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Zhe Han

$2M NIH grant for treating disease linked to APOL1

Zhe Han

Children’s researcher Zhe Han, Ph.D., has received a $2 million award from the National Institutes of Health (NIH) to study new approaches to treat kidney disease linked to inheriting Apolipoprotein L1 (APOL1) risk alleles. These risk alleles are particularly common among persons of recent African descent, and African Americans are disproportionately affected by the increased risk in kidney disease associated with these risk alleles.

Han, an associate professor in Children’s Center for Genetic Medicine Research, has established a leading research program that uses the fruit fly Drosophila as a model system to study how genetic mutations lead to disease.

Drosophila is a very basic model, but studies in the fly have led to major breakthroughs in understanding fundamental biological processes that underlie health and disease in humans,” Han says. “Since coming to Children’s National five years ago, I have focused a significant part of my research studying particular fly cells called nephrocytes that carry out many of the important roles of human kidney glomeruli, units within the kidney where blood is cleaned. Working together with clinician colleagues here, we have demonstrated that these Drosophila cells can be used to very efficiently study different types of renal disease caused by genetic mutations.”

The APOL1 risk alleles are genetic variants, termed G1 and G2, found almost exclusively in people of African ancestry and can lead to a four-fold higher risk of end-stage kidney disease, the last of five stages of chronic kidney disease. Exactly how inheriting these risk alleles increases the risk of kidney disease remains an unanswered question and the focus of considerable research activity. Han’s laboratory has developed a Drosophila model of APOL1-linked renal disease by producing the G1 and G2 forms of APOL1 specifically in nephrocytes. This led to defects in fly renal cells that strikingly overlap with disease-associated changes in experimental model and human kidney cells expressing APOL1 risk alleles.

The new NIH award will fund large-scale screening and functional testing to identify new treatment targets and new drugs to treat kidney disease linked to APOL1. Using a genetic screening approach, Han’s lab will identify nephrocyte “modifier” genes that interact with APOL1 proteins and counter the toxic effects of risk-associated G1 and G2 variants.

The team also will identify nephrocyte genes that are turned on or off in the presence of APOL1 risk alleles, and confirm that such “downstream” APOL1-regulated genes are similarly affected in experimental model and human kidney cells. The potential of the newly identified “modifier” and “downstream” genes to serve as targets of novel therapeutic interventions will be experimentally tested in fly nephrocytes in vivo and in cultured mammalian kidney cells.

Finally, the Drosophila model will be used as a drug screening platform for in vivo evaluation of positive “hits” from a cell-based APOL1 drug screening study in order to identify compounds that are most effective with the fewest side effects.

“These types of studies can be most efficiently performed in Drosophila,” Han adds.  “They take advantage of the speed and low cost of the fly model system and the amazing array of well-established, sophisticated genetic tools available for the fly. Using this model to elucidate human disease mechanisms and to identify new effective therapies has truly become my research passion.”

Nichole Jefferson and Patrick Gee

African American stakeholders help to perfect the APOLLO study

Nichole Jefferson and Patrick Gee

Nichole Jefferson and Patrick O. Gee

African Americans who either donated a kidney, received a kidney donation, are on dialysis awaiting a kidney transplant or have a close relative in one of those categories are helping to perfect a new study that aims to improve outcomes after kidney transplantation.

The study is called APOLLO, short for APOL1 Long-Term Kidney Transplantation Outcomes Network. Soon, the observational study will begin to enroll people who access transplant centers around the nation to genotype deceased and living African American kidney donors and transplant recipients to assess whether they carry a high-risk APOL1 gene variant.

The study’s Community Advisory Council – African American stakeholders who know the ins and outs of kidney donation, transplantation and dialysis because they’ve either given or  received an organ or are awaiting transplant – are opening the eyes of researchers about the unique views of patients and families.

Already, they’ve sensitized researchers that patients may not be at the same academic level as their clinicians, underscoring the importance of informed consent language that is understandable, approachable and respectful so people aren’t overwhelmed. They have encouraged the use of images and color to explain the apolipoprotein L1 (APOL1) gene. The APOL1 gene is found almost exclusively in people of recent African descent, however only 13 percent of these people carry the high-risk APOL1 variant that might cause kidney problems.

