Altered nonrenal drug clearance in ESRD

It is well recognized that end-stage renal disease (ESRD) significantly impacts the systemic clearance of renally cleared drugs. As such, dosing guidelines are routinely used to tailor regimens of renally cleared drugs in these patients at high risk of adverse drug events. Recent studies in experimental models of uremia and humans have mechanistically evaluated the effects of ESRD on specific nonrenal clearance pathways. The present review summarizes these studies and critically assesses the proposed mechanisms and clinical implications of altered nonrenal clearance in ESRD.

ESRD differentially affects the pathways predominantly responsible for nonrenal drug clearance, namely cytochrome P450 metabolic enzymes, and P-glycoprotein, organic anion-transporting polypeptide, and multidrug resistance-associated protein transporters in the liver and gastrointestinal tract. Transcriptional, translational, and acute posttranslational modifications have been reported, and uremic toxins have been implicated as the cause.

ESRD-induced alterations in nonrenal clearance pathways may manifest as increased bioavailability or decreased hepatic clearance, which may then result in significantly increased exposure to drugs, particularly if they occur simultaneously. Drugs undergoing nonrenal clearance need to be identified, novel approaches to predict their pharmacokinetic behavior are needed, and dosing guidelines must be developed to optimize outcomes in patients with ESRD.