Design of the Nephrotic Syndrome Study Network (NEPTUNE) to evaluate primary glomerular nephropathy by a multidisciplinary approach
2013; Elsevier BV; Volume: 83; Issue: 4 Linguagem: Inglês
10.1038/ki.2012.428
ISSN1523-1755
AutoresCrystal A. Gadegbeku, Debbie S. Gipson, Lawrence B. Holzman, Akinlolu Ojo, Peter X.‐K. Song, Laura Barisoni, Matthew G. Sampson, Jeffrey B. Kopp, Kevin V. Lemley, Peter J. Nelson, Chrysta Lienczewski, Sharon G. Adler, Gerald B. Appel, Daniel C. Cattran, Michael Choi, Gabriel Contreras, Katherine MacRae Dell, Fernando C. Fervenza, Keisha L. Gibson, Larry A. Greenbaum, Joel D. Hernandez, Stephen M. Hewitt, Sangeeta Hingorani, Michelle Hladunewich, Marie C. Hogan, Susan L. Hogan, Frederick J. Kaskel, John C. Lieske, Kevin Meyers, Patrick H. Nachman, Cynthia C. Nast, Alicia M. Neu, Heather N. Reich, John R. Sedor, Christine B. Sethna, Howard Trachtman, Katherine R. Tuttle, Olga Zhdanova, Gastón E. Zilleruelo, Matthias Kretzler,
Tópico(s)Amyloidosis: Diagnosis, Treatment, Outcomes
ResumoThe Nephrotic Syndrome Study Network (NEPTUNE) is a North American multicenter collaborative consortium established to develop a translational research infrastructure for nephrotic syndrome. This includes a longitudinal observational cohort study, a pilot and ancillary study program, a training program, and a patient contact registry. NEPTUNE will enroll 450 adults and children with minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy for detailed clinical, histopathological, and molecular phenotyping at the time of clinically indicated renal biopsy. Initial visits will include an extensive clinical history, physical examination, collection of urine, blood and renal tissue samples, and assessments of quality of life and patient-reported outcomes. Follow-up history, physical measures, urine and blood samples, and questionnaires will be obtained every 4 months in the first year and biannually, thereafter. Molecular profiles and gene expression data will be linked to phenotypic, genetic, and digitalized histological data for comprehensive analyses using systems biology approaches. Analytical strategies were designed to transform descriptive information to mechanistic disease classification for nephrotic syndrome and to identify clinical, histological, and genomic disease predictors. Thus, understanding the complexity of the disease pathogenesis will guide further investigation for targeted therapeutic strategies. The Nephrotic Syndrome Study Network (NEPTUNE) is a North American multicenter collaborative consortium established to develop a translational research infrastructure for nephrotic syndrome. This includes a longitudinal observational cohort study, a pilot and ancillary study program, a training program, and a patient contact registry. NEPTUNE will enroll 450 adults and children with minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy for detailed clinical, histopathological, and molecular phenotyping at the time of clinically indicated renal biopsy. Initial visits will include an extensive clinical history, physical examination, collection of urine, blood and renal tissue samples, and assessments of quality of life and patient-reported outcomes. Follow-up history, physical measures, urine and blood samples, and questionnaires will be obtained every 4 months in the first year and biannually, thereafter. Molecular profiles and gene expression data will be linked to phenotypic, genetic, and digitalized histological data for comprehensive analyses using systems biology approaches. Analytical strategies were designed to transform descriptive information to mechanistic disease classification for nephrotic syndrome and to identify clinical, histological, and genomic disease predictors. Thus, understanding the complexity of the disease pathogenesis will guide further investigation for targeted therapeutic strategies. Primary noninflammatory glomerular diseases that include minimal change disease (MCD), focal and segmental glomerulosclerosis (FSGS), and membranous nephropathy (MN) are rare diseases that cause serious morbidity and high mortality, accounting for ∼15% of prevalent ESRD cases (2008) at an annual cost in the United States of more than $3 billion.1.Maisonneuve P. Agodoa L. Gellert R. et al.Distribution of primary renal diseases leading to end-stage renal failure in the United States, Europe, and Australia/New Zealand: results from an international comparative study.Am J Kidney Dis. 2000; 35: 