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286 SECTION V Renal Disease
undergo partial remission. Initial therapy should include angiotensin
II receptor blockade, a low-salt diet (<4 g/day), a low-protein diet (0.8
to 1 g/kg/day), and lipid control. If spontaneous remission occurs, it
usually does so within the first 12 to 24 months.
Early treatment should be given to patients with severe nephrotic
syndrome (e.g., proteinuria >10 g/24 h) and high or increasing antiPLA2R antibody titers, while conservative therapy is continued in
asymptomatic patients, who maintain proteinuria at less than 4 g/24 h
and have low or decreasing anti-PLA2R antibody titers.
Rituximab has recently garnered attention as a potential breakthrough in the treatment of membranous nephropathy. A recent
multicenter randomized controlled trial of rituximab versus cyclosporine in patients with severe membranous nephropathy (MENTOR)
revealed that rituximab is not inferior to cyclosporine in inducing
complete or partial remission of proteinuria but is superior in maintaining long-term remission of proteinuria and will likely become the
first-line therapy for the treatment of membranous nephropathy.
The probability of renal survival is more than 80% at 5 years and
about 60% at 15 years. Patients with an accelerated course should
be evaluated for superimposed anti-GBM disease, acute interstitial
nephritis, or renal vein thrombosis.
IMMUNE-COMPLEX GLOMERULONEPHRITIS
Infection-Related Glomerulonephritis
Poststreptococcal glomerulonephritis (PSGN) is a classic form of acute
glomerulonephritis that develops 1 to 4 weeks after a pharyngitis or
skin infection with specific (nephritogenic) strains of group A β-he-
molytic streptococci. It typically occurs in children and usually has a
benign course. More recently, however, infection-related glomerulonephritis has been recognized to have a broader spectrum, affecting
elderly and immunocompromised patients and associated with different bacteria, particularly staphylococci. Unlike classic PSGN, the
variant occurs when the infection is still active and has an unfavorable
prognosis. The term infection-related GN is often used to include both
PSGN and GN occurring in the setting of a concurrent infection.
Infection-related glomerulonephritis manifests clinically with the
abrupt onset of nephritic syndrome. In patients with PSGN, cultures
are usually negative, but elevated titers of antistreptolysin O (ASO),
antistreptokinase, antihyaluronidase, and anti-deoxyribonuclease
(anti-DNAse B) antibodies may provide evidence of recent streptococcal infection. Activation of the alternative complement pathway is
reflected by low C3 complement levels. C4 levels are usually normal or
mildly decreased. Other nephrologic conditions associated with low
complement are C3 glomerulopathy, lupus nephritis, cryoglobulinemic glomerulonephritis, fibrillary glomerulonephritis, IgG4-mediated
renal disease, and cholesterol emboli (Table 26.2).
Renal biopsy typically shows diffuse glomerular hypercellularity
and infiltration of polymorphonuclear leukocytes, monocytes, or macrophages on light microscopy. Immunofluorescence shows granular
deposition of IgG, C3, and occasionally immunoglobulin M (IgM). On
TABLE 26.2 Glomerular Diseases
Associated With Hypocomplementemia
Acute lupus nephritis
C3 glomerulopathy (C3 glomerulonephritis and dense deposit disease)
Cholesterol emboli
Cryoglobulinemic glomerulonephritis
Postinfectious glomerulonephritis
IgG4-related nephropathy
Fibrillary glomerulonephritis
electron microscopy, characteristic dome-shaped subepithelial deposits (“humps”) can be seen along the GBM (Fig. 26.5).
Treatment is supportive and aims to minimize fluid overload, optimize blood pressure control, and eradicate ongoing infection. For children, the prognosis is excellent, with most patients recovering renal
function in 1 to 2 months. Some patients have persistent microscopic
hematuria, proteinuria, hypertension, and renal dysfunction and are
said to have atypical, persistent, or resolving PSGN. Some of these patients
have mutations or autoantibodies to proteins in the alternative complement cascade and as such represent patients with C3 glomerulopathy.
Immunoglobulin A (IgA) Nephropathy
IgA nephropathy (formerly called Berger disease) is the most common
form of primary glomerulopathy. On light microscopy, mesangial proliferation is seen, along with mesangial deposition of IgA on immunofluorescence and electron-dense deposits in the mesangium on
electron microscopy (Fig. 26.6).
Patients may have episodes of macroscopic hematuria accompanying an intercurrent upper respiratory tract infection (synpharyngitic)
or have asymptomatic hematuria, with or without proteinuria, detected
on routine urinalysis. Proteinuria is common, but nephrotic syndrome
occurs in less than 10% of cases and raises the possibility of a primary
podocytopathy (e.g., MCD) superimposed on the IgA nephropathy.
The pathogenesis of IgA nephropathy has been linked to galactose-deficient IgA1 (GD-IgA1) molecules and increased formation
of anti–GD-IgA1 autoantibodies, with deposition of IgG or IgA anti–
GD-IgA1 immune complexes in the mesangium, resulting in activation of complement and cytokine cascades. Secondary causes of IgA
nephropathy include chronic liver disease, celiac disease, dermatitis
herpetiformis, and ankylosing spondylitis.
