Faculty Collaboration Database

Acute Response of Hepatocyte MRP2 Internalization as an Indicator of Ischemia-reperfusion Injury in Liver Transplantation. Transplantation 2025 Sep 01;109(9):1495-1505

Date

05/05/2025

Pubmed ID

40320583

DOI

10.1097/TP.0000000000005418

Scopus ID

2-s2.0-105005150072 (requires institutional sign-in at Scopus site)   2 Citations

Abstract

BACKGROUND: The introduction of normothermic machine perfusion (NMP) offers new opportunities to evaluate liver graft viability before liver transplantation (LT). Under ischemic stress, multidrug resistance-associated protein 2 (MRP2) translocates from the hepatocyte membrane to the cytoplasm, resulting in loss of function.

METHODS: We measured the cytoplasmic proportion of MRP2 (MRP2 internalization index, MII) by immunofluorescence colocalization analysis using CD13 as a canalicular membrane marker.

RESULTS: The data showed that MII significantly correlated with ischemia time in both in situ ischemia-reperfusion injury and NMP rat models (R 2  = 0.331, P < 0.0001; R 2  = 0.632, P < 0.0001, respectively). Perfusate levels of liver injury markers at the end of NMP showed a significant positive correlation with MII for aspartate aminotransferase (R² = 0.444, P = 0.0013) and arginase 1 (R² = 0.637, P < 0.0001). Conversely, bile production exhibited a significant inverse correlation with MII (R² = 0.618, P < 0.0001). The maximum transport rate of MRP2 ( Vmax,MRP2 ), derived from kinetic modeling of sodium fluorescein biliary excretion, showed a significant inverse correlation with ischemia time (R 2  = 0.326, P = 0.0086) and MII (R 2  = 0.554, P = 0.0002). In human LT, MII values from donor liver biopsies preLT correlated significantly with peak postLT serum aminotransferase levels (R 2  = 0.398, P = 0.0007).

CONCLUSIONS: MRP2 is a putative biomarker for the assessment of hepatic ischemia-reperfusion injury. The biliary excretion kinetics of sodium fluorescein reflects MRP2-mediated transport activity, providing a novel diagnostic method for predicting liver graft viability after LT.

Author List

Monti C, Hong SK, Lee A, Hong JC, Eriksen CM, Joshi A, Dash RK, Audi SH, Lee W, Kumar SN, Kim J

Authors

Said Audi PhD Professor in the Biomedical Engineering department at Marquette University
Ranjan K. Dash PhD Professor in the Biomedical Engineering department at Medical College of Wisconsin
Amit Joshi PhD Professor in the Biomedical Engineering department at Medical College of Wisconsin
Suresh Kumar PhD Associate Professor in the Pathology and Laboratory Medicine department at Medical College of Wisconsin
Whayoung Lee MD Assistant Professor in the Pathology and Laboratory Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

ATP-Binding Cassette Transporters
Animals
Bile
Biomarkers
Disease Models, Animal
Hepatocytes
Humans
Liver
Liver Transplantation
Male
Perfusion
Rats
Reperfusion Injury
Time Factors