overcome are presented. The chapter then describes a vision for the future development and use of kidney safety biomarkers in drug development. The workshop’s breakout session on kidney safety biomarkers, summarized at the end of the chapter, focused on what needs to be done to achieve this vision.

THE CURRENT STATE

The current state of kidney drug development is characterized by several notable deficiencies: a limited ability to screen compounds to predict kidney toxicities; problems in identifying agents that would result in human kidney toxicity; difficulties in confirming that in some instances, kidney toxicities are specific for the tested animal species and are not necessarily relevant to humans; and a limited ability to monitor kidney damage associated with drugs that have been approved for use in humans despite their potential for nephrotoxicity because they provide health benefits or address unmet medical needs. Current approaches to toxicity testing and decision making can waste time and resources and may not identify or support development of the best lead candidates for human use.

The kidney is a major site of drug metabolism and elimination, so it is not surprising that toxicologic findings are more common in the kidney than in most other organs. Merck has reported that renal injury is the second-leading cause of drug attrition, after liver toxicity (Merck, unpublished findings). Indeed, commercially marketed drugs with known nephrotoxic potential are contributing factors in at least 25 percent of acute kidney injury in critically ill humans, causing significant increases in mortality, morbidity, and health care costs (Pannu and Nadim, 2008).

As noted, the current biomarker gold standard for kidney toxicity is levels of serum creatinine and BUN. These measures of kidney function are not sensitive indicators of structural injury, however, in part because of the excess capacity—or “renal reserve”—of the kidneys (Ferguson et al., 2008; Parikh and Devarajan, 2008). In the absence of more sensitive biomarkers to detect acute changes in renal damage, early indications of kidney injury cannot be monitored without histologic examination.

Histology provides accurate detection of kidney injury in preclinical animal studies. However, the current standard of care for evaluation of potentially nephrotoxic agents in human studies does not extend to surveillance with renal biopsies. As a result of this inability to monitor for early indications of kidney injury in human subjects, the development of compounds found to cause kidney damage in preclinical animal studies may be suspended, even when the relevance of the findings to humans has not been established. Drug toxicities seen in animal studies account for more than 30 percent of the attrition of compounds from drug development (Kola and



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