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Journal of Clinical Endocrinology and Metabolism
Copyright © 1998 by The Endocrine Society
Vol. 83, No. 6
Printed in U.S.A.
THERAPEUTIC CONTROVERSY
Pancreas Transplantation for Type I Diabetes*
R. PAUL ROBERTSON, THOMAS V. HOLOHAN, and SAUL GENUTH
“Therapeutic Controversies” are an occasional feature of The Journal of Clinical Endocrinology
and Metabolism. They present the opposing views of invited contributors on a topic. All reprints must
include the complete Therapeutic Controversy, so that each section can be read in context.
Has Pancreatic Transplantation Arrived as a
Therapeutic Option in IDDM?
Simple and Circumspect Answers
R. Paul Robertson, MD
Pacific Northwest Research Foundation and
Division of Metabolism, Endocrinology, and Nutrition
University of Washington,
Seattle, Washington 98122
F
ROM my point of view, there are two responses to this
important clinical question—the simple one and a circumspect one.
The simple answer is “yes.” In one respect this question is
a nonquestion because pancreases are being transplanted
therapeutically all over the United States and Europe on a
daily basis. Over 1200 pancreases were provided to insulindependent melitus (IDDM) diabetic patients at transplant
centers throughout the world in 1997, and almost 10,000 have
been transplanted since the procedure became feasible in
1978 (1). Most frequently, pancreases are transplanted simultaneously with kidneys in patients who have renal failure and who have had IDDM for greater than 20 yr. After
establishment of initial immunosuppression, their daily drug
regimen usually consists of prednisone, cyclosporin, and
immuran. More recently, tacrolimus and mycophenolate
mofetil are often substituted for cyclosporin and immuran,
respectively. Ironically, all of these drugs are uniquely problematic for IDDM patients because they all adversely affect
pancreatic islet b-cell function. Nonetheless, conservative
estimates of pancreas survival post-transplant run between
70 –90% at 1 yr; even higher rates are reported by some
groups who are highly restrictive in their choice of recipients.
When the procedure is successful, recipients are totally insulin-independent, have normal levels of glycemia and normal to nearly normal levels of HbA1c (2, 3), and report
improved qualities of life (4, 5). However, at first glance, the
patient mortality rate (1) is very sobering (12% the first year,
Received October 30, 1997. Accepted March 3, 1998.
* Address correspondence regarding these controversies and requests for reprints to: Saul Genuth, Division of Endocrinology, Mt. Sinai
Health Care System, Case Western Reserve University, One Mt. Sinai
Drive, Cleveland, Ohio 44106-4198. Reprints of the Therapeutic Controversies will include all authors and all pages, as they appear in the
journal.
with a gradual increase thereafter). Yet, this rate is uninterpretable because it resembles the natural history of IDDM of
greater than 20 yr duration, and no randomized or even a
case-matched study of pancreas transplantation has ever
been performed. Significantly, the majority of deaths are
cardiovascular in nature and occur beyond 3 months posttransplant, which is outside the perioperative period.
But now the cat is out of the bag—no controlled studies.
Thus arises the need to embrace a more circumspect
response.
Surgical history is replete with examples of operative procedures, some good, some bad, that were developed to the
point of daily use by the trial and error approach with rarely
a thought about including sham operations or controls. So,
too, with pancreas transplantation. While one can understand this approach because of the surgeon’s focus on relieving human suffering, it is not very amenable to an evaluation of therapeutic efficacy. Hence, one can only hedge
when pressed for conclusions about the impact of successful
pancreas transplantation on secondary complications of diabetes, graft (both pancreas and kidney) survival rates, and,
most importantly, patient survival rates. In other words,
while it can be said truthfully that successful pancreas transplantation reestablishes insulin independence and normoglycemia and improves quality of life measures, less certainty exists about its impact on chronic diabetic
complications such as retinopathy, nephropathy, and neuropathy. Probably more than 95% of recipients receive their
transplanted pancreases after more than 20 yr of IDDM. The
vast majority already have clinically evident complications,
and many likely have subclinical ones. In the absence of
randomized trials, this makes drawing defensible conclusions difficult, if not impossible. For example, simultaneous
pancreas and kidney transplantation has been shown to protect the transplanted kidney from the adverse effects of hyperglycemia (6 –7), but it is not clear whether the deranged
function or structure of the native, previously damaged kidney is either arrested or improved. Most recently, however,
evidence suggesting improvement in renal structure 10 years
after successful pancreas transplantation has been presented
(8). No visual benefits have been found for patients with
retinopathy (9), but because no controlled studies have ever
been done, no defensible conclusion is possible. On the other
hand, it has been shown that motor and sensory peripheral
nerve conduction velocities benefit from successful pancreas
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THERAPEUTIC CONTROVERSY
transplantation (10). In fact, a generally underappreciated
but hugely important reported benefit is that the 5-yr life
survival rate of patients with autonomic dysfunction jumps
impressively from 50% to 90% after successful pancreas
transplantation (11).
