Rapidly Progressive Glomerulonephritis

Meet the patient

A 64-year-old man presents to the emergency department with haemoptysis, increasing breathlessness, and urine that has turned the colour of cola. Over eight days his creatinine has risen from 95 to 380 micromol/L. His urine shows dysmorphic red cells and red-cell casts. His C3 and C4 are normal.[4]

The window to save his kidneys — and his lungs — is measured in days. The two questions that decide everything: what is destroying his glomeruli (anti-GBM, ANCA, or immune-complex)? and can I start treatment before the biopsy report comes back? The answer to the second is always yes.[1][3]

The syndrome — and the single rule that runs the whole page

RPGN is not a disease but a syndrome of rapid glomerular destruction, defined clinically by loss of more than 50 percent of GFR within under 3 months and unified histologically by crescents — half-moon accumulations of fibrin, proliferating parietal epithelial cells and macrophages in Bowman's space — in over 50 percent of glomeruli. Untreated, it progresses to ESKD within days to weeks.[1][4]

The guiding principle is treat first, refine later. Because the window for salvage is narrow and the damage is largely irreversible once crescents become fibrous, begin high-dose intravenous methylprednisolone on clinical suspicion of crescentic GN, arrange urgent renal biopsy and serology, then tailor therapy — adding cyclophosphamide or rituximab, and plasma exchange where the type dictates.[8][11]

The three immunofluorescence types span very different diseases that converge on the same histological endpoint:[4]

• Type I — anti-GBM disease (Goodpasture): linear IgG against the alpha-3 chain of type IV collagen; pulmonary haemorrhage; plasma exchange is essential.
• Type II — immune-complex: granular deposits; lupus nephritis, post-infectious GN with crescents, IgA nephropathy; treat the underlying disease.
• Type III — pauci-immune (ANCA-associated vasculitis): minimal deposits; granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA); the commonest cause of RPGN in adults; treat with steroids plus rituximab or cyclophosphamide.[4][11]

The three IF types — the discriminator that sets treatment

RPGN is classified by the immunofluorescence pattern on renal biopsy, which reflects the immunopathogenic mechanism and determines treatment. The three types differ in antibody, complement, IF pattern, and the role of plasma exchange.[8]

Defining the syndrome — clinical and histological

Who gets what — epidemiology and the three types

The relative frequency of the RPGN types has shifted over the past two decades with better ANCA testing.[4]

• Type III (pauci-immune / ANCA-associated vasculitis) is now the commonest cause of RPGN in adults, about 60 to 70 percent of cases, peak age 60 to 70.[4]
• Type II (immune-complex) accounts for about 20 to 30 percent. In children the dominant causes are crescentic post-infectious GN and IgA vasculitis (Henoch-Schonlein purpura) nephritis; in young women lupus nephritis class IV dominates.
• Type I (anti-GBM) is the rarest at about 10 to 20 percent, incidence about 0.5 to 1 per million per year, with a bimodal age distribution: a first peak in young men (20 to 30) with pulmonary haemorrhage, and a second peak in older women (over 60) with more renal-limited disease.[1][3]

ANCA-associated vasculitis subtypes — demographics and antibodies:[4]

Risk factors:[1]

• Genetic: HLA-DRB1*15 and HLA-DRB4 (anti-GBM); HLA-DP variants and SERPINA1 (alpha-1 antitrypsin deficiency, strongly associated with GPA); HLA-DQ (MPO-ANCA).[1]
• Environmental: silica, hydrocarbon and farm-pesticide exposure increase ANCA vasculitis risk; smoking increases pulmonary haemorrhage risk in anti-GBM.[4]
• Drug-induced ANCA: hydralazine, propylthiouracil, levamisole-adulterated cocaine, minocycline, allopurinol — typically anti-MPO with anti-histone and sometimes anti-elastase co-positivity.[4][5]
• Chronic infection: hepatitis B and C, subacute bacterial endocarditis, deep abscess/shunt infection (immune-complex RPGN).
• Chronic inflammatory disease: SLE, rheumatoid arthritis.
• Malignancy: a modest association with ANCA and with membranoproliferative patterns.
• Recent infection: upper respiratory infection precipitates GPA relapse and IgA nephropathy flares.

