REVIEW J Am Soc Nephrol 13: 1109 1118, 2002 Pancreas after Kidney Transplantation SUNDARAM HARIHARAN,* JOHN D. PIRSCH, CHRISTOPHER Y. LU, LAURENCE CHAN, TODD E. PESAVENTO, STEVEN ALEXANDER, GINNY L. BUMGARDNER, GIACOMO BAASADONA, # DONALD E. HRICIK,** MARK D. PESCOVITZ, NINA T. RUBIN, and ROBERT J. STRATTA *Division of Nephrology, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Transplant Surgery, University of Wisconsin, Madison, Wisconsin; Division of Nephrology, University of Texas, Dallas, Texas; Division of Nephrology, University of Colorado, Denver, Colorado; Division of Nephrology, Ohio State University, Columbus, Ohio; Division of Pediatric Nephrology, Stanford University, Stanford, California; #Department of Transplant Surgery, Yale University, New Haven, Connecticut; **Division of Nephrology, Case Western Reserve University, Cleveland, Ohio; Department of Transplant Surgery, Indiana University, Indianapolis, Indiana; Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts; and Department of Transplant Surgery, Wake Forest University, Winston-Salem, North Carolina. Received September 10, 2001. Accepted October 12, 2001. Correspondence to Dr. Sundaram Hariharan, Division of Nephrology, Medical College of Wisconsin, 9200 W. Wisconsin Avenue, Milwaukee, WI 53226. Phone: 414-456-6730; Fax: 414-456-6207; E-mail: hari@mcw.edu; American Society of Transplantation, 236 Route 38 West, Suite 100, Moorestown, NJ 08057; Phone: 856-608-1104; Fax: 856-608-1103; E-mail: ast@ahint.com 1046-6673/1304-1109 Journal of the American Society of Nephrology Copyright 2002 by the American Society of Nephrology After three decades of controversy surrounding the therapeutic validity of pancreas transplantation, the procedure has become accepted as the preferred treatment for patients with insulindependent diabetes mellitus (IDDM) and advanced diabetic nephropathy with end-stage renal disease (ESRD) and for those approaching ESRD. Vascularized pancreas transplantation is currently the only available form of autoregulating, total endocrine replacement therapy that reliably achieves an insulinindependent euglycemic state and normal glucose homeostasis, resulting in the successful management of diabetes mellitus. The trade-offs for normal glucose homeostasis are the operative risks of the pancreas transplant procedure and the need for chronic immunosuppression. Free islet grafts have the same potential, but their efficacy requires further evaluation. With improvements in organ retrieval and preservation technology, refinements in diagnostic methods and surgical techniques, advances in clinical immunosuppression and anti-infective prophylaxis, and increased experience with donor and recipient selection, success rates for pancreas transplantation have continued to improve. From 1966 through October 2000, 15,000 pancreas transplants were performed throughout the world and reported to the International Pancreas Transplant Registry (IPTR) (1). In the past decade, the majority (83%) of pancreas transplants were performed in combination with a kidney transplant [simultaneous pancreas/kidney transplants (SPKT)] for patients with ESRD attributable to diabetic nephropathy. The current 1-yr actuarial patient, kidney, and pancreas (with complete insulin independence) graft survival rates after SPKT are 95, 92, and 84%, respectively (1). Solitary pancreas transplants comprised the remaining cases, including sequential pancreas after kidney transplants (PAKT) (12%) and pancreas transplants alone (PTA) (5%) (1). Although the annual rate of pancreas transplants has steadily increased, the number of solitary pancreas transplants has increased disproportionately in recent years; in 1999, 75% of transplants were SPKT, 18% PAKT, and 7% PTA. The current 1-yr patient survival rate after solitary pancreas transplantation is 95%, and the 1-yr actuarial pancreas graft survival rates are 73% for PAKT and 70% for PTA (1). The differences in graft survival rates for SPKT, PAKT, and PTA have been attributed to increased rates of graft loss resulting from rejection and thrombosis after solitary pancreas transplantation. Pancreas transplantation should be considered an acceptable therapeutic alternative to continued insulin therapy for diabetic patients with imminent or established ESRD who have undergone or plan to undergo a kidney transplant, because the successful addition of a pancreas does not jeopardize patient survival rates, may improve kidney graft survival rates, and will restore normoglycemia (2). PAKT is advocated for diabetic patients with well functioning kidney transplants, because these patients already require chronic immunosuppression and the additional risk is primarily that of the surgical procedure (3,4). Currently, many transplant centers are experienced in performing SPKT; only a few centers have accumulated much experience with PAKT. The improved success of SPKT has prompted many centers to offer pancreas transplantation for patients with type 1 diabetes mellitus who have undergone successful kidney transplantation. PAKT increases the likelihood of more diabetic recipients receiving a pancreas transplant and eliminates many of the organ-allocation issues associated with SPKT. The increased interest in PAKT is attributable to several factors. New immunosuppressive medications have reduced acute rejection
1110 Journal of the American Society of Nephrology J Am Soc Nephrol 13: 1109 1118, 2002 rates and enhanced pancreas graft survival rates (5). Better surgical techniques, patient selection, and immunologic monitoring have also improved short- and long-term success rates after pancreas transplantation (6). Finally, the recent decision by Medicare to reimburse providers for the procedure has eliminated the financial burden for many potential recipients. Despite these advancements, there are no clear guidelines for donor and recipient selection, immunologic monitoring, the choice of immunosuppressive agents, or the timing of PAKT. This lack has prompted the Pancreas Committee of the American Society of Transplantation to review the current status of PAKT. History and Background Dr. Richard Lillehei performed the first pancreas transplant at the University of Minnesota in 1966 (7). Pancreas transplantation was abandoned at that center in 1973, after 14 transplants had been performed with only one successful pancreas graft functioning for 1 yr. The program was resumed in 1978. Throughout the world, only 1157 pancreas transplants were performed between 1966 and 1987, with three-fourths of the transplants being performed after 1982 (8). Despite a multitude of surgical approaches for duct drainage and the use of cyclosporin A (CsA) after 1983, the 1-yr patient and pancreas graft survival rates were only 76 and 37%, respectively (8). During this early experience, it became evident that SPKT was associated with better graft survival rates than was either PAKT or