Nephrotic Syndrome (NS) from Focal and Segmental Glomerulosclerosis (FSGS), Minimal Change Disease (MCD) and Membranous Nephropathy (MN) is a group of rare diseases that can cause catastrophic complications and end stage kidney disease. Despite their rarity, this disease group generates an enormous individual and societal economic burden. The currently employed, histopathology-based taxonomy of NS is inadequate and fails to capture the molecular bases of these diseases. Recent discoveries, which have identified causal genes in familial [mendelian] FSGS, the target podocyte antigen characterizing MN, and the association of APOL1 variants with FSGS histology in African American NS patients, provides indisputable evidence that multiple, unique disease mechanisms can present with indistinguishable histopathology. A Precision Medicine approach is necessary to identify and to execute specific therapies for each of the many unique glomerular diseases that result in NS. This requires understanding of the molecular bases of glomerular disease. Over the past 4 years NEPTUNE has advanced the care of NS patients by establishing a robust investigative infrastructure encompassing 21 sites, which has recruited more than 500 rigorously phenotyped NS patients, with biological materials and associated detailed clinical data. In addition, NEPTUNE has established robust training and ancillary study programs open to all interested investigators. In this renewal proposal, we propose to leverage these resources to further associate clinically meaningful endpoints with shared and specific genetic, molecular and structural features of glomerular diseases to generate a new, molecular NS taxonomy that will permit discovery of novel therapeutic targets and trial design. Two cohort studies will enroll NS individuals with (1) severe NS enriched for African Americans and (2) pediatric cohort with NS at time of first presentation prior to biopsy. These cohorts will add critical segments of NS disease phenotypes to reflect the full NS disease spectrum in NEPTUNE. Training and pilot programs will continue to leverage the unique resources in NEPTUNE and outreach in conjunction with patient interest group NephCure engaging lay communities, clinicians and scientists to advance NS research

Public Health Relevance

NEPTUNE aims to define Nephrotic Syndrome in functional terms to identify novel molecular predictors and targeted therapies. Together with the patient interest group NephCure we will expand the translational research pipeline to enable a precision medicine approach in NS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
2U54DK083912-06
Application #
8764274
Study Section
Special Emphasis Panel (ZTR1-CI-8 (01))
Program Officer
Moxey-Mims, Marva M
Project Start
2009-09-08
Project End
2019-06-30
Budget Start
2014-09-20
Budget End
2015-06-30
Support Year
6
Fiscal Year
2014
Total Cost
$1,250,000
Indirect Cost
$399,469
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Hommos, Musab S; Zeng, Caihong; Liu, Zhihong et al. (2018) Global glomerulosclerosis with nephrotic syndrome; the clinical importance of age adjustment. Kidney Int 93:1175-1182
Park, Sun-Ji; Kim, Yeawon; Chen, Ying Maggie (2018) Endoplasmic reticulum stress and monogenic kidney diseases in precision nephrology. Pediatr Nephrol :
Miyata, Kana N; Nast, Cynthia C; Dai, Tiane et al. (2018) Renal matrix Gla protein expression increases progressively with CKD and predicts renal outcome. Exp Mol Pathol 105:120-129
Grayson, Peter C; Eddy, Sean; Taroni, Jaclyn N et al. (2018) Metabolic pathways and immunometabolism in rare kidney diseases. Ann Rheum Dis 77:1226-1233
Czerniecki, Stefan M; Cruz, Nelly M; Harder, Jennifer L et al. (2018) High-Throughput Screening Enhances Kidney Organoid Differentiation from Human Pluripotent Stem Cells and Enables Automated Multidimensional Phenotyping. Cell Stem Cell 22:929-940.e4
Zee, Jarcy; Hodgin, Jeffrey B; Mariani, Laura H et al. (2018) Reproducibility and Feasibility of Strategies for Morphologic Assessment of Renal Biopsies Using the Nephrotic Syndrome Study Network Digital Pathology Scoring System. Arch Pathol Lab Med 142:613-625
Mariani, Laura H; Martini, Sebastian; Barisoni, Laura et al. (2018) Interstitial fibrosis scored on whole-slide digital imaging of kidney biopsies is a predictor of outcome in proteinuric glomerulopathies. Nephrol Dial Transplant 33:310-318
Mitrofanova, Alla; Molina, Judith; Varona Santos, Javier et al. (2018) Hydroxypropyl-?-cyclodextrin protects from kidney disease in experimental Alport syndrome and focal segmental glomerulosclerosis. Kidney Int 94:1151-1159
Troost, Jonathan P; Trachtman, Howard; Nachman, Patrick H et al. (2018) An Outcomes-Based Definition of Proteinuria Remission in Focal Segmental Glomerulosclerosis. Clin J Am Soc Nephrol 13:414-421
Nair, Viji; Komorowsky, Claudiu V; Weil, E Jennifer et al. (2018) A molecular morphometric approach to diabetic kidney disease can link structure to function and outcome. Kidney Int 93:439-449

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