| 1. |
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| 2. |
- Foss, Stein, et al.
(författare)
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First Scandinavian Protocol for Controlled Donation After Circulatory Death Using Normothermic Regional Perfusion
- 2018
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Ingår i: Transplantation direct. - : LIPPINCOTT WILLIAMS & WILKINS. - 2373-8731. ; 4:7
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Tidskriftsartikel (refereegranskat)abstract
- Background. Donation after circulatory death (DCD) can increase the pool of available organs for transplantation. This pilot study evaluates the implementation of a controlled DCD (cDCD) protocol using normothermic regional perfusion in Norway. Methods. Patients aged 16 to 60 years that are in coma with documented devastating brain injury in need of mechanical ventilation, who would most likely attain cardiac arrest within 60 minutes after extubation, were eligible. With the acceptance from the next of kin and their wish for organ donation, life support was withdrawn and cardiac arrest observed. After a 5-minute no-touch period, extracorporeal membrane oxygenation for post mortem regional normothermic regional perfusion was established. Cerebral and cardiac reperfusion was prevented by an aortic occlusion catheter. Measured glomerular filtration rates 1 year postengraftment were compared between cDCD grafts and age-matched grafts donated after brain death (DBD). Results. Eight cDCD were performed from 2014 to 2015. Circulation ceased median 12 (range, 6-24) minutes after withdrawal of life-sustaining treatment. Fourteen kidneys and 2 livers were retrieved and subsequently transplanted. Functional warm ischemic time was 26 (20-51) minutes. Regional perfusion was applied for 97 minutes (54-106 minutes). Measured glomerular filtration rate 1 year postengraftment was not significantly different between cDCD and donation after brain death organs, 75 (65-76) vs 60 (37-112) mL/min per 1.73 m(2) (P = 0.23). No complications have been observed in the 2 cDCD livers. Conclusion. A protocol for cDCD is successfully established in Norway. Excellent transplant outcomes have encouraged us to continue this work addressing the shortage of organs for transplantation.
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| 3. |
- Abadpour, Shadab, et al.
(författare)
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Glial cell-line derived neurotrophic factor protects human islets from nutrient deprivation and endoplasmic reticulum stress induced apoptosis
- 2017
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- One of the key limitations to successful human islet transplantation is loss of islets due to stress responses pre- and post-transplantation. Nutrient deprivation and ER stress have been identified as important mechanisms leading to apoptosis. Glial Cell-line Derived Neurotrophic Factor (GDNF) has recently been found to promote islet survival after isolation. However, whether GDNF could rescue human islets from nutrient deprivation and ER stress-mediated apoptosis is unknown. Herein, by mimicking those conditions in vitro, we have shown that GDNF significantly improved glucose stimulated insulin secretion, reduced apoptosis and proinsulin: insulin ratio in nutrient deprived human islets. Furthermore, GDNF alleviated thapsigargin-induced ER stress evidenced by reduced expressions of IRE1 alpha and BiP and consequently apoptosis. Importantly, this was associated with an increase in phosphorylation of PI3K/AKT and GSK3B signaling pathway. Transplantation of ER stressed human islets pre- treated with GDNF under kidney capsule of diabetic mice resulted in reduced expressions of IRE1 alpha and BiP in human islet grafts with improved grafts function shown by higher levels of human C-peptide post-transplantation. We suggest that GDNF has protective and anti-apoptotic effects on nutrient deprived and ER stress activated human islets and could play a significant role in rescuing human islets from stress responses.
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| 4. |
- Aberg, Fredrik, et al.
(författare)
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Differences in long-term mortality among liver transplant recipients and the general population: A population-based Nordic study.
- 2015
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Ingår i: Hepatology (Baltimore, Md.). - : Ovid Technologies (Wolters Kluwer Health). - 1527-3350 .- 0270-9139. ; 61:2, s. 668-677
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Tidskriftsartikel (refereegranskat)abstract
- Dramatic improvement in first-year outcomes post-liver transplantation (LT) has shifted attention to long-term survival, where efforts are now needed to achieve improvement. Understanding the causes for premature death is a prerequisite for improving long-term outcome. Overall and cause-specific mortality of 3299 Nordic LT patients (1985-2009) having survived 1 year post-LT were divided by expected rates in the general population, adjusted for age, sex, calendar time, and country to yield standardized mortality ratios (SMRs). Data came from the Nordic Liver-Transplant Registry and WHO mortality-indicator database. Stagnant patient survival rates >1 year post-LT were 21% lower at 10 years than expected survival for the general population. Overall SMR for death before age 75 (premature mortality) was 5.8 (95%CI 5.4-6.3), with improvement from 1985-1999 to 2000-2010 in hepatitis C (HCV) (SMR change 23.1-9.2), hepatocellular carcinoma (HCC) (SMR 38.4-18.8), and primary sclerosing cholangitis (SMR 11.0-4.2), and deterioration in alcoholic liver disease (8.3-24.0) and acute liver failure (ALF) (5.9-7.6). SMRs for cancer and liver disease (recurrent or transplant-unrelated disease) were elevated in all indications except primary biliary cirrhosis (PBC). Absolute mortality rates underestimated the elevated premature mortality from infections (SMR 22-693) and kidney disease (SMR 13-45) across all indications, and from suicide in HCV and ALF. SMR for cardiovascular disease was significant only in PBC and alcoholic liver disease, owing to high mortality in the general population. Transplant-specific events caused 16% of deaths. Conclusion: standardized premature mortality provided an improved picture of long-term post-LT outcome, showing improvement over time in some indications, not revealed by overall absolute mortality rates. Causes with high premature mortality (infections, cancer, kidney and liver disease, and suicide) merit increased attention in clinical patient follow-up and future research. (Hepatology 2014;).
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| 5. |
- Berstad, Audun E., et al.
