Feasibility and efficacy of combined pancreatic islet-lung transplantation in cystic fibrosis-related diabetes-PIM study: A multicenter phase 1-2 trial

Abstract

Cystic fibrosis-related diabetes (CFRD) is a common complication of cystic fibrosis (CF), and restoring metabolic control in these patients may improve their management after lung transplantation. In this multicenter, prospective, phase 1-2 trial, we evaluate the feasibility and metabolic efficacy of combined pancreatic islet-lung transplantation from a single donor in patients with CFRD, terminal respiratory failure, and poorly controlled diabetes. Islets were infused via the portal vein under local anesthesia, 1 week after lung transplantation. At 1 year, the primary outcome was transplant success as evaluated by a composite score including four parameters (weight, fasting glycemia, HbA1c, and insulin requirements). Ten participants (age: 24 years [17-31], diabetes duration: 8 years [4-12]) received a combined islet-lung transplant with 2892 IEQ/kg [2293-6185]. Transplant success was achieved in 7 out of 10 participants at 1-year post transplant. Fasting plasma C-peptide increased from 0.91 μg/L [0.56-1.29] to 1.15 μg/L [0.77-2.2], HbA1c decreased from 7.8% [6.5-8.3] (62 mmol/mol [48-67]) to 6.7% [5.5-8.0] (50 mmol/mol [37-64]), with 38% decrease in daily insulin doses. No complications related to the islet injection procedure were reported. In this pilot study, combined pancreatic islet-lung transplantation restored satisfactory metabolic control and pulmonary function in patients with CF, without increasing the morbidity of lung transplantation.

Trial registration: ClinicalTrials.gov NCT01548729.

Keywords: cystic fibrosis; islet transplantation; lung transplantation; respiratory failure; secondary diabetes.

FIGURE 1

Metabolic results at baseline and 3 (3 M), 6 (6 M), and 12 (12 M) months after combined islet‐lung transplantation: (A) fasting glycemia, (B) BMI, (C) insulin requirements, (D) HbA1c, and (E) plasma C‐peptide. Results are expressed as boxplots with median, minimum, maximum values and IQR

FIGURE 2

CGM data at baseline and 1 year after combined lung‐islet transplantation. For each participant, CGM data are shown at baseline (left column) and at 1‐year follow‐up (right column). Presentation of data using (A) the more stringent TIR employed for the composite score of this study (70–140 mg/dl) and (B) the standard TIR (70–180 mg/dl). The percentage of time spent in different glycemic ranges is indicated by different shades of gray according to the key. CGM, continuous glucose measurement; TIR, time in range; TAR, time above range; TBR, time below range; #, patient number [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 3

Respiratory function parameters. FEV1 expressed in (A) liters and (B) percentages and FVC expressed in (C) liters and (D) percentages at baseline and at 3 (3 M), 6 (6 M), and 12 (12 M) months after combined lung‐islet transplantation. The error bars indicate the ranges. FEV1, forced expiratory volume expired in 1 s; FVC, forced vital capacity. Results are expressed as boxplots with median, minimum, maximum values and IQR