Several lines of emerging evidence indicate that kidney disease differentially affects uptake and efflux transporters and metabolic enzymes in the liver and gastrointestinal (GI) tract, and uremic toxins have been implicated as the cause. In patients with kidney disease, even drugs that are eliminated by nonrenal transport and metabolism could lead to important unintended consequences if they are administered without dose adjustment for reduced renal function. This is particularly so in the case of drugs with narrow therapeutic windows and may translate into clinically significant variations in exposure and response.
The past two decades have witnessed an alarming increase in the size of the population with chronic kidney disease (CKD) in the United States. The prevalence of CKD in the US adult population was recently estimated to be >13% (over 25 million adults), and the number of patients with end-stage renal disease (ESRD) alone has risen from 209,000 in 1991 to 472,000 in 2004.1 If this rapid increase continues, there will be an estimated 136,000 incident and >700,000 prevalent ESRD patients in the United States by the year 2015 (ref. 1). A better understanding of the effects of kidney disease on drug disposition, particularly the enzymes and transporters that predominantly determine nonrenal drug clearance, as well as the mechanism and the clinical relevance of the alterations, may help guide dosing and thereby optimize pharmacotherapy in these patients, who comprise a considerable proportion of the US population.