(författare)
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Microbubble contrast-enhanced ultrasound in the vascular evaluation after pancreas transplantation : a single-center experience
- 2019
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Ingår i: Acta Radiologica. - : SAGE PUBLICATIONS LTD. - 0284-1851 .- 1600-0455. ; 60:10, s. 1224-1231
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Tidskriftsartikel (refereegranskat)abstract
- Background Arterial and venous thrombosis are feared complications of pancreas transplantation (PTx). Microbubble contrast-enhanced ultrasound (CEUS) is a non-invasive imaging technique that can augment diagnostic capabilities of transplant organ perfusion. Purpose To document the state to which CEUS can improve the vascular evaluation of PTx compared to conventional Doppler ultrasound (US) directly after surgery. Material and Methods A total of 129 consecutive PTx in 128 adult patients were eligible for inclusion. The duodenal segment of the graft was anastomosed to the native duodenum. Within 12 h postoperatively, graft circulation was monitored by Doppler US in 116 PTx performed in 116 patients (69 men, 47 women; mean age =41 years). CEUS was performed with a sulfur hexafluoride-containing contrast agent (SonoVue) intravenously if the examiner was not able to confirm normal graft circulation. Image quality was documented by two independent observers on a 4-point scale: 1 = excellent; 2 = minor diagnostic limitations; 3 = major diagnostic limitations; and 4 = non-diagnostic. Results In the early postoperative phase, 79 (68%) of 116 PTx were examined with Doppler US only. Of these, 52 were of excellent quality (grade 1), 22 of good quality (grade 2), and five were of grade 3 or 4 quality. Thirty-seven (32%) examinations were supplemented by CEUS. CEUS significantly improved examination quality compared to Doppler US alone (median visualization score 1.5 vs. 2.5, respectively; P < 0.0001). Conclusion CEUS can significantly improve vascular evaluation of PTx compared to Doppler US alone in the early postoperative phase.
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| 6. |
- Brandhorst, Heide, 1962-, et al.
(författare)
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A new oxygen carrier for improved long-term storage of human pancreata before islet isolation
- 2010
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 89:2, s. 155-60
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Pancreas oxygenation during cold storage has been established in islet isolation and transplantation to prevent ischemic tissue damage using perfluorodecalin (PFD) as hyperoxygen carrier. However, studies in humans and pigs provided conflicting results about the efficiency of PFD for pancreas oxygenation. The aim of this study was to compare PFD with a newly developed oxygen carrier composed of perfluorohexyloctane and polydimethylsiloxane 5 (F6H8S5) for long-term storage of human pancreata.METHODS: After 24-hr storage in preoxygenated PFD or F6H8S5, pancreata were processed using Liberase HI for pancreas dissociation and a Ficoll gradient for islet purification. Islet quality assessment was performed measuring glucose-stimulated insulin release, viability, islet ATP content, and posttransplant function in diabetic nude mice.RESULTS: Compared with PFD, F6H8S5 significantly increased the intrapancreatic partial oxygen pressure and islet ATP content. This corresponded to an increase of islet yield, recovery after culture, glucose stimulation index, viability, and improved graft function in diabetic nude mice.CONCLUSIONS: The present findings indicate clearly that F6H8S5 improves isolation outcome after prolonged ischemia compared with PFD. This observation seems to be related to the significant lipophilicity and almost pancreas-specific density of F6H8S5. Moreover, these characteristics facilitate pancreas shipment without using custom-made transport vessels as required for PFD.
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| 7. |
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| 8. |
- Brandhorst, Heide, 1962-, et al.
(författare)
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The importance of tryptic-like activity in purified enzyme blends for efficient islet isolation
- 2009
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 87:3, s. 370-5
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The isolation of islets from the human pancreas critically depends on an efficient enzyme blend. Previous studies have solely focused on the presence of collagenase and neutral protease/thermolysin. Despite improved characterization of these components, the lot-related variability in efficacy still persists suggesting that additional so far disregarded enzymes are required for efficient islet cleavage. METHODS: Varying activities of a tryptic-like enzyme were identified within collagenase NB1 lots, which were selected according to a matched ratio between tryptic-like and collagenase activity (TLA-ratio). Rat and human pancreata were processed with current standard procedures. RESULTS: Increasing the TLA-ratio from 1.3% to 10% reduced pancreas dissociation time in rats by 50% without affecting islet yield, viability, or posttransplant function in diabetic nude mice. Enhancing the TLA-ratio from 1.3% to 12.6% for human pancreas processing resulted in a significant reduction of recirculation time and increased incrementally human islet yield without affecting purity, in vitro function or recovery after culture. Optimized pancreas digestion correlated with a higher percentage of islet preparations fulfilling quality criteria for clinical transplantation. CONCLUSIONS: We conclude that TLA is an effective component that should be included in moderate amounts in enzyme blends for human islet isolation to optimize the efficiency and minimize the lot-related variability.
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| 9. |
- Caballero-Corbalán, José, et al.
(författare)
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No beneficial effect of two-layer storage compared with UW-storage on human islet isolation and transplantation
- 2007
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Ingår i: Transplantation. - : Ovid Technologies (Wolters Kluwer Health). - 0041-1337 .- 1534-6080. ; 84:7, s. 864-869
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Tidskriftsartikel (refereegranskat)abstract
- Background. Shipment of pancreata between distant centers is frequently associated with prolonged cold ischemia time (CIT) that leads to poorer outcomes for islet transplantation. Clinical pilot trials have indicated that oxygenation of explanted human pancreata utilizing the two-layer method (TLM) allows the use of marginal donor pancreata for islet transplantation. The present study aimed to clarify whether TLM enhances the ischemic tolerance of human pancreata. Methods. We analyzed retrospectively the outcome of 200 human islet isolations performed after TLM preservation or storage in University of Wisconsin solution (UWS). Results. Donor characteristics and digestion parameters did not vary significantly between TLM-preserved and UWS-stored pancreata. No differences were observed between experimental groups with regard to islet yield, purity, or dynamic glucose stimulation index after either short or prolonged CIT. However, CIT and stimulation index were negatively correlated in each experimental group. The isolation outcome in donors aged ≥60 years was not increased after TLM preservation when compared to UWS storage. No effect was observed regarding islet posttransplant function in recipients with established kidney grafts. Conclusions. The present study suggests that the ischemic tolerance of human pancreata cannot be extended by TLM preservation. In addition, TLM does not seem to improve the isolation outcome for pancreata from elderly donors.
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| 10. |
- Caballero-Corbalán, José, et al.
