Pigment Nephropathy

Pigment nephropathy is acute kidney injury caused by the toxic and obstructive effects of haem containing proteins in the renal tubules, principally myoglobin from skeletal muscle injury and haemoglobin from intravascular haemolysis. Both are filtered at the glomerulus, concentrated in the tubules and, in acidic urine, bind Tamm-Horsfall protein to form casts.

Mechanisms:

• Tubular obstruction: pigment casts in the distal tubule, favoured by volume depletion, aciduria (urine pH below 5.5) and low urine flow
• Direct toxicity: free haem iron generates hydroxyl radicals and lipid peroxidation in proximal tubule cells
• Renal vasoconstriction: depletion of nitric oxide and activation of the renin angiotensin system
• Associated factors: hypovolaemia, hypotension, sepsis, acidosis

Sources of pigment:

• Myoglobin: rhabdomyolysis from crush injury, exertion, seizures, drugs and toxins (statins, cocaine, alcohol), infections, heat stroke, metabolic disturbance, inherited metabolic myopathy
• Haemoglobin: transfusion reactions, G6PD deficiency with oxidant exposure, malaria (blackwater fever), paroxysmal nocturnal haemoglobinuria, thrombotic microangiopathy, mechanical haemolysis, snake envenomation, clostridial sepsis, burns

The risk of kidney injury rises with the amount of pigment released, volume depletion and acidosis.

• Dark red, brown or tea coloured urine, with a positive dipstick for blood but few or no red cells on microscopy
• Oliguria or anuria developing over 12 to 72 hours
• Muscle pain, swelling and weakness in rhabdomyolysis; compartment syndrome with tense, painful limbs and paraesthesia
• Jaundice, pallor, fever and back pain in haemolysis
• Hyperkalaemia, hyperphosphataemia, hypocalcaemia, hyperuricaemia and anion gap metabolic acidosis (greater in rhabdomyolysis)
• Disseminated intravascular coagulation in severe cases

Red flags: potassium above 6.0 mmol/L, anuria, compartment syndrome, creatine kinase above 20 000 U/L, haemoglobin falling rapidly with haemoglobinuria, ABO-incompatible transfusion.

• Urinalysis: dipstick positive for blood, microscopy negative or with few red cells; granular and pigmented casts
• Differentiate source: creatine kinase above 5 times the upper limit (above 1000 U/L; typically above 5000 U/L in kidney injury) and urine myoglobin point to muscle; low haptoglobin, raised LDH, raised free haemoglobin, reticulocytosis, positive direct antiglobulin test and haemoglobinuria with pink plasma point to haemolysis
• Serum myoglobin is cleared rapidly, so a normal result does not exclude rhabdomyolysis
• Electrolytes, calcium, phosphate, urate, bicarbonate, coagulation screen, blood film
• Compartment pressure measurement if limbs are tense (pressure above 30 mmHg or delta pressure below 30 mmHg)
• Renal ultrasound; biopsy rarely required (pigment casts, tubular injury)

Differentials: haematuria (red cells present), porphyria, medication discolouration, ischaemic tubular injury, interstitial nephritis.

Early volume expansion (most effective prevention)

• Isotonic saline or balanced crystalloid at 1 to 2 L/h initially, then 200 to 300 mL/h, titrated to urine output 200 to 300 mL/h (about 3 mL/kg/h), continued until creatine kinase is below 1000 U/L or haemoglobinuria clears. Monitor for overload, hyperkalaemia and hypocalcaemia.
• In entrapment or crush injury, begin 1 L/h before extrication.

Specific adjuncts (limited evidence)

• Bicarbonate to urinary pH above 6.5 and mannitol 0.5 to 1 g/kg are not routinely required and may worsen hypocalcaemia or volume status.
• Loop diuretics only for overload.

Complications

• Hyperkalaemia: calcium gluconate 10% 10 mL for ECG changes, insulin 10 units with glucose 25 g, salbutamol 10 to 20 mg nebulised.
• Hypocalcaemia: treat only if symptomatic or with severe hyperkalaemia (calcium gluconate 10% 10 to 20 mL), because of rebound hypercalcaemia in recovery.
• Compartment syndrome: fasciotomy when compartment pressure exceeds 30 mmHg or perfusion is threatened.

Cause directed treatment

• Stop causative agent (statin, drug, oxidant); treat seizures, hyperthermia and infection.
• Haemolysis: stop incompatible transfusion, maintain urine output at 100 mL/h or more, transfuse compatible blood, treat the underlying condition.

Renal replacement therapy for refractory hyperkalaemia, pH below 7.15, overload and uraemic complications; haemoperfusion or high cutoff dialysis does not improve outcomes.

Follow up. Creatinine until baseline; most recover in 1 to 3 weeks.