Residency · Residency · Nephrology

Membranous Nephropathy

Introduction

Membranous nephropathy is the most common cause of nephrotic syndrome in White adults over the age of 40, characterized pathologically by subepithelial immune complex deposits along the glomerular basement membrane with uniform thickening of the capillary walls. Primary membranous nephropathy, accounting for 75 to 80 percent of cases, is an autoimmune disease driven by antibodies against podocyte surface antigens, most commonly the phospholipase A2 receptor (PLA2R) and thrombospondin type 1 domain-containing 7A (THSD7A). Secondary membranous nephropathy, comprising the remaining 20 to 25 percent, is associated with malignancy, infections, autoimmune disease, and drugs. The natural history of primary membranous nephropathy follows the "rule of thirds": approximately one-third of patients experience spontaneous remission, one-third have persistent proteinuria with stable renal function, and one-third progress to chronic kidney disease and eventual renal failure.

Pathogenesis

Primary Membranous Nephropathy

The discovery of anti-PLA2R antibodies in 2009 transformed the understanding and management of membranous nephropathy. PLA2R is a transmembrane glycoprotein expressed on the surface of podocyte foot processes, and circulating IgG4-subclass autoantibodies bind to PLA2R in situ, forming immune complexes on the subepithelial surface of the GBM. These antibodies are present in 70 to 80 percent of primary MN cases and have a specificity exceeding 99 percent for distinguishing primary from secondary disease. Antibody titers correlate with disease activity, treatment response, and relapse risk. The concept of epitope spreading describes the sequential development of reactivity against different domains of PLA2R, beginning with the CysR domain and progressing to CTLD1 and CTLD7 domains, with reactivity to more epitopes predicting more refractory disease.

Anti-THSD7A antibodies are present in 3 to 5 percent of primary MN cases and are also of the IgG4 subclass. Notably, THSD7A-associated MN carries an approximately 20 percent association with malignancy, necessitating thorough cancer screening in these patients. Additional podocyte antigens continue to be identified, including NELL-1, semaphorin 3B, PCDH7, HTRA1, and NTNG1, with NELL-1-associated MN being linked to a segmental pattern and malignancy.

Complement activation in primary MN occurs predominantly through the lectin and terminal pathways rather than the classical pathway, as IgG4 does not fix complement through C1q binding. The membrane attack complex C5b-9 inserts into the podocyte membrane, producing sublytic injury that disrupts the podocyte cytoskeleton, causes foot process effacement, and leads to proteinuria.

Secondary Membranous Nephropathy

Secondary causes should be systematically evaluated in all cases of MN. Malignancy is found in 5 to 20 percent of cases, particularly solid tumors of the lung, colon, prostate, stomach, and breast, with risk increasing substantially with age, especially in patients over 65 and those who are anti-PLA2R negative. Lupus nephritis class V produces a membranous pattern distinguished by its "full-house" immunofluorescence. Hepatitis B is the most common infectious cause worldwide. Drug-induced MN can result from NSAIDs, penicillamine, gold, bucillamine, and checkpoint inhibitors. Secondary MN typically has IgG1 or IgG2 subclass deposits rather than the IgG4 predominance of primary disease, and may demonstrate mesangial or subendothelial deposits in addition to the characteristic subepithelial deposits.

<image>Pathogenesis diagram of primary membranous nephropathy. Show a cross-section of the glomerular capillary wall with a podocyte foot process expressing PLA2R on its surface. Depict circulating anti-PLA2R IgG4 antibodies binding to the PLA2R antigen, forming in situ immune complexes on the subepithelial surface of the GBM. Show complement activation via the lectin pathway (MBL binding to IgG4) leading to C5b-9 (membrane attack complex) formation and insertion into the podocyte membrane. Illustrate the downstream effects: podocyte cytoskeletal disruption, foot process effacement, slit diaphragm disruption, and proteinuria. Include a separate inset showing the stages of GBM remodeling: Stage I (subepithelial deposits without GBM changes), Stage II (GBM spikes between deposits), Stage III (deposits incorporated into thickened GBM), Stage IV (irregular thickening with lucent deposits).</image>

Diagnosis

Clinical Presentation

Membranous nephropathy presents with the insidious onset of nephrotic syndrome, typically manifesting as progressive peripheral edema and frothy urine. Proteinuria is usually heavy, often exceeding 3.5 grams per day and frequently reaching levels above 10 grams per day. Microscopic hematuria is present in approximately 50 percent of cases but is not accompanied by red blood cell casts. Hypertension is less common at presentation than in other forms of glomerulonephritis. MN carries the highest thromboembolic risk among the nephrotic diseases, with renal vein thrombosis occurring in 5 to 35 percent of cases, along with pulmonary embolism and deep venous thrombosis. Thromboembolic risk correlates with the severity of proteinuria and hypoalbuminemia, with serum albumin below 2.8 g/dL representing a threshold for high risk.

