These pages are best viewed with Netscape version 3.0 or higher or Internet Explorer version 3.0 or higher. When viewed with other browsers, some characters or attributes may not be rendered correctly.ORIGINAL ARTICLE Risks and Benefits of Kidney and Pancreas Transplantation for Diabetic Patients Connie L. Manske, MD Type 1 diabetic patients with end-stage renal disease can choose dialysis or transplantation for renal replacement therapy. For patients choosing transplantation, a kidney from a living related donor is associated with longer allograft and patient survival. When a living donor is not available, then a combined cadaveric kidney and pancreas transplant can be considered. The addition of a pancreas transplant incurs greater morbidity and may require higher levels of immunosuppression. However, there may be substantial benefits, including improvement in quality of life and stabilization of neuropathy. Patients with type 1 diabetes younger than 45 years with little or no atherosclerotic vascular disease are ideal candidates for a combined kidney and pancreas transplant. Patients who do not meet these criteria but who have life-threatening hypoglycemia may also wish to consider pancreas transplantation, but have an increased risk of serious complications. The risks and benefits of combined kidney and pancreas transplantation are outlined in this review and should be carefully considered by potential transplant recipients and their physicians. Diabetes Care 22 (Suppl. 2):B114–B120, 1999 Over one-third of type 1 diabetic patients develop end-stage renal disease (1). Several nonrandomized studies have suggested a survival benefit for younger diabetic patients choosing transplantation rather than dialysis for renal replacement therapy (2,3). In addition, transplantation offers an improved quality of life when compared with dialysis. For diabetic patients considering renal transplantation, an important question is whether to undergo combined kidney and pancreas transplantation, which would eliminate the need for both insulin and dialysis. Some investigators have argued that a pancreas transplant should be considered by most kidney transplant candidates with type 1 diabetes. However, pancreas transplantation is technically more complex than kidney transplantation, and the combined procedure is associated with increased morbidity (4–16). This review outlines the history of kidney and pancreas transplantation and the risks and benefits of transplantation in diabetic patients, focusing on donor selection, recipient evaluation, and the risks and benefits of obtaining a combined kidney and pancreas transplant. When comparing the potential risks and benefits of pancreas transplantation, it is important to consider the limitations of the published data. First, pancreas transplantation has only been performed routinely for 10–15 years; therefore, the number of patients available for long-term follow-up studies is limited. This becomes important when attempting to evaluate the potential effect of normoglycemia on long-term complications, such as neuropathy or atherosclerosis. Second, the number of patients transplanted at any one center is small, and both surgical techniques and immunosuppressive strategies are evolving rapidly. This makes accurate assessment of potential perioperative morbidity more difficult. Third, available studies are not randomized. However, it is unlikely that a randomized trial of pancreas transplantation versus insulin treatment for diabetes will ever be performed, so conclusions must be based on nonrandomized data. HISTORY OF TRANSPLANTATION IN DIABETES: U.S. EXPERIENCE— Public funding for the End-Stage Renal Disease (ESRD) Program began in the U.S. in 1973. When the government first became involved, ESRD treatment was provided for only 9,000 people, at a relatively low cost (17). The median patient age was 40 years, and there were specific exclusion criteria, including diabetes. Therefore, many patients with diabetes died at a relatively young age without the benefit of dialysis or transplantation. Once ESRD treatment became easier to pay for, diabetic patients were increasingly started on dialysis (18). The option of transplantation for diabetic patients was introduced even more recently. In 1977, only 75 diabetic patients received a cadaveric renal transplant in the U.S. (19). By the early 1980s, it had been shown that diabetic patients had acceptable survival with a renal transplant, and the number of diabetic kidney transplant recipients has steadily increased (19,20). Renal transplantation has become a remarkably successful treatment option for diabetic patients, with demonstrated superiority to remaining on dialysis (2).Improvements in immunosuppression and antiviral therapy have decreased the incidence of both acute rejection and