Brazilian Network of Pediatric Nephrotic Syndrome (REBRASNI)

Pediatric nephrotic syndrome (PNS) is a major medical problem without a known cure nor clear treatment regimen and has been the focus of intense investigation. Its most severe manifestion is steroid-resistant nephrotic syndrome (SRNS), the second most frequent cause of pediatric end-stage kidney disease (ESKD).1Stokman M.F. Renkema K.Y. Giles R.H. et al.The expanding phenotypic spectra of kidney diseases: insights from genetic studies.Nat Rev Nephrol. 2016; 12: 472-483Crossref PubMed Scopus (39) Google Scholar New concepts about PNS have been built on fundamental genetic discoveries. Aided considerably by the advent of next-generation sequencing and its application to familial cases in the research setting, more than 60 single gene (“Mendelian”) causes of SRNS have been discovered. Non-Mendelian genetic forms of nephrotic syndrome (NS) also have been identified, including high-risk APOL1 genotypes with focal and segmental glomeruloesclerosis2Genovese G. Friedman D.J. Ross M.D. et al.Association of trypanolytic ApoL1 variants with kidney disease in African Americans.Science. 2010; 329: 841-845Crossref PubMed Scopus (1220) Google Scholar,3Tzur S. Rosset S. Shemer R. et al.Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene.Hum Genet. 2010; 128: 345-350Crossref PubMed Scopus (407) Google Scholar and HLA-DQ alleles with pediatric steroid-sensitive NS.4Gbadegesin R.A. Adeyemo A. Webb N.J. et al.HLA-DQA1 and PLCG2 are candidate risk loci for childhood-onset steroid-sensitive nephrotic syndrome.J Am Soc Nephrol. 2015; 26: 1701-1710Crossref PubMed Scopus (62) Google Scholar The translation of scientific knowledge into clinical outcomes requires robust clinical trials and epidemiological studies with appropriate size, design, and comprehensiveness. Studies in the United States, the United Kingdom, and the European Union, such as NEPTUNE, PodoNet, and PredNos, are driving forward rigorous and novel scientific inquiries in PNS. However, there is a noted lack of similar studies being performed outside of developed countries. It is already clear that the prevalence and natural history of NS differs by geographic location and genetic ancestry, with prevalence of Mendelian SRNS differing across countries, and APOL1-associated NS being a condition specific to those of recent African ancestry. This creates an opportunity for studies of NS in developing countries to add significant information to the field. Brazil is the fifth largest country in the world, with a highly admixed population, derived mainly from European colonizers and immigrants, African slaves, and indigenous Amerindians. The diversity of people and climates provides an opportunity to study the genetic and environmental influence on NS, in a way that has not been matched elsewhere around the world. It is possible, moreover, that the prevalent tropical climate present in Brazil may influence the prevalence and diversity of infections, potentially affecting PNS epidemiology. In the past 6 years, research on the genetics of PNS in Brazil has gained momentum in main universities of São Paulo. This interest has been translated into some reports (Watanabe A, Neves PD, Watanabe EH, et al. APOL1 risk alleles are critical for the development of collapsing glomerulopathy in Brazilian children [abstract]. J Am Soc Nephrol. 2018;29:716).5Guaragna M.S. Lutaif A.C. Piveta C.S. et al.Two distinct WT1 mutations identified in patients and relatives with isolated nephrotic proteinuria.Biochem Biophys Res Commun. 2013; 441: 371-376Crossref PubMed Scopus (7) Google Scholar, 6Guaragna M.S. Lutaif A.C. Piveta C.S. et al.NPHS2 mutations account for only 15% of nephrotic syndrome cases.BMC Med Genet. 2015; 16: 88Crossref PubMed Scopus (14) Google Scholar, 7Guaragna M.S. Cleto T.L. Souza M.L. et al.NPHS1 gene mutations confirm congenital nephrotic syndrome in four Brazilian cases: a novel mutation is described.Nephrology (Carlton). 