Search

To determine if islet autotransplantation (IAT) independently improves the quality of life (QoL) in patients after total pancreatectomy and islet autotransplantation (TP-IAT).TP-IAT is increasingly being used for intractable chronic pancreatitis. However, the impact of IAT on long-term islet function and QoL is unclear.TP-IAT patients at our center1 year after TP-IAT with ≥1 Short Form-36 QoL measure were included. Patients were classified as insulin-independent or insulin-dependent, and as having islet graft function or failure by C-peptide. The associations of insulin use and islet graft function with QoL measures were analyzed by using a linear mixed model, accounting for time since transplant and within-person correlation.Among 817 islet autograft recipients, 564 patients [median (interquartile range) age: 34 (20, 45) years, 71% female] and 2161 total QoL surveys were included. QoL data were available for5 years after TP-IAT for 42.7% and for10 years for 17.3%. Insulin-independent patients exhibited higher QoL in 7 of 8 subscale domains and for Physical Component Summary and Mental Component Summary scores ( P0.05 for all). Physical Component Summary was 2.91 (SE=0.57) higher in insulin-independent patients ( P0.001). No differences in QoL were observed between those with and without graft function, but islet graft failure was rare (15% of patients). However, glycosylated hemoglobin was much higher with islet graft failure.QoL is significantly improved when insulin independence is present, and glycosylated hemoglobin is lower with a functioning islet graft. These data support offering IAT, rather than just performing total pancreatectomy and treating with exogenous insulin.

Total pancreatectomy with islet autotransplantation is performed to treat chronic pancreatitis in children. Successful islet isolation must address the challenges of severe pancreatic fibrosis and young donor age. We have progressively introduced modifications to optimize enzymatic and mechanical dissociation of the pancreas during islet isolation. We evaluated 2 islet isolation metrics in 138 children-digest islet equivalents per gram pancreas tissue (IEQ/g) and digest IEQ per kilogram body weight (IEQ/kg), using multiple regression to adjust for key disease and patient features. Islet yield at digest had an average 4569 (standard deviation 2949) islet equivalent (IEQ)/g and 4946 (4009) IEQ/kg, with 59.1% embedded in exocrine tissue. Cases with very low yield (

Background A total pancreatectomy and intraportal islet cell autotransplant (TPIAT) is increasingly being offered to patients with chronic pancreatitis (CP). The benefits include removal of the root cause of pain and amelioration of diabetes. However, the long-term durability of this operation remains unclear. Study Design Of the 742 patients who have undergone a TPIAT at our center, 215 who did so between 1998 and 2008 now have at least 10 years of follow-up time and were eligible for this single-center observational study. Our outcomes measures included abdominal pain relief, narcotic use, islet graft function (subdivided into 3 groups: insulin independence; partial graft function, defined by C-peptide level > 0.6 mg/dL; and no function, defined by C-peptide level Results The 10-year actuarial survival rate was 72%. A BMI > 30 kg/m2 (p = 0.04) predicted 10-year mortality. The rates of pain relief were 82% at 10 years and 90% at 15 years. Narcotic use declined with time: the rates were 50% at 5 years and 37% at 10 years. At 10 years, the rate of insulin independence was 20%; the rate of partial graft function, 32%. Transplantation of islet equivalents/kg > 4,000 was the strongest predictor of islet graft function at 10 years. Pediatric patients were more likely to have islet function than adults (p = 0.01). Health-related quality of life continued to improve at 10 years, even in patients on narcotics. Conclusions This represents the first and largest series to examine long-term outcomes (10 years or more) in TPIAT patients. In our series, this dual procedure produced durable pain relief and sustained islet graft function, even past 10 years postoperatively.

OBJECTIVES Chronic pancreatitis (CP) is an infrequent but debilitating complication associated with CFTR mutations. Total pancreatectomy with islet autotransplantation (TPIAT) is a treatment option for CP that provides pain relief and preserves β-cell mass, thereby minimizing the complication of diabetes mellitus. We compared outcomes after TPIAT for CP associated with CFTR mutations to CP without CTFR mutations. METHODS All TPIATs performed between 2002 and 2014 were retrospectively reviewed: identifying 20 CFTR homozygotes (cystic fibrosis [CF] patients), 19 CFTR heterozygotes, and 20 age-/sex-matched controls without CFTR mutations. Analysis of variance and χ tests were used to compare groups. RESULTS Baseline demographics were not different between groups. Postoperative glycosylated hemoglobin and C-peptide levels were similar between groups, as were islet yield and rate of postoperative complications. At 1 year, 40% of CF patients, 22% of CFTR heterozygotes, and 35% of control patients were insulin independent. CONCLUSION Total pancreatectomy with islet autotransplantation is a safe, effective treatment option for CF patients with CP, giving similar outcomes for those with other CP etiologies.