Although circumspection is needed about the consequences of successful pancreas transplantation on the
chronic complications of IDDM, we need not be too pessimistic if one recalls the heartening results of the Diabetes
Control and Complications Trial (DCCT). The DCCT, an
impeccably conducted randomized study of IDDM therapy,
demonstrated definitively that establishment of nearly normal glycemia provides approximately 50% reduction in the
prevalence rates of nephropathy, neuropathy, and retinopathy (12). Arguing from these results, one would expect to do
at least as well, if not better, with successful pancreas transplantation because it achieves even better glycemic results
than the DCCT. In another sense, DCCT underscores the
frustrating lack of controlled trials of the efficacy of pancreas
transplantation.
The Future
If either the simple or circumspect answer I offer were
totally acceptable, Tom Holohan, my worthy opponent in
this debate, would not need to write his opinion following,
nor would Saul Genuth need to find a Solomonic position for
the final piece of this trio. Not knowing what Tom or Saul
will write, I will conclude with some thoughts for the future.
Pancreas transplantation is here to stay until something
better—presumably islet transplantation— comes along and
is proven to be more efficacious. From all reports, closed loop
systems for insulin delivery and gene transfer methods are
even more remotely available to the daily life of diabetic
patients. So why not make the most of a procedure that is
already being performed at least 1000 times annually? Why
not design a controlled trial of this procedure earlier in the
course of diabetes, before secondary complications are manifest? One could easily envision a DCCT-like multicentered
paradigm, wherein primary and secondary prevention arms
are employed in conventionally treated and transplanted
groups to determine cost-benefit ratios, consequences on
secondary complications, and quality of life. If randomization should prove to be unacceptable, then a carefully casecontrolled approach could be designed. Initial caveats that
would need consideration include the lower age limit that
would be acceptable for immunosuppression, who would
pay for the operative procedure and follow-up, and critical
elements of informed consent, to name a few. Designing such
a trial may be a difficult task, but the opposite strategy, just
ignoring this effective procedure because it may seem unfamiliar and perhaps extreme, represents to me a somewhat
ostrich-like position (one not well designed for circumspection) and a not entirely fair proposition for prospective
recipients.
References
1. International Pancreas Transplant Registry Annual Report. 1997;9:1.
2. Robertson RP. 1992 Pancreatic and islet transplantation— cures or curiosities?
N Engl J Med. 327:1861–1868.
3. Robertson RP, Sutherland DER, Kendall DM, et al. 1996 Metabolic charac-
4.
5.
6.
7.
8.
9.
10.
11.
12.
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terization of long-term successful pancreas transplants in type I diabetes. J Inv
Med. 44:1–7.
Piehlmeier W, Bullinger M, Nusser J, et al. 1991 Quality of life in type I
(insulin-dependent) diabetic patients prior to and after pancreas and kidney
transplantation in relation to organ function. Diabetologia. 34 (suppl 1):
S150 –157.
Zehrer CL, Gross CR. 1994 Comparison of quality of life between pancreas/
kidney and kidney transplant recipients: One year follow-up. Transplant Proc.
26:508 –509.
Bohman S-O, Tydén G, Wilczek H, et al. 1985 Prevention of kidney graft
diabetic nephropathy by pancreas transplantation in man. Diabetes.
34:306 –308.
Bilous RW, Mauer SM, Sutherland DER, Najarian JS, Goetz FC, Steffes MW.
1989 The effects of pancreas transplantation on the glomerular structure of
renal allografts in patients with insulin-dependent diabetes. N Engl J Med.
321:80 – 85.
Fioretto P, Steffes MW, Sutherland DER, et al. 1997 Successful pancreas
transplantation (PT) alone reverses established lesions of diabetic nephropathy
(DN) in man. J Am Soc Nephrol. 8:111A.
Ramsay RC, Goetz FC, Sutherland DER, et al. 1988 Progression of diabetic
retinopathy after pancreas transplantation for insulin-dependent diabetes mellitus. N Engl J Med. 318:208 –214.
