Crystal Induced Acute Kidney Injury

Crystal induced acute kidney injury is kidney injury resulting from precipitation of crystals within the tubular lumen, causing intratubular obstruction, direct epithelial injury and inflammation. Crystallisation depends on supersaturation of the solute in the urine, urine pH, urine flow rate and the presence of inhibitors or promoters.

Causes by crystal type:

• Uric acid: tumour lysis syndrome, rhabdomyolysis, haemolysis, severe volume depletion in hyperuricaemia; precipitates at urine pH below 5.5
• Calcium phosphate: tumour lysis syndrome, oral sodium phosphate bowel preparation, hypercalcaemia
• Calcium oxalate: ethylene glycol ingestion, primary hyperoxaluria, enteric hyperoxaluria (fat malabsorption, bariatric surgery, orlistat), high dose vitamin C, star fruit (carambola)
• Drug crystals: aciclovir (particularly rapid infusion or dehydration), methotrexate, sulphadiazine and sulphamethoxazole, ciprofloxacin, indinavir, atazanavir, triamterene, foscarnet, amoxicillin at high dose, cefotaxime, ceftriaxone
• Monoclonal light chain precipitation (myeloma cast nephropathy), classified separately

Risk factors are volume depletion, pre-existing chronic kidney disease, acid urine (or alkaline urine for calcium phosphate and ciprofloxacin), high drug dose or rapid infusion, and low urine output.

• Oliguria, flank or abdominal pain, haematuria and crystalluria
• Rising creatinine within hours to days of drug or toxin exposure
• Tumour lysis syndrome: hyperkalaemia, hyperphosphataemia, hypocalcaemia, hyperuricaemia, seizures, arrhythmia within 12 to 72 hours of chemotherapy (or spontaneous in bulky disease)
• Ethylene glycol: intoxication, high anion gap acidosis, osmolal gap, hypocalcaemia, calcium oxalate crystals in urine
• Aciclovir: neurotoxicity (confusion, tremor) with renal failure
• Nausea, vomiting and abdominal pain; renal colic with stone passage (indinavir, atazanavir)

Red flags: potassium above 6.0 mmol/L, phosphate above 2.1 mmol/L with falling calcium, uric acid above 480 micromol/L (8 mg/dL), anuria, osmolal gap above 10 mOsm/kg, pH below 7.2.

• History of high risk drug or chemotherapy, toxin ingestion, bowel preparation or malabsorption
• Urinalysis: crystalluria on fresh warm urine (rhomboid uric acid, envelope or dumbbell oxalate, needle shaped aciclovir and sulphadiazine, star shaped indinavir); haematuria
• Urine pH: below 5.5 (uric acid), above 7 (calcium phosphate)
• Creatinine, urea, electrolytes, calcium, phosphate, uric acid, LDH, lactate, blood gas, osmolal gap
• Drug levels (methotrexate)
• Renal ultrasound: hydronephrosis if stones obstruct; echogenic papillae
• Biopsy: birefringent crystals within tubules and interstitial inflammation

Differentials: acute tubular injury from other causes, interstitial nephritis, stone obstruction, rhabdomyolysis.

General

• Stop the offending drug or exposure.
• Vigorous hydration with isotonic saline or balanced crystalloid to achieve urine output above 100 to 150 mL/h (2 to 3 L/m2 daily), unless overloaded.
• Correct electrolyte disturbance: hyperkalaemia with calcium gluconate 10% 10 mL, insulin 10 units with glucose 25 g, salbutamol 10 to 20 mg nebulised.

Tumour lysis syndrome

• Prophylaxis: hydration and allopurinol 300 to 600 mg daily (reduce to 100 to 200 mg in eGFR below 30) starting 24 to 48 hours before chemotherapy; rasburicase 0.2 mg/kg intravenously daily for up to 5 days (single dose usually) in high risk patients, after excluding G6PD deficiency. Rasburicase degrades urate and samples must be kept on ice.
• Avoid urine alkalinisation, since it increases calcium phosphate precipitation.
• Treat hyperphosphataemia with phosphate binders; avoid calcium infusions unless symptomatic hypocalcaemia.
• Dialysis for potassium above 6.5 mmol/L, phosphate above 3 mmol/L with symptomatic hypocalcaemia, uric acid refractory to rasburicase, or oliguria with overload.

Methotrexate

• Hydration 3 L/m2 daily, urinary alkalinisation with sodium bicarbonate 150 mmol in 1 L of 5% glucose to urine pH above 7.0, leucovorin rescue, glucarpidase 50 units/kg intravenously in delayed clearance.

Ethylene glycol and other toxic alcohols

• Fomepizole 15 mg/kg intravenously, then 10 mg/kg every 12 hours for four doses, then 15 mg/kg every 12 hours; haemodialysis for pH below 7.3, osmolal gap above 10 mOsm/kg with renal failure or visual change; pyridoxine 50 mg and thiamine 100 mg intravenously daily.

Aciclovir, sulphonamides, ciprofloxacin, indinavir

• Stop or switch; hydrate (aciclovir infusion over 1 hour or more, dose adjusted for eGFR: 5 to 10 mg/kg every 12 hours at eGFR 25 to 50, every 24 hours at 10 to 25).
• Sulphadiazine: alkalinise urine to pH above 7.5.
• Haemodialysis can remove aciclovir in neurotoxicity with renal failure.

Oxalate nephropathy

• Calcium carbonate or citrate 500 mg elemental calcium with meals three times daily to bind oxalate; low oxalate and moderate fat diet; stop vitamin C and orlistat; pyridoxine 100 to 200 mg daily in primary hyperoxaluria type 1.

Renal replacement therapy for refractory hyperkalaemia, acidosis, overload or toxin removal.

Follow up. Creatinine until recovery; imaging for obstructing stones; metabolic evaluation if calcium oxalate injury was unexplained.