Nephritic Syndrome & Acute Glomerulonephritis

Meet the patient

A 7-year-old boy is brought in with tea-coloured urine, puffy eyes, and a headache. Two weeks ago he had a sore throat. His blood pressure is 150/95, his urine shows blood 3+ with protein 1+, and phase-contrast microscopy reveals dysmorphic red cells and red-cell casts. His C3 is low.[1]

Across the ward, a 64-year-old man presents with haemoptysis, rapidly worsening renal function, and red-cell casts — his C3 and C4 are normal.[15]

Two exam questions span both beds: what does the complement tell me? and is this a self-limiting GN or a renal emergency? The first sorts the differential; the second decides whether you reach for supportive care or for methylprednisolone and plasma exchange within the hour.[2][14]

The pentad — and the complement split that runs the whole page

Nephritic syndrome is the clinical expression of active glomerular inflammation. Where the nephrotic glomerulus leaks protein, the nephritic glomerulus is inflamed and proliferating: cellular proliferation, inflammatory-cell infiltration, and capillary-wall disruption let blood — red cells and red-cell casts — leak into the urine alongside subnephrotic protein. The defining pentad:[1]

• Haematuria — dysmorphic red cells and red-cell casts (the cardinal microscopy finding).
• Subnephrotic proteinuria — typically under 3.5 g/day (nephrotic-range may occur in overlap, especially lupus class IV/V).
• Hypertension — from sodium/water retention and renin-angiotensin activation.
• Oedema — periorbital and dependent, from sodium retention and reduced GFR.
• Acute kidney injury (AKI) — a rapid creatinine rise with oliguria from inflamed, failing glomeruli.[1][13]

The single most important triage tool at the bedside is serum complement (C3 and C4). A low C3 points to immune-complex and infectious causes (PSGN, MPGN and C3 glomerulopathy, lupus, endocarditis- and shunt-associated GN, cryoglobulinaemia); a normal complement points to IgA nephropathy, IgA vasculitis, anti-GBM disease, and ANCA-associated vasculitis. The pivotal clinical decision is to distinguish a self-limiting PSGN from a renal emergency such as RPGN — the latter destroys glomeruli within days and demands urgent immunosuppression.[2][14]

Nephritic vs nephrotic vs RPGN vs asymptomatic haematuria

Classification — complement at the bedside, immunofluorescence at the biopsy

Nephritic syndrome is classified along two axes: complement level (the bedside discriminator) and histological pattern on immunofluorescence (the biopsy discriminator that defines RPGN).[1]

Rapidly progressive GN — the three immunofluorescence types

RPGN is not a single disease but a syndrome of rapid glomerular destruction unified by crescents in over 50 percent of glomeruli. It is classified by immunofluorescence:[1]

• Type I — anti-GBM (linear IgG): anti-GBM disease/Goodpasture; antibody against the non-collagenous domain of the alpha-3 chain of type IV collagen (alpha3(IV)NC1); typically a pulmonary-renal syndrome with diffuse alveolar haemorrhage.[3][14]
• Type II — immune-complex (granular): lupus nephritis class IV, post-infectious GN, IgA nephropathy, cryoglobulinaemia; the underlying disease dictates treatment.[8]
• Type III — pauci-immune (little/no deposition): ANCA-associated vasculitis — granulomatosis with polyangiitis (GPA, PR3/c-ANCA), microscopic polyangiitis (MPA, MPO/p-ANCA), eosinophilic granulomatosis with polyangiitis (EGPA/Churg-Strauss).[15]

Who gets what — epidemiology and the nephritogenic strep

IgA nephropathy (Berger disease) is the commonest primary glomerulonephritis worldwide, with biopsy-detected incidence highest in Asian populations (China, Japan, Korea) and a peak in young adult men. Many cases are never biopsied, so the true prevalence is higher than registry data suggest.[1]

• Post-streptococcal GN is the commonest post-infectious GN globally and the commonest acute GN in children (ages 2 to 12), endemic in resource-limited tropical regions (impetigo/pyoderma-related) but still sporadic worldwide.
• ANCA-associated vasculitis has an annual incidence of around 10 to 20 per million, peaking in older adults (60 to 70). MPA is slightly more common than GPA in Asian populations; the reverse in European populations.
• Anti-GBM disease is rare (0.5 to 1 per million per year) with a bimodal age distribution: young men (20 to 30) typically with severe pulmonary haemorrhage and rapidly progressive GN, and older women (60+) more often with renal-limited disease.[14]
• Lupus nephritis affects young women of childbearing age (female:male around 9:1); class IV diffuse proliferative is the most nephritic class.
• IgA vasculitis (Henoch-Schonlein purpura) is the commonest systemic vasculitis of childhood, peaking at ages 4 to 6, with a slight male predominance.[10][11]

Nephritogenic streptococcal strains. PSGN is caused by group A beta-haemolytic streptococcus (Streptococcus pyogenes) of certain M types carrying nephritogenic antigens — notably SpeB (streptococcal pyrogenic exotoxin B, a cysteine protease) and NAPlr (nephritis-associated plasmin receptor, glyceraldehyde-3-phosphate dehydrogenase). These deposit in glomeruli, activate complement, and form the characteristic subepithelial humps.[1][2]

