Session Type: ACR Concurrent Abstract Session
Session Time: 2:30PM-4:00PM
Background/Purpose: Clinical trials in rare diseases typically test therapeutic efficacy in one disease defined by a particular clinical phenotype. Improved understanding of the molecular mechanisms of disease may identify shared pathways across different clinical diseases that could be leveraged to develop stratified approaches to treatment and enable novel disease classification strategies based upon molecular rather than clinical phenotyping. An unbiased analysis of kidney diseases suggests many rare kidney diseases share common molecular profiles (Martini et al., 2014). To expand on these findings, we explored shared transcriptional responses in patients with ANCA-associated vasculitis (AAV) and nephrotic syndrome (NS) to identify common targetable disease mechanisms.
Methods: Patients with various forms of NS (minimal change disease, focal segmental glomerulosclerosis and membranous nephropathy) were recruited from the NEPTUNE cohort (n=126) and the European Renal cDNA Bank (ERCB, n=61). Patients with AAV (granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA)) recruited from the ERCB cohort (n=80) and healthy living donors (n=37) were also studied. Patients with NS and AAV underwent standardized diagnostic kidney biopsies performed as routine clinical care. Biopsy material was micro-dissected into glomerular and tubulointerstitial compartments. Transcriptomic profiles across the two tissue compartments were generated on Affymetrix U133 and ST2.1 microarray platforms. Differential gene expression across the transcriptome was compared between patients with NS and AAV versus living donors, and shared transcriptional responses were assessed relative to living donors. Functional networks were interrogated for cross-cutting disease mechanisms, upstream regulators and potential therapeutic targets shared between both diseases.
Results: Overall, 5%-25% of expressed transcripts were differentially regulated compared to living donor in both NS and AAV in the glomerular and tubulointerstitial compartments (fold change ≥ 1.3, FDR<0.05). Findings were replicated and cross-validated across the different microarray platforms. There was significant overlap in shared directionality of change of differentially expressed genes between patients with AAV and NS in both tissue compartments (FDR<0.05). Functional analysis identified conserved, therapeutically targetable transcriptional networks in the glomeruli from patients with NS and AAV including activation of Tec kinase, IL-8 signaling, TNF, IFNG, TGFB1, and NFkappaB, while alpha catenin and retinoid-related signaling were suppressed. Transcripts causally downstream of TNF were used to develop a TNF pathway activity score across diseases, and increased TNF-related inflammatory signaling was observed in specific subsets of patients.
Conclusion: AAV and NS, two rare kidney diseases, share common intra-renal transcriptional profiles that can be readily mined to identify shared molecular targets. Shared molecular targets can be leveraged for drug development and repurposing efforts in these rare kidney diseases.
To cite this abstract in AMA style:Eddy S, Nair V, Parikh H, Lindenmeyer M, Mariani L, Eichinger FH, Huang H, Ju W, Greene C, Grayson PC, Cohen C, Krischer J, Merkel PA, Kretzler M. Inflammatory Pathways As Shared Molecular Targets Across ANCA-Associated Vasculitis and Nephrotic Syndrome [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). http://acrabstracts.org/abstract/inflammatory-pathways-as-shared-molecular-targets-across-anca-associated-vasculitis-and-nephrotic-syndrome/. Accessed February 21, 2018.
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