Estimation of Early Graft Function Using the BETA-2 Score Following Clinical Islet Transplantation

Abstract

Little is known about how early islet graft function evolves in the clinical setting. The BETA-2 score is a validated index of islet function that can be calculated from a single blood sample and lends itself to frequent monitoring of graft function. In this study, we characterized early graft function by calculating weekly BETA-2 score in recipients who achieved insulin independence after single transplant (group 1, n = 8) compared to recipients who required a second transplant before achieving insulin independence (group 2, n = 7). We also determined whether graft function 1-week post-transplant was associated with insulin independence in individuals who received initial transplant between 2000–2017 (n = 125). Our results show that graft function increased rapidly reaching a plateau 4–6 weeks post-transplant. The BETA-2 score was higher in group 1 compared to group 2 as early as 1-week post-transplant (15 + 3 vs. 9 + 2, p = 0.001). In an unselected cohort, BETA-2 at 1-week post-transplant was associated with graft survival as defined by insulin independence during median follow up of 12 months (range 2–119 months) with greater survival among those with BETA-2 score >10 (p < 0.001, log-rank test). These findings suggest that primary graft function is established within 4–6 weeks post-transplant and graft function at 1-week post-transplant predicts long-term transplant outcomes.

Paired box 6 gene delivery preserves beta cells and improves islet transplantation efficacy

“…On the other hand, the TUNEL assay showed that more apoptotic cells were detected in T2D‐Ctrl islet grafts, which could be reduced by AAV‐PAX6 transduction (Fig 6F). Previous studies have found that loss of transplanted islets can be detected in the first few days after transplantation (Biarnes et al , 2002; Eich et al , 2007), while the early graft function is closely associated with long‐term transplantation outcome (Vantyghem et al , 2009; Lam et al , 2022). We, therefore, harvested the graft‐bearing kidneys 1 week post‐transplant and found that PAX6 replenishment enhanced the early graft survival by reducing cell apoptosis (Appendix Fig S7B).…”

“…For all these reasons, a substantial proportion of the islet graft becomes damaged and is lost due to apoptosis. Of note, clinical studies suggest that islet graft function plays a predominant role to determine the long‐term transplantation outcome (Vantyghem et al , 2009; Lam et al , 2022). Therefore, significant progress remains necessary to enhance islet potency and to reduce the early loss of islets after transplantation, which could have a major impact on the long‐term success of islet transplantation and the number of diabetic patients that could benefit from the procedure.…”

“…Generally, multiple islet donors are required in a single transplantation to achieve insulin independence (Shapiro et al , 2000; Markmann et al , 2003), primarily because a substantial portion of the transplanted islets undergo apoptosis due to the exposure to a toxic environment of hyperglycemia, hypoxia, and immunosuppressant soon after transplantation (Shapiro et al , 2017; Gamble et al , 2018). In particular, clinical studies suggest that primary islet graft function has an overwhelming influence on the long‐term transplantation outcome (Vantyghem et al , 2009; Lam et al , 2022). These observations highlight the urgent need for the development of islet replacement strategies with improved islet graft survival after transplantation.…”