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Pancreas Transplantation for Type 1 Diabetes— A Summation

R. Paul Robertson, MD

Thomas V. Holohan, M.D., FACP

Saul Genuth,

Pacific Northwest Research Foundation and Division of Metabolism, Endocrinology, and Nutrition University of Washington, Seattle, Washington 98122
Chief of Patient Care Services Veterans Health Administration Department of Veterans Affairs Washington, DC 20420
Division of Endocrinology Mt. Sinai Health Care System Case Western Reserve University Cleveland, Ohio 44106-4198

Has Pancreatic Transplantation Arrived as a Therapeutic Option in IDDM? Simple and Circumspect Answers

FROM 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 insulin-dependent 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 ß-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, 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 post-transplant, 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 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 case-controlled 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.

AT 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 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, 20, 21, 22, 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.

THAT 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 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, 5, 6, 7, 8, 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 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, 15, 16), serious infections (17, 18), immune complications (19), and even unexpected malignancies (20) cast some pall over this procedure.

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 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.
   
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 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 self-blood 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-ß 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 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 ß-cell equivalent therapy, the better.

Footnotes

¹ 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.

² 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.

Received October 30, 1997.

Accepted March 3, 1998.

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