14.3 Rapidly Progressive Glomerulonephritis

3. Rapidly Progressive Glomerulonephritis (RPGN / Crescentic GN)

RPGN is a clinical syndrome characterized by a rapid loss of renal function (frequently a doubling of serum creatinine within days to weeks) accompanied by an active nephritic sediment and pathologically defined by extensive crescent formation in > 50% of glomeruli on renal biopsy.

Crescent Pathophysiology

Severe transmural necrosis of glomerular capillary walls leads to extravasation of fibrin, inflammatory cytokines, tissue factor, and red blood cells directly into Bowman's space. This triggers rapid proliferation of parietal epithelial cells and recruitment of circulating monocytes and T-lymphocytes, forming multiple layers of cells (cellular crescents) that compress the glomerular tuft. Left untreated, cellular crescents organize into irreversible fibrous scars.

                             RPGN Classification (by Immunofluorescence)
                                                  |
         +----------------------------------------+----------------------------------------+
         |                                        |                                        |
      Type I                                   Type II                                  Type III
  (Anti-GBM Disease)                    (Immune-Complex Mediated)                 (Pauci-Immune AAV)
         |                                        |                                        |
Linear IgG on IF                        Granular IgG/C3 on IF                    Negative / Scant IF
Auto-Ab to alpha-3(IV)NC1               - Lupus Nephritis (Full House)           - GPA (PR3-ANCA / c-ANCA)
Goodpasture Syndrome:                   - Cryoglobulinaemia (HCV, low C4)        - MPA (MPO-ANCA / p-ANCA)
Pulmonary Haemorrhage + GN              - Post-infectious GN / IgA               - EGPA (eosinophilia, asthma)
Emergency Plasmapheresis                Pulsed Steroids + MMF / Cyclo            Pulsed Steroids + Rituximab

Type I: Anti-GBM Disease & Goodpasture's Syndrome

• Immunology: Autoantibodies directed against the non-collagenous domain 1 of the alpha-3 chain of type IV collagen [alpha-3(IV)NC1]. When associated with necrotizing pulmonary alveolar haemorrhage (presenting with dyspnoea, haemoptysis, iron-deficiency anaemia, bilateral diffuse alveolar infiltrates, and increased carbon monoxide gas transfer KCO), it is termed Goodpasture's syndrome.
• Immunofluorescence: Diagnostic, pathognomonic continuous smooth linear IgG (and C3) deposition along the entire glomerular basement membrane.
• Management: Medical emergency! Requires immediate daily plasma exchange (plasmapheresis) for 14 days (or until circulating anti-GBM antibodies become undetectable) to physically remove circulating pathogenic IgG, combined with high-dose intravenous pulsed methylprednisolone followed by oral prednisolone, and oral cyclophosphamide. Dialysis-dependent patients with 100% crescents at presentation have a dismal renal prognosis.

Type II: Immune-Complex Mediated Crescentic GN

• Systemic Lupus Erythematosus (Lupus Nephritis): Categorized by the ISN/RPS classification into classes I through VI. Class IV (Diffuse Proliferative Lupus Nephritis) is the most aggressive, characterized by extensive subendothelial immune deposits producing "wire-loop" lesions on LM. IF reveals pathognomonic "full-house" staining (simultaneous granular positivity for IgG, IgA, IgM, C3, and C1q). Serology demonstrates high-titre anti-dsDNA and profound hypocomplementaemia (both low C3 and low C4). Induction therapy comprises intravenous pulsed methylprednisolone combined with either mycophenolate mofetil (MMF) or intravenous cyclophosphamide (Euro-Lupus regimen), often with belimumab.
• Cryoglobulinaemic Glomerulonephritis: Mixed cryoglobulinaemia (Types II and III) containing monoclonal IgM with rheumatoid factor activity directed against polyclonal IgG. Strongly associated with chronic Hepatitis C virus (HCV) infection. Presents with Meltzer's triad (palpable purpura, arthralgias, weakness) and membranoproliferative GN. Serology reveals markedly depressed C4 (characteristically undetectable, with near-normal C3), positive rheumatoid factor, and detectable HCV RNA. Managed with direct-acting antivirals (DAAs), rituximab, and plasma exchange for severe flares.

