Five-Year Metabolic, Functional, and Safety Results of Patients With Type 1 Diabetes Transplanted With Allogenic Islets Within the Swiss-French GRAGIL Network

OBJECTIVE To describe the 5-year outcomes of islet transplantation within the Swiss-French GRAGIL Network. RESEARCH DESIGN AND METHODS Retrospective analysis of all subjects enrolled in the GRAGIL-1c and GRAGIL-2 islet transplantation trials. Parameters related to metabolic control, graft function, and safety outcomes were studied. RESULTS Forty-four patients received islet transplantation (islet transplantation alone [ITA] 24 patients [54.5%], islet after kidney [IAK] transplantation 20 patients [45.5%]) between September 2003 and April 2010. Recipients received a total islet mass of 9,715.75 ± 3,444.40 IEQ/kg. Thirty-four patients completed a 5-year follow-up, and 10 patients completed a 4-year follow-up. At 1, 4, and 5 years after islet transplantation, respectively, 83%, 67%, and 58% of the ITA recipients and 80%, 70%, and 60% of the IAK transplant recipients reached HbA1c under 7% (53 mmol/mol) and were free of severe hypoglycemia, while none of the ITA recipients and only 10% of the IAK transplant recipients met this composite criterion at the preinfusion stage. Thirty-three of 44 patients (75%) experienced insulin independence during the entire follow-up period, with a median duration of insulin independence of 19.25 months (interquartile range 2–58). Twenty-nine of 44 recipients (66%) exhibited at least one adverse event; 18 of 55 adverse events (33%) were possibly related to immunosuppression; and complications related to the islet infusion (n = 84) occurred in 10 recipients (11.9%). CONCLUSIONS In a large cohort with a 5-year follow-up and in a multicenter network setting, islet transplantation was safe and efficient in restoring good and lasting glycemic control and preventing severe hypoglycemia in patients with type 1 diabetes.

[1]  F. Pattou,et al.  Randomised, prospective, medico-economic nationwide French study of islet transplantation in patients with severely unstable type 1 diabetes: the STABILOT study protocol , 2017, BMJ Open.

[2]  J. Markmann,et al.  Islet Cell Transplantion: Update on Current Clinical Trials , 2016, Current Transplantation Reports.

[3]  Maciej Henneberg,et al.  Type 1 diabetes prevalence increasing globally and regionally: the role of natural selection and life expectancy at birth , 2016, BMJ Open Diabetes Research and Care.

[4]  S. Fuggle,et al.  The UK Pancreas Allocation Scheme for Whole Organ and Islet Transplantation , 2015, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[5]  T. Berney,et al.  Absence of amyloid deposition in human islets transplantation after 13 years insulin independence. , 2015, Transplantation.

[6]  T. Berney,et al.  Islet of Langerhans isolation from pediatric and juvenile donor pancreases , 2014, Transplant international : official journal of the European Society for Organ Transplantation.

[7]  K. Badenhoop,et al.  Cystic fibrosis‐related diabetes compared with type 1 and type 2 diabetes in adults , 2013, Diabetes/metabolism research and reviews.

[8]  R. Gruessner,et al.  The current state of pancreas transplantation , 2013, Nature Reviews Endocrinology.

[9]  F. Pattou,et al.  Continuous glucose monitoring after islet transplantation in type 1 diabetes: an excellent graft function (β-score greater than 7) Is required to abrogate hyperglycemia, whereas a minimal function is necessary to suppress severe hypoglycemia (β-score greater than 3). , 2012, The Journal of clinical endocrinology and metabolism.

[10]  N. Shah,et al.  Increased Mortality of Patients With Diabetes Reporting Severe Hypoglycemia , 2012, Diabetes Care.

[11]  Nicole A. Turgeon,et al.  Improvement in Outcomes of Clinical Islet Transplantation: 1999–2010 , 2012, Diabetes Care.

