Findings Support Wake Forest Genetic Research on Kidney Transplantation

Nephrologists who recently convened in Philadelphia for an International Conference learned that transplanted kidneys were more likely to fail if they came from deceased donors with two risk variants in a major kidney failure gene.

The study confirms findings from Barry I. Freedman, MD, chief of nephrology at Wake Forest Baptist Medical Center. The new results were based on data from 675 kidney transplantations from deceased African-American organ donors; transplantations were performed at 55 U.S. centers.

Freedman has worked for more than 20 years to prove that kidney failure in African-Americans was often the result of gene mutations. In 2010, his group was part of a three-center team that published a study showing that people with two renal risk variants in the APOL1 gene were more susceptible to kidney failure. Kidney disease risk variants in the APOL1 gene are limited in most cases to populations with recent African ancestry, including African-Americans.

One year later, Freedman published a single-center Wake Forest study demonstrating that transplanted kidneys from donors with two APOL1 gene kidney disease risk variants failed more quickly after transplantation than did kidneys from donors with fewer than two risk variants.

Kidney-Transplantation

The latest results reported at the 2014 American Society of Nephrology Kidney Week came from a multicenter study including the University of Alabama at Birmingham, Emory University, the University of Minnesota and Wake Forest.

“Based on the confirmatory results, routine genotyping for APOL1 kidney disease risk variants should be considered at the time of organ harvest to assist in the allocation process,” Freedman said. “The new results show that APOL1 genotyping is no longer simply a research tool, but may have clinical benefit.”

Why Genotyping for Kidney Transplantation?

Approximately 13 percent of African-Americans possess two APOL1 renal risk variants and are at increased risk for kidney disease. The new study found that 22.3 percent of kidney transplants from deceased donors with two APOL1 renal risk variants failed within three years, compared with 14.8 percent of those from donors with fewer than two renal risk variants.

Freedman said that this is a dramatic difference and shows that “APOL1 gene variants in deceased donor kidneys, more so than those in transplant recipients underlie earlier transplant kidney failures related to the powerful APOL1 gene.”

A paper detailing the study was published in the March 24 issue of the American Journal of Transplantation.

Freedman said that these data may lead to routine genotyping of deceased kidney donors with recent African ancestry, so those with two APOL1 gene renal risk variants can be identified quickly.

Kidneys from donors with two renal risk variants, although at higher risk for allograft failure after transplantation, should not be eliminated from consideration for transplantation, he said. Rather, these higher risk kidneys could be considered for “expanded criteria” donation. Younger and healthier patients who require a kidney transplant may prefer to wait for genetically lower risk kidneys to become available.

Freedman is working with Wake Forest Innovations to help develop an easy, affordable genotyping test for providers.

A National Reputation in Kidney Transplantation

Wake Forest Baptist has long been a national leader in the study of chronic kidney disease in African-Americans, as a result of Freedman’s observations in patients treated in the nation’s largest academic network of dialysis centers.

Freedman challenged the accepted theory that kidney disease in African-Americans was often caused by high blood pressure, because he saw that blood pressure medications did little to remediate or prevent progression of kidney disease.

When the APOL1 gene renal risk variants were shown to be a cause of the kidney disease, it proved Freedman’s theory. It was the patient’s genetic make-up that caused the kidney disease and resulted in secondarily elevated blood pressure, not the other way around.

Freedman said that in addition to rapid genotyping to improve kidney transplant outcomes, further research should lead to breakthroughs that may counter the effects of renal risk variants in APOL1 and prevent kidney disease from developing.

“Most people with two APOL1 renal risk variants do not develop kidney disease,” he said. “Modifiable second hits that trigger APOL1-associated kidney disease appear to exist, and such factors provide great hope for a cure for this spectrum of kidney disease.”

Contact Wake Forest Innovations to learn more about Dr. Freedman’s research and schedule a meeting to discuss potential partnerships.

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