Five-Year Metabolic, Functional, and Safety Results of Patients With Type 1 Diabetes Transplanted With Allogenic Islets Within the Swiss-French GRAGIL Network
Abstract
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.
Introduction
Over the last decade, islet transplantation has emerged as a promising treatment for type 1 diabetes. Currently, islet transplantation can be offered to patients with type 1 diabetes who are experiencing major glucose variability and lack of predictability and unawareness of hypoglycemic episodes despite intensive insulin therapy and who use innovative technologies such as continuous glucose monitoring and continuous subcutaneous pump. Islet transplantation is associated with improvement in kidney graft function and survival in patients with type 1 diabetes who have already undergone kidney transplantation (1). Consequently, islet transplantation has been offered to patients with type 1 diabetes with a functional kidney allograft who are not candidates for pancreas transplantation.
The results of islet transplantation have improved significantly in recent years. Before 1999, the achievement of insulin independence was obtained in <10% of transplant recipients. Evolution of the immunosuppression regimen, an increase in transplanted islet mass (2), and improvement in islet preparation quality (3) have allowed to obtain insulin independence in >60% of patients at 1 year in experienced centers (4,5). Insulin independence was not well maintained in the initial period, with only 27% of patients remaining insulin free after 5 years (4). More recently, mainly thanks to more potent immunosuppressive protocols, insulin independence rates have improved, reaching up to 50% at 5 years (6). Despite the overall low rate of long-term insulin independence, islet transplantation is beneficial in allowing improvements in quality of life (7), metabolic control (4), prevention of hypoglycemic events (8), and protection of recipients against the progression of microangiopathy (9,10). Despite these long-term benefits, islet transplantation exhibits variable success depending on the experience of the center and the protocols used. Moreover, beneficial metabolic effects may be counterbalanced by adverse events, especially due to immunosuppressive treatment.
The GRAGIL consortium is a French-Swiss Network (11) comprising several transplant centers (Geneva, Switzerland, and Besançon, Grenoble, Lyon, Montpellier, Nancy, Strasbourg, and Clermont-Ferrand, France), each of which permits pancreas procurement, recipient recruitment, performance of transplant procedures, and clinical follow-up, whereas islet isolation is performed in two facilities sharing the same procedure (Geneva and, more recently, Grenoble).
In the 2003–2010 period, the following two trials were conducted within the network, in two different settings: islet after kidney (IAK) transplantation (GRAGIL-1C trial, clinical trial reg. no. NCT00639600, clinicaltrials.gov) and islet transplantation alone (ITA) (GRAGIL-2 trial, clinical trial reg. no. NCT00321256, clinicaltrials.gov) (12,13). The purpose of the current study was to describe the 5-year outcome and safety profile of islet transplantation in the GRAGIL-1c and GRAGIL-2 patients with type 1 diabetes.
Research Design and Methods
Patients
Data from the GRAGIL-1c and GRAGIL-2 trials were retrospectively analyzed. All study subjects were receiving the original immunosuppressive regimen of the Edmonton protocol. The GRAGIL-2 trial was designed for C-peptide–negative patients with type 1 diabetes, with age between 18 and 65 years, and a minimum disease duration of 5 years. Islet transplantation was considered if patients experienced frequent episodes of severe hypoglycemia despite well-conducted, intensive insulin therapy. The main exclusion criteria were kidney diseases (glomerular filtration rate <50 mL/min/1.73 m2, proteinuria >500 mg/24 h), liver and coagulation abnormalities, unstable ischemic diabetic retinopathy, and poor cardiovascular prognosis. Patients who were overweight (body weight >70 kg in women and ≥75 kg in men, or BMI ≥26 kg/m2) and/or needed excessive doses of exogenous insulin (0.7 UI/kg/day or 50 UI/day) were excluded from the study. Details about this trial have been published previously (12). The GRAGIL-1c trial targeted patients with type 1 diabetes with a functional kidney graft (13). Inclusion criteria for islet transplantation were creatinine clearance >50 mL/min, proteinuria <0.5 g/day, daily insulin requirement < 0.7 units/kg/day, BMI <26 kg/m2, and a body weight of <75 kg (male) or <70 kg (female). Metabolic lability and hypoglycemia unawareness were not a prerequisite for study inclusion. The main exclusion criteria were liver and coagulation abnormalities, unstable diabetic retinopathy, and poor cardiovascular prognosis. All inclusions were reviewed and approved by the GRAGIL Network steering committee.
