Membranous Nephropathy & FSGS

Meet the patient

A 55-year-old man watches his ankles swell over six weeks, his urine turn frothy, and two kilograms arrive he cannot explain. The laboratory picture is nephrotic-range proteinuria with hypoalbuminaemia, and the biopsy shows subepithelial immune deposits in a thickened capillary wall with granular IgG4 along it. This is primary membranous nephropathy — and two questions decide his admission before any immunosuppression is started.[1][4]

First, is there a renal vein thrombosis? The thrombotic risk of nephrotic syndrome climbs as serum albumin falls, and membranous is the nephrotic disease in which thrombosis is most common — in the classic series, two-thirds of nephrotic patients with renal vein thrombosis had membranous pathology, and the acute form presents with sudden flank pain and macroscopic haematuria, so in this man that combination is a renal vein thrombosis until proven otherwise. Second, is there an underlying cancer? Malignancy is over-represented in membranous nephropathy — it was the pathology in nearly half of paraneoplastic nephrotic syndrome, the nephrotic syndrome preceded the tumour diagnosis in over a third of cases, and older patients warrant a thorough, sustained hunt for a hidden solid tumour — especially if anti-THSD7A is positive.[12][13][24][22][21][20]

Two diseases, one nephrotic presentation

Membranous is an antibody disease; FSGS is a podocyte disease. They share a nephrotic presentation — proteinuria over 3.5 g per 24 hours with hypoalbuminaemia, oedema and hyperlipidaemia — and the same supportive-care agenda, but the microscope parts them: membranous thickens the capillary wall with subepithelial immune complexes; FSGS scars individual tuft segments through podocyte injury and detachment. Teach them together because the bedside and the supportive care converge, then let the biopsy do the splitting.[24][1][2]

The clinician's three jobs never change: biopsy every adult with nephrotic syndrome (children with classic steroid-sensitive disease are treated empirically); split primary from secondary, because secondary disease is cured by removing the cause, not by immunosuppression; and stratify risk with proteinuria, renal function, histology, and — in membranous — the anti-PLA2R titre. About a third of membranous patients remit on their own, and primary FSGS still needs a long, genuinely high-dose steroid trial. Confusing the two wastes time and kidneys.[7][8][29]

The classification that changes management — primary or secondary

The classification that changes management is aetiological, not histological. Primary disease is antibody-driven and needs immunosuppression; secondary disease is cured by removing the cause — resect the tumour, treat the hepatitis, stop the drug.[1]

Membranous nephropathy — split by cause:[1]

• Primary (about 80%): antibody-mediated. Anti-PLA2R positive in about 70 to 80% (IgG4 subclass — Beck, NEJM 2009); anti-THSD7A positive in about 2 to 5% (Tomas, NEJM 2014 — and a markedly enriched malignancy risk, so a positive THSD7A demands a harder malignancy hunt). Linked to HLA-DQA1 and PLA2R1 risk alleles.[7][35][4][6][20]
• Secondary (about 20%): solid-organ malignancy (lung, colorectal and breast carry the strongest association, and the yield rises with age), hepatitis B and C, lupus class V, drugs (NSAIDs, penicillamine, gold, bucillamine, tiopronin, captopril), syphilis, thyroid disease, sarcoidosis, graft-versus-host disease, and de novo after transplant. Anti-PLA2R is typically negative.[23][7][22]

FSGS — five aetiologies in the Columbia and Vanderbilt framework:[2][5]

• Primary: a circulating permeability factor (candidates suPAR, CLCF-1, anti-CD40, anti-nephrin) injures the podocyte; diffuse foot-process effacement on electron microscopy; a steroid-responsive subset exists; recurs after transplant.
• Genetic: APOL1 (G1 and G2 — recent West-African ancestry), NPHS1, NPHS2, TRPC6, INF2, ACTN4, WT1, COL4A3, COL4A4, COL4A5. Steroid-resistant nephrotic disease driven by podocyte gene variants.[2]
• Virus-associated: HIV-associated nephropathy (HIVAN) — collapsing variant, APOL1 background, rapid AKI; also parvovirus B19 and CMV.
• Drug-induced: heroin, pamidronate, interferon, lithium, anabolic steroids, sirolimus.
• Adaptive and structural (hyperfiltration): obesity, reduced renal mass (agenesis, nephrectomy, reflux, sickle cell), cyanotic congenital heart disease — typically focal, not diffuse, foot-process effacement.[2]

