Nephrotoxic Acute Tubular Injury

Nephrotoxic acute tubular injury is epithelial damage to renal tubules produced by exogenous or endogenous toxins that are concentrated, taken up or metabolised in the kidney. The tubule is exposed to high concentrations because the kidney filters and concentrates solutes, receives about 20% of cardiac output, and expresses transporters that import drugs into proximal cells.

Mechanisms:

• Mitochondrial toxicity and oxidative stress (cisplatin, tenofovir, aminoglycosides)
• Lysosomal injury and phospholipidosis (aminoglycosides)
• Membrane damage and ion leak (amphotericin B)
• Pigment toxicity and obstruction (myoglobin, haemoglobin)
• Direct tubular obstruction by crystals (methotrexate, aciclovir)
• Osmotic nephrosis (intravenous immunoglobulin with sucrose, hydroxyethyl starch, mannitol)
• Haemodynamic enhancement of toxicity (NSAIDs, contrast)

Principal agents:

• Antimicrobials: aminoglycosides, vancomycin, amphotericin B, polymyxins (colistin), bacitracin, foscarnet, cidofovir, tenofovir
• Antineoplastics: cisplatin, ifosfamide, high dose methotrexate, streptozocin
• Contrast: iodinated radiocontrast
• Analgesics: NSAIDs
• Bisphosphonates: zoledronate
• Toxins: ethylene glycol, heavy metals (lead, cadmium, mercury), paraquat, organic solvents, herbal remedies, snake and bee venoms
• Endogenous: myoglobin, haemoglobin, light chains, uric acid

Risk increases with volume depletion, chronic kidney disease, diabetes, older age, sepsis, hypoalbuminaemia and combinations of nephrotoxins.

• Creatinine rises 2 to 7 days after exposure (aminoglycosides typically after 5 to 10 days)
• Non-oliguric injury is characteristic of aminoglycosides
• Tubular dysfunction: polyuria, hypokalaemia, hypomagnesaemia, hypophosphataemia, glycosuria, aminoaciduria, low molecular weight proteinuria (cisplatin, tenofovir, ifosfamide, aminoglycosides)
• Hearing loss and vestibular toxicity with aminoglycosides; ototoxicity with cisplatin
• Specific features: hypercalcaemia (zoledronate misuse), metabolic acidosis with osmolal gap (ethylene glycol), flank pain and crystalluria (methotrexate, aciclovir)

Red flags: creatinine rising more than 50% from baseline within 48 hours, potassium above 6.0 mmol/L, anuria, drug levels in the toxic range (gentamicin trough above 2 mg/L, vancomycin area under the curve above 600 mg·h/L), ethylene glycol or methanol ingestion with osmolal gap above 10 mOsm/kg.

• Exposure history including prescribed drugs, over-the-counter and herbal products, occupational and recreational toxins, contrast and timing
• Creatinine, urea, electrolytes, magnesium, phosphate, glucose, bicarbonate; urinary glucose, phosphate and low molecular weight protein for tubular dysfunction
• Urinalysis: granular casts, tubular epithelial cells, crystals (examine under polarised light)
• Drug levels: gentamicin trough, vancomycin, methotrexate, lithium, salicylate
• Osmolal gap, blood gas, lactate and serum ethanol if toxic alcohol is suspected
• Renal ultrasound to exclude obstruction
• Biopsy if the diagnosis is uncertain or recovery is delayed

Differentials: ischaemic injury, interstitial nephritis, glomerulonephritis, obstruction, rhabdomyolysis.

Core measures

• Stop or substitute the toxin immediately.
• Restore euvolaemia with isotonic crystalloid before and during exposure to unavoidable nephrotoxins.
• Dose adjust renally cleared drugs and monitor levels; avoid combinations of nephrotoxins.
• Avoid diuretics unless overloaded.

Specific agents

• Aminoglycosides: once daily dosing (gentamicin 5 to 7 mg/kg, trough below 1 mg/L), shortest course, daily creatinine; use alternatives where possible.
• Vancomycin: loading 25 to 30 mg/kg, then dosing to area under the curve 400 to 600 mg·h/L; trough 15 to 20 mg/L if area under the curve cannot be measured.
• Amphotericin B: liposomal preparation 3 to 5 mg/kg daily; isotonic saline 500 to 1000 mL before each dose; correct potassium and magnesium.
• Cisplatin: hydration with 0.9% saline 1 to 2 L before and after, magnesium sulphate 8 to 16 mmol, mannitol 12.5 to 25 g, avoid concomitant aminoglycosides; hold if creatinine rises by 30% or more; usual cycle dose 75 to 100 mg/m2.
• High dose methotrexate: hydration 3 L/m2 daily, urine alkalinisation to pH above 7.0 with sodium bicarbonate, leucovorin rescue, glucarpidase 50 units/kg intravenously (single dose) when levels are above 10 micromol/L at 24 hours or 1 micromol/L at 48 hours with creatinine rising.
• Ethylene glycol or methanol: 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 glycolate levels high.
• Tenofovir: stop and substitute; tubular function returns over weeks to months.
• Contrast: use lowest dose, isotonic crystalloid 1 mL/kg/h for 6 to 12 hours before and after when eGFR is below 30 mL/min/1.73 m2.
• Lithium: stop, give 0.9% saline; haemodialysis for level above 4 mmol/L or above 2.5 mmol/L with renal failure or neurological signs.

Renal replacement therapy for the usual indications and for dialysable toxins (ethylene glycol, methanol, lithium, salicylate, methotrexate with high flux dialysis).

Follow up. Creatinine at 1, 4 and 12 weeks; tubular function tests if cisplatin, ifosfamide, tenofovir or aminoglycoside exposure was prolonged.