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]

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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]

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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: a nephritic syndrome progressing rapidly toward end-stage renal disease — the indicators are proteinuria, dysmorphic erythrocytes, red-cell casts, impaired kidney function and newly developed hypertension. The tempo is what distinguishes crescentic GN: a nephritic syndrome that runs to ESKD over weeks rather than following the course of acute or chronic GN. RPGN is a nephrological emergency requiring immediate inpatient evaluation and treatment.^[13][14]

A systematic "look beyond the kidney" search often reveals the diagnosis before serology returns — ANCA vasculitis commonly affects the kidneys, lungs, upper respiratory tract, skin, eyes and peripheral nerves:^[4]

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:^[18][20][21]

• Airway/Breathing — oxygen, and secure the airway early if diffuse alveolar haemorrhage causes hypoxaemic respiratory failure; pulmonary haemorrhage complicates roughly half of anti-GBM cases.^[18]
• Circulation — treat volume overload and pulmonary oedema; dialysis may be required if the renal injury does not resolve.^[21]
• Hyperkalaemia — intravenous calcium salts (indicated with ECG changes or potassium at or above 6.5 mmol/L), insulin-glucose therapy, nebulised (inhaled beta-agonist) salbutamol — synergistic with insulin — and haemodialysis as the definitive option in refractory cases.^[20]

Hypertensive emergency — lower blood pressure in a controlled, titrated way: the intensity of reduction depends on the type and presence of acute organ injury, balancing the benefit of a lower pressure against the risk of organ hypoperfusion when autoregulation is impaired.^[22]

• Intravenous options include labetalol, nicardipine and hydralazine (also nitroprusside, nitroglycerin, esmolol and others); choose by pharmacology and patient-specific factors such as comorbidity and end-organ damage.^[23]
• In severe hypertension in pregnancy, options include oral nifedipine (may be preferred as the first-line agent), IV or oral labetalol, IV hydralazine and IV nicardipine — a systematic review found no difference between drugs in maternal hypotension or maternal and fetal outcomes.^[24]

^{[20] [21]}

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 — infection above all. Severe infection on strong immunosuppression is a leading cause of morbidity and mortality in ANCA vasculitis:^[19]

• Pneumocystis jirovecii (PJP) prophylaxis — guidelines conditionally recommend trimethoprim-sulfamethoxazole (co-trimoxazole) for ANCA vasculitis patients on immunosuppressive treatment; it is the most commonly used and best-studied prophylactic agent (dose per local protocol).^[19]
• Infection surveillance — active intercurrent infection is a leading reason to defer or hold cyclophosphamide or rituximab; the evidence base for prophylaxis strategies overall remains limited.^[19]

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]

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Step 1 — Glucocorticoid induction (all types)

• High-dose glucocorticoid pulse then taper — the MEPEX comparator arm used 3000 mg of intravenous methylprednisolone as the pulse; follow with oral glucocorticoids tapered per regimen.^[8]
• A reduced-dose oral glucocorticoid regimen was noninferior to a standard-dose regimen for the composite of death or ESKD in PEXIVAS — KDIGO 2024 notes the evidence for lower-dose induction (or even complete glucocorticoid replacement) has become stronger.^[9][12]
• Avacopan (C5a receptor inhibitor, approved late 2021) is a glucocorticoid-sparing option — see Step 5.^[12]
• PJP prophylaxis with co-trimoxazole alongside induction — see the steroid-cover section above.^[19]

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 (the RAVE and RITUXVAS regimen; RITUXVAS added two intravenous cyclophosphamide pulses). Preferred where a non-cyclophosphamide strategy is wanted and in relapsing disease.^[6][7]
• Cyclophosphamide — 2 mg/kg/day oral OR 15 mg/kg IV pulses every 2 to 3 weeks (CYCLOPS): equal remission by 9 months (88.1% vs 87.7%) with a lower cumulative dose (8.2 g vs 15.9 g) and less leukopenia.^[17]

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 — with plasma exchange and glucocorticoids — to prevent ongoing autoantibody production; this combination is what transformed a historically fatal disease into one with a real chance of renal recovery.^[18]