157-165Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar,2.Collins A.J. Foley R.N. Chavers B. et al.US Renal Data System 2011. Annual Data Report.Am J Kidney Dis. 2012; 59: e1-e420Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar Our limited knowledge of underlying glomerular disease mechanisms is a major barrier to successful therapeutic intervention. To date, this void has not been overcome by surrogate clinical and histopathology-based classification methods, which are of limited value in reliably predicting natural history of diseases or responsiveness to therapy. Hence, there is a need for basic and translational investigation to identify underlying disease mechanisms, specific biomarkers, and therapeutic targets for further testing in clinical trials. Integration of large-scale multidimensional molecular and clinical data sets obtained from a well-characterized patient population could enhance our ability to understand the spectrum of molecular disease entities that present as a common histological phenotype, elucidate pathogenesis, and expedite scientific innovation toward safe and effective treatments for glomerular diseases.3.Kretzler M. Cohen C.D. Integrative biology of renal disease: toward a holistic understanding of the kidney’s function and failure.Semin Nephrol. 2010; 30: 439-442Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar To facilitate studies of this type, the Nephrotic Syndrome Study Network (NEPTUNE), supported by the National Institutes of Diabetes and Digestive and Kidney Disease (NIDDK), the Office for Rare Diseases Research (ORDR) at the National Institutes of Health (NIH), and The NephCure and Halpin Foundations, was designed to conduct multidisciplinary innovative research to address the ‘translational gap,’ which is a barrier to successful management of adults and children with FSGS, MCD, and MN. The overall objectives of the NEPTUNE network (Table 1) are incorporated into the NEPTUNE observational cohort study that is designed to address the following general and disease-specific hypotheses:After accounting for types, duration, and frequency of immunomodulating therapy, the probability of remission of FSGS, MCD, and MN, defined as change in urinary protein excretion and/or renal function, will be predicted by baseline demographics, clinical, genetic, and histopathological characteristics at the time of presentation.Genome-wide molecular profiles obtained from renal biopsy tissue at the time of diagnosis of FSGS, MCD, and MN will independently predict the proportion of subjects entering remission.Individual genetic causes of FSGS and MCD activate specific transcriptional pathways in renal tissue and the molecular characterization of these transcriptional pathways will identify novel therapeutic targets, yielding more complete and sustained disease remission.The use of non-immunomodulating therapy (including anti-hypertensive, lipid-lowering, antithrombotic agents, and dietary manipulation) will have an independent effect on the probability of remission of nephrotic syndrome (NS).The composite rates of major medical complications (vascular thrombosis, complications of the kidney biopsy procedure, infection, and death) will vary according to the baseline characteristics and types of treatment in patients.NS, its treatment, and clinical outcomes will have a varied measurable effect on the quality of the life of patients.Table 1Objectives of the Nephrotic Syndrome Study Network (NEPTUNE)Objectives of the Nephrotic Syndrome Study NetworkTo establish a collaborative, integrated, cost-effective investigational infrastructure to conduct clinical and translational research in FSGS, MCD, and MNTo conduct a longitudinal observational cohort study on patients with incipient biopsy proven NSTo establish Pilot and Ancillary Projects Programs using the unique resources, clinical data, or specimens collected by NEPTUNETo establish a Training Program for post-doctoral/junior faculty trainees to prepare for clinical and translational research in glomerular diseaseTo collaborate with the ORDR Data Management and Coordinating Center and the NephCure Foundation to establish a web-based exchange platform for lay people, physicians, and scientists.Abbreviations: FSGS, focal and segmental glomerulosclerosis; MCD, minimal change disease; MN, membranous nephropathy; NS, nephrotic syndrome. Open table in a new tab Abbreviations: FSGS, focal and segmental glomerulosclerosis; MCD, minimal change