Renal disease is the most frequent outcome of diabetes and hypertension, two pathological conditions with high prevalence in contemporary Portuguese and European societies. Inflammation is a consistent finding in renal disease patients and is strongly related to worsening of patient?s conditions and to higher morbidity and mortality rate. In hemodialysis (HD) long-term intradialytic contact of blood with large surfaced artificial materials leads to continuous leukocyte activation, with release of oxygen metabolites and granule constituents, such as neutrophilic elastase (NE). Furthermore, degranulation of primed circulating neutrophils may amplify inflammation and oxidative stress, thus exposing endothelial cells to chronic injury by NE, promoting atherosclerosis, the main cause of death in HD patients.
This application focuses on advancing breakthrough discoveries in basic and preclinical research into a new technological platform that can halt progression of renal disease. Based on preliminary results showing the beneficial role reported in the use of vitamin E-modified dialysis membranes for the reduction of oxidative stress, we hypothesise that dialysis membranes incorporating potent and selective NE inhibitors will significantly reduce the inflammatory response. Our research strategy will focus in:
(i) Developing NE inhibitors for this specific purpose , which can be adsorbed to the membrane surface and display adequate stability to be incorporated into the initial membrane formulation; the NE inhibitors need to be highly selective to NE when compared to homologous serine hydrolyses to avoid off-target effects;
(ii) Simulating hemodialysis, using a prototype that affords fluid management; this unique device houses a microdialysis unit that allows simple integration of bioactive polysulfone membranes with controlled porosity and thickness, similar to those used in clinical practice, prepared by spin-coating technique;
(iii) Assessing the robustness of the platform using complementarity experiences that include animal models of chronic renal failure induced by (5/6) nephrectomy and LPS -induced inflammation.
To address this innovative approach, we have set up a highly interdisciplinary team that comprise expertise in the medicinal chemistry of selective enzyme inhibitors, biomaterial engineering, analytical chemistry, pharmacology, pathophysiology, nephrology, hematology and clinical biochemistry. When complete, this project will afford an innovative approach to deal with the burden of renal disease, with a major societal impact by improving the quality of life of renal patients, mostly aging patients.