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

• DOI: 10.1016/j.kint.2023.11.028
• Publication Date: 2023-12-22T16:25:13Z
• Authors: Precil D. Neves; Andreia Watanabe; Elieser H. Watanabe; Amanda M. Narcizo; Kelly Nunes; Antonio M. Lerario; Frederico M. Ferr...; Lívia B. Cavalcante; Janewit Wongboonsin; Denise M. Malheiros; Lectícia B. Jorge; Matthew G. Sampson; Irene L. Noronha; Luiz F. Onuchic
• Keywords: Mendelian inheritance

Collapsing glomerulopathy (CG) is most often associated with fast progression to kidney failure an incidence apparently higher in Brazil than other countries. However, the reason for this occurrence unknown. To better understand this, we performed integrated analysis of clinical, histological, therapeutic, causative genetic and ancestry data a highly genetically admixed cohort 70 children adult patients idiopathic CG (ICG). The disease onset occurred at 23 (interquartile range: 17-31) years approximately half progressed chronic requiring replacement therapy (CKD-KRT) 36 months after diagnosis. Causative bases, assessed by targeted-gene panel or whole-exome sequencing, were identified 58.6% patients. Among these cases, 80.5% harbored APOL1 high-risk genotypes (HRG) 19.5% Mendelian variants (MV). Self-reported non-White more frequently had HRG. MV was independent risk factor CKD-KRT end follow-up, while remission protective factor. All HRG manifested 9-44 age, whereas those low-risk genotype, arose throughout life. HRGs proportion African ancestry. Novel MVs COL4A5, COQ2 PLCE1 previously described MYH9, TRPC6, COQ2, COL4A3 TTC21B. Three displayed combined variant uncertain significance (ITGB4, LAMA5 PTPRO). worse prognosis. Thus, our reveal that status plays major role ICG pathogenesis, accounting cases Brazilian population. Lay SummaryCollapsing severe leads dialysis transplantation. expand its understanding, broad clinical patient population collapsing glomerulopathy. Interestingly, cause evaluated Moreover, significant majority form, presence both alleles gene, which are ethnicity. These patients, fact, due genes, being classified as forms. failure, all 2 between 9 44 age. entity first Weiss et al.1Weiss M.A. Daquioag E. Margolin E.G. Pollak V.E. Nephrotic syndrome, progressive irreversible renal glomerular "collapse": new clinicopathologic entity?.Am J Kidney Dis. 1986; 7: 20-28Abstract Full Text PDF PubMed Scopus (161) Google Scholar 6 who presented nephrotic syndrome (NS) underwent requirement (CKD-KRT). As per Columbia classification, histologic subtype focal segmental glomerulosclerosis (FSGS), authors recommend it be separately from FSGS, using term CG.2D'Agati V.D. Fogo A.B. Bruijn J.A. Jennette J.C. Pathologic classification glomerulosclerosis: working proposal.Am 2004; 43: 368-382Abstract (611) Scholar,3Schwimmer Markowitz G.S. Valeri A. Appel G.B. glomerulopathy.Semin Nephrol. 2003; 23: 209-218Abstract (81) A recent study sought investigate protein signatures through proteomic extracellular matrix could potentially differentiate FSGS forms.4Merchant M.L. Barati M.T. Caster D.J. al.Proteomic identifies distinct glomerulosclerosis.J Am Soc 2020; 31: 1883-1904Crossref (32) In support concept entity, different expression profiles cathepsins B C compared subtypes. available studies addressing prevalence, however, setting subtype.5D'Agati Alster J.M. al.Association trial presenting features outcomes.Clin 2013; 8: 399-406Crossref (115) although reported 4% 12% cases,5D'Agati Scholar, 6Deegens J.K.J. Steenbergen E.J. Borm G.F. Wetzels J.F.M. Pathological Dutch population—epidemiology outcome.Nephrol Dial Transplant. 