Improved renal ischemia tolerance in females influences kidney transplantation outcomes

Acute kidney injury occurs with kidney transplantation and too frequently progresses to the clinical diagnosis of delayed graft function (DGF). Poor kidney function in the first week of graft life is detrimental to the longevity of the allograft. Challenges to understand the root cause of DGF include several pathologic contributors derived from the donor (ischemic injury, inflammatory signaling) and recipient (reperfusion injury, the innate immune response and the adaptive immune response). Progressive demand for renal allografts has generated new organ categories that continue to carry high risk for DGF for deceased donor organ transplantation. New therapies seek to subdue the inflammatory response in organs with high likelihood to benefit from intervention. Future success in suppressing the development of DGF will require a concerted effort to anticipate and treat tissue injury throughout the arc of the transplantation process. ©2011 The Authors Journal compilation © 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.

Several useful behavioral tests exist for measuring behavioral recovery after ischemia in higher-order animals and rats. With the increasing use of mice in focal stroke research, simple, reliable, and reproducible behavioral testing has become a priority. As neuroprotective agents are tested, long-term outcome must be assessed, especially in studies focused on neuronal plasticity and regeneration after ischemia. Our laboratory and others have previously shown that estrogen (E2) is neuroprotective in rodent stroke paradigms. We examined a battery of behavioral tests in male and female mice subjected to 90 min of middle cerebral artery occlusion (MCAO) to determine the most sensitive tests for detecting sensorimotor dysfunction after stroke, and to determine the functional significance of E2-mediated neuroprotection. Only two tests, the corner test and the cylinder test, were able to differentiate between groups (sham and stroke) after several days of repeated testing. The cylinder test was sensitive to the neuroprotective/neurorestorative effects of E2, but 2 weeks after stroke, the cylinder test was unable to distinguish between sham and stroke animals treated with E2. In contrast, the corner test was able to differentiate stroke and sham animals even 6 weeks after stroke, but did not distinguish animals treated with E2 vs. vehicle. These tests provide a simple, rapid, reliable assessment of sensorimotor dysfunction in the mouse after focal ischemia. Hormonal status influences speed of recovery on cylinder testing in animals of both genders. This suggests that a short battery of tests including the neurological score, cylinder, and corner test may be adequate to rapidly and repeatedly assess sensorimotor dysfunction in mice of both genders.

Postischemic organ dysfunction is influenced by gender and sexual steroids. To compare the susceptibility of the kidney to postischemic failure between sexes, the left vascular pedicle was clamped for 50 minutes in anesthetized male and female Wistar rats. Survival rate, renal and systemic hemodynamics and renal prepro-endothelin (pp-ET) mRNA expression were measured. Eight percent of males as compared to 75% of females survived for more than 7 days. Previous orchidectomy of mature rats or sexual immaturity improved the rate of 7 day survival to 67% and 58%, respectively, as compared to intact males (P < 0.05). Estradiol treatment of mature male animals also resulted in a significantly better survival. Ovariectomy, sexual immaturity or testosterone treatment had no impact on the course of renal failure in females. The early postischemic recovery of renal blood flow was delayed due to a dramatic increase in renal vascular resistance in male versus female rats. The expression of pp-ET gene in the kidneys was increased at 5 minutes following reperfusion and was significantly higher 2 hours after ischemia in males, but not in females. Pretreatment with the endothelin A receptor antagonist LU 135252 provided indistinguishable survival rates in intact male and female rats after warm renal ischemia. Female rats enjoy relative protection against postischemic renal failure. Furthermore, in intact males the effects of androgens upon ischemic kidney damage seem to be mediated by endothelin-induced vascular changes.