PTA. Historically, major impediments to successful pancreas transplantation were the management of exocrine secretions, the inability to monitor the pancreas for rejection, and high rates of rejection, thrombosis, and pancreatitis. In the past two decades, significant improvements in the surgical and medical management of pancreas transplants have occurred. The management of pancreatic exocrine secretions improved with the development of bladder drainage, which allowed for measurement of urinary amylase levels, facilitating prediction of acute rejection episodes (9). Improvements in immunosuppression made possible a return to enteric drainage of the exocrine secretions by preventing episodes of acute rejection and eliminating the need for high-dose steroid therapy, which impaired healing of the enteric anastomosis. Finally, techniques were developed for the diagnosis of rejection via percutaneous biopsy, facilitating monitoring for rejection among recipients of either PAKT or PTA (10). Current Status As indicated in Table 1, advances in immunosuppression and surgical techniques have improved the overall results for SPKT, as reported by the IPTR (1). Some individual centers have reported 90% survival rates for pancreatic allografts at 1 yr(11 13). Although previously there was debate regarding the appropriateness of SPKT in the therapy of type 1 diabetes mellitus (14,15), excellent outcomes after SPKT are now being achieved (1,11 13,16,17). The American Society of Transplantation (18) and the American Diabetes Association (2) consider SPKT an appropriate treatment for diabetic patients with ESRD attributable to type 1 diabetes mellitus. Moreover, SPKT and PAKT are now (since July 1999) reimbursed by Medicare. Table 1 presents the results observed for PAKT in different eras, indicating that outcomes have improved with time. Notably, in every era, outcomes of PAKT lag behind those achieved with SPKT. PAKT performed after livingdonor kidney transplantation has two major benefits (3,19). Living-donor transplants demonstrate the best long-term survival rates, and use of a living-donor kidney does not remove a cadaveric donor kidney from the pool of organs available for potential transplant recipients. Donor Selection Donor selection and organ procurement are of paramount importance for the success of PAKT. Most heart-beating donors who have been declared brain-dead and are suitable for kidney, liver, and heart donation are also suitable for pancreas donation (Table 2). Although there is some evidence to suggest that donor hyperglycemia may have an adverse effect on initial and long-term allograft function, the presence of hyperglycemia or hyperamylasemia is not a contraindication for pancreas donation. In general, ideal pancreas donors range in age from 10 to 40 yr and range in weight from 30 to 80 kg. As the results of pancreas transplantation have improved and experience has increased, previous contraindications for pancreas donation have become mere risk factors for successful outcomes (Table 2). According to IPTR data, the following variables are associated with increased risks of pancreas allograft thrombosis: (1) donor age of 40 yr, (2) cardiovascular or cerebrovascular cause of brain death, and (3) pancreas preservation time of Table 1. One-year survival results after SPKT, PAKT, and PTA a Era Survival Rate (%) SPKT PAKT PTA 1987 to 1989 patient 90 90 93 pancreas 74 56 50 kidney 83 1992 to 1993 patient 92 90 89 pancreas 79 51 61 kidney 84 1996 to 1997 patient 95 95 96 pancreas 85 74 69 kidney 91 1998 to 2000 patient 95 94 98 pancreas 84 72 71 kidney 92 a SPKT, simultaneous pancreas/kidney transplant; PAKT, pancreas after kidney transplant; PTA, pancreas transplant alone.
J Am Soc Nephrol 13: 1109 1118, 2002 Pancreas after Kidney Transplantation 1111 Table 2. Cadaveric pancreas donation a Indications declaration of brain death informed consent age of 6 to 55 yr (ideal, 10 to 40 yr) weight of 30 to 100 kg (ideal, 30 to 80 kg) hemodynamic stability, with adequate perfusion and oxygenation absence of infectious or transmissible diseases (i.e., tuberculosis, syphilis, hepatitis B and C, and AIDS) negative serologic findings (HIV and hepatitis B and C) absence of malignancy (except skin or low-grade brain cancer) absence of parenchymal/intrinsic pancreatic disease Contraindications history of diabetes mellitus (type 1, type 2, or gestational) previous pancreatic surgery moderate to severe pancreatic trauma pancreatitis (active acute or chronic) significant intra-abdominal contamination major (active) infection chronic alcohol abuse recent history of intravenous drug abuse recent history of high-risk sexual behavior prolonged hypotension or hypoxemia, with evidence of significant end-organ (kidney or liver) damage severe atherosclerosis inexperienced retrieval team severe fatty infiltration of pancreatic parenchyma severe pancreatic edema severe obesity ( 150% of ideal body weight or BMI of 30 kg/m 2 ) Risk factors massive transfusions prior splenectomy mild to moderate obesity (125 to 150% of ideal body weight or BMI of 27.5 kg/m 2 ) aberrant hepatic artery anatomic features positive VDRL/RPR serologic results prolonged hospital stay donor age of 45 yr cardiovascular or cerebrovascular cause of brain death mild to moderate fatty infiltration mild to moderate pancreatic edema donor instability mild pancreatic trauma mild to moderate atherosclerosis a VDRL, Venereal Disease Research Laboratory; RPR, rapid plasma reagin; BMI, body mass index. 24 h (1). The results of anecdotal experience suggest that (1) 150% of ideal body weight or a body mass index (BMI) of 30 kg/m 2 for the donor may be associated with an increased risk of early pancreas graft loss (attributable to thrombosis, pancreatitis, infection, or primary nonfunction); (2) a donor liver biopsy with 25 to 30% macrovascular steatosis may be associated with a fatty pancreas, leading to an increased risk of early graft loss; and (3) fatty infiltration of the pancreas (as opposed to peripancreatic fat) may be associated with an increased risk of early graft loss (20,21). The presence of donor obesity or a fatty pancreas may be an underappreciated cause of early graft loss after PAKT. There are currently no data available regarding the utility of donor pancreas biopsies, particularly with respect to steatosis. The importance of an experienced retrieval team for in situ assessment of pancreatic anatomic features must be emphasized. Pancreas donors may be categorized as ideal, good, or marginal. By using donor age, weight/bmi, and the cause of brain death as the three most important factors, rapid accurate assessments of the quality of the donor pancreas can usually be made before actual intraoperative assessment, which is the next most important factor. PAKT donors must be either ideal or good. If either the donor or recipient is marginal, then there is a greater likelihood of a