disease; MN, membranous nephropathy; NS, nephrotic syndrome. The NEPTUNE study is a prospective observational study that will enroll 450 children and adults with FSGS, MCD, and MN at the time of first clinically indicated renal biopsy for diagnosis of proteinuria. Enrollment from 18 clinical centers in the United States and Canada (Table 2) will occur over 30 months, with a minimum follow-up of 30 months. The two primary study outcomes are change in urinary protein excretion and change in renal function as indicated in Table 3. Secondary study outcomes are quality of life assessment, development of new-onset diabetes, malignancies, infections, thromboembolic events, hospitalization, acute kidney injury, and death.Table 2Nephrotic Syndrome Study Network Clinical CentersNEPTUNE clinical centersaFor full list of sites enrolling NEPTUNE participants, see www.neptune-study.org.Recruitment populationCase Western Medical Center, Cleveland, OHAdult and pediatricCohen’s Children’s Medical Center, Manhasset, NYPediatricColumbia University, New York, NYAdultEmory University, Atlanta, GAPediatricHarbor Biomedical Research Institute, Torrance, CAAdultJohns Hopkins Medical Center, Baltimore, MDAdult and pediatricMontefiore Medical Center, Bronx, NYAdult and pediatricThe Mayo Clinic, Rochester, MNAdult and pediatricNational Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MDAdultNew York University School of Medicine, New York, NYAdult and pediatricTemple University Health Systems, Philadelphia, PAAdultUniversity Health Network, Toronto, CanadaAdultUniversity of Michigan Health Systems, Ann Arbor, MIAdult and pediatricUniversity of Miami Medical Center, Miami, FLAdult and pediatricUniversity of North Carolina, Chapel Hill, NCAdult and pediatricUniversity of Pennsylvania, Philadelphia, PAAdult and pediatricUniversity of Southern California Children’s Hospital, Los Angeles, CAPediatricUniversity of Washington, Seattle, WAAdult and pediatrica For full list of sites enrolling NEPTUNE participants, see www.neptune-study.org. Open table in a new tab Table 3NEPTUNE primary outcome variables and definitionsRate of change in urinary protein excretion from baseline (UP:C ratio)Rate of change in renal function from baseline Cohort studyDefinitionsStandardCohort studyReduction in UP:C ratio of ≤0.3Complete remissionComplete/partial remission25ml/min/1.73m2 reduction in eGFR*Reduction in UP:C ratio >50% and final U:C ratio ≥0.3 and ≤3.5Partial remissionReduction in UP:C ratio >50% and final >3.5Limited responseNo response50% Decline in eGFR from baselineReduction in UP:C ratio <50% (includes increases 50%Progressive proteinuriaNew development of UP:C ratio >3.5 after complete or partial remissionRelapseRelapseESRD (initiation of dialysis, kidney transplantation or eGFR ≤ 10ml/min/1.73m2)Abbreviations: eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; UP:C, urine protein: creatinine (g/g). Open table in a new tab Abbreviations: eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; UP:C, urine protein: creatinine (g/g). The NEPTUNE consortium infrastructure consists of a Steering Committee, a Central Digitized Histopathological Archive at the NIH, a central biorepository, biochemical laboratory, and Data Analysis and Coordinating Center at the University of Michigan, an Observational Study Monitoring Board at the NIDDK, and an external Scientific Advisory Board. The overall design of the NEPTUNE cohort study is depicted in Figure 1 and described in detail below. NEPTUNE is registered at clinicaltrials.gov under NCT01209000. The NEPTUNE study will enroll a diverse population reflective of the disease burden in North America. Eligible candidates for the NEPTUNE study are individuals of any age scheduled for a clinically indicated renal biopsy with proteinuria ≥500mg/day estimated from a 24-h or spot (protein to creatinine ratio) urine collection. Patients with sub-nephrotic proteinuria are included to capture the broad spectrum of clinical presentations.4.Hladunewich M.A. Troyanov S. Calafati J. et al.The natural history of the non-nephrotic membranous nephropathy patient.Clin J Am Soc Nephrol. 2009; 4: 1417-1422Crossref PubMed Scopus (92) Google Scholar,5.Schwartz M.M. Evans J. Bain R. et al.Focal segmental glomerulosclerosis: prognostic implications of the cellular lesion.J Am Soc Nephrol. 