Primary Glomerulonephritis

Overview

Major primary GN entities — distinct pathogenesis/morphology/behaviour, several converge on same clinical syndrome (nephritic/nephrotic).

Acute post-streptococcal GN

Classic cause of acute nephritic syndrome. Children 2-14yr (10% adults >40). Sudden onset 1-2wk post strep pharyngitis/impetigo.

Etiopathogenesis: IMMUNE-COMPLEX disease. Evidence: epidemiologic link, latent period matches antibody formation, ↑ASO/anti-DNAse B/ASKase/anti-NADase/AHase titres, hypocomplementaemia, endostreptosin antigen. Nephritogenic strains: group A β-haemolytic strep types 12,4,1, Red Lake.

Morphology: enlarged kidneys (1.5-2x), petechial haemorrhages = “FLEA-BITTEN KIDNEY.” LM: diffuse hypercellularity (mesangial/endothelial/epithelial proliferation + neutrophil/monocyte infiltration), RBC casts. EM: subepithelial “HUMPS” (immune complexes). IF: IgG+C3, granular/irregular.

Clinical: classic nephritic syndrome in child. HTN = poor prognostic sign. Children recover ~95%; adults more complications (RPGN, chronic GN, uraemia).

Non-streptococcal (~1/3 of acute GN): other bacteria/viruses/parasites/syphilis. Similar morphology, WORSE prognosis.

RPGN (crescentic/extracapillary GN)

Acute renal decline over weeks-months. CRESCENTS = proliferating parietal epithelial cells + visceral epithelial + mononuclear cells, stimulated by fibrin in capsular space. Adults, slight male predominance, generally POOR prognosis.

3 types (by serum C3/anti-GBM Ab/ANCA):

Goodpasture’s syndrome (Type I example): RPGN + pulmonary haemorrhage, males, 3rd decade. Anti-GBM Ab cross-reacts with ALVEOLAR basement membrane (shared type IV collagen epitope = Goodpasture antigen). Evidence: linear IgG+C3, circulating anti-GBM Ab, experimental induction. Lung lesions need prior lung injury to manifest.

Type II: small % of post-strep/non-strep GN progresses. Granular IgG+C3, low complement, circulating complexes.

Type III (pauci-immune): Wegener’s, microscopic PAN. Mostly ANCA+. Normal complement, no anti-GBM, minimal deposits.

Morphology (shared): “large white kidney.” LM: pathognomonic crescents obliterating Bowman’s space, fibrin deposition, tuft hypercellularity, fibrin thrombi.

Clinical: post-infectious resembles acute GN/ARF. Goodpasture’s: renal failure ± haemoptysis. Post-infectious = better outcome; overall poor.

Minimal change disease (MCD)

= lipoid nephrosis/foot process disease/nil deposit disease. Nephrotic syndrome, NO glomerular abnormality on LM. ~80% of childhood nephrotic syndrome (<16yr, boys:girls 2:1).

Etiopathogenesis: mostly idiopathic; assoc. Hodgkin’s, HIV, drugs (NSAIDs, rifampicin, IFN-α). Immunologic evidence: no IF deposits, normal complement (± circulating complexes), universal steroid response, ↑suppressor T-cell activity → IL-8/TNF → foot process flattening + altered GBM charge. Nephrin gene mutation (congenital MCD) = genetic basis in that subset.

Selective proteinuria mechanism (children): loss of GBM heparan sulfate proteoglycan (↓negative charge) + loss of sialoglycoprotein coat (foot process flattening). Adults: non-selective (more extensive defect).

Morphology: grossly normal. LM: no abnormality (±minimal mesangial matrix ↑); tubular lipid vacuolation. EM: DIFFUSE FOOT PROCESS FLATTENING (defining lesion), normal GBM, NO deposits. IF: no deposits.

Clinical: massive HIGHLY SELECTIVE proteinuria, HTN unusual. Peak 6-8yr. Onset may follow URI/allergy/immunisation. Excellent steroid response, good long-term prognosis.