2016; 21: 753-757Crossref PubMed Scopus (7) Google Scholar, 8Feltran L.S. Varela P. Silva E.D. et al.Targeted next-generation sequencing in brazilian children with nephrotic syndrome submitted to renal transplant.Transplantation. 2017; 101: 2905-2912Crossref PubMed Scopus (12) Google Scholar In light of the need to better understand the etiology and natural history of NS, and the unique opportunity to do this in Brazil, physicians and physician scientists from the Divisions of Pediatric Nephrology and Nephrology of 3 renowned Brazilian medical schools, University of São Paulo, Federal University of São Paulo, and State University of Campinas, created the Brazilian Network of Pediatric Nephrotic Syndrome (REBRASNI, Rede Brasileira de Sindrome Nefrótica na Infância, in Portuguese) early in 2018 (Figure 1). The mission of REBRASNI is to generate knowledge to improve diagnosis, evaluate prognosis, and contribute to personalized treatment and potential cure of PNS. REBRASNI uses an electronic platform (www.rebrasni.sites.unifesp.br) to register cases of PNS within the Brazilian territory. Epidemiologic, clinical, and laboratory data will be prospectively obtained from all patients with NS, whereas biosamples will be initially collected from individuals with SRNS. Patient samples (whole blood and urine) and a fragment of kidney biopsy (when clinically indicated) will be stored in biorepositories, according to Brazilian regulations (see the section Research Plans later in the article, Supplementary Methods, and Figure 2). Preliminary data have been collected in the state of Sao Paulo. There were 454 patients with NS within the age range of 0.1 to 18 years followed between 2017 and 2018 at State University of Campinas and University of São Paulo, and 1 major affiliated center: University of São Paulo at Ribeirão Preto. The median age of NS onset was 3.1 (0.3–14.9) years; 268 patients (57.3%) were male, and 349 (76.9%) were Caucasian and 95 (20.9%) were mixed race/black (Table 1). Eighty-seven of them (19.2%) harbored the clinical diagnosis of SRNS/congenital nephrotic syndrome. Of these 87 patients, 30 (34.5%; or 6.6% of all patients with NS) developed ESKD.Table 1Demographics and age of onset of patients with pediatric nephrotic syndrome followed at State University of Campinas, University of São Paulo-São Paulo, and University of São Paulo-Ribeirão PretoVariableResultTotal number of patients454Sex, %Male: 57.3Female: 42.7Median age at onset (range) of nephrotic syndrome, yr3.1 (0.1–14.9)Ethnicity, %Caucasian: 76.9Mixed/Black: 20.9Other: 2.2 Open table in a new tab Seventy of the 87 patients with SRNS (80.4%) had undergone a kidney biopsy. Forty-four (62.9%) had the diagnosis of focal and segmental glomeruloesclerosis and 8 (11.4%) collapsing glomerulopathy. Seven of the patients with collapsing glomerulopathy (87.5%) developed ESKD, a condition not reached by any patient with minimal change disease during the 2-year follow-up. In biopsied patients with steroid-dependent NS, the most common diagnosis was minimal change disease (Table 2).Table 2Histological diagnoses of biopsied pediatric patients with nephrotic syndrome followed at State University of Campinas, University of São Paulo-São Paulo, and University of São Paulo-Ribeirão PretoVariableSteroid-resistant nephrotic syndromeSteroid-dependent nephrotic syndromeNumber of biopsied patients, n/N (%)70/87 (80.4)67/147 (45.6)Minimal change disease, %18.656.7Focal and segmental glomerulosclerosis, %62.934.3Collapsing glomerulopathy, %11.40.0Diffuse mesangial sclerosis, %4.30.0Acute tubular necrosis, %0.03.0Tubulointerstitial nephropathy, %0.01.5Proliferative mesangial glomerulopathy, %2.91.5Focal interstitial fibrosis, %0.01.5Membranous nephropathy, %0.01.5 Open table in a new tab Among the 1606 children with ESKD submitted to kidney transplantation at Federal University of São Paulo, University of São Paulo-São Paulo, and State University of Campinas (1982–2018), 154 (9.6%) had the primary diagnosis of NS. A total of 135 patients have