[12]  B. Hering,et al.  Potent Induction Immunotherapy Promotes Long‐Term Insulin Independence After Islet Transplantation in Type 1 Diabetes , 2012, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[13]  N. Kneteman,et al.  Portal Vein Thrombosis Is a Potentially Preventable Complication in Clinical Islet Transplantation , 2011, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[14]  T. Berney,et al.  Impact of the Number of Infusions on 2-Year Results of Islet-After-Kidney Transplantation in the GRAGIL Network , 2011, Transplantation.

[15]  G. Warnock,et al.  Reduced Progression of Diabetic Microvascular Complications With Islet Cell Transplantation Compared With Intensive Medical Therapy , 2011, Transplantation.

[16]  T. Berney,et al.  Influence of Donor Age on Islet Isolation and Transplantation Outcome , 2010, Transplantation.

[17]  T. Berney,et al.  Combined Pancreatic Islet–Lung Transplantation: A Novel Approach to the Treatment of End‐Stage Cystic Fibrosis , 2010, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[18]  R. Tanenberg,et al.  Confirmation of hypoglycemia in the "dead-in-bed" syndrome, as captured by a retrospective continuous glucose monitoring system. , 2010, Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists.

[19]  F. Pattou,et al.  Primary Graft Function, Metabolic Control, and Graft Survival After Islet Transplantation , 2009, Diabetes Care.

[20]  B. Hering,et al.  Body mass index of pancreatic donors: a decisive factor for human islet isolation. , 2009, Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association.

[21]  E. Renard,et al.  Quality of life after islet transplantation: data from the GRAGIL 1 and 2 trials , 2009, Diabetic medicine : a journal of the British Diabetic Association.

[22]  James D. Johnson,et al.  A Multi-Year Analysis of Islet Transplantation Compared With Intensive Medical Therapy on Progression of Complications in Type 1 Diabetes , 2008, Transplantation.

[23]  C. Ricordi,et al.  Restoration of Hypoglycemia Awareness After Islet Transplantation , 2008, Diabetes Care.

[24]  B. Hering,et al.  Prolonged Insulin Independence After Islet Allotransplants in Recipients with Type 1 Diabetes , 2008, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[25]  F. Pattou,et al.  Quantitative in vivo islet potency assay in normoglycemic nude mice correlates with primary graft function after clinical transplantation. , 2008, Transplantation.

[26]  R. Lehmann,et al.  Has Time Come for New Goals in Human Islet Transplantation? , 2008, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[27]  E. Bonifacio,et al.  Transplant Estimated Function , 2008, Diabetes Care.

[28]  G. Brons.  One more step along the road. , 2007, Transplantation.

[29]  E. Renard,et al.  Expectations and Strategies Regarding Islet Transplantation: Metabolic Data From the GRAGIL 2 Trial , 2007, Transplantation.

[30]  Philippe Morel,et al.  International trial of the Edmonton protocol for islet transplantation. , 2006, The New England journal of medicine.

[31]  T. Berney,et al.  Sequential Kidney/Islet Transplantation: Efficacy and Safety Assessment of a Steroid‐Free Immunosuppression Protocol , 2006, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[32]  T. Berney,et al.  Impairment of renal function after islet transplant alone or islet‐after‐kidney transplantation using a sirolimus/tacrolimus‐based immunosuppressive regimen , 2005, Transplant international : official journal of the European Society for Organ Transplantation.

[33]  S. Matsumoto,et al.  The start of an islet transplantation program in Japan. , 2005, Transplantation proceedings.

[34]  D. Dunn,et al.  Department of Surgery, University of Minnesota, Minneapolis. , 2005, Archives of surgery.

[35]  A. Shapiro,et al.  Five-year follow-up after clinical islet transplantation. , 2005, Diabetes.

[36]  B. Hering,et al.  Single-donor, marginal-dose islet transplantation in patients with type 1 diabetes. , 2005, JAMA.

[37]  A. Shapiro,et al.  β-Score: An assessment of β-cell function after islet transplantation , 2005 .

