Dyslipidemia in renal transplant recipients treated with a sirolimus and cyclosporine–based immunosuppressive regimen: incidence, risk factors, progression, and prognosis1

Chueh, Shih-Chieh; Kahan, Barry D.

doi:10.1097/01.tp.0000074310.40484.94

Cited by 94 publications

(48 citation statements)

References 28 publications

(25 reference statements)

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“…Our present studies indicate that sirolimus-treated diabetic recipient mice were associated with dyslipidemia, as reflected in markedly elevated plasma VLDL-triglyceride levels. These results were consistent with previous observation that chronic use of sirolimus is closely associated with the pathogenesis of hyperlipidemia (25)(26)(27). More recently, clinical application of sirolimus monotherapy in kidney transplants has been linked to the development of posttransplantation insulin resistance and impaired glucose metabolism (42).…”

Section: Fig 6 Effect Of Sirolimus On Islet Function Asupporting

confidence: 82%

“…Impact of sirolimus on plasma lipid metabolism in diabetic recipient mice. Sirolimus-based immunotherapy has been linked to the pathogenesis of diabetic dyslipidemia in transplants (25)(26)(27). To study the effect of sirolimus on plasma lipid metabolism, plasma levels of triglyceride, cholesterol, and FFAs were determined in diabetic recipient mice 30 days posttransplantation.…”

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confidence: 99%

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Sirolimus Is Associated With Reduced Islet Engraftment and Impaired β-Cell Function

et al. 2006

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Successful islet transplantation depends on the infusion of sufficiently large quantities of islets, but only a fraction of transplanted islets can survive and become engrafted, and yet the underlying mechanism remains unclear. In this study, we examined the effect of sirolimus, a key component of the immunosuppressive regimen in clinical islet transplantation, on islet engraftment and function. To distinguish the effect of sirolimus on immune rejection from its effect on islet engraftment, we used a syngeneic model. Diabetic mice were transplanted with 250 islets under the renal capsule, followed by treatment with sirolimus or vehicle for 14 days. Thirty days posttransplantation, islet grafts were retrieved for the determination of insulin content and vascular density. Compared with mocktreated controls, diabetic recipient mice receiving sirolimus exhibited impaired blood glucose profiles and reduced glucose-stimulated insulin secretion, correlating with reduced intragraft insulin content and decreased vascular density. Islets exposed to sirolimus for 24 h in culture displayed significantly diminished glucose-stimulated insulin release, coinciding with decreased pancreas duodenum homeobox-1 and GLUT2 expression in cultured islets. Furthermore, sirolimus-treated diabetic recipient mice, as opposed to mock-treated controls, were associated with dyslipidemia. These data suggest that sirolimus, administered in the early posttransplantation phase, is a confounding factor for reduced islet engraftment and impaired ␤-cell function in transplants. Diabetes 55:2429 -2436, 2006 T he Edmonton protocol for islet transplantation depends on the infusion of ϳ10,000 IE (islet equivalents)/kg body wt, requiring multiple cadaver pancreata per diabetic recipient (1-4). Despite the implantation of such a large quantity of islets, Ͻ30% of transplanted islets can survive the procedure and gain stable engraftment, and yet the mechanism underlying the loss of a vast majority of islet mass in the early posttransplantation phase remains elusive (4,5). Unlike whole-organ transplantation, by which grafts are implanted as vascularized tissue, islets are transplanted as single islets or islet clusters that are considered avascular following collagenase digestion and isolation. Although residual endothelial cells in isolated islets may contribute to islet revascularization (6,7), adequate intraislet blood flow requires the formation of a functional microvascular network that links engrafted islets to surrounding tissues. These data suggest that microvascular perfusion to newly transplanted islets does not resume immediately after transplantation and can take up to 2 weeks before the reestablishment of a functional microvasculature in islet grafts (8,9). This delay in islet revascularization can potentially deprive islets of oxygen and nutrients, resulting in islet cell death, particularly within the core of engrafted islets. There is mounting evidence that impaired islet revascularization is an independent factor that limits the success rate...

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Section: Fig 6 Effect Of Sirolimus On Islet Function Asupporting

confidence: 82%

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confidence: 99%

Sirolimus Is Associated With Reduced Islet Engraftment and Impaired β-Cell Function

et al. 2006

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“…In fact, switching from cyclosporine to tacrolimus to improve hyperlipidemia, especially in a patient who is intolerant to statin therapy, can significantly improve levels of cholesterol and LDL (49). Sirolimus has the greatest effect on lipid profiles and elevates both cholesterol and triglycerides in a dosage-dependent manner (50,51). Because of the antiproliferative effect of sirolimus on the vascular endothelium, some have postulated that elevated lipid levels are not as much of a risk in patients who take sirolimus, with some clinical data to support this hypothesis (52).…”

Section: Role Of Immunosuppressive Agentsmentioning

confidence: 99%

Management of Cardiovascular Disease in Renal Transplant Recipients

Shirali¹,

Bia²

2008

Clinical Journal of the American Society of Nephrology

110

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Cardiovascular disease is a major cause of graft loss and the leading cause of death in renal transplant recipients. Although there are robust data on the frequency of risk factors and their contributions to cardiovascular disease in this population, few trials have demonstrated the benefit of modifying these risk factors to reduce cardiovascular events. Nevertheless, it is widely accepted that the clinical acumen filtered through the best available studies in the general population be used to treat individual renal transplant recipients given their high cardiovascular mortality. Transplant task forces and the Kidney Disease Outcomes Quality Initiative have created guidelines for this purpose. This review examines the data available for prevention and treatment of major risk factors contributing to cardiovascular disease in renal transplant recipients. The contribution of immunosuppressive agents to each risk factor and the evidence to support lifestyle modification as well as drug therapy are examined. Reducing cardiovascular risk factors requires an integrative approach that is best accomplished by a team of health care professionals. It creates a significant challenge but one that must be met if allograft survival is to improve.

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“…D'autres effets secondaires ne semblent pas imputables aux propriétés antiprolifératives de la Rapa. À titre d'exemple, l'utilisation de Rapa est associée à la survenue de dyslipidémies mixtes chez 40 % à 80 % des patients sensibles aux statines, souvent réversibles à l'arrêt du traitements et pour lesquelles il n'a pu être mis en évidence de majoration du risque cardiovasculaire [30].…”

Section: Effets Indésirables Liés à L'utilisation Des Inhibiteurs De unclassified

Inhibiteurs de mTOR : Des antiprolifératifs pléiotropiques

et al. 2006

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Dyslipidemia in renal transplant recipients treated with a sirolimus and cyclosporine–based immunosuppressive regimen: incidence, risk factors, progression, and prognosis1

Abstract: The dyslipidemia associated with sirolimus therapy, albeit persistent, does not seem to represent a major risk factor for the early emergence of cardiovascular complications.

Cited by 94 publications

References 28 publications

Sirolimus Is Associated With Reduced Islet Engraftment and Impaired β-Cell Function

Sirolimus Is Associated With Reduced Islet Engraftment and Impaired β-Cell Function

Management of Cardiovascular Disease in Renal Transplant Recipients

Inhibiteurs de mTOR : Des antiprolifératifs pléiotropiques

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