Andreia Watanabe1,2, Mara Sanches Guaragna3, Vera Maria Santoro Belangero4, Fernanda Maria Serafim Casimiro5, João Bosco Pesquero5, Luciana de Santis Feltran6, Lilian Monteiro Pereira Palma7, Patrícia Varela5, Precil Diego Miranda de Menezes Neves2,8, Antonio Marcondes Lerario9, Marcela Lopes de Souza3, Maricilda Palandi de Mello3, Anna Cristina Gervásio de Brito Lutaif7, Cassio Rodrigues Ferrari7, Matthew Gordon Sampson10,11,12, Luiz Fernando Onuchic13,14, Paulo Cesar Koch Nogueira15. 1. Department of Pediatrics, University of São Paulo School of Medicine, São Paulo, Brazil. 2. Division of Molecular Medicine, University of São Paulo School of Medicine, São Paulo, Brazil. 3. Center for Molecular Biology and Genetic Engineering, State University of Campinas, Campinas, Brazil. 4. Department of Pediatrics, State University of Campinas, Campinas, Brazil. vmsbelangero@gmail.com. 5. Center for Diagnosis and Research on Genetic Diseases, Department of Biophysics, Federal University of São Paulo School of Medicine, São Paulo, Brazil. 6. Department of Nephrology, Federal University of São Paulo School of Medicine, São Paulo, Brazil. 7. Department of Pediatrics, State University of Campinas, Campinas, Brazil. 8. Division of Nephrology, University of São Paulo School of Medicine, São Paulo, Brazil. 9. Division of Endocrinology, University of Michigan, Ann Arbor, MI, USA. 10. Division of Pediatric Nephrology, Boston Children's Hospital, Boston, MA, USA. 11. Harvard Medical School, Boston, MA, USA. 12. Broad Institute, Cambridge, MA, USA. 13. Division of Molecular Medicine, University of São Paulo School of Medicine, São Paulo, Brazil. lonuchic@usp.br. 14. Division of Nephrology, University of São Paulo School of Medicine, São Paulo, Brazil. lonuchic@usp.br. 15. Department of Pediatrics, Federal University of São Paulo School of Medicine, São Paulo, Brazil. pckoch@uol.com.br.
Abstract
BACKGROUND: APOL1 high-risk genotypes (HRG) are associated with increased risk of kidney disease in individuals of African ancestry. We analyzed the effects of APOL1 risk variants on an ethnically diverse Brazilian pediatric nephrotic syndrome (NS) cohort. METHODS: Multicenter study including 318 NS patients, categorized as progressors to advanced CKD [estimated glomerular filtration rate (eGFR)] < 30 mL/min/1.73 m2] and slow/non-progressors (eGFR > 30 mL/min/1.73 m2 through the study). We employed Cox regression with progression time as the outcome and APOL1 genotype as the independent variable. We tested this association in the entire cohort and three subgroups; (1) focal segmental glomerulosclerosis (FSGS), (2) steroid-resistant NS (SRNS), and (3) those who underwent kidney biopsy. RESULTS: Nineteen patients (6%) had an HRG. Of these, 47% were self-reported White. Patients with HRG manifested NS at older ages and presented higher frequencies of FSGS and SRNS. HRG patients progressed to advanced CKD more often than low-risk-genotype (LRG) children in the whole NS cohort (p = 0.001) and the three subgroups. In SRNS and biopsied patients, a single risk variant was associated with trends of higher CKD progression risk. CONCLUSIONS: Novel discoveries include a substantial prevalence of HRG among patients self-reported White, worse kidney outcomes in HRG versus LRG children in the FSGS subgroup, and a trend of higher CKD progression risk associated with a single risk variant in the SRNS cohort. These findings suggest APOL1-associated NS extends beyond patients self-reported non-White, the HRG effect is independent of FSGS, and a single risk variant may have a detrimental impact in children with NS.
BACKGROUND: APOL1 high-risk genotypes (HRG) are associated with increased risk of kidney disease in individuals of African ancestry. We analyzed the effects of APOL1 risk variants on an ethnically diverse Brazilian pediatric nephrotic syndrome (NS) cohort. METHODS: Multicenter study including 318 NS patients, categorized as progressors to advanced CKD [estimated glomerular filtration rate (eGFR)] < 30 mL/min/1.73 m2] and slow/non-progressors (eGFR > 30 mL/min/1.73 m2 through the study). We employed Cox regression with progression time as the outcome and APOL1 genotype as the independent variable. We tested this association in the entire cohort and three subgroups; (1) focal segmental glomerulosclerosis (FSGS), (2) steroid-resistant NS (SRNS), and (3) those who underwent kidney biopsy. RESULTS: Nineteen patients (6%) had an HRG. Of these, 47% were self-reported White. Patients with HRG manifested NS at older ages and presented higher frequencies of FSGS and SRNS. HRG patients progressed to advanced CKD more often than low-risk-genotype (LRG) children in the whole NS cohort (p = 0.001) and the three subgroups. In SRNS and biopsied patients, a single risk variant was associated with trends of higher CKD progression risk. CONCLUSIONS: Novel discoveries include a substantial prevalence of HRG among patients self-reported White, worse kidney outcomes in HRG versus LRG children in the FSGS subgroup, and a trend of higher CKD progression risk associated with a single risk variant in the SRNS cohort. These findings suggest APOL1-associated NS extends beyond patients self-reported non-White, the HRG effect is independent of FSGS, and a single risk variant may have a detrimental impact in children with NS.
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