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L9 Renal Glomerulonephritis

Glomerulonephritis — Walker

What this lecture is about

This lecture builds a framework for understanding glomerulonephritis (GN) as a set of immune-mediated patterns of glomerular injury. It works from the basic immunology (antigens, immunoglobulins, complement, T cells) through the three core injury patterns (proliferative, non-proliferative/podocyte, and rapidly progressive/crescentic), then anchors each pattern to a clinical syndrome (nephritic, nephrotic, RPGN). Three cases scaffold it: APSGN (proliferative/nephritic), membranous GN (podocyte/nephrotic), and anti-GBM disease (crescentic/RPGN). The unifying idea: where the immune deposit forms determines whether it can contact the circulation, which determines whether inflammatory cells are recruited, which determines the clinical picture.

1. Normal glomerular architecture (the baseline you injure)

  • Understand the cellular components of the glomerulus and where each sits: endothelial cell (lines the capillary, in contact with blood), mesangial cell (central support, between capillary loops), podocyte (visceral epithelial cell, on the urinary side), parietal epithelial cell (lines Bowman’s capsule).
  • Understand the three layers of the filtration barrier, from blood to urine: fenestrated endothelium with its glycocalyx, the glomerular basement membrane (GBM), and the podocyte foot processes with their slit diaphragms (~40 nm filtration slit).
  • Understand the juxtaglomerular apparatus sits at the vascular pole, with afferent and efferent arterioles.
  • Key principle you will reuse all lecture: the barrier is both size-selective and charge-selective, and the GBM is not a solid barrier. Podocyte function is essential to keeping protein in.

2. Initiating events — how the immune system targets the glomerulus

  • Understand the central premise: GN begins with a host immune response to an antigen (pathogen-derived or self), generating specific immunoglobulins (B cell arm) and sensitised T cells. The result is deposition of immunoglobulin or accumulation of activated T cells within the glomerulus.

  • Know the three antigen sources that can drive GN:

    1. Exogenous — bacterial or viral product.
    2. Exogenous-derived self — circulating DNA/ENA in SLE, or altered IgA.
    3. Endogenous (local glomerular component) — e.g. non-collagenous domain of collagen alpha-4 (the Goodpasture antigen), or a podocyte foot-process component.

  • Understand the role of immunoglobulin: antibody binds antigen to form an immune complex. The where, how, and which isotype of immunoglobulin modifies the downstream response (e.g. complement-fixing vs non-fixing, capacity to recruit cells).

Couser's humoral antigen classification (slide 10)

  • Antigens to normal glomerular constituents: Goodpasture antigen (collagen alpha-4, in the GBM); podocyte anti-PLA2R antigen.
  • Non-renal self antigens that localise in the glomerulus: SLE DNA fragments, cryoglobulins.
  • Exogenous antigens: localise according to charge and size, either free or as circulating immune complexes. Nephrogenic potential depends on the type of protein recognition.

3. Mechanisms of immune glomerular injury

  • Know the pathways by which B cells (IgG) and T cells produce glomerular injury:
    • Antibody can directly induce injury.
    • Antibody-activated complement, with the membrane attack complex (C5b-9) directly injuring cells.
    • Complement chemotaxis (C3a, C5a) recruiting PMNs (neutrophils).
    • Macrophage recruitment and activation via Fc fragments on deposited immunoglobulin.
    • Lymphokines from activated T cells (delayed-type hypersensitivity, DTH).
  • Principle: these mechanisms are not GN-specific; they apply to all immune-mediated disease.