• Pharyngitis-associated M types: 1, 2, 4, 12.
• Skin/pyoderma-associated M types: 2, 49, 55, 57, 60.
• Seasonal pattern: pharyngitis-related PSGN peaks in winter/early spring; pyoderma-related in summer/early autumn (tropical climates).[1]

Risk factors: recent group A streptococcal infection (pharyngitis, pyoderma, cellulitis); chronic infection (endocarditis, deep abscess, ventriculoatrial shunt, osteomyelitis, chronic hepatitis B/C, HIV); systemic autoimmune disease (SLE, rheumatoid arthritis, Sjogren); drugs (hydralazine, propylthiouracil, levamisole-adulterated cocaine, allopurinol, penicillamine, sulfasalazine); malignancy (monoclonal gammopathies); family history (Alport carriers, familial IgA nephropathy, complement regulatory gene mutations).[8][16]

Why the glomerulus bleeds — the mechanism of inflammation

In nephritic syndromes the injury is to the endothelium, mesangium and GBM — not the podocyte. Immune-complex deposition, complement activation, leucocyte infiltration and cellular proliferation physically rupture the capillary wall, allowing red cells to pass through and form casts in the tubule.[1]

Post-streptococcal GN — the archetype

The classical sequence in PSGN:[1]

1. Nephritogenic streptococcal infection (pharyngitis or pyoderma) with circulating SpeB and NAPlr antigens.
2. Antigenaemia forms immune complexes that deposit in glomeruli, especially in situ in the subepithelial space, cross-linked by antibodies into large subepithelial humps.
3. Complement activation — predominantly the alternative and lectin pathways, consuming C3 (early classical components C1q and C4 are typically normal or only mildly reduced).
4. Inflammation and proliferation — neutrophils and macrophages infiltrate the tuft, mesangial and endocapillary cells proliferate, producing a diffuse endocapillary proliferative pattern.
5. Capillary-wall disruption lets red cells and red-cell casts enter the urine and subnephrotic protein leak; the inflamed glomerulus under-filters (oliguria, AKI) and avidly reabsorbs sodium (oedema, hypertension).[1][2]

Complement C3 typically normalises within 6 to 8 weeks as the immune complexes are cleared; persistence beyond this signals an alternative diagnosis (MPGN, C3 glomerulopathy, lupus).[1]

IgA nephropathy — the four-hit hypothesis

The currently accepted four-hit pathogenesis explains why IgA nephropathy runs in families and in certain ethnic groups:[1]

• Hit 1 — production of galactose-deficient IgA1 (Gd-IgA1), an aberrantly glycosylated IgA1 hinge-region O-glycan (a heritable trait).
• Hit 2 — formation of autoantibodies (IgG or IgA) that recognise the exposed GalNAc residues on Gd-IgA1.
• Hit 3 — formation of large circulating immune complexes (Gd-IgA1 plus autoantibody) that deposit in the mesangium.
• Hit 4 — mesangial cell activation with release of cytokines (IL-6, TNF-alpha), chemokines and growth factors, driving mesangial proliferation, matrix expansion, podocyte injury and oxidative stress.[1]

The same mechanism underlies IgA vasculitis (Henoch-Schonlein purpura), in which IgA immune complexes deposit systemically in skin, gut, joint and kidney.[1]

Anti-GBM disease — the linear antibody

Autoantibodies (IgG, rarely IgA) target the non-collagenous domain of the alpha-3 chain of type IV collagen (alpha3(IV)NC1), sequestered in the mature GBM and alveolar basement membrane. Binding produces linear IgG deposition along the GBM on immunofluorescence, activates complement (C3) and triggers Fc-receptor-mediated neutrophil and macrophage injury that ruptures the capillary wall, causing crescents and (in the lung) alveolar haemorrhage. The disease is the prototype of a tissue-fixed antibody disease — hence the central role of plasma exchange to remove circulating antibody.[3][14]

ANCA-associated vasculitis — the NET/alternative-complement loop

ANCA are IgG autoantibodies against neutrophil granule proteins: anti-MPO (perinuclear p-ANCA) and anti-PR3 (cytoplasmic c-ANCA). The pathogenesis:[1]

1. Priming — cytokines (IL-1, TNF) during infection or inflammation move MPO and PR3 to the neutrophil surface.
2. Binding — ANCA bind and cross-link surface antigens, activating the neutrophil via Fc-gamma receptors.
3. Degranulation and NETosis — release of reactive oxygen species, proteolytic enzymes and neutrophil extracellular traps (NETs) that damage the endothelium.
4. Necrotising, crescentic GN with little or no immune deposition (pauci-immune on IF), and (depending on subtype) granulomatous inflammation in the upper and lower respiratory tract (GPA) or asthma and eosinophilia (EGPA).[15]

Drugs such as hydralazine, propylthiouracil and levamisole-adulterated cocaine can induce MPO-ANCA vasculitis, often with anti-histone and anti-MPO co-positivity.[1]

