Glomerulonephritis Pathology — Specific Types

IMMUNE COMPLEX-MEDIATED GN

• In situ immune complex deposition occurs when antibodies bind directly to planted antigens (foreign or self-antigen) within the glomerular basement membrane (GBM) or along the subendothelial space
• Circulating immune complex (CIC) deposition results from formation of antigen-antibody complexes in slight antigen excess that deposit in glomeruli via charge and size interactions with the GBM
• Activation of classical complement pathway via C1q binding to IgG or IgM immune complexes, generating C3a and C5a (potent chemotaxins) and C3b/iC3b opsonins
• Recruitment of neutrophils, macrophages, and T cells through chemokine and complement receptors (CR1, CR3, C5aR)
• Release of proteolytic enzymes, reactive oxygen species (ROS), and cytokines (TNF-α, IL-1, IL-6) causing podocyte injury, endothelial activation, and mesangial proliferation
• Charge-selective and size-selective proteinuria results from disruption of the filtration barrier (endothelium, basement membrane, podocytes)

ANTI-GBM DISEASE (Linear IgG Deposits)

• Type II hypersensitivity reaction with IgG autoantibodies targeting NC1 domain of type IV collagen (α3 chain of basement membrane)
• Antibodies bind along the entire GBM length in a linear pattern on immunofluorescence
• Complement-mediated injury via classical pathway activation leads to GBM disruption and crescentic formation
• Molecular mimicry (e.g., post-streptococcal) or genetic predisposition (HLA-DR15) may trigger autoimmunity
• Pulmonary-renal syndrome occurs when antibodies cross-react with alveolar basement membrane, causing pulmonary hemorrhage

ANCA-ASSOCIATED VASCULITIS (Pauci-Immune GN)

• Cytoplasmic ANCA (c-ANCA) directed against proteinase-3 (PR3) or perinuclear ANCA (p-ANCA) against myeloperoxidase (MPO)
• Mechanism: ANCA-IgG binds to PR3/MPO on primed neutrophil surfaces, causing neutrophil activation, degranulation, and NETosis (neutrophil extracellular trap formation)
• NET-associated release of granule proteins (PR3, elastase, cathepsin G) damages endothelial cells and podocytes
• Minimal or absent immune complex deposition distinguishes from immune complex GN
• Crescentic proliferation develops from necrotic injury to glomerular tuft

MEMBRANE DISEASE (Membranous GN)

• Subepithelial immune complex deposition creates characteristic "spike and dome" appearance on electron microscopy
• IgG4-mediated antibodies target phospholipase A2 receptor (PLA2R) (70% of primary membranous GN) or other podocyte-associated antigens
• In situ formation of immune complexes at the subepithelial space between podocyte foot processes and GBM
• Complement activation via classical pathway generates C5b-C9 membrane attack complex (MAC), creating podocyte holes and blebs
• Massive selectivity-selective proteinuria (predominantly albumin) due to loss of charge barrier
• Minimal or absent proliferation (hence name "membranous," not proliferative)

PROLIFERATIVE GN MECHANISMS

• Mesangial proliferation occurs from VEGF, FGF, PDGF, and TGF-β signaling in response to immune complex or complement activation
• Endocapillary proliferation represents intraluminal neutrophil and endothelial cell proliferation with swollen endothelium occluding capillary loops
• Extracapillary proliferation (crescents) involves parietal epithelial cell proliferation surrounding Bowman's capsule; crescents are hallmark of aggressive GN
• Fibrinogen deposition in crescents indicates active fibrinolytic injury

PATHOLOGICAL CONSEQUENCES

• Loss of glomerular filtration surface area due to proliferation, crescent formation, and sclerosis
• Increased intraglomerular pressure from mesangial contraction and inflammation
• Podocyte detachment and apoptosis from cytokine injury and complement-mediated damage
• Progressive fibrosis and sclerosis with chronic glomerulonephritis, leading to irreversible ESRD

POSTINFECTIOUS GN (Immune Complex-Mediated)

