloidosis have levels of circulating SAA protein no greater than those patients with inflammatory diseases who do not have amyloid deposition.
Therefore, some additional unknown stimulus is required
for amyloid fibrils to form and precipitate. In AL amyloid
biochemical characteristics of the light chain, such as an
aberrant amino acid composition at certain sites, appear
important in determining amyloid formation.569 This may
account for the reproducibility of a given form of renal
disease (cast nephropathy versus amyloid) in animal models
infused with monoclonal light chains from affected
patients.569 Certain light chains may also form highmolecular-weight aggregates in vitro. Patients with AL
amyloid more frequently produce abnormal excessive λthan κ-light chains, and among AL amyloid patients with
renal disease λ-light chains predominate over κ-light chains
(by ratio of 12 : 1) as opposed to patients without renal
disease (4 : 1).552-554 Macrophage-dependent generation of
preamyloid fragments with chemical properties allowing
aggregation may also play a role. Mesangial cells have receptors for light chains and may modify them as well. Amyloid
P component may also prevent degradation of amyloid
fibrils once formed.570
AL AND AA AMYLOIDOSIS
In AL amyloidosis, fibrils are composed of the N-terminal
amino acid residues of the variable region of an immunoglobulin light chain. λ-Light chains predominate over κlight chains, and there is an increased incidence of
monoclonal λ subtype VI.552-554 The diagnosis of AL amyloidosis may be suspected on clinical grounds but requires
biopsy documentation. The kidneys are the most common
major organ involved by AL amyloid and most patients eventually develop renal amyloid.552-554,571 In the past, up to 10%
to 20% of patients older than 60 years with presumed idiopathic nephrotic syndrome had amyloidosis on renal
biopsy.572 Multiple myeloma occurs in up to 20% of primary
amyloidosis cases. Amyloidosis should be suspected in all
patients with circulating serum monoclonal M proteins, and
approximately 90% of primary amyloid patients will have a
paraprotein spike in the serum or urine by immunofixation,552,553,571 and a greater percentage will have an elevation
and predominance of one circulating light chain. While all
AL amyloid patients will have an increased production of
amyloidogenic light chains, not all patients with renal
disease and a monoclonal protein in the serum will have
amyloid. This is especially true in older patients, since 5%
of patients older than 70 years of age will have a benign
monoclonal gammopathy.
The incidence of AL amyloid is about 8 per million annually but varies greatly in different locations.553 Most patients
with AL amyloidosis are older than 50 years (median age,
59 to 63) and less than 1% are younger than 40 years of age.
Men are affected twice as often as women.552,553,571 Presenting
symptoms include weight loss, fatigue, lightheadedness,
shortness of breath, peripheral edema, pain due to peripheral neuropathy, and orthostatic hypotension. Patients may
have cardiomyopathy, hepatosplenomegaly, macroglossia,
or rarely enlarged lymph nodes. Multisystem organ
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CHAPTER 33 — Secondary Glomerular Disease
involvement is typical with most commonly affected organs
being the kidney (50%), heart (40%), and peripheral nerves
(up to 25%).552,553,571 In one series 25% of AL amyloid
patients had one major organ system involved, 36% had two
organ systems involved, and 38% had three or more
involved.573
AA amyloidosis occurs in chronic inflammatory diseases
and is composed of the N-terminal end of the acute phase
reactant SAA protein.552,554,565,567,574,575 SAA is produced in the
liver and circulates in association with high-density lipoprotein. While in Westernized countries AA amyloid is most
commonly found in association with rheumatoid arthritis
and other inflammatory arthritides, it is also seen with
inflammatory bowel disease, familial Mediterranean fever,
quadriplegics with chronic urinary infections and decubitus
ulcers, bronchiectasis, poorly treated osteomyelitis, and in
chronic heroin addicts who inject drugs subcutaneously.552,554,565,575-578 In one large multicenter study of 374
patients with AA amyloid, 60% had chronic inflammatory
arthritis, 15% chronic infections, 9% periodic fever syndromes, 5% inflammatory bowel disease, 6% other etiologies, and in 6% no etiology was found.574 In an autopsy study
of 150 addicts, 14% of subcutaneous and 26% of those with
chronic suppurative infections had renal amyloidosis.577 AA
amyloid typically occurs in older addicts with a long history
of substance abuse who have exhausted sites of intravenous
access and resorted to “skin popping.”578
The diagnosis of amyloid is usually established by tissue
biopsy of an affected organ.552-554 Liver and kidney biopsy
are positive in as many as 90% of clinically affected cases. A
diagnosis may be made less invasively with fat pad aspirate
(60% to 90%), rectal biopsy (50% to 80%), bone marrow
aspirate (30% to 50%), gingival biopsy (60%), or dermal
biopsy (50%).579 Serum amyloid P whole body scintigraphy
following injection of radiolabeled SAP allows the noninvasive diagnosis of amyloidosis as well as allowing a quantification of the extent of organ system involvement and
assessment of the response to treatment.580 This test may be
positive even when tissue biopsy has been negative and may
be more accurate in AA than in AL amyloidosis. In AL amyloidosis detection of an abnormal ratio of free κ- to λ-light
chains in the serum is a technique to detect plasma cell
dyscrasias which has a higher sensitivity than either serum
or urinary protein electrophoresis and immunofixation.581
It also allows assessment of response to therapy by following
the level of abnormal free light chain in the serum.576
Patients with hereditary amyloidosis due to deposition of
abnormal transthyretin, apolipoproteins, lysozyme, or
fibrinogen Aa may present in a fashion similar to AL amyloid.
In one series 10% of 350 cases of hereditary amyloidosis
were misdiagnosed as having AL amyloid.559
Although hereditary amyloidoses may present at any age,
most patients are adults and present with higher serum
creatinines and less proteinuria than those with AL or AA
amyloidosis.552 Some hereditary types lead to amyloid deposition in the tubulointerstitial and medullary compartment
(e.g., amyloid due to apo A-I, A-II, A-IV) while others are
associated with massive glomerular obliteration (AFib),552
and still others such as LECT2 deposit in all compartments
of the kidney.556 Although the course of hereditary amyloid
is often more prolonged and more benign than that of AL
amyloid, presentation can be identical. Establishing the
1129
correct diagnosis is crucial since the treatment of hereditary
amyloid may include liver transplantation rather than chemotherapy or stem cell transplantation as in AL amyloid.556
Laser dissection of involved glomeruli and proteomic analysis by mass spectrometry, a test currently available in few
specialized centers, can accurately diagnose all types of glomerular amyloid.561
Clinical manifestations of renal disease depend on the
location and extent of amyloid deposition. Renal involvement predominates in AL amyloidosis with one third to
one half of patients having renal manifestations at
presentation.552-554 Most patients have proteinuria, approximately 25% have nephrotic syndrome at diagnosis, and
others present with varying degrees of azotemia.552-554,571
Over time as many as 40% will develop nephrotic syndrome
while others will have lesser degrees of proteinuria or azotemia. Urinalysis is typically bland, but microhematuria and
cellular casts have been reported. Proteinuria is typically
nonselective and almost 90% of patients with more than
1 g/day urinary protein will have a monoclonal protein in
the urine. Hypercholesterolemia is less common than in
other forms of nephrotic syndrome. The amount of glomerular amyloid deposition by light microscopy does not
correlate well with the degree of proteinuria or renal dysfunction.552,553 Despite the literature’s suggestion of enlarged
kidneys in AL amyloid, by ultrasonography most patients
have normal-sized kidneys.552 Hypertension is found in from
20% to 50% of patients, but many will have orthostatic
hypotension due to peripheral neuropathy, autonomic neuropathy, and/or nephrotic syndrome. Patients with AA
amyloid typically also have proteinuria and renal dysfunction with a progressive course. Patients with predominantly
vascular involvement may have little proteinuria but rather
renal insufficiency due to decreased renal blood flow. Infrequently patients will have predominantly tubulointerstitial
deposition of amyloid with renal insufficiency and tubular
defects such as distal renal tubular acidosis, Fanconi’s syndrome, and nephrogenic diabetes insipidus.552,553,571
PATHOLOGY
In patients with clinical renal disease, the diagnostic sensitivity of an adequate renal biopsy approaches 100%.553,557,582,583
Renal biopsy distinguishes AL amyloid from AA amyloid and
excludes involvement by other renal disease in patients with
known amyloidosis of other organs.
By light microscopy there is glomerular deposition of
amorphous hyaline material that usually begins in the
mesangium and extends into the peripheral capillary walls
(Figure 33.23). Affected glomeruli appear hypocellular and
may have a nodular aspect. This deposited material is lightly
eosinophilic, weakly PAS positive, and nonargyrophilic in
contrast to the findings in diabetic nodular glomerulosclerosis. In the peripheral GBM, amyloid deposits form spicular hairlike projections (Figure 33.24). Congo red stain gives
an orange staining reaction and diagnostic apple green birefringence under polarized light (Figure 33.25). Amyloid
deposits stain metachromatically with crystal or methyl
violet and fluoresce under ultraviolet light following thioflavin T staining. Amyloid deposition may be confined to the
glomeruli or involve tubular basement membranes, interstitium, and blood vessels, as well. The immunofluorescence
in AL amyloidosis gives strong staining with antisera to the
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1130
SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
Figure 33.23 Amyloidosis. The glomerular tuft contains segmental
deposits of amorphous eosinophilic hyaline material involving the
vascular pole and some mesangial regions. (Hematoxylin and eosin
stain, ×375.)
Figure 33.24 Amyloidosis. The amyloid deposits expand the
mesangium and form focal spicular projections through the glomerular capillary walls, resembling spikes (arrows). (Jones’ methenamine
silver stain, ×800.)
Figure 33.25 Amyloidosis. Congo red stain of a glomerulus that is
largely replaced by amyloid demonstrates the characteristic birefringence under polarized light. (×450.)
Figure 33.26 Amyloidosis. Immunofluorescence photomicrograph
showing glomerular staining for λ-light chain in the distribution of the
glomerular amyloid deposits in a patient with AL amyloidosis and
plasma cell dyscrasia. (×600.)
Figure 33.27 Amyloidosis. Immunoperoxidase staining for SAA
protein stains the amyloid deposits in the glomeruli and arteries of a
patient with secondary (AA) amyloidosis due to rheumatoid arthritis.
(×125.)
pathogenic light chain, usually λ (Figure 33.26). Some less
common forms of amyloid derived from Ig precursor proteins contain only Ig heavy chain (AH amyloid) or both
heavy and light chain (AHL amyloid). The heavy chain is
usually γ (derived from IgG), with less frequent α (IgA) and
µ (IgM) forms. In AA amyloidosis, immunostaining for
immunoglobulins and complement components is usually
negative or gives a generalized weak reactivity due to nonspecific trapping. Diagnosis depends on the demonstration
of strong reactivity for SAA protein by immunofluorescence
or immunoperoxidase staining (Figure 33.27). Hereditary
amyloidoses neither stain selectively for a single light chain
nor for AA protein, but stain with antisera to the particular
precursor protein. Nonspecific trapping of circulating proteins, including Ig and light chains, may lead to equivocal
immunofluorescence results. In difficult cases, mass
spectrometry–based proteomic analysis of the amyloid
deposits extracted by laser capture microdissection from
renal biopsy sections is required to identify the amyloid
subtype.561 By electron microscopy in all glomerular amyloidosis, typical nonbranching 8- to 12-nm-wide fibrils are
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CHAPTER 33 — Secondary Glomerular Disease
Figure 33.28 Amyloidosis. Electron micrograph showing extensive
infiltration of the glomerular basement membrane by 10-nm fibrils that
project toward the urinary space. (×8000.)
randomly distributed in the mesangium and frequently
along the GBM in the subepithelial, intramembranous, and
subendothelial locations (Figure 33.28). Mild cases may
have deposition limited to the mesangium. More severe
cases usually have more extensive deposition in the peripheral capillary walls and obliterating the lumina. By electron
microscopy glomerular capillary wall infiltration by amyloid
may form characteristic spicular, cockscomb-like projections
along the subepithelial aspect of the GBMs.
COURSE, PROGNOSIS, AND TREATMENT
The prognosis of patients with AL amyloidosis in the past
has been poor with some series having a median survival
rate of less than 2 years.552,553,571 The serum creatinine and
the degree of proteinuria at baseline as well as hematologic
response are predictive of the progression to ESKD. In older
series, the median time from diagnosis to dialysis was 14
months, and from dialysis to death only 8 months.552,553,571
Recent data suggest improved survival. Factors associated
with decreased patient survival include evidence of cardiac
involvement, renal dysfunction, and interstitial fibrosis on
renal biopsy.552,553,571 Cardiac involvement with associated
heart failure and arrhythmias is the primary cause of death
in amyloidosis, followed by renal disease.552,553,571,584
The course of AA amyloidosis has recently been defined
in a study of 374 patients followed for a median time of
more than 7 years.576 Therapy to suppress the inflammatory
disease was used whenever possible. The predominant manifestation and influence on the course of the disease was
renal dysfunction and the median survival was more than
10 years. The SAA concentration correlated with overall
mortality, amyloid burden, and renal prognosis. Amyloid
deposits regressed (as assessed by SAP scans) in patients
whose SAA concentration was kept low, and patient survival
was superior in this group compared to those with no
amyloid regression.576
The optimal treatment for AL amyloid depends on
patient’s age, organ system involvement, and overall
health.553,571,585 Treatment strategies focus on methods to
decrease the production of monoclonal light chains. Promising chemotherapeutic agents used successfully in
1131
conjunction with dexamethasone include a number of
agents used in myeloma, including melphalan, lenalidomide, thalidomide, bortezomib, and cyclophosphamide.586-592
In some patients there is resolution of proteinuria, stabilization of renal function, improvement of symptoms, and occasionally evidence of decreased organ involvement such as
reduced hepatosplenomegaly. In an older review of 153 AL
amyloid patients treated with melphalan and prednisone
only, 18% of the patients had a regression of organ manifestations of amyloidosis with responders having a 5-year
survival of 78% versus only 7% in the nonresponders.587
Patients with renal amyloidosis fared best with 25% having
a 50% resolution in nephrotic-range proteinuria and stable
or improved GFR. Other therapies used experimentally to
treat AL amyloid, including dimethyl sulfoxide, colchicine,
4′-iodo-4′-deoxydoxorubicin, fludarabine, vitamin E, highdose dexamethasone monotherapy, and interferon alfa-2,
have not been effective.585,588,592
Reports using high-dose melphalan followed by allogeneic bone marrow transplant or stem cell transplant have
given promising results.593,594 Such regimens have led
to resolution of nephrotic syndrome and biopsy-proven
improvement of amyloid organ involvement in some cases.
However, a renal complication of autologous stem cell transplantation (AKI) developed in 20% of one series of 173
amyloid patients. Although there was a high mortality in
early reports (20% in the first 3 months), many survivors
had a complete hematologic response, and many with renal
involvement survived with a major decrease in proteinuria
without a worsening of GFR. One retrospective study analyzed 65 AL amyloid patients with more than 1 g/day proteinuria treated with dose-intensive ablative chemotherapy
followed by autologous blood stem cell transplantation.595
Three fourths of the patients survived the first year, and
among those, a good renal response was found in 36% at 1
year and 52% at 2 years. Patients with a complete hematologic response were more likely to have a good renal
response, and patient survival was superior in younger
patients with fewer than three organ systems involved and
those able to tolerate higher doses of the ablative therapy.
Toxicities included mucositis, edema, elevated liver function tests, pulmonary edema, gastrointestinal bleeding, and,
in 23%, transient acute renal failure. Thus, for some younger
patients with predominantly renal involvement stem cell
transplantation is currently a reasonable alternative therapy.
Some studies have supported stem cell transplantation as a
beneficial therapy for some AL amyloid patients.596 Even
patients with ESKD due to amyloidosis may undergo this
form of therapy with results no different from non-ESKD
patients with AL amyloidosis.597 However, the only large randomized trial of stem cell transplantation for amyloid found
this treatment to be inferior to standard chemotherapy.598
In this multicenter French trial, 100 patients were randomized to hematopoietic cell transplantation or melphalan
plus dexamethasone. The chemotherapeutic group had a
better overall survival. Although this study has been criticized for patient selection and the high subsequent mortality, it is the only large randomized trial. Regardless of
whether chemotherapy or marrow transplant is used, the
treatment of nephrotic amyloid patients requires supportive
care. This may include judicious use of diuretics and salt
restriction in those with edema, and treatment of orthostatic
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1132
SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
hypotension with compression stockings, fludrocortisone,
and, in some, midodrine, an oral α-adrenergic agonist.
The treatment of AA amyloid focuses on the control of
the underlying inflammatory disease process.567,574,576,599 This
has included surgical debridement of inflammatory tissue,
antibiotic therapy of infectious processes, and antiinflammatory and immunosuppressive agents in rheumatoid
arthritis and inflammatory bowel disease. Therapy may lead
to stabilization of renal function, reduction in proteinuria,
and resolution of amyloid deposits.567,574,576,599 Prognosis may
be good if the underlying disease can be controlled and
there is not already extensive amyloid deposition. Immunosuppressives, antiinflammatory agents, and anticytokine
therapy have been used in rheumatologic diseases and
Crohn’s disease, with evidence of increased GFR and
decreased proteinuria, and in some cases with regression of
renal amyloid deposits.574,576,599,600 In familial Mediterranean
fever (FMF)—an autosomal recessive disease caused by
pyrin mutation primarily found in Sephardic Jews, Turks,
Armenians, and Arabs—recurrent attacks of fever and serositis lead to the development of AA amyloidosis in up to 90%
of untreated patients.574 Colchicine can prevent effectively
the febrile attacks and stabilize or reduce the development
of proteinuria. However, renal function did deteriorate in
patients with nephrotic syndrome at presentation. A retrospective analysis of FMF patients with milder renal clinical
involvement and at least 5 years’ follow-up concluded that
high doses of colchicine were more effective in preventing
renal dysfunction and that patients with lower levels of
serum creatinine at presentation responded better to
therapy. Once the serum creatinine level was elevated,
however, increasing the dose of colchicine did not prevent
progression. AA amyloidosis seen in drug abusers and
patients with inflammatory states such as Behçet’s disease
and inflammatory bowel disease have occasionally responded
to colchicine therapy, although it is unclear if this was due
to cessation of drug abuse or treatment of the underlying
inflammatory disease process.578,601
A multicenter randomized controlled trial compared a
glycosaminoglycan mimetic (used to block fibrillogenesis)
to placebo in 183 patients with AA amyloid. Although the
drug had no significant effect on preventing progression to
ESKD or risk of death, the glycosaminoglycan mimetic did
reduce the rate of progression of the renal disease.602 This
study clearly shows the need for newer therapies for amyloidosis and the value of controlled trials in studying these
agents. Several promising experimental therapies for treating amyloid include the use of anti-amyloid antibodies and
the use of an inhibitor of the binding of amyloid P component to amyloid fibrils.599
END-STAGE KIDNEY DISEASE IN AMYLOIDOSIS
In most series the median survival of amyloid patients with
ESKD is less than 1 year with the primary cause of death
being complications of cardiac amyloid.603,604 However, for
patients who survive the first month of ESKD replacement
therapy, the survival rate is more than 50% at 2 years and
30% at 5 years.604 There is no survival difference between
peritoneal dialysis or hemodialysis.604 A report of survival
data in 19 dialysis patients with AL amyloid found an 80%
mortality at 35 months’ follow-up, while 20 AA amyloid
dialysis patients had a 15% mortality in this time period.605
Likewise, another series found a shorter than 1 year median
survival for hemodialysis patients with AL amyloidosis.
