Islet Transplantation
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.
Immunosuppression
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.
Complications
Procedural complications
• 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.