poor outcome. Compared with SPKT, the inherent risk of thrombosis is much higher (two- to threefold) for PAKT (22). In contrast to other transplanted organs, the solitary pancreas is susceptible to thrombosis because of its low microcirculatory flow based on collateral circulation. In the absence of the antiplatelet and anticoagulative effects of uremia, PAKT recipients may be prone to vascular thrombosis. For this reason, cold ischemia should be kept to a minimum and serious consideration should be given to routine perioperative anticoagulation therapy for the recipient. Recipient Selection In the past, most pancreas transplants were performed with younger recipients. However, the most recent analysis by the IPTR indicated that 25% of the recipients in 1998 and 1999 were 44 yr of age (1). Recipient age remains a significant risk factor for death after SPKT but not PAKT. These data must be interpreted with caution, because there were fewer recipients of PAKT in the analysis. Specific selection criteria for PAKT are based on the presence of established secondary diabetic complications or hyperlabile diabetes mellitus, with adequate cardiac and renal functional reserve (23). Indications for pancreas transplantation include IDDM and the predicted ability of the patient to tolerate the operative procedure, the requisite intense immunosuppression after transplantation, and possible associated complications (Table 3). Patient selection is facilitated by a comprehensive medical evaluation before transplantation, performed by a multidisciplinary team, that confirms the diagnosis of IDDM, determines the ability of the patient to withstand the operative procedure, establishes the absence of any exclusion criteria (Table 4), and documents end-organ complications for monitoring after transplantation. The primary determinants for recipient selection are the presence of diabetic complications, the degree of nephropathy, and cardiovascular risks (Table 3). With increasing experience, previous absolute contraindications have become relative contraindications, and relative contraindications have become risk factors for pancreas transplantation (Table 4). Diabetic patients who have previously received a renal al-
1112 Journal of the American Society of Nephrology J Am Soc Nephrol 13: 1109 1118, 2002 Table 3. Indications for pancreas transplantation and eligibility guidelines Medical necessity presence of insulin-treated diabetes mellitus documentation of insulin dose type 1 diabetes mellitus ability to withstand surgery and immunosuppression (as assessed by pretransplant medical evaluation) adequate cardiopulmonary function cardiac stress testing, with or without coronary angiography, to exclude significant coronary artery disease and other cardiac contraindications significant coronary artery disease should be corrected before transplantation absence of organ system failure (other than kidney) emotional and sociopsychological suitability presence of well defined diabetic complications (any two) proliferative retinopathy symptomatic peripheral or autonomic neuropathy microangiopathy accelerated atherosclerosis (macroangiopathy) glucose hyperlability, insulin resistance, or hypoglycemic unawareness, with significant impairment of quality of life absence of contraindications Sequential PAKT creatinine clearance of 40 ml/min (with calcineurin inhibitor) or 55 ml/min (without calcineurin inhibitor) lograft, from either a living or cadaveric donor, are considered potential candidates for PAKT if their creatinine clearance values are 40 ml/min with either CsA or tacrolimus (FK) immunosuppression (23). If the patient is not receiving a calcineurin inhibitor for the kidney transplant, a minimal creatinine clearance value of 55 ml/min is recommended (Table 3). Addition of a calcineurin inhibitor (or an increase in the dose for PAKT) generally results in a 25% decrease in baseline creatinine clearance. It is unclear how to factor the level of proteinuria into the decision-making, particularly because the use of a calcineurin inhibitor decreases the actual level of proteinuria. In this setting, a trial of high-dose CsA or FK before pancreas transplantation (CsA or FK challenge) may be indicated, to ascertain the effects of the drug on the patient s creatinine clearance, serum creatinine levels, and protein excretion (24,25). Patients with significant nephropathy of the previously transplanted kidney, renal dysfunction because of CsA/FK toxicity, or acute or chronic rejection, with lower creatinine clearance values, may not be suitable recipients for PAKT. A baseline kidney biopsy is important, for documentation, quantification, and monitoring of the progression of nephropathy after PAKT. However, there are few data on the use of the biopsy results to guide recipient selection. The presence of chronic allograft nephropathy might be a contraindication to PAKT for patients with otherwise stable renal allograft function. Table 4. Absolute and relative contraindications and risk factors for pancreas transplantation Absolute contraindications insufficient cardiovascular reserve, with one or more of the following coronary angiographic evidence of significant uncorrectable or untreatable coronary artery disease recent myocardial infarction poor ejection fraction active infection history of malignancy diagnosed within the previous 2 to 3 yr (excluding nonmelanoma skin cancer) positive HIV serologic results positive hepatitis B surface antigen serologic results active, untreated, peptic ulcer disease ongoing substance abuse (drug or alcohol) major ongoing psychiatric illness recent history of noncompliance inability to provide informed consent any systemic illness that would severely limit life expectancy or compromise recovery significant, irreversible, hepatic or pulmonary dysfunction positive crossmatch Relative contraindications age of 65 yr recent retinal hemorrhage symptomatic cerebrovascular or peripheral vascular disease absence of appropriate social support network extreme obesity ( 150% of ideal body weight or BMI of 30 kg/m 2 ) active smoking severe aortoiliac vascular disease Risk factors history of myocardial infarction, congestive heart failure, previous open heart surgery, or cardiac intervention history of major amputation or peripheral bypass graft history of cerebrovascular event or carotid endarterectomy history of hypercoagulable syndrome The cardiac status of each candidate must be carefully assessed, because significant (and silent) coronary artery disease is not uncommon in this population. The cardiac evaluation should include a noninvasive functional assessment, such as an exercise or pharmacologic stress test, in addition to echocardiography. Coronary angiography is reserved for specific indications, such as age of 45 yr, diabetes mellitus for 25 yr, a positive smoking history, longstanding hypertension, a previous major amputation attributable to peripheral vascular disease, a history of cerebrovascular disease, or an abnormality indicated by the history, physical examination, or noninvasive cardiac studies (23). Histories of previous myocardial infarctions, angioplasty, stenting, or coronary artery bypass grafting are not contraindications for PAKT, because excellent outcomes have been reported for patients who have undergone
