Islets Transplantation

Anatomy and Physiology

The pancreas is made up of three parts: a head, body, and tail. The head receives its blood supply from the superior and inferior pancreaticoduodenal arteries, while branches from the splenic artery supply the body and tail. It has both exocrine and endocrine functions. A network of open circulation exists between the exocrine and endocrine pancreas physically linking the two via an integrated vascular system.

Islet cells are clusters of cells that are found throughout the pancreas and are responsible for its endocrine function. Islet cells are made up of five different types of cells, each secreting a unique hormone. Alpha cells secrete glucagon, delta somatostatin, beta insulin, gamma pancreatic polypeptide, and epsilon ghrelin. These hormones are secreted directly into the bloodstream in response to various stimuli.[3][4][5][6]

Indications

Islet cell transplantation is currently approved for patients with type I diabetes mellitus who experience unrecognized hypoglycemic episodes that are refractory to medical management. Long term follow-up has shown as many as 50 to 70% of patients remain insulin independent five years after transplant. These results show promising potential for allograft islet cell transplantation use for the treatment of type I diabetes mellitus. One of the major deterrents to this procedure gaining acceptance as a definitive cure is the requirement of lifelong immunosuppressants to prevent graft loss. Promising research in mice has shown improved graft survival with inhibition of a Prostaglandin D2 receptor. This receptor, GPR44/DP2, results in impaired insulin secretion once activated. 

Inclusion criteria:

• Mentally stability and able to adhere to protocols
• History consistent with type I diabetes, age of onset <40 years, insulin-dependent for >5 years
• Age range 18 to 65
• Despite adherence to intense insulin regimen and expert direction, the patient has at least two documented episodes of symptomatic hypoglycemia within a six month time interval.[2][7]

Contraindications

Donor pancreatic islet cells are infused into the recipient via the portal system. A portal venous pressure above 20 mmHg at baseline is a contraindication to transplantation due to the significantly increased risk of thrombosis. After a patient receives an islet cell allograft, they require lifelong immunosuppression. Because of this requirement, an inability to tolerate immunosuppression is a contraindication to transplantation.

Grafts also do not survive well when the body is fighting an active infection making active infection another contraindication. Malignancy is another contraindication, except for patients that have been cancer-free for more than five years after the excision of cutaneous basal cell or squamous cell carcinoma.[8][9]

Equipment

There are varying techniques involving variations in types of equipment used for islet cell transplantation. The equipment listed will be for the procedure that is the current standard and was first described in 1987 by Ricordi. 

• Two 16-20 gauge angiocatheters 
• collagenase and a serine-protease inhibitor
• Ricordi chamber (chamber separated by a filter with pores)
• Nine stainless steel balls
• peristaltic pump
• Hank's solution
• Heating circuit
• Dithizone stain
• Coils and gelatin sponges
• Interventional radiologic imaging modality (ultrasound, fluoroscopy) [10]

Personnel

This procedure is rapidly evolving as technology changes. Due to the radiologic equipment, the procedure routinely uses radiologists and radiologic personnel during the infusion of the cells. Transplant surgeons historically drove islet cell therapy, but now interventional radiologists are positioned in an important role for both clinical performance and research. Interventional radiologists and their team can share some of the roles and responsibilities of transplant surgeons and their technologists. Personnel typically required to perform the procedure may include, but are not limited to:

• Transplant surgeon
• Surgical technologist
• Radiologist
• anesthesiologist/C.R.N.A
• Nurse [11]

Preparation

Patients that may benefit from the procedure are first assessed and identified by endocrinologists. Patients that meet the criteria are then evaluated by a psychologist to determine their motivation and ability to commit to therapy. Transplant surgeons harvest the islet cells from deceased donors.

After harvesting islet cells, they must be separated from the exocrine pancreas in an enzymatic and density centrifugation process. Grafts then undergo assessment and rate as adequate when they contain 5,000 high-quality islets per Kg (recipient). Typically recipients are infused with islet cells from multiple donors. Infusing a larger number of islets increases the chances that an adequate number will survive.[12] 

Technique or Treatment

Islets are isolated from the donor, but first, the duodenum and spleen are detached from the pancreas as well as lymph nodes, vessels, and peri-pancreatic fat. The head of the pancreas is then transected, and the catheters are placed into the main pancreatic duct. The pancreas is then perfused with the collagenase solution. The pancreas undergoes 10 minutes of cold perfusion and is then sliced into smaller pieces before being placed into the inferior portion of the Ricordi chamber. The digestive, enzymatic solution is then infused into the chamber. Hank's solution is subsequently released as a pump cycles the mixture.

