Robert J. Stratta, M.D.
Department of Surgery (Divison of Transplantation)
University of Tennessee Memphis
DCCT: Diabetes Control and Complications Trial
ESRD: End Stage Renal Disease
HLA: Human Leukocyte Antigen
IDDM: Insulin Dependent Diabetes Mellitus
IPTR: International Pancreas Transplant Registry
KTA: Kidney Transplant Alone
MMF: Mycophenolate Mofetil
PA: Pancreas Alone
PAKT: Pancreas After Kidney Transplant
PTX: Pancreas Transplant
SKPT: Simultaneous Kidney-Pancreas Transplant
UNOS: United Network for Organ Sharing
US: United States
USRDS: United States Renal Data System
We gratefully acknowledge the expertise of Joyce Lariviere in preparation of the manuscript.
Diabetes mellitus afflicts approximately 6% of the population and is the third most common disease and the fourth leading cause of death by disease in the United States (US). Of the estimated 16 million diabetic patients in the US, about 10 million are diagnosed, 4 million take insulin, and 1 million have insulin-dependent diabetes mellitus (IDDM).1 Nearly 30 000 new cases of IDDM are diagnosed each year, and the incidence is increasing. The syndrome of IDDM includes not only abnormal glucose metabolism but also specific long-term complications such as retinopathy, nephropathy, and neuropathy. Although some patients escape the problems associated with IDDM, many patients develop symptomatic complications within an average of 15-20 years following diagnosis and may manifest several complications concurrently. Diabetes mellitus is currently the leading cause of blindness in adults, the number one disease cause of amputations and impotence, and ranks among the leading chronic diseases of childhood. In addition, diabetes mellitus is associated with accelerated atherosclerosis, abnormal lipid metabolism, cardiovascular disease, and directly accounts for more than 170 000 deaths per year in the US. Life expectancy for patients with IDDM is at least ten years less than for those without diabetes. IDDM has been found to be an independent risk factor for both coronary artery disease and cardiac death with an estimated 80% of diabetic patients dying of atherosclerotic complications. The relative mortality from cardiovascular disease is increased 40-fold in IDDM patients with diabetic nephropathy as compared to the non-diabetic population.2,3
Approximately 35% of patients with IDDM develop clinical nephropathy, making diabetes the leading cause of end stage renal disease (ESRD) in the US.2 In IDDM patients with persistent proteinuria, greater than 75% will develop ESRD (or die) after an average of six years. The 2000 US Renal Data System Annual Report noted that of 323 821 patients receiving either dialytic therapy or a kidney transplant through 1998, 107 613 had diabetes, which is a prevalence rate of 33.2%.3 Furthermore, of the 85 520 new cases of ESRD in 1998, 36 904 (43.2%) were listed as diabetic. In 1998, diabetes mellitus was also the single leading cause of ESRD for both cadaver donor and living-donor kidney recipients. The incidence of end-stage diabetic nephropathy is increasing at nearly twice the average rate compared to all other causes of ESRD. It is estimated that as many as one-half of all newly treated ESRD patients will have diabetes in the new millennium.
The discovery of insulin in 1922 changed IDDM from an acute, rapidly fatal disease into a chronic, inexorable illness. Delivering insulin in a physiologic manner has been an ongoing goal and challenge since insulin was first purified for administration. Although exogenous insulin therapy is effective at preventing acute metabolic decompensation and is life-saving, most patients with IDDM have one or more end-organ complications during their lifetime. Over the past decade, it has become increasingly evident that the microvascular complications of diabetes mellitus result from hyperglycemia. Long-term hyperglycemia may result in excessive glycosylation of circulating and membrane-bound proteins, leading to basement membrane thickening and microangiopathy. Tight glucose control is even more important than previously recognized, as demonstrated by the results of the Diabetes Control and Complications Trial (DCCT).4 The DCCT demonstrated that intensive control of glucose reduced the adjusted mean risk of retinopathy by 76%, slowed the progression of retinopathy by 54%, reduced the occurrence of albuminuria by 54%, and decreased the appearance of clinical neuropathy at five years by 60%. In addition, intensive insulin therapy reduced the development of hypercholesterolemia by 34% and the risk of macrovascular disease by 41%. The results of the DCCT clearly indicated that intensive control of glucose can significantly reduce, but not completely protect against, the long-term microvascular complications of diabetes mellitus. Furthermore, the DCCT suggested the absence of a glycemic threshold for the development of diabetic complications, with total lifetime exposure to glycemia as the principal determinant of risk.5 Therefore, the goal of therapy is to achieve normoglycemia as early and as long as possible. However, intensive therapy in the DCCT had no effect on mortality and was accompanied by a three-fold increase in the risk of severe hypoglycemia, was more expensive, and was more resource-intensive.
