Improved survival of intraportal pancreatic islet cell allografts in patients with type-1 diabetes mellitus by refined peritransplant management

Bretzel, R. G.; Brandhorst, Daniel; Brandhorst, Heide; Eckhard, Michael; Ernst, Wolfgang; Friemann, S; Rau, W. S.; Weimar, B.; Rauber, K.; Hering, Bernhard J.; Brendel, Mathias D.

doi:10.1007/s001090050322

Cited by 97 publications

(60 citation statements)

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“…Surprisingly, we observed the presence of circulating ␤-cells in venous blood during a period of 6 days to 10 weeks posttransplantation. Although vulnerability of intraportally injected human islets is well known, previous studies have focused on local cell death due to peri-and posttransplant injuries (11,(15)(16)(17), and this is the first report of intact islet cell release into the circulation. The presence of circulating ␤-cells may be a marker for acute or chronic islet injury, although this needs to be clearly established; however, it suggests islet loss through dissociation.…”

Section: Discussionmentioning

confidence: 91%

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Molecular Detection of Circulating β-Cells After Islet Transplantation

et al. 2002

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Islet transplantation is a promising treatment for type 1 diabetes. However, islet grafts are submitted to multiple injuries, including immunosuppressive drug toxicity, hyperglycemia, hypoxia, unspecific inflammatory reactions, as well as allo-and autoimmune destruction. Therapeutic approaches to these damage mechanisms require early detection of islet injury, which is currently not feasible because of the lack of efficient markers. Based on the hypothesis of islet dissociation and release of islet cells into the circulation during islet injury, we designed a highly sensitive and specific molecular assay, able to detect two ␤-cells per milliliter of venous blood by RT-PCR of insulin mRNA. We report that circulating ␤-cells can be demonstrated up to 10 weeks after intraportal islet transplantation, as assessed after six islet grafts in four type 1 diabetic patients. Furthermore, our results suggest that the time during which circulating islet cells can be detected may depend on the graft environment and the immunosuppressive regimen. This test may allow better estimation of islet cell loss and identification of factors involved in islet graft injury. Diabetes 51:557-561, 2002 R eplacement of insulin-producing cells through islet transplantation is a promising approach for treatment of type 1 diabetes. This procedure is safe and relatively simple with rare complications, but, up to recently, only moderate success rates have been achieved at 1 year posttransplantation (with 41% graft survival, as defined by C-peptide Ն0.5 ng/ml, and 11% insulin independence) (1). The Edmonton protocol, including an immunosuppressive strategy without steroids, presently leads to 100% graft survival and 75% insulin independence in a median follow-up of 10.2 months (2,3).Whereas blood flow monitoring and amylase/lipase clearance (in case of bladder drainage), as well as serum amylase/lipase and nitric oxide concentrations, are used to asses pancreatic graft rejection (4), for islet transplantation, no early and reliable markers are available to monitor islet injury. Anti-GAD 65 antibodies are observed more frequently in patients experiencing an islet graft loss (5), but no systematic correlation can be found. Similarly, monitoring of serum GAD 65 levels could not be used as a marker of acute islet cell destruction (6). At present, islet graft survival is controlled by monitoring of glycemia, serum C-peptide, and HbA 1c levels; however, their sensitivity is low, and onset of hyperglycemia and C-peptide levels Ͻ0.5 ng/ml are end-stage events indicating the loss of Ͼ85% of the transplant (7,8). Evaluation of the functional reserve of transplanted islets by glucose tolerance tests or calculation of the proinsulin-to-insulin ratio seems to be more indicative for islet dysfunction, but still not sensitive enough for an early detection of graft loss (6,7). Our aim is to develop a reliable and early marker of the rejection process as well as a diagnostic tool for islet engraftment. As a first study, we set up a highly sensitive and specific m...

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Section: Discussionmentioning

confidence: 91%

“…Mean follow-up was 8.5 months (range [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] after the last transplantation. The first C-peptide measurement was performed 12 h after the injection and demonstrated a transient peak reaching 1.79 ng/ml (P Ͻ 0.05 vs. 1-month values).…”

Section: Resultsmentioning

confidence: 99%

Molecular Detection of Circulating β-Cells After Islet Transplantation

et al. 2002

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“…Patients 25,26,28,30,32,34,35,38,40 and 41 also received a treatment based on pentoxyfillin (1200 mg/ day), nicotinamide (1500 mg/day) [10] and metformin (1000 mg/day) to improve islet engraftment. During follow-up, exogenous insulin was administered to maintain glycaemic values within 4.4 to 9.9 mmol/l.…”

