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PA27.5-6 | Glomerular Diseases — SDL Guide (Part 2)

Focal Segmental Glomerulosclerosis (FSGS)

A four-panel renal pathology diagram explaining FSGS as focal and segmental glomerular scarring with causes, IF/EM findings, and clinical outcomes. — **Panel A:** Low-power renal biopsy with normal glomeruli, affected juxtamedullary glomeruli, focal involvement, segmental sclerosis, hyalinosis, collapsed capillary loops, adhesion to Bowman's capsule, and biopsy sampling error.. **Panel B:** Cause map showing HIV-associated nephropathy/collapsing variant, heroin or drug-associated FSGS, obesity-related hyperfiltration, reduced nephron mass, and genetic mutations NPHS2/podocin, TRPC6, and INF2 leading to podocyte injury.. **Panel C:** Split IF and EM view showing nonspecific IgM and C3 trapping in sclerotic segments and diffuse podocyte foot process effacement in both sclerotic and non-sclerotic segments, with contrast to minimal change disease.. **Panel D:** Clinical timeline showing nephrotic syndrome in adults, poor steroid response with about 30% responding, progression to ESRD in about 50% within 10 years, and recurrence after kidney transplantation..

Focal segmental glomerulosclerosis means sclerosis (scarring/collapse) affecting some glomeruli (focal = < all) and only part of each affected glomerulus (segmental = < whole tuft). It is the most common cause of nephrotic syndrome in adults in many series.

Causes — remember the triad: HIV, heroin (or other drugs), obesity
• Primary (idiopathic): Circulating permeability factors; suPAR implicated
• HIV-associated nephropathy (HIVAN): collapsing variant; severe course
• Heroin nephropathy: now rare; similar histology to idiopathic FSGS
• Obesity-related: Hyperfiltration-induced podocyte stress (maladaptive FSGS)
• Secondary to reduction in nephron mass: post-unilateral nephrectomy, reflux nephropathy
• Genetic: mutations in NPHS2 (podocin), TRPC6, INF2

Pathology:
• LM: Focal and segmental areas of glomerular sclerosis — hyalinosis (insudation of plasma proteins), collapse of capillary loops, adhesion to Bowman's capsule. The JUXTAMEDULLARY glomeruli are affected first (sampling error on biopsy is real).
• IF: Non-specific IgM and C3 in sclerotic segments (entrapped, not deposited immunologically).
• EM: Foot process effacement in sclerotic AND non-sclerotic segments — this is the key difference from MCD where only the foot processes are abnormal.

Clinical course: Poor. Only 30% respond to steroids. ~50% progress to ESRD within 10 years. Recurs in transplanted kidneys (especially if circulating permeability factor is the cause), making FSGS one of the most feared diagnoses in nephrology.

Membranous Nephropathy

Membranous nephropathy is the commonest cause of primary nephrotic syndrome in adults (especially 30-60 years). It is defined by subepithelial immune-complex deposits that thicken the GBM.

Primary (70-80%): Autoantibody against phospholipase A2 receptor (PLA2R) on podocytes. PLA2R antibody titre correlates with disease activity and is now used clinically to monitor response.

Secondary (20-30%): Solid tumours (lung, colon — paraneoplastic), hepatitis B, SLE (lupus membranous = Class V), drugs (gold, penicillamine, NSAIDs), infections.

Rule of 1/3: ~1/3 spontaneous complete remission, ~1/3 persistent proteinuria without progression, ~1/3 progressive CKD.

Pathology:
• LM: GBM thickening without hypercellularity (this is important — no proliferation, no inflammation). Silver methenamine stain shows a characteristic 'spike and dome' pattern — the 'spikes' are projections of GBM matrix growing up between the subepithelial deposits ('domes').
• IF: Granular IgG (and C3) deposits in a diffuse, global, subepithelial distribution — like a string of pearls along the capillary loop.
• EM: Subepithelial electron-dense deposits separated by GBM spikes. In advanced disease, deposits are incorporated into the GBM (intramembranous stage) and eventually resorb, leaving lucent holes in the GBM (post-deposit stage).