1999; 10: 1900-1907PubMed Google Scholar Exclusion criteria include patients with clinical, serological, or histological evidence of other renal diseases (e.g., diabetic nephropathy, systemic lupus erythematosus, etc), prior solid organ transplant, life expectancy <6 months, and those who are unwilling or unable to consent. Cohort assignment is based on detailed renal histopathological analysis. Participants whose histopathology is not determined to be consistent with FSGS, MCD, and MN are assigned to an ‘Other Glomerulopathies’ cohort and retained in the study to serve as a comparison group and for future studies addressing these histopathologically distinct entities. Eligible candidates over the age of 18 are enrolled after providing written, informed consent. Children are an important population affected by NS and are enrolled in the NEPTUNE study at many clinical centers as indicated in Table 2. The NEPTUNE study will enroll eligible children after parental written consent (and child assent when appropriate) before the diagnostic renal biopsy. Information on medications prescribed for NS before enrollment will be collected in all participants, including children who may have a longer exposure to pre-biopsy therapies consistent with standard pediatric NS management.6.Gipson D.S. Massengill S.F. Yao L. et al.Management of childhood onset nephrotic syndrome.Pediatrics. 2009; 124: 747-757Crossref PubMed Scopus (208) Google Scholar Additional funding to enroll children from initial NS presentation is currently being pursued. The enrollment process includes a screening visit to assess eligibility and willingness to participate, a baseline visit for collection of clinical and demographic information, and a renal biopsy visit to obtain renal tissue samples. Renal biopsy material will be used to confirm assignment into the specific study cohort and for research purposes. The baseline visit includes collection of a detailed medical history, sociodemographic information, physical measures, and blood and urine samples (see https://rarediseasesnetwork.epi.usf.edu/NEPTUNE/professional/studynetwork.htm# for details). In addition to age-appropriate questionnaires to assess quality of life, self-reported health will be evaluated using the Patient-Reported Outcomes Measurement Information System (PROMIS, www.nihpromis.org). After enrollment, NEPTUNE participants are evaluated at 4-month intervals during the first year and every 6 months thereafter, with similar data collection as carried out in the baseline visit. Pathology material including glass slides, immunofluorescence images, and electron-micrographs will be scanned into high resolution digital images and stored in the NEPTUNE pathology database along with copies of the local pathology reports. This database can be accessed remotely by the NEPTUNE Histopathology committee for review, scoring, and cohort assignment by disease classification. The NEPTUNE Histopathology Committee has developed a novel strategy for scoring renal biopsies designed to standardize morphological analysis.7.Working Group of the International IgA Nephropathy Network and the Renal Pathology Society Cattran D.C. Coppo R. Cook H.T. et al.The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification.Kidney Int. 2009; 76: 534-545Abstract Full Text Full Text PDF PubMed Scopus (900) Google Scholar,8.Barisoni L. Jennette J.C. Colvin R. Sitaraman S. Bragat A. Castelli J. Boudes P. A novel quantitative method to evaluate GL-3 inclusions in renal peritubular capillaries by virtual microscopy in patients with Fabry’s disease.Arch Pathol Lab Med. 2012; 136: 816-824Crossref PubMed Scopus (21) Google Scholar The pathology protocol is designed to provide (1) multilevel annotation of glomeruli for multidimensional reconstruction to allow simultaneous review and scoring of the same glomerulus on each digital slide, and (2) identification and scoring of specific predefined morphological ‘descriptors’. This approach for kidney tissue analysis has the potential to redefine histopathological classification and link these novel criteria to clinical and molecular phenotypes. In addition, the NEPTUNE pathology database will serve as a major resource available to investigators for future pilot and ancillary studies. Systems biology is an emerging scientific approach that aims to address the ‘pluralism of cause and effects in biological networks’9.Sauer U. Heinemann M. Zamboni N. Genetics. Getting closer to the whole picture.Science. 