J Am Soc Nephrol 13: 1109 1118, 2002 Pancreas after Kidney Transplantation 1113 previous cardiac interventions (26). However, sudden cardiac death, in the absence of significant structural heart disease, continues to be a major cause of cardiac death after pancreas transplantation (27). For this reason, a number of centers are beginning to test cardiac autonomic function for these patients, using laboratory cardiovascular tests and 24-h heart rate variability measurements (28). These new methods may be able to detect alterations in autonomic function before the onset of disabling symptoms. In general, age of 65 yr, heavy smoking, a left ventricular ejection fraction of 40%, a recent myocardial infarction, and severe obesity ( 150% of ideal body weight or BMI of 30 kg/m 2 ) are viewed as contraindications for PAKT (Table 4) (23). Most patients who are 45 yr of age are acceptable candidates for PAKT, provided that no significant coronary artery disease is present. Diabetic patients who are 45 yr of age are not candidates until proven otherwise and must undergo extensive cardiovascular and peripheral vascular evaluation. Prolonged immunosuppressive therapy for kidney transplantation may be associated with multiple medical complications, and these factors should be considered before PAKT. Recipient weight criteria are similar to those used for donor selection. Male recipients of 100 kg and female recipients of 80 kg, depending on their height and body habitus, demonstrate higher rates of surgical complications after pancreas transplantation (29). Therefore, a BMI of 30 kg/m 2 is considered an absolute contraindication and a BMI of 27.5 kg/m 2 is a relative contraindication for PAKT. A history of compliance with medication regimens and scheduled follow-up monitoring is an important factor in patient selection. Other exclusion criteria that are applicable to all solid-organ transplant recipients include the presence of active infection or recent malignancy, active substance abuse or dependence, a recent history of noncompliance or psychiatric illness, and positive HIV or hepatitis B virus serologic results (Table 4). Timing of PAKT A major dilemma for recipients with a suitable living donor is whether to proceed with the kidney transplant, followed by a pancreas transplant, or to undergo a SPKT. Because the results of PAKT are now approaching those of SPKT, the need for another surgical procedure and enhanced immunosuppressive therapy should be weighed against the limited organ availability, the prolonged waiting time for a cadaveric donor kidney/pancreas transplant, and the increased mortality rates during dialysis. Under these circumstances, it may be preferable to consider a living-donor kidney transplant followed by a cadaveric pancreas transplant. There are several factors to be considered in determining the optimal timing of PAKT. Ideally, some time should elapse after the kidney transplant, to ensure stability of graft function, surgical recovery, and reduced immunosuppression before pancreas transplantation. However, long-term recipients may experience significant complications secondary to diabetes mellitus and chronic immunosuppression. Recently, Humar et al. (4), from the University of Minnesota, compared outcomes for pancreas transplants performed 4 or 4 mo after kidney transplantation. Of the 123 PAKT procedures, 25 involved pancreas transplantation 4 mo after kidney transplantation, with the remaining 98 being performed 4 mo after kidney transplantation. Rates of complications such as intra-abdominal infections, cytomegalovirus infections, thrombosis, bleeding, exocrine leaks, and pancreatitis were similar for the two groups. Acute pancreas rejection rates at 3 mo and graft and patient survival rates at 3 yr for early ( 4 mo) PAKT were 20, 76, and 100%, respectively. Corresponding values for late ( 4 mo) PAKT were 20, 62, and 91%, respectively. These values were not statistically different. One innovative approach is to transplant the cadaveric pancreas during the same surgical procedure as the living-donor kidney transplantation. This obviously requires both the living donor and the recipient to wait until a suitable cadaveric pancreas becomes available. However, centers practicing this approach have performed such procedures within a few weeks after listing patients for transplantation (30). The major advantages of such an approach are the avoidance of another surgical procedure and the use of a single course of high-dose immunosuppressive therapy. Fifty simultaneous living-donor kidney/cadaveric pancreas transplants from a single center have been reported; the 1-yr pancreas, kidney, and patient survival rates were 88, 95, and 95%, respectively (30). However, inconvenience to the donor, complicated logistic requirements, and potential risks to the recipient undergoing dialysis during the wait may limit this approach. Infectious complications and sensitization attributable to exposure to various HLA antigens after kidney transplantation require further evaluation. Patients considered for PAKT should undergo appropriate evaluation of their post-kidney transplant infection history and serologic results. In addition, panel-reactive antibody levels, sensitization profiles, and unacceptable antigens should be assessed in an immunologic evaluation, to facilitate appropriate organ allocation. In practice, HLA matching for PAKT may involve matching the pancreas donor not only with the recipient but also with the recipient s previous kidney donor (so-called shared mismatching). The possibility of graft-versus-host disease remains a theoretical risk. The timing of PAKT must be determined on an individual basis, depending on donor availability and recipient condition. Despite these concerns, kidneys obtained from living donors for PAKT recipients marginally increase the cadaveric kidney/kidney recipient ratio. Events between Kidney and Pancreas Transplantation Data on post-kidney transplant events that affect the outcome of subsequent pancreas transplantation are not available. Events that occur after kidney transplantation may preclude some recipients from receiving PAKT. Such events include the following: immunologic problems (acute/chronic rejection), renal dysfunction (CsA/FK nephrotoxicities, recurrent disease, or donor vascular disease), active infections (bacterial, viral, or fungal infections), cardiovascular events (acute myocardial infarction, congestive heart failure, stroke, or peripheral vascular disease), and malignancies.