Vascularized pancreas transplantation (PTX) was first developed as a means to re-establish endogenous insulin secretion responsive to normal feedback controls. PTX is currently the only known therapy that reliably establishes an insulin-independent euglycemic state with complete normalization of glycosylated hemoglobin levels.6 Increasingly, PTX is being offered to patients who either would benefit from a kidney transplant (simultaneous kidney-pancreas transplant: SKPT) or have had a previously successful kidney transplant (sequential pancreas after kidney transplant: PAKT).7 An increasing number of centers are also performing PTX alone (PA) in diabetic patients with hyperlability and severe hypoglycemic unawareness in the absence of advanced nephropathy.8 With improvements in organ retrieval technology, surgical techniques, clinical immunosuppression, anti-microbial prophylaxis, donor and recipient selection, and diagnostic methodology, success rates for vascularized PTX have increased dramatically.9 As early graft survival rates have improved, the long-term consequences of PTX have become much more important, because the benefits must be balanced against the costs and risks of the procedure and the consequences of chronic immunosuppression. The propriety of PTX has been questioned because of the morbidity associated with the procedure and the lack of controlled trials that demonstrate a significant benefit on secondary complications of diabetes. Despite these concerns, PTX has continued to gain acceptance as an important option for diabetic patients with complications because it is the single most effective method of achieving tight glucose control in the ambulatory setting.
With increasing experience in PTX, short-term patient and graft survival rates have steadily improved in recent years. According to United Network for Organ Sharing (UNOS) Registry Data, the one-year patient, kidney, and pancreas graft survival rates after SKPT from 1996 to 1999 were 95%, 91%, and 85%, respectively.9 In addition to correcting dysmetabolism and freeing the patient from exogenous insulin therapy, data on the long-term aspects of pancreas transplantation and its effect on quality of life are emerging. In this chapter, we will review data pertinent to long-term outcomes and quality of life after PTX.
Improving short-term outcomes following PTX have been reported, but it was not until recently that long-term data have become available. One of the earliest studies on long-term outcomes following SKPT with systemic-bladder (S-B) drainage was reported Sollinger et al.10 The five-year actuarial patient, kidney, and pancreas graft survival rates in 200 consecutive SKPT recipients were 90%, 80%, and 79%, respectively. A total of 23 patients had follow-up of greater than five years. These authors noted that patient and graft survival rates were “very stable” after the second post-transplant year. In 1995, Sutherland and Gruessner analyzed long-term pancreas graft function (>5 years) in 596 cases from the International PTX Registry (IPTR) database.11 For patients who had a functioning pancreas graft at five years, the subsequent ten-year actuarial patient survival rate was 90%, and the pancreas graft survival rate was 76%. Based on this analysis, the authors concluded that insulin independence over a normal life span is “almost certainly possible” with PTX and that patients with stable endocrine function at five years have a low susceptibility to chronic rejection.
In 1996, Bruce et al. reported on 50 SKPT recipients who had good graft function at one year post-transplant and a minimum follow-up of three years.12 Five-year actuarial patient, kidney, and pancreas graft survival rates were 94%, 85%, and 86%, respectively, with a mean follow-up of 4.3 years. Estimated kidney and pancreas half-lives were 15 ± 2 and 23 ± 7 years, respectively. Rejection and death with functioning grafts were the major causes of graft loss. Hospitalizations, acute rejection, graft pancreatitis, dehydration, and severe infections all decreased dramatically after the first year post-transplant. Beyond two years post-transplant, hospital admissions became relatively infrequent, as did transplant-related complications. Psychosocial adjustment and quality of life assessment were both remarkably positive.