2008; 186-192Crossref (74) 7Raja R. Nada Yadav A.K. al.A prospective glomerulosclerosis.Ren Fail. 2016; 38: 894-898Crossref (10) rate reached up 36.6% population.8Testagrossa L. Azevedo Neto Resende al.Immunohistochemical podocyte markers glomerulosclerosis.Nephrol 28: 91-98Crossref (14) frequent presentation isolated NS, some may hematuria hypertension. Of note, many already exhibit loss function upon admission progress rapidly CKD-KRT,9Albaqumi M. Soos T.J. Barisoni Nelson P.J. glomerulopathy.J 2006; 17: 2854-2863Crossref (130) Scholar,10Cutrim É.M.M. Neves PDM. de Campos M.A.G. al.Collapsing glomerulopathy: review Consortium.Front Med (Lausanne). 2022; 9846173PubMed facing scenario limited response immunosuppression.11Valeri al.Idiopathic study.Kidney Int. 1996; 50: 1734-1746Abstract (244) 12Laurinavicius Hurwitz S. Rennke H.G. HIV non-HIV patients: clinicopathological follow-up 1999; 56: 2203-2213Abstract (159) 13Laurin L.P. Gasim A.M. Derebail V.K. al.Renal survival not otherwise specified FSGS.Clin 11: 1752-1759Crossref (35) diagnosed biopsy identifying least 1 glomerulus loop collapse hypertrophy/hyperplasia podocytes covering capillary loops.2D'Agati Scholar,14Fogo Lusco Najafian B. Alpers C.E. AJKD Atlas Renal Pathology: glomerulopathy.Am 2015; 66: e3-e4Abstract (5) addition, express dedifferentiation including Ki-67 PAX2, fail maturity such podocin, synaptopodin, WT1.10Cutrim Scholar,15Barisoni Kriz W. Mundel P. D'agati V. dysregulated phenotype: novel pathogenesis HIV-associated nephropathy.J 10: 51-61Crossref (7) has been infections (HIV, HCV, parvovirus B19, COVID-19, Mycobacterium tuberculosis, Schistosoma mansoni),16Teixeira Júnior A.A.L. Lages J.S. al.Brazilian consortium on diseases COVID-19: multicentric effort SARS-CoV-2-related nephropathy.Front 7584235PubMed 17Neves P.D. Caires R.A. Guimarães M.P. following SARS-CoV-2 adenovirus-vector–based vaccine: report cases.Kidney 101: 637-639Abstract 18Muehlig Gies Huber T.B. Braun F. viral infections.Front Immunol. 12800074Crossref (17) vaccines (COVID-19),17Neves systemic autoimmune (systemic lupus erythematosus, hematologic malignancies, diabetes mellitus, sickle cell disease),19Salvatore S.P. L.M.C. Herzenberg 19 erythematosus lupus-like disease.Clin 2012; 914-925Crossref (63) Scholar,20Salvatore Reddi A.S. Chandran C.B. superimposed diabetic nephropathy: insights into etiology under-recognized, pattern injury.Nephrol 2014; 29: 392-399Crossref (36) drug use (interferon, anabolic steroids, bisphosphonates),21Markowitz Nasr S.H. Stokes M.B. D'Agati Treatment IFN-α, -β, -γ glomerulosclerosis.Clin 2010; 5: 607-615Crossref (176) Scholar,22Barri Y.M. Munshi N.C. Sukumalchantra al.Podocyte injury glomerulopathies induced pamidronate.Kidney 65: 634-641Abstract (97) micro- macrovascular ischemia.23Buob D. Decambron Gnemmi common thrombotic microangiopathy native kidney.Kidney 90: 1321-1331Abstract (46) When secondary causes investigation, defined predominance African/African descendant previous series cases9Albaqumi suggested factors linked ethnicity might predispose individuals nephropathy. sense, (HRGs) have recognized prevalent susceptibility development descendants.24Kopp J.B. Winkler C.A. Zhao X. al.Clinical histology apolipoprotein L1-associated nephropathy trial.J 26: 1443-1448Crossref (101) 25Freedman B.I. Limou Ma Kopp APOL1-associated key contributor racial disparities CKD.Am 2018; 72: S8-S16Abstract (102) 26Genovese G. Friedman Ross M.D. trypanolytic ApoL1 Americans.Science. 