Charting New Waters


Barry Freedman’s Quest to Redefine Kidney Disease and Revolutionize Kidney Transplantation

During his 30-year career in nephrology at Wake Forest Baptist Medical Center, Barry Freedman, MD, has treated hundreds of African-American patients.

Many have been referred to him for hypertension. When they first come into his office, he runs the standard tests. To many, he delivers the same news: they have easily treatable high blood pressure, their kidney function is normal and they have no evidence of a kidney disease.

In the face of what should be relatively good news, many patients still have the same response—they ask their doctor when the dialysis treatments will start.

At the dawn of his career, this question seemed surprising. Why would a patient who was just told their kidneys were fine assume they would eventually need dialysis?

To a person, they gave the same answer: everyone in their family had been told that their kidneys were fine when they were first diagnosed with hypertension. But after a few years, all ended up on dialysis.

The question from his patients raised a question of its own, one that would launch a 20-year odyssey for Freedman:

Do our patients know something that we don’t?

Listening to the Call


“Part of being a good doctor is listening to your patients,” Freedman says. And his patients will tell you that he does listen.

“He’s a blessing,” says Eric McAllister. “We are close. He knows my family, and he’s a brother. We’re like cornbread and pinto beans, peanut butter and jelly.”

McAllister has been on dialysis for 30 years, since he was a freshman in college. For 29 of those year, Freedman has been his doctor.

Kidney disease is a serious concern for McAllister and many other people of African descent. In the United States, African-Americans are more than three times as likely as European-Americans to develop kidney failure in their lifetime. African-Americans comprise 13 percent of the United States population; however, they make up 32 percent of patients requiring kidney dialysis treatments—a disproportionate percentage.

Freedman had learned what all nephrologists are taught in medical school: that essential hypertension often leads to kidney disease in African-Americans. Doctors called this condition “hypertensive kidney failure,” meaning that high blood pressure directly damaged the kidneys.

But Freedman noticed an unrecognized factor in his African-American patients.

Within these patients’ families, there was strong clustering of kidney disease. Within a single family, four or five members were often on dialysis, and they had different causes of kidney disease, including cases attributed to hypertension—something that Freedman never saw in his European-American patients.

Freedman became suspicious that genetics was playing a role in this pattern of kidney disease, a thought contrary to textbook knowledge.

“I couldn’t ignore it,” says Freedman. “For decades, conventional wisdom said that kidney disease was caused by hypertension, but what I was seeing in the clinic was a hereditary component to kidney disease. There was likely a genetic cause, and my patients knew it, even if their doctors didn’t.”

By the early 1990s, Freedman was convinced of a link and openly proposed that many families with African ancestry were inheriting gene variants that predisposed them to several different kidney diseases caused by a variety of factors, including lupus, HIV infection and glomerulosclerosis. Different triggers might lead to different kinds of kidney disease in a family, but their susceptibility to kidney disease had the same genetic root.

Freedman’s assertion began an arduous journey. Not only would he need to identify the genetic culprit, he would also need to convince the medical community.

Crossing the Threshold


To follow his theory about the cause of his patients’ kidney disease, Freedman would have to enter uncharted waters.

“I was trained as a clinician, but I would have to become a clinician-researcher,” Freedman says.

In 1991, he approached geneticists at Wake Forest Baptist about helping to identify the genetic cause of kidney disease.

“The beauty of working at Wake Forest Baptist is that it is a community of clinicians and researchers who complement each other’s expertise,” says Freedman.

The genetics team, led by Donald Bowden, PhD, director of Wake Forest Baptist’s Center for Diabetes Research, initially gave him $5,000 to collect DNA samples from African-Americans with kidney disease.

“They thought I’d bring back 50 samples,” he says with a smile. Instead, with the help of patients like McAllister, who donated a blood sample, Freedman brought hundreds in just a couple of months.

Those samples would become the basis for one of the largest DNA repositories in existence of samples from African-Americans with kidney disease, one that has now grown to some 30,000 samples. This repository makes Wake Forest Baptist a leading institution in kidney disease research.

Tackling the Obstacles


Freedman’s search for a genetic cause of kidney disease had many detractors, and they weren’t shy about saying so.

Early in his research career, Freedman and his colleagues would write grants for studies that were met with tremendous resistance. Journals rejected some of their work, and reviewers reviled their findings.

“But the best time to do research is when no one believes in you: there’s less competition,” Freedman says. “I’m pretty persistent, and I knew in my gut that we were right.”

Freedman’s allies on his journey were instrumental to the discovery of the APOL1 kidney failure gene. As his research made it increasingly likely that there was a genetic basis for kidney disease in African-Americans, other groups began to search for these genes as well. Freedman teamed up with investigators from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and from Beth Israel Deaconess Medical Center in Boston, Massachusetts.

It would take several years, but these institutions eventually found evidence that changed the narrative on kidney disease.

In 2010, researchers at Beth Israel identified APOL1 as the gene causing focal segmental glomerulosclerosis (FSGS), a common cause of non-diabetic kidney disease in African-Americans. Freedman’s DNA samples proved that APOL1 was further associated with other kidney diseases in people with recent African ancestry.

Kidney Disease Infographic

For many African-Americans, finding APOL1 explained the origins of their disease, which would not have been possible without the generous donation of patients.

Twenty years after Freedman first asserted that a genetic cause of kidney disease existed in many African-Americans, Wake Forest Baptist, Beth Israel and NIDDK published their findings on APOL1 in the journal Science—forever changing the way the medical field looks at kidney failure.

