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REVIEW J Am Soc Nephrol 13: 1109–1118, 2002

Pancreas after

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.

After three decades of controversy surrounding the therapeutic creas (with complete insulin independence) survival rates validity of transplantation, the procedure has become after SPKT are 95, 92, and 84%, respectively (1). Solitary accepted as the preferred treatment for patients with insulin- pancreas transplants comprised the remaining cases, including dependent mellitus (IDDM) and advanced diabetic sequential pancreas after kidney transplants (PAKT) (12%) and nephropathy with end-stage renal disease (ESRD) and for those pancreas transplants alone (PTA) (5%) (1). Although the an- approaching ESRD. Vascularized pancreas transplantation is nual rate of pancreas transplants has steadily increased, the currently the only available form of autoregulating, total en- number of solitary pancreas transplants has increased dispro- docrine replacement therapy that reliably achieves an insulin- portionately in recent years; in 1999, 75% of transplants were independent euglycemic state and normal glucose homeostasis, SPKT, 18% PAKT, and 7% PTA. The current 1-yr patient resulting in the successful management of diabetes mellitus. survival rate after solitary pancreas transplantation is 95%, and The trade-offs for normal glucose homeostasis are the opera- the 1-yr actuarial pancreas graft survival rates are 73% for tive risks of the pancreas transplant procedure and the need for PAKT and 70% for PTA (1). The differences in graft survival chronic . Free islet grafts have the same rates for SPKT, PAKT, and PTA have been attributed to potential, but their efficacy requires further evaluation. increased rates of graft loss resulting from rejection and throm- With improvements in organ retrieval and preservation tech- bosis after solitary pancreas transplantation. nology, refinements in diagnostic methods and surgical tech- Pancreas transplantation should be considered an acceptable niques, advances in clinical immunosuppression and anti-in- therapeutic alternative to continued insulin therapy for diabetic fective prophylaxis, and increased experience with donor and patients with imminent or established ESRD who have under- recipient selection, success rates for pancreas transplantation gone or plan to undergo a kidney transplant, because the have continued to improve. From 1966 through October 2000, successful addition of a pancreas does not jeopardize patient Ͼ 15,000 pancreas transplants were performed throughout the survival rates, may improve kidney graft survival rates, and world and reported to the International Pancreas Transplant will restore normoglycemia (2). PAKT is advocated for dia- Registry (IPTR) (1). In the past decade, the majority (83%) of betic patients with well functioning kidney transplants, because pancreas transplants were performed in combination with a these patients already require chronic immunosuppression and kidney transplant [simultaneous pancreas/kidney transplants the additional risk is primarily that of the surgical procedure (SPKT)] for patients with ESRD attributable to diabetic ne- (3,4). Currently, many transplant centers are experienced in phropathy. The current 1-yr actuarial patient, kidney, and pan- performing SPKT; only a few centers have accumulated much experience with PAKT. Received September 10, 2001. Accepted October 12, 2001. The improved success of SPKT has prompted many centers Correspondence to Dr. Sundaram Hariharan, Division of Nephrology, Medical to offer pancreas transplantation for patients with type 1 dia- College of Wisconsin, 9200 W. Wisconsin Avenue, Milwaukee, WI 53226. betes mellitus who have undergone successful kidney trans- Phone: 414-456-6730; Fax: 414- 456-6207; E-mail: [email protected]; American plantation. PAKT increases the likelihood of more diabetic Society of Transplantation, 236 Route 38 West, Suite 100, Moorestown, NJ 08057; Phone: 856-608-1104; Fax: 856-608-1103; E-mail: [email protected] recipients receiving a pancreas transplant and eliminates many 1046-6673/1304-1109 of the organ-allocation issues associated with SPKT. The in- Journal of the American Society of Nephrology creased interest in PAKT is attributable to several factors. New Copyright © 2002 by the American Society of Nephrology 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 ESRD attributable to mellitus. Moreover, surgical techniques, patient selection, and immunologic mon- SPKT and PAKT are now (since July 1999) reimbursed by itoring have also improved short- and long-term success rates Medicare. Table 1 presents the results observed for PAKT in after pancreas transplantation (6). Finally, the recent decision different eras, indicating that outcomes have improved with by Medicare to reimburse providers for the procedure has time. Notably, in every era, outcomes of PAKT lag behind eliminated the financial burden for many potential recipients. those achieved with SPKT. PAKT performed after living- Despite these advancements, there are no clear guidelines for donor kidney transplantation has two major benefits (3,19). donor and recipient selection, immunologic monitoring, the Living-donor transplants demonstrate the best long-term sur- choice of immunosuppressive agents, or the timing of PAKT. vival rates, and use of a living-donor kidney does not remove This lack has prompted the Pancreas Committee of the Amer- a cadaveric donor kidney from the pool of organs available for ican Society of Transplantation to review the current status of potential transplant recipients. PAKT. Donor Selection History and Background Donor selection and are of paramount Dr. Richard Lillehei performed the first pancreas transplant importance for the success of PAKT. Most heart-beating do- at the University of Minnesota in 1966 (7). Pancreas transplan- nors who have been declared brain-dead and are suitable for tation was abandoned at that center in 1973, after 14 trans- kidney, , and heart donation are also suitable for pancreas plants had been performed with only one successful pancreas donation (Table 2). Although there is some evidence to suggest graft functioning for 1 yr. The program was resumed in 1978. that donor hyperglycemia may have an adverse effect on initial Throughout the world, only 1157 pancreas transplants were and long-term allograft function, the presence of hyperglyce- performed between 1966 and 1987, with three-fourths of the mia or hyperamylasemia is not a contraindication for pancreas transplants being performed after 1982 (8). Despite a multitude donation. of surgical approaches for duct drainage and the use of cyclo- In general, ideal pancreas donors range in age from 10 to 40 sporin A (CsA) after 1983, the 1-yr patient and pancreas graft yr and range in weight from 30 to 80 kg. As the results of survival rates were only 76 and 37%, respectively (8). During pancreas transplantation have improved and experience has this early experience, it became evident that SPKT was asso- increased, previous contraindications for pancreas donation ciated with better graft survival rates than was either PAKT or have become mere risk factors for successful outcomes (Table PTA. 2). According to IPTR data, the following variables are asso- Historically, major impediments to successful pancreas ciated with increased risks of pancreas allograft : (1) transplantation were the management of exocrine secretions, donor age of Ͼ40 yr, (2) cardiovascular or cerebrovascular the inability to monitor the pancreas for rejection, and high cause of brain death, and (3) pancreas preservation time of rates of rejection, thrombosis, and . In the past two decades, significant improvements in the surgical and medical management of pancreas transplants have occurred. The man- Table 1. One-year survival results after SPKT, PAKT, agement of pancreatic exocrine secretions improved with the and PTAa development of bladder drainage, which allowed for measure- Survival Rate (%) ment of urinary amylase levels, facilitating prediction of acute Era rejection episodes (9). Improvements in immunosuppression SPKT PAKT PTA made possible a return to enteric drainage of the exocrine secretions by preventing episodes of acute rejection and elim- 1987 to 1989 inating the need for high-dose therapy, which impaired patient 90 90 93 healing of the enteric anastomosis. Finally, techniques were pancreas 74 56 50 developed for the diagnosis of rejection via percutaneous bi- kidney 83 opsy, facilitating monitoring for rejection among recipients of 1992 to 1993 either PAKT or PTA (10). patient 92 90 89 pancreas 79 51 61 Current Status kidney 84 As indicated in Table 1, advances in immunosuppression 1996 to 1997 and surgical techniques have improved the overall results for patient 95 95 96 SPKT, as reported by the IPTR (1). Some individual centers pancreas 85 74 69 have reported Ͼ90% survival rates for pancreatic allografts at kidney 91 1yr(11–13). Although previously there was debate regarding 1998 to 2000 the appropriateness of SPKT in the therapy of type 1 diabetes patient 95 94 98 mellitus (14,15), excellent outcomes after SPKT are now being pancreas 84 72 71 achieved (1,11–13,16,17). The American Society of Transplan- kidney 92 tation (18) and the American Diabetes Association (2) consider a SPKT, simultaneous pancreas/kidney transplant; PAKT, SPKT an appropriate treatment for diabetic patients with 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 donationa with Ͼ25 to 30% macrovascular steatosis may be associated with a fatty pancreas, leading to an increased risk of Indications early graft loss; and (3) fatty infiltration of the pancreas (as declaration of brain death opposed to peripancreatic fat) may be associated with an in- informed consent creased risk of early graft loss (20,21). The presence of donor age of 6 to 55 yr (ideal, 10 to 40 yr) obesity or a fatty pancreas may be an underappreciated cause weight of 30 to 100 kg (ideal, 30 to 80 kg) of early graft loss after PAKT. There are currently no data hemodynamic stability, with adequate perfusion and available regarding the utility of donor pancreas biopsies, oxygenation particularly with respect to steatosis. The importance of an absence of infectious or transmissible diseases (i.e., experienced retrieval team for in situ assessment of pancreatic tuberculosis, syphilis, hepatitis B and C, and AIDS) anatomic features must be emphasized. negative serologic findings (HIV and hepatitis B and C) Pancreas donors may be categorized as ideal, good, or mar- absence of malignancy (except skin or low-grade brain ginal. By using donor age, weight/BMI, and the cause of brain cancer) death as the three most important factors, rapid accurate as- absence of parenchymal/intrinsic pancreatic disease sessments of the quality of the donor pancreas can usually be Contraindications made before actual intraoperative assessment, which is the next history of diabetes mellitus (type 1, type 2, or gestational) most important factor. PAKT donors must be either ideal or previous pancreatic surgery good. If either the donor or recipient is marginal, then there is moderate to severe pancreatic trauma a greater likelihood of a poor outcome. Compared with SPKT, pancreatitis (active acute or chronic) the inherent risk of thrombosis is much higher (two- to three- significant intra-abdominal contamination fold) for PAKT (22). In contrast to other transplanted organs, major (active) the solitary pancreas is susceptible to thrombosis because of its chronic alcohol abuse low microcirculatory flow based on collateral circulation. In recent history of intravenous drug abuse the absence of the antiplatelet and anticoagulative effects of recent history of high-risk sexual behavior uremia, PAKT recipients may be prone to vascular thrombosis. prolonged hypotension or hypoxemia, with evidence of For this reason, cold ischemia should be kept to a minimum significant end-organ (kidney or liver) damage and serious consideration should be given to routine perioper- severe atherosclerosis ative anticoagulation therapy for the recipient. inexperienced retrieval team severe fatty infiltration of pancreatic parenchyma Recipient Selection severe pancreatic edema In the past, most pancreas transplants were performed with Ͼ severe obesity ( 150% of ideal body weight or BMI of younger recipients. However, the most recent analysis by the Ͼ 2 30 kg/m ) IPTR indicated that Ͼ25% of the recipients in 1998 and 1999 Risk factors were Ͼ44 yr of age (1). Recipient age remains a significant massive transfusions risk factor for death after SPKT but not PAKT. These data prior splenectomy must be interpreted with caution, because there were fewer mild to moderate obesity (125 to 150% of ideal body recipients of PAKT in the analysis. Specific selection criteria Ͼ 2 weight or BMI of 27.5 kg/m ) for PAKT are based on the presence of established secondary aberrant hepatic artery anatomic features diabetic complications or hyperlabile diabetes mellitus, with positive VDRL/RPR serologic results adequate cardiac and renal functional reserve (23). Indications prolonged hospital stay for pancreas transplantation include IDDM and the predicted Ͼ donor age of 45 yr ability of the patient to tolerate the operative procedure, the cardiovascular or cerebrovascular cause of brain death requisite intense immunosuppression after transplantation, and mild to moderate fatty infiltration possible associated complications (Table 3). Patient selection mild to