Chapter 28. Membranoproliferative Glomerulonephritis

• Characterized by persistent hypocomplementemia.
• Disease is most often primary or idiopathic.
• Fifty percent of patients progress to end-stage renal disease over 10–15 years.
• Prednisone is effective in pediatric patients but there is no proven treatment in adults.
• Disease recurs posttransplantation in approximately 25% of patients.

Membranoproliferative glomerulonephritis (MPGN) is the classic renal nomenclature monstrosity that spreads fear among house officers and practitioners. This disease was first described by Rene Habib in 1961 and was linked to decreased serum complement levels in 1965. Since then it has been a recognized cause of serious glomerular disease in pediatric and adult patients throughout the world and represents an important cause of end-stage renal disease. It is defined by a characteristic histopathologic appearance that consists of a lobulated shape to the glomerular tuft, glomerular hypercellularity, thickening of the capillary wall, and splitting of the glomerular basement membrane with a double contour (“tram tracking”). On ultrastructural examination of renal tissue, there are electron-dense deposits in the capillary wall and the distinctive localization of the deposits results in classification of MPGN into type I (subendothelial and mesangial), type II (intramembranous dense deposits), and type III (subendothelial, mesangial, and subepithelial).

The general mechanism of disease for the development of MPGN is dysregulated complement protein activation. Under normal circumstances complement activity, composed of various chemotactic factors and the membrane attack complex, is triggered either through the classical or alternative pathways. The third component of the cascade, C3, occupies a pivotal position in both pathways and is essential to the effector functions of the system. Therefore, a number of regulatory proteins are synthesized to modulate C3 convertase (C3bBb) activity and to prevent the deleterious consequences of uninterrupted complement activation. These include factors H and I, membrane cofactor protein (MCP), and decay accelerating factor.

MPGN is classified into primary and secondary forms. The pathogenesis of MPGN is linked to the underlying etiology of the glomerulopathy (Table 28–1). In the primary forms of MPGN, the mechanism of disease centers around abnormal activation of the complement cascade. In-depth studies of all components of the complement cascade suggest that there are three distinct patterns of complement activation in the three types of MPGN. Thus, in type I disease, the process is initiated by immune complex deposition within the glomerulus and involvement of the classical pathway. The source of the immune complexes is unknown in the idiopathic form of the disease. These patients have low levels of C3, C4, C6, C7, and/or C9. MPGN type I is sometimes associated with the presence of a circulating immunoglobulin (Ig)G or IgM autoantibody that stabilizes the C3 convertase (eg, C3 nephritic factor), thus engendering low C3 levels. A C4 nephritic factor has also been described. In the type II variant, the continuous overactivity of the complement cascade involves an amplification loop in the alternative pathway, characterized mainly by markedly depressed C3 levels. Abnormal complement activation in MPGN can also occur as a consequence of genetic mutations that result in reduced levels of endogenous inhibitors of the process, such as factor H, or because of the presence of C3 nephritic factor, the latter occurring in the majority of patients with MPGN type II (also called dense deposit disease). Animal models in mice and pigs demonstrate the importance of factor H in regulating complement activation and the occurrence of MPGN when circulating levels of this protein are reduced. It is worth noting that unlike hemolytic uremic syndrome, which can develop in patients who have heterozygous genetic defects in factor H, MPGN occurs only in patients who carry homozygous mutations. Other genetic causes of MPGN include isolated C4 deficiency. Finally, the pathogenesis of MPGN type III appears to have features in common with type I disease as well as evidence of activation of the terminal complement pathway with low C3, C5, and properdin levels. In adults, the type III form frequently occurs in association with systemic infection, inflammation, or neoplasm. The presence of MGPN type III in adults should stimulate a search for an underlying systemic process causing it.

Secondary forms of MPGN can occur as a result of various infections including hepatitis B and C, bacterial endocarditis, mixed cryoglobulinemia, malignancies, collagen vascular disease, and chronic liver disease (including specific entities such as α1-antitrypsin deficiency). Indeed, most cases of MPGN, particularly in adults, are attributable to hepatitis C. The genetic forms of MPGN are rarely seen in adults. There are other entities that occur in rare association with MPGN such as Lyme disease and autoimmune thyroiditis. Moreover, the use of some newer medications has been linked to the occurrence of MPGN type I such as granulocyte colony-stimulating factor. Under these various circumstances, it is presumed that there is immune complex-mediated activation of the complement cascade. In animal models of cryoglobulinemia, overexpression of the membrane complement inhibitor, complement receptor 1-related gene/protein y (Crry), does not prevent the development of MPGN.

