Rapidly Progressive Kidney Failure

Rapidly progressive kidney failure is loss of kidney function over days to weeks, with serum creatinine doubling within approximately 3 months and often within 1 to 4 weeks, that continues without a reversible cause being identified. It is a clinical syndrome rather than a single disease, and it defines a group in which delayed diagnosis commonly causes permanent loss of kidney function.

The causes divide into groups:

• Rapidly progressive glomerulonephritis: pauci-immune (ANCA-associated), anti-GBM disease and immune complex disease (lupus nephritis, IgA vasculitis, cryoglobulinaemia, post-infectious)
• Acute interstitial nephritis from drugs, infection or autoimmunity
• Thrombotic microangiopathy: haemolytic uraemic syndrome, thrombotic thrombocytopenic purpura, scleroderma renal crisis, malignant hypertension
• Paraprotein disease: myeloma cast nephropathy, light chain deposition
• Vascular: bilateral renal artery occlusion, atheroembolic disease, renal vein thrombosis
• Obstruction and persistent tubular necrosis that has not been recognised

The central principle is to separate treatable inflammatory and vascular lesions from tubular injury quickly, because glomerular crescents, interstitial infiltrates and thrombotic lesions respond to immunosuppression or plasma exchange only in the first days to weeks.

• Oliguria or nonoliguria with rising creatinine, hypertension and oedema
• Glomerular pattern: macroscopic or microscopic haematuria, red cell casts, proteinuria
• Pulmonary renal pattern: haemoptysis, hypoxia, infiltrates (ANCA vasculitis, anti-GBM disease, lupus)
• Systemic vasculitis: purpura, mononeuritis multiplex, sinusitis, epistaxis, scleritis, arthralgia
• Thrombotic microangiopathy: anaemia, thrombocytopenia, neurological signs, fever
• Interstitial nephritis: rash, fever, eosinophilia, sterile pyuria, recent new drug
• Myeloma: bone pain, hypercalcaemia, anaemia, low anion gap
• Atheroembolic: livedo reticularis, blue toes, recent arterial catheterisation

Red flags: haemoptysis, alveolar haemorrhage on imaging, oliguria below 400 mL daily, potassium above 6.0 mmol/L, schistocytes, hypercalcaemia with anaemia, creatinine above 500 micromol/L at presentation (urgent need for decision on dialysis and biopsy).

Targets are speed and the combination of serology with tissue.

• Urinalysis and urine microscopy on a fresh sample; urine protein:creatinine ratio
• Full blood count, film, reticulocytes, LDH, haptoglobin, creatine kinase, calcium, urate
• Serology sent together and the same day: ANCA (MPO and PR3 by immunoassay), anti-GBM antibody, antinuclear antibody, anti-dsDNA, C3, C4, cryoglobulins, serum protein electrophoresis with serum free light chains and urine protein electrophoresis, hepatitis B surface antigen, hepatitis C antibody, HIV, blood cultures and ASO titre
• Renal ultrasound: size, obstruction, vein thrombosis; Doppler or CT angiography for suspected vascular occlusion
• Chest radiograph or CT for pulmonary haemorrhage

Kidney biopsy within 24 to 48 hours unless contraindicated. Findings direct therapy: crescents in more than 50% of glomeruli, linear IgG on immunofluorescence (anti-GBM), fibrinoid necrosis without immune deposits (pauci-immune), granular deposits (immune complex), interstitial infiltrates (interstitial nephritis), casts (myeloma), fibrin thrombi (thrombotic microangiopathy), cholesterol clefts (atheroemboli).

Differentials: severe acute tubular injury (usually follows a clear ischaemic or toxic insult, has muddy brown casts and bland proteinuria below 1 g daily), obstruction and sepsis related injury.

Immediate for all

• Exclude obstruction and hypovolaemia; stop nephrotoxins and new drugs.
• Manage hyperkalaemia, acidosis and fluid overload with the usual measures; start dialysis for refractory complications.
• Do not wait for biopsy results when ANCA or anti-GBM serology is strongly positive with pulmonary haemorrhage.

Empirical immunosuppression when vasculitis or anti-GBM disease is likely

• Methylprednisolone 500 mg to 1 g intravenously daily for 3 days, followed by prednisolone 1 mg/kg daily (maximum 60 mg) tapering over 6 months.
• Rituximab 375 mg/m2 weekly for 4 weeks, or 1 g on days 1 and 15.
• Alternatively cyclophosphamide 15 mg/kg intravenously (maximum 1.2 g) at weeks 0, 2 and 4, then every 3 weeks for 3 to 6 months; reduce to 12.5 mg/kg at ages 60 to 70, to 10 mg/kg above age 70, and by 20% to 30% for eGFR below 30 mL/min/1.73 m2.
• Plasma exchange: 60 mL/kg with 4% albumin replacement, seven sessions in 14 days, for anti-GBM disease, for ANCA disease with creatinine above 300 micromol/L or alveolar haemorrhage, and for thrombotic thrombocytopenic purpura (daily until platelets above 150 x 10^9/L for two days). Use fresh frozen plasma replacement in thrombotic thrombocytopenic purpura and in patients at risk of bleeding.
• Prophylaxis: co-trimoxazole 480 mg daily (or 960 mg three times weekly) when eGFR is above 30; omeprazole 20 mg daily; calcium and vitamin D.

Other causes

• Interstitial nephritis: stop the drug; prednisolone 1 mg/kg daily (maximum 60 mg) for 2 to 4 weeks, then taper over 4 to 8 weeks, if no improvement by 7 days after withdrawal.
• Myeloma cast nephropathy: dexamethasone 40 mg daily for 4 days, early bortezomib based chemotherapy; treat hypercalcaemia with hydration and zoledronic acid 4 mg intravenously (adjust to eGFR).
• Atypical haemolytic uraemic syndrome: eculizumab 900 mg weekly for 4 weeks then 1200 mg at week 5 and every 2 weeks; meningococcal vaccination at least 2 weeks before or with antibiotic cover.
• Scleroderma renal crisis: captopril 6.25 mg orally, titrated every 6 hours to maximum 50 mg three times daily.
• Malignant hypertension: gradual lowering with labetalol or nicardipine, no more than 25% mean arterial pressure fall in the first hour.
• Atheroembolic: no specific therapy; stop anticoagulants if possible, statin and blood pressure control.

Futility. Anti-GBM disease with creatinine above 600 micromol/L or dialysis dependence at presentation, 100% crescents and no pulmonary haemorrhage has negligible chance of kidney recovery; plasma exchange is not helpful and immunosuppression is generally withheld.

Referral. All patients with rapid creatinine rise and haematuria or proteinuria need same day nephrology contact.