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Simultaneous Pancreas-Kidney and Pancreas Transplantation

2001; American Society of Nephrology; Volume: 12; Issue: 11 Linguagem: Inglês

10.1681/asn.v12112517

1533-3450

Bryan N. Becker, Jon S. Odorico, Yolanda T. Becker, Marilyn Groshek, Cathy Werwinski, John D. Pirsch, Hans W. Sollinger,

Diabetes and associated disorders

The discovery of insulin in 1922 changed the treatment of type 1 diabetes mellitus (DM) forever. Insulin was the first effective therapy for type 1 DM; however, its success engendered a terrible paradox for patients with this disease. The use of insulin transformed type 1 DM from a rapidly fatal condition to a chronic incurable illness, revealing the long-term complications associated with DM, e.g., nephropathy, vasculopathy, retinopathy, and neuropathy, and the terrible toll that they take throughout a lifetime. DM now affects approximately 20 million individuals in the United States, with at least 2 million individuals having classic type 1 DM (1). Hyperglycemia, alone or in concert with hypertension, is the primary factor influencing the development of major diabetic complications (2,3). Therefore, correcting hyperglycemia is an obvious strategy for altering the course of DM and its complications. The Diabetes Control and Complications Trial (4) demonstrated that glycemic control could limit the rate of progression of complications in type 1 DM. However, the best available method for achieving a steady euglycemic state among individuals with type 1 DM is wholepancreas transplantation. The goals of pancreas transplantation have developed beyond simply restoring normoglycemia for a period of time and improving the quality of life (QOL) (5). Pancreas transplantation, as simultaneous pancreas-kidney (SPK) transplantation or pancreas transplantation alone (PTA), is now a functional and effective therapy that can reverse metabolic abnormalities (6) and prevent or minimize many of the secondary complications of DM (7). Perhaps even more significantly, pancreas transplantation now seems to be a therapy that can improve survival rates in the setting of type 1 DM (8). Candidates for Pancreas Transplants Pancreas transplantation was first performed in 1966 (9). Since then, nearly 14,000 pancreas transplants have been reported to the International Pancreas Transplant Registry (10). C-peptide-deficient, insulin-dependent patients with type 1 DM and significant nephropathy or end-stage renal disease (ESRD) are potential candidates for SPK transplantation if they are 45 yr), recipient age of >45 yr, and retransplantation (26). Interestingly, cold ischemia time (if <30 h), degree of HLA mismatch, choice of exocrine drainage procedure, and use of anti-T cell antibody therapy do not strongly affect outcomes (26). The increases in graft function rates for PTA are more dramatic than those for SPK transplantation. The United Network for Organ Sharing/International Pancreas Transplant Registry now reports 1-yr pancreatic graft function rates of 76% for PAK transplantation and 72% for PTA (26). These rates represent marked improvements over the 20 to 50% 1-yr graft survival rates for such transplants in the era before University of Wisconsin solution and cyclosporine A (CsA). Several centers have reported even better results, i.e., 85 to 90% 1-yr graft function rates (38). Modern immunosuppression after pancreas transplantation generally includes anti-T cell antibody induction therapy in conjunction with a tacrolimus (TAC)/mycophenolate mofetil (MMF)-based regimen. SPK transplant recipients treated with TAC and MMF experienced 1-yr acute rejection rates of 22% for kidney grafts and 0 to 3% for pancreatic grafts, compared with 77 to 86% and 31 to 51% for kidney and pancreas, respectively, among patients treated with CsA and azathioprine (39). Patients treated with CsA and MMF experienced rejection rates slightly greater than those for TAC/MMF-treated patients (34% for kidney grafts and 5 to 10% for pancreatic grafts) (39). The current 1-yr graft function rates for pancreas (83%) and kidney (90%) reflect these remarkable improvements in decreasing the rate of rejection (26). Benefits of Pancreas Transplantation Survival Rates Early studies suggested that the morbidity and mortality rates associated with SPK transplantation offset any potential survival advantage. In the middle 1990s, there was gradual reassessment of the effectiveness of SPK transplantation, with Douzdjian et al. (40) highlighting the improved 5-yr survival rates for SPK transplant recipients, compared with diabetic KTA recipients. Recently, the group at the University of Wisconsin demonstrated a similarly significant improvement after SPK transplantation with a different measure of survival, i.e., the observed/expected survival ratio (27). These studies have been criticized for the lack of a true control population and selection biases that could affect SPK and KTA recipients. Even the well controlled study reported by Tyden et al. (41), which noted a reduction in 10-yr mortality rates after SPK transplantation, is susceptible to this criticism. Therefore, the data reported by Smets et al. (8) are of great significance. That group analyzed 415 patients with type 1 DM for whom renal replacement therapy was initiated in the Netherlands between 1985 and 1996. In one area, SPK transplantation was offered to patients. In another region, KTA was the transplant modality. SPK transplantation was associated with a