Glomerulonephritis

Immune-complex (low-complement) causes

• Infection-related GN: group A Streptococcus (post-streptococcal, after pharyngitis or impetigo), *Staphylococcus*-associated GN, and infective endocarditis. Mechanistically these split by complement pathway: PSGN activates complement chiefly through the alternative and lectin pathways, giving a markedly depressed C3 with a normal or near-normal C4, whereas endocarditis-associated GN, cryoglobulinemic/hepatitis-associated membranoproliferative GN, and lupus nephritis engage the classical pathway, lowering both C3 and C4.
• Hepatitis C with cryoglobulinemia and hepatitis B: chronic antigenemia drives membranoproliferative patterns.
• Systemic lupus erythematosus: anti-dsDNA/nucleosome complexes deposit in mesangium and subendothelium.
• **IgA nephropathy and IgA vasculitis (Henoch–Schönlein purpura)**: galactose-deficient IgA1 is recognized by autoantibody, forming mesangial complexes; complement is typically normal.

Pauci-immune (ANCA) causes

• GPA, MPA, EGPA: anti-PR3/anti-MPO antibodies activate primed neutrophils. Most disease is idiopathic; a minority of cases are drug-induced by hydralazine, propylthiouracil, minocycline, or levamisole-adulterated cocaine (classically high-titer, often dual MPO/PR3 positivity).

Anti-GBM disease

• Autoantibody to the α3 chain NC1 domain of type IV collagen, with strong *HLA-DRB1\*15:01* association; an inhaled injury is usually needed to expose alveolar epitopes before lung hemorrhage occurs.

Non-modifiable risk factors

• Age and sex: PSGN peaks in school-age children; IgA nephropathy in young adult males; ANCA vasculitis in older adults; anti-GBM has a bimodal distribution (young men, older women).
• Ancestry and genetics: higher IgA nephropathy prevalence in East Asian populations; APOL1 high-risk variants in people of West African ancestry accelerate progression; family history of nephritis or deafness suggests Alport syndrome rather than GN.

Modifiable risk factors

• Smoking and hydrocarbon/solvent inhalation: the classic precipitant of alveolar hemorrhage in anti-GBM disease; silica exposure is linked to ANCA vasculitis.
• Untreated infection and crowding/poor hygiene: streptococcal skin infection, scabies, injection drug use with endocarditis, untreated HBV/HCV/HIV.
• Culprit drugs, as above — stopping the agent is part of therapy.
• Uncontrolled hypertension, heavy proteinuria, obesity, and NSAID use: drive progression to ESRD regardless of the initiating immune lesion (KDIGO).

• In situ immune complex deposition: Antibodies bind directly to planted antigens or native GBM epitopes, activating complement via classical pathway (C3 and C4 deposition on immunofluorescence)
• Formation of circulating immune complexes (antigen-antibody) that deposit in glomeruli based on charge and size; large complexes typically deposit in subendothelial space causing subendothelial humps
• Complement activation (C5a generation) recruits neutrophils and macrophages, causing inflammatory infiltration, glomerular basement membrane damage, and epithelial cell proliferation
• Examples: post-streptococcal GN (PSGNs), lupus nephritis, IgA nephropathy, membranoproliferative GN

• Cytoplasmic (c-ANCA) or perinuclear (p-ANCA) antineutrophil cytoplasmic antibodies against myeloperoxidase (MPO) or proteinase-3 (PR3)
• Antibodies activate primed neutrophils in absence of significant immune complex deposition ("pauci-immune"), causing direct endothelial injury and necrotizing inflammation
• Leads to necrotizing crescents (proliferation of Bowman's capsule epithelium with fibrin deposition)
• Examples: granulomatosis with polyangiitis (GPA, formerly Wegener's), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss)

• Straight-line IgG deposition along GBM on immunofluorescence; antibodies directly target NC1 domain of type IV collagen
• Type II hypersensitivity reaction; can present as isolated anti-GBM disease or concurrent with pulmonary hemorrhage (Goodpasture syndrome)
• Crescentic proliferation with rapid progression to ESRD if untreated

Glomerular Structural Changes

• Proliferative response: Mesangial proliferation (mild), endocapillary proliferation (moderate), or extracapillary proliferation (crescents with fibrin)
• Glomerular basement membrane injury: Focal segmental necrosis, splits, or duplication (creating "basket-weave" appearance on electron microscopy in membranoproliferative GN)
• Proteinuria mechanism: Loss of negative charge and structural integrity of filtration barrier; increased glomerular permeability to albumin and other proteins

• Cola-colored or tea-colored hematuria with red blood cell casts on urinalysis; hallmark sign indicating glomerular origin of bleeding
• Hypertension from sodium and fluid retention; may present with headache, visual changes, or signs of hypertensive emergency
• Edema: Periorbital edema (morning), lower extremity dependent edema; reflects sodium retention and decreased GFR
• Mild-to-moderate proteinuria (typically <3.5 g/day in acute GN, though varies by type); nephrotic-range proteinuria suggests chronicity or membranous features