In up to 60% of the patients, IgA nephropathy has a benign clinical
course, and patients maintain proteinuria of less than 500 mg/24 h and
preserved renal function. However, progression to ESRD occurs in up
to 40% of patients over 10 to 25 years. Clinical predictors of progression include proteinuria greater than 1 g/24 h, hypertension, presence of
crescents on renal biopsy, and impaired renal function at diagnosis. Any
degree of proteinuria carries a worse prognosis for a patient with IgA
nephropathy. IgA nephropathy frequently recurs after renal transplantation, but loss of the allograft from recurrent disease is uncommon.
The use of angiotensin II system blockade and high-dose corticosteroids has been beneficial in slowing or halting progression of renal
disease. Henoch-Schönlein purpura is the systemic form of IgA nephropathy. The prognosis is generally good for children but varies in adults.
In patients with normal renal function, treatment is supportive
only. Patients with persistent proteinuria greater than 1 g/24 h and/or
progressive renal failure should be considered for treatment with highdose corticosteroids with or without cytotoxic medication.
Membranoproliferative Glomerulonephritis
MPGN is not a specific disease entity but a pattern of glomerular injury
resulting from predominantly subendothelial and mesangial deposition
of immune complexes or complement factors and their products. On
light microscopy, mesangial hypercellularity, endocapillary proliferation,
and capillary wall remodeling with double-contour formation are characteristic, and they result in a lobular accentuation of the glomerular tufts.
Immunofluorescence microscopy shows immunoglobulins or complement factors, depending on the underlying cause of MPGN. Electron
microscopy typically shows mesangial and subendothelial deposits, and,
less commonly, intramembranous and subepithelial deposits (Fig. 26.7).
Based on a recent proposal, MPGN can be classified as immune complex
mediated or complement mediated. Immune complex–mediated MPGN
shows immunoglobulin and complement factors on immunofluorescence
CHAPTER 26 Glomerular Diseases
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A B C
287
D
Fig. 26.5 Postinfectious glomerulonephritis. (A and B) Light microscopy shows diffuse endocapillary prolif-
erative glomerulonephritis. Notice the prominent neutrophil infiltration in the glomerular capillaries (A, hematoxylin and eosin; B, silver methenamine; both ×40). (C and D) Immunofluorescence studies show granular
immunoglobulin G and C3 deposition along the capillary walls (both ×20). (E and F) Electron microscopy
shows subendothelial deposits (white arrows) and subepithelial humplike deposits (black arrows). The subendothelial deposits likely result from circulating immune complexes that are deposited along the glomerular
capillary walls and drive the inflammatory response (E, ×5800). The subepithelial deposits likely represent in
situ immune complex formation (F, ×2850).
E F
A
Fig. 26.6 Immunoglobulin A (IgA) nephropathy. (A) Light microscopy shows mesangial hypercellularity (black
arrow) (silver methenamine, ×40). (B) Immunofluorescence microscopy shows bright mesangial IgA staining.
(C) Electron microscopy shows large mesangial electron-dense deposits (arrow) (×7860).
microscopy. Complement-mediated MPGN shows complement factors and a lack of significant immunoglobulin on immunofluorescence
microscopy (Fig. 26.8). Immune complex/Ig–mediated MPGN results
from chronic infections, autoimmune diseases, and monoclonal gammopathies. Complement-mediated MPGN is caused by genetic or acquired
dysregulation of the alternative pathway of complement (C3 glomerulopathy) and can be further subclassified as C3 glomerulonephritis and dense
deposit disease (DDD) based on electron microscopy examination.
Immune complex–mediated MPGN precipitated by an infection
is most commonly caused by HCV (i.e., cryoglobulinemic glomerulonephritis). The clinical presentation varies and can include nephrotic
and nephritic features. In patients with cryoglobulinemic MPGN, the
levels of C3, C4, and CH50 are persistently low, reflecting activation
of classical complement pathway. Patients with C3 glomerulonephritis
or DDD may have a persistently low level of C3 but a normal level of
C4. A C3 nephritic factor is found in many cases. C3 nephritic factor
is an autoantibody to alternative pathway C3 convertase, resulting in
persistent breakdown of C3.
The absence of well-designed studies based on the current insights in
the pathogenesis of MPGN make it impossible to give strong treatment
recommendations. From a practical point of view, patients with MPGN
due to chronic infections (e.g., HCV, endocarditis), autoimmune disease,
and plasma cell dyscrasias (monoclonal gammopathy) should undergo
treatment of the underling disease. Patients with normal kidney function,
no active urinary sediment, and non–nephrotic-range proteinuria can be
treated conservatively with angiotensin II blockade to control blood pressure and reduce proteinuria, because the long-term outcome is relatively
benign in this setting. Follow-up is required to detect early deterioration in
kidney function. Patients with C3 glomerulonephritis or DDD with proteinuria greater than 1000 mg/24 h and/or abnormal kidney function but
not rapidly progressive disease, and who do not have a genetic mutation
leading to factor H deficiency, can be considered for additional treatment
288 SECTION V Renal Disease
A
B
DC
Fig. 26.7 Immune complex–mediated membranoproliferative glomerulonephritis due to hepatitis C virus
infection. (A) Light microscopy shows a membranoproliferative pattern of injury with mesangial expansion,
endocapillary proliferation, double-contour formation along the capillary walls, and lobular accentuation of
the glomerular tufts (silver methenamine, ×40). (B and C) Immunofluorescence microscopy shows bright
capillary wall staining for immunoglobulin M (B, ×40) and for C3 (C, ×40). (D) Electron microscopy shows capillary wall thickening and a double-contour formation due to accumulation of subendothelial electron-dense
deposits (black arrows), cellular elements, and new basement membrane formation (i.e., duplication) (yellow
arrow) that produces the double contour. The thick white arrow indicates the old basement membrane, and
fibrin tactoids (white arrows) in glomerular capillary loops indicate a prothrombotic state (×1350).