(författare)
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Using HTK for Prolonged Pancreas Preservation Prior to Human Islet Isolation
- 2012
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Ingår i: Journal of Surgical Research. - : Elsevier BV. - 1095-8673 .- 0022-4804. ; 175:1, s. 163-168
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Tidskriftsartikel (refereegranskat)abstract
- Background. Histidine-tryptophan-ketoglutarate (HTK) has been established as an alternative to University-of-Wisconsin solution (UWS) for abdominal organ preservation, but data about HTK efficiency to preserve pancreata during prolonged cold ischemia time (CIT) are conflicting. In human islet transplantation, HTK provided similar isolation outcomes after short CIT. The present study aimed to investigate whether islets can be successfully isolated from HTK-preserved pancreata after prolonged CIT compared with UWS. Materials and Methods. Sixty-four human pancreata retrieved from donors meeting criteria for kidney donation were perfused utilizing either HTK or UWS and preserved for more or less than 10 h prior to islet isolation. Along with parameters related to isolation and islet quality assessment, the dry-to-wet weight ratio was evaluated. Results. Donor-and procurement-related factors did not vary between HTK- and UWS-perfused pancreata. The dry-to-wet weight ratio was lower in HTK-preserved pancreata indicated tissue edema (21.0% +/- 3.5% versus 24.8% +/- 2.0%, P = 0.007). Isolation-related variables differed between experimental groups after prolonged CIT with respect to purified packed tissue volume (9.1 +/- 5.0 versus 17.2 +/- 8.1 mu L/g, P = 0.004) and islet yield (1910 +/- 980 versus 3150 +/- 1420 IE/g, P = 0.012). Islet purity and survival after culture were similar after HTK or UWS perfusion. The preservation solution did not affect in vitro function and transplantability of isolated islets. Conclusions. Compared with UWS, HTK has similar efficiency to preserve human pancreata for subsequent islet isolation during <10 h CIT but seems to be limited for prolonged cold storage. (C) 2012 Elsevier Inc. All rights reserved.
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| 11. |
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| 12. |
- Cabric, Sanja, et al.
(författare)
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Islet Surface Heparinization Prevents the Instant-Blood Mediated Inflammatory Reaction in Islet Transplantation
- 2007
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 56:8, s. 2008-2015
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE—In clinical islet transplantation, the instant blood-mediated inflammatory reaction (IBMIR) is a major factor contributing to the poor initial engraftment of the islets. This reaction is triggered by tissue factor and monocyte chemoattractant protein (MCP)-1, expressed by the transplanted pancreatic islets when the islets come in contact with blood in the portal vein. All currently identified systemic inhibitors of the IBMIR are associated with a significantly increased risk of bleeding or other side effects. To avoid systemic treatment, the aim of the present study was to render the islet graft blood biocompatible by applying a continuous heparin coating to the islet surface.RESEARCH DESIGN AND METHODS—A biotin/avidin technique was used to conjugate preformed heparin complexes to the surface of pancreatic islets. This endothelial-like coating was achieved by conjugating barely 40 IU heparin per full-size clinical islet transplant.RESULTS—Both in an in vitro loop model and in an allogeneic porcine model of clinical islet transplantation, this heparin coating provided protection against the IBMIR. Culturing heparinized islets for 24 h did not affect insulin release after glucose challenge, and heparin-coated islets cured diabetic mice in a manner similar to untreated islets.CONCLUSIONS—This novel pretreatment procedure prevents intraportal thrombosis and efficiently inhibits the IBMIR without increasing the bleeding risk and, unlike other pretreatment procedures (e.g., gene therapy), without inducing acute or chronic toxicity in the islets.
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| 13. |
- Dueland, Svein, et al.
(författare)
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Chemotherapy or Liver Transplantation for Nonresectable Liver Metastases From Colorectal Cancer?
- 2015
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Ingår i: Annals of Surgery. - 0003-4932 .- 1528-1140. ; 261:5, s. 956-960
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The primary objective was to compare overall survival (OS) in patients with colorectal cancer (CRC) with nonresectable liver-only metastases treated by liver transplantation or chemotherapy. Background: CRC is the third most common cancer worldwide. About 50% of patients will develop metastatic disease primarily to the liver and the lung. The majority of patients with liver metastases receive palliative chemotherapy, with a median OS of trial patients of about 2 years, and less than 10% are alive at 5 years. Methods: Patients with nonresectable liver-only CRC metastases underwent liver transplantation in the SECA study (n = 21). Disease-free survival (DFS) and OS of patients included in the SECA study were compared with progression-free survival (PFS) and OS in a similar cohort of CRC patients with liver-only disease included in a first-line chemotherapy study, the NORDIC VII study (n = 47). PFS/DFS and OS were estimated by the Kaplan-Meier method. Results: DFS/PFS in both groups were 8 to 10 months. However, a dramatic difference in OS was observed. The 5-year OS rate was 56% in patients undergoing liver transplantation compared with 9% in patients starting first-line chemotherapy. The reason for the large difference in OS despite similar DFS/PFS is likely different metastatic patterns at relapse/progression. Relapse in the liver transplantation group was often detected as small, slowly growing lung metastases, whereas progression of nonresectable liver metastases was observed in the chemotherapy group. Conclusions: Compared with chemotherapy, liver transplantation resulted in a marked increased OS in CRC patients with nonresectable liver-only metastases.
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| 14. |
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| 15. |
- Friman, Styrbjörn, 1948, et al.
(författare)
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Liver transplantation for cholangiocarcinoma: Selection is essential for acceptable results.
- 2011
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Ingår i: Scandinavian journal of gastroenterology. - : Informa UK Limited. - 1502-7708 .- 0036-5521. ; 46:3, s. 370-375
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Background and aims. Cholangiocarcinoma (CCA) is considered a contraindication for liver transplantation by most liver transplant centers. The aim of this study has been to report our results as well as to explore factors that influence patient survival after liver transplantation for CCA. Patients. All transplant patients with CCA in Norway, Sweden and Finland during 1984-2005 were included (n = 53). Thirty-three patients (62%) had intrahepatic CCA. Twenty-one patients (40%) had a more advanced tumor (>TNM stage 2). Thirty-four of the 53 recipients (64%) had primary sclerosing cholangitis (PSC). Results. Patients with TNM stage ≤2 transplanted after 1995 had a 5-year survival rate of 48%. The overall 5-year patient survival rate was 25%. There was no difference in survival between patients with extrahepatic and intrahepatic CCA. The 5-year survival rate among patients with TNM stage ≤2 was 36%. Patients with TNM stage >2 had a 10% 5-year survival rate; the difference was significant at p < 0.01. Patients transplanted after 1995 had a significantly better 5-year survival rate than pre-1995 patients (38% vs. 0%, p < 0.01). Patients transplanted after 1995 with TNM ≤2 and CA 19-9 ≤100 had the 5-year survival of 58%. Conclusion. By selecting CCA patients with TNM stage ≤2 and a CA 19-9 ≤100 a reasonable 5-year survival rate is possible. We think that CCA in selected cases can be an acceptable indication for liver transplantation.
