Allogenic transplantation refers to the method of removing and processing stem cells from a donor individual, and subsequently inserting them into a patient in need of replacing his or her diseased cells or tissue. In type 1 diabetes, beta cells or islet cells are gradually destroyed by autoimmunity over six months to four years. Proper regeneration or replacement of islet cells is the ultimate treatment of type 1 diabetes.

Allogenic islet cell transplantation (ICT) research started in 2000. After 20 years of investigative experience, we now have the current essential prospective study. A group of 28 subjects with end-stage type 1 diabetes, as documented by severe hypoglycemia of unawareness, was followed for ten years after allogenic ICT. Study participants received two to three intraportal infusions of islet cells within 60 days. Immunosuppression was induced with IL-2 receptor antibody and then maintained with sirolimus or tacrolimus.

The goal of the study was to reach A1c <6.5% without external insulin therapy or injections. Impressively, 39% and 28% of participants achieved an A1c <6.5% in 5 and 10 years. Moreover, 50% of subjects obtained and maintained A1c <7% without significant side effects. Outcomes were similar whether or not patients underwent a kidney transplant. The authors found that allogenic ICT was associated with a lower risk of adverse events compared to the traditional pancreas transplantation.

The current study marks a significant step forward in healing patients with end-stage type 1 diabetes suffering from severe hypoglycemia of unawareness. It is central for physicians to identify such high-risk persons and refer them appropriately to academic centers involved in allogenic islet cell transplant technology.

Also see:

Type 1 Diabetes

Hypoglycemia

Islet Cell

Diabetes Care

prospective

November 2019

OBjective

The long-term outcome of allogeneic islet transplantation is unknown. The aim of this study was to evaluate the 10-year outcome of islet transplantation in patients with type 1 diabetes and hypoglycemia unawareness and/or a functioning kidney graft.

Design

We enrolled in this prospective parallel-arm cohort study 28 subjects with type 1 diabetes who received islet transplantation either alone (ITA) or after a kidney graft (IAK).

Islet transplantation consisted of two or three intraportal infusions of allogeneic islets administered within median of 68 days.

Immunosuppression was induced with interleukin-2 receptor antibodies and maintained with sirolimus and tacrolimus.

As expected, islet infusion was associated with a significant risk of complications. However, the overall risk profile of intraportal islet infusion observed in the current study appears lower than reported after pancreas transplantation.

Importantly, the mean decline of eGFR in the entire cohort was similar to the rate expected in the general population >40 years old. This was also true for patients with a previous renal graft. Our study, which is in line with some other results but in contrast to earlier ones, suggests that improved metabolic control obtained after islet transplantation may exert a favorable effect on kidney function in type 1 diabetes, such as after pancreas transplantation.

One limitation of this study is the lack of a control group of patients receiving optimized insulin therapy or a pancreas transplant. Therefore, whether the improved metabolic control resulting from islet transplantation is balancing the associated risks remains to be demonstrated. Another limitation is the sample size of our study, which was calculated according to its primary metabolic end point. This limits the conclusions that can be drawn about kidney function and macro-angiopathic complications. One may also remain cautious when interpreting the difference in early graft function because all participants initially received the same intervention. Moreover, the proposed strategy of initial repeated islet infusion for optimizing primary graft function can be hampered by donor pancreas availability. Finally, we could not explore the impact of the immunosuppression regimen on the islet transplantation long-term outcome. Of note, all participants in our study received low-dose tacrolimus and sirolimus, a drug combination associated with a favorable outcome in the CITR. In contrast, immunosuppression was induced here with anti–interleukin-2 receptor antibodies, and not T-cell depletion or TNF-α inhibitors.

To conclude, the current study provides direct evidence that islet transplantation performed alone or after a kidney graft in patients with type 1 diabetes can markedly improve metabolic control and suppress SHEs during 10 years.