One issue arose early, during one of the group’s first monthly meetings, as they discussed when to tell patients and living donors about the APOLLO study. Someone suggested the day of the transplant.

“The Community Advisory Council told them that would not be appropriate. These conversations should occur well before the day of the transplant,” recalls Nichole Jefferson.

“The person is all ready to give a kidney. If you’re told the day of transplant ‘we’re going to include you in this study,’ that could possibly stop them from giving the organ,” Jefferson says. “We still remember the Tuskegee experiments. We still remember Henrietta Lacks. That is what we are trying to avoid.”

Patrick O. Gee, Ph.D., JLC, another Community Advisory Council member, adds that it’s important to consider “the mental state of the patient and the donor. As a patient, you know you are able to endure a five- to eight-hour surgery. The donor is the recipient’s hero. As the donor, you want to do what is right. But if you get this information; it’s going to cause doubt.”

Gee received his kidney transplant on April 21, 2017, and spent 33 days in the hospital undergoing four surgeries. His new kidney took 47 days to wake up, which he describes as a “very interesting journey.” Jefferson received her first transplant on June 12, 2008. Because that kidney is in failure, she is on the wait list for a new kidney.

“All I’ve ever known before APOLLO was diabetes and cardiovascular issues. Nobody had ever talked about genetics,” Gee adds. “When I tell people, I tread very light. I try to stay in my lane and not to come off as a researcher or a scientist. I just find out information and just share it with them.”

As he spoke during a church function, people began to search for information on their smart phones. He jotted down questions “above his pay grade” to refer to the study’s principal investigator. “When you start talking about genetics and a mutated gene, people really want to find out. That was probably one of the best things I liked about this committee: It allows you to learn, so you can pass it on.”

Jefferson’s encounters are more unstructured, informing people who she meets about her situation and kidney disease. When she traveled from her Des Moines, Iowa, home to Nebraska for a transplant evaluation, the nephrologist there was not aware of the APOL1 gene.

And during a meeting at the Mayo Clinic with a possible living donor, she asked if they would test for the APOL1 gene. “They stopped, looked at me and asked: ‘How do you know about that gene?’ Well, I’m a black woman with kidney failure.”

Patrick O. Gee received his kidney transplant on April 21, 2017, and spent 33 days in the hospital undergoing four surgeries. His new kidney took 47 days to wake up, which he describes as a “very interesting journey.”

About 100,000 U.S. children and adults await a kidney transplant. APOLLO study researchers believe that clarifying the role that the APOL1 gene plays in kidney-transplant failure could lead to fewer discarded kidneys, which could boost the number of available kidneys for patients awaiting transplant.

Gee advocates for other patients and families to volunteer to join the APOLLO Community Advisory Council. He’s still impressed that during the very first in-person gathering, all researchers were asked to leave the table. Only patients and families remained.

“They wanted to hear our voices. You rarely find that level of patient engagement. Normally, you sit there and listen to conversations that are over your head. They have definitely kept us engaged,” he says. “We have spoken the truth, and Dr. Kimmel is forever saying ‘who would want to listen to me about a genotype that doesn’t affect me? We want to hear your voice.’ ”

(Paul L. Kimmel, M.D., MACP, a program director at the National Institute of Diabetes and Digestive and Kidney Diseases, is one of the people overseeing the APOLLO study.)

Jefferson encourages other people personally impacted by kidney disease to participate in the APOLLO study.

“Something Dr. Kimmel always says is ‘You’re in the room.’ We’re in the room while it’s happening. It’s a line from Hamilton. That’s a good feeling,” she says. “I knew right off, these are not necessarily improvements I will see in my lifetime. I am OK with that. With kidney disease, we have not had advances in a long time. As long as my descendants don’t have to go through the same things I have gone through, I figure I have done my part. I have done my job.”

little girl in hosptial corridor

A growing list of factors that impact CKD severity for kids

little girl in hosptial corridor

Myriad biological and societal factors can impact the occurrence and accelerate progression of chronic kidney disease for children of African descent – including preterm birth, exposure to toxins during gestation and lower socioeconomic status – and can complicate these children’s access to effective treatments.