To enhance selection of appropriate deceased donors for pancreas transplants, we sought to determine whether HLA matching improved posttransplantation outcomes. In this single-center study of 1219 pancreas transplants, we correlated posttransplantation outcomes with HLA-A, -B, -C, -DR, and -DQ matches and mismatches. Rejection was linearly correlated with the number of mismatches. The individual number of HLA mismatches reached significance at four or more with a 2.3- to 2.9-fold increase in rejection. The effect was most predominant with HLA-B (1.8-fold with one mismatch and 2.0-fold with two mismatches) and -DR (1.9-fold with two mismatches) loci, whereas HLA-A, -C, and -DQ matches or mismatches did not independently predict acute rejection. The affect was strongest in solitary pancreas transplants, with little impact for simultaneous pancreas and kidney (SPK). In contrast, HLA matching did not affect graft or patient survival rates but was associated with a reduced risk of opportunistic infection. Avoidance of acute rejection saved an estimated $32 000 for solitary pancreas recipients and $52 000 for SPK recipients in hospital costs. Our data do not support the use of HLA matching for predicting pancreas graft survival but do support its significance for the reduction of acute rejection, particularly for solitary pancreas recipients.

Background/Objectives Total pancreatectomy and islet autotransplant (TP-IAT) is a potential treatment for children with severe refractory chronic pancreatitis. Cultures from the resected pancreas and final islet preparation are frequently positive for microbes. It is unknown whether positive cultures are associated with adverse outcomes in pediatric patients. Methods We reviewed the medical records of children (n = 86) who underwent TP-IAT from May 2006–March 2015 with emphasis on demographics, previous pancreatic interventions, culture results, islet yield, hospital days, posttransplant islet function, and posttransplant infections. We compared outcomes in patients with positive (n = 57) and negative (n = 29) cultures. Results Patients with positive cultures had higher rates of previous pancreas surgery ( P = 0.007) and endoscopic retrograde cholangiopancreatography ( P P = 1.00) or prolonged hospital length of stay ( P = 0.29). Patients with positive final islet preparation culture showed increased rates of graft failure at 2 years posttransplant ( P = 0.041), but not when adjusted for islet mass transplanted ( P = 0.39). Conclusions Positive cultures during pediatric TP-IATs do not increase the risk of posttransplant infections or prolong hospital length of stay. Endocrine function depends on islet mass transplanted.

The development of minimally invasive surgical approaches to donor nephrectomy (DN) has been driven by the potential advantages for the donor, with questions remaining about long-term outcomes.All living DN performed from June 1963 through December 2014 at the University of Minnesota were reviewed. Outcomes were compared among 4 DN techniques.We performed 4286 DNs: 2759 open DN (ODNs), 1190 hand-assisted (HA) laparoscopic DNs (LDNs), 203 pure LDN (P-LDNs), and 97 robot-assisted-LDN. Laparoscopic DN was associated with an older (P0.001) and heavier (P0.001) donor population. Laparoscopic DN was associated with a higher probability of left kidney procurement (P0.001). All 3 LDN modalities required a longer operative time (P0.001); robot-assisted-LDN took significantly longer than HA-LDN or P-LDN. Laparoscopic DN decreased the need for intraoperative blood transfusion (P0.001) and reduced the incidence of intraoperative complications (P0.001) and hospital length of stay (P0.001). However, LDN led to a significantly higher rate of readmissions, both short-term (30 day, P0.001) and long-term (30 day, P0.001). Undergoing HA-LDN was associated with a higher rate of an incisional hernia compared with all other modalities (P0.001). For recipients, LDN seemed to be associated with lower rates of graft failure at 1 year compared with ODN (P = 0.002). The odds of delayed graft function increased for kidneys with multiple arteries procured via P-LDN compared with HA-LDN (OR 3 [1,10]) and ODN (OR 5 [2, 15]).In our experience, LDN was associated with decreased donor intraoperative complications and hospital length of stay but higher rates of readmission and long-term complications.