hazard ratio for death of 0.53 (95% confidence interval, 0.36 to 0.77; P < 0.0001) when all eligible individuals with ESRD were evaluated. This hazard ratio decreased to 0.4 (95% confidence interval, 0.20 to 0.77; P = 0.008) when only transplant recipients were evaluated. Therefore, SPK transplantation seems to be a therapy that can reduce mortality rates among individuals with type 1 DM and ESRD. Quality of Life Pancreas transplantation counteracts many of the difficult aspects of type 1 DM, including hypoglycemic unawareness, metabolic derangements, fluctuating glycemic control, insulin dependence, glucose monitoring, and dietary restrictions. Therefore, it could be anticipated that pancreas transplantation would significantly improve the QOL for individuals with type 1 DM. The overwhelming majority of QOL studies that examined pancreas transplantation assessed SPK transplant recipients. Interestingly, researchers observed only a few areas in which QOL scores for SPK transplant recipients significantly exceeded QOL scores for diabetic KTA recipients (42). Pancreas transplantation, however, consistently improved patient perceptions of health, health management, and diet flexibility (42,43). Matas et al. (43) examined whether the QOL among SPK transplant recipients changed with time. The average scores on SF-36 questionnaires for diabetic transplant recipients (SPK transplantation and KTA) were higher than the reported normal values for patients with congestive heart failure, chronic obstructive pulmonary disease, or depression and were similar to those for patients with hypertension. The timing of QOL assessments may be exceedingly important in determination of the effects of SPK transplantation. In one study, SPK transplant recipients rescored their pretransplantation QOL significantly lower after transplantation, compared with scores before the procedure (44). In general, there is a QOL benefit from the transplant procedure and the additional QOL improvements attributable to the pancreas transplant itself focus on the obvious transition from the diabetic state to a nondiabetic state. Nephropathy Obviously, a successful dual transplant with a pancreas and a kidney is one means of treating nephropathy in type 1 DM. However, most studies comparing renal function among SPK transplant recipients versus diabetic KTA recipients did not demonstrate significant differences during the early posttransplantation time period (45,46), although diabetic KTA recipients may readily redevelop microalbuminuria after transplantation (47). The lack of long-term renal graft data has led to a greater reliance on histologic studies comparing SPK transplant and diabetic KTA recipients. Mesangial expansion is the hallmark of clinical diabetic nephropathy. Therefore, its presence heralds recurrent diabetic nephropathy in allografts. SPK transplant recipients are less likely to display the pathologic changes of diabetic nephropathy early after transplantation, compared with diabetic KTA recipients (48). Moreover, PAK transplantation seemed to prevent the development of diabetic nephropathy in biopsy samples from individuals who underwent PAK transplantation 1 to 7 yr after successful KTA (49,50). This suggests that even late restoration of normoglycemia may have significant beneficial effects on intrarenal architecture. Ophthalmologic Manifestations of DM The Diabetes Control and Complications Trial (4) suggested that restoration of tight glycemic control led to biphasic effects on retinopathy. There was an exacerbation of retinopathy early after the restitution of glycemic control. This was followed by a late phase of retinopathy stabilization and even mild improvement. It could be anticipated that SPK transplantation would have the same effect. In fact, 20 to 35% of PTA and SPK transplant recipients demonstrate early deterioration of retinopathy after the transplant event. Severe proliferative diabetic retinopathy, treated with pan-retinal laser therapy, was a common peritransplantation finding in most studies (51). The severity of these ophthalmologic changes may obviate a clear salutary effect of PTA or SPK transplantation on retinopathy. Alternatively, the correction of uremia alone with SPK transplantation or KTA among diabetic individuals may improve retinopathy, thus complicating analyses comparing the two. Nevertheless, a number of controlled studies described stabilization or clear improvement of retinopathy after successful SPK transplantation, especially when retinopathy was in its early stages, without exposure to laser treatment (52,53). The studies also described a corollary finding; SPK and pancreas transplant recipients experienced less deterioration of their retinopathy than did diabetic KTA recipients (52,53). Visual acuity is variable after PTA and SPK transplantation, however. It remains stable in the majority of patients but can deteriorate or fluctuate in up to 30% of PTA and SPK transplant recipients (54). Preretinal macular fibrosis, vitreous hemorrhage, diabetic retinopathy severity, and grade and type of cataract all affect visual acuity after transplantation. Notably, all forms of cataracts increased after transplantation in almost every study that examined this parameter among PTA and SPK transplant recipients with time (55). Therefore, in the absence of severe retinopathy, PTA or SPK transplantation can stabilize or improve DM-related ophthalmologic findings. However, visual acuity may vary as a result of other associated