A B
DEF
Fig. 26.8 C3 glomerulonephritis. Light microscopy shows features of mesangial proliferative glomerulonephri-
tis (A, periodic acid–Schiff, ×40) and membranoproliferative glomerulonephritis (B, silver methenamine stain,
×40) in the same biopsy. Immunofluorescence microscopy shows bright granular mesangial and capillary wall
staining for C3 (C) and negative staining for immunoglobulin G (D). (E) Electron microscopy shows a large
accumulation of smudgy mesangial deposits (arrow) (×10,000). (F) Electron microscopy shows subendothelial deposits (black arrow) and subepithelial humplike deposits (white arrows) (×150,000). The subepithelial
deposits sometimes make it difficult to distinguish C3 glomerulonephritis from postinfectious glomerulonephritis. However, C3 glomerulonephritis may not show Ig (as in this case), and the term atypical postinfectious
glomerulonephritis sometimes is applied in cases of C3 glomerulonephritis with subepithelial humplike deposits.
C
CHAPTER 26 Glomerular Diseases
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with mycophenolate mofetil plus oral corticosteroids. Patients who have
advanced renal insufficiency and severe tubulointerstitial fibrosis of renal
biopsy are unlikely to benefit from immunosuppressive therapy.
Lupus Nephritis
Lupus nephritis occurs in up to 50% to 70% of patients with SLE and
is associated with a poor prognosis. Proteinuria is the most common
TABLE 26.3 Abbreviated International
Society of Nephrology/Renal Pathology
Society 2003 Classification of Lupus Nephritis
Type Morphologic Class Renal Manifestation
I Minimal mesangial lupus
nephritis
I Mesangial proliferative
lupus nephritis
III Focal lupus nephritis Active sediment, proteinuria
IV Diffuse lupus nephritis Nephritic and nephrotic syndromes
V Membranous lupus nephritis Nephrotic syndrome
VI Advanced sclerosing lupus
nephritis
Modified from Weening JJ, D’Agati VD, Schwartz MM, et al: The
classification of glomerulonephritis in systemic lupus erythematosus
revisited, J Am Soc Nephrol 15:241-250, 2004.
Normal urinary sediment
Low-grade hematuria and/or
proteinuria
Normal renal function
<3 g/1.73 m2/day
Hypertension; progressive renal
failure
Inactive urinary sediment
Chronic renal failure
initial manifestation, and it is often in the nephrotic range and accompanied by a decline in renal function. Urinalysis does not always
reflect the severity of the glomerular lesion, and kidney biopsy is indicated in those with proteinuria or active urinary sediment, or both,
because the type of renal lesion influences the therapeutic decisions.
The International Society of Nephrology/Renal Pathology Society
(ISN/RPS) classification of lupus nephritis recognizes six morphologic classes of renal involvement (Table 26.3). However, patients may
migrate from one class to another spontaneously or after treatment.
Immunofluorescence typically shows glomerular deposition of IgG,
IgM, IgA, C1q, and C3 (i.e., full-house pattern). On electron microscopy, tubuloreticular inclusions are common within glomerular and
vascular endothelial cells. Electron-dense deposits sometimes show
fingerprint-like substructures) (Fig 26.9). Histologic lesions correlate
with the prognosis; classes III and IV have the worst prognosis (see
Fig 26.9). Other manifestations of SLE include acute and chronic tub-
ulointerstitial nephritis and glomerular capillary thrombi in patients
with antiphospholipid antibodies.
Three guidelines for the management of lupus nephritis have
been published recently by the American College of Rheumatology,
the Kidney Disease-Improving Global Outcomes (KDIGO) working group, and the Joint European League Against Rheumatism and
European Renal Association–European Dialysis and Transplant
Association (EULAR/ERA-EDTA). For class I lupus nephritis, the
prognosis is excellent, and no immunosuppression is required.
Patients with class II lupus nephritis and proteinuria less than 1 g/24 h
should be treated as dictated by the extrarenal clinical manifestations
of lupus. Patients with class II lupus nephritis and proteinuria greater
than 3 g/24 h should be treated with corticosteroids or calcineurin
inhibitors.