In a similar analysis, Sudan et al. reported on 57 SKPT recipients with a minimum follow-up of 4.5 years and a maximum of 7 years.13 Ten-year actuarial patient, kidney, and pancreas graft survival rates were 93%, 82%, and 79%, respectively, with a mean follow-up of 5.7 years. Chronic rejection was a major cause of graft loss. The number of hospital admissions decreased significantly with increasing time after SKPT from a mean of 1.2 admissions per patient during the second year after SKPT to a mean of 0.2 admissions by year six.
In 1997, Martin et al. evaluated the post-transplant outcome of 89 patients with pancreas graft function for more than three years (range 3-13 years) and concluded that long-term pancreas graft function is now comparable to other transplanted organs.14 Long-term stable endocrine function was better with total (versus segmental) pancreas grafts and improvements in diabetic neuropathy (sensory and motor nerve function, bladder function) and stabilization of retinopathy were found after five years of normoglycemia. Chronic rejection was the most important cause of late graft loss, but the incidence of late graft loss was low after three years of function.
In 1997, Bloom et al. evaluated long-term pancreas allograft outcomes in 71 SKPT recipients including 37 with bladder and 34 with enteric exocrine drainage.15 Five patients in each group experienced early pancreas graft loss and were excluded from further analysis. In the remaining 61 patients, the mean follow-up for bladder and enteric drainage was 76 and 46 months, respectively. The incidence of volume depletion, acidosis, pancreatitis, and urinary tract infection was lower in patients with enteric drainage. In addition, 19% of patients with bladder drainage subsequently required conversion to enteric drainage for intractable complications. Moreover, the number of readmissions and in-hospital days were less in patients with enteric drainage. Actuarial patient and pancreas allograft survival rates up to four years after transplant were similar between groups and in excess of 80%. Therefore, the findings of this study suggested that long-term outcomes may be improved with enteric drainage, particularly with regard to pancreas-related morbidity.
In 1998, Sollinger et al. reported their experience with 500 consecutive SKPTs, including 388 with bladder drainage and 112 with enteric drainage.16 Ten-year actuarial patient, kidney, and pancreas graft survival rates were 76%, 67%, and 67%, respectively. Conversion from bladder to enteric drainage was required in 24% of cases, but no graft was lost as a result of enteric conversion. There was no difference in one-year graft survival rates between enteric and bladder drainage. Leading causes of pancreas graft loss were rejection in 45 patients and death with functioning grafts in 27 patients. Since June 1995, a total of 109 SKPT recipients were managed with mycophenolate mofetil (MMF) therapy. In this latter group, one-year patient and graft survival rates were in excess of 90% and a marked reduction in rejection was noted. These authors concluded that ten-year graft survival rates exceed those of all other transplants, with the exception of human leukocyte antigen (HLA)-identical living related kidney grafts.
In 1998, Najarian et al. analyzed long-term pancreas graft function (>10 years) in 34 cases performed at the University of Minnesota.17 The authors concluded that “indefinite pancreas graft function seems possible,” with the longest functioning graft currently at 17 years. In patients with stable endocrine function at one-year, a low rate of chronic rejection was noted, similar to that of other transplanted organs. Also in 1998, Henry et al. reported long-term outcomes in 300 consecutive SKPT recipients.18 Five-year patient, kidney, and pancreas graft survival rates were 80%, 68%, and 68%, respectively. Death remote to transplantation, but with functioning grafts, was the most common cause of graft loss. The authors concluded that SKPT provides a superior alternative for the IDDM patient with ESRD.
In 1999, Peddi et al. analyzed retrospectively long-term outcomes in 59 SKPT recipients with both grafts functioning at one year post-transplant.19 At a mean follow-up of 50 months (range 24-101), there were 5 deaths (8.5%), 11 renal allograft losses (19%), and 9 pancreas graft losses (15%). The 5-year Kaplan-Meier patient, kidney, and pancreas graft survival rates were 88%, 79%, and 82%, respectively. Death with functioning grafts and chronic rejection were the major causes of graft loss. Pre-existing cardiac and vascular disease contributed to ongoing morbidity and mortality in these patients.
