The effect of HMG-CoA reductase inhibitors on chronic allograft rejection.
Hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors have pleiotropic actions that affect many systems other than lowering blood cholesterol concentrations. Hypercholesterolaemia is an adverse effect of immunosuppressive drug therapy and hence it is a common finding after organ transplantation. HMG-CoA reductase inhibitors lower cholesterol concentrations in transplant recipients but they also offer additional benefits. Since they impair the production of mevalonate, they reduce the concentrations of downstream products including farnesyl and geranyl phosphate. These isoprenoid moieties are required for protein prenylation and HMG-CoA reductase inhibitors impair this function in some cells. This action affects the immune system, especially in patients taking cyclosporin, and has been proposed as the mechanism whereby these drugs increase the half-life of transplanted organs. Other mechanisms have also been proposed including an increase in the free fraction of cyclosporin and a reduction in the time that low density lipoprotein (LDL) spends in blood. The latter effect reduces the extent of oxidation of LDL and hence reduces the damage caused by oxidised LDL. Chronic rejection is poorly understood but appears to involve both immune and non-immune processes. HMG-CoA reductase inhibitors affect both processes. At present, the evidence of benefit from statin prescription is confined to heart and kidney transplant recipients but it is likely that recipients of other organ transplants would also benefit. Drug interactions between cyclosporin and HMG-CoA reductase inhibitors are a limiting factor to their use. Pravastatin appears to be the best HMG-CoA reductase inhibitor for organ transplant recipients because of its lesser potential to interact with cyclosporin and hence cause myositis, which may thus allow higher doses to be used. Other, non-immunosuppressive drugs (including diltiazem and ketoconazole) have been shown to reduce transplant organ damage by unknown mechanisms and are widely prescribed in some transplant centres. More specific inhibitors of protein prenylation may afford useful immunosuppression, thereby prolonging transplant organ half-lives and also reducing the risk of cancer.
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The Queen Elizabeth Hospital, Woodville, South Australia 5011, Australia. terryej@hotmail.com