*Purpose: Ischemia-reperfusion injury (IRI) is a major risk factor for early allograft dysfunction and rejection in orthotopic liver transplantation (OLT). The influence of sex on IRI has been studied in cardiac and renal transplant models, with females showing enhanced protection against IR-stress. Moreover, little is known as to whether and how the donor -recipient sex disparity may affect the severity of IRI in OLT. Here, we evaluated human liver transplant biopsies (Bx) and mouse OLT samples to elucidate clinical relevance and underling mechanisms of donor – recipient sex disparities in OLT settings.

*Methods: In the clinical arm, under IRB protocol, clinical data and Bx histology at 2h post-reperfusion were collected from 477 of primary liver transplant recipients. Among them, additional evaluiation (WB/RT-PCR) was available in 60 LT patients at 2h after reperfusion (prior to the abdominal closure). In the experimental arm, we studied syngeneic OLTs (C56/BL6) subjected to extended period of cold storage (18h/4C), followed by liver/blood sampling at 6h post-reperfusion. Clinical patients and experimental mouse recipients were divided into four “donor – recipient” groups, as follows: (i) male donor/male recipient (M/M); (ii) female donor/male recipient (F/M); (iii) male donor/female recipient (M/F); and (iv) female donor/female recipient (F/F).

*Results: In the clinical arm of a large patient cohort (M/M=207; M/F=88; F/M= 85; F/F= 97) the peak of sALT levels (hepatocellular function) and prevalence of moderate-severe IRI (based on histological finding) showed significant differences between the groups (p<0.05 each). The highest sALT was found in M/M and the lowest in F/M, while the highest IRI occurrence was noted in M/M and the lowest in F/F combination. Clinical liver Bx (M/M=22; M/F=7; F/M= 20; F/F= 11) revealed that cleaved caspase-3 (apoptotic marker) had similar while LC3B (autophagy marker) showed reversed trend (WB) of groups to the characteristic of hepatocellular injury. In the experimental arm (n=4/gr), the differences between the groups were prominent at 6h after reperfusion: M/M showed most severe IRI, while F/M markedly alleviated IRI (p<0.05). To elucidate the trigger for the protective F/M effect, additional 2h samples from M/M, F/M and F/F OLT and sham groups were evaluated. Interestingly F/M group showed higher p53 expression than M/M; while F/F group failed to keep p53 up-regulation. These changes negatively correlated with hepatic p-JNK expression (2h). Moreover, at 6h after reperfusion, increased LC3B and decreased cleaved caspase-3 expression levels in F/M were prominent as compared with M/M group.

*Conclusions: The results of this translational study shed new light on putative sex-dependent stress resistance in liver transplantation; and provide the rationale for personalized and precise organ matching to reduce IRI risks and improve clinical OLT outcomes.

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