Navarro X, Sutherland DER, Kennedy WR. 1997 Long-term effects of pancreatic transplantation on diabetic neuropathy. Ann Neurol. 42:727–736.
Navarro X, Kennedy WR, Sutherland DER. 1991 Autonomic neuropathy and
survival in diabetes mellitus: effects of pancreas transplantation. Diabetologia.
34:(Suppl 1):S108 –S112.
DCCT Research Group. 1983 The effect of intensive treatment of diabetes on
the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 329:977–985.
Pancreas Transplantation:
A Wine Before Its Time†
Thomas V. Holohan M.D., FACP
Chief of Patient Care Services
Veterans Health Administration
Department of Veterans Affairs
Washington, DC 20420
A
T its core, this controversy regarding pancreas transplantation is not directed toward what benefits can be
expected in which groups of patients provided simultaneous
(SPK) or sequential (PAK) pancreas-kidney transplant.
Rather, it transcends that topic and reaches a far more critical
issue: what quality and weight of evidence should be required to permit a reasonable conclusion that an intervention
is of proven benefit and thus suitable for widespread
application?
A comprehensive analysis of published data was prepared
for the U.S. Public Health Service (PHS) in 1995 (1). The
assessment, reviewed by PHS and by nonfederal content
experts, found that evidence was insufficient to compel a
judgement that SPK or PAK transplant resulted in prevention or reduction of the secondary complications of diabetes,
improvements in quality of life (QOL), or increased survival
compared with kidney transplant alone with continued insulin treatment. Information published since completion of
the PHS assessment has provided little new data that would
dispute the conclusions of that document.
Despite those findings of uncertain benefit to secondary
complications, and the American Diabetes Association report that reduction of complications was not sufficient justification for transplant (2), advocates continue to claim such
advantages. In 1994 Sutherland (3) stated that the effects of
pancreas-kidney transplant on secondary complications
† The opinions expressed herein are those of the author, and do not
necessarily reflect the views of the Veterans Health Administration or
the Department of Veterans Affairs.
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ROBERTSON ET AL.
were “variable;” in 1996 the same author claimed the procedure can “improve or stabilize neuropathy,” and “new”
nephropathy would be prevented (4). Larsen et al. (5) also
reported that nephropathy is prevented and that “greater
stabilization” of retinopathy results (5). Both of these recent
reports cited Bilous et al. (6) as evidence of a favorable effect
of SPK/PAK upon diabetic nephropathy. That paper, reviewed in detail in the assessment (1), continues to be referenced as a basis for a number of unwarranted conclusions.
Bilous’ study evaluated only 12 PAK recipients, selected in
an unspecified manner from a much larger group. Renal
grafts were present from 1–7 yr before pancreas transplant,
and biopsies were performed between 2 and 10 yr after
pancreas transplant. The controls (13 kidney recipients) had
less than optimal blood glucose control (glycohemoglobin
levels up to 15.3%) and were poorly matched to PAK recipients for duration of diabetes. PAK recipients were reported
to have “minimal” mesangial expansion and kidney recipients “minimal to marked” expansion, but no differences
were noted in basement membrane thickness or creatinine
clearance over 5.0 – 8.6 yr of followup. These data are insufficient to permit conclusions reaching to prevention of clinically relevant nephropathy.
Improvements in QOL were reported after pancreas transplant; almost two dozen studies have been reviewed (1).
Their findings differed as to the degree and even the existence of measurable benefit resulting from SPK or PAK.
Moreover, those reports variably illustrated significant methodological flaws, including but not limited to their retrospective nature; lack of comparable patient groups; dissimilar measurement instruments of undemonstrated relevance
to transplant patients; evaluation of index and comparison
cases at differing time periods post-transplant; and absent or
inadequate safeguards against selection bias. Subsequent reports of QOL in pancreas recipients share some of those
shortcomings. For example, Adang et al. (7) compared only
17 recipients of successful SPK to 5 recipients with subsequent pancreas graft failure. QOL was assessed by a composite of questionnaires. While differences in some measures
marginally favored SPK, the authors themselves noted that
“the study design produces a negative bias” for the failed
graft group, and “a better controlled comparison” would be
between SPK and kidney transplant alone. Piehlmeier et al.
(8) administered the SF-36 to 110 subjects, divided among 5
groups of pre- and posttransplant patients. In only two subscales were QOL measures significantly higher in successful
pancreas-kidney transplants than in those with pancreatic
failure. No comparison was made between recipients of pancreas-kidney and kidney transplant alone.