ophthalmologic disorders (notably cataract formation) after pancreas transplantation. Peripheral Vascular Disease Two major factors likely influence peripheral vascular disease after PTA and SPK transplantation. The duration of DM before transplantation certainly increases the risk for posttransplantation macrovascular disease. In addition, hyperinsulinemia, with its theoretical atherogenic risks, could exacerbate macrovascular disease. Unfortunately, there have been no controlled trials evaluating the effects of PTA and SPK transplantation on type 1 DM macrovascular complications after transplantation. In general, lower-extremity peripheral vascular occlusive disease remains stable after kidney transplantation (56). Not surprisingly, Monaco and colleagues (15) suggested that euglycemia after SPK transplantation did not improve peripheral vascular disease. A surrogate measure for significant lower-extremity vascular disease is the amputation rate among at-risk individuals. Pancreas transplantation did not significantly affect lower-extremity amputation rates in the largest retrospective study examining this subject to date (57). These findings suggest that, despite the improvements in lipid profiles among pancreas transplant recipients (6), other risk factors may inhibit improvements in macrovascular disease and that macrovascular complications may be differentially affected by pancreas transplantation, in contrast to many of the microvascular complications of DM. Hypertension Hypertension is a major risk factor for coronary artery disease and commonly affects individuals with DM. Several small studies have examined whether SPK transplantation alters the prevalence of posttransplantation hypertension, with mixed results. Data from the early 1990s suggested that 60% of SPK transplant recipients exhibited posttransplantation hypertension, with 15 to 30% rates of BP improvement after SPK transplantation (58,59). Improvement was defined as a reduction in the number of BP medications or improvement in measured BP. Unfortunately, nocturnal BP remained significantly elevated, suggesting that 24-h BP control merited greater attention among hypertensive SPK transplant recipients (60). Recent data suggested that the prevalence of post-SPK transplantation hypertension may be decreasing (only 40%) with the increasing use of TAC and MMF after SPK transplantation (61). Some authors have suggested that the type of pancreatic exocrine drainage could affect the prevalence of post-pancreas transplantation hypertension. BD leads to urinary losses of sodium and bicarbonate, with a constant state of mild volume depletion and metabolic acidosis. Indeed, hypertension seems to be more common with primary ED, compared with BD (62). However, conversion from BD to ED is not associated with an increase in BP (62). This suggests that factors other than those noted above have greater effects on post-PTA or SPK transplantation BP than previously suspected. Cardiovascular Disease Early reports suggested that there was no improvement in cardiac risk among SPK transplant recipients (63). Indeed, a history of preexisting myocardial dysfunction or congestive heart failure significantly increased the mortality risk after pancreas transplantation (63). With greater experience, patients with lower cardiac risks were selected for PTA and SPK transplantation. It is not surprising, therefore, that cardiac death rates for SPK transplant recipients are now equivalent to or better than cardiac death rates for other transplant recipients with type 1 DM (27). Certainly, individuals with histories of coronary artery disease and revascularization procedures are potential candidates for pancreas transplantation. However, their cardiac death rates remain significantly greater than those for individuals without pretransplantation coronary artery disease (relative risk, 4.3; P < 0.001) (14). Such information is important for patient counseling as well as the establishment of optimal post-PTA or SPK transplantation cardiac follow-up monitoring. The transplant itself may affect cardiac function. Data from several small studies suggested that pancreas transplantation improved echocardiographically measured left ventricular systolic and diastolic function, as well as left ventricular geometry (64,65). These physical changes seem to occur in concert with improvements in cardiac autonomic function (66). Overall, among individuals at low risk, PTA or SPK transplantation seems to provide some demonstrable benefits with respect to cardiac function. Long-term, prospectively collected data will be necessary to definitively establish whether pancreas transplantation has beneficial effects on coronary artery disease after transplantation. Neuropathy The effects of PTA and SPK transplantation may be most evident in evaluations of the improvement of diabetic neuropathy after transplantation. SPK transplantation leads to rapid initial improvement and at least stabilization of peripheral diabetic neuropathy (42,67). Serial action potential amplitude studies of the median, ulnar, peroneal, and tibial nerves, as well as orthodromic sensory conduction velocity studies, demonstrated improvement by 6 mo after transplantation (68). Interestingly, action potential amplitudes (a measure of nerve fibers capable of conducting impulses) demonstrated prolongation of recovery after SPK transplantation, with improvements extending for at least 5 yr and potentially continuing for as long as 8 yr after