Experience with renal transplantation in AL amyloid is
limited, but transplantation may be performed either before
or after autologous stem cell transplantation.596,597 An earlier
series on transplantation in amyloid included 45 patients (42
with AA amyloid) and found an overall low patient survival,
particularly in the early posttransplant period in older
patients because of infectious and cardiovascular complications.606 Graft survival, however, was not decreased despite
rates of recurrence of amyloidosis in the allograft as high as
20% to 33%.606,607 Survival rates at 5 and 10 years of renal
transplant patients with AA amyloid, largely FMF patients,
who received living related allografts have been as high as
80% and 66%, respectively. In hereditary amyloidosis due to
fibrinogen A α-chain disease, recurrence occurred in 50% of
allografts with frequent graft loss. Better results are reported
with combined liver and kidney transplantation.
FIBRILLARY GLOMERULONEPHRITIS AND
IMMUNOTACTOID GLOMERULONEPHRITIS
Some uncommon glomerular diseases have fibrillar deposits
differing in size from those of amyloid.608,609 Many investigators subdivide these patients into two major groups depending on clinical associations and fibril size.608-611 In fibrillary
glomerulonephritis the fibrils are approximately 16 to
24 nm (mean, 20 nm) in diameter, and in immunotactoid
glomerulonephritis the deposits form larger hollow microtubules of 30 to 50 nm in diameter. Both of these fibrillar
organized deposits may represent a slow-acting cryoprecipitate of polyclonal or monoclonal immunoglobulin. A third,
rare form of fibrillary renal disease is fibronectin glomerulopathy in which the glomeruli are infiltrated by massive
deposits of fibronectin.612,613
Although some classify both fibrillary glomerulonephritis
and immunotactoid glomerulonephritis as a single disease
entity, most clinicians and nephropathologists divide them
into distinct disorders.341,608-611 Almost 90% of cases have the
smaller 20-nm fibrils of fibrillary glomerulonephritis. Fibrillary glomerulonephritis occurs mostly in adults, in both
sexes, in all age groups, and most commonly in Caucasians.
Although usually considered an isolated idiopathic renal
entity, it has been associated in some series with malignancies, monoclonal gammopathies, and autoimmune disorders.613 Patients with immunotactoid glomerulonephritis
tend to be older, may have a less rapidly progressive course,
and in all series are more likely to have underlying lymphoproliferative disease, (e.g., chronic lymphocytic leukemia or
B cell lymphoma), often with a circulating paraprotein and
sometimes with hypocomplementemia.608-611 Patients with
both diseases usually have proteinuria, and most have hypertension and hematuria. About 70% to 75% have nephrotic
syndrome at biopsy. At presentation renal insufficiency is
common and most patients progress to ESKD. Fibrillary
glomerulonephritis and immunotactoid glomerulonephritis may be associated with HCV infection.611
Diagnosis of these disorders requires a renal biopsy
to demonstrate the defining ultrastructural features.608-611
Light microscopic findings in fibrillary glomerulonephritis
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CHAPTER 33 — Secondary Glomerular Disease
Figure 33.29 Fibrillary glomerulonephritis. The mesangium is mildly
expanded and the glomerular capillary walls appear thickened with
segmental double contours. (Periodic acid–Schiff stain, ×300.)
1133
Figure 33.31 Fibrillary glomerulonephritis. Electron micrograph
showing the characteristic randomly oriented fibrils, measuring
16-20 nm within the glomerular basement membrane. The foot processes are effaced. (×8000.)
Figure 33.30 Immunotactoid glomerulonephritis. There is lobular
expansion of the glomerular tuft by abundant mesangial deposits of
silver-negative material. Segmental extension of deposits into the
subendothelial aspect of some glomerular capillaries is also seen.
(Jones’ methenamine silver stain, ×500.)
Figure 33.32 Immunotactoid glomerulonephritis. Electron micrograph showing abundant mesangial deposits of microtubular structures measuring approximately 35 nm in diameter. (×10,000.)
are highly variable and include mesangial proliferation;
mesangial expansion by amorphous amyloid-like material;
membranous, membranoproliferative, and crescentic glomerulonephritis (Figure 33.29).608 In immunotactoid glomerulonephritis, glomerular lesions are often nodular and
sclerosing, whereas others are proliferative or membranous
(Figure 33.30). The pathognomonic findings seen on electron microscopy consist of nonbranching fibrils of 16 to
24 nm diameter in fibrillary glomerulonephritis (as opposed
to 8 to 12 nm for amyloid) (Figure 33.31) and hollow microtubules of 30 to 50 nm in immunotactoid glomerulonephritis (Figure 33.32). In fibrillary glomerulonephritis, fibrils
are arranged randomly in the mesangial matrix and GBMs.
By contrast, the microtubules of immunotactoid glomerulonephritis are often arranged in parallel stacks in the mesangium, subendothelial, and/or subepithelial regions. The
fibrils and microtubules do not stain with Congo red or
thioflavin T. In fibrillary glomerulonephritis, immunofluorescence is almost always positive for IgG (Figure 33.33)
(especially subclasses IgG1 and IgG4), C3, and both κ- and
λ-chains, indicating polyclonal deposits.608-611 Staining for
IgM, IgA, and C1 has been reported in a minority of cases.
In immunotactoid glomerulonephritis, the immunoglobulin deposits are often monoclonal, consisting of IgG with a
restricted light-chain isotype (either κ or λ). IgG subtypes
IgG1 and IgG3 are most common and have the capacity to
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1134
SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
eventually progresses to nephrotic syndrome and slowly
deteriorating renal function.612,613 It is caused by an inherited mutation in the gene encoding fibronectin-1.613 Patients
who progress to ESKD may develop recurrent fibronectin
glomerulopathy in the allograft.
MONOCLONAL IMMUNOGLOBULIN
DEPOSITION DISEASE
Figure 33.33 Fibrillary glomerulonephritis. Immunofluorescence
photomicrograph showing smudgy deposits of IgG throughout the
mesangium, with segmental extension into the peripheral glomerular
capillary walls. (×800.)
fix complement, leading to glomerular co-deposits of C1q
and C3. In both diseases, the deposits are usually limited to
the glomerulus. In fibrillary glomerulonephritis, the fibrils
may be focally admixed with more granular immune-type
electron-dense deposits.608 Rare patients with fibrillary glomerulonephritis have been reported to have extrarenal
deposits involving alveolar capillaries and, in the case of
immunotactoid glomerulonephritis, the bone marrow.614,615
Almost half of patients with fibrillary glomerulonephritis
or immunotactoid glomerulonephritis develop ESKD within
2 to 6 years of presentation.608,610 Those with crescentic
lesions, sclerosing glomerulonephritis, and diffuse proliferative glomerulonephritis fare worse than those with
mesangioproliferative glomerulonephritis and those with a
membranous pattern. Younger patients, patients with a
normal GFR, and those with subnephrotic-range proteinuria have a more benign renal course.608
Although there is no proven therapy for fibrillary glomerulonephritis, some clinicians choose to treat the light
microscopy pattern observed on renal biopsy (e.g., membranous, membranoproliferative, crescentic, etc.).608 Prednisone, cyclophosphamide, and colchicine have not led to
consistent benefit in most patients.608 However, in some with
crescentic glomerulonephritis, cyclophosphamide and corticosteroid therapy has led to a dramatic improvement in
GFR and proteinuria. Cyclosporine has also been used successfully in some patients with fibrillary glomerulonephritis
and a membranous pattern on light microscopy. Rituximab
has been used in those with MPGN pattern although recent
larger series have given less promising results.320,608,616,617 In
some patients with associated chronic lymphocytic leukemia, treatment with chemotherapy has been associated with
improved renal function and decreased proteinuria.608,610
Dialysis and transplantation have been performed in both
fibrillary glomerulonephritis and immunotactoid glomerulonephritis, but there is a significant recurrence rate in the
allograft in both diseases.608,618,619 Some have found a higher
recurrence rate in those with an associated monoclonal
gammopathy.619
Fibronectin glomerulopathy is a familial disease
with autosomal dominant inheritance that presents with
proteinuria and hematuria usually in adolescents and
Monoclonal immunoglobulin deposition disease (MIDD)
includes light-chain deposition disease (LCDD), combined
light- and heavy-chain deposition disease (LHCDD),
and heavy-chain deposition disease (HCDD). MIDD is a
systemic disease caused by the overproduction and extracellular deposition of a fragment of monoclonal immunoglobulins.620-622 LCDD is by far the most common pattern. As
opposed to amyloidosis, in LCDD the deposits in more than
80% of cases are composed of κ-light chains, most often of
the VkIV subgroup, rather than λ-light chains.620-623 In LCDD
the deposits are granular in nature, do not have the biochemical properties necessary to form fibrils or β-pleated
sheets and thus do not bind Congo red stain or thioflavin T,
and are not associated with amyloid P protein.620-623 In
amyloid the fibrils are usually derived primarily from the
variable region of the light chains, while in LCDD the deposits are predominantly composed of the constant region of
the light chain. This may explain the far brighter immunofluorescence staining for light chains found in LCDD as
opposed to amyloidosis. The nature of the light chains may
also explain the far more common occurrence of light-chain
cast nephropathy in LCDD than in amyloidosis.620-623 The
pathogenesis of the glomerulosclerosis in LCDD involves
promotion of a profibrotic mesangial cell phenotype with
production of transforming growth factor-β, which acts as
an autacoid to stimulate mesangial cell synthesis of extracellular matrix proteins such as type IV collagen, laminin, and
fibronectin.624
Patients with MIDD are generally older than 45 years.620-623
However, in one recent series with a median age of 56 years,
more than one third of the patients were younger than 50
years of age.621 Many such patients develop frank myeloma,
and some may have a lymphoplasmacytic B cell disease such
as lymphoma or Waldenström’s macroglobulinemia.620-622 As
in amyloidosis, the clinical features vary with the location
and extent of organ deposition of the monoclonal protein.
Patients typically have cardiac, neural, hepatic, and renal
involvement, but other organs such as the skin, spleen,
thyroid, adrenal glands, and gastrointestinal tract may be
involved.620-623 Patients with renal disease usually have significant glomerular involvement and present with proteinuria,
nephrotic syndrome, and hypertension. Renal insufficiency
is present in most, and some require dialysis. While by
serum protein electrophoresis (SPEP) or urine protein electrophoresis (UPEP) 15% to 30% of patients may have no
identifiable M spike, by analysis of serum-free light-chain
assay, 100% have an abnormal protein and 80% have high
levels of production.621 Some patients may have greater
tubulointerstitial involvement and less proteinuria along
with renal insufficiency.624
The glomerular pattern by light microscopy is most often
nodular sclerosing with mesangial nodules of acellular
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CHAPTER 33 — Secondary Glomerular Disease
Figure 33.34 Light-chain deposition disease. There is nodular glomerulosclerosis with marked global expansion of the mesangium by
intensely periodic acid–Schiff—positive material but without appreciable thickening of the glomerular capillary walls. (Periodic acid–
Schiff stain, ×375.)
Figure 33.35 Light-chain deposition disease. Immunofluorescence
photomicrograph showing linear staining for κ-light chain involving
glomerular and tubular basement membranes, the mesangial nodules,
Bowman’s capsule, and vessel walls. (×250.)
eosinophilic material resembling the nodular glomerulosclerosis seen in diabetic patients (Figure 33.34).620-622 Glomerular capillary microaneurysms also may occur.625 Some
glomeruli have associated membranoproliferative features.
In LCDD the nodules are more strongly PAS positive and
less argyrophilic than in diabetes, and the GBMs in LCDD
are not usually visibly thickened by light microscopy.620,621
Other glomeruli may be entirely normal or have only mild
mesangial sclerosis. Immunofluorescence is usually diagnostic by demonstration of a monoclonal light chain (κ in 80%)
staining in a diffuse linear pattern along the GBMs, in the
nodules, and along the tubular basement membranes and
vessel walls (Figure 33.35).620,621 Staining for complement
components is usually negative. By electron microscopy,
deposition of a finely granular punctate, highly electrondense material occurs along the lamina rara interna of the
GBM, in the mesangium, and along tubular and vascular
basement membranes.620-623
1135
Figure 33.36 Heavy-chain deposition disease. Electron micrograph
showing bandlike, finely granular electron-dense deposits involving
the glomerular basement membrane, with greatest concentration
along the inner aspect (×5000.)
The prognosis for patients with LCDD is variable. Death
is often attributed to heart failure, infectious complications, or the development of frank myeloma and renal
failure.620-623 In one series of 63 MIDD patients, 65% of
patients developed myeloma and 36 patients developed
uremia.622 In another series of 64 patients with MIDD,
including 51 with LCDD, with a median follow-up of over 2
years, 57% had stable or improved renal function, 4% worsening of renal function, and 39% progression to ESKD.621
Patient survival is about 90% at 1 year and 70% at 5 years,
with renal survival 67% and 37% at 1 and 5 years,
respectively.620-622,626,627 Predictors of worse renal outcome
included increased age, associated light-chain cast nephropathy, and elevated serum creatinine at presentation.620-622
Predictors of worse patient survival included increased age,
occurrence of myeloma, higher initial serum creatinine,
and extrarenal deposition of light chains.620-622
Treatment, akin to the treatment of myeloma or amyloidosis, has been with dexamethasone in combination with
other agents, including melphalan, cyclophosphamide,
bortezomib, thalidomide, and lenalidomide, and has led to
stabilized or improved renal function in some MIDD
patients.620-622 However, this therapy is not usually successful
in patients with significant renal dysfunction and a plasma
creatinine above 4 mg/dL at initiation of treatment.627 In
one series of 32 patients treated with chemotherapy, 34%
progressed to ESKD.622 Marrow or stem cell transplantation
is a therapeutic option for some patients with LCDD.620,622
Although there are little data on dialysis and renal transplantation in LCDD, patients appear to fare as well as those
with amyloidosis. Recurrences in the renal transplant have
been reported620,621,626-628 and recurrence rates in some series
are as high as 70% to 75%.596,621,628 Thus, suppression of the
abnormal paraprotein producing cell clone is crucial prior
to renal transplantation.
In some patients with a plasma cell dyscrasia, monoclonal
light and heavy immunoglobulin chains combined (LHCDD)
or short monoclonal truncated heavy chains alone (HCDD)
are deposited in the tissue (Figure 33.36).620,623,629,630 As in
LCDD, the electron microscopy deposits are granular and
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1136
SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
biopsies are Congo red negative. The clinical features are
similar to those of LCDD and amyloidosis.630 Most patients
are middle age or older. They present with renal insufficiency, hypertension, proteinuria, and often nephrotic syndrome. In most patients a monoclonal protein is detected
in the serum or urine. In contrast to amyloid and LCDD,
HCDD may be associated with hypocomplementemia if the
heavy chain avidly binds complement (especially γ–heavychain subtypes G1 and G3).630 All patients with HCDD have
a deletion of the CH1 domain of the heavy chain, which
causes the heavy chain to be secreted prematurely by the
plasma cell.630,631,643-645 The characteristic light microscopic
finding in HCDD is a nodular sclerosing glomerulopathy at
times with small crescents.620,630-632 The diagnosis is made by
immunofluorescence with linear positivity for the heavy
chain of immunoglobulin (usually γ) and negativity for both
κ- and λ-light chains.630 The distribution is diffuse involving
glomerular, tubular, and vascular basement membranes.
Treatment has been similar to LCDD, and many patients
have progressed to renal failure.630,633 Recurrence in the
renal transplant has been documented.620
OTHER GLOMERULAR DISEASES AND
DYSPROTEINEMIA
Recent series have described patients with a proliferative
glomerulonephritis resembling immune complex glomerulonephritis in association with a monoclonal gammopathy.634,635 This newly described entity is known as
proliferative glomerulonephritis with monoclonal IgG
deposits (PGNMID). These patients presented with renal
insufficiency and proteinuria, sometimes associated with
nephrotic syndrome, but no evidence of cryoglobulinemia.
Light microscopy shows an MPGN pattern in more than one
half and an endocapillary proliferative pattern with membranous features in more than one third. All had ordinaryappearing granular nonorganized electron-dense deposits
in the mesangial, subendothelial, and subepithelial sites,
but by immunofluorescence these were restricted to a single
monoclonal γ subclass and light-chain isotype (e.g., IgG1κ,
IgG2λ, or IgG3κ). Although infrequent patients have had a
pure membranous pattern by light microscopy and electron
microscopy, they still have the same monoclonal restriction
by immunofluorescence microscopy. M spike was identified
in the serum in 30% of cases, but no patient developed
overt myeloma or lymphoma during the follow-up period.
In one large series at 2.5 years of follow-up, 38% of patients
had had a complete recovery, 38% had persistent renal
dysfunction, and 22% had progressed to ESKD.635 Higher
presenting serum creatinine, higher percentage of glomerulosclerosis, and more interstitial fibrosis on biopsy predicted
progression to ESKD. Proliferative glomerulonephritis with
monoclonal IgG deposits commonly recurs in the transplant
and may in some cases be amenable to either rituximab or
cyclophosphamide therapy.636,637
Other rare patients with dysproteinemia have had intracellular glomerular crystals within the podocytes, sometimes
in association with tubular epithelial crystalline deposits.638
Pamidronate-induced collapsing focal sclerosis has been
noted in myeloma,639 as has crescentic glomerulonephritis.
MPGN has been reported rarely, particularly in patients with
associated cryoglobulinemia (see “Mixed Cryoglobulinemia” section).
WALDENSTRÖM’S MACROGLOBULINEMIA
In Waldenström’s macroglobulinemia, patients have an
abnormal circulating monoclonal IgM protein in association
with a B cell lymphoproliferative hematologic disorder.640-643
This slowly progressive disorder occurs in older patients
(median age, 60) who present with constitutional symptoms
of fatigue and weight loss, bleeding, visual disturbances, neurologic symptoms, hepatosplenomegaly, lymphadenopathy,
anemia, and often hyperviscosity syndrome.640-643 Although
renal involvement occurs in less than 5% of patients, glomerular lesions can present with microscopic hematuria,
proteinuria, and nephrotic syndrome.643,644 Patients may
have enlarged kidneys. The renal pathology in Waldenström’s macroglobulinemia is varied.643-645 Some patients will
have invasion of the renal parenchyma by neoplastic lymphoplasmacytic cells. Others have AKI with intraglomerular
occlusive thrombi of the IgM paraprotein. These cases have
large eosinophilic, amorphous, PAS-positive deposits occluding the glomerular capillary lumens with little or no glomerular hypercellularity (Figure 33.37). By immunofluorescence
these glomerular “thrombi” stain for IgM and a single lightchain isotype, consistent with monoclonal IgM deposits, but
complement components are usually negative or only weakly
positive. By electron microscopy the deposits contain nonamyloid fibrillar or amorphous electron-dense material.
