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Procedures

As previously noted, the original 1966 pancreas transplant was simultaneous with a kidney transplant; this is the most common transplant procedure involving a pancreas today. Simultaneous Kidney/Pancreas transplant (SKP) is followed in number performed by Pancreas After Kidney (PAK) transplants and finally, by Pancreas Transplant Alone (PTA). Statistics from the International Pancreas Transplant Registry (IPTR) show the distribution among the procedures:

One reason that the first pancreas transplants were done in conjunction with kidney transplants, and the reason that most are still SKP, is that for any transplant, immunosuppression is required. Immunosuppression is never without risk; each drug has its own syndrome of side effects. Among these side effects are: Increased susceptibility to infections, bone and joint weakness (sometime leading to hip or knee replacement), accelerated cataract formation, additional functional loads on kidney and pancreas, elevated cholesterol, gastric problems including ulcers, elevated blood pressure, and increased cancer risk. In addition, there are numerous less severe side effects like insomnia, hirsutism, night sweats, nightmares, and mood swings.

Section through normal kidney

While diabetes is treatable with insulin injections (or other medications) and frequent blood glucose monitoring, many diabetics eventually develop complications from the disease, among them, retinal damage, cardiovascular problems including arteriosclerosis, kidney failure, neuropathy, and amputation of extremities due to poor circulation.

Kidney failure is treatable with dialysis, but dialysis, too, has its problems. Fluid intake and diet must be monitored closely. Anemia can be severe if not monitored and treated. Bone loss (osteopenia, osteodystrophy, osteomalacia) can occur with hyperparathyroidism, often requiring surgery to remove the parathyroid gland. Arteriovenous access (graft or fistula) can clot and require surgery; access via catheter can lead to infection in the bloodstream.

In both conditions, diabetes and renal failure, life span is shortened, compared to individuals affected by neither condition, and quality of life is compromised.

Since there are several compromises with insulin therapy, with dialysis, and with transplantation, it is a judgment call by physician and patient which choice is the best choice. In very broad terms, kidney failure is the more immediately dangerous of the two conditions. Transplantation is the treatment of choice for many renal patients who may also have diabetes mellitus. The logical argument, then, is the following: If the renal patient must be on immunosuppressant drugs for the kidney transplant, why not transplant a pancreas at the same time and eliminate the diabetes (which, quite often, is the cause of the renal failure)? Many physicians are reluctant to transplant a pancreas alone for diabetes without renal failure, feeling that the side effects of the immunosuppressant drugs are more detrimental than the complications of diabetes. So, while PTA procedures are far fewer in number than those accompanying kidneys, their number is growing.

Pancreas alone transplants are more easily justified in several situations. For example, in cases where hypoglycemic unawareness has developed, the sudden, unnoticed onset of very low blood sugar could have disabling or even life-threatening effects. Very labile or "brittle" diabetes, in which blood sugar control is extremely difficult, is another condition that makes a stronger case for use of a pancreas transplant and immunosuppression. Advanced neuropathy can also be helped by pancreas transplantation. Unfortunately, early in the disease it is very difficult to predict which patients will develop complications and which patients will not. While tight glycemic control is always the goal, and there are correlations between glycemic control and fewer complications, there is no absolute correlation between tight glycemic control and absence of complications, there is no absolute guarantee that somewhat looser glycemic control will produce accelerated development of complications in all patients. Only after complications begin to develop can a responsible decision about transplantation and immunosuppression be made.

Several diabetic complications stabilize after transplant, and a few can even be demonstrated to improve. Proliferative retinopathy tends to stabilize following a pancreas transplant, although extant damage to the retina from neovascularization does not reverse. "Neuropathy improves or stabilizes in most pancreas transplant recipients. Nerve conduction velocities and evoked muscle action potentials increase." (7) Effects on cardiovascular complications of diabetes are less clear, although there is some evidence that there is some improvement in peripheral vascular function, evidenced by improved oxygenation of the tissues and decreased capillary leakage.

