Pancreatic Transplantation

The information on pancreatic transplantation was kindly provided by Professor Nadey S. Hakim MD, PhD, FRCS, FACS.

Introduction

The aim of pancreas transplantation is to improve the quality of life and ameliorate secondary complications by establishing an insulin-independent euglycaemic state in patients with Type I insulin dependent diabetes mellitus (IDDM) by engrafting insulin producing beta cells within the islets of Langerhans.

The syndrome of IDDM includes not only abnormal glucose metabolism but also specific microvascular complications that include retinopathy, nephropathy, and neuropathy. Diabetes mellitus is currently the leading cause of kidney failure and blindness in adults, the number one disease cause of amputations and impotence, and one of the leading chronic diseases of childhood.

Over the past decade, it has become increasingly evident that the microvascular complications of diabetes mellitus result from hyperglycaemia. Exogenous insulin therapy prevents acute metabolic decompensation and, when delivered so as to achieve near-normal glucose concentrations, reduces the frequency of many complications. Yet even in a patient with tight control, no method of exogenous insulin administration is comparable to endogenous insulin secretion that responds to moment-to-moment changes in glucose concentration.

Pancreas transplantation is the only treatment of type I diabetes that is able to induce insulin independence consistently and normalize glycosylated haemoglobin.

With improvements in organ retrieval technology, refinements in surgical techniques and advances in clinical immunosuppression, the success rates of pancreatic transplantation have increased dramatically. The penalties for normal glucose homeostasis are the operative risks of the transplant procedure and the need for chronic immunosuppression.

Indications for Pancreas Transplantation

Pancreas transplantation of all types is indicated for patients with IDDM. Patient selection is aided by a comprehensive multidisciplinary pretransplant evaluation with additional work-up according to the specific problems of each patient. The evaluation confirms the diagnosis of IDDM, determines the patient's ability to tolerate a major operation (based primarily on the patient's cardiovascular status), establishes the absence of any exclusion criteria, and documents end-stage organ complications for future tracking following transplantation. In a suitable candidate, the evaluation is also used to determine the type of pancreas transplantation (based mainly on degree of nephropathy). The degree of renal dysfunction (creatinine clearance below 40ml/min) is used to select patients for simultaneous pancreas-kidney transplantation versus pancreas transplantation alone (creatinine clearance above 70ml/min).

Procurement and Preservation of the Pancreas

The vast majority of pancreas transplants have been from cadaver donors, but more than 90 have been segmental grafts from living related sources. As the number of pancreas transplants being currently performed are fewer than the number of pancreas cadaver donors theoretically available, the only reason to use living related donors for segmental pancreas transplants is the immunologic advantage.

Advances in organ retrieval and preservation technology have played an important role in improving the results of pancreas transplantation. Combined liver, kidney and whole-organ pancreaticoduodenal retrieval can now be safely performed in virtually all donors irrespective of vascular anomalies. Pancreas donors usually range in age from 15 to 50 years and range in weight from 40 to 100 Kg.

The procurement of the pancreas must be meticulous and as perfect as possible so that the transplant procedure can take place with minimal difficulties and complications. The selection criteria for cadaver pancreas donors are similar to those for other solid organs. Specific criteria depend on donor pancreatic function. A history of diabetes mellitus, acute necrotizing pancreatitis and a chronic history of pancreatitis are obvious contraindications. Despite a reported history of pancreatitis, it is always worthwhile to examine the pancreas at the time of procurement to assess the suitability of the organ. It should be remembered that after brain death the serum amylase levels are often high in the absence of pancreatitis, and hyperglycaemia may occur in the absence of diabetes. The direct inspection of the pancreas is therefore justified before deciding whether or not to use it.

The use of University of Wisconsin (UW) solution in clinical practice has permitted safe and extended cold-storage preservation of the pancreas up to 30 hours without compromise of graft function. The safety of extended preservation has increased the capability for distant organ procurement and sharing, minimised organ wastage, improved the efficiency of organ retrieval, allowed time for crossmatching and adequate preparation of the recipient, and has enabled semi-elective performance of the transplant procedure. More important, the quality of preservation has been improved, resulting in better post-transplant graft function and less complications such as pancreatitis or vascular thrombosis.

The bench work preparation of the pancreatic graft must be very meticulous. Surgical techniques to reconstruct the pancreatic vasculature are standard. The most common method is to connect the superior mesenteric and splenic arteries with a Y-graft of donor iliac vessels and then anastamose the latter to the recipient's iliac artery.

Recipient Operation

The majority of pancreas transplants are performed in conjunction with a kidney transplant from the same donor through a midline intraperitoneal approach. The surgical approach to pancreas transplantation is similar to that for kidneys in many aspects. Usually the graft vessels are anastomosed to the recipient iliac vessels resulting in systemic drainage of the graft venous effluent.

Several surgical techniques have been used to manage the exocrine secretions of the pancreatic graft, including enteric drainage, polymer injection or urinary drainage. Urinary drainage is currently the most popular, but enteric drainage and duct injection still predominate at some European centres. A major advantage of urinary drainage is the ability to detect pancreas rejection episodes early (before hyperglycaemia) by monitoring amylase excreted directly into the urine by the graft. Antirejection therapy begun as soon as urine amylase activity decreased can usually reverse the process, allowing endocrine function to be maintained.

