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The effects of exendin-4 treatment on graft failure: an animal study using a novel re-vascularized minimal human islet transplant model.

ABSTRACT: Islet transplantation has become a viable clinical treatment, but is still compromised by long-term graft failure. Exendin-4, a glucagon-like peptide 1 receptor agonist, has in clinical studies been shown to improve insulin secretion in islet transplanted patients. However, little is known about the effect of exendin-4 on other metabolic parameters. We therefore aimed to determine what influence exendin-4 would have on revascularized minimal human islet grafts in a state of graft failure in terms of glucose metabolism, body weight, lipid levels and graft survival. Introducing the bilateral, subcapsular islet transplantation model, we first transplanted diabetic mice with a murine graft under the left kidney capsule sufficient to restore normoglycemia. After a convalescent period, we performed a second transplantation under the right kidney capsule with a minimal human islet graft and allowed for a second recovery. We then performed a left-sided nephrectomy, and immediately started treatment with exendin-4 with a low (20?g/kg/day) or high (200?g/kg/day) dose, or saline subcutaneously twice daily for 15 days. Blood was sampled, blood glucose and body weight monitored. The transplanted human islet grafts were collected at study end point and analyzed. We found that exendin-4 exerts its effect on failing human islet grafts in a bell-shaped dose-response curve. Both doses of exendin-4 equally and significantly reduced blood glucose. Glucagon-like peptide 1 (GLP-1), C-peptide and pro-insulin were conversely increased. In the course of the treatment, body weight and cholesterol levels were not affected. However, immunohistochemistry revealed an increase in beta cell nuclei count and reduced TUNEL staining only in the group treated with a low dose of exendin-4 compared to the high dose and control. Collectively, these results suggest that exendin-4 has a potential rescue effect on failing, revascularized human islets in terms of lowering blood glucose, maintaining beta cell numbers, and improving metabolic parameters during hyperglycemic stress.

SUBMITTER: Sahraoui A

PROVIDER: S-EPMC4368803 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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The effects of exendin-4 treatment on graft failure: an animal study using a novel re-vascularized minimal human islet transplant model.

Sahraoui Afaf A Winzell Maria Sörhede MS Gorman Tracy T Smith Dave M DM Skrtic Stanko S Hoeyem Merete M Abadpour Shadab S Johansson Lars L Korsgren Olle O Foss Aksel A Scholz Hanne H

PloS one 20150320 3

Islet transplantation has become a viable clinical treatment, but is still compromised by long-term graft failure. Exendin-4, a glucagon-like peptide 1 receptor agonist, has in clinical studies been shown to improve insulin secretion in islet transplanted patients. However, little is known about the effect of exendin-4 on other metabolic parameters. We therefore aimed to determine what influence exendin-4 would have on revascularized minimal human islet grafts in a state of graft failure in term ...[more]

PMID: 25793295

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Project description:BackgroundTreatment of nerve injuries proves to be a worldwide clinical challenge. Vascularized nerve grafts are suggested to be a promising alternative for bridging a nerve gap to the current gold standard, an autologous non-vascularized nerve graft. However, there is no adequate clinical evidence for the beneficial effect of vascularized nerve grafts and they are still disputed in clinical practice.ObjectiveTo systematically review whether vascularized nerve grafts give a superior nerve recovery compared to non-vascularized nerve autografts regarding histological and electrophysiological outcomes in animal models.Material and methodsPubMed and Embase were systematically searched. The inclusion criteria were as follows: 1) the study was an original full paper which presented unique data; 2) a clear comparison between a vascularized and a non-vascularized autologous nerve transfer was made; 3) the population study were animals of all genders and ages. A standardized mean difference and 95% confidence intervals for each comparison was calculated to estimate the overall effect. Subgroup analyses were conducted on graft length, species and time frames.ResultsFourteen articles were included in this review and all were included in the meta-analyses. A vascularized nerve graft resulted in a significantly larger diameter, higher nerve conduction velocity and axonal count compared to an autologous non-vascularized nerve graft. However, during sensitivity analysis the effect on axonal count disappeared. No significant difference was observed in muscle weight.ConclusionTreating a nerve gap with a vascularized graft results in superior nerve recovery compared to non-vascularized nerve autografts in terms of axon count, diameter and nerve conduction velocity. No difference in muscle weight was seen. However, this conclusion needs to be taken with some caution due to the inherent limitations of this meta-analysis. We recommend future studies to be performed under conditions more closely resembling human circumstances and to use long nerve defects.