[7] [16]

The Columbia variants — tip best, collapsing worst

FSGS is the disease where the histological variant IS the prognosis. D'Agati's 2004 Columbia classification is examinable for exactly this — name the variant and you have named the outlook.[5]

[5]

The discriminator beneath the table: tip equals steroid-responsive and behaves like minimal change; collapsing equals AKI on nephrotic syndrome — think HIV and APOL1, and expect ESKD inside 2 to 3 years. Examiners love the ordering best to worst: tip, then cellular, then NOS, then perihilar, then collapsing.[5]

[7] [1] [4] [23] [13] [15] [14] [16] [30] [32] [9] [3]

How common, and who

Membranous is the commonest primary nephrotic in white adults; FSGS is a leading cause, particularly among African Americans. The 2009 discovery of anti-PLA2R turned an idiopathic immune-complex disease into a defined autoimmune disease whose titre tracks immunological and clinical activity, and eight in ten membranous patients present with the full nephrotic syndrome. FSGS is a leading cause of idiopathic nephrotic syndrome in adults, driven by obesity, drugs and recognition of APOL1 risk alleles — and the collapsing variant is the signature lesion of HIV-associated nephropathy.[7][4][15][2][18]

[35] [7] [8] [14] [16]

The risk-factor-to-cause table — screen actively:[23][22]

[23] [7] [22] [2]

Pathophysiology — the filtration barrier, attacked two ways

Both diseases attack the same glomerular filtration barrier — the fenestrated endothelium, the glomerular basement membrane (GBM), and the podocyte foot processes with their slit diaphragm (nephrin to nephrin via NPHS1, nephrin to podocin). Break the charge and size selectivity of that barrier and albumin pours out as non-selective proteinuria. Membranous attacks it with antibody from outside; FSGS attacks it by killing the podocyte from within.[2]

Membranous — the antibody attack, step by step:[1][4]

1. Autoantibody forms. In susceptible people, circulating IgG4 autoantibodies bind antigens on the podocyte surface — PLA2R in most, THSD7A in a small subgroup with an enriched malignancy risk.[1][35][20]
2. Complexes form in situ. The antibody binds antigen on the podocyte, and the deposits accumulate in the subepithelial space of the glomerular filtration barrier — the histomorphological signature of the disease.
3. Injury follows the deposits. The autoantibodies are pathogenic — considerable clinical and experimental data support antibody-mediated podocyte injury, and the deposits thicken the capillary wall.
4. The result is nephrotic-range proteinuria with oedema — the clinical hallmark — and, in a subset, progression as the barrier is remodelled.[1][7]

FSGS — podocyte injury, detachment, scar:[2][5]

1. The podocyte is injured — by a circulating permeability factor in primary FSGS, by a defective slit diaphragm or cytoskeleton in genetic disease, by HIV genes (nef, vpr) or drugs directly, or by chronic hyperfiltration in adaptive disease.
2. The podocyte detaches and dies. It is terminally differentiated and does not regenerate, so denuded GBM is left exposed.
3. Synechia and segmental sclerosis. The exposed GBM adheres to Bowman capsule (a synechia); plasma protein leaks in, hyalin (PAS-positive) accumulates, and the segment scars. Because the lesion is focal (some glomeruli) and segmental (part of each tuft), early disease is missed on a thin biopsy — which is why you need at least 10 to 20 glomeruli with light, immunofluorescence and electron microscopy.
4. Collapse, in the collapsing variant. Dysregulated parietal-cell proliferation collapses the whole tuft, producing rapid AKI on nephrotic syndrome; tubulointerstitial damage then drives the GFR loss.
5. Transplant recurrence argues for a circulating factor — idiopathic FSGS recurred in about a third of grafted adults in the TANGO cohort, with 39% of those losing the graft.[16]

Why nephrotic patients clot, swell, and get infected (both diseases):[2]

• Oedema — the defining fluid accumulation of the syndrome, driven by heavy urinary protein loss and disordered sodium handling.[25]
• Hyperlipidaemia — cholesterol, triglycerides and apoB-containing lipoproteins (VLDL, IDL, LDL) all rise; the lipid abnormalities are mediated by changes in the machinery of lipid biosynthesis and clearance.[19]
• Hypercoagulability (the highest-yield complication) — the syndrome produces dysregulation of coagulation; the venous thromboembolism risk rises as serum albumin falls, hypoalbuminaemia is the strongest independent predictor, and the risk is highest of all in membranous nephropathy, where renal vein thrombosis leads.[25][24][11][13]
• Infection — dysregulated immunity with loss of urinary immunoglobulin and complement factors; watch for serious infections such as spontaneous bacterial peritonitis alongside clots as the two classic complications to monitor for.[25][30]

