In the current issue of the Journal, Dr Krämer and co-investigators measured several cardiovascular (CV) risk factors in kidney transplant recipients randomized to receive either tacrolimus or cyclosporin A (microemulsion) (1). Based on lipid levels, blood pressure and glucose measured early post-transplant the authors conclude that men treated with cyclosporin have higher CV risk than those treated with tacrolimus. Of interest, this difference was not observed in women. Although the validity of this conclusion could be argued it would have been interesting to know the reasons for the gender differences in calculated CV risk.
We should be cautious interpreting these results as evidence that one treatment regimen is superior to another with respect to CV risk. Indeed, Dr Krämer, to his credit, carefully avoids this conclusion. We simply do not have sufficient information to decide, for example, whether dyslipidemia is a stronger or a weaker determinant of post-transplant CV risk than say hyperglycemia. This manuscript addresses a question that is being asked with increasing frequency, what is the contribution of immunosuppressive drugs to the overall CV risk of transplant patients? It is unfortunate that this question is being frequently framed in the context of its possible commercial implications. Dr Krämer is quite sensitive to the possible attribution of his findings to a commercial interest and states emphatically that this analysis was investigator driven. This clarification is welcomed.
It is clear that most immunosuppressive drugs affect CV risk factors (2). However, to interpret correctly the possible relevance of those changes we need to understand better the pathogenesis of CV disease in transplant patients. In that respect, we would like to consider briefly three questions: (1) how much of the CV risk of transplant recipients can be attributed to CV disease present prior to transplantation? (2) What is the impact of ‘traditional’ CV risk factors in transplant recipients? (3) What is the contribution of nontraditional risk factors to this patient's CV disease?
Prior to the transplant, many patients have significant CV disease. The development of this pathology starts during the earliest stages of chronic kidney disease and progresses as kidney function declines. There is evidence that the cardiac functional abnormalities (LVH and dilated cardiomyopathy) improve after the transplant but they do not normalize (3). Unfortunately, we have no information about changes in atherosclerotic burden after successful transplantation. Given this evidence, we believe that it is important to compare the CV risk of transplant recipients not to that of the general population but rather to that of nontransplant patients with known heart disease. Comparing transplant patients to the general population may be misleading and, at the least, gives us an unrealistic therapeutic goal.
The question then is what is the impact of traditional CV risk factors (age, diabetes, hypertension, smoking and dyslipidemia) in patients with CV disease? Prospective, randomized studies in the general population clearly showed that treatment of these risk factors (notably hypertension, diabetes, and dyslipidemia) reduces the mortality of patients with heart disease. There are no prospective studies analyzing this issue in transplant patients but it is reasonable to assume that management of CV risk factors would be effective in these patients. Correlative analyses showed that traditional CV risk factors relate to the CV disease of transplanted patients (4). These studies support Dr Krämer's conclusion that medications that cause dyslipidemia or hypertension may increase CV risk. Less clear in Dr Krämer's analysis is the contribution of altered glucose metabolism to the CV risk profile of their patients. The original study, from which these data are derived, defined diabetes as ‘the need for insulin for more than 30 consecutive days in patients previously not known to be diabetic’ (1), a definition that in our opinion has no scientific justification. Previous studies consistently identified diabetes as the strongest (statistically) correlate of CV risk in transplant patients. We would argue that this is the ‘tip of the iceberg’ because it is now clear that even ‘borderline hyperglycemia’ and insulin resistance, without hyperglycemia, are associated with a significant CV risk. Thus, the question of how much do disorders of glucose metabolism contribute to the CV risk of transplant recipients remains unanswered.
The list of nontraditional factors that possibly contribute to the CV risk of transplant recipients is long, including: the renin/angiotensin/aldosterone system, oxidative stress, inflammation, homocysteine and others. Immosuppressive drugs alter several of these variables but whether those changes have an impact on CV risk remain theoretical. What is not theoretical is that compared with the general population, the CV risk of transplant patients is greatly magnified (5). There is strong evidence that management of risk factors and angiotensin converting enzyme blockade reduces the risk of nontransplant patients with heart disease. We believe that it is quite reasonable to apply these therapies to transplant patients. The availability of several effective immunosuppressive drugs suggests the possibility of tailoring these drugs to the patient's CV risk profile. However, with the exception of azathioprine and mycophenolate mofetil, all other drugs used for maintenance immunosuppression have adverse effects on CV risk factors. Dr Krämer's study may be a first step towards identifying ‘the least bad’ of those drugs.