MPGN is either idiopathic or secondary to an underlying condition. The former category of diseases cannot be prevented. Secondary causes can be avoided by minimizing exposure to the etiologic agent or by primary prevention of the underlying disease.

Symptoms and Signs

The incidence of MPGN is low and accounts for 5–30% of patients with new-onset nephrotic syndrome. It is lower in adults than in children. Several reports suggest that the incidence of MPGN has been declining over the past 10–20 years. Further epidemiologic studies are needed to clarify this issue. The disease is generally sporadic and familial cases are rare. Overall, the disease is equally prevalent in male and female patients but appears to be more common in white compared to black patients.

MPGN can present in a variety of fashions ranging from asymptomatic hematuria to a severe acute glomerulonephritis. In children, MPGN most often presents either as idiopathic nephrotic syndrome or an acute glomerulonephritis that closely resembles acute postinfectious nephritis. It accounts for 5–10% of pediatric cases of new-onset nephrotic syndrome. The profile of MPGN is distinct from minimal change disease and focal segmental glomerulonephritis, which occur more frequently in younger boys, because it is more common in female patients over 8 years of age. The clinical suspicion of MPGN in a child with acute nephritis rises when the C3 levels fail to normalize during the standard 8–12 week observation period or the C4 level is decreased at the onset of disease because it is only rarely decreased in acute postinfectious glomerulonephritis. Cases such as these account for nearly 30% of all instances of MPGN and may have concomitant reduction in the glomerular filtration rate (GFR). Hypertension is present in 50–80% of cases of MPGN and can be severe. Because of concern that corticosteroid therapy may exacerbate the elevation in blood pressure and trigger malignant hypertension, it is advisable to rule out MPGN in a high-risk patient such as an older female child before initiation of daily treatment with steroids, in cases where steroids might otherwise be indicated.

Occasional patients with persistent glomerular hematuria lasting longer than 6 months and hypocomplementemia with MPGN detected on renal biopsy have been reported. Reports from Japan confirm early detection of MPGN in pediatric patients following findings of hematuria and/or proteinuria on routine annual screening urinalyses. Although this testing enables detection of disease prior to the onset of significant hypertension, proteinuria, and/or azotemia, the cost effectiveness of this kind of program requires confirmation in other patient populations. In fact, there are even cases of typical MPGN in children being diagnosed because of persistent hypocomplementemia in the complete absence of any urinary findings. In patients with asymptomatic urinary abnormalities, type III MPGN is more likely to be detected than type I or II disease.

In adult patients, the clinical presentation may be the consequence solely of the renal involvement with edema, hypertension, or gross hematuria. However, in those patients with secondary disease the symptoms and signs usually reflect the underlying cause. Thus, patients with cryoglobulinemia may have weakness, arthralgias involving the knees, hips, and shoulders, and palpable vasculitic lesions on the buttocks and lower extremities. These symptoms may fluctuate over time. The distribution of the purpura is reminiscent of Henoch–Schönlein purpura. Those patients with disease secondary to infection, malignancy, or collagen vascular disease will have manifestations associated with the underlying disease. Interestingly, MPGN may be the first manifestation of hepatitis C infection because affected patients often have no clinical evidence of hepatic disease.

Laboratory Findings

MPGN is characterized by hypocomplementemia, namely reduced C3 and CH50 levels, which is confirmed in 80–90% of patients. In patients with type I MPGN, approximately 40% of those with a low C3 level will also have a low serum C4 level. This is less common in patients with type II or III MPGN. Although the different patterns of circulating complement component levels described above (see Pathogenesis) are useful in discriminating the types of MPGN, this testing is generally not performed in clinical chemistry laboratories and is available only in select research facilities. C3 nephritic factor activity is more common in type II disease, namely 60–70% of patients, compared to 20–25% of patients with type I or III disease. Interestingly, this autoantibody is also detectable in up to 50% of patients with secondary forms of MPGN. It is uncertain whether the presence of C3 nephritic factor indicates an increased risk of progression to end-stage renal disease. C3 nephritic factor can be measured in a hemolytic or a solid phase assay. In adults with cryoglobulinemia, testing should be performed for hepatitis B and C infection. Hepatitis serology should also be evaluated in pediatric patients with MPGN even in the absence of mixed cryoglobulinemia. Other laboratory abnormalities will be present depending upon the underlying disease.

