African Americans are disproportionately affected by chronic and end stage kidney disease: while 35% of patients on dialysis are African American, only 13.2% of the U.S. population is African American. One factor contributing to this disparity is the high incidence of autoimmune disease, especially systemic lupus erythematosus (SLE), present in the African American population. Lupus nephritis is a common complication of SLE that leads to end stage renal disease (ESRD) in 5.4% of affected individuals. African Americans and Hispanics are known to have worse outcomes with lupus nephritis compared to Caucasians. The incidence of reduced GFR or other renal disease in African Americans is 38% compared to 19% in Caucasians with SLE [1]. The current classification scheme of lupus nephritis, put forth as a joint effort between the International Society of Nephrology and the Renal Pathology Society (ISN/RPS) recognizes 6 subclasses, based entirely on morphological criteria, ranging from minimal (Class I) to advanced sclerosing kidney disease (Class VI) [2]. However, this classification system is markedly deficient in that it poorly predicts outcomes, especially in identifying those patients with early disease at greatest risk for progressing to ESRD. What is needed is an improved classification system based on the pathophysiology of the disease process. Such a classification is expected to better predict outcomes and would therefore be more useful in guiding therapy of patients with lupus nephritis. The two major types of lupus nephritis (LN) associated with progression to ESRD are proliferative LN (Classes III and IV) and membranous LN (Class V), all of which are driven by immune complexes that accumulate in the glomerulus and tubulointerstitium. Patients with membranous LN are especially problematic to manage, as they may remain quiescent or actively progress to ESRD, and the current classification system offers no guidance into which patients will progress, nor how best to manage this challenging patient population. Arkana plans to develop an improved classification system for membranous LN based on the antigenic composition of the immune complexes present in glomeruli. At the conclusion of Phase I, we expect to have defined a proteomic profile of autoantigens and complement factors that drive membranous LN. In addition, we will correlate these drivers of autoimmunity with those present in other forms of membranous glomerulopathy, including PLA2R- and THSD7A-associated membranous glomerulopathy. In the Phase II, we will begin to determine outcomes in patients with different subclasses of membranous LN, and we will also develop antibodies against these autoantigens into serological, immunohistochemical and immunofluorescence assays that can be deployed in diagnostic assays. In the Phase III, we will commercialize these assays and continue to study outcomes and response to therapy in the post-market setting.
Public Health Relevance Statement: PROJECT NARRATIVE Lupus nephritis is a disease that is markedly over-represented in minority populations, leading in many cases to end-stage renal disease, with associated significant morbidity and mortality. The current classification system for lupus nephritis poorly predicts which patients will progress to end-stage renal disease, as well as which therapeutic interventions are most likely to be efficacious. In this Phase I application, we will identify antigenic proteins and other inflammatory factors present in immune complexes in the kidneys of patients with membranous lupus nephritis. Such information is likely to lead to improved understanding of the mechanism of renal injury in patients with different types of membranous lupus nephritis. In turn, these results will guide the development of improved classification systems and diagnostic assays that can inform clinicians of which patients need more aggressive immunosuppressive therapy.
NIH Spending Category: Autoimmune Disease; Biotechnology; Clinical Research; Health Disparities; Kidney Disease; Lupus; Minority Health; Women's Health
Project Terms: Affect; African American; Antibodies; Antigen-Antibody Complex; Antigens; Archives; Arteries; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmunity; base; Basement membrane; biobank; Biological Assay; Biological Markers; biomarker development; candidate validation; Caucasians; Chronic; Classification; Classification Scheme; Clinical; Complement; Complication; Deposition; Detection; Development; Diagnosis; diagnostic assay; Dialysis procedure; Disease; End stage renal failure; Functional disorder; Glomerular capsule structure; Goals; Healthcare; Hispanics; Immune; Immunofluorescence Immunologic; Immunoglobulin G; improved; Incidence; Incubated; Individual; Inflammatory; Injury; International; Joints; Kidney; kidney biopsy; Kidney Diseases; laser capture microdissection; Lead; Lupus Nephritis; Mass Spectrum Analysis; Membranous Glomerulonephritis; Minority; Morbidity - disease rate; mortality; Nephrology; Notification; novel; novel marker; Outcome; outcome prediction; Outcome Study; Pathogenicity; Pathology; patient population; Patients; Peptides; Phase; phase 2 study; Physical shape; Population; post-market; Process; programs; Proteins; Proteome; Proteomics; Reaction; Renal Tissue; Reporting; Residual state; response; Risk; Serological; Societies; Stains; Subgroup; success; System; Systemic Lupus Erythematosus; Testing; Therapeutic immunosuppression; Therapeutic Intervention; Time; Tissue Sample; Tissues; Tubular formation; Western Blotting