Project description:Introduction: Despite progress in whole-organ decellularization and recellularization, maintaining long-term perfusion in vivo remains a hurdle to realizing clinical translation of bioengineered kidney grafts. The objectives for the present study were to define a threshold glucose consumption rate (GCR) that could be used to predict in vivo graft hemocompatibility and utilize this threshold to assess the in vivo performance of clinically relevant decellularized porcine kidney grafts recellularized with human umbilical vein endothelial cells (HUVECs). Materials and methods: Twenty-two porcine kidneys were decellularized and 19 were re-endothelialized using HUVECs. Functional revascularization of control decellularized (n = 3) and re-endothelialized porcine kidneys (n = 16) was tested using an ex vivo porcine blood flow model to define an appropriate metabolic glucose consumption rate (GCR) threshold above which would sustain patent blood flow. Re-endothelialized grafts (n = 9) were then transplanted into immunosuppressed pigs with perfusion measured using angiography post-implant and on days 3 and 7 with 3 native kidneys used as controls. Patent recellularized kidney grafts underwent histological analysis following explant. Results: The glucose consumption rate of recellularized kidney grafts reached a peak of 39.9 ± 9.7 mg/h at 21 ± 5 days, at which point the grafts were determined to have sufficient histological vascular coverage with endothelial cells. Based on these results, a minimum glucose consumption rate threshold of 20 mg/h was set. The revascularized kidneys had a mean perfusion percentage of 87.7% ± 10.3%, 80.9% ± 33.1%, and 68.5% ± 38.6% post-reperfusion on Days 0, 3 and 7, respectively. The 3 native kidneys had a mean post-perfusion percentage of 98.4% ± 1.6%. These results were not statistically significant. Conclusion: This study is the first to demonstrate that human-scale bioengineered porcine kidney grafts developed via perfusion decellularization and subsequent re-endothelialization using HUVEC can maintain patency with consistent blood flow for up to 7 days in vivo. These results lay the foundation for future research to produce human-scale recellularized kidney grafts for transplantation.

Project description:BackgroundLong-term high-dose lithium therapy in bipolar disorder is known to adversely affect kidney function. However, recent animal studies have revealed that low amounts of lithium are beneficial for the kidney when it is damaged by exposure to nephrotoxic compounds, inflammation or oxidative stress. This study aimed to investigate whether urinary lithium excretion, reflecting dietary lithium intake, is associated with adverse long-term kidney graft outcomes and patient survival.MethodsUrinary lithium concentration was measured using inductively coupled plasma mass spectrometry in 642 stable kidney transplant recipients (KTRs). Graft failure was defined as the start of dialysis or retransplantation and kidney function decline was defined as a doubling of serum creatinine.ResultsThe median urinary lithium excretion was 3.03 μmol/24 h [interquartile range (IQR) 2.31-4.01]. Urinary lithium excretion was associated with energy, plant protein and water intake. During a median follow-up of 5.3 years (IQR 4.5-6.0), 79 (12%) KTRs developed graft failure and 127 (20%) KTRs developed kidney function decline. Higher urinary lithium excretion was associated with a lower risk of graft failure {hazard ratio [HR] per doubling 0.54 [95% confidence interval (CI) 0.38-0.79]} and kidney function decline [HR per doubling 0.73 (95% CI 0.54-0.99)]. These associations remained independent of adjustment for potential confounders and in sensitivity analyses. There was a significant effect modification with the use of proliferation inhibitors (P = .05) and baseline estimated glomerular filtration rate (eGFR; P < .001), with higher urinary lithium excretion being more protective in KTRs not using proliferation inhibitors and in KTRs with lower baseline eGFR. Furthermore, higher urinary lithium excretion was associated with a reduced risk of all-cause mortality [HR 0.64 (95% CI 0.49-0.83); P = .001].ConclusionDietary lithium intake may be a potentially modifiable, yet rather overlooked, risk factor for adverse long-term kidney graft outcomes and patient survival.Trial registrationhttps://clinicaltrials.gov/ct2/show/NCT02811835.

Dataset Information

The effects of exendin-4 treatment on graft failure: an animal study using a novel re-vascularized minimal human islet transplant model.

Publications

The effects of exendin-4 treatment on graft failure: an animal study using a novel re-vascularized minimal human islet transplant model.

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