Genetics of Childhood Nephrotic Syndrome

Studies of hereditary steroid resistant nephrotic syndrome (SRNS) and focal segmental glomerulosclerosis (FSGS) have generated data to improve our understanding of the pathogenesis of nephrotic syndrome (NS); however, little progress has been made in identifying genetic factors associated with the predominant form of NS, childhood onset steroid sensitive nephrotic syndrome (SSNS). SSNS is responsible for more than 80% of cases seen by Pediatric Nephrologists, yet the biologic basis for disparity in incidence and severity of SSNS between different ethnicities is unknown, neither is the biologic basis for variable therapy response. As a first step towards understanding the more common SSNS, in the last ten years we have created a robust biorepository for childhood onset NS. We now have phenotype and biosamples from over 1000 children with NS. We recently used a novel study design to identify, for the first time, an unbiased exome wide risk locus for childhood SSNS in a subset of our cohort. The locus provided an unbiased genetic evidence that adaptive immunity is important in the pathogenesis of NS. We have continued to build network to study this disease and we have extended our reach to multiple Investigators in the US, UK, Japan, sub-Saharan African countries, South Asian countries, and the Middle East. These collaborations have resulted in the identification of other genetic risk factors for childhood onset nephrotic syndrome. The body of work from these International collaborations have reinforced our initial findings that childhood nephrotic syndrome is largely due to perturbation of adaptive immunity, and these findings has now set the stage for discovery of novel and specific therapeutics for nephrotic syndrome.