In 2001, Lo et al. retrospectively reviewed long-term outcomes in SKPT recipients with either portal-enteric (P-E) or S-B drainage.20 A total of 45 patients were alive with functioning grafts one year after SKPT and were followed for a minimum of three years (mean 7 years) including 26 with P-E and 19 with S-B drainage. In both groups, hospital admissions decreased significantly with increasing time after SKPT. Renal and pancreas allograft functions were similar between the two groups. At one year post-transplant, stabilization in most diabetic complications was reported. Four quality of life surveys that provided 29 scores were completed 6-24 months (mean 18.5 months) after SKPT. Improved quality of life was reported in all but one of the scales, with many dimensions showing significant improvements. At three years after transplant, no activity limitation was reported in 76% of patients after P-E versus 53% after S-B drainage. Five-year actuarial patient, kidney, and pancreas graft survival rates were 92% P-E and 84% S-B, 81% P-E and 79% S-B, and 88% P-E and 74% S-B, respectively (P=NS). The authors concluded that SKPT with P-E drainage is a safe and effective method to treat advanced diabetic nephropathy and is associated with decreasing morbidity, improving rehabilitation and quality of life, and stable metabolic function over time. Long-term prognosis after the first year was excellent and was at least comparable to the results achieved with S-B drainage.
In 1997, Tibell et al. reported an eight-year patient survival rate of 86% after SKPT versus 47% in diabetic patients undergoing kidney transplantation alone (KTA).21 The control group consisted of patients originally considered eligible for SKPT but either the donor pancreas was not deemed suitable during procurement or the pancreatic graft was lost early after transplant. In a follow-up study from this group, Tyden et al. presented ten-year data on 14 patients with IDDM who underwent SKPT versus a control group of 15 IDDM patients receiving KTA.22 The ten-year patient survival rate was 79% after SKPT versus 20% after KTA. The SKPT recipients were noted to have normal glucose control, improved nerve conduction and autonomic function, better quality of life, and a significantly lower mortality than the control group of IDDM patients undergoing KTA.
In 1999, Smets et al. performed a registry study in the Netherlands of 415 IDDM patients with ESRD between the ages of 18 to 52 years who began renal replacement therapy between 1985 and 1996.23 The patients were divided into two geographic areas based on whether the primary intention to treat was with SKPT versus KTA. In the Leiden region, 41 (73%) of 56 transplanted patients received SKPT, while only 59 (37%) of 158 transplanted patients in the non-Leiden area underwent SKPT. The authors compared mortality in the two regions after making adjustments for age, gender, and duration of dialysis pretransplant. In the region in which SKPT was the preferred treatment option, transplant recipients had a 60% lower five-year mortality (hazard ratio for mortality was 0.4). The ten-year actuarial patient survival after transplant was nearly 80% in the Leiden area versus 40% in the region in which KTA was the predominant treatment. The authors concluded that the 50% reduction in mortality in patients transplanted in the Leiden area was attributable to the higher rate of SKPT versus KTA in this region.
In the largest single center report from the University of Wisconsin, Becker et al. demonstrated that SKPT recipients (n=335) have an increased observed/expected life span compared with cadaveric kidney (n=147) and living donor kidney (n=160) IDDM recipients.24 The annual mortality rate was 1.5% for SKPT recipients compared to 6.3% for cadaveric kidney recipients and 3.7% for living donor kidney recipients. In a follow-up study from the University of Wisconsin, Rayhill et al. used a longitudinal database to compare survival rates among IDDM patients undergoing either HLA-identical living donor KTA (n=43), haplo-identical living donor KTA (n=87), cadaver donor KTA (n=296), or SKPT (n=379).25 Patient and graft survival rates were comparable for living donor KTA and SKPT, but significantly lower in cadaveric donor KTA recipients. Cardiovascular disease was the primary cause of death in all groups. Acute rejection, chronic rejection, and death with a functioning graft were the predominant causes of graft loss. Five-year patient (94%) and graft (85%) survival rates were slightly higher in HLA-identical living donor KTA recipients, but no differences were noted between SKPT and haplo-identical KTA recipients. In another follow-up study, Sollinger and colleagues from the University of Wisconsin analyzed their single center experience with 335 SKPTs compared to IDDM patients undergoing either cadaveric or living donor KTA.26 According to life-table analysis, diabetic recipients attained more of their projected life expectancy when transplanted with both organs. SKPT increased the observed versus expected life span compared to KTA (regardless of donor source), and was associated with reduced annual mortality rates.
