Elevated portal vein drug levels of sirolimus and tacrolimus in islet transplant recipients: local immunosuppression or islet toxicity?1

Desai, Niraj M.; Goss, John A.; Deng, Shaoping; Wolf, Bryan A.; Markmann, Eileen; Palanjian, Maral; Shock, Angela P.; Feliciano, Susan; Brunicardi, F. Charles; Barker, Clyde F.; Naji, Ali; Markmann, James F.

doi:10.1097/01.tp.0000081043.23751.81

Cited by 144 publications

(104 citation statements)

References 7 publications

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“…The initial stages in the process leading to these pathological conditions were hepatocyte steatosis and glycogen deposits in the vicinity of the transplanted islets, findings that are analogous to those reported in patients from several transplant centres [37,38]. In addition, islets in the liver are exposed to toxic products from the gastrointestinal tract, including high concentrations of the immunosuppressive drugs being administered [7,8].…”

Section: Revisiting the Rationale For Selecting The Intraportal Routementioning

confidence: 56%

“…Even a minor reduction in beta cell mass in a patient not receiving insulin but with only 20-40% of normal islet mass would lead to the patient requiring exogenous insulin therapy at a low dose. This reduction in endocrine function may depend on the side effects of immunosuppression [7,8], but is likely to be reinforced by phenomena such as glucose [9] and lipid toxicity [10,11].…”

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confidence: 99%

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Optimising islet engraftment is critical for successful clinical islet transplantation

et al. 2007

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Clinical islet transplantation is currently being explored as a treatment for persons with type 1 diabetes and hypoglycaemia unawareness. Although 'proof-of-principle' has been established in recent clinical studies, the procedure suffers from low efficacy. At the time of transplantation, the isolated islets are allowed to embolise the liver after injection in the portal vein, a procedure that is unique in the area of transplantation. A novel view on the engraftment of intraportally transplanted islets is presented that could explain the low efficacy of the procedure.

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Section: Revisiting the Rationale For Selecting The Intraportal Routementioning

confidence: 56%

mentioning

confidence: 99%

Optimising islet engraftment is critical for successful clinical islet transplantation

et al. 2007

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“…Together these data raise a serious concern that sirolimus-based immunotherapy in islet transplantation, intended primarily for mitigating islet allograft rejection, may play a causative role in impairing ␤-cell function and retarding islet revascularization in the immediate posttransplantation phase. In support of this notion, two recent studies (43,44) report that the blood levels of immunosuppressants in the portal vein are about twofold higher than in the peripheral circulation following intraportal delivery of islets in diabetic recipients. This elevated local level of immunosuppressants in the portal vein, interpreted as "portal storm of immunosuppression," is considered harmful to islets, particularly during the immediate posttransplantation period when the survival and function of newly transplanted islets depends on rapid revascularization for deriving blood from the host for oxygen and nutrient supplies (44).…”

Section: Fig 6 Effect Of Sirolimus On Islet Function Amentioning

confidence: 91%

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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“…Instant blood-mediated inflammatory reaction (IBMIR), which consists of thrombus formation on the islet surface, complement-mediated islet cell lysis, and a local inflammatory response 8 2. Immunosuppressant toxicity, 9 which may be exacerbated by higher drug levels in the portal venous blood 10 3. Poor reestablishment of extracellular matrix connections, which may exacerbate islet cell death by anoikis 11 4.…”

Section: Review Articlementioning

confidence: 99%

Intraportal Islet Oxygenation

Suszynski

Avgoustiniatos

Papas

2014

J Diabetes Sci Technol

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Islet transplantation (IT) is a promising therapy for the treatment of diabetes. The large number of islets required to achieve insulin independence limit its cost-effectiveness and the number of patients who can be treated. It is believed that >50% of islets are lost in the immediate post-IT period. Poor oxygenation in the early post-IT period is recognized as a possible reason for islet loss and dysfunction but has not been extensively studied. Several key variables affect oxygenation in this setting, including (1) local oxygen partial pressure (pO 2 ), (2) islet oxygen consumption, (3) islet size (diameter, D), and (4) presence or absence of thrombosis on the islet surface. We discuss implications of oxygen-limiting conditions on intraportal islet viability and function. Of the 4 key variables, the islet size appears to be the most important determinant of the anoxic and nonfunctional islet volume fractions. Similarly, the effect of thrombus formation on the islet surface may be substantial. At the University of Minnesota, average size distribution data from clinical alloislet preparations (n = 10) indicate that >150-µm D islets account for only ~30% of the total islet number, but >85% of the total islet volume. This suggests that improved oxygen supply to the islets may have a profound impact on islet survivability and function since most of the β-cell volume is within large islets which are most susceptible to oxygen-limiting conditions. The assumption that the liver is a suitable islet transplant site from the standpoint of oxygenation should be reconsidered.

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Elevated portal vein drug levels of sirolimus and tacrolimus in islet transplant recipients: local immunosuppression or islet toxicity?1

Cited by 144 publications

References 7 publications

Optimising islet engraftment is critical for successful clinical islet transplantation

Optimising islet engraftment is critical for successful clinical islet transplantation

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

Intraportal Islet Oxygenation

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