Details on the management of the network have been published previously (11,14). The protocols were approved by the institutional review board (Person Protection Committee of Grenoble University Hospital), and each patient gave written informed consent. Patients underwent transplantation between September 2003 and April 2010 within the GRAGIL Network at the University Hospitals of Grenoble, Besançon, Lyon, Montpellier, Nancy, and Strasbourg. Islet preparations with the number of islets >5,000 IEQ/kg/injection and islet purity >50% were released. As per the protocol, patients were scheduled to receive up to three islet infusions with a target islet mass of 10,000 IEQ/kg body wt. Regardless of the achievement of insulin independence, second and third infusions were performed ideally within a time frame of 3 months when previous islet infusions did not permit achievement of the 10,000 IEQ/kg body wt threshold.
Islet Isolation and Transplantation
Pancreata were obtained from brain-dead multiorgan donors through the Swiss Transplant Agency and the French Biomedicine Agency (Agence de la Biomédecine). Standard donor criteria for pancreas acceptance were used as previously described (14). Islets were isolated using the automated method described by Ricordi et al. (15), with local modifications as previously reported (16). Islet preparations were conditioned in gas-permeable transfer bags (Biorep Technologies, Miami, FL) in CMRL 1066 Medium supplemented with human albumin (4%) and heparin (35 units/kg recipient body wt), and were shipped by ambulance to the transplant centers. Transit time never exceeded 4 h. Islets were transplanted intraportally through a percutaneous transhepatic procedure with embolization of the punction tract using the original Edmonton steroid-free immunosuppressive regimen combining sirolimus and tacrolimus with daclizumab or basiliximab induction (17). Immunosuppression comprised high-dose sirolimus (Rapamune; Wyeth, New York, NY), with target trough levels of 12–15 mg/L for the first 3 months and 10–12 mg/L thereafter, and low-dose tacrolimus (Prograf; Astellas, Tokyo, Japan), with target trough levels of 4–6 mg/L. Induction was performed with intravenous daclizumab (Zenapax; Roche, Basel, Switzerland) at a dosage of 1 mg/kg infused immediately before islet infusion and repeated biweekly for up to five doses. For the second islet transplantation, a full daclizumab protocol was started again, regardless of the time that had elapsed since the first injection. After commercial withdrawal of daclizumab in 2009, basiliximab (Simulect; Novartis, Basel, Switzerland) was used for induction at a dosage of 20 mg on days 0 and 4 of each islet infusion.
Follow-up
The protocol required a monthly supervision of patients by the diabetologist investigator for the first year after the first infusion. After year 1, patients were required to see the diabetologist investigator every 6 months. For each visit, fasting plasma glucose level, basal C-peptide level, exogenous insulin requirement, glycated hemoglobin (HbA1c) level, creatinine level, proteinuria, insulin antibody (insulin binding capacity of serum threshold >3.5%) (radioimmunological assay kit; CisBio International), the number of mild-to-moderate hypoglycemic events (hypoglycemia symptoms or glycemia <4 mmol/L) experienced during the preceding week, the number of severe hypoglycemic events that occurred since the last follow-up visit (hypoglycemia without possibility of self-treatment), and the occurrence of adverse events were assessed and recorded. Severe hypoglycemic events were declared prospectively as adverse events. Adverse events were classified according to their severity as life threatening, serious, moderate, or mild. A life-threatening event was defined as an event in which the patient was at risk for death at the time of the event. It does not refer to an event that hypothetically might have caused death if it was more severe. A serious adverse event is defined as any medical occurrence that results in death, that is life threatening, that requires inpatient hospitalization or prolongation of an existing hospitalization, and that results in persistent or significant disability/incapacity or induces a congenital anomaly/birth defect. A moderate adverse event is an event requiring corrective/complementary treatment. A mild adverse event does not require any corrective/complementary treatment (18).