2007; 316: 550-551Crossref PubMed Scopus (195) Google Scholar that defines the steady state and its disturbances in health and disease.10.Keller B.J. Martini S. Sedor J.R. et al.A systems view of genetics in chronic kidney disease.Kidney Int. 2012; 81: 14-21Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 11.Velic A. Macek B. Wagner C.A. Towards quantitative proteomics of organ substructures: implications for renal physiology.Sem Nephrol. 2010; 30: 487-499Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 12.Perco P. Oberbauer R. Integrative analysis of ‘-omics’ data and histological scoring in renal disease and transplantation: renal histogenomics.Sem Nephrol. 2010; 30: 520-530Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 13.Ju W. Brosius F.C. Understanding kidney disease: toward the integration of regulatory networks across species.Sem Nephrol. 2010; 30: 512-519Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar, 14.He J.C. Chuang P.Y. Ma’ayan A. et al.Systems biology of kidney diseases.Kidney Int. 2012; 81: 22-39Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar The NEPTUNE study aims to integrate comprehensive clinical and pathological phenotypes with extensive analysis of the molecular regulatory networks active in glomerular diseases. As depicted in Figure 2, NEPTUNE will prospectively procure human samples for analyses focused on genome-wide profiling of genetic variation, epigenetic markers and transcriptomic, proteomic, and metabolomic profiles. Emerging systems biology approaches will be used to define associations between these multiphasic and interrelated genome-scale profiles and the detailed clinical and structural phenotypes. The NEPTUNE study will establish a core molecular data set containing genetic profiles and renal tissue, compartment-specific, genome-wide mRNA expression data to facilitate multidisciplinary and transdisciplinary research exploration along the genotype–phenotype continuum.10.Keller B.J. Martini S. Sedor J.R. et al.A systems view of genetics in chronic kidney disease.Kidney Int. 2012; 81: 14-21Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 11.Velic A. Macek B. Wagner C.A. Towards quantitative proteomics of organ substructures: implications for renal physiology.Sem Nephrol. 2010; 30: 487-499Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 12.Perco P. Oberbauer R. Integrative analysis of ‘-omics’ data and histological scoring in renal disease and transplantation: renal histogenomics.Sem Nephrol. 2010; 30: 520-530Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 13.Ju W. Brosius F.C. Understanding kidney disease: toward the integration of regulatory networks across species.Sem Nephrol. 2010; 30: 512-519Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar The NEPTUNE core data sets will provide a foundation to link mechanistic information with clinical disease presentation, and link molecular information from model systems to human NS data sets. Patient subgroups with activation of specific molecular mechanisms can be used to assess the efficacy of novel therapeutics in a highly targeted manner. Defining patients by the underlying disease mechanism will reduce the heterogeneity inherent to the current histology-based glomerular disease classification and, as a result, will focus the analysis and interpretation of clinical trials. The core and ancillary data generated in NEPTUNE can be a significant resource to the renal research community. NEPTUNE will utilize Nephromine (www.Nephromine.org), a renal-specific systems biology search engine, to enable large-scale data analysis by nephrology investigators with and without systems biology expertise. The aims of the research will be explored separately in FSGS, MCD cohort, and MN cohort. The primary objective of the statistical analysis plan is to build a predictive model that utilizes multiple sources of data, including molecular biomarkers and auxiliary predictors (e.g., race/ethnicity, edema), to classify patients according to the proteinuria outcome (remission) as the primary endpoint. Secondary study endpoints include longitudinal measures of renal function. The primary analysis plan involves deriving a prediction model to rigorously evaluate and identify potential predictors for study endpoints. Subsequently, the overall prediction model will be used to assess relative risk and association through odds ratios for targeted sub-group analysis. In analysis of data from the network, random effects models will be used to account for potential heterogeneity and unstructured interventions across and within the clinical centers. In addition, the analysis is tailored to handle dropouts, incomplete longitudinal data, and other types of missing data.15.Diggle P. Heagerty P. Liang K.