Reddy et al. studied the UNOS database and analyzed 18 549 patients with IDDM and ESRD who received a kidney transplant between 1987 and 1996.27 Of these, 9956 underwent cadaveric donor KTA, 3991 living donor KTA, and 4602 SKPT. Mean follow-up was 4.8 years in survivors. The eight-year actuarial survival rates were 72% for both SKPT and living donor KTA recipients as compared to 55% for cadaver donor KTA recipients. Using a proportional hazards model, the survival advantage for SKPT recipients over cadaveric donor KTA recipients diminished but persisted after adjusting for donor and recipient variables and kidney graft function as time-varying covariants. SKPT recipients had a high mortality risk relative to living donor KTA recipients for the first 18 months post-transplant (RR=2.2), but had a lower mortality risk thereafter (RR=0.86). In SKPT recipients, maintenance of a functioning pancreas graft was associated with a significant survival benefit. In a similar analysis, Hunsicker et al. analyzed outcomes from the 1997 UNOS Center- Specific report in 2304 SKPT recipients with kidney graft function at one year.28 Of these, the pancreas graft was still functioning at one year in 2010 patients and had failed in 294. Presence of a functioning pancreas graft was associated with a 53% reduction in mortality after one year, a 47% reduction in total renal graft failure, and a 45% reduction in renal graft failure censored for death with a functioning graft. Patient survival was 15-20% better at ten years in the patients with functioning pancreas grafts at one year. Each of these studies concluded that SKPT is a life-saving procedure.
Ojo et al. used data from the US Scientific Renal Transplant Registry and from the US Renal Data System (USRDS) database to analyze long-term outcomes in IDDM patients with ESRD who were placed on the active transplant waiting list between 10/01/88 and 06/30/97. A total of 13 467 evaluable wait-listed patients were followed until 06/30/98.29 Time-dependent mortality risks and life expectancy were calculated for the study group which included 4718 SKPT recipients, 4127 cadaveric donor KTA recipients, 671 living donor KTA recipients, and 3951 wait-listed but never transplanted patients on maintenance dialysis. Adjusted ten-year patient survival rates were 67% for SKPT, 65% for living donor KTA, and 46% for cadaveric donor KTA recipients. The excess initial mortality normally associated with kidney transplantation and the risk of early infectious death were two-fold higher in SKPT recipients. However, the adjusted five-year mortality risk (RR) using maintenance dialysis therapy as the reference were 0.40 for SKPT, 0.45 for living donor KTA, and 0.75 for cadaveric donor KTA. The projected life expectancy was 23.4 years for SKPT, 20.9 years for living donor KTA, and 12.6 years for cadaveric donor KTA recipients. No survival benefit was found for SKPT recipients above 50 years of age. The authors concluded that SKPT before the age of 50 years is associated with a long-term improvement in survival compared to either KTA or dialysis.
In 2000, Tyden et al. analyzed 515 patients undergoing transplantation between 1981 and 1988, including 69 SKPT recipients and 44 IDDM patients receiving KTA.30 The actual ten-year patient survival rate in non-diabetic KTA recipients was 72% compared to 60% after SKPT. In SKPT recipients in which the pancreas graft failed within two years, the actual ten-year patient survival rate was 33%, similar to the 37% survival rate seen in IDDM patients undergoing KTA. The authors concluded that a functioning pancreas graft contributes to superior life expectancy after transplantation.
The ultimate goal of PTX is to restore normal glucose homeostasis to prevent secondary complications of diabetes. Several studies have previously demonstrated that short-term metabolic control is more nearly normalized by PTX than any other form of diabetic therapy. A number of recent reports have analyzed long-term metabolic control after PTX. Robertson et al. reported that successful PTX recipients are capable of maintaining insulin secretion that is sufficient to allow maintenance of normoglycemia and normal glycosylated hemoglobin levels for periods extending up to 11 years.6 These authors concluded that PTX, when successful, is the most consistently reliable means of restoring normal insulin secretion and glucose homeostasis in patients with IDDM. In 1998, Tajra et al. studied the long-term metabolic status of 80 patients with functioning PTXs with follow-up ranging from 3-13 years.31 Recipients of whole organ pancreatic grafts had consistently better long-term metabolic control, but segmental pancreatic grafts were able to maintain normal serum glucose and glycosylated hemoglobin levels up to 13 years after PTX. Also in 1998, Tyden et al. studied 33 SKPT recipients with graft function for at least five years, including 21 segmental and 12 whole organ PTXs.32 Excellent metabolic control was documented with both techniques, although recipients of whole-organ PTX had slightly higher stimulated C-peptide levels. The authors concluded that long-term glycemic control remains normal in both recipients of segmental and whole organ PTXs.
