RESUMO
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.
RESUMO
BACKGROUND: Islet transplantation offers an effective treatment for selected people with type 1 diabetes and intractable hypoglycaemia. Long-term experience, however, remains limited. We report outcomes from a single-centre cohort up to 20 years after islet transplantation. METHODS: This cohort study included patients older than 18 years with type 1 diabetes undergoing allogeneic islet transplantation between March 11, 1999, and Oct 1, 2019, at the University of Alberta Hospital (Edmonton, AB, Canada). Patients who underwent islet-after-kidney transplantation and islet transplantation alone or islet transplantation before whole-pancreas transplantation (follow-up was censored at the time of whole-pancreas transplantation) were included. Patient survival, graft survival (fasting plasma C-peptide >0·1 nmol/L), insulin independence, glycaemic control, and adverse events are reported. To identify factors associated with prolonged graft survival, recipients with sustained graft survival (≥90% of patient follow-up duration) were compared with those who had non-sustained graft survival (<90% of follow-up duration). Multivariate binary logistic regression analyses were done to determine predictors of sustained graft survival. FINDINGS: Between March 11, 1999, and Oct 1, 2019, 255 patients underwent islet transplantation and were included in the analyses (149 [58%] were female and 218 [85%] were White). Over a median follow-up of 7·4 years (IQR 4·4-12·2), 230 (90%) patients survived. Median graft survival was 5·9 years (IQR 3·0-9·5), and graft failure occurred in 91 (36%) patients. 178 (70%) recipients had sustained graft survival, and 77 (30%) had non-sustained graft survival. At baseline, compared with patients with non-sustained graft survival, those with sustained graft survival had longer median type 1 diabetes duration (33·5 years [IQR 24·3-41·7] vs 26·2 years [17·0-35·5]; p=0·0003), median older age (49·4 years [43·5-56·1] vs 44·2 years [35·4-54·2]; p=0·0011), and lower median insulin requirements (0·53 units/kg per day [0·45-0·67] vs 0·59 units/kg per day [0·48-0·70]; p=0·032), but median HbA1c concentrations were similar (8·2% [7·5-9·0] vs 8·5% [7·8-9·2]; p=0·23). 201 (79%) recipients had insulin independence, with a Kaplan-Meier estimate of 61% (95% CI 54-67) at 1 year, 32% (25-39) at 5 years, 20% (14-27) at 10 years, 11% (6-18) at 15 years, and 8% (2-17) at 20 years. Patients with sustained graft survival had significantly higher rates of insulin independence (160 [90%] of 178 vs 41 [53%] of 77; p<0·0001) and sustained improvements in glycaemic control mixed-main-effects model group effect, p<0·0001) compared with those with non-sustained graft survival. Multivariate analyses identified the combined use of anakinra plus etanercept (adjusted odds ratio 7·5 [95% CI 2·7-21·0], p<0·0001) and the BETA-2 score of 15 or higher (4·1 [1·5-11·4], p=0·0066) as factors associated with sustained graft survival. In recipients with sustained graft survival, the incidence of procedural complications was lower (23 [5%] of 443 infusions vs 17 [10%] of 167 infusions; p=0·027), whereas the incidence of cancer was higher (29 of [16%] of 178 vs four [5%] of 77; p=0·015) than in those with non-sustained graft survival; most were skin cancers (22 [67%] of 33). End-stage renal disease and severe infections were similar between groups. INTERPRETATION: We present the largest single-centre cohort study of long-term outcomes following islet transplantation. Although some limitations with our study remain, such as the retrospective component, a relatively small sample size, and the absence of non-transplant controls, we found that the combined use of anakinra plus etanercept and the BETA-2 score were associated with improved outcomes, and therefore these factors could inform clinical practice. FUNDING: None.
Assuntos
Diabetes Mellitus Tipo 1 , Transplante das Ilhotas Pancreáticas , Estudos de Coortes , Diabetes Mellitus Tipo 1/cirurgia , Etanercepte/uso terapêutico , Feminino , Sobrevivência de Enxerto , Humanos , Insulina/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Masculino , Estudos Retrospectivos , Resultado do TratamentoRESUMO
ß-cell replacement therapy, available currently as pancreas or islet transplantation, has developed without a clear definition of graft functional and clinical outcomes. The International Pancreas and Islet Transplant Association and European Pancreas and Islet Transplantation Association held a workshop to develop consensus for an International Pancreas and Islet Transplant Association and European Pancreas and Islet Transplant Association Statement on the definition of function and failure of current and future forms of ß-cell replacement therapy. There was consensus that ß-cell replacement therapy could be considered as a treatment for ß-cell failure, regardless of etiology and without requiring undetectable C-peptide, accompanied by glycemic instability with either problematic hypoglycemia or hyperglycemia. Glycemic control should be assessed at a minimum by glycated hemoglobin (HbA1c) and the occurrence of severe hypoglycemia. Optimal ß-cell graft function is defined by near-normal glycemic control (HbA1c ≤6.5% [48 mmol/mol]) without severe hypoglycemia or requirement for insulin or other antihyperglycemic therapy, and with an increase over pretransplant measurement of C-peptide. Good ß-cell graft function requires HbA1c less than 7.0% (53 mmol/mol) without severe hypoglycemia and with a significant (>50%) reduction in insulin requirements and restoration of clinically significant C-peptide production. Marginal ß-cell graft function is defined by failure to achieve HbA1c less than 7.0% (53 mmol/mol), the occurrence of any severe hypoglycemia, or less than 50% reduction in insulin requirements when there is restoration of clinically significant C-peptide production documented by improvement in hypoglycemia awareness/severity, or glycemic variability/lability. A failed ß-cell graft is defined by the absence of any evidence for clinically significant C-peptide production. Optimal and good function are considered successful clinical outcomes.