BACKGROUND: Inhibition of the renin-angiotensin system (RAS) prevents development of chronic allograft dysfunction in experimental animals. Whether this therapeutic approach is effective even if started when signs of allograft nephropathy are already manifested has not been investigated. METHODS: To address this issue, we studied the effect of a late treatment with the angiotensin-convertine enzyme (ACE) inhibitor trandolapril in the Fisher 344 to Lewis rat kidney transplant model. Seven months after transplant a renal biopsy was done for graft histology examination. Thereafter rats received either no treatment (allograft-none) or trandolapril until sacrifice at month 13. RESULTS: All animals were alive at the end of the study with the exception of a rat in the untreated group that died of renal insufficiency at day 292. Despite the fact that the grafts had already signs of structural injury and function impairment at the time treatment was stated, trandolapril completely restored renal function to baseline pretransplant values. Trandolapril also halted the progression of glomerular damage and suppressed intragraft T-lymphocyte infiltration and reduced the expression of the chemokine monocyte chemoattractant protein-1 (MCP-1). However, trandolapril had no direct effect on T cell function, since in vivo treatment did not modify recipient T-cell alloreactivity against donor antigens. CONCLUSION: These findings provide the basis for a novel treatment intervention with RAS blockade that, together with pharmacologic inhibition of the immune response, could interrupt progression of chronic allograft dysfunction and injury.
BACKGROUND: Inhibition of the renin-angiotensin system (RAS) prevents development of chronic allograft dysfunction in experimental animals. Whether this therapeutic approach is effective even if started when signs of allograft nephropathy are already manifested has not been investigated. METHODS: To address this issue, we studied the effect of a late treatment with the angiotensin-convertine enzyme (ACE) inhibitor trandolapril in the Fisher 344 to Lewis rat kidney transplant model. Seven months after transplant a renal biopsy was done for graft histology examination. Thereafter rats received either no treatment (allograft-none) or trandolapril until sacrifice at month 13. RESULTS: All animals were alive at the end of the study with the exception of a rat in the untreated group that died of renal insufficiency at day 292. Despite the fact that the grafts had already signs of structural injury and function impairment at the time treatment was stated, trandolapril completely restored renal function to baseline pretransplant values. Trandolapril also halted the progression of glomerular damage and suppressed intragraft T-lymphocyte infiltration and reduced the expression of the chemokine monocyte chemoattractant protein-1 (MCP-1). However, trandolapril had no direct effect on T cell function, since in vivo treatment did not modify recipient T-cell alloreactivity against donor antigens. CONCLUSION: These findings provide the basis for a novel treatment intervention with RAS blockade that, together with pharmacologic inhibition of the immune response, could interrupt progression of chronic allograft dysfunction and injury.
Authors: Matheus Correa-Costa; Patricia Semedo; Ana Paula F S Monteiro; Reinaldo C Silva; Rafael L Pereira; Giselle M Gonçalves; Georgia Daniela Marcusso Marques; Marcos A Cenedeze; Ana C G Faleiros; Alexandre C Keller; Maria H M Shimizu; Antônio C Seguro; Marlene A Reis; Alvaro Pacheco-Silva; Niels O S Câmara Journal: PLoS One Date: 2010-12-13 Impact factor: 3.240
Authors: Sandra M Cockfield; Sam Wilson; Patricia M Campbell; Marcelo Cantarovich; Azim Gangji; Isabelle Houde; Anthony M Jevnikar; Tammy M Keough-Ryan; Felix-Mauricio Monroy-Cuadros; Peter W Nickerson; Michel R Pâquet; G V Ramesh Prasad; Lynne Senécal; Ahmed Shoker; Jean-Luc Wolff; John Howell; Jason J Schwartz; David N Rush Journal: Am J Transplant Date: 2019-02-01 Impact factor: 8.086