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 — gross (cola-coloured) or microscopic; urinalysis shows haematuria in most reported APSGN series, and IgA nephropathy usually declares itself with haematuria on urinalysis.^[20][21]
• Subnephrotic proteinuria — IgA nephropathy, the archetype of the nephritic presentation, most often declares itself with haematuria or proteinuria on urinalysis; overt nephrotic syndrome accounts for under 5 percent of IgAN presentations.^[21]
• Hypertension — one of the classical manifestations of the acute nephritic presentation.^[19][20]
• Oedema — a classical manifestation of APSGN alongside hypertension, gross haematuria and oliguria.^[20]
• Acute kidney injury (AKI) — oliguria is a classical manifestation; severe AKI and rapidly progressive GN are recognised complications that may need kidney replacement therapy.^[19][20]

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]

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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]

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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]

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• Airway/Breathing — oxygen if hypoxic; alveolar haemorrhage occurs in 40 to 60 percent of anti-GBM disease and is life-threatening, so anticipate airway compromise and involve critical care early.^[14]
• Circulation — IV access; treat hyperkalaemia with calcium gluconate 10 percent, 10 mL intravenously for membrane stabilisation (10 mL calcium chloride if in cardiac arrest), plus a nebulised beta-agonist and intravenous insulin with dextrose (guided by initial and serial glucose) to shift potassium into cells.^[17]
• Potassium removal — dialysis is the most efficient means of removing excess potassium; loop and thiazide diuretics can also be useful, sodium polystyrene sulfonate is not efficacious, and the newer gastrointestinal potassium binders (patiromer, sodium zirconium cyclosilicate) hold promise.^[17]
• Pulmonary oedema — one of the most common forms of organ damage in hypertensive emergencies: sit upright, give oxygen, and treat blood pressure and fluid overload with diuretic-based supportive therapy.^[18][19]

Hypertensive emergency — hypertensive emergencies account for about 0.5 percent of emergency-room visits, and ischaemic stroke and heart failure/pulmonary oedema are the most common forms of organ damage, so prompt but controlled blood-pressure reduction protects exactly the organs the nephritic patient is failing in. Parenteral options with recent data documenting their safety and efficacy are IV labetalol and IV nicardipine, among many therapeutic choices with varied mechanisms of action; large randomised controlled trial evidence in this area is lacking.^[18]

Fluid overload and oedema: treatment is primarily supportive with diuretics and antihypertensive therapy; hypertensive emergency and congestive cardiac failure are the complications to identify and treat promptly, and only a small number of patients require kidney replacement therapy.^[19]

When to dialyse: only a small minority of patients with post-infectious GN need kidney replacement therapy — it is reserved for severe complications such as refractory hyperkalaemia (dialysis is the most efficient means of removing excess potassium), hypertensive emergency, congestive cardiac failure, severe AKI or rapidly progressive GN.^[17][19]

Supportive care for all causes: prevention of streptococcal throat and skin infections, early diagnosis, identification of complications and prompt initiation of treatment are the cornerstones of APSGN management. Treatment primarily consists of supportive care along with diuretics and antihypertensive therapy; most patients make a full recovery, though persistent proteinuria, hypertension and progression to chronic kidney disease may require long-term monitoring.^[19] In published Nepali series the classical manifestations were oedema, hypertension, gross haematuria and oliguria, and most children were managed conservatively with diuretics and anti-hypertensives.^[20]

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 — the IgA nephropathy template (KDIGO 2025)

• Behavioural modification — dietary sodium under 2 g/day, smoking cessation, weight control and exercise.^[21]
• Blood pressure — antihypertensive therapy to a goal blood pressure under 120/70 mmHg.^[21]
• RAAS inhibition — a renin-angiotensin system inhibitor to manage IgAN-induced nephron loss; a dual endothelin-angiotensin receptor antagonist (sparsentan) can be used for the same purpose.^[21]
• SGLT2 inhibition — dapagliflozin 10 mg once daily reduced kidney and cardiovascular events in patients with chronic kidney disease and albuminuria, with or without type 2 diabetes (DAPA-CKD).^[23]

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

1. Optimised supportive care is the mainstay — behavioural modification (dietary sodium under 2 g/day, smoking cessation, weight control, exercise), antihypertensives to a goal blood pressure under 120/70 mmHg, and a renin-angiotensin system inhibitor — alone or combined with a sodium-glucose cotransporter 2 inhibitor or dual endothelin-angiotensin receptor antagonist — to manage IgAN-induced nephron loss, per the KDIGO 2025 IgAN guideline.^[21] Dapagliflozin 10 mg once daily reduced the risk of sustained eGFR decline, end-stage kidney disease, or renal or cardiovascular death in patients with chronic kidney disease and albuminuria, with or without type 2 diabetes (DAPA-CKD).^[23]
2. Systemic glucocorticoids for high-risk disease — the 2021 KDIGO guideline suggests considering a 6-month course of systemic corticosteroid therapy for patients at high risk of progression, although efficacy is under debate and serious adverse effects are common.^[22] In the TESTING trial (proteinuria over 1 g/day after at least 3 months of renin-angiotensin blockade), oral methylprednisolone 0.6 to 0.8 mg/kg/day (maximum 48 mg/day) for 2 months, weaned over 4 to 6 months, showed potential renal benefit but excess serious infections, and recruitment was stopped early.^[24]
3. Targeted-release budesonide (Nefecon) 16 mg/day for 9 months — an oral formulation designed to act at the gut mucosal level; the NefIgArd phase 3 trial showed a clinically relevant reduction in eGFR decline and a durable reduction in proteinuria over 2 years.^[25]
4. Sparsentan (dual endothelin-angiotensin receptor antagonist; target dose 400 mg once daily versus irbesartan 300 mg) significantly reduced proteinuria and slowed eGFR decline over 110 weeks in the PROTECT trial,^[26] and iptacopan-style complement blockade is an emerging option to reduce immune complex-mediated glomerular injury.^[21]

