Long-term Outcomes With Islet-Alone and Islet-After-Kidney Transplantation for Type 1 Diabetes in the Clinical Islet Transplantation Consortium: The CIT-08 Study

Abstract

Objective: To determine long-term outcomes for islet-alone and islet-after-kidney transplantation in adults with type 1 diabetes complicated by impaired awareness of hypoglycemia.

Research design and methods: This was a prospective interventional and observational cohort study of islet-alone (n = 48) and islet-after-kidney (n = 24) transplant recipients followed for up to 8 years after intraportal infusion of one or more purified human pancreatic islet products under standardized immunosuppression. Outcomes included duration of islet graft survival (stimulated C-peptide ≥0.3 ng/mL), on-target glycemic control (HbA1c <7.0%), freedom from severe hypoglycemia, and insulin independence.

Results: Of the 48 islet-alone and 24 islet-after-kidney transplantation recipients, 26 and 8 completed long-term follow-up with islet graft function, 15 and 7 withdrew from follow-up with islet graft function, and 7 and 9 experienced islet graft failure, respectively. Actuarial islet graft survival at median and final follow-up was 84% and 56% for islet-alone and 69% and 49% for islet-after-kidney (P = 0.007) with 77% and 49% of islet-alone and 57% and 35% of islet-after-kidney transplantation recipients maintaining posttransplant HbA1c <7.0% (P = 0.0017); freedom from severe hypoglycemia was maintained at >90% in both cohorts. Insulin independence was achieved by 74% of islet-alone and islet-after-kidney transplantation recipients, with more than one-half maintaining insulin independence during long-term follow-up. Kidney function remained stable during long-term follow-up in both cohorts, and rates of sensitization against HLA were low. Severe adverse events occurred at 0.31 per patient-year for islet-alone and 0.43 per patient-year for islet-after-kidney transplantation.

Conclusions: Islet transplantation results in durable islet graft survival permitting achievement of glycemic targets in the absence of severe hypoglycemia for most appropriately indicated recipients having impaired awareness of hypoglycemia, with acceptable safety of added immunosuppression for both islet-alone and islet-after-kidney transplantation.

Figure 1

CONSORT diagram. Withdrew, subjects withdrawing with continued function. *Further information can be found in Supplementary Material, Section 3.

Figure 2

Persistence of islet graft function and HbA_1c control by cohort. Red lines, islet-alone transplantation (IA) recipients; blue lines, islet-after-kidney transplantation (IAK) recipients. Time 0 for all panels was the day of first PHPI transplant. Fraction of subjects with continued PHPI graft function by C-peptide criterion at median and final follow-up: islet-alone, 0.84 and 0.56, respectively; islet-after-kidney, 0.69 and 0.49) (A). Fraction of subjects with continued HbA_1c <7% (American Diabetes Association criterion) at median and final follow-up: islet-alone, 0.77 and 0.49; islet-after-kidney, 0.57 and 0.35) (B). Fraction of subjects with continued HbA_1c ≤6.5% (American Association of Clinical Endocrinologists criterion) at median and final follow-up: islet-alone, 0.73 and 0.00; islet-after-kidney, 0.59 and 0.17) (C). D: Median HbA_1c at baseline and modeled median HbA_1c by years following initial PHPI transplant.

Figure 3

Freedom from severe hypoglycemia and insulin requirements for islet transplant recipients. A–C: Red lines, islet-alone (IA) recipients; blue lines, islet-after-kidney (IAK) recipients. Fraction of subjects remaining free from severe hypoglycemia following initial PHPI transplant at both median and final follow-up: islet-alone, 0.90; islet-after kidney, 0.93 (A). B: Fraction of subjects achieving insulin independence following initial PHPI transplant. C: Fraction of subjects remaining insulin independent following achievement of insulin independence. D: Fraction of subjects in each of four states following initial PHPI transplant: functioning graft, not yet insulin independent; functioning graft, insulin independent; functioning graft, resumed daily insulin; and failed graft. Additional information about insulin use and glucose control at each state, 1–3, can be found in Supplementary Material, Section 6.