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| 16. |
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| 17. |
- Johansson, Helena, et al.
(författare)
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Tissue factor produced by the endocrine cells of the islets of Langerhans is associated with a negative outcome of clinical islet transplantation
- 2005
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 54:6, s. 1755-62
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Tidskriftsartikel (refereegranskat)abstract
- There are strong indications that only a small fraction of grafts successfully engraft in clinical islet transplantation. One explanation may be the instant blood-mediated inflammatory reaction (IBMIR) elicited by tissue factor, which is produced by the endocrine cells. In the present study, we show that islets intended for islet transplantation produce tissue factor in both the transmembrane and the alternatively spliced form and that the membrane-bound form is released as microparticles often associated with both insulin and glucagon granules. A low-molecular mass factor VIIa (FVIIa) inhibitor that indirectly blocks both forms of tissue factor was shown in vitro to be a promising drug to eliminate the IBMIR. Thrombin-antithrombin complex (TAT) and FVIIa-antithrombin complex (FVIIa-AT) were measured in nine patients who together received 20 infusions of isolated human islets. Both the TAT and FVIIa-AT complexes increased rapidly within 15-60 min after infusion. When the initial TAT and FVIIa-AT levels were plotted against the increase in C-peptide concentration after 7 days, patients with an initially strong IBMIR showed no significant increase in insulin synthesis after 7 days. In conclusion, tissue factor present in both the islets and the culture medium and elicits IBMIR, which affects the function of the transplanted islets.
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| 18. |
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| 19. |
- Kloster-Jensen, Kristine, et al.
(författare)
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Intracellular sirolimus concentration is reduced by tacrolimus in human pancreatic islets invitro
- 2015
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Ingår i: Transplant International. - : Frontiers Media SA. - 0934-0874 .- 1432-2277. ; 28:10, s. 1152-1161
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Tidskriftsartikel (refereegranskat)abstract
- Main problemIslet transplantation has become a promising treatment for type 1 diabetes. However, immunosuppressive drugs used today cause islet deterioration and modification strategies are necessary. But little is known about pharmacokinetics interactions and intracellular concentrations of immunosuppressive drugs in human islets. MethodsWe determined the pharmacokinetics of tacrolimus and sirolimus in islets by measuring intracellular concentration after exposure alone or in combination at two different doses up to 48h. A quantification technique established in our laboratory using a Micromass Quattro micro API MS/MS-instrument with electrospray ionization was used. Islets function was measured by oxygen consumption rates. Presence of drug transporters OATP1B1 and ABCB1 and metabolizing enzyme CYP3A4 in islets were quantified using real-time quantitative PCR. ResultsIslets incubated with tacrolimus and sirolimus had a significant decrease in intracellular concentration of sirolimus compared to sirolimus alone. Reduced intracellular sirolimus concentration was followed by increased p70S6k phosphorylation suggesting preservation of the mTOR-signaling pathway. Drug transporters OATP1B1 and ABCB1 and enzyme CYP3A4 were expressed in human islets, but were not involved in the reduced sirolimus concentration by tacrolimus. ConclusionThese findings provide new knowledge of the drug interaction between tacrolimus and sirolimus, suggesting that tacrolimus has an inhibitory effect on the intracellular concentration of sirolimus in human islets.
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| 20. |
- Kloster-Jensen, Kristine, et al.
(författare)
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Treatment with Tacrolimus and Sirolimus Reveals No Additional Adverse Effects on Human Islets In Vitro Compared to Each Drug Alone but They Are Reduced by Adding Glucocorticoids
- 2016
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Ingår i: Journal of Diabetes Research. - : Hindawi Limited. - 2314-6745 .- 2314-6753.
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Tidskriftsartikel (refereegranskat)abstract
- Tacrolimus and sirolimus are important immunosuppressive drugs used in human islet transplantation; however, they are linked to detrimental effects on islets and reduction of long-term graft function. Few studies investigate the direct effects of these drugs combined in parallel with single drug exposure. Human islets were treated with or without tacrolimus (30 mu g/L), sirolimus (30 mu g/L), or a combination thereof for 24 hrs. Islet function as well as apoptosis was assessed by glucose-stimulated insulin secretion (GSIS) and Cell Death ELISA. Proinflammatory cytokines were analysed by qRT-PCR and Bio-Plex. Islets exposed to the combination of sirolimus and tacrolimus were treated with or without methylprednisolone (1000 mu g/L) and the expression of the proinflammatory cytokines was investigated. We found the following: (i) No additive reduction in function and viability in islets existed when tacrolimus and sirolimus were combined compared to the single drug. (ii) Increased expression of proinflammatory cytokines mRNA and protein levels in islets took place. (iii) Methylprednisolone significantly decreased the proinflammatory response in islets induced by the drug combination. Although human islets are prone to direct toxic effect of tacrolimus and sirolimus, we found no additive effects of the drug combination. Short-term exposure of glucocorticoids could effectively reduce the proinflammatory response in human islets induced by the combination of tacrolimus and sirolimus.
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| 21. |
- Korsgren, Olle, et al.
(författare)
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Optimising islet engraftment is critical for successful clinical islet transplantation
- 2008
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 51:2, s. 227-32
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Tidskriftsartikel (refereegranskat)abstract
- 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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| 22. |
- Lund, Tormod, et al.
