Nephrotoxicity

It is estimated that drugs are responsible for approximately 20% of acute renal failure episodes; this figure increases dramatically in the elderly where the incidence of drug-induced nephrotoxicity is reported to be as high as 66%^1,2,3,4. This increased incidence in the elderly is thought to be a consequence of underlying conditions such as diabetes, cardiovascular disease and renal insufficiency as well as exposure to a greater number of co-administered drugs⁵.

The kidneys have a rich blood supply, have significant transporter activity and act as a highly structured filtration network. These features can result in the kidneys being exposed to high concentrations of drugs or metabolites, which ultimately increases their susceptibility to drug-induced toxicity⁶.

Due to the incidence of drug-induced nephrotoxicity, it is important to understand the risks of this liability prior to reaching the clinic. In vitro human cell-based kidney models using RPTECs (renal proximal tubule epithelial cells) are now becoming popular for early-stage testing of nephrotoxicity. These are the predominant cells in the proximal kidney tubule, which is one of the main sites for reabsorption and drug accumulation.

Cyprotex, a wholly owned subsidiary of Evotec, offers a multiparametric high content screening (HCS) assay which evaluates the chronic exposure of test articles over 9 days and measures multiple relevant cell health markers including glutathione content (GSH), phospholipidosis (PLD), mitochondrial mass and mitochondrial membrane potential, as well as cellular ATP levels in a human kidney relevant in vitro cell-based model utilising RPTECs.

_{1) Kaufman J et al., (1991) Community-acquired acute renal failure. Am J Kidney Dis 17(2): 191-198
2) Nash K et al., (2002) Hospital-acquired renal insufficiency. Am J Kidney Dis 39(5): 930-936
3) Bellomo R (2006) The epidemiology of acute renal failure: 1975 versus 2005. Curr Opin Crit Care 12(6): 557-560
4) Kohli HS et al., (2000) Treatment-related acute renal failure in the elderly: a hospital-based prospective study. Nephrol Dial Transplant 15(2): 212-217
5) Naughton CA (2008) Drug-induced nephrotoxicity. Am Fam Physician 78(6): 743-750}