Clinical presentation — frothy urine and swollen ankles

Both present insidiously with dependent oedema, periorbital puffiness that is worse in the morning, frothy urine, and weight gain from salt and water. The nephrotic picture is proteinuria over 3.5 g per 24 hours with hypoalbuminaemia, oedema and hyperlipidaemia. In membranous, 80% of patients present with the full nephrotic syndrome; FSGS frequently adds a raised creatinine at presentation — which does not by itself predict a worse steroid response.[24][25][7][28]

Membranous reads as a quiet, purely nephrotic illness until a thrombus announces it. Renal vein thrombosis may be the presenting event: in the classic series the acute form brought sudden flank pain, marked costovertebral-angle tenderness and macroscopic haematuria, and membranous was the underlying pathology in two-thirds of the nephrotic patients with renal vein thrombosis — with anticoagulation, renal function improved. Deep vein thrombosis and pulmonary embolism, even bilateral renal vein thrombosis, can all be the first manifestation of the disease.[12][24]

FSGS reads louder — frank nephrotic syndrome in primary disease, or proteinuria with kidney dysfunction in secondary and adaptive disease. The collapsing variant presents as rapid kidney failure on nephrotic syndrome, classically in a patient with HIV (HIVAN) or APOL1 risk alleles; in children, FSGS masquerades as steroid-resistant nephrotic syndrome after a minimal-change-like start.[2][18][32]

Complication-level features to actively hunt: sudden flank pain with haematuria (renal vein thrombosis); dyspnoea and pleuritic chest pain (pulmonary embolism); fever with abdominal peritonism (spontaneous bacterial peritonitis); cellulitis and pneumonia; frothy urine.[30][12]

Differential — the finite nephrotic list

Distinguish by bedside features, serology and biopsy:[1][2]

• Minimal change disease — the commonest nephrotic in children, abrupt oedema, generally steroid-responsive (about 85% of children remit on glucocorticoids) with frequent relapses; FSGS by contrast is usually steroid-resistant.[30][32]
• Lupus nephritis class V — ANA, anti-dsDNA, low complement, full-house immunofluorescence on biopsy.
• Amyloidosis (AL or AA) — Congo-red apple-green birefringence, macroglossia, periorbital purpura; serum free light chains and electrophoresis.
• Membranoproliferative GN — low complement, a mixed nephrotic and nephritic picture, tram-track double contour; HCV, cryoglobulins, HBV.
• Pre-eclampsia — pregnancy over 20 weeks, hypertension, raised uric acid, low platelets, abnormal LFTs; resolves post-partum.
• Crescentic transformation of membranous — anti-PLA2R disease with superimposed anti-GBM or ANCA vasculitis; rapidly declining GFR, active sediment; re-biopsy shows crescents.[1]

When is biopsy indicated? All adults with nephrotic syndrome. Children with classic steroid-sensitive disease are treated empirically; biopsy only if atypical (age under 1 or over 10, hypertension, haematuria, low complement, renal impairment) or steroid-resistant — and steroid resistance is often the first sign that apparent MCD is actually FSGS.[1]

Investigations — confirm, classify, biopsy

First line — confirm and quantify the nephrotic syndrome:[1]

• Urinalysis and microscopy — dipstick heavy proteinuria with a relatively bland sediment (few cells or casts), which is what separates nephrotic from nephritic presentations.[24][25]
• Quantify proteinuria — 24-hour urine protein over 3.5 g (the Casey definition: nephrotic-range proteinuria above 3.5 g per 24 hours); serial measurements track activity and response.[24]
• Serum albumin, renal function, electrolytes, lipid profile, full blood count and inflammatory markers.[24]
• Renal ultrasound — assess kidney size and exclude obstruction; image the renal veins (Doppler or CT venography) when thrombosis is suspected.[12][25]

Serology to classify the cause (high-yield):[1][4][35]

