Pancreas Transplantation BMJ State-of-the-Art Review Summary

(Another medical student orientated summary of a recent review, this time Pancreas Transplantation.)
Successful pancreas transplantation can result in durable glycemic control and improved survival for patients with diabetes. There seems to be no other treatment in medicine that has the same improving success rates over time and is being applied less and less (the number of pancreas transplants performed in the US has decreased every year during the past decade). In other words, more patients could probably benefit from pancreas transplantation than currently undergo the procedure. 

Most people are diagnosed with type 2 diabetes, with type 1 diabetes accounting for 8-10% of all diabetes cases.
In the UK 3.5 million people are diagnosed with diabetes, with approximately 0.5 million still to be diagnosed. The incidence is increasing.

First successful pancreas transplant was in 1966, at the University of Minnesota.
The number of transplants increased steadily until 1996.
Survival at this point (1996) was 91% at one year and 84% at three years.
The introduction of ciclosporin in the 1980s dramatically increased survival, further efficacy of transplant was enhanced with introduction of tacrolimus and mycophenolate in the 1990s.

Between 2005 and 2014 pancreas transplantation number decreased by 20%. Reasons for this decline were probably; improved medical management of diabetes, decline in organ donor quality (more obese and old), lack of consistent referral of transplant candidates from endocrinologists.

Three main pancreas transplantation types:

• PAK = pancreas after kidney transplant (the main role of this type is avoid the morbidity and mortality asociated with dialysis therapy; patients with type 1 diabetes have at least a 33% mortality in teh first five years after starting dialysis). 
• PTA = pancreas transplantation alone (has higher rates of technical graft loss and acute cellular rejection, however a very small number of this type are performed, no no reports have rigorously studied the efficacy or quality of life benefits)
• SPK = simultaneous pancreas kidney transplant (most common type of pancreas transplant, typically both organs from the same donor)

Success rates of pancreas transplantation have improved with time likely due to increasing experience with these complex patients.

UK current survival rates SPK five year survival 88%, Pancreas only transplants five year survival 78%.

No real studies have directly compared the costs of pancreas transplant vs conventional medical therapy but there have been theoretical models that concluded that SPK is the most cost effective strategy after accounting for varying probabilities of patient and graft survival.

• To date there have been no randomised controlled trials comparing the different forms of pancreas transplantation against for example intensive insulin therapy, islet transplantation. 
• However many single centre studies and registry analyses suggest that pancreas transplantation provides a net benefit compared to kidney transplant alone for patients with both diabetes and chronic kidney disease. 
• More controversial is the impact of pancreas transplantation on patient survival in patients with diabetes and preserved renal function. One analysis of transplant registry data reported a survival disadvantage for PAK and PTA recipients. 

Because pancreas transplantation can also establish normoglycemia it is reasonable to infer that this intervention would also improve or stabilise end organ complications (eg. retinopathy, nephropathy).

Complications:
Diabetic nephropathy (a microvascalur complication of diabetes) is one of the most important complications of diabetes.
Single centre studies with small cohorts have suggested that pancreas transplantation has a beneficial effect on secondary complications of diabetes.
Data is limited on the long term complications, have been reports of increased infections and hematologic cancers after transplantation.

Quality of life:
QoL improved rapidly after transplantation (measured at four months), the effect did however flatten out later. A minority had decreased QoL emphasising the importance of pre-transplant education to establish realistic expectations for the patient.

Clinical trials:
No multicentre trial has been designed to truly evaluate the true efficacy of transplant compared to best medical therapy in type 1 diabetes.

Islet transplantation (ITA):
ITA is less invasive.
Has good short term results but five year insulin Independence rate are around 11%, despite this these patients achieved avoidance of hypoglycemia and near normal glucose control.
Comparison of ITA vs PTA; PTA has higher morbidity, authors of mentioned study concluded that ITA produces similar outcomes to PTA.

Artificial pancreas:
A closed loop system with a subcutaneous sensor that transmits glucose measurements to an external insulin pump that deliver insulin subcutaneously when needed.
Addition of glucagon in the future could prevent hypoglycemia.
The use of such devices requires the patient reaches a certain level of understanding.
Results from international diabetes closed-loop trial conducted on real patients will be out in 2019.

Future directions:

"Pancreas transplantation stands at a crossroads—without a systematic approach to the procedure and its outcomes, transplant volumes, especially those for PTA and PAK, may continue to decline and the procedure take second stage to therapies such as islet transplantation and closed loop insulin and glucagon delivery systems..... a more systematic approach to characterizing the successes and limitations of pancreas transplantation is needed."

Need to develop a uniform definition of graft failure. The most common definition of graft failure at the moment is the requirement of exogenous insulin therapy.
Need the development of biomarkers to diagnose rejection and monitor patient immune status.

UK guidelines:

In the UK, patients with the following conditions are considered for pancreas transplantation135: 

•  Pancreas transplantation alone or islet transplantation alone: patients with severe hypoglycemic unawareness but normal or near normal renal function

•  Simultaneous pancreas and kidney transplantation or simultaneous islet and kidney transplantation: patients with renal failure and insulin dependent diabetes 

•  Pancreas after kidney transplantation or islet after kidney transplantation: patients with functioning kidney transplants and diabetes. Most patients who are considered have type 1 diabetes but some patients with insulin dependent type 2 diabetes may also be suitable candidates.

This summary was for the following paper: http://www.bmj.com/content/357/bmj.j1321
(all the information and images were from the above paper).