For these potential but indeterminate benefits, the SPK or
PAK recipient pays a price beyond that of kidney transplant
alone. This must be considered in light of the most recent data
from the United Network for Organ Sharing (UNOS), which
indicate the 5-yr pancreas graft survival is 22.6% for PAK and
61.8% for SPK (9). While SPK does not appear to reduce renal
graft survival below that of cadaver kidney transplant, selection of SPK versus living related donor kidney transplant
(LRD) may not be the most prudent choice. The UNOS data
indicate a significantly higher 5-yr renal graft survival rate
for LRD than cadaver kidney transplant in diabetics (72% vs.
66%). Patient survival rates slightly favor LRD over SPK in
diabetics. However, this must be viewed in the context of the
selection processes for SPK/PAK, which exclude the highest
risk (and least compliant) patients who are provided kidney
transplant alone or no transplant, as well as the fact that
many abnormalities found in pretransplant evaluation (e.g.,
coronary stenoses) are routinely corrected before SPK/PAK
(1, 10, 11). The higher levels of immunosuppression required
in SPK have been associated with increased infections (12, 13)
and malignant disease (14). Length of stay, readmission rates,
morbidity, and number of acute rejection episodes are higher
for pancreas than for kidney transplant (1), and a 12% technical failure rate has been reported for pancreas transplant
(15).
Publication bias favors reports claiming benefit. Moreover,
it is well established that nonrandomized trials generally
overestimate the benefits of an intervention (16, 17). Comparison of the validity and reliability of case series to prospective controlled trials demonstrates the latter’s superiority. For example, extracranial-intracranial bypass surgery to
prevent stroke was utilized and justified on the basis of
published case series for 16 yr before a large multicenter
prospective randomized trial demonstrated the procedure
was both ineffective and harmful (18). Many advocates for
pancreas transplant have commented on the need for prospective studies (19 –23); none have yet been completed by
those authors or by others. They are reminiscent of the character Dickens likened to “a direction post, which is always
telling the way to a place, and never goes there.” Resources
expended for pancreas transplantation have far exceeded the
cost of even the largest multicenter study yet have produced
only marginal evidence from a number of case series. Belief
that concern for individual patients’ well-being mandates the
provision of pancreas transplant to diabetics is misguided.
Indeed, the overriding ethical obligation is to demonstrate
unequivocal efficacy and the elaboration of risks and benefits
of treatments before their routine employment.
The provision of high quality reliable evidence through
methodologically sound investigation is critical to medicine,
and its importance cannot be overemphasized. The current
environment is marked by increasingly costly care, limited
resources, administrative ascendancy over medical practice,
and escalating debate and acrimony over the management of
health care at governmental and private sector levels. In such
a milieu we owe it to our patients, our profession, and our
citizenry to investigate carefully, to form precise and discrete
judgments, and to be as certain as possible that the interventions we offer will provide unambiguous benefit before
proposing their application as a standard of care.
References
1. Holohan TV. 1995 Simultaneous pancreas-kidney and sequential pancreas
after kidney transplantation. Public Health Service, Agency for Health Care
Policy and Research. Health Technol Assess. 4:1–53.
2. American Diabetes Association. 1992 Pancreas transplantation for patients
with diabetes mellitus. Diabetes Care. 15:1668 –1672.
3. Sutherland DE. 1994 State of the art in pancreas transplantation. Transpl Proc.
26:316 –20.
4. Sutherland DE. 1996 The case for pancreas transplantation. Diab Metab.
22:132–138.
5. Larsen JL, Stratta RJ. 1996 Pancreas transplantation: a treatment option for
insulin-dependent diabetes mellitus. Diab Metab. 22:139 –146.
THERAPEUTIC CONTROVERSY
6. Bilous RW, Mauer SM, Sutherland DE et al. 1989 The effects of pancreas
transplantation on the glomerular structure of renal allografts in patients with
insulin-dependent diabetes. N Engl J Med. 321:80 – 85.
7. Adang EM, Engel JL, van Hoof JP, et al. 1996 Comparison before and after
transplantation of pancreas-kidney and pancreas-kidney with loss of pancreas—a prospective controlled quality of life study. Transplantation. 62:754 –758.
8. Piehlmeier W, Bullinger M, Kircheberger I, et al. 1996 Evaluation of the
quality of life of patients with insulin-dependent diabetes mellitus before and
after organ transplantation with the SF-36 health survey. Eur J Surg.
162:933–940.
9. Annual Report. 1996 The United Network for Organ Sharing.
10. Elkhammas EA, Henry ML, Tesi RJ, et al. 1992 Combined kidney-pancreas
transplantation at the Ohio State University hospitals. Clin Transpl. 191–197.
