LAUSR

D to increasing disparity between number of transplant candidates on the waiting list and donor organ availability leading to growing need of accepting marginal extended criteria allografts, an optimized donor-to-recipient matching is mandatory to improve liver transplantation (LT) outcome and to reduce risk of retransplantation. Apart from disparities regarding age, body size, virological status, and immunological vulnerability, donor-torecipient gender mismatch was shown to significantly affect post-LT outcome. In particular, female donation to male recipient was assessed as a powerful risk factor of poor outcome, with body and graft size discrepancies, anastomotic incongruity, and hepatic estrogen signaling processes discussed to be underlying morphological, functional, and metabolic mechanisms. Because of transplant urgency and donor organ shortage, sex matching is, however, not yet an accepted standard criterion for decision making process in LT using deceased donors (DDLT). In contrast, living donor liver transplantation (LDLT) may be performed more electively and is not limited by rigid allocation rules and threshold outcome requirements. Two large Eastern LDLT series have in the past identified female-to-male liver donation as an independent risk factor for graft failure and mortality in non-hepatocellular carcinoma indications. Unfortunately, the authors did not discriminate data according to consanguinity, which finally did not allow to analyze another relevant genderrelated issue. Unexpectedly, inferior allograft and patient survival has recently been suggested in recipients of offspring versus nonoffspring living-related kidney donors, although superior outcome had to be expected in view of excellent HLA matching and generally young donor age. Since this outcome phenomenon was most pronounced in female recipients, maternal-fetal allosensitization had been suggested as causal factor. In this issue of Transplantation, Dagan et al present the results of a retrospective cohort study elucidating whether offspring-to-parent LDLT yields inferior outcome as well. By using the UNOS/OPTN database, 279 offspring and 241 nonoffspring living partial liver donations with comparable HLA match were compared. Notably, among female but not male recipients, decreased graft and patient survival was found in offspring compared to nonoffspring liver donation, and these survival differences remained significant after adjustment of donor and recipient factors. In addition, male but not female sex of offspring donors proved to be independently associated with inferior graft and patient survival. Thus, on first sight, the study seems to provide a strong incentive for rejecting male offspring liver donors particularly for maternal recipients, whenever another suitable related or unrelated donor is available. However, there are too many critical issues, no least owing to registry database insufficiencies, that have to be addressed before such a consequent recommendation may be given. The key question remained, why results of the presented trial entirely contradicted previous reports that have identified male liver donation to provide superior recipient outcome in both DDLT and LDLT. Presuming male donors to be associated with larger split liver grafts, higher graftweight to recipient-weight ratios and, thereby, lower risks of vascular complications and small-for-size syndrome as compared to female livers, a strong nongraft factor most likely related to immunology must be assumed to jeopardize the suggested survival benefit. However, lacking data on frequency and severity of acute and chronic allograft rejection in the context of respective immunosuppressive loads made it impossible for the authors to search for indirect evidence on immunological incompatibilities. Besides, the finding of significant survival differences between female recipients of male versus female offspring donor livers did not support the hypothesis of pregnancy-related immune exposition to promote immunological attacks, since this should be expected to be relevant for liver allografts of both donor sexes. Therefore, apart from androgen signaling mechanisms, shared environmental factors have to be considered as being causal for the reported outcome discrepancy. In this context, it seems worthwhile to take a closer look at the respective survival curve patterns. Of note, the authors demonstrated an early (during 1-year post-LDLT) and a late (beyond 8-year post-LDLT) “drifting apart” of graft and patient survival rates between female recipients of offspring versus nonoffspring donors. Assuming male donor sex to be an independent factor of inferior outcome, its prognostic role in the context of different post-LDLT periods and related causes of mortality should be clarified. Commentary