-Y. Zeger S.L. Analysis of Longitudinal Data. 2nd edn. Oxford University Press, New York2002Google Scholar For further details on statistical methodology, see Supplementary material. Download .doc (.08 MB) Help with doc files Supplementary material For biomarker discovery and validation, the sample will be split into the training and the validation sets at the ratio of 23n:13n.16.Dudoit S.F.J. Speed T.P. Comparison of discrimination methods for tumor classification based on microarray data.JASA. 2002; 97: 77-87Crossref Scopus (1918) Google Scholar,17.Ma S. Song X. Huang J. Regularized binormal ROC method in disease classification using microarray data.BMC Bioinformatics. 2006; 7: 253Crossref PubMed Scopus (18) Google Scholar With regard to the primary endpoint, selection of biomarkers (e.g., gene expression levels or serum or urine proteomic markers) will proceed in two steps: first, univariate variable screening will identify a small pool of promising biomarkers and, subsequently, joint screening to narrow identified candidate biomarkers to those with the optimal predictive power. Using selected biomarkers, a prediction model will be developed that is further validated through the test cohort by the criteria of ROC curves and net reclassification index.18.Zhou X. Obuchowski A. McClish D.K. Statistical Methods in Diagnostic Medicine. Wiley, New York2002Crossref Google Scholar,19.Pencina M.J. D’Agostino R.B. D’Agostino R.B. et al.Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond.Stat Med. 2008; 27 (discussions and rejoinders 173–212): 157-172Crossref PubMed Scopus (4785) Google Scholar In the analysis of secondary endpoints, similar strategies will be applied to build prediction models to classify longitudinal trajectories (e.g., estimated GFR). The NEPTUNE study will have adequate power to identify important molecular biomarkers predicting the primary endpoints. Power calculations were based on the probability of correct classification.20.Dobbin K.K. Simon R.M. Sample size planning for developing classifiers using high-dimensional DNA microarray data.Biostatistics. 2007: 101-117Crossref Scopus (97) Google Scholar The expected probability of probability of correct classification is a weighted average of sensitivity (probability of remission) and specificity (probability of non-remission). An estimate 20,000 genes (probes) and 75 auxiliary predictors will be screened to identify true gene expression markers and true auxiliary predictor for the defined endpoints (Table 4). The probability of correct classifications are 0.874, 0.942, and 0.966 for the sample sizes of 100, 150, and 200, respectively, based on the identification of 50 true gene expression markers and 10 true auxillary markers. The goal of the NEPTUNE study enrollment is to enroll 450 subjects.Table 4Sample size and classification power for the NEPTUNE StudyPrevalence=0.6Prevalence=0.3rm=5rC=10rm=5rC=10δm/σmPCC*PCCPCC*PCCn=100n=150n=200n=100n=150n=2000.20.7880.6380.6670.6870.8120.6700.6750.6900.30.8810.7760.8030.8180.8920.7790.8070.822rm=50rC=10rm=50rC=10δm/σmPCC*PCCPCC*PCCn=100n=150n=200n=100n=150n=2000.20.9410.6390.6950.7530.9480.6940.6970.7540.30.9900.8660.9380.9640.9910.8670.9390.964Abbreviations: NEPTUNE, Nephrotic Syndrome Study Network; PCC, probability of correct classification.Sample size and power determination are based on a classification model for the primary endpoints with significant predictors. PCC* is the maximal classification power that would be obtained under genetic predictors (of 20,000 genes) and clinical predictors (of 75 clinical parameters) with respect to the standardized effect-sizes, δm/σm, where δm and σm are the effect size and s.d. of an important biomarker, respectively. In parallel, PCC is the achievable power in the actual study with n patients enrolled in the FSGS, MCD, or MN subcohorts in NEPTUNE. Open table in a new tab Abbreviations: NEPTUNE, Nephrotic Syndrome Study Network; PCC, probability of correct classification. Sample size and power determination are based on a classification model for the primary endpoints with significant predictors. PCC* is the maximal classification power that would be obtained under genetic predictors (of 20,000 genes) and clinical predictors (of 75 clinical parameters) with respect to the standardized effect-sizes, δm/σm, where δm and σm are the effect