(författare)
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Glucocorticoids reduce pro-inflammatory cytokines and tissue factor in vitro and improve function of transplanted human islets in vivo
- 2008
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Ingår i: Transplant International. - : Frontiers Media SA. - 0934-0874 .- 1432-2277. ; 21:7, s. 669-678
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Tidskriftsartikel (refereegranskat)abstract
- Factors that upregulate the inflammatory status of islets probably contribute to detrimental processes leading to islet loss and impaired post-transplant function. Glucocorticoids have the potential to counteract inflammation and thus improve islet quality and function. However, glucocorticoids have diabetogenic properties and are known to hamper islet function in vivo. We examined the effect of glucocorticoids on human islets in vitro and in vivo after 48 h of exposure to different concentrations of methylprednisolone. Protein and/or mRNA levels of insulin, interleukin (IL)-8, macrophage chemoattractant protein (MCP)-1, tissue factor (TF), and IL-10 were assessed by enzyme immunosorbent assay and real time quantitative reverse transcription-polymerase chain reaction. Viability was assessed with fluorescein diacetate-propidium iodide staining, adenosine triphosphate (ATP) content and caspase activity. Six-hundred islet equivalents (IEQ) were transplanted to severe combined immunodeficiency disease mice and graft function assessed by glucose measurements and intraperitoneal glucose tolerance tests. Glucocorticoids reduce mRNA and protein levels of TF, MCP-1 and IL-8, and enhance ATP content. Insulin secretion was initially inhibited; however, after 7 days in culture, it was superior to controls. Islets exposed to methylprednisolone cured diabetic mice more effectively than control islets. In conclusion, glucocorticoids have potent anti-inflammatory properties on human islets without permanent effects on insulin metabolism. Brief glucocorticoid exposure improves function of transplanted human islets in vivo.
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| 23. |
- Lund, Tormod, et al.
(författare)
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Sustained Reversal of Diabetes Following Islet Transplantation to Striated Musculature in the Rat
- 2010
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Ingår i: Journal of Surgical Research. - : Elsevier BV. - 0022-4804 .- 1095-8673. ; 160:1, s. 145-154
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: There is an increasing emphasis in the islet transplant community on the development of alternative sites for islet implantation. Striated musculature constitutes a potential alternative, which has been successfully employed in autotransplantation of parathyroid glands for decades. In the present study, a technique for intramuscular islet transplantation was developed and compared with intraportal islet transplantation in a syngeneic rat model. MATERIALS AND METHODS: Lewis rats were used. Pancreata were digested using Liberase. Islets were either transplanted into m. biceps femoris in a pearls-on-a-string fashion or intraportally, and the ability to reverse diabetes was compared. Eight weeks after transplantation an IVGTT was performed. Real-time quantitative RT-PCR was employed on muscle biopsies to investigate mRNA levels of cytokines in response to the transplant procedure. Explanted livers, muscles, and pancreata were harvested at the end of the experiment for histopathological analyses. RESULTS: 2000 IEQ repeatedly cured diabetic rats at the intraportal site, while 4000 IEQ was required at the intramuscular site. Time to reversal of diabetes, post-transplant weight development, and IVGTT curves did not differ between the groups. Normoglycemia was sustainable to the end of the study (>100 days) for all animals. The transplant procedure upregulated pro-inflammatory cytokines (IL-6 and IL-8) in striated muscle, and peri-islet fibrosis was observed in intramuscular grafts. CONCLUSIONS: Islet transplantation into striated musculature is feasible; however, in its present form the intramuscular site is less efficient compared with the liver in rats. The intramuscular site allows manipulation of the graft and implantation site prior to transplantation and may therefore have implications for islet transplantation in humans.
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| 24. |
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| 25. |
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| 26. |
- Sahraoui, Afaf, et al.
(författare)
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Anakinra and Tocilizumab Enhance Survival and Function of Human Islets During Culture : Implications for Clinical Islet Transplantation
- 2014
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Ingår i: Cell Transplantation. - 0963-6897 .- 1555-3892. ; 23:10, s. 1199-1211
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Tidskriftsartikel (refereegranskat)abstract
- Pretreatment culture before islet transplantation represents a window of opportunity to ameliorate the pro-inflammatory profile expressed by human beta-cells in duress. Analcinra (IL-1 receptor antagonist) and tocilizumab (monoclonal IL-6 receptor antibody) are two known anti-inflammatory agents successfully used in the treatment of inflammatory states like rheumatoid arthritis. Both compounds have also been shown to reduce blood glucose and glycosylated hemoglobin in diabetic patients. We therefore sought to evaluate the impact of anakinra and tocilizumab on human p-cells. The islets were precultured with or without anakinra or tocilizumab and then transplanted in a marginal mass model using human islets in immunodeficient mice. Islet viability was evaluated in an in vitro model. The pretreatment culture led to a significantly improved engraftment in treated islets compared to the vehicle. Anakinra and tocilizumab are not toxic to human islets and significantly reduce markers of inflammation and cell death. These results strongly support a pretreatment culture with anakinra and tocilizumab prior to human islet transplantation.
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| 27. |
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| 28. |
- Sahraoui, Afaf, et al.
(författare)
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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
- 2015
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:3
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Tidskriftsartikel (refereegranskat)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 mu g/kg/day) or high (200 mu 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.
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| 29. |
- Schive, Simen W., et al.
(författare)
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Cost and clinical outcome of islet transplantation in Norway 2010-2015
- 2017
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Ingår i: Clinical Transplantation. - : Wiley. - 0902-0063 .- 1399-0012. ; 31:1
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Tidskriftsartikel (refereegranskat)abstract
- Islet transplantation is a minimally invasive β-cell replacement strategy. Islet transplantation is a reimbursed treatment in Norway. Here, we summarize the cost and clinical outcome of 31 islet transplantations performed at Oslo University Hospital (OUS) from January 2010 to June 2015. Patients were retrospectively divided into three groups. Thirteen patients received either one or two islet transplantation alone (ITA), while five patients received islet transplantation after previous solid organ transplantation. For the group receiving 2 ITA, Kaplan-Meier estimates show an insulin independence of 20% more than 4 years after their last transplantation. An estimated 70% maintain at least partial graft function, defined as fasting C-peptide >0.1 nmol L−1, and 47% maintain a HbA1c below 6.5% or 2 percent points lower than before ITA. For all groups combined, we estimate that 44% of the patients have a 50% reduction in insulin requirement 4 years after the initial islet transplantation. The average cost for an islet transplantation procedure was 347 297±60 588 NOK, or 35 424±6182 EUR, of which isolation expenses represent 34%. We hereby add to the common pool of growing experience with islet transplantation and also describe the cost of the treatment at our center.
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| 30. |
- Schive, Simen W., et al.
