Haemoglobin Induced Acute Kidney Injury

Haemoglobin induced acute kidney injury is kidney injury caused by free haemoglobin released into plasma during intravascular haemolysis. Haemoglobin dissociates into dimers (32 kDa) filtered at the glomerulus; haptoglobin binding capacity is saturated when free haemoglobin exceeds about 1 g/L, after which free haemoglobin and haem enter the tubules.

Mechanisms:

• Tubular cast formation with Tamm-Horsfall protein in acidic urine
• Haem iron generating reactive oxygen species and lipid peroxidation
• Scavenging of nitric oxide by free haemoglobin, causing renal vasoconstriction
• Hypovolaemia, hypotension, acidosis and sepsis acting as co-factors
• Superimposed injury from the underlying disorder (thrombotic microangiopathy, sepsis, snake venom)

Causes of intravascular haemolysis:

• Acute haemolytic transfusion reaction (ABO incompatibility)
• G6PD deficiency after oxidant drugs (primaquine, dapsone, nitrofurantoin, rasburicase, sulphonamides) or fava beans
• Malaria: severe falciparum malaria, blackwater fever (quinine or mefloquine), post-artesunate delayed haemolysis
• Paroxysmal nocturnal haemoglobinuria
• Thrombotic microangiopathy (thrombotic thrombocytopenic purpura, haemolytic uraemic syndrome), mechanical heart valves, extracorporeal circuits
• Snake envenomation, spider bite, clostridial sepsis, hypotonic fluid infusion, copper toxicity, water irrigation during surgery
• Autoimmune haemolytic anaemia with warm or cold antibodies, drug induced haemolysis, burns

• Dark red or cola coloured urine
• Pallor, jaundice, fatigue, dyspnoea, tachycardia
• Fever, rigors, back or flank pain, hypotension (transfusion reaction)
• Oliguria developing within hours to 2 days
• Hyperkalaemia, metabolic acidosis, raised LDH, indirect hyperbilirubinaemia
• Disseminated intravascular coagulation: bleeding, oozing from venepuncture sites
• Splenomegaly in chronic haemolytic states

Red flags: acute haemolysis during transfusion, haemoglobin falling by more than 20 g/L in 24 hours, potassium above 6.0 mmol/L, anuria, parasitaemia above 10% in malaria, thrombocytopenia with schistocytes, hypotension.

• Urinalysis: dipstick blood positive with few red cells; free haemoglobin in plasma (pink supernatant)
• Haemolysis markers: haemoglobin, reticulocytes, LDH (raised), haptoglobin (low or absent), indirect bilirubin, blood film (spherocytes, schistocytes, bite cells, blister cells, parasites), direct antiglobulin test
• Transfusion reaction: stop, check clerical record, repeat group and crossmatch, direct antiglobulin test, free haemoglobin
• G6PD activity (may be falsely normal during acute haemolysis; repeat at 2 to 3 months)
• Malaria rapid test and thick and thin films
• Flow cytometry for PNH clones (CD55 and CD59 deficiency)
• ADAMTS13 activity (below 10%) if thrombotic thrombocytopenic purpura is suspected
• Electrolytes, creatinine, coagulation screen, potassium (haemolysed samples falsely high; repeat with blood gas)

Differentials: rhabdomyolysis, haematuria, porphyria, sepsis with tubular injury, thrombotic microangiopathy.

All patients

• Remove the cause: stop the incompatible transfusion, the oxidant drug or the infusion.
• Volume expansion: isotonic saline or balanced crystalloid 1 to 2 L over the first hour, then to maintain urine output 100 to 200 mL/h; avoid overload.
• Transfusion with compatible blood for haemoglobin below 70 g/L or haemodynamic compromise; crossmatch with the laboratory and use washed or compatible units in autoimmune haemolysis.
• Treat hyperkalaemia: calcium gluconate 10% 10 mL, insulin 10 units with glucose 25 g, salbutamol 10 to 20 mg nebulised.
• Alkalinisation and mannitol are of unproven benefit.

Cause directed management

• Acute haemolytic transfusion reaction: furosemide 40 to 80 mg intravenously once volume restored if urine output is below 100 mL/h; manage disseminated intravascular coagulation with fresh frozen plasma and platelets; report to the transfusion service.
• Severe malaria: artesunate 2.4 mg/kg intravenously at 0, 12 and 24 hours, then daily until oral therapy is possible (minimum 3 doses), followed by a full course of oral artemisinin combination therapy; exchange transfusion is not routinely used.
• Delayed post-artesunate haemolysis: monitor haemoglobin and LDH weekly for 4 weeks.
• G6PD deficiency: stop oxidant, transfuse if needed, avoid fava beans, recheck G6PD at 3 months.
• Autoimmune haemolytic anaemia: prednisolone 1 mg/kg daily (maximum 80 mg), rituximab 375 mg/m2 weekly for 4 weeks for refractory or cold agglutinin disease.
• Paroxysmal nocturnal haemoglobinuria: eculizumab 600 mg weekly for 4 weeks, then 900 mg at week 5 and every 2 weeks (after meningococcal vaccination), or ravulizumab.
• Thrombotic thrombocytopenic purpura: plasma exchange 1.5 plasma volumes daily, prednisolone 1 mg/kg daily, caplacizumab 10 mg daily, rituximab 375 mg/m2.
• Snakebite haemolysis: antivenom according to species and clinical severity, with volume resuscitation.

Renal replacement therapy for refractory hyperkalaemia, acidosis (pH below 7.15), overload or uraemic complications.

Follow up. Creatinine, haemoglobin and LDH until normal; renal recovery usually within 1 to 4 weeks.