Serologic Testing

Serum anti-PLA2R antibody testing by ELISA or cell-based indirect immunofluorescence assay has a sensitivity of 70 to 80 percent and a specificity exceeding 99 percent for primary MN. If anti-PLA2R is negative, anti-THSD7A should be tested. Complement C3 and C4 levels are usually normal in primary MN. ANA and anti-dsDNA testing rules out lupus, and hepatitis B and C serologies exclude infectious etiologies. Age-appropriate cancer screening is essential, particularly in anti-PLA2R-negative patients and those over age 65.

Renal Biopsy

On light microscopy, diffuse GBM thickening without hypercellularity is the characteristic finding. Silver staining reveals the "spike and dome" pattern, in which GBM spikes project between the subepithelial deposits, and PAS staining shows uniformly thickened capillary walls. On immunofluorescence, granular IgG and C3 are deposited along capillary walls in a subepithelial pattern, with IgG4 subclass predominance in primary MN. PLA2R staining on tissue sections is positive in approximately 80 percent of primary MN cases, even when serum anti-PLA2R is negative. A full-house pattern indicates lupus class V MN. Electron microscopy reveals subepithelial electron-dense deposits that progress through four stages of GBM remodeling: stage I with small deposits and normal GBM, stage II with deposits and intervening GBM spikes, stage III with deposits incorporated into thickened GBM, and stage IV with irregularly thickened GBM containing lucent, resolving deposits.

Risk Stratification and Prognosis

Anti-PLA2R Antibody Levels

Higher anti-PLA2R titers at diagnosis predict a lower probability of spontaneous remission and higher risk of disease progression. A critically important clinical concept is that immunologic remission, defined by the decline in anti-PLA2R antibody levels, precedes the clinical response of proteinuria reduction by 3 to 6 months. Persistent antibody positivity after treatment predicts relapse. Serial monitoring of anti-PLA2R levels guides treatment decisions: if antibody levels decline, a clinical proteinuria response is likely to follow, and treatment should not be prematurely judged as having failed.

Clinical Risk Factors

Additional clinical risk factors for progression include sustained proteinuria exceeding 8 grams per day over 6 months, decline in eGFR during the observation period, male sex, older age, and severe hypoalbuminemia below 2.0 g/dL.

KDIGO 2024 Risk-Based Approach

The KDIGO 2024 guidelines recommend a risk-stratified approach to management. Low-risk patients with proteinuria below 3.5 grams per day, normal GFR, and low anti-PLA2R levels should receive supportive care with monitoring. Moderate-risk patients with proteinuria between 3.5 and 8 grams per day and stable GFR should undergo a 6-month observation period on supportive care, with immunosuppression initiated if there is no improvement. High-risk patients with sustained proteinuria exceeding 8 grams per day, declining GFR, or very high anti-PLA2R levels should be considered for earlier immunosuppression. Very high-risk patients with rapidly declining GFR or nephrotic complications warrant immediate immunosuppressive therapy.

Treatment

Supportive Care (All Patients)

Supportive care is indicated for all patients regardless of risk stratification. RAAS blockade with an ACE inhibitor or ARB reduces proteinuria and provides renoprotection. SGLT2 inhibitors are emerging as an important adjunctive therapy for additional antiproteinuric effect. Sodium restriction to less than 2 grams per day, diuretics for edema management, and statin therapy for nephrotic dyslipidemia are standard components. Prophylactic anticoagulation should be strongly considered when serum albumin falls below 2.5 g/dL, given the exceptionally high thromboembolic risk in MN. Although no randomized controlled trials guide this decision, observational data and the Leiden thrombophilia risk model support this approach. Both direct oral anticoagulants and warfarin are used, with some experts preferring DOACs for convenience.

Immunosuppressive Regimens

Rituximab (First-Line per KDIGO 2024)

Rituximab has emerged as the first-line immunosuppressive therapy for primary MN based on three pivotal trials. The MENTOR trial in 2019 demonstrated that rituximab was non-inferior to cyclosporine at 12 months and superior at 24 months for achieving complete or partial remission, with 60 percent versus 20 percent maintaining remission at 24 months. The STARMEN trial in 2023 showed comparable efficacy between tacrolimus-rituximab sequential therapy and the modified Ponticelli regimen. The RI-CYCLO trial in 2021 demonstrated similar remission rates between rituximab and cyclophosphamide-steroid therapy at 24 months. Dosing typically employs either 1000 mg intravenously on day 1 and day 15 or 375 mg/m2 weekly for 4 doses, with retreatment guided by anti-PLA2R levels and proteinuria response. CD20 B-cell counts are monitored, and redosing is considered if B cells return and proteinuria persists or anti-PLA2R levels rise.

Cyclophosphamide-Corticosteroid (Modified Ponticelli)

The modified Ponticelli regimen employs alternating monthly cycles of intravenous methylprednisolone followed by oral prednisone and oral cyclophosphamide over 6 months. Months 1, 3, and 5 begin with methylprednisolone 1 gram intravenously for 3 days followed by oral prednisone at 0.5 mg/kg/day, while months 2, 4, and 6 consist of cyclophosphamide at 2.0 to 2.5 mg/kg/day. This regimen achieves remission rates of 70 to 80 percent but carries significant toxicity, including infections, cytopenias, malignancy risk, and infertility. It is now reserved for refractory cases or when rituximab is unavailable or contraindicated.