transplantation (69). Autonomic function also demonstrated long-term improvement, with the greatest recovery being evident 8 yr after transplantation (42,69). These findings demonstrate significantly greater improvements than those observed for diabetic KTA recipients, and they mimic the improvements in neuropathy observed in the Diabetes Control and Complications Trial (4). Sexual Dysfunction and Reproduction Sexual dysfunction is a common complication that affects approximately 50 to 75% of all individuals with DM and renal failure. Erectile dysfunction is a primary complaint among diabetic male patients, affecting 75 to 90% of all such men, especially those with renal disease. Female sexual dysfunction is just as common in DM and is manifested in a similar way, with decreased vaginal lubrication in response to stimulation, failure of normal genital engorgement, and loss of orgasmic potential (70). There are minimal data examining whether PTA or SPK transplantation improves sexual dysfunction after transplantation. Among men, there is actually a risk that the surgical dissection for the procedure could precipitate erectile dysfunction. However, at least in one study, SPK transplantation was associated with modest improvements in erectile function, although a large percentage of male SPK transplant recipients still required at least one additional therapy to improve sexual function (71). Unfortunately, there are no data available to indicate whether pancreas transplantation restores female sexuality. However, there are data demonstrating that pancreas transplantation is associated with fertility in women. The National Transplantation Pregnancy Registry recently reported on a group of 18 SPK transplant recipients whose 23 pregnancies resulted in 20 live births (72). Prematurity and low birth weight occurred in 70% of the pregnancies. The children, however, were developing well at the time of the last follow-up examinations. Hypertension complicated the pregnancies (91% frequency), as did urinary tract infections (70% frequency). Notably, 25% of the mothers also were preeclamptic and two recipients lost three grafts (one kidney transplant and one SPK transplant) within 2 yr after the pregnancy. One additional risk complicating pregnancy after SPK transplantation involves the potential teratogenic effects of certain immunosuppressive agents. TAC, CsA, and azathioprine are all safe for use during pregnancy. Unfortunately, despite its profound effect in transplantation, there is limited information regarding the use of MMF during pregnancy. It was associated with adverse developmental effects in preclinical studies. Therefore, although case reports of successful pregnancies during MMF therapy have been documented (73), at this time it is not recommended that women continue MMF treatment during pregnancy or during periods when they anticipate becoming pregnant. Clinical practice dictates the substitution of azathioprine for MMF in these instances. Finally, 17 male SPK transplant recipients have fathered 20 pregnancies to date, without major complications (72). Therefore, it is possible for SPK transplant and PTA recipients to safely bear children after the transplant event, although these are definitely high-risk pregnancies. Whether transplantation has direct effects on fertility requires further analysis. Summary The advantages of PTA and SPK transplantation are now more obvious as improvements in surgical techniques and new immunosuppressive agents have made an increasing number of PTA and SPK transplants viable and functional in the long term. The obvious benefits of normoglycemia would theoretically be even more profound if it becomes possible to perform PTA for patients without significant renal dysfunction or for patients early in the progression of DM-related renal disease. Nevertheless, SPK transplantation can be touted as a therapeutic advance for type 1 DM. It can improve survival rates and limit many DM-related complications, while improving QOL. The effects of SPK transplantation and PTA on other aspects of DM, e.g., advanced glycosylation end products and lipid profiles, are also intriguing (6,61,74,75). More studies must be performed to determine whether early changes in these metabolic and biochemical parameters predict good outcomes after SPK transplantation and PTA. Finally, the recent study by Shapiro et al. (76) again raises the question of why the whole pancreas should be transplanted. Their provocative article suggested that islet cell transplantation may be a feasible form of transplantation in the near future. It is hoped that islet cell transplantation will convey the same benefits, with respect to survival rates and diabetic complications, as do PTA and SPK transplantation today. This transplantation approach to the treatment of type 1 DM is the first real alternative to insulin therapy. It does carry the risks of immunosuppression, and it is unable to eradicate the consequences of preexisting disease. However, PTA and SPK transplantation, and perhaps islet cell transplantation in the future, bring with them the possibility for normoglycemia and restoration of a sense of normalcy to life for individuals with type 1 DM. Acknowledgments We thank all of the nursing staff, coordinators, and, most importantly, our patients at the University of Wisconsin for their enthusiasm, interest, and trust as they continually educate us regarding everything good and bad associated with kidney-pancreas and pancreas transplantation.