Immune-mediated glomerular disorders represent the third-most common cause of end-stage renal disease (ESRD), accounting for 14% of the dialysis population. IgA nephropathy (IgAN), membranous nephropathy (MN), and lupus nephritis (SLE-N) are the leading causes of primary and secondary immune-complex glomerular diseases. There are significant ethnic/racial differences in the prevalence and outcomes of these disorders. In particular, black and Hispanic patients are significantly more likely to progress to ESRD than whites across the spectrum of these glomerulopathies. These disparities are not solely attributable to environmental or socioeconomic factors. Recent studies, including from our group, have begun to delineate the contribution of genetic factors to variation in prevalence rates and renal outcomes in numerous glomerular diseases. The goal of this application is to systematically determine the degree to which genetic risk factors account for ethnicity-specific variation in prevalence, disease course, and overall outcomes of IgAN, MN, and SLE-N.
In Aim 1, we will enrich our bio repository for specimens of glomerular disease patients with (a) preferential recruitment of black and Hispanic patients with IgAN, MN, and SLE-N and (b) DNA extraction from 3,000 anonymized kidney biopsy samples of these diseases.
In Aim 2, we will use this bio repository to establish ethnicity-specific normative value for emerging biomarkers in IgAN, MN, and SLE-N that, to date, have primarily been tested in European and Asian populations.
In Aim 3, we will incorporate genetic and biomarker data to better define differences in disease presentation and outcomes among ethnic/racial populations. We anticipate that there will be both distinct and shared genetic risk factors between both the subpopulations (Europeans, Asians, Hispanics, and African-Americans) and immune-mediated diseases under study. These findings will help identify individuals at high risk of IgAN, MN, and SLE-N; more precisely define the role of socio-economic and environmental cofactors in disease phenotypes; allow for discovery of new therapeutic interventions across the spectrum of immune-mediated diseases; and, finally, serve as an important resource for future investigations into the pathophysiology of these immune-mediated kidney diseases.

Public Health Relevance

Glomerular diseases, such as IgA nephropathy (IgAN), membranous nephropathy (MN), and lupus nephritis (SLE-N), are the third leading cause of kidney failure in the United States. Outcomes in these diseases are worst in black and Hispanic patients. Advances in our understanding of the complex genetics of glomerular diseases have begun to question the assumption that socioeconomic and environmental factors are responsible for these discrepancies. This project investigates the role of shared and distinct genetic factors among Europeans, Asians, Hispanics, and African-Americans in the onset, course, and ultimate outcomes of IgAN, MN, and SLE-N.

Agency
National Institute of Health (NIH)
Institute
National Institute on Minority Health and Health Disparities (NIMHD)
Type
Research Project (R01)
Project #
5R01MD009223-04
Application #
9250639
Study Section
Special Emphasis Panel (ZMD1)
Program Officer
Rajapakse, Nishadi
Project Start
2014-07-10
Project End
2019-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
4
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Lata, Sneh; Marasa, Maddalena; Li, Yifu et al. (2018) Whole-Exome Sequencing in Adults With Chronic Kidney Disease: A Pilot Study. Ann Intern Med 168:100-109
Kiryluk, Krzysztof; Bomback, Andrew S; Cheng, Yim-Ling et al. (2018) Precision Medicine for Acute Kidney Injury (AKI): Redefining AKI by Agnostic Kidney Tissue Interrogation and Genetics. Semin Nephrol 38:40-51
Kil, Byum Hee; Zachariah, Teena; Husain, S Ali et al. (2018) Membranous Nephropathy in a Patient With Common Variable Immune Deficiency. Kidney Int Rep 3:738-742
Bomback, Andrew S (2018) Management of Membranous Nephropathy in the PLA2R Era. Clin J Am Soc Nephrol 13:784-786
Bomback, Andrew S (2017) After 4 Decades of Lupus Nephritis Trials, Is There a ""Best"" Therapy? Am J Kidney Dis 70:309-310
Kiryluk, Krzysztof; Li, Yifu; Moldoveanu, Zina et al. (2017) GWAS for serum galactose-deficient IgA1 implicates critical genes of the O-glycosylation pathway. PLoS Genet 13:e1006609
Avasare, Rupali S; Rosenstiel, Paul E; Zaky, Ziad S et al. (2017) Predicting Post-Transplant Recurrence of IgA Nephropathy: The Importance of Crescents. Am J Nephrol 45:99-106
Bomback, Andrew S (2017) A Pregnant Woman with Lupus and Nephrotic-Range Proteinuria. Clin J Am Soc Nephrol 12:1534-1537
Fernandez, Hilda E (2017) Application and interpretation of histocompatibility data in pediatric kidney transplantation. Curr Opin Organ Transplant 22:426-432
Bomback, Andrew S (2017) An Elderly Man with Fatigue, Dyspnea, and Kidney Failure. Clin J Am Soc Nephrol 12:836-838

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