1114 Journal of the American Society of Nephrology J Am Soc Nephrol 13: 1109 1118, 2002 Acute rejection is associated with lower long-term kidney graft survival rates (31). It is not known whether patients who experience an acute rejection episode after kidney transplantation may exhibit greater susceptibility to acute rejection after PAKT. Kidney half-lives are also shortened by acute rejection episodes. Patients with shorter kidney half-lives because of renal dysfunction (CsA/FK nephrotoxicities, recurrent disease, or donor vascular disease) should be referred for PAKT with caution. PAKT is contraindicated in the presence of acute infections such as viral (cytomegalovirus or Epstein-Barr virus), bacterial, or fungal infections. Progression of systemic diabetic complications, such as cardiovascular, peripheral vascular, and cerebrovascular diseases, should be weighed against the benefits of pancreas transplantation. Patients who experience significant decreases in cardiac function and those with coronary artery disease, cerebrovascular accidents with neurologic deficits, or aortoiliac vascular disease that is not amenable to surgery should not be considered for PAKT. In general, patients with limited life expectancies, those at higher risk for graft failure, and those with active immunosuppression-related complications should be excluded from PAKT. Surgical Procedures The success rates for pancreas transplantation continue to improve, in part because of refinements in surgical techniques. The surgical procedure consists of three phases, as follows: first, the pancreas is procured and prepared; second, the blood supply to and from the pancreas graft is restored; finally, the exocrine drainage is established. These techniques are not different from those for SPKT. The management of pancreatic exocrine secretions represents a surgical challenge and is a potential cause of complications after transplantation. Historically, the urinary bladder has been the preferred route for drainage of exocrine secretions from the transplanted pancreas (13). Bladder drainage permits the measurement of urinary amylase levels for a designated period (usually 8 h), for monitoring of pancreatic graft function and diagnosis of rejection. However, this technique can be associated with several complications, such as hematuria, reflux pancreatitis, urinary tract infections, bladder stone formation, urinary leaks, and metabolic acidosis. Alternatively, the pancreatic exocrine secretions can be drained into the small bowel. This technique has grown in popularity and has been adopted by an increasing number of transplant centers (32). According to recent data from the IPTR, approximately 67% of SPKT, 49% of PAKT, and 40% of PTA are drained enterically (1). Complications of this procedure include graft vascular thrombosis, anastomotic leaks, and sepsis. Recent data indicate that enteric drainage is a safe practical alternative to bladder drainage for pancreas transplants. However, enteric drainage has traditionally been reserved for pancreas transplants combined with kidney transplants from the same donors. In such cases, the measurement of urinary amylase levels is not required for the diagnosis of rejection, because renal function monitoring offers sufficient information on the immunologic status of the recipient. In contrast, bladder drainage has been considered the surgical technique of choice for PAKT, because urinary amylase monitoring remains a reliable method for the detection of rejection (3,26). Moreover, there is some evidence suggesting that solitary pancreas transplantation with enteric exocrine drainage, coupled with portal venous delivery of insulin, may be associated with less rejection and lower immunologic graft loss rates, compared with other transplantation techniques (33). Immunosuppression for PAKT Recipients The number of immunosuppressive drug combinations available for pancreas transplant recipients has greatly increased in the past 6 yr. The IPTR recently reported allograft survival rates associated with various immunosuppressive regimens for patients who received PAKT between 1996 and 1999 (notably, before Food and Drug Administration approval of sirolimus) (1). The results are presented in Table 5. Approximately two-thirds of PAKT recipients were given anti-t cell antibodies for induction therapy. All patients reported to the IPTR received corticosteroids, at least during the induction and early maintenance phases of immunosuppression. Among patients who received anti-t cell antibody therapy, the 1-yr pancreas graft survival rates, according to the immunosuppressive combinations used, were as follows: mycophenolate mofetil (MMF)/FK (n 167), 82%; CsA/MMF (n 48), 76%; azathioprine/csa (n 13), 61%. There was a trend toward better survival rates with the MMF/FK combination. For patients who did not undergo anti-t cell antibody induction, the 1-yr pancreas graft survival rates were as follows: MMF/FK (n 80), 76%; CsA/MMF (n 30), 50%; azathioprine/csa (n 14), 25% (P 0.01). In conclusion, the IPTR analysis suggested that the use of anti-t cell antibody induction therapy was associated with higher 1-yr pancreas graft survival rates. In addition, the maintenance combination of MMF and FK demonstrated a trend toward higher 1-yr pancreas graft survival rates. Although these data must be confirmed in a prospective randomized study, it may be difficult to implement such a study because of the small number of cases at each center and the high immunologic risks associated with PAKT. Because FK at higher doses has been associated with impaired Table 5. One-year pancreas graft survival rates after PAKT (1996 to 1999) a With Antibody Induction No. of Patients Survival Rate (%) Without Antibody Induction No. of Patients Survival Rate (%) MMF FK 167 82 80 76 MMF CsA 48 76 30 50 AZA CsA 13 61 14 25 b a MMF, mycophenolate mofetil; FK, tacrolimus; CsA, cyclosporin A; AZA, azathioprine. b P 0.01.