• Anti-PLA2R antibody — primary membranous (about 70 to 80%, IgG4); the titre guides diagnosis, immunological activity, treatment response, relapse and transplant timing.
• Anti-THSD7A antibody — rare (2 to 5% in most cohorts); associated with malignancy in 13% of THSD7A-positive patients in the largest cohort — a thorough malignancy screen if positive.[7][35][20]
• ANA, anti-dsDNA, complement C3 and C4 — lupus class V (low complement, full-house IF).
• HBsAg, anti-HBs, anti-HCV, HIV serology — secondary membranous or HIVAN.
• Serum electrophoresis, serum free light chains, urine Bence-Jones — myeloma or AL amyloid.
• Anti-GBM and ANCA — if crescents or a rapidly declining GFR (superimposed vasculitis).
• TSH, rheumatoid factor and anti-CCP, cryoglobulins — autoimmune thyroiditis, rheumatoid exposure, HCV cryoglobulinaemia.[1]

Malignancy screen in membranous: older age and THSD7A positivity are the red flags — in the Deegens series, solid malignancies appeared in patients over 65 (10 of 24 with tumours were over 65, none under 55); membranous accounted for 49% of paraneoplastic nephrotic syndrome and the nephrotic syndrome preceded the tumour diagnosis in 36%. Screen with CT chest, abdomen and pelvis plus age-appropriate colonoscopy, PSA and mammography, guided by local policy.[21][22][20]

Renal biopsy — the defining investigation:[1][5]

• Membranous: thickened glomerular capillary walls from subepithelial immune-complex deposition; granular IgG4 (the predominant subclass) along the capillary wall on immunofluorescence; subepithelial deposits on electron microscopy.[1][4][7]
• FSGS: focal (some glomeruli) and segmental (part of each tuft) sclerosis with hyalinosis and synechiae to Bowman capsule (light microscopy); collapse and parietal-cell proliferation define the collapsing variant; nonspecific IgM and C3 in scars (immunofluorescence); diffuse foot-process effacement in primary FSGS versus focal in adaptive (electron microscopy). An adequate sample — at least 10 to 20 glomeruli — is required, because FSGS is focal and a thin biopsy misses it.[1]

Before any immunosuppression: glucose and HbA1c, hepatitis B and C and HIV, a TB screen (interferon-gamma release assay or chest X-ray), bone density (DEXA), vaccination status, and a pregnancy test in women of childbearing age.[1]

[1]

Management — the shared nephrotic-care agenda

Start the supportive agenda at diagnosis, in parallel with disease-specific treatment. It is shared by membranous and FSGS, and it is where most of the hard work of looking after a nephrotic patient actually happens.[1][2]

Fluid, sodium and oedema:[2]

• Salt restriction and a modest fluid restriction if hyponatraemic; daily weights and a fluid balance chart.
• Loop diuretics are the symptomatic mainstay for oedema — Kopp's primer lists diuretics among the core symptomatic measures in podocytopathies.[2][25]
• Refractory anasarca — intravenous diuretics with albumin as clinically indicated; nephrology input; avoid over-diuresis, which precipitates kidney injury.[25]

Antiproteinuric cornerstone — for every cause:[1]

• ACE inhibitor or ARB — renin-angiotensin system antagonists help control proteinuria and slow the progression of fibrosis; use the maximum tolerated dose, accepting a modest creatinine rise, and continue long-term.[2][26][27]

Lipids: statins are first-line for nephrotic dyslipidaemia — Kong's Cochrane review found no direct RCT evidence of cardiovascular benefit in nephrotic patients, so treat by general cardiovascular risk, not by proteinuria alone.[19][2]

Anticoagulation — the highest-yield exam point in membranous:[13] the thrombotic risk (DVT, PE, renal vein thrombosis) climbs as albumin falls, and is highest of all in membranous nephropathy. Lee's decision-analysis found anticoagulation favoured when albumin is under 3 g/dL (benefit-to-harm about 4.5 to 1) and strongly favoured under 2 g/dL (about 13 to 1), while patients at high bleeding risk are unlikely to benefit — so the decision is individualised, not automatic. Treat any thrombotic event fully — image with renal Doppler or CT venography and anticoagulate for at least the duration of nephrotic-range proteinuria; in the classic series, renal function improved after anticoagulating renal vein thrombosis.[11][24][12]

Vaccination: immunisation before immunosuppression where possible; avoid live vaccines while immunosuppressed.[2][25]

Suspected infection: treat promptly — spontaneous bacterial peritonitis is the classic nephrotic infection, alongside clots one of the two complications to actively monitor for; do not wait for cultures in the septic nephrotic patient.[30][25]

