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.
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.