Fig. 26.9 Light microscopy (A to C) and electron microscopy (D) are used to identify lupus nephritis. (A) Mild
mesangial proliferative glomerulonephritis (International Society of Nephrology/Renal Pathology Society [ISN/
RPS] class II) has mesangial hypercellularity (arrows) (periodic acid–Schiff, ×40). (B) Diffuse endocapillary
proliferation with cryoglobulins in the glomerular capillaries, identified as pale, silver-negative material (arrow)
(silver methenamine, ×20). (C) In diffuse proliferative glomerulonephritis (ISN/RPS class IV), the glomerulus
on top shows a large cellular crescent (black arrows), and the glomerulus at the bottom shows diffuse endocapillary proliferation (white arrows) (silver methenamine, ×20). (D) Electron-dense deposits have fingerprint
substructures (arrow) (×46,000).
DC
290 SECTION V Renal Disease
TABLE 26.4 Cryoglobulins and Associated
Diseases
Cryoglobulinemia
Type
I. Monoclonal
immunoglobulins
II. Mixed cryoglobulins
with monoclonal
immunoglobulins
III. Mixed polyclonal
immunoglobulins
A, IgA; BJP, Bence Jones protein (κ light chain); G, IgG; M, IgM; SLE,
systemic lupus erythematosus.
Patients with class III or IV lupus nephritis should undergo induction therapy with corticosteroids plus cyclophosphamide or mycophenolate mofetil because both are considered equivalent. Pure class V
(membranous) lupus nephritis usually has a benign prognosis, and
initial therapy should be supportive. However, patients with progressive or persistent nephrotic-range proteinuria should be treated with
corticosteroids plus an additional immunosuppressive agent (e.g., cyclosporine, tacrolimus, mycophenolate mofetil or rituximab). Patients
with ESRD should be considered for renal transplantation because
there is a low rate of recurrence in the transplanted kidney.
Immunoglobulin
Class
M > G > A > BJP Myeloma, Waldenström
M/G ≫ G/G Sjögren syndrome,
M/G Infection, SLE, vasculi-
Associated
Diseases
macroglobulinemia
Waldenström
macroglobulinemia,
lymphoma, essential
cryoglobulinemia
tis, neoplasia, essential cryoglobulinemia
Cryoglobulinemic Glomerulonephritis
Cryoglobulins are immunoglobulins that precipitate at low temperatures
and redissolve on rewarming. Cryoglobulinemia usually leads to a systemic
inflammatory syndrome with weakness, arthralgias or arthritis, palpable
purpura, peripheral neuropathy, and glomerulonephritis. Serum levels
of C4 are typically low due to activation of complement by the classical
pathway. The disease mainly involves small to medium-sized blood vessels
and causes vasculitis due to cryoglobulin-containing immune complexes.
Cryoglobulinemia is classified as type I, II, or III on the basis of immunoglobulin composition. It can be idiopathic or occur in association with autoimmune diseases (see Fig. 26.11B), malignancy, or infection (Table 26.4).
HCV infection is the most common cause of cryoglobulinemia.
Renal disease occurs in 20% to 60% of patients with cryoglobulinemia and manifests as proteinuria, microscopic hematuria, nephrotic
syndrome, or renal impairment. Hypertension is common and may
be severe, particularly in the setting of acute nephritic syndrome. The
cryocrit values correlate poorly with disease activity. On light microscopy, renal biopsy specimens show an immune complex–mediated
membranoproliferative pattern of injury, and on electron microscopy,
diffuse, dense subendothelial deposits with a microtubular or crystalline appearance may be seen occluding the capillary loops.
Treatment targets the underlying pathologic process to minimize or
eliminate the associated cryoglobulinemia. Patients with active HCV
infection, for example, should receive antiviral therapy when possible,
and those with a monoclonal gammopathy should receive appropriate
antimyeloma therapy. Immunosuppressive therapy (including the use
of rituximab) with or without plasmapheresis should be considered for
patients with a rapidly progressive, organ- or life-threatening course,
regardless of the cause of the mixed cryoglobulinemia. Overall, the
renal prognosis is usually good, with few patients progressing to ESRD.
The long-term outcome reflects the underlying process.
Fibrillary Glomerulonephritis and Immunotactoid
Glomerulopathy
Fibrillary glomerulonephritis and immunotactoid glomerulopathy are
uncommon disorders, being present in 0.5 to 1% of native kidney biopsies. Fibrillary glomerulonephritis is by far more common, accounting
for approximately 85% to 90% of cases. The identification of the protein DnaJ heat shock protein family (Hsp40) member B9 (DNAJB9)
in the glomeruli of patients with fibrillary glomerulonephritis but not
in those with immunotactoid glomerulopathy has established that the
two are distinct, pathogenically unrelated disease entities (Fig. 26.10).
In approximately one third of patients with fibrillary glomerulonephritis a history of malignancy, monoclonal gammopathy or autoimmune
disease can be documented. By contrast, immunotactoid glomerulopathy is more frequently associated with chronic lymphocytic leukemia
and related B-cell lymphomas or multiple myeloma.