serious infection. Current 5-year renal allograft survival in diabetic recipients receiving transplants in the U.S. in 1991 is 60% with a cadaveric donor and 70% with a living related donor (19). Pancreas transplantation was introduced in the mid 1960s, but the procedure was not performed frequently until the mid 1980s (21). Much of the initial work was done at the University of Minnesota, where of 14 pancreas transplants performed in the late 1960s, only 1 functioned 1 year later. The program was discontinued for 5 years but restarted in 1978. One-year graft survival for the pancreas, whether placed alone or after a kidney transplant, was initially poor with a 1-year survival of only one in four allografts (22). In 1984, the simultaneous kidney and pancreas transplant operation was introduced. Pancreas survival was dramatically improved with this procedure, with two-thirds of pancreas allografts functioning for at least 1 year. Presumably, this was secondary to an increased ability to treat pancreatic rejection based on signs of concomitant kidney rejection. The most recent statistics for simultaneous pancreas and kidney (SPK) transplants performed in 1994–1996 show a steady improvement in outcome, with a 1-year graft survival rate of 79% (Fig. 1) (22,23).
RENAL TRANSPLANTATION IN DIABETIC RECIPIENTS: DONOR CHOICE— Both allograft and patient survival are significantly improved when a living related donor (LRD) kidney is available (10-year allograft and patient survival for patients transplanted in 1986 were 47 and 60% for diabetic LRD transplant recipients vs. 23 and 36% for diabetic cadaveric transplant recipients) (19). There are several possible reasons for this. First, the incidence of acute tubular necrosis (ATN) in the postoperative period is 30–40% when a cadaveric donor is used but is infrequent with LRD. Posttransplant ATN is associated with decreased graft survival at 5 years (24), presumably secondary to both residual renal damage and to the difficulty in recognizing an acute rejection episode in a patient with ATN.Second, a potential renal allograft from a living donor can be more thoroughly evaluated before transplantation than can a cadaveric allograft. Third, LRD recipients require less immunosuppression and may have less risk of subsequent infection or malignancy. Fourth, patients with an LRD undergo transplantation as an elective procedure and therefore may be healthier when they receive their transplant. For patients not yet on dialysis, the transplant can be performed at the time the patient would ordinarily begin dialysis, rather than 2 or 3 years later. For these reasons, a kidney from a living kidney donor is the preferred choice for patients with a willing donor. In recent years, the use of biologically unrelated, emotionally related donors (principally spouses) has increased, with graft survival rates nearly as good as those with a related donor (25). However, this donor choice remains somewhat controversial (26). Cadaveric renal transplantation remains the option most frequently chosen by diabetic transplant candidates. Unfortunately, there are now nearly 40,000 patients on the waiting list for a cadaveric kidney transplant but <10,000 cadaveric transplant operations performed yearly in the U.S. (19). Therefore, the average waiting time for a transplant is now nearly 3 years. One- and five-year allograft and patient survival for diabetic cadaveric transplant recipients are 92 and 93% at 1 year, and 60 and 72% at 5 years (19). PANCREAS TRANSPLANTATION— For potential cadaveric kidney recipients, an important question is whether to choose an SPK transplant or a kidney transplant alone (KTA). Because the combined procedure is technically more difficult, it is important to weigh the increased perioperative risk against the potential benefits of establishing normoglycemia. Higher rates of serious perioperative complications have been reported in SPK transplant recipients (4–11). According to a recent International Pancreas Transplant Registry Report, between 11 and 21% of pancreas grafts are lost in the perioperative period because of surgical complications (11). In addition, the incidence of acute rejection is increased, requiring the use of increased immunosuppression (4,5,8,28,29). One author suggests that the increased number of rejections associated with SPK transplants may have a negative impact on long-term renal allograft survival (29). TECHNICAL COMPLICATIONS— The majority of pancreas transplants are bladder-drained pancreaticoduodenal grafts, with the attached duodenal segment (5–10 cm of the second portion of the duodenum) anastomosed to the patient's bladder. Technical complications involving the pancreas allograft include pancreas thrombosis requiring pancreatectomy (4–11,30,31), wound infections and peri-allograft abscesses (4–11,32–35), urologic problems secondary to bladder drainage of the pancreas (4–11,36), pancreatitis (5,30), and complications related to the duodenal segment (37,38). Graft thrombosis occurs in 10–15% of pancreas allografts (12,30,31). Identified risk factors for graft thrombosis include male recipient, longer cold ischemic time, advanced donor age, cardiocerebrovascular cause of donor death, graft pancreatitis, and the need for a surgical technique other than the standard placement of the graft on the right side using the native vessels (30,31). Specific surgical techniques associated with an increased risk of thrombosis include the use of an aortic Carrel patch; arterial pancreatic graft reconstruction using the splenic artery to superior mesenteric artery anastomosis or interposition of the graft between the splenic artery and the superior mesenteric artery; the use of a portal vein extension graft; or left-sided implantation into the recipient. To avoid this complication, recommendations include avoiding older donors or those who have died of cardiocerebrovascular disease; minimizing preservation time; and avoiding left-sided implantation, portal vein extensions, and arterial reconstructions other than the y-graft. Perioperative heparin is used in some institutions, whereas others advocate calcium-channel blockers or octreotide to decrease the risk of graft pancreatitis (30,39). Once graft thrombosis occurs, graft removal is virtually unavoidable. Wound infections and peri-allograft abscesses occur in 20–30% of recipients (7–12,35). In one series, the rate of intra-abdominal infection was significantly higher for LRD (42%) versus cadaveric donor (18%) recipients and for those with enterically drained (39%) versus bladder-drained (18%) transplants (12). Graft and patient survival rates were significantly lower for recipients with intra-abdominal infection, and outcome was particularly poor for fungal versus bacterial infections. Intra-abdominal fungal infections, which are particularly difficult to treat, occurred in 9% of 445 pancreas recipients in one series (32). Graft survival rate for recipients with a fungal infection was lower (17 vs. 65%) and patient survival rate was also significantly lower (70 vs. 90%) for patients with versus those without fungal infection (33). The rate of infection was decreased to 6% for recipients given antifungal prophylaxis with fluconazole 400 mg/day for 7 days after transplantation. In another series, the source of the infection was present at the time of transplantation in 25% of patients (documented in a preoperative urine culture or duodenal segment culture) and 25% percent of infections developed in relation to ureteral or duodenal leakage (40). Urologic problems are common in bladder-drained pancreas transplant recipients. One review noted that the incidence of complications was between 50 and 60% when all complications are included (13). This high prevalence of complications is not surprising, considering that a large percentage of patients undergoing transplantation have autonomic bladder dysfunction with large capacity, decreased flow rate, decreased sensation, and increased residual urine. These functional abnormalities result in a predilection for urinary tract infections, which is exacerbated by anastomosing a segment of the duodenum into the bladder wall. In addition, the exocrine secretions of the pancreas, including bicarbonate, amylase, lipase, and other enzymes result in a wide variety in changes in the bladder mucosa ranging from nonspecific inflammation to transitional cell papilloma. Clinical urologic complications include urinary tract infections, dysuria, urethritis, duodenocystostomy fistulas, hematuria, and reflux pancreatitis. In addition, the loss of large quantities of bicarbonate can result in dehydration and acidosis requiring hospitalization, with a reported incidence of up to 38% in warmer climates (36). The most serious complication is fistula formation, with a reported incidence of 7–14% (13). These generally occur in the early posttransplant period and are often associated with duodenal ischemia. In addition, anastomotic duodenal stump leaks occur in ~10% of patients (12). The presence of a fistula or an anastomotic leak generally requires surgical repair. Urinary tract infections are generally easy to treat but may require repetitive courses of antibiotics. Patients with recurrent urinary tract infections or hematuria may benefit from cystoscopy to look for retained sutures, bladder stones, bladder mucosal lesions, or ulcerative lesions in the duodenal segment. Reflux pancreatitis is treated with urinary catheter insertion and continuous drainage for 7 to 14 days. Although most bladder complications can be treated, some patients will require enteric conversion for permanent resolution of