Islet graft function was assessed by calculating the β-score developed by the University of Alberta (Edmonton, AB, Canada). This previously validated scoring system is a composite score that allocates 2 points each for normal fasting glucose, HbA1c, and stimulated C-peptide and the absence of insulin or oral hypoglycemic agent use. No point is awarded if the fasting glucose was in diabetic range, HbA1c was >6.9% (51.9 mmol/mol), C-peptide secretion was absent on stimulation, or daily insulin use was in excess of 0.24 units/kg. One point is given for intermediate values. The score ranges between 0 (no graft function) and 8 (excellent graft function) (19). The β-score is a simple clinical scoring system that correlates with physiological measures of β-cell functions such as postprandial glycemia (19) and arginine-induced insulin secretion (20). This score represents an overall assessment of β-cell transplant functions. It gives a β-cell transplant evaluation as a continuum that may be more informative than the too stringent insulin independence criteria. The β-score is now well correlated with islet graft outcomes (21,22). Insulin independence was predefined as the ability to maintain HbA1c <6.5% (48 mmol/mol), a 2-h postprandial glucose <10 mmol/L, and a mean amplitude of glycemic excursion index of <3.33 mmol/L, without exogenous insulin and with a basal plasma C-peptide ≥0.5 ng/mL. Complete graft failure was defined by an undetectable C-peptide level (<0.3 ng/mL).
Statistical Analysis
Islet characteristics are expressed as the mean ± SEM. Continuous variables were expressed as the median and interquartile range (Q1; Q3) and were compared using repeated-measures ANOVA. The threshold of significance was set at 5%. All data were processed and analyzed using XLStat-Pro Software (Addinsoft, Paris, France).
Results
Recipient Characteristics
This analysis was based on 44 recipients of allogenic islet transplants performed between September 2003 and April 2010. ITA was performed in 24 patients (54.5%), and IAK grafts were performed in 20 patients (45.5%). Recipient characteristics at baseline are summarized in Table 1.
Recipient clinical and biological characteristics at baseline
Islet Infusion Characteristics
Eighty-four infusions were performed in 44 patients: 8 patients (18%) received one infusion, 32 patients (73%) received two infusions, and 4 patients received three infusions (9%). The median cold ischemia time was 7.2 h (3.5–11.5). The total mean IEQ infused was 606,617 ± 214,695 IEQ per recipient (9,715.75 ± 3,444.40 IEQ/kg), with a median stimulation index of 1.9 (1.2; 2.3) and a viability of 92% (81; 95). The median time frame between the first and second infusions was 6.35 months (1.9; 12.6).
Metabolic Results
A significant and lasting improvement in HbA1c was observed: HbA1c was 6.20% (44 mmol/mol) (4.60; 9.60 [27; 81]), 6.60% (49 mmol/mol) (5.50; 9.40 [37; 79]), and 6.70% (50 mmol/mol) (5.40; 9.60 [36; 81]), respectively, at 12, 48, and 60 months after islet transplantation vs. 8% (64 mmol/mol) (7.6; 9 [60; 75]) at baseline (P < 0.05) in the whole cohort (Fig. 1A). No significant difference was observed in the improvement in HbA1c between ITA and IAK transplant patients (Fig. 1B and C). At 12, 48, and 60 months after islet transplantation, respectively, 84%, 70%, and 59% of the recipients reached HbA1c of ≤7% (53 mmol/mol) or exhibited a drop in HbA1c of ≥2% (14 mmol/mol) vs. only 9% before islet infusion (P < 0.005) (Supplementary Fig. 1E). Fasting blood glucose improved significantly and lastingly after islet transplantation: 8.19 mmol/L (1.56; 22.4) at baseline vs. 6.44 mmol/L (4.11; 11.3), 6.57 mmol/L (3.4; 11.8), and 7.28 mmol/L (4.1; 15.1) at 12, 48, and 60 months after islet infusion in the global population (P < 0.05). Severe hypoglycemia was mainly prevalent in ITA candidates before transplantation with 4.31 events/patient/year in ITA candidates and 0.29 events/patient/year in IAK transplant candidates. The number of severe hypoglycemic events/patient/year had fallen to 0.27 in IAT recipients and 0.02 in IAK transplant recipients 1 year after islet transplantation. This benefit was lasting and persisted throughout the 5-year follow-up period with no hypoglycemic event occurring in ITA recipients and 0.01 severe hypoglycemia/patient/year occurring in IAK transplant recipients (P < 0.005 vs. preinfusion) (Fig. 1D). As an overall evaluation of metabolic results of islet transplantation, 83%, 67%, and 58% of the ITA recipients and 80%, 70%, and 60% at 1, 4, and 5 years reached HbA1c of <7% (53 mmol/mol) and were free of severe hypoglycemia, while none of the ITA recipients and only 10% of IAK transplant recipients met this criterion before infusion (Supplementary Fig. 1F).
