From one gene, many deaths
Black Americans are disproportionately affected by kidney disease, and there’s a genetic factor to blame
In a Zoom call this spring with 19 leaders of AME Zion church congregations in North Carolina, Dr. Opeyemi Olabisi, a kidney specialist at Duke University, asked a personal question: How many of you know someone — a friend, a relative, a family member — who has had kidney disease?
The anguished replies tumbled out from the assembled pastors:
A childhood friend died, leaving a daughter behind.
A father and sister felled by the disease.
Uncles and sons lost.
Three cousins and a brother-in-law on dialysis.
None of this surprised Olabisi, who disclosed that he, too, had lost family members to the disease.
His best friend, who had taught him to ride a bike in his native Nigeria, died of kidney failure in his early 30s.
Kidney specialists have long known that Black Americans are disproportionately affected by kidney disease. Although Black people make up about 12% of the U.S. population, they account for 35% of Americans with kidney failure. Black patients tend to contract kidney disease at younger ages, and damage to their organs often progresses faster.
Social disparities and systemic racism contribute to this burden, but there is also a genetic factor. Many with sub-saharan ancestry have a copy of a variant of the gene APOL1 inherited from each parent, which puts them at high risk. Researchers have known for a decade that APOL1 is one of the most powerful genes underlying a common human disease.
But there is hope now that much of this suffering can be alleviated. As many as 10 companies are working on drugs to target the APOL1 variants. And Olabisi has a federal grant to test whether baricitinib, a drug that treats rheumatoid arthritis, can help kidney patients with the variants.
Yet the promise of treatments comes with difficult questions. Should genetic testing be offered and, if so, to whom? Although the variants increase risk, they do not preordain kidney disease. If someone knows that they have the variants, will they live in fear of kidney failure?
Farmer provides a clue
Although it has long been known that kidney failure occurs in African Americans five times as often as it does in white Americans, “We had never been able to understand all the reasons,” said Dr. Neil Powe, a professor of medicine and an epidemiologist at the University of California, San Francisco.
Researchers began looking for a genetic cause. Finally, a little more than a decade ago, a Harvard team led by Giulio Genovese, Dr. David Friedman and Dr. Martin Pollak found it: variants of APOL1 that ramped up the gene’s activity.
It was a complete surprise. APOL1 is part of the immune system and can destroy trypanosomes — protozoa that can cause illnesses. But no one expected it to have anything to do with the kidneys.
It turns out that the variants rose to a high frequency among people in sub-saharan Africa because they offer powerful protection against deadly African sleeping sickness, a disease caused by trypanosomes.
It is reminiscent of another gene variant that protects against malaria but causes sickle cell disease in those who inherit two copies. That variant became prominent in parts of Africa and other areas of the world where malaria is common, but sickle cell variants are much less common than
APOL1 risk variants.
About 39% of Black Americans have one copy of the gene’s risk variants; another 13%, or nearly 5.5 million, have two copies. Those with two copies are at increased risk for fast progressing kidney disease that often starts in young adulthood. Approximately 15% to 20% of those with two copies develop kidney disease.
In contrast, 7.7% of Americans with African ancestry have one copy of the sickle cell variant, and 0.3% have two copies.
“What nature gave with one hand, it took away with the other,” Olabisi said.
One way to treat kidney disease might be using medicines that block the gene and its variants from acting in the body. But
researchers had to find out if APOL1 was necessary for kidney function. If it was, drugs that blocked it might do more harm than good.
Researchers found an answer: A farmer in India had no APOL1 gene. His kidneys were totally healthy.
Often, in drug development, Friedman said, the drug dose has to be fine-tuned — too much is dangerous and too little is useless. The discovery of the farmer, he said, “tells you you can probably drive the level of the APOL1 protein very low.”
But ethical issues have tempered some experts’ enthusiasm about the genetic discoveries.
Harriet Washington, a lecturer in ethics at Columbia
University and author of the book “Medical Apartheid,” worries that knowledge of the role of APOL1 variants can drive the medical establishment toward “a blame-the-victim approach signaling an inherent flaw in African Americans.”
The implication, she said: “This is something happening in nature, so what can we do about it?” Such an attitude, she added, “invites futility and absolves health care from treating sufferers.”
From a gene to drugs
While Olabisi is waiting to start his study, a drug company, Vertex, has forged ahead with its own research. But there was no agreement on how APOL1 variants caused kidney disease, so it was not clear what a drug was supposed to block.
“If you don’t understand the mechanism, that means you can’t measure effects in a lab,” said Dr. David Altshuler, chief scientific officer at Vertex. “And if you can’t measure effects in the lab, that means you can’t correct them.”
It was known how the APOL1 protein protected against sleeping sickness — it punched holes in the disease-causing trypanosomes, making them swell with fluid and burst. Vertex researchers hypothesized that the variants spurred APOL1 proteins to punch holes not just in trypanosomes but also in kidney cells.
What followed was years of work in lab studies and in animals given genes for human APOL1 variants and then screening about 1 million compounds that might block APOL1.
Finally, the researchers settled on a drug that worked in animal models.
Vertex tested the experimental drug in a 13-week study in patients with advanced kidney disease. The drug reduced the amount of protein in their urine by 47.6%, a sign of improved kidney function.
Recently, the company announced it would take the next step — a clinical trial that would enroll approximately 66 patients in the first phase, to find the best dose, and 400 in the next phase, to see if the drug could improve kidney functions in patients with the risk variants and kidney damage and protect them from developing kidney failure or dying.
Using their pulpits
At the meeting with the pastors in North Carolina, Olabisi said he hoped to test 5,000 Black members of the community for kidney disease with a simple urine test and to use a saliva test to detect APOL1 variants. Testing of the arthritis drug would follow.
“I’m in,” said the Rev. Daran Mitchell, pastor of Trinity AME Zion Church in Greensboro.
He and the other pastors were enthusiastic. It would be a community effort and promoted on social media. Subjects could be tested in churches or in community centers or in their homes. And it was a way to advance the day when a treatment would be available.
Olabisi smiled.
“This gives me energy and a lot of hope,” he said.