• Rapid decline in renal function over days to weeks; creatinine doubling in 1-2 weeks suggests crescentic GN
• Dyspnea, hemoptysis, or pulmonary infiltrates (Goodpasture syndrome specifically; also seen in pulmonary-renal syndromes with ANCA vasculitis)
• Constitutional symptoms: Fever, malaise, arthralgias, arthritis (especially in GPA, EGPA)
• Upper and lower respiratory tract involvement: Sinusitis, nasal crusting, epistaxis, cavitary lung lesions in GPA

• Microscopic hematuria or asymptomatic proteinuria discovered on routine screening
• Intermittent gross hematuria often following upper respiratory tract infection (IgA-associated)
• Slow progressive renal dysfunction over years; 20-40% progress to ESRD

• Onset 1-3 weeks after pharyngitis or skin infection (impetigo) with group A Streptococcus
• Acute nephritic syndrome: Hematuria, hypertension, edema, mild proteinuria
• Typically self-limited; complete recovery in children, variable in adults
• Systemic findings minimal; no significant systemic vasculitis or pulmonary involvement

Systemic Disease-Associated GN

• SLE: Arthritis, malar rash, photosensitivity, serositis, low complement (C3, C4), positive ANA and anti-dsDNA
• ANCA vasculitis: May include purpura, nodules, cutaneous involvement in addition to renal and respiratory findings

Laboratory Studies

• Serum creatinine and BUN: Assess degree and acuity of renal impairment; rapid rise suggests crescentic GN
• Urinalysis with microscopy: RBC casts, dysmorphic RBCs (evidence of glomerular hematuria), WBC casts, protein; epithelial cells or broad casts suggest chronic disease
• 24-hour urine protein or urine protein-to-creatinine ratio: Quantify proteinuria; nephrotic-range (>3.5 g/day) seen with membranous features or chronic disease
• Serum albumin: Hypoalbuminemia suggests nephrotic syndrome or chronic GN with significant proteinuria

• Complement levels (C3, C4): Low in immune-complex GN (SLE, PSGN, membranoproliferative GN); normal in ANCA-associated and anti-GBM disease
• ANCA serology (c-ANCA, p-ANCA): Positive in 90% of ANCA-associated vasculitis; order with anti-PR3 and anti-MPO antibodies
• Anti-GBM antibodies: Positive in anti-GBM disease and Goodpasture syndrome; highly specific
• ANA, anti-dsDNA, anti-Smith: For SLE-related GN
• Serologic studies for infection: ASO titers, anti-DNase B, blood cultures (if endocarditis suspected)
• Cryoglobulins, rheumatoid factor: Membranoproliferative GN with hepatitis C

Imaging

• Renal ultrasound: Assess kidney size (normal or enlarged in acute GN; shrunken in chronic GN), echogenicity, rule out obstruction
• Chest X-ray: Evaluate for pulmonary edema, infiltrates (ANCA vasculitis, Goodpasture), or pleural effusion

• Light microscopy: Identify proliferative pattern (endocapillary, mesangial, extracapillary with crescents), necrosis

Immediate stabilisation

• Volume and blood pressure control: loop diuretic (furosemide) for pulmonary edema and hypertensive volume overload; IV antihypertensives for hypertensive emergency; treat hyperkalemia and consider urgent dialysis for refractory overload, acidosis, hyperkalemia, or uremia.
• Suspected RPGN is a nephrologic emergency: obtain ANCA, anti-GBM, complements and arrange urgent kidney biopsy — but per KDIGO 2021, start empiric high-dose glucocorticoids (methylprednisolone pulse) when crescentic disease is strongly suspected rather than waiting for histology.

Disease-specific first-line therapy

• ANCA-associated GN: glucocorticoids plus a remission-induction agent — rituximab (anti-CD20) or cyclophosphamide; the ACR/Vasculitis Foundation 2021 guideline favors rituximab for severe disease. Avacopan, an oral C5a receptor antagonist, is an approved glucocorticoid-sparing addition. Maintenance is typically rituximab or azathioprine.
• Anti-GBM disease: urgent plasma exchange plus cyclophosphamide plus glucocorticoids — the one GN where plasmapheresis is standard, and treatment must not await biopsy if alveolar hemorrhage is present.
• Lupus nephritis (class III/IV): glucocorticoids plus mycophenolate mofetil or low-dose IV cyclophosphamide, with belimumab or voclosporin as add-on; hydroxychloroquine for all patients (ACR/KDIGO).
• IgA nephropathy: maximally tolerated RAS blockade (ACE inhibitor or ARB) plus blood-pressure and lifestyle optimisation before immunosuppression; KDIGO supports adding an SGLT2 inhibitor for persistent proteinuric CKD, with targeted-release budesonide or sparsentan as newer options and glucocorticoids reserved for high residual risk.
• Post-streptococcal GN: supportive only — salt restriction, diuretics, antihypertensives; antibiotics eradicate the organism but do not reverse established nephritis.

