NEW YORK (GenomeWeb) – In the Journal of the American Society of Nephrology this week, researchers described how the apolipoprotein L1 (APOL1) risk allele for chronic kidney disease affects disease presentation and progression.
African Americans have a four-fold increased risk of chronic kidney disease as compared to European Americans, and much of that risk has been attributed to the APOL1 risk allele.
As part of the Focal Segmental Glomerulosclerosis (FSGS) Clinical Trial, researchers led by Frederick Kaskel at the Albert Einstein College of Medicine genotyped nearly 100 patients with primary focal segmental glomerulosclerosis, a type of kidney disease, to determine whether they carried the risk allele.
Nearly a third of the patients carried two copies of the allele, including almost three-quarters of the self-identified African American patients, as well as six percent of patients who did not identify as African American. Patients with the risk variants tended to be older at the time of diagnosis and their disease progressed more swiftly.
"[We] found the APOL1 risk genotype in two individuals of Hispanic descent, which is well known, and in two individuals who self-identified as white, or European American, which has not been reported before," said first author Jeffrey Kopp from the US National Institute of Diabetes and Digestive and Kidney Diseases in a statement. "This last finding suggests that APOL1 risk variants can be present in individuals who self-identify in various ways."
In turn, this suggested to Nephropath's Christopher Larsen and Barry Freedman at Wake Forest School of Medicine that screening patients for this risk allele based on the presentation of collapsing glomerulopathy in African Americans would only capture a portion of patients with these variants, as they wrote in a related editorial in the Journal of the American Society of Nephrology.
The FSGS Clinical Trial aims to uncover whether patients with primary FSGS who don't respond to first-line glucocorticoid therapy will respond better to other therapies like cyclospoin or mycopehnolate in combination with dexamethasone by following 138 children and young adults randomized to receive such second-line treatments. For this sub-study, DNA was available for 94 of the research participants, which Kopp and his colleagues used to genotype those patients with Taqman PCR assays.
Some two-thirds of the patients had no or one APOL1 risk allele, while just shy of a third of patients had two risk alleles. Seventy-two percent of non-Hispanic African Americans in the cohort had two risk alleles, while 7 percent of the non-Hispanic European Americans did.
Patients with two risk alleles tended to come down with FSGS at an older age, the researchers found. However, they had lower baseline levels of eGFR; higher levels of glomeruli with segmental glomerulosclerosis, global glomerulosclerosis, and total glomerulosclerosis; and greater tubular atrophy and fibrosis, all of which, the researchers noted, was indicative of faster disease progression.
There was, Kopp and his colleagues said, no difference in complete remission or complete remission plus partial remission rate between the APOL1 risk allele group and the group lacking the risk allele. This, they added, suggests that risk genotype status doesn't influence drug response. It further implied that either treatment approach could be considered in patients who don't respond to first-line treatment.
However, Larsen and Freedman noted in their editorial that the majority of patients in the study showed little response to either treatment.
After some 78 weeks into the trial, the researchers noted that renal survival was lower in patients with two APOL1 risk alleles, even after controlling for factors like baseline eGFR and tubular atrophy or interstitial fibrosis.
As the APOL1 risk allele was present in patients who did not self-identify as having African ancestry, Kopp and his colleagues said that testing for the allele might instead be based on the patient's disease characteristics, no matter their ancestry.
And as APOL1-associated FSGS progresses rapidly, Kopp and his colleagues further said that early treatment of the disease should be "aggressive."
"The strongest argument for APOL1 genetic testing in clinical practice might be that individuals carrying two risk alleles should be treated aggressively with remittive agents from the initial diagnosis of FSGS," they said.
Larsen and Freedman added in their editorial that, in the future, there might be specific treatment for APOL1-associated FSGS that could be directed by such testing.
"Routine use of these new technologies [such as next-generation sequencing] will allow for more accurate pathogenesis-based classification schemes in FSGS," they said. "This will ultimately enable precise treatment options and likely improve the outcomes for many patients with CKD."
Kopp and his colleagues noted that their study is limited by its small size and that they did not determine the fraction of recent African ancestry in their patients.