Association between primary graft function and 5-year outcomes of islet allogeneic transplantation in type 1 diabetes: a retrospective, multicentre, observational cohort study in 1210 patients from the Collaborative Islet Transplant Registry

Abstract

Background: Allogeneic islet transplantation is a validated therapy in type 1 diabetes; however, there is decline of transplanted islet graft function over time and the mechanisms underlying this decline are unclear. We evaluated the distinct association between primary graft function (PGF) and 5-year islet transplantation outcomes.

Methods: In this retrospective, multicentre, observational cohort study, we enrolled all patients from the Collaborative Islet Transplant Registry who received islet transplantation alone (ITA recipients) or islet-after-kidney transplantation (IAK recipients) between Jan 19, 1999, and July 17, 2020, with a calculable PGF (exposure of interest), measured 28 days after last islet infusion with a validated composite index of islet graft function (BETA-2 score). The primary outcome was cumulative incidence of unsuccessful islet transplantation, defined as an HbA_1c of 7·0% (53 mmol/mol) or higher, or severe hypoglycaemia (ie, requiring third-party intervention to correct), or a fasting C-peptide concentration of less than 0·2 ng/mL. Secondary outcomes were graft exhaustion (fasting C-peptide <0·3 ng/mL); inadequate glucose control (HbA_1c ≥7·0% [53 mmol/mol] or severe hypoglycaemia); and requirement for exogenous insulin therapy (≥14 consecutive days). Associations between PGF and islet transplantation outcomes were explored with a competing risk analysis adjusted for all covariates suspected or known to affect outcomes. A predictive model based on PGF was built and internally validated by using bootstraps resampling method.

Findings: In 39 centres worldwide, we enrolled 1210 patients with a calculable PGF (of those without missing data, mean age 47 years [SD 10], 712 [59·5%] were female, and 865 (97·9%) were White), who received a median of 10·8 thousand islet-equivalents per kg of bodyweight (IQR 7·4-13·5). 986 (82·4%) were ITA recipients and 211 (17·6%) were IAK recipients. Of 1210 patients, 452 (37·4%) received a single islet infusion and 758 (62·6%) received multiple islet infusions. Mean PGF was 14·3 (SD 8·8). The 5-year cumulative incidence of unsuccessful islet transplantation was 70·7% (95% CI 67·2-73·9), and was inversely and linearly related to PGF, with an adjusted subhazard ratio (sHR) of 0·77 (95% CI 0·72-0·82) per 5-unit increase of BETA-2 score (p<0·0001). Secondary endpoints were similarly related to PGF. The model-adjusted median C-statistic values of PGF for predicting 5-year cumulative incidences of unsuccessful islet transplantation, graft exhaustion, inadequate glucose control, and exogenous insulin therapy were 0·70 (range 0·69-0·71), 0·76 (0·74-0·77), 0·65 (0·64-0·66), and 0·72 (0·71-0·73), respectively.

Interpretation: This global multicentre study reports a linear and independent association between PGF and 5-year clinical outcomes of islet transplantation. The main study limitations are its retrospective design and the absence of analysis of complications.

Funding: Public Health Service Research, National Institutes of Health, Juvenile Diabetes Research Foundation International, Agence National de la Recherche, Fondation de l'Avenir, and Fonds de Dotation Line Renaud-Loulou Gasté.

Figure 1:. Flow chart of the 1210 recipients enrolled in the study analysis

* PGF (Beta2-score measured at day 28 after the last islet infusion) was not calculable, even after imputations (all data missing) in 101 patients. Abbreviations: IAK= Islet-After-Kidney recipient; ITA= Islet Transplantation Alone recipient; PGF=Primary Graft Function.

Figure 2:. 5-year cumulative incidence of unfavorable outcomes of islet transplantation: unsuccessful IT (Panel 2A), graft exhaustion (Panel 2B), inadequate glucose control (Panel 2C) and exogenous insulin therapy (Panel 2D).