Evolution of HbA1c after islet transplantation in the global population (A), in IAK transplant recipients (B), and in ITA recipients (C). D: Percentage of patients experiencing severe hypoglycemia at preinfusion and after islet transplantation in the global population and in IAK transplant and ITA recipients. M, month; Pre inf, preinfusion.
Graft Function
The median basal C-peptide level was 1.43 ng/mL (0; 3.95), 1.49 ng/mL (0; 3.14), and 1.54 ng/mL (0; 3.73) 12, 48, and 60 months after islet transplantation vs. 0.1 ng/mL (0; 0.24) at baseline (P < 0.005). In the global population, 39 of 44 patients (89%) had a basal C-peptide level of >0.3 ng/mL (i.e., functional islet graft) 12 months after islet infusion. The decline of islet function over 5 years of follow-up was limited, as 33 of 44 patients (75%) and 25 of 34 patients (74%) kept a functional islet graft at 48 and 60 months post-transplant (Fig. 2A). The median insulin dose was significantly reduced, as follows: 0.15 UI/kg (0; 0.47), 0.17 UI/kg (0; 0.7), and 0.18 UI/kg (0; 0.57) at 12, 48, and 60 months after islet transplantation vs. 0.5 UI/kg (0.42; 0.58) at baseline (P < 0.05) (Fig. 2B). Among recipients, 91%, 70%, and 75% exhibited a β-score of ≥3 at 12, 48, and 60 months post-transplant, with 25%, 14%, and 4% of recipients having an optimal β-score of ≥7 (Fig. 2C). No significant differences in β-score were observed between the IAK transplant and ITA populations (Supplementary Fig. 2E and F).
Percentage of patients with a C-peptide level of >0.3 ng/mL at preinfusion and after islet transplantation in the global population, in IAK transplant recipients, and in ITA recipients (A); the evolution of insulin dose (UI/kg/day) after islet transplantation in the global population, in IAK transplant recipients, and in ITA recipients (B); and the β-score over the follow-up period in the global population (C). D: Percentage of patients experiencing insulin independence during follow-up in relation to infused islet mass. M, month; Pre inf, preinfusion.
Regarding IAK transplant recipients, 45%, 40%, 40%, 35%, and 31.5% met the criteria of insulin independence at 12, 24, 36, 48, and 60 months, respectively. Regarding IAT recipients, 37.5%, 45.8%, 37.5%, 25%, and 14% met the criteria of insulin independence at 12, 24, 36, 48, and 60 months, respectively (P = NS). In the whole cohort, during the entire follow-up period, 33 of 44 patients (75%) experienced an insulin independence period with a median duration of insulin independence of 19.2 months (2; 58). Regarding the total islet mass infused, no significant difference was observed in terms of insulin independence rate (Fig. 2D). In ITA recipients, the mean duration of insulin independence was 20.18 ± 14.06 months in recipients infused with ≥10,000 IEQ/kg vs. 12 ± 17.34 months in recipients infused with ≤10,000 IEQ/kg (P = 0.4 [difference was not significant]). In IAK transplant recipients, the duration of insulin independence was 27.5 ± 26.08 months in recipients infused with ≥10,000 IEQ/kg vs. 22.6 ± 19.59 months in recipients infused with ≤10,000 IEQ/kg (P = 0.3 [difference not significant]). A total of 26% of recipients (9 of 34 recipients) remained insulin independent at 60 months (Fig. 3).