Why the glomerulus dies — the crescent and the three mechanisms

Whatever the trigger, severe capillary-wall injury tears the GBM, and the breach is what ignites crescent formation.[1]

The normal filtration barrier has three layers — a fenestrated endothelium, the GBM rich in type IV collagen (alpha-3, -4, -5 chains — the target of anti-GBM disease), and podocyte foot processes joined by the slit diaphragm (nephrin, podocin). In RPGN the injury is to the endothelium, GBM and capillary wall: severe inflammation physically ruptures the capillary wall, and the breach allows fibrin and cells into Bowman's space, igniting crescent formation.[1]

Crescent formation — the convergent endpoint:[8]

1. Fibrin, macrophages and plasma proteins enter Bowman's space.
2. Parietal epithelial cells — and podocytes that detach and adopt a proliferative phenotype — divide into a crescent-shaped cellular and fibrocellular mass that compresses and obliterates the tuft.
3. Tubular atrophy and interstitial fibrosis from secondary ischaemia as the tuft collapses.[1]

Crescents evolve from cellular (early, salvageable) to fibrocellular to fibrous (irreversible). This evolution underpins the cardinal rule of RPGN: treat fast, before the crescent scars.[1][11]

Type I — anti-GBM disease: the linear antibody

The pathogenesis is a textbook example of a tissue-fixed antibody disease.[12]

• Autoantibodies (IgG, rarely IgA or IgM) target the non-collagenous domain of the alpha-3 chain of type IV collagen — the alpha3(IV)NC1 antigen — normally sequestered in the mature GBM and alveolar basement membrane.[1]
• These deposit in a continuous, ribbon-like LINEAR pattern along the GBM (and the alveolar BM).
• Binding activates complement (C3) and triggers Fc-receptor-mediated neutrophil and macrophage injury, which ruptures the capillary wall, producing crescents and alveolar haemorrhage.
• The lung is affected in about 40 to 70 percent (Goodpasture syndrome); the alveolar BM shares the same target. Smoking, respiratory infection and fluid overload increase pulmonary bleeding risk.

Because the pathogenic antibody is fixed in tissue and also circulates, removing the circulating antibody by plasma exchange is central — unlike pauci-immune ANCA disease, where the antibody is against soluble neutrophil granule proteins and plasma exchange has a narrower role.[2][3]

Type III — ANCA vasculitis: the NET/alternative-complement loop

ANCA are IgG autoantibodies against neutrophil granule proteins — myeloperoxidase (MPO, perinuclear p-ANCA) and proteinase 3 (PR3, cytoplasmic c-ANCA). The currently accepted pathogenesis is the NET/alternative-complement-pathway amplification loop:[4]

1. Priming — cytokines (IL-1, TNF, G-CSF) during infection or inflammation cause resting neutrophils to translocate MPO and PR3 to the cell surface.
2. Binding — circulating ANCA bind surface MPO/PR3 and cross-link them, activating the neutrophil via Fc-gamma receptors.
3. Effector release — activated neutrophils degranulate, release reactive oxygen species, proteases and neutrophil extracellular traps (NETs) that damage the endothelium.
4. Amplification — NETs activate the alternative complement pathway, generating C5a, which recruits more primed neutrophils — a self-sustaining loop producing necrotising small-vessel vasculitis and crescentic GN.
5. Pauci-immune appearance — because the antibody is directed against soluble neutrophil granule proteins, not fixed tissue, little immunoglobulin or complement deposits in the glomerulus.[4]

This explains why avacopan (a C5a receptor blocker) works as a steroid-sparing agent in ANCA vasculitis (ADVOCATE): it interrupts the amplification loop at the C5a-neutrophil recruitment step.[4][12]

Type II — immune-complex RPGN: granular deposition

Here the mechanism depends on the parent disease, but the unifying feature is circulating immune complexes depositing in the mesangium, subendothelium and subepithelium, activating the classical complement pathway, recruiting neutrophils and macrophages, and rupturing the capillary wall to form crescents:[4]

• Lupus nephritis class IV — defective clearance of apoptotic debris drives autoantibodies to nuclear antigens; immune complexes produce full-house IF (IgG, IgA, IgM, C3, C1q, C4); complement low (C3 and C4).
• Post-infectious GN with crescents — nephritogenic streptococcal antigens (SpeB, NAPlr) form subepithelial humps; C3 is low.
• IgA nephropathy with crescents — galactose-deficient IgA1 immune complexes deposit in the mesangium; IgA-dominant IF.[4]