329: 841-845Crossref (1579) It currently proposed APOL1-HRG–mediated involves 2-hit mechanism, where functions event, second hit nature (potentially or/and inflammatory disorders) triggers process.10Cutrim Scholar,27McNicholas B.A. Immunity unmasks glomerulopathy.Kidney 87: 270-272Abstract (6) 28Yusuf A.A. Govender Brandenburg J.T. APOL1.Hum Mol Genet. 2021; 30: R129-R137Crossref (24) 29Friedman M.R. genetics applications.Clin 16: 294-303Crossref (103) 30Daneshpajouhnejad Rosenberg A.Z. evolving story L1 beginning.Nat Rev 18: 307-320Crossref can also occur pathogenic genes whose products directly involved mitochondrial function, COQ2,31Drovandi Lipska-Ziętkiewicz B.S. Ozaltin al.Variation spectrum genotype-phenotype associations coenzyme Q10 deficiency 102: 592-603Abstract (13) COQ6,31Drovandi COQ8B,31Drovandi PDSS2.32Gasser D.L. Peng al.Focal PDSS2 haplotype and, independently, decreased content Q 10.Am Physiol Physiol. 305: F1228-F1238Crossref (38) encode proteins belong biogenesis pathway, CG. Mutations MYH9,33Reeves-Daniel Iskandar S.S. Bowden D.W. al.Is C1q another MYH9-associated disease? case report.Am 55: e21-e24Abstract TRPC6,34Nagano C. Hara Yoshikawa N. al.Clinical, pathological, characteristics glomerulosclerosis.Kidney360. 3: 1384-1393Crossref (3) Scholar,35Gigante Caridi Montemurno al.TRPC6 mutations steroid-resistant atypical phenotype.Clin 2011; 6: 1626-1634Crossref (84) INF2,34Nagano Scholar,36Morales-Alvarez M.C. Knob Denker B.M. Clinical pathological heterogeneity INF2 mutations.Kidney Int Rep. 2741-2745Abstract NUP93,37Cason R.K. Williams Chryst-Stangl siblings compound heterozygous NUP93 phenotypes nucleoporin gene mutations.Front Pediatr. 10915174Crossref NUP107,34Nagano RNASEH2B,38Fenaroli Rossi G.M. Angelotti complication type I interferon–mediated RNASEH2B-related Aicardi-Goutières syndrome.Am 78: 750-754Abstract (12) TMEM173,39Abid Q. Best Rocha Larsen C.P. al.APOL1-associated stimulator interferon (STING)-associated vasculopathy infancy (SAVI).Am 75: 287-290Abstract (44) SCARB2,40Berkovic S.F. Dibbens L.M. Oshlack al.Array-based discovery three unrelated subjects shows SCARB2/LIMP-2 myoclonus epilepsy glomerulosclerosis.Am Hum 82: 673-684Abstract (209) MSH641Jain N.G. Ahram D.F. Marasa real-time genome sequencing solve complex confounded child multiple malignancies.Kidney 2312-2316Abstract (2) assessment features, treatment, lack large numbers well specific issues. number questions, therefore, remain unclear. unknown how distributed Along line, unclear forms age ranges. do know if non-African background impacts effect. address fundamental points, current evaluate molecular-genetic, parameters large, pediatric ICG. Adult diagnosis established initially selected screened potential disorder based evaluation complementary tests. Those negative included retrospective cohort. then submitted comprehensive demographic, laboratory, therapeutic responsiveness characterization. Therapeutic course proteinuria estimated filtration (eGFR). 2021 Disease: Improving Global Outcomes (KDIGO) diseases,42Rovin B.H. Adler S.G. Barratt J. al.KDIGO practice guideline management diseases.Kidney 100: S1-S276Abstract (869) reduction 50% baseline, however without reaching normal levels, considered partial remission, full return range deemed complete remission. Progression primary analyzed outcome, outcomes comprised time reach CKD-KRT, therapy—categorized no response—and graft. biopsies specialized pathologists. approved ethics committee Hospital das Clínicas da Faculdade Medicina Universidade São Paulo under CAAE 17279219.8.0000.0068 