Lupus nephritis — full-house immune-complex deposition

In SLE, defective clearance of apoptotic debris drives autoantibodies against nuclear antigens (dsDNA, nucleosomes, ribonucleoproteins). Immune complexes deposit in the mesangium, subendothelium and subepithelium, activating complement via the classical pathway (hence low C3 and C4) and producing full-house immunofluorescence (IgG, IgA, IgM, C3, C1q, C4). The ISN/RPS 2003 classification recognises six classes, of which class IV (diffuse proliferative) is the most nephritic and severe and class III (focal proliferative) is also nephritic; class V (membranous) is predominantly nephrotic but can overlap.[1]

Crescent formation — the histological hallmark of RPGN

Whatever the cause, severe capillary-wall injury ruptures the GBM, allowing fibrin, macrophages and plasma proteins into Bowman's space. This stimulates parietal epithelial cells (and detached podocytes) to divide into crescent-shaped cellular and fibrocellular masses that compress and ultimately obliterate the tuft. Crescents in over 50 percent of glomeruli defines RPGN; once fibrous (chronic), they are irreversible — which is why treatment must be rapid.[1]

Why hypertension, oedema and AKI happen

In nephritic syndromes the dominant oedema mechanism is sodium retention from a reduced GFR with intact tubular reabsorption (the overfill mechanism), in contrast to the underfill (hypoalbuminaemia) mechanism of nephrotic syndrome. Hypertension results from volume expansion plus activation of the intrarenal RAAS by ischaemic juxtaglomerular cells. AKI is glomerular in origin — the inflamed, proliferative tuft simply under-filters.[1]

The bedside round — find the cause in the skin, ENT and chest

Focused examination sorts the differential in minutes, because the nephritic causes wear their systemic clues on the surface.[1]

• Volume status and BP — accurate blood pressure (often raised), JVP, weight, serial fluid balance; periorbital, sacral and pedal oedema; basal crackles and pulmonary oedema.
• Abdomen — hepatosplenomegaly, ascites (especially lupus with serositis), renal masses, palpable bladder.
• Skin — malar rash, palpable purpura (lower limbs in HSP, cryoglobulinaemia, ANCA), livedo reticularis, necrotising lesions (GPA, antiphospholipid), oral and nasal ulcers.
• ENT — sinus tenderness, nasal crusting, septal perforation, saddle nose (GPA); red strawberry tongue (in PSGN from preceding pharyngitis).
• Chest — crackles (pulmonary oedema, pulmonary haemorrhage), pleural effusion, consolidations (GPA cavities).
• Cardiovascular — new or changing murmur (endocarditis), pericardial rub (lupus, uraemia).
• Neurological — focal deficits, mononeuritis multiplex (vasculitis), seizures or reduced GCS (hypertensive encephalopathy, lupus cerebritis).
• Fundoscopy — hypertensive retinopathy, cytoid bodies (lupus), Roth spots (endocarditis).
• Joints — synovitis (lupus, HSP, rheumatoid-associated vasculitis).[1]

Targeted history: recent infection (sore throat, skin sores; onset-to-symptom interval); drugs (hydralazine, propylthiouracil, allopurinol, penicillamine, sulfasalazine, minocycline, levamisole-cocaine, anti-TNF); chronic infection (hepatitis B/C, HIV, endocarditis risk); systemic symptoms (rash, arthralgia, mouth ulcers, alopecia, photosensitivity, sinus disease, haemoptysis, abdominal pain, neuropathy); travel, exposure, family history (TB, renal disease, deafness — Alport, autoimmune disease); pregnancy (pre-eclampsia, postpartum lupus flare).[1]

Investigations — the cardinal specimen is the urine

The workup confirms the syndrome, splits the differential by complement, and biopsies the cause.[1][13]

Urine — the cardinal specimen

Red-cell casts are the single most discriminating microscopy finding: their presence confirms a glomerular source and mandates a glomerular work-up. Their absence does not exclude a GN, especially in ANCA vasculitis where the lesion may be focal.[1]

Baseline bloods and the serological workup

• Urea, creatinine, eGFR — quantify AKI; trend daily.
• FBC — anaemia of chronic inflammation; PRCA in GPA (anti-PR3); eosinophilia in EGPA; thrombocytopenia in lupus.
• ESR/CRP — markedly raised in vasculitis, endocarditis.
• Albumin — low in nephrotic overlap.
• Electrolytes — hyperkalaemia, hyperphosphataemia, metabolic acidosis in AKI.[1]

• Complement — C3 and C4 (and CH50 if C3/C4 normal but suspicion high). In PSGN, C3 is low and returns to normal by 6 to 8 weeks; persistent low C3 beyond 8 weeks is atypical and mandates biopsy to exclude MPGN/C3G, lupus, endocarditis.[1]
• Anti-streptococcal serology — ASO titre rises after pharyngitis (but not reliably after pyoderma) and anti-DNase B rises after both; a rising titre over 2 to 3 weeks is more useful than a single value.
• Autoimmune — ANA, anti-dsDNA (high specificity for lupus), anti-Sm, complement; anti-C1q (lupus nephritis activity); lupus anticoagulant and anticardiolipin (antiphospholipid).
• ANCA with MPO and PR3 specificities — anti-PR3 (cytoplasmic c-ANCA) → GPA; anti-MPO (perinuclear p-ANCA) → MPA. Drug-induced ANCA is often high-titre p-ANCA with anti-MPO and anti-histone.
• Anti-GBM antibody — enzyme immunoassay against the alpha3(IV)NC1 antigen; positive in Goodpasture.[3]
• Infection screen — HBsAg, anti-HCV with PCR if positive, HIV, cryoglobulins (with RF and C4), blood cultures and echocardiography if endocarditis suspected.
• Monoclonal gammopathy work-up — SPEP, serum free light chains, urine for Bence-Jones; consider bone marrow if abnormal.[1]