Graft function over the follow-up period in the global population. M, month.
Adverse Events and Survival
No deaths related to islet transplantation occurred in recipients during the entire post-transplant follow-up period (two patients died as the result of a cardiovascular event at 55 and 48 months post-transplant). With all types of severity taken together, 29 of 44 recipients (66%) experienced at least one adverse event during the 5-year follow-up period. Fifty-five adverse events occurred in these 29 patients, as follows: mild adverse events 14%, moderately adverse events 9%, serious adverse events 67%, and life-threatening adverse events 9%. A total of 55% of the adverse events occurred during the first year post-transplant. Eighteen of 55 adverse events (33%) were related to or possibly related to immunosuppression (Supplementary Table 2). Regarding the islet infusion procedure, 10 of 84 islet infusions (11.9%) were complicated by an adverse event (cytolysis 1, abdominal pain 1, segmental portal vein thrombosis resolved after anticoagulation 1, and hemorrhages 7; 4 patients required blood transfusion, 2 patients required laparotomy, and 1 patient was treated by interventional radiology) (Supplementary Table 3). The length of hospitalization was not significantly increased in patients with bleeding (6.3 vs. 5.8 days/islet infusion/patient in the whole cohort). Regarding renal function, creatinine levels remained stable over the follow-up period in the global population and ITA recipients: after 5 years of follow-up, the median creatinine levels were 102.5 µmol/L (74.7; 139.25) and 80 µmol/L (72; 104) in the global population and among ITA recipients, respectively, vs. 100 µmol/L (75; 111) and 77 µmol/L (69; 93) at baseline, respectively. After 5 years of follow-up, the median clearance creatinine rate was 83 mL/min (60; 93) in ITA recipients vs. 79.5 mL/min (69; 95) at baseline, respectively (P = NS). In IAK transplant recipients, we described the following nonsignificant increase in creatinine levels: after 5 years of follow-up, the median creatinine level was 140 µmol/L (112.5; 154.5) vs. 108.5 µmol/L (103; 136.2) at baseline. In IAK transplant recipients, creatinine clearance remained stable over the follow-up period: at study inclusion, the median creatinine clearance rate was 59.5 mL/min (51.5; 69) vs. 51 mL/min (47; 66) after 5 years of follow-up (P = NS).
Conclusions
This retrospective cohort study showed that long-term islet graft survival and significant glycemic improvement have been achieved after islet transplantation in most recipients with type 1 diabetes who underwent transplantation within the GRAGIL Network. Few data are available on 5-year outcomes of islet transplantation using a typical Edmonton protocol (4,6,23). In our cohort, 1 year and 5 years after undergoing islet grafting, a good metabolic control (HbA1c ≤7% [53 mmol/mol] or a decrease in HbA1c of ≥2% [14 mmol/mol]) was achieved in 84% and 59% of recipients, respectively, compared with only 9% before islet transplantation. A total of 89% and 74% of patients kept a functional islet graft 12 and 60 months after islet infusion. Insulin independence for at least 1 month was achieved in 33 of 44 patients (75%) and persisted for a median duration of 19.2 months. This result was obtained with a significant and lasting reduction in insulin requirements and in the rate of severe hypoglycemia. Our study is an actual analysis and not actuarial, as in the study by Ryan et al. (23), in which only four patients completed the 5-year follow-up. In our cohort, we reported a higher long-term insulin independence rate and higher insulin independence duration compared with the study by Ryan et al. (23) (10% of 5-year insulin independence in Ryan et al. [23] vs. 29% in our cohort; 15 months of insulin independence duration in Ryan et al. [23] vs. 19 months in our cohort). The 5-year islet graft survival rate reported in our cohort is concordant with what is described by Ryan et al. (23) (∼80%).