Complement, applied to GN

  • Understand the three activation routes converging on C3:
    • Classical: IgG1/IgG3/IgM with C1q, C2, C4 (also CRP). Forms C4bC2a (C3 convertase).
    • Lectin: MBL/MASPs binding microbial surfaces, agalactosyl IgG, IgG4, IgA, SpeB.
    • Alternate: spontaneous “C3 tickover”, damaged cells, LPS, IgA. Forms C3bBb (AP C3 convertase), amplified by properdin and factor B.
  • Understand the two key effector outputs (the slide labels them “key mediators”):
    • C5a = chemotactic factor (recruits inflammatory cells).
    • C5b-9 = membrane attack complex.
  • Know the regulators that hold complement in check: circulating CRPs (factor H, factor I, MCP) and cell-bound CD59. Their relevance: loss of regulation drives complement-mediated GN.

Tie-in to APSGN

APSGN consumes complement (C3 degradation), which is why low serum C3 is a hallmark lab finding.

4. Innate and adaptive integration

  • Understand the overall schematic (Couser): an etiologic event generates PAMPs/DAMPs, which feed:
    • the innate arm (complement → C5a/C5b-9; TLRs/NLRs) acting on resident glomerular cells and recruiting circulating inflammatory cells, and
    • the adaptive arm (antigen-presenting cell → CD4 T cells → Th1/Th2/Th17, regulated by Tregs; B cells producing autoantibodies and immune complexes).
  • Both converge on effectors (proteases, oxidants, cytokines, chemokines, growth factors, eicosanoids) that produce glomerular tissue injury. The point to absorb: GN is a combined innate + adaptive process, not purely antibody-driven.

5. Where deposits form determines the disease (the central organising concept)

  • Understand that the consequences of an immune deposit depend on:

    • Site of deposit: mesangial, subendothelial, or subepithelial.
    • Biological properties of the immunoglobulin: complement fixation, serine protease activation, ability to evoke a cellular inflammatory response.
    • Mechanism of formation: in situ immune complexes are more nephritogenic than trapped circulating complexes.
    • Amount of deposit.

  • Understand the mechanisms of deposit formation (Couser panels A–C), and which diseases map to each:

    • A — circulating immune complex trapping (subendothelial/mesangial side, in contact with blood): post-infectious (streptococcal) GN, membranoproliferative GN (chronic infection), IgA nephropathy.
    • B — in situ formation with non-renal/planted antigen: lupus nephritis (non-renal self antigens), exogenous bacterial antigens.
    • C — in situ formation against endogenous antigen: anti-GBM GN (antigen = collagen), membranous GN (antigen = PLA2R).

The rule that explains everything downstream

Subendothelial / mesangial deposits contact the circulation → C5a can recruit neutrophils → inflammatory, proliferative, NEPHRITIC picture. Subepithelial (podocyte-side) deposits are separated from the circulation by the GBM → complement still forms C5b-9 but in the urinary space → C5a CANNOT recruit PMNs → non-inflammatory, non-proliferative, NEPHROTIC picture.

6. The two (three) injury patterns

Endothelial / proliferative pattern (contact with circulation)

  • Understand: deposits in contact with blood cause leucocyte accumulation, endothelial injury, endocapillary proliferation.
  • Associated with immune-complex deposition and mesangial proliferation. Examples: post-infectious GN, lupus nephritis, IgA nephropathy.
  • Understand the severity spectrum: if severe, capillary wall destruction and crescent formation occur (anti-GBM GN, vasculitis, lupus nephritis class IV, membranoproliferative GN).

Epithelial / podocyte pattern (no contact with circulation)

  • Understand: antibodies and complement inflict cytotoxic injury on the podocyte, producing a non-exudative, non-proliferative capillary wall lesion. The archetype is membranous GN.

Rapidly progressive / crescentic pattern

  • Understand this as the severe end: capillary wall rupture, fibrin into Bowman’s space, macrophage proliferation forming crescents, progressing to renal failure over days to weeks.

7. Case 1 — Acute Post-Streptococcal GN (APSGN): the proliferative/nephritic exemplar

Clinical anchor

  • Know the presentation: 18-year-old with macroscopic haematuria, oliguria, periorbital oedema, hypertension, on a background of skin infection (impetigo). This is acute nephritic syndrome with acute kidney injury.

