Cardiovascular disease management in renal transplant recipients: more or less treatment?

The successful development of immunosuppression for solid organ transplantation has reduced the incidence of acute rejection and improved graft survival. However, this success has seen the emergence of unforeseen complications including premature cardiovascular disease (CVD). Ageand sex-adjusted cardiovascular risk is increased approximately fivefold higher in renal transplant recipients (RTR). The determinants of cardiovascular (CV) risk in RTR appear similar to the general population— hyperlipidemia, hypertension, cigarette smoking, and new-onset diabetes after transplantation (NODAT) being the major modifiable factors (1). However, there are three unique factors. Firstly, time spent on dialysis prior to transplantation (where risk of CVD is increased 20-fold) contributes to the burden of preexisting CV disease at the time of transplantation. Secondly, immunosuppressive medications increase CV risk factors, and thirdly, poor graft function is the strongest, independent, adverse CV risk factor. Thus, the immunosuppressive agents that have revolutionized transplantation have direct effects on CV risk factors and contribute, not only to premature CVD, but also to the increased risk of malignant disease and death due to infection (Figure 1). These observations present a quandary: should CV risk factors be dealt with by addition of medications such as antihypertensive agents or lipid lowering agents, thus increasing the number of tablets that patients take— or should immunosuppressive therapy be tailored to reduce individual risk factors with the possibility of rejection and reduced graft survival? To date, most transplant physicians and surgeons have opted to “add in” medication, rather than interfere with immunosuppression. In our experience, patients also opt for an approach that they perceive is least likely to lead to “rejection,” regardless of the potential benefits on asymptomatic disorders such as hypertension or hyperlipidemia. Recently, the situation has been complicated by large-scale clinical trial evidence supporting the use of statin (“add-on”) therapy to reduce myocardial infarction and cardiac deaths in RTR (2, 3). It is clear that a clinical trial would be required to compare the effects of tailored immunosuppression with “add-on” therapy. However, in the absence of a large-scale outcome trial, studies like that of Wissing and colleagues in this issue provide useful information (4). Previous studies— both crossover and comparative trials— have suggested that Tacrolimus (Tac) has a lesser impact on blood pressure and plasma lipids than cyclosporine (CsA), whereas CsA is less likely to cause posttransplant diabetes. This information provides a rationale for the use of CsA in patients at high risk for developing (such as the elderly and overweight) or who have developed NODAT. In theory, it may offer a similar rationale for the use of Tac in patients at risk, or who have developed, hypertension or hyperlipidemia, rather than giving additional medication. Wissing and colleagues have addressed this question by comparing the effect of switching immunosuppression to addition of statin therapy. Twelve patients received sequentially CsA, CsA plus atorvastatin, Tac, then Tac plus atorvastatin. The study phases lasted approximately two months with a washout following the first atorvastatin treatment prior to the switch to Tac. In keeping with expectation and published data, Tac was associated with lower blood pressure and higher hemoglobin A1c than CsA (albeit nonsignificant), and with a significant reduction in low density lipoprotein (LDL) and total cholesterol. However, the most important finding is that there was no differ-