their problems. The enteric conversion rate varies between 15 and 19% in different institutions (29,37,41). Because of the high incidence of problems associated with bladder drainage, a number of investigators have advocated a return to primary enteric drainage (36,41). Several investigators have identified recipient risk factors for poor outcome, defined as graft loss or death. The major risk factors are older age and atherosclerotic vascular disease (ASVD). SPK recipients >45 years of age have lower graft survival and a higher patient death rate than recipients <45 years of age (42–44). Patients with advanced vascular disease or congestive heart failure often have a poor outcome after pancreas transplantation (27,45,46). In one series, patients with a history of congestive heart failure were significantly more likely to develop peripancreatic infection and subsequent sepsis, leading to the speculation that patients with vascular disease or marginal cardiac output may not perfuse the pancreas sufficiently, increasing the risk of peritransplant pancreatitis (45). Many centers consider pancreas transplantation to be contraindicated in patients with cardiovascular disease. However, several centers will consider a pancreas transplant for older patients with ASVD if coronary lesions are corrected before transplantation (47,48). Other recipient risk factors for poor outcome include obesity (49) and hepatitis C infection (50). In addition to recipient risk factors, several donor risk factors have been identified, as outlined above. In summary, pancreas transplantation is associated with a significant number of serious technical complications. However, these can be minimized by the appropriate choice of both recipient and donor and by the use of right-side implantation and standard surgical techniques. In addition, it is probably advisable for patients to undergo pancreas transplantation in a center where surgical volume is high enough that the surgical staff is prepared to deal expeditiously with the wide variety of complications that may occur with this procedure. BENEFITS OF PANCREAS TRANSPLANTATION— The potential benefits of normoglycemia are of great interest to potential SPK recipients. However, because pancreas transplantation has only been performed on a routine basis for the past 10 years, data are limited with respect to the effect on long-term diabetic complications. Unfortunately, an extended period of exposure to hyperglycemia has occurred before the patient presents for a renal transplant, so retinopathy, neuropathy, and atherosclerosis are likely to be in more advanced stages (51,52). Early type 1 diabetes is characterized by increased microvascular pressure and flows (53). Injury to the microvascular endothelium then leads to microvascular sclerosis and a loss a vasodilatory reserve and autoregulation (54). Endothelial dysfunction appears to precede the development of clinical complications (55) and is likely secondary to hyperglycemia and the formation of advanced glycation end products (AGEs), which accumulate on long-lived proteins in the vessel wall (56,57). The rate of accumulation of AGEs is proportional to the time-integrated blood glucose level over long periods of time (57). In addition, hyperglycemia results in accumulation of polyols through the aldose reductase pathway (51). Although initial functional abnormalities are reversible with correction of hyperglycemia, later structural changes, such as capillary sclerosis or retinal neovascularization, are not. Because patients receiving a renal transplant have generally been diabetic for at least 15 years, many complications resulting from advanced structural changes are not likely to be reversible with a pancreas transplant. The best one could hope for would be that further changes in vascular structural abnormalities would be prevented by normoglycemia. Pancreas transplantation has little demonstrated benefit for established diabetic retinopathy, largely because most patients receiving a combined transplant have advanced eye disease. In the three largest available series with follow-up periods between 6 and 31 months, patients receiving a pancreas had a similar outcome to those who did not receive a pancreas (58–60). Approximately half of the patients in each group had no change in their retinopathy and half had progression. All three studies had relatively short follow-up periods, so no statement can be made about whether results might have improved if more time had elapsed. Presumably, pancreas transplantation was performed too late to be of benefit for retinopathy. The influence of normoglycemia on the progression of neuropathy is somewhat more encouraging (61–67). One early study demonstrated a lack of progression in neuropathy in patients with a functioning pancreas transplant for 3 years