In experimental models of canine diabetes, retinopathy, neuropathy, and nephropathy have been shown to develop within five years. Hawthorne et al. performed segmental pancreas autotransplantation with residual pancreatectomy in 35 outbred mongrel dogs with follow-up to five years.33 The authors showed that segmental pancreatic autografts are capable of providing satisfactory metabolic control for up to five years. None of the dogs with functioning PTX developed any evidence for retinopathy, neuropathy, or nephropathy. The authors concluded that the metabolic control achieved by a functioning PTX can prevent the development of long-term microvascular complications of diabetes.
Although successful PTX results in excellent metabolic control with complete insulin independence, there have been sporadic reports of patients returning to insulin therapy either for the development of Type 2 diabetes caused by insulin resistance or autoimmune disease recurrence. In 1996, Jones et al. reported an isolated case of a patient undergoing successful SKPT who subsequently developed fastening hyperglycemia despite hyperinsulinemia.34 This patient experienced rapid weight gain after transplantation, which may have contributed to the development of insulin resistance. However, preliminary experience with SKPT has been favorable in patients with Type 2 diabetes, high C-peptide levels, and presumed peripheral insulin resistance.35 Also in 1996, Tyden et al. reported two cases of autoimmune disease recurrence after SKPT.36 Both patients developed a gradual reduction in fasting C-peptide levels, a more marked reduction in stimulated C-peptide levels, and histologic evidence for selective beta-cell destruction and insulitis in the absence of rejection. In one patient, histologic evidence for insulitis occurred in association with the development of anti-islet cell and anti-glutamic acid decarboxylase (GAD) antibodies. However, in another study monitoring markers for humoral autoimmunity in a longitudinal fashion, no correlation was found between the detection of anti-islet cell or anti-GAD antibodies and pancreas allograft function.37 Since chronic immunosuppression is a requisite for PTX, it is currently believed that recurrent autoimmune diabetes is not inevitable and is probably rare. In addition, because most techniques of PTX result in systemic or peripheral hyperinsulinemia, the development of insulin resistance over the long-term is a theoretical concern that has yet to be borne out by clinical studies.
Based on these analyses, it is concluded that SKPT is a safe and effective method to treat advanced diabetic nephropathy and is associated with decreasing morbidity, improving rehabilitation, and stable metabolic function over time. Long-term prognosis after the first year is excellent and at least provides the potential for improved survival with stabilization of diabetic complications.
The dramatic increase in post-transplant patient and graft survival rates over the last decade has resulted in great interest in quality of life. This is of particular importance for those patients with ESRD and IDDM who not only have symptoms associated with uremia, but complications related to long-standing diabetes. Quality of life is a multi-dimensional construct reflecting an individual’s perception of health, well-being, and happiness. Conceptual aspects include physical function, social function, psychologic function, the burden of symptoms and treatments, and sense of well-being. Various questionnaires and survey instruments are available that assess indices of well-being, affect, satisfaction, activities and daily living, and health care burden. Quality of life surveys do not specifically address any particular physiologic consequence, but they do take into account various factors that are most important to the transplant recipient. These factors include opportunities for social interaction, ability to return to work or maintain employment, overall energy level, and psychological adjustment. There is no question that impaired or poor quality of life is a “secondary complication” of diabetes, particularly in IDDM patients with ESRD.
Most quality of life studies are observational, cross-sectional, retrospective, and non-randomized in design. Another methodologic difficulty is in selecting an appropriate “control” group to compare to PTX recipients such as “matched” patients with diabetes, patients with diabetes on dialysis, patients with diabetes after KTA (cadaver versus living donor), or patients with diabetes after SKPT with a failed pancreas (or kidney) graft. In spite of these limitations, there are at least 30 studies in the recent literature reporting on quality of life after PTX.38-46 Twelve of these studies are prospective and longitudinal, while the remainder are cross-sectional in design, and none are randomized. With regard to methodology, five of these studies involve SKPT, eight SKPT versus KTA, five SKPT versus failed SKPT, six SKPT versus failed SKPT versus KTA, three SKPT versus KTA versus IDDM, two SKPT versus failed SKPT versus IDDM, and one SKPT versus IDDM patients. All but one of these studies show some improvement in quality of life after SKPT, although the differences are not always significant.
