INDEX nephrotoxicity

Cyclosporine has no myelotoxicity but the drug is nephrotoxic. It is because of this nephrotoxicity that cyclosporine has a narrow therapeutic index that makes blood level monitoring necessary. Other toxicities include hypertension, hepatotoxicity, neurotoxicity, hirsutism, gingival hyperplasia and gastrointestinal disturbances. 

Before the introduction of specific vasopressin receptor antagonists, pharmacological treatments for hyponatremia centered on the use of loop diuretics and nonspecific inhibitors of vasopressin signaling, such as lithium carbonate and demeclocycline.11 The utility of such therapies has been limited by a range of sideeffects. Loop diuretic use can result in electrolyte imbalances and suffers from poor response predictability.11 Lithium carbonate suffers from a low therapeutic index and a risk of renal damage as well as limited effectiveness in many patients. Lithium carbonate has therefore been nearly completely supplanted by demeclocycline, a tetracycline antibiotic, in the treatment of chronic hyponatremia.12 Demeclocycline use is itself limited by its nephrotoxicity (particularly in cirrhotic patients), ability to cause reversible uremia, and ability to induce photosensitivity.1,11... 

Ciclosporin is a calcineurin immunosuppressant with a narrow therapeutic index that is widely used in organ transplantation and causes nephrotoxicity. Its bioavailability is highly variable and significantly dependent on multiple factors, for example ... 

Sirolimus is a substrate and inhibitor of CYP3A4 with a narrow therapeutic index and is associated with cognitive impairment and nephrotoxicity. There is a synergistic effect when it is co-administered with ciclosporin, possibly because both are substrates of CYP3A4 (and thus compete at metabolic sites) and are P-gp substrates that may competitively inhibit each other at the efflux pump. There is considerable interindividual variability, with a 10-fold range in plasma concentration in renal transplant recipients when it is given at a dosage of 5 mg per day. 

It has a narrow therapeutic index and is associated with nephrotoxicity and cognitive impairment in overdose, There is less potential for interactions when it is administered topically,... 

Acute reduction in renal perfusion is considered important in the pathophysiology of contrast agent-induced nephrotoxicity. Color-coded duplex sonography has been used in assessing intrarenal vascular resistance in 10 patients (mean age 51 years) after intravenous injection of 100 ml of the low-osmolar contrast medium iopamidol (iodine 300 mg/ml) (182). The resistive index was measured at 1-minute intervals over 10 minutes after injection in each patient. There was a statistically significant rise in resistive index at 2, 3, 4, and 5 minutes after injection, mean values 0.74, 0.75, 0.72, and 0.75... 

Based on its considerable nephrotoxic potential, cisplatin should be given after, rather than before, other anticancer drugs and other drugs with a low therapeutic index (for example aminoglycoside antibiotics or bleomycin) that are primarily excreted in the urine in unchanged form. Concomitant use of potentially nephrotoxic agents (for example conventional amphotericin, tacrohmus) with cis-platin should be avoided (279,280). 

Early in the development of cisplatin, more than 70% of patients developed acute renal failure that appeared to be cisplatin dose-related [34, 35]. Despite aggressive hydration, especially with NaCl solutions, which are routinely apphed in the clinical setting to prevent nephrotoxicity [36], renal failure still occurs [37,38,39]. Therefore several attempts have been made to reduce nephrotoxicity by either co administration of other compounds, alternate method of administration, or by developing analogues with an improved therapeutic index. 

These results indicate that the metabolic disposition and thereby the pharmacological activity, whether efficacious or toxicological, could be modified by selective substitution of deuterium for hydrogen. A new combination antibacterial contains 3-fluoro-D-alanine-2-d which is an excellent example of selective deuteration to enhance the pharmacological activity of a therapeutic agent.7 The metabolism in vivo of 3-fluoro-D-alanine is reduced several-fold by substitution of deuterium for hydrogen on the 2-position without loss of antibacterial activity. This enhances the therapeutic index of the compound because metabolism of 3-fluoro-D-alanine leads to the formation of an inactive antibacterial and fluoride which is nephrotoxic. 

Chan P, Chapman JR, Morris PJ. Glycosuria an index of cyclosporine nephrotoxicity. Transplant Proc 1987 19 1780. Nakahama FI. Stimulatory effect of cyclosporine A on endothelin secretion by a cultured renal epithelial cell line, LLC-PK1 cells. Eur J Pharmacol 1990 180 191-192. 

The most important approach to decreasing P-lac-tam nephrotoxicity is judicious use of these drugs. If a P-lactam is uniquely advantageous for a patient, a carefully controlled rechallenge can be considered to more precisely identify a cause-effect relationship. When P-lactams are used in neonates, accurate determination of the dosage is required, especially for compounds with low therapeutic index and in patients with renal failure. 

Nephrotoxicity is intrinsic to the pharmacological effect of certain anticancer drugs. Because anti-neoplastic drugs have a narrow therapeutic index, the amount of drug required to significantly reduce tumor burden usually induces significant nephrotoxicity. Furthermore, the dosage used in clinical trials often represents the maximum tolerated doses determined dur-... 

Table 7. Criteria for diagnostic use of urinary enzymes. Table 8. Some enzymes used as index of nephrotoxicity.

Obatomi DK. Plummer DT, Flaslam JD. Enzymuria as an index of nephrotoxicity over long term exposure of rats to gentamicin. In Nephrotoxicity mechanism, early diagnosis and therapeutic management. Bach PFI, Gregg NJ, Wilks MF, Oelacruz L (editors). Marcel Dekker Inc, New York 1991 p. 555-561. 

Poor therapeutic index (toxic at therapeutic dose). Fever/chills, nephrotoxicity (reduce risk by hydrating patient), nausea, headache, thrombophlebitis (add heparin to reduce risk), anemia, hepatotoxicity, cardiotoxicity. 

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