Section: Methodsmentioning

confidence: 99%

Succesful transplantation of human islets in recipients bearing a kidney graft

Bertuzzi

Grohovaz²,

Maffi³

et al. 2002

Diabetologia

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Refinements in procedures of pancreas enzymatic digestion, and new immunosuppression strategies have allowed clinical trials of islet transplantation in patients with Type I (insulin-dependent) diabetes mellitus [1]. Until recently, the majority of transplants were done in patients who also receive kidney allografts [2]. Clinical results in these patients have not been satisfactory, with a 12 month survival of islet allografts (as defined by basal C-peptide > 0.17 nmol/l) being achieved in less than 40 % of recipients, and insulin independence in only 13 % of recipients [2]. The number of recipients who become insulin independent after transplantation is low and so the procedure has also been considered successful when recipients maintained detectable serum C-peptide during follow-up [3±4] or HbA 1 c was normalized [5]. Regardless of which outcome measure is used, around 30 % of the cases reported in the International Registry of Transplantation (ITR) showed the absence of islet function af- Diabetologia (2002) Abstract Aims/hypothesis. Islet transplantation is a minimally invasive approach to curing Type I (insulin-dependent) diabetes mellitus. Success has recently been reported in patients receiving solitary islet transplants but the outcome in patients receiving islets together with, or after, kidney transplants has been limited and unpredictable. Methods. Here we report successful islet transplantation in a cohort of 15 patients with Type I diabetes who were followed for at least 1 year after islet transplantation, after having already received kidney allografts because of end-stage nephropathy. Results. C-peptide after transplantation was higher than 0.17 nmol/l in all 15 recipients, reflecting the absence of primary non-function. Insulin requirement was reduced by over 50 % in all but one patient, and insulin independence was achieved in 10 (66 %) recipients, five of whom now have stable, prolonged insulin independence, well controlled fasting glycaemia, a substantial first-phase and normal secondphase response to glucose, normal insulin sensitivity (HOMA analyses) and HbA 1 c of under 6.2 % (33, 26, 18, 13 and 12 months after transplantation respectively). Of importance for patient management, an assessment of fasting blood glucose and proinsulin values following overnight withdrawal of insulin administration one month after transplantation was a potent predictor of insulin independence, and could be used to decide patients who should have further islet preparations. Conclusion/interpretation. These findings support the use of islet transplantation as a cure for Type I diabetes in patients with severe complications. [Diabetologia (2002) 45: 77±84]

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“…Moreover, exocrine tissue has been reported to inhibit angiogenesis and vascularization of the islet graft [10]. Furthermore, due to the low Pancreas and islet transplantation are the only treatment regimens currently available to achieve a constant insulin-independent normoglycaemic state in patients with Type 1 diabetes mellitus [1,2]. Pancreas allotransplantation is surgically complex and is associated with a high morbidity [3,4,5,6].…”

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confidence: 99%

Stable transplantation results of magnetically retracted islets: a novel method

et al. 2003

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Aims/hypothesis. Large quantities of pure viable donor islets are necessary for clinical transplantation. At present, low yields and low viability of pancreatic islets after transplantation necessitate the use of multiple donors for a single recipient. In this study an improved method for obtaining large quantities of pure viable islets of Langerhans for transplantation was developed in the rat. Methods. Islets of Langerhans were isolated from Albino Oxford rats. The donor pancreata were perfused in situ with iron oxide, which resulted in entrapment of iron particles in the capillaries of the islets. Subsequently, the islets were isolated by magnetic retraction. Islets obtained with this method were compared with islets obtained by density gradient-isolated islets with respect to yields, purity, and insulin production capacity. Islets isolated with the magnetic retraction method were transplanted under the renal capsule of streptozotocin-induced diabetic recipients. Blood-glucose levels in the recipients were monitored for 2 months after transplantation.Results. This method yielded more pure and viable islets than the conventional protocol. No contamination of exocrine tissue was observed after isolation. Furthermore, the islets isolated by magnetic retraction stained strongly positive for insulin during the entire observation period in vitro, and produced high amounts of insulin upon a challenge with glucose. The islets that were obtained by this new protocol were suitable for safe and effective transplantation. Conclusions/interpretation. We have shown that both the quantity and quality of islets obtained with this method were sufficient to induce insulin independence in a diabetic recipient using islets from only one donor. [Diabetologia (2004) 47:55-61]

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Improved survival of intraportal pancreatic islet cell allografts in patients with type-1 diabetes mellitus by refined peritransplant management

Cited by 97 publications

References 10 publications

Molecular Detection of Circulating β-Cells After Islet Transplantation

Molecular Detection of Circulating β-Cells After Islet Transplantation

Succesful transplantation of human islets in recipients bearing a kidney graft

Stable transplantation results of magnetically retracted islets: a novel method

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