Effect of immunosuppressive agents on long-term survival of renal transplant recipients: focus on the cardiovascular risk

Abstract

In the control of acute rejection, attention is being focused more and more on the long-term adverse effects of the immunosuppressive agents used. Since cardiovascular disease is the main cause of death in renal transplant recipients, optimal control of cardiovascular risk factors is essential in the long-term management of these patients. Unfortunately, several commonly used immunosuppressive drugs interfere with the cardiovascular system. In this review, the cardiovascular adverse effects of the immunosuppressive agents currently used for maintenance immunosuppression are thoroughly discussed. Optimising immunosuppression means finding a balance between efficacy and safety. Corticosteroids induce endothelial dysfunction, hypertension, hyperlipidaemia and diabetes mellitus, and impair fibrinolysis. The use of corticosteroids in transplant recipients is undesirable, not only because of their cardiovascular effects, but also because they induce such adverse effects as osteoporosis, obesity, and atrophy of the skin and vessel wall. Calcineurin inhibitors are the most powerful agents for maintenance immunosuppression. The calcineurin inhibitor ciclosporin (cyclosporine) not only induces these same adverse effects as corticosteroids but is also nephrotoxic. Tacrolimus has a more favourable cardiovascular risk profile than ciclosporin and is also less nephrotoxic. It has little or no effect on blood pressure and serum lipids; however, its diabetogenic effect is more prominent in the period immediately following transplantation, although at maintenance dosages, the diabetogenic effect appears to be comparable to that of ciclosporin. The diabetogenic effect of tacrolimus can be managed by reducing the dose of tacrolimus and early corticosteroid withdrawal. The effect of tacrolimus on endothelial function has not been completely elucidated. The proliferation inhibitors azathioprine and mycophenolate mofetil (MMF) have little effect on the cardiovascular system. Yet, indirectly, by inducing anaemia, they may lead to left ventricular hypertrophy. MMF is an attractive alternative to azathioprine because of its higher potency and possibly lower risk of malignancies. Sirolimus also induces anaemia, but may be promising because of its antiproliferative features. Whether the hyperlipidaemia induced by sirolimus counteracts its beneficial effects is, as yet, unknown. It may be combined with MMF, however, initial attempts resulted in severe mouth ulcers.