Sex-specific differences have been observed in preclinical models of renal ischemic injury. In particular, females recover more readily from ischemia-reperfusion injury (IRI) than males, and testosterone has been shown to have a negative effect on renal ischemia tolerance. The factors that underlie these sex-dependent discrepancies are poorly understood, and it is not clear if these same differences extend to humans. In this episode, Matthew Levine and David Aufhauser describe the development of several murine renal ischemia and transplant models used to evaluate sex-specific effects on recovery after IRI. Their results demonstrate that recipient, not donor, sex determines transplantation outcomes. Moreover, evaluation of patient data from the United Network for Organ Sharing revealed that male recipients had increased delayed graft function compared to female recipients.
Experimentally, females show an improved ability to recover from ischemia-reperfusion injury (IRI) compared with males; however, this sex-dependent response is less established in humans. Here, we developed a series of murine renal ischemia and transplant models to investigate sex-specific effects on recovery after IRI. We found that IRI tolerance is profoundly increased in female mice compared with that observed in male mice and discovered an intermediate phenotype after neutering of either sex. Transplantation of adult kidneys from either sex into a recipient of the opposite sex followed by ischemia at a remote time resulted in ischemia recovery that reflected the sex of the recipient, not the donor, revealing that the host sex determines recovery. Likewise, renal IRI was exacerbated in female estrogen receptor α–KO mice, while female mice receiving supplemental estrogen before ischemia were protected. We examined data from the United Network for Organ Sharing (UNOS) to determine whether there is an association between sex and delayed graft function (DGF) in patients who received deceased donor renal transplants. A multivariable logistic regression analysis determined that there was a greater association with DGF in male recipients than in female recipients. Together, our results demonstrate that sex affects renal IRI tolerance in mice and humans and indicate that estrogen administration has potential as a therapeutic intervention to clinically improve ischemia tolerance.
David D. Aufhauser Jr., Zhonglin Wang, Douglas R. Murken, Tricia R. Bhatti, Yanfeng Wang, Guanghui Ge, Robert R. Redfield III, Peter L. Abt, Liqing Wang, Nikolaos Svoronos, Arwin Thomasson, Peter P. Reese, Wayne W. Hancock, Matthew H. Levine