Design of the Nephrotic Syndrome Study Network (NEPTUNE) to evaluate primary glomerular nephropathy by a multi-disciplinary approach

Gadegbeku, Crystal A.; Gipson, Debbie S.; Holzman, Larry; Ojo, Akinlolu O.; Song, Peter I.; Barisoni, Laura; Sampson, Matthew G.; Kopp, Jeffrey B; Lemley, Kevin V.; Nelson, Peter A.; Lienczewski, Chrysta; Adler, Sharon G.; Appel, Gerald B; Cattran, Daniel C.; Choi, Michael; Contreras, Gabriel; Dell, Katherine MacRae; Fervenza, Fernando C; Gibson, Keisha; Greenbaum, Larry A; Hernandez, Joel; Hewitt, Stephen
Nakazawa; Hingorani, Sangeeta; Hladunewich, Michelle A; Hogan, Marie C.; Hogan, Susan Leininger; Kaskel, Frederick; Lieske, John Charles; Meyers, Kevin E.C.; Nachman, Patrick; Nast, Cynthia C.; Neu, Alicia M.; Reich, Heather N.; Sedor, John R.; Sethna, Christine; Trachtman, Howard; Tuttle, Katherine R.; Zhdanova, Olga; Zilleruelo, Gaston E.; Kretzler, Matthias

doi:10.1038/ki.2012.428

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Design of the Nephrotic Syndrome Study Network (NEPTUNE) to evaluate primary glomerular nephropathy by a multi-disciplinary approach

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Author(s): Crystal A. Gadegbeku , MD ¹ , Debbie S. Gipson , MD ² , Larry Holzman , MD ³ , Akinlolu O. Ojo , MD MPH PhD ² , Peter Song , PhD ² , Laura Barisoni , MD ⁴ , Matthew G. Sampson , MD MSCE ² , Jeffrey Kopp , MD ⁵ , Kevin V. Lemley , MD PhD ⁶ , Peter Nelson , MD ⁷ , Chrysta Lienczewski ² , Sharon Adler , MD ⁸ , Gerald Appel , MD ⁹ , Daniel Cattran , MD ¹⁰ , Michael Choi , MD ¹¹ , Gabriel Contreras , MD ¹² , Katherine Dell , MD ¹³ , Fernando C. Fervenza , MD PhD ¹⁴ , Keisha Gibson , MD ¹⁵ , Larry A. Greenbaum , MD PhD ¹⁶ , Joel Hernandez , MD ¹⁷ , Stephen Hewitt , MD PhD ¹⁸ , Sangeeta Hingorani , MD ²⁰ , Michelle Hladunewich , MD ¹⁰ , Marie Hogan , MD PhD ¹⁴ , Susan Hogan , PhD MPH ¹⁵ , Frederick Kaskel , MD PhD ²⁰ , John Lieske , MD ¹⁴ , Kevin E.C. Meyers , MBBCh ³ , Patrick Nachman , MD ¹⁵ , Cynthia Nast , MD ⁸ , Alicia M. Neu , MD ¹¹ , Heather Reich , PhD ¹⁰ , John Sedor , MD ¹³ , Christine Sethna , MD EdM ²¹ , Howard Trachtman , MD ⁴ , Katherine Tuttle , MD ¹⁷ , Olga Zhdanova , MD ⁴ , Gastòn E. Zilleruelo , MD ¹² , Matthias Kretzler , MD ²

Publication date (Electronic): 16 January 2013

Journal: Kidney international

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Abstract

The Nephrotic Syndrome Study Network (NEPTUNE) is a North American multi-center collaborative consortium established to develop a translational research infrastructure for Nephrotic Syndrome. This includes a longitudinal observational cohort study, a pilot and ancillary studies 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, histopathologic, 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 bi-annually, thereafter. Molecular profiles and gene expression data will be linked to phenotypic, genetic, and digitalized histologic 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.

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Most cited references 41

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COQ2 nephropathy: a newly described inherited mitochondriopathy with primary renal involvement.