Renal biopsy — when and what it shows

Indications: all adults with nephritic syndrome (unless classic self-limiting PSGN with rapid resolution); any RPGN or pulmonary-renal syndrome; persistent low complement (over 8 weeks) or atypical features; children with atypical PSGN, nephrotic-range proteinuria, or steroid-resistant disease.[1]

Special tests: C3 nephritic factor and anti-factor H for suspected C3 glomerulopathy; ANCA subtyping (MPO, PR3); anti-GBM titre quantitation to monitor plasma exchange; renal biopsy MEST-C score for IgA nephropathy prognostication (Mesangial hypercellularity, Endocapillary hypercellularity, Segmental sclerosis, Tubular atrophy/interstitial fibrosis, Crescents); ISN/RPS 2003 lupus nephritis class (I to VI) and activity/chronicity indices.[1]

Imaging: renal ultrasound (kidney size — normal to enlarged in acute GN, small and echogenic in chronic disease; exclude obstruction; small kidneys contraindicate aggressive immunosuppression); chest X-ray/CT (pulmonary oedema, diffuse alveolar haemorrhage, cavitating nodules in GPA); CT sinuses in suspected GPA; echocardiography and blood cultures if endocarditis suspected.[1]

Resuscitation — ABC, hypertension, fluid, and the dialysis indications

The immediate bundle stabilises the patient while the workup runs.[1]

• Airway/Breathing — oxygen if hypoxic; secure the airway if massive pulmonary haemorrhage (anti-GBM/ANCA) with anaesthetic support.
• Circulation — IV access; treat hyperkalaemia (calcium gluconate 10 mL of 10 percent IV over 5 to 10 min for membrane stabilisation; insulin 10 units with 25 to 50 g of 50 percent dextrose IV; salbutamol 10 to 20 mg nebulised; sodium bicarbonate if acidotic; calcium resonium or RRT for removal).
• Pulmonary oedema — sit upright, high-flow oxygen, IV furosemide 40 to 80 mg, nitrates if hypertensive, consider non-invasive ventilation and RRT if refractory.[1]

Hypertensive emergency — reduce BP gradually, no more than 25 percent in the first hour, then to 160/100 mmHg over 2 to 6 hours to avoid cerebral and coronary hypoperfusion:[1]

• IV labetalol 20 to 80 mg bolus every 10 min, or infusion 0.5 to 2 mg/min.
• IV nicardipine infusion 5 to 15 mg/h (titrate).
• IV clevidipine infusion 1 to 16 mg/h.
• Oral nifedipine long-acting or amlodipine for urgent but non-emergency hypertension.
• AVOID sublingual nifedipine (erratic absorption, precipitous hypotension, stroke risk).
• In eclampsia, IV magnesium sulphate 4 g loading then 1 to 2 g/h.[1]

Fluid overload and oedema: salt restriction under 2 g/day; fluid restriction to previous day's urine output plus 500 mL insensible losses; loop diuretic — oral furosemide 40 mg daily, titrate to weight; IV furosemide 40 to 80 mg if severe or gut oedema; add a thiazide (metolazone 2.5 to 5 mg) or amiloride for resistant oedema; dialysis for refractory pulmonary oedema, oligoanuric AKI, or hyperkalaemia.[1]

[1]

Supportive care for all causes: treat the precipitating infection (antibiotics for PSGN do not change the GN course once established — the immune injury is underway — but they treat the source, prevent rheumatic fever and limit spread; use oral penicillin V or benzathine penicillin IM for GAS pharyngitis, erythromycin or clindamycin if penicillin-allergic); bed rest during the acute phase; daily monitoring of weight, BP, urine output, electrolytes, creatinine; adequate calories, controlled protein (0.8 g/kg/day), potassium/phosphate restriction in AKI; VTE prophylaxis if immobilised or nephrotic-range proteinuria; PJP prophylaxis during immunosuppression — trimethoprim-sulfamethoxazole 480 mg daily (or 960 mg three times weekly).[1]

Definitive therapy — supportive care first, then immunosuppression by cause

The principle: PSGN is supportive and self-limiting; IgA nephropathy uses ACEi/ARB-led supportive care with immunosuppression for high-risk disease; RPGN (anti-GBM, ANCA, severe immune-complex) requires urgent induction immunosuppression.[1]

The supportive care bundle for all glomerular disease (KDOQI/KDIGO)