PUBLICATIONS

  • Lane BM, Chryst-Stangl M, Wu G, Shalaby M, El Desoky S, Middleton CC, Huggins K, Sood A, Ochoa A, Malone AF, Vancini R, Miller SE, Hall G, Kim SY, Howell DN, Kari JA, Gbadegesin R. Steroid-sensitive nephrotic syndrome candidate gene CLVS1 regulates podocyte oxidative stress and endocytosis. JCI Insight. 2022 Jan 25;7(2):e152102. doi: 10.1172/jci.insight.152102. PMID: 34874915
  • Kumar R, Keskinyan V, Stangl MC, Lane BM, Buckley AF, Barisoni L, Howell DN, Gbadegesin RA. Case Report: Unusual Aggregation of Different Glomerulopathies in a Family Resolved by Genetic Testing and Reverse Phenotyping. Front Pediatr. 2022 Feb 28;10:826330. doi: 10.3389/fped.2022.826330. PMID: 35295700; PMCID: PMC8918647
  • Adeyemo AA, Shriner D, Bentley AR, Gbadegesin RA, Rotimi CN. Evolutionary genetics and acclimatization in nephrology. Nat Rev Nephrol. 2021 Dec;17(12):827-839. doi: 10.1038/s41581-021-00483-7. Epub 2021 Sep 28. PMID: 34584272; PMCID: PMC8478000
  • Shaw BI, Ochoa A, Chan C, Nobuhara C, Gbadegesin R, Jackson AM, Chambers ET. HLA Loci and Recurrence of Focal Segmental Glomerulosclerosis in Pediatric Kidney Transplantation. Transplant Direct. 2021 Aug 26;7(10):e748. doi: 10.1097/TXD.0000000000001201. PMID: 34476293; PMCID: PMC8405131.
  • Williams AE, Gbadegesin RA. Steroid Regimen for Children with Nephrotic Syndrome Relapse. Clin J Am Soc Nephrol. 2021 Feb 8;16(2):179-181. doi: 10.2215/CJN.19201220. Epub 2021 Jan 21. PMID: 33478977; PMCID: PMC7863643.
  • Esezobor C, Ademola AD, Adetunji AE, Anigilaje EA, Batte A, Jiya-Bello FN, Furia FF, Muoneke U, McCulloch M, Nourse P, Obiagwu P, Odetunde O, Okyere P, Solarin A, Tannor EK, Noone D, Gbadegesin R, Parekh RS; Human Hereditary and Health in Africa Kidney Disease Research Network. Management of idiopathic childhood nephrotic syndrome in sub-Saharan Africa: Ibadan consensus statement. Kidney Int. 2021 Jan;99(1):59-67. doi: 10.1016/j.kint.2020.07.045. Epub 2020 Aug 29. PMID: 32866504.
  • Jia X, Yamamura T, Gbadegesin R, McNulty MT, Song K, Nagano C, Hitomi Y, Lee D, Aiba Y, Khor SS, Ueno K, Kawai Y, Nagasaki M, Noiri E, Horinouchi T, Kaito H, Hamada R, Okamoto T, Kamei K, Kaku Y, Fujimaru R, Tanaka R, Shima Y; Research Consortium on Genetics of Childhood Idiopathic Nephrotic Syndrome in Japan, Baek J, Kang HG, Ha IS, Han KH, Yang EM; Korean Consortium of Hereditary Renal Diseases in Children, Abeyagunawardena A, Lane B, Chryst-Stangl M, Esezobor C, Solarin A; Midwest Pediatric Nephrology Consortium (Genetics of Nephrotic Syndrome Study Group), Dossier C, Deschênes G; NEPHROVIR, Vivarelli M, Debiec H, Ishikura K, Matsuo M, Nozu K, Ronco P, Cheong HI, Sampson MG, Tokunaga K, Iijima K.Common risk variants in NPHS1 and TNFSF15 are associated with childhood steroid-sensitive nephrotic syndrome.
    Kidney Int. 2020 Nov;98(5):1308-1322. Epub 2020 Jun 14. PMID: 32554042.
  • Gbadegesin RA, Adeyemo A, Webb NJ, Greenbaum LA, Abeyagunawardena A, Thalgahagoda S, Kale A, Gipson D, Srivastava T, Lin JJ, Chand D, Hunley TE, Brophy PD, Bagga A, Sinha A, Rheault MN, Ghali J, Nicholls K, Abraham E, Janjua HS, Omoloja A, Barletta GM, Cai Y, Milford DD, O'Brien C, Awan A, Belostotsky V, Smoyer WE, Homstad A, Hall G, Wu G, Nagaraj S, Wigfall D, Foreman J, Winn MP; Mid-West Pediatric Nephrology Consortium. HLA-DQA1 and PLCG2 Are Candidate Risk Loci for Childhood-Onset Steroid-Sensitive Nephrotic Syndrome.
    J Am Soc Nephrol. 2015 Jul;26(7):1701-10. Epub 2014 Oct 27. PMID: 25349203; PMCID: PMC4483579.
  • Dufek S, Cheshire C, Levine AP, Trompeter RS, Issler N, Stubbs M, Mozere M, Gupta S, Klootwijk E, Patel V, Hothi D, Waters A, Webb H, Tullus K, Jenkins L, Godinho L, Levtchenko E, Wetzels J, Knoers N, Teeninga N, Nauta J, Shalaby M, Eldesoky S, Kari JA, Thalgahagoda S, Ranawaka R, Abeyagunawardena A, Adeyemo A, Kristiansen M, Gbadegesin R, Webb NJ, Gale DP, Stanescu HC, Kleta R, Bockenhauer D. Genetic Identification of Two Novel Loci Associated with Steroid-Sensitive Nephrotic Syndrome.
    J Am Soc Nephrol. 2019 Aug;30(8):1375-1384.  Epub 2019 Jul 1. PMID: 31263063; PMCID: PMC6683715.
  • Adeyemo A, Esezobor C, Solarin A, Abeyagunawardena A, Kari JA, El Desoky S, Greenbaum LA, Kamel M, Kallash M, Silva C, Young A, Hunley TE, de Jesus-Gonzalez N, Srivastava T, Gbadegesin R. HLA-DQA1 and APOL1 as Risk Loci for Childhood-Onset Steroid-Sensitive and Steroid-Resistant Nephrotic Syndrome.
    Am J Kidney Dis. 2018 Mar;71(3):399-406. Epub 2017 Dec 23. PMID: 29277510; PMCID: PMC5828864.