70756317.7.0000.0068 DNA extracted peripheral blood QIAamp Blood Mini Kit (Qiagen). Samples target customized panels (WES). assembled capture 845 regions exons 42 NS (ACTN4, ADCK4, ARHGDIA, NPHS2, CD2AP, CRB2, CUBN, DGKE, EMP2, EYA1, COQ6, FAT1, INF2, ITGA3, ITGB4, KANK1, KANK2, KANK4, LAMB2, LMX1B, MYO1E, NPHS1, PDSS2, PLCE1, PODXL, PTPRO, SCARB2, SMARCAL1, TTC21B, WDR73, WT1, XPO5, APOL1, ARHGAP24, MEFV, NXF5, NUP107, NUP205, NUP93), mean coverage >99%. libraries prepared applying Nextera Rapid Capture enrichment protocol (Illumina) manufacturer's instructions. designed generate 579 20 related and/or (NEIL1, COL4A3, COL4A4, CFH, CFI, CD46, C3, CFHR5, ADAMTS13, FN1, MCP1, ANLN, MAGI2, TNS2, DLC1, CDK20, ITSN1, ITSN2), case, Ampliseq according orientations. MiSeq platform used sequence targeted regions. This task carried out Reagent v2 dual index paired-end runs (2 × 150 cycles 250 Ampliseq). WES protocols. one, Exome (Illumina). NextSeq500 cycles) NextSeq High-Output Kit. protocol, Illumina kit developed Mendelics Genomic Analysis facility (Mendelics). approach 33 MB regions, 95% ≥10 reads horizontal coverage, 100× depth. Each allele located autosomes X chromosomes women therefore represented reads. Nova Seq 6000 sequencing. generated aligned human reference GRCh37/hg19 Burrows-Wheeler Aligner (BWA-MEM aligner, GNU General Public License version 0.7.17; MIT License) duplicate Biobambam tool. Variant calling FreeBayes resulting call formats annotated ANNOVAR software package (http://annovar.openbioinformatics.org).43Wang K. Li Hakonarson H. ANNOVAR: functional annotation high-throughput data.Nucleic Acids Res. e164Crossref (9312) warrant similar same panels. filtered targeting 10 low frequency (≤0.1% American College Medical Genetics Genomics [ACMG] guidelines) control populations (gnomAD [https://gnomad.broadinstitute.org/], AbraOM [https://abraom.ib.usp.br/], SELAdb [http://intranet.fm.usp.br/sela/]). must noted databases state, Brazil, represent study. but live/lived state. ranked thereafter their pathogenicity potential. Stop-gain, splice-site disrupting, frameshift considered, since they function. Prediction missense silico programs, PolyPhen2, Mutation Assessor, SIFT, PROVEAN. visually inspected Integrative Viewer. Sanger confirm variants, proceed segregation when parental available, G1 G2 variants. Pathogenicity ACMG criteria.44Richards Aziz Bale al.Standards guidelines interpretation variants: joint consensus recommendation Association Molecular Pathology.Genet Med. 405-424Abstract (19424) Variants (VUSs) (coenzyme Q2), high scores predicted programs strongly correlated mutated additional molecular mechanics significantly strengthen pathogenicity. recently manuscript group, supported VUSs.45Watanabe Patogênese Genética-Molecular Síndrome Nefrótica Córtico-Resistente, Congênita e Glomeruloesclerose Segmentar Focal: Realidade Contribuições Análise Uma População Pediátrica Brasileira.Doctoral thesis. University School Medicine. 2023Crossref ACMG-based likely VUSs disease. Segregation pedigrees structure information. monogenic APOL1-HRG genotyping confirmed genotyped specifically high-density single nucleotide polymorphism (SNP) array (Infinium Screening Array 3.0; Illumina) ascertain individual cleaned recommendations GWASTools pipeline.46Gogarten S.M. Bhangale T. Conomos al.GWASTools: R/Bioconductor quality genome-wide association studies.Bioinformatics. 3329-3331Crossref (138) Relatedness analyses methodology contained R SNPRelate package.47Zheng Levine Shen high-performance computing toolset relatedness princi