moderate pancreatic edema is facilitated by a comprehensive medical evaluation before donor instability transplantation, performed by a multidisciplinary team, that mild pancreatic trauma confirms the diagnosis of IDDM, determines the ability of the mild to moderate atherosclerosis patient to withstand the operative procedure, establishes the a VDRL, Venereal Disease Research Laboratory; RPR, rapid absence of any exclusion criteria (Table 4), and documents plasma reagin; BMI, body mass index. end-organ complications for monitoring after transplantation. The primary determinants for recipient selection are the pres- ence of diabetic complications, the degree of nephropathy, and Ͼ24 h (1). The results of anecdotal experience suggest that (1) cardiovascular risks (Table 3). With increasing experience, Ͼ150% of ideal body weight or a body mass index (BMI) of previous absolute contraindications have become relative con- Ͼ30 kg/m2 for the donor may be associated with an increased traindications, and relative contraindications have become risk risk of early pancreas graft loss (attributable to thrombosis, factors for pancreas transplantation (Table 4). pancreatitis, infection, or primary nonfunction); (2) a donor 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 Table 4. Absolute and relative contraindications and risk eligibility guidelines factors for pancreas transplantation

Medical necessity Absolute contraindications presence of insulin-treated diabetes mellitus insufficient cardiovascular reserve, with one or more of documentation of insulin dose the following type 1 diabetes mellitus coronary angiographic evidence of significant ability to withstand surgery and immunosuppression (as uncorrectable or untreatable coronary artery disease assessed by pretransplant medical evaluation) recent myocardial infarction adequate cardiopulmonary function poor ejection fraction cardiac stress testing, with or without coronary active infection angiography, to exclude significant coronary artery history of malignancy diagnosed within the previous 2 to disease and other cardiac contraindications 3 yr (excluding nonmelanoma skin cancer) significant coronary artery disease should be positive HIV serologic results corrected before transplantation positive hepatitis B surface antigen serologic results absence of organ system failure (other than kidney) active, untreated, peptic ulcer disease emotional and sociopsychological suitability ongoing substance abuse (drug or alcohol) presence of well defined diabetic complications (any two) major ongoing psychiatric illness proliferative retinopathy recent history of noncompliance symptomatic peripheral or autonomic neuropathy inability to provide informed consent microangiopathy any systemic illness that would severely limit life accelerated atherosclerosis (macroangiopathy) expectancy or compromise recovery glucose hyperlability, insulin resistance, or hypoglycemic significant, irreversible, hepatic or pulmonary dysfunction unawareness, with significant impairment of quality positive crossmatch of life Relative contraindications absence of contraindications age of Ͼ65 yr Sequential PAKT recent retinal hemorrhage creatinine clearance of Ն40 ml/min (with calcineurin symptomatic cerebrovascular or peripheral vascular inhibitor) or Ͼ55 ml/min (without calcineurin inhibitor) disease absence of appropriate social support network extreme obesity (Ͼ150% of ideal body weight or BMI of Ͼ 2 lograft, from either a living or cadaveric donor, are considered 30 kg/m ) potential candidates for PAKT if their creatinine clearance active smoking values are Ͼ40 ml/min with either CsA or (FK) severe aortoiliac vascular disease immunosuppression (23). If the patient is not receiving a Risk factors calcineurin inhibitor for the kidney transplant, a minimal cre- history of myocardial infarction, congestive heart failure, atinine clearance value of 55 ml/min is recommended (Table previous open heart surgery, or cardiac intervention 3). Addition of a calcineurin inhibitor (or an increase in the history of major amputation or peripheral bypass graft dose for PAKT) generally results in a 25% decrease in baseline history of cerebrovascular event or carotid endarterectomy creatinine clearance. It is unclear how to factor the level of history of hypercoagulable syndrome 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 The cardiac status of each candidate must be carefully as- before pancreas transplantation (CsA or FK challenge) may be sessed, because significant (and silent) coronary artery disease indicated, to ascertain the effects of the drug on the patient’s is not uncommon in this population. The cardiac evaluation creatinine clearance, serum creatinine levels, and protein ex- should include a noninvasive functional assessment, such as an cretion (24,25). Patients with significant nephropathy of the exercise or pharmacologic stress test, in addition to echocar- previously transplanted kidney, renal dysfunction because of diography. Coronary angiography is reserved for specific in- CsA/FK toxicity, or acute or chronic rejection, with lower dications, such as age of Ͼ45 yr, diabetes mellitus for Ͼ25 yr, creatinine clearance values, may not be suitable recipients for a positive smoking history, longstanding hypertension, a pre- PAKT. A baseline kidney biopsy is important, for documen- vious major amputation attributable to peripheral vascular dis- tation, quantification, and monitoring of the progression of ease, a history of cerebrovascular disease, or an abnormality nephropathy after PAKT. However, there are few data on the indicated by the history, physical examination, or noninvasive use of the biopsy results to guide recipient selection. The cardiac studies (23). Histories of previous myocardial infarc- presence of chronic allograft nephropathy might be a contra- tions, angioplasty, stenting, or coronary artery bypass grafting indication to PAKT for patients with otherwise stable renal are not contraindications for PAKT, because excellent out- allograft function. comes 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 transplantation. Of the 123 PAKT procedures, 25 involved death, in the absence of significant structural heart disease, pancreas transplantation Յ4 mo after kidney transplantation, continues to be a major cause of cardiac death after pancreas with the remaining 98 being performed Ͼ4 mo after kidney transplantation (27). For this reason, a number of centers are transplantation. Rates of complications such as intra-abdomi- beginning to test cardiac autonomic function for these patients, nal , cytomegalovirus infections, thrombosis, bleed- using laboratory cardiovascular tests and 24-h heart rate vari- ing, exocrine leaks, and pancreatitis were similar for the two ability measurements (28). These new methods may be able to groups. Acute pancreas rejection rates at 3 mo and graft and detect alterations in autonomic function before the onset of patient survival rates at 3 yr for early (Յ4 mo) PAKT were 20, disabling symptoms. 