• Post-streptococcal GN (PSGN): Group A Streptococcus (GAS) nephritogenic strains (M1, M49, M60, M61); most common acute GN in children worldwide
• Latency period: 10 days (pyoderma) or 3 weeks (pharyngitis) after infection
• Streptococcal antigen (hyaluronic acid, M protein, streptococcal glyceraldehyde-3-phosphate dehydrogenase [GAPDH]) planted in GBM or circulating immune complex deposition
• Other bacterial infections: Staphylococcus aureus (PSGN-like variant, especially in older adults and IV drug users), Streptococcus pneumoniae, Enterococcus
• Viral infections: Hepatitis B, Hepatitis C, HIV, Parvovirus B19, EBV, CMV
• Parasitic/fungal: Schistosomiasis, malaria, coccidioidomycosis

SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

• Systemic autoimmune disease with antibodies against dsDNA, histone, nucleosomes, and C1q
• Lupus nephritis occurs in 40-50% of SLE patients; most common cause of GN in women of childbearing age
• Multiple morphological classes (I-VI per ISN/RPS classification) with varying immune complex patterns
• Risk factors: Female sex (9:1 ratio), African/Hispanic ancestry, HLA-DR2/DR3 alleles, complement deficiencies (C1q, C4)

ANCA-ASSOCIATED VASCULITIS

• Granulomatosis with polyangiitis (GPA) (formerly Wegener granulomatosis): c-ANCA/PR3+ in 90%; involves upper/lower respiratory tract and glomeruli
• Microscopic polyangiitis (MPA): p-ANCA/MPO+ in 70%; limited to small vessels; frequent pulmonary hemorrhage
• Eosinophilic granulomatosis with polyangiitis (EGPA) (formerly Churg-Strauss): p-ANCA/MPO+, asthma, eosinophilia, necrotizing vasculitis
• Risk factors: Genetic predisposition (HLA-DP-B1*0401), environmental triggers (silica, propylene glycol, fume exposure), infections (mimicry)

ANTI-GBM DISEASE

• IgG autoantibodies against α3(IV)NC1 collagen domain; rare, accounts for 1-5% of GN
• Goodpasture syndrome when pulmonary-renal involvement occurs
• Risk factors: HLA-DR15 positivity (90% of patients), prior infection, smoking (synergistic with antibodies for pulmonary hemorrhage), male predominance

IMMUNOGLOBULIN A NEPHROPATHY (IgAN)

• Most common primary GN worldwide (30-40% of GN in Asia, 10% in North America)
• Excessive IgA1 production with galactose-deficient IgA1 (Gd-IgA1) becoming target of anti-Gd-IgA1 antibodies
• Immune complex deposition in mesangium (IgA, C3, C4, fibrinogen)
• Risk factors: Genetic predisposition (Chr6q23 locus), mucosal IgA stimulation (respiratory/GI infection, celiac disease), secondary IgAN (Henoch-Schönlein purpura, liver disease, inflammatory bowel disease)

MEMBRANOUS GLOMERULONEPHRITIS

• Primary (idiopathic): PLA2R antibodies (70%), thrombospondin type-1 domain-containing 7A (THSD7A) antibodies (3-5%)
• Secondary: Medications (NSAIDs, ACE inhibitors, penicillamine, mercury), infections (hepatitis B, syphilis, malaria), malignancy (lung, breast, colon cancer), systemic diseases (SLE, sarcoidosis)
• Risk factors: Age >50 years for primary; underlying disease for secondary

POST-INFECTIOUS GN VARIANTS

• IgM-dominant PSGN without immunoglobulin-dominated deposits
• IgA-dominant PSGN after streptococcal infection
• IgG-dominant membranoproliferative GN (MPGN) post-staphylococcal infection

C3 GLOMERULOPATHY

• Dysregulation of alternative complement pathway
• C3 glomerulonephritis (C3GN) and post-infectious GN with dominant C3 deposits (C3-dominant PIGN)
• Mutations in Factor H, Factor I, Membrane Cofactor Protein (MCP/CD46), C3, Factor B
• Autoantibodies against Factor H, Factor B, C3 convertase stabilizing Factor P

MEMBRANOPROLIFERATIVE GN (MPGN)