The deposits appear granular on IF, in contrast to the linear pattern of anti-GBM and the absence of deposits in pauci-immune disease.[1]

The renal failure and the pulmonary-renal link

Crescents compress the tuft and collapse glomerular capillaries, reducing the filtering surface area — producing oliguria and a rapidly rising creatinine. Tubular atrophy and interstitial fibrosis from secondary ischaemia compound the damage. Diffuse alveolar haemorrhage occurs in anti-GBM and ANCA disease because the alveolar capillary bed shares the same antibody/inflammatory mechanism as the kidney; immune-complex disease generally spares the alveolus.[12]

Meet the bedside round — find the cause beyond the kidney

The classical RPGN presentation: rapidly progressive AKI (rising creatinine and falling urine output over days to weeks — the temporal signature that distinguishes RPGN from acute GN and chronic GN); haematuria — macroscopic (cola, smoky, tea-coloured) or microscopic, with dysmorphic red cells (acanthocytes) and red-cell casts; subnephrotic proteinuria (typically under 3.5 g/day); oedema; hypertension; and constitutional symptoms (malaise, fatigue, fever, weight loss, myalgia, arthralgia — especially prominent in ANCA vasculitis).[7]

A systematic "look beyond the kidney" search often reveals the diagnosis before serology returns:[7]

Atypical presentations:[4]

• Elderly — may present with fatigue, anorexia, weight loss or unexplained AKI rather than visible haematuria; ANCA vasculitis is the dominant cause of crescentic GN here; a low threshold for ANCA/anti-GBM testing is essential.
• Diabetic patients — may have diabetic nephropathy with superimposed crescentic GN; biopsy if the AKI is rapid, RBC casts are present, complement is low, or there is no diabetic retinopathy.
• Children — crescentic post-infectious GN and IgA vasculitis (HSP) nephritis dominate; anti-GBM is rare.
• Pregnancy — lupus nephritis may flare (especially postpartum); pre-eclampsia mimics RPGN but has no RBC casts, no dysmorphic RBCs, no ANCA/anti-GBM.
• Double-positive (ANCA + anti-GBM) — presents as a pulmonary-renal syndrome but should be managed as anti-GBM (add plasma exchange); ANCA positivity predicts a relapsing course.[1]

The pulmonary-renal syndrome — recognise early, treat within the hour

The combination of haemoptysis (or rapidly progressive dyspnoea from diffuse alveolar haemorrhage) with rapidly progressive GN is a medical emergency. The dominant causes are anti-GBM disease (Goodpasture) and ANCA-associated vasculitis (GPA, MPA); lupus and cryoglobulinaemia are rarer. Immediate management is plasma exchange plus high-dose steroids plus cyclophosphamide (or rituximab) — delay costs the kidney and the lung.[1][3][4]

Investigations — the serology panel splits the three types

The urine is the cardinal specimen, the serology splits the types, and the biopsy is the gold standard.[1]

Urine — the cardinal specimen

Red-cell casts are the single most discriminating microscopy finding: their presence confirms a glomerular source. Their absence does not exclude RPGN — in focal ANCA disease the lesion may be patchy.[1]

Baseline bloods and the serological workup

• Urea, creatinine, eGFR — quantify the AKI; trend daily.
• CBC — anaemia of chronic disease or iron deficiency (pulmonary bleeding in anti-GBM); eosinophilia (EGPA); thrombocytopaenia (lupus, TMA).
• ESR and CRP — markedly raised in ANCA vasculitis (a clue).
• Electrolytes including bicarbonate — hyperkalaemia, metabolic acidosis.
• Blood cultures and echocardiography if endocarditis suspected (immune-complex RPGN).[2]

Practical points:[1]

• Antigen-specific immunoassay (anti-PR3, anti-MPO) is now preferred over indirect immunofluorescence (IIF) alone — more specific; IIF patterns (c-ANCA, p-ANCA) remain useful but can be confounded by non-specific ANCA (IBD, infection).
• Complement C3 and C4 — low in immune-complex RPGN (lupus both low; post-infectious C3 low, C4 often normal); normal in anti-GBM and pauci-immune.
• Anti-GBM antibody titre correlates with disease activity and is used to monitor plasma exchange (continue until undetectable).[9]

Renal ultrasound and biopsy — the gold standard

Renal ultrasound: exclude obstruction; assess kidney size (normal to slightly enlarged in acute disease; small, scarred kidneys under 9 cm indicate chronic, irreversible damage and contraindicate aggressive immunosuppression); Doppler to exclude renal vein thrombosis.[7]

