NephrologyTier 1Disease (DEADMAN)

Membranous nephropathy

Description

Subepithelial immune complex deposition on the podocyte side of the GBM -> thickened capillary wall, no inflammatory infiltrate
- Deposits are outside the endothelium, so there is no cellular reaction and no nephritic picture
Commonest cause of primary nephrotic syndrome in white adults over 50
~80% primary (autoantibody-mediated), ~20% secondary
The most thrombogenic glomerular disease

The rule of thirds (untreated)

1/3 spontaneous remission (up to 30-40% over 5 yrs)
1/3 persistent proteinuria, stable function
1/3 progressive -> ESKD

Epidemiology

~1-2 per 100,000 per year; ~20-30% of adult nephrotic syndrome
Peak 40-60 yrs; M:F ~2:1
Rare under 20 - membranous in a child or adolescent means look hard for a secondary cause (hepatitis B, SLE)

Aetiopathogenesis

Primary - target antigen defines it

Anti-PLA2R (M-type phospholipase A2 receptor): ~70-80% - the pathogenic autoantibody, mostly IgG4
Anti-THSD7A: ~1-3% - associated with occult malignancy; screen for cancer if positive
Newer podocyte/GBM antigens on biopsy staining: NELL-1 (malignancy, traditional medicines), EXT1/EXT2 (autoimmune, lupus-like), Semaphorin-3B (paediatric), PCDH7, NCAM1, HTRA1, PLA2R-negative subtypes
HLA-DQA1 and PLA2R1 risk alleles

Mechanism

IgG4 binds the podocyte antigen in situ -> subepithelial deposits
-> complement via the lectin and alternative pathways (IgG4 does not fix classical complement)
-> C5b-9 (MAC) sublytic injury to the podocyte -> cytoskeletal disruption, foot process effacement
-> proteinuria without inflammation
GBM material laid down between deposits -> 'spikes' then a double contour

Secondary causes - always exclude

Malignancy (~5-20%, higher over 65) - lung, colon, breast, stomach, prostate; often diagnosed within 12 months either side of the nephropathy
Infection - hepatitis B (esp. children and endemic areas), hepatitis C, syphilis, malaria, schistosomiasis
Autoimmune - SLE (class V lupus nephritis), rheumatoid arthritis, Sjogren, thyroiditis, IgG4-related disease, sarcoid
Drugs - NSAIDs, penicillamine, gold, captopril, anti-TNF agents, mercury-containing skin-lightening creams
Post-transplant / GVHD

Diagnosis

Presentation

Nephrotic syndrome ~80% - insidious oedema, frothy urine
Sub-nephrotic proteinuria found incidentally ~20%
Microscopic haematuria ~50%, HTN ~30%; renal function normal at presentation in most
Presenting with a DVT, PE or renal vein thrombosis is classic

Anti-PLA2R serology - has changed practice

Positive anti-PLA2R + nephrotic syndrome + no secondary cause -> biopsy may be omitted
- Specificity for primary disease ~99%
Titre tracks disease activity:
- Antibody falls before proteinuria does - immunological remission precedes clinical remission by months
- Rising titre predicts relapse
- High titre (>150 RU/mL) predicts non-remission and progression
Biopsy still needed if: PLA2R-negative, renal impairment, atypical features, or diagnostic doubt

Biopsy

LM: uniformly thickened capillary walls, no hypercellularity; silver stain shows spikes
IF: granular IgG + C3 along capillary loops (IgG4-dominant in primary; IgG1/2/3 + C1q in secondary/lupus)
EM (Ehrenreich-Churg stages I-IV): subepithelial electron-dense deposits, foot process effacement
*Full house IF, mesangial/subendothelial deposits, tubuloreticular inclusions = lupus (class V), not primary*

Secondary work-up

Hepatitis B, C, HIV, syphilis; ANA, anti-dsDNA, C3/C4; anti-THSD7A
Age-appropriate malignancy screening in everyone over 50 (and CT chest/abdomen if THSD7A or NELL-1 positive, or PLA2R-negative)
Drug history including NSAIDs and skin-lightening creams