Some patients develop MPGN with an associated type I or
type II cryoglobulinemia (Figure 33.38). Cases of LCDD with
intratubular casts similar to those of light-chain cast nephropathy and examples of renal amyloidosis have also been
reported in patients with Waldenström’s macroglobulinemia. Treatment of Waldenström’s macroglobulinemia is
directed against the lymphoproliferative disease with alkylating agents, melphalan, corticosteroids, rituximab, bone
marrow transplantation, and at times plasmapheresis for
hyperviscosity signs and symptoms.646-648
Figure 33.37 Waldenström’s macroglobulinemia. Large “protein
thrombi” corresponding to the monoclonal immunoglobulin M deposits fill the glomerular capillary lumens, with minimal associated glomerular hypercellularity. (Jones’ methenamine silver stain, ×600.)
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CHAPTER 33 — Secondary Glomerular Disease
Figure 33.38 Waldenström’s macroglobulinemia. An example with
cryoglobulinemic glomerulonephritis showing the characteristic intraluminal deposits, infiltrating leukocytes, and double-contoured glomerular basement membranes. (Jones’ methenamine silver stain,
×600.)
MIXED CRYOGLOBULINEMIA
Cryoglobulinemia is caused by circulating immunoglobulins that precipitate on cooling and resolubilize on
warming.649 Cryoglobulinemia is associated with a variety of
infections, especially HCV, as well as collagen-vascular
disease, and lymphoproliferative diseases.383,649 Cryoglobulins have been divided into three major groups based on the
nature of the circulating immunoglobulins.649 In type I cryoglobulinemia, the cryoglobulin is a single monoclonal
immunoglobulin often found associated with Waldenström’s
macroglobulinemia or myeloma. Type II and type III cryoglobulinemia are defined as mixed cryoglobulins, containing at least two immunoglobulins. In type II, a monoclonal
immunoglobulin (IgMκ in more than 90%) is directed
against polyclonal IgG and has rheumatoid factor activity.
In type III, the antiglobulin is polyclonal in nature with
both polyclonal IgG and IgM in most cases. The majority
of patients with type II and III mixed cryoglobulins have
now been shown to have HCV infection.622,650-655 To establish
a diagnosis of cryoglobulinemia, the offending cryoglobulins or the characteristic renal tissue involvement must be
demonstrated.
In the past, there was often no obvious cause of cryoglobulinemia and the name “essential mixed cryoglobulinemia”
was appropriate.650 It is now clear that many such patients
had HCV-related disease.652,656,657 Systemic manifestations of
mixed cryoglobulinemia include weakness, malaise, Raynaud’s phenomenon, arthralgias-arthritis, hepatosplenomegaly with abnormal liver function tests in two thirds to three
fourths of patients, peripheral neuropathy, and purpuricvasculitic skin lesions.383,649 Hypocomplementemia, especially of the early components (low C4 level), is a characteristic
and often helpful finding. Renal disease occurs at presentation in less than 25% of patients but develops in as many as
50% over time.650,658,659 In one review of 279 patients with
severe life-threatening HCV-associated cryoglobulinemic
vasculitis, 205 had AKI.653 In those renal patients who died,
sepsis was the most common cause of death, while for other
patients, vasculitis of the gastrointestinal tract, central
1137
Figure 33.39 Cryoglobulinemic glomerulonephritis. There is global
endocapillary proliferative glomerulonephritis with membranoproliferative features and focal intraluminal cryoglobulin deposits, forming
“immune thrombi.” (Periodic acid–Schiff stain, ×375.)
nervous system, and pulmonary system led to death. These
causes of death are similar to those of 242 patients in a review
of noninfectious mixed cryoglobulinemic vasculitis.654 In
most, an acute nephritic picture with hematuria, hypertension, proteinuria, and progressive renal insufficiency develops, and 20% of patients have nephrotic syndrome. Few
patients develop RPGN with oliguria. The majority of
patients with renal disease have a slow, indolent renal course
characterized by proteinuria, hypertension, hematuria, and
renal insufficiency.
Many older studies of type II cryoglobulinemia have
shown evidence of HBV infection or other viral infections
(e.g., Epstein-Barr virus).655 However, recent studies have
clearly documented HCV as a major cause of cryoglobulin
production in most patients previously thought to have
essential mixed cryoglobulinemia. Antibodies to HCV antigens have been documented in the serum, and HCV RNA
and anti-HCV antibodies are enriched in the cryoglobulins
of these patients.652,656,658,659 This is true even for patients with
normal levels of aminotransferases and no clinical evidence
of hepatitis. HCV antigens have also been localized by
immunohistochemistry to the glomerular deposits.656
In cryoglobulinemia, immunoglobulin complexes
deposit in the glomeruli and small- and medium-sized
arteries, binding complement and inciting a proliferative
response.652,658 The serum cryoglobulin participates in the
formation of the glomerular immune complex deposits. In
vitro studies have shown that IgM-κ rheumatoid factor from
patients with type II cryoglobulinemia is much more likely to
bind to cellular fibronectin (a component of the glomerular
mesangium) than IgM from normal controls or IgMcontaining rheumatoid factor from rheumatoid arthritis
patients.660 The particular physicochemical characteristics of
the variable region of the immunoglobulin cryoglobulin
may be important in the localization of the renal deposits.
Although by light microscopy the glomerular lesions of
cryoglobulinemia may show a variety of proliferative and
sclerosing features (Figure 33.39), certain features help to
distinguish cryoglobulinemic glomerulonephritis from
other proliferative glomerulonephritides.650,658,659 These features include massive glomerular exudation of monocytes/
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1138
SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
Figure 33.40 Cryoglobulinemic glomerulonephritis. Immunofluorescence photomicrograph showing deposits of immunoglobulin M corresponding to the large glomerular intracapillary deposits, with more
finely granular subendothelial deposits outlining the glomerular capillary walls. (×900.)
macrophages and, to a lesser degree, polymorphonuclear
leukocytes; amorphous eosinophilic PAS-positive, Congo
red negative deposits along the subendothelial aspect of the
glomerular capillary wall and focally filling the capillary
lumens, forming “immune thrombi”; membranoproliferative features with double-contoured GBMs and interposition
of deposits, mesangial cells, and monocytes; and the rarity
of extracapillary proliferation (crescents) despite the intense
intracapillary proliferation. The glomerular lesions may be
accompanied by an acute vasculitis of small- or mediumsized vessels. The monocytes of patients with active cryoglobulinemia and associated nephritis have been shown to
phagocytose cryoglobulins but to be unable to catabolize
them efficiently. By immunofluorescence (Figure 33.40),
the glomeruli in type II or type III cryoglobulinemia contain
deposits of both IgM as well as IgG, κ- and λ-light chains,
and C3 and C1q in the distribution of subendothelial and
mesangial deposits and the intracapillary “thrombi.” Staining for both IgM and κ are often dominant, reflecting the
deposition of type II cryoglobulins containing a monoclonal
IgM-κ component. By electron microscopy (Figure 33.41),
deposits in the subendothelial location or filling the capillary lumens often appear as either amorphous electrondense deposits or organized deposits of curvilinear parallel
fibrils or annular-tubular curvilinear structures with a diameter of 20 to 35 nm.650,658 The infiltrating macrophages are
in close contact with the subendothelial deposits and contain
prominent phagolysosomes, suggesting active phagocytosis
of the immune deposits. In some cases, the phagocytosis is
so effective that immune deposits are difficult to detect by
both immunofluorescence and electron microscopy.
Some patients with mixed cryoglobulinemia will have a
partial or total remission of their disease while most have
episodic exacerbations of their systemic and renal
disease.650,658 Before the association between mixed cryoglobulinemia and HCV was discovered, many patients were
treated successfully with prednisone and cytotoxic agents
such as cyclophosphamide and chlorambucil.651 Treatments
were not used in a controlled fashion. In patients with
severe renal disease, in those with digital necrosis from the
Figure 33.41 Cryoglobulinemic glomerulonephritis. Electron micrograph showing organized subendothelial deposits with an annulartubular substructure. These curvilinear tubular structures measure
approximately 30 nm in diameter. (×30,000.)
cryoglobulins, and in those with life-threatening organ
involvement, plasmapheresis was used in combination with
steroids and cytotoxics.651,661 Most patients with cryoglobulinemia in the past did not die of renal disease but rather of
cardiac or other systemic disease and infectious complications.651 Currently, most patients with HCV-associated cryoglobulinemia are treated with antiviral agents 662 (see the
“Hepatitis C” section under “Glomerular Manifestations of
Liver Disease”). Aggressive immunosuppressive therapy
carries the risk of promoting HCV replication in HCVinfected patients and of lymphoma in others. Rituximab has
recently been used successfully for treatment of type II
mixed cryoglobulinemia in patients with or without evidence of HCV infection and with and without prior antiviral
therapy.663-666 Rituximab has also been used successfully in
small numbers of patients with HCV-related glomerulonephritis and mixed cryoglobulinemia.667,668 Dialysis and transplantation in cryoglobulinemia have been used, but
recurrences in the allograft have been reported.669
HEREDITARY NEPHRITIS, INCLUDING
ALPORT’S SYNDROME
Alport’s syndrome is an inherited (usually X-linked) disorder with characteristic glomerular pathology, frequently
associated with hearing loss and ocular abnormalities.
Guthrie first reported a family with recurrent hematuria.670
Alport reported additional observations on this family, the
occurrence of deafness associated with hematuria, and the
observation that affected males died of uremia, whereas
affected females lived to an old age.671 Alport’s syndrome
and other hereditary and familial disease account for 0.4%
of adults with ESKD in the United States.672
CLINICAL FEATURES
The disease usually manifests in children or young
adults.673-675 Males have persistent microscopic hematuria,
with episodic gross hematuria, which may be exacerbated
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CHAPTER 33 — Secondary Glomerular Disease
by respiratory infections or exercise. There may be flank
pain or abdominal discomfort accompanying these episodes. Proteinuria is usually mild at first and increases progressively with age. Nephrotic syndrome has also been
described.676 Hypertension is a late manifestation. Slowly
progressive renal failure is common in males. ESKD usually
occurs in males between the ages of 16 and 35. In some
kindred, the course may be more delayed, with renal failure
occurring between 45 and 65 years of age. In most females,
the disease is mild and only partially expressed; however,
some females have experienced renal failure.677 In the European Community Alport Syndrome Concerted Action
(ECASCA) cohort, hematuria was observed in 95% of
female carriers and consistently absent in the other 5%.
Proteinuria, hearing loss, and ocular defects developed in
75%, 28%, and 15%, respectively.678 This variability in
disease severity in females can be explained by the degree
of random inactivation of the mutated versus wild type X
chromosome during lyonization.
High-frequency sensorineural deafness occurs in 30% to
50% of patients. Hearing impairment is always accompanied
by renal involvement. The severity of hearing loss is variable,
and there is no relation between the severity of hearing loss
and of the renal disease. Based on brainstem auditory
evoked responses, the site of the aural lesion is in the
cochlea.679,680 Families with hereditary nephritis but without
sensorineural hearing loss have been described.680,681
Ocular abnormalities occur in 15% to 30% of patients.682
Anterior lenticonus, which is the protrusion of the central
portion of the lens into the anterior capsule, is virtually
pathognomonic of Alport’s syndrome. Other ocular abnormalities include keratoconus, spherophakia, myopia, retinal
flecks, cataracts, retinitis pigmentosa, and amaurosis.673,674,683
Aortic disease, including dissections, aneurysms, dilation,
and aortic insufficiency, may be an unusual feature in some
patients.684
Other variants of presumed Alport’s syndrome, now
known to be distinct entities with different genetic bases,
include the association of hereditary nephritis with thrombocytopathia (megathrombocytopenia; so-called Epstein’s
syndrome),685,686 diffuse leiomyomatosis,687 ichthyosis and
hyperprolinuria,688 and Fechtner’s syndrome (nephritis,
macrothrombocytopenia, Döhle-like leukocyte inclusions,
deafness, and cataract).689
PATHOLOGY
The light microscopic appearance of biopsies is nonspecific.
The diagnosis rests on the electron microscopy findings.
By light microscopy most biopsies have glomerular and
tubulointerstitial lesions. In the early stages (<5 years
of age), the kidney biopsy may be normal or nearly normal.
The only abnormality may be the presence of superficially
located fetal glomeruli involving 5% to 30% of the glomeruli or interstitial foam cells.690,691 In the older child
(5 to 10 years of age), mesangial and glomerular capillary
wall lesions may be visible. These consist of segmental to
diffuse mesangial cell proliferation, matrix increase, and
thickening of the glomerular capillary wall.692 Special stains
such as Jones’ methenamine silver or periodic acid–Schiff
may reveal thickening and lamellation of the GBM. Segmentally or globally sclerosed glomeruli may be present.
1139
Tubulointerstitial changes may include interstitial fibrosis,
tubular atrophy, focal tubular basement membrane thickening, and interstitial foam cells. The glomerular and tubular
lesions progress over time. A pattern of focal segmental and
global glomerulosclerosis with hyalinosis is common in
advanced cases, especially those with nephrotic-range proteinuria. Tubulointerstitial lesions progress from focal to
diffuse involvement.690,693
By immunofluorescence many specimens are negative,690,694 but some may have nonspecific granular deposits
of C3 and IgM within the mesangium and vascular pole and
along the glomerular capillary wall in a segmental or global
distribution.673,680 The finding in rare cases of nonspecifically trapped electron-dense material with positivity for IgG
and C1q within the lamellated GBMs and paramesangial
regions may lead to an erroneous diagnosis of immune
complex glomerulonephritis.695 With segmental sclerosis,
subendothelial deposits of IgM, C3, properdin, and C4 are
found.673,690 The GBM of males with Alport’s syndrome frequently lacks reactivity with sera from patients with antiGBM antibody disease, or with monoclonal antibodies
directed against the Goodpasture epitope.696,697 This abnormality can help in diagnosing equivocal cases where the
electron microscopic findings are not specific.698
In the mature kidney, collagen IV is composed of heterotrimers made up of six possible α-chains. Chains composed
of α1, α1, and α2 are distributed in all renal basement
membranes. Collagen IV chains composed of α3, α4, and
α5 are present in mature GBM and some distal thin basement membrane. Chains of α5, α5, and α6 are distributed
in Bowman’s capsule and collecting duct thin basement
membrane, as well as in epidermal basement membrane.
Commercially available antisera to the subunits of collagen
IV reveal preservation of the α1- and α2-subunits but loss of
immunoreactivity for the α3-, α4-, and α5-subunits from the
GBM of affected males with X-linked disease. In addition,
there is loss of α5 staining from Bowman’s capsule, distal
tubular basement membranes, and skin in affected males
with X-linked disease. Females are chimeras with segmental
loss of α5 in glomerular and epidermal basement membranes due to random inactivation of the mutated X chromosome in podocytes and basal keratinocytes. Patients with
autosomal recessive forms of Alport’s disease typically lack
the α3-, α4- and α5-subunits in GBM but retain α5 immunoreactivity in Bowman’s capsule, collecting ducts, and skin
(where α5 forms a heterotrimer with α6). Thus, absence of
α5 staining in skin biopsies is highly specific for the diagnosis
of X-linked Alport’s syndrome.699
On electron microscopy the earliest change in young
males is thinning of the GBM (which is not specific for
hereditary nephritis and can occur in thin basement membrane disease).The cardinal ultrastructural abnormality is
the variable thickening, thinning, basket weaving, and lamellation of the GBM (Figure 33.42). These abnormalities
may also be seen in some patients without a family history
of nephritis700; these patients may be offspring of asymptomatic carriers or may represent new mutations. The endothelial cells are intact, and foot process effacement may be seen
overlying the altered capillary walls. The mesangium may be
normal in early cases, but with time, matrix and cells increase
and mesangial interposition into the capillary wall may be
observed.673,694 In males, the number of glomeruli showing
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SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
lamellation increases from about 30% by age 10 to more
than 90% by age 30. In females with mild disease, less than
30% of the glomeruli may be affected.701 Some affected
females have a predominantly thin basement membrane
phenotype with only rare segmental areas of lamellation.
The specificity of the GBM findings has been questioned.702 Foci of lamina densa lamellation and splitting
have been seen in 6% to 15% of unselected renal biopsies.
These changes also may be seen focally in other glomerulopathies. Thus clinical correlation and immunofluorescence examination are essential when the ultrastructural
features suggest Alport’s syndrome. Although diffuse thickening and splitting of the GBM strongly suggests Alport’s
syndrome, not all Alport kindreds show these characteristic
Figure 33.42 Alport’s syndrome. Electron micrograph showing a
thickened, lamellated glomerular basement membrane with the characteristic “split and splintered” appearance. (×4000.)
features. Thick, thin, normal, and nonspecific changes have
also been described.
PATHOGENESIS AND GENETICS
There are three genetic forms of hereditary nephritis (Table
33.2). In the majority of cases, the disease is transmitted via
an X-linked inheritance (i.e., father-to-son transmission
does not occur), and women tend to be carriers because of
lyonization. Autosomal dominant and recessive inheritance
have also been described, as has sporadic occurrence.673,703,704
The frequency of the Alport gene has been estimated to be
1 : 5000 in Utah705 and 1 : 10,000 in the United States.706
Hereditary nephritis is caused by defects in type IV collagen. Six genes for type IV collagen have been characterized.
Mutations in the COL4A5 gene (encoding the α5-subunit of
collagen type IV) on the X chromosome are responsible for
the more frequent X-linked form of hereditary nephritis.707
The identified mutations include deletions, insertions, substitutions, and duplications.707-711 However, there are other
abnormalities that are not encoded by the COL4A5 gene.
Other type IV collagen peptides are abnormally distributed.
The α1 and α2 peptides, which are normally confined to the
mesangial and subendothelial regions of the mature glomerulus, become distributed throughout the full thickness of
the GBM in hereditary nephritis. With progressive glomerular obsolescence, these peptide chains disappear, with an
increase in collagen types V and VI.712 Moreover, the basement membranes of these patients do not react with antiGBM antibodies. This implies that the NC1 domain of the
α3-subunit of type IV collagen is not incorporated normally
into the GBM, probably because the α5-subunit is required
for normal assembly of the minor α-chains of collagen type
IV into heterotrimers.713 Cationic antigenic components are
also absent.714 The reason why these GBM abnormalities
occur is not known but may be due to alteration in the
Table 33.2 Classification of Familial Hematurias
Locus
Progressive
Nephropathy
Deafness
Ocular
Changes
GBM
Changes
Hematologic
Features
+
+
+
Thickening
−
+
+
+
−
+
+
+
−
+
+
−
−
Thickening
Thickening
Thickening
Thinning
−
−
−
−
Thrombocytopenia
May-Hegglin
anomaly
Thrombocytopenia
Type IV Collagen Disorders
Alport’s syndrome
X-linked
X-linked + diffuse
Leiomyomatosis
Autosomal recessive
Autosomal dominant
Thin basement membrane
nephropathy*
COL4A5
COL4A5
COL4A3
COL4A3
COL4A3
+ COL4A6
or COL4A4
or COL4A4
or COL4A4
Noncollagen Disorders
Fechtner’s syndrome
MYH9
+
+
+
Thickening
Epstein’s syndrome
MYH9
+
+
+
Thickening
*Some families with thin basement membrane disease have mutations at loci other than the type IV collagen genes.