Membranous GN

= epimembranous nephropathy. Diffuse capillary wall thickening. COMMONEST cause of ADULT nephrotic syndrome. ~85% idiopathic; rest secondary (SLE, malignancy, chronic hep B/C, syphilis, malaria, drugs).

Etiopathogenesis: idiopathic = immune-complex, but LOCAL deposit formation (circulating complexes <25% cases). NO leucocytic infiltration — damage via MEMBRANE ATTACK COMPLEX (C5b-C9) on podocytes directly. Idiopathic antigen unknown; secondary = endogenous (DNA-SLE) or exogenous (HBV, tumour Ag, treponemal Ag, penicillamine).

Morphology: enlarged, pale, smooth kidneys. LM: diffuse uniform capillary wall thickening, GBM “DUPLICATION” (silver=black, PAS=pink), NO cellular proliferation. EM: subepithelial deposits, GBM “SPIKES” between them. IF: granular IgG+C3.

Clinical: insidious adult nephrotic syndrome, NON-selective proteinuria. Largely IRREVERSIBLE — ~50% → ESRD in 2-20yr. Renal vein thrombosis complication. Steroid benefit debated.

MPGN (mesangiocapillary GN)

Important cause of nephrotic syndrome in children/young adults (peak 15-20yr). 2 combined features: mesangial hypercellularity + GBM thickening.

Morphology: pale firm kidneys. LM: enlarged glomeruli, lobular pattern, mesangial proliferation, GBM “DOUBLE CONTOUR”/“TRAM-TRACK” (silver stain). Interstitial inflammation+foam cells.

Clinical: similar across types, peak 15-20yr, nephrotic syndrome common.

FSGS

= focal sclerosis/hyalinosis. Sclerosis+hyalinosis of SOME glomeruli, PART of tuft (<50%) — genuinely focal+segmental (unlike others’ diffuse pattern). ~1/3 adult nephrotic syndrome now, rising.

Etiopathogenesis — 3 groups:

1. Idiopathic (majority) — children/young adults. Differs from MCD: non-selective proteinuria, STEROID-RESISTANT, may → CRF
2. Superimposed (with MCD=steroid-responsive; or IgA nephropathy)
3. Secondary — HIV, diabetes, reflux nephropathy, heroin, analgesic nephropathy

Hallmark: injury to VISCERAL EPITHELIAL CELLS (podocytes) → disruption → nephron loss. HIV variant: collapsing glomerulopathy (tuft collapse, podocyte hyperplasia, pseudo-crescent, rapid decline).

Morphology: LM — some glomeruli segmental sclerosis/hyalinosis (PAS+), others normal; mesangial hypercellularity; interstitial fibrosis+tubular atrophy. EM: foot process effacement + electron-dense deposits in sclerotic regions. IF: IgM+C3.

Clinical: any age, male predominance. Heavy proteinuria; haematuria+HTN MORE frequent than MCD; renal failure may present at onset.

IgA nephropathy (Berger’s disease)

EMERGING as commonest glomerulopathy worldwide, rising. Mesangial IgA deposits. Berger 1968 (≠ Buerger’s disease).

Etiopathogenesis: mostly idiopathic; also HSP; assoc. chronic inflammatory conditions (liver disease, IBD, interstitial pneumonitis, leprosy, dermatitis herpetiformis, uveitis, AS, Sjögren’s, monoclonal IgA gammopathy). Mechanisms: mesangial IgA-complex ENTRAPMENT (↑serum IgA/complexes), alternate complement activation (C3+properdin, early components absent), mucosal infection link (↑mucosal IgA secretion theory), HLA-B35 association, possible genetic ↑circulating IgA.

Morphology: LM varies (focal proliferative GN, FSGS, MPGN-like, rarely RPGN). EM: finely granular MESANGIAL deposits. IF (diagnostic): mesangial IgA ± IgG, usually +C3+properdin.