J Am Soc Nephrol 13: 1109 1118, 2002 Pancreas after Kidney Transplantation 1115 glucose tolerance, FK-sparing regimens may be useful for this select population. To date, there has been no published experience with sirolimus-based immunosuppression among PAKT recipients. However, a recent report of an uncontrolled study of SPKT recipients suggested very low rates of allograft rejection among patients who received sirolimus in combination with low doses of FK (34). Taken together with the recent report of successful islet cell transplantation using sirolimus and FK without corticosteroids (35), it seems likely that the use of sirolimus-based regimens and steroid withdrawal in the treatment of PAKT recipients will increase in the next few years. Immunologic Monitoring after PAKT Monitoring of the pancreas transplant for rejection is an integral part of posttransplant management and is especially important after PAKT. With SPKT, the clinical manifestations of kidney transplant rejection usually precede pancreas rejection. Therefore, the serum creatinine concentration can be used as a surrogate marker of rejection and the need for therapy. Monitoring of the pancreas transplant for PAKT recipients is more difficult, because surrogate markers such as serum amylase levels, lipase levels, and concentrations of other pancreatic enzymes are nonspecific. The development of hyperglycemia is a particularly ominous sign of rejection and is usually indicative of a severe rejection episode. The routine use of FK can also be associated with hyperglycemia, which may confound the diagnosis of rejection. Multiple modalities have been used for surveillance and diagnosis of pancreas rejection. The most commonly used surveillance tools are measurement of serum amylase and lipase levels and, for bladder-drained pancreas transplants, measurement of urinary amylase levels (36). Increasing serum amylase or lipase levels suggest possible rejection but exhibit poor sensitivity and specificity for diagnosis. Levels of other serum markers, such as serum anodal trypsinogen, pancreatitisassociated protein, pancreas-specific protein, and pancreatic secretory trypsin inhibitor, become elevated during pancreas transplant rejection, but such assays are not widely available and are not superior to the use of serum amylase or lipase measurements for the diagnosis of rejection (37). The use of radiologic methods such as Doppler ultrasonography, nuclear imaging with technetium-99-sestamibi, and magnetic resonance angiography for the diagnosis of rejection has also been examined (38,39). Although each of these modalities provides excellent imaging of the pancreas, the diagnostic sensitivity is poor and the utility for the diagnosis of rejection is not well established. Finally, the glucose disappearance rate after glucose challenge has been demonstrated to exhibit greater sensitivity and specificity than either urinary amylase or serum anodal trypsinogen measurements for the diagnosis of rejection (40) among patients receiving CsA but not FK. The standard method for the diagnosis of pancreas rejection is now pancreas biopsy (10,41). Two major modalities have been developed for the diagnosis of rejection, i.e., transcystoscopic and percutaneous biopsy with ultrasonographic guidance. Transcystoscopic biopsy is used only for bladder-drained pancreas transplants and requires instrumentation of the bladder for acquisition of pancreatic tissue (41). Percutaneous biopsy is the technique of choice and is a safe reliable method to obtain tissue (10). It can be used for both enteric and bladder-drained pancreas transplants. A histologic grading system was recently proposed by Drachenberg et al. (42); grading of rejection ranges from 0 (normal) to V (severe rejection) and is based on the presence of lymphocytic inflammation, endotheliitis, eosinophilia, acinar or ductal inflammation, and arteritis. The grading system was observed to predict the responses to corticosteroids or antilymphocyte therapy. Benefits of PAKT General Considerations The benefits of euglycemia after SPKT have been well documented. However, benefits observed after PAKT have not been well studied. This lack is attributable to the fact that fewer PAKT are performed at each center, although a recent increase in activity has occurred with newer immunosuppressive agents such as MMF and FK. It is reasonable to extrapolate the advantages observed after SPKT to PAKT. Retinopathy Most of the studies that failed to demonstrate a benefit with respect to retinopathy involved short follow-up periods and irreversible baseline retinopathy. Studies with longer follow-up periods demonstrated stabilization of retinopathy among diabetic patients who received SPKT during the early stages of retinopathy and those who did not undergo laser therapy before transplantation, compared with deterioration of retinopathy among diabetic patients who received kidney transplants only (43 45). Neuropathy Diabetic patients who underwent SPKT demonstrated significant improvements in heart rate variability measures, compared with diabetic patients who underwent kidney transplantation only (28). Gastropathy was demonstrated to improve among recipients who underwent SPKT, compared with diabetic patients who received only kidney transplants (46). Peripheral neuropathy has also been demonstrated to improve, with subsequent long-term stabilization (47). Nephropathy Improved glucose control would be expected to retard the development of diabetic nephropathy, as suggested in the Diabetes Control and Complications Trial. It was demonstrated that, after 10 yr of normoglycemia after PTA, established histologic findings of diabetic nephropathy could be reversed, with reductions in glomerular and tubular basement membrane thickness and mesangial volume (48). Vasculopathy Changes in the microcirculation have been demonstrated to improve after SPKT, compared with diabetic patients who received only kidney transplants (49). It has been demonstrated
