Islet-After-Lung Transplantation in a Patient With Cystic Fibrosis–Related Diabetes

Cystic fibrosis–related diabetes (CFRD) is the most common comorbidity of cystic fibrosis (1). The incidence and prevalence of CFRD have increased due to lifesaving advances, especially lung transplantation (2). In the pancreas, acinar fibrosis and fat cell infiltration are associated with decreased β-cell mass and β-cell dysfunction. Delayed gastric emptying contributes to dysregulation of glucose homeostasis (3). We report the case of a successful intraportal islet transplantation 7 years after bilateral lung transplantation in a patient with CFRD.

A 48-year-old woman was referred to our clinic with CFRD duration of 30 years, complicated by severe gastrointestinal autonomic neuropathy with delayed gastric emptying. She had received a bilateral lung transplantation 7 years earlier. Immunosuppressive agents included mycophenolate mofetil (1,000 mg/day) and tacrolimus (6 mg/day). She had used steroids during the first 2 postoperative years. Lung function was stable (forced vital capacity 3,140 mL and forced expiratory volume in 1 second 2,570 mL, 81.8% of forced vital capacity). Following lung transplantation, she suffered progressively from labile glucose regulation with frequent hypoglycemic episodes and hypoglycemia unawareness despite insulin pump therapy (0.7 IU/kg/day) and continuous glucose monitoring. HbA_1c was 6.0–7.5% (42–58 mmol/mol) in the preceding year. Low basal insulin concentrations were present but no insulin secretory response to 1 mg of glucagon occurred (basal C-peptide 0.13 nmol/L; stimulated C-peptide 0.14 nmol/L).

Pancreatic islets from two organ donors were isolated within 3 days, showing more than threefold induction of insulin secretion after glucose stimulation in vitro. Under local anesthesia, 4.95 mL of islet tissue with a purity of 67.5% (1.4 million islet equivalents) was administered in the portal vein using ultrasound guidance. Induction immunosuppressive therapy consisted of basiliximab (20 mg before transplantation and 1 day posttransplantation). As maintenance therapy, mycophenolate mofetil and tacrolimus were continued in combination with prednisolone (6 weeks of 10 mg/day, 5 mg/day afterward). Additional therapy included antibiotic prophylaxis, liraglutide, and continuation of insulin pump therapy. The patient left the hospital 3 days posttransplantation without complications. Glucose control improved considerably within days without hypoglycemic episodes. She was hesitant to stop insulin pump therapy and slowly reduced the daily insulin dose. At 6 months, insulin pump therapy was stopped. The HbA_1c was 4.7% (28 mmol/mol). She underwent a mixed-meal challenge test and showed a fasting plasma glucose concentration of 4.8 mmol/L and a maximal concentration of 6.5 mmol/L. Serum C-peptide concentration increased from 0.84 nmol/L to 1.25 nmol/L (Fig. 1). After 1.5 years, long-acting insulin was restarted (3 IU/day) due to postprandial hyperglycemia, but no episodes of hypoglycemia were reported. No donor-specific antibodies developed and pulmonary function remained stable.

Life expectancy for cystic fibrosis has increased, but extrapulmonary complications, such as progressive β-cell failure and diabetes-related complications, can occur. We report an islet-after-lung transplantation in a patient with CFRD, resulting in glycemic stability and absence of previously severe and disabling hypoglycemia. We propose that islet-after-lung transplantation is a safe and effective intervention for patients that could not benefit from simultaneous islet-lung or pancreas-lung allotransplantation (4,5). Although sufficient islet mass may result in insulin independence, the main goal is to eliminate hypoglycemia-related problems and achieve stable glycemia, thereby improving quality of life.