Renal biopsy — any suspected RPGN is an indication for urgent biopsy, because the IF pattern discriminates the three types and dictates treatment. Correct coagulopathy before biopsy (vitamin K, fresh frozen plasma); consider transjugular biopsy if anticoagulated.[8]

The percentage of glomeruli with crescents and the proportion of fibrous (chronic) crescents are the most powerful prognostic features — a high proportion of fibrous crescents predicts poor renal recovery.[8]

Diffuse alveolar haemorrhage — confirm at the bedside

• Bronchoalveolar lavage (BAL) — progressively bloodier serial aspirates (pathognomonic).
• Chest X-ray / CT — bilateral alveolar infiltrates (typically perihilar, sparing apices).
• Diffusion capacity (DLCO) — raised from haemoglobin in the alveoli.[1]

Resuscitation — ABC, hypertension, and the dialysis indications

The overriding principle is treat first, refine later: do not wait for biopsy or serology. If the clinical picture (rapidly rising creatinine, haematuria with RBC casts, rapidly progressive AKI) is consistent with crescentic GN, start high-dose IV methylprednisolone immediately while arranging urgent biopsy and serology. The window for salvage is narrow because crescents become fibrous and irreversible within days to weeks.[1][11]

ABC and life-threats:[8]

• Airway/Breathing — high-flow oxygen; secure the airway if massive pulmonary haemorrhage (anti-GBM/ANCA) with anaesthetic and intensive-care support; protective lung ventilation if intubated.
• Circulation — IV access; treat volume overload (pulmonary oedema) with oxygen, sit upright and IV furosemide 40 to 80 mg; renal replacement therapy if refractory.
• Hyperkalaemia — calcium gluconate 10 mL of 10 percent IV (cardioprotection), insulin-dextrose (10 units soluble insulin in 25 g dextrose), nebulised salbutamol 10 to 20 mg, then removal (dialysis or gut potassium binders).[8]

Hypertensive emergency — reduce BP gradually, no more than 25 percent of mean arterial pressure in the first hour, then to 160/100 mmHg over 2 to 6 hours:[1]

• IV labetalol 20 to 80 mg bolus every 10 minutes, or infusion 0.5 to 2 mg/min.
• IV nicardipine infusion 5 to 15 mg/hour (titrate).
• Avoid sublingual nifedipine (unpredictable, precipitous falls).
• In pregnancy, IV hydralazine or labetalol are first-line.[8]

[8]

Dialysis-dependence at presentation is a poor prognostic sign and, in ANCA vasculitis, is one of the indications for adding plasma exchange to induction.[8][9]

Steroid cover — PJP, bone, glucose, gastric. High-dose steroids demand prophylaxis:[8]

• Pneumocystis jirovecii (PJP) prophylaxis — co-trimoxazole 480 mg once daily (or 960 mg three times weekly) for the duration of high-dose steroids plus cyclophosphamide/rituximab. PJP pneumonia is a leading cause of death in immunosuppressed vasculitis patients.
• Gastric protection — proton pump inhibitor (e.g. oral pantoprazole 40 mg daily).
• Bone protection — calcium and vitamin D; bisphosphonate if long-term steroids.
• Glucose monitoring — steroid-induced hyperglycaemia.
• Infection surveillance — hold cyclophosphamide/rituximab for active infection.[6]

Definitive therapy — type-specific, but urgent induction for all

Definitive treatment is type-specific but shares the principle of urgent induction immunosuppression (steroids plus a cytotoxic/B-cell agent), with plasma exchange layered in for anti-GBM and selected ANCA disease, followed by maintenance to prevent relapse.[9]

[1]

Step 1 — Glucocorticoid induction (all types)

• Methylprednisolone 500 to 1000 mg IV daily for 3 days (pulse), then
• Oral prednisolone 1 mg/kg/day (max 60 to 80 mg) tapering over weeks to months to about 5 to 10 mg by 3 to 6 months.[4][5]
• Reduce the pulse dose in the elderly, in diabetics and in active infection; consider avacopan to spare steroids in ANCA disease.
• PJP prophylaxis (co-trimoxazole 480 mg daily) and gastric/bone/glucose cover throughout.

