Drug nephrotoxicity

Abstract

The kidney is responsible for the elimination and metabolism of many foreign organic compounds, including pharmacologic agents. In some instances drugs must undergo transformation into metabolites, a reaction that may actually take place within tubular cells before secretion into the tubular lumen. While performing its role as an excretory and metabolic organ, the kidney may be at risk for drug-induced toxicity. Factors that contribute to the susceptibility of the kidney to injury include the magnitude of blood flow through glomerular and peritubular vessels; the large surface area available for uptake of potentially harmful compounds; the concentration of specific substrates with¬in tubular fluid which may induce injury or promote accumulation of the toxin within the renal tubular cell; dependence of the renal tubular cell on a high metabolic rate to maintain function; and the distribution of unique transport systems that concentrate drugs or toxins within the tubular cell. Nephrotoxins may preferentially damage specific nephron segments, depending on the area of maximal exposure, the location of specific uptake systems, and the tubular location of specific intracellular sites that are susceptible to the toxin. The concentration of a drug within the renal tubular cell may be affected by the disso¬ciation constant of the compound, its lipid solubility, tubular secretory or reabsorptive activity, water handling, competitive tubular transport mechanisms, urinary pH, and urinary flow rate. The concentration also may be affected by the distribution of enzymes that metabolize individual drugs and intracellular protective systems im¬portant in the maintenance of normal cell metabolism. The principle renal transport systems, which contribute to drug nephrotoxicities, reside in the proximal tubule. These transporters are involved in both secretion and reabsorption and share properties with hepatic drug transporters. Since the number of carrier molecules is limited, secretion is saturable and subject to competition between substrates. Renal injury caused by drugs classified into acute renal failure, nephrotic syndrome and chronic renal failure. Potential mechanisms for drug-induced renal dysfunc¬tion include Vasoconstriction, Altered intraglomerular hemodynamic, Interstitial nephritis, Tubular cell toxicity, Crystal deposition, Drug-induced thrombotic microangiopathy, Osmotic nephrosis, Rhabdomyolysis, redox recycling and may be by inflammatory Glumerulonephritis making Changes in the glomerulus, renal tubular cells, and the surrounding interstitium, leading to fibrosis and renal scarring. Toxicants can decrease the glomerular filtration rate (GFR) by increasing afferent arteriolar resistance, resulting in a decrease in hydrostatic pressure, although most nephrotoxicity occurs in the proximal part of the nephron, some chemicals damage distal structures. Patients who are at the greatest risk for drug-induced nephrotoxicity are those with 1 or more of the following: age older than 60 years, baseline renal insufficiency (GFR < 60 mL/minute/1.73 m2), volume depletion, multiple exposures to nephrotoxins, diabetes, heart failure, and sepsis. General preventive measures include using equally effective but non-nephrotoxic drugs whenever possible, correcting risk factors for nephrotoxicity, assessing baseline renal function before initiating therapy, adjusting the dose of medications for renal function, and avoiding nephrotoxic drug combinations.