From Kasthan CE: Familial hematurias: what we know and what we don’t. Pediatr Nephrol 20:1027-1035, 2005.
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CHAPTER 33 — Secondary Glomerular Disease
incorporation of other collagens into the GBM.715 Autosomal
recessive and autosomal dominant hereditary nephritis have
been shown to involve the α3- or α4-chain. The genes for these
proteins are encoded on chromosome 2. An abnormality of
any of these chains could impair the integrity of the basement
membranes in the glomerulus and cochlea, leading to similar
clinical findings.
According to “Expert Guidelines for the Management of
Alport Syndrome and Thin Basement Membrane Nephropathy,”716 the term Alport’s syndrome should be reserved for
patients with the characteristic clinical features and a lamellated GBM with an abnormal collagen IV composition, and
in whom a COL4A5 mutation (X-linked disease) or two
COL4A3 or two COL4A4 mutations in trans (autosomal
recessive disease) are identified or expected. The term thin
basement membrane nephropathy (TBMN) should be reserved
for individuals with persistent isolated glomerular hematuria who have a thinned GBM due to a heterozygous COL4A3
or COL4A4 (but not COL4A5) mutation. This distinction is
to ensure patients who have X-linked Alport’s syndrome are
not falsely reassured by the usually benign prognosis seen
in TBMN. In those patients with renal impairment together
with a heterozygous COL4A3 or COL4A4 mutation, there is
likely to be a coincidental renal disease, such as IgA glomerulonephritis, or autosomal recessive Alport’s syndrome,
or a second, undetected COL4 mutation. The correct diagnosis may be adjudicated after discussions among the
nephrologist, pathologist, clinical geneticist, ophthalmologist, and audiologist, and interpretation of the relevant test
results.716 Genetic testing may be utilized when the diagnosis
of Alport’s syndrome is suspected but cannot be confirmed
with other techniques and when TBMN is suspected but
X-linked Alport’s syndrome must be excluded. With current
genetic techniques, the mutation detection rate is over 90%
and more likely to be identified in individuals with earlyonset renal failure and extrarenal manifestations.716
Minor causes of familial hematuria (Fechtner’s syndrome
and Epstein’s syndrome), along with two other genetic conditions featuring macrothrombocytes (Sebastian’s syndrome
and May-Hegglin anomaly), result from heterozygous mutations in the gene MYH9, which encodes nonmuscle myosin
heavy-chain II isoform A (NMMHC-IIA).717
COURSE AND TREATMENT
Recurrent hematuria and proteinuria may be present for
many years, followed by the insidious onset of renal failure.
Virtually all affected males reach ESKD, but there is considerable interkindred variability in the rate of progression.
The rate of progression within male members of an affected
family is usually but not always relatively constant.673,718,719
The presence of gross hematuria in childhood, nephrotic
syndrome, sensorineural deafness, anterior lenticonus, and
diffuse GBM thickening are indicative of an unfavorable
outcome in females.677 In the ECASCA, a 90% probability
rate of progression to end-stage renal failure by age 30 years
in patients with large deletions, nonsense mutations, or
frameshift mutations was noted. The same risk was of 50%
and 70%, respectively, in patients with missense or splice
site mutations. The risk of developing hearing loss before
30 years of age was approximately 60% in patients with missense mutations, compared to 90% for the other types of
1141
mutations.720 Female carriers with the COL4A5 mutation
generally have less severe disease. In the ECASCA cohort
described earlier, the probability of developing ESKD before
the age of 40 years was 12% in females versus 90% in males.
The risk of progression to ESKD appears to increase after the
age of 60 years in women. Risk factors for renal failure in
women included the development and progressive increase
in proteinuria and the occurrence of a hearing defect.678
There is no proven therapy for Alport’s syndrome.
Proteinuria-reduction strategies, such as aggressive control
of hypertension and use of ACEIs, might slow the rate of
progression in patients with hereditary nephritis.721-723 The
addition of an aldosterone antagonist may further reduce
proteinuria.724 A small number of patients showed apparent
stabilization when treated long term with cyclosporine725;
however, calcineurin inhibitor toxicity can occur with longterm use.726
Renal replacement therapy (either dialysis or transplantation) may be performed in patients with hereditary nephritis. Allograft and patient survival rates were comparable to
survival rates in the United Network for Organ Sharing
(UNOS) database.727 In approximately 2% to 4% of male
patients receiving a renal transplant, anti-GBM antibody
disease may develop.728 These antibodies are directed against
the α-5 noncollagenous (NC1) subunit of the intact α345
hexamer of collagen IV.729 This antigen, which presumably
does not exist in the native kidney of patients with hereditary nephritis, is present in normal donor kidneys and is
thus recognized as foreign.730,731 A profile of these patients
has been compiled.698 The patients are usually male, always
deaf, and likely to have reached ESKD before the age of 30.
There is a suggestion that certain mutations in the COL4A5
gene, such as deletions (which account for 11% to 12% of
Alport’s cases), may predispose patients to the development
of allograft anti-GBM nephritis.731 In 75% of cases, the onset
of anti-GBM nephritis occurs within the first year after transplantation, and 76% of the allografts were lost.
THIN BASEMENT
MEMBRANE NEPHROPATHY
TBMN (also known as benign familial hematuria and thin
GBM nephropathy) describes a condition that differs from
Alport’s disease in its generally benign course and lack of
progression. The typical finding on renal pathology is
diffuse thinning of the GBM. However, thin GBM may be
found in other conditions as well (including early Alport’s
disease and IgA nephropathy).732 The true incidence of
TBMN is unknown but is estimated to affect at least 1% of
the population; reports evaluating patients with isolated
hematuria suggest that 20% to 25% of such patients have
TBMN.733-735
CLINICAL FEATURES
Patients usually present in childhood with microhematuria.
Hematuria is usually persistent but may be intermittent in
some patients. Episodic gross hematuria may occur, particularly with upper respiratory infections.736,737 Patients do not
typically have overt proteinuria, but when present, this may
suggest progression of disease.733,738
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1142
SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
Table 33.3 Immunostaining Patterns for α5-Subunit of Type IV Collagen in Kidney and Epidermal
Basement Membranes
Normal
X-linked Alport’s syndrome males
X-linked Alport’s syndrome female carriers
Autosomal recessive Alport’s syndrome
Thin basement membrane disease
Glomerular Basement
Membrane
Bowman’s Capsule
Epidermal Basement
Membrane
Present/normal
Absent
Present segmentally/mosaic
Absent
Present/normal
Present/normal
Absent
Present segmentally/mosaic
Present/normal
Present/normal
Present/normal
Absent
Present focally/mosaic
Present/normal
Present/normal
parent was an asymptomatic carrier.735,736,745 There appears
to be a reduction or loss of the subepithelial portion of the
basement membrane, which apparently contains normal
relative amounts of type IV collagen.746 The degree of GBM
thinning does not appear to affect the clinical presentation
or outcome.747
DIFFERENTIAL DIAGNOSIS OF
FAMILIAL HEMATURIAS
Figure 33.43 Thin basement membrane disease. By electron
microscopy, the glomerular basement membranes are diffusely and
uniformly thinned, measuring less than 200 nm in thickness. (×2500.)
PATHOLOGY
Renal biopsies typically show no histologic abnormalities
with the exception of focal erythrocyte casts. By immunofluorescence, no glomerular deposits of immunoglobulins
or complement are found. By electron microscopy, there is
diffuse and relatively uniform thinning of the GBM (Figure
33.43). The normal thickness of the GBM is age and gender
dependent. Vogler739 has defined normal ranges for children: birth, 169 ± 30 nm; 2 years of age, 245 ± 49 nm; 11
years, 285 ± 39 nm. Steffes740 has defined normal ranges for
adults: males, 373 ± 42; females, 326 ± 45 nm. Each laboratory should attempt to establish its own normals for GBM
thickness. A cutoff value of 250 nm has been reported by
some authors,741-743 whereas other groups have used a cutoff
of 330 nm.738 There is often accentuation of the lamina rara
interna and externa. Focal GBM gaps may be identified
ultrastructurally. Immunostaining for the α-subunits of collagen IV reveals a normal distribution in the GBM.
PATHOGENESIS
About 40% of TBMN disease has been linked to mutations
of the COL4A3 and COL4A4 genes.744 In most kindreds with
TBMN, the disorder appears to be transmitted in an autosomal dominant pattern. In a few families with several
affected children and apparently unaffected parents, the
findings suggest a recessive mode of inheritance or that one
Type IV collagen defects can cause both TBMN and
Alport’s syndrome. Patients with TBMN can be considered
carriers of autosomal recessive Alport’s syndrome.748,749
With advances in molecular biology and immunopathology,
hereditary forms of hematuria have been better characterized. Table 33.2 shows a summary of the clinical, pathologic,
and genetic features of the various forms of hereditary
nephritis.750
Since GBM thinning may be seen in early cases of Alport’s
syndrome, immunohistochemical analysis of α3, α4, and α5subunits should be undertaken (since genetic tests are not
always practical). Table 33.3 shows the typical immunostaining patterns in the kidney and skin basement membranes.
NAIL-PATELLA SYNDROME (HEREDITARY
OSTEO-ONYCHODYSPLASIA)
Nail-patella syndrome (NPS) is an autosomal dominant condition affecting tissues of both ectodermal and mesodermal
origin, manifested as symmetric nail, skeletal, ocular, and
renal anomalies.
CLINICAL FEATURES
The classical tetrad of anomalies of the nails, elbows, knees,
and iliac horns was described by Mino and coworkers in
1948.751 Nail dysplasia and patellar aplasia or hypoplasia are
essential features for the diagnosis of NPS. The presence of
triangular nail lunulae is a pathognomonic sign for NPS.
Other skeletal abnormalities include dysplasia of the elbow
joints, posterior iliac horns, and foot deformities. Various
ocular anomalies have sporadically been found in NPS
patients, including microcornea, sclerocornea, congenital
cataract, iris processes, pigmentation of the inner margin of
the iris, and congenital glaucoma.752
Renal involvement is variable, being present in up to 38%
of patients. Renal manifestations first appear in children
and young adults and may include proteinuria, hematuria,
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CHAPTER 33 — Secondary Glomerular Disease
A
1143
B
Figure 33.44 Nail-patella syndrome. A, Routine electron micrograph showing thickening of a glomerular basement membrane (GBM) with
focal irregular internal lucencies. (×15,000.) B, Phosphotungstic acid–stained electron micrograph demonstrating the characteristic banded
collagen fibrils within the rarefied segments of GBM. (×15,000.)
hypertension, or edema. Nephrotic syndrome and progressive renal failure may occasionally occur. The course is generally benign with renal failure being a late feature.753,754
Congenital malformations of the urinary tract and nephrolithiasis are also more frequent in these patients. Cases with
renal lesions typical of NPS but without skeletal abnormalities have been reported.755
PATHOLOGY
The findings on light microscopy are nonspecific and
include focal and segmental glomerular sclerosis, segmental
thickening of the glomerular capillary wall, and mild mesangial hypercellularity.756 Immunofluorescence microscopy
is nonspecific, and IgM and C3 have been observed in
sclerosed segments. Ultrastructural studies show a thickened basement membrane that contains irregular lucencies,
imparting a “moth-eaten” appearance (Figure 33.44A).
The presence of intramembranous fibrils with the periodicity of collagen is revealed by phosphotungstic acid stains in
electron microscopic sections, corresponding to the distribution of the intramembranous lucencies (see Figure
33.44B). These must be distinguished from the occasional
collagen fibrils that can accumulate nonspecifically in the
sclerotic mesangium in a variety of sclerosing glomerular
conditions.756
PATHOGENESIS
The genetic locus for this syndrome is on chromosome 9
and results from mutations in the LIM homeodomain
protein LMX1B gene, which is transmitted in an autosomal
dominant pattern. Lmx1b plays a central role in dorsoventral patterning of the vertebrate limb.757,758 The mechanism
of disease-causing mutations is not fully elucidated, but haploinsufficiency may be associated with expression of podocyte structural proteins such as CD2AP.755
TREATMENT
There is no specific treatment for this condition; occasional patients with renal failure have been successfully
transplanted.759
FABRY’S DISEASE (ANGIOKERATOMA
CORPORIS DIFFUSUM UNIVERSALE)
Fabry’s disease760 is an X-linked inborn error of glycosphingolipid metabolism involving a lysosomal enzyme,
α-galactosidase A (also known as ceramide trihexosidase).
The enzyme deficiency leads to the accumulation of globotriaosylceramide (ceramide trihexoside) and related neutral
glycosphingolipids, leading to multisystem involvement and
dysfunction. Clinical guidelines for the diagnosis and treatment of Fabry’s disease have been published.761
CLINICAL FEATURES
Fabry’s disease has been reported in all ethnic groups, and
the estimated incidence in males is 1 in 40,000 to 1 in
60,000. In male hemizygotes, the initial clinical presentation
usually begins in childhood with episodic pain in the
extremities and acroparesthesias. Renal involvement is
common in male hemizygotes and is occasional in female
heterozygotes. The disease presents with hematuria and
proteinuria, which often progresses to nephrotic levels. In
men, progressive renal failure generally develops by the fifth
decade. Data from the Fabry Registry suggest that proteinuria is a strong determinant of renal outcome.762 In the
United States, Fabry’s disease accounts for 0.02% of patients
who began renal replacement therapy.763
The skin is commonly involved with reddish-purple
macules (angiokeratomas) typically found “below the belt”
on the abdomen, buttocks, hips, genitalia, and upper thighs.
Other findings include palmar erythema, conjunctival and
oral mucous membrane telangiectasia, and subungual splinter hemorrhages. The nervous system is involved with
peripheral and autonomic neuropathy. Premature arterial
disease of coronary vessels leads to myocardial ischemia and
arrhythmias at a young age. Similarly, cerebrovascular
involvement leads to early onset of strokes. In the heart,
valvular disease and hypertrophic cardiomyopathy have also
been reported. Corneal opacities are seen in virtually all
hemizygotes and most heterozygotes. Posterior capsular
cataracts, edema of retina and eyelids, and tortuous retinal
and conjunctival vessels also may occur. Generalized
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SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
Figure 33.45 Fabry’s disease. By light microscopy, the visceral
epithelial cells (podocytes) are markedly enlarged with foamyappearing cytoplasm. (Trichrome stain, ×800.)
Figure 33.46 Fabry’s disease. Electron micrograph showing abundant whorled myelin figures within the cytoplasm of the podocytes.
A few similar inclusions are also identified within the glomerular endothelial cells. (×2000.)
lymphadenopathy, hepatosplenomegaly, aseptic necrosis of
the femoral and humeral heads, myopathy, hypoalbuminemia, and hypogammaglobulinemia have been reported.
In carrier females, clinical manifestations may range from
asymptomatic to severe disease similar to male hemizygotes.
Up to one third of female carriers have been reported to
have significant disease manifestations.764
on immunofluorescence microscopy are usually negative
except in areas of segmental sclerosis, where IgM and complement may be demonstrated. Orange autofluorescence
corresponding to the lipid inclusions may be found in podocytes and other renal cells.
PATHOLOGY
The mutations in the GLA gene generally are “private,” with
specific molecular defects that vary from family to family,
and include rearrangements, deletions, and point mutations.769 Deficiency of the enzyme leads to accumulation of
globotriaosylceramide especially in the vascular endothelium, with subsequent ischemic organ dysfunction. Patients
with blood groups B and AB have earlier and more severe
symptoms, likely related to accumulation of the terminal
α-galactose substance during the synthesis of the B antigen
on red blood cell membranes.770 Globotriaosylceramide
accumulation in podocytes may lead to proteinuria and
renal dysfunction, but functional abnormalities are not
always noted, especially in female heterozygotes. A geneknockout mouse model of Fabry’s disease has been produced, which shows the characteristic changes.771
Glycosphingolipid accumulation begins early in life,765 and
the major renal site of accumulation is the podocyte (visceral epithelial cells). By light microscopy, these cells are
enlarged with numerous clear, uniform vacuoles in the cytoplasm causing a foamy appearance (Figure 33.45). These
vacuoles can be shown to contain lipids when fat stains
(such as Oil Red O) are used or when viewed under the
polarizing microscope, where they exhibit a double refractile appearance before being processed with lipid solvents.
All renal cells may accumulate the lipid. These include (in
addition to podocytes) parietal epithelial cells, glomerular
endothelial cells, mesangial cells, interstitial capillary endothelial cells, distal convoluted tubular cells, and to a lesser
extent, cells of the loops of Henle and proximal tubular
cells. Indeed, vascular endothelial cells are involved in virtually every organ and tissue.766 In the kidney, the myocytes
and endothelial cells of arteries also are commonly involved.
In heterozygotes, similar changes are present but with
less severity.767 Characteristic findings are noted on
electron microscopy (Figure 33.46). The major finding
is large numbers of “myelin figures” or “zebra bodies”
within the cytoplasm of the podocytes and, to a variable
extent, in other renal cell types. These intracytoplasmic
vacuoles consist of single membrane-bound dense bodies
with a concentric whorled or multilamellar appearance.
