The Role of APOL1 Gene Variants in Kidney Disease: A Q&A with Madhav Menon and Shuta Ishibe

More than one in seven U.S. adults—or 14%—are estimated to have kidney disease, in which kidneys lose their ability to filter waste and toxins from the blood. When a person’s kidneys stop working, treatments such as dialysis or kidney transplant are necessary to stay alive. While diabetes and high blood pressure are risk factors for developing the disease, genetics also play a role.

Yale School of Medicine’s Madhav Menon, MD, associate professor of medicine (nephrology), and Shuta Ishibe, MD, professor of medicine (nephrology), are investigating the link between the apolipoprotein L1 (APOL1) gene and kidney disease. Below, they discuss the health disparities caused by this genetic predisposition, their recent discoveries, and the future of kidney disease treatment.

Madhav Menon: In the United States, people of African ancestry have a disproportionate risk of kidney disease. How do we know that? People of African ancestry represent 12% to 13% of the general population but represent 35% of the dialysis population with irreversible kidney failure. This suggests that they have an increased risk of kidney disease. We’ve known for some time that this risk of kidney disease has a familial clustering because it’s not always explained by high blood pressure, diabetes, or even socioeconomic status. This all points toward a genetic predisposition.

Shuta Ishibe: This significant health disparity is partly attributed to mutations in APOL1, which were discovered a little over a decade ago. To gain a comprehensive understanding of the pathobiology of this disease and advance research, Madhav and I are collaborating to learn more about how APOL1 variants increase the risk of kidney disease.

Menon: We recently studied a cohort of transplanted patients to see if there was an association between having these APOL1 variants in people who received transplants and failure of the transplanted kidney. We uncovered that transplant recipients who had the mutation seemed to have an increased risk of losing their kidney graft. This put a new spin on this research because this would suggest that there's a risk of increased graft loss associated with the person receiving the transplant, in addition to the donated kidney itself.

We found that people with APOL1 variants not only have an increased risk of graft failure but also have an increased risk of acute rejection of the graft. We then focused on immune cells, cells that would mediate this rejection of the transplanted kidney in transplant recipients with the APOL1 variants. We studied their lymphocytes, a type of white blood cell that mediates rejection, and showed that APOL1 can cause these particular cells to be activated—to be revved up—leading them to attack and reject a kidney that they recognize as foreign. So we brought out a new role of APOL1 in cells other than kidney cells.

Ishibe: Limited understanding of this disease process has hindered novel treatments, especially due to the lack of suitable animal models for study. To address this issue, we successfully created a mouse model expressing physiologic levels of human APOL1 variants.

When exposed to an inflammatory agent, interferon, these mice exhibit significant protein loss in the urine and develop kidney features like those seen in human focal segmental glomerulosclerosis, a disease in which the kidney becomes scarred. Through our investigations involving human data, we have observed that the immune system, apart from kidney cells, may significantly contribute to this disease process. Our hypothesis suggests that specific immune cells in individuals carrying G1/G2 APOL1 risk alleles release higher levels of interferon and/or other mediators, leading to kidney filtration barrier damage.

Menon: Learning more about APOL1 will advance our understanding of kidney disease in everybody, and specifically kidney disease in people of African ancestry. It will also enable us to better understand organ rejection, especially of the transplanted kidney. It is important for the kidney community to be able to classify which people who have these variants can safely donate a kidney, and what they should do once they’ve donated. For example, should they restrict salt? Should they take blood pressure medicine? Our work will have multiple, important impacts.

Ishibe: Through our research, we can establish a fundamental understanding of whether the APOL1 risk-genotype in immune cells contributes to the development of progressive kidney injury. This will fill a gap in current knowledge and could lead to the identification of new therapeutic opportunities that target either immune cells or the kidney, potentially revolutionizing the way we approach treatment for kidney diseases related to APOL1.

Yale’s Section of Nephrology is committed to excellence in patient care, research, and education with the goal for both their faculty and trainees to be national and international leaders in the field of academic nephrology. To learn more about their mission and work, visit Nephrology.