Membranous nephropathy

1. What is membranous nephropathy (MN)?

MN is a common immune-mediated glomerular disease that remains the leading cause of nephrotic syndrome in white adults. It is a histologic diagnosis based on the presence of immunoglobulins (Ig; usually IgG and C3) deposition along the capillary walls on immunofluorescence microscopy and subepithelial deposits along the glomerular basement membrane (GBM) on electron microscopy (EM). MN can be either a primary or secondary disease. Secondary MN is caused by:

• Autoimmune diseases

  • Systemic lupus erythematosus

  • Autoimmune thyroiditis

  • Rheumatoid arthritis

  • Sjögren syndrome

• Infections

  • Hepatitis B

  • Hepatitis C

  • Malaria

  • Schistosomiasis

  • Tuberculosis

  • Leprosy

• Drugs

  • Penicillamine

  • Gold

  • Nonsteroidal antiinflammatory drugs

  • Captopril

• Malignancies

  • Prostate cancer

  • Lung cancer

  • Colon cancer

  • Stomach cancer

  • Breast cancer

  • Cervical cancer

  • Lymphoma

  • Leukemia

2. What are the kidney biopsy findings of MN?

The diagnosis of MN is based on the following findings:

• Thickened GBM, often showing pinholes or spikes on silver and periodic acid–Schiff stains, and occasionally subepithelial fuchsinophilic deposits on trichrome stains

• Immunofluorescence microscopy showing granular Ig (usually IgG and C3) along the capillary walls

• Subepithelial deposits on EM.

However, in the early stages of the disease, light microscopy may be completely normal. Based on the location of the deposits on EM, MN has been divided into four stages:

• Stage I, sparse small deposits without thickening of the GBM

• Stage II, more extensive subepithelial deposits with formation of basement membrane spikes between the deposits and thickening of the GBM

• Stage III, combination of stage II along with deposits completely surrounded by basement membrane (intramembranous deposits)

• Stage IV, incorporation of deposits in the GBM and irregular thickening of the GBM

• However, these stages have no correlation with clinical outcome.

3. What are the clinical manifestations of MN?

At presentation, 60% to 70% of patients have nephrotic syndrome, with the remaining 30% to 40% of patients presenting with proteinuria <3.5 g/24 hours in an otherwise asymptomatic patient. Although more than 90% of patients have no evidence of impaired kidney function at the time of presentation, hypertension at onset is found in 10% to 20% of patients. The presence of microscopic hematuria is common (30% to 40%), but macroscopic hematuria and red cells casts are rare and these findings should suggest an alternative diagnosis. Findings of physical examination may vary from mild peripheral edema to full-blown nephrotic syndrome, including ascites and pericardial and pleural effusions.

4. What is the cause of primary MN?

M-type phospholipase A2 receptor (PLA2R) on the human podocytes is the target antigen in at least 70% of patients with primary MN, and anti-PLA ₂ R autoantibodies have been detected in the sera of these patients. Thrombospondin type-1 domain containing 7A (THSD-7A) is another podocyte antigen that accounts for an additional 10% of patients with primary MN that are negative for anti-PLA ₂ R antibody. As a rule, patients with positive anti-THSD-7A autoantibodies have negative sera for anti-PLA ₂ R antibodies, although rare cases of dual positivity have been reported. Taken together, autoantibodies to these podocyte-specific antigens are the cause of primary MN in almost 80% of patients. Although these findings do not explain the cause in all cases of MN, they suggest that additional antibodies against podocyte proteins are likely to be identified.

5. Can kidney biopsy findings be helpful in identifying secondary causes of MN?

Although it is often difficult to determine whether the MN is primary or secondary based on kidney pathology, certain features are helpful in identifying a primary versus secondary cause. Commercial tests are available that allow for staining of kidney tissue for anti-PLA ₂ R and THSD-7A, which aids in identifying primary forms of MN. Features in favor of a secondary cause, in particular an autoimmune disease, include the following:

• Proliferative features (mesangial or endocapillary)

• Full-house pattern of Ig staining including staining for C1q on immunofluorescence microscopy

• Glomerular deposits predominantly containing Ig other than IgG4 on immunofluorescence microscopy

• Electron-dense deposits in the subendothelial location of the capillary wall and mesangium or along the tubular basement membrane and vessel walls

• Endothelial tubuloreticular inclusions on EM (EM showing only few superficial scattered subepithelial deposits may suggest a drug-associated secondary MN)

6. What is the clinical course of MN?

MN is a chronic disease, with spontaneous remission and relapses clearly documented. The clinical course is characterized by great variability in the rate of disease progression, and the natural course is difficult to assess in part because of the selection criteria, geographic variability, and genetic characteristics of the subjects presented in different studies. Although in most patients the disease progresses relatively slowly, approximately 40% of patients eventually develop ESKD after focal segmental glomerulosclerosis and lupus nephritis.

7. What evaluation should be considered if there is rapid loss of kidney function?

When progressive loss of kidney function occurs faster than usual, patient should be evaluated for other causes of worsening kidney function, such as acute tubular necrosis, acute interstitial nephritis, kidney vein thrombosis, or urinary tract obstruction. A superimposed crescentic glomerulonephritis should also be considered in the differential, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and anti-GBM disease in particular. A repeat kidney biopsy may be indicated in these patients.