Clinical: children/young adults. RECURRENT HAEMATURIA precipitated by mucosal infection (“synpharyngitic haematuria” — flares WITH infection, unlike post-strep GN’s fixed 1-2wk lag). Mild proteinuria usual; occasional nephrotic syndrome.

Chronic GN (end-stage kidney)

FINAL COMMON PATHWAY of glomerular diseases → irreversible impairment. Progression rates (descending): RPGN (90%) > membranous GN (50%) > MPGN (50%) > FSGS (50%) > IgA nephropathy (40%) > acute post-strep GN (~1%). ~20% idiopathic (no preceding GN identified).

Morphology: small contracted kidneys (as low as 50g), adherent capsule, granular cortical surface, narrow atrophic cortex. Micro: glomeruli reduced, mostly HYALINISED (acellular, PAS+ masses); tubular loss/atrophy, hyaline casts; interstitial fibrosis; arterial/arteriolar sclerosis (if hypertensive).

Clinical relevance

Dramatically different chronic-GN progression risk (RPGN 90% vs post-strep GN ~1%) = single most important prognostic fact — explains why post-strep GN in a child is self-limited illness while RPGN is a nephrological emergency, despite both being “acute” presentations. Goodpasture’s combined renal-pulmonary disease = ONE antibody (anti-type IV collagen) hitting shared epitope in two organs — not coincidental comorbidity. MCD/membranous/MPGN/FSGS collectively show “nephrotic syndrome” = shared clinical output of ≥4 mechanistically distinct lesions — syndrome name describes clinical picture not one disease, why biopsy is essential not optional. IgA nephropathy’s infection-flare haematuria pattern (vs post-strep GN’s fixed lag) = useful bedside discriminator between the two commonest causes of episodic haematuria in young patients — TIMING relationship to infection is diagnostic, not just haematuria presence.

Overview

This note covers the major primary glomerulonephritis entities in the classification set out in Glomerular Diseases - Nephritic and Nephrotic Syndromes — each with a genuinely distinct pathogenesis, morphology, and clinical behaviour, though several converge on the same clinical syndrome (nephritic or nephrotic).

Acute (Post-Streptococcal) Glomerulonephritis

Synonyms: acute diffuse proliferative GN, diffuse endocapillary GN. The classic cause of acute nephritic syndrome. Common in developing countries, mostly children 2–14 years (10% in adults >40). Sudden onset 1–2 weeks after streptococcal pharyngitis or skin infection (impetigo).

Etiopathogenesis — an immune-complex disease, well-established via: epidemiologic link to preceding strep throat/skin infection; a latent period matching antibody-formation time; elevated ASO, anti-DNAse B, anti-streptokinase, anti-NADase, anti-hyaluronidase titres; hypocomplementaemia (complement consumption in the deposits); identification of a streptococcal cytoplasmic antigen, endostreptosin. Nephritogenic strains: group A β-haemolytic streptococcus types 12, 4, 1, and Red Lake.

Morphology: grossly symmetrically enlarged kidneys (1.5–2× normal weight) with petechial cortical haemorrhages — “flea-bitten kidney.” Light microscopy: diffuse glomerular hypercellularity from mesangial/endothelial/occasional epithelial proliferation plus neutrophil/monocyte infiltration; red cell casts in tubules. EM: characteristic subepithelial electron-dense “humps” — the immune complex deposits. Immunofluorescence: IgG + C3, irregular/granular pattern.

Clinical features: classic acute nephritic syndrome in a child — haematuria, red cell casts, mild non-selective proteinuria, hypertension, periorbital oedema, variable oliguria (adults present more atypically — sudden hypertension, oedema, azotaemia). Hypertension is a poor prognostic sign. Children recover completely in ~95%; adults more often develop complications (RPGN, chronic GN, uraemia).

Acute non-streptococcal GN (~1/3 of acute GN) — other bacteria (staph, pneumococci, meningococci, Salmonella, Pseudomonas), viruses (HBV, mumps, EBV, varicella), parasites (malaria, toxoplasmosis, schistosomiasis), syphilis. Similar morphology; worse prognosis than post-streptococcal disease.