Myriad biological and societal factors can impact the occurrence and accelerate progression of chronic kidney disease (CKD) for children of African descent – including preterm birth, exposure to toxins during gestation and lower socioeconomic status – and can complicate these children’s access to effective treatments, according to an invited commentary published in the November 2018 edition of American Journal of Kidney Diseases.

Clinicians caring for “these vulnerable children should be mindful of these multiple competing and compounding issues as treatment options are being considered along the continuum from CKD to kidney failure to transplantation,” writes Marva Moxey-Mims, M.D., chief of the Division of Nephrology at Children’s National Health System.

The supplemental article was informed by lessons learned from The Chronic Kidney Disease in Children (CKiD) longitudinal study and conversations that occurred during the Frank M. Norfleet Forum for Advancement of Health, “African Americans and Kidney Disease in the 21st Century.”

African American children represent 23 percent of the overall population of kids with CKD in the CKiD study. While acquired kidney diseases can get their start during childhood when the diseases betray few symptoms, the full impact of illness may not be felt until adulthood. A number of factors can uniquely affect children of African descent, heightening risk for some kids who already are predisposed to suffering more severe symptoms. These include:

  • Preterm birth. African American children make up 36 percent of patients in CKiD with glomerular disease, which tends to have faster progression to end-stage renal disease. These diseases impair kidney function by weakening glomeruli, which impairs the kidneys’ ability to clean blood. Patients with a high-risk apolipoprotein L1 (APOL1) genotype already are at higher risk for focal segmental glomerulosclerosis (FSGS) and CKD. Researchers hypothesize that preterm birth may represent “a second hit that facilitates the development of glomerular damage resulting from the high-risk genotype.” According to the Centers for Disease Control and Prevention, 1 in 10 U.S. infants in 2016 was born preterm, e.g., prior to 37 weeks gestation.
  • APOL1 genotype. Compared with children who had a low-risk genotype and FSGS, children with a high-risk genotype had higher rates of uncontrolled hypertension, left ventricular hypertrophy, elevated C-reactive protein levels and obesity.
  • Human immunodeficiency viral (HIV) status. About 65 percent of U.S. children with HIV-1/AIDS are African American. In a recent nested case-control study of children infected with HIV in the womb, infants with high-risk APOL1 genotypes were 3.5 times more likely to develop CKD with viral infection serving as “a likely second hit.”
  • Access to kidney transplant. African American adults experience a faster transition to end-stage renal disease and are less likely to receive kidney transplants. African American children with CKD from nonglomerular diseases begin renal replacement therapy 1.6 years earlier than children of other races, after adjusting for socioeconomic status. Their wait for dialysis therapy was 37.5 percent shorter. However, these African American children waited 53.7 percent longer for transplants. Although donor blood types, genetic characteristics and other biological factors each play contributing roles, “these findings may reflect sociocultural and institutional differences not captured by socioeconomic status,” Dr. Moxey-Mims writes.

To alleviate future health care disparities, she suggests that additional research explore the impact of expanding services to pregnant women to lower their chances of giving birth prematurely; early childhood interventions to help boost children’s educational outcomes, future job prospects and income levels; expanded studies about the impact of environmental toxicities on prenatal and postnatal development; and heightened surveillance of preterm infants as they grow older to spot signs of kidney disease earlier to slow or prevent disease progression.

“Clinicians can now begin to take into account genetics, socioeconomic status and the impact of the built environment, rather than blaming people and assuming that their behavior alone brought on kidney disease,” Dr. Moxey-Mims adds. “Smoking, not eating properly and not exercising can certainly make people vulnerable to disease. However, there are so many factors that go into developing a disease that patients cannot control: You don’t control to whom you’re born, where you live or available resources where you live. These research projects will be useful to help us really get to the bottom of which factors we can impact and which things can’t we prevent but can strive to mitigate.”

The article covered in this post is part of a supplement that arose from the Frank M. Norfleet Forum for Advancement of Health: African Americans and Kidney Disease in the 21st Century, held March 24, 2017, in Memphis, Tennessee. The Forum and the publication of this supplement were funded by the Frank M. Norfleet Forum for Advancement of Health, the Community Foundation of Greater Memphis and the University of Tennessee Health Science Center.