Step 2 — Add an immunosuppressant (cyclophosphamide or rituximab)

For ANCA vasculitis (Type III): add rituximab OR cyclophosphamide — both guideline-endorsed first-line.[4][5]

• Rituximab — 375 mg/m² IV weekly for 4 weeks (RAVE regimen) OR 1 g IV at day 0 and day 14 (RITUXVAS regimen). Preferred in relapsing disease, in women of childbearing potential (less gonadal toxicity), and where cyclophosphamide is contraindicated.
• Cyclophosphamide — 2 mg/kg/day oral (max 200 mg/day) adjusted for age and renal function, OR IV pulse 15 mg/kg every 2 weeks (CYCLOPS). Co-prescribe mesna and hydration to protect the bladder, and counsel on gonadal toxicity and infertility (offer sperm/ova cryopreservation).[7]

RAVE trial (Stone 2010): rituximab was non-inferior to cyclophosphamide for induction and superior in relapsing disease — establishing rituximab as first-line for ANCA vasculitis.[6]

RITUXVAS trial (Jones 2010, 2-year 2015): rituximab plus cyclophosphamide was non-inferior to cyclophosphamide alone in renal-limited ANCA vasculitis, with sustained remission at 2 years.[7]

For anti-GBM disease (Type I): add cyclophosphamide 2 mg/kg/day oral (dose-reduce for age and renal function) to suppress ongoing antibody production, alongside plasma exchange.[1][3]

For immune-complex RPGN (Type II): treat the underlying disease — lupus induction (mycophenolate or cyclophosphamide plus steroids plus voclosporin), supportive PSGN, steroids ± cyclophosphamide for crescentic IgA nephropathy.[7]

Step 3 — Plasma exchange (selected patients)

For anti-GBM disease — plasma exchange is ESSENTIAL.[1][3]

• Daily or alternate-day plasma exchange.
• 4-litre exchanges with 5 percent human albumin; add fresh frozen plasma (150 to 300 mL per session) if there is active bleeding or within 72 hours of renal biopsy.
• Continue until anti-GBM antibody is undetectable — typically 2 to 3 weeks (9 to 12 sessions).
• Rationale: removes the circulating pathogenic antibody (a tissue-fixed antibody disease).[9]

For ANCA vasculitis — plasma exchange is now RESTRICTED.[9]

• MEPEX trial (Jayne 2007): plasma exchange was superior to methylprednisolone pulse for renal recovery in severe renal ANCA vasculitis — the historical basis for plasma exchange in dialysis-dependent disease.[8]
• PEXIVAS trial (Walsh 2020): plasma exchange did NOT reduce the composite of death or ESKD in severe ANCA vasculitis — narrowing its routine use.[9]
• Current indications (KDIGO 2024, ACR/VF 2021): plasma exchange is reserved for (i) anti-GBM or double-positive disease; (ii) ANCA with dialysis-dependence and rapidly falling GFR (creatinine over 5.7 mg/dL or 500 umol/L) where there is a chance of renal recovery; and (iii) life-threatening diffuse alveolar haemorrhage with hypoxaemia.[4][5][12]

Risks of plasma exchange: central venous catheter infection and bleeding, hypocalcaemia (citrate anticoagulant — give calcium replacement), allergic reaction to fresh frozen plasma, hypotension, and mild coagulopathy. Monitor calcium, fibrinogen and platelets.[9]

Step 4 — Maintenance (ANCA vasculitis)

ANCA vasculitis relapses in 30 to 50 percent within 5 years without maintenance; relapse risks irreversible renal damage. MAINRITSAN (Guillevin 2014): rituximab was superior to azathioprine for maintenance, reducing relapse.[10]

• Rituximab — 1 g IV at day 0 and day 14, then 500 mg to 1 g every 4 to 6 months for 18 to 36 months (longer if PR3-positive and high relapse risk). Guideline-preferred.[4][10]
• Azathioprine — 2 mg/kg/day oral (alternative if rituximab unavailable).
• Methotrexate or mycophenolate — alternatives if azathioprine not tolerated.
• Co-trimoxazole — for localised upper-respiratory GPA and to reduce Staphylococcus aureus carriage.

