Pancreas Transplantation

Pancreas Transplantation

PANCREAS TRANSPLANTATION

by G.P. Basadonna, MD,
PhD
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.

Results

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.

Discussion

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.

Glossary:

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