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APOL1 in an ethnically diverse pediatric population with nephrotic syndrome: implications in focal segmental glomerulosclerosis and other diagnoses

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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.

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Funding

This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo: grant 2013/02162–8 to LFO as one of the four principal investigators; grant 2014/27198–8 to JBP and PCKN as two of the four principal investigators and grant 2015/20502-6 to MPM.

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Author notes

  1. Andreia Watanabe and Mara Sanches Guaragna contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics, University of São Paulo School of Medicine, São Paulo, Brazil

    Andreia Watanabe

  2. Division of Molecular Medicine, University of São Paulo School of Medicine, São Paulo, Brazil

    Andreia Watanabe, Precil Diego Miranda de Menezes Neves & Luiz Fernando Onuchic

  3. Center for Molecular Biology and Genetic Engineering, State University of Campinas, Campinas, Brazil

    Mara Sanches Guaragna, Marcela Lopes de Souza & Maricilda Palandi de Mello

  4. Department of Pediatrics, State University of Campinas, Campinas, Brazil

    Vera Maria Santoro Belangero, Lilian Monteiro Pereira Palma, Anna Cristina Gervásio de Brito Lutaif & Cassio Rodrigues Ferrari

  5. Center for Diagnosis and Research on Genetic Diseases, Department of Biophysics, Federal University of São Paulo School of Medicine, São Paulo, Brazil

    Fernanda Maria Serafim Casimiro, João Bosco Pesquero & Patrícia Varela

  6. Department of Nephrology, Federal University of São Paulo School of Medicine, São Paulo, Brazil

    Luciana de Santis Feltran

  7. Division of Nephrology, University of São Paulo School of Medicine, São Paulo, Brazil

    Precil Diego Miranda de Menezes Neves & Luiz Fernando Onuchic

  8. Division of Endocrinology, University of Michigan, Ann Arbor, MI, USA

    Antonio Marcondes Lerario

  9. Division of Pediatric Nephrology, Boston Children’s Hospital, Boston, MA, USA

    Matthew Gordon Sampson

  10. Harvard Medical School, Boston, MA, USA

    Matthew Gordon Sampson

  11. Broad Institute, Cambridge, MA, USA

    Matthew Gordon Sampson

  12. Department of Pediatrics, Federal University of São Paulo School of Medicine, São Paulo, Brazil

    Paulo Cesar Koch Nogueira

Authors
  1. Andreia Watanabe
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  2. Mara Sanches Guaragna
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  3. Vera Maria Santoro Belangero
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  6. Luciana de Santis Feltran
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Contributions

A.W. carried out experiments, analyzed and interpreted data, drafted and critically revised the article; M.S.G. analyzed and interpreted data, drafted and critically revised the article; V.M.S.B. analyzed and interpreted data, critically revised the article; F.M.S.C. carried out experiments, analyzed and interpreted data, critically revised the article; J.B.P. critically revised the article; L.S.F. analyzed and interpreted data, critically revised the article; L.M.P. acquisition of data; P.V. carried out experiments, analyzed and interpreted data, critically revised the article; P.D.M.M.N. carried out experiments, analyzed and interpreted data; A.M.L. acquisition of data; M.L.S. carried out experiments; M.P.M. analyzed and interpreted data; A.C.G.B.L. acquisition of data; C.R.F. acquisition of data; M.G.S. design of the study, critically revised the article; L.F.O. design of the study, critically revised the article; P.C.K.N. design of the study, analyzed and interpreted data and critically revised the article. All authors approved the final version of the manuscript.

Corresponding authors

Correspondence to Vera Maria Santoro Belangero, Luiz Fernando Onuchic or Paulo Cesar Koch Nogueira.

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Watanabe, A., Guaragna, M.S., Belangero, V.M.S. et al. APOL1 in an ethnically diverse pediatric population with nephrotic syndrome: implications in focal segmental glomerulosclerosis and other diagnoses. Pediatr Nephrol 36, 2327–2336 (2021). https://doi.org/10.1007/s00467-021-04960-w

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