Idiopathic Membranous Nephropathy (MN) is a group of rare diseases that results in often catastrophic complications of nephrotic syndrome and end stage kidney disease. There is growing consensus that the presently employed histopathology-based classification of MN is inadequate because it is not based on an understanding of the molecular basis of these diseases, and because it does not well predict the heterogeneous natural history or response to therapy of those affected. Given these shortcomings, it is not surprising that our therapeutic approach to these diseases is imperfect. We propose that several major barriers must be addressed to allow for more effective interventional studies of primary non-inflammatory glomerular disease. Among these barriers is the absence of specific biomarkers of glomerular disease that would allow refined, biologically relevant sub-classification of glomerular disease useful for defining subject inclusion and exclusion criteria in clinical studies. Such disease sub-classification might overcome the effects of study population heterogeneity that likely have complicated interpretation of past studies of these glomerular diseases. New glomerular disease biomarkers might also predict disease natural history, allow proper selection of and prediction of response to specific therapeutic intervention, allow early detection of disease, or provide indicators of disease activity. Importantly, a robust investigative infrastructure is presently lacking that would facilitate collection, cultivation, and access to human biological material and associated clinical data necessary for biomarker identification, for the identification of clinically relevant study endpoints, and for conducting pilot clinical studies that would advance the care of MN patients. This application proposes a collaborative prospective observational cohort study of patients who present with histopathology characteristic of membranous glomerulopathy. After collecting 200 patients with this kidney biopsy characteristic, and their associated clinical data, kidney tissue, blood, and urine, the initial goals of the MN Cohort study are: (a) to develop and use a combination of molecular phenotypes, quantifiable histological parameters, and discrete clinical features to predict clinical outcomes;and (b) to classify patients according to their molecular phenotype into discrete subgroups. Given the paucity of knowledge in this area, these initial experiments are meant as hypothesis generating. Additional confirmatory studies will be required to validate initial observations. These studies hold out the promise to the clinician of being able to predict the natural history of MN.

Public Health Relevance

Membranous histopathology is a common presentation of a group of rare diseases that cause serious morbidity and high mortality, generating enormous individual and societal economic burden. This prospective observational cohort study will provide a readily accessible resource that will significantly advance our ability to study, classify, characterize, diagnose, and treat non-inflammatory glomerular diseases

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54DK083912-05
Application #
8538363
Study Section
Special Emphasis Panel (ZRG1-HOP-Y)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$987,136
Indirect Cost
$221,815
Name
University of Michigan Ann Arbor
Department
Type
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
de Boer, Ian H; Afkarian, Maryam; Tuttle, Katherine R (2016) The Surging Tide of Diabetes: Implications for Nephrology. Am J Kidney Dis 67:364-6
Haas, Mary E; Levenson, Amy E; Sun, Xiaowei et al. (2016) The Role of Proprotein Convertase Subtilisin/Kexin Type 9 in Nephrotic Syndrome-Associated Hypercholesterolemia. Circulation 134:61-72
Merkel, Peter A; Manion, Michele; Gopal-Srivastava, Rashmi et al. (2016) The partnership of patient advocacy groups and clinical investigators in the rare diseases clinical research network. Orphanet J Rare Dis 11:66
Laurin, Louis-Philippe; Gasim, Adil M; Derebail, Vimal K et al. (2016) Renal Survival in Patients with Collapsing Compared with Not Otherwise Specified FSGS. Clin J Am Soc Nephrol :
Gipson, Debbie S; Troost, Jonathan P; Lafayette, Richard A et al. (2016) Complete Remission in the Nephrotic Syndrome Study Network. Clin J Am Soc Nephrol 11:81-9
Sampson, Matthew G; Gillies, Christopher E; Robertson, Catherine C et al. (2016) Using Population Genetics to Interrogate the Monogenic Nephrotic Syndrome Diagnosis in a Case Cohort. J Am Soc Nephrol 27:1970-83
Gillies, Christopher E; Otto, Edgar A; Vega-Warner, Virginia et al. (2016) tarSVM: Improving the accuracy of variant calls derived from microfluidic PCR-based targeted next generation sequencing using a support vector machine. BMC Bioinformatics 17:233
Bassi, Roberto; Fornoni, Alessia; Doria, Alessandro et al. (2016) CTLA4-Ig in B7-1-positive diabetic and non-diabetic kidney disease. Diabetologia 59:21-9
Hogan, Marie C; Reich, Heather N; Nelson, Peter J et al. (2016) The relatively poor correlation between random and 24-hour urine protein excretion in patients with biopsy-proven glomerular diseases. Kidney Int 90:1080-1089
Pullen, Nick; Fornoni, Alessia (2016) Drug discovery in focal and segmental glomerulosclerosis. Kidney Int 89:1211-20

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