Improving Kidney Donation


For Freedman, the identification of these gene variants—made possible by the contributions of many organizations—was only the first phase of the journey.

Performing a genetic screen for APOL1 is not complicated, but it takes time—sometimes weeks—to get results. Freedman thought that if he could shorten the time, rapid screening could be used in a critical area: decisions on kidney donation and allocation.

“Kidney transplants are unique procedures; they rapidly bring sick people back to good health,” says Freedman. “However, it’s been known for years that kidneys donated by African-Americans failed more quickly after transplantation than kidneys donated by European-Americans.”

Where does APOL1 come from and how many people are affected?


APOL1 is a gene that all humans possess. Two specific variations in the APOL1 gene cause non-diabetic kidney disease and are present almost exclusively in people with recent African ancestry, including African-Americans. If people inherit two copies of the risk variants—one from each parent—they are at increased risk for kidney disease.

No one knew why this discrepancy existed.

“Anytime different outcomes exist for kidney disease in African-Americans and European-Americans, an APOL1 influence needs to be investigated,” says Freedman.

He studied the function and survival of African-American deceased donor kidneys that were transplanted. He found that kidneys with two APOL1 risk variants had a higher rate of early graft failure when compared to kidneys with no risk variants or even one risk variant.

Transplanted kidneys are precious. There simply aren’t enough to go around. Freedman believed that the APOL1 gene test could be used to identify African-American kidney donors at lower risk for kidney disease. The test could also reduce the number of kidneys that were discarded from deceased kidney donors—increasing the number of transplantations performed and helping more patients get off dialysis.

His focus became making the APOL1 gene test easily accessible to organ donors and physicians.

Moving It Forward


To take the next step, Freedman needed an ally.

“When Barry came knocking at my door, he had a research approved test and outcomes data from clinical research programs, but he needed a way to change kidney donation,” says Sarah Haigh Molina.

Haigh Molina is the associate director of innovation with the Center for Technology Innovation & Commercialization at Wake Forest Innovations. The Center accelerates the development and commercialization of inventions at Wake Forest Baptist, and Haigh Molina runs the development program for diagnostics technologies.

Freedman approached Wake Forest Innovations seeking assistance in developing and commercializing a clinical APOL1 test for organ donation.

Kidney Donation Infographic

“This was unlike anything that we had commercialized before,” says Haigh Molina. But the evidence was overwhelming. Given the robustness of the data that Freedman presented, making the test available was not just an option—it was an ethical obligation.

“We called it the ‘Oprah Winfrey test,’ Haigh Molina says with a laugh. “We couldn’t stand on Oprah’s stage and defend not making this test.”

Wake Forest Innovations, led by Haigh Molina, continues to work with Beth Israel to pursue patent protection for the use of the APOL1 gene test as a method of selecting kidneys for transplantation and provided some of the necessary resources and funding to create an approved Clinical Laboratory Improvement Amendment (CLIA) test—the regulatory standard for this type of diagnostic test—that could be administered on kidney donations.

Commercialization is not easy, and many groups and individuals contributed to getting the test CLIA-approved, including the Human Leukocyte Antigen (HLA) CLIA Laboratory at Wake Forest Baptist that advanced the test through the regulations.

Getting the test CLIA-approved was just the first obstacle. Transplantation is a complex business that requires the seamless integration of many systems including clinical, regulatory, billing, organ procurement and many more.

“We got to a point where I didn’t know how to navigate this system to get the test in the hands of physcians who could, in turn, impact our patients lives,” says Haigh Molina.

Freedman, however, was not daunted. He called a meeting of the minds. He gathered a cadre of people from different areas of the hospital: transplant surgeons, commercialization experts, workers from finance and operating divisions, as well as representatives from organ procurement organizations.

Looking back, Haigh Molina says that meeting was essential. “Answers started cropping up,” says Haigh Molina. “The round table of experts each offered resources to make this technology a reality.”

Reaping the Rewards


Today the APOL1 Testing Service is available through Wake Forest Baptist as an inexpensive and convenient personalized genetic test that reports on risk for non-diabetic nephropathy and accelerated failure of transplanted kidneys from organ donors.

Wake Forest Baptist offers the only “rapid turn-around” CLIA-approved APOL1 test in the United States. Results can be provided in less than 72 hours of receipt of the blood or tissue sample or, in some cases, within four hours for deceased donors. This swift turn-around could help transplant physicians make quick decisions on kidney allocations.

“The APOL1 test is highly predictive of kidney transplantation outcomes and kidney disease, more predictive than many other factors currently used,” says Freedman.

For this reason, Freedman and his colleagues are advocating that all deceased African-American donors of kidneys be screened for the risk variants in this gene. Potential African-American living kidney donors should also be aware that testing is available and discuss being tested with their physicians.

“Medical centers, organ donation organizations and physicians can send blood samples here to perform quick screenings for APOL1 kidney disease variants, whether for diagnosing patients or organ donation,” says Haigh Molina.

But Freedman is not done yet.

Freedman6

APOL1 holds the clue to curing kidney disease in many of our patients,” he says. “I expect that in my practice lifetime novel treatments for kidney disease will be developed based on APOL1. It’s opening up new horizons for therapy.”

“We are going to find a cure,” says Freedman. “It’s simply a matter of time.”

For more information on APOL1 testing, go to Wake Forest’s APOL1 Testing Service and learn about our rapid turn-around test for kidney donation.

Story by Jessica Brown.

 

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