[38]  C. Ricordi,et al.  Rescue Purification Maximizes the Use of Human Islet Preparations for Transplantation , 2005, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[39]  T. Berney,et al.  LOGISTICS AND TRANSPLANT COORDINATION ACTIVITY IN THE GRAGIL SWISS-FRENCH MULTICENTER NETWORK OF ISLET TRANSPLANTATION , 2004, Transplantation.

[40]  J. Lakey,et al.  The Standardization of Pancreatic Donors for Islet Isolations , 2004, Transplantation.

[41]  T. Berney,et al.  Morbidity associated with intraportal islet transplantation. , 2004, Transplantation proceedings.

[42]  T. Berney,et al.  Islet of Langerhans allogeneic transplantation at the University of Geneva in the steroid free era in islet after kidney and simultaneous islet-kidney transplantations. , 2004, Transplantation proceedings.

[43]  T. Berney,et al.  Serva collagenase NB1: a new enzyme preparation for human islet isolation. , 2004, Transplantation proceedings.

[44]  T. Berney,et al.  INFLUENCE OF ISLET TRANSPORTATION ON PANCREATIC ISLET ALLOTRANSPLANTATION IN TYPE 1 DIABETIC PATIENTS WITHIN THE SWISS-FRENCH GRAGIL NETWORK , 2004, Transplantation.

[45]  P. Morel,et al.  Cost analysis of human islet transplantation for the treatment of type 1 diabetes in the Swiss-French Consortium GRAGIL. , 2004, Diabetes care.

[46]  T. Berney,et al.  Islet transplantation in multicenter networks: the GRAGIL example , 2004 .

[47]  F. Brunicardi,et al.  Development of a human pancreatic islet-transplant program through a collaborative relationship with a remote islet-isolation center , 2004, Transplantation.

[48]  A. Secchi,et al.  Islet transplantation is associated with improvement of renal function among uremic patients with type I diabetes mellitus and kidney transplants. , 2003, Journal of the American Society of Nephrology : JASN.

[49]  P. Morel,et al.  Reduction of blood glucose variability in type 1 diabetic patients treated by pancreatic islet transplantation: interest of continuous glucose monitoring. , 2002, Diabetes care.

[50]  A. Shapiro,et al.  Successful islet transplantation: continued insulin reserve provides long-term glycemic control. , 2002, Diabetes.

[51]  F. Ris,et al.  Human islet transplantation network for the treatment of Type I diabetes: first data from the Swiss-French GRAGIL consortium (1999–2000) , 2001, Diabetologia.

[52]  L. Molinari,et al.  Epidemiology of Type I diabetes mellitus in Switzerland: steep rise in incidence in under 5 year old children in the past decade , 2001, Diabetologia.

[53]  E. Ryan,et al.  Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. , 2000, The New England journal of medicine.

[54]  C. Elger,et al.  Localizing value of epileptic visual auras. , 2000, Brain : a journal of neurology.

[55]  P. Morel,et al.  Human islet transplantation: lessons from 13 autologous and 13 allogeneic transplantations. , 2000, Transplantation.

[56]  Matthew D. Davis,et al.  Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. , 2000, The New England journal of medicine.

[57]  C. Ricordi,et al.  Improved Human Islet Isolation Using a New Enzyme Blend, Liberase , 1997, Diabetes.

[58]  B. Hering,et al.  Immunosuppression in pancreatic islet cell transplantation. , 1994, Transplantation proceedings.

[59]  Camillo Ricordi,et al.  Automated Method for Isolation of Human Pancreatic Islets , 1988, Diabetes.

[60]  A. S. Wiener,et al.  Transplantation , 1963 .

[61]  T. Berney,et al.  Beta-Cell Replacement: Pancreas and Islet Cell Transplantation. , 2016, Endocrine development.

[62]  A. Shapiro,et al.  Beta-score: an assessment of beta-cell function after islet transplantation. , 2005, Diabetes care.

[63]  Ames,et al.  Islet Transplantation in Seven Patients with Type 1 Diabetes Mellitus Using a Glucocorticoid-Free Immunosuppressive Regimen , 2000 .