(författare)
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Graft function 1 year after pregnancy in an islet-transplanted patient
- 2015
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Ingår i: Transplant International. - : Frontiers Media SA. - 0934-0874 .- 1432-2277. ; 28:10, s. 1235-1239
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Tidskriftsartikel (refereegranskat)abstract
- Pancreatic islet transplantation is a treatment option for patients with type 1 diabetes (T1D), but pregnancy has generally not been advised for women after receiving an islet allograft. We hereby describe what is to our knowledge the first successful pregnancy and persistent graft function in a woman 4years after her initial islet transplantation. A 37-year-old woman with brittle type 1 diabetes was transplanted with two separate islet graft infusions, eventually becoming insulin independent. Ten months after her second transplantation, her immunosuppression was switched from tacrolimus and sirolimus to tacrolimus, azathioprine, and prednisolone, due to her wish to become pregnant. She became pregnant one year later, and after 38weeks of uncomplicated pregnancy, she gave birth to a healthy child by C-section. The current report suggests that pregnancy and childbirth can be accomplished after islet transplantation without loss of islet graft function.
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| 31. |
- Schive, Simen W., et al.
(författare)
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Human Adipose-Derived Mesenchymal Stem Cells Respond to Short-Term Hypoxia by Secreting Factors Beneficial for Human Islets In Vitro and Potentiate Antidiabetic Effect In Vivo
- 2017
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Ingår i: Cell Medicine. - 2155-1790. ; 9:3, s. 103-116
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Tidskriftsartikel (refereegranskat)abstract
- Adipose-derived mesenchymal stem cells (ASCs) release factors beneficial for islets in vitro and protect against hyperglycemia in rodent models of diabetes. Oxygen tension has been shown to induce metabolic changes and alter ASCs' release of soluble factors. The effects of hypoxia on the antidiabetic properties of ASCs have not been explored. To investigate this, we incubated human ASCs for 48 h in 21% (normoxia) or 1% O-2 (hypoxia) and compared viability, cell growth, surface markers, differentiation capability, and soluble factors in the conditioned media (CM). Human islets were exposed to CM from ASCs incubated in either normoxia or hypoxia, and islet function and apoptosis after culture with or without proinflammatory cytokines were measured. To test hypoxic preconditioned ASCs' islet protective effects in vivo, ASCs were incubated for 48 h in normoxia or hypoxia before being injected into Balb/c Rag 1(-/-) immunodeficient mice with streptozotocin-induced insulitis. Progression of diabetes and insulin content of pancreas were measured. We found that incubation in hypoxia was well tolerated by ASCs and that levels of VEGF-A, FGF-2, and bNGF were elevated in CM from ASCs incubated in hypoxia compared to normoxia. while levels of HGF, IL-8, and CXCL1 were reduced. CM from ASCs incubated in hypoxia significantly improved human islet function and reduced apoptosis after culture, and reduced cytokine-induced apoptosis. In our mouse model, pancreas insulin content was higher in both groups receiving ASCs compared to control, but the mice receiving preconditioned ASCs had lower random and fasting blood glucose, as well as improved oral glucose tolerance compared to untreated mice. In conclusion, our in vitro results indicate that the islet protective potential of ASCs improves in hypoxia, and we give insight into factors involved in this. Finally we show that hypoxic preconditioning potentiates ASCs' anti-diabetic effect in vivo.
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| 32. |
- Scholz, Hanne, et al.
(författare)
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The synthetic liver X receptor agonist GW3965 reduces tissue factor production and inflammatory responses in human islets in vitro
- 2009
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 52:7, s. 1352-62
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Optimising islet culture conditions may be one strategy for reducing islet loss prior to, and immediately after, islet transplantation. Liver X receptor (LXR) agonism has previously been shown to increase insulin release from pancreatic islets and reduce inflammation in leucocytes. Our aim was to investigate whether the synthetic LXR agonist GW3965 could modulate the inflammatory status of human pancreatic islets. METHODS: Levels of pro-inflammatory cytokines and tissue factor in isolated human islets were determined by TaqMan low density array and/or real-time quantitative RT-PCR (mRNA levels) and enzyme immunoassay (EIA) (protein levels). Islet viability was measured using intracellular ATP content, ADP/ATP ratio, mitochondrial dehydrogenase activity (XTT assay) and insulin secretion in a dynamic glucose-challenge model. Apoptosis was determined by EIA measurement of histone-DNA complexes present in cytoplasm and by assaying caspase-3/-7 activity. RESULTS: Treatment of LPS-stimulated human islets with the synthetic LXR agonist GW3965 (1 micromol/l) for 24 h reduced mRNA and protein levels of selected pro-inflammatory cytokines (IL-8, monocyte chemotactic protein-1 and tissue factor). Moreover, GW3965 had no adverse effect on insulin secretion, islet viability or apoptosis. No excess of lipid accumulation could be detected with the dosage and exposure time used. CONCLUSIONS/INTERPRETATION: LXR activation suppresses inflammation in human islets in vitro without adverse effects on islet viability. Short-term moderate activation of LXR prior to islet transplantation may represent a possible strategy for improving post-transplant islet survival.
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| 33. |
- Schramm, Christoph, et al.
(författare)
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Primary liver transplantation for autoimmune hepatitis: a comparative analysis of the European Liver Transplant Registry.
- 2010
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Ingår i: Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. - : Ovid Technologies (Wolters Kluwer Health). - 1527-6473. ; 16:4, s. 461-9
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Tidskriftsartikel (refereegranskat)abstract
- The principal aim of this study was to compare the probability of and potential risk factors for death and graft loss after primary adult and pediatric liver transplantation in patients undergoing transplantation for autoimmune hepatitis (AIH) to those in patients undergoing transplantation for primary biliary cirrhosis (PBC; used as the reference group) or alcoholic cirrhosis (used as an example of a nonautoimmune liver disease). The 5-year survival of patients undergoing transplantation for AIH (n = 827) was 0.73 [95% confidence interval (CI) = 0.67-0.77]. This was similar to that of patients undergoing transplantation for alcoholic cirrhosis (0.74, 95% CI = 0.72-0.76, n = 6424) but significantly worse than that of patients undergoing transplantation for PBC (0.83, 95% CI = 0.80-0.85, n = 1588). Fatal infectious complications occurred at an increased rate in patients with AIH (hazard ratio = 1.8, P = 0.002 with PBC as the reference). The outcome of pediatric AIH patients was similar to that of adult patients undergoing transplantation up to the age of 50 years. However, the survival of AIH patients undergoing transplantation beyond the age of 50 years (0.61 at 5 years, 95% CI = 0.51-0.70) was significantly reduced in comparison with the survival of young adult AIH patients (0.78 at 18-34 years, 95% CI = 0.70-0.86) and in comparison with the survival of patients of the same age group with PBC or alcoholic cirrhosis. In conclusion, age significantly affects patient survival after liver transplantation for AIH. The increased risk of dying of infectious complications in the early postoperative period, especially above the age of 50 years, should be acknowledged in the management of AIH patients with advanced-stage liver disease who are listed for liver transplantation. It should be noted that not all risk factors relevant to patient and graft survival could be analyzed with the European Liver Transplant Registry database.