In fibrillary glomerulonephritis, light microscopic findings are
nondiagnostic and variable, showing patterns that may be seen in
other glomerulonephritides. Immunofluorescence microscopy is positive for IgG, C3, and usually both kappa and lambda (i.e., polyclonal)
light chains. Electron microscopy shows random fibrillar deposits in
the mesangium and glomerular capillary walls that are clearly distinct
from those seen in amyloidosis. The fibrils are larger than those in
amyloidosis (16 to 24 nm in fibrillary glomerulonephritis and 30 to 50
nm in immunotactoid glomerulopathy (with microtubular formation)
versus 10 nm in diameter in amyloidosis).
The presenting clinical features of fibrillary glomerulonephritis and
immunotactoid glomerulopathy are similar to those in other forms of
glomerular disease, including hypertension, hematuria, proteinuria,
and abnormal renal function.
No therapies have been clearly shown to be beneficial for either
fibrillary glomerulonephritis or immunotactoid glomerulopathy.
Patients with an associated malignancy, monoclonal gammopathy or
autoimmune disease, may benefit from treatment of the underlying
disorder.
Pauci-Immune Glomerulonephritis: Antineutrophil
Cytoplasmic Antibody–Associated Vasculitides
The ANCA-associated vasculitides (AAVs) are a group of three heterogeneous syndromes: granulomatosis with polyangiitis (GPA, formerly Wegener’s granulomatosis), microscopic polyangiitis (MPA),
and eosinophilic granulomatosis with polyangiitis (EGPA, formerly
Churg-Strauss syndrome). The unifying feature is a necrotizing small
vessel vasculitis with a predilection for the kidneys, lungs, and peripheral nervous system that occurs in association with autoantibodies
against antigens in the cytoplasm of neutrophils (i.e., myeloperoxidase
[MPO] and proteinase 3 [PR3]).
Approximately 75% of the patients with GPA are PR3-ANCA positive, and 20% are MPO-ANCA positive, whereas about 50% of patients
with MPA are MPO-ANCA positive and about 40% are PR3-ANCA
positive. Necrotizing granulomatous inflammation, which affects the
upper and lower respiratory tract and frequently precedes other disease
manifestations, is characteristic of GPA but not MPA. EGPA is characterized by asthma and eosinophilia in addition to features of small
vessel vasculitis such as mononeuritis multiplex. AAV is the most common cause of a RPGN in patients older than 60 years. AAV is associated with signs and symptoms ranging from limited renal disease to
RPGN and pulmonary-renal syndrome (Table 26.5). Renal biopsy is
characterized by a focal, necrotizing, and crescentic glomerulonephritis with pauci-immune immunofluorescence (Fig. 26.11).
Patients with newly diagnosed severe AAV vasculitis can be treated
with a combination of high-dose corticosteroids and cyclophosphamide or high-dose corticosteroids and rituximab. The PEXIVAS trial
CHAPTER 26 Glomerular Diseases
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291
AB
D
Fig. 26.10 Fibrillary glomerulonephritis. (A-B) Light microscopy showing mesangial expansion with increase
in cellularity (white arrow) and thickened capillary walls (black arrow) (A, hematoxylin and eosin ×40; B, periodic acid–Schiff stain ×40). (C) Congo red stain is negative (×40). (D) Immunohistochemistry for DNAJB9 is
positive. (E) Immunofluorescence studies show IgG staining in the mesangium and along capillary walls, and
(F) electron microscopy shows fibrillary deposits (thick arrows) along the capillary walls (×30000).
TABLE 26.5 Signs and Symptoms of
Antineutrophil Cytoplasmic Autoantibody
Vasculitis
Abdominal pain and gastrointestinal bleeding
Cutaneous purpura, petechiae, nodules, ulcerations, and necrosis
Facial pain, necrotizing (hemorrhagic) sinusitis, and septal perforation
Hematuria, proteinuria, and renal failure
Hemoptysis and pulmonary infiltrates or nodules
Muscle and pancreatic enzymes in blood
Myalgias and arthralgias
Peripheral neuropathy (mononeuritis multiplex)
showed that addition of plasma exchange in patients with pulmonary
hemorrhage, respiratory compromise, or severe renal failure (i.e.,
serum creatinine >5.5 mg/dL) is of no benefit. The prognosis for AAV
varies. Those with severe renal failure have the worst prognosis, and
even after successful therapy AAVs have a relapse rate of 30% to 50%
in the first 5 years. In patients with renal involvement, rising ANCA
titers are predictors of relapse. Patients with GPA or who are PR3ANCA positive or presenting with relapsing disease are at higher risk
for future relapses.
Anti–Glomerular Basement Membrane Antibody–
Mediated Glomerulonephritis
Anti-GBM antibody–mediated glomerulonephritis (anti-GBM GN,
formerly called Goodpasture disease) is a pulmonary-renal syndrome
caused by circulating anti-GBM antibodies. On immunofluorescence
staining of biopsy specimens, a linear pattern of IgG staining is seen
along the GBM and alveolar basement membrane (Fig. 26.12) using
antibodies directed against the α3 chain of type IV collagen (COL4A3
E F
protein). Patients usually have RPGN and various degrees of pulmonary hemorrhage.
