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Membranoproliferative Glomerulonephritis

(Mesangiocapillary Glomerulonephritis; Lobular Glomerulonephritis)

by Navin Jaipaul, MD, MHS

Membranoproliferative glomerulonephritis is a heterogeneous group of disorders that share mixed nephritic and nephrotic features and microscopic findings. They mostly affect children. Cause is immune complex deposition that is idiopathic or secondary to a systemic disorder. Diagnosis is by renal biopsy. Prognosis is generally poor. Treatment, when indicated, is with corticosteroids and antiplatelet drugs.

Membranoproliferative glomerulonephritis (GN) is a group of immune-mediated disorders characterized histologically by glomerular basement membrane (GBM) thickening and proliferative changes on light microscopy. There are 3 types, each of which may have primary (idiopathic) or secondary causes. Primary forms affect children and young adults between ages 8 and 30 and account for 10% of cases of nephrotic syndrome in children; secondary causes tend to affect adults > 30. Men and women are affected equally. Reported familial cases of some types suggest genetic factors play a role in at least some cases. Many factors contribute to hypocomplementemia.

Type I (mesangial proliferation with immune deposits) accounts for 80 to 85% of cases. The idiopathic form is rare. Type I most commonly occurs secondary to one of the following:

  • Systemic immune complex disorder (eg, SLE, mixed cryoglobulinemia, Sjögren syndrome)

  • Chronic infection (eg, bacterial endocarditis, HIV infection, hepatitis B or C infection, visceral abscess, ventriculoatrial shunt infection)

  • Cancer (eg, chronic lymphocytic leukemia, lymphomas, melanoma)

  • Other disorders (eg, partial lipodystrophy, C2 or C3 deficiencies, sarcoidosis, thrombotic microangiopathies)

Type II (similar to type I with less mesangial proliferation and with GBM dense deposits) accounts for 15 to 20%. It is probably an autoimmune disorder in which an IgG autoantibody (C3 nephritic factor) binds C3 convertase, rendering C3 resistant to inactivation; immunofluorescent staining identifies C3 around dense deposits and in mesangium.

Type III is thought to be a disorder similar to type I and accounts for few cases. Cause is unknown but may be related to immune complex (IgG, C3) deposition. An IgG autoantibody against the terminal component of complement is found in 70% of patients. Subepithelial deposits can occur focally and appear to disrupt the GBM.

Symptoms and Signs

Symptoms and signs are those of nephrotic syndrome in 60 to 80% of cases. Symptoms and signs of nephritic syndrome (acute GN) are presenting features in 15 to 20% of cases of type I and III disease and in a higher percentage of type II disease. At diagnosis, 30% of patients have hypertension and 20% have renal insufficiency; hypertension often develops even before GFR declines. Patients with type II disease have a greater incidence of ocular abnormalities (basal laminar drusen, diffuse retinal pigment alterations, diskiform macular detachment, choroidal neovascularization), which ultimately impair vision.

Diagnosis

  • Renal biopsy

  • Serum complement profile

  • Serologic tests

Diagnosis is confirmed by renal biopsy. The location of immune complex deposits can help differentiate between types; typically subendothelial and mesangial in type I, intra-membranous in type II, and subepithelial in type III. Other tests are also done.

Serum complement profiles are more frequently abnormal in membranoproliferative GN than in other glomerular disorders and provide supportive evidence of the diagnosis. C3 levels are often low. In type I disease, the classic complement pathway is activated and C3 and C4 are decreased. C3 may be decreased more often than C4 at diagnosis and decreases further during follow-up, but eventually normalizes. In type II disease, the alternate complement pathway is activated and C3 is more frequently and severely reduced than in type I while C4 levels are normal. In type III disease, C3 is reduced but C4 is normal. C3 nephritic factor is detectable in 80% of patients with type II and in some patients with type I disease. Terminal complement nephritic factor is detectable in 20% of patients with type I, rarely in patients with type II, and 70% of patients with type III disease.

Serum Complement Profiles in Membranoproliferative Glomerulonephritis

Type

Complement Profile

Comments

Type I

Classic complement pathway activated

C3: Decreased

C4: Decreased

C3 may be decreased more often than C4 at diagnosis, decreases further during follow-up, and eventually normalizes.

C3 nephritic factor can be detected in some patients.

Terminal complement nephritic factor can be detected in 20% of patients.

Type II

Alternate complement pathway activated

C3: Frequently and severely reduced

C4: Normal

C3 nephritic factor can be detected in 80% of patients.

Terminal complement nephritic factor can rarely be detected.

Type III

C3: Reduced

C4: Normal

Terminal complement nephritic factor can be detected in 70% of patients.

Serologic tests (eg, for SLE, hepatitis B and C virus, and cryoglobulinemia) are warranted to check for secondary causes of type I disease.

CBC, often obtained in the course of diagnostic evaluation, demonstrates normochromic-normocytic anemia, often out of proportion to the stage of renal insufficiency (possibly because of hemolysis), and thrombocytopenia from platelet consumption.

Prognosis

Prognosis is good if a condition causing secondary membranoproliferative GN is successfully treated. Idiopathic type I membranoproliferative GN often progresses slowly; type II progresses more rapidly. In general, the long-term prognosis is poor. End-stage renal disease occurs in 50% of patients at 10 yr and in 90% at 20 yr. Spontaneous remission occurs in < 5% with type II. Type I membranoproliferative GN recurs in 30% of kidney transplantation patients; type II recurs in 90% but, despite this high recurrence rate, leads to graft loss only infrequently. Outcome tends to be worse if proteinuria is in the nephrotic range.

Treatment

  • Corticosteroids for children with nephrotic-range proteinuria

  • Dipyridamole and aspirin for adults

  • Kidney transplantation for patients with end-stage renal disease

Underlying disorders are treated when possible. Specific therapy is probably not indicated for patients with non-nephrotic–range proteinuria because the disorder usually progresses slowly.

Among children with nephrotic-range proteinuria, treatment with corticosteroids (eg, prednisone 2.5 mg/kg po once/day on alternate days [maximum 80 mg/day]) for 1 yr, followed by tapering to a maintenance dose of 20 mg on alternate days for 3 to 10 yr, may stabilize renal function. However, corticosteroid treatment may retard growth and cause hypertension.

Among adults, dipyridamole 225 mg po once/day with aspirin 975 mg po once/day for 1 yr may stabilize renal function at 3 to 5 yr, but at 10 yr there is no difference from placebo. Studies of antiplatelet therapy yield inconsistent results.

Alternate therapies are sometimes substituted for the usual treatments (eg, corticosteroids could exacerbate underlying hepatitis C). Alternative therapies include pegylated interferon alfa 2A or 2B (with addition of ribavirin if creatinine clearance is > 50 mL/min) for hepatitis C virus–associated disease and plasma exchange with corticosteroids for concomitant severe cryoglobulinemia or rapidly progressive GN. ACE inhibitors may decrease proteinuria and help control hypertension.

Key Points

  • Membranoproliferative GN is a group of immune-mediated disorders with some common histologic features.

  • Patients most often present with nephrotic syndrome, but they may present with nephritic syndrome.

  • Confirm the diagnosis with renal biopsy and obtain serum complement profile and serologic tests.

  • Treat children who have nephrotic range proteinuria with corticosteroids.

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Drugs Mentioned In This Article

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  • VIRAZOLE
  • PERSANTINE
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  • RAYOS

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