76, and 100%, respectively. Corresponding values for late (Ͼ4 In general, age of Ͼ65 yr, heavy smoking, a left ventricular mo) PAKT were 20, 62, and 91%, respectively. These values ejection fraction of Ͻ40%, a recent myocardial infarction, and were not statistically different. severe obesity (Ͼ150% of ideal body weight or BMI of Ͼ30 One innovative approach is to transplant the cadaveric pan- kg/m2) are viewed as contraindications for PAKT (Table 4) (23). creas during the same surgical procedure as the living-donor Most patients who are Ͻ45 yr of age are acceptable candidates for kidney transplantation. This obviously requires both the living PAKT, provided that no significant coronary artery disease is donor and the recipient to wait until a suitable cadaveric present. Diabetic patients who are Ͼ45 yr of age are not candi- pancreas becomes available. However, centers practicing this dates until proven otherwise and must undergo extensive cardio- approach have performed such procedures within a few weeks vascular and peripheral vascular evaluation. Prolonged immuno- after listing patients for transplantation (30). The major advan- suppressive therapy for kidney transplantation may be associated tages of such an approach are the avoidance of another surgical with multiple medical complications, and these factors should be procedure and the use of a single course of high-dose immu- considered before PAKT. Recipient weight criteria are similar to nosuppressive therapy. Fifty simultaneous living-donor kid- those used for donor selection. Male recipients of Ͼ100 kg and ney/cadaveric pancreas transplants from a single center have female recipients of Ͼ80 kg, depending on their height and body been reported; the 1-yr pancreas, kidney, and patient survival habitus, demonstrate higher rates of surgical complications after rates were 88, 95, and 95%, respectively (30). However, in- pancreas transplantation (29). Therefore, a BMI of Ͼ30 kg/m2 is convenience to the donor, complicated logistic requirements, considered an absolute contraindication and a BMI of Ͼ27.5 and potential risks to the recipient undergoing dialysis during kg/m2 is a relative contraindication for PAKT. the wait may limit this approach. A history of compliance with medication regimens and Infectious complications and sensitization attributable to scheduled follow-up monitoring is an important factor in pa- exposure to various HLA antigens after kidney transplantation tient selection. Other exclusion criteria that are applicable to all require further evaluation. Patients considered for PAKT solid-organ transplant recipients include the presence of active should undergo appropriate evaluation of their post-kidney infection or recent malignancy, active substance abuse or de- transplant infection history and serologic results. In addition, pendence, a recent history of noncompliance or psychiatric panel-reactive antibody levels, sensitization profiles, and un- illness, and positive HIV or hepatitis B virus serologic results acceptable antigens should be assessed in an immunologic (Table 4). evaluation, to facilitate appropriate organ allocation. In prac- tice, HLA matching for PAKT may involve matching the Timing of PAKT pancreas donor not only with the recipient but also with the A major dilemma for recipients with a suitable living donor recipient’s previous kidney donor (so-called shared mismatch- is whether to proceed with the kidney transplant, followed by ing). The possibility of graft-versus-host disease remains a a pancreas transplant, or to undergo a SPKT. Because the theoretical risk. The timing of PAKT must be determined on an results of PAKT are now approaching those of SPKT, the need individual basis, depending on donor availability and recipient for another surgical procedure and enhanced immunosuppres- condition. Despite these concerns, kidneys obtained from liv- sive therapy should be weighed against the limited organ ing donors for PAKT recipients marginally increase the cadav- availability, the prolonged waiting time for a cadaveric donor eric kidney/kidney recipient ratio. kidney/pancreas transplant, and the increased mortality rates during dialysis. Under these circumstances, it may be prefer- Events between Kidney and able to consider a living-donor kidney transplant followed by a Pancreas Transplantation cadaveric pancreas transplant. Data on post-kidney transplant events that affect the out- There are several factors to be considered in determining the come of subsequent pancreas transplantation are not available. optimal timing of PAKT. Ideally, some time should elapse Events that occur after kidney transplantation may preclude after the kidney transplant, to ensure stability of graft function, some recipients from receiving PAKT. Such events include the surgical recovery, and reduced immunosuppression before following: immunologic problems (acute/chronic rejection), pancreas transplantation. However, long-term recipients may renal dysfunction (CsA/FK nephrotoxicities, recurrent disease, experience significant complications secondary to diabetes or donor vascular disease), active infections (bacterial, viral, or mellitus and chronic immunosuppression. Recently, Humar et fungal infections), cardiovascular events (acute myocardial al. (4), from the University of Minnesota, compared outcomes infarction, congestive heart failure, stroke, or peripheral vas- for pancreas transplants performed Յ4orϾ4 mo after kidney cular 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 on the immunologic status of the recipient. In contrast, bladder graft survival rates (31). It is not known whether patients who drainage has been considered the surgical technique of choice experience an acute rejection episode after kidney transplanta- for PAKT, because urinary amylase monitoring remains a tion may exhibit greater susceptibility to acute rejection after reliable method for the detection of rejection (3,26). Moreover, PAKT. Kidney half-lives are also shortened by acute rejection there is some evidence suggesting that solitary pancreas trans- episodes. Patients with shorter kidney half-lives because of plantation with enteric exocrine drainage, coupled with portal renal dysfunction (CsA/FK nephrotoxicities, recurrent disease, venous delivery of insulin, may be associated with less rejec- or donor vascular disease) should be referred for PAKT with tion and lower immunologic graft loss rates, compared with caution. other transplantation techniques (33). PAKT is contraindicated