• RAAS blockade — ACE inhibitor (e.g. ramipril 2.5 to 10 mg daily) or ARB (e.g. losartan 50 to 100 mg daily) to reduce proteinuria and intraglomerular pressure; titrate to BP and potassium.
• BP target — under 130/80 mmHg (under 125/75 mmHg if proteinuric), per KDIGO.
• SGLT2 inhibitor — dapagliflozin 10 mg daily (or empagliflozin) for proteinuric CKD.
• Statin for hyperlipidaemia and cardiovascular risk.
• Smoking cessation, weight management, salt restriction.
• Vaccination (influenza annually, pneumococcal, hepatitis B).[1]

IgA nephropathy — supportive-first, then risk-stratified immunosuppression

1. Optimised supportive care for at least 90 days — ACEi/ARB titrated, BP target under 130/80 mmHg, SGLT2 inhibitor, salt restriction, smoking cessation, weight, statin.
2. If persistent proteinuria over 0.75 to 1 g/day despite optimised supportive care: a 6-month course of glucocorticoids (KDIGO 2021/2024, informed by TESTING and STARPROM) — typically prednisolone 0.6 to 0.8 mg/kg/day tapering over 6 months, with gastroprotection, bone protection and PJP prophylaxis.
3. Targeted-release budesonide (Nefecon) — locally acting steroid in the ileal Peyer patches, reducing Gd-IgA1 production.
4. Sparsentan (dual endothelin-A and angiotensin-II type-1 antagonist; PROTECT trial) and complement inhibitors (avacopan C5aR inhibitor; iptacopan factor B inhibitor) for selected patients.
5. Fish oil (omega-3 fatty acids) has modest, debated efficacy and is widely used because of low toxicity.[1][12][13]

ANCA-associated vasculitis — induction

• Glucocorticoid pulse — methylprednisolone 500 to 1000 mg IV daily for 3 days (avoid in severe infection; consider reduced dose in elderly).
• Then oral prednisolone 1 mg/kg/day (max 60 to 80 mg), tapering over months to under 5 mg/day.
• PLUS rituximab 375 mg/m² IV weekly for 4 weeks (RAVE trial showed non-inferiority to cyclophosphamide and superiority for relapsing disease), OR cyclophosphamide 15 mg/kg IV every 2 weeks for 3 doses then every 3 weeks (6-month course, dose-reduce for age and renal function).[4][15]
• Avacopan (C5a receptor inhibitor) 30 mg twice daily can allow earlier steroid taper in selected patients (ADVOCATE trial).
• Plasma exchange (MEPEX regimen) for severe renal failure (creatinine over 5.7 mg/dL or dialysis-dependence) or diffuse alveolar haemorrhage — 7 to 14 exchanges of 60 mL/kg over 2 to 4 weeks.[5]

Anti-GBM disease — plasma exchange plus steroids plus cyclophosphamide

• Plasma exchange — daily or alternate-day, 4 L exchanges with 5 percent human albumin and fresh frozen plasma if bleeding; continue until anti-GBM antibody undetectable (typically 2 to 3 weeks).
• Methylprednisolone pulse 500 to 1000 mg IV daily for 3 days, then oral prednisolone 1 mg/kg/day tapering over months.
• Cyclophosphamide 2 mg/kg/day orally (dose-reduce for age and renal function) for 2 to 3 months.
• Avoid late transplantation until anti-GBM antibody has been undetectable for at least 6 months.[3][14]

Lupus nephritis class III/IV — induction and maintenance

• Induction (3 to 6 months): mycophenolate mofetil (MMF) 2 to 3 g/day (target 3 g/day) OR low-dose IV cyclophosphamide (Euro-Lupus regimen 500 mg every 2 weeks for 6 doses), PLUS glucocorticoids (methylprednisolone pulse then prednisolone 0.5 to 0.8 mg/kg/day tapering).[6]
• Add voclosporin 23.7 mg twice daily (AURORA 1 and 2 trials showed higher renal response with voclosporin triple therapy) or tacrolimus.[7]
• Hydroxychloroquine 200 to 400 mg daily for all lupus patients (improves renal and overall outcomes).
• Maintenance (after induction): MMF 1 to 2 g/day or azathioprine 1 to 2 mg/kg/day plus low-dose prednisolone (target under 5 mg/day); consider rituximab for refractory disease.
• Class V (membranous) lupus nephritis with nephrotic-range proteinuria treated as membranous nephropathy (calcineurin inhibitor or MMF plus steroids).[7]

Crescentic immune-complex GN, C3G/MPGN, and cryoglobulinaemia

• Crescentic immune-complex GN — treat the underlying disease (lupus, post-infectious with crescents, severe IgA) with glucocorticoid pulse plus cyclophosphamide or mycophenolate.[1]
• C3 glomerulopathy and MPGN — supportive care (ACEi/ARB, BP, SGLT2i); mycophenolate for proteinuria and progressive decline; complement blockade — eculizumab (anti-C5) or pegcetacoplan (anti-C3) in selected patients with progressive disease and confirmed alternative pathway dysregulation; treat the underlying cause of immune-complex MPGN (antivirals for hepatitis B/C, treat lupus, treat monoclonal gammopathy).[8][9]
• Cryoglobulinaemic vasculitis — hepatitis C-related: direct-acting antivirals achieve sustained virological response in most; severe vasculitis adds rituximab ± plasma exchange. Essential and non-HCV: rituximab plus steroids; plasma exchange for crisis (hyperviscosity, severe renal failure, neuropathy).[16]

