Idiopathic collapsing glomerulopathy is associated with APOL1 high-risk genotypes or Mendelian variants in most affected individuals in a highly admixed population

Collapsing glomerulopathy (CG) is most often associated with fast progression to kidney failure with an incidence apparently higher in Brazil than in other countries. However, the reason for this occurrence is unknown. To better understand this, we performed an integrated analysis of clinical, histological, therapeutic, causative genetic and genetic ancestry data in a highly genetically admixed cohort of 70 children and adult patients with idiopathic CG (ICG). The disease onset occurred at 23 (interquartile range: 17-31) years and approximately half of patients progressed to chronic kidney disease requiring kidney replacement therapy (CKD-KRT) 36 months after diagnosis. Causative genetic bases, assessed by targeted-gene panel or wholeexome sequencing, were identified in 58.6% of patients. Among these cases, 80.5% harbored APOL1 high -risk genotypes (HRG) and 19.5% causative Mendelian variants (MV). Self-reported non -White patients more frequently had HRG. MV was an independent risk factor for progression to CKD-KRT by 36 months and the end of follow-up, while remission was an independent protective factor. All patients with HRG manifested CG at 9-44 years of age, whereas in those with APOL1 low-risk genotype, the disease arose throughout life. HRGs were associated with higher proportion of African genetic ancestry. Novel causative MVs were identified in COL4A5, COQ2 and PLCE1 and previously described causative MVs were identified in MYH9, TRPC6, COQ2, COL4A3 and TTC21B. Three patients displayed HRG combined with a variant of uncertain significance (ITGB4, LAMA5 or PTPRO). MVs were associated with worse kidney prognosis. Thus, our data reveal that the genetic status plays a major role in ICG pathogenesis, accounting for more than half of cases in a highly admixed Brazilian population. Kidney International (2024) 105, 593-607; https://doi.org/10.1016/ j.kint.2023.11.028 Lay Summary Collapsing glomerulopathy is a severe kidney disease that often leads to chronic dialysis or kidney transplantation. To expand its understanding, we performed a broad clinical and genetic analysis of a highly admixed patient population with idiopathic collapsing glomerulopathy. Interestingly, we identified a genetic cause in more than half of the 70 evaluated patients. Moreover, in a significant majority of the cases with a genetic form, the disease was associated with the presence of risk variants in both alleles of the APOL1 gene, which are genetic variants associated with African ethnicity. These patients, in fact, displayed a higher proportion of African genetic ancestry. The other genetic cases occurred due to causative variants in other genes, being classified as Mendelian forms. Mendelian cases had a higher risk of progression to kidney failure, and all patients with 2 APOL1 risk alleles manifested collapsing glomerulopathy between 9 and 44 years of age.