After extensive experimentation, outcomes of a first clinical normothermic machine perfusion (NMP) liver trial in the United Kingdom demonstrated feasibility and clear safety, with improved liver ...function compared with standard static cold storage (SCS). We present a preliminary single‐center North American experience using identical NMP technology. Ten donor liver grafts were procured, four (40%) from donation after circulatory death (DCD), of which nine were transplanted. One liver did not proceed because of a technical failure with portal cannulation and was discarded. Transplanted NMP grafts were matched 1:3 with transplanted SCS livers. Median NMP was 11.5 h (range 3.3–22.5 h) with one DCD liver perfused for 22.5 h. All transplanted livers functioned, and serum transaminases, bilirubin, international normalized ratio, and lactate levels corrected in NMP recipients similarly to controls. Graft survival at 30 days (primary outcome) was not statistically different between groups on an intent‐to‐treat basis (p = 0.25). Intensive care and hospital stays were significantly more prolonged in the NMP group. This preliminary experience demonstrates feasibility as well as potential technical risks of NMP in a North American setting and highlights a need for larger, randomized studies.
This paper describes a preliminary Canadian single‐center experience with clinical ex vivo normothermic liver perfusion and transplantation. See the video at amjtransplant.com/videos.
Percutaneous transhepatic portal access avoids surgery but is rarely associated with bleeding or portal venous thrombosis (PVT). We herein report our large, single‐center experience of percutaneous ...islet implantation and evaluate risk factors of PVT and graft function. Prospective data were collected on 268 intraportal islet transplants (122 subjects). A portal venous Doppler ultrasound was obtained on Days 1 and 7 posttransplant. Therapeutic heparinization, complete ablation of the portal catheter tract with Avitene paste and limiting packed cell volume (PCV) to <5 mL completely prevented any portal thrombosis in the most recent 101 islet transplant procedures over the past 5 years. In the previous cumulative experience, partial thrombosis did not affect islet function. Standard liver volume correlated negatively (r =−0.257, p < 0.001) and PCV correlated positively with portal pressure rise (r = 0.463, p < 0.001). Overall, partial portal thrombosis occurred after 10 procedures (overall incidence 3.7%, most recent 101 patient incidence 0%). There were no cases of complete thrombosis and no patient developed sequelae of portal hypertension. In conclusion, portal thrombosis is a preventable complication in clinical islet transplantation, provided therapeutic anticoagulation is maintained and PCV is limited to <5 mL.
In 268 percutaneous islet transplants, complete thrombosis of the portal vein never occurred, partial thrombosis occurred with an incidence of 3.7%, and by limiting the packed tissue volume to <5cc, combined with therapeutic heparin and track plugging, was preventable entirely in the most recent 100 cases.
The epidemiology of cytomegalovirus infection (CMV) in islet transplantation (IT) is not well defined. This study defines incidence, transmission and clinical sequelae of CMV reactivation or disease ...in 121 patients receiving 266 islet infusions at a single institution. The donor (D)/recipient (R) serostatus was D+/R– 31.2%, D+/R+ 26.3%, D–/R+ 13.2% and D–/R– 29.3%. CMV prophylaxis with oral ganciclovir/valganciclovir was given in 68%. CMV infection occurred in 14/121 patients (11.6%); six had asymptomatic seroconversion and eight others had positive viremia (six asymptomatic and two with CMV febrile symptoms). Median peak viral loads were 1755 copies/mL (range 625–9 100 000). Risk factors for viremia included lymphocyte depletion (thymoglobulin or alemtuzumab, p < 0.001). Viremia was more common in D+/R+ versus D+/R– (p = 0.12), occurring mostly late after transplant (median 306 days). Presumed transmission from IT occurred in 8/83 of D+/R– procedures (9.6%). Of the two cases of CMV disease, one resulted from islet transmission from a CMV positive donor (D+/R–); the other was due to de novo exogenous infection (D–/R–). Therefore, CMV transmission presents rarely after IT and with low incidence compared to solid organ transplantation, but occurs late posttransplant. The use of lymphocyte depleting therapies is a primary risk factor.
The authors find that cytomegalovirus transmission presents infrequently after islet transplantation, occurs late posttransplant, and is associated with T cell depletion.