Therefore, the aim of the current study was to evaluate the 10-year outcome, in intention to treat, with islet transplantation in patients with type 1 diabetes and hypoglycemia unawareness and/or a functioning kidney graft initially included in two clinical trials.
The secondary objectives were to explore the determinants of long-term successful β-cell replacement with islet transplantation.

In the current study, we evaluated the long-term outcome of allogenic islet transplantation in patients with type 1 diabetes and hypoglycemia unawareness and/or a previous kidney graft. After 10 years, graft function was maintained in 75% of patients, and 28% percent of patients met the study primary outcome: insulin independence with A1C ≤6.5%.

In contrast to previous long-term reports of a single case or a small series of selected patients, we analyzed the 10-year outcome of an entire cohort, with minimal attrition and no secondary rescue islet infusion. Overall, the 10-year results appear comparable to those reported after pancreas transplantation when proposed for the same indications. Furthermore, half of our patients still maintained A1C level <7% without SHEs, the alternative end point considered for licensure of islet transplantation in the U.S

Importantly, we observed equivalent results when islet transplantation was performed after a kidney graft, in patients with more vascular complications and who had often been refuted for simultaneous pancreas-kidney transplantation. Preexisting immunosuppression and a lower BMI may have contributed to these favorable results. Another key aspect was the stringent selection of the study participants, who had not experienced any acute rejection, uncontrolled hypertension, or macroalbuminuria after kidney transplantation. A progressive switch from mycophenolate to sirolimus was warranted prior to the registration on the islet waiting list, as well as a tapering of steroids.

As expected, islet infusion was associated with a significant risk of complications. However, the overall risk profile of intraportal islet infusion observed in the current study appears lower than reported after pancreas transplantation.

The primary outcome was met by 39% and 28% of patients 5 and 10 years after islet transplantation, respectively.
Graft function persisted in 82% and 78% of case subjects after 5 and 10 years, respectively, and was associated with improved glucose control, reduced need for exogenous insulin, and a marked decrease of severe hypoglycemic events.
ITA and IAK had similar outcomes.
Primary graft function, evaluated 1 month after the last islet infusion, was significantly associated with the duration of graft function and insulin independence.

Conclusions

Islet transplantation with the Edmonton protocol can provide 10-year markedly improved metabolic control without SHEs in three-quarters of patients with type 1 diabetes, kidney transplanted or not.

More from the publication:

The demonstration in 2000 that β-cell replacement with allogenic islet transplantation could restore endogenous insulin secretion and near-normal glucose homeostasis was an important landmark for the treatment of type 1 diabetes. Since then, islet transplantation has been offered worldwide in >1,000 patients with type 1 diabetes and hypoglycemia unawareness and/or a kidney graft for end-stage renal disease.

The favorable early benefit-risk profile of islet transplantation has been reported by numerous single and multicenter studies and confirmed in the international Collaborative Islet Transplantation Registry (CITR). Furthermore, islet transplantation appeared superior to optimized medical treatment in several case-control studies, and a multicenter randomized controlled trial recently demonstrated that islet transplantation was associated with better glucose control at 6 months.

Other studies also suggest that islet transplantation improves quality of life and may favorably impact chronic diabetes complications. On the other hand, islet graft function may decline with time, and chronic immunosuppression has been associated with serious adverse events (SAEs) and a decrement in renal function. Moreover, the persistence of the early benefit of islet transplantation beyond 5 years can only be speculated from a few series of selected cases.

Therefore, the aim of the current study was to evaluate the 10-year outcome, in intention to treat, with islet transplantation in patients with type 1 diabetes and hypoglycemia unawareness and/or a functioning kidney graft initially included in two clinical trials.
The secondary objectives were to explore the determinants of long-term successful β-cell replacement with islet transplantation.

In the current study, we evaluated the long-term outcome of allogenic islet transplantation in patients with type 1 diabetes and hypoglycemia unawareness and/or a previous kidney graft. After 10 years, graft function was maintained in 75% of patients, and 28% percent of patients met the study primary outcome: insulin independence with A1C ≤6.5%.

