Public Release: 

Penn researchers find females more resistant to organ damage following kidney transplant

Study compares male and female recovery to determine impact of gender, hormones on graft function

University of Pennsylvania School of Medicine

PHILADELPHIA - After a kidney transplant, women may experience decreased kidney damage from ischemia reperfusion injury compared to men due to the impact of gender-specific hormones, suggests a new preclinical study and an analysis of patient data published online in the Journal of Clinical Investigation from researchers at the Perelman School of Medicine at the University of Pennsylvania.

The stopping and starting of blood flow to an organ can cause tissue damage called ischemia reperfusion injury (IRI), which is a common cause of kidney injury. Specifically in kidney transplantation, this damage can be severe enough to cause a condition known as delayed graft function (DGF), in which the transplanted kidney does not function immediately following transplantation, causing the patient to remain on dialysis as the organ recovers. However, animal data has suggested that females may be better protected from renal IRI.

To study these effects, researchers transplanted kidneys from male-to-male, male-to-female, female-to-female, and female-to-male mice and assessed whether the change in hormonal environment changed the tolerance of an IRI event. They found that females experienced less renal IRI, even with a kidney from a male donor. The renal function was assessed by blood urea nitrogen (BUN), a blood test used to measure kidney function, and later the kidneys were examined for the formation of fibrosis -- evidence of long-lasting damage. Importantly, females treated with estrogen had even better tolerance of IRI than untreated female mice.

"What's interesting is that when a male kidney was transplanted into a female recipient, the organ eventually reacted based on the recipient's gender, and the reverse was also true," said Matthew Levine, MD, PhD, an assistant professor of Transplant Surgery and principal investigator of the study. "This indicates that the kidney's ischemia tolerance reflects its hormonal environment and indicates that hormonal treatment can have a positive effect. Males did not respond to estrogen treatment favorably, likely due to the negative impact of testosterone, but neutered male mice -- with a lack of testosterone -- did see beneficial effects with estrogen treatment."

Levine and his team also analyzed the effects of gender on human transplantation using data collected by the United Organ Sharing Network (UNOS). Evaluating kidney recipients from 1997 to 2011, researchers examined delayed draft function within the first week after transplantation in both male and female patients. The occurrence of IRI in these patients supported the earlier finding that female recipients experienced less delayed graft function, and that this effect was not explained by differences in the body size of the recipients.

"The findings from the mouse models illustrating that estrogen leads to a lower occurrence of ischemia reperfusion injury was supported by national human kidney transplant data comprised of nearly 47,000 transplant recipients," said David Aufhauser, MD, a fourth-year general surgery resident, research fellow, and a co-author of the study. "As this is the first study to our knowledge to evaluate gender effects on IRI in kidney transplantation, this data justifies further investigation into using hormones to improve kidney function after ischemia."

The data show that gender significantly affects renal IRI tolerance in mice and humans.

"While our primary interest is in transplantation, there is potential for these findings to impact the treatment of patients in other areas, such as heart and vascular surgery and trauma," said Levine. "While more research is definitely needed, these initial results imply a potential for therapeutic intervention with estrogen to improve ischemia tolerance, at least in female patients."

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Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.

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