235.5: Poly (ADP-Ribose) Polymerase (PARP) Expression in Renal Allografts Augments the Development of Epithelial-Tomesenchymal Transition (EMT), Transplant Glomerulopathy, And Interstitial Fibrosis in Pediatric Patients With Antibodymediated Rejection

Abstract

Introduction: PARP activation is known to increase inflammation, but its role in developing EMT, interstitial fibrosis (IF), and transplant glomerulopathy (TG) are still unclear. Therefore we investigate the role of PARP in the development of EMT, IF, and TG in recipients with antibody-mediated rejection (AMR). Method: Expressions of tubular and glomerular PARP, α-SMA, TNF-α, TGF-β, and HLA-DR, were studied in 45 pediatric cases with AMR. Tubular α-SMA expression was noted as tubular EMT. Peritubular capillary (PTC) and interstitial leukocytes were highlighted with PARP, TNF-α, HLA-DR, and CD68. Follow-up biopsies were analyzed for IF and TG development. Results: PARP expression in tubules, glomeruli, and infiltrated leukocytes was positively correlated with PTC, glomerular, and interstitial leukocyte and macrophage infiltration (p<0.001). Tubular and glomerular PARP expression also correlated with PTC and interstitial leukocyte PARP, TNF- α, TGF-β, and HLA-DR expression (p<0.001). Tubular α-SMA expression (EMT development) positively correlated with tubular, glomerular, PTC, interstitial, PARP, TNF-α, HLA-DR, and CD68 expression (p<0.01). PARP expression increased in tubules, PTCs, interstitium, and glomeruli with the intensity of C4d expression (p<0.01). Response to rejection treatment decreases with increasing tubular, interstitial, PTC, glomerular PARP, TNF-α, HLA-DR, and CD68 expression (p<0.01). IF development time was negatively correlated with the increasing PTC and interstitial leukocyte and macrophage infiltration (p<0.001). The incidence of IF and TG development was found to increase with an increasing degree of renal PARP expression and tubular EMT development (p<0.01). Additionally, the IF development time shortened with increasing PARP, HLA-DR, TNF-α, TGF-β, α-SMA expression in inflammatory and tubular cells (P<0.01). The mean graft survival time decreased with increasing interstitial, tubular PARP, and α-SMA expression (p<0.01). The 5-year graft survival was 96% for recipients with negative tubular PARP while 60%, 19%, and 18% for recipients with grade1, grade 2, and grade 3 tubular PARP expression, respectively (p<0.001). Conclusion: Increased PARP activation leads to early graft loss by augmenting inflammation and IF by activating inflammatory signaling pathways and tubular cells myofibroblastic differentiation (EMT). Therefore, we suggest that PARP inhibitor drugs combined with immunosuppressive therapy may control inflammation and fibrosis to prevent early graft loss.