Membranous — risk-stratified immunosuppression

The framework stratifies by risk because about a third remit on their own and immunosuppression carries real toxicity. Do not treat someone who is about to remit — but do not let high-risk disease sit either: with proper management, 10% or fewer reach ESRD over the subsequent decade, versus a third of untreated patients.[7][8]

[7] [8] [3] [9] [34]

First-line immunosuppressive regimens — doses verbatim from their trials:[7][3]

• Rituximab (anti-CD20 B-cell depletion) — two 1000-mg intravenous infusions 14 days apart, repeated at six months in case of partial response. The MENTOR trial (Fervenza, NEJM 2019) enrolled patients with proteinuria of at least 5 g per 24 hours already on angiotensin-system blockade: rituximab was non-inferior to cyclosporine at 12 months (60% vs 52% complete or partial remission) and superior at maintaining remission to 24 months (60% vs 20%), with a faster, greater and more sustained fall in anti-PLA2R antibody levels and serious adverse events in 17% vs 31%. Screen for hepatitis B and tuberculosis before starting.[3][7]
• Ponticelli regimen (steroid alternating with alkylating agent over six months). The original 1998 schedule: intravenous methylprednisolone 1 g daily for three days then oral methylprednisolone 0.4 mg per kg per day for 27 days, alternating with oral cyclophosphamide 2.5 mg per kg per day for 30 days (or chlorambucil 0.2 mg per kg per day), for three alternating cycles. The modified schedule substitutes oral prednisolone 0.5 mg per kg per day and cyclophosphamide 2 mg per kg per day. The Cochrane review confirms an alkylating agent plus corticosteroid brings short- and long-term benefits — at the price of more adverse events; monitor blood counts during cyclophosphamide.[9][10][8]
• Calcineurin inhibitor — cyclosporine starting at 3.5 mg per kg per day (the MENTOR comparator, given for 12 months) or tacrolimus-based regimens. Induction efficacy is broadly comparable to alkylating agents, but relapse on stopping is the rule — the Cochrane review found CNI-induced remissions were less well maintained. Watch nephrotoxicity, hypertension, diabetes (tacrolimus), gingival hyperplasia and hirsutism (ciclosporin).[3][8][23][36]
• Mycophenolate mofetil — 1 g twice daily with prednisolone 0.5 mg per kg — a less-proven option described in modern reviews; salvage or combination use.[10][7]

Secondary membranous is treated by removing the cause — resect the tumour, treat the hepatitis, stop the drug, treat the lupus; around a third of membranous patients overall remit spontaneously and secondary disease often remits with cause control alone.[23][7]

FSGS — the steroid trial you cannot shortcut

Primary FSGS demands a prolonged, genuinely high-dose steroid trial before resistance is ever declared. This is the single most tested and most mistaught point in FSGS.[2][1]

• Maximal conservative therapy first — an ACE inhibitor or ARB (they help control proteinuria and slow fibrosis), blood pressure control, salt restriction, lipid management, anticoagulation and vaccination as above.[2][14]
• The steroid trial — and it must be genuinely prolonged. Pokhariyal's series showed duration was the only independent predictor of remission: patients treated beyond 16 weeks entered remission far more often, and the conclusion was explicit — treat for at least 16 weeks before labelling anyone steroid non-responsive. In Jafry's adult cohort the median steroid course was five months and half achieved remission; interstitial fibrosis over 25% predicted a poor response.[29][28][14]
• Steroid-resistant primary FSGS — a calcineurin inhibitor: ciclosporin for at least six months, which the Cochrane review found increases complete remission versus no immunosuppression; rituximab and mycophenolate are alternatives. Persisting nephrotic proteinuria despite at least four months of therapy defines refractory disease in recent series.[14][33]
• Genetic FSGS does not respond to immunosuppression — manage conservatively, plan transplant (genetic disease does not recur), and offer genetic counselling.[2]
• Adaptive and secondary FSGS — treat the cause (obesity and hyperfiltration, reduced renal mass, sickle cell); immunosuppression is usually not needed.[2]
• Collapsing FSGS and HIVAN — HIV-associated nephropathy has become rare where combination antiretroviral therapy is available; treat HIV with antiretrovirals plus an ACE inhibitor or ARB, with corticosteroids described in severe disease.[18][31][2]