For immune-complex RPGN (Type II): treat the underlying disease — lupus induction (voclosporin plus mycophenolate and low-dose steroids, or low-dose IV cyclophosphamide followed by azathioprine), supportive PSGN, steroids ± cyclophosphamide for crescentic IgA nephropathy.^[15][16]

Step 3 — Plasma exchange (selected patients)

For anti-GBM disease — plasma exchange is part of the standard of care.^[1][18]

• Plasma exchange combined with cyclophosphamide and glucocorticoids has significantly improved outcomes, particularly in patients not dialysis-dependent at presentation.^[18]
• Rationale: it rapidly removes the circulating pathogenic autoantibody, while cyclophosphamide and glucocorticoids stop ongoing production and tissue inflammation.^[1][3]
• For scale: in severe ANCA trials a course meant seven plasma exchanges within 14 days (PEXIVAS); anti-GBM schedules are at least as intensive — follow local protocol for exchange volume and replacement fluid.^[9]

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

• MEPEX trial (Jayne 2007): in biopsy-proven ANCA vasculitis presenting with creatinine over 500 micromol/L (5.8 mg/dL), seven plasma exchanges beat 3000 mg IV methylprednisolone for dialysis-independence at 3 months (69% vs 49%, P = 0.02) and cut progression to ESRD at 12 months (19% vs 43%).^[8]
• PEXIVAS trial (Walsh 2020): in severe ANCA vasculitis, seven plasma exchanges within 14 days did NOT reduce the composite of death or ESKD (28.4% vs 31.0%; HR 0.86, P = 0.27).^[9]
• Bottom line: routine plasma exchange for ANCA is not justified; it remains part of the standard of care for anti-GBM and double-positive disease, and at most for selected dialysis-dependent ANCA renal vasculitis where the kidney may still recover.^[8][9][18]

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)

Relapse rates remain high even on conventional maintenance with azathioprine or methotrexate, and relapse risks irreversible organ damage. MAINRITSAN (Guillevin 2014): scheduled rituximab 500 mg IV on days 0 and 14 and at months 6, 12 and 18 beat daily azathioprine — major relapse at month 28 in 5% vs 29% (HR 6.61, P = 0.002).^[10]

• Rituximab — 500 mg IV on days 0 and 14, then at months 6, 12 and 18 (the MAINRITSAN regimen). Guideline-preferred for remission maintenance in GPA and MPA.^[5][10]
• Azathioprine — daily oral (the MAINRITSAN comparator, given to month 22); methotrexate is an alternative, though relapse rates remain high on conventional maintenance.^[10]
• Co-trimoxazole — see PJP prophylaxis above; robust evidence for non-PJP prophylaxis strategies is lacking.^[19]

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 oral C5a receptor antagonist avacopan (30 mg twice daily), on a background of cyclophosphamide or rituximab, was noninferior (but not superior) to a prednisone taper for remission at week 26 and superior for sustained remission at week 52 in ANCA vasculitis (65.7% vs 54.9%, P = 0.007 for superiority). It interrupts the alternative-complement amplification loop at the C5a-neutrophil step. KDIGO 2024 notes avacopan's late-2021 regulatory approval and increasingly strong evidence for lower-dose glucocorticoid induction.^[27][12]

Step 6 — Supportive care (all types)

• Blood pressure control — slows kidney-disease progression and reduces cardiovascular events.^[25]
• RAAS blockade — prevents or slows CKD progression and reduces cardiovascular events; monitor potassium and kidney function as clinically indicated.^[25]
• SGLT2 inhibitors — lower blood pressure and further reduce the risk of CKD progression in randomised trials in diabetic kidney disease.^[25]
• Long-term view — with acute disease-related mortality falling, the long-term focus shifts to CKD and cardiovascular disease; smoking cessation and cardiovascular risk management are part of vasculitis care.^[4]