Pathology

The characteristic pathology in MPGN is diffuse mesangial and endothelial cell proliferation, thickening of the capillary wall, and splitting of the glomerular basement membrane (Figure 28–1). Depending upon the severity of the disease, crescent formation may be noted in a substantial percentage of glomeruli. The hypercellularity is enhanced by leukocyte and monocyte infiltration of the glomerular tuft. Special stains such as silver methenamine may be required to visualize the splitting and broadening of the glomerular basement membrane and the trichrome stain to facilitate localization of deposits (Figure 28–2). This is important in classifying the three types of primary MPGN—type I with subendothelial and mesangial, type II with intramembranous, and type III with subendothelial, mesangial, and subepithelial deposits. The trichrome stain is also useful in assessing fibrosis. Special stains such as thioflavin T have been advocated to detect intramembranous dense deposits, especially in cases with focal distribution of the material. The extent of the basement membrane broadening, thought by some to be due to mesangial interposition into the basement membrane, may be a marker of disease severity, with those patients with diffuse changes having a more guarded prognosis compared to those with focal abnormalities. Thus, in type I MPGN focal changes may represent an early manifestation of the disease and explain the more favorable outcome in response to treatment. The histopathologic appearance of cryoglobulinemic MPGN, which is the most common secondary variant in children, closely resembles type I disease.

Immunofluorescence staining is usually positive for C3, IgG, and IgM in a capillary wall and mesangial distribution. Classical complement cascade components are seen in type I but not type II and III MPGN. Electron microscopy confirms the precise location of the deposits, namely subendothelial, mesangial, intramembranous, or subepithelial. The deposits can be numerous or sparse in number, are homogeneous in density, and have no defining ultrastructural appearance.

Other entities that need to be considered in a patient who is being evaluated for MPGN depend upon the specific clinical circumstances. Patients with urinary findings alone may have a mild postinfectious nephritis, hereditary nephritis, or immunoglobulin A (IgA) nephropathy. In those with an overt nephritic syndrome, possibilities include postinfectious nephritis, lupus nephritis, Henoch–Schönlein purpura nephritis, and vasculitis. The likelihood of the last two diseases is increased in patients with a rash, arthralgias, or fever. In those patients who present with the nephrotic syndrome, depending upon the age, the differential diagnosis includes minimal change nephrotic syndrome, focal segmental glomerulosclerosis, and membranous nephropathy. Paraproteinemias (light chain nephropathy), thrombotic microangiopathies, and fibrillary glomerulonephritis can cause a histologic picture that resembles MPGN. Other than systemic lupus erythematosis (SLE) nephritis and atheroembolic renal disease, what distinguishes MPGN from all other diagnostic considerations is persistent hypocomplementemia.

Patients with MPGN can develop sequelae related to the renal manifestations of the disease or the underlying illness. Thus, patients with acute nephritis may experience severe hypertension or congestive heart failure. Those patients with nephrotic syndrome may develop local infections, peritonitis, or thromboembolic events.

Patients with type II disease, which is more common in children than in adults, manifest partial lipodystrophy in nearly 25% of cases. This is characterized by a gradual loss of subcutaneous fat tissue in the face and upper body regions. In vitro studies demonstrate that addition of C3 nephritic factor to murine adipocytes results in cell lysis via a process that requires the presence of factor D and divalent cations. These findings may explain the linkage between MPGN and lipodystrophy. Leptin treatment of lipodystrophy in patients with MPGN for 4–36 months normalizes hyperfiltration and reduces proteinuria. The long-term consequences of this therapy on the progression of the renal disease have not been studied. Finally, there may be other associated findings in patients with MPGN such as mild visual fields and color defects. Retinal angiography demonstrates the presence of choroidal neovascularization.

Patients with MPGN in association with cryoglobulinemia may have ulcerative skin lesions, Raynaud's phenomenon, peripheral neuropathy, hepatomegaly, and signs of cirrhosis.