Glomerular podocytes exhibit variable foot process effacement. The GBMs are initially normal, but with progression
of disease, there may be thickening and collapse of the
GBM, focal and segmental glomerular sclerosis, with accompanying tubular atrophy and interstitial fibrosis.768 Findings
PATHOGENESIS
DIAGNOSIS
The diagnosis in affected males can be established by measuring levels of α-galactosidase A in plasma or peripheral
blood leukocytes followed by mutation analysis when positive. Hemizygotes have almost no measurable enzyme activity. Female carriers may have enzyme levels in the low to
normal range; to diagnose female carriers, the specific
mutation in the family must be demonstrated.716 The measurement of urinary ceramide digalactoside and trihexoside
levels may also be of use to identify the carrier state. Prenatal
diagnosis can be made by measuring amniocyte enzyme
levels in amniotic fluid. Screening of dialysis and renal transplant patients with undiagnosed renal failure, patients with
hypertrophic cardiomyopathy, and patients with strokes has
yielded the diagnosis of Fabry’s disease in 1% to 5%.772
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CHAPTER 33 — Secondary Glomerular Disease
1145
TREATMENT
Two forms of recombinant α-galactosidase A are available:
agalsidase alfa (Replagal; Shire Human Genetic Therapies,
Boston, MA) and agalsidase beta (Fabrazyme; Genzyme,
Cambridge, MA). Agalsidase alfa is produced in a continuous human cell line and is administered as an intravenous
infusion over 40 minutes at a dose of 0.2 mg/kg body weight
every 2 weeks. Agalsidase beta is produced in Chinese
hamster ovary (CHO) cells and is given as an intravenous
infusion over a 4-hour period at a dose of 1.0 mg/kg body
weight every 2 weeks.761 Two pivotal randomized controlled
trials have shown that recombinant human α-galactosidase
A enzyme replacement therapy (ERT) is safe and can
improve clinical parameters. In one short-term study,
α-galactosidase A treatment was associated with improved
neuropathic pain, decreased mesangial widening, and
improved creatinine clearance.773 In the second study,
repeat renal biopsies showed decreased microvascular endothelial deposits of globotriaosylceramide.766,774 However, a
systematic review that included five trials and 187 patients
did not provide robust evidence for the use of replacement
therapy.775 From a renal standpoint, open-label extension
studies showed that renal function remained stable in the
long term in most patients with normal renal function at
baseline.776,777 However, patients with impaired baseline
renal function may show continued decline despite ERT.777
Since there is a paucity of data showing hard outcomes
(ESKD, doubling of creatinine, death), the recommendation is to start ERT only in patients with CKD stages 1 and
2 and only in the context of a clinical trial (interventional
or observational).761 Dose reduction of ERT or a switch from
agalsidase beta to agalsidase alfa (which occurred during a
shortage of agalsidase beta) has been associated with worsening albuminuria, decline in eGFR (in the switch group),
and worsening pain scores (in the dose reduction group).778
The experience with ERT in female carriers is limited. Clinical recommendations for the treatment of Fabry’s disease
have been published.761
The ERA–EDTA Registry in Europe reported that patient
survival on dialysis was 41% at 5 years; cardiovascular complications (48%) and cachexia (17%) were the main causes
of death. Graft survival at 3 years in 33 patients was not
inferior to that of other nephropathies (72% vs. 69%), and
patient survival after transplantation was comparable to that
of patients younger than 55 years of age.779 In the U.S. population, survival of patients with Fabry’s disease was lower
than nondiabetic renal failure patients.763 Long-term
allograft function in patients with Fabry’s disease has been
reported. Glycosphingolipid deposits recur in allografts but
have not been reported to cause graft failure.780
SICKLE CELL NEPHROPATHY
Renal disease associated with sickle cell disease includes
gross hematuria, papillary necrosis, nephrotic syndrome,
renal infarction, inability to concentrate urine, renal medullary carcinoma, and pyelonephritis.781,782 Microscopic or
gross hematuria is likely the result of microinfarcts in the
renal medulla.783 Glomerular lesions, however, are less commonly encountered and may be seen in patients with sickle
Figure 33.47 Sickle cell disease. An example of sickle cell glomerulopathy with membranoproliferative features. There are double contours of the glomerular basement membrane associated with
segmental mesangiolysis. (Jones’ methenamine silver stain, ×500.)
cell hemoglobin (HbSS) disease, sickle–hemoglobin C
(HbSC) disease, and sickle cell thalessemia.784
CLINICAL FEATURES
In one study, the prevalence of proteinuria (>1+ on a dipstick) in HbSS disease was 26%.784 The majority of proteinuric patients had less than 3 g/day and elevated serum
creatinine levels were present in 7% of patients. In another
study, 4.2% with HbSS disease and 2.4% with HbSC disease
developed renal failure. The median age of disease onset
for these patients was 23.1 and 49.9 years, respectively. Survival time for patients with HbSS anemia after the diagnosis
of renal failure, despite dialysis, was 4 years, and the median
age at the time of death was 27 years. The risk for renal
failure was increased in patients with the Central African
Republic β S–gene cluster haplotype, hypertension, proteinuria, and severe anemia.785 The course of HbSS renal disease
is progressive; in one series, 18% of patients with HbSS
disease progressed to ESKD.786
PATHOLOGY
Early glomerular lesions in patients with HbSS include
enlarged glomeruli and dilated and congested capillaries
containing sickled erythrocytes (some of these patients may
have nephrotic proteinuria).787 Heterogeneous patterns of
glomerular injury have been reported. A membranoproliferative pattern exhibits mesangial proliferation with mild to
moderate capillary wall thickening due to GBM reduplication and mesangial interposition (Figure 33.47). Some of
these patients also exhibit features of chronic thrombotic
microangiopathy, with narrow double contours of the GBM
and mesangiolysis. A pattern of membranous glomerulonephritis has also been described. On immunofluorescence
microscopy, irregular granular deposits of IgG and C3 have
been reported in those cases with membranous features and
in a subgroup of cases with membranoproliferative pattern
on light microscopy.787,788 Ultrastructural studies show granular dense deposits in the mesangial and subepithelial area.
More commonly, those cases with membranoproliferative
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1146
SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
observed in 51% of HbSS patients correlated positively with
lower hemoglobin levels and reticulocyte counts, implying
that the hemolysis-related vasculopathy may be contributing.797 A role for reactive oxygen species as mediator
of chronic vascular endothelial injury has also been
proposed.798
Recently, polymorphisms in the MYH9 and APOL1 genes
have been associated with risk for proteinuria in patients
with HbSS disease. GFR was negatively correlated with proteinuria (P < 0.0001) and was significantly predicted by an
interaction between MYH9 and APOL1 in a multivariable
model.799
TREATMENT
Figure 33.48 Sickle cell disease. An example with focal segmental
glomerulosclerosis. The nonsclerotic glomerular capillaries are congested with sickled erythrocytes. (Hematoxylin and eosin stain, ×500.)
features have no detectable deposits but exhibit subendothelial accumulation of electron lucent “fluff” resembling
the changes in chronic thrombotic microangiopathies. Mild
mesangial proliferation and peripheral mesangial interposition are frequently seen. Sickled erythrocytes containing
paracrystalline inclusions may be identified within glomerular capillaries.788-792
In the second form of sickle glomerulopathy, FSGS occurs
in association with glomerulomegaly (Figure 33.48). Two
patterns of FSGS may be observed: a “collapsing” pattern
and an “expansive” pattern.781,784,793-795 Using the modern
classification of FSGS, collapsing, perihilar, tip, and not otherwise specified (NOS) variants have been reported.787 On
immunofluorescence, nonspecific IgM and C3 are seen in
sclerosed segments. In all these forms, there may be prominent intracapillary erythrocyte sickling and congestion.
PATHOGENESIS
The mechanism(s) for glomerular abnormalities in HbSS
patients is not fully understood. One theory proposes that
mesangial cells are activated by the presence of fragmented
red blood cells in glomerular capillaries. Activated mesangial cells promote synthesis of matrix proteins and migrate
into the peripheral capillary wall, leading to GBM reduplication.796 In another study, renal tubular epithelial antigens
and complement components were detected in a granular
pattern along the GBM, leading the authors to hypothesize
that glomerulonephritis was mediated by glomerular deposition of immune complexes containing renal tubular epithelial antigen and specific antibody to renal tubular
epithelial antigen (the antigen possibly released after
tubular damage secondary to decreased oxygenation and
hemodynamic alterations related to HbSS disease).788
In patients with the FSGS pattern, it is proposed that
there is an initial but progressive obliteration of the glomerular capillary bed by red blood cell sickling that cannot
be compensated by further glomerular hypertrophy. Hemodynamic glomerular injury ensues from the sustained or
increasing hyperfiltration in a diminishing capillary bed,
manifesting morphologically as the expansive pattern of
sclerosis.784,793 According to one report, the hyperfiltration
The treatment of renal disease has generally been unsatisfactory. Treatment of patients with sickle cell nephropathy
with ACEIs reduces the degree of proteinuria.784,800 However,
their effectiveness in preserving renal function remains to
be established.801 Hematopoietic stem cell transplantation
in selected patients with sickle cell disease was found to be
effective in preventing renal function decline compared to
nontransplanted patients.802
HbSS nephropathy accounts for 0.1% of ESKD patients
in the United States, with a higher mortality compared to
other causes of ESKD (including diabetes).803 Renal transplantation has been performed in HbSS patients. One-year
graft survival in HbSS patients was similar to other transplanted patients; however, long-term renal outcome was
worse, as was short- and long-term mortality.804 Transplanted
HbSS patients commonly experience sickle crises.805,806
Recurrent sickle cell nephropathy has been reported in the
transplanted kidney.794,807 Patient survival has improved
compared to previously, with survival rates comparable to
diabetic recipients.808
LIPODYSTROPHY
Lipodystrophies are rare diseases associated with insulin
resistance in which there is loss of fat, which may be localized to the upper part of the body in partial lipodystrophy
(PLD) or more diffuse in generalized lipodystrophy
(GLD).809,810
A majority of patients with GLD (both genetic and
acquired) are proteinuric and have an elevated GFR (reflecting hyperfiltration). Renal biopsy showed FSGS as the most
common finding, followed by MPGN type I and only rarely
diabetic nephropathy.811
PLD is commonly associated with dense deposit disease.
PLD most often presents in girls between ages 5 and 15
years. In addition to the loss of fat, the lipodystrophies
are associated with a wide variety of metabolic and
systemic abnormalities. Hyperinsulinism, insulin resistance,
and diabetes are common. Other metabolic abnormalities
include hyperlipidemia, hyperproteinemia, and euthyroid
hypermetabolism. Clinical findings may include tall
stature, muscular hypertrophy, hirsutism, macroglossia,
abdominal distension, subcutaneous nodules, acanthosis
nigricans, hepatomegaly, cirrhosis, clitoral or penile enlargement, febrile adenopathy, cerebral atrophy, cerebral
ventricular dilation, hemiplegia, mental retardation, and
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CHAPTER 33 — Secondary Glomerular Disease
cardiomegaly.809,810 Renal disease occurs in 20% to 50% of
patients with PLD,809,810 and PLD occurs in 10% of patients
with dense deposit disease.812,813 Patients usually have asymptomatic proteinuria and microhematuria, but some may
develop nephrotic syndrome.814,815 Diminished C3 levels in
association with the C3 nephritic factor (C3NeF) is the most
prominent serologic abnormality. The course of glomerular
disease is fairly rapid progression to ESKD, and the prognosis of PLD is determined mainly by renal disease.810
In GLD, nephrotic syndrome, nonnephrotic proteinuria,
and hypertension have been reported.809 A total of 88%
of these patients had albumin excretion greater than
30 mg/24 hr, 60% had macroalbuminuria (>300 mg/24 hr),
and 20% had nephrotic-range proteinuria greater than
3500 mg/24 hr.816
The pathogenesis of PLD and GLD is poorly understood.
Acquired forms of lipodystrophy are believed to be autoimmune disorders. Most patients with PLD possess an IgG
autoantibody, C3 nephritic factor (C3NeF), which binds
to and stabilizes the alternate pathway convertase C3
convertase–C3bBb. In the presence of C3NeF, C3bBb
becomes resistant to its regulatory proteins, factors H and
I. Although the majority of patients with partial dystrophy
have low serum C3, not all patients will exhibit nephritis.817
There is no effective therapy for PLD, and although renal
transplantation is the treatment of choice when ESKD
ensues, recurrence in transplants has been reported.810,818,819
In GLD, leptin therapy has been associated with improvement of renal parameters.820 A single GLD patient has
undergone renal transplantation.821
1147
Figure 33.49 Lecithin-cholesterol acyltransferase deficiency. The
glomerular basement membranes and mesangium have a vacuolated
appearance, resembling stage 3 membranous glomerulopathy.
(Jones’ methenamine silver stain, ×800.)
LECITHIN-CHOLESTEROL
ACYLTRANSFERASE DEFICIENCY
Gjone and Norum reported a familial disorder characterized by proteinuria, anemia, hyperlipidemia, and
corneal opacity.822,823 Most of the initial patients were of
Scandinavian origin; subsequently lecithin-cholesterol acyltransferase (LCAT) deficiency was reported from other
countries.824,825
CLINICAL FEATURES
The triad of anemia, nephrotic syndrome, and corneal
opacities suggests this disorder. Renal disease is a universal
finding with albuminuria noted early in life. Proteinuria
increases in severity during the fourth and fifth decades,
often with development of nephrotic syndrome. The latter
is accompanied by hypertension and progressive renal
failure. Most patients are mildly anemic with target cells and
poikilocytes on the peripheral smear. There is evidence of
low-grade hemolysis. During childhood, corneal opacities
appear as grayish spots over the cornea, accompanied by a
lipoid arcus. Visual acuity is unimpaired. Fish eye disease
results from a partial deficiency of LCAT and presents with
corneal disease and without renal manifestations. Patients
have reduced plasma high-density lipoprotein cholesterol
concentrations (usually <0.3 mmol/L; 11.6 mg/dL) and
plasma levels of apo A-I below 50 mg/dL. Premature atherosclerosis is unusual in complete LCAT deficiency but
may occur from unknown reasons in fish eye disease.826
Figure 33.50 Lecithin-cholesterol acyltransferase deficiency. Electron micrograph showing intramembranous lacunae with rounded
structures containing an electron-dense membranous core and
electron-lucent periphery. (×5000.)
PATHOLOGY
Abnormalities are found mainly in the glomeruli, but arteries and arterioles may also be affected.822,823,827,828 By light
microscopy (Figure 33.49), the glomerular capillary walls
are thickened and there is mesangial expansion. Basement
membranes are irregular and often appear to contain vacuoles, resembling stage 3 membranous alterations. Double
contouring of capillary walls is occasionally present. Similar
vacuoles in the mesangium impart a honeycomb appearance. There is no associated glomerular hypercellularity,
with the exception of occasional endocapillary foam cells.
By immunofluorescence microscopy, there is typically negative staining for all immunoglobulin and complement components. On electron microscopy (Figure 33.50), the
vacuolated areas seen by light microscopy correspond to
extracellular irregular lucent zones (lacunae) in the mesangial matrix and GBM containing lipid inclusions. These
inclusions consist of rounded, small, structures, either solid
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1148
SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
or with a lamellar substructure containing electron-lucent
and electron-dense zones.
PATHOGENESIS
The disorder is inherited in an autosomal recessive pattern.
Patients have little or no LCAT activity in their blood circulation because of mutations in the LCAT gene.829,830 LCAT is
an enzyme that circulates in the blood primarily bound to
high-density lipoprotein and catalyzes the formation of cholesteryl esters via the hydrolysis and transfer of the sn-2 fatty
acid from phosphatidylcholine to the 3-hydroxyl group of
cholesterol. Thus patients with LCAT deficiency have high
levels of phosphatidylcholine and unesterified cholesterol,
with corresponding low levels of lysophosphatidylcholine
and cholesteryl ester in the blood. An abnormal lipoprotein,
lipoprotein-X (Lp-X) is present in patients’ plasma. Lp-X is
thought to arise from the surface of chylomicron remnants
that are not further metabolized due to the absence of active
LCAT. Accumulation of lipid component occurs in both
intra- and extracellular sites. Lipid accumulation in the
GBM results in proteinuria. Endothelial damage and resulting vascular insufficiency may contribute to renal insufficiency. It has been proposed that Lp-X stimulates mesangial
cells, leading to the production of MCP-1 (monocyte chemoattractant protein-1), promoting monocyte infiltration,
foam cell formation, and progressive glomerulosclerosis in
a manner similar to atherosclerosis.831 Rarely, acquired autoimmune LCAT deficiency may occur, with renal biopsy findings similar to familial LCAT deficiency with coexisting
lesion of membranous nephropathy.832
DIAGNOSIS
In patients suspected of having LCAT deficiency, measurements of plasma enzyme should be performed. The enzyme
levels and activity vary among kindreds833; thus, enzyme
measurements should include activity as well as mass.
TREATMENT
Neither a low-lipid diet nor lipid-lowering drugs have shown
to be of benefit.827 Plasma infusions may provide reversal of
erythrocytic abnormalities, but long-term benefits have yet
to be demonstrated.834 The lesions may recur in the allograft,
but renal function is adequately preserved.835
LIPOPROTEIN GLOMERULOPATHY
Lipoprotein glomerulopathy (LPG) is characterized by dysbetalipoproteinemia and lipid deposition in the kidney,
leading to glomerulosclerosis and renal failure. The majority of patients have been from Japan.836,837
The histologic hallmark of LPG is the presence of laminated thrombi consisting of lipids within the lumina of
dilated glomerular capillaries. The pathogenesis of LPG is
unknown, but the presence of thrombi consisting of lipoproteins suggests a primary abnormality in lipid metabolism.838 Indeed type III hyperlipidemia (elevated LDL and
high apo E levels) have been reported in Japanese patients,
associated with apo E variants (commonly apo E-II as
opposed to apo E-III).837,839-843 Other genetic variants, such
as apo E (Las Vegas), have been reported in Caucasians of
European descent in the United States.844 Furthermore,
LPG-like deposits were detected in apo E–deficient mice
transfected with apo E (Sendai), one of the apo E variants
associated with LPG.
There is no uniformly effective therapy for LPG; however,
intensive lipid-lowering therapy has been reported to be
effective in one patient with LPG.845 Recurrence of lesions
of LPG have occurred in renal allografts.846,847
GLOMERULAR INVOLVEMENT WITH
BACTERIAL INFECTIONS
INFECTIOUS ENDOCARDITIS
The natural history of endocarditis-associated glomerulonephritis has changed significantly in parallel with the changing epidemiology of infectious endocarditis and the advent
of antibiotics.848 In the pre-antibiotic era, Streptococcus viridans was the commonest organism and glomerulonephritis
occurred in 50% to 80% of endocarditis cases.849 During
that era, glomerulonephritis was less common in association
with acute endocarditis.850,851 With the use of prophylactic
antibiotics in patients with valvular heart disease, and an
increase in intravenous drug use, Staphylococcus aureus has
replaced S. viridans as the primary pathogen. Glomerulonephritis in these patients with acute infectious endocarditis
occurs as commonly as in subacute endocarditis.849,852-854 The
incidence of glomerulonephritis with endocarditis with
S. aureus ranges from 22% to 78%,852,855 being higher in
those series consisting predominantly of intravenous drug
users.855,856
CLINICAL FEATURES
Renal complications of infectious endocarditis include
infarcts, abscesses, and glomerulonephritis (all of which
may coexist). In focal glomerulonephritis, mild asymptomatic urinary abnormalities, including hematuria, pyuria, and
albuminuria, may be noted. Infrequently, with severe focal
glomerulonephritis, renal insufficiency or uremia may be
present. Renal dysfunction, microhematuria or gross hematuria, and nephrotic-range proteinuria may be present with
diffuse glomerulonephritis.849,852,857 Rapidly progressive
renal failure with crescents has been reported.849,858 Rarely,
patients may present with vasculitic features (including
purpura).859 Although hypocomplementemia is frequent, it
is neither invariable (occurring in 60% to 90% of patients
with glomerulonephritis) nor specific for renal involvement.854,855 The majority of patients demonstrate activation
of the classical pathway.855,860 Alternate pathway activation
has been described in some cases of S. aureus endocarditis.855
The degree of complement activation correlates with the
severity of renal impairment,855 and the complement levels
normalize with successful therapy of the infection. Circulating immune complexes have been found in the serum in
up to 90% of patients.860,861 Mixed cryoglobulins and rheumatoid factor may also be present in the serum of
patients.854,862 ANCA positivity has been occasionally reported
in biopsy-proven immune complex glomerulonephritis associated with infectious endocarditis, some of which have
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CHAPTER 33 — Secondary Glomerular Disease
necrotizing and crescentic features.863 Anti-GBM antibody
in eluates from diseased glomeruli has been reported
rarely.864
PATHOLOGY
On light microscopy, focal and segmental endocapillary proliferative glomerulonephritis with focal crescents is the most
typical finding. Necrotizing lesions may be present. Some
patients may exhibit a more diffuse endocapillary proliferative and exudative glomerulonephritis with or without crescents.849,850,852,865,866 Immunofluorescence reveals granular
capillary and mesangial deposits of IgG and C3, C3 alone,
or varying combinations of IgM, IgG, and C3.849,852,865 The
finding of predominant IgM staining may be associated with
Bartonella endocarditis.867 Electron microscopy shows
electron-dense deposits in mesangial, subendothelial, and
occasionally subepithelial locations, with varying degrees of
mesangial and endocapillary proliferation.849,852,865,868 Rarely,
patients with endocarditis may be ANCA positive with renal
biopsy showing concomitant necrotizing lesions and proliferative lesions with relatively scant immune complex
deposition.869
PATHOGENESIS
The diffuse deposition of immunoglobulin, the depression
of complement, and electron-dense deposits supports an
immune complex mechanism for the production of this
form of glomerulonephritis. The demonstration of specific
antibody in kidney eluates and the detection of bacterial
antigen in the deposits further support this view. Both S.
aureus870 and hemolytic Streptococcus871 antigens have been
identified.