Management

Risk stratification drives everything

KDIGO risk categories over 6 months of supportive therapy

Risk	Features	Treatment
Low	Normal eGFR, proteinuria <3.5 g/day or falling, albumin >30	Supportive only
Moderate	Normal eGFR, proteinuria >3.5 g/day, not falling >50% after 6 months supportive care	Supportive; consider immunosuppression
High	eGFR <60 or falling, proteinuria >8 g/day >6 months, albumin <25, anti-PLA2R >150 RU/mL, selectivity index >0.20	Immunosuppress
Very high	Life-threatening nephrotic syndrome, rapid unexplained eGFR decline	Immunosuppress immediately

Supportive therapy - everyone

Maximally tolerated ACEi/ARB, Na restriction, loop diuretic for oedema
Statin; SGLT2i for residual proteinuric CKD
Anticoagulation - membranous has the highest VTE risk of any GN (~7-30%)
- Prophylactic anticoagulation if serum albumin <20-25 g/L and bleeding risk acceptable
- Warfarin has the evidence; DOACs increasingly used
- Renal vein thrombosis: sudden flank pain, haematuria, dec eGFR

Immunosuppression - moderate/high risk

Rituximab - now first-line in most patients
- 1 g x2 two weeks apart, or 375 mg/m2 weekly x4
- MENTOR: rituximab non-inferior to ciclosporin at 12 months and superior at 24 months for maintaining remission
- Less effective at very high anti-PLA2R titres and with impaired eGFR
Cyclophosphamide + corticosteroid (modified Ponticelli) - alternating monthly steroid and alkylating agent over 6 months
- Highest remission rate and the strongest long-term evidence - preferred for high/very high risk, declining eGFR (RI-CYCLO, STARMEN)
- Cost: infertility, marrow suppression, haemorrhagic cystitis, later malignancy
Calcineurin inhibitor (tacrolimus or ciclosporin) +/- rituximab - for those wishing to avoid alkylating agents
- High relapse rate on withdrawal; nephrotoxic; avoid if eGFR reduced
*Corticosteroids alone are ineffective - never use them as monotherapy*
Refractory: repeat rituximab, obinutuzumab, bortezomib, belimumab; anti-CD38 (daratumumab, felzartamab) shows early promise

Secondary disease

Treat the cause - antivirals for hepatitis B, remove the drug, treat the malignancy. Nephropathy usually follows

Monitoring

Proteinuria, albumin, eGFR, and anti-PLA2R titre 3-monthly
- Judge response by antibody first; proteinuria lags by up to 6-12 months and does not mean treatment failure

Associations

Malignancy - lung, colon, breast, stomach, prostate, renal; ~5-20%, higher over 65
Hepatitis B (commonest secondary cause worldwide), hepatitis C, syphilis, malaria, schistosomiasis
SLE (class V), rheumatoid arthritis, Sjogren, Hashimoto thyroiditis, sarcoidosis, IgG4-related disease
NSAIDs, penicillamine, gold, captopril, anti-TNF, mercury (skin-lightening creams)
Venous thromboembolism, renal vein thrombosis - the defining complication
Sickle cell, GVHD, de novo post-transplant membranous
*HLA-DQA1, PLA2R1 polymorphisms*

Natural history & complications

Rule of thirds untreated: 1/3 spontaneous remission, 1/3 persistent proteinuria with preserved function, 1/3 progressive
- Spontaneous remission is common and can take up to 2 years - the reason for 6 months of supportive therapy before immunosuppression in low/moderate risk
10-yr renal survival ~65-85%; ~40% of untreated nephrotic patients reach ESKD by 10 yrs

Predictors of progression

Persistent proteinuria >8 g/day for >6 months
eGFR at presentation and its slope
High anti-PLA2R titre and failure to deplete it
Male sex, age >50, tubulointerstitial fibrosis, HTN
Ehrenreich-Churg histological stage does NOT predict outcome

Complications

VTE, renal vein thrombosis, PE - highest of any nephrotic disease; risk rises steeply below albumin 20-25 g/L
Accelerated atherosclerosis (hyperlipidaemia), infection (urinary IgG loss), vitamin D deficiency, hypothyroidism (thyroxine-binding globulin loss), AKI
Rituximab: hypogammaglobulinaemia, hepatitis B reactivation (screen before treating)

Transplant

Recurs in ~30-40% of allografts, usually within the first year; anti-PLA2R positivity at transplant predicts recurrence
Responds to rituximab

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