The temperature is manipulated, and the solution circulated until islets are cleared from acinar tissue. The islets are collected and then stained with dithizone to evaluate them. Once the purity, viability, potency, and stability are verified through digital computer analysis, the islets are ready for the infusion process. Islet cells have a stability time of 72 hours after the harvesting process. They must be infused within 72 hours of harvesting to promote the best chance at survival. 

The donor islets must not exceed a tissue volume of 5 ml, which are then diluted with heparin and 40 to 60 ml of a solution, such as lactated Ringer. Graft implantation can be in multiple ways. Mini laparotomy with cannulation of one of the mesenteric or omental veins is one method performed by transplant surgeons. Another technique that is typically performed by interventional radiologists is accessing the portal vein under image guidance. It takes approximately 15 minutes to infuse the bag of islets, heparin, and solution once a vein has been cannulated. The portal vein pressure is monitored and must be kept at or below 22 mmHg. Once the infusion is complete and the catheter is removed from the vein, the gelatin sponges and coils are placed into the cannulation site.[10]

Complications

As with any surgical procedure, there can be possible complications. One of the most common complications is portal vein thrombosis. Thrombosis can lead to complete loss of the graft; however, since the addition of heparin in the infusion process, life-threatening thrombosis is rare.

Bleeding is another among the most frequent complications, occurring in up to 8% of islet transplant procedures. Mycotic aneurysms, infections, pancreatic fistulas, bile leak, and pancreatitis are some of the other complications that may occur with islet cell transplantation. As many as 30% of patients that undergo the procedure will need a repeat operation.[13]

Clinical Significance

In the clinical setting, the majority of grafts fail in the immediate post-infusion period; this is due to an extreme inflammatory response that occurs called the instant blood mediated inflammatory reaction. In this process, tissue factor on islet cells attracts and activates platelets resulting in a cascade of additional immune cell recruitment and clot formation. Anticoagulants and intense anti-inflammatory agents aim to minimize this process and subsequently prevent immediate rejection.

One of the main goals of islet cell transplantation is that patients will be able to achieve some form of insulin independence. The rate of insulin independence varies widely among centers, 20 to 90%. Long-standing experience with the infusion process appears to be the most influential factor in regards to the center's success rate. Insulin independence from islet cell infusion has an expiration date. Results are not lifelong and require another round of infusions after approximately three years to maintain independence. Beta cells can retain some function up to 5 years after infusion. 

Islet cell transplantation is now in use in the clinical setting; however, the harvesting, curating, and infusion process continues to evolve as ongoing discoveries occur in the experimental setting. This process will continue, which will produce more consistent and sustainable results in the clinical setting.[14][15]

Enhancing Healthcare Team Outcomes

The coordination and management of all physicians, nurses, technicians, and office staff needed for a single patient to undergo pancreatic islet cell transplantation requires clear communication between various teams and strict protocol adherence. Endocrinologists initiate the first step with the identification of potential patients. They must clearly communicate the patient's medical history, failed attempts at medical management, and recurrent episodes of unrecognized hypoglycemia to the transplant surgeon. The endocrinologist must also disclose the patient's history to a psychologist. Details of the patient's course become essential for a psychologist for them to understand and assess the patient's motivation to undergo the procedure. 

Communication, coordination, and standardization of how the islets are transplanted are of paramount importance. An Australian trial demonstrated that standardization of islet isolation allowed for results of trials performed at different sites to be comparable. Diminishing these procedural variations, which could be affecting outcomes, will enable further discovery as to what promotes graft survival. Improving graft survival will decrease patient morbidity as well as the need for repeat transplantation and additional medications. [Level 2]

Posttransplantation, patients require lifelong immunosuppression. A team of pharmacists, physicians, and psychologists are needed to ensure the medications chosen are tailored to the patient. Patients will continue to need blood glucose checks and regular appointments with different teams. Interprofessional communication amongst the various groups is essential to ensure regimen adherence, identify barriers to adherence, monitoring for side effects (mental and physical), and checking for graft functionality over time.[16] [Level 3]