Pancreatic metastases from renal cell carcinoma (RCC) may have a chronic and highly indolent course, and may be resected for cure after considerable delay following treatment of the primary tumor, in ...contrast to other more common pancreatic tumors. Surgical resection is the treatment of choice, which may lead to postpancreatectomy diabetes mellitus in the case of extensive resection. We present a 70‐year‐old patient with multifocal pancreatic metastases from RCC causing obstructive jaundice. A total pancreatectomy was required to excise two distant tumors in the head and tail of the pancreas, together with a segment VI liver resection. An autologous islet transplant (AIT) prepared from the central, uninvolved pancreas was carried out to prevent postpancreatectomy diabetes. The patient was rendered insulin‐free and remains so with excellent glycemic control for 1 year of follow‐up, and there is no evidence of tumor recurrence. The patient has been treated with adjuvant sunitinib to minimize risk of further recurrence. In conclusion, AIT after pancreatectomy may represent a useful option to treat patients with metastatic RCC. A critical component of this approach was dependent upon elaborate additional testing to exclude contamination of the islet preparation by cancerous cells.
The authors report on successful autologous islet transplantation after central pancreatectomy for a low‐grade pancreatic malignancy.
Islet transplantation is an effective means of treating severe type 1 diabetes in patients with life‐threatening hypoglycemia. Improvements in glycemic control with correction of HbA1C enhance ...quality of life irrespective of insulin independence. By antagonizing the Natural Killer Group 2, member D (NKG2D) receptor expression on NK and CD8+ T cells, in combination with blocking CTLA‐4 binding sites, we demonstrate a significant delay of graft rejection in islet allotransplant. Anti‐NKG2D combined with CTLA‐4 Ig (n = 15) results in prolonged allograft survival, with 84.6 ± 10% of the recipients displaying insulin independence compared to controls (n = 10, p < 0.001). The effect of combination therapy on graft survival is superior to treatments alone (CTLA‐4 Ig vs. combination p = 0.024, anti‐NKG2D vs. combination p < 0.001) indicating an interaction between these pathways. In addition, combination treatment also improves glucose tolerance when compared to controls (n = 10, p = 0.018). Histologically, NKG2D+ cells were significantly decreased within the allograft after 7 days of combination treatment (n = 6, p = 0.029). T cell proliferation was significantly reduced with anti‐NKG2D therapy and CD8+ T cell daughter fractions were also significantly decreased with mAb and combination treatment when measured by in vitro mixed lymphocyte reaction (n = 5, p = 0.015, p = 0.005 and p = 0.048). These results demonstrate that inhibition of NKG2D receptors and costimulatory pathways enhance islet allograft survival.
Antagonizing the Natural Killer Group 2, member D receptor expression on NK and CD8+ T cells, in combination with blocking CTLA‐4 binding sites, significantly prolongs islet allograft survival.
Abstract Background The shipment of human islets (IE) from processing centers to distant laboratories is beneficial for both research and clinical applications. The maintenance of islet viability and ...function in transit is critically important. Gas-permeable silicone rubber membrane (SRM) vessels reduce the risk of hypoxia-induced death or dysfunction during high-density islet culture or shipment. SRM vessels may offer additional advantages: they are cost-effective (fewer flasks, less labor needed), safer (lower contamination risk), and simpler (culture vessel can also be used for shipment). Method IE were isolated from two manufacturing centers and shipped in 10-cm2 surface area SRM vessels in temperature- and pressure-controlled containers to a distant center after at least 2 days of culture (n = 6). Three conditions were examined: low density (LD), high density (HD), and a microcentrifuge tube negative control (NC). LD was designed to mimic the standard culture density for IE preparations (200 IE/cm2 ), while HD was designed to have a 20-fold higher tissue density, which would enable the culture of an entire human isolation in 1–3 vessels. Upon receipt, islets were assessed for viability (measured by oxygen consumption rate normalized to DNA content OCR/DNA)), quantity (measured by DNA), and, when possible, potency and function (measured by dynamic glucose-stimulated insulin secretion measurements and transplants in immunodeficient B6 Rag+/− mice). Postshipment OCR/DNA was not reduced in HD vs LD and was substantially reduced in the NC condition. HD islets exhibited normal function postshipment. Based on the data, we conclude that entire islet isolations (up to 400,000 IE) may be shipped using a single, larger SRM vessel with no negative effect on viability and ex vivo and in vivo function.