TREATMENT
With the initiation of antibiotic therapy, the manifestations
of glomerulonephritis begin to subside. Rarely, microhematuria and proteinuria may persist for years.849 Plasmapheresis and corticosteroids have been reported to promote
renal recovery in some patients with renal failure.858,872
However, this approach should be taken cautiously because
of the risk of promoting infectious aspects of the disease
while ameliorating the immunologic manifestations. Immunosuppression has also been used to treat patients with
concomitant ANCA and immune complex–associated
glomerulonephritis.869
SHUNT NEPHRITIS
Ventriculovascular (ventriculoatrial, ventriculojugular)
shunts (which are rarely used nowadays) for the treatment
of hydrocephalus were colonized commonly with micro­
organisms, particularly Staphylococcus albus (75%).873 Less
often, other bacteria (e.g., Propionibacterium acnes) have
been implicated.874,875 Ventriculoperitoneal shunts are more
resistant to infection. However, glomerulonephritis has
been reported with these shunts as well.876
Patients commonly present with fever. Anemia, hepatosplenomegaly, purpura, arthralgias, and lymphadenopathy
are found on examination. Renal manifestations include
hematuria (microscopic or gross), proteinuria (nephrotic
syndrome in 30% of patients), azotemia, and hypertension.
Laboratory abnormalities include presence of rheumatoid
1149
factor, cryoimmunoglobulins, elevated sedimentation rate
and CRP levels, hypocomplementemia, and presence of circulating immune complexes.877,878 Shunt nephritis usually
presents within a few months of shunt placement, but
delayed manifestations as late as 17 years have been
reported.879 By light microscopy, glomeruli exhibit mesangial proliferation or membranoproliferative pattern of
glomerulonephritis. Immunofluorescence reveals diffuse
granular deposits of IgG, IgM, and C3. IgM is often the
predominant Ig deposited in shunt nephritis. Electrondense mesangial and subendothelial deposits are found by
electron microscopy.875,880 Antibiotic therapy and prompt
removal of the infected catheter usually lead to remission
of the glomerulonephritis.881 However, cases progressing to
chronic renal failure have been reported.882 Rarely, patients
have elevated PR3-specific ANCA titers, which also improved
after removal of the infected shunt, with or without corticosteroid therapy.883
VISCERAL INFECTION
Visceral infections in the form of abdominal, pulmonary,
and retroperitoneal abscesses are known to be associated
with glomerulonephritis.884 The clinical and pathologic features of the syndrome resemble those of infective endocarditis. Beaufils and colleagues reported on 11 patients who
had visceral abscesses and in whom acute renal failure developed. Circulating cryoglobulins, decreased serum complement levels, and circulating immune complexes were found
in some of these patients. All renal biopsies showed a diffuse
proliferative and crescentic glomerulonephritis. The evolution of the glomerulonephritis, documented by serial biopsies, closely paralleled the course of the infection. A complete
recovery of renal function occurred in those cases in which
a rapid and complete cure of the infection was obtained.
For those patients in whom the infection was not cured or
in whom therapy was delayed, chronic renal failure also
developed.885 Outcome is worse in older patients and in
diabetics.848
OTHER BACTERIAL INFECTIONS AND
FUNGAL INFECTIONS
Congenital, secondary, and latent forms of syphilis rarely
may be complicated by glomerular involvement. Patients
are typically nephrotic, and proteinuria usually responds to
penicillin therapy.886-890 Membranous nephropathy with
varying degrees of proliferation and with granular IgG and
C3 deposits is the commonest finding on biopsies. Treponemal antigen and antibody have been eluted from deposits.
Rarely minimal change lesions891 and crescentic glomerulonephritis892 or amyloidosis may be seen.
Bartonella henselae is the organism responsible for bartonellosis (cat scratch disease), which typically manifests as a skin
papule followed by regional lymphadenopathy. Rarely, endocarditis, central nervous system involvement (encephalopathy), generalized skin rash, and the Parinaud oculoglandular
syndrome (fever, regional lymphadenopathy, and follicular
conjunctivitis) may occur. Renal manifestations are rare and
can include IgA nephropathy,893 postinfectious glomerulonephritis with IgM dominance,867,894 or necrotizing glomerulonephritis.895 In general, spontaneous recovery may occur
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1150
SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
with control of infection; however, end-stage renal failure has
been reported with aggressive renal disease.895
Renal involvement, including azotemia, proteinuria,
nephrotic syndrome, renal tubular defects, and hematuria,
is not uncommon in leprosy, especially with the lepra
reaction.896-901 Rarely, patients present with RPGN902 or
ESKD.903 Mesangial proliferation, diffuse proliferative glomerulonephritis, crescentic glomerulonephritis, membranous nephropathy, MPGN, microscopic angiitis, and
amyloidosis may all be seen in kidney biopsies. Organisms
consistent with Mycobacterium leprae have been found in
glomeruli.
Aspergillosis has been associated with immune complex–
mediated glomerulonephritis.904 Membranous nephropathy, MPGN, crescentic glomerulonephritis, and amyloidosis
have been associated with Mycobacterium tuberculosis.905,906-908
Mycoplasma has been reported to be associated with
nephrotic syndrome and RPGN. Antibiotics do not seem to
alter the course of the disease. Mycoplasmal antigen has
been reported to be present in the glomerular lesions.909-913
Acute glomerulonephritis with hypocomplementemia has
been reported with pneumococcal infections. Proliferative
glomerulonephritis with deposition of IgG, IgM, complements C1q, C3, and C4, and pneumococcal antigens have
been observed in renal biopsies.914,915 Nocardiosis has been
associated with mesangiocapillary glomerulonephritis.916 In
infections with Brucella, patients may present with hematuria, proteinuria (usually nephrotic), and varying degrees of
renal functional impairment. There usually is improvement
after antibiotics, but histologic abnormalities, proteinuria,
and hypertension may persist. Glomerular mesangial proliferation, focal and segmental endocapillary proliferation,
diffuse proliferation, and crescents may be found in renal
biopsies. Immunofluorescence may show no deposits, IgG,
or occasionally IgA.917-921 Asymptomatic urinary abnormalities may be seen in up to 80% of patients infected with
Leptospira. Patients usually present with acute renal failure
due to tubulointerstitial nephritis. Rarely, mesangial or
diffuse proliferative glomerulonephritis may be seen.922,923
From 1% to 4% of patients with typhoid fever secondary to
Salmonella experience glomerulonephritis. Asymptomatic
urinary abnormalities may be more frequent. Renal manifestations are usually transient, resolving within 2 to 3 weeks.
Serum C3 may be depressed. Mesangial proliferation with
deposits of IgG, C3, and C4 is the commonest finding. IgA
nephropathy has also been reported.924-926
GLOMERULAR INVOLVEMENT WITH
PARASITIC DISEASES
MALARIA
Four strains of malaria parasite cause human disease: Plasmodium vivax, Plasmodium falciparum, Plasmodium malariae
(causing quartan malaria), and Plasmodium ovale. Of these,
renal involvement has been extensively documented and
studied in P. malariae and P. falciparum. In P. falciparum
malaria, clinically overt glomerular disease is uncommon.
Asymptomatic urinary abnormalities may occur with
subnephrotic-range proteinuria and hematuria or pyuria.
Renal function is usually normal. Renal biopsies show
mesangial proliferation or membranoproliferative lesions.927
Severe malaria may be manifest with hemoglobinuric acute
renal failure.928 In initial reports, quartan malaria was
strongly associated with nephrotic syndrome in infected
children. There was progression to end-stage renal failure
within 3 to 5 years with no improvement following antimalarial treatment or steroids.929 Renal biopsies in Ugandan
adults and children with quartan malaria showed some form
of proliferative glomerulonephritis (diffuse, focal, lobular,
or minimal). Membranous nephropathy had also been
described in these patients.930 However, in Nigerian children, the most common lesion was a localized or diffuse
thickening of glomerular capillary walls with focal or generalized double-contouring and segmental glomerular sclerosis.931 Immunofluorescence examination revealed deposits
of IgG, IgM, C3, and P. malariae antigen in the glomeruli.
By electron microscopy, electron-dense material was
observed within the irregularly thickened GBM.932 Of note,
a recent report from endemic areas in Nigeria has not
found any cases of childhood nephrotic syndrome associated with quartan malaria.933 The propensity of malaria to
cause glomerular disease may be related to impaired clearance of immune complexes owing to reduced expression of
complement receptor 1 (CR1) on monocytes/macrophages
by the parasite. CR1 binds complement-bound immune
complexes, which is critical to their clearance from the
circulation.934
SCHISTOSOMIASIS
Schistosomiasis is a visceral parasitic disease caused by the
blood flukes of the genus Schistosoma. Schistosoma mansoni
and Schistosoma japonicum cause cirrhosis of the liver and
Schistosoma hematobium causes cystitis. Glomerular involvement in S. mansoni includes mesangial proliferation, focal
sclerosis, membranoproliferative lesions, crescentic changes,
membranous nephropathy, amyloidosis, and eventually endstage kidney disease.935-937 Schistosomal antigens have been
demonstrated in renal biopsies in such patients.938 Treatment with antiparasitic agents does not appear to influence
progression of renal disease.939 S. hematobium is occasionally
associated with nephrotic syndrome, which may respond to
treatment of the parasite.935 In some patients with schistosomiasis, renal involvement may be related to concomitant
Salmonella infection.940
LEISHMANIASIS, TRYPANOSOMIASIS,
AND FILARIASIS
Leishmaniasis, also known as kala-azar, is caused by Leishmania donovani. Renal involvement in kala-azar appears to be
mild and reverts with anti-leishmanial treatment. Renal
biopsies show glomerular mesangial proliferation or focal
endocapillary proliferation. IgG, IgM, and C3 may be
observed in areas of proliferation. Amyloidosis may also
complicate kala-azar.941,942 In trypanosomiasis, Trypanosoma
brucei, Trypanosoma gambiense, and Trypanosoma rhodesiense
cause African sleeping sickness and have rarely been associated with proteinuria.943 Filariasis is caused by organisms in
the genera Onchocerca, Brugia, Loa, and Wuchereria. Hematuria and proteinuria (including nephrotic syndrome) have
been described. Renal manifestations may appear with
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CHAPTER 33 — Secondary Glomerular Disease
treatment of infection. Renal biopsy findings have included
mesangial proliferative glomerulonephritis with C3 deposition, diffuse proliferative glomerulonephritis, and collapsing glomerulopathy with loiasis.944-949 In patients with
lymphatic filariasis of the renal hilus, chyluria (the passage
of milky white urine containing lymphatic fluid) may mimic
nephrotic syndrome by producing nephrotic-range proteinuria but is distinguished by the absence of hypoalbuminemia or glomerular disease on biopsy.950
OTHER PARASITIC DISEASES
Trichinosis, caused by Trichinella spiralis, may be associated
with proteinuria and hematuria, which abated after specific
treatment. Renal biopsies in patients with loiasis have shown
mesangial proliferative glomerulonephritis with C3 deposition.951,952 Echinococcus granulosus and Echinococcus multilocularis cause hydatid disease, or echinococcosis, in humans.
Mesangiocapillary glomerulonephritis and membranous
nephropathy have occasionally been associated with hepatic
hydatid cysts.953,954 Toxoplasmosis may be associated with
nephrotic syndrome in infants and, rarely, in adults. Mesangial and endothelial proliferation may be found, with deposition of IgG, IgA, IgM, C3, and fibrinogen in areas of
proliferation.955-957
GLOMERULAR INVOLVEMENT WITH
VIRAL INFECTIONS
Viruses have been postulated to cause glomerular injury by
various mechanisms, including direct cytopathic effects, the
deposition of immune complexes, or by initiation of autoimmune mechanisms.
In a study of previously healthy people with nonstreptococcal upper respiratory infections, 4% had erythrocyte
casts and glomerulonephritis on biopsy. A reduction in
serum complement and serologic evidence of infection with
adenovirus, influenza A, or influenza B were observed in
some. Initial renal biopsy showed either focal or diffuse
mesangial proliferation in all nine specimens, with mesangial C3 deposits in six specimens. Sequential creatinine
clearances were reduced in about half these patients during
follow-up.958
Nephrotic syndrome has been described with EpsteinBarr virus (EBV) infections.959 Renal biopsies in patients
with urinary abnormalities have shown immune complex–
mediated glomerulonephritis with tubulointerstitial nephritis,960 minimal glomerular lesions with IgM deposition,961
membranous nephropathy,962 and widespread glomerular
mesangiolysis sometimes admixed with segmental mesangial sclerosis.963 In addition, the presence of EBV DNA in
the glomerulus is thought to worsen glomerular damage in
chronic glomerulopathies.964 Other viruses have rarely been
associated with glomerulonephritis, including herpes zoster,
mumps, adenovirus, echovirus, coxsackievirus, and influenza A and B.965
HIV-RELATED GLOMERULOPATHIES
An estimated 35.3 million people are living with HIV worldwide, with more than 2 million new infections appearing
1151
each year.966 A variety of glomerular lesions—and in particular, a unique form of glomerular damage, HIV-associated
nephropathy (HIVAN)—are associated with HIV-infected
patients.967,968 Following the introduction of combination
antiretroviral therapy (cART) in 1996, patients with acquired
immunodeficiency syndrome (AIDS) are living longer with
a concomitant change in the epidemiology of renal diseases.969 The incidence of ESKD from HIVAN appears to
have plateaued at 800 to 900 new cases each year, with an
accompanying rise in prevalence on account of patients
surviving longer because of cART.672 Corresponding to this
observation, the histologic diagnosis of HIVAN decreased
from 80% to 20% from 1997 to 2004 in HIV-infected
patients. However, in resource-poor countries, HIVAN
remains a common cause of ESKD.969
HIV-ASSOCIATED NEPHROPATHY
CLINICAL FEATURES
In 1984, the first detailed account of a new pattern of
sclerosing glomerulopathy in HIV-infected patients was
reported.970 Subsequent studies largely from large urban
centers confirmed the occurrence and described the features of HIVAN.970-980 In these largely urban East Coast
centers, the prevalence of HIVAN approached 90% in
nephrotic HIV-positive patients in contrast to a prevalence
of only 2% in San Francisco where most seropositive patients
were white homosexuals.981-983
There is a strong predilection for HIVAN among black
HIV-infected patients. The black-to-white ratio among
patients with HIVAN is 12 : 1.984 HIVAN is the third leading
cause of ESKD among black Americans aged 20 to 64, following diabetes and hypertension.977,985 Racial factors may
influence rates of mutations in HIV receptors, which may
in part explain some differences in the racial predisposition
to HIV infection and HIVAN.986-988 Mapping by admixture
linkage disequilibrium has linked HIVAN and sporadic
FSGS to variants in the MHY9 gene and in a subsequent
study showed a stronger association to the closely linked
APOL1 gene on chromosome 22, thereby explaining most
of the strong black racial predominance in these
conditions.989,990
Although intravenous drug use has been the most
common risk factor for HIVAN, the disease has been seen
in all groups at risk for AIDS, including homosexuals, perinatally acquired disease, heterosexual transmission, and
exposure to contaminated blood products.967 HIVAN usually
occurs in patients with a low CD4 count, but full-blown AIDS
is certainly not a prerequisite for the disease. In one New
York study, the onset of HIVAN was most common in otherwise asymptomatic HIV-infected patients (i.e., 12 of 26 were
asymptomatic patients).970,974 There is no relationship
between the development of HIVAN and patient age and
duration of HIV infection or types of opportunistic infections or malignancies.967 The prevalence of HIVAN in
patients who test positive for HIV is reported to be 3.5% in
patients screened in the clinic setting991; the same investigative group reported that HIVAN was found in 6.9% of autopsies in HIV-infected patients.992
The clinical features of HIVAN include presenting features of proteinuria (typically in the nephrotic range and
often massive) and renal insufficiency. Other manifestations
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1152
SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
Figure 33.51 HIV-associated nephropathy. Glomeruli have collapsed tufts with capping of the overlying podocytes and dilation of
the urinary space. The tubules are dilated, forming microcysts with
abundant proteinaceous casts. (Periodic acid–Schiff stain, ×125.)
Figure 33.52 HIV-associated nephropathy. The characteristic
pattern of collapsing glomerular sclerosis is depicted. Glomerular
capillary lumens are occluded by wrinkling and retraction of the glomerular capillary walls associated with marked hypertrophy and
hyperplasia of the visceral epithelial cells, forming a pseudocrescent.
(Periodic acid–Schiff stain, ×325.)
of nephrotic syndrome, including edema, hypoalbuminemia, and hypercholesterolemia, have been common in
some series but less so in others despite the heavy proteinuria.967,970,973,974,978,980,993 Likewise, the incidence of hypertension has been variable even in patients with severe renal
failure. Some patients, however, present with subnephroticrange proteinuria and urinary sediment findings of microhematuria and sterile pyuria.994 The renal sonograms in
HIVAN show echogenic kidneys with preserved or enlarged
size with an average of larger than 12 cm in spite of the
severe renal insufficiency.974,978 Echogenicity may correlate
with the histopathologic tubulointerstitial changes better
than the glomerular changes.978
PATHOLOGY
The term HIVAN is reserved for the characteristic light
microscopy pattern of FSGS of the “collapsing” type with
retraction of the glomerular capillary walls and luminal
occlusion either in a segmental or global distribution968,972,995
(Figure 33.51). There is striking hypertrophy and hyperplasia of the visceral epithelial cells, which form a cellular
crown over the collapsed glomerular lobules (Figure 33.52).
