One of the main characteristics of Bright's disease is the presence of hypertension and significant arteriolar alterations of small arteries. More recently, the contribution of increased stiffness of large arteries has been documented in Bright's disease and shown to be independent of increased blood pressure (BP) and atherosclerosis . The finding has been mainly observed in advanced renal failure but can be extended to milder forms of chronic renal failure. Increased arterial stiffness is now observed in patients with renal transplantation, irrespective of whether the kidney graft is obtained from deceased or living donors.
In 101 living kidney donors and their 101 corresponding recipients [2,3], aortic (carotid–femoral) pulse wave velocity (PWV), a classical marker of arterial stiffness, has been measured noninvasively and compared with healthy volunteers [2,3]. Healthy volunteers (n = 263) were divided into two groups: one was a recipient-related group, that is, influenced by consistent familial links, and the other was a nonrecipient-related (NRR) group. Independent of age, sex, and BP, PWV was significantly elevated in donors and recipients when compared with the two groups of healthy volunteers. It was significantly higher in the recipient-related than in the NRR healthy group. Although in healthy volunteers, PWV was exclusively related to age, sex, and BP, in donors and recipients, it was rather associated with a cluster of cardiovascular risk factors, including smoking habits or plasma glucose or both. However, the major factors related to PWV were of renal origin: time elapsed since nephrectomy (donation date) in donors, in whom pulse pressure was specifically associated with proteinuria, and in recipients with acute renal rejection. In renal transplant patients, doubling of plasma creatinine secondary to chronic allograft nephropathy was significantly associated not only with renal rejection but also with PWV of the donor, independent of age and BP. These findings strongly suggest the presence of consistent interactions (including familial factors) between kidney function in transplanted patients and donor parameters such as age and arterial stiffness.
Few studies on increased arterial stiffness in transplants from deceased donors have been performed in recent years [4–6]. Delahousse et al. evaluated aortic PWV in 74 kidney recipients at 3 and 12 months after transplantation [3,7]. At 3 months, aortic stiffness was associated exclusively with recipient-related factors: age, sex, and mean BP. At 12 months, the age of the kidney donor emerged as an additional determinant. The change in aortic PWV between 3 and 12 months strongly correlated with donor age; the stiffness improved in recipients of young kidneys (first tertile of donor age) and worsened in recipients of older kidneys (upper tertile of donor age). At 12 months, PWV was greater than 1 m/s higher in recipients of the oldest kidneys than in the recipients of younger kidneys. The association between the donor age and aortic stiffness was independent of recipient's age, sex, mean BP and all other confounding factors. In a recent article by Verbeke et al., reduced glomerular filtration rate interfered significantly. These results showed that the impact of kidney transplantation on recipient aortic stiffness is dependent on the donor age and suggested that ongoing damage to large arteries might contribute to the mechanism underlying the association of old donor kidneys and increased cardiovascular mortality. Such findings are consistent with those indicating that reduced carotid distensibility predicts cardiovascular complications in patients after renal transplantation . Taken together, all these results indicate that aortic stiffness is increased in kidney transplant recipients irrespective of whether the graft is harvested from deceased or living donors. Furthermore, the same studies indicated that the characteristics of surgical intervention or drug treatment or both did not influence the results [1–8].
In the present issue of this journal, Seckinger et al. have suggested that the immunosuppressive regimen in renal transplant might contribute to the modifications of arterial stiffness. Calcineurin inhibitors have been the cornerstones of transplant immunosuppression for more than 20 years. Calcineurin inhibitor-free immunosuppressive strategies could be beneficial in the long term because of less nephrotoxicity and a lower incidence of skin and possibly cancer. On the contrary, the long-term impact of mammalian target of rapamycin (mTOR) inhibitors on cardiovascular events is unknown. Thus, the comparison of the impact of two immunosuppressive strategies on recipient aortic stiffness, the one with a switch from cyclosporine to everolimus at 6 months, the other with ongoing immunosuppression with cyclosporine is a pertinent question that, to the best of our knowledge, has not yet been properly investigated in a prospective randomized study. The main weakness of the present study, as recognized by the authors, is the very small number of patients in each arm. Only 27 patients were included but with a very high dropout, especially in the cyclosporine arm, with only 10 patients available for analysis.
The main finding of the study by Seckinger et al. was a significant increase in PWV in the cyclosporine arm. In contrast, it did not change significantly in the everolimus arm. As a result, 9 months after the switch, PWV was significantly higher in the cyclosporine arm than in the everolimus arm. The change in PWV seems to be independent of potential confounding factors such as mean blood pressure and other medications. However, with such a small sample size, the risk of type II error in comparing with potential confounders is quite high. Furthermore, the main result of the present study is in conflict with several previous studies with serial assessment of PWV in kidney transplant recipients under immunosuppression and studied within the first year after graft. In these studies, PWV did not increase but rather decreased or was unchanged after adjustment for concomitant mean blood pressure change [4–8]. This could suggest that analysis obtained from the 10 patients included in the cyclosporine arm may not be truly representative of what generally happens. Furthermore, it is well established that in the same subject, the affinity and binding of cyclosporine may modify the drug effect differently in the various vascular tissues [2,3,9]. Therefore, as the authors recognize, all these difficulties do not allow these results to be regarded as providing indisputable evidence for a protective effect of everolimus. Further controlled studies are needed to show that immunosuppressive strategy is able to modify per se arterial stiffness in kidney transplants.
We thank Dr Anne Safar for helpful and stimulating discussions.
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