Islet transplantation is a well-established therapeutic treatment for a subset of patients with complicated type I diabetes mellitus. Prior to the Edmonton Protocol, only 9% of the 267 islet ...transplant recipients since 1999 were insulin independent for >1 year. In 2000, the Edmonton group reported the achievement of insulin independence in seven consecutive patients, which in a collaborative team effort propagated expansion of clinical islet transplantation centers worldwide in an effort to ameliorate the consequences of this disease. To date, clinical islet transplantation has established improved success with insulin independence rates up to 5 years post-transplant with minimal complications. In spite of marked clinical success, donor availability and selection, engraftment, and side effects of immunosuppression remain as existing obstacles to be addressed to further improve this therapy. Clinical trials to improve engraftment, the availability of insulin-producing cell sources, as well as alternative transplant sites are currently under investigation to expand treatment. With ongoing experimental and clinical studies, islet transplantation continues to be an exciting and attractive therapy to treat type I diabetes mellitus with the prospect of shifting from a treatment for some to a cure for all.
Background: Prolonged warm ischemia times in kidney transplantation (KT) have been associated with worse outcomes. During organ procurement, and after ice removal, kidneys located in the ...retroperitoneum are at risk of rewarming during the time taken to retrieve other abdominal and thoracic organs. The purpose of this study is to evaluate the impact of prolonged kidney procurement (PKP) time on kidney transplantation outcomes. Methods: A total of 145 patients were reviewed. We defined PKP as more than 65 minutes from aortic cross-clamp to final organ extraction versus standard procurement (SP) time (< 65 min). Results: No statistically significant differences were seen in outcomes when we compared kidney-only (KOP) versus multiorgan procurements, even though KOP organs have a higher incidence of Kidney Donor Profile Index (KDPI) greater than 50% (p < 0.01). However, when kidney procurement took more than 65 minutes, there was a higher rate of 3-month graft loss (6.6% v. 0%, p < 0.01), a higher incidence of de novo donor specific antibodies formation (10% v. 0.9%, p < 0.01), and an inferior 5-year graft survival of 90% versus 97.4% (p = 0.03). Left kidneys had an average ischemia time 10 minutes longer than that of right grafts, and their 5-year survival was significantly lower than that of their mate organs (p = 0.03). Conclusion: Procurement time, when longer than 65 minutes, is an important and potentially modifiable factor that influences not only early but also long-term graft survival. Preventive measures to reduce the exposure of kidney procurements to rewarming may influence long-term outcomes.
Background: The Metroticket project produced prognostic calculators for patients undergoing liver transplant (LT) for hepatocellular carcinoma (HCC). Radiology-based and pathology-based calculators ...predict 5-year HCC-specific and overall survival, respectively. Our objective was to evaluate how viable tumour burden at explant affects the predictive capability of the Metroticket model. Methods: A retrospective cohort analysis of HCC LT patients from 1996 to 2019 was conducted. Locoregional therapy (LRT) data, radiographic parameters and explant pathology findings including tumour viability were collected. Metroticket predicted survival was calculated. Tumour response to LRT was assessed. Radiographic total tumour volume (TTV) and explant total viable tumour volume (TVV) were correlated. HCC-specific survival of these subgroups was assessed using Kaplan-Meier curves and compared via log-rank testing. Finally, predicted versus observed survival was compared by patient subgroups. Results: Eighty patients were included. TTV and TVV correlated strongly (Pearson r = 0.98, p < 0.01), with imaging overestimating TVV by 42.1%. There was no significant difference in HCC-specific survival if patients underwent LRT (p = 0.50), regardless of tumour response (p = 0.85), nor if tumours were viable (p = 0.10), regardless of viable tumour burden (p = 0.74). Similarly, the presence of microvascular invasion (p = 0.73) or satellitosis (p = 0.99) did not influence HCC-specific survival. Observed 5-year overall survival was significantly lower than predicted by the Metroticket model for patients with viable tumours (66.3% v. 61.8, p = 0.03). This finding was amplified in patients without vascular invasion (78.9 v. 66.7%, p < 0.01). Patients with viable tumours and presence of microvascular invasion demonstrated overall survival significantly greater than predicted by the Metroticket model (60.6 v. 51.7%, p < 0.01). Conclusion: In our study, HCC-specific survival does not appear to be affected by LRT or the burden of viable tumours. However, tumour viability does appear to influence the predictive capability of the Metroticket model, varying with the presence of microvascular invasion. Integrating tumour viability in the Metroticket model may augment its efficacy.
PDF
