Table 2.

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.