Numerous studies have demonstrated that successful SKPT results in improvements in physical function, activities and daily living, energy level, mobility, vocational rehabilitation, social well-being, communication, role function, health perception, self-image, psychologic function, future expectations, sense of well-being, overall satisfaction, diet flexibility, diabetes-related concerns, time to manage health, health impact on family, and autonomy.38-46 The major benefits of PTX are an enhanced quality of life characterized by the following: (1) rehabilitation to “normal” living with physical, social, and psychologic well-being with near normal activities and daily living and a self-perception of normality; (2) global improvement in quality of life with the perception of being healthy and having control over one’s destiny; and (3) fewer restrictions and enhanced capacities leading to an improved sense of well-being and independence.45 Freedom from daily insulin injections and blood glucose monitoring are important advantages for patients with a successful PTX. Although the long-term commitment to immunosuppression is a major trade-off, most patients with diabetes find the transition to transplantation easier than continued insulin therapy because of an improved sense of well-being with fewer dietary and activity restrictions. Immunosuppression is perceived to be easier to manage and less demanding than diabetes.41 Despite the morbidity of SKPT and its increased perceived burden of treatment, when questioned most patients would opt for pancreas re-transplantation.
With the increasing short and long-term success of PTX, the emphasis has shifted from survival outcomes to health-related quality of life. A recent quantitative analysis of the literature revealed 218 studies that examined quality of life following kidney, pancreas, kidney-pancreas, heart, lung, heart-lung, liver, and bone marrow transplantation for nearly 15 000 recipients.40 The majority of studies were cross-sectional with limited follow-up, as 56% evaluated quality of life within one year of transplant, 36% evaluated 1-3 years post-transplant, and 8% evaluated 3 or more years following transplantation. Despite these limitations in study designs, quality of life was found to be universally and substantially improved after transplant for all quality of life domains examined (physical, mental, social, and global). Physical function was more likely to demonstrate improvements than were the other domains. In the few studies that did employ longitudinal designs, quality of life was either stable or improved during the first 7 years following transplantation. These studies indicate that transplantation does improve quality of life, at least in the short-term and perhaps in the long-term as well. Although transplantation has not returned individuals to a totally normal life, the overall majority of successful recipients perceived a marked improvement in quality of life.
It is known from the exercise physiology literature that even mild regular exercise and deep breathing may improve autonomic function. Preliminary data obtained from transplant recipients also indicate that moderate levels of exercise are beneficial for transplant recipients in terms of improving autonomic function. While one can logically infer that physiologic consequences of treatment, such as autonomic neuropathy, are linked with patient perceptions of quality of life, this relationship has been investigated to only limited extent. In a 1994 study, a Path analysis conducted with 56 patients with diabetes found that 15% of the variation and functional variability could be accounted for by measures of autonomic neuropathy.38 If relationships do exist between the physiological consequences of treatment and quality of life, then interventions to facilitate patients’ attainment of optimal quality of life may result in further improvements in autonomic function. Painter et al. studied cardiorespiratory fitness in 25 SKPT and 16 KTA recipients with a mean follow-up of approximately two years.47 SKPT recipients were younger and in general achieved higher levels of cardiorespiratory fitness than KTA recipients. In both groups, patients who self-reported themselves as physically active scored higher than inactive patients, although this difference did not achieve significance.
Because transplant recipients are living longer, interest in long-term quality of life outcomes is emerging. Given the projection that many recipients will live well into the second decade following transplantation, it is important to note that some forms of neuropathy continue to demonstrate improvement in these later years, that neuropathy is associated with mortality as well as quality of life in the transplant population, and that some interventions may be available that improve neuropathic function long-term.48-50 Therefore, it seems apparent that well-designed, longitudinal studies are needed not only to assess quantity but quality of life as well as physiologic function.
