Preventive handling of drug nephrotoxicity with antioxidant cotherapies: Preclinical studies and clinical perspectives

Worldwide, nephrotoxicity poses a considerable health and economic burden. Nearly 25% of the top 100, most used drugs in intensive care units are potentially nephrotoxic. Moreover, nephrotoxicity causes 10-20% of the acute renal failure cases (ARF). ARF is a very serious condition with high incidence and mortality rate, which is estimated at approximately 50% of the cases despite dialysis application, especially within critically ill patients. Mortality increases to 80% when ARF courses with multi-organ damage. The clinical handling of renal injury and ARF is difficult and expensive because, other than dialysis, there are no available treatments. For this reason the search for strategies to prevent nephrotoxicity constitute an active area of investigation. In addition to drug targeting and medical chemistry for new and safer molecules, a line of interest is the identification of renoprotective adjuvants for co-administration along with potentially nephrotoxic drugs.

At the preclinical level, many chemically unrelated antioxidants have been shown to protect the kidneys from cisplatin nephrotoxicity, especially in experimental animal models. They include curcumin, N-acetylcysteine, naringenin, selenium, vitamin C, vitamin E and other dietary components that scavenge free radicals formed by exposure to cisplatin. Although promising, antioxidants have not yet demonstrated a clear benefit in the clinical research conducted so far, which requires further investigation. In this line, a pre-clinical selection of candidates to be assayed at the clinical level must be pursued in order to (i) improve the efficacy of the preclinical-to-clinical transition; and (ii) to reduce early failure rate in clinical assays through the drug discovery process.

One of the main problems identified in the translation of antioxidants to the clinical practice is their very low bioavailability derived from a very low absorption upon oral administration. Our research line has been focused on the effect of the natural antioxidants resveratrol and quercetin, and the antidiabetic metformin, at preventing drug nephroxicity. Our studies clearly show their renoprotective effect at the preclinical level. We are testing these molecules in the clinical setting and developing new nanoformulations which will enhance their solubility and, hence, their bioavailability to prospectively achieve clinical utility.