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• W2000739539 abstract "In his letter Dr. Blum suggests that the increased risk of graft loss we observed in patients with hypercholesterolemia and previous acute rejection might be the consequence of reduced concentrations of unbound cyclosporine, due to higher uptake by low density lipoprotein. Cyclosporine is a potent inhibitor of acute rejection but whether it slows the progressive deterioration of graft function that characterizes chronic rejection is still a subject of debate. A maintenance dose of less than 5 mg/kg has been reported as a risk factor for chronic graft loss (1) but other studies have suggested that cyclosporine does not decrease the incidence of chronic rejection (2). Conversion of renal transplant patients from cyclosporine to azathioprine in three prospective, randomized trials (3–5) did not increase chronic graft loss during a follow-up reaching 10 years. However, graft survival was not reported separately in patients with and without previous acute rejection. These studies, therefore, do not allow to draw definite conclusions for the subpopulation of renal transplant patients with previous acute rejection. To clarify the role of cyclosporine in the long-term maintenance of graft function, unbound cyclosporine should certainly be monitored in prospective interventional studies of patients with hypercholesterolemia. Based on our observation that cholesterol levels higher than 250 mg/dl are a risk factor for graft loss from chronic rejection in case of previous acute rejection, Dr. Blum made calculations to assess how this could affect long-term graft survival of patients treated with sirolimus. This point is of interest, as sirolimus, available since 1999 in the US, has recently received marketing approval in Europe also. Although sirolimus efficiently prevents rejection, it induces both hypercholesterolemia and hypertriglyceridemia. We agree with Dr. Blum’s extrapolations that sirolimus-induced hypercholesterolemia is unlikely to offset on the long term its beneficial effect on early acute rejection rates. In addition, recent data indicate that targeting sirolimus blood levels between 5 and 15 ng/ml allows to further reduce both the rejection rate and the incidence of hypercholesterolemia (6). Interestingly, sirolimus therapy is associated with an increase of both low density lipoprotein and high density lipoprotein cholesterol blood levels, so that the low density lipoprotein/high density lipoprotein ratio, a risk factor for cardiovascular events, remains unchanged (7). Nevertheless, the control of hyperlipemia required the administration of fibrates and statins in 20 and 60% of patients, respectively (7). With these measures, mean serum cholesterol and triglyceride levels were 247 and 224 mg/dl at 1 year. Importantly, detailed pharmacokinetic analyses revealed that there are no interactions between sirolimus and atorvastatin (Burke JT, personal communication, Wyeth-Ayerst Ressearch, Paris, France). Regarding fibrates, gemfibrozil does not cause the troublesome decrease in renal function that sometimes complicates treatment with fenofibrate, bezafibrate, and ciprofibrate (8). Therefore, gemfibrozil should be the fibrate of choice in this patient population. Whatever effective these measures are, long-term follow-up of patients on sirolimus will be required to properly appreciate its impact on chronic rejection and cardiovascular events. K. Martin Wissing Daniel Abramowicz" @default.
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• W2000739539 date "2001-08-01" @default.
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• W2000739539 title "HYPERCHOLESTEROLEMIA AND CHRONIC REJECTION OF RENAL ALLOGRAFTS" @default.
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• W2000739539 doi "https://doi.org/10.1097/00007890-200108270-00038" @default.
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