or longer (63). However, although some improvement in a composite index of clinical symptoms and nerve conduction velocities was demonstrated, the end value remained well below the normal range. In a recent investigation, follow-up was reported for 12 patients with a functioning pancreas for 8 years (65). The degree of polyneuropathy expressed as an index was significantly better in SPK recipients than in KTA recipients at the end of 8 years but remained >3 SDs below normal. In another study, investigators followed 44 patients up to 8 years after SPK transplant. Late improvement in nerve action and potential amplitudes and partial reversal of diabetic neuropathy was more likely to occur in patients with less severe initial neuropathy, smaller body weight, and longer duration of diabetes (66). As in retinopathy, presumably pancreas transplantation is of most benefit when advanced neuropathy is not yet present. Many patients seek a pancreas transplant after they develop ESRD, in the hope that pancreas transplantation will prevent a recurrence of diabetic nephropathy in a renal allograft. However, from a practical point of view, allograft loss secondary to diabetic nephropathy remains a rare occurrence, possibly secondary to the relatively short life expectancy of diabetic renal transplant recipients. Only 36% of diabetic LRD recipients and 23% of diabetic KTA recipients survive 10 years, a statistic that has remained unchanged for the past 10 years (13). For patients with long-term pancreas allograft function, recurrent diabetic nephropathy appears to be unlikely. For example, when KTA recipients and SPK recipients underwent renal biopsies 1–6 years after transplantation, changes consistent with early diabetic nephropathy were present in biopsy specimens from 11/24 KTA recipients but in only 1/15 SPK recipients (68). Vascular disease remains the major cause of both morbidity and mortality after transplantation in diabetic recipients (27,69,71). The risk to an individual patient of sustaining a vascular complication is related to the degree of vascular disease before transplantation (71,72). When coronary angiography is performed before transplantation, patients found to have one or more coronary artery stenoses >50% at the time of transplant evaluation have a risk of a vascular event (myocardial infarction, cerebrovascular accident, or amputation) within 3 years of 55%, independent of the type of transplant (71). Unfortunately, many patients have established vascular disease at the time of transplantation (71–73). For this reason, it is of great interest to know whether a pancreas transplant might decrease the incidence of ASVD events after transplantation. The effect of pancreas transplantation on atherosclerotic complications remains largely unstudied. Carotid atherosclerotic lesions documented with carotid ultrasound continue to progress in both SPK and KTA recipients, although progression is faster in patients with poor glycemic control and hypertension (74). Several authors have documented a higher incidence of myocardial infarction within the first year after transplantation in SPK recipients compared to KTA recipients (27,45). However, this is likely to be related to the degree of pretransplant ASVD and to the increased complexity of the combined transplant surgery. On a positive note, left ventricular function appears to improve to a greater degree after a successful SPK transplant than with a KTA (75). The pathogenesis of atherosclerosis is complex. Hyperglycemia is thought to contribute to atherosclerotic plaque formation in a number of ways, including glycation of collagen, alteration of endothelial cell function (including a reduction in the releases of NO), glycoxidation of LDL cholesterol, and increased platelet reactivity (54–57,76–80). Pancreas transplantation cannot be expected to reverse established atherosclerotic vascular lesions, but normoglycemia might contribute to atherosclerotic plaque stabilization by restoring endothelial reactivity and reversing functional changes. Early investigators reported favorable lipid profiles in SPK recipients compared with KTA recipients, with lower LDL cholesterol levels, lower triglyceride levels, and higher HDL levels (81–82). However, another investigator described atherogenic disturbances in lipid transport that persist after pancreas transplantation, presumably secondary to nonportal venous drainage resulting in systemic hyperinsulinemia (83). One author has demonstrated that levels of the AGE peptide pentosidine in skin collagen remain unchanged 80 months after SPK transplantation (84). This supports the hypothesis that the structural vascular changes induced by hyperglycemia and contributing to ASVD are unlikely to be reversible. However, no studies are available that document the effect of prolonged