1116 Journal of the American Society of Nephrology J Am Soc Nephrol 13: 1109 1118, 2002 that carotid atherosclerotic lesions progress faster among patients with poor glycemic control and hypertension (50). Additionally, a number of studies have demonstrated improvement in most lipid parameters after SPKT, with reductions in cholesterol and triglyceride levels and improved HDL cholesterol levels (51). Quality of Life Studies comparing diabetic recipients of SPKT versus kidney transplants alone have reported improvements in qualityof-life measures, including physical well-being, function, and self-perception (52,53). It is hoped that recipients who undergo PAKT will also experience these benefits. Overall Mortality Rates It has been reported that SPKT recipients exhibit increased early mortality rates, compared with diabetic patients who receive only kidney transplants (54,55). However, those studies were nonrandomized, and the results may be related to the complex nature of SPKT. With long-term follow-up monitoring, 5-yr mortality rates were the same (55). Data from groups in Sweden and Leiden demonstrated decreased mortality rates after SPKT, compared with kidney transplants (56,57). However, those studies experienced difficulty in obtaining appropriate control groups. SPKT recipients with both grafts functioning were compared with patients who had either refused or lost their pancreas transplants (56). Diabetic recipients who resided in a geographic area where SPKT were performed were compared with patients in a different geographic area where kidney-only transplants were performed (57). More convincing would be a study comparing SPKT versus kidney transplantation versus dialysis treatment of patients on the same transplant waiting list (58). A recent analysis by the United States Renal Data System registry revealed superior 10-yr patient survival rates for living-donor kidney-only transplants (67%) and cadaveric SPKT (65%), compared with cadaveric donor kidney-only transplants (46%) (P 0.001) (59). Patient mortality rates were higher soon after SPKT; however, the relative risk of death by 5 yr was lower, compared with living-donor and cadaveric donor kidney-only transplantation. Long-term follow-up data for PAKT are not yet available. The reversal of hyperglycemia associated with PAKT should have similar effects on survival rates, as well as progressive diabetic complications. However, this remains to be evaluated with a large patient pool, such as that of the IPTR. Future In the foreseeable future, whole-organ pancreas transplantation should remain the most feasible way for diabetic recipients to achieve insulin independence. The major advantage of PAKT, compared with SPKT, is the ability to use a kidney from a living donor, followed by successful cadaveric pancreas transplantation. Such an approach does not have a negative effect on the cadaveric donor pool for kidney transplant recipients. Reports of successful islet transplantation for nonuremic recipients, using sirolimus and FK, have generated considerable interest (35). Obviously, islet transplantation eliminates the need for a major surgical procedure, with its potential complications. These results have not yet been confirmed at other centers, however, and long-term follow-up monitoring is needed. In addition, the use of a single donor for the pancreas transplant remains a distinct advantage of whole-organ transplantation, compared with islet transplantation. At this time, the clinical results of PAKT justify the use of the procedure for appropriately selected diabetic kidney transplant recipients. Conclusion In conclusion, the proportion and total number of PAKT procedures performed annually have steadily increased in recent years, because of a number of factors. (1) The results have continued to improve with advances in immunosuppressive therapy (the current 1-yr pancreas graft survival rate for PAKT recipients who undergo antibody induction in conjunction with FK and MMF therapy is 83%) (1). (2) Living-donor kidney transplantation followed by PAKT expands the kidney donor pool and permits preemptive transplantation as a scheduled event. (3) Waiting times for PAKT are much shorter than those for SPKT. (4) Increasing the number of solitary pancreas transplants may improve donor utilization and enhance sharing. References 1. Gruessner AC, Sutherland DER: Pancreas transplant outcomes for United States cases reported to the United Network for Organ Sharing (UNOS) and non-us cases reported to the International Pancreas Transplant Registry (IPTR) as of October, 2000. In: Clinical Transplants 2000, edited by Cecka JM, Terasaki PI, Los Angeles, UCLA Immunogenetics Center, 2001, pp 45 72 2. Robertson RP, Davis C, Larsen J, Stratta RJ, Sutherland DER: Pancreas and islet transplantation for patients with diabetes. Diabetes Care 23: 112 116, 2000 3. Humar A, Ramcharan T, Kandaswamy R, Matas AJ, Gruesnar RW: Pancreas after kidney transplants: A viable alternative to simultaneous pancreas-kidney transplants. Ann Surg 2001, in press 4. Humar A, Sutherland DE, Ramcharan T, Gruessner RW, Gruessner AC, Kandaswamy R: Optimal timing for a pancreas transplant after a successful kidney transplant. Transplantation 70: 1247 1250, 2000 5. Stratta RJ: Simultaneous use of tacrolimus and mycophenolate mofetil in combined pancreas kidney transplant recipients: A multi-center report: The FK/MMF Multi-Center Study Group. Transplant Proc 29: 654 655, 1997 6. Hricik DE: Kidney-pancreas transplantation for diabetic nephropathy. Semin Nephrol 20: 188 198, 2000 7. Kelly KD, Lillehei KC, Merkle FK, Idezuki Y, Goetz FC: Allotransplantation of pancreas and duodenum along with kidney in diabetic nephropathy. Surgery 61: 827 837, 1967 8. Sutherland DER, Moudry KC: Report on International Pancreas Transplant Registry. In: Clinical Transplants 1986, Los Angeles, UCLA Tissue Typing Laboratory, 1987, pp 63 101 9. Stratta RJ, Sollinger HW, Perlman SB, D Alessandro AM, Groshek M, Kalayoglu M, Pirsch JD, Belzer FO: Early detection of rejection in pancreas transplantation. Diabetes 38: 63 67, 1989