Background Living donor segmental pancreas transplants (LDSPTx) have been performed selectively to offer a preemptive transplant option for simultaneous pancreas-kidney recipients and to perform a single operation decreasing the cost of pancreas after kidney transplant. For solitary pancreas transplants, this option historically provided a better immunologic match. Although short-term donor outcomes have been documented, there are no long-term studies. Methods We studied postdonation outcomes in 46 segmental pancreas living donors. Surgical complications, risk factors (RF) for development of diabetes mellitus (DM) and quality of life were studied. A risk stratification model (RSM) for DM was created using predonation and postdonation RFs. Recipient outcomes were analyzed. Results Between January 1, 1994 and May 1, 2013, 46 LDSPTx were performed. Intraoperatively, 5 (11%) donors received transfusion. Overall, 9 (20%) donors underwent splenectomy. Postoperative complications included: 6 (13%) peripancreatic fluid collections and 2 (4%) pancreatitis episodes. Postdonation, DM requiring oral hypoglycemics was diagnosed in 7 (15%) donors and insulin-dependent DM in 5 (11%) donors. RSM with three predonation RFs (oral glucose tolerance test, basal insulin, fasting plasma glucose) and 1 postdonation RF, greater than 15% increase in body mass index from preoperative (Δ body mass index >15), predicted 12 (100%) donors that developed postdonation DM. Quality of life was not significantly affected by donation. Mean graft survival was 9.5 (±4.4) years from donors without and 9.6 (±5.4) years from donors with postdonation DM. Conclusions LDSPTx can be performed with good recipient outcomes. The donation is associated with donor morbidity including impaired glucose control. Donor morbidity can be minimized by using RSM and predonation counseling on life style modifications postdonation.

In this article, we will review the changes that have occurred in islet transplantation at the birth of Pancreas 30 years ago. The first attempts at β-cell replacement in humans, pancreas and islet transplantation, were performed in the 1960s and 1970s. Although pancreas transplantation has been an accepted treatment for severe labile diabetes predating the emergence of the journal, allogeneic islet transplantation remains experimental. Current investigations within islet transplantation focus to improve islet function after transplantation. Improving islet viability during isolation, exploring ways to increase engraftment, and protection from the host immune system are some of the goals of these investigative efforts. The major barriers to clinical islet transplantation are shortage of human pancreas, the need for immunosuppression, and the inadequacy of the islet isolation process. It is generally accepted that islet encapsulation is an immunoisolation tool with good potential to address the first 2 of those barriers. We have therefore devoted a major part of this review to the critical factors needed to make it a clinical reality. With improved islet isolation techniques and determination of the best site of engraftment as well as improved encapsulation techniques, we hope that islet transplantation could someday achieve routine clinical use.

Pancreas retransplantation is associated with increased rates of technical failure and rejection compared to other organ transplants. As such, it is not routinely done, and outcomes are mostly known through registry data. Here we analyze the outcomes of primary versus retransplant for all pancreas transplants done in our program over nearly 35 years.Donor and recipient characteristics and outcomes data were prospectively gathered and recorded in our institutional database. Outcomes of primary and retransplants were reported overall, and then subgrouped by number (second, third, fourth). An in-depth analysis of transplants done after 2003 was included. Rates of technical failure, 1 year acute rejection, graft survival, and patient survival were compared.Two thousand one hundred forty-five pancreas transplants were performed at our institution between 1978 and 2012. Four hundred fifteen of these were retransplants. Improvements were seen in technical failure rates and graft survival for both primary and retransplants over time. There were no significant differences in technical failure or patient survival for primary versus retransplants overall, or by transplant number (second, third, fourth). Modern era retransplants had more acute rejection in the first year after transplantation. Retransplants (vs primary) had decreased mid-term death censored graft survival. Transplant type continues to be an important driver of outcome.Retransplant outcomes have improved over time, yet increased rejection and immunologic graft loss rates remain associated with pancreas retransplantation. In contrast, risk of technical failure and patient death for primary versus retransplants are similar. Therefore, pancreas retransplantation in highly selected candidates should be considered in experienced centers.

