D. D. Aufhauser1, D. R. Murken1, Z. Wang1, G. Ge1, T. Bhatti4, W. W. Hancock3,4, M. H. Levine1,2 1University Of Pennsylvania,Surgery,Philadelphia, PA, USA 2Children’s Hospital Of Philadelphia,Surgery,Philadelphia, PA, USA 3University Of Pennsylvania,Pathology And Laboratory Medicine,Philadelphia, PA, USA 4Children’s Hospital Of Philadelphia,Pathology And Laboratory Medicine,Philadelphia, PA, USA
Introduction: Renal ischemia-reperfusion injury (IRI) commonly complicates cardiac, vascular, trauma, urologic and transplant surgery. Prior studies described superior renal IRI tolerance in female rodents, but translational applications of hormonal therapy to prevent renal complications in major surgery are unexplored.
Methods: Mice underwent standardized 28-min warm IRI with clamping of the left renal pedicle and contralateral nephrectomy. BUN was measured daily for 4 days following injury and kidneys were collected for histology after 28 days.
Results: Females treated with 2 doses of β -estradiol at 16- and 1-hr pre-IRI (n=5) had lower serum BUN levels following IRI compared to vehicle treated controls (n=5, p<0.01), and less fibrosis on Sirius Red staining (p<0.01). Hormonally intact male mice subjected to 28 min of IRI all died of renal failure by 48 hr in vehicle (n=5) or estrogen (n=5) treated groups (Fig. 1, *). Male mice subjected to orchiectomy one wk prior to ischemia exhibited improved renal IRI tolerance and universal survival (n=5, Figure 1). Neutered male mice treated with estrogen (n=5) demonstrated further improvement in post-IRI renal function compared to vehicle treated neutered mice (n=5, p=0.03, Figure 1).
Conclusion: Gender-specific protection from renal IRI can arise from the presence of estrogens or the absence of androgens. Administration of β -estradiol beginning at 16-hrs pre-injury mitigates renal IRI in female and manipulated mice. This time course is compatible with perioperative use in procedures anticipated to involve a period of renal ischemia. While further investigations are warranted to test whether these exciting data can translate to beneficial outcomes in larger animals, we conclude that hitherto unrecognized effects of estrogens on IRI have profound consequences for renal function post-surgery.
