Development of biomarkers for improved classification of membranous lupus nephritis - SUMMARY/ABSTRACT
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.
