Effects of chronic kidney disease on liver transport: quantitative intravital microscopy of fluorescein transport in the rat liver

Abstract

Ryan JC, Dunn KW, Decker BS. Effects of chronic kidney disease on liver transport: quantitative intravital microscopy of fluorescein transport in the rat liver. Am J Physiol Regul Integr Comp Physiol 307: R1488 -R1492, 2014. First published October 22, 2014 doi:10.1152/ajpregu.00371.2014.-Clinical studies indicate that hepatic drug transport may be altered in chronic kidney disease (CKD). Uremic solutes associated with CKD have been found to alter the expression and/or activity of hepatocyte transporters in experimental animals and in cultured cells. However, given the complexity and adaptability of hepatic transport, it is not clear whether these changes translate into significant alterations in hepatic transport in vivo. To directly measure the effect of CKD on hepatocyte transport in vivo, we conducted quantitative intravital microscopy of transport of the fluorescent organic anion fluorescein in the livers of rats following 5/6th nephrectomy, an established model of CKD. Our quantitative analysis of fluorescein transport showed that the rate of hepatocyte uptake was reduced by ϳ20% in 5/6th nephrectomized rats, consistent with previous observations of Oatp downregulation. However, the overall rate of transport into bile canaliculi was unaffected, suggesting compensatory changes in Mrp2-mediated secretion. Our study suggests that uremia resulting from 5/6th nephrectomy does not significantly impact the overall hepatic clearance of an Oatp substrate. chronic kidney disease; uremia; cytochrome P-450; hepatic transport; Mrp2; Oatp; sodium fluorescein PATIENTS WITH END-STAGE RENAL disease (ESRD) receiving dialysis take on average 12 medications to manage the complications of their renal failure and their comorbid disease, which places them at a substantial risk for adverse drug events (8,12,13). Currently, modifications in drug dosing to improve safety for ESRD patients have largely been confined to those medications excreted renally. This has likely improved the safety of these medications for the ESRD population, yet it remains an incomplete approach, since it does not include the hepatically metabolized medications. This oversight is significant because evidence increasingly indicates that hepatic drug metabolism and transport are reduced in patients with [14][15][16][17][18][19][20][21][22][25][26][27][28]30). Consequently, administering the full dose of a hepatically metabolized medication may place an ESRD patient at similar risk for an adverse drug event as administering the full dose of a renally eliminated medication.Experimental evidence suggests multiple mechanisms by which uremic solutes might influence hepatic drug disposition (20,25). Studies from the Pichette laboratory demonstrated that the activity and expression of cytochrome P-450 (CYP450) was reduced in the 5/6th nephrectomy (5/6N) rat model of chronic renal failure (6, 10, 11). Their work elucidated a direct role for uremic solutes with the observation that CYP450 activity and expression were reduced in primary rat hepatocytes incubated wit...

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