Primary graft function, metabolic control, and graft survival after islet transplantation

Abstract

OBJECTIVE To investigate the influence of primary graft function (PGF) on graft survival and metabolic control after islet transplantation with the Edmonton protocol. RESEARCH DESIGN AND METHODS A total of 14 consecutive patients with brittle type 1 diabetes were enrolled in this phase 2 study and received median 12,479 islet equivalents per kilogram of body weight (interquartile range 11,072-15,755) in two or three sequential infusions within 67 days (44-95). PGF was estimated 1 month after the last infusion by the beta-score, a previously validated index (range 0-8) based on insulin or oral treatment requirements, plasma C-peptide, blood glucose, and A1C. Primary outcome was graft survival, defined as insulin independence with A1C < or =6.5%. RESULTS All patients gained insulin independence within 12 days (6-23) after the last infusion. PGF was optimal (beta-score > or =7) in nine patients and suboptimal (beta-score < or =6) in five. At last follow-up, 3.3 years (2.8-4.0) after islet transplantation, eight patients (57%) remained insulin independent with A1C < or =6.5%, including seven patients with optimal PGF (78%) and one with suboptimal PGF (20%) (P = 0.01, log-rank test). Graft survival was not significantly influenced by HLA mismatches or by preexisting islet autoantibodies. A1C, mean glucose, glucose variability (assessed with continuous glucose monitoring system), and glucose tolerance (using an oral glucose tolerance test) were markedly improved when compared with baseline values and were significantly lower in patients with optimal PGF than in those with suboptimal PGF. CONCLUSIONS Optimal PGF was associated with prolonged graft survival and better metabolic control after islet transplantation. This early outcome may represent a valuable end point in future clinical trials.

Figure 1

The Kaplan-Meier estimates of the proportions of patients with insulin independence and A1C ≤6.5% (A and B) and with persisting graft function (basal C-peptide ≥0.5 ng/ml) (C and D). Left panels represent these proportions among the entire cohort (number at risk: 14 at baseline and at 2 years, 7 at 3 years, and 3 at 4 years) and right panels in patients with optimal initial graft function (solid line) (n = 9) and in those with suboptimal initial graft function (interrupted line) (n = 5). Circles indicate censored data. *Mantel-Cox log-rank test, optimal PGF vs. suboptimal PGF.

Figure 2

Graft function and metabolic control in 14 patients before and after islet transplantation. A1C (A and B), mean blood glucose (Glc) (C and D), glucose SD (E and F), and low glucose excursion (time with blood glucose <3.8 mmol/l) (G and H) associated with poor (□), suboptimal (▨), or optimal (■) graft function as reflected by insulin requirements (A, C, E, and G) or by the β-score (B, D, F, and H). *P < 0.05 vs. poor function; †P < 0.05 vs. suboptimal function. The number of separate measurements reflected by each bar is as follows: 20 (□), 14 (▨), and 58 (■) (insulin requirements); 28 (□), 24 (▨), and 40 (■) (β-score). Data are means ± SD.