Long-term use of cyclosporine after renal transplantation results in nephrotoxicity and an increased cardiovascular risk profile. Tacrolimus may be more favorable in this respect. In this randomized controlled study in 124 renal transplant patients, the effects of conversion from cyclosporine to tacrolimus on renal function, cardiovascular risk factors, and perceived sideeffects were investigated after a follow-up of 2 years. After conversion from cyclosporine to tacrolimus renal function remained stable, whereas continuation of cyclosporine was accompanied by a rise in serum creatinine from 142 ± 48 lmol/L to 157 ± 62 lmol/L (p < 0.05 comparing both groups). Conversion to tacrolimus resulted in a sustained reduction in systolic and diastolic blood pressure, and a sustained improvement in the serum lipid profile, leading to a reduction in the Framingham risk score from 5.7 ± 4.3 to 4.8 ± 5.3 (p < 0.05). Finally, conversion to tacrolimus resulted in decreased scores for occurrence of and distress due to side-effects. In conclusion, conversion from cyclosporine to tacrolimus in stable renal transplant patients is beneficial with respect to renal function, cardiovascular risk profile, and side-effects. Therefore, for most renal transplant patients tacrolimus will be the drug of choice when long-term treatment with a calcineurin inhibitor is indicated.

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.

Abstract. Cyclosporine is considered to contribute to the high cardiovascular morbidity and mortality in patients after renal transplantation. Tacrolimus may be more favorable in this respect, but controlled data are scarce. In this prospective randomized study in 124 stable renal transplant patients, the effects of conversion from cyclosporine to tacrolimus on cardiovascular risk factors and renal function were investigated. Follow-up was 6 mo. Statistical analysis was performed by ANOVA for repeated measurements. The serum creatinine level decreased from 137 Ϯ 30 mol/L to 131 Ϯ 29 mol/L (P Ͻ 0.01). Three months after conversion from cyclosporine to tacrolimus, mean BP significantly decreased from 104 Ϯ 13 to 99 Ϯ 12 mmHg (P Ͻ 0.001). Serum LDL cholesterol decreased from 3.48 Ϯ 0.80 to 3.11 Ϯ 0.74 mmol/L (P Ͻ 0.001,) and serum apolipoprotein B decreased from 1018 Ϯ 189 to 935 Ϯ 174 mg/L (P Ͻ 0.001). Serum triglycerides decreased from 2.11 Ϯ 1.12 to 1.72 Ϯ 0.94 mmol/L (P Ͻ 0.001). In addition, both rate and extent of LDL oxidation were reduced. The fibrinogen level decreased from 3638 Ϯ 857 to 3417 Ϯ 751 mg/L (P Ͻ 0.05). Plasma homocysteine concentration did not change. Three months after conversion, plasma fasting glucose level temporarily increased from 5.4 Ϯ 1.3 mmol/L to 5.8 Ϯ 1.9 mmol/L (P Ͻ 0.05). Conversion to tacrolimus resulted in a significant reduction of the Framingham risk score. In conclusion, conversion from cyclosporine to tacrolimus in stable renal transplant patients has a beneficial effect on renal function, BP, serum concentration and atherogenic properties of serum lipids, and fibrinogen.During the past two decades, cyclosporine has proved to be a valuable immunosuppressive drug that has contributed to a significant reduction in the incidence of acute rejection after renal transplantation. However, cyclosporine also increases cardiovascular risk profiles (1). Ultimately, up to 63% of renal transplant patients die of cardiovascular disease (2). The increased cardiovascular risk profile as a result of cyclosporine is ascribed to both a quantitative increase in LDL particles and an increased oxidizability of the LDL particles (3-5). Use of cyclosporine is also associated with increased plasma lipoprotein(a) (Lp[a]) (6) and homocysteine levels (7), but these effects are not unequivocal (8). In addition, unfavorable effects on the fibrinolytic system by cyclosporine have been described (9). Apart from these disadvantageous effects of cyclosporine on several metabolic cardiovascular risk factors, cyclosporine leads to an elevation of BP (4). These side effects not only contribute to the high cardiovascular morbidity in renal transplant patients but also may lead to an accelerated loss of graft function (10 -12).Tacrolimus is like cyclosporine, a calcineurin inhibitor, with even more potent immunosuppressive properties. The use of tacrolimus after renal transplantation is associated with a less unfavorable effect on BP and serum lipid levels, but evidence from controlled studies is scarce (4,13). L...

Although there are experimental reports of cytochrome P450 3A4 iso-enzyme (CYP3A4) induction by glucocorticoids, there are no clinical reports about an interaction between tacrolimus and steroids. Therefore, tacrolimus trough level and dose were compared after dose-normalization before and after withdrawal of prednisolone. After withdrawal of 5 mg prednisolone, the median tacrolimus dose-normalized level increased by 14% in the retrospective ( n=54), and by 11% in the prospective ( n=8) part of the study. After withdrawal of 10 mg, this increase was 33% ( n=30) and 36% ( n=14), respectively. An additional pharmacokinetic part of the study ( n=8) revealed an 18% increase in AUC ( P=0.05) after withdrawal of 5 mg prednisolone, which is compatible with a reduced metabolism after steroid withdrawal. The significant increase in tacrolimus exposure after steroid withdrawal may on the one hand counteract the reduction in immunosuppression intended by steroid withdrawal, and, on the other hand, may result in an increase of serum creatinine which could be misinterpreted as rejection.

Compared with tapering in 3 to 6 months, stopping steroids 1 week posttransplantation results in comparable patient and graft survival and in a similar incidence of acute rejections. The incidence of new-onset diabetes may be reduced. The immunosuppressive benefit of adding 10 mg prednisolone to tacrolimus seems to be limited.