Despite great achievements in the field of renal transplantation (RT), long-term results are still not optimal. Several studies have shown that various factors such as early inflammation and/or the presence of interstitial fibrosis (IF) are associated with a worse graft prognosis, but this issue is still controversial and far from being resolved. In this study, we analyzed the inflammatory state (Banff, CD68 + macrophages, M1-M2 phenotypes, among others) and the gene expression of multiple factors related to both inflammation and IF (TGF-β1, metalloproteinases, extracellular matrix proteins, among others) in grafts from cadaveric donors (CD) and they were compared with a control group from living donors (LD). We also analyzed the potential association of all these factors with several clinical variables with medium and/or long-term renal function. Among other findings, we confirm that organs from CD have a greater CD68+ macrophage infiltration and we describe that the expression of several proinflammatory and and profibrotic molecules is significantly increased in CD even before grafting. We also observed an increased gene expression of proteins related to graft leukocyte infiltration, mainly macrophages, such as MCP-1 or ICAM-1, as well as of inflammatory mediators such as TNFα or IL1β. We also observed an increased gene expression of macrophage membrane cell receptors related to their inflammatory (M1) or anti-inflammatory (M2) phenotype. Finally, we described a significant increase of IF precursors and mediators in CD. It is noteworthy that multiple parameters (both inflammatory and profibrotic) were associated with the estimated glomerular filtration rate (MDRD) at different times. Multiple regression analysis revealed that delayed renal function as well as graft TGF-β1 gene expression four months after RT were independent predictors of the last renal function control during follow-up (5. 8 1. 0 years). In conclusion, we confirm the existence of an especially close interconnection between inflammation and fibrosis, especially in the CD RT setting, starting before engraftment and progressing after RT, and that these very early (potentially treatable) factors may already devise its long-term graft prognosis.
|Date of Award||13 Nov 2018|
|Supervisor||David Gomez Guillen (Director), Montserrat M. Díaz Encarnación (Director), Jose Aurelio Ballarin Castan (Director) & Salvador Benito Vales (Tutor)|