Immunopathogenesis

  • Understand: triggered by recent infection with specific strains of group A beta-haemolytic streptococcus. It is an immune-complex disease driving complement activation and inflammation.
  • Understand the deposit mechanism: in situ IC formation from streptococcal antigens deposited in the GBM with antibody binding, and/or glomerular trapping of circulating IC.
  • Understand complement involvement: C3 degradation via the classical pathway, then C3a/C5a chemotaxis → neutrophil recruitment → protease activation → injury. This is the proliferative form of GN.

Microbiology of Group A Strep (GAS)

  • Know GAS = Streptococcus pyogenes, Group A beta-haemolytic; causes most GAS infections. Can cause pharyngitis, impetigo, scarlet fever, necrotising fasciitis, sepsis, acute rheumatic fever, APSGN, etc. Classified by Lancefield serotyping.

  • Know a key clinical fact: rheumatic fever and APSGN do not tend to occur in the same patient (different strain tropisms/mechanisms).

  • Know the GAS virulence factors and what each does:

    • M protein: promotes epithelial adherence and escape from phagocytosis (when no opsonising antibody); encoded by the emm gene with >230 emm-types. Antibodies to M protein are protective but type-specific (low cross-reactivity) — the basis for vaccine development difficulty.
    • Superantigens (SPE-A1, SPE-B): cause toxic shock. SPE-B also cleaves C3b and degrades neutrophil extracellular traps (immune evasion).
    • Fibronectin-binding proteins: promote invasion.
    • Capsule (hyaluronic acid): inhibits phagocytosis.
    • Cytolysins (streptolysin O, hyaluronidase, DNAse): kill host cells.

  • Understand the immunology contrast on slide 20: conventional antigen presentation (antigen in MHC II groove read by TCR) vs superantigen (bridges MHC II and TCR outside the groove → massive non-specific T-cell activation).

  • Know the emm epidemiology point: 3 major emm pattern groups, associated with tissue tropism (pharynx = A–C + E; skin = D + E), and all pattern groups can cause APSGN.

Epidemiology (NZ context)

  • Know: APSGN is the leading cause of acute nephritis worldwide; risk greatest in children (peak 5–9 yo) and older adults (>60 yo); males > females.
  • Know the NZ inequity data: total incidence 9.7/100,000 children/yr, but Māori 15.7 and Pacific 45.5, and NZDep 9–10 (45.3) vastly exceeds NZDep 1–2 (0.8). Deprivation and ethnicity are major drivers.

Clinical/lab features and outcome (NZ children)

  • Know the frequencies: low C3 in 93%, gross haematuria 87%, hypertension 72%, oedema 62%, raised creatinine in 68%. Strep isolated from skin (40%, ~10.9 days prior) more often than pharynx (32%, ~9.1 days prior).
  • Know the outcome: most children recover completely; resolution begins within the first 2 weeks. Severe acute renal failure is uncommon in NZ (~2%). Some present with extra-renal complications (encephalopathy, CHF). Australian Aboriginal data show 3–4x increased CKD risk at 5 years.

Histology and resolution

  • Understand the histological signature: diffuse endocapillary proliferation with large numbers of PMNs (nephritic). On EM, subepithelial “hump” deposits.
  • Understand resolution: clearance of infection → removal of circulating immune complexes → glomerular repair. It is a self-limiting GN.

8. Case 2 — Membranous GN: the podocyte/nephrotic exemplar

Clinical anchor

  • Know the presentation: 60-year-old male, progressive oedema, frothy urine. Labs: albumin 20 g/L, 24-hr urine protein 5.5 g, protein/creatinine ratio markedly raised — i.e. nephrotic. Creatinine normal (80), normal renal ultrasound, negative autoantibody screen, normal electrophoresis. Note the preserved renal function typical of nephrotic disease.

Histology

  • Understand the defining negatives and positive: no influx of inflammatory cells, no mesangial expansion, no capillary lumen occlusion, but expansion (thickening) of the basement membrane. Granular IgG deposition on immunofluorescence.