The treatment of anti-GBM GN is based on high-dose pulse methylprednisolone (1 g/day for 1 to 3 days) followed by corticosteroids
(prednisone, 1 mg/kg/day up to 80 mg daily) in combination with oral
cyclophosphamide (2 to 3 mg/kg/day up to 200 mg daily, adjusted for age
and creatinine level) and plasma exchange. The prognosis is predicted in
part by the percentage of circumferential crescents on the renal biopsy
specimen, oliguria, and the need for dialysis. Those with an initial serum
creatinine level less than 5.0 mg/dL have a 90% probability of renal survival at 5 years; but those with 100% circumferential crescents and on
dialysis do not recover renal function, and immunosuppressive regimens
should be avoided except in the case of pulmonary hemorrhage.
Anti-GBM GN rarely recurs. Patients with ESRD are candidates for
renal transplantation after the antibody has disappeared (6 to 12 months).
GLOMERULAR DISEASES CAUSED BY PLASMA
CELL DYSCRASIAS
Amyloidosis
Amyloidosis is characterized by systemic extracellular deposition of
randomly arranged fibrils 8 to 12 nm in diameter that stain positive
with Congo red (i.e., orange-green birefringence with polarized light)
or thioflavin T. Several processes, including malignancy, genetic mutations, and aging, can produce at least 24 amyloidogenic proteins. With
renal deposition, amyloid in biopsy specimens appears as pale, amorphous, extracellular deposits that are periodic acid–Schiff (PAS) and
methenamine silver stain negative (Fig. 26.13).
The affinity for kidney compared with other target organs varies
according to the type of amyloid protein. Renal manifestations include
proteinuria, nephrotic syndrome, and renal failure. Affected patients
typically have large kidneys on ultrasound, but the diagnosis depends
C
292 SECTION V Renal Disease
BC
A B
Fig. 26.11 Crescentic glomerulonephritis in a patient with MPO-ANCA associated vasculitis. (A and B) Light
microscopy and silver methenamine staining show a large cellular crescent (black arrow) with fibrinoid necrosis (blue arrow), hemorrhage into the Bowman capsule (yellow arrow), and collapse of capillary tufts (A, ×20;
B, ×40). (C and D) Electron microscopy shows fibrinoid necrosis (i.e., necrotizing lesion) in the Bowman
space (white arrow) and capillary loops (short white arrow) (both, ×11100).
DC
A
Fig. 26.12 Anti–glomerular basement membrane–mediated disease. (A) Light microscopy shows a large,
circumferential crescent (arrow), with collapse of the glomerular capillary tufts and many infiltrating neutrophils in the crescent (periodic acid–Schiff, ×20). Immunofluorescence microscopy shows linear staining for
anti–immunoglobulin G antibody (B) along the glomerular capillary walls and bright staining for fibrinogen in
the Bowman tuft (C), indicating crescent formation and fibrinoid necrosis (both, ×40).
on demonstration of amyloid deposits. After amyloid is detected,
typing should be performed when possible because treatments vary
according to the protein involved. The most common approach to
amyloid typing involves immunofluorescence or immunohistochemistry, but genetic testing and liquid chromatography mass spectrometry are also helpful for high-resolution amyloid typing.
Treatment of amyloidosis depends on the origin of the amyloidogenic protein. In patients with amyloid light chain (AL) amyloidosis, antimyeloma therapy can be beneficial. In selected cases, bone
marrow transplantation has led to resolution of the disease. Secondary
amyloid A (AA) amyloidosis is most common in patients with rheumatoid arthritis, inflammatory bowel disease, chronic infection, or
familial Mediterranean fever. Treatment of AA amyloidosis is directed
at the underlying inflammatory process with antimicrobials or anti-inflammatory medications.
Light Chain Deposition Disease
Light chain deposition disease is a paraprotein-associated disorder.
The peak incidence is in the sixth decade of life, and men are affected
more commonly than women. Approximately 30% to 50% of patients
with light chain deposition disease have multiple myeloma. Most have
a detectable monoclonal protein (usually κ light chain) in the serum
or urine, but no hematologic abnormality is identified in about 10%
of cases. The clinical presentation is very heterogeneous and can vary
from mild renal dysfunction, proteinuria without nephrotic syndrome,
to clinically overt acute renal failure. Fanconi syndrome, characterized
by normoglycemic glycosuria, aminoaciduria, and phosphaturia, is the
classic presentation. Immunoglobulin deposits in other organs may
result in myriad of associated clinical symptoms.
Renal biopsy specimens show acellular, eosinophilic mesangial
nodules that stain strongly positive with PAS, often mimicking diabetes
CHAPTER 26 Glomerular Diseases
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Fig. 26.13 Amyloidosis. (A) Light microscopy shows amyloid deposits characterized by mesangial expansion
(small arrows) with material negative for staining. The material is also seen in vessel walls, where the arrow
points to vascular deposits (periodic acid–Schiff stain, ×20). (B) Congo red staining is positive for amyloid and
shows reddish-brown material in the glomeruli, interstitium, and vessel walls (×10). (C) Amyloid deposits
show apple green to orange-yellow birefringence under polarized light (×20). (D) Electron microscopy shows
randomly oriented amyloid fibrils. The fibrils measured 9 nm thick (×49,000).