Rapidly Progressive Glomerulonephritis (RPGN)

Synonyms: crescentic GN, extracapillary GN. Acute renal function decline over weeks-months, defined by crescents — proliferating parietal (Bowman’s capsule) epithelial cells, plus visceral epithelial and invading mononuclear cells, stimulated by fibrin in the capsular space. Adults, slight male preponderance, generally poor prognosis.

Three etiopathogenetic types, distinguished by three serologic markers (serum C3, anti-GBM antibody, ANCA):

Type I — Goodpasture’s syndrome (the characteristic anti-GBM example): acute RPGN plus pulmonary haemorrhage, males, 3rd decade. Anti-GBM antibodies cross-react with alveolar basement membrane (both contain the same type IV collagen epitope — the Goodpasture antigen), producing combined renal and pulmonary disease. Evidence: linear IgG+C3 deposits along GBM, circulating anti-GBM antibodies, experimental induction with anti-GBM antibody injection. Pulmonary lesions require prior lung injury (viral/bacterial infection, hydrocarbon exposure) to manifest experimentally.

Type II — post-infectious RPGN: a small proportion of post-streptococcal (or non-streptococcal) GN progresses to RPGN, evidenced by granular IgG+C3 deposits, low complement, circulating immune complexes.

Type III — pauci-immune GN: Wegener’s granulomatosis, microscopic polyarteritis nodosa. Pathogenesis incompletely defined; most patients ANCA-positive; normal complement, negative anti-GBM, minimal glomerular immune deposits (hence “pauci-immune”).

Morphology (shared across types): grossly enlarged, pale kidneys (“large white kidney”). Light microscopy: pathognomonic crescents obliterating Bowman’s space and compressing the tuft, with fibrin deposition; tuft hypercellularity/leucocytic infiltration; fibrin thrombi. EM/IF vary by type as in the table above.

Clinical features: post-infectious RPGN resembles acute GN presenting as acute renal failure. Goodpasture’s presents with renal failure ± recurrent haemoptysis from pulmonary haemorrhage. Post-infectious cases have relatively better outcomes; overall prognosis poor.

Minimal Change Disease (MCD)

Synonyms: lipoid nephrosis, foot process disease, nil deposit disease. Nephrotic syndrome with no apparent glomerular abnormality on light microscopy. Accounts for ~80% of nephrotic syndrome in children under 16 (boys:girls 2:1) — historically the first condition linked to nephrotic syndrome.

Etiopathogenesis: mostly idiopathic; some associated with Hodgkin’s disease, HIV, or drugs (NSAIDs, rifampicin, interferon-α). Immunologic mechanism suggested by: no immunofluorescence deposits, normal complement (but circulating immune complexes in some), universal steroid responsiveness, evidence of increased suppressor T-cell activity releasing cytokines (IL-8, TNF) that flatten podocyte foot processes and alter GBM charge. Nephrin gene mutation found in congenital MCD points to a genetic basis in that subset.

Selective proteinuria mechanism (children): loss of GBM heparan sulfate proteoglycan reduces its normal negative charge; loss of the epithelial sialoglycoprotein coat flattens foot processes. (Adults with MCD instead show non-selective proteinuria, implying a more extensive permeability defect.)

Morphology: grossly normal kidneys. LM: no glomerular abnormality (occasionally minimal mesangial matrix increase); tubules show lipid vacuolation (“lipoid nephrosis”). EM: diffuse podocyte foot process flattening — the defining lesion (“foot process disease”); GBM normal, no deposits. IF: no complement/immunoglobulin deposits (“nil deposit disease”).

Clinical features: classic fully-developed nephrotic syndrome with massive, highly selective proteinuria; hypertension unusual. Peak age 6–8 years; onset sometimes follows URI, atopic allergy, or immunisation. Excellent steroid response; very good long-term prognosis despite relapses.