in the presence of acute infections such as viral (cytomegalovirus or Epstein-Barr virus), bacte- Immunosuppression for PAKT Recipients rial, or fungal infections. Progression of systemic diabetic The number of combinations complications, such as cardiovascular, peripheral vascular, and available for pancreas transplant recipients has greatly in- cerebrovascular diseases, should be weighed against the ben- creased in the past 6 yr. The IPTR recently reported allograft efits of pancreas transplantation. Patients who experience sig- survival rates associated with various immunosuppressive reg- nificant decreases in cardiac function and those with coronary imens for patients who received PAKT between 1996 and 1999 artery disease, cerebrovascular accidents with neurologic def- (notably, before Food and Drug Administration approval of icits, or aortoiliac vascular disease that is not amenable to sirolimus) (1). The results are presented in Table 5. Approxi- surgery should not be considered for PAKT. In general, pa- mately two-thirds of PAKT recipients were given anti-T cell tients with limited life expectancies, those at higher risk for antibodies for induction therapy. All patients reported to the graft failure, and those with active immunosuppression-related IPTR received , at least during the induction and complications should be excluded from PAKT. early maintenance phases of immunosuppression. Among pa- tients who received anti-T cell antibody therapy, the 1-yr Surgical Procedures pancreas graft survival rates, according to the immunosuppres- The success rates for pancreas transplantation continue to sive combinations used, were as follows: mycophenolate improve, in part because of refinements in surgical techniques. mofetil (MMF)/FK (n ϭ 167), 82%; CsA/MMF (n ϭ 48), The surgical procedure consists of three phases, as follows: 76%; /CsA (n ϭ 13), 61%. There was a trend first, the pancreas is procured and prepared; second, the blood toward better survival rates with the MMF/FK combination. supply to and from the pancreas graft is restored; finally, the For patients who did not undergo anti-T cell antibody induc- exocrine drainage is established. These techniques are not tion, the 1-yr pancreas graft survival rates were as follows: different from those for SPKT. MMF/FK (n ϭ 80), 76%; CsA/MMF (n ϭ 30), 50%; azathio- The management of pancreatic exocrine secretions repre- prine/CsA (n ϭ 14), 25% (P Ͻ 0.01). In conclusion, the IPTR sents a surgical challenge and is a potential cause of compli- analysis suggested that the use of anti-T cell antibody induction cations after transplantation. Historically, the urinary bladder therapy was associated with higher 1-yr pancreas graft survival has been the preferred route for drainage of exocrine secretions rates. In addition, the maintenance combination of MMF and from the transplanted pancreas (13). Bladder drainage permits FK demonstrated a trend toward higher 1-yr pancreas graft the measurement of urinary amylase levels for a designated survival rates. Although these data must be confirmed in a period (usually 8 h), for monitoring of pancreatic graft function prospective randomized study, it may be difficult to implement and diagnosis of rejection. However, this technique can be such a study because of the small number of cases at each associated with several complications, such as hematuria, re- center and the high immunologic risks associated with PAKT. flux pancreatitis, urinary tract infections, bladder stone forma- Because FK at higher doses has been associated with impaired tion, urinary leaks, and metabolic acidosis. Alternatively, the pancreatic exocrine secretions can be drained into the small bowel. This technique has grown in Table 5. One-year pancreas graft survival rates after PAKT popularity and has been adopted by an increasing number of (1996 to 1999)a transplant centers (32). According to recent data from the IPTR, approximately 67% of SPKT, 49% of PAKT, and 40% With Antibody Without Antibody of PTA are drained enterically (1). Complications of this Induction Induction procedure include graft vascular thrombosis, anastomotic No. of Survival No. of Survival leaks, and sepsis. Patients Rate (%) Patients Rate (%) Recent data indicate that enteric drainage is a safe practical alternative to bladder drainage for pancreas transplants. How- MMF ϩ FK 167 82 80 76 ever, enteric drainage has traditionally been reserved for pan- MMF ϩ CsA 48 76 30 50 b creas transplants combined with kidney transplants from the AZA ϩ CsA 13 61 14 25 same donors. In such cases, the measurement of urinary amy- a MMF, mycophenolate mofetil; FK, tacrolimus; CsA, lase levels is not required for the diagnosis of rejection, be- cyclosporin A; AZA, azathioprine. cause renal function monitoring offers sufficient information b P Ͻ 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 pancreas transplants and requires instrumentation of the blad- select population. der for acquisition of pancreatic tissue (41). Percutaneous To date, there has been no published experience with siroli- biopsy is the technique of choice and is a safe reliable method mus-based immunosuppression among PAKT recipients. How- to obtain tissue (10). It can be used for both enteric and ever, a recent report of an uncontrolled study of SPKT recip- bladder-drained pancreas transplants. ients suggested very low rates of allograft rejection among A histologic grading system was recently proposed by patients who received sirolimus in combination with low doses Drachenberg et al. (42); grading of rejection ranges from 0 of FK (34). Taken together with the recent report of successful (normal) to V (severe rejection) and is based on the presence of islet cell transplantation using sirolimus and FK without cor- lymphocytic inflammation, endotheliitis, eosinophilia, acinar ticosteroids (35), it seems likely that the use of sirolimus-based or ductal inflammation, and arteritis. The grading system was regimens and steroid withdrawal in the treatment of PAKT observed to predict the responses to corticosteroids or antilym- recipients will increase in the next few years. phocyte therapy.