Immunosuppression

Immunosuppression for pancreas transplantation is very similar to that for other solid organs. Since the mid-80s, nearly every program has used cyclosporine in combination with azathioprine and prednisone for maintenance of immunosuppression; most also use anti-T cell agents for induction of immunosuppression. Recently most institutions have started to use FK506 instead of cyclosporine for maintenance therapy with promising results. Some centres have combined FK506 with Mycophenolic acid.

Although transplantation requires a life long commitment to immunosuppression, most diabetic patients find that they have fewer dietary and activity restrictions and a much better quality of life after pancreas transplantation.

Post-Transplant Complications

Rejection is the most common cause of graft loss due to difficulties in its early detection. Transplantation of a pancreas and a kidney from the same donor allows manifestations of kidney allograft rejection to guide treatment as kidney graft rejection is believed to precede or parallel pancreas rejection. Urinary drainage of exocrine secretions enables direct access to exocrine function that can be monitored by urinary assays, and both urine amylase and cytology have been used as non-invasive markers of early rejection. Currently, no non-invasive method is accurate enough to replace histopathologic examinations. However, open biopsy is rarely required as safe cystoscopic and percutaneous biopsy techniques of the pancreas allograft have been developed.

Other causes of pancreas graft loss include vascular thrombosis, pancreatitis, and infection. Vascular thrombosis may occur, in part, because of the low microcirculatory flow through the pancreas but can also accompany pancreatitis or rejection. Hyperamylasaemia is common after transplantation and may be either asymptomatic or indicative of symptomatic pancreatitis. Patients with a 'diabetic'-neurogenic bladder can develop 'reflux pancreatitis' from inadequate bladder emptying. Surgical problems related to exocrine pancreatic drainage and allograft pancreatitis are usually due to technical errors (leak or fistula) or injection leading to fluid collections, pseudocysts or abscesses surrounding the pancreatic graft.

In the post-transplant period, urinary tract infections are common and pancreatic enzyme activation can lead to 'chemical' cystitis or urethritis. In several cases, patients may develop urethral stricture or disruption, haematuria, or perforation of the bladder or duodenal segment.

Finally, because of the loss of pancreatic secretions rich in sodium and bicarbonate into the urinary tract, pancreas transplant recipients are quite susceptible to metabolic acidosis and dehydration. The tendency for volume depletion can cause or aggravate pre-existing orthostatic hypotension but may ameliorate pretransplant hypertension. All recipients must increase fluid and salt intake, but may require additional oral bicarbonate supplementation.

Results

From 1966 through 1994, over 6300 pancreas transplants were performed world-wide, the majority in the last ten years. According to the United Network for Organ Sharing (UNOS) Registry established in 1987, most pancreas transplants have been performed in conjunction with a simultaneous kidney transplantation (84%) in patients who had imminent renal failure or were on dialysis. The remaining pancreas transplants were performed as a sequential pancreas-after-kidney transplant (8%), as a solitary transplant (6%), or in conjunction with a single organ other than the kidney or multiple organs.

The results of pancreas transplantation have improved progressively since the introduction of cyclosporine and refinement of surgical techniques. In an analysis of 3,569 cadaver donor cases reported worldwide between 1987 and 1994 the overall 1-year patient survival rate was 91% and the 1-year insulin independent rate was 72%.

The effect of Pancreas Transplantation on the secondary complications of Diabetes

In addition to correcting dysmetabolism and freeing the patient from exogenous insulin therapy, information on the course of secondary diabetic complications after pancreas transplantation is emerging:

Retinopathy

In some studies with follow-up of four years or more after successful pancreas transplantation stabilisation of retinopathy was observed, more than that observed in patients followed for the same period of time but whose pancreas transplants have failed.

Nephropathy

Both prospective and cross-sectional studies have suggested that pancreatic transplantation prevents recurrence of diabetic nephropathy in a newly transplanted kidney.

Neuropathy

A number of studies have reported improvements in both motor and sensory nerve function as assessed by nerve conduction velocity in pancreas-kidney transplant recipients when compared to recipients of kidney transplants alone or patients with pancreas graft failure. Studies of autonomic function following pancreas transplantation are less clear. In some studies pancreas transplantation was associated with greater improvements in autonomic symptoms, even if they were accompanied by little objective evidence of change.

Studies are unanimous in finding that patients with successful transplants rate their lives better after than before the transplant. For uraemic diabetic patients the effect of a double transplant can be dramatic, patients rate their quality of life higher than diabetic kidney transplant alone recipients.

The future of Pancreas Transplantation

The advances in immunosuppresive strategies and diagnostic technology will only enhance the already good results achieved with pancreas transplantation. Further documentation of the long-term benefits and effects of pancreas transplantation may lead to wider availability and acceptance. Effective control of rejection with earlier diagnosis or better prevention may soon permit solitary pancreas transplantation to become an accepted treatment option in diabetic patients without advanced secondary complications of diabetes. Although there is significant morbidity after pancreas transplantation, this is usually manageable without influencing the outcome. Other strategies for the treatment of IDDM are being actively investigated, including islet cell and fetal pancreas transplants, gene therapy, implantable insulin pumps, and bio-hybrid artificial pancreas units. Although any or all of these methods may have a role in the treatment of IDDM in the future, it will be difficult for these alternative strategies to improve upon the metabolic efficiency of the vascularised pancreas transplantation. With the improvement in quality of life and the potential reversing effect on diabetic complications, pancreas transplantation may become a frequent transplant procedure and, perhaps, in the future may become the treatment of choice for IDDM.