Maintenance, prophylaxis and relapse

• ANCA vasculitis maintenance — rituximab 1 g at 0 and 2 weeks, then every 4 to 6 months for 18 to 24 months; or azathioprine 2 mg/kg/day.[4]
• Lupus nephritis maintenance — MMF or azathioprine plus low-dose steroid; hydroxychloroquine indefinitely.
• PJP prophylaxis — trimethoprim-sulfamethoxazole 480 mg daily (or 960 mg three times weekly) for the duration of high-dose steroids, cyclophosphamide or rituximab.
• Mesna and forced hydration with high-dose cyclophosphamide to prevent haemorrhagic cystitis; PCV and cervical screening (cyclophosphamide carcinogenicity); fertility preservation (sperm/embryo banking) where possible.[1]

Subtypes and scenarios

Post-streptococcal GN (PSGN). Presents 1 to 3 weeks after GAS pharyngitis or 2 to 4 weeks after pyoderma in a child (or adult); periorbital oedema, cola-coloured urine, hypertension, AKI. Low C3 returning to normal by 6 to 8 weeks; raised ASO and anti-DNase B; dysmorphic RBCs and RBC casts; biopsy (rarely needed) shows diffuse endocapillary proliferative GN with subepithelial humps. Management is supportive — fluid and sodium balance, BP control, loop diuretic; treat the streptococcal infection with penicillin; dialysis rarely needed. Excellent in children (over 95 percent complete recovery); adults have a higher rate of residual impairment, especially elderly diabetics. Atypical features (heavy proteinuria, persistent low C3 beyond 8 weeks, rapidly progressive course) warrant biopsy.[1][2]

IgA nephropathy (Berger disease). Synpharyngitic gross haematuria in a young adult, or incidental microscopic haematuria with mild proteinuria; occasionally RPGN with crescents. Normal complement; mesangial IgA-dominant deposits; MEST-C score for prognosis. ACEi/ARB plus SGLT2i for proteinuria; 6-month steroids or targeted-release budesonide for persistent proteinuria over 0.75 to 1 g/day despite 90 days of supportive care. Variable — 20 to 40 percent progress to ESKD over 20 to 30 years; predictors are sustained proteinuria over 1 g/day, hypertension, reduced eGFR at diagnosis, high-score MEST-C lesions.[1]

IgA vasculitis (Henoch-Schonlein purpura). Palpable purpura on extensor surfaces and buttocks, arthritis, abdominal pain (intussusception risk), and renal disease with IgA nephritis; children under 10. Normal complement; serum IgA may be raised; biopsy of skin (leucocytoclastic vasculitis with IgA deposition) or kidney (IgA-dominant mesangial deposits). Supportive in most; steroids for severe GI disease, severe arthritis, or nephritis with proteinuria over 1 g/day or crescents; severe nephritis treated as IgA nephropathy. Usually self-limiting in children; adults have higher CKD risk; recurrence after transplant is recognised.[10][11]

Rapidly progressive GN (RPGN) — the renal emergency. Loss of over 50 percent of GFR within under 3 months, with crescents on biopsy. Types: I anti-GBM, II immune-complex (lupus, post-infectious, IgA), III pauci-immune (ANCA). Management is urgent — methylprednisolone pulse plus cyclophosphamide or rituximab; plasma exchange for anti-GBM and severe ANCA; supportive care and RRT if needed; biopsy should not delay immunosuppression if the picture is classic.[1]

Lupus nephritis. Class IV diffuse proliferative is the most nephritic and severe; class III focal proliferative is also nephritic; class V membranous is predominantly nephrotic but can overlap. Low C3 AND C4, ANA, anti-dsDNA, anti-Sm; biopsy with ISN/RPS 2003 classification and activity/chronicity indices. Induction with MMF or cyclophosphamide plus steroids and voclosporin/tacrolimus; maintenance with MMF or azathioprine plus low-dose steroid; hydroxychloroquine throughout.[6][7]

ANCA-associated vasculitis — the three subtypes:[15]

Induction with rituximab or cyclophosphamide plus steroids; plasma exchange for severe renal failure or pulmonary haemorrhage; PJP prophylaxis throughout.[4][15]

Membranoproliferative GN and C3 glomerulopathy. Immune-complex MPGN — hepatitis B/C, lupus, monoclonal gammopathy; full immunoglobulin and complement staining; treat the underlying cause. C3 glomerulopathy — alternative pathway dysregulation (C3 nephritic factor, factor H/I deficiency); C3-dominant staining; low C3 with normal C4; risk of recurrence after transplant; complement blockade (eculizumab, pegcetacoplan) in selected cases.[8][9]

Cryoglobulinaemic vasculitis. Type II mixed (IgM kappa with RF activity against polyclonal IgG) is classically associated with chronic hepatitis C. Tetrad: palpable purpura, weakness, arthralgia, neuropathy; low C4 out of proportion to C3; renal biopsy shows MPGN-like pattern with intracapillary thrombi. Management: DAAs for HCV; rituximab and plasma exchange for severe disease.[16]