11. Rosen CB, Frohnert PP, Velosa JA, et al. 1991 Morbidity of pancreas transplantation during cadaveric renal transplantation. Transplantation.
51:123–127.
12. Benedetti E, Greussner AC, Troppman C, et al. 1996 Intra-abdominal fungal
infections after pancreatic transplantation: incidence, treatment, and outcome.
J Am Coll Surg. 183:307–316.
13. Lumbreras C, Fernandez I, Velosa J, et al. 1995 Infectious complications
following pancreatic transplantation: incidence, microbiological and clinical
characteristics, and outcome. Clin Infect Dis. 20:514 –520.
14. Martinenghi S, Dell’ Antonio G, Secchi A, et al. 1997 Cancer arising after
pancreas and/or kidney transplantation in a series of 99 diabetic patients.
Diabetes Care. 20:272–275.
15. Sutherland DE, Greussner A, Moudry-Munns K. 1994 International pancreas
transplant registry report. Transpl Proc. 26:407– 411.
16. Sacks H, Chalmers TC, Smith H. 1982 Randomized versus historical controls
for clinical trials. Am J Med. 72:233–240.
17. Schulz KF, Chalmers I, Hays RJ, et al. 1995 Empirical evidence of bias:
dimensions of methodological quality associated with estimates of treatment
effects in controlled trials. JAMA. 273:408 – 412.
18. Barnett HJ, Peerless SJ, Fox AJ, et al. 1985 Failure of extracranial-intracranial
arterial bypass to reduce the risk of ischemic stroke: Results of an international
randomized trial. Report of the EC/IC Bypass Study Group. N Engl J Med.
313:1191–1200.
19. Sutherland DE, Greussner R, Gillingham K, et al. 1991 A single institution’s
experience with solitary pancreas transplantation: a multivariate analysis of
factors leading to improved outcome. Clin Transpl. 141–52.
20. Van Oosterhout EC, van der Woude FJ, Lemkes HH, et al. 1992 Simultaneous
pancreas and kidney transplantation: a feasible procedure in selected patients.
Netherlands J Med. 41:194 –207.
21. Konigsgrainer A, Miller K, Kieselbach D, et al. 1990 Course of diabetic
retinopathy after pancreas transplantation. Transpl Proc. 22:689 – 690.
22. Piehlmeier W, Bullinger M, Nusser J, et al. 1992 Quality of life in diabetic
patients prior to or after pancreas transplantation in relation to organ function.
Transpl. Proc. 24:871– 873.
23. Milde FK, Hart L, Zehr P. 1992 Quality of life of pancreatic transplant recipients. Diabetes Care. 15:1459 –1463.
Pancreas Transplantation for Type 1 Diabetes—
A Summation
Saul Genuth
Division of Endocrinology
Mt. Sinai Health Care System
Case Western Reserve University
Cleveland, Ohio 44106-4198
T
HAT the current status of pancreas transplantation in
the treatment of Type 1 diabetes is controversial is clear
from the two sharply drawn opinions of Dr. Holohan, who
expresses the skeptic’s view, and Dr. Robertson, who expresses the cautious advocate’s view. Is one position right
and the other position wrong, or is there a middle ground to
occupy?
Over 9,000 pancreas transplants have now been reported
to the International Registry, approximately 70% of them
performed in the United States. For the past 2 years, the
yearly rate has exceeded 1,000 worldwide (1). Thus in one
sense, Dr. Robertson is correct: the procedure has become de
facto, a clinical option being offered to substantial numbers
of patients with Type 1 diabetes. On the other hand, if one
conducts a search of recent literature on pancreas transplantation, one is inundated by papers. This indicates a treatment
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still under study, whose practitioners feel obligated to report
both their good and bad experiences with it— but only as case
series, not as controlled trials.
Perhaps a referee should start by asking what ought to be
demanded of a pancreas transplant, what can it currently
deliver, and what is the clinical cost?
Practically speaking, patients want freedom from insulin
injections, hypoglycemia, blood glucose monitoring, dietary
restrictions, and insufficiently spontaneous lifestyles. Diabetes scientists would like complete normalization of carbohydrate, fat, and protein metabolism. Conscientious physicians could do without the enormous demands on their time
and the too frequent feelings of frustration and inadequacy
generated by inability to manipulate insulin regimens, dietary intake, and exercise patterns according to blood glucose
monitoring so as to achieve the goals of metabolic control
currently urged upon them (2, 3). Everyone would like to
prevent the long-term complications of diabetes and stop
their progression or even reverse them in patients already
afflicted. All of this should be achieved with acceptably low
rates of surgical morbidity and mortality, with satisfactory
functioning life spans of the grafts and of the patients, and
with no serious consequences from the required immunosuppressed state.
