Many Black Americans thought to be at high risk of developing kidney disease have a protective genetic variant that negates the extra risk, according to a new study by Columbia researchers.
The study found that high-risk individuals who carry this variant have a risk of developing kidney disease much closer to that of the general population.
The findings will have an immediate impact on clinical practice, says study leader Simone Sanna-Cherchi, MD, associate professor of medicine at Columbia’s Vagelos College of Physicians and Surgeons.
Physicians should take a closer look at their patients and determine whether they should be reclassified based on this finding. And if their reclassified patients have kidney disease, they should look for another cause to explain their kidney problems.”
Simone Sanna-Cherchi, MD, associate professor of medicine at Columbia’s Vagelos College of Physicians and Surgeons
Based on the people in the study, Sanna-Cherchi says between 4% and 10% of patients could be reclassified, though more studies are needed to make more precise estimates.
Risk reversal
Black Americans develop kidney disease at a rate five times higher than Americans of predominantly European descent.
Much of the increased risk comes from two variants of the APOL1 gene, G1 and G2, which are more common among Africans and people of African descent. The risk for kidney disease, particularly focal segmental glomerulosclerosis (FSGS) that can lead to kidney failure, is manifested in individuals who carry two of these variants at the same time (ie, two G1, one G1 and one G2, or two G2).
About 13% of Black Americans carry one of these high-risk APOL1 combinations, which make proteins that tend to damage kidney cells.
But only a fraction of high-risk APOL1 carriers eventually develop kidney disease, suggesting that many people carry other genetic modifiers that affect risk.
The new study shows that such a modifier is hidden within the APOL1 gene itself. The researchers found that people who carry a high-risk APOL1 genotype that contains the G2 variant (that is, G1/G2 or G2/2) that also contains a second variant called N264K have a much lower risk of developing kidney disease.
“People with both of these variants have about one-eighth the risk of kidney disease than those with only APOL1 G2, essentially reducing the risk for FSGS to that of people without high-risk APOL1 genotypes,” says Sanna-Cherchi.
The finding is consistent with previous research by Sanna-Cherchi’s colleagues, who found that the N264K variant protects kidney cells grown in the lab from hyperactive APOL1 proteins created by the high-risk variants.
Implications for kidney transplantation, new drugs
Because individuals carrying G1 and G2 variants have such a high risk of developing kidney disease, kidney donations from such individuals are often discouraged because, on the one hand, a high-risk APOL1 donor would have a high risk of kidney failure after kidney donation and , on the other hand, the recipient of a high-risk kidney would have a shorter graft survival.
“This finding could expand the pool of potential kidney donors,” says Sanna-Cherchi. “We can now transfer high-risk APOL1 G2 carriers to the low-risk donor category if they are also N264K positive.”
The presence of N264K also has important implications for the APOL1-specific drugs currently in development. The new finding adds to evidence suggesting that reducing APOL1 activity would be an effective way to prevent or treat APOL1-driven kidney disease.
Consideration of N264K will also be critical for testing new APOL1 drugs.
“Individuals with N264K should not be included in the intervention arm of these clinical trials, as these individuals do not have hyperactive APOL1 proteins or a high risk of APOL1-related kidney disease,” says Sanna-Cherchi. “Our findings should allow for more precise study design.”
Next steps
Other hidden modifiers probably exist that reduce or enhance the risk of developing kidney disease among high-risk APOL1 carriers, Sanna-Cherchi says.
Because N264K is never found in individuals with the G1/G1 genotype, G1-specific genetic modifiers may exist and could be found with genotype-specific APOL1 studies that require larger sample sizes.
Source:
Journal Reference:
Gupta, Y., et al. (2023). Potent protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and renal disease. Nature communications. doi.org/10.1038/s41467-023-43020-9.