Arterial fistulas and pseudoaneurysms are rarely described significant arterial complications associated with pancreas transplantation that sometimes present with herald or catastrophic bleeding. We herein describe our institutional case series with a focus on management and outcomes. Of 2256 pancreas transplants, 24 arterial complications were identified in 23 recipients. Chart review was performed to describe the clinical characteristics, treatments and outcomes of the complications (pseudoaneurysm, arterial enteric/cystic/ureteric fistula, or arteriovenous fistula). Of these 23 patients, 57% had a failed allograft at the time of the complication. Nine patients underwent primary surgical repair of 10 complications, 13 were treated by endovascular methods, and one patient by medical management. In total, 3 embolized patients rebled, 2 of which had failed allografts prior to treatment. Of those with graft function that were treated by embolization alone, all retained graft function. Diagnosis of arterial complications requires a high degree of suspicion and should involve early systemic angiography to evaluate the pancreatic vasculature. Management can be endovascular or surgical and should be individualized. We report our center's evolution from a predominantly surgical to endovascular approach as a definitive vs stabilizing therapy, with selective coiling mostly reserved for well-defined peripheral lesions in patients with a functioning allograft. This article is protected by copyright. All rights reserved.

We used intravenous arginine with measurements of insulin, C-peptide, and glucagon to examine β-cell and α-cell survival and function in a group of 10 chronic pancreatitis recipients 1–8 years after total pancreatectomy and autoislet transplantation. Insulin and C-peptide responses correlated robustly with the number of islets transplanted (correlation coefficients range 0.81–0.91; P < 0.01–0.001). Since a wide range of islets were transplanted, we normalized the insulin and C-peptide responses to the number of islets transplanted in each recipient for comparison with responses in normal subjects. No significant differences were observed in terms of magnitude and timing of hormone release in the two groups. Three recipients had a portion of the autoislets placed within their peritoneal cavities, which appeared to be functioning normally up to 7 years posttransplant. Glucagon responses to arginine were normally timed and normally suppressed by intravenous glucose infusion. These findings indicate that arginine stimulation testing may be a means of assessing the numbers of native islets available in autologous islet transplant candidates and is a means of following posttransplant α- and β-cell function and survival.

Describe the surgical technique, complications, and long-term outcomes of total pancreatectomy and islet autotransplantation (TP-IAT) in a large series of pediatric patients.Surgical management of childhood pancreatitis is not clear; partial resection or drainage procedures often provide transient pain relief, but long-term recurrence is common due to the diffuse involvement of the pancreas. Total pancreatectomy (TP) removes the source of the pain, whereas islet autotransplantation (IAT) potentially can prevent or minimize TP-related diabetes.Retrospective review of 75 children undergoing TP-IAT for chronic pancreatitis who had failed medical, endoscopic, or surgical treatment between 1989 and 2012.Pancreatitis pain and the severity of pain statistically improved in 90% of patients after TP-IAT (P0.001). The relief from narcotics was sustained. Of the 75 patients undergoing TP-IAT, 31 (41.3%) achieved insulin independence. Younger age (P = 0.032), lack of prior Puestow procedure (P = 0.018), lower body surface area (P = 0.048), higher islet equivalents (IEQ) per kilogram body weight (P = 0.001), and total IEQ (100,000) (P = 0.004) were associated with insulin independence. By multivariate analysis, 3 factors were associated with insulin independence after TP-IAT: (1) male sex, (2) lower body surface area, and (3) higher total IEQ per kilogram body weight. Total IEQ (100,000) was the single factor most strongly associated with insulin independence (odds ratio = 2.62; P0.001).Total pancreatectomy and islet autotransplantation provides sustained pain relief and improved quality of life. The β-cell function is dependent on islet yield. Total pancreatectomy and islet autotransplantation is an effective therapy for children with painful pancreatitis that failed medical and/or endoscopic management.

