What are the teaching points on membranous glomerulonephritis?

Teaching Points on Membranous Glomerulonephritis

Pathophysiology and Classification

Membranous nephropathy (MN) is an autoimmune glomerular disease characterized by subepithelial immune complex deposition along the glomerular basement membrane, causing capillary wall thickening and nephrotic syndrome. 1

• Primary (idiopathic) MN accounts for approximately 75-80% of adult cases, with the remaining 20-25% secondary to malignancies, infections (hepatitis B/C, HIV), autoimmune diseases (SLE), or medications 2, 1
• The disease is mediated by circulating autoantibodies targeting podocyte surface antigens, with PLA2R (phospholipase A2 receptor) being the culprit antigen in approximately 60% of cases 3, 1
• Newly identified target antigens include NELL1, THSD7A, EXT1/EXT2, NCAM1, SEMA3B, PCDH7, FAT1, CNTN1, NTNG1, PCSK6, and NDNF, each with distinctive clinical associations and therapeutic implications 3, 4

Diagnostic Approach

Kidney biopsy remains mandatory for definitive diagnosis, as clinical features alone cannot distinguish MN from other causes of nephrotic syndrome. 5, 6

• Screen all patients for secondary causes: malignancy (age-appropriate cancer screening), hepatitis B and C, HIV, syphilis, and autoimmune markers (ANA, anti-dsDNA, complement levels) 5
• Serologic testing for anti-PLA2R and anti-THSD7A antibodies should be performed in all cases, as these are currently the only commercially available antibody tests 3
• Immunohistochemistry or immunofluorescence on biopsy tissue can identify target antigens when serology is negative 3
• Laser capture microdissection followed by mass spectrometry represents an emerging one-stop diagnostic approach for detecting rare antigens 3

Natural History and Risk Stratification

The untreated disease follows the "rule of thirds": approximately one-third achieve spontaneous remission, one-third have persistent proteinuria with stable function, and one-third progress to end-stage renal disease over 5-15 years. 2

Poor prognostic factors predicting progression include:

• Male gender and older age at onset 2
• Persistent nephrotic-range proteinuria (>4 g/day) for >6 months despite conservative therapy 5
• Serum albumin <2.5 g/dL (using bromocresol green method) or <2.0 g/dL (using bromocresol purple) 5
• Rising serum creatinine (≥30% increase within 6-12 months) with eGFR still >25-30 mL/min/1.73m² 5
• Concomitant tubular proteinuria and advanced tubulointerstitial fibrosis on biopsy 2

Supportive Care (Foundation of All Treatment)

All patients require aggressive supportive care regardless of whether immunosuppression is initiated. 5, 7

Blood Pressure and Proteinuria Management

• Uptitrate ACE inhibitor or ARB to maximum tolerated dose as first-line therapy, targeting systolic BP <120 mmHg 5, 7
• In children, target 24-hour mean arterial pressure at 50th percentile for age, sex, and height 5, 7
• Restrict dietary sodium to <2.0 g/day (<90 mmol/day), which synergistically enhances antiproteinuric effects 5, 7
• Use potassium-wasting diuretics or potassium binders to manage hyperkalemia and enable continued RAS blockade 5, 7
• Counsel patients to hold ACE inhibitor/ARB and diuretics during intercurrent illnesses with volume depletion risk 5, 7

Edema Management

• Loop diuretics (furosemide) as first-line agents, administered as bolus or continuous infusion 7
• Add mechanistically different diuretics (thiazides, mineralocorticoid receptor antagonists) if response is insufficient 7

Cardiovascular Risk Reduction

• Initiate statin therapy for persistent hyperlipidemia, particularly with additional cardiovascular risk factors (hypertension, diabetes) 5, 7
• Assess ASCVD risk based on LDL-C, apolipoprotein B, triglycerides, and lipoprotein(a) levels 5, 7

Thromboembolism Prophylaxis

• Consider prophylactic anticoagulation when serum albumin <2.5 g/dL (BCG method) or <2.0 g/dL (BCP method), especially with additional risk factors 5
• Weigh bleeding risk using validated tools before initiating warfarin 5

Immunosuppressive Therapy: Who and When to Treat

Initiate immunosuppression only in patients meeting ALL of the following criteria: 5

