Insulin-Heparin Infusions Peritransplant Substantially Improve Single-Donor Clinical Islet Transplant Success

Koh, Angela; Senior, Peter; Salam, Abdul; Kin, Tatsuya; Imes, Sharleen; Dinyari, Parastoo; Malcolm, Andrew J.; Toso, Christian; Nilsson, Bo; Korsgren, Olle; Shapiro, A.M. James

doi:10.1097/tp.0b013e3181c478fd

Cited by 109 publications

(95 citation statements)

References 28 publications

(30 reference statements)

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“…Strong deposition of xenoreactive antibody combined with C1q, C3 and C4 was observed. LMWDS was more effective than heparin in minimizing IBMIR (29). In allogenic and xenogenic islet studies, we observed mild elevation of sC5b-9 levels during islet infusion and at days 3-7; however, little C3a and C4d response during the peritransplant period was seen.…”

Section: Moberg Et Almentioning

confidence: 81%

Evidence for Instant Blood-Mediated Inflammatory Reaction in Clinical Autologous Islet Transplantation

Naziruddin

Iwahashi

Kanak

et al. 2014

American Journal of Transplantation

168

149

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y These authors contributed equally.A nonspecific inflammatory and thrombotic reaction termed instant blood-mediated inflammatory reaction (IBMIR) has been reported when allogenic or xenogenic islets come into contact with blood. This reaction is known to cause significant loss of transplanted islets. We hypothesized that IBMIR occurs in patients undergoing total pancreatectomy followed by autologous islet transplantation (TP-AIT) and tested this hypothesis in 24 patients and in an in vitro model. Blood samples drawn during the peritransplant period showed a significant and rapid increase of thrombinanti-thrombin III complex (TAT) and C-peptide during islet infusion, which persisted for up to 3 h, along with a decreased platelet count. A concomitant increase in levels of inflammatory proteins IL-6, IL-8 and interferoninducible protein-10 was observed. An in vitro model composed of pure islets plus autologous blood also demonstrated significantly increased levels of TAT (p < 0.05), C-peptide (p < 0.05), tumor necrosis factoralpha (p < 0.05) and MCP-1 (p < 0.05), as well as strong tissue factor expression in islets. Islet viability decreased significantly but was rescued by the presence of low-molecular-weight dextran sulfate. In conclusion, AIT-induced elevation of TAT and destruction of islets suggests that IBMIR might occur during AIT. Modulating this process may help improve islet engraftment and the insulin independence rate in TP-AIT patients.

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Section: Moberg Et Almentioning

confidence: 81%

Evidence for Instant Blood-Mediated Inflammatory Reaction in Clinical Autologous Islet Transplantation

Naziruddin

Iwahashi

Kanak

et al. 2014

American Journal of Transplantation

168

149

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show abstract

“…Although the Edmonton protocol introduced various suggestions for the improvement of islet transplantation, 1 there is a concern of deteriorating graft function over time. 2 In addition, while single-donor islet transplantation success has been achieved, [3][4][5] most centers still rely on multiple donor organs to achieve initial insulin independence. 6 A possible explanation for this problem is that many islets are destroyed immediately following transplantation, before a vascular network is reestablished.…”

Section: Introductionmentioning

confidence: 99%

Nerve growth factor is associated with islet graft failure following intraportal transplantation

Saito

Chan

Sakata

et al. 2012

Islets

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Nerve growth factor (NGF) has recently been recognized as an angiogenic factor with an important regulatory role in pancreatic b-cell function. We previously showed that treatment of pancreatic islets with NGF improved their quality and viability. Revascularization and survival of islets transplanted under the kidney capsule were improved by NGF. However, the usefulness of NGF in intraportal islet transplantation was not previously tested. To resolve this problem, we transplanted syngeneic islets (360 islet equivalents per recipient) cultured with or without NGF into the portal vein of streptozotocin-induced diabetic BALB/c mice. Analysis revealed that 44.4% (4/9) of control and 12.5% (1/8) of NGF-treated mice attained normoglycemia (# 200 mg/dL) (p = 0.195). NGF-treated islets led to worse graft function (area under the curve of intraperitoneal glucose tolerance tests (IPGTT) on post-operative day (POD) 30, control; 35,800 ± 3,960 min*mg/dl, NGF-treated; 47,900 ± 3,220 min*mg/dl: *p = 0.0348). NGF treatment of islets was also associated with increased graft failure [the percentage of TdT-mediated dUTP-biotin nick-end labeling (TUNEL)-positive and necrotic transplanted islets on POD 5, control; 23.8% (5/21), NGF-treated; 52.9% (9/17): p = 0.0650] following intraportal islet transplantation. Nonviable (TUNEL-positive and necrotic) islets in both groups expressed vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1a (HIF-1a). On the other hand, viable (TUNEL-negative and not necrotic) islets in both groups did not express VEGF and HIF-1a. In the present study, pre-transplant NGF treatment was associated with impaired survival and angiogenesis of intraportal islet grafts. The effect of NGF on islet transplantation may significantly vary according to the transplant site.

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“…Twelve patients received 1 implant, 38 patients 2 implants within 3 months (IQR 2.4-3.5 months) after the first implantation and 1 patient received 3 implants (at 2.5 and 5 months posttransplantation). Based on a possible beneficial effect of intravenous heparin infusion peritransplant as reported by Koh et al (13), heparin was administered in 3 patients undergoing laparoscopic implantation at 70 U/kg using continuous infusion of heparin containing saline (10U/ml) at 500 U/h (50ml/h) up to 24 hours post-transplantation (PT).…”

Section: Preparation Of Islet Beta Cell Grafts and Transplantationmentioning

confidence: 99%

Age and Early Graft Function Relate With Risk-Benefit Ratio of Allogenic Islet Transplantation Under Antithymocyte Globulin-Mycophenolate Mofetil-Tacrolimus Immune Suppression

Lee

Keymeulen²,

Hilbrands³

et al. 2017

Transplantation

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Insulin-Heparin Infusions Peritransplant Substantially Improve Single-Donor Clinical Islet Transplant Success

Cited by 109 publications

References 28 publications

Evidence for Instant Blood-Mediated Inflammatory Reaction in Clinical Autologous Islet Transplantation

Evidence for Instant Blood-Mediated Inflammatory Reaction in Clinical Autologous Islet Transplantation

Nerve growth factor is associated with islet graft failure following intraportal transplantation

Age and Early Graft Function Relate With Risk-Benefit Ratio of Allogenic Islet Transplantation Under Antithymocyte Globulin-Mycophenolate Mofetil-Tacrolimus Immune Suppression

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