In our cohort, per protocol, transplantation of ≥10,000 IEQ/kg in up to three infusions was planned. However, eight patients (18%) declined the administration of a second infusion, which is responsible for the lower total islet mass infused per recipient that was observed in our cohort compared with recent studies (21). If higher numbers of injections have been associated with better overall long-term functional results (13), the high number of infused IEQ per kilogram of body weight seems to be better correlated with long-term graft survival and better metabolic control. Indeed, since the landmark Edmonton Trial, 10,000 IEQ/kg was classically recommended to reach short-term insulin independence (24,25), but this is less clear-cut in more extensive cohorts in which >20% of patients required 15,000 IEQ/kg to achieve insulin independence (23). Interestingly, in our cohort, the total dose of transplanted islets did not seem to significantly affect the rate of insulin independence. Since islet functionality is heterogeneous and depends on several factors, importantly, donor factors, it explains why a transplanted islet mass is not strictly correlated to graft function (26). In fact, some studies (27,28) have demonstrated that human islet function in vivo correlated poorly with transplanted islet numbers. In more recent studies, a better rate of insulin independence (57% at 3 years) was achieved with a rate >10,000 IEQ/kg. In our cohort, probably due to the lower total mean islet mass infused per recipient, primary graft function and graft survival (i.e., insulin independence with HbA1c <7% [53 mmol/mol]) are lower than described in the study by Vantyghem et al. (21). Nevertheless, despite this lower level of primary graft function, our cohort exhibited results that were similar, in terms of metabolic control (HbA1c, insulin requirement and reduction in severe hypoglycemia), at 5 years post-transplant to those of recent studies.
The criteria defining islet graft success remain largely a matter of debate. The U.S. Food and Drug Administration, in its guidance for allogeneic pancreatic islet cell products (29), defined islet transplantation success as a composite end point consisting of an HbA1c level in the normal range or a substantial reduction in HbA1c and the elimination of hypoglycemia, independently of achievement of insulin independence. Moreover, we and others argue (12,16) that, when addressing patients with unawareness of severe hypoglycemia, insulin independence should not be the unique criterion for the assessment of islet transplantation success. According to these authors, a realistic goal for islet transplantation should be the conversion from a state of brittle diabetes to more easily manageable diabetes, and, more precisely, the achievement of HbA1c of <7% (53 mmol/mol) with complete avoidance of severe hypoglycemic events (30). This goal is achievable with minimal endogenous insulin production, as even partial graft function is sufficient to prevent severe hypoglycemia (22). Taking into account the scarcity of organs, the morbidity associated with percutaneous transhepatic injection, the waiting lists, and the potential risks of HLA immunization, our group defends the view that the aims of islet transplantation should be to release patients from hypoglycemia among those experiencing severe hypoglycemia, to improve metabolic control and prevent chronic complications, and to improve quality of life. Consequently, the goal of islet transplantation should be the achievement of HbA1c of <7% (53 mmol/mol) with complete avoidance of severe hypoglycemic events. Using these composite criteria, in our cohort, islet transplantation can be considered a success, despite the somewhat low rate of insulin independence.
The chronic complications related to immunosuppressive treatment remain of major concern in islet transplantation and must be considered in the light of the improvement in glucose stability: in our cohort, one-third of adverse events were related to immunosuppression and might counterbalance the clinical benefit of islet transplantation, particularly recipient quality of life. The main question to address in this context is whether the clinical benefit of islet transplantation is good enough to justify the risk of immunosuppression. First of all, it is important to note that IAK transplant recipients benefit from the immunosuppressive treatment for renal grafts and do not require an additive immunosuppressive regimen for islet transplantation, and that no additive immunosuppression risk exists regarding islet transplantation. Regarding ITA recipients, it is important to take into account that severe hypoglycemia is associated with a 3.2 increased risk of death (31,32) and that glucose variability is associated with a higher risk of microangiopathy progression (33). In this context, islet transplantation not only might restore good glucose control and glucose stability, but also might reduce mortality and complication risks in this particular population with brittle type 1 diabetes. Further long-term studies are needed to rigorously analyze the balance between the clinical benefits of islet transplantation and the chronic complications of immunosuppressive treatment, collectively addressing the mortality risk, the microangiopathic and macroangiopathic complication risks, renal graft outcomes (for IAK transplantation), and quality of life.
