Myoglobin Induced Acute Kidney Injury

Myoglobin induced acute kidney injury is kidney injury caused by myoglobin released from damaged skeletal muscle in rhabdomyolysis. Rhabdomyolysis is defined by creatine kinase above 5 times the upper limit of normal (above 1000 U/L), and acute kidney injury occurs in 15% to 50% of patients, rising with peak creatine kinase above 5000 U/L.

Myoglobin (17 kDa) is filtered freely, taken up by proximal tubular cells and degraded to haem, which causes oxidative injury, and in acidic, concentrated urine binds Tamm-Horsfall protein to form obstructing casts. Muscle injury also causes fluid sequestration into damaged muscle (up to 10 to 15 L), activating the renin angiotensin system and reducing renal perfusion.

Causes:

• Traumatic: crush injury, compartment syndrome, prolonged immobilisation (long lie), electrical injury, burns
• Exertional: marathon, military training, seizures, status epilepticus, delirium tremens, sickle cell trait
• Drugs and toxins: statins (especially with fibrates, macrolides or ciclosporin), cocaine, amphetamines, alcohol, neuroleptic malignant syndrome, serotonin syndrome, propofol infusion syndrome, snake and insect venoms
• Heat stroke, malignant hyperthermia
• Infections: influenza, HIV, pyomyositis, Legionella, Clostridium
• Metabolic: hypokalaemia, hypophosphataemia, hypothyroidism, diabetic ketoacidosis, hyperosmolar states
• Inherited: McArdle disease, carnitine palmitoyltransferase deficiency, mitochondrial disorders

• Myalgia, weakness, swelling and tenderness of muscle groups, though 50% have no muscle symptoms
• Dark brown urine
• Compartment syndrome: tense swollen limb, pain on passive stretch, paraesthesia, loss of pulses (late)
• Hyperkalaemia, hyperphosphataemia, early hypocalcaemia (calcium deposition in damaged muscle) with later rebound hypercalcaemia, hyperuricaemia, hypoalbuminaemia, anion gap metabolic acidosis
• Disseminated intravascular coagulation and cardiac arrhythmia

Red flags: potassium above 6.0 mmol/L or ECG changes, oliguria, creatine kinase above 20 000 U/L, tense compartments, hyperthermia above 40 degrees Celsius, pH below 7.2, lactate above 4 mmol/L.

• Creatine kinase: peaks at 24 to 72 hours and falls by about 40% to 50% daily; repeat every 6 to 12 hours initially
• Urine dipstick positive for blood with few or no red cells; urine myoglobin (unreliable, short half life)
• Potassium (measure frequently, 4 to 6 hourly), calcium, phosphate, urate, creatinine, bicarbonate, lactate, aspartate aminotransferase (elevated from muscle), coagulation screen
• ECG for hyperkalaemia
• Compartment pressure measurement; delta pressure (diastolic minus compartment pressure) below 30 mmHg indicates fasciotomy
• Cause search: toxicology, thyroid function, viral serology, genetic testing for recurrent episodes

Differentials: haemoglobinuria, myocardial infarction (CK-MB raised), acute tubular injury from other causes, hepatitis, hypothyroid myopathy.

Fluid resuscitation

• Early and aggressive: isotonic saline or balanced crystalloid 1 to 2 L/h for the first hours, then 200 to 300 mL/h, targeting urine output 200 to 300 mL/h (about 3 mL/kg/h) until creatine kinase falls below 1000 U/L (some stop below 5000 U/L) and urine clears.
• Reduce the rate in heart failure, oliguric kidney injury or pulmonary oedema; use central venous pressure or ultrasound assessment.
• In crush victims, start 1 L/h before extrication and continue 1.5 L/h for 4 hours.

Metabolic

• Hyperkalaemia: calcium gluconate 10% 10 mL intravenously over 10 minutes, repeated if ECG changes persist; insulin 10 units with glucose 25 g; salbutamol 10 to 20 mg nebulised; sodium zirconium cyclosilicate 10 g three times daily for up to 48 hours. Avoid suxamethonium.
• Hypocalcaemia: replace only if symptomatic or with severe hyperkalaemia.
• Acidosis: bicarbonate only if pH is below 7.1 or for hyperkalaemia; routine alkalinisation is not beneficial.
• Mannitol and bicarbonate have no proven advantage.

Specific

• Compartment syndrome: fasciotomy when pressure exceeds 30 mmHg or delta pressure is below 30 mmHg.
• Stop causative drugs (statin, fibrate, neuroleptic), cool hyperthermia (target 38.5 degrees Celsius), control seizures.
• Neuroleptic malignant syndrome: dantrolene 1 to 2.5 mg/kg intravenously, then 1 mg/kg every 6 hours; malignant hyperthermia: dantrolene 2.5 mg/kg.
• Replace phosphate when below 0.3 mmol/L.

Renal replacement therapy for refractory hyperkalaemia, pH below 7.15, anuria with overload, or progressive uraemia; continuous therapy for unstable patients; high flux membranes do not alter outcome.

Follow up. Creatinine at 1, 4 and 12 weeks; recurrent episodes need metabolic myopathy evaluation; resumption of statins only after normalisation of creatine kinase and then at lower dose.