Updated testing protocol may improve kidney disease diagnosis in Black patients

A closer examination of the APOL1 gene in Black patients with kidney disease can provide more accurate diagnoses than current protocols, a new study from researchers at Columbia University Vagelos College of Physicians and Surgeons has found. Accurate diagnosis is important as treatments for kidney disease depend on the disease’s root causes and will take on more importance when treatments in development for APOL1 kidney disease become available.

Genes raise risk of kidney disease in Black Americans

Kidney disease is five times more common in Black Americans than Americans with predominantly European ancestry. Most of the increased risk is genetic: About 13% of people with West and Central African ancestry have inherited versions of the APOL1 gene that raise the risk of developing kidney disease.

However, most people who carry these high-risk APOL1 genotypes never develop kidney disease, making it difficult for physicians to determine when APOL1 is truly the cause in individual patients.

Looking within APOL1

The new study, published in JAMA Network Open, shows that a closer examination of the APOL1 gene in patients with chronic kidney disease can more accurately determine the cause of their kidney disease, and potentially alter their diagnosis, risk stratification, transplant evaluation, and treatment.

The findings build on the group’s earlier research, which demonstrated that in some seemingly high-risk APOL1 genotype carriers, the presence of a genetic safeguard called M1 (APOL1 p.N264K) neutralizes the harmful effects of a high-risk APOL1 genetic variant. (The high-risk genotypes produce a protein that can damage the kidney.)

The new study asked if the presence of M1 could help doctors determine the true cause of a patient’s kidney disease. The researchers examined the health records and available biopsy data from approximately 107,000 individuals from two large academic medical centers. They found that nearly all patients with chronic kidney disease who carried both an APOL1 high-risk genotype and M1 did not have APOL1 kidney disease.

“When patients with APOL1 high-risk genotypes also carry M1, clinicians should conduct a complete diagnostic work-up, which might include a kidney biopsy, to evaluate for alternative, non-APOL1—potentially treatable—causes of kidney disease, rather than assuming that APOL1 is responsible,” says study leader Simone Sanna-Cherchi, MD, associate professor of medicine at Columbia’s Vagelos College of Physicians and Surgeons.

In this large cohort, approximately 3% of individuals with chronic kidney disease classified as APOL1 high-risk had the M1 variant and may warrant reclassification following comprehensive clinical evaluation.

Reducing the risk of misdiagnosis

“These results reinforce the knowledge that APOL1 genetic testing is incomplete without reporting M1 status,” says Elena Martinelli, MD, the first author of the paper and a postdoctoral research fellow in the Sanna-Cherchi lab. “It’s important to realize that even if a person with kidney disease has a high-risk APOL1 genotype, those variants are not always the cause of the disease. Because APOL1 risk variants are frequent in individuals of genetic African ancestry and, even in the absence of M1, APOL1 is not the cause of kidney disease in everyone. With APOL1 genetic analyses being progressively more accessible, even in real-time with point-of-care testing, the risk of misdiagnosis, with consequent inadequate management and therapy, is real.”

The researchers emphasize that incorporating M1 into routine APOL1 genetic testing could be implemented quickly, as most sequencing panels already capture it.

The findings also have implications for clinical trials of APOL1-targeted therapies. More precise genetic classification could improve trial design by ensuring that participants who are most likely to benefit from APOL1-directed treatments are appropriately selected.

The team will also continue to investigate additional genetic and environmental modifiers that may explain why only a subset of individuals with APOL1 high-risk genotypes develop kidney disease.