Anti-GBM disease generally does not require long-term maintenance (it is usually monophasic), but double-positive patients should receive ANCA-style maintenance because of the relapsing component.[1]

Step 5 — Avacopan (C5a receptor blocker), steroid-sparing

ADVOCATE trial: the C5a receptor antagonist avacopan (10 mg twice daily) was glucocorticoid-sparing, non-inferior for remission at 26 weeks and superior for sustained remission at 52 weeks in ANCA vasculitis. It interrupts the alternative-complement amplification loop. KDIGO 2024 endorses avacopan as a steroid-sparing option.[4][12]

Step 6 — Supportive care (all types)

• RAAS blockade — ACE inhibitor (e.g. ramipril 2.5 to 10 mg daily) or ARB (e.g. losartan 50 to 100 mg daily) once the creatinine has stabilised; monitor potassium.
• SGLT2 inhibitor for proteinuric CKD; BP target under 130/80 mmHg.
• Salt restriction under 2 g/day; fluid restriction to urine output plus 500 mL insensible losses if oliguric.
• Smoking cessation (reduces pulmonary haemorrhage risk in anti-GBM).
• Vaccination (influenza, pneumococcal, hepatitis B) before immunosuppression; avoid live vaccines during treatment. Statins for cardiovascular risk.[1]

Subtypes and scenarios

Anti-GBM disease (Goodpasture syndrome) — Type I. IgG against alpha3(IV)NC1; linear IF. Acute haemoptysis, rapidly progressive renal failure, iron-deficiency anaemia from pulmonary bleeding; bimodal age. Triple therapy: (i) plasma exchange — daily or alternate-day, 4 L exchanges with 5 percent albumin and FFP if bleeding, until anti-GBM antibody undetectable (about 2 to 3 weeks, 9 to 12 sessions); (ii) methylprednisolone pulse 500 to 1000 mg IV daily for 3 days then oral prednisolone 1 mg/kg/day tapering; (iii) cyclophosphamide 2 mg/kg/day oral (dose-reduce). High ESKD risk if oligoanuric at presentation (over 50 percent); significant early mortality from pulmonary haemorrhage. Transplant: wait until anti-GBM antibody undetectable for at least 6 months.[1][3]

Granulomatosis with polyangiitis (GPA) — Type III. Anti-PR3 (c-ANCA) in 75 to 90 percent. ENT (nasal crusting, epistaxis, saddle-nose deformity, sinusitis, subglottic stenosis), pulmonary (nodules, cavities, infiltrates, haemorrhage), ocular (scleritis, orbital pseudotumour), renal (crescentic GN), mononeuritis multiplex. Induction: methylprednisolone pulse then oral prednisolone PLUS rituximab (preferred) or cyclophosphamide. Maintenance: rituximab 1 g every 4 to 6 months for 18 to 36 months; PR3 positivity predicts relapse. Localised upper respiratory disease may respond to co-trimoxazole. Relapse rate 30 to 50 percent over 5 years without maintenance.[4]

Microscopic polyangiitis (MPA) — Type III. Anti-MPO (p-ANCA) in 50 to 70 percent. Renal-predominant, pulmonary haemorrhage (capillaritis) but NO granulomatous ENT disease, palpable purpura, mononeuritis multiplex, GI involvement. Induction and maintenance as for GPA. Less likely to relapse.[10]

Eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss) — Type III. Triad of adult-onset asthma, eosinophilia (over 1.5 x10^9/L or 10 percent), sinusitis; plus mononeuritis multiplex and (often) cardiac involvement (eosinophilic myocarditis — a leading cause of death). Anti-MPO in about 40 percent. Mepolizumab (anti-IL-5) for the eosinophilic/ANCA-negative phenotype; steroids plus rituximab or cyclophosphamide for ANCA-positive severe disease.[6]

Crescentic lupus nephritis (class IV) — Type II. Low C3 AND C4, ANA and anti-dsDNA positive; full-house IF; wire-loop deposits; crescents. Induction (3 to 6 months): MMF 2 to 3 g/day OR low-dose IV cyclophosphamide (Euro-Lupus 500 mg every 2 weeks for 6 doses) PLUS glucocorticoids, with voclosporin 23.7 mg twice daily or tacrolimus as triple therapy, and hydroxychloroquine 200 to 400 mg daily. Maintenance: MMF 1 to 2 g/day or azathioprine plus low-dose steroids.[8]

Crescentic IgA nephropathy — Type II. Synpharyngitic gross haematuria; mesangial IgA-dominant deposits. Supportive RAAS blockade; steroids (and cyclophosphamide for fulminant crescentic disease with rapidly falling GFR).[6]