Pediatric Patients

Children with primary forms of MPGN who are clinically well and free of any symptoms, and who have only minor urinary abnormalities, generally do not require aggressive therapy. These patients may be treated with antihypertensive agents, specifically angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, to reduce proteinuria and prevent progressive renal damage. However, after identification of the disease in 1965 and clarification of the ominous prognosis in the majority of patients, efforts were initiated to implement therapy to retard progression of MPGN. Initial studies performed by Clark West and colleagues at Cincinnati Children's Hospital indicated that prolonged alternate daily therapy with oral steroids favorably impacted on the disease course. The experience in 45 patients treated at that center was summarized in 1986. These patients were given prednisone 60 mg/m2 or 2–2.5 mg/kg every other day for an average period of 6.5 years with an improved outcome compared to historic controls or patients treated at other centers. Hematuria resolved in 80%, renal function remained normal or improved in 73%, and 62% of those with nephrotic syndrome had normalization of serum albumin concentration. Hypocomplementemia resolves within 4–12 months of initiation of therapy in most patients. However, it may persist in some patients and does not necessarily indicate deteriorating renal histopathology. Repeat biopsies performed after 2 years of therapy indicated an increase in open capillary loops and a reduction in mesangial matrix expansion. However, it is important to note that there was an increase in glomerulosclerosis despite clinical improvement. This may reflect irreversible damage to nephrons prior to initiation of therapy. The efficacy of therapy was greater in patients who began treatment within 1 year of disease onset. In Japan where school urinary screening programs facilitate early detection of MPGN, treatment with prolonged alternate day steroids (4–12 years) after prednisolone pulse or cyclophosphamide therapy achieved remission and resulted in normalization of the urinalysis and stabilization of GFR in 15 patients and mild proteinuria in 4 others who were followed for 10–24 years.

The open-label treatment findings of the Cincinnati group have been confirmed in a randomized clinical trial performed by the International Study of Kidney Diseases in Children. Eighty children with MPGN (42 type I, 14 type II, 17 type III, and 7 nontypable) were assigned to prednisone 40 mg/m2 every other day or placebo for an average of 41 months. All patients had significant proteinuria and a GFR >70 mL/minute/1.73 m2. Treatment failure, defined as a 30% increase in the baseline serum creatinine or >35 μmol/L increment, occurred in 55% of placebo versus 40% of prednisone-treated patients. Life table analysis indicated 61% renal survival at 130 months in prednisone-treated patients versus 12% in placebo-treated patients (p = 0.07). The response was comparable in type I and III MPGN. Although the outcome was less clear in type II disease, a response to more prolonged alternate day steroids in this subtype has been documented.

Based on this experience, it is recommended that alternate steroid therapy be given to all pediatric patients for at least 2 years if the GFR is well preserved (>70 mL/minute/1.73 m2). The beneficial impact of treatment in patients with more advanced disease has not been established. The dose should be approximately 40–60 mg/m2 every other day. Some investigators have reported good outcomes in a small series of patients given lower steroid doses; however, the minimum effective dose has not been systematically assessed. The need for prolonged therapy should be guided by the clinical response (serum complement level, degree of hematuria, urinary protein excretion, and calculated GFR) and repeat renal histopathologic assessment (after 2 years of steroid treatment, later in a course of therapy, or if there is evidence of recurrent disease).

Adult Patients

Steroid Therapy

There is widespread concern about the risks of prolonged steroid therapy in adults. Therefore, the current evidence-based medicine recommendation is to prescribe steroids only for adults with nephrotic syndrome or impaired kidney function. Treatment is maintained for 6 months. The therapy may be extended until remission is achieved using the lowest possible dose of steroids. Patients with asymptomatic urinary findings and patients who fail to respond to steroids should be treated conservatively. Angiotensin-converting enzyme inhibitors have been demonstrated to be effective in reducing proteinuria in patients with MPGN.

Antiplatelet and Anticoagulant Therapy

It has been suggested that administration of the antiplatelet drug dipyridamole slowed deterioration in kidney function in patients with MPGN. However, a follow-up study failed to demonstrate efficacy of a combination of dipyridamole, cyclophosphamide, and warfarin. In a meta-analysis of five studies of antiplatelet therapy, no beneficial effect was discernible if the timing of the onset of treatment relative to the time of disease onset was accounted for. Thus, based on currently available evidence, these treatments are not recommended.