Endocarditis- and shunt-associated GN. Chronic bacteraemia drives immune-complex deposition; low C3 and C4. Treat the infection — antibiotics and (for endocarditis) valve surgery; for shunt nephritis, removal of the infected shunt.[1]

Complications, pitfalls and prognosis

Acute complications: severe hypertension (hypertensive encephalopathy, seizures, PRES, intracerebral haemorrhage); pulmonary oedema and AKI requiring dialysis; pulmonary haemorrhage in anti-GBM and ANCA (catastrophic); thrombosis (renal vein in nephrotic overlap); infection from immunosuppression (PJP, herpes zoster, CMV, opportunistic fungal and mycobacterial); contrast nephropathy from imaging.[1]

Chronic complications: progression to CKD/ESKD (particularly anti-GBM with oligoanuria at presentation, severe ANCA, crescentic lupus, IgA with persistent proteinuria); persistent hypertension and cardiovascular disease; recurrent disease (IgA 30 to 50 percent recurrence in transplant grafts but graft loss only 5 to 10 percent; ANCA relapse 30 to 50 percent over 5 years; C3 glomerulopathy high recurrence); drug toxicity (cyclophosphamide — haemorrhagic cystitis, infertility, myelodysplasia, bladder cancer; steroids — diabetes, osteoporosis, avascular necrosis, cataract, infection; rituximab — hypogammaglobulinaemia; calcineurin inhibitors — nephrotoxicity, hypertension; MMF — teratogenic, cytopenia).[1]

Classic pitfalls: assuming all nephritic presentations are PSGN and missing RPGN; not checking complement in a young person with haematuria; failing to biopsy a rapidly progressive AKI with haematuria and RBC casts; delaying plasma exchange in anti-GBM with pulmonary haemorrhage; giving high-dose immunosuppression without excluding infection (active TB, hepatitis B reactivation, HIV, untreated endocarditis); forgetting PJP prophylaxis; missing double-positive (ANCA + anti-GBM) disease (manage as anti-GBM, add plasma exchange); forgetting mesna with high-dose cyclophosphamide; treating a chronic lesion aggressively — fibrous crescents and small kidneys will not respond and only expose the patient to immunosuppressive harm.[1]

Prognosis by cause

Predictors of poor renal outcome — the four that recur across every GN: sustained heavy proteinuria over 1 g/day (the single most powerful predictor), hypertension at presentation, reduced eGFR at presentation, crescents on biopsy (especially over 50 percent) and interstitial fibrosis with tubular atrophy.[1]

Special populations

Children. PSGN is commonest and usually self-limiting — supportive care only; biopsy reserved for atypical features. IgA vasculitis (HSP) nephritis is treated as IgA nephropathy in severe cases. Weight-based dosing of all drugs.[1]

Elderly. ANCA vasculitis is the dominant cause of crescentic GN. Higher mortality from immunosuppression; reduce cyclophosphamide dose for age and renal function. Balance immunosuppression against infection and malignancy risk; consider rituximab-based regimens. Vasculitis in older patients may present non-specifically (weight loss, fatigue, raised inflammatory markers) — a high index of suspicion is needed.[1]

Pregnancy. Lupus nephritis may flare, especially postpartum. Pre-eclampsia mimics nephritic/nephrotic syndrome (hypertension, oedema, AKI, proteinuria) but has normal complements and no RBC casts, and uric acid is often high; serum sFlt-1 is high and PlGF low in pre-eclampsia. Switch ACEi/ARB (teratogenic) to labetalol, nifedipine, methyldopa. Avoid mycophenolate and cyclophosphamide (teratogenic) — use azathioprine, tacrolimus, hydroxychloroquine and steroids. Antiphospholipid syndrome co-exists in some lupus patients — needs aspirin ± LMWH.[1]

Diabetic patients. May have superimposed glomerular disease (diabetic nephropathy plus another GN); biopsy if atypical (rapid onset, RBC casts, low complement, no diabetic retinopathy). SGLT2 inhibitor is the cornerstone. Avoid iodinated contrast in AKI where possible.[1]

Immunocompromised (HIV, transplant, post-chemotherapy). HIVICK and collapsing FSGS; treat the underlying HIV with antiretrovirals. Hepatitis B and C with MPGN, membranous or cryoglobulinaemic GN; antiviral therapy transforms the outlook. Transplant patients: drug interactions (calcineurin inhibitors with azoles, macrolides); consider transplant recurrence per disease.[1]

Anticoagulated patients. Weigh bleeding risk against the need for renal biopsy (consider transjugular biopsy if INR not correctable). Warfarin interacts with steroids and azathioprine; DOACs require renal dose adjustment.[1]

Evidence, guidelines and regional differences

Guidelines: KDIGO 2021 Glomerular Diseases Guideline and the 2024/2025 KDIGO IgA Nephropathy Update — the international standard, with the supportive-care-first philosophy for IgA and the immunosuppressive induction regimens for RPGN and lupus.[12][13] EULAR 2023 for lupus nephritis; ACR/VF 2021 for ANCA-associated vasculitis (rituximab or cyclophosphamide induction, plasma exchange in severe disease).[4]

