ACE inhibition limits chronic injury of kidney transplant even with treatment started when lesions are established.
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.


CONCLUSIONS
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.
Noris
Marina
M
Department of Medicine and Transplantation, Ospedali Riuniti Bergamo-Mario Negri Institute for Pharmacological Research, Bergamo, Italy. noris@marionegri.it
Mister
Marilena
M
Pezzotta
Anna
A
Azzollini
Nadia
N
Cassis
Paola
P
Benigni
Ariela
A
Gagliardini
Elena
E
Perico
Norberto
N
Remuzzi
Giuseppe
G
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors; D007211:Indoles / Q000494:pharmacology*; D007668:Kidney / Q000473:pathology / Q000503:physiopathology*; D007674:Kidney Diseases / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D016030:Kidney Transplantation / Q000009:adverse effects*; D007959:Lymphocyte Culture Test, Mixed; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D020127:Recovery of Function; D013601:T-Lymphocytes / Q000276:immunology
D000806:Angiotensin-Converting Enzyme Inhibitors; D018932:Chemokine CCL2; D007211:Indoles; C052035:trandolapril