*Membranous Nephropathy

Chapter: Membranous Nephropathy
McMaster Section Editor(s): Christine M. Ribic, Karen C.Y. To
Section Editor(s) in Interna Szczeklika: Franciszek Kokot, Robert Drabczyk
McMaster Author(s): Matthew Miller
Author(s) in Interna Szczeklika: Marian Klinger, Ilona Dziemianko, Krzysztof Kazimierczak, Robert Drabczyk
Additional Information

Definition, Etiology, PathogenesisTop

Membranous nephropathy (MN) is a histologic diagnosis characterized by thickening of the glomerular basement membrane (GBM) on light microscopy without cellular proliferation. It is an immune-mediated disease with immune complex deposition near or on the foot processes of the podocytes. Deposition and subsequent complement activation lead to GBM damage and podocyte effacement, resulting in substantial proteinuria.

The majority (approximately two-thirds) of cases are idiopathic. The inciting event for antibody deposition in primary MN is unknown. Circulating antibodies against phospholipase A2 receptors on the podocyte are observed in 70% to 80% of patients with primary MN but not in those with secondary causes. Causes of secondary MN include malignancy (primarily solid tumors, including lung and gastrointestinal tumors), connective tissue diseases (especially systemic lupus erythematosus), hepatitis B and C infections, drugs (penicillamine, gold salts, nonsteroidal anti-inflammatory drugs, captopril), and sarcoidosis.

Clinical Features Top

MN may develop in patients of all ages but is most frequently seen in middle-aged individuals and is rare in children. It is more common in males and in whites. The majority of patients present with nephrotic syndrome, with the remainder having non–nephrotic range proteinuria. Microscopic hematuria occurs in approximately 30% of patients. Hypertension and decreased glomerular filtration rate (GFR) at presentation are uncommon but can develop over the course of the disease. Reported rates of thromboembolic events vary considerably and range between 5% and 50%. Approximately one-third of patients have spontaneous remissions, which are more likely in individuals with lower degrees of proteinuria.

DiagnosisTop

Diagnosis is based on histology. The classic finding is thickening of the GBM with “spikes” of the GBM projecting around immune complex deposits on light microscopy with the silver stain. Assays are available for antibodies to phospholipase A2 receptors, which can assist in differentiating primary MN from secondary MN.

TreatmentTop

Treatment of primary MN is based upon the risk of progression of renal disease. Patients with proteinuria <4 g/d and normal renal function over 6 months of observation progress rarely. Individuals with normal or near-normal renal function and proteinuria between 4 and 8 g per day despite conservative management are at increased risk (approximately 55% are at risk of progressing to chronic kidney disease), and those with persistent proteinuria >8 g/d or worsening renal function are at high risk of progression.

Conservative management for all patients should include renin-angiotensin system blockade to control hypertension and proteinuria. Patients should also be treated for complications of nephrotic syndrome. Treating the underlying cause of secondary MN usually results in remission.

Immunosuppressive therapy for primary MN is recommended in patients who have any of the following:

1) Persistent proteinuria >4 g/d despite maximal conservative management for 6 months.

2) Severe symptoms or complications of nephrotic syndrome.

3) Rising serum creatinine levels (>30%) within 6 to 12 months of diagnosis.

When initiating immunosuppression, glucocorticoids alone are ineffective at treating MN. The Ponticelli regimen is the recommended initial therapy, which consists of alternating months of IV methylprednisolone followed by oral prednisone for 1 month and then an alkylating agent (oral cyclophosphamide or chlorambucil) for 1 monthEvidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision. Ponticelli C, Altieri P, Scolari F, et al. A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy. J Am Soc Nephrol. 1998 Mar;9(3):444-50. PubMed PMID: 9513907.; cyclophosphamide is preferred due to fewer adverse effects. This cycle is repeated for 6 months. Calcineurin inhibitors (cyclosporine [INN ciclosporin] with low-dose prednisone or tacrolimus without prednisone) can be considered as alternatives.

PrognosisTop

In the majority of patients successful treatment of the underlying condition leads to the resolution of secondary MN. In drug-induced MN, discontinuation of the causative agent almost always leads to resolution of MN, although remission can be delayed (up to years with gold and penicillamine). The prognosis in idiopathic MN depends largely on the degree of proteinuria, with end-stage renal disease occurring after 15 years in approximately 40% of patients.

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