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| 34. |
- Ståhle, Magnus, 1973-, et al.
(författare)
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Clostripain, the Missing Link in the Enzyme Blend for Efficient Human Islet Isolation
- 2015
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Ingår i: Transplantation Direct. - 2373-8731. ; 1:5, s. 1-6
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Tidskriftsartikel (refereegranskat)abstract
- Background: Effective digestive enzymes are crucial for successful islet isolation. Supplemental proteases are essential as they synergize with collagenase for effective pancreas digestion. The presence of tryptic-like activity has been implicated in efficient enzyme blends and the present study aimed to evaluate if addition of clostripain, an enzyme with tryptic-like activity, could improve efficacy of the islet isolation procedure.Methods: Clostripain was added to the enzyme blend just before pancreas perfusion. Islets were isolated per standard method and numerous isolation parameters, islet quality control, and the number of isolations fulfilling standard transplantation criteria were evaluated. Two control organs per clostripain organ were chosen by blindly matching against body mass index, cold ischemia time, hemoglobin A1c, donor sex, and donor age.Results: There were no differences in pancreas weight, dissection time, digestion time, harvest time, percent digested pancreas, or total pellet volume before islet purification between control or clostripain pancreases. Glucose-stimulated insulin release results were similar between groups. Total isolation islet equivalents, purified tissue volume and islet equivalents/g pancreas as well as fulfillment of transplantation criteria favored clostripain processed pancreases.Conclusions: The addition of clostripain to the enzyme blend soundly improved islet yields and transplantation rates. It gently aided pancreas digestion and maintained proper islet functionality. The addition of clostripain to the enzyme blend has now been implemented into standard isolation protocols at the isolation centers in Uppsala and in Oslo.
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| 35. |
- Ståhle, Magnus, et al.
(författare)
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Evaluation of perfluorohexyloctane/polydimethylsiloxane for pancreas preservation for clinical islet isolation and transplantation
- 2016
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Ingår i: Cell Transplantation. - 0963-6897 .- 1555-3892. ; 25:12, s. 2269-2276
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Tidskriftsartikel (refereegranskat)abstract
- This study aimed to evaluate a 50:50 mix of perfluorohexyloctane/polydimethylsiloxane 5 (F6H8S5) preservation of pancreases in a clinical setting compared with standard solutions for 1) cold ischemia time (CIT) <10 h and 2) an extended CIT >20 h. Procured clinical-grade pancreases were shipped in either F6H8S5 or in standard preservation solutions, that is, University of Wisconsin (UW) or Custodiol. F6H5S5 was preoxygenated for at least 15 min. Included clinical-grade pancreases were procured in UW or Custodiol. Upon arrival at the islet isolation laboratory, the duodenum was removed followed by rough trimming while F6H8S5 was oxygenated for 15–20 min. Trimmed pancreases were immersed into oxygenated F6H8S5 and stored at 4°C overnight followed by subsequent islet isolation. Pancreas preservation using F6H8S5 proved as effective as UW and Custadiol when used within CIT up to 10 h, in terms of both isolation outcome and islet functionality. Preservation in F6H8S5 of pancreases with extended CIT gave results similar to controls with CIT <10 h for both isolated islet functionality and isolation outcome. This study of clinically obtained pancreases indicates a clear benefit of using F6H8S5 on pancreases with extended CIT as it seems to allow extended cold ischemic time without affecting islet function and islet numbers.
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| 36. |
- Ståhle, Magnus, 1973-, et al.
(författare)
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Evaluation of the new pancreas preservation solution, I-Let Protect, for clinical islet isolation and transplantation
- 2015
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundThis prospective study aimed to evaluate polydimethylsiloxane 5 (F6H8S5) preservation of pancreases in a clinical setting compared with standard solutions for 1) cold ischemia-time (CIT) <10 hour and 2) a prolonged CIT > 20 hour.MethodsPart 1. Procured clinical grade pancreases were shipped in either F6H8S5 or in standard preservation solutions, i.e., University of Wisconsin (UW) or Custodiol. F6H5S5 were pre-oxygenated for at least 15 minutes.Part 2. Included clinical grade pancreases were procured in UW or Custodiol. Upon arrival at the islet isolation laboratory, duodenum was removed followed by rough trimming while F6H8S5 was oxygenated for 15-20 minutes. Trimmed pancreases were immersed into oxygenated F6H8S5 and stored at 4°C over night followed by subsequent islet isolation.ResultsPancreas preservation using F6H8S5 proved as effective as UW and Custadiol when used within CIT up to 10 hour, both in terms of isolation outcome and islet functionality. Preservation in F6H8S5 of pancreases with prolonged CIT gave results similar to controls with CIT< 10 hours for both isolated islet functionality and isolation outcome.ConclusionsThis prospective study of clinically obtained pancreases indicate a clear benefit of using F6H8S5 on pancreases with prolonged CIT when compared with other organ preservation solutions. F6H8S5 preserved islet quality and quantity compared with islets isolated from pancreases with CIT of less than 10 hour.
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| 37. |
- Sund, Fredrik, et al.
