The interrelation between liver disease and kidney function is becoming increasingly researched, as hepatic- derived systemic inflammation can have a profound effect on the physiology of the kidney. This is a vital factor to consider with respect to precision medicine, as these changes can disrupt the proper metabolism and elimination of the 32% of marketed therapeutics that rely upon renal function for excretion. Among the liver diseases that affect renal physiology is nonalcoholic fatty liver disease (NAFLD), characterized by a series of mechanistic events that mediate the transition from simple steatosis to nonalcoholic steatohepatitis (NASH), which include inflammatory events. Our lab has identified NASH-induced phenotypic conversions of several drug metabolizing enzyme and transport proteins that significantly alter the pharmacokinetic profiles of certain drugs and xenobiotics. Interestingly, in a profiling study of various rodent models of NASH, we have also identified NASH-induced phenoconversion of renal transport proteins, a phenomenon that also contributes to altered pharmacokinetics of xenobiotic substrates in vivo. To date, no studies have been published examining human NASH-related phenoconversion of renal drug transporters, and that will be the first item we address in this application. Our central hypothesis is that NASH alters the expression and function of major renal drug transporters, thereby increasing the risk of adverse drug reactions and environmental toxicities in patients with NASH. Our study design seeks not only to identify phenoconversion of specific renal transporters in NASH, but also to pinpoint the associated secretory pathways to better narrow down mechanisms of altered pharmacokinetics for certain therapeutics and environmental contaminants.
Our aims are to: 1) Determine the changes in expression and localization of renal transporters in human NASH patients, 2) Determine the functional changes in individual secretion pathways and resulting potential for environmental toxicity in a rodent model of NASH, and 3) Determine the impact of NASH on GFR and select secretion pathways in human patients. By completing these aims, we will be able to identify classes of drugs that present a greater risk of adverse drug events for NASH patients.
Humans vary widely in their response to drugs and toxicants, which is the result of differences in the way their bodies metabolize and eliminate these compounds. Disease states that alter the ability of the kidney to eliminate these compounds could result in increased toxicity. The current application focuses on the effect of liver disease on renal secretion pathways for drug elimination and whether altered secretion makes these individuals at greater risk of toxicity.