Indications for islet transplantation
1. Islet transplantation alone (ITA) is indicated for life-threatening hypoglycaemic unawareness.
2. Islet after kidney transplantation (IAK), where patients are already taking immunosuppression and have life-threatening complications of their diabetes.
3. Autologous islet transplantation in patients with chronic pancreatitis undergoing pancreatectomy. Their pancreas is processed, the islets extracted and then infused into their liver.
Assessment for transplantation
Optimisation of insulin therapy is the first part of the assessment to see whether diabetic management can be improved without transplantation. This may involve more frequent insulin injections or a trial of insulin-pump therapy.
The assessment of fitness for the transplant procedure is similar to that required for whole pancreas transplantation, except that the patient does not need to be as cardiovascularly robust. Never-theless, major cardiac disease is still a contraindication if it precludes long-term patient survival.
Islet isolation and transplantation
Purification and transplantation
Islet transplantation has been the goal of research ever since Banting and Best proved that it was the islets that produced insulin. However, the islets are scattered throughout the pancreas so the process of separating them from the acinar pancreatic tissue (which makes the digestive enzymes) has proved a formidable challenge.
The current process involves separate stages.
· Digestion. The enzyme collagenase is injected into the pancreatic duct to break down the collagen holding the islets in place. This takes place in a chamber at 37°C.
· Blocking of digestion. As the islets break free they pass out of the digestion chamber into another container where the enzyme digestion is stopped by cooling to 4°C.
· Purification. The islet tissue, together with a lot of pancreatic acinar tissue, is centrifuged over density gradients to isolate the islets.
· Transplantation. Purified islets are then injected via a needle inserted through the skin, through the liver and into the portal vein, where they embolise into the smaller venous tributaries.
The whole process is rather wasteful of islets; typically only a half of the 1 million islets in a pancreas finish up as purified, transplantable islets; the remainder fragment into smaller clusters of cells due to too much exposure to collagenase, or remain adherent to the gland due to too little exposure.
Following transplantation only around a half of the transplanted islets successfully implant into the liver and produce insulin. Typically more than 5000 islet equivalents are required to be transplanted per kilogram weight of the recipient.
Patients receive similar immunosuppression to kidney transplant recipients, with the exception of avoiding steroids. The current immunosuppressants do not facilitate successful transplantation.
· Calcineurin inhibitors such as tacrolimus are islet toxic.
· Sirolimus appears to reduce engraftment, possibly via inhibition of vascular endothelial growth factor.
· Mycophenolate and azathioprine are insufficient to prevent rejection.
• Abnormalities of liver biochemistry.
• Bleeding from the punctured liver is common (15%), and may occasionally require blood transfusion. It often presents with abdominal and right shoulder tip pain. The risk is reduced by injection of sealant along the track (e.g. fibrin glue), although that increases the risk of thrombosis.
• Portal vein thrombosis (4%) arising as a complication of embolisation. Diabetic patients are often procoagulant and thrombosis is a risk.
• Biliary leak, resulting in abdominal pain.
• Gall bladder puncture, resulting in biliary leak; other inadvertent organ puncture is also possible.
• Fatty liver (hepatic steatosis) occurs in the long term, usually focally along portal tracts where islets are functional. These appearances may return to normal after the graft fails.
• Portal hypertension may occur with repeated islet infusions. As the islets embolise into the portal vein they progressively block more and more tributaries.
Complications of transplantation
• Immunosuppression. Islet transplantation requires equivalent levels of immunosuppression to those needed in kidney transplantation, with the associated drug specific side effects (especially nephrotoxicity) and the adverse consequences of immunosuppression including infection and malignancy.
• Sensitisation to HLA antigens on the donor, occurring as part of the rejection process, reduces the pool of donors suitable for sub- sequent transplants (islets or other organs, e.g. the kidney).
Islet graft failure
Islet graft failure is common, with a 5-year graft survival of around 12%. Although the patient may have returned to insulin, there is often useful insulin production still occurring (as evidenced by the presence of C-peptide in the serum). This is frequently sufficient to stabilise diabetic management and prevent life-threatening hypoglycaemia.
The cause of graft failure is often unclear. There is no way to monitor for rejection, which probably accounts for a significant proportion of graft failures. The innate immune system is very active in the liver and probably accounts for other graft losses, and the concept of ‘islet exhaustion’ is also proposed to explain poor long term outcomes.
Pancreas or islets?
The results of pancreas transplantation are superior to those of islet transplantation; grafts function better (insulin independence is common) and last longer. However, pancreas transplantation is a large surgical undertaking with significant morbidity and mortality. Islet transplantation is a minor procedure with few complications, but with disappointing long-term results.
At present it is difficult to justify equal access to pancreases for whole organ and islet transplantation, so islet transplantation will remain a secondary procedure.