Francesca Diomedi Camassei, Luisa Murer, Anna Pastore … (2007)

Primary coenzyme Q(10) (CoQ(10)) deficiency includes a group of rare autosomal recessive disorders primarily characterized by neurological and muscular symptoms. Rarely, glomerular involvement has been reported. The COQ2 gene encodes the para-hydroxybenzoate-polyprenyl-transferase enzyme of the CoQ(10) synthesis pathway. We identified two patients with early-onset glomerular lesions that harbored mutations in the COQ2 gene. The first patient presented with steroid-resistant nephrotic syndrome at the age of 18 months as a result of collapsing glomerulopathy, with no extrarenal symptoms. The second patient presented at five days of life with oliguria, had severe extracapillary proliferation on renal biopsy, rapidly developed end-stage renal disease, and died at the age of 6 months after a course complicated by progressive epileptic encephalopathy. Ultrastructural examination of renal specimens from these cases, as well as from two previously reported patients, showed an increased number of dysmorphic mitochondria in glomerular cells. Biochemical analyses demonstrated decreased activities of respiratory chain complexes [II+III] and decreased CoQ(10) concentrations in skeletal muscle and renal cortex. In conclusion, we suggest that inherited COQ2 mutations cause a primary glomerular disease with renal lesions that vary in severity and are not necessarily associated with neurological signs. COQ2 nephropathy should be suspected when electron microscopy shows an increased number of abnormal mitochondria in podocytes and other glomerular cells.

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Changing etiologies of unexplained adult nephrotic syndrome: a comparison of renal biopsy findings from 1976-1979 and 1995-1997.

M Haas, S M Meehan, T G Karrison … (1997)

Data compiled during the 1970s and early 1980s indicated that during these periods, membranous nephropathy was the most common cause of unexplained nephrotic syndrome in adults, followed in order of frequency by minimal-change nephropathy and focal segmental glomerulosclerosis (FSGS). However, we and others recently reported an increase in the incidence of FSGS over the past two decades, and the number of cases of FSGS diagnosed by renal biopsies in these centers now exceeds the number of cases of membranous nephropathy. Nonetheless, as a substantial fraction of patients with FSGS do not have the nephrotic syndrome, it remained unclear as to what extent the relative frequencies of FSGS and other glomerulopathies as causes of the nephrotic syndrome have changed over this time. To address this concern, we reviewed data from 1,000 adult native kidney biopsies performed between January 1976 and April 1979 and from 1,000 biopsies performed between January 1995 and January 1997, identified all cases with a full-blown nephrotic syndrome of unknown etiology at the time of biopsy, and compared the relative frequencies with which specific diseases were diagnosed in these latter cases between the two time intervals. The main findings of this study were that, first, during the 1976 to 1979 period, the relative frequencies of membranous (36%) and minimal-change (23%) nephropathies and of FSGS (15%) as causes of unexplained nephrotic syndrome were similar to those observed in previous studies during the 1970s and early 1980s. In contrast, from 1995 to 1997, FSGS was the most common cause of this syndrome, accounting for 35% of cases compared with 33% for membranous nephropathy. Second, during the 1995 to 1997 period, FSGS accounted for more than 50% of cases of unexplained nephrotic syndrome in black adults and for 67% of such cases in black adults younger than 45 years. Third, although the relative frequency of nephrotic syndrome due to FSGS was two to three times higher in black than in white patients during both study periods, the frequency of FSGS increased similarly among both racial groups from the earlier to the later period. Fourth, the frequency of minimal-change nephrotic syndrome decreased from the earlier to the later study period in both black and white adults. Fifth, the relative frequency of membranoproliferative glomerulonephritis as a cause of the nephrotic syndrome declined from the 1976 to 1979 period to the 1995 to 1997 period, whereas that of immunoglobulin A nephropathy appeared to increase; the latter accounted for 14% of cases of unexplained nephrotic syndrome in white adults during the latter study period. Finally, 10% of nephrotic adults older than 44 years had AL amyloid nephropathy; none of these patients had multiple myeloma or a known paraprotein at the time of renal biopsy.

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A proposed taxonomy for the podocytopathies: a reassessment of the primary nephrotic diseases.

