Membranous Nephropathy

Definition, Etiology, PathogenesisTop

Membranous nephropathy (MN) is a histologic diagnosis characterized by thickening of the glomerular basement membrane (GBM) on light microscopy. It is an immune-mediated disease with immune complex deposition affecting the podocytes. This leads to complement activation causing GBM and podocyte damage, resulting in nephrotic-range proteinuria.

The majority (approximately two-thirds) of cases are idiopathic. Circulating antibodies against phospholipase A2 receptors on the podocyte are observed in 70% of patients with primary MN but not in those with secondary causes. Causes of secondary MN include malignancy, connective tissue diseases (especially systemic lupus erythematosus), hepatitis B and C virus 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 ~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 from 5% to 15%.

DiagnosisTop

Diagnosis can be obtained based on histology. The classic finding is thickening of the GBM and demonstration of immune complex deposits on light microscopy. Diagnosis can also be confirmed by the presence of antibodies against phospholipase A2 receptors (PLA2R), in which case kidney biopsy is not required to confirm the diagnosis and can also assist in differentiating primary MN from secondary MN. An age-appropriate screen for malignancy should be undertaken in all patients with 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 follow-up 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 (~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 high-risk features of progression and in the presence of antibodies against phospholipase A2 receptors. The initial choice of immunosuppression depends on the presence of worsening kidney function. When initiating immunosuppression, glucocorticoids alone are ineffective at treating MN.

If there is normal estimated GFR (eGFR) but severe symptoms or complications of nephrotic syndrome occur (eg, pulmonary embolism), then rituximab is recommended.Evidence 1Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Fervenza FC, Appel GB, Barbour SJ, et al; MENTOR Investigators. Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy. N Engl J Med. 2019 Jul 4;381(1):36-46. doi: 10.1056/NEJMoa1814427. PMID: 31269364. Calcineurin inhibitors (CNIs) (eg, tacrolimus/cyclosporin) with low-dose prednisone or without prednisone can be considered as alternatives; however, CNI monotherapy has a higher risk of relapse upon discontinuation.

If eGFR <60 mL/min, then a combination of oral cyclophosphamide and pulse methylprednisolone followed by oral prednisone for 6 months (the modified Ponticelli regimen) can be considered.Evidence 2Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision and indirectness. 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. doi: 10.1681/ASN.V93444. PMID: 9513907. Longitudinal monitoring of anti-PLA2R antibody levels after starting therapy may be useful for evaluating treatment response in patients with MN and can be used to guide therapy adjustments.

Based on risk factors, anticoagulation therapy should be considered in patients with nephrotic syndrome whose serum albumin is <28 g/L, especially in those with MN who are at higher risk of deep vein thrombosis.

PrognosisTop

The prognosis in (primary) MN largely depends on the degree of proteinuria. Approximately one-third of patients have spontaneous remissions, which are more likely in those with lower degrees of proteinuria, whereas end-stage kidney disease develops after 15 years in ~40% of patients with high-risk features. If untreated with immunosuppression, primary MN with nephrotic syndrome can be associated with a high risk of renal function deterioration. With immunosuppression treatment, the incidence of progressive kidney function impairment leading to end-stage kidney disease has drastically declined.

In the majority of patients, successful treatment of the underlying condition leads to 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.