In one study analyzing the expression pattern of podocyte
differentiation and proliferation markers, there was disappearance of all podocyte differentiation markers from
collapsed glomeruli, associated with cell proliferation, suggesting that the podocyte phenotype is dysregulated.996 Subsequent studies have emphasized the proliferation of
parietal epithelial cells to replace lost podocytes.997 Patients
with HIVAN have a higher percentage of glomerular collapse, less hyalinosis, and greater visceral cell swelling than
patients with classic idiopathic FSGS or heroin nephropathy
even when matched for serum creatinine and degree of
proteinuria.972 The tubulointerstitial disease is also more
severe in HIVAN, including tubular degenerative and regenerative features, interstitial edema, fibrosis, and inflammation.968,972 Tubules are often greatly dilated into microcysts
containing proteinaceous casts (see Figure 33.51). By immunofluorescence, IgM and C3 are present; however, by electron microscopy, immune deposits are not detected (Figure
33.53). In almost all biopsies of untreated HIVAN, there are
Figure 33.53 HIV-associated nephropathy. Electron micrograph
showing wrinkling of glomerular basement membranes with marked
podocyte hypertrophy, complete foot process effacement, and
numerous intracytoplasmic protein resorption droplets. (×2500.)
numerous tubuloreticular inclusions within the glomerular
and vascular endothelial cells (Figure 33.54).967,968,972,995
These 24-nm interanastomosing tubular structures are
found within the dilated cisternae of the endoplasmic reticulum. Of note, patients who develop HIVAN while receiving
cART usually lack collapsing features but display classic
FSGS lesions on biopsy.998
PATHOGENESIS
Experimental evidence strongly supports a role for direct
HIV-1 infection of renal parenchymal cells. By in situ hybridization, HIV-1 RNA was detected in renal tubular epithelial
cells, glomerular epithelial cells (visceral and parietal), and
interstitial leukocytes.999 Renal epithelial cells may be an
important reservoir for HIV because HIV RNA was found
in the kidney of patients with undetectable viral loads in
peripheral blood.999 Moreover, HIV-infected tubular epithelium can support viral replication, as evidenced by the
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CHAPTER 33 — Secondary Glomerular Disease
1153
COURSE AND TREATMENT
Figure 33.54 HIV-associated nephropathy. Electron micrograph
showing a typical tubuloreticular inclusion within the endoplasmic
reticulum of a glomerular endothelial cell. (×6000.)
detection of different HIV quasispecies in kidney epithelial
cells compared to peripheral blood mononuclear cells of
the same patient.1000
A replicative-deficient transgenic mouse model of HIVAN
has been developed with lesions identical to HIV nephropathy,1001-1003 suggesting that expression of viral gene products
in renal epithelium underlies the development of
nephropathy.
The lesions of collapsing glomerulopathy are associated
with podocyte proliferation and dedifferentiation.996 The
expression of two cyclin-dependent kinase inhibitors (which
regulate cell cycle), p27 and p57, were decreased in podocytes from HIVAN biopsies while expression of another
inhibitor, p21, was increased.1004 The specific HIV gene(s)
required to produce these changes have been investigated.
The nef gene (which is thought to act by activation of tyrosine kinases) was found to be essential in producing HIVinduced changes in podocyte cultures1005 and in one murine
model of HIVAN.1006 There appears to be a synergistic
role for nef and vpr on podocyte dysfunction and progressive
glomerulosclerosis.1007 Vpr has a role in G2 cell cycle
arrest and possibly the induction of apoptosis.1008 There are
several other abnormalities seen in the podocyte that are
associated with an immature phenotype and subsequent loss
of podocyte function. Synthesis of retinoic acid (an important differentiation factor) is impaired, associated with
reduced expression of the enzyme retinol dehydrogenase
9.1009 The expression of TERT, a telomerase protein, is
increased in HIVAN podocytes. TERT increases upregulation of the Wnt pathway, which also is associated with podocyte dedifferentiation. Suppressing TERT or Wnt signaling
led to amelioration of podocyte lesions.1010
The APOL1 gene, which encodes apolipoprotein L-1, in
a recessive model, is associated with a 29-fold higher odds
for HIVAN in black patients. The lifetime risk of developing
HIVAN is 50% in untreated HIV-infected black patients with
two APOL1 risk alleles.1011 Furthermore, the majority of
patients with two APOL1 risk alleles had FSGS on kidney
biopsies, whereas with one or no risk alleles, immune
complex glomerulonephritis was more common.1012 The
mechanism whereby APOL1 variants associate with HIVAN
is currently unknown.
The natural history of HIVAN during the early part of the
AIDS epidemic was characterized by rapid progression to
ESKD. Case series from the United States that were published during the years that HIVAN was first described demonstrated an almost universal requirement for dialysis within
1 year of diagnosis.970 The role of combined antiviral therapies and the use of newer agents in the treatment of HIVAN
have been associated with beneficial effects.998,1013-1015 The
development of HIVAN is now considered an indication for
antiretroviral therapy. Corresponding to the introduction of
highly active antiretroviral therapy (HAART), the rise in
new cases of ESKD due to HIVAN slowed markedly.1016
There have been a few studies using corticosteroids in
HIVAN. In an early study, prednisone was not associated
with improvement in children with HIVAN.1017,1018 Remissions in HIV-infected children with the minimal change
pattern (seen on biopsy) who were treated with steroids
have been noted but not in children with sclerosing or collapsing lesions.967 In adults, however, several retrospective
studies have shown short-term improvement in clinical
parameters.1019-1021
Three pediatric patients with HIVAN on biopsy had sustained remissions of nephrotic syndrome when treated with
cyclosporine.1017 They eventually developed opportunistic
infections, requiring the cyclosporine to be discontinued
and subsequently experienced relapses of the nephrotic
proteinuria and renal failure.
In isolated patients and in several small trials, use of
ACEIs has been shown to decrease proteinuria in HIVAN
and to slow the progression to renal failure.1022-1024 Serum
angiotensin-converting enzyme levels are elevated in HIV
patients, and ACEIs may prevent proteinuria and glomerulosclerosis by either hemodynamic mechanisms or through
modulation of matrix production and mesangial cell proliferation or even by affecting HIV protease activity.1022-1024
Although some of these studies used control groups of
untreated HIV patients of similar age, sex, race, and degree
of renal insufficiency and proteinuria, the studies were not
randomized, blinded trials. Nevertheless, in each study the
ACEI-treated group had less proteinuria, less rise in serum
creatinine, and less progression to ESKD.
At present the therapy of HIVAN should include use of
multiple antiviral agents as in HIV-infected patients without
nephropathy. Use of ACEIs or perhaps angiotensin II receptor blockers, with careful attention to hyperkalemia and
acute rises in the serum creatinine, may be beneficial.
Several studies have documented favorable outcomes in
HIVAN patients who received renal transplants.1025-1027 The
current opinion is that renal transplantation is no longer a
contraindication in HIV-positive patients who have undetectable viral loads and a CD4 count greater than 200
cells/µL for at least 6 months.1028
OTHER GLOMERULAR LESIONS IN PATIENTS
WITH HIV INFECTION
In the pre-HAART era, HIVAN was the most common form
of glomerulopathy found in HIV-infected patients, but other
lesions had been reported as well. In one series of more
than 100 biopsies for glomerular disease in HIV-positive
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1154
SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
patients, 73% were classic HIVAN, but other lesions included
MPGN in 10%, minimal change disease in 6%, amyloid in
3%, lupus-like nephritis in 3%, acute postinfectious glomerulonephritis in 2%, membranous nephropathy in 2%,
and 1% each of focal and segmental necrotizing glomerulonephritis, thrombotic microangiopathy, IgA nephropathy,
and immunotactoid nephropathy.968 Collapsing FSGS is
most common in urban centers with large black populations, while higher rates of immune complex glomerulonephritis are found in other cities and especially among
European white populations.1029,1030 In a study from Paris,
immune complex glomerulonephritis was found in more
than 50% of the white HIV-seropositive patients but in only
21% of the blacks.1029,1030 Likewise, in a study from northern
Italy of 26 biopsies on HIV-infected patients, most cases were
of immune complex glomerulonephritis but none of classic
HIVAN.1031 In the present era with the availability of HAART,
a renal biopsy in an HIV-positive patient with viral loads of
less than 400 copies/mL is more likely to show hypertensive
nephrosclerosis1032 or diabetic nephropathy.1033
IgA nephropathy has been reported in a number of investigative series of HIV-infected patients.1034-1038 This has
occurred in both whites and blacks despite the rarity of
typical IgA nephropathy in black populations. The clinical
features usually include hematuria, proteinuria, and some
renal insufficiency. Cases with leukocytoclastic angiitis of the
skin (consistent with HSP) have also been noted. The histology shows a variety of changes from mesangial proliferative
glomerulonephritis to collapsing glomerulosclerosis with
mesangial IgA deposits. IgA anti-HIV immune complexes
have been eluted from the kidneys of several such patients,
and several patients have had circulating immune complexes containing IgA idiotypic antibodies directed against
viral proteins, either anti-HIV p24 or HIV gp41.1037
MPGN may be the most common pattern of immune
complex–mediated glomerulonephritis seen in HIV-infected
patients. Two series document a high occurrence in intravenous drug abusers coinfected with HIV and HCV.1039,1040 Most
patients have had microscopic hematuria, nephrotic-range
proteinuria, and renal insufficiency at biopsy. Cryoglobulins
are commonly positive, as is hypocomplementemia, and
some have had both HBV and HCV infection. The pathology
of the glomerulopathy may be similar to idiopathic MPGN
type I or type III although some patients also have segmental
membranous or mesangioproliferative features.1041
A lupus-like immune complex glomerulonephritis has
been reported in a number of patients.977,1042-1045 Most of
these patients have had positive serology for SLE with positive ANA, anti-DNA, and low complement levels. This contrasts with a low incidence of ANA positivity and almost no
anti-DNA positivity in the general HIV-infected population.1046 These patients are generally treated with corticosteroids with or without mycophenolate and concomitant
HAART therapy. The results have been variable.1045
An occasional association in both white and black HIVinfected patients has been TTP. Most have been in an
advanced stage of HIV infection and had renal involvement
with hematuria, proteinuria, and variable renal insufficiency. Other typical findings of TTP, such as fever, neurologic symptoms, thrombocytopenia, and microangiopathic
hemolytic anemia, are often present. The initiation/
reinitiation of cART and plasma exchange with or without
adjunctive immunosuppression can lead to remission.1047
ADAMTS13 may be decreased (as in idiopathic TTP) and
may be associated with a better prognosis.1048 Other entities
such as malignant hypertension, angioinvasive infections
such as Kaposi’s sarcoma, and direct HIV-associated hemolytic uremic syndrome need to be excluded.1049
GLOMERULAR MANIFESTATIONS
OF LIVER DISEASE
HEPATITIS B
Hepatitis B antigenemia has been associated with glomerulonephritis for more than 30 years. Hepatitis B has a worldwide distribution. In countries where the virus is endemic
(sub-Saharan Africa, Southeast Asia, and Eastern Europe),
there is vertical transmission from mother to infant and
horizontal transmission between siblings. Hepatitis B–
associated nephropathy occurs in these children with a 4 : 1
male preponderance.1050-1052 In the United States and
Western Europe, where hepatitis B is acquired by parenteral
routes or sexually, the nephropathy affects mainly adults
and has a different clinical course from the endemic
form.1053-1055 However, hepatitis B–associated nephropathy is
rare in hepatitis B carriers.1056 PAN has also been associated
with hepatitis B.1057
CLINICAL FEATURES
Most patients present with proteinuria or nephrotic syndrome. In endemic areas, there may not be a preceding
history of hepatitis. The majority of patients have normal
renal function at time of presentation. There may be urinary
erythrocytes, but the majority have a bland sediment. Liver
disease may be absent (carrier state) or chronic, and clinically mild. Serum aminotransferases may be normal or modestly elevated (between 100 and 200 IU/L). Liver biopsies
in these patients often show chronic active hepatitis. Some
patients ultimately develop cirrhosis. There is often spontaneous resolution of the carrier state with resolution of renal
abnormalities. Spontaneous resolution of HBV-associated
nephropathy is particularly common in children from
endemic areas. The probability of a spontaneous remission
may be as high as 80% after 10 years.1058,1059
PATHOLOGY
Most cases of hepatitis B–associated nephropathy manifest
membranous nephropathy, although mesangial proliferation and sclerosis have also been reported.1050,1051,1053-1055,1060,1061
In a cohort of Chinese patients with membranous nephropathy, HBV was found in 12%. There are fewer reports of
MPGN with mesangial cell interposition, reduplication of
the GBM, and subendothelial glomerular deposits.1053,1055,1060
In a few series, cases of type III MPGN have been reported
in which there are electron-dense subepithelial deposits in
addition to the changes seen in type I MPGN.1055 Crescentic
glomerulonephritis in association with membranous
changes and primary crescentic glomerulonephritis have
also been described.1062,1063
The glomerular lesions appear to be immune complex
mediated. HBsAg, HBcAg, and HBeAg1064 have all been
demonstrated in glomerular lesions, as has HBV DNA.1052,1065
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CHAPTER 33 — Secondary Glomerular Disease
1155
TREATMENT
In children with the mild endemic form of hepatitis B–
associated nephropathy, no treatment other than supportive
care is advocated. In patients with progressive renal dysfunction, interferon has been used with mixed results.1066-1069
Steroids that do not significantly improve proteinuria may
potentially enhance viral replication.1070,1071 Nucleoside
analogs, including lamivudine, telbivudine, adefovir, entecavir, or tenofovir, that suppress HBV replication by inhibiting viral DNA polymerase have demonstrated clinical utility
in treating hepatitis B infection; lamivudine was shown to
reduce proteinuria and lead to a lesser incidence of ESKD
in 10 patients with hepatitis B–associated nephropathy.1072
Preemptive lamivudine therapy in renal transplant recipients has shown improved survival compared to historical
controls.1073,1074 A recent meta-analysis confirmed that corticosteroids did not ameliorate proteinuria, but antiviral
therapy was associated with HBeAg clearance and improvement of proteinuria.1075 Current recommendations for HBV
treatment discourage the use of lamivudine in view of a high
rate of drug resistance; tenofovir, entecavir, and pegylated
interferon alfa-2a are suggested.1076 However, there are no
data on the response of hepatitis B–related glomerulonephritis to these newer regimens.
Figure 33.55 Hepatitis C–associated membranoproliferative glomerulonephritis type I. The mesangium is expanded by global mesangial hypercellularity associated with numerous double contours of the
glomerular basement membranes. (Periodic acid–Schiff stain, ×500.)
HEPATITIS C
Renal disease associated with HCV infection includes MPGN
with or without associated mixed cryoglobulinemia and
membranous glomerulopathy. The MPGN is most often
type I, with fewer cases of type III.1077-1079 Rare cases of diffuse
proliferative and exudative glomerulonephritis, polyarteritis, and fibrillary and immunotactoid glomerulopathy have
also been described in association with HCV.1080,1081 Most
patients have evidence of liver disease as reflected by elevated plasma transaminase levels. However, transaminase
levels are normal in some cases and a history of acute hepatitis is often absent.
PATHOGENESIS
The pathogenesis of HCV-related nephropathies is immune
complex mediated. A clonal expansion of B cells secreting
IgM rheumatoid factors has been seen in patients with
chronic HCV infection. HCV-specific proteins have been
isolated from glomerular lesions.1082 The disappearance of
viremia in response to interferon (see later) is associated
with a diminution of proteinuria; a relapse of viremia is
accompanied by rising proteinuria.
CLINICAL AND PATHOLOGIC FEATURES
Mixed cryoglobulinemia is associated with HCV and may
cause systemic vasculitis; patients may exhibit constitutional
systemic symptoms, palpable purpura, peripheral neuropathy, and hypocomplementemia. The renal manifestations
include hematuria, proteinuria (often in the nephrotic
range), and renal insufficiency. The histologic findings
resemble those in idiopathic MPGN type I or type III
(Figures 33.55 and 33.56) except for intraluminal protein
“thrombi” on light microscopy and the organized annulartubular substructure of the electron-dense deposits on electron microscopy. Prior to the advent of hepatitis C serologic
Figure 33.56 Hepatitis C–associated membranoproliferative glomerulonephritis (MPGN) type III. There are mixed features of MPGN
type I (with mesangial proliferation and duplication of glomerular
basement membrane [GBM]) and membranous glomerulopathy (with
GBM spikes). (Jones’ methenamine silver stain, ×325.)
tests, mixed cryoglobulinemia was considered an idiopathic
disease (“essential” mixed cryoglobulinemia). Up to 95% of
these patients show signs of HCV infection.1083 Few patients
with thrombotic microangiopathy associated with cryoglobulinemia have been described.1084 MPGN without associated
cryoglobulinemia may occur but is much less common.1078
Rarely, membranous nephropathy may be associated with
HCV infection. Patients present with nephrotic syndrome
or proteinuria. Complement levels tend to be normal, and
neither cryoglobulins nor rheumatoid factors are present in
HCV-associated membranous nephropathy.1085 Now that
staining for phospholipase A2 receptor (PLA2R), the major
target antigen in primary membranous nephropathy, is
being performed on renal biopsies, it has become evident
that some HCV-infected patients with membranous
nephropathy actually have a primary form.1086
Both type I MPGN (with and without cryoglobulinemia)
and membranous nephropathy may recur in the allograft
after renal transplantation, sometimes leading to graft
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1156
SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
loss.1087-1090 Similar lesions have occurred in native kidneys
after liver transplantation in HCV-positive patients.1091,1092
TREATMENT
The treatment of HCV-associated renal disease is limited to
case reports and small randomized trials.1093 Although a
number of early reports demonstrated a beneficial response
to α-interferon therapy,1085,1094,1095 cessation of interferon
therapy was associated with recurrence of viremia and cryoglobulinemia in a majority of patients in these studies. Interferon therapy may paradoxically exacerbate proteinuria and
hematuria that appears to be unrelated to viral antigenic
effects.1096 Currently combination therapy with ribavirin and
pegylated interferon is considered to be standard therapy
for HCV.1097 Combination therapy appeared to improve biochemical parameters of renal dysfunction in 20 HCVglomerulonephritis patients, which was not accompanied by
a significant virologic response.1098 Another report on 18
patients showed sustained virologic responses in two thirds
of patients, a finding that was associated with improvement
in renal parameters.1099 Combination therapy (especially
ribavirin) may not be well tolerated in the presence of significant renal dysfunction.1100 Interferon alfa treatment of
renal transplant patients with HCV has been associated with
acute renal failure1101 and acute humoral rejection1102 and
is not recommended. Recent groundbreaking trials using
interferon-free oral direct antiviral regimens have shown
dramatic sustained viral remission rates over the short
term.1103
In patients with symptomatic cryoglobulinemia, immunosuppressive therapy may provide symptomatic relief prior to
the use of antiviral therapy. Cyclophosphamide treatment
has been used successfully in HCV-glomerulonephritis,1104
even if interferon resistant.1105 Cyclophosphamide treatment may be associated with a temporary, reversible increase
in viral load and a change of quasispecies.1106 Fludarabine
has been reported to decrease proteinuria in HCV-associated
cryoglobulinemic MPGN.1107 Rituximab has been associated
with remissions of proteinuria in HCV-glomerulonephritis.1108-1110 In renal transplant patients with HCV-glomerulonephritis, similar improvements in renal parameters have
been reported, albeit with a higher incidence of infectious
complications.1111 It has been suggested that in patients with
moderate proteinuria and slowly progressive renal dysfunction, interferon with or without ribavirin should be considered. When there is an acute flare of disease with nephrotic
proteinuria or RPGN, treatment with plasma exchange and
immunosuppressive drugs (rituximab or cyclophosphamide, with corticosteroids) followed by antiviral therapy
may be considered.1093
AUTOIMMUNE CHRONIC ACTIVE HEPATITIS
Autoimmune chronic hepatitis is a distinctive progressive
necrotic and fibrotic disorder of the liver with clinical and/
or serologic evidence of a generalized autoimmune disorder.1112 Two distinct clinical lesions have been associated
with this disorder: glomerulonephritis and interstitial
nephritis. Patients with the glomerular lesion present with
nephrotic syndrome or renal insufficiency. On renal biopsy
they have membranous glomerulonephritis or MPGN. In
two patients with membranous nephropathy, circulating
Figure 33.57 Hepatic glomerulopathy. A paramesangial electrondense deposit corresponding to immune staining for IgA is seen. In
addition, there are irregular lucencies containing dense granular and
rounded membranous structures within the mesangial matrix and
extending into the subendothelial space. (×6000.)
immune complexes containing U1RNP (ribonucleoprotein) and IgG have been reported. Eluates from the kidney
tissue revealed higher concentrations of anti-U1RNP antibody. It is not known whether immunosuppressive therapy
ameliorates the renal disorder.1112 It is unclear if coexistent
HCV infection had been present in many of these patients.
