Malaria Associated Acute Kidney Injury

Malaria associated acute kidney injury is acute kidney injury complicating severe malaria, most often Plasmodium falciparum and, less commonly, P. knowlesi and P. vivax. In adults with severe falciparum malaria it occurs in 25% to 40%; in children it is less frequent but increasingly recognised, occurring in 10% to 30% of those with severe disease. It is an indicator of severe malaria and independently predicts death (mortality 15% to 45% in those requiring dialysis in adults).

Mechanisms combine:

• Sequestration of parasitised red cells in renal microvessels, microvascular obstruction and endothelial activation
• Hypovolaemia from vomiting, fever, sweating and poor intake, with vasodilation and third space loss
• Intravascular haemolysis with haemoglobinuria (blackwater fever), pigment nephropathy
• Rhabdomyolysis
• Systemic inflammation and cytokine release, disseminated intravascular coagulation, thrombotic microangiopathy
• Hypotension and shock (algid malaria), and concomitant bacterial sepsis (non-typhoidal Salmonella, Gram negative bacteraemia)
• Nephrotoxic drugs (quinine, aminoglycosides, NSAIDs)
• Post-artesunate delayed haemolysis (1 to 3 weeks after treatment of hyperparasitaemia) adding haemoglobin mediated injury

Plasmodium malariae produces a distinct chronic glomerular disease (quartan malarial nephropathy): immune complex nephritis presenting with nephrotic syndrome in children in endemic areas, progressing slowly and resistant to corticosteroids.

Severe malaria criteria relevant to the kidney: serum creatinine above 265 micromol/L (3 mg/dL) or urea above 20 mmol/L in adults (urea above 10 mmol/L in children), plus parasitaemia above 10%, jaundice (bilirubin above 50 micromol/L with parasitaemia above 100 000/microL), haemoglobin below 70 g/L, hypoglycaemia (glucose below 2.2 mmol/L), acidosis (bicarbonate below 15 mmol/L), impaired consciousness, shock, pulmonary oedema, abnormal bleeding.

• Fever, rigors, headache, vomiting, myalgia, jaundice, hepatosplenomegaly
• Oliguria or anuria; dark (blackwater) urine
• Impaired consciousness, seizures (cerebral malaria), hypoglycaemia, lactic acidosis, severe anaemia, bleeding, hypotension, respiratory distress
• Multi-organ involvement: jaundice and liver dysfunction, thrombocytopenia (platelets below 50 x 10^9/L in many)
• Hyperkalaemia, hyponatraemia, hypocalcaemia, hyperphosphataemia
• Chronic quartan nephropathy: oedema, heavy proteinuria, hypertension in a child with recurrent fever

Red flags: parasitaemia above 10%, Glasgow Coma Scale below 11, lactate above 5 mmol/L, hypotension, bicarbonate below 15 mmol/L, glucose below 2.2 mmol/L, haemoglobin below 50 g/L in children, anuria, potassium above 6.0 mmol/L, pregnancy.

• Malaria diagnosis: rapid diagnostic test and thick and thin blood films for species and parasitaemia (percentage of infected red cells); repeat every 12 hours until negative.
• Creatinine, urea, electrolytes, bicarbonate, lactate, glucose (every 4 to 6 hours initially), calcium, phosphate, liver tests, bilirubin.
• Full blood count, haemoglobin, platelets; haemolysis markers (LDH, haptoglobin, free haemoglobin), coagulation screen, G6PD status.
• Blood cultures (bacteraemia in 5% to 15% of severe cases), urinalysis (haemoglobinuria, proteinuria), chest radiograph, lumbar puncture if meningitis cannot be excluded.
• Creatine kinase when muscle involvement is suspected.
• Renal ultrasound; kidney biopsy for suspected quartan malarial nephropathy or unexplained persistent proteinuria (immune complex deposition).