The risk of death after islet transplantation has been extremely low, with a 3% 1-year mortality rate reported by the Collaborative Islet Transplant Registry (34), while Gruessner and Gruessner (35) have described a patient survival rate for pancreas transplantation of nearly 80% at 5 years. In our cohort, no deaths related to islet transplantation occurred in recipients during the entire post-transplant follow-up period, although two patients died as a result of cardiovascular events at 55 and 48 months of follow-up. Regarding acute complications, portal vein thrombosis and peritoneal hemorrhages are two frequent complications that are related to islet infusion: the occurrence of portal vein thrombosis has become rare (3.7% in the study by Kawahara et al. [36], 2% in our cohort) since the start of treatment with systemic heparin and the infusion of a limited islet cell volume. Interestingly, the rate of intraperitoneal bleeding remained relatively stable (15% in the study by Bucher et al. [37], 11.3% in the study by Kawahara et al. [36], and 8.3% in our cohort). The mean length of hospitalization was 5.8 days/islet infusion/patient. Our group previously published a 1-year cost analysis of islet transplantation and described a mean hospitalization length of 15.6 days/patient over 1 year with total costs slightly higher than the costs of whole-organ pancreas transplantation (38). During the entire 5 years of follow-up, mean hospitalization duration, including all hospitalization stays for each islet infusion, and eventually for the occurrence of adverse events, fell to 7.05 days/patient/year. Even if an accurate cost analysis has not been performed in this study, islet transplantation costs might be lower than those of whole pancreas transplantation in view of its significant rates of morbidity and surgical reinterventions. Further long-term cost analysis studies are necessary to accurately address this question and will be performed in a French national trial to be launched in the coming months.
In conclusion, islet transplantation within the multicenter GRAGIL Network provided important and lasting clinical benefits to patients with type 1 diabetes, permitting improvement of glucose variability and preventing the occurrence of severe hypoglycemia. The benefits of islet transplantation are somewhat tarnished by decreasing long-term insulin independence and immunosuppression-related adverse events. Safer immunosuppression and further strategies to promote long-term islet graft survival or other sources of islets remain an absolute prerequisite for improving islet transplantation outcomes and increasing the availability of the procedure.
Article Information
Acknowledgments. The authors thank the technical staff of the Cell Isolation and Transplantation Centers of Geneva (Solange Masson, David Matthey-Doret, Nadine Pernin, Caroline Rouget, and Corinne Sinigaglia, Department of Surgery, Islet Isolation, and Transplantation Center, Geneva University Hospitals, Geneva, Switzerland) and Grenoble (Harald Egelhofer, Virginie Persoons, Florence de Fraipont, Anaick Moisan, and Marie-Jeanne Richard, Cellular Therapy Unit [EFS Rhône-Alpes, Grenoble University Hospital, Grenoble, France]); the transplant coordinators (Grenoble University Hospital, Geneva University Hospital); the radiology teams (Grenoble University Hospital); the clinical research associates (Grenoble University Hospital); all of the Swiss and French surgical procurement teams (Grenoble University Hospital, Geneva University Hospital); and Laure Nasse (Grenoble University Hospital) for data management.
Funding. The GRAGIL-1c and GRAGIL-2 trials were supported by grants from ALFEDIAM, Association Française des Diabétiques, Aide aux Jeunes Diabétiques, Agir pour les Maladies chroniques, and the PHRC (Hospital Program for Clinical Research) from the French Ministry of Health and by grant 3200B0-102134 from the Swiss National Foundation for Scientific Research.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.
Author Contributions. S.L., T.B., and P.-Y.B. participated in the research design, the performance of the research, the data analysis, and the writing of the article. S.B., A.P., L.K., C.B., and D.B. participated in the performance of the research and in the writing of the article. A.W., F.B., R.T., L.B., C.T., E.M., L.F., and C.C. participated in the performance of the research. I.T. participated in the writing of the article. S.L. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Footnotes
Clinical trial reg. nos. NCT00639600 and NCT00321256, clinicaltrials.gov.
This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc15-0094/-/DC1.
↵* Members of the GRAGIL Network can be found in the Supplementary Data online.
- Received January 15, 2015.
- Accepted May 25, 2015.
- © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
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