Cumulative incidence curves following the 5 years follow-up are shown as solid lines and 95% confidence intervals as dashed lines for the four unfavorable outcomes: unsuccessful IT (green), graft exhaustion (blue), inadequate glucose control (black), and the need for exogenous insulin therapy (red). Unsuccessful islet transplantation was defined by glycated hemoglobin level greater than or equal to 7.0 % (53 mmol/mol) and/or with at least one episode of severe hypoglycemia since the last visit and/or with serum fasting C-peptide secretion less than 0.2 ng/mL. Graft exhaustion was defined by fasting C-peptide level inferior to 0.3 ng/mL. Inadequate glucose control was defined by glycated hemoglobin greater than or equal to 7.0 % (53 mmol/mol) and/or with at least one episode of severe hypoglycemia since the last visit. The need for exogenous insulin therapy was defined as the administration of exogenous insulin during at least 14 consecutive days. For each islet transplantation outcomes (unsuccessful IT, graft exhaustion, inadequate glucose control and the need for exogenous insulin therapy), we estimated the cumulative incidence using the Kalbfleisch and Prentice method, considering the day 28 after the last islet infusion as the date of origin (corresponding time point 0 in the figures), and by treating death and delayed islet re-infusion (defined as an islet infusion performed at least one year after the previous islet infusion) as competing events. To handle missing data in Beta2-score components and pre-specified covariates adjustment, we used multiple imputations using the regression-switching approach (chained equations with m = 60 imputations) using all pre-transplant patients characteristics, transplantation characteristics and Beta2-score components at day 28 after the last islet infusion. No imputations were performed on the 4 study outcomes. Abbreviations: N.= Number; CI= Cumulative Incidence; IT= Islet Transplantation.

Figure 3:. Association of primary graft function and 5-year cumulative incidence of unfavorable islet transplantation outcomes in the whole cohort.

Association of PGF (defined by the Beta2-score at day 28 after the last islet infusion) with cumulative incidence of the four unfavorable islet transplantation outcomes in the whole population: unsuccessful IT (green), graft exhaustion (blue), inadequate glucose control (black), and the need for exogenous insulin therapy (red) are represented with Forest plot. These associations between PGF and islet transplantation unfavorable outcomes were explored using Fine and Gray regression models before and after adjustment on prespecified covariates suspected or known to impact islet transplantation outcomes and available in the database. SubHazard ratio (sHR) were calculated for 5 units increase of primary graft function. sHR, 95%CI, and p-values were calculated after handling missing values by multiple imputations using the regression-switching approach (chained equations with m = 60 imputations) using all pre-transplant patients characteristics, transplantation characteristics and Beta2-score components at day 28 after the last islet infusion. sHR and 95% CI are represented in a logarithmic scale. sHR were adjusted* on baseline (before islet transplantation) recipient age, sex, baseline body mass index, diabetes duration before transplantation, daily exogenous insulin needs at baseline, baseline fasting C-peptide, number of islet infusions, total islet mass transplanted per kg of bodyweight, total cell volume transplanted, type of recipient (ITA or IAK), and the use of specific immunosuppression agents (interleukin 2 receptor antagonist, TNF alpha antagonist, T-cell depleting agent, calcineurin inhibitor and m-TOR inhibitor). Abbreviations: IT= Islet Transplantation; sHR= subhazard Ratio; 95% CI= 95% Confidence Interval; Inadequate GC= Inadequate Glucose Control

Figure 4:. Association of primary graft function and 5-year cumulative incidence of unfavorable islet transplantation outcomes, sensitivity analyses in recipients with single vs. multiple islet infusions transplantation (Panel 4A), and in recipients with ITA vs. IAK recipients (Panel 4B).

Association of PGF (defined by the Beta2-score at day 28 after the last islet infusion) with cumulative incidence of the four unfavorable islet transplantation outcomes in single vs. multiple islet infusions and in ITA and IAK recipients subgroups: unsuccessful IT (green), graft exhaustion (blue), inadequate glucose control (black), and the need for exogenous insulin therapy (red) are represented with Forest plot. These associations between PGF and islet transplantation unfavorable outcomes were explored using Fine and Gray regression models before and after adjustment on prespecified covariates suspected or known to impact islet transplantation outcomes and available in the database. SubHazard ratio (sHR) were calculated for 5 units increase of primary graft function. sHR, 95%CI, and p-values were calculated after handling missing values by multiple imputations using the regression-switching approach (chained equations with m = 60 imputations) using all pre-transplant patients characteristics, transplantation characteristics and Beta2-score components at day 28 after the last islet infusion. sHR and 95% CI are represented in a logarithmic scale. sHR were adjusted* on baseline (before islet transplantation) recipient age, sex, baseline body mass index, diabetes duration before transplantation, daily exogenous insulin needs at baseline, baseline fasting C-peptide, number of islet infusions, total islet mass transplanted per kg of bodyweight, total cell volume transplanted, type of recipient, and the use of specific immunosuppression agents (interleukin 2 receptor antagonist, TNF alpha antagonist, T-cell depleting agent, calcineurin inhibitor and m-TOR inhibitor). Abbreviations: IT= Islet Transplantation; sHR= subhazard Ratio; 95% CI= 95% Confidence Interval; Inadequate GC= Inadequate Glucose Control; p het=p-value for heterogeneity; ITA -= Islet Transplantation Alone; IAK=Islet-After-Kidney