Development of biomarkers for improved classification of membranous lupus nephritis

SUMMARY ABSTRACT African Americans are disproportionately affected by chronic and end stage kidney diseasewhileof patients on dialysis are African Americanonlyof the U Spopulation is African AmericanOne factor contributing to this disparity is the high incidence of autoimmune diseaseespecially systemic lupus erythematosusSLEpresent in the African American populationLupus nephritis is a common complication of SLE that leads to end stage renal diseaseESRDinof affected individualsAfrican Americans and Hispanics are known to have worse outcomes with lupus nephritis compared to CaucasiansThe incidence of reduced GFR or other renal disease in African Americans iscompared toin Caucasians with SLEThe current classification scheme of lupus nephritisput forth as a joint effort between the International Society of Nephrology and the Renal Pathology SocietyISN RPSrecognizessubclassesbased entirely on morphological criteriaranging from minimalClass Ito advanced sclerosing kidney diseaseClass VIHoweverthis classification system is markedly deficient in that it poorly predicts outcomesespecially in identifying those patients with early disease at greatest risk for progressing to ESRDWhat is needed is an improved classification system based on the pathophysiology of the disease processSuch a classification is expected to better predict outcomes and would therefore be more useful in guiding therapy of patients with lupus nephritisThe two major types of lupus nephritisLNassociated with progression to ESRD are proliferative LNClasses III and IVand membranous LNClass Vall of which are driven by immune complexes that accumulate in the glomerulus and tubulointerstitiumPatients with membranous LN are especially problematic to manageas they may remain quiescent or actively progress to ESRDand the current classification system offers no guidance into which patients will progressnor how best to manage this challenging patient populationArkana plans to develop an improved classification system for membranous LN based on the antigenic composition of the immune complexes present in glomeruliAt the conclusion of Phase Iwe expect to have defined a proteomic profile of autoantigens and complement factors that drive membranous LNIn additionwe will correlate these drivers of autoimmunity with those present in other forms of membranous glomerulopathyincluding PLA Rand THSD A associated membranous glomerulopathyIn the Phase IIwe will begin to determine outcomes in patients with different subclasses of membranous LNand we will also develop antibodies against these autoantigens into serologicalimmunohistochemical and immunofluorescence assays that can be deployed in diagnostic assaysIn the Phase IIIwe will commercialize these assays and continue to study outcomes and response to therapy in the post market setting PROJECT NARRATIVE Lupus nephritis is a disease that is markedly over represented in minority populationsleading in many cases to end stage renal diseasewith associated significant morbidity and mortalityThe current classification system for lupus nephritis poorly predicts which patients will progress to end stage renal diseaseas well as which therapeutic interventions are most likely to be efficaciousIn this Phase I applicationwe will identify antigenic proteins and other inflammatory factors present in immune complexes in the kidneys of patients with membranous lupus nephritisSuch information is likely to lead to improved understanding of the mechanism of renal injury in patients with different types of membranous lupus nephritisIn turnthese results will guide the development of improved classification systems and diagnostic assays that can inform clinicians of which patients need more aggressive immunosuppressive therapy