Pathogenesis

  • Understand the antigen: PLA2R (and THSD7A) on the podocyte; the antibody is characteristically IgG4. Co-localisation of PLA2R and IgG4 is demonstrable (Beck NEJM 2009).
  • Understand primary vs secondary: in situ immune complex against a native podocyte antigen (primary) vs a planted/nonnative antigen (secondary) — Glassock NEJM panels B and C.
  • Understand the critical mechanistic point (slide 36): the immune complex is not active until formed on the podocyte. Complement forms C5b-9 in the urinary space, so there is no contact with the circulation and C5a cannot recruit PMNs — hence no inflammation, no proliferation. This is why membranous is nephrotic rather than nephritic.
  • Understand how C5b-9 damages the podocyte without lysing it (sublytic injury, Hoxha/Nangaku): cytoskeletal/actin disturbance, ROS and eicosanoid generation, slit-diaphragm protein dissociation (nephrin/CD2AP), ER stress, COX-2, GBM degradation by proteases. Downstream: TGF-beta and MMP9 → laminin/collagen IV deposition → GBM thickening, and slit-diaphragm disruption → proteinuria.
  • Understand progression mechanisms: podocyte apoptosis, detachment, DNA damage (p21 up, p57 down), lack of proliferation → effective podocyte depletion → glomerulosclerosis → ESKD.

Natural history

  • Know the untreated course: spontaneous remission 20–30%; 10-year renal survival 60–80%; of those with persistent nephrotic syndrome, 40–50% develop kidney failure over 10 years.
  • Understand the podocyte-depletion fork (slide 41): no depletion → no sclerosis → no ESKD; effective depletion (necrosis/apoptosis/detachment, glomerular enlargement, phenotype switch) → glomerulosclerosis → ESKD.

9. Case 3 — Anti-GBM / Rapidly Progressive (Crescentic) GN

Clinical anchor

  • Know the presentation: 54-year-old male, 2-month prodrome (arthralgia, myalgia, low-grade fever), then acute 48-hr deterioration with breathlessness and haemoptysis (pulmonary involvement), oliguria, haematuria. Examination: hypertensive, fluid overloaded (raised JVP, pulmonary and peripheral oedema).
  • Know the labs: creatinine 1500, urea 48, pH 7.12, K+ 6.8 — severe AKI with metabolic acidosis and hyperkalaemia. Albumin normal. This is acute nephritic / severe rapidly progressive GN.

Urinalysis (the nephritic sediment)

  • Know: dysmorphic RBCs and RBC casts plus haematuria and proteinuria. Understand that RBC casts and dysmorphic RBCs indicate a glomerular bleeding source.

Pathogenesis and histology

  • Understand: antibody against the GBM (collagen antigen) → crescentic GN. Immunofluorescence shows a linear IgG stain along the GBM (contrast with the granular pattern of immune-complex disease).
  • Understand crescent formation: capillary wall rupture lets fibrin and macrophages into Bowman’s space; proliferating macrophages and fibrin form the crescent.
  • Understand the Segerer phase model of inflammatory progression:
    • Initiation: primary insult (immune complex) → proinflammatory mediators (cytokines, chemokines, lipid mediators, ROS) → leukocyte rolling/adhesion via selectins.
    • Amplification: infiltrating cells and activated intrinsic renal cells amplify the signal; spillover of mediators into peritubular capillaries and urinary space; proteinuria.
    • Progression: persistent mediator release → interstitial infiltration, mesangial proliferation, tubular damage, Bowman’s capsule rupture, progressive fibrosis.

Mechanism summary (UpToDate schematic)

  • Understand the split between non-inflammatory pathways (antibody/complement directly damaging GEC/GEN/MC → capillary wall damage and proteinuria) and inflammatory pathways (C5a recruiting PMNs/platelets/macrophages, plus sensitised T cells → oxidants and proteases → proteinuria, fibrin, and crescents).