(författare)
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CMV-specific T-cell immunity, viral load, and clinical outcome in seropositive renal transplant recipients : a pilot study
- 2010
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Ingår i: Clinical Transplantation. - : Wiley. - 0902-0063 .- 1399-0012. ; 24:3, s. 401-409
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cytomegalovirus (CMV) infection is still the leading opportunistic infection following solid organ transplantation. The aim of this prospective study of renal transplant recipients was to evaluate the dynamics of CMV-specific T-cells, viral load, and clinical symptoms of CMV infection.Methods: Levels of tetramer-selected CD8+ T-cells (TetraCD8), CMV-specific interferon-γ producing CD8+ T-cells (IFNγCD8), and CD4+ T-cells (IFNγCD4), measured using major histocompatibility complex-tetramer and cytokine flow cytometry techniques, and CMV DNA were monitored monthly in 17 CMV-seropositive patients up to one yr (median 12 months, range 3–12) after transplantation and correlated to clinical outcome.Results: CMV DNAemia was detected in 94% of the patients, but only one patient developed CMV disease. CMV DNAemia >1 million copies/mL was seen in asymptomatic patients. CMV-specific T-cells decreased rapidly after transplantation. TetraCD8 and IFNγCD8 regenerated within three months, whereas IFNγCD4 recovery was impaired up to one yr after transplantation. The proportion of IFNγCD4 at two months post-transplantation as compared with baseline, correlated strongly with the magnitude of the CMV DNAemia.Conclusions: Monitoring the reduction of IFNγCD4 compared with baseline during the first months after transplantation could be considered in predicting risk for high-grade CMV DNAemia and in deciding strategic approaches for pre-emptive and prophylactic therapy.
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| 38. |
- Thorsen, Trygve, et al.
(författare)
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Liver transplantation with deceased ABO-incompatible donors is life-saving but associated with increased risk of rejection and post-transplant complications.
- 2015
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Ingår i: Transplant International. - : Frontiers Media SA. - 0934-0874 .- 1432-2277. ; 28:7, s. 800-12
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Tidskriftsartikel (refereegranskat)abstract
- ABO-incompatible (ABOi) liver transplantation (LT) with deceased donor organs is performed occasionally when no ABO-compatible (ABOc) graft is available. From 1996 to 2011, 61 ABOi LTs were performed in Oslo and Gothenburg. Median patient age was 51 years (range 13-75); 33 patients were transplanted on urgent indications, 13 had malignancy-related indications, and eight received ABOi grafts for urgent retransplantations. Median donor age was 55 years (range 10-86). Forty-four patients received standard triple immunosuppression with steroids, tacrolimus, and mycophenolate mofetil, and forty-four patients received induction with IL-2 antagonist or anti-CD20 antibody. Median follow-up time was 29 months (range 0-200). The 1-, 3-, 5-, and 10-year Kaplan-Meier estimates of patient survival (PS) and graft survival (GS) were 85/71%, 79/57%, 75/55%, and 59/51%, respectively, compared to 90/87%, 84/79%, 79/73%, and 65/60% for all other LT recipients in the same period. The 1-, 3-, 5-, and 10-year GS for A2 grafts were 81%, 67%, 62%, and 57%, respectively. In conclusion, ABOi LT performed with non-A2 grafts is associated with inferior graft survival and increased risk of rejection, vascular and biliary complications. ABOi LT with A2 grafts is associated with acceptable graft survival and can be used safely in urgent cases.
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| 39. |
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| 40. |
- Thorsen, Trygve, et al.
(författare)
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Transplantation With Livers From Deceased Donors Older Than 75 Years
- 2015
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 99:12, s. 2534-2542
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Tidskriftsartikel (refereegranskat)abstract
- Background. The availability of donor organs limits the number of patients in need who are offered liver transplantation. Measures to expand the donor pool are crucial to prevent on-list mortality. The aim of this study was to evaluate the use of livers from deceased donors who were older than 75 years. Methods. Fifty-four patients who received a first liver transplant (D75 group) from 2001 to 2011 were included. Donor and recipient data were collected from the Nordic Liver Transplant Registry and medical records. The outcome was compared with a control group of 54 patients who received a liver graft from donors aged 20 to 49 years (D20-49 group). Median donor age was 77 years (range, 75-86 years) in the D75 group and 41 years (range, 20-49 years) in the D20-49 group. Median recipient age was 59 years (range, 31-73 years) in the D75 group and 58 years (range, 31-74 years) in the D20-49 group. Results. The 1-, 3-, and 5-year patient/graft survival values were 87/87%, 81/81%, and 71/67% for the D75 group and 88/87%, 75/73%, and 75/73% for the D20-49 group, respectively. Patient (P = 0.89) and graft (P = 0.79) survival did not differ between groups. The frequency of biliary complications was higher in the D75 group (29.6/13%, P = 0.03). Conclusions. Selected livers from donors over age 75 years should not be excluded based on age, which does not compromise patient or graft survival despite a higher frequency of biliary complications.
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| 41. |
- von Zur-Mühlen, Bengt, Docent, 1966-, et al.
(författare)
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Open Randomized Multicenter Study to Evaluate Safety and Efficacy of Low Molecular Weight Sulfated Dextran in Islet Transplantation
- 2019
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Ingår i: Transplantation. - : LIPPINCOTT WILLIAMS & WILKINS. - 0041-1337 .- 1534-6080. ; 103:3, s. 630-637
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Tidskriftsartikel (refereegranskat)abstract
- Background. When transplanted human pancreatic islets are exposed to blood during intraportal infusion, an innate immune response is triggered. This instant blood-mediated inflammatory reaction (IBMIR) activates the coagulation and complement cascades and leads to the destruction of 25% of all transplanted islets within minutes, contributing to the need, in most patients, for islets from more than 1 donor. Low molecular dextran sulfate (LMW-DS) has been shown in experimental settings to inhibit IBMIR. Methods. The Clinical Islet Transplantation consortium 01 study was a phase II, multicenter, open label, active control, randomized study. Twenty-four subjects were randomized to peritransplant intraportal and systemic treatment with either LMW-DS or heparin, targeting an activated partial thromboplastin time of 150 +/- 10 seconds and 50 +/- 5 seconds, respectively. C-peptide response was measured with a mixed meal tolerance test at 75 and 365 days after transplant. Results. Low molecular dextran sulfate was safe and well tolerated with similar observed adverse events (mostly attributed to immunosuppression) as in the heparin arm. There was no difference in the primary endpoint (stimulated C-peptide 75 +/- 5 days after the first transplant) between the 2 arms (1.33 +/- 1.10 versus 1.56 +/- 1.36 ng/mL, P = 0.66). Insulin requirement, metabolic parameters, Clarke and HYPO score, quality of life, and safety were similar between the 2 treatments groups. Conclusions. Even with low dosing, LMW-DS showed similar efficacy in preventing IBMIR to promote islet engraftment when compared to "state-of-the art" treatment with heparin. Furthermore, no substantial differences in the efficacy and safety endpoints were detected, providing important information for future studies with more optimal dosing of LMW-DS for the prevention of IBMIR in islet transplantation.
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| 42. |
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