Novel renoprotective strategies for the prevention of acute kidney injury following cardiac surgery

• Main Author: Patel, Nishith N.
• Published: University of Bristol 2013
• Subjects: 616.6
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.683689

Acute kidney injury (AKI) following cardiac surgelY is common, is associated with a 4-fold increased risk of in-hospital death, a doubling of healthcare costs and prolonged hospital stay. The aim of this thesis was to develop novel renoprotective strategies by systematically reviewing current preventative sh·ategies, developing a large animal model of post-cardiopulmonalY bypass (CPB) AKI and assessing the interaction of red blood cell (RBC) transfusion and CPB in the pathogenesis of AKI. This thesis has found that cUlTently there are no effective renoprotective strategies for the prevention of post-CPB AKI. By developing a novel large animal porcine recovery model, we have shown that post-CPB AKI is characterised by endothelial injury, activation and dysfunction, nitric oxide depletion, inflammation, tubular epithelial cell stress and apoptosis with no evidence of acute tubular necrosis. Targeting endothelial pathways using Sitaxsentan sodium, an endothelin-A receptor antagonist, and Sildenafil citrate, a phosphodiesterase-5 inhibitor given intravenously at the start of CPB prevented AKI. Contrary to observational studies, we found that allogeneic porcine RBC transfusion did not cause AKI. Instead RBC transfusion prevented post-CPB AKI by reversing haemodilutional anaemia and improving systemic haemodynamics in the porcine model. However, RBC transfusion did cause Transfusion-Related Acute Lung Injury (TRALI). The severity of TRALI was storage dependent and therefore older RBCs caused greater injUly than younger RBCs. RBC transfusion in the presence of CPB exacerbated TRALI. TRALI was characterised by endothelial activation, inflammation, platelet activation and dysfunction, and coagulopathy. Washing of old, stored RBCs ameliorated TRALI. This thesis has contributed two novel large animal recovery models: a model of postCPB AKI and a model ofTRALI. These models have been utilised as platforms for the development of novel organ protection strategies. This thesis has identified three such strategies that can be rapidly translated into clinical trials, namely, endothelin-A receptor antagonism using Sitaxsentan sodium, phosphodiesterase-5 inhibition using sildenafil citrate and washing of stored human RBCs prior to transfusion.