Diagram of membranous nephropathy on electron microscopy showing subepithelial immune deposits, GBM spikes, podocyte foot process effacement, and Jones-based stages I to IV. — **Panel A:** High-magnification EM schematic showing capillary lumen, fenestrated endothelium, GBM, subepithelial electron-dense deposits, GBM spike formation, urinary space, and podocyte foot process effacement.. **Panel B:** Stage I membranous nephropathy with subepithelial deposits and no GBM spikes.. **Panel C:** Stage II membranous nephropathy with GBM spikes forming between subepithelial deposits.. **Panel D:** Stage III membranous nephropathy with deposits surrounded by GBM material and becoming intramembranous.. **Panel E:** Stage IV membranous nephropathy with deposit resorption and irregular thickened GBM..

Stages (Jones-based staging): Stage I (subepithelial deposits, no spikes) → Stage II (spikes present) → Stage III (deposits surrounded, intramembranous) → Stage IV (resorption, irregular GBM) — useful for prognostication on biopsy reports.

Membranoproliferative GN (MPGN)

Educational diagram of MPGN showing tram-track GBM thickening, immune versus complement-mediated classification, immunofluorescence patterns, electron microscopy deposits, and key clinical clues. — **Panel A:** Large glomerular capillary loop cross-section showing mesangial hypercellularity, GBM thickening, tram-track/double-contour GBM, endothelial cell, mesangial cell interposition, capillary lumen, and subendothelial region.. **Panel B:** Immune-based classification comparing Ig-mediated MPGN with immune-complex deposition, hepatitis C, cryoglobulinaemia, SLE, low C3 and C4, versus complement-mediated MPGN / Dense Deposit Disease with C3 nephritic factor or factor H deficiency, alternative pathway activation, and low C3 only.. **Panel C:** Immunofluorescence patterns showing granular C3 plus Ig along capillary walls in Ig-mediated MPGN and C3-only staining with no Ig in complement-mediated MPGN.. **Panel D:** Electron microscopy schematic showing subendothelial and mesangial deposits in Ig-mediated MPGN and intramembranous ribbon-like dense deposits in Dense Deposit Disease.. **Clinical strip:** Clinical clues: older children and young adults, low complement as key clue, hepatitis C serology essential, poor prognosis with about 50 percent reaching ESRD in 10 years..

Membranoproliferative glomerulonephritis combines features of both nephrotic and nephritic syndrome — it is the great 'overlap' disease.

Classification (modern immune-based):
• Ig-mediated MPGN (former Type I): Immune-complex deposition in mesangium and subendothelium; causes = hepatitis C (most common), cryoglobulinaemia, SLE. C3 + C4 both low (classical pathway activation).
• Complement-mediated MPGN (former Type II / Dense Deposit Disease): Uncontrolled alternative pathway due to C3 nephritic factor (C3NeF, autoantibody stabilising C3 convertase) or factor H deficiency. Only C3 low (alternative pathway). IF: C3 only, no Ig.

Pathology:
• LM: Mesangial hypercellularity + GBM thickening + 'tram-track' or double-contour GBM (PAS/silver stain). The double contour is created by mesangial cell interposition between the endothelium and the GBM — the mesangium literally grows into the capillary wall.
• IF: Granular C3 ± Ig along capillary walls (pattern depends on type).
• EM: Subendothelial + mesangial deposits (Ig-mediated); intramembranous ribbon-like dense deposits (Dense Deposit Disease).

Clinical: Presents in older children and young adults. Low complement is the clue. Hepatitis C serology essential. Poor prognosis; ~50% reach ESRD in 10 years.

SELF-CHECK

A 4-year-old with nephrotic syndrome has a biopsy showing normal glomeruli on LM, negative IF, and diffuse foot process effacement on EM. Which finding on urinalysis is most expected?

A. Red cell casts in urine

B. Oval fat bodies with Maltese-cross birefringence under polarised light

C. White cell casts indicating tubular infection

D. Granular casts indicating tubular necrosis

Reveal Answer

Answer: B. Oval fat bodies with Maltese-cross birefringence under polarised light

This is minimal change disease (MCD). The massive proteinuria (> 3.5 g/day) leads to urinary loss of lipoproteins, which appear as oval fat bodies and Maltese-cross birefringence under polarised light — classic findings of nephrotic syndrome. Red cell casts are a nephritic, not nephrotic, feature. MCD is characterised by selective proteinuria without haematuria.