The subtypes and scenarios that bite

• Anti-PLA2R-positive membranous — the titre is a dynamic biomarker: Ramachandran's randomised comparison found titres correlated with proteinuria and albumin and that monitoring antibody levels could track disease activity; in MENTOR the anti-PLA2R decline was faster, greater and more sustained with rituximab than cyclosporine; remember proteinuria can persist for months after the antibody is no longer detectable (immunological remission precedes clinical remission).[36][3][7]
• Anti-THSD7A membranous (about 3 to 5%) — IgG4-mediated and subepithelial like PLA2R disease, but with an enriched malignancy association (13% in the largest cohort) — screen hard for cancer.[7][35][20][6]
• Collapsing FSGS and HIVAN — the worst prognosis, rapid kidney failure; antiretrovirals plus ACE-inhibitor/ARB-based therapy transformed a disease that is now rare where combination antiretroviral therapy is available.[18][31]
• Tip-lesion FSGS — the best prognosis of the Columbia variants, often steroid-responsive; a steroid trial first.[5]
• APOL1-associated nephropathy — a spectrum from FSGS to hypertension-attributed nephropathy in people of recent West-African ancestry; genetic variants interact with environmental triggers; no APOL1-directed therapy was available at the time of the primer.[2]
• FSGS recurrence after transplant — about a third of grafted adults with idiopathic FSGS in the TANGO cohort, with over a third of those losing the graft; treat with plasmapheresis plus rituximab — remission in 72.7% in the pooled meta-analysis. Genetic FSGS does not recur.[16][17][2]
• Membranous after transplant — can recur or arise de novo; monitor the anti-PLA2R titre to time immunosuppression.[3][7]
• Crescentic transformation of membranous — superimposed anti-GBM or ANCA vasculitis with a rapidly declining GFR; re-biopsy shows crescents; treat as a crescentic glomerulonephritis.[1]

Complications and the preventable-harm list

Complications of heavy proteinuria (both diseases):[1][2]

• Thromboembolism — renal vein thrombosis (flank pain, macroscopic haematuria, a rising creatinine), DVT, pulmonary embolism; risk rises as serum albumin falls, is highest in membranous, and anticoagulation is favoured when albumin is under 3 g/dL (strongly under 2 g/dL) provided bleeding risk is low; image and treat any event.[24][13][11][12]
• Infection — spontaneous bacterial peritonitis is the classic, alongside clots one of the two complications to actively monitor for; vaccinate and treat promptly.[30][25]
• Hyperlipidaemia — cholesterol, triglycerides and apoB lipoproteins rise; a statin, treating by cardiovascular risk.[19][2]
• Acute kidney injury — over-diuresis, hypovolaemia, bilateral renal vein thrombosis, collapsing transformation.[12][25]

Immunosuppression-related complications:[1][3]

• Corticosteroid — diabetes, hypertension, infection, osteoporosis (bisphosphonate, calcium and vitamin D, DEXA), cataracts, peptic ulcer, mood change or psychosis, growth retardation and delayed puberty in children, avascular necrosis.
• Cyclophosphamide — leucopenia and infection (a weekly full blood count), haemorrhagic cystitis and bladder cancer (MESNA, generous hydration), infertility by cumulative dose (counsel on storage), secondary malignancy, nausea, alopecia.
• Calcineurin inhibitor — nephrotoxicity (afferent arteriolar vasoconstriction, chronic interstitial fibrosis), hypertension, diabetes (tacrolimus), gingival hyperplasia and hirsutism (ciclosporin), hyperkalaemia, tremor; monitor troughs and renal function.
• Rituximab — infusion reactions (premedicate with paracetamol, antihistamine and steroid), infection (hepatitis B reactivation — screen and prophylaxe; PJP; rarely PML), late-onset neutropenia, hypogammaglobulinaemia.[3]

The classic pitfalls:[11][2]