Type III: Pauci-Immune ANCA-Associated Vasculitis (AAV)

Characterized on renal biopsy by necrotizing crescentic glomerulonephritis with scant or absent immunoglobulin/complement deposition ("pauci-immune") on immunofluorescence.

• Granulomatosis with Polyangiitis (GPA, formerly Wegener's): Systemic necrotizing granulomatous vasculitis. Manifests with upper respiratory tract involvement (chronic sinusitis, epistaxis, nasal crusting, saddle-nose deformity, subglottic stenosis), pulmonary cavitating nodules or alveolar haemorrhage, and necrotizing crescentic GN. Strongly associated with c-ANCA (cytoplasmic) directed against Proteinase 3 (PR3-ANCA) in > 90% of cases.
• Microscopic Polyangiitis (MPA): Non-granulomatous small-vessel vasculitis causing pulmonary-renal syndrome (alveolar haemorrhage and rapidly progressive GN) without destructive upper respiratory granulomatous disease. Strongly associated with p-ANCA (perinuclear) directed against Myeloperoxidase (MPO-ANCA) in > 75–85% of cases.
• Eosinophilic Granulomatosis with Polyangiitis (EGPA, Churg-Strauss): Severe late-onset asthma, peripheral eosinophilia, transient pulmonary infiltrates, mononeuritis multiplex, and p-ANCA/MPO positivity in 40–50%.
• Management of Severe AAV: High-dose pulsed intravenous methylprednisolone followed by oral prednisolone plus rituximab (or intravenous cyclophosphamide) for remission induction. The oral C5a receptor antagonist avacopan allows significant steroid reduction (ADVOCATE trial). Maintenance is achieved with rituximab or azathioprine.

Investigation Sequence

Time is nephrons. The moment crescentic disease is suspected — a rising creatinine over days with dysmorphic red cells and red cell casts on urine microscopy — send the immunological screen in parallel rather than in sequence:

A low C3 with low C4 points to immune complex disease (lupus, cryoglobulinaemia, endocarditis-associated); a low C3 with normal C4 points to post-streptococcal disease or C3 glomerulopathy; normal complement is typical of pauci-immune and anti-GBM disease. Renal biopsy is the definitive investigation and should be arranged urgently, but treatment must not wait for histology in a rapidly deteriorating patient.

Immunosuppressive Protocols

Induction for organ-threatening disease is high-dose corticosteroid (often intravenous methylprednisolone) plus either rituximab or cyclophosphamide, followed by maintenance with rituximab or azathioprine. Plasma exchange is standard and urgent in anti-GBM disease, where it removes circulating antibody, and remains the treatment of choice in the patient with pulmonary haemorrhage. In ANCA-associated vasculitis the PEXIVAS trial showed no overall benefit of routine plasma exchange on death or end-stage renal disease, so its use is now restricted to selected severe presentations — a genuine change from older teaching that examiners are alert to.

Prognosis and Pitfalls

• Patients with anti-GBM disease who are dialysis-dependent at presentation with 100% crescents rarely recover renal function, though pulmonary haemorrhage still justifies plasma exchange.
• Anti-GBM disease shows a strong association with HLA-DRB1*15:01, and smoking or hydrocarbon exposure precipitates the pulmonary component.
• Roughly a third of patients with anti-GBM disease are also ANCA positive (usually MPO), the so-called double-positive group, which relapses like vasculitis and needs prolonged maintenance.
• All patients on cyclophosphamide or rituximab require Pneumocystis jirovecii prophylaxis with co-trimoxazole and bone protection.