293
mellitus. The deposited monoclonal proteins do not form fibrils and
are Congo red negative. Immunofluorescence microscopic findings are
diagnostic, with diffuse linear immunoglobulin light chain deposition
(κ in 80% of cases) along the GBM and tubular basement membranes.
On electron microscopy punctate powdery granular electron dense
deposits are seen along the GBM and TBM (Fig. 26.14).
Encouraging results have emerged with the use of anti-plasma cells
targeted therapy and autologous stem cell transplantation. Unless
remission is achieved after chemotherapy, the disease will recur in the
kidney allograft.
FIBRILLARY GLOMERULONEPHRITIS AND
IMMUNOTACTOID GLOMERULOPATHY
See section on immune-complex glomerulonephritis.
GLOMERULONEPHRITIS ASSOCIATED WITH VIRAL
INFECTIONS
Hepatitis B
HBV-mediated glomerular disease usually manifests as membranous
nephropathy, especially in children. The diagnosis of HBV-mediated
glomerular disease requires detection of the virus in the blood and the
exclusion of other causes of glomerular diseases.
HBV-mediated glomerular disease usually has a favorable prognosis, with a high spontaneous remission rate in children, but it is often
progressive in adults. Patients with HBV infection and glomerulonephritis should receive antiviral therapy (e.g., entecavir) as recommended by standard clinical practice guidelines for management of
HBV infection. Those with severe vasculitis or RPGN may be candidates for immunosuppressive therapy in combination with antiviral
therapy. Rituximab treatment of patients who are positive for HBV
has been associated with fatal acute hepatitis. Rituximab is therefore
contraindicated in patients with chronic HBV unless antiviral therapy
is also given and in patients with an active hepatitis flare.
Hepatitis C
See the section on cryoglobulinemic glomerulonephritis.
HIV-Associated Nephropathy
Patients with HIV infection can have many forms of kidney injury due
to sepsis, co-infection with HBV or HCV, nephrotoxic drugs, and use
of antiretroviral agents. HIV-associated nephropathy (HIVAN) is a
clinicopathologic entity characterized by nephrotic-range proteinuria
and a collapsing form of FSGS, often with microcystic tubular dilation.
On electron microscopy, tubuloreticular inclusions (i.e., interferon
fingerprints) may be seen within the glomerular and vascular endothelial cells.
HIVAN occurs almost exclusively in patients of African descent
when CD4 levels are low. It is thought to be caused by infection and
subsequent expression of HIV viral genes in podocytes. The onset of
proteinuria is typically acute. Proteinuria can be greater than 10 g/day,
and renal insufficiency can progress rapidly.
THROMBOTIC MICROANGIOPATHIES
Thrombotic microangiopathy is characterized by thrombocytopenia,
microangiopathic hemolytic anemia, and microvascular occlusion,
resulting in various degrees of organ dysfunction. Markers of hemolysis include low haptoglobin levels, increased levels of lactate dehydrogenase and unconjugated bilirubin, and a high reticulocyte count.
Schistocytes are seen in peripheral blood smears.
294 SECTION V Renal Disease
A B C
D E
Fig. 26.14 Light chain deposition disease. (A) Light microscopy shows glomeruli with silver-positive mesangial
nodules (arrow) and thickened tubular basement membranes (silver methenamine, ×10). (B) Periodic acid–
Schiff staining shows thickened, wavy tubular basement membranes (arrow) (×10). Immunofluorescence
studies found negative staining for λ light chains (C) and bright staining for κ light chains (D) along the tubular
basement membranes (both ×10). (E) Electron microscopy shows granular, punctate, electron-dense deposits (arrows) along the tubular basement membranes (×5800).
The quintessential forms of thrombotic microangiopathy include
hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). Although previously thought to represent different manifestations of the same disease, these disorders are distinct
clinically and mechanistically. In adults, predominant neurologic
involvement suggests a diagnosis of TTP, and predominant renal
involvement points to HUS. In most cases, the clinical presentations
are very similar, making it difficult to distinguish between HUS and
TTP on clinical grounds alone. Other causes of thrombotic microangiopathy include malignant hypertension, drugs (e.g., cocaine, quinidine, ticlopidine), autoimmune diseases (e.g., SLE, scleroderma,
antiphospholipid antibody syndrome), malignancy, HIV infection,
and antibody-mediated rejection.
Kidney biopsy in HUS and TTP reveals microthrombi in glomerular capillaries and arterioles, and mesangial expansion with loose
granular material, called mesangiolysis, may be seen in HUS and
TTP and in malignant hypertension or autoimmune diseases (Fig.
26.15). Malignant hypertension and autoimmune diseases may also
show thickening and intimal fibrosis of arteries and onion-skinning
(i.e., laminated deposition of basement membrane–type material)
of the vessel walls. Thrombi are common and may occlude the vascular lumen.
