by G.P. Basadonna, MD,
Division of Organ Transplantation and Immunology Department of Surgery
Yale University School of Medicine
Pancreas transplantation is the only treatment for type I diabetes that establishes an insulin-independent, euglycemic state; glycosylated hemoglobin levels are normalized for as long as the graft functions. But the penalty for constant normoglycemia is the need for immunosuppression. Thus, for nonuremic patients, pancreas transplants are currently performed only when the problems of diabetes are perceived to be more serious than the potential side effects of the anti-rejection drugs required by transplantation.
For uremic diabetic patients who need a kidney transplant, the addition of a pancreas has become routine. Such patients are already obligated to immunosuppression, thus there is usually no reason not to make them insulin- independent as well as dialysis-free.
Adding a Pancreas to a Kidney in Diabetic Transplant Recipients
Since constant euglycemia is unachievable for diabetic patients by any practical mode of exogenous insulin administration, and since hypoglycemia is intolerable, chronic hyperglycemia (as documented by measurements of glycosylated hemoglobin) is the norm. However, after years of debate, it has now been unequivocally shown that the rates of development of neuropathy, retinopathy, and nephropathy are related to the degree to which glycemia is controlled. Complication secondary to dysmetabolism afflict the eyes, nerves, and kidneys of more than 50 percent of the patients who have had diabetes more than 20 years. A successful pancreas transplant, with the resulting achievement of euglycemia, significantly improves both general health and life expectancy. Thus, a rationale for pancreas transplantation, as a method of providing perfect metabolic control, exists.
Although one of the long-range goals of pancreas transplantation is to ameliorate the secondary complications; not every diabetic patient gets complications, and it is difficult to predict, at the onset of the disease, who is at risk for complications. Thus, pancreas transplantation is usually performed after complications have appeared, and at a time when they may be self-perpetuating. Because immunosuppression also has side- effects, and it is uncertain if these would be more or less severe than those that might occur from diabetes, the reluctance to transplant early is understandable.
Complications involving the eyes and nerves are often far advanced in diabetic patients who have kidney failure. However, it is generally accepted that quality of life is better for people who are immunosuppressed and not dialysis dependent, compared with those who are not immunosuppressed but are dialysis dependent. Thus, almost all uremic diabetic patients are best treated with a kidney transplant. In such patients, correction of diabetes can be achieved, with only the surgical risks of adding a pancreas graft to be considered, and the quality of life is improved even if insulin-independence is the only benefit achieved other than the correction of uremia.
At the moment, pancreas transplantation is most widely applied to the diabetic renal failure population. But it is clear that diabetic control problems are obviated by a successful pancreas transplant. Thus, pancreas transplants alone (not alongside kidney replacement) are being performed at this time for individual diabetic patients who are labile or have hypoglycemia unawareness, and should be considered as the therapeutic option for any patient in whom the management of diabetes is so difficult as to seriously interfere with day-to-day living. For such patients, managing their diabetes should be more of a problem than being immunosuppressed.
This is a judgment call. However, a successful pancreas transplant can compensate for the impairment in counter-regulatory mechanisms that occurs in some patients with long-standing diabetes. A retrospective study of recipients of solitary pancreas transplants found them to be nearly unanimous in stating that being immunosuppressed and insulin-independent gave them a better quality of life than before the transplant.
In nonuremic patients, a successful pancreas transplant can induce regression of early, but not advanced, microscopic lesions of diabetic nephropathy. In renal allograft recipients, a successful pancreas transplant, performed either simultaneously with or within a few years after the kidney transplant, will prevent recurrence of diabetic nephropathy in the new graft. In this situation, immunosuppression is necessary in order to have renal function at all; by keeping diabetic lesions from re- occurring, long-term renal graft function is likely to be improved.
In contrast to the positive effect on kidneys, the probability that advanced retinopathy will progress is not altered in the first one to two years after a pancreas transplant. However, in patients with long-term functioning grafts, retinopathy tends to stabilize; in those with failed grafts it continues to deteriorate.
Neuropathy improves or stabilizes in most pancreas transplant recipients. Nerve conduction velocities and evoked muscle action potential increase. Indeed, in patients with severe autonomic neuropathy, those who undergo a successful pancreas transplant have a significantly higher probability of survival than those who are not transplanted, or who have unsuccessful transplants.
Pancreas transplants in patients with hyperlabile diabetes and extreme difficulty with metabolic control can improve quality of life, simply by inducing insulin independence. Kidney transplants also improve quality of life in uremic patients by obviating the need for dialysis. For diabetic patients with both problems, the effect of a double transplant can be dramatic. With one surgical procedure, two difficult clinical problems are corrected-- for as long as rejection is prevented by immunosuppression. For diabetic patients without nephropathy, however, the price (immunosuppression) is paid simply to be rid of their diabetes. Although some diabetologists have expressed doubt as to whether such benefit is worth that price, pancreas transplant recipients have emphatically stated that it is.
Over 6,000 cadaver donor cases were reported world-wide between October 1987 and July 1994. The overall one-year patient survival rate was 91 percent, and the one-year insulin-independent rate (graft functional survival) was 70 percent in the U.S. (n=2573). Five years after surgery, patient survival is 78 percent and pancreas survival (insulin independence) is 60 percent. At all locations, most were SPK (Simultaneous Pancreas and Kidney transplant). At Yale since June 1994, 20 pancreas transplants have been performed. (11 patients received simultaneous pancreas and kidney, 11 received a pancreas following a previous renal transplant and one received a pancreas transplant alone.) Overall patient survival in these cases is 95 percent and pancreas survival (insulin independence) is 85 percent.