pancreas allograft function on the incidence of myocardial infarction, cerebrovascular accident, or amputation. For the rare pancreas transplant candidate without advanced secondary complications, there is now evidence that early microangiopathy may be reversible after pancreas transplantation. One recent study demonstrated regression of the pathological changes of diabetic nephropathy in the native kidneys of pancreas transplant recipients who had been successfully transplanted for 10 years, although no improvement was evident 5 years after transplantation (85). This demonstrates that long-term normoglycemia established by pancreas transplantation may prevent and even reverse early microvascular changes. Numerous series have demonstrated an improvement in quality of life in SPK recipients, which can be particularly dramatic for patients with hypoglycemic unawareness, brittle diabetes, or gastroparesis (86–92). In addition, there is likely to be an overall improvement in health for patients with long-term pancreas function. One investigator compared 8 KTA recipients and 10 SPK recipients with a minimum follow-up time of 7 years after transplantation. During the year before the study, the pancreas recipients missed significantly fewer work days due to illness (19 vs. 88), required significantly fewer hospital days (4.3 vs. 20), and had a significantly lower need for hospitalization (no hospitalization needed for 71 vs. 33%) (90). CADAVERIC PANCREAS TRANSPLANTATION AFTER KIDNEY TRANSPLANTATION— The option of procuring a pancreas transplant once a functioning renal allograft is in place is an attractive and underutilized option for patients with a living related kidney donor. Historically, pancreas function has not been as good for solitary pancreas transplants when compared with SPK allografts (84,93). However, the recent introduction of MMF and FK506 has been associated with a dramatic improvement in solitary pancreas allograft survival (94,95) such that these two procedures may now be equivalent. Long-term follow-up will be necessary to determine how enthusiastically this procedure can be recommended, given the increased frequency of posttransplant lymphoproliferative disease documented in pancreas recipients receiving FK506 (96,97). In addition, the overall thrombosis incidence is higher in patients receiving a pancreas after a kidney than in patients receiving an SPK transplant (20 vs. 12% in one series) (26), possibly secondary to the loss of uremic inhibition of clotting. However, this may improve with the introduction of postoperative heparization in some centers. SUMMARY— Diabetic patients with ESRD may have improved longevity and quality of life if they receive a kidney transplant rather than dialysis treatments. Superior allograft function is achieved with a living donor. If no donor is available, a cadaveric kidney is a reasonable form of renal replacement therapy. Patients with type 1 diabetes who are younger than 45 years and do not have advanced coronary or peripheral vascular disease or congestive heart failure may be candidates for an SPK transplant (45,84). Patients who do not meet these criteria but have life-threatening hypoglycemic unawareness or a poor quality of life because of brittle diabetes may also wish to be considered for a pancreas transplant. A functioning pancreas transplant is associated with increased perioperative morbidity and a higher level of immunosuppressive drugs, but it results in improved quality of life and stabilization of neuropathy. The risks and benefits of these procedures need to be carefully considered by all diabetic transplant candidates. References 2. Khauli RB, Steinmuller DR, Novick AC, Buszta C, Coormastic M, Nakamoto D, Vidt DG, Magnussen M, Paganini E, Schreiber MJ: A critical look at survival of diabetics with end-stage renal disease: transplanation vs. dialysis therapy. Transplantation 41:598–602, 1986 3. Port FK, Wolfe RA, Mauger EA, Berling DP, Jiang K: Comparison of survival probabilities for dialysis patients vs. cadaveric renal transplant recipients. JAMA 270:1339–1343, 1993 4. 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Received for publication 29 June 1998 and accepted in revised form 20 August 1998. Abbreviations: AGE, advanced glycation end product; ASVD, atherosclerotic vascular disease; ATN, acute tubular necrosis; ESRD, end-stage renal disease; KTA, kidney transplant alone; LRD, living related donor; SPK, simultaneous pancreas and kidney. This article is based on a presentation at a satellite symposium of the 16th International Diabetes Federation Congress. The symposium and the publication of this article were made possible by educational grants from Hoechst Marion Roussel AG. Copyright © 1999 American Diabetes Association For Technical Issues contact webmaster@diabetes.org |