The major factors perceived to affect quality of life are immunosuppression and its side effects after SKPT, rejection and physical symptoms after KTA, and diabetes and its complications after a failed pancreas allograft.41 Furthermore, studies have shown that failure of a pancreas allograft after SKPT results in increased fatigue, less energy, an increased need for social support, a net reduction in quality of life, and higher mortality when compared with both SKPT and KTA.41-48 Thus, any studies designed to evaluate the cost-effectiveness of PTX need to balance these factors, particularly a recipient’s ability to return to employment as well as cost savings from prevention or reversal of diabetic complications in addition to the costs associated with the operative procedure, immunosuppression, and graft failure.
Because of the impact that PTX has on quality of life, we are conducting comprehensive, prospective studies examining quality of life changes in this patient population. Since 1990, UT Memphis has included three measurements of quality of life in order to capture as many dimensions as possible.45,51 Functional disability is measured by the Sickness Impact Profile (SIP), while a more positive view of health is measured by the Quality of Life Index (QLI). Psychoemotional dimensions are measured with the Adult Self-Image Scale (ASIS). Each instrument has been used in the transplant population and has documented reliability and validity.45,51 All patients are asked to participate by completing a battery of quality of life instruments that provide a multi-dimensional assessment of this construct. Combined, the instruments yield over 20 scores reflecting specific dimensions of quality of life such as mobility, work, family, anxiety, and independence; composite scores that group specific dimensions into five categories (health-related, physical, psychological, disability, and self-esteem); and one global measure of quality of life that does not separate specific dimensions. These instruments are repeated at 6 and 12 months after PTX and yearly thereafter. This provides us with prospective, longitudinal data regarding the influence of PTX on quality of life.
With the improving short-term success of PTX, long-term prognosis after the first year is excellent and at least provides the potential for stabilization of diabetic complications. We retrospectively reviewed remote SKPT recipients with P-E drainage; 26 patients (65%) were alive with functioning grafts one year after SKPT and were followed for a minimum of three years (mean 5 years).52 Hospital admissions decreased significantly from a mean of 2.4 admissions per patient in the first year to 0.6 by year four. At one year post-transplant, improvements in most diabetic complications were noted. No activity limitations were reported in 80% of patients at one year after SKPT compared to 23% pre-transplant. Four quality of life surveys that provided 29 scores were completed 6-24 months (mean 18 months) after SKPT. Improved quality of life was reported in all but one of the scales. Actual patient, kidney, and pancreas graft survival rates were 92%, 81%, and 89%, respectively. These results demonstrated that SKPT with P-E drainage is associated with decreasing morbidity and improving quality of life over time with intermediate term follow-up.
Improvement in quality of life is one of the major goals of PTX. Current data document the presence of poor overall quality of life in patients with diabetes as compared to their non-diabetic counterparts. It is interesting to note that the baseline quality of life reported for our more recent diabetic patients has generally improved from previous reports. We can only surmise that advances in medical care (erythropoietin) and/or earlier transplant referral may have influenced this outcome. When comparing SKPT to non-diabetic KTA recipients, patients with diabetes pretransplant had a poor quality of life in two of five measures, primarily reflecting greater physical dysfunction and a less positive view of their overall health.45,51,53 Following transplantation, quality of life improved in four of the five categories for both groups. However, at 24 months, a lingering disparity was still noted between non-diabetic KTA and SKPT recipients with respect to physical function and overall health perspective.
Vascularized PTX has assumed an increasingly important role in the treatment of IDDM. SKPT is gaining acceptance as a viable alternative to KTA in transplant recipients with diabetes because of its ability to provide superior glycemic control, improve quality of life, and enhance life expectancy. The greater morbidity (and early mortality) of SKPT can be justified by the mounting evidence that a functioning pancreas graft may prevent, stabilize, or induce regression of diabetic complications coincident with a beneficial effect on quality as well as quantity of life. Although PTX results in euglycemia and complete insulin independence, these results occur at the expense of hyperinsulinemia and chronic immunosuppression. The net result of these changes on diabetic complications in the long-term is currently being studied. In the short-term, improvement in quality of life and possible prevention of further morbidity and mortality associated with diabetes makes PTX an important therapeutic option for selected patients with IDDM. In the future, PTX will remain an important option in the treatment of IDDM until other strategies are developed that can provide equal glycemic control with less or no immunosuppression or less overall morbidity.