Laura Barisoni, H. William Schnaper, Jeffrey B Kopp (2007)

A spectrum of proteinuric glomerular diseases results from podocyte abnormalities. The understanding of these podocytopathies has greatly expanded in recent years, particularly with the discovery of more than a dozen genetic mutations that are associated with loss of podocyte functional integrity. It is apparent that classification of the podocytopathies on the basis of morphology alone is inadequate to capture fully the complexity of these disorders. Herein is proposed a taxonomy for the podocytopathies that classifies along two dimensions: Histopathology, including podocyte phenotype and glomerular morphology (minimal-change nephropathy, focal segmental glomerulosclerosis, diffuse mesangial sclerosis, and collapsing glomerulopathy), and etiology (idiopathic, genetic, and reactive forms). A more complete understanding of the similarities and differences among podocyte diseases will help the renal pathologist and the nephrologist communicate more effectively about the diagnosis; this in turn will help the nephrologist provide more accurate prognostic information and select the optimal therapy for these often problematic diseases. It is proposed that final diagnosis of the podocytopathies should result from close collaboration between renal pathologists and nephrologists and should whenever possible include three elements: Morphologic entity, etiologic form, and specific pathogenic mechanism or association.

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Author and article information

Journal

Journal ID (nlm-journal-id): 0323470

Journal ID (pubmed-jr-id): 5428

Journal ID (nlm-ta): Kidney Int

Journal ID (iso-abbrev): Kidney Int.

Title: Kidney international

ISSN (Print): 0085-2538

ISSN (Electronic): 1523-1755

Publication date Nihms-submitted: 4 December 2012

Publication date (Electronic): 16 January 2013

Publication date (Print): April 2013

Publication date PMC-release: 01 October 2013

Volume: 83

Issue: 4

Pages: 749-756

Affiliations

[1 ]Temple University, Philadelphia, PA

[2 ]University of Michigan, Ann Arbor, MI

[3 ]University of Pennsylvania, Philadelphia, PA

[4 ]New York University, New York, NY

[5 ]National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD

[6 ]Children’s Hospital Los Angeles, Los Angeles, CA

[7 ]University of Washington, Seattle, WA

[8 ]Harbor – University of California Los Angeles Medical Center, Los Angeles, CA

[9 ]Columbia University Medical Center, New York, New York

[10 ]University Health Network/University of Toronto, Toronto, ON

[11 ]Johns Hopkins University, Baltimore, MD

[12 ]University of Miami, Miami, FL

[13 ]Case Western Reserve University, Cleveland, OH

[14 ]Mayo Clinic, Rochester MN

[15 ]University of North Carolina, Chapel Hill, NC

[16 ]Emory University and Children’s Healthcare of Atlanta, Atlanta, GA

[17 ]Providence Medical Research Center, Sacred Heart Medical Center, Spokane, WA

[18 ]National Institutes of Health, National Cancer Institute, Bethesda, MD

[19 ]Seattle Children’s Hospital, Seattle WA

[20 ]Montefiore Medical Center, Bronx, NY

[21 ]Cohen Children’s Medical Center of New York, New Hyde Park, NY

Author notes

Corresponding Author: MATTHIAS KRETZLER, M.D., Nephrology/Internal Medicine, Center for Computational Medicine and Bioinformatics, University of Michigan, 1560 MSRB II, 1150 W. Medical Center Dr.-SPC5676, Ann Arbor, MI 48109-5676, 734-615-5757; fax: 734-763-0982; kretzler@ 123456umich.edu

Article

Manuscript ID: NIHMS425834

DOI: 10.1038/ki.2012.428

PMC ID: 3612359

PubMed ID: 23325076

SO-VID: 14636b64-5d69-454a-9d8d-435596686967

History

Funding

Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK

Award ID: U54 DK083912 || DK

Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK

Design of the Nephrotic Syndrome Study Network (NEPTUNE) to evaluate primary glomerular nephropathy by a multi-disciplinary approach

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Most cited references 41

COQ2 nephropathy: a newly described inherited mitochondriopathy with primary renal involvement.

Changing etiologies of unexplained adult nephrotic syndrome: a comparison of renal biopsy findings from 1976-1979 and 1995-1997.

A proposed taxonomy for the podocytopathies: a reassessment of the primary nephrotic diseases.

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