Calcineurin Inhibitors

Cyclosporine at 3.5 to 5 mg/kg/day or tacrolimus at 0.05 to 0.075 mg/kg/day can achieve remission, but relapse rates exceed 50 percent upon discontinuation, and chronic nephrotoxicity limits long-term use. They may serve as bridge therapy or be combined with rituximab as in the STARMEN protocol.

<image>Treatment algorithm for primary membranous nephropathy. Begin with confirmed diagnosis (positive anti-PLA2R or biopsy-proven). All patients receive supportive care (RAAS blockade, SGLT2 inhibitor, sodium restriction, statins, anticoagulation assessment based on albumin level). Risk stratify: Low risk (proteinuria <3.5 g/day, negative or low anti-PLA2R) → monitor with supportive care for 6-12 months. Moderate risk (proteinuria 3.5-8 g/day) → 6-month observation period on supportive care; if no improvement, initiate rituximab (first-line). High risk (proteinuria >8 g/day or declining GFR) → rituximab first-line (1000 mg x 2 doses, day 1 and 15); monitor anti-PLA2R at 3 and 6 months; if immunologic remission (anti-PLA2R negative), continue monitoring; if persistent, re-dose rituximab or switch to cyclophosphamide-steroid (Ponticelli). Refractory → consider CNI, cyclophosphamide-steroid, or clinical trial. Include monitoring timeline showing serial anti-PLA2R levels and proteinuria measurements at 3, 6, 9, and 12 months.</image>

Special Considerations

Thromboembolic Risk Management

MN has the highest rate of venous thromboembolism among all nephrotic diseases. Renal vein thrombosis may present with flank pain, gross hematuria, worsening proteinuria, and AKI, and is diagnosed by CT venography. Prophylactic anticoagulation is recommended when serum albumin falls below 2.5 g/dL, using either warfarin with a target INR of 2 to 3 or a direct oral anticoagulant. Anticoagulation should continue until albumin is consistently above 3.0 g/dL.

Secondary MN Workup

When anti-PLA2R is negative, an intensified investigation for secondary causes is essential. CT of the chest, abdomen, and pelvis should be performed to evaluate for occult malignancy, especially in patients over 65. Hepatitis B surface antigen and HBV DNA should be checked, as hepatitis B-associated MN requires antiviral therapy rather than immunosuppression. ANA, anti-dsDNA, and complement levels should be assessed for lupus class V. IgG4 levels should be measured to evaluate for IgG4-related disease. A thorough drug history review is mandatory.

Recurrence After Transplant

Anti-PLA2R-positive patients have an allograft recurrence rate of approximately 40 to 50 percent, and pre-transplant anti-PLA2R levels predict recurrence risk. Post-transplant monitoring of anti-PLA2R levels is recommended, as rising levels may herald clinical recurrence. Treatment of recurrence employs rituximab with or without plasmapheresis.

Key Clinical Pearls

• Anti-PLA2R has transformed MN management: it diagnoses primary MN (specificity >99%), guides treatment decisions, monitors response, predicts relapse, and assesses transplant recurrence risk
• Immunologic remission (anti-PLA2R negativity) precedes clinical remission (proteinuria reduction) by 3-6 months; do not judge treatment failure too early
• Rituximab is now first-line immunosuppressive therapy for primary MN based on MENTOR, RI-CYCLO, and STARMEN trials
• MN carries the highest thromboembolic risk among nephrotic diseases; strongly consider prophylactic anticoagulation when albumin <2.5 g/dL
• Always rule out secondary causes (especially malignancy and hepatitis B) before initiating immunosuppression; anti-PLA2R-negative MN warrants aggressive secondary workup

References

1. Fervenza FC, Appel GB, Barbour SJ, et al. Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy (MENTOR). N Engl J Med. 2019;381(1):36-46.
2. Fernandez-Juarez G, Rojas-Rivera J, Logt AV, et al. The STARMEN trial: tacrolimus-rituximab versus Ponticelli in membranous nephropathy. Kidney Int. 2023;103(3):571-581.
3. Scolari F, Delbarba E, Manenti C, et al. Rituximab or Cyclophosphamide in the Treatment of Membranous Nephropathy (RI-CYCLO). J Am Soc Nephrol. 2021;32(4):972-982.
4. Beck LH Jr, Bonegio RGB, Lambeau G, et al. M-type Phospholipase A2 Receptor as Target Antigen in Idiopathic Membranous Nephropathy. N Engl J Med. 2009;361(1):11-21.
5. Cattran DC, Brenchley PE. Membranous Nephropathy: Integrating Basic Science into Improved Clinical Management. Kidney Int. 2017;91(1):76-89.

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