• Not weighing anticoagulation in a severely hypoalbuminaemic membranous patient — the highest-yield miss; the benefit-to-harm balance is decided by the albumin and the bleeding risk.[11]
• Missing renal vein thrombosis (flank pain plus haematuria in a nephrotic patient equals renal vein thrombosis until proven otherwise — it was the presenting event in the classic series).[12]
• Declaring FSGS steroid-resistant before at least 16 weeks of therapy — confirm adherence and duration first; the median successful course in adults is about five months.[29][28]
• Missing secondary causes — malignancy in the older membranous patient (it preceded tumour diagnosis in over a third); HBV and HCV; adaptive FSGS (obesity, reduced renal mass); HIV in collapsing FSGS.[22][23][2]
• Treating genetic or adaptive FSGS with immunosuppression — they do not respond; manage the cause and counsel on transplant.[2]
• Forgetting blood-count monitoring on cyclophosphamide (more adverse events than CNI-based treatment) and calcineurin-inhibitor nephrotoxicity.[8]
• Missing FSGS recurrence after transplant (proteinuria returning soon after engraftment equals recurrent FSGS — act fast with plasmapheresis and rituximab).[16][17]
• Biopsy sampling error in FSGS — the lesion is focal and segmental, so a thin sample misses it and mislabels FSGS as MCD.[2]

Prognosis — the rule of thirds, and steroid responsiveness

Membranous obeys the rule of thirds: about a third remit spontaneously (especially those with absent or low anti-PLA2R levels), about a third remain with non-progressive proteinuria, and about a third progress to ESRD over about 10 years untreated; with proper management, 10% or fewer reach ESRD over the subsequent decade. The Cochrane review confirms immunosuppression beats supportive care alone for inducing remission and reducing progression to kidney failure — balanced against drug toxicity.[7][8]

Predictors of outcome in membranous: the anti-PLA2R level (high at diagnosis flags those who need early immunosuppression; falling titres track remission), persistent nephrotic proteinuria, and interstitial fibrosis on biopsy; older series put 10-year renal survival between 70% and 90%.[7][26][36][27]

FSGS prognosis tracks steroid responsiveness and the variant. Only about 20% enter remission with treatment, and about half progress to kidney failure; individuals who do not achieve resolution of proteinuria have a poor renal prognosis, and the collapsing variant is the most aggressive. Secondary and adaptive FSGS may stabilise if the cause is treated; genetic FSGS often reaches kidney failure but does not recur after transplant.[14][2][29]

Disposition: nephrology referral for all adults with nephrotic syndrome and biopsy confirmation; plan transplant evaluation with recurrence counselling (FSGS recurs in about a third of grafts; anti-PLA2R-guided timing for membranous); plan dialysis for progressive disease; supportive care throughout.[16][7]

Special populations

• Children — childhood steroid-resistant nephrotic syndrome is often FSGS: the international paediatric consensus defines steroid resistance as no remission after four to six weeks of glucocorticoids, and genetic testing matters (NPHS1, NPHS2 and others) because genetic FSGS does not respond to immunosuppression and does not recur after transplant.[32][2]
• Elderly — membranous in the older adult carries the highest solid-malignancy risk (the Deegens tumours clustered over 65, none under 55); thrombotic risk is higher; weigh immunosuppression toxicity against benefit.[21][22][13]
• Pregnancy — distinguish glomerular disease from pre-eclampsia (proteinuria pre-dating pregnancy, low complement, or biopsy-proven GN favours glomerular disease); stop the ACE inhibitor or ARB; thrombosis and infection risk mirror the albumin and proteinuria — manage with nephrology and obstetrics jointly.[24][2]
• Patients of recent West-African ancestry — consider APOL1 risk genotypes when FSGS or hypertension-attributed nephropathy presents; counsel on transplant and genetics.[2]
• Transplant recipients — FSGS recurs in about a third of grafts, early and with heavy proteinuria: plasmapheresis plus rituximab (remission 72.7% in pooled data). Membranous can recur or arise de novo; anti-PLA2R-guided timing reduces recurrence risk.[16][17][3]
• Immunocompromised and HIV — collapsing FSGS (HIVAN) is now rare where combination antiretroviral therapy is available: treat with antiretrovirals plus ACE-inhibitor/ARB-based therapy; hepatitis B and C drive secondary membranous — screen and treat.[18][31][23]