One other matter to consider in PTA is the handling of the pancreatic exocrine secretions. In SKP, with both organs from the same donor, kidney function can be monitored as a surrogate for direct monitoring of pancreas rejection. This enables enteric drainage for the transplanted pancreas' exocrine secretions (the pancreatic duct drains into the duodenum), which is essentially the way the native pancreas handles this function. In the absence of an HLA-identical kidney, the best way to monitor the transplanted pancreas is by draining the exocrine secretions into the bladder; urine can then be sampled for pancreatic enzymes, particularly amylase, and these levels are used to indicate potential rejection episodes. There are additional factors to be considered in either technique. In a bladder-drained transplant, numerous chemical elements (which would have been reabsorbed by the intestine with an enteric-drained procedure) are lost through the exocrine secretions/urine mix and must be replaced with supplements. Significant fluid is lost through exocrine secretions/urine with bladder-drained transplant, and dehydration must be avoided. Particular care must be given to bicarbonate replacement because without it metabolic acidosis can result. The enzymes and the pH of the exocrine secretions can aggravate noninfectious chemical cystitis and reflux pancreatitis. While these complications are generally manageable, their potential should be taken into consideration.

While at first glance it may seem that a pancreas transplant is a quick, simple and permanent way to "cure" diabetes. It is not. It is not quick: The evaluation and waiting list time can vary from 1-3 years. It is not simple: The procedure is major surgery, and is very stressful to the body, as are the immunosuppressant drugs, which require a lifetime commitment. And it is not necessarily permanent " Long-term insulin independence is achieved in 80% of recipients of pancreas grafts placed simultaneously with a kidney, in >70% of recipients of a pancreas after a kidney, and in >60% of non uremic recipients of a pancreas alone." (8) The required use of immunosuppressant drugs can lead to non-autoimmune diabetes mellitus, or even recurrence of the original autoimmune DM. (A few recent studies debate whether insulin resistance or beta-call damage is a more common cause of post-transplant diabetes. [Transplantation, 2001;71:1417-1423])

This procedure is possible because an individual can survive quite well with a single healthy kidney. While the human body provides a pair of highly adaptive kidneys, it gives us only a single pancreas to work with. While a few transplants have been done by excision of a section of pancreatic tissue from a living related donor, these segmented-graft survival rates have been disappointing. Almost all pancreas grafts are taken from cadaveric donors. (A side-note here on cadaveric renal transplants versus living donor transplants: The best graft survival rates in kidney transplantation are grafts taken from a living, related donor, whose HLA typing is frequently closer to that of the recipient than matches from cadaveric donors; ischemic time is minimized with living donors.)

Again regarding the length of time on a waiting list, several sources in the US have vastly divergent views on times for SPK transplants.

"In an interview with Reuters Health, Dr. Humar commented that the main stumbling block to broader use of pancreas transplantation for potential cure of Type 1 diabetes is the supply of donor organs, because the waiting list for a combined kidney/pancreas transplant is currently between 2 and 3 years in the US." (9) Contrarily "…the number of pancreas transplants being performed is less than the number of cadaver donors theoretically available." (7) My experience at Carolinas Medical Center, Charlotte, NC, is that for Type A blood group, 6-9 months is an average wait, and anything over a year is rare for SPK transplants. The list for pancreas-kidney transplants is significantly shorter than the list for kidney alone, principally because of the more strident screening before acceptance in the SKP program. SPK is a more stressful surgical procedure so fewer people are good candiates for it.

Recently, islet cell transplantation shows promise as an alternative to PTA or even to PAK transplants. Dr. A.M. James Shapiro and his colleagues at the University of Alberta in Edmonton harvested islet cells from cadaveric donors and inject the cells into the recipient's hepatic artery. The cells attach to the liver tissue. Although immunosuppressants are required to prevent rejection, corticosteroids generally are not, because the individual cells are not subject to the same inflammatory response as is a solid organ.

Variations of the Edmonton protocol are spreading rapidly across the US; still, large-scale, long-term studies of islet cell transplant function are not easily available.

Another recent experimental project involves the University of Alberta's Drs. Ray V. Rajotte and Gregory S. Korbutt, Carolinas Medical Center's Drs. Paul F. Gores and Craig Halberstadt, and Dr. Helena P. Selawry, formerly of the University of Tennessee Medical Center. This project will utilize modified Sertoli cells. The native Sertoli cells provide privileged immunity to developing spermatozoa. The modified Sertoli cells would provide a privileged immunity zone around islet cells, or even around solid organ allografts, thus reducing or even eliminating the need for immunosuppressant drugs.

Transplantation is not a cure for either diabetes or renal failure; it is another treatment option; with improved surgical techniques, new drug therapies, and more specific techniques of manipulating genetic immunology, it will become a more and more desirable choice.