Genotyping patients with chronic kidney disease (CKD) for the apolipoprotein L1 (APOL1) gene should go deeper than looking at high- and low-risk variants to include a further mutation that can modify such risk, shows research led by Columbia University.
Writing in JAMA Network Open, Elena Martinelli, PhD, from Columbia University Irving Medical Center, and co-authors explain that two high-risk (HR) variants (G1 and G2) in the APOL1Â gene significantly increase the risk for CKD and rapid progression to kidney failure, particularly in individuals of African ancestry.
However, most people who carry these APOL1-HR genotypes never develop kidney disease, making it difficult for physicians to determine when APOL1 is truly the cause in individual patients.
Another mutation—M1 (p.N264K)—has previously been shown to protect people with APOL1-HR variants against a type of kidney disease called focal segmental glomerulosclerosis (FSGS) as well as CKD but the value of knowing an individual’s M1 status in guiding kidney disease diagnosis and other clinical scenarios remains underexplored.
“Routine incorporation of M1 in the APOL1 genetic testing might enable physicians and genetic counselors to reclassify patients with an APOL1-HR genotype as not having kidney disease due to APOL1 and prompt the investigation for an alternative and potentially treatable cause of CKD not associated with APOL1,” Martinelli et al remark.
“This will not only help improve diagnosis, prognosis, and treatment strategies, but may also avoid the possibility of substandard treatment for vulnerable populations, where ancestry and the presence of APOL1-HR genotypes might result in an unsubstantiated label diagnosis of APOL1 kidney disease with resulting incomplete diagnostic work up and inadequate care.”
Martinelli and team investigated the importance of measuring M1 in 3460 people with FSGS or steroid-resistant nephrotic syndrome (SRNS; another type of kidney disease associated with APOL1); 24,382Â people with non-FSGS CKD; and 79,854 controls without kidney disease. APOL1-HR genotypes were detected in 9.2%, 1.8%, and 0.8%, respectively, with rates higher among participants of African ancestry than among those of multiethnic or European ancestry.
They found that, among individuals with APOL1-HR genotypes, the prevalence of the M1 genotype was significantly lower among people with FSGS or SRNS than among those with non-FSGS CKD or among controls (0.6% vs 2.9% and 4.0%).
Importantly, electronic health record and biopsy review identified an alternative, non-APOL1 cause for CKD in nearly all APOL1-HR-M1 cases.
This suggests that “M1 completely protects against APOL1 FSGS or SRNS, such that in individuals with APOL1-HR-M1 genotypes and FSGS or SRNS, the latter is likely a coincidental diagnosis,” the researchers remark.
Martinelli concluded that the results “reinforce the knowledge that APOL1 genetic testing is incomplete without reporting M1 status.”