• MPGN Type I (now reclassified as immune complex MPGN): subendothelial immune complex deposits; associated with SLE, chronic hepatitis C, cryoglobulinemia
• MPGN Type II (Dense Intramembranous Deposits, DIMD): "ribbon-like" electron-dense deposits within GBM lamina densa; rare; genetic predisposition
• MPGN Type III: Subepithelial and subendothelial deposits; associated with post-streptococcal GN variants

CRYOGLOBULINEMIA

• Mixed cryoglobulins (IgM anti-IgG complexes) associated with Hepatitis C infection
• Type II (Mixed) cryoglobulinemia: IgM k monoclonal antibody to IgG; most common form
• Vasculitis of small/medium vessels; glomerular injury via immune complex deposition

LUPUS NEPHRITIS CLASSES (ISN/RPS 2003)

• Class I: Minimal mesangial (normal by LM, IgA/IgG/IgM by IF)
• Class II: Mesangial proliferation (mesangial cell/matrix expansion; IgA/IgG/IgM/C3/C1q by IF)
• Class III: Focal endocapillary/extracapillary proliferation (<50% glomeruli affected)
• Class IV: Diffuse proliferation (>50% glomeruli; subdivided into segmental IV-S or global IV-G)
• Class V: Membranous (subepithelial deposits; may coexist with Class III or IV as mixed lesion)
• Class VI: Advanced sclerosing (>90% global glomerulosclerosis; irreversible)

ACUTE PROLIFERATIVE GN (e.g., Post-Streptococcal GN)

• Hematuria (microscopic or gross "cola-colored" urine) appearing 10-21 days post-infection; RBC casts in urine (indicating glomerular bleeding)
• Proteinuria (typically <3 g/day, non-nephrotic range), occasionally nephrotic syndrome
• Hypertension from increased extracellular volume and renin-angiotensin-aldosterone system (RAAS) activation; headache, visual disturbances
• Edema (periorbital, peripheral) from salt and water retention and decreased plasma oncotic pressure (if nephrotic)
• Azotemia (elevated BUN/Cr) from reduced glomerular filtration rate (GFR) due to swollen endothelium obstructing capillaries and loss of filtration surface area
• Pulmonary edema from volume overload and increased hydrostatic pressure in pulmonary capillaries
• Constitutional symptoms: Malaise, low-grade fever (from immune activation and release of IL-1, TNF-α)
• Oliguria or anuria in severe cases from acute kidney injury (AKI)

ANTI-GBM DISEASE (Goodpasture Syndrome)

• Acute, progressive dyspnea and hemoptysis from diffuse pulmonary alveolar hemorrhage (immune complex deposition in alveolar basement membrane)
• Hemoptysis may precede renal involvement by weeks to months
• Rapidly progressive glomerulonephritis (RPGN) with rapid decline in GFR over days to weeks
• Hematuria (gross or microscopic), RBC and WBC casts, proteinuria
• Severe hypertension, oliguria, azotemia, progressing to anuria and ESRD without treatment
• Anemia from both hemoptysis and hemolytic anemia (complement-mediated RBC lysis)
• Systemic symptoms: Fatigue, pallor, orthopnea

ANCA-ASSOCIATED VASCULITIS (GPA, MPA, EGPA)

• GPA: Upper respiratory tract involvement (sinusitis, epistaxis, saddle nose deformity from cartilage necrosis), lower respiratory tract (hemoptysis, pulmonary infiltrates), necrotizing GN with crescentic formation
• Rapidly progressive renal failure (RPGN) with rapid rise in creatinine (days to weeks)
• Hematuria, RBC casts, proteinuria; proteinuria typically <2 g/day (non-nephrotic unless secondary membranous component)
• Systemic symptoms: Fever, weight loss, arthralgias, myalgias from systemic small/medium vessel vasculitis
• MPA: Primarily renal/pulmonary involvement; pulmonary hemorrhage, rapidly progressive GN
• EGPA: Asthma, eosinophilia, skin rash (palpable purpura), pulmonary infiltrates, glomerulonephritis
• ESR elevated, normal complement levels (distinguishing from immune complex GN)