In contrast to previous long-term reports of a single case or a small series of selected patients, we analyzed the 10-year outcome of an entire cohort, with minimal attrition and no secondary rescue islet infusion. Overall, the 10-year results appear comparable to those reported after pancreas transplantation when proposed for the same indications. Furthermore, half of our patients still maintained A1C level <7% without SHEs, the alternative end point considered for licensure of islet transplantation in the U.S

Importantly, we observed equivalent results when islet transplantation was performed after a kidney graft, in patients with more vascular complications and who had often been refuted for simultaneous pancreas-kidney transplantation. Preexisting immunosuppression and a lower BMI may have contributed to these favorable results. Another key aspect was the stringent selection of the study participants, who had not experienced any acute rejection, uncontrolled hypertension, or macroalbuminuria after kidney transplantation. A progressive switch from mycophenolate to sirolimus was warranted prior to the registration on the islet waiting list, as well as a tapering of steroids.

As expected, islet infusion was associated with a significant risk of complications. However, the overall risk profile of intraportal islet infusion observed in the current study appears lower than reported after pancreas transplantation.

Importantly, the mean decline of eGFR in the entire cohort was similar to the rate expected in the general population >40 years old. This was also true for patients with a previous renal graft. Our study, which is in line with some other results but in contrast to earlier ones, suggests that improved metabolic control obtained after islet transplantation may exert a favorable effect on kidney function in type 1 diabetes, such as after pancreas transplantation.

One limitation of this study is the lack of a control group of patients receiving optimized insulin therapy or a pancreas transplant. Therefore, whether the improved metabolic control resulting from islet transplantation is balancing the associated risks remains to be demonstrated. Another limitation is the sample size of our study, which was calculated according to its primary metabolic end point. This limits the conclusions that can be drawn about kidney function and macro-angiopathic complications. One may also remain cautious when interpreting the difference in early graft function because all participants initially received the same intervention. Moreover, the proposed strategy of initial repeated islet infusion for optimizing primary graft function can be hampered by donor pancreas availability. Finally, we could not explore the impact of the immunosuppression regimen on the islet transplantation long-term outcome. Of note, all participants in our study received low-dose tacrolimus and sirolimus, a drug combination associated with a favorable outcome in the CITR. In contrast, immunosuppression was induced here with anti–interleukin-2 receptor antibodies, and not T-cell depletion or TNF-α inhibitors.

To conclude, the current study provides direct evidence that islet transplantation performed alone or after a kidney graft in patients with type 1 diabetes can markedly improve metabolic control and suppress SHEs during 10 years.

Primary outcome was insulin independence with A1C ≤6.5% .
Secondary outcomes were patient and graft survival, severe hypoglycemic events (SHEs), metabolic control, and renal function.

Results

The primary outcome was met by 39% and 28% of patients 5 and 10 years after islet transplantation, respectively.
Graft function persisted in 82% and 78% of case subjects after 5 and 10 years, respectively, and was associated with improved glucose control, reduced need for exogenous insulin, and a marked decrease of severe hypoglycemic events.
ITA and IAK had similar outcomes.
Primary graft function, evaluated 1 month after the last islet infusion, was significantly associated with the duration of graft function and insulin independence.

Conclusions

Islet transplantation with the Edmonton protocol can provide 10-year markedly improved metabolic control without SHEs in three-quarters of patients with type 1 diabetes, kidney transplanted or not.

More from the publication:

The demonstration in 2000 that β-cell replacement with allogenic islet transplantation could restore endogenous insulin secretion and near-normal glucose homeostasis was an important landmark for the treatment of type 1 diabetes. Since then, islet transplantation has been offered worldwide in >1,000 patients with type 1 diabetes and hypoglycemia unawareness and/or a kidney graft for end-stage renal disease.