ANCA-associated vasculitis — induction

• Rituximab 375 mg/m² IV weekly for 4 weeks — the RAVE trial showed it was non-inferior to daily cyclophosphamide (2 mg/kg/day) for remission induction in severe ANCA-associated vasculitis and superior in relapsing disease, and as effective as cyclophosphamide in patients with major renal disease or alveolar haemorrhage; glucocorticoids are part of both regimens and are tapered off.^[4]
• Overall management is moving away from reliance on cytotoxic medications towards targeted biological medications for both induction and maintenance of remission.^[15]
• Plasma exchange for severe renal vasculitis — in the MEPEX trial, patients presenting with serum creatinine over 500 micromol/L (5.8 mg/dL) received seven plasma exchanges: 69 percent were alive and dialysis-independent at 3 months versus 49 percent given IV methylprednisolone, with a reduced risk of progression to ESRD at 12 months.^[5]

Anti-GBM disease — plasma exchange plus steroids plus cyclophosphamide

• Plasmapheresis to remove the circulating anti-GBM antibodies, PLUS corticosteroids and cyclophosphamide to prevent continued autoantibody production — an early diagnosis and prompt treatment initiation are crucial to prevent a poor outcome, as anti-GBM disease left untreated leads rapidly to end-stage kidney disease.
• Renal outcomes are poor when patients present already requiring dialysis or with a high proportion of glomerular crescents at biopsy; good renal outcomes may be achieved with prompt treatment initiation.
• Relapses are rare — when renal involvement recurs, suspect concomitant disease such as ANCA-associated vasculitis or membranous nephropathy.^[3][14]

Lupus nephritis class III/IV — induction and maintenance

• Induction: mycophenolate mofetil (target dosage 3 g/day) OR intravenous cyclophosphamide (0.5 to 1.0 g/m² in monthly pulses), PLUS glucocorticoids (prednisone tapered from a maximum starting dosage of 60 mg/day) — the ALMS induction trial found no significant difference in response between MMF and IV cyclophosphamide.^[6]
• Add voclosporin 23.7 mg twice daily on a background of MMF 1 g twice daily and rapidly tapered low-dose steroids — AURORA 1 achieved complete renal response at 52 weeks in 41 percent versus 23 percent with placebo.^[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 — after remission induced with cyclophosphamide and glucocorticoids, rituximab 500 mg IV on days 0 and 14 and at months 6, 12 and 18 kept major relapse at 5 percent by month 28 versus 29 percent with daily azathioprine (MAINRITSAN trial).^[27]
• More broadly, ANCA-vasculitis management is moving away from reliance on cytotoxic medications towards targeted biological medications for both induction and maintenance of remission.^[15]

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). The commonest immune-mediated glomerular disease worldwide, typically presenting as nephritic syndrome in younger adults (mean age at diagnosis 34 to 45; incidence highest in East Asia). About 60 percent of cases are detected incidentally with haematuria or proteinuria on urinalysis; up to 30 percent present with episodic visible synpharyngitic haematuria concurrent with an upper respiratory or gastrointestinal infection; nephrotic syndrome and RPGN each account for under 5 percent. Diagnosis requires biopsy — IgA-dominant mesangial immune deposits after excluding mimics — recommended when proteinuria is 0.5 g/day or more. Treatment is optimised supportive care (dietary sodium under 2 g/day, blood-pressure goal under 120/70 mmHg, renin-angiotensin system inhibitor, SGLT2 inhibitor), with targeted-release budesonide, systemic glucocorticoids, iptacopan or sparsentan for higher-risk disease. Up to 50 percent develop kidney failure within 10 years of diagnosis.^[21]

IgA vasculitis (Henoch-Schonlein purpura). Palpable purpura (round, oval or retiform, predominantly on the lower legs), arthralgia or arthritis, gastrointestinal bleeding or pain, and glomerulonephritis with mesangial IgA deposits. Systemic IgAV affects children far more often than adults (around 150 to 200 paediatric cases for every adult case); in adults the disease more often leads to chronic renal disease. Short-term outcome depends on the severity of the gastrointestinal manifestations while long-term prognosis depends on the severity of the nephritis. Self-limited disease needs only symptomatic treatment; corticosteroids — combined with immunosuppressive drugs in some studies — are used for severe nephritis or gastrointestinal disease, although the evidence is not established. Children should be followed for at least 6 months with regular urine testing for proteinuria and haematuria and blood pressure measurement.^[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: in APSGN, persistent proteinuria and hypertension define the group needing long-term monitoring for progression to chronic kidney disease.^[19] In ANCA-associated vasculitis, renal failure at presentation carries an increased risk of ESRD and death despite immunosuppressive therapy.^[5] In anti-GBM disease, dialysis-dependence at presentation and a high proportion of glomerular crescents on biopsy predict poor renal outcomes.^[14]

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?ShowHide

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?ShowHide

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?ShowHide

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?ShowHide

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.ShowHide

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]

References27ShowHide

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