Immunologic Monitoring after PAKT Benefits of PAKT Monitoring of the pancreas transplant for rejection is an General Considerations integral part of posttransplant management and is especially The benefits of euglycemia after SPKT have been well important after PAKT. With SPKT, the clinical manifestations documented. However, benefits observed after PAKT have not of kidney usually precede pancreas rejec- been well studied. This lack is attributable to the fact that fewer tion. Therefore, the serum creatinine concentration can be used PAKT are performed at each center, although a recent increase as a surrogate marker of rejection and the need for therapy. in activity has occurred with newer immunosuppressive agents Monitoring of the pancreas transplant for PAKT recipients is such as MMF and FK. It is reasonable to extrapolate the more difficult, because surrogate markers such as serum amy- advantages observed after SPKT to PAKT. lase levels, lipase levels, and concentrations of other pancreatic enzymes are nonspecific. The development of hyperglycemia Retinopathy is a particularly ominous sign of rejection and is usually Most of the studies that failed to demonstrate a benefit with indicative of a severe rejection episode. The routine use of FK respect to retinopathy involved short follow-up periods and can also be associated with hyperglycemia, which may con- irreversible baseline retinopathy. Studies with longer follow-up found the diagnosis of rejection. periods demonstrated stabilization of retinopathy among dia- Multiple modalities have been used for surveillance and betic patients who received SPKT during the early stages of diagnosis of pancreas rejection. The most commonly used retinopathy and those who did not undergo laser therapy before surveillance tools are measurement of serum amylase and transplantation, compared with deterioration of retinopathy lipase levels and, for bladder-drained pancreas transplants, among diabetic patients who received kidney transplants only measurement of urinary amylase levels (36). Increasing serum (43–45). amylase or lipase levels suggest possible rejection but exhibit poor sensitivity and specificity for diagnosis. Levels of other Neuropathy serum markers, such as serum anodal trypsinogen, pancreatitis- Diabetic patients who underwent SPKT demonstrated sig- associated protein, pancreas-specific protein, and pancreatic nificant improvements in heart rate variability measures, com- secretory trypsin inhibitor, become elevated during pancreas pared with diabetic patients who underwent kidney transplan- transplant rejection, but such assays are not widely available tation only (28). Gastropathy was demonstrated to improve and are not superior to the use of serum amylase or lipase among recipients who underwent SPKT, compared with dia- measurements for the diagnosis of rejection (37). The use of betic patients who received only kidney transplants (46). Pe- radiologic methods such as Doppler ultrasonography, nuclear ripheral neuropathy has also been demonstrated to improve, imaging with technetium-99-sestamibi, and magnetic reso- with subsequent long-term stabilization (47). nance angiography for the diagnosis of rejection has also been examined (38,39). Although each of these modalities provides Nephropathy excellent imaging of the pancreas, the diagnostic sensitivity is Improved glucose control would be expected to retard the poor and the utility for the diagnosis of rejection is not well development of diabetic nephropathy, as suggested in the Di- established. Finally, the glucose disappearance rate after glu- abetes Control and Complications Trial. It was demonstrated cose challenge has been demonstrated to exhibit greater sen- that, after 10 yr of normoglycemia after PTA, established sitivity and specificity than either urinary amylase or serum histologic findings of diabetic nephropathy could be reversed, anodal trypsinogen measurements for the diagnosis of rejection with reductions in glomerular and tubular basement membrane (40) among patients receiving CsA but not FK. thickness and mesangial volume (48). The standard method for the diagnosis of pancreas rejection is now pancreas biopsy (10,41). Two major modalities have Vasculopathy been developed for the diagnosis of rejection, i.e., transcysto- Changes in the microcirculation have been demonstrated to scopic and percutaneous biopsy with ultrasonographic guid- improve after SPKT, compared with diabetic patients who ance. Transcystoscopic biopsy is used only for bladder-drained 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 pa- able interest (35). Obviously, islet transplantation eliminates tients with poor glycemic control and hypertension (50). Ad- the need for a major surgical procedure, with its potential ditionally, a number of studies have demonstrated improve- complications. ment in most lipid parameters after SPKT, with reductions in These results have not yet been confirmed at other centers, cholesterol and triglyceride levels and improved HDL choles- however, and long-term follow-up monitoring is needed. In terol levels (51). addition, the use of a single donor for the pancreas transplant remains a distinct advantage of whole-, Quality of Life compared with islet transplantation. At this time, the clinical Studies comparing diabetic recipients of SPKT versus kid- results of PAKT justify the use of the procedure for appropri- ney transplants alone have reported improvements in quality- ately selected diabetic kidney transplant recipients. of-life measures, including physical well-being, function, and self-perception (52,53). It is hoped that recipients who undergo Conclusion PAKT will also experience these benefits. In conclusion, the proportion and total number of PAKT procedures performed annually have steadily increased in re- Overall Mortality Rates cent years, because of a number of factors. (1) The results have It has been reported that SPKT recipients exhibit increased continued to improve with advances in immunosuppressive early mortality rates, compared with diabetic patients who therapy (the current 1-yr pancreas graft survival rate for PAKT receive only kidney transplants (54,55). However, those stud- recipients who undergo antibody induction in conjunction with ies were nonrandomized, and the results may be related to the FK and MMF therapy is 83%) (1). (2) Living-donor kidney complex nature of SPKT. With long-term follow-up monitor- transplantation followed by PAKT expands the kidney donor ing, 5-yr mortality rates were the same (55). Data from groups pool and permits preemptive transplantation as a scheduled in Sweden and Leiden demonstrated decreased mortality rates event. (3) Waiting times for PAKT are much shorter than those after SPKT, compared with kidney transplants (56,57). How- for SPKT. (4) Increasing the number of solitary pancreas ever, those studies experienced difficulty in obtaining appro- transplants may improve donor utilization and enhance priate control groups. SPKT recipients with both grafts func- sharing. tioning 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 References compared with patients in a different geographic area where 1. Gruessner AC, Sutherland DER: Pancreas transplant outcomes for United States cases reported to the United Network for Organ kidney-only transplants were performed (57). More convincing Sharing (UNOS) and non-US cases reported to