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
04/2023
Journal Article
Authors:
Chetboun, M.;
Drumez, E.;
Ballou, C.;
Maanaoui, M.;
Payne, E.;
Barton, F.;
Kerr-Conte, J.;
Vantyghem, M. C.;
Piemonti, L.;
Rickels, M. R.;
Labreuche, J.;
Pattou, F.;
Collaborative Islet Transplant Registry Investigators study, group
Volume:
11
Pagination:
391-401
Issue:
6
Journal:
Lancet Diabetes Endocrinol
PMID:
37105208
URL:
https://www.ncbi.nlm.nih.gov/pubmed/37105208
DOI:
10.1016/S2213-8587(23)00082-7
Keywords:
Humans Female Middle Aged Male *Diabetes Mellitus, Type 1/surgery/complications *Islets of Langerhans Transplantation/methods Blood Glucose Retrospective Studies C-Peptide/therapeutic use Glycated Hemoglobin Treatment Outcome Transplantation, Homologous
Insulin/therapeutic use *Hypoglycemia/complications Registries
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 Gaste.
