Individual risk factors

Individuals may be at increased risk for developing nephrotoxicity from various drugs based on unique circumstances. For example, several antibiotics are well recognized as having nephrotoxic potential [121] but it must be appreciated that they are often administered under clinical circumstances in which acute renal insults co-exist, i.e., hypotension, reduced cardiac output, depressed liver function, etc. Rasmussen & Ibels used multivariant analysis to determine the role of acute insults such as hypotension, dehydration, pig-menturia, liver disease, sepsis, aminoglycoside administration and contrast media for patients developing ARF without a prior history of renal disease [4]. In 41 of 121 patients a single insult was considered to be responsible for ARF, 80% of the time this was hypotension. The remaining 80 patients were exposed to 140 insults or 1.75/patient giving support to the concept of the multifactorial basis for inducing nephrotoxic renal injury. This same pattern of multiple insults causing ARF is evident from the report of Kohli et al. [98]. Contrast-associated nephropathy has been evaluated extensively for possible clinical conditions in which patients are at additional risk for the induction of ARF [122] Swartz et al. [122] using a retrospective analysis of factors related to renal failure following major an-giography, reported that in addition to renal insufficiency, abnormal liver function tests, hypoalbumin-emia, diabetes mellitus and proteinuria all were significantly correlated with the patient group which developed renal failure. They also noted a prevalence of 2.5-risk factors/case of contrast-associated nephr-opathy. Cochran et al. [123] used an odds-ratio analysis of 28 clinical factors that might correlate with increased risk for the development of contrast-associated nephropathy. In addition to underlying renal disease and elevated serum creatinine, their data confirmed proteinuria as a risk factor but failed to substantiate diabetes mellitus or abnormal liver function. They did demonstrate that male gender, hypertension, and vascular disease all were associated with significant additional risk as well as the amount and type of contrast administered. In a review of 6 publications which analyzed risk factors for contrast-associated nephropathy in 1416 patients, renal insufficiency was the only uniformly consistent factor for all studies [110], however, in 3 of 5 studies in which it was tested, the amount of contrast was found to correlate in a positive way. Cigarroa et al. [124] have used a modified contrast media dosing scheme for patients at high risk for contrast-associated nephropathy and reported that virtually every case of post procedure contrast-associated neph-ropathy occurred when the recommended limits of the calculated dose of contrast were exceeded.

In a similar vein, Leehey et al. [125] have reported on the frequency of aminoglycoside-induced nephro-toxicity using three different dosing schemes, including two that were based on pharmacokinetic principles.

It is noteworthy that despite careful calculation of the dosing scheme, this did not alter the incidence of neph-rotoxicity. However, the duration of dosing correlated positively with nephrotoxicity incidence, as did treatment with furosemide, old age, and liver disease.

While cyclosporine is an intrinsically nephrotoxic drug due to a direct action on the kidney, under other circumstances it can become nephrotoxic in the presence of a second drug, exhibiting a so-called drug-drug interaction. For example, drugs that inhibit the hepatic P-450 drug-metabolizing enzymes can cause a significant change in cyclosporine pharmacokinetics and, thus, render an otherwise stable dose nephrotoxic [126]. Drugs that induce such changes in cyclosporine levels include: erythromycin, fluconazole, ketoconazole, ci-metidine.

Another example of drug-drug interaction occurs when non-steroidal anti-inflammatory drugs are given to patients receiving anti-hypertensive drugs [127]. Due to the action of the NSAID to inhibit prostaglandin synthesis, the loss of endogenous induced vasodilatation causes the blood pressure to become uncontrolled often necessitating increasing the current anti-hypertensive drug dosage or prescribing additional anti-hypertensive drugs [128]. Recently, Mehta et al. [129] have called attention to the increased mortality and permanent residual renal impairment in ARF patients who are treated with diuretics. Once again we are reminded that empirical treatment, for which pathophysiologic rationale can be developed, must be evaluated in a controlled clinical trial before being universal accepted as standard therapy. So not only is it important to understand the patients diseases, but also a complete list of all medications that the patient takes on a regular basis including those purchased over the counter.

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