Membranous Glomerulonephritis

Synonym: epimembranous nephropathy. Diffuse thickening of the glomerular capillary wall — the most common cause of nephrotic syndrome in adults. ~85% idiopathic; remainder secondary (SLE, malignancy, chronic hepatitis B/C, syphilis, malaria, drugs).

Etiopathogenesis: idiopathic disease is immune-complex-mediated, but deposits form locally (circulating immune complexes found in <25% of cases). No leucocytic infiltration — damage is complement-mediated directly, currently attributed to the membrane attack complex (C5b–C9) acting on podocytes. Idiopathic disease’s nephritogenic antigen is unknown; secondary disease’s antigen may be endogenous (DNA in SLE) or exogenous (HBV, tumour antigen, treponemal antigen, penicillamine).

Morphology: grossly enlarged, pale, smooth kidneys. LM: diffuse, uniform capillary wall thickening; advancing deposits become incorporated into a markedly thickened GBM, producing GBM “duplication” (best seen with silver stain — black — or PAS — pink); no cellular proliferation. EM: subepithelial electron-dense deposits with GBM material protruding between them as “spikes.” IF: granular IgG + C3.

Clinical features: insidious adult-onset nephrotic syndrome, usually non-selective proteinuria; microscopic haematuria and hypertension may occur. Largely irreversible — ~50% progress to end-stage renal disease over 2–20 years. Renal vein thrombosis is a recognised complication (hypercoagulability). Steroid/immunosuppressive benefit is debated.

Membranoproliferative Glomerulonephritis (MPGN)

Synonym: mesangiocapillary GN. An important cause of nephrotic syndrome in children/young adults (peak age 15–20). Defined by two combined histologic features: mesangial hypercellularity plus GBM thickening.

Three types:

Morphology: grossly pale, firm kidneys. LM: enlarged glomeruli, accentuated lobular pattern, mesangial proliferation/matrix increase; GBM markedly thickened with a “double contour”/“tram-track” appearance on silver stain (two basement membranes separated by a clear zone). Tubular vacuolation; interstitial chronic inflammation with foam cells; hypertensive vascular changes when hypertension develops.

Clinical features: similar presentation across types, peak age 15–20; nephrotic syndrome is a common presentation.

Focal Segmental Glomerulosclerosis (FSGS)

Synonyms: focal sclerosis, focal hyalinosis. Sclerosis and hyalinosis of some glomeruli, affecting only part of the tuft (<50% in a section) — genuinely focal and segmental, unlike the other entities’ diffuse/global patterns. Now responsible for ~1/3 of adult nephrotic syndrome, with rising incidence.

Etiopathogenesis — three groups:

1. Idiopathic (majority) — children/young adults, nephrotic syndrome; differs from MCD by non-selective proteinuria, steroid resistance, and risk of progression to chronic renal failure.
2. Superimposed on primary glomerular disease — FSGS with MCD (steroid-responsive) or IgA nephropathy.
3. Secondary — HIV, diabetes, reflux nephropathy, heroin abuse, analgesic nephropathy.

Pathogenetic hallmark: injury to visceral epithelial cells (podocytes), causing their disruption and consequent nephron loss. A distinct HIV-associated variant, collapsing glomerulopathy, shows segmental/global tuft collapse with podocyte hyperplasia/hypertrophy (pseudo-crescent) and rapid renal decline.

Morphology: LM shows some glomeruli with segmental sclerosis/hyalinosis (PAS-positive homogeneous material on the inner aspect of affected capillary loops), others normal; mesangial hypercellularity in many cases; interstitial fibrosis and tubular atrophy. EM: diffuse foot process effacement (as in MCD) plus electron-dense deposits in the sclerotic/hyalinised regions. IF: IgM + C3 in the lesions.

Clinical features: any age, male preponderance; nephrotic syndrome with heavy proteinuria; haematuria and hypertension more frequent than in MCD; renal failure may be present at onset.