Of the desired outcomes of pancreas transplantation, several are met. Blood glucose profiles (and hemoglobin A1c)
are maintained at virtually normal levels at the cost of mild
insulin resistance and peripheral hyperinsulinemia, probably related to the systemic rather than portal delivery of
insulin by pancreas transplants (4 –9). Patient lifestyles are
much freer, although they are impacted by the need to take
immunosuppressive drugs and endure their side effects, to
have periodic blood testing, to be alert to any signs of either
pancreas rejection or serious infection, and to be treated
promptly for such occurences. The burden of diabetes care
of these patients is often shifted from primary care physicians, diabetologists, and endocrinologists to a team of transplant physicians. While the discussants disagree on whether
improvement in quality of life has been rigorously proven,
some patients at least are certainly enthusiastic and grateful
for the change in their lives wrought by a successful pancreas
transplant. Because the vast majority of pancreas transplants
have been and are being performed simultaneously with
kidney transplants, most recipients already have quite advanced retinopathy and neuropathy accompanying their final stage of nephropathy. Thus, it may be unrealistic to
expect a metabolically successful pancreas transplant very
often to reverse proliferative retinopathy or clinically significant macular edema that has already required laser therapy,
or neuropathy that has already led to amputation or to debilitating gastropathy, enteropathy, severe orthostatic hypotension, or impotence. It may even be too much to expect a
pancreas transplant to halt whatever progression might still
be possible in the late stages of these complications. Thus, the
real nub of the value argument comes down to the question
of whether retinopathy, nephropathy, and neuropathy could
be prevented if a pancreas transplant were provided alone
and much earlier in the course of Type 1 diabetes. This
possibility is suggested by some DCCT data (10, 11). This
position is reached by both discussants in the debate, and
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ROBERTSON ET AL.
each would like a randomized clinical trial to answer the
question. Dr. Holohan demands it before accepting pancreas
transplantation into clinical practice, and Dr. Robertson
urges that one be done even though he already approves of
continued careful use of pancreas transplants without a trial.
What are the surgical success and safety rates that can be
expected presently? Dr. David Sutherland, a surgical pioneer
and advocate for almost routine addition of a pancreas to
kidney transplantation, and in carefully selected instances
pancreas-after-kidney transplantation or even pancreas
transplantation alone (1, 12), recently reported functioning
graft survival rates over the past decade (1). These are shown
in Table 1. The best results are obtained with simultaneous
pancreas-kidney transplants, presumably because kidney rejection is detected earlier than pancreas rejection, causing
antirejection therapy to be instituted sooner and preserving
the pancreas. More recent figures from the United States
covering the period of 1994 –96 show 1-yr patient survival of
93%, kidney survival 88%, and pancreas survival 81%; and
all these figures are only slightly lower at 2 yr (1). Dr. Robertson cites an even higher 1-yr patient mortality rate of 12%
and considers this figure “reminiscent of the natural history
of IDDM of more than 20 yr duration.” However, the death
rate in Type 1 diabetes from the period of 20 – 40 yr duration
averaged only 2% per year in a large series of patients followed regularly in Denmark (13) in an era before many broad
spectrum antibiotics or aggressive interventional treatment
of coronary artery disease were available. Thus, I believe that
pancreas transplantation does significantly accelerate the
mortality rate in the first year after the operation is performed. In addition, numerous nonfatal surgical complications (12, 14 –16), serious infections (17, 18), immune complications (19), and even unexpected malignancies (20) cast
some pall over this procedure.
Dr. Holohan also emphasizes the high cost of the pancreas
transplant; one recent estimate was $106,000 (21). In addition,
early readmissions to the hospital after transplantation can
average 1.5 per patient (22). The financial argument, however, does not sway me much against use of pancreas transplantation. Why should not individual diabetic patients receive the best treatment specific for them, even granting that
pancreas transplant cannot be considered immediate or directly life-saving treatment, as are liver, heart-lung, and kidney transplants?