Evidence, guidelines and regional deltas

• KDIGO 2021 Glomerular Diseases Guideline — the international framework: risk-stratified care for membranous and conservative care plus immunosuppression for FSGS; KDIGO recommends corticosteroids first for primary FSGS, though the Cochrane review notes no randomised evidence underpins that choice.[34][14]
• MENTOR (Fervenza et al., NEJM 2019) — in proteinuria of at least 5 g per 24 hours on angiotensin blockade, rituximab (two 1000-mg infusions 14 days apart) was non-inferior to cyclosporine at 12 months (60% vs 52% in complete or partial remission) and superior in maintaining remission to 24 months (60% vs 20%), with fewer serious adverse events (17% vs 31%) — establishing rituximab as a preferred option for high-risk membranous.[3]
• Beck 2009 (NEJM) — PLA2R identified as the target antigen of idiopathic membranous (about 70%, IgG4) — the discovery that turned membranous from an idiopathic into a defined autoimmune disease.[4]
• Tomas 2014 (NEJM) — THSD7A identified as a second podocyte antigen (15 of 154 patients in the discovery cohort, all PLA2R-negative) — a distinct subgroup; later cohorts found malignancy in 13%, reinforcing the antigen-specific autoimmune model.[6][20]
• Cochrane reviews (von Groote 2022; Hodson FSGS) — immunosuppression is probably superior to supportive care alone in membranous, with alkylating-plus-steroid regimens effective but more toxic and CNI remissions less well maintained; in FSGS, ciclosporin for at least six months increases complete remission. The TANGO cohort quantified post-transplant recurrence at 32%.[8][14][16]
• Columbia FSGS classification (D'Agati et al., 2004) — the standard morphological classification of variants (collapsing, tip, cellular, perihilar, NOS) — the framework used worldwide.[5]

Regional deltas — the framework is global, the agents are local:[1]

[1] [1] [1]

The mnemonic and the mantra

[2] [1] [23]

The mantra: biopsy the adult, weigh anticoagulation in the severely hypoalbuminaemic, rituximab the high-risk membranous, steroid-trial the FSGS for at least sixteen weeks.[11][3][29][7]

Ward-round test — three stems, thirty seconds each

Stem 1 — membranous with severe hypoalbuminaemia (answer)

A 55-year-old with biopsy-proven primary membranous nephropathy has a serum albumin of 19 g/L and proteinuria of 9 g/day. He asks why you are starting a blood thinner when he has never had a clot. What is your answer, and at what threshold? Model: The hypercoagulability of the nephrotic syndrome climbs as serum albumin falls — hypoalbuminaemia is the strongest independent predictor of venous thromboembolism — and membranous is the nephrotic disease in which thrombosis is most common, with renal vein thrombosis the signature event. Anticoagulation is favoured when serum albumin is under 3 g/dL (benefit-to-harm about 4.5 to 1 in Lee's decision analysis) and strongly favoured under 2 g/dL (about 13 to 1), but unlikely to help if bleeding risk is high — so the decision is individualised, not automatic. He gets the anticoagulant now, not after a clot, because renal vein thrombosis can be the presenting event of his disease.[11][13][24][12]

Stem 2 — new membranous in a 62-year-old (answer)

A 62-year-old man is found to have membranous nephropathy on biopsy, anti-PLA2R positive. He is a smoker who has lost 6 kg over three months. Beyond the kidney, what is mandatory, and why? Model: New membranous in an older adult mandates a thorough malignancy screen. In the Deegens series every solid tumour occurred in a patient over 55, with 10 of 24 over 65; membranous accounts for about 49% of paraneoplastic nephrotic syndrome (median age 60), and the nephrotic syndrome preceded the tumour diagnosis in 36% — a negative screen today does not close the book. Run CT chest, abdomen and pelvis, age-appropriate colonoscopy, PSA, and mammography if female, plus HBsAg, anti-HCV and HIV. If anti-THSD7A is positive instead of PLA2R, the malignancy rate rises to 13% and the hunt is even more aggressive. Secondary membranous often remits when the underlying tumour is treated.[21][22][20][23]

Stem 3 — FSGS declared steroid-resistant (answer)

A 28-year-old with primary FSGS is referred as steroid-resistant after six weeks of steroids. The team wants to start a calcineurin inhibitor today. What is the right call? Model: Stop. FSGS is steroid-resistant only after at least 16 weeks of steroid therapy — in Pokhariyal's series, duration beyond 16 weeks was the only independent predictor of remission, and adults who remitted had a median course of about five months. Six weeks is not a trial, it is an interruption. Confirm adherence and duration first, continue maximal conservative therapy (ACE inhibitor or ARB, blood pressure and salt control), and only if nephrotic proteinuria persists — refractory disease is typically defined as persistence despite at least four months of therapy — move to a calcineurin inhibitor; ciclosporin given for at least six months increases complete remission in the Cochrane review. Declaring resistance early denies the patient the one intervention — steroid responsiveness — that best predicts a good outcome.[29][28][33][14]

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