Anti-thrombin Therapy During Warm Ischemia and Cold Preservation Prevents Chronic Kidney Graft Fibrosis in a DCD Model

Abstract

†Authors contributed equally to this paper. Ischemia reperfusion injury (IRI) is pivotal for renal fibrosis development via peritubular capillaries injury.Coagulation represents a key mechanism involved in this process. Melagatran R (M), a thrombin inhibitor, was evaluated in an autotransplanted kidney model, using Large White pigs. To mimic deceased after cardiac death donor conditions, kidneys underwent warm ischemia (WI) for 60 min before cold preservation for 24 h in University of Wisconsin solution. Treatment with M before WI and/or in the preservation solution drastically improved survival at 3 months, reduced renal dysfunction related to a critical reduction in interstitial fibrosis, measured by Sirius Red staining. Tissue analysis revealed reduced expression of transforming growth factor-b (TGF-b ) and activation level of its effectors phospho-Smad3, Smad4 and connective tissue growth factor (CTGF) after M treatment. Fibrinolysis activation was also observed, evidenced by downregulation of PAI-1 protein and gene expression. In addition, M reduced S100A4 expression and vimentin staining, which are markers for epithelial mesenchymal transition, a major pathway to chronic kidney fibrosis. Finally, expression of oxidative stress markers Nox2 and iNOS was reduced. We conclude that inhibition of thrombin is an effective therapy against IRI that reduces chronic graft fibrosis, with a significantly positive effect on survival.

Low-Level Laser Therapy Decreases Renal Interstitial Fibrosis

“…1,4,5 As a result, the Smads induce fibroblasts to differentiate into myofibroblasts. 7,8 Unilateral ureteral obstruction (UUO) is a well-established experimental model for the study of the mechanisms behind renal interstitial fibrosis (IF) and for evaluating potential therapeutic approaches that might ameliorate the fibrosis. 9,10 Although most patients with CKD are diagnosed well before they reach end-stage renal failure, effective treatments that can completely halt the progressive decline in renal functions have not yet been developed.…”

Strategies to optimize kidney recovery and preservation in transplantation: specific aspects in pediatric transplantation

“…The sterile inflammation induced by ischemia-reperfusion is linked to coagulation through the activation of tissue factor, thrombin production, fibrin deposition and the activation of the protease-activated receptors [72]. Using our pediatric porcine preclinical model of kidney transplantation, we observed that a direct inhibitor of thrombin prevented delayed graft function [73]. Due to their close contact with blood flow, endothelial cells are an easy-to-reach therapeutic target during organ preservation.…”

Magnetic Resonance Spectroscopy (MRS) in Kidney Transplantation: Interest and Perspectives

“…This suggested that PEG associated to an intracellular solution improved oxidative metabolism and reduced renal medulla injury, also in a concentration-dependent manner. Furthermore, the addition of antioxidative (Baumert et al, 1999) or anticoagulant (Favreau et al, 2010) molecules, trimetazidine and melagatran respectively, into the preservation solution increased the performance of the hypothermic conservation. The effect of trimetazidine during conservation with EC or UW showed interesting results.…”