Table 2.

Risk factors for drug nephrotoxicity

Drug factors
 Prolonged dosing periods and nephrotoxic drug exposure
 Potent direct nephrotoxic drug effects
 Combinations of toxins/drugs promoting enhanced nephrotoxicity
 Competition between endogenous and exogenous toxins for transporters, increasing drug accumulation within the tubular cell
 Insoluble drug and/or metabolite with intratubular crystal precipitation
 Drug that accumulates in lysosome due to lack of enzymes to metabolize the drug
Patient factors
 Female sex
 Old age (>65 yr of age)
 Nephrotic syndrome
 Cirrhosis/obstructive jaundice (nephrotoxic bile acids)
 True or effective volume depletion (kidney hypoperfusion)
  Decreased GFR
  Enhanced proximal tubular toxin reabsorption
  Sluggish distal tubular urine flow rates
 Metabolic perturbations
  Hypokalemia, hypomagnesemia, hypercalcemia
  Alkaline or acid urine pH
 Immune response genes increasing allergic drug response
 Pharmacogenetics favoring drug toxicity
  Gene mutations in hepatic and kidney P450 system
  Gene mutations in kidney transporters and transport proteins
Kidney factors
 High rate of blood delivery to the kidneys (approximately 25% of cardiac output)
 Increased drug concentrations within the kidney medulla and interstitium
 Biotransformation of drugs to nephrotoxic metabolites and reactive oxygen species
 High metabolic rate of tubular cells (i.e., loop of Henle) within a hypoxic environment
 Proximal tubular uptake of drugs
  Apical drug uptake via endocytosis or pinocytosis with drug accumulation
  Basolateral drug transport via hOAT or hOCT with drug accumulation
  Reduced drug efflux via apical transporters with drug accumulation
  • hOAT, human organic anion transporters; hOCT, human organic cation transporters.