Effect of HMG-CoA reductase inhibitors on chronic allograft rejection

Background. Although chronic rejection is the most important cause of late allograft loss, none of the currently available immunosuppressive agents successfully target this problem. Clinical and laboratory studies suggest that 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors (HRIs) may decrease the incidence of and pathophysiologic factors leading to chronic rejection. Methods. A number of clinical and laboratory investigations have been designed to evaluate the effect of HRIs on chronic rejection. Results. Clinical trials in heart transplant patients suggest that HRIs decrease the incidence of chronic rejection in a manner that may be independent of lipid lowering. Subsequent studies in animal transplant models confirm that HRIs reduce chronic rejection. In further studies to elucidate the possible mechanisms of this effect, it has been observed that HRIs have an inhibitory effect on an number of lymphoid cell lines and vascular smooth muscle cells. HRIs may also prevent chronic rejection by protecting the endothelium from injury and dysfunction, perhaps by up-regulating nitric oxide synthesis. Conclusions. HRIs may be the first agents to be effective in preventing chronic rejection. Although the mechanism behind this protective effect is unclear, it seems likely that HRIs may affect multiple factors that could lead to chronic rejection.