MEMBRANOUS GLOMERULONEPHRITIS

• Nephrotic syndrome (>3.5 g/day proteinuria, hypoalbuminemia, hyperlipidemia, edema) in 50% of patients at presentation
• Proteinuria ("frothy urine") is often the initial presentation; microscopic hematuria in 50%, gross hematuria rare
• Hypercoagulability from **loss of

Initial evaluation (establish glomerular origin)

• Urinalysis with microscopy: dysmorphic RBCs, acanthocytes, and RBC casts localize bleeding to the glomerulus; lipiduria with Maltese cross oval fat bodies suggests nephrotic-range injury
• Quantify proteinuria: spot urine protein-to-creatinine ratio or 24-hour collection; >3.5 g/day (UPCR >3 g/g) defines nephrotic range, favoring membranous or lupus class V over pauci-immune GN
• Serum creatinine/eGFR trend: a rise over days to weeks defines rapidly progressive GN and mandates urgent biopsy

Serologic triage before biopsy

• Complements: low C3 with normal C4 suggests alternative-pathway disease (PSGN, C3 glomerulopathy, dense deposit disease with C3 nephritic factor); low C3 and C4 suggests classical-pathway consumption (lupus nephritis, cryoglobulinemic MPGN); normal complements favor IgA nephropathy, ANCA GN, and anti-GBM disease
• Targeted antibodies: ANA/anti-dsDNA and anti-Smith; ANCA with PR3/MPO ELISA; anti-GBM (anti-α3[IV]NC1); anti-PLA2R for membranous; ASO/anti-DNase B for recent streptococcal infection; hepatitis B/C serology and cryoglobulins

Named classification systems

• ISN/RPS classes I–VI for lupus nephritis, with activity and chronicity indices guiding immunosuppression
• Oxford MEST-C score for IgA nephropathy (mesangial and endocapillary hypercellularity, segmental sclerosis, tubular atrophy/interstitial fibrosis, crescents) — prognostic
• Berden classification for ANCA GN (focal, crescentic, mixed, sclerotic)
• Crescents in >50% of glomeruli on biopsy corroborate the clinical RPGN syndrome regardless of immune mechanism

Immediate stabilization

• Rapidly progressive GN and diffuse alveolar hemorrhage are emergencies: treat empirically with pulse IV glucocorticoids (methylprednisolone) while biopsy and serologies return; do not wait for tissue if pulmonary hemorrhage is present
• Manage hyperkalemia, volume overload, and refractory acidosis with loop diuretics (furosemide) and urgent dialysis if indicated

Disease-directed therapy (KDIGO 2021 Glomerular Diseases guideline)

• Anti-GBM disease: plasmapheresis to remove circulating antibody, plus cyclophosphamide and glucocorticoids — the one GN where plasma exchange is standard of care; start before dialysis dependence, since dialysis-requiring patients with near-100% crescents rarely recover
• ANCA-associated GN: glucocorticoids plus rituximab or cyclophosphamide for induction; the C5a receptor antagonist avacopan permits steroid sparing; azathioprine or rituximab for maintenance
• Lupus nephritis (ISN/RPS III/IV): glucocorticoids plus mycophenolate mofetil or low-dose IV cyclophosphamide (Euro-Lupus regimen), with belimumab or voclosporin as add-on; ACR recommends hydroxychloroquine for essentially all SLE patients
• IgA nephropathy: maximal supportive care first — RAAS blockade (ACE inhibitor or ARB) titrated to maximum tolerated dose, BP control, and an SGLT2 inhibitor; persistent proteinuria above ~1 g/day despite this may warrant glucocorticoids or targeted-release budesonide, weighed against infection risk
• Primary membranous nephropathy: supportive therapy for low-risk disease; rituximab, calcineurin inhibitors, or alternating cyclophosphamide/steroid (Ponticelli) for high-risk disease
• Post-streptococcal GN: supportive only — sodium restriction, diuretics, antihypertensives; antibiotics eradicate infection but do not alter nephritis

Contraindicated/avoid

• ACE inhibitors and ARBs in pregnancy (fetal renal dysgenesis) — all agents, captopril included
• Immunosuppression in untreated active infection or unscreened hepatitis B (rituximab risks reactivation)
• Live vaccines during induction immunosuppression

