The kidney is inherently prone to toxicity. It is highly vascularised, receiving ~25% of cardiac output, and as a consequence is especially vulnerable to drug-induced injury. Moreover, it is a primary site for the elimination of drugs, which further increases exposure of the kidney to potentially toxic substances. Drug-induced nephrotoxicity is common in clinical practice; drugs account for ~20% of acquired cases of acute renal failure and even more in at-risk populations, such as the elderly or those with underlying chronic kidney disease. A number of widely-used drug classes have been implicated in nephrotoxicity, including the NSAIDs, antibiotics and anticancer agents such as cisplatin.
Drug-induced renal injury is also a major cause of drug attrition in clinical development, accounting for 2% of candidate failures during preclinical studies and 19% during Phase III There is therefore a pressing need to improve prediction of renal toxicity, through the development of biomarkers, in vitro experimental models and better use of legacy information.
With this in mind, the Safety Intelligence Program now includes a rich set of assertions around renal toxicity to complement the existing in-depth intelligence for drug induced liver, muscle, cardiac and vascular injury, carcinogenicity and genotoxicity. This new intelligence includes:
- Over 35,000 assertions for compounds causing kidney effects, curated and integrated from a variety of public data sources, with intelligence for 6,500 compounds including over 1000 drug molecules.
- More than 1300 renal observations, including major pathophysiological events such as interstitial nephritis, kidney tubular necrosis and altered glomerular filtration rate.
- 6,000 assertions describing the effects of 1899 compounds on 73 key body fluid markers of renal function, such as creatinine level and blood urea nitrogen.