Regional differences. Globally, empiric supportive management for classic paediatric PSGN avoids biopsy unless atypical. India and resource-limited settings: endemic PSGN from skin infection (tropical climates); limited renal biopsy access; rising IgA nephropathy in young adults; cost and access constraints for rituximab, complement inhibitors, sparsentan and voclosporin; cyclophosphamide and steroids remain first-line for RPGN. Hepatitis B/C-endemic regions: higher incidence of MPGN, membranous and cryoglobulinaemic GN; direct-acting antivirals transform HCV-cryoglobulinaemia management.[1]

The mantra

RBC casts mean glomerular bleeding; complement splits the differential; crescents mean a renal emergency — treat fast.[1][13]

Ward-round test

A child with tea-coloured urine two weeks after a sore throat, low C3, raised ASO — diagnosis and management?

Classic post-streptococcal GN — supportive care: fluid and sodium balance, BP control, loop diuretic for oedema, penicillin for the infection. C3 normalises in 6 to 8 weeks; over 95 percent of children recover completely. Biopsy only if atypical.[1][2]

A young man with haematuria during an URTI, normal complement — what is it, and what distinguishes it from PSGN?

IgA nephropathy — synpharyngitic (haematuria with the URTI, 0 to 2 days), normal complement, mesangial IgA deposits. PSGN is 1 to 3 weeks after pharyngitis with low C3. The latency from infection is the discriminator.[1]

Haemoptysis, rapidly progressive AKI, red-cell casts — what is the syndrome, and the first three drugs?

A pulmonary-renal syndrome — anti-GBM (Goodpasture) or ANCA vasculitis. Send anti-GBM and ANCA, and start plasma exchange plus IV methylprednisolone plus cyclophosphamide within the hour. Delay costs the kidney and the lung.[3][14][15]

PSGN with low C3 still low at 10 weeks — what now?

Low C3 persisting beyond 8 weeks is atypical and mandates renal biopsy to exclude MPGN, C3 glomerulopathy, lupus or endocarditis-associated GN. In uncomplicated PSGN, C3 normalises by 6 to 8 weeks.[1]

Name the three RPGN immunofluorescence types and the role of plasma exchange in each.

Type I anti-GBM (linear IgG) — plasma exchange essential (tissue-fixed antibody). Type II immune-complex (granular) — treat the underlying disease; plasma exchange rarely, except severe lupus or rapidly progressive cryoglobulinaemia. Type III pauci-immune (ANCA) — plasma exchange only if dialysis-dependent or diffuse alveolar haemorrhage.[1][8][15]

References

1. [1]Balasubramanian R, Marks SD. Post-infectious glomerulonephritis Paediatr Int Child Health, 2017.PMID 28891413
2. [2]Rodriguez-Iturbe B. Autoimmunity in Acute Poststreptococcal GN: A Neglected Aspect of the Disease J Am Soc Nephrol, 2021.PMID 33531351
3. [3]Ponticelli C, Calatroni M, Moroni G Anti-glomerular basement membrane vasculitis Autoimmun Rev, 2023.PMID 36252931
4. [4]Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis N Engl J Med, 2010.PMID 20647199
5. [5]Jayne DR, Gaskin G, Rasmussen N, et al. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis J Am Soc Nephrol, 2007.PMID 17582159
6. [6]Appel GB, Contreras G, Dooley MA, et al. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis J Am Soc Nephrol, 2009.PMID 19369404
7. [7]Rovin BH, Teng YKO, Ginzler EM, et al. Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial Lancet, 2021.PMID 33971155
8. [8]Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis: pathogenetic heterogeneity and proposal for a new classification Semin Nephrol, 2011.PMID 21839367
9. [9]Bomback AS Eculizumab in the treatment of membranoproliferative glomerulonephritis Nephron Clin Pract, 2014.PMID 25402185
10. [10]Pillebout E, Sunderkötter C IgA vasculitis Semin Immunopathol, 2021.PMID 34170395
11. [11]McCarthy HJ, Tizard EJ. Clinical practice: Diagnosis and management of Henoch-Schönlein purpura Eur J Pediatr, 2010.PMID 20012647
12. [12]Floege J, Barbour SJ, Cattran DC, et al. Management and treatment of glomerular diseases (part 1): conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference Kidney Int, 2019.PMID 30665568
13. [13]Rovin BH, Caster DJ, Cattran DC, et al. Management and treatment of glomerular diseases (part 2): conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference Kidney Int, 2019.PMID 30665569
14. [14]Reggiani F, L'Imperio V, Calatroni M, et al. Goodpasture syndrome and anti-glomerular basement membrane disease Clin Exp Rheumatol, 2023.PMID 36995324
15. [15]Kronbichler A, Bajema IM, Bruchfeld A, et al. Diagnosis and management of ANCA-associated vasculitis Lancet, 2024.PMID 38368016
16. [16]Terrier B, Marie I, Lacraz A, et al. Non HCV-related infectious cryoglobulinemia vasculitis: Results from the French nationwide CryoVas survey and systematic review of the literature J Autoimmun, 2015.PMID 26320984