TY - JOUR T1 - Renal Transporter Alterations in Patients with Chronic Liver Diseases: Nonalcoholic Steatohepatitis, Alcohol-associated, Viral Hepatitis, and Alcohol-Viral Combination JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.122.001038 SP - DMD-AR-2022-001038 AU - Kayla L. FROST AU - Joseph L. Jilek AU - Shripad Sinari AU - Robert R Klein AU - Dean Billheimer AU - Stephen H. Wright AU - Nathan J. Cherrington Y1 - 2022/01/01 UR - http://dmd.aspetjournals.org/content/early/2022/11/03/dmd.122.001038.abstract N2 - Alterations in hepatic transporters have been identified in pre-cirrhotic chronic liver diseases (CLD) that result in pharmacokinetic variations causing adverse drug reactions (ADRs). However, the effect of CLD on the expression of renal transporters is unknown despite the overwhelming evidence of kidney injury in CLD patients. This study determines the transcriptomic and proteomic expression profiles of renal drug transporters in patients with defined CLD etiology. Renal biopsies were obtained from patients with a history of CLD etiologies, including nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcohol-associated liver disease (ALD), viral hepatitis C (HCV), and combination ALD/HCV. A significant decrease in organic anion transporter 3 (OAT3) was identified in NASH, ALD, HCV, and ALD/HCV (1.56{plus minus} 1.10; 1.01{plus minus} 0.46; 1.03{plus minus} 0.43; 0.86{plus minus} 0.57 pmol/mg protein) relative to control (2.77{plus minus} 1.39 pmol/mg protein). Additionally, a decrease was shown for OAT4 in NASH (24.9{plus minus} 5.69 pmol/mg protein) relative to control (43.8{plus minus} 19.9 pmol/mg protein) and in urate transporter 1 (URAT1) for ALD and HCV (1.56{plus minus} 0.15 and 1.65{plus minus} 0.69 pmol/mg protein) relative to control (4.69{plus minus} 4.59 pmol/mg protein). These decreases in organic anion transporter expression could result in increased and prolonged systemic exposure to drugs and possible toxicity. Renal transporter changes, in addition to hepatic transporter alterations should be considered in dose adjustments for CLD patients for a more accurate disposition profile. It is important to consider a multi-organ approach to altered pharmacokinetics of drugs prescribed to CLD patients to prevent ADRs and improve patient outcomes. Significance Statement Chronic liver diseases are known to elicit alterations in hepatic transporters that result in a disrupted pharmacokinetic profile for various drugs. However, it is unknown if there are alterations in renal transporters during chronic liver disease, despite strong indications of renal dysfunction associated with chronic liver disease. Identifying renal transporter expression changes in patients with chronic liver disease facilitates essential investigations on the multifaceted relationship between liver dysfunction and kidney physiology to offer dose adjustments and prevent adverse drug reactions. ER -