1. Nephrotic syndrome present (proteinuria >3.5 g/day with hypoalbuminemia)
2. At least ONE of these conditions:
   • Proteinuria persistently >4 g/day and remains >50% of baseline despite 6 months of optimal supportive care 5
   • Severe, disabling, or life-threatening nephrotic symptoms (refractory edema, recurrent infections, thromboembolism) 5
   • Serum creatinine rising ≥30% within 6-12 months with eGFR still >25-30 mL/min/1.73m² 5

Do NOT treat with immunosuppression if:

• Non-nephrotic proteinuria (<3.5 g/day) 5
• eGFR <25-30 mL/min/1.73m² with advanced interstitial fibrosis/tubular atrophy on biopsy 5
• Active infection or malignancy 5

First-Line Immunosuppressive Regimens

The strongest evidence supports a 6-month course of alternating monthly cycles of corticosteroids and alkylating agents (cyclophosphamide or chlorambucil). 5

Modified Ponticelli Regimen (Months 1,3,5):

• Methylprednisolone 1 g IV daily for 3 days, followed by
• Oral prednisone 0.5 mg/kg/day for remainder of month 5

Months 2,4,6:

• Oral cyclophosphamide 2.0 mg/kg/day (adjust for age and renal function) 5

Alternative regimen for patients with contraindications to alkylating agents or corticosteroids:

• Calcineurin inhibitors (cyclosporine or tacrolimus) for minimum 6 months 5
• However, relapse rates are higher when CNIs are discontinued compared to cyclophosphamide 1

Rituximab (anti-CD20 therapy):

• Emerging as alternative first-line option, though remission rates are lower than cyclophosphamide, particularly in patients with high PLA2R antibody titers 1
• Typical dosing: 375 mg/m² weekly for 4 weeks or 1 g on days 1 and 15 1

Special Considerations for Regimen Selection:

Avoid high-dose corticosteroids in patients with:

• Obesity and family history of diabetes (significantly increases steroid-related complications) 5
• Consider CNI-based regimen instead in these patients 5

Pre-Treatment Screening and Monitoring

Before initiating immunosuppression, mandatory screening includes: 5, 8

• Tuberculosis (PPD or interferon-gamma release assay) 5, 8
• Hepatitis B surface antigen, hepatitis C antibody, HIV 5, 8
• Syphilis serology 5, 8
• Strongyloides serology in patients from endemic tropical regions with eosinophilia 5
• Pregnancy test in women of childbearing age 5

Prophylaxis during immunosuppression:

• Trimethoprim-sulfamethoxazole for Pneumocystis jirovecii prophylaxis when using high-dose prednisone, rituximab, or cyclophosphamide 5
• Pneumococcal, influenza, and herpes zoster (Shingrix) vaccination before starting immunosuppression 5

Treatment Response Monitoring

Proteinuria reduction is the primary surrogate endpoint for treatment response. 5, 6

• Complete remission: proteinuria <0.3 g/day with stable renal function 6
• Partial remission: proteinuria <3.5 g/day with ≥50% reduction from baseline 6
• Monitor anti-PLA2R antibody titers serially (when initially positive) as declining titers predict clinical remission 1, 4
• A ≥40% decline in eGFR from baseline over 2-3 years indicates treatment failure and progression toward kidney failure 5, 6

Secondary Membranous Nephropathy: Critical Distinctions

When secondary causes are identified, treat the underlying condition first. 5

• Hepatitis C-associated MN: Direct-acting antivirals to achieve sustained viral response 8
• Hepatitis B-associated MN: Antiviral therapy (entecavir or tenofovir) 8
• HIV-associated nephropathy: Immediate antiretroviral therapy regardless of CD4 count 8
• Malignancy-associated MN: Treatment of underlying cancer often leads to remission of nephropathy 2
• Lupus membranous nephropathy: Generally has better renal prognosis than idiopathic MN and responds to lupus-specific immunosuppression 9

Common Pitfalls to Avoid

• Do not delay treatment in high-risk patients waiting for the full 6 months of conservative therapy if albumin is critically low (<2.0 g/dL), creatinine is rising, or thromboembolism risk is very high 5
• Do not use long-term CNIs in immune complex-mediated glomerulonephritis due to risk of CNI-associated angiopathy and thrombotic microangiopathy 5
• Do not withhold immunosuppression in patients with eGFR <30 mL/min if there is active crescentic or necrotizing GN without significant fibrosis on biopsy 5
• Do not classify all PLA2R-negative cases as "PLA2R-negative MN" without attempting to identify the specific target antigen, as this has therapeutic and prognostic implications 3