The double-positive (ANCA + anti-GBM) patient. Manage as anti-GBM disease — add plasma exchange, methylprednisolone and cyclophosphamide. ANCA positivity predicts a relapsing course once anti-GBM antibody is suppressed — give maintenance rituximab or azathioprine after the acute episode.[1][2]

Drug-induced ANCA vasculitis. Causative drugs: hydralazine, propylthiouracil, levamisole-adulterated cocaine, minocycline, allopurinol. Typically anti-MPO with anti-histone and sometimes anti-elastase co-positivity. Stop the offending drug; immunosuppression as for idiopathic ANCA if severe.[9]

Complications, pitfalls and the cyclophosphamide risks

Acute complications: irreversible ESKD requiring dialysis (especially anti-GBM with oligoanuria and dialysis-dependent ANCA); diffuse alveolar haemorrhage and respiratory failure (anti-GBM, ANCA — a leading cause of early death); hypertensive encephalopathy and intracerebral haemorrhage; pulmonary oedema; hyperkalaemia and metabolic acidosis; opportunistic infection (PJP — prevent with co-trimoxazole, CMV, fungal); thromboembolism; cyclophosphamide toxicity (haemorrhagic cystitis, bladder cancer, infertility, cytopaenias).[7]

Chronic complications: progression to CKD/ESKD; cardiovascular disease accelerated by CKD and chronic inflammation; long-term steroid effects (osteoporosis, diabetes, cataracts, hypertension, infection, avascular necrosis); cyclophosphamide effects (gonadal toxicity, bladder cancer, myelodysplasia, secondary malignancy); relapse (especially PR3-ANCA/GPA, 30 to 50 percent over 5 years without maintenance).[7]

Classic pitfalls:[8]

• Delaying treatment while awaiting biopsy or serology — the cardinal error; start high-dose steroids on suspicion.
• Assuming all rapidly progressive AKI is ATN and missing RBC casts — the active sediment redirects to a glomerular cause.
• Treating ANCA with routine plasma exchange after PEXIVAS — restrict to dialysis-dependent crescentic ANCA with rapidly falling GFR and life-threatening alveolar haemorrhage.
• Failing to PJP-prophylax — PJP is a leading cause of death.
• Missing a double-positive (ANCA + anti-GBM) patient — these need plasma exchange (manage as anti-GBM).
• Biopsying small, scarred kidneys aggressively — small kidneys (under 9 cm) indicate chronic irreversible damage and contraindicate aggressive immunosuppression.
• Underestimating the mortality of diffuse alveolar haemorrhage — secure the airway, involve ITU early.
• Forgetting cryopreservation before cyclophosphamide in younger patients.[8]

Cyclophosphamide-specific risks and mitigations:[7]

Plasma exchange risks: central venous catheter infection and bleeding; hypocalcaemia from citrate (paraesthesia, tetany — give calcium replacement); allergic reaction to FFP; hypotension and mild coagulopathy — monitor fibrinogen and platelets.[8]

Prognosis and disposition

The single most important modifiable factor in prognosis is the speed of treatment — once crescents are fibrous the damage is irreversible. Other predictors: percentage of glomeruli with crescents and the proportion of fibrous crescents on biopsy; GFR and dialysis-dependence at presentation; antibody type (anti-GBM and dialysis-dependent ANCA do worst); age and comorbidity.[11][5]

Patient survival: ANCA vasculitis — 1-year mortality about 10 to 20 percent; infection and active vasculitis are the leading causes of death, followed by cardiovascular disease and malignancy.[4] Anti-GBM — significant early mortality from pulmonary haemorrhage; survives into long-term remission if the acute episode is weathered.

Relapse prediction in ANCA disease: PR3-ANCA positivity, GPA phenotype, persistent ANCA positivity after induction, and upper respiratory involvement predict relapse; relapse rate is 30 to 50 percent over 5 years without maintenance, markedly reduced by maintenance rituximab (MAINRITSAN).[10]

Disposition: emergency admission for any suspected RPGN or pulmonary-renal syndrome (haemoptysis, rapidly progressive GN); severe hypertension or hypertensive encephalopathy; pulmonary oedema; hyperkalaemia. Urgent nephrology referral for all suspected crescentic GN — for urgent biopsy and induction immunosuppression.[8]

Transplant: suitable once disease is quiescent. Anti-GBM — wait until anti-GBM antibody undetectable for at least 6 months. ANCA — quiescent for 6 to 12 months on maintenance. IgA recurs in 30 to 50 percent of grafts (graft loss lower); MPGN/C3G high recurrence; lupus recurrence rare (under 5 percent).[1]

The mantra

Treat first, refine later — crescents scar in days, so steroids go in before the biopsy report. Plasma exchange is essential for anti-GBM and restricted for ANCA.[1][11]

Ward-round test

A 64-year-old with haemoptysis, creatinine rising from 95 to 380 over a week, red-cell casts, normal complement — what do you do in the next hour?

