Nephritis is a frequent and severe manifestation of human SLE. Long- term immunosuppression is usually necessary. Relapse is common. SLE nephritis is the result of glomerular accumulation of immune complexes (IC). The risk factors for renal involvement, as well as the determinants of relapse and severity, are poorly understood. We postulate that 1) The dominant mechanism for glomerular IC accumulation is genetic and/or acquired defects of IC clearance proteins. Furthermore, the concurrence of 2 or more defective/deficient IC clearance proteins predisposes to severe nephritis. 2) IC mediate renal inflammation by regulating the local expression of chemotactic cytokines (chemokines). 3) Specific, quantifiable clinical events are triggers for SLE nephritis relapse, and influence disease severity. These hypotheses will be tested by 4 interrelated projects. Projects 1 and 2 analyze genetic polymorphisms of key IC clearance proteins (C2, C4, CR1, FcgammaRIIa, and FcgammaRIIIa), to determine which are susceptibility genes for human SLE nephritis. Project 3 examines genetic, molecular, and cellular mechanisms that regulate chemokine activity in human SLE nephritis. Project 3 examines genetic, molecular, and cellular mechanisms that regulate chemokine activity in human SLE nephritis. The genetic testing of Projects 1, 2, and 3 will involve 250 SLE nephritis patients (biopsy proven), 250 SLE patients who have never had nephritis, and 250 matched normals. Patients and siblings of the SLE patients will also be used for transmission disequilibrium testing (TDT). Project 4 is a meticulous, prospective study designed to determine the relationship between SLE relapse and genetic, immunologic, and clinical parameters. One hundred SLE patients with relapsing disease (50 with and 50 without renal manifestations) will be studied longitudinally over 5 years. In collaboration with Projects 1-3, serial quantitative measures of IC clearance proteins, chemokines, and specific clinical factors (stress, sex hormones, infection, UV radiation) will be obtained before, during, and after each of the more than 300 SLE relapses expected during follow-up. These variables will be correlated to disease activity and severity to determine which are """"""""triggers"""""""" for SLE relapse, and which are determinants of the renal manifestations of SLE. From this analysis should emerge, for the first time, a clear picture of the risk factors for SLE nephritis and its relapse in humans. Summary: Concepts fundamental to understanding the genetic and clinical risk factors for human SLE nephritis should be revealed, thus providing tools for predicting SLE nephritis relapse and severity, and strategies for its management.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK055546-04
Application #
6729987
Study Section
Special Emphasis Panel (ZDK1-GRB-6 (J2))
Program Officer
Flessner, Michael Francis
Project Start
2001-06-01
Project End
2006-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
4
Fiscal Year
2004
Total Cost
$950,223
Indirect Cost
Name
Ohio State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Birmingham, Daniel J; Merchant, Michael; Waikar, Sushrut S et al. (2017) Biomarkers of lupus nephritis histology and flare: deciphering the relevant amidst the noise. Nephrol Dial Transplant 32:i71-i79
Lintner, Katherine E; Wu, Yee Ling; Yang, Yan et al. (2016) Early Components of the Complement Classical Activation Pathway in Human Systemic Autoimmune Diseases. Front Immunol 7:36
Birmingham, Daniel J; Bitter, Joshua E; Ndukwe, Ezinne G et al. (2016) Relationship of Circulating Anti-C3b and Anti-C1q IgG to Lupus Nephritis and Its Flare. Clin J Am Soc Nephrol 11:47-53
Parikh, Samir V; Nagaraja, Haikady N; Hebert, Lee et al. (2014) Renal flare as a predictor of incident and progressive CKD in patients with lupus nephritis. Clin J Am Soc Nephrol 9:279-84
Birmingham, Daniel J; Shidham, Ganesh; Perna, Annalisa et al. (2014) Spot PC ratio estimates of 24-hour proteinuria are more unreliable in lupus nephritis than in other forms of chronic glomerular disease. Ann Rheum Dis 73:475-6
Freedman, Barry I; Langefeld, Carl D; Andringa, Kelly K et al. (2014) End-stage renal disease in African Americans with lupus nephritis is associated with APOL1. Arthritis Rheumatol 66:390-6
Hebert, Lee A; Parikh, Samir; Prosek, Jason et al. (2013) Differential diagnosis of glomerular disease: a systematic and inclusive approach. Am J Nephrol 38:253-66
Young, Nicholas A; Friedman, Alexandra K; Kaffenberger, Benjamin et al. (2013) Novel estrogen target gene ZAS3 is overexpressed in systemic lupus erythematosus. Mol Immunol 54:23-31
Fukuda, Akihiro; Wickman, Larysa T; Venkatareddy, Madhusudan P et al. (2012) Urine podocin:nephrin mRNA ratio (PNR) as a podocyte stress biomarker. Nephrol Dial Transplant 27:4079-87
Birmingham, D J; Hebert, L A; Song, H et al. (2012) Evidence that abnormally large seasonal declines in vitamin D status may trigger SLE flare in non-African Americans. Lupus 21:855-64

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