Hemolytic Uremic Syndrome
Two subtypes of HUS are recognized: a sporadic or diarrhea-associated form (D+ HUS) and an atypical or non–diarrhea-associated form
(D− HUS). D+ HUS is the most frequently encountered form, and it is
linked strongly to ingestion of meat contaminated with enterohemorrhagic
Escherichia coli or other infectious agents. The bacterium produces a Shigalike toxin that binds to a glycolipid receptor on renal endothelial cells and
triggers activation of the alternative complement cascade, leading to endothelial damage. Therapy for D+ HUS is supportive. Children with D+ HUS
have a good prognosis (90% recover renal function), but older patients
have increased mortality rates and unfavorable long-term renal survival.
Atypical or D− HUS represents 10% to 15% of the cases of HUS
and is more common in adults. The disease results from genetic mutations or autoantibodies against complement factors or complement
factors regulating proteins (i.e., C3, factor B, factor H, factor I, MCP,
CFHR1, and CFHR3) that control the activity of C3 convertase of the
alternative complement pathway. The resulting defective control of C3
convertase leads to widespread activation of the complement cascade.
The complement inhibitor eculizumab has been approved for the treatment of patients with atypical HUS. Eculizumab and plasma infusion may
also be considered in the treatment of children with D+ HUS and severe
central nervous system involvement such as seizures, stroke, or coma.
CHAPTER 26 Glomerular Diseases
AB
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Fig. 26.15 Thrombotic microangiopathy. (A) Light microscopy shows multiple, small thrombi (arrows) in glo-
merular capillaries in the setting of hemolytic uremic syndrome (Masson trichrome, ×40). (B) Light microscopy shows a thrombus (arrow) in a small artery in the setting of scleroderma (silver methenamine, ×20).
295
ABC
Fig. 26.16 Alport syndrome. (A) Light microscopy shows focal segmental glomerulosclerosis (arrow) (peri-
odic acid–Schiff, ×40). (B) Light microscopy shows numerous foam cells (arrow) in the interstitium (silver
methenamine, ×40). (C) Electron microscopy shows thickening of the glomerular capillary walls with multiple
lamellations of basement membrane material (arrow) and formation of the classic basket-weave appearance
(×212,000).
Thrombotic Thrombocytopenic Purpura
TTP results from mutations in the von Willebrand factor (VWF)–
cleaving protease (ADAMTS13) or development of an autoantibody
against ADAMTS13. ADAMTS13 cleaves large multimers of VWF,
and abnormalities or deficiency of ADAMTS13 activity affects VWF
function. Patients can have acute or chronic (i.e., relapsing) TTP.
Microthrombi rich in large VWF multimers develop in the arterioles
and capillaries of the brain and other organs.
Genetic or acquired forms of ADAMSTS13 deficiency can be
treated by plasma infusion or exchange to supply functional protease.
Plasma exchange should be initiated promptly, based on findings of
microangiopathic hemolytic anemia and thrombocytopenia without
evidence of other causes of thrombotic microangiopathy (e.g., scleroderma, malignancy, antiphospholipid syndrome). Treatment should
not await test results for the levels or activity of ADAMTS13.
DISEASES WITH GLOMERULAR BASEMENT
MEMBRANE ABNORMALITIES
Alport Syndrome
Alport syndrome is an inherited disorder of basement membranes. In
more than one half of patients, the disease results from a mutation
in the COL4A5 gene that codes for the α5 chain of type IV collagen
(α5[IV]). The mutation in COL4A5 disables a developmental switch
in the GBM collagen that retains its embryonic phenotype and results
in a friable GBM.
Alport syndrome is frequently associated with sensorineural hearing loss and ocular abnormalities (e.g., lenticonus of the anterior
lens capsule). Patients characteristically have persistent or intermittent hematuria and usually have mild proteinuria, which progresses
with age and may reach nephrotic range in up to 30%. The disease is
X-linked in approximately 85% of patients, but autosomal recessive
and autosomal dominant patterns of inheritance have been described.
often before the age of 30 years. The disease is usually mild in heterozygous women, but some develop ESRD, usually after the age of 50 years.
The rate of progression to ESRD is fairly constant among affected men
within individual families, but it varies markedly from family to family.
The degree of deafness correlates with the rate of progression to ESRD.
Diagnostic features are usually seen on electron microscopy. At an
early stage, thinning of the GBM may be the only visible abnormality and may suggest thin basement membrane disease. With time, the
GBM thickens, and the lamina densa splits into several irregular layers
that may branch and rejoin, producing a characteristic basket-weave
appearance (Fig. 26.16).
of α3(IV), α4(IV), and α5(IV) chains from the GBM and distal tubular
basement membrane. This abnormality occurs only in patients with
Alport syndrome and is diagnostic. In families with an unquestionable
diagnosis, evaluation of patients with newly diagnosed hematuria can
be limited to kidney ultrasound and urinary tract examination in most
cases. If a defined mutation has been previously identified, molecular
diagnosis of affected men or gene-carrying women is possible. In other
cases, confirmation of the diagnosis can be obtained by examination of
skin biopsy by immunofluorescence for the expression of the α5(IV)
In virtually all male patients, the syndrome progresses to ESRD,
On light microscopy, the glomerular changes are nonspecific.
Immunohistochemical studies of type IV collagen show the absence
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