Cryoglobulinemic Mpgn Secondary to Hepatitis C

In patients with hepatitis C infection and MPGN, interferon-α therapy for 6–12 months can achieve remission in 60% of patients. However, most will relapse within 3–6 months. Use of pegylated interferon and the addition of ribavirin to the regimen may improve the response. Current practice is to administer the combination of antiviral agents for 6 months and then switch to low dose every other day steroids. Removal of cryoglobulins with cryofiltration is an experimental modality that may work by removing cryoglobulins from the circulation. Dosing regimens for both pegylated interferon and ribavirin are controversial in patients with diminished renal function. Serious side effects have been observed in patients treated with these agents whose renal function is impaired.

Other Therapies

There have been isolated case reports claiming that plasmapheresis is a useful therapy in patients with severe idiopathic MPGN and acute renal failure or rapidly deteriorating disease. However, the response was not uniform. Moreover, this treatment modality is invasive and costly. Therefore, it should not be utilized routinely as a first-line treatment. Mycophenolate mofetil has been tried in patients with cryoglobulinemic MPGN related to hepatitis B infection. Although treatment resulted in reduced proteinuria, viral replication was induced by the drug. Therefore, caution is advisable when considering this immunosuppressive agent for the treatment of MPGN. Plasmapheresis may be useful short term during the acute phase of treatment in patients with serious vasculitic flares from hepatitis C-associated cryoglobulinemia, although activation of the hepatitis is a concern.

Pediatric Patients

In general, the long-term outlook for untreated patients with MPGN is guarded. Although occasional children and adolescents have been described who achieve a spontaneous remission, nearly 50% of patients progress to end-stage renal disease over 10–15 years. An elevated serum creatinine concentration at the time of diagnosis, nephrotic-range proteinuria, severe hypertension, crescents in >50% of glomeruli, diffuse interstitial fibrosis and tubular atrophy, and a reduced calculated GFR after 1 year of treatment are indicators of a poor outcome. The prognosis is worse in patients with primary versus secondary forms of MPGN. In addition, type II MPGN may have a more ominous long-term outlook compared to type I and III disease.

Recent reports confirm the poor prognosis of MPGN in pediatric patients. For example, in a series of 53 children, ranging in age from 13 months to 15 years, who were treated at two English centers over a 20-year period from January 1980 to December 1999, the mean renal survival time was 12.2 years. Interestingly, the histologic subtype, level of proteinuria below the nephrotic range, and specific therapy had no impact on the long-term outcome. However, the favorable experience in Japan, where MPGN is diagnosed as a result of school urinary screening programs, suggests that the prognosis may be improved following early detection and prompt implementation of corticosteroid therapy.

Adult Patients

Although there is an unstated concern that adults with MPGN do worse than children and adolescents, in general, the outcome of MPGN is comparable in adult versus pediatric patients. Thus, 50% of patients progress to end-stage renal disease within 5 years of the diagnostic renal biopsy and this percentage rises to 64% after 10 years of follow-up. The features associated with a poor prognosis are similar to those noted in pediatric patients, namely nephrotic syndrome at onset, more extensive tubulointerstitial lesions and interstitial fibrosis, and a reduced GFR. This is a compelling argument in favor of optimal control of blood pressure, preferably with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Treatment for hepatitis C with antivirals before renal involvement occurs may alter the incidence and natural history of secondary MPGN as treatment becomes more commonly implemented.

Recurrence Posttransplantation

One of the more discouraging features about primary MPGN is that the disease recurs in 20–30% of patients who receive a kidney transplant. The risk approaches 90% in those with type II disease. Time after transplant, HLA B8DR3, and a living related donor may be risk factors for recurrent MPGN. Hepatitis C MPGN can also recur in transplants or develop de novo. It is important to distinguish recurrent MPGN from allograft nephropathy, which can have a similar histopathologic appearance. The presence of immune deposits points toward recurrent disease. Nearly 40% of patients with recurrent MPGN will experience irreversible loss of graft function. This compounds the problem immeasurably because the likelihood of recurrent MPGN increases with each subsequent transplant procedure. There is no therapy to reduce this risk and patients should be managed on a case by case basis.

The Web site www.medicine.uiowa.edu/kidneeds/ is organized by Dr. Richard Smith at the University of Iowa and deals with MPGN type II. It is highly recommended by C. Fred Strife, MD, at the University of Cincinnati Children's Hospital.