IgA Nephropathy (Berger’s Disease)

Emerging as the most common glomerulopathy worldwide, rising in incidence. Defined by mesangial IgA deposits. First described by Berger (1968) — not to be confused with Buerger’s disease (thromboangiitis obliterans).

Etiopathogenesis: mostly idiopathic; also seen in Henoch-Schönlein purpura, and associated with chronic inflammatory conditions across systems (liver disease, IBD, interstitial pneumonitis, leprosy, dermatitis herpetiformis, uveitis, ankylosing spondylitis, Sjögren’s, monoclonal IgA gammopathy). Proposed mechanisms: mesangial entrapment of circulating IgA-immune complexes (elevated serum IgA/IgA-complexes); alternate complement pathway activation (C3/properdin present, early components absent); a link to mucosal infection (respiratory/GI/urinary), suggesting increased mucosal IgA secretion as the source; HLA-B35 association and a possible genetically-determined tendency to raised circulating IgA in some cases.

Morphology: LM pattern varies — focal proliferative GN, FSGS, MPGN-like change, rarely RPGN. EM: finely granular electron-dense mesangial deposits. IF (diagnostic): mesangial IgA ± IgG, usually with C3 and properdin.

Clinical features: children/young adults; classic picture is recurrent haematuria bouts precipitated by mucosal infection (the “synpharyngitic haematuria” pattern); mild proteinuria usual; nephrotic syndrome occasionally develops.

Chronic Glomerulonephritis (End-Stage Kidney)

The final common pathway of multiple glomerular diseases progressing to irreversible renal impairment. Progression rates, in descending order: RPGN (90%) → membranous GN (50%) → MPGN (50%) → FSGS (50%) → IgA nephropathy (40%) → acute post-streptococcal GN (only ~1%). ~20% of chronic GN is idiopathic, with no identifiable preceding GN type.

Morphology: grossly small, contracted kidneys (as low as 50 g each), capsule adherent, diffusely granular cortical surface, narrow atrophic cortex. Microscopy: glomeruli reduced in number, most completely hyalinised (acellular, eosinophilic, PAS-positive masses); tubular loss/atrophy with hyaline casts; fine interstitial fibrosis with chronic inflammatory cells; prominent arterial/arteriolar sclerosis in hypertensive cases.

Clinical Relevance

• The dramatically different progression risk to chronic GN across entities (RPGN’s 90% versus post-streptococcal GN’s ~1%) is the single most clinically important prognostic fact in this whole topic — it directly explains why acute post-streptococcal GN in a child is treated as a self-limited illness while RPGN is treated as a nephrological emergency, despite both being “acute” presentations.
• Goodpasture’s syndrome’s combined renal-pulmonary presentation is a clean, mechanistically-grounded example of one antibody (anti-type-IV-collagen) producing disease in two organs sharing the same target antigen — recognising the shared epitope is what explains why renal and pulmonary disease occur together rather than being coincidental comorbidities.
• MCD, membranous GN, MPGN, and FSGS collectively illustrate that “nephrotic syndrome” is a shared clinical output of at least four mechanistically distinct lesions (podocyte foot-process disease with no deposits; complement-mediated subepithelial deposits; combined mesangial-proliferative-and-membranous change; and segmental scarring from podocyte injury) — the syndrome name describes the clinical picture, not a single disease, which is why biopsy is essential rather than optional once nephrotic syndrome is diagnosed clinically.
• The IgA nephropathy pattern of haematuria flaring with mucosal infection (in contrast to post-streptococcal GN’s fixed 1–2 week latency) is a genuinely useful bedside discriminator between the two most common causes of episodic haematuria in young patients — the timing relationship to infection, not just the presence of haematuria, is diagnostic.

• Immune complex deposit locations across GN types (subepithelial humps, subendothelial, intramembranous, mesangial) mapped to disease
• RPGN’s three types compared: anti-GBM, immune complex, and pauci-immune pathogenesis
• Goodpasture’s syndrome: shared type IV collagen epitope producing combined renal and pulmonary disease
• Progression-to-chronic-GN risk ranked across the major primary GN entities

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