To give an indication as to whether the addition of a pancreas to a kidney transplant in uremic diabetic patients influences patient and renal allograft survival rates one way or another, an analysis was performed by the University of California at Los Angeles (UCLAIUNOS Kidney Transplant Registry) on the cases of renal allotransplantation from cadaver donors in type I diabetic recipients reported to the registry since October 1987. The recipients were divided into those who underwent a kidney transplant alone (KTA-D n=5853), versus those who received a simultaneous kidney/pancreas (SKP, n=1772) transplant. The results in both groups were compared to a non-diabetic cohort who underwent cadaver kidney transplants alone to treat renal failure from glomerulonephritis (KTAGN, n-6615). The patient survival rate curves for the two diabetic groups were superimposed, with 92 percent of SKP and 91 percent of KTA-D recipients alive after one year, while renal allograft survival rates were slightly, but significantly higher in the SKP than in the KTA group (83 percent versus 78 percent at one year). Patient survival rates were slightly higher for the KTA-GN groups than either of the SKP or KTS-D groups, but interestingly, the KTA-GN renal allograft survival rates were lower than in the SPK group.
Thus, there is no apparent difference in mortality risks for uremic diabetic patients undergoing a simultaneous pancreas/kidney versus a kidney transplant alone. If anything, those selected for a SKP transplant have a lower risk of renal allograft loss. This was true in all categories, with one year kidney graft survival rates for SPK vs. KTA recipients being 84 percent (n=425) vs. 80 percent (n=670) in those 21-30 years old, 83 percent (n=831) vs. 79 percent (n=t7l4) in those 31-40 years old, and 82 percent (n=437) vs. 78 percent (n=3176) in those more than 40 years old.
Quality of Life
Although much has been written about the potential for pancreas transplantation to have a favorable effect on secondary complications of diabetes, it is the overall impact on quality of life, including that associated with insulin independence per se, that should be emphasized. The studies conducted so far are nearly unanimous in finding that patients with successful pancreas transplants rate their quality of life to be better after than before the transplant. In the largest study to date, 131 patients were analyzed one to 10 years post-transplant; half had functioning grafts (n=65) and half had grafts that ultimately failed (n=66). Overall, 92 percent felt that managing immunosuppression was easier than managing diabetes. When asked which was more demanding on their families' time and energy, the transplant or diabetes, 63 percent felt that their diabetes was more demanding, 29 percent felt the two were equal, and 9 percent felt that the transplant was more demanding. Of the 65 patients with functioning grafts, 89 percent stated that they were more healthy than before the transplant. Indices of well-being as quantified by standard tests were significantly higher in patients with functioning grafts than those without. Virtually 100 percent of the patients with continuous graft function and 85 percent of those whose grafts ultimately failed would encourage others with similar complications of diabetes to consider pancreas transplantation. In addition, most of the patients with failed grafts desired retransplantation, and those with functioning grafts said they would undergo a retransplant if their current graft failed.
Currently, the major role of pancreas transplantation is as an adjunct to kidney transplantation in pre-uremic, uremic, or post-uremic diabetic patients. Nonuremic patients with hyperlabile diabetes or emerging complications must be carefully selected for the procedure. Current immunosuppressive regimens have many side effects. HLA matching, though it improves the probability of long-term success, cannot eliminate the need for immunosuppression. Immunosuppression sufficient to prevent rejection is usually sufficient to prevent recurrence of disease. Again, the recipient's problems with diabetes must be such that the potential side-effects of immunosuppression are an acceptable trade-off, as is true in choosing between dialysis and a kidney transplant for treatment of renal failure.
Nearly all uremic diabetic candidates for a kidney transplant are also candidates for a pancreas transplant. The best treatment option is to receive a living related donor kidney transplant first, followed later by a pancreas transplant. For those without a living related donor for a kidney, a pancreas transplant can be performed simultaneously with a kidney transplant from a cadaver donor. A living-related kidney donor is associated with the highest long-term renal allograft functional survival rates, and coupled with a subsequent pancreas transplant kidney transplant first is more compelling than ever, since the insulin-independence rates with a PAK can be as good as with a SPK transplant.
Euglycemic, Normoglycemia: both terms denote blood glucose levels in the consistently normal range
Uremic: uremia is the end result of kidney failure-- the buildup of unexcreted toxins in the blood
Immunosuppression: suppression, by medication, of the body's natural graft-rejection system; necessary to maintain a viable transplant
Exogenous insulin administration: insulin dosage by injection
Chronic hyperglycemia: extended periods of blood glucose levels above normal range
Dysmetabolism: improper or unbalanced metabolic process
Labile, Hyperlabile: uncontrolled, "brittle"
Allograft: a graft from another individual
Glomerulonephritis: A serious kidney inflammation, which may seriously impair kidney function; extreme cases require dialysis or transplant
Allotransplantation: transplantation from another individual, live or cadaver
Diabetic lesions: in nephropathy, microscopic damage to the kidneys; most often the result of chronic hyperglycemia
Cyclosporine: a widely-used immunosuppressive medication
Nerve conduction velocities: a measure of the speed at which electrical impulses travel a nerve path; decreases with increasing neuropathy
Evoked Muscle Action Potential: efficiency of muscle response to measurable stimulus; decreases with increasing neuropathy
HLA matching: "Human Leucocyte Antibody," a test of genetic compatibility between donor and recipient