size and s.d. of an important biomarker, respectively. In parallel, PCC is the achievable power in the actual study with n patients enrolled in the FSGS, MCD, or MN subcohorts in NEPTUNE. In the spirit of accelerating NS research, NEPTUNE has organized a pilot and ancillary study program to facilitate high-quality investigation within the research community utilizing the resources provided by the NEPTUNE infrastructure. The ancillary study mechanism is open to investigators regardless of institutional affiliation. Details on the available data, specimens, and process required to gain access to these resources are provided at https://rarediseasesnetwork.epi.usf.edu/NEPTUNE/professional/studynetwork.htm#. Further, NEPTUNE supports a training program for post-doctoral fellows and junior faculty to promote career development in clinical and translational research in glomerular disease (https://rarediseasesnetwork.epi.usf.edu/NEPTUNE/professional/fellowship/). Finally, NEPTUNE has organized a contact registry within the Rare Diseases Clinical Research Network (www.neptune-study.org) for patients with NS. This registry contains self-reported information, including diagnostic, demographic, and contact information that can be used for patient education and to facilitate enrollment of patients into clinical trials and other research studies. At the time of this publication, over 1400 patients are actively enrolled in the NEPTUNE contact registry, and a substantial number of registrants have provided consent to be directly approached for participation in clinical studies. Primary NS is a debilitating clinical entity affecting individuals of all ages and associated with end-stage renal disease and premature death. We remain limited in our ability to effectively treat the specific diseases presenting as NS because of our lack of understanding of disease mechanisms and lack of predictors to identify clinical course and therapeutic responsiveness. The NEPTUNE cohort study is designed to address these gaps in knowledge in prominent NS disorders, FSGS, MCD, and MN, by developing a platform for comprehensive longitudinal assessment of patients with incipient disease. This study represents strong commitment to bring together expertise from a broad range of disciplines focused on large-scale integration of clinical, histopathological, and molecular data. This state-of-the-art approach to identify pathogenic mechanisms and novel biomarkers has the greatest potential to advance medical management of these complex diseases. Epidemiological data demonstrate an increased incidence of primary NS due to FSGS over several decades in adults and children.21.Srivastava T. Simon S.D. Alon U.S. High incidence of focal segmental glomerulosclerosis in nephrotic syndrome of childhood.Pediatr Nephrol. 1999; 13: 13-18Crossref PubMed Scopus (166) Google Scholar In young children, MCD remains the predominant etiology of primary NS. However, 10–15% of primary NS is caused by MCD in adults. FSGS and MCD are often considered related entities because of their similarities in clinical presentation, renal pathological features, and common genetic polymorphisms,22.Weber S. Gribouval O. Esquivel E.L. et al.NPHS2 mutation analysis shows genetic heterogeneity of steroid-resistant nephrotic syndrome and low post-transplant recurrence.Kidney Int. 2004; 66: 571-579Abstract Full Text Full Text PDF PubMed Scopus (305) Google Scholar,23.Vats A. Nayak A. Ellis D. et al.Familial nephrotic syndrome: clinical spectrum and linkage to chromosome 19q13.Kidney Int. 2000; 57: 875-881Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar but a systematic comparative analysis in sporadic patients is lacking. Although the clinical course can be highly variable, patients with FSGS are more likely resistant to glucocorticoid therapy and have greater risks for kidney failure. A variety of monogenetic mutations (both dominant and recessive patterns) with distinct functional consequences have been identified that present with indistinguishable FSGS-type lesions, signifying heterogeneity in disease pathogenesis.22.Weber S. Gribouval O. Esquivel E.L. et al.NPHS2 mutation analysis shows genetic heterogeneity of steroid-resistant nephrotic syndrome and low post-transplant recurrence.Kidney Int. 2004; 66: 571-579Abstract Full Text Full Text PDF PubMed Scopus (305) Google Scholar, 24.Barisoni L. Schnaper H.W. Kopp J.B. A proposed taxonomy for the podocytopathies: a reassessment of the primary nephrotic diseases.Clin J Am Soc Nephrol. 