Abstract: TH-OR23
Idiopathic Collapsing Glomerulopathy Is Associated with APOL1 High-Risk Genotypes or Mendelian Variants in Most Affected Individuals in a Highly Admixed Population
Session Information
- Glomerular Diseases: Clinical and Translational Studies
November 02, 2023 | Location: Room 103, Pennsylvania Convention Center
Abstract Time: 04:48 PM - 04:57 PM
Category: Glomerular Diseases
- 1402 Glomerular Diseases: Clinical, Outcomes, and Trials
Authors
- Neves, Precil D., Universidade de Sao Paulo Faculdade de Medicina, Sao Paulo, São Paulo, Brazil
- Watanabe, Andreia, Universidade de Sao Paulo Faculdade de Medicina, Sao Paulo, São Paulo, Brazil
- Watanabe, Elieser H., Universidade de Sao Paulo Faculdade de Medicina, Sao Paulo, São Paulo, Brazil
- Narcizo, Amanda M., Universidade de Sao Paulo Faculdade de Medicina, Sao Paulo, São Paulo, Brazil
- Nunes, Kelly, Universidade de Sao Paulo Faculdade de Medicina, Sao Paulo, São Paulo, Brazil
- Ferreira, Frederico Moraes, Universidade de Sao Paulo Faculdade de Medicina, Sao Paulo, São Paulo, Brazil
- Wongboonsin, Janewit, Boston Children's Hospital, Boston, Massachusetts, United States
- Cavalcante, Livia Barreira, Universidade de Sao Paulo Faculdade de Medicina, Sao Paulo, São Paulo, Brazil
- Malheiros, Denise M., Universidade de Sao Paulo Faculdade de Medicina, Sao Paulo, São Paulo, Brazil
- Jorge, Lectícia, Universidade de Sao Paulo Faculdade de Medicina, Sao Paulo, São Paulo, Brazil
- Sampson, Matt G., Boston Children's Hospital, Boston, Massachusetts, United States
- Noronha, Irene L., Universidade de Sao Paulo Faculdade de Medicina, Sao Paulo, São Paulo, Brazil
- Onuchic, Luiz F., Universidade de Sao Paulo Faculdade de Medicina, Sao Paulo, São Paulo, Brazil
Background
Collapsing glomerulopathy (CG) is most often associated with fast progression to chronic kidney disease requiring renal replacement therapy (CKD-RRT). Its incidence is apparently higher in Brazil than in other countries, however the reason for this occurrence is unknown.
Methods
We performed an integrated analysis of clinical, histological, therapeutic, causative genetic and genetic ancestry data in a highly genetically-admixed cohort with 70 idiopathic CG (ICG) patients, including children and adults. Genetic analyses included targeted-gene panel or whole exome sequencing and a high-density SNP array for ancestry assessment.
Results
The disease onset occurred at 23 (17-31) years and 51.4% of patients progressed to CKD-RRT 36 months after diagnosis. Causative genetic bases 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 presented more frequently HRG. MV was an independent risk factor for progression to CKD-RRT at 36 months (HR: 2.583, 95%CI 1.151-7.076, p=0.024) and the end of follow-up (HR: 2.355, 95%CI 1.018-5.447, p=0.045). Older age at kidney biopsy and remission were independent protective factors against progression to CKD-RRT at 36 months (HR: 0.961, 95%CI 0.927-0.996, p=0.029; and HR: 0.230, 95%CI 0.085-0.623, p=0.004, respectively), and remission also at the end of follow-up (HR: 0.155, 95%CI 0.069-0.351, p<0.001). All HRG patients manifested CG at 9-44 years of age whereas in those with APOL1 low-risk genotype the disease arose throughout life. HRG associated with higher proportion of African genetic ancestry. Novel causative MVs were identified in COL4A5, COQ2, and PLCE1 and previously described causative MVs in MYH9, TRPC6, COQ2, COL4A3, and TTC21B. Three patients displayed HRG combined with a VUS (ITGB4, LAMA5 or PTPRO). MVs was associated with worse kidney prognosis.
Conclusion
Our data revealed that the genetic status plays a major role in ICG pathogenesis, accounting for more than half of cases in a highly-admixed Brazilian population.