J Am Soc Nephrol 13: 1109 1118, 2002 Pancreas after Kidney Transplantation 1117 10. Allen RD, Wilson TG, Grierson JM, Greenberg ML, Earl MJ, Nankivell BJ, Pearl TA, Chapman JR: Percutaneous biopsy of bladder-drained pancreas transplants. Transplantation 51: 1213 1216, 1991 11. Freise CE, Narumi S, Stock PG, Melzer JS: Simultaneous pancreas kidney transplantation: An overview of indications, complications, and outcomes. West J Med 170: 11 18, 1999 12. Kaufman DB, Leventhal JR, Stuart J, Abecassis MM, Fryer JP, Stuart FP: Mycophenolate mofetil and tacrolimus as primary maintenance immunosuppression in simultaneous pancreas-kidney transplantation: Initial experience in 50 consecutive cases. Transplantation 67: 586 593, 1999 13. Sollinger HW, Odorico JS, Knechtle SJ, D Alessandro AM, Kalayoglu M, Pirsch JD: Experience with 500 simultaneous pancreas-kidney transplants. Ann Surg 228: 284 296, 1998 14. Tattersall R: Is pancreas transplantation for insulin-dependent diabetics worthwhile? N Engl J Med 321: 112 114, 1989 15. Remuzzi G, Ruggenenti P, Mauer SM: Pancreas and kidney/ pancreas transplants: Experimental medicine or real improvement? Lancet 343: 27 31, 1994 16. Sutherland DE: Pancreas and pancreas-kidney transplantation. Curr Opin Nephrol Hypertens 7: 317 325, 1998 17. White SA, Nicholson ML, London NJ: Vascularized pancreas allotransplantation: Clinical indications and outcome. Diabet Med 16: 533 543, 1999 18. Pirsch JD, Andrews A, Hricik DE, Josephson MA, Leichtman AB, Lu CY, Melton LB, Rao VK, Riggio RR, Stratta RJ, Weir MR: Pancreas transplantation for diabetes mellitus. Am J Kidney Dis 27: 444 450, 1996 19. Douzdjian V, Escobar F, Kupin WL, Venkat KK, Abouljoud MS: Cost-utility analysis of living-donor kidney transplantation followed by pancreas transplantation versus simultaneous pancreas-kidney transplantation. Clin Transplant 13: 51 58, 1999 20. Stratta RJ: Donor age, organ import, and cold ischemia: Effects on early outcome after simultaneous kidney-pancreas transplantation. Transplant Proc 29: 3291 3292, 1997 21. Odorico JS, Heisey DM, Voss BJ, Voss BJ, Steiner DS, Knechtle SJ, D Alessandro AM, Hoffmann RM, Sollinger HW: Donor factors affecting outcome after pancreas transplantation. Transplant Proc 30: 276 277, 1998 22. Troppmann C, Gruessner AC, Benedetti E, Papalois BE, Dunn DL, Najarian JS, Sutherland DE, Gruessner RW: Vascular graft thrombosis after pancreatic transplantation: Univariate and multivariate operative and nonoperative risk factor analysis. JAm Coll Surg 182: 285 316, 1996 23. Stratta RJ, Taylor RJ, Wahl TO, Duckworth WC, Gallagher TF, Knight TF, Fischer JL, Neumann TV, Miller S, Langnas AN: Recipient selection and evaluation for vascularized pancreas transplantation. Transplantation 55: 1090 1096, 1993 24. Brennan DC, Stratta RJ, Lowell JA, Miller SA, Taylor RJ: Cyclosporine challenge in the decision of combined kidneypancreas versus solitary pancreas transplantation. Transplantation 57: 1606 1611, 1994 25. Lane JT, Ratanasuwan T, Mack-Shipman LR, Taylor RJ, Leone JP, Miller SA, Lyden ER, Larsen JL: Cyclosporine challenge test revisited: Does it predict outcome after solitary pancreas transplantation? Clin Transplant 15: 28 31, 2001 26. Sutherland DER, Gruessner RWG, Dunn DL, Matas AJ, Humar A, Kandaswamy R, Mauer SM, Kennedy WR, Goetz FC, Robertson RP, Gruessner AC, Najarian JS: Lessons learned from more than 1,000 pancreas transplants at a single institution. Ann Surg 233: 463 501, 2001 27. Hathaway DK, El-Gebely S, Cardoso S, Elmer DS, Gaber AO: Autonomic cardiac dysfunction in diabetic transplant recipients succumbing to sudden cardiac death. Transplantation 59: 634 637, 1995 28. Cashion AK, Hathaway DK, Milstead EJ, Reed L, Gaber AO: Changes in patterns of 24-hour heart rate variability after kidney and kidney-pancreas transplant. Transplantation 68: 1846 1850, 1999 29. Bumgardner GL, Henry ML, Elkhammas E, Wilson GA, Tso P, Davies E, Qiu W, Ferguson RM: Obesity as a risk factor after combined pancreas/kidney transplantation. Transplantation 60: 1426 1430, 1995 30. Farney AC, Cho E, Schweitzer EJ, Wilson GA, Tso P, Davies E, Qiu W, Ferguson RM: Simultaneous cadaver pancreas livingdonor kidney transplantation: A new approach for the type 1 diabetic uremic patient. Ann Surg 232: 696 703, 2000 31. Hariharan S, Johnson CP, Bresnahan BA, MacIntosh M, Stablein D: Improved short and long-term graft survival after transplantation in the US, 1988 1996. N Engl J Med 342: 605 612, 2000 32. Douzdjian V, Rajagopalan RP: Primary enteric drainage of the pancreas allograft revisited. J Am Coll Surg 185: 471 475, 1997 33. Philosophe B, Farney AC, Schweitzer EJ, Colonna JO, Jarrell BE, Krishnamurthi V, Wiland AM, Bartlett ST: The superiority of portal venous drainage over systemic venous drainage in solitary pancreas transplantation [Abstract]. In: Proceedings of the 17th International Congress of the Transplantation Society, Rome, Italy, Transplantation Society, 2000, p 115 34. McAlister VC, Gao Z, Peltekian K, Domingues J, Mahalati K, MacDonald AS: Sirolimus-tacrolimus combination immunosuppression. Lancet 355: 376 377, 2000 35. Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV: Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 343: 230 238, 2000 36. Munn SR, Engen DE, Barr D, Carpenter HA, Perkins JD: Differential diagnosis of hypoamylasuria in pancreas allograft recipients with urinary exocrine drainage. Transplantation 49: 359 362, 1990 37. Douzdjian V, Cooper JL, Abecassis MM, Corry RJ: Markers for pancreatic allograft rejection: Comparison of serum anodal trypsinogen, serum amylase, serum creatinine and urinary amylase. Clin Transplant 8: 79 82, 1994 38. Gilabert R, Bru C, Ricart MJ, Astudillo E, Saenz A, Llovera JM, Lopez-Boado MA, Sanfey H, Fernandez-Cruz L: Pancreatic transplant rejection: Evaluation by duplex-doppler ultrasound with urinary amylase monitoring correlation. Transplant Proc 24: 11, 1992 39. Krebs TL, Daly B, Wong-You-Cheong JJ, Carroll K, Bartlett ST: Acute pancreatic transplant rejection: Evaluation with dynamic contrast-enhanced MR imaging compared with histopathologic analysis. Radiology 210: 437 442, 1999 40. Elmer DS, Hathaway DK, Bashar AA, Hughes TA, Shokouh- Amiri H, Gaber LW, Gaber AO: Use of glucose disappearance rates (k G ) to monitor endocrine function of pancreas allografts. Clin Transplant 12: 56 64, 1998 41. Benedetti E, Najarian JS, Gruessner AC, Nakhleh RE, Troppmann C, Hakim NS, Pirenne J, Sutherland DE, Gruessner RW: Correlation between cystoscopic biopsy results and hypoamyla-