2007; 2: 529-542Crossref PubMed Scopus (201) Google Scholar, 25.Albaqumi M. Barisoni L. Current views on collapsing glomerulopathy.J Am Soc Nephrol. 2008; 19: 1276-1281Crossref PubMed Scopus (102) Google Scholar, 26.Winn M.P. Conlon P.J. Lynn K.L. et al.Clinical and genetic heterogeneity in familial focal segmental glomerulosclerosis. 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The paucity of conclusive clinical interventional studies for glomerular disease in general underscores the need to establish predictive biomarkers and therapeutic targets for future trials in molecularly defined NS cohorts.30.Gipson D.S. Trachtman H. Kaskel F.J. et al.Clinical trial of focal segmental glomerulosclerosis in children and young adults.Kidney Int. 2011; 80: 868-878Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar Recent discovery of genetic risk loci in linkage disequilibrium with APOL1 and MYH931.Kopp J.B. Smith M.W. Nelson G.W. et al.MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis.Nat Genet. 2008; 40: 1175-1184Crossref PubMed Scopus (588) Google Scholar, 32.Tzur 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 (460) Google Scholar, 33.Genovese G. Tonna S.J. Knob A.U. et al.A risk allele for focal segmental glomerulosclerosis in African Americans is located within a region containing APOL1 and MYH9.Kidney Int. 2010; 78: 698-704Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar among people of African descent with FSGS (and potentially other kidney disease) is a major step toward understanding racial/ethnic disparities in kidney disease. Recruitment of a diverse study population from sites located across North America provides opportunities to explore, in a longitudinal manner, the clinical manifestations and therapeutic implications of these and other genetic variants. MN is a common cause of primary NS in adults34.Cameron J.S. Membranous nephropathy and its treatment.Nephrol Dial Transplant. 1992; 7: 72-79PubMed Google Scholar,35.Haas M. Meehan S.M. 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Advances in membranous nephropathy: success stories of a long journey.Clin Exp Pharmacol Physiol. 2011; 38: 410-416Crossref PubMed Scopus (3) Google Scholar A major emphasis for the MN cohort in NEPTUNE is to understand the value of these new biomarkers in predicting disease progression and response to treatment. In line with the major goals of the consortium, the NEPTUNE pathology protocol for scoring renal biopsies has the potential to redefine morphological descriptors, utilizing innovative digital methodology and serve as an extensive resource for future ancillary studies. This approach to renal biopsy analysis has potential applicability for risk stratification, disease classification, and clinical trial design. There is rapid expansion of information on monogenetic diseases and genetic loci associated with NS. However, discovering the functional links that bridge the gap from genetic risk to disease phenotype is one of the main challenges ahead. The NEPTUNE cohort study has been designed to bridge this genotype–phenotype gap using the integrated approaches of systems biology. These emerging innovative strategies will be the first steps toward identifying and testing rational interventions in primary NS. Overall, the NEPTUNE study and its complementary programs provide unparalleled opportunities to make fundamental observations using state-of-the-art research methodology, foster collaborative scientific activity, and facilitate research career development to stimulate progress in the management of glomerular diseases. See Supplementary material for a more detailed definition of statistical methodology. NEPTUNE is a part of NIH Rare Diseases Clinical Research Network (RDCRN). Funding and/or programmatic support for this project has been provided by U54 DK083912 from the Office of Rare Diseases Research (ORDR)/NCATS, NIDDK, the NephCure Foundation, and the University of Michigan. The views expressed in written materials or publications do not necessarily reflect the official policies of the Department of Health and Human Services, nor does the mention by trade names, commercial practices, or organizations imply endorsement by the US Government. We thank D. Taylor-Moon for assistance in manuscript preparation. Supplementary material is linked to the online version of the paper at http://www.nature.com/ki
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