Islet autotransplant (IAT) may ameliorate postsurgical diabetes following total pancreatectomy (TP), but outcomes are dependent upon islet mass, which is unknown prior to pancreatectomy. We evaluated whether preoperative metabolic testing could predict islet isolation outcomes and thus improve assessment of TPIAT candidates. We examined the relationship between measures from frequent sample IV glucose tolerance tests (FSIVGTT) and mixed meal tolerance tests (MMTT) and islet mass in 60 adult patients, with multivariate logistic regression modeling to identify predictors of islet mass ≥2500 IEQ/kg. The acute C-peptide response to glucose (ACRglu) and disposition index from FSIVGTT correlated modestly with the islet equivalents per kilogram body weight (IEQ/kg). Fasting and MMTT glucose levels and HbA1c correlated inversely with IEQ/kg (r values -0.33 to -0.40, p ≤ 0.05). In multivariate logistic regression modeling, normal fasting glucose (

Technical failure (TF) continues to have a significant impact on the success of pancreas transplantation. We assessed risk factors for TF in 1115 pancreas transplants performed at a single center between 1998 and 2011. The overall TF rate was 10.2%. In a multivariable model, donor BMI ≥ 30 (HR 1.87, p = 0.005), donor Cr ≥ 2.5 (HR 3.16, p = 0.007), donor age >50 (HR 1.73, p = 0.082) and preservation time >20 h (HR 2.17, p < 0.001) were associated with TF. Bladder drainage of exocrine secretions was protective (HR 0.54, p = 0.002). We incorporated these factors in a Composite Risk Model. In this model the presence of one risk factor did not significantly increase risk of TF (HR 1.35, p = 0.346). Two risk factors in combination increased risk greater than threefold (HR 3.65, p < 0.001) and three risk factors increased risk greater than sevenfold (HR 7.66, p =

Total pancreatectomy with islet autotransplantation (TPIAT) is increasingly performed with remote islet cell processing and preparation, i.e., with islet cell isolation performed remotely from the primary surgical site at an appropriately equipped islet isolation facility. We aimed to determine whether TPIAT using remote islet isolation results in comparable long-term glycemic outcomes compared with TPIAT performed with standard local isolation.We performed a retrospective cohort study of adult patients who underwent TPIAT at three tertiary care centers from 2010 to 2013. Two centers performed remote isolation and one performed local isolation. Explanted pancreata in the remote cohort were transported ∼130 miles to and from islet isolation facilities. The primary outcome was insulin independence 1 year following transplant.Baseline characteristics were similar between groups except the remote cohort had higher preoperative hemoglobin A1c (HbA1c; 5.43 vs. 5.25, P=0.02) and there were more females in the local cohort (58% vs. 76%, P=0.049). At 1 year, 27% of remote and 32% of local patients were insulin independent (P=0.48). Remote patients experienced a greater drop in fasting c-peptide (-1.66 vs. -0.64, P=0.006) and a greater rise in HbA1c (1.65 vs. 0.99, P=0.014) at 1-year follow-up. A preoperative c-peptide2.7 (odds ratio (OR) 4.4, 95% confidence interval (CI) 1.6-14.3) and3,000 islet equivalents/kg (OR 11.0, 95% CI 3.2-37.3) were associated with one-year insulin independence in the local group.At 1 year after TPIAT, patients undergoing remote surgery have equivalent rates of long-term insulin independence compared with patients undergoing TPIAT locally, but metabolic control is superior with local isolation.

BACKGROUND The optimal enzyme blend that maximizes human islet yield for transplantation remains to be determined. In this study, we evaluated eight different enzyme combinations (ECs) in an attempt to improve islet yield. The ECs consisted of purified, intact or truncated class 1 (C1) and class 2 (C2) collagenases from Clostridium histolyticum (Ch), and neutral protease (NP) from Bacillus thermoproteolyticus rokko (thermolysin) or Ch (ChNP). METHODS We report the results of 249 human islet isolations, including 99 deceased donors (research n=57, clinical n=42) and 150 chronic pancreatitis pancreases. We prepared a new enzyme mixture (NEM) composed of intact C1 and C2 collagenases and ChNP in place of thermolysin. The NEM was first tested in split pancreas (n=5) experiments and then used for islet autologous (n=21) and allogeneic transplantation (n=10). Islet isolation outcomes from eight different ECs were statistically compared using multivariate analysis. RESULTS The NEM consistently achieved higher islet yields from pancreatitis (P