available medical records for appropriate studies. Eighty-three of them (61.5%) were male, the median age of NS onset was 4.0 (0.2–15.0) years, the median time to ESKD was 4.0 (1.0–15.2) years, and the median age of first kidney transplantation was 12.0 (2.5–18.7) years. Thirty-one patients (23.0%) had NS recurrence after transplantation (Table 3).Table 3Demographics and clinical features of kidney transplantation in patients with pediatric nephrotic syndrome followed at Federal University of São Paulo, University of São Paulo-São Paulo, and State University of CampinasDemographic and clinical featuresResultTime period1982–2018Number of transplanted patients with nephrotic syndrome with available data135Sex, %Male: 61.5Female: 38.5Median age at onset (range) of nephrotic syndrome, yr4.0 (0.2–15.0)Median time to end-stage of kidney disease (range), yr4.0 (1.0–15.2)Median age at first kidney transplantation (range), yr12.0 (2.5–18.7)Number of patients with recurrence of nephrotic syndrome in the graft (first kidney transplantation), n/N (%)31/135 (23.0) Open table in a new tab The high proportion of SRNS, ESKD, and steroid dependency observed in our cohort is likely explained by the fact that State University of Campinas, University of São Paulo, and Federal University of São Paulo are tertiary pediatric nephrology units to which a significant number of patients with difficult-to-treat NS and ESKD cases are referred. One of the most important aims of REBRASNI is to discover the genetic architecture and describe the epidemiologic characteristics of PNS in Brazil. To accomplish these goals, our network will prioritize performance of a number studies in the settings itemized as follows, summarized in Figure 2, and more comprehensively described in the Supplementary Methods. (i)Genotype–phenotype correlations based on whole exome sequencing (including APOL1 genotyping) and a broad spectrum of clinical, biopsy, imagenologic, and laboratory characterization, will address the following outcomes:•ESKD;•onset when younger than 3 years old; and•familial and/or syndromic NS.(ii)Clinical analyses will aim to identify and characterize potential risk factors for occurrence of NS relapse following kidney transplantation, treatment efficacy, and safety. (i)Establish a prospective Brazilian PNS cohort:•to evaluate the influence of environmental factors associated with the onset and/or clinical course of PNS;•to compare failure of steroid and calcineurin inhibitor treatments as prognostic predictors of progression of chronic kidney disease in PNS;•to study the potential roles of persistent microscopic hematuria, selective proteinuria index, level of hypoalbuminemia, and/or new biomarkers in the PNS clinical course; and•to study steroid-dependent patients with a particular focus on steroid pharmacokinetics. (i)Children without a known Mendelian cause of their disease will undergo expanded, exome-wide genetic analysis. Molecular genetics data will be integrated into worldwide, NS databases and are also expected to provide independent families to strengthen Mendelian claims of new SRNS-associated genes.(ii)Analyze the clinical impact of APOL1 risk alleles in Brazilian patients with SRNS and factors that modify its penetrance.(iii)Study glomerular and tubulointerstitial transcriptomic analyses in kidney biopsies of SRNS REBRASNI patients using RNA sequencing. (i)Create access to medical information in PNS through scientific papers and clinical discussions via online site and provide educational material to patients focused on diet, activities, and specific treatments. Funding from grant mechanisms, including binational ones, are expected to be the main source of financial support along the next years, followed by private donations. Applications to government funds and private health institutions are under way. Brazilian pediatric nephrology is hoping and expecting that the success of REBRASNI may bring a major step forward in PNS knowledge and actions in our country and worldwide.