Subtypes and scenarios

Anti-GBM disease (Goodpasture syndrome) — Type I. Autoantibodies against the alpha-3 chain of type IV collagen; linear IgG along the GBM on biopsy. Rapidly progressive crescentic GN with pulmonary haemorrhage in roughly 40 to 60 percent of patients (about half in recent series). Standard of care is the combination of plasma exchange plus cyclophosphamide and glucocorticoids — introduced together, they significantly improved outcomes, especially in patients not dialysis-dependent at presentation; dialysis-dependent patients have a lower likelihood of renal recovery, so biopsy findings, clinical severity and contraindications must shape the decision to treat. Relapses are rare and long-term maintenance is not routinely required, but double-positive (anti-GBM plus ANCA) patients have a higher relapse risk and need maintenance immunosuppression. Relapse and recurrent disease after kidney transplantation are both uncommon.^[1][18]

Granulomatosis with polyangiitis (GPA) — Type III. Necrotising vasculitis that commonly affects the kidneys, lungs, upper respiratory tract, skin, eyes and peripheral nerves; granulomatous inflammation with multinucleated giant cells is the pathological hallmark (absent in MPA). Anti-PR3 (c-ANCA) is positive in roughly 80 to 90 percent on antigen-specific assays. Induction: rituximab (noninferior to cyclophosphamide and superior in relapsing disease — RAVE) or cyclophosphamide, plus glucocorticoids. Maintenance: rituximab 500 mg on days 0 and 14 and at months 6, 12 and 18 (MAINRITSAN) — major relapse 5% vs 29% with azathioprine at month 28.^{[4][26][6][10]}

Microscopic polyangiitis (MPA) — Type III. Necrotising vasculitis affecting the same organs as GPA — kidneys, lungs, upper respiratory tract, skin, eyes, peripheral nerves — but without granulomatous inflammation and multinucleated giant cells (the histological separator from GPA); anti-MPO (p-ANCA) is the dominant antibody specificity. Induction and maintenance as for GPA.^[4][26]

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 III/IV) — Type II. Active renal lupus is flagged by proteinuria, hypocomplementaemia, raised anti-dsDNA antibodies and an active urinary sediment, confirmed by biopsy showing immune-complex GN. Induction (AURORA 1): voclosporin 23.7 mg twice daily plus mycophenolate mofetil 1 g twice daily and low-dose steroids — complete renal response at 52 weeks in 41% vs 23% with placebo. Alternative (Euro-Lupus): six fortnightly IV cyclophosphamide pulses of 500 mg (cumulative 3 g) followed by azathioprine — renal remission 71%, comparable to high-dose cyclophosphamide with less severe infection.^[28][15][16]

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?ShowHide

This is a pulmonary-renal syndrome — anti-GBM or ANCA until proven otherwise. RPGN is a nephrological emergency requiring immediate inpatient evaluation and treatment: send ANCA (anti-PR3, anti-MPO), anti-GBM antibody, complement and arrange urgent biopsy — but start high-dose IV methylprednisolone now, before results come back. If anti-GBM is positive, add plasma exchange plus cyclophosphamide and continued glucocorticoids — the combination that significantly improved outcomes in anti-GBM disease.^[14][18]

ANCA-positive crescentic GN — induction regimen?ShowHide

High-dose glucocorticoid induction (the MEPEX comparator used 3000 mg intravenous methylprednisolone) followed by tapering oral glucocorticoids, PLUS rituximab 375 mg/m² IV weekly for 4 weeks (RAVE: noninferior to cyclophosphamide and superior in relapsing disease) or cyclophosphamide 2 mg/kg/day oral / 15 mg/kg IV pulses every 2 to 3 weeks (CYCLOPS). Add PJP prophylaxis with co-trimoxazole.^{[8][6][17][19]}

Should you plasma-exchange every ANCA vasculitis?ShowHide

No. PEXIVAS (2020): seven plasma exchanges within 14 days did not reduce death or ESKD (28.4% vs 31.0%; HR 0.86, P = 0.27). Plasma exchange stays part of the standard of care for anti-GBM disease (with cyclophosphamide and glucocorticoids — including double-positive patients), and its historical ANCA evidence comes from MEPEX, restricted to biopsy-proven vasculitis presenting with creatinine over 500 micromol/L (5.8 mg/dL) — where it beat IV methylprednisolone for dialysis-independence at 3 months (69% vs 49%).^[9][18][8]

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

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.ShowHide

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]

References28ShowHide

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