Risk factors that increase renal vulnerability to nephrotoxinsa
| Patient-Specific Factors |
| Female sex |
| Old age (>65 yr) |
| Nephrotic syndrome |
| Cirrhosis/obstructive jaundice |
| Acute/Chronic kidney disease |
| True or effective volume depletion |
| Decreased glomerular filtration rate |
| Enhanced proximal tubular toxin reabsorption |
| Sluggish distal tubular urine flow rates |
| Metabolic perturbations |
| Hypokalemia, hypomagnesemia, hypercalcemia |
| Alkaline or acid urine pH |
| Immune response genes |
| Pharmacogenetics favoring drug toxicity |
| Gene mutations in hepatic and renal P450 system |
| Gene mutations in renal transporters and transport proteins |
| Kidney-Specific Factors |
| High rate of blood delivery (20-25% of cardiac output) |
| Increased toxin concentration in renal medulla & interstitium |
| Biotransformation of substances to reactive oxygen species |
| High metabolic rate of tubular cells (loop of Henle) |
| Proximal tubular uptake of toxins |
| Apical uptake via endocytosis/pinocytosis |
| Basolateral transport via OAT and OCT |
| Drug-Specific Factors |
| Prolonged dosing periods and toxin exposure |
| Potent direct nephrotoxic effects of the drug or compound |
| Combinations of toxins/drugs promoting enhanced nephrotoxicity |
| Competition between endogenous and exogenous toxins for transporters, increasing toxin accumulation within the tubular cell |
| Insoluble parent compound and metabolite with intratubular crystal precipitation |
↵a OAT, organic anion transporters; OCT, organic cation transporters.