10. Clinical syndromes — the pathophysiology to be able to derive

Classification by clinical presentation (slide 52)

  • Asymptomatic urinary abnormalities: subnephrotic proteinuria and/or microscopic haematuria, no impairment/oedema/hypertension.
  • Nephritic syndrome: recent-onset haematuria + proteinuria, renal impairment, salt and water retention causing hypertension.
  • Rapidly progressive GN: renal failure over days to weeks, usually nephritic context, with extensive crescents on biopsy.
  • Nephrotic syndrome: proteinuria >3.5 g/1.73m²/24h, hypoalbuminaemia, hyperlipidaemia, oedema; complicated by venous thrombosis and infection risk.
  • Chronic GN: persistent proteinuria ± haematuria with slowly progressive impairment.

Nephrotic syndrome — derive the cascade

  • Know the tetrad: proteinuria >3 g/24h, hypoalbuminaemia, oedema, hyperlipidaemia (renal function often normal).
  • Understand the oedema mechanism using Starling’s law: increased filtration of protein → proteinuria → hypoalbuminaemia → fall in plasma oncotic pressure → fluid shifts intravascular → interstitial → oedema; the perceived low arterial filling activates RAAS and SNS → tubular Na+ retention → plasma volume expansion → more oedema.
  • Understand the primary intrarenal sodium-retention mechanism (Sidall): filtered plasminogen is converted to plasmin by urokinase-type plasminogen activator in the cortical collecting duct; plasmin cleaves the gamma inhibitory domain of ENaC, opening the channel → Na+ reabsorption. This means Na+ retention in nephrosis is partly intrinsic to the nephron, not purely a downstream RAAS effect.

Acute nephritic syndrome — derive the cascade

  • Know the features: haematuria, oliguria, acute kidney injury, hypertension. Understand the structural basis: proliferation has occluded capillary loops.
  • Understand the chain (slide 57): glomerular injury → haematuria + proteinuria, and a fall in GFR → sodium retention (amplified by RAAS/SNS/AVP) → hypertension; water retention → oedema, oliguria, raised JVP, cardiomegaly.

The single contrast to hold onto

Nephritic = inflammatory, proliferative, capillary loops occluded → haematuria (active sediment), reduced GFR, hypertension, oliguria. Nephrotic = non-inflammatory podocyte injury → heavy proteinuria, hypoalbuminaemia, oedema, often preserved GFR.

Self-test checklist

Can you explain...?

  • The three layers of the glomerular filtration barrier and which cell faces blood vs urine?
  • The three sources of antigen that initiate GN, with an example disease for each?
  • Why in situ immune complexes are more nephritogenic than trapped circulating ones?
  • Why subendothelial deposits cause a nephritic picture but subepithelial deposits cause a nephrotic one (in terms of C5a and PMN recruitment)?
  • The three complement activation pathways and the roles of C5a vs C5b-9?
  • The full immunopathogenesis of APSGN, from infection to low C3 and PMN-rich proliferation?
  • Each GAS virulence factor and its function, and why SPE-B specifically aids immune evasion?
  • Why M-protein-based GAS vaccines are difficult to make?
  • The NZ epidemiology of APSGN and the role of deprivation and ethnicity?
  • The histological and immunofluorescence signature of membranous GN, and its target antigen and antibody isotype?
  • How sublytic C5b-9 damages the podocyte to produce proteinuria without inflammation?
  • The podocyte-depletion pathway from membranous GN to ESKD?
  • The clinical and laboratory features distinguishing anti-GBM/RPGN, including the linear IgG stain and the meaning of RBC casts?
  • How a crescent forms, and the Segerer initiation/amplification/progression model?
  • The full Starling-based derivation of nephrotic oedema, plus the plasmin–ENaC intrarenal sodium-retention mechanism?
  • The pathophysiological chain of acute nephritic syndrome from glomerular injury to hypertension and oedema?
  • The five clinical classifications of GN by presentation, and how to define each?

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