Given the above facts, no one can really disagree with the
assertion of both discussants that a randomized clinical trial
comparing pancreas transplantation to exogenous insulin
TABLE 1. Functioning pancreas transplant graft survival rates
1987–1996
Number
SPK
PAK
PTA
3989
375
229
Percent survival
1 yr
3 yr
79
60
57
71
40
40
SPK, simultaneous pancreas-kidney transplant; PAK, pancreas
after kidney transplant; PTA, pancreas transplant alone. Results in
the table are for bladder drainage procedures. Results for SPK with
enteric drainage were 72% at 1 yr and 64% at 3 yr. (Data from
Sutherland DR and Gruessner RWG; ref. 1).
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therapy would be very desirable. Dr. Robertson envisions “a
DCCT-like multicentered paradigm wherein primary and
secondary prevention arms are employed in conventionally
treated and transplanted groups.” The outcomes to be compared should include patient survival rates, incidence of
retinopathy, nephropathy, neuropathy, quality of life, and
long-term cost. However, the more one thinks about designing and implementing such a randomized clinical trial, the
more difficult the project seems, even by comparison to the
DCCT (which was hard enough to bring off successfully). A
number of significant problems may have to be solved:
1. What does Dr. Robertson mean by the term “conventionally treated”? In the DCCT sense of the term, conventional treatment meant no more than 2 injections of
mixed insulin preparations a day. But the DCCT results
clearly demonstrated the inferiority of such therapy,
with respect to microvascular and neuropathic complications, which is why current standards of care call for
DCCT-like intensive treatment in Type 1 diabetes
whenever safely possible (3). It would not be proper to
use a conventional insulin regimen like that of the
DCCT as a comparison group to pancreas transplant.
Rather, the comparison group would have to receive
intensive insulin treatment consisting of blood glucose
monitoring 3– 4 times a day, with insulin being delivered either by 3– 4 syringe injections or by continuous
sc infusion with an external pump, the doses being
adjusted by blood glucose algorithms. Assuming an
achievable mean HbA1c of 7.0% in a research medical
treatment group and a mean HbA1c of 6.0% in the
pancreas transplant group, the published DCCT analyses of the risk of retinopathy vs. HbA1c (23) would lead
to estimates of absolute retinopathy event rates in these
two groups of patients of 1.17 vs. 0.52 events per 100
patient years. Either a very large sample size or a very
long trial duration would be needed to demonstrate
such a relatively small difference between surgical and
medical treatment in the prevention of retinopathy and
likely of nephropathy and neuropathy as well.
2. The investigators would have to agree to an “intention
to treat” analysis of efficacy. If only transplants that
functioned throughout the trial follow-up period
counted, i.e. a “treatment or protocol-implemented
analysis,” it would almost be a foregone conclusion that
HbA1c and, therefore, rates of microvascular complications would be lower in the transplant group. This
follows from the secondary analyses of the DCCT results, which suggest (but do not prove) that hyperglycemia is a major contributing cause of retinopathy, nephropathy, and neuropathy (23). Therefore, we can
almost be sure that pancreas transplants that function
as they are supposed to will prevent complications
more effectively than the best exogenous insulin treatment we can currently muster. However, there is still a
“technical failure rate,” quoted at 9% for pancreases
transplanted in 1994 –1996 (1). Therefore, the real question a clinical trial must answer is which patients would
have better outcomes in the long run, no matter what
the early post-operative fate of the transplant is.
THERAPEUTIC CONTROVERSY
3. Another analytical problem one can envision is how
properly to compare the safety of surgical and medical
insulin replacement therapy. The only important adverse effect of treatment they have in common is death;
in the one case, death from surgical complications, from
serious infections or from malignancies caused by immunosuppression, in the other case, death from severe
hypoglycemic episodes or from autonomic dysfunction, and in both cases, premature death from cardiac
disease. But how would one make a quantitative comparison of the serious but nonfatal surgical and immunosuppressive adverse effects of pancreas transplantation with the serious but nonfatal episodes of coma,
convulsions, neurological injury, or major trauma
caused by severe hypoglycemia? Disagreement regarding quality of life assessments pale in importance when
contrasted with the problem of comparing the relative
gravity of serious but dissimilar adverse effects of the
two treatments.
4. Recruitment difficulties, alluded to by Dr. Robertson,
can also be expected. How many patients would be
willing to accept random assignment either to intensive
medical therapy or to a major operation and lifetime
immunosuppression not dictated by a life-saving kidney transplant, even if institutional review boards
would approve such a trial as ethically acceptable? How
could some selection bias be avoided? Such a research
trial could only be performed at centers with long experience and excellent results with pancreas transplants. In such centers, might the surgeon investigator
unconsciously steer the best surgical candidates to the
clinical transplantation program leaving the poorer surgical (and possibly medical) candidates for the research
transplant study. The very study cited by Dr. Holohan,
a randomized clinical trial that showed no benefit of
extracranial bypass surgery over medical therapy in the
prevention of stroke (24) was later criticized (25, 26) for
the very fact that many more patients were operated on
at the participating centers outside the clinical trial than
as research volunteers. This phenomenon may cast
some doubt on the representative nature of the research
sample of subjects in a trial and the generalizability of
its results.
