Crescentic Glomerulonephritis

Crescentic glomerulonephritis is glomerular inflammation with extracapillary proliferation (crescents) involving at least 50% of glomeruli. It is the histological correlate of rapidly progressive glomerulonephritis, in which kidney function falls by 50% or more within days to 3 months.

It is a nephrological emergency. Without treatment most patients progress to kidney failure within weeks. Causes are classified by immunofluorescence:

• Type 1 (linear IgG along the basement membrane) is anti-glomerular basement membrane disease, about 3 to 5% of cases.
• Type 2 (granular immune complex) includes lupus nephritis, IgA nephropathy and vasculitis, post-infectious glomerulonephritis, cryoglobulinaemia, membranoproliferative glomerulonephritis and C3 glomerulopathy.
• Type 3 (pauci-immune, few or no deposits) is ANCA-associated, about 50 to 60% of cases.
• Double positive disease (ANCA and anti-GBM antibodies) occurs in about 5%.

Pathophysiology. Breaks in the glomerular basement membrane let fibrin, plasma proteins and inflammatory cells enter Bowman space, where proliferating parietal epithelial cells and macrophages form crescents. Cellular crescents are reversible with early treatment; fibrous crescents are not.

• Rapid rise in creatinine, oliguria or anuria, haematuria (often macroscopic), proteinuria (usually under 3 g daily), hypertension (variable), oedema, fatigue, anorexia.
• Systemic features pointing to cause: haemoptysis or dyspnoea (pulmonary haemorrhage), sinusitis, epistaxis, saddle nose, purpura, arthralgia, fever, mononeuritis multiplex, malar rash, recent infection.
• Anaemia and raised inflammatory markers.

Red flags

• Creatinine above 500 micromol/L at presentation, oliguria, or dialysis requirement (lower recovery rates).
• Pulmonary haemorrhage with hypoxia.
• Over 50% fibrous crescents (low likelihood of recovery).
• Haemoptysis and falling haemoglobin with kidney injury.

• Urinalysis with microscopy (dysmorphic red cells, red cell casts), protein:creatinine ratio, creatinine and trend, urea, electrolytes, bicarbonate, full blood count and film, CRP, coagulation, liver tests.
• Serology (urgent, results within 24 hours): ANCA (PR3 and MPO antigen specific assays), anti-GBM antibody, antinuclear antibodies, anti-dsDNA, C3 and C4, cryoglobulins and rheumatoid factor, hepatitis B and C, HIV, anti-streptolysin O, blood cultures, serum protein electrophoresis and free light chains.
• Chest radiograph or CT chest for infiltrates and haemorrhage; renal ultrasound (normal or enlarged kidneys).
• Kidney biopsy as soon as possible (do not delay treatment in severe disease if strongly suspected): crescents (cellular, fibrocellular, fibrous), fibrinoid necrosis, immunofluorescence for type, electron microscopy for deposits, and chronicity score.

Differential diagnosis

• Acute tubular injury, acute interstitial nephritis, thrombotic microangiopathy, cholesterol embolism, scleroderma renal crisis, malignant hypertension, obstruction, severe acute post-infectious glomerulonephritis.

Emergency first line (start within 24 hours when diagnosis is probable)

• Methylprednisolone 500 mg to 1 g intravenously daily for 3 days, then prednisolone 1 mg/kg daily (maximum 60 mg), reduced to 20 mg by week 6 and 5 to 10 mg by 6 months.
• Cause directed immunosuppression:
  • Pauci-immune (ANCA): rituximab 375 mg/m² intravenously weekly for 4 doses (or 1 g on days 1 and 15), or cyclophosphamide intravenously 15 mg/kg (maximum 1.2 g) every 2 weeks for 3 doses, then every 3 weeks for 3 to 6 months.
  • Cyclophosphamide age reductions: 12.5 mg/kg at age 60 to 70 and 10 mg/kg over age 70. Reduce a further 20% if creatinine is above 300 micromol/L.
  • Oral cyclophosphamide alternative: 2 mg/kg daily (maximum 200 mg), reduced to 1.5 mg/kg above age 60 and 1 mg/kg above age 75.
  • Anti-GBM disease: daily plasma exchange with 50 mL/kg of 4% albumin (maximum 4 L) for 14 days or until anti-GBM antibodies are undetectable. Use fresh frozen plasma 150 to 300 mL at the end if pulmonary haemorrhage or recent biopsy.
  • Add cyclophosphamide 2 mg/kg orally daily (reduced above age 60) for 3 months and prednisolone 1 mg/kg daily reduced to 20 mg by week 6.
  • Anti-GBM disease needs dialysis independence at presentation for a good outcome. Dialysis dependent patients with 100% crescents and no lung haemorrhage rarely recover.
  • Immune complex crescentic disease (lupus, IgA, cryoglobulinaemia, post-infectious): treat the cause. Lupus nephritis: mycophenolate mofetil 1 g twice daily or cyclophosphamide with steroids. IgA: steroids with cyclophosphamide. Infection: control the organism first.
• Plasma exchange (7 exchanges of 60 mL/kg over 14 days) is reserved for diffuse pulmonary haemorrhage, anti-GBM disease, double positive disease, and selected severe ANCA disease (creatinine above 300 micromol/L) after weighing infection risk.

Prophylaxis during immunosuppression

• Co-trimoxazole 480 mg orally daily (960 mg three times weekly if eGFR is above 30; atovaquone 1500 mg daily for sulphonamide allergy) for pneumocystis.
• Proton pump inhibitor; bone protection (calcium and vitamin D); hepatitis B screening before rituximab.
• Vaccinations (influenza, pneumococcus) before or early in therapy.

Supportive and organ support

• Blood pressure control; fluid and electrolyte management; dialysis for refractory hyperkalaemia above 6.5 mmol/L, pH under 7.15, overload or uraemic complications. Ventilatory support for pulmonary haemorrhage.

Monitoring. Creatinine, urinalysis and ANCA or anti-GBM titres weekly during induction; infection surveillance; repeat biopsy if no recovery after 4 to 6 weeks. Maintenance after induction depends on disease type (rituximab 500 mg every 6 months for 18 months or azathioprine 2 mg/kg daily).

Referral and escalation. Same day nephrology; intensive care for pulmonary haemorrhage; haematology for plasma exchange; rheumatology for systemic disease. Withdraw immunosuppression in dialysis dependent patients without extrarenal disease after 3 months.

Special groups

• Elderly: lower cyclophosphamide doses, higher infection risk; consider rituximab based induction.
• Children: methylprednisolone 10 to 30 mg/kg (maximum 1 g) for 3 days, cyclophosphamide 500 mg/m² every 2 to 3 weeks, or rituximab 375 mg/m² weekly for 4 doses.
• Pregnancy: avoid cyclophosphamide and mycophenolate; use azathioprine and steroids with plasma exchange for severe disease.