Differentials: sepsis, leptospirosis, dengue, typhoid, viral haemorrhagic fever, haemolytic uraemic syndrome, rhabdomyolysis, hepatorenal syndrome, meningitis.

Antimalarial treatment

• Intravenous or intramuscular artesunate 2.4 mg/kg (3 mg/kg for children under 20 kg) at 0, 12 and 24 hours, then once daily until the patient can take oral therapy (minimum 24 hours of parenteral therapy). Dose adjustment is not required in kidney failure.
• When oral therapy is possible, complete treatment with a full 3-day course of an artemisinin combination therapy, for example artemether-lumefantrine given as 4 tablets (20 mg/120 mg) at 0, 8, 24, 36, 48 and 60 hours for weights of 35 kg and above (3 tablets for 25 to 34 kg, 2 tablets for 15 to 24 kg, 1 tablet for 5 to 14 kg), with fat containing food.
• Quinine only if artesunate is unavailable: loading 20 mg/kg salt over 4 hours (omit if quinine or mefloquine was given in the previous 24 hours), then 10 mg/kg every 8 hours; reduce the maintenance dose by one third to one half after 48 hours in acute kidney injury. Monitor glucose and QT.
• Pregnancy: artesunate is used in all trimesters.

Fluid and haemodynamic management

• Avoid fluid overload: adults with severe malaria are prone to pulmonary oedema and acute respiratory distress syndrome. Give maintenance crystalloid and replace deficits cautiously (500 mL boluses with reassessment) in hypovolaemic adults with oliguria.
• Hypotensive or shocked patients: balanced crystalloid 250 to 500 mL aliquots, then noradrenaline 0.05 to 0.5 microg/kg/min; add broad spectrum antibiotics (ceftriaxone 2 g daily; 80 mg/kg daily in children) for presumed bacteraemia.
• Children with severe malaria and no shock: avoid routine fluid boluses; use maintenance fluids and oral rehydration.

Metabolic and organ support

• Hypoglycaemia: 50 mL of 50% glucose intravenously in adults (5 mL/kg of 10% glucose in children) followed by a 10% glucose infusion; check glucose every 4 hours, particularly with quinine.
• Anaemia: transfuse for haemoglobin below 50 g/L in children (below 70 g/L in adults with severe disease) using screened blood.
• Seizures: lorazepam 4 mg intravenously (0.1 mg/kg in children); treat cerebral oedema.
• Hyperkalaemia: calcium gluconate 10% 10 mL, insulin 10 units with glucose 25 g, salbutamol 10 to 20 mg nebulised.
• Avoid NSAIDs, aminoglycosides and unnecessary nephrotoxins; paracetamol 1 g four times daily for fever.

Renal replacement therapy

• Indications: creatinine above 500 micromol/L with oliguria, potassium above 6.5 mmol/L, pH below 7.15, overload unresponsive to diuretics, uraemic complications. Start early in hypercatabolic patients with oliguria and rapidly rising creatinine.
• Haemodialysis or continuous haemofiltration is preferred over peritoneal dialysis in adults (lower mortality, faster correction); peritoneal dialysis is acceptable where extracorporeal therapy is unavailable, using 1.5 to 2 L exchanges hourly and then less frequently.
• Most survivors recover renal function within 1 to 3 weeks; dialysis dependence is uncommon.

Post-artesunate delayed haemolysis. Check haemoglobin and LDH weekly for 4 weeks after treatment of hyperparasitaemia (parasitaemia above 10%); transfuse for symptomatic anaemia or haemoglobin below 70 g/L.

Quartan malarial nephropathy. Treat the infection (artemether-lumefantrine for 3 days) and optimise supportive therapy with an ACE inhibitor (enalapril 2.5 to 10 mg daily in adults); corticosteroids and immunosuppressants are ineffective; refer to nephrology for progression.

Prevention of recurrence. Insecticide treated nets, chemoprevention in pregnancy and young children according to local epidemiology, and prompt treatment of fever.