This is a pulmonary-renal syndrome — anti-GBM or ANCA until proven otherwise. Send ANCA (PR3, MPO), anti-GBM antibody, complement, and arrange urgent biopsy — but start IV methylprednisolone 500 to 1000 mg now, before results. If anti-GBM is positive, add plasma exchange plus cyclophosphamide within the day.[1][3]

ANCA-positive crescentic GN — induction regimen?

Methylprednisolone 500 to 1000 mg IV daily for 3 days, then oral prednisolone 1 mg/kg/day tapering, PLUS rituximab 375 mg/m² weekly for 4 weeks (or cyclophosphamide 2 mg/kg/day). RAVE established rituximab as non-inferior and superior in relapsing disease. Add PJP prophylaxis.[4][6]

Should you plasma-exchange every ANCA vasculitis?

No. PEXIVAS (2020) showed no survival or ESKD benefit. Reserve plasma exchange for anti-GBM (essential), double-positive disease, dialysis-dependent ANCA with rapidly falling GFR (creatinine over 5.7 mg/dL), and life-threatening diffuse alveolar haemorrhage.[8][9]

A patient is both ANCA- and anti-GBM-positive — how do you manage?

Manage as anti-GBM disease — add plasma exchange, methylprednisolone and cyclophosphamide. The anti-GBM antibody drives early pulmonary and renal mortality. The ANCA positivity predicts a relapsing course once anti-GBM is suppressed, so follow with maintenance rituximab or azathioprine.[1][2]

Name the three RPGN immunofluorescence types and the antibody of each.

Type I anti-GBM — linear IgG, anti-alpha3(IV)NC1 (Goodpasture). Type II immune-complex — granular (lupus full-house, IgA-dominant, PSGN humps). Type III pauci-immune — minimal deposits, ANCA (anti-PR3 = GPA, anti-MPO = MPA).[1][4]

References

1. [1]McAdoo SP, Pusey CD. Anti-Glomerular Basement Membrane Disease. Clinical Journal of the American Society of Nephrology, 2017.PMID 28515156
2. [2]Ponticelli C, Cresseri D, Tarantino A, Moroni G. Anti-glomerular basement membrane vasculitis. Autoimmunity Reviews, 2023.PMID 36252931
3. [3]Reggiani F, Esposito P, Togliatto L, et al. Goodpasture syndrome and anti-glomerular basement membrane disease. Clinical and Experimental Rheumatology, 2023.PMID 36995324
4. [4]Kronbichler A, Subramanian AK, Smith RM, Jayne DRW. Diagnosis and management of ANCA-associated vasculitis. The Lancet, 2024.PMID 38368016
5. [5]Chung SA, Langford CA, Maz M, et al. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Arthritis and Rheumatology, 2021.PMID 34235894
6. [6]Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis (RAVE trial). The New England Journal of Medicine, 2010.PMID 20647199
7. [7]Jones RB, Furuta S, Terveaert JWC, et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis: 2-year results of a randomised trial (RITUXVAS). Annals of the Rheumatic Diseases, 2015.PMID 25739829
8. [8]Jayne DR, Gaskin G, Rasmussen N, et al. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis (MEPEX). Journal of the American Society of Nephrology, 2007.PMID 17582159
9. [9]Walsh M, Merkel PA, Peh CA, et al. Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis (PEXIVAS). The New England Journal of Medicine, 2020.PMID 32053298
10. [10]Guillevin L, Pagnoux C, Karras A, et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis (MAINRITSAN). The New England Journal of Medicine, 2014.PMID 25372085
11. [11]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 International, 2019.PMID 30665569
12. [12]Kidney Disease: Improving Global Outcomes (KDIGO) ANCA Vasculitis Work Group. KDIGO 2024 Clinical Practice Guideline for the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis (corrigendum). Kidney International, 2025.PMID 39848754