Feasibility and Safety of Pancreatic Islet Transplantation in the Liver by Portal Vein Catheterization using the Transjugular Route

Up to now, the vast majority of islet transplantations have been performed in the liver. Access to the portal vein in order to infuse the cell preparations has been achieved by percutaneous transhepatic route (1–3). Under these conditions the risk of bleeding and thrombosis in segmental branches of the portal vein during and shortly after the procedure is far from negligible (4, 5). The transjugular approach has been used for the catheterization of portal vein for different purposes for many years (6). We describe the feasibility and safety of islet transplantation in the liver by portal vein catheterization using the transjugular route. The pancreas was removed from a brain-dead multiorgan donor (ABO compatibility and a negative serum cross match for T cells) following vascular flushing with cold University of Wisconsin solution. Immediately after arrival, the pancreatic duct was cannulated and perfused with collagenase using an automated method. The islets were purified with a continuous density gradient in a COBE 2991 (Gambro BCT, Lakewood, CO). Islet number was quantified in duplicate and expressed as Islet Equivalent Number (IEN). A final pellet containing 220,600 IEN was suspended in medium 199 before injection. Heparin was administered: 70 U per kg body weight, 1/3 in cell suspension and 2/3 directly in the portal vein during the procedure. The recipient was a 56-year-old C-peptide negative women (50 kg body weight) with a T1D of 35 years duration. She had received simultaneous kidney-pancreas transplantation 15 years before with an immediate failure of the pancreas allograft because of venous thrombosis. At the time of islet transplantation, renal function was preserved. In spite of insulin treatment with multiple doses, her metabolic control was very deficient with erratic and recurrent hypoglycemia. The previous 12 month HbA1c values were between 9–10%. Conditioning regime, immunosuppression and posttransplantation therapy was performed following the Edmonton protocol (7). The local Ethics Committee of our hospital approved the procedure. Under conscious sedation by the administration of midazolam (0.04 mg/kg body weight) and meperidine (50 mg i.v.) and local anesthesia, a 10 F venous catheter introducer was placed in the right jugular vein under ultrasound guidance using the Seldinger technique. The right hepatic vein was then catheterized under fluoroscopic control. The portal vein was punctured using a transjugular biopsy needle under fluoroscopic control and ultrasound guidance (Fig. 1). After successful puncture, the portal vein was catheterized and baseline measurements of portal venous pressure (PVP), inferior vena cava pressure and the portacaval pressure gradient (PPG) were obtained (8). A single puncture attempt was successful and the cell suspension was injected into the main trunk portal vein (40 min). Portal venous flow was assessed before and 24 h posttransplantation using a duplex ultrasound. Portal vein pressure rose from a basal value of 8.5 mmHg to 17.0 mmHg at the end of the infusion procedure and PPG rose from 4.0 to 12.5 mmHg. There were no complications during the procedure and the duplex ultrasound assessment 24 hr after the procedure did not find any thrombus in the portal circulation. Two weeks After of islet transplantation, basal C-peptide was 1.8 ng/ml and the insulin dose was reduced to less than 50% of the pretransplant dose (from 34 U7 day to 14 U/day).FIGURE 1.: A 5-F catheter was placed in the main trunk of the portal vein through the transjugular approach. The portal vein during i.v. contrast injection is shown.The liver has long been the site of choice for human pancreatic islet transplantation, and while almost certainly safer than whole-organ pancreas transplantation, the islet transplant method using the percutaneous transhepatic portal vein cannulation is not completely risk free. The most important and potentially serious complications related to islet infusion by this route are major bleeding and portal vein thrombosis (4, 5). In fact, and even in the most experienced groups, the rate of this type of complication may occur in more than 10% of the procedures. In the very recent publication by the Edmonton Group (128 procedures in 65 subjects), they reported 15 major bleeding episodes related to the procedure with blood transfusion being used on 7 occasions and 2 subjects requiring a laparotomy (9). As these authors pointed out, this major adverse event may occur despite the placement of coils in the hepatic parenchyma tract immediately after the transplant and avoiding the use of aspirin. In a more recent paper, it has been shown that the cumulative transplant procedure number and heparin dose are independent risk factors for bleeding. However, this complication could be prevented with an effective sealing of intraparenchymal liver tract (10). The transjugular approach for venous portal vein catheterization has been used in our centre since 1992 for the treatment of the complications of portal hypertension in patients with liver cirrhosis and Budd-Chiari Syndrome with a transjugular intrahepatic portosystemic shunt (11). Up to now, we have carried out more than 300 procedures with an extremely low incidence of complications, including capsule perforation and bleeding, even in patients with severe coagulopathy (11). Ryan et al. also described thrombosis of segmental branches of the portal vein in 5 patients and puncture of the gall bladder in two subjects (9). Intraportal thrombosis in the course of islet transplantation is closely related to the packed cell volume, the purity and the thrombogenicity of the islet cell preparation. This adverse event can be prevented with the use of heparin. The use of the transjugular route and its low risk of hemorrhagic complications may allow the use of anticoagulation with fewer limitations. It should be pointed out that, in addition to a lower number of adverse events, the transjugular route allows the measurement of PPG, which is a better estimate of hepatic hemodynamics and may better reflect the impact of pancreatic islet transplantation on liver circulation. Summarizing, pancreatic islet transplantation in the liver after portal vein cannulation using a transjugular route is a feasible and safe procedure and may be considered as an alternative to the traditional percutaneous approach. The possible advantages of this method warrant further investigation. ACKNOWLEDGMENTS We are indebted to all of those from the Endocrinology and Diabetes, Hepatology, Radiology, Kidney Transplant, Surgery and Transplant Coordination Units of the Hospital Clínic i Universitari of Barcelona who are involved in the Islet Transplantation Program of our Center. Ignacio Conget Sandra Piquer Marta Julià Ramón Gomis Enric Esmatjes Department of Endocrinology and Diabetes IDIBAPS (Institut d’Investigacions Biomèdicas August Pi i Sunyer) Hospital Clínic i Universitari Barcelona, Spain Juan Carlos García-Pagán Jaume Bosch Department of Hepatology IDIBAPS (Institut d’Investigacions Biomèdicas August Pi i Sunyer) Hospital Clínic i Universitari Barcelona, Spain Rosa Gilabert Department of Radiology IDIBAPS (Institut d’Investigacions Biomèdicas August Pi i Sunyer) Hospital Clínic i Universitari Barcelona, Spain Maria Jose Ricart Department of Kidney Transplantation IDIBAPS (Institut d’Investigacions Biomèdicas August Pi i Sunyer) Hospital Clínic i Universitari Barcelona, Spain Laureano Fernández-Cruz Department of Surgery IDIBAPS (Institut d’Investigacions Biomèdicas August Pi i Sunyer) Hospital Clínic i Universitari Barcelona, Spain Marti Manyalich Department of Transplant Coordination IDIBAPS (Institut d’Investigacions Biomèdicas August Pi i Sunyer) Hospital Clínic i Universitari Barcelona, Spain

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