5. Other practical issues such as the cost and length of such
a trial, the willingness of funding agencies to underwrite it, and the desirable long-term stability of clinical
investigators in the current uncertain academic environment need to be considered. All of the above problems lead me to the pessimistic view that a definitive
randomized clinical trial, as desired by both discussants, that compares pancreatic transplantation alone to
standard of care medical therapy of Type 1 diabetes is
not likely to be conducted soon.
If that is true, then physicians, especially endocrinologists,
and patients will continue to have to make individual decisions based on the de facto availability of pancreas transplantation, the accumulating scientifically imperfect evidence regarding its efficacy and safety, and the locally available
options and results. How should this controversial therapy
1873
be used? Recommending a pancreas transplant to go along
with a kidney does not add much of an extra immunosuppressive burden, but the extra surgical morbidity and mortality argues against automatically and always “throwing in
a pancreas.” Pancreas after kidney transplant or pancreas
transplant alone should be used very sparingly. The best
candidates for pancreas transplant are patients with Type 1
diabetes whose lives are literally miserable and who are in
danger of metabolic death from exogenous insulin treatment
because of severe hypoglycemic reactions. These can be
caused either by hypoglycemia unawareness or by patient
behavior that cannot be modified by persistent education or
experience. A second less attractive group of candidates are
patients who have frequent inexplicable episodes of diabetic
ketoacidosis despite extensive and exhaustive efforts by the
diabetes care team to prevent them. Such patients are often
adolescents, and in that group surgery should probably seldom be offered unless the same pattern persists into young
adult life, when the patient can at least make a decision less
influenced by adolescent emotional storms. On the other
hand, success rates are generally better under age 45 (1, 12).
The hardest patients for whom to assess the suitability of
pancreas transplantation are those adults who simply hate
their diabetes and no longer wish to tolerate frequent selfblood glucose monitoring, insulin injections or use of a
pump, and regimented meal planning. Such patients may be
chronically depressed and feel unable to function or lead
reasonable lives because of their treatment regimen. Here we
leave the realm of science and enter the realm of whatever is
left of the “art of medicine” in the 20th century. The physician’s obligation to the truly desperate patient is to make as
certain as possible that the patient and family completely
understand that the choice of pancreas transplantation, with
or without a kidney, may lead to early death or to misery
from surgical complications equal to the misery they ascribe
to medical treatment; that no reversal of existing retinopathy,
nephropathy, or peripheral neuropathy can be promised;
that a different medical regimen of immunosuppressive
drugs, blood drawing, and rejection surveillance will replace
the diabetic regimen. Having comprehended all that, if the
patient still insists he/she wants a pancreas transplant, preferably when a kidney transplant is required, the diabetes
physician should not stand in the way but should facilitate
exploring the option by appropriate referral. Finally and
obviously, if a pancreas transplant turns out badly, the physician should never descend to an “I warned you” position
but should support the patient through his/her tribulations
and reassume responsibility for excellent glycemic control.
The decision to advocate or to receive a pancreas transplant today will also depend on how soon competitive and
likely superior methods of insulin replacement (16), such as
islet allotransplants or even xerotransplants, autotransplantation of non-b cells genetically reengineered to secrete insulin physiologically, or long-lasting closed-loop implantable insulin delivery systems, achieve clinical realization in
practice. Till then, we endocrinologists have little choice but
to add very selective use of a pancreas transplant, almost
always simultaneous with a kidney transplant, to the treatment options for Type 1 diabetes. We should be well-versed
in its advantages and disadvantages and have a clear idea
1874
ROBERTSON ET AL.
when to recommend it or to facilitate a patient’s request for
it. The longer it takes for less invasive and less risky forms
of superior insulin replacement to be perfected, the more
pancreas transplants will likely be performed, unless some
new piece of evidence interdicts their use. However, just as
with current intensive exogenous insulin treatment regimens, pancreas transplantation should only represent a transient phase in the history of diabetes. The sooner both these
forms of therapy are replaced by islet transplantation or other
b-cell equivalent therapy, the better.
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