the International would be a study comparing SPKT versus kidney transplanta- Pancreas Transplant Registry (IPTR) as of October, 2000. In: tion versus dialysis treatment of patients on the same transplant Clinical Transplants 2000, edited by Cecka JM, Terasaki PI, Los waiting list (58). Angeles, UCLA Immunogenetics Center, 2001, pp 45–72 A recent analysis by the United States Renal Data System 2. Robertson RP, Davis C, Larsen J, Stratta RJ, Sutherland DER: registry revealed superior 10-yr patient survival rates for liv- Pancreas and islet transplantation for patients with diabetes. ing-donor kidney-only transplants (67%) and cadaveric SPKT Diabetes Care 23: 112–116, 2000 (65%), compared with cadaveric donor kidney-only transplants 3. Humar A, Ramcharan T, Kandaswamy R, Matas AJ, Gruesnar (46%) (P Ͻ 0.001) (59). Patient mortality rates were higher RW: Pancreas after kidney transplants: A viable alternative to soon after SPKT; however, the relative risk of death by 5 yr simultaneous pancreas-kidney transplants. Ann Surg 2001, in was lower, compared with living-donor and cadaveric donor press 4. Humar A, Sutherland DE, Ramcharan T, Gruessner RW, Gruess- kidney-only transplantation. Long-term follow-up data for ner AC, Kandaswamy R: Optimal timing for a pancreas trans- PAKT are not yet available. The reversal of hyperglycemia plant after a successful kidney transplant. Transplantation 70: associated with PAKT should have similar effects on survival 1247–1250, 2000 rates, as well as progressive diabetic complications. However, 5. Stratta RJ: Simultaneous use of tacrolimus and mycophenolate this remains to be evaluated with a large patient pool, such as mofetil in combined pancreas kidney transplant recipients: A that of the IPTR. multi-center report: The FK/MMF Multi-Center Study Group. Transplant Proc 29: 654–655, 1997 Future 6. Hricik DE: Kidney-pancreas transplantation for diabetic ne- In the foreseeable future, whole-organ pancreas transplanta- phropathy. Semin Nephrol 20: 188–198, 2000 tion should remain the most feasible way for diabetic recipients 7. Kelly KD, Lillehei KC, Merkle FK, Idezuki Y, Goetz FC: to achieve insulin independence. The major advantage of of pancreas and duodenum along with kidney in diabetic nephropathy. Surgery 61: 827–837, 1967 PAKT, compared with SPKT, is the ability to use a kidney 8. Sutherland DER, Moudry KC: Report on International Pancreas from a living donor, followed by successful cadaveric pancreas Transplant Registry. In: Clinical Transplants 1986, Los Angeles, transplantation. Such an approach does not have a negative UCLA Tissue Typing Laboratory, 1987, pp 63–101 effect on the cadaveric donor pool for kidney transplant recip- 9. Stratta RJ, Sollinger HW, Perlman SB, D’Alessandro AM, Gro- ients. Reports of successful islet transplantation for nonuremic shek M, Kalayoglu M, Pirsch JD, Belzer FO: Early detection of recipients, using sirolimus and FK, have generated consider- 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, 27. Hathaway DK, El-Gebely S, Cardoso S, Elmer DS, Gaber AO: Nankivell BJ, Pearl TA, Chapman JR: Percutaneous biopsy of Autonomic cardiac dysfunction in diabetic transplant recipients bladder-drained pancreas transplants. Transplantation 51: 1213– succumbing to sudden cardiac death. Transplantation 59: 634– 1216, 1991 637, 1995 11. Freise CE, Narumi S, Stock PG, Melzer JS: Simultaneous pan- 28. Cashion AK, Hathaway DK, Milstead EJ, Reed L, Gaber AO: creas kidney transplantation: An overview of indications, com- Changes in patterns of 24-hour heart rate variability after kidney plications, and outcomes. West J Med 170: 11–18, 1999 and kidney-pancreas transplant. Transplantation 68: 1846–1850, 12. Kaufman DB, Leventhal JR, Stuart J, Abecassis MM, Fryer JP, 1999 Stuart FP: Mycophenolate mofetil and tacrolimus as primary 29. Bumgardner GL, Henry ML, Elkhammas E, Wilson GA, Tso P, maintenance immunosuppression in simultaneous pancreas-kid- Davies E, Qiu W, Ferguson RM: Obesity as a risk factor after ney transplantation: Initial experience in 50 consecutive cases. combined pancreas/kidney transplantation. Transplantation 60: Transplantation 67: 586–593, 1999 1426–1430, 1995 13. Sollinger HW, Odorico JS, Knechtle SJ, D’Alessandro AM, 30. Farney AC, Cho E, Schweitzer EJ, Wilson GA, Tso P, Davies E, Kalayoglu M, Pirsch JD: Experience with 500 simultaneous Qiu W, Ferguson RM: Simultaneous cadaver pancreas living- pancreas-kidney transplants. Ann Surg 228: 284–296, 1998 donor kidney transplantation: A new approach for the type 1 14. Tattersall R: Is pancreas transplantation for insulin-dependent diabetic uremic patient. Ann Surg 232: 696–703, 2000 diabetics worthwhile? N Engl J Med 321: 112–114, 1989 31. Hariharan S, Johnson CP, Bresnahan BA, MacIntosh M, Sta- 15. Remuzzi G, Ruggenenti P, Mauer SM: Pancreas and kidney/ blein D: Improved short and long-term graft survival after pancreas transplants: Experimental medicine or real improve- transplantation in the US, 1988–1996. N Engl J Med 342: ment? Lancet 343: 27–31, 1994 605– 612, 2000 16. Sutherland DE: Pancreas and pancreas-kidney transplantation. 32. Douzdjian V, Rajagopalan RP: Primary enteric drainage of the Curr Opin Nephrol Hypertens 7: 317–325, 1998 pancreas allograft revisited. J Am Coll Surg 185: 471– 475, 17. White SA, Nicholson ML, London NJ: Vascularized pancreas 1997 allotransplantation: Clinical indications and outcome. Diabet 33. Philosophe B, Farney AC, Schweitzer EJ, Colonna JO, Jarrell Med 16: 533–543, 1999 BE, Krishnamurthi V, Wiland AM, Bartlett ST: The superiority 18. Pirsch JD, Andrews A, Hricik DE, Josephson MA, Leichtman of portal venous drainage over systemic venous drainage in AB, Lu CY, Melton LB, Rao VK, Riggio RR, Stratta RJ, Weir solitary pancreas transplantation [Abstract]. In: Proceedings of MR: Pancreas transplantation for diabetes mellitus. Am J Kidney the 17th International Congress of the Transplantation Society, Dis 27: 444–450, 1996 Rome, Italy, Transplantation Society, 2000, p 115 19. Douzdjian V, Escobar F, Kupin WL, Venkat KK, Abouljoud 34. McAlister VC, Gao Z, Peltekian K, Domingues J, Mahalati K, MS: Cost-utility analysis of living-donor kidney transplantation MacDonald AS: Sirolimus-tacrolimus combination immunosup- followed by pancreas transplantation versus simultaneous pan- pression. Lancet 355: 376–377, 2000 creas-kidney transplantation. Clin Transplant 13: 51–58, 1999 35. Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, 20. Stratta RJ: Donor age, organ import, and cold ischemia: Effects Warnock GL, Kneteman NM, Rajotte RV: Islet transplanta- on early outcome after simultaneous kidney-pancreas transplan- tion in seven patients with type 1 diabetes mellitus using a tation. Transplant Proc 29: 3291–3292, 1997 glucocorticoid-free immunosuppressive regimen. N Engl 21. Odorico JS, Heisey DM, Voss BJ, Voss BJ, Steiner DS, Knechtle SJ, D’Alessandro AM, Hoffmann RM, Sollinger HW: Donor J Med 343: 230–238, 2000 factors affecting outcome after pancreas transplantation. Trans- 36. Munn SR, Engen DE, Barr D, Carpenter HA, Perkins JD: Dif- plant Proc 30: 276–277, 1998 ferential diagnosis of hypoamylasuria in pancreas allograft re- 22. Troppmann C, Gruessner AC, Benedetti E, Papalois BE, Dunn cipients with urinary exocrine drainage. Transplantation 49: DL, Najarian JS, Sutherland DE, Gruessner RW: Vascular graft 359–362, 1990 thrombosis after pancreatic transplantation: Univariate and mul- 37. Douzdjian V, Cooper JL, Abecassis MM, Corry RJ: Markers for tivariate operative and nonoperative risk factor analysis. JAm pancreatic allograft rejection: Comparison of serum anodal Coll Surg 182: 285–316, 1996 trypsinogen, serum amylase, serum creatinine and urinary amy- 23. Stratta RJ, Taylor RJ, Wahl TO, Duckworth WC, Gallagher TF, lase. Clin Transplant 8: 79–82, 1994 Knight TF, Fischer JL, Neumann TV, Miller S, Langnas AN: 38. Gilabert R, Bru C, Ricart MJ, Astudillo E, Saenz A, Llovera JM, Recipient selection and evaluation for vascularized pancreas Lopez-Boado MA, Sanfey H, Fernandez-Cruz L: Pancreatic transplantation. Transplantation 55: 1090–1096, 1993 transplant rejection: Evaluation by duplex-Doppler ultrasound 24. Brennan DC, Stratta RJ, Lowell JA, Miller SA, Taylor RJ: with urinary amylase monitoring correlation. Transplant Proc Cyclosporine challenge in the decision of combined kidney- 24: 11, 1992 pancreas versus solitary pancreas transplantation. Transplanta- 39. Krebs TL, Daly B, Wong-You-Cheong JJ, Carroll K, Bartlett ST: tion 57: 1606–1611, 1994 Acute pancreatic transplant rejection: Evaluation with dynamic 25. Lane JT, Ratanasuwan T, Mack-Shipman LR, Taylor RJ, Leone contrast-enhanced MR imaging compared with histopathologic JP, Miller SA, Lyden ER, Larsen JL: Cyclosporine challenge test analysis. Radiology 210: 437–442, 1999 revisited: Does it predict outcome after solitary pancreas trans- 40. Elmer DS, Hathaway DK, Bashar AA, Hughes TA, Shokouh- plantation? Clin Transplant 15: 28–31, 2001 Amiri H, Gaber LW, Gaber AO: Use of glucose disappearance

26. Sutherland DER, Gruessner RWG, Dunn DL, Matas AJ, Humar rates (kG) to monitor endocrine function of pancreas allografts. A, Kandaswamy R, Mauer SM, Kennedy WR, Goetz FC, Rob- Clin Transplant 12: 56–64, 1998 ertson RP, Gruessner AC, Najarian JS: Lessons learned from 41. Benedetti E, Najarian JS, Gruessner AC, Nakhleh RE, Tropp- more than 1,000 pancreas transplants at a single institution. Ann mann C, Hakim NS, Pirenne J, Sutherland DE, Gruessner RW: Surg 233: 463–501, 2001 Correlation between cystoscopic biopsy results and hypoamyla- 1118 Journal of the American Society of Nephrology J Am Soc Nephrol 13: 1109–1118, 2002

suria in bladder-drained pancreas transplants. Surgery 118: 864– 51. Landgraf R: Impact of pancreas transplantation on diabetic sec- 872, 1995 ondary complications and quality of life. Diabetologia 39: 1415– 42. Drachenberg CB, Papadimitriou JC, Klassen DK, Racusen LC, 1424, 1996 Hoehn-Saric EW, Weir MR, Kuo PC, Schweitzer EJ, Johnson 52. Nakache R, Tyden G, Groth CG: Quality of life in diabetic LB, Bartlett ST: Evaluation of pancreas transplant needle biopsy: patients after combined pancreas-kidney or kidney transplanta- Reproducibility and revision of histologic grading system. tion. Diabetes 38: 40–42, 1989 Transplantation 63: 1579–1586, 1997 53. Zehrer CL, Gross CR: Quality of life of pancreas transplant 43. Scheider A, Meyer-Schwickerath V, Nusser J, Land W, Landgraf recipients. Diabetologia 34: 145–149, 1991 R: Diabetic retinopathy and pancreas transplantation: A 3-year 54. Manske CL, Wang Y, Thomas W: Mortality of cadaveric kidney follow-up. Diabetologia 34: 95–99, 1991 transplantation versus combined kidney-pancreas transplantation 44. Di Landro D, Koenigsrainer L, Oefner D, Aichberger C, Rom- in diabetic patients. Lancet 346: 1658–1662, 1995 agnoli GF, Margreiter R: Experience with 100 combined pan- 55. Douzdjian V, Abecassis MM, Corry RJ, Hunsicker LG: Simul- creatic renal transplantations in a single center. Nephron 72: taneous pancreas-kidney versus kidney-alone transplants in dia- 547–551, 1996 betics: Increased risk of early cardiac death and acute rejection 45. Chow VCC, Pai RP, Chapman JR, O’Connell PJ, Allen RD, Mitch- following pancreas transplants. Clin Transplant 8: 246–251, ell P, Nankivell BJ: Diabetic retinopathy after combined kidney- 1994 pancreas transplantation. Clin Transplant 13: 356–362, 1999 56. Tyden G, Bolinder J, Solders G, Brattstrom C, Tibell A, Groth 46. Hathaway DK, Abell T, Cardoso S, Hartwig MS, El Gebely S, CG: Improved survival in patients with insulin-dependent diabe- Gaber AO: Improvement in autonomic and gastric function follow- tes mellitus and end-stage diabetic nephropathy 10 years after ing pancreas-kidney versus kidney-alone transplantation and the combined pancreas and kidney transplantation. Transplantation correlation with quality of life. Transplantation 57: 816–822, 1994 67: 645–648, 1999 47. Allen RDM, Al-Harbi IS, Morris JG, Clouston PD, O’Connell 57. Smets YF, Westendorp RG, van der Pijl JW, de Charro FT, PJ, Chapman JR, Nankivell BJ: Diabetic neuropathy after pan- creas transplantation: Determinants of recovery. Transplantation Ringers J, De Fijter JW, Lemkes HH: Effect of simultaneous 63: 830–838, 1997 pancreas-kidney transplantation on mortality of patients with 48. Fioretto P, Steffes MW, Sutherland DER, Goetz FC, Mauer M: type 1 diabetes mellitus and end-stage renal failure. Lancet 353: Reversal of lesions of diabetic nephropathy after pancreas trans- 1915–1919, 1999 plantation. N Engl J Med 339: 69–75, 1998 58. Wolfe RA, Ashby VB, Milford EL, Ojo OA, Ettensohn CA, 49. Abendroth D, Schmand J, Landgraf R, Illner WD, Land W: Agodoa LYC, Held PJ, Port FK: Comparison of mortality in all Diabetic microangiopathy in type 1 (insulin-dependent) diabetic patients on dialysis, patients on dialysis awaiting transplantation, patients after successful pancreatic and kidney or solitary kidney and recipients of a first cadaveric transplant. N Engl J Med 341: transplantation. Diabetology 34: 131–134, 1991 1725–1730, 1999 50. La Rocca E, Minicucci F, Secchi A, Ciurlino D, Bonfatti D, 59. Ojo AO, Kriesche-Meier HU, Hanson JA, Leichtman A, Magee Ferrari G, Castoldi R, Di Carlo V, Pozza G: Evolution of carotid JC, Cibrik D, Wolfe RA, Port FK, Agodoa L, Kaufman DB, vascular lesions in kidney-pancreas and kidney-alone trans- Kaplan B: The impact of simultaneous pancreas-kidney trans- planted insulin-dependent diabetic patients. Transplant Proc 27: plantation on long-term patient survival. Transplantation 71: 3072, 1995 82–90, 2001