Disease-related — emergencies

• Diffuse alveolar hemorrhage (anti-GBM, MPA, GPA): antibody or ANCA-driven capillaritis of alveolar basement membrane; signaled by hemoptysis, hypoxemia, dropping hematocrit, and diffuse ground-glass infiltrates — airway and immediate immunosuppression/plasma exchange emergency
• Hyperkalemia with AKI: reduced distal potassium secretion; peaked T waves progressing to widened QRS and sine wave — treat with calcium, insulin/dextrose, and dialysis
• Hypertensive emergency and volume overload: salt/water retention plus RAAS activation; pulmonary edema, encephalopathy, or posterior reversible encephalopathy syndrome (PRES), classically in pediatric PSGN
• Irreversible crescentic destruction: fibrous organization of cellular crescents within weeks — a delayed biopsy is how the window for immunosuppression is lost

Disease-related — subacute

• Venous thromboembolism, including renal vein thrombosis: urinary loss of antithrombin III and altered protein C/S; highest risk in membranous nephropathy with severe hypoalbuminemia; signaled by flank pain, sudden proteinuria increase, or pulmonary embolism
• Infection: urinary loss of IgG and complement factor B; encapsulated organisms, with spontaneous bacterial peritonitis classic in nephrotic children
• Hyperlipidemia and protein malnutrition from hepatic compensatory synthesis and ongoing urinary losses
• CKD progression to ESRD: glomerulosclerosis and tubulointerstitial fibrosis; anemia, hyperphosphatemia, and secondary hyperparathyroidism follow

Treatment-related

• Cyclophosphamide: acrolein metabolite causes hemorrhagic cystitis (gross hematuria; prevent with mesna and hydration), plus later bladder cancer, gonadal failure, and myelosuppression
• Rituximab: hypogammaglobulinemia, hepatitis B reactivation (screen HBsAg/anti-HBc first), and rare PML
• Glucocorticoids: hyperglycemia, osteoporosis, avascular necrosis, adrenal suppression; all patients on high-dose regimens need Pneumocystis jirovecii prophylaxis
• Calcineurin inhibitors: afferent arteriolar vasoconstriction causing rising creatinine that mimics disease relapse
• Plasma exchange: coagulopathy, hypocalcemia from citrate, and catheter-related infection

• Immunofluorescence pattern is the discriminator: linear ribbon-like IgG = anti-GBM disease; granular "lumpy-bumpy" or starry sky = immune complex GN; pauci-immune (negative IF) = ANCA vasculitis. This single distinction resolves most RPGN stems.
• Electron microscopy buzzwords: subepithelial humps = post-streptococcal GN; spike and dome on silver stain with subepithelial deposits = membranous; tram-track double-contour GBM with subendothelial deposits = MPGN; ribbon-like intramembranous dense deposits = dense deposit disease.
• Wire loop lesions = massive subendothelial immune complexes of lupus nephritis class IV, with full-house IF (IgG, IgA, IgM, C3, C1q). Full-house staining is essentially pathognomonic for lupus.
• Timing separates IgA nephropathy from PSGN: IgA gives synpharyngitic hematuria within 1–3 days of a mucosal infection with normal C3; PSGN follows by 1–3 weeks with low C3 that normalizes in about 6–8 weeks. Persistently low C3 beyond that should redirect you toward C3 glomerulopathy.
• Single best next step in suspected RPGN is renal biopsy — but if pulmonary hemorrhage is present, start pulse glucocorticoids first and biopsy in parallel.
• The association examiners love: anti-GBM disease with HLA-DR15 and smoking as the trigger for lung involvement; and dense deposit disease with C3 nephritic factor plus partial lipodystrophy.
• Highest thrombotic risk of any nephrotic lesion is membranous nephropathy — sudden flank pain and hematuria in a nephrotic adult means renal vein thrombosis until excluded.
• Common distractor: giving steroids or antibiotics to "treat" post-streptococcal GN. Management is supportive; children recover, and antibiotics treat the infection, not the nephritis. A second distractor is calling normal complements reassuring — ANCA and anti-GBM disease, the most destructive GNs, have normal C3 and C4.