The favorable early benefit-risk profile of islet transplantation has been reported by numerous single and multicenter studies and confirmed in the international Collaborative Islet Transplantation Registry (CITR). Furthermore, islet transplantation appeared superior to optimized medical treatment in several case-control studies, and a multicenter randomized controlled trial recently demonstrated that islet transplantation was associated with better glucose control at 6 months.

Other studies also suggest that islet transplantation improves quality of life and may favorably impact chronic diabetes complications. On the other hand, islet graft function may decline with time, and chronic immunosuppression has been associated with serious adverse events (SAEs) and a decrement in renal function. Moreover, the persistence of the early benefit of islet transplantation beyond 5 years can only be speculated from a few series of selected cases.

Therefore, the aim of the current study was to evaluate the 10-year outcome, in intention to treat, with islet transplantation in patients with type 1 diabetes and hypoglycemia unawareness and/or a functioning kidney graft initially included in two clinical trials.
The secondary objectives were to explore the determinants of long-term successful β-cell replacement with islet transplantation.

In the current study, we evaluated the long-term outcome of allogenic islet transplantation in patients with type 1 diabetes and hypoglycemia unawareness and/or a previous kidney graft. After 10 years, graft function was maintained in 75% of patients, and 28% percent of patients met the study primary outcome: insulin independence with A1C ≤6.5%.

In contrast to previous long-term reports of a single case or a small series of selected patients, we analyzed the 10-year outcome of an entire cohort, with minimal attrition and no secondary rescue islet infusion. Overall, the 10-year results appear comparable to those reported after pancreas transplantation when proposed for the same indications. Furthermore, half of our patients still maintained A1C level <7% without SHEs, the alternative end point considered for licensure of islet transplantation in the U.S

Importantly, we observed equivalent results when islet transplantation was performed after a kidney graft, in patients with more vascular complications and who had often been refuted for simultaneous pancreas-kidney transplantation. Preexisting immunosuppression and a lower BMI may have contributed to these favorable results. Another key aspect was the stringent selection of the study participants, who had not experienced any acute rejection, uncontrolled hypertension, or macroalbuminuria after kidney transplantation. A progressive switch from mycophenolate to sirolimus was warranted prior to the registration on the islet waiting list, as well as a tapering of steroids.

As expected, islet infusion was associated with a significant risk of complications. However, the overall risk profile of intraportal islet infusion observed in the current study appears lower than reported after pancreas transplantation.

Importantly, the mean decline of eGFR in the entire cohort was similar to the rate expected in the general population >40 years old. This was also true for patients with a previous renal graft. Our study, which is in line with some other results but in contrast to earlier ones, suggests that improved metabolic control obtained after islet transplantation may exert a favorable effect on kidney function in type 1 diabetes, such as after pancreas transplantation.

One limitation of this study is the lack of a control group of patients receiving optimized insulin therapy or a pancreas transplant. Therefore, whether the improved metabolic control resulting from islet transplantation is balancing the associated risks remains to be demonstrated. Another limitation is the sample size of our study, which was calculated according to its primary metabolic end point. This limits the conclusions that can be drawn about kidney function and macro-angiopathic complications. One may also remain cautious when interpreting the difference in early graft function because all participants initially received the same intervention. Moreover, the proposed strategy of initial repeated islet infusion for optimizing primary graft function can be hampered by donor pancreas availability. Finally, we could not explore the impact of the immunosuppression regimen on the islet transplantation long-term outcome. Of note, all participants in our study received low-dose tacrolimus and sirolimus, a drug combination associated with a favorable outcome in the CITR. In contrast, immunosuppression was induced here with anti–interleukin-2 receptor antibodies, and not T-cell depletion or TNF-α inhibitors.

To conclude, the current study provides direct evidence that islet transplantation performed alone or after a kidney graft in patients with type 1 diabetes can markedly improve metabolic control and suppress SHEs during 10 years.