Contraindicated or to avoid

• Cyclophosphamide and mycophenolate in pregnancy (teratogenic); ACE inhibitors and ARBs are contraindicated in pregnancy — captopril's short half-life makes it a titration drug, not a pregnancy drug.
• Immunosuppression in untreated infection-related GN, live vaccines during induction, and NSAIDs.
• Routine plasma exchange in ANCA vasculitis is not recommended for all comers after PEXIVAS; reserve it for selected severe presentations.

Emergencies

• Diffuse alveolar hemorrhage: capillaritis in anti-GBM disease or ANCA vasculitis; signalled by hemoptysis (which may be absent), falling hematocrit with rising DLCO, and bilateral airspace opacities — requires immediate immunosuppression and, for anti-GBM, plasma exchange.
• Hypertensive emergency/encephalopathy and pulmonary edema: sodium and water retention from a fallen GFR; headache, seizures, papilledema, or flash pulmonary edema — classically the way a child with PSGN decompensates.
• Life-threatening hyperkalemia and uremic complications: impaired potassium excretion producing peaked T waves and widened QRS; pericardial friction rub or encephalopathy indicates need for urgent dialysis.
• Dialysis-dependent crescentic GN: extensive crescents, and fibrous rather than cellular crescents, predict irreversible loss; delayed diagnosis and delayed initiation of immunosuppression are major modifiable contributors to irreversible renal loss.

Disease-related complications

• Progression to CKD and ESRD: nephron loss triggers hyperfiltration, glomerulosclerosis and interstitial fibrosis; heralded by persistent proteinuria, shrunken echogenic kidneys, and anemia/hyperphosphatemia.
• Relapse: ANCA vasculitis, especially PR3-positive disease, relapses frequently — rising creatinine, new hematuria with dysmorphic RBCs, or recurrent sinonasal symptoms.
• Nephrotic-range proteinuria with thrombosis and infection: loss of antithrombin and immunoglobulin when the lesion has membranous or heavy proteinuric features.

Treatment-related complications

• Opportunistic infection: Pneumocystis jirovecii pneumonia is the classic hazard of high-dose glucocorticoids combined with cyclophosphamide or rituximab — the ACR/Vasculitis Foundation 2021 guideline conditionally recommends PJP prophylaxis (trimethoprim-sulfamethoxazole) in this setting, and KDIGO 2021 likewise advises prophylaxis during cyclophosphamide/rituximab-based induction.
• Cyclophosphamide toxicity: acrolein metabolite causes hemorrhagic cystitis and later urothelial carcinoma (mitigated by hydration and mesna), plus gonadal failure, myelosuppression, and teratogenicity.
• Rituximab: hepatitis B reactivation (screen before dosing), hypogammaglobulinemia, infusion reactions.
• Glucocorticoids: hyperglycemia, osteoporosis, adrenal suppression, psychosis. Avacopan carries a hepatotoxicity signal requiring transaminase monitoring.

• RBC casts and dysmorphic RBCs localise bleeding to the glomerulus — the single finding that separates nephritic syndrome from urologic hematuria (stone, tumor, cystitis). If the stem says "cola-colored urine" plus casts, stop looking for a stone.
• Split the differential by complement: low C3 → PSGN, lupus nephritis, membranoproliferative GN, cryoglobulinemia, endocarditis-associated GN. Normal C3 → IgA nephropathy, IgA vasculitis, ANCA vasculitis, anti-GBM disease, Alport syndrome.
• Latency is the discriminator between IgA nephropathy and PSGN: IgA gives synpharyngitic hematuria within 1–2 days of a URI; PSGN appears 1–3 weeks after pharyngitis (or 3–6 weeks after impetigo). The classic distractor is calling a same-day post-URI hematuria "post-streptococcal."
• Immunofluorescence is the pattern-recognition question: linear IgG = anti-GBM; granular "lumpy-bumpy" = immune complex (PSGN, lupus); mesangial IgA = IgA nephropathy; pauci-immune (scant staining) = ANCA vasculitis. PSGN's electron microscopy hallmark is the subepithelial hump.
• Best next step in suspected RPGN is urgent serologies plus kidney biopsy — but pulse glucocorticoids are started empirically when crescentic disease is strongly suspected (KDIGO). Waiting for the biopsy while creatinine doubles is the wrong answer.
• Anti-GBM plus hemoptysis in a smoker is the association examiners love: smoking or hydrocarbon inhalation unmasks the alveolar α3(IV) epitope, and plasma exchange is the treatment that distinguishes this from ANCA disease.
• PSGN in a child is supportive care and has an excellent prognosis — steroids and antibiotics do not alter the nephritis. Do not choose immunosuppression.
• A positive ASO titre does not confirm current PSGN; anti-DNase B is more sensitive after skin infection, and hypocomplementemia should normalise within about 6–8 weeks — persistent low C3 should redirect you toward membranoproliferative GN or lupus.