LIVER CIRRHOSIS
Glomerulonephritis is a rare manifestation of liver cirrhosis.
Glomerular morphologic abnormalities with IgA deposition
have been noted in more than 50% of patients with cirrhosis
at both necropsy and biopsy,1113,1114 although this has also
been found in some autopsies of noncirrhotic kidneys.1115
Clinically, there may be mild proteinuria and/or hematuria.
There are two patterns on histology: a mesangial sclerosis
(“cirrhotic glomerular sclerosis”) or MPGN. The latter
may be associated with more severe renal symptoms and a
depression of serum complement C3 levels.1116 Again, it is
unclear if some patients had coexistent HCV infection.
Rarely, HSP with RPGN has been described in association
with cirrhosis.1117
Renal biopsies of patients with cirrhosis on light microscopy show an increase in mesangial matrix with little or no
increase in mesangial cellularity, a lesion known as “hepatic
glomerulopathy.” Less commonly, the distinctive pathologic
findings consist of mesangial proliferative glomerulonephritis with mesangial IgA deposits, usually accompanied by
complement deposition and less intense IgG and/or
IgM.1113,1118,1119 By electron microscopy, the mesangium and
subendothelial regions contain lucencies with dense granular and rounded membranous structures consistent with
lipid inclusions (Figure 33.57). Increased serum IgA levels
are found in more than 90% of cirrhotic patients with glomerular IgA deposition. Other authors have reported IgM
as the dominant immunoglobulin.1114 Cirrhotic glomerulonephritis is usually a clinically silent disease; however, the
diagnosis can be suspected by finding proteinuria or abnormalities of the urine sediment. Kidney biopsies in cirrhotic
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CHAPTER 33 — Secondary Glomerular Disease
patients at the time of liver transplantation may show glomerular lesions (predominantly IgA nephropathy or diabetic nephropathy) even if there is no clinical evidence of
renal involvement. Diabetic lesions were associated with significantly worse renal function 5 years after transplantation
compared to patients with IgA nephropathy.1120
The pathogenesis may relate to defective hepatic clearance of IgA as well as altered processing and/or portacaval
shunting of circulating immune complexes.1121 This theory
is bolstered by the finding of increased deposits of IgA in
skin and hepatic sinusoids in cirrhotic patients.1122 Moreover, in patients with noncirrhotic portal fibrosis who underwent portal-systemic bypass procedures, there was an
increase in the incidence of clinically overt glomerulonephritis (from 78% to 32%) associated with deposition of IgA
after the procedure. In the latter group, there was also a
significant incidence of renal failure (50% after 5 years).1123
Similar findings were noted in children with end-stage liver
disease from α1-antitrypsin deficiency or biliary atresia,
which resolved after liver transplantation.1124
GLOMERULAR LESIONS ASSOCIATED
WITH NEOPLASIA
The occurrence of glomerular syndromes, both nephrotic
and nephritic, may be associated with malignancy but is rare
(<1%). Glomerular disease may be seen with a wide variety
of malignancies. Carcinomas of the lung, stomach, breast,
and colon are most frequently associated with glomerular
lesions.1125 Membranous nephropathy is the most common
lesion associated with carcinoma.1125 Patients older than age
50 presenting with nephrotic syndrome should be reviewed
for the presence of a malignancy.1126,1127
CLINICAL AND PATHOLOGIC FEATURES
Clinically, the glomerulopathy of neoplasia may be manifested by proteinuria or nephrotic syndrome, an active
urine sediment, and/or diminished glomerular filtration.
Significant renal impairment is uncommon and is usually
associated with the proliferative forms of glomerulonephritis. In evaluating an ESR in patients with nephrotic syndrome, it should be noted that most such patients have an
ESR above 60 mm/hr, with roughly 20% being above
100 mm/hr. As a result, an elevated ESR alone in a patient
with nephrotic syndrome (or with ESKD) is not an indication to evaluate the patient for an occult malignancy or
underlying inflammatory disease.1128,1129
Membranous nephropathy may be associated with malignancies in 10% to 40% of cases.1125,1127,1130,1131 These include
carcinoma of the bronchus,1132 breast,1133 colon,1134,1135
stomach, ovary,1136 kidney,1137 pancreas,1138 and prostate,1139,1140 as well as testicular seminoma,1141 parotid adenolymphoma, carcinoid tumor,1142,1143 Hodgkin’s disease, and
carotid body tumor.1144 In some cases of membranous
nephropathy associated with malignancy, tumor antigens
have been detected within the glomeruli. It is postulated
that tumor antigen deposition in the glomerulus is followed
by antibody deposition, causing “in situ” immune complex
formation, and subsequent complement activation.1145,1146
Immune complexes and complement have been found in
1157
cancer patients without overt renal disease.1145 Antibody to
phospholipase A2 receptor (PLA2R), the target antigen in
primary membranous nephropathy, has not been identified
in the sera of patients with membranous nephropathy secondary to malignancy. Removal of the tumor may lead to
remission of nephrotic syndrome, which may then recur,
following the development of metastasis. In many instances
successful treatment of the neoplasm has induced a partial
or complete remission of the associated glomerulopathy.
Minimal change disease or focal glomerulosclerosis may
occur in association with Hodgkin’s disease,1147-1149 less often
with non-Hodgkin’s lymphoma or leukemia,1148 and rarely
with thymoma,1125,1150 mycosis fungoides,1151 renal cell carcinoma,1152 or other solid tumors.1153-1155 Secretion of a lymphokine by abnormal T cells may underlie glomerular
injury in these disorders.1130,1156,1157
Secondary amyloidosis (AA type) has been described with
a number of malignancies, particularly renal cell carcinoma,
Hodgkin’s disease, and chronic lymphocytic leukemia.1,2,4 In
Hodgkin’s disease, for example, renal amyloidosis is generally a late event resulting from a chronic inflammatory state;
by comparison, minimal change disease most often occurs
at the time of initial presentation.5
Both MPGN and RPGN have been described in patients
with solid tumors and lymphomas, although the causal relationship between these conditions is not proven.1155,1158 The
association is probably strongest for MPGN and chronic
lymphocytic leukemia and may be associated with circulating cryoglobulins or glomerular deposition of monoclonal
immunoglobulins.1159,1160 Mesangial proliferation with IgA
deposition has been associated with mucosa-associated lymphoid tissue lymphoma, which resolved following treatment
of the malignancy with chlorambucil.1161 Although the association between crescentic glomerulonephritis and vasculitis with tumors may be coincidental, it has been suggested
that the malignancy may act as a trigger for the vasculitis.1162-1164
In contrast to the nephrotic states described earlier in which
renal function is generally well preserved at presentation
and the urine sediment is usually benign, patients with proliferative glomerulonephritis often have an acute decline in
renal function and an active urine sediment.
Both HUS and the related disorder TTP can occur in
patients with malignancy. An underlying carcinoma of the
stomach, pancreas, or prostate may be associated with HUS.
More commonly, however, antitumor therapy is implicated:
mitomycin, gemcitabine, the combination of bleomycin and
cisplatin, and radiation plus high-dose cyclophosphamide
prior to bone marrow transplantation all can lead to HUS,
which may become apparent months after therapy has been
discontinued.1165 Anti-VEGF agents are newly identified
causes of glomerular thrombotic microangiopathy, leading
to proteinuria, renal insufficiency, and hypertension.1130,1166
GLOMERULAR DISEASE ASSOCIATED
WITH DRUGS
HEROIN NEPHROPATHY
In the 1970s, reports began to appear linking heroin abuse
to nephrotic syndrome and renal biopsy findings of lesions
of FSGS. This syndrome was referred to as heroin-associated
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1158
SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
nephropathy (HAN).1167-1172 Similar lesions were seen in
users of intravenous pentazocine (Talwin), and tripelennamine (Pyribenzamine), so-called Ts and Blues.1173 This syndrome occurred almost exclusively in blacks; it has been
suggested that blacks may have a genetic predisposition for
developing HAN.1174,1175 The mean age was younger than 30
years old with 90% of the patients being males. The duration of drug abuse varied from 6 months to 30 years (mean,
6 years) prior to the onset of renal disease. Most patients
presented with nephrotic syndrome. The course of HAN
was relentless progression to ESKD over many years in those
addicts who continued to use heroin, whereas a regression
of abnormalities was seen in patients who were able to stop
using the drug. Kidney biopsies of these patients showed
lesions of focal segmental and global sclerosis. Nonspecific
trapping leads to the deposition of IgM and C3 in areas of
sclerosis. There was usually significant interstitial inflammation associated with the glomerular lesion. The pathogenesis of HAN is unknown. Abnormalities of cellular and
humoral immunity have been well described in heroin
addicts.1176 It has been suggested that morphine itself could
act as an antigen and that contaminants used to “cut” the
heroin could contribute to the pathogenesis. Morphine
(the active metabolite of heroin) has been shown to stimulate proliferation and sclerosis of mesangial cells and fibroblasts.1177,1178 The syndrome of HAN has almost disappeared
among drug addicts presenting with renal failure; for
example, there has been a sharp decline in incident cases
of HAN and there were no reported cases of HAN-associated
ESKD from Brooklyn, New York, during the period from
1991 to 1993.1179,1180 In part this trend coincides with the rise
of HIV infection and HIVAN.
NONSTEROIDAL ANTIINFLAMMATORY DRUG–
INDUCED NEPHROPATHY
NSAIDs are being used by approximately 50 million of the
general public in the United States at any point in time.
Approximately 1% to 3% of patients exposed to NSAIDs will
manifest one of the renal abnormalities associated with its
use, which include fluid and electrolyte disturbances, acute
renal failure, nephrotic syndrome with interstitial nephritis,
and papillary necrosis.1181 The combination of acute interstitial nephritis and nephrotic syndrome is characteristic of
this group of compounds. Essentially all NSAIDs can cause
this type of renal disease,1182-1184 including the cyclooxygenase-2 inhibitors.1185,1186
CLINICAL AND PATHOLOGIC FEATURES
Minimal Change Disease with Interstitial Nephritis
The onset of NSAID-induced nephrotic syndrome is usually
delayed, with a mean time of onset of 5.4 months (range, 2
weeks to 18 months) after initiation of NSAID therapy.
Patients may present with edema and oliguria. Systemic
signs of allergic interstitial nephritis are usually absent.
The urine exhibits microhematuria and pyuria. Proteinuria
is usually in the nephrotic range. The extent of renal dysfunction may be mild to severe. On light microscopy the
findings consist of minimal change disease with interstitial
nephritis. A focal or diffuse interstitial infiltrate consists
predominantly of cytotoxic T lymphocytes (also other T cell
subsets, B cells, and plasma cells).1187,1188 The syndrome
usually reverses after discontinuing therapy, and the time to
recovery may be between 1 month and 1 year.1184 Complete
remission is usually seen.1189 Relapse of proteinuria has been
reported.1190 Treatment of nephrotic syndrome is usually
unnecessary, since the disorder is self-limiting. However, a
short course of corticosteroids may be beneficial in patients
in whom no response is seen after several weeks of discontinuation of the drug.1191 Plasma exchange was reported
with being associated with rapid recovery of renal function
in two patients.1192
Other Patterns
Minimal change nephrotic syndrome without interstitial
disease has been occasionally reported.1193 Granulomatous
interstitial disease without glomerular changes has also
been described.1194 Membranous nephropathy has also been
reported in association with NSAID use,1195 including the
newer cyclo-oxygenase-2 inhibitors.1186 As in minimal change
nephrotic syndrome, there is rapid recovery after drug withdrawal in NSAID-induced membranous nephropathy.
PATHOGENESIS
The mechanism of NSAID-induced nephrotic syndrome has
not been defined. It has been proposed that inhibition of
cyclo-oxygenase by NSAIDs inhibits prostaglandin synthesis
and shunts arachidonic acid pathways toward the production of leukotrienes. These by-products of arachidonic acid
metabolism may promote T lymphocyte activation and
enhanced vascular permeability, leading to minimal change
disease.1182-1184
ANTI–RHEUMATOID ARTHRITIS THERAPY–
INDUCED GLOMERULOPATHY
GOLD SALTS
Proteinuria and nephrotic syndrome have been reported to
occur in association with both oral and parenteral gold.1196,1197
Dermatitis may occur concurrently. Membranous nephropathy and, rarely, minimal change disease have been
reported.1198 A higher incidence of nephropathy has been
reported in patients with HLA-B8/DR3.1199,1200
D-PENICILLAMINE
Proteinuria in association with membranous nephropathy is
the most common lesion reported. Less commonly, minimal
change disease and mesangial proliferative lesions have
been reported.1200 Goodpasture-like syndrome,1201 minimal
change nephrotic syndrome,1202 and membranous nephropathy concurrently with vasculitis1203 have been described
rarely. HLA-B8/DR3 haplotypes are also associated with
penicillamine nephropathy.1204 Tiopronin and bucillamine
(a penicillamine-like compound) have also been associated
with the same renal lesions described for penicillamine.1205,1206 The onset of proteinuria with gold or penicillamine therapy is usually between 6 and 12 months after
starting therapy. Proteinuria usually resolves after withdrawing the offending agent; persistent renal dysfunction is
uncommon.1200,1204,1207 Under close supervision, gold and
penicillamine have been continued in patients with
nephropathy with no obvious adverse effect on renal function.1208 Anti–TNF-α agents have been reported to promote
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CHAPTER 33 — Secondary Glomerular Disease
the development of lupus-like nephritis and ANCAassociated glomerulonephritis in patients with rheumatoid
arthritis.1209
OTHER MEDICATIONS
Organic mercurial exposure can occur with diuretics,
skin lightening creams, gold refining, and industrial exposure. Proteinuria and nephrotic syndrome have been
reported.1210-1212 Renal biopsy in such patients has shown
membranous nephropathy1213,1214 or minimal change
disease.1215 Nephrotic syndrome has been associated with the
anticonvulsants ethosuccimide,1216 trimethadione,1217 and
paradione.1218 Diffuse proliferative glomerulonephritis may
be seen with mephenytoin (Mesantoin).1219 ANCA-associated
vasculitis as well as a lupus-like nephritis has been reported
with propylthiouracil1220-1223 and hydralazine.1224 Captopril
has been associated with the development of proteinuria
and nephrotic syndrome due to membranous nephropathy.1225 Substituting enalapril for captopril has been reported
to ameliorate nephrotic syndrome.1226 IFN-α has been associated with interstitial nephritis, minimal change disease,
FSGS, and acute renal failure.1227,1228 In patients with collapsing FSGS due to interferon therapy, discontinuation of
therapy usually leads to improvement in both renal function
and proteinuria.1229 Cases of thrombotic microangiopathy1230,1231 and crescentic glomerulonephritis1232 have also
been reported. Mercaptopropionylglycine (2-MPG) used in
the treatment of cystinuria has been associated with membranous glomerulopathy.1233Lithium use has been associated
with minimal change disease,1234,1235 membranous nephropathy,1236 and FSGS.1237,1238 The use of high-dose pamidronate
in patients with malignancies has been associated with HIVnegative collapsing FSGS.1239 Cocaine may be contaminated
with levamisole, a veterinary antihelmintic that is a known
immunomodulator. This combination may result in a ANCApositive systemic vasculitis with a predilection for skin necrosis and arthralgia; renal and pulmonary involvement may
occur.1240 Abuse of anabolic steroids in conjunction with a
body-building regimen may produce FSGS with variable histologic subtypes. Roles for both increased glomerular filtration demand and potential direct toxic effects of anabolic
steroids on glomerular cells have been proposed.1241 Treatment of C3 glomerulopathies with eculizumab, a humanized
monoclonal antibody directed to C5, may lead to binding of
the drug to C5 deposits in renal tissue, producing de novo
positivity for IgG-κ that mimics.1242
MISCELLANEOUS DISEASES ASSOCIATED
WITH GLOMERULAR LESIONS
Well-documented cases exist of nephrotic syndrome associated with unilateral renal artery stenosis, which improved
after correction of the stenosis. The mechanism of proteinuria presumably relates to high levels of angiotensin
II.1243-1245
Acute silicosis has been associated with a proliferative
glomerulonephritis with IgM and C3 deposits, leading to
renal failure.1246 A patient with dense lamellar inclusions in
swollen glomerular epithelial cells, similar to those seen in
Fabry’s disease, has also been described.1247
1159
Membranous nephropathy and MPGN1248 have been
described in association with ulcerative colitis.1249
Kimura’s disease and angiolymphoid hyperplasia with
eosinophilia (ALHE) produce skin lesions that appear as
single or multiple red-brown papules or as subcutaneous
nodules with a predilection for the head and neck region.
Other associated features include eosinophilia and elevated
IgE levels. Both Kimura’s disease and the similar ALHE are
frequently associated with glomerular disease. Mesangial
proliferative glomerulonephritis1250 and minimal change
disease1251 have been described.
Renal complications of Castleman’s disease (angiofollicular lymph node hyperplasia) are uncommon. The reported
cases are very heterogeneous, and their renal pathology
includes minimal change disease, mesangial proliferative
membranous
nephropathy,1253
glomerulonephritis,1252
1254
1255
crescentic glomerulonephritis,
fibrillary gloMPGN,
merulonephritis,1256 and amyloidosis.1257 Serum IL-6 levels
appear to be elevated and they decline with corticosteroid
therapy.1252 Removal of tumor mass or treatment with steroids appears to ameliorate the renal manifestations in
some cases.
Angioimmunoblastic lymphadenopathy has been associated with diffuse proliferative glomerulonephritis with necrotizing arteritis and minimal change disease.1148,1258
Hemophagocytic syndrome related to infections or lymphoproliferative disease has been associated with collapsing
FSGS.1259
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1160.e17
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1160.e18
870.
871.
872.
873.
874.
875.
876.
877.
878.
879.
880.
881.
882.
883.
884.
885.
886.
887.
888.
889.
890.
891.
892.
893.
894.
895.
SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
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1160.e24
SECTION V — DISORDERS OF KIDNEY STRUCTURE AND FUNCTION
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