Rapid discontinuation of prednisone after kidney transplantation potentially allows for minimization of steroid-related side effects. Although intermediate-term data with rapid discontinuation of prednisone have been promising, concern still exists regarding long-term outcomes. The 10-year experience is reported herein.Between October 1, 1999 and December 31, 2010, 1241 adult primary kidney transplants (791 living donor and 450 deceased donor) were performed using a protocol in which prednisone is discontinued after postoperative day 5. The 10-year actuarial recipient and graft survival rates and prednisone-related side effects were studied.Ten-year actuarial patient survival was 71% for living donor transplants and 62% for deceased donor transplants; 10-year graft survival was 61% for living donor transplants and 51% for deceased donor transplants, and was comparable to 10-year Scientific Registry of Transplant Recipients national data. Ten-year death-censored graft survival was 79% for living donor transplants and 80% for deceased donor transplants. Ten-year acute rejection rates were 25% for deceased donor transplants and 31% for living donor transplants; 10-year chronic rejection (interstitial fibrosis/tubular atrophy) rates were 39% for deceased donor transplants and 47% for living donor transplants. For nondiabetic recipients of living donor or deceased donor allografts, the incidence of new-onset diabetes was significantly lower than in historical controls on prednisone (P0.001). We also found significantly reduced rates of cataracts, avascular necrosis, and cytomegalovirus infection in some subgroups.Prednisone-related side effects can be minimized in a protocol incorporating rapid discontinuation of prednisone for maintenance immunosuppression. Ten-year patient and graft outcomes remain acceptable.

Purpose of review More than 160 living donor segmental pancreas/islet transplants have been done since the first in 1977, more than three-quarters at one institution. We review this three-decade experience to project future application. Initially, living donor pancreas transplants were done because the results with deceased donors were poor. As the results with deceased donors improved, the incentive to do living donor transplants declined but never disappeared. A living donor simultaneous pancreas-kidney transplant in a uremic diabetic can correct diabetes and pre-empt dialysis with one operation, obviating the high mortality rate of waiting for a deceased donor. Solitary pancreas transplant candidates with preformed human leukocyte antigen antibodies but a negative cross match to a living donor volunteer also benefit. Recent findings The technical failure rate of living donor pancreas transplants was high in the initial cases (>1/3), nearly double that for deceased donors, but has since declined to nearly zero. Living donor segmental pancreatectomy has little surgical morbidity (currently done laparoscopically) with only a small risk for diabetes by strict selection criteria. living donor and deceased donor graft survival rates are equivalent. Islet allografts have been done from three living donors, the last one successfully, showing the potential for further application. Summary The incentives for living donor transplants are to eliminate long-wait times for a deceased donor organ and to improve outcomes. With both the incentive is high, but either by itself is sufficient. As the number of pancreas transplant candidates increase, so will wait times for a deceased donor organ. For this reason, living donor pancreas/islet transplant volume will likely increase in the years to come.

Pancreas transplantation provides the only proven method to restore long-term normoglycemia in patients with insulin-dependent diabetes mellitus. Although many studies describe the very important risk factors for short-term survival of a pancreas transplant, there is not a lot of information available about factors that distinguish short-term from long-term graft function.The analysis of 18,159 pancreas transplants from the International Pancreas Transplant Registry, performed from 25 July 1978 to 31 December 2005, showed an improvement not only in short-term but also in long-term graft function. Most recent 5-year, 10-year and 20-year graft function for transplants with the appropriate follow-up time showed 80, 68 and 45%, respectively, for simultaneous pancreas/kidney transplants; 62, 46 and 16%, respectively, for pancreas after kidney; and 59, 39 and 12%, respectively, for pancreas transplants alone. Important factors influencing long-term function were factors that described the quality of the deceased donor. Pancreas transplants in younger or African-American recipients showed a higher risk of graft failure. Anti-T-cell induction therapy had a significant impact on long-term survival in solitary transplants.With a careful donor selection, not only short-term but also long-term pancreas graft function and, therefore, good metabolic control can be achieved for the diabetic patient.

Pancreatic acinar cells are commonly cotransplanted along with islets during auto- and allotransplantations. The aims of this study were to identify how acinar cell proteases cause human islet cell loss before and after transplantation of impure islet preparations and to prevent islet loss and improve function with supplementation of α-1 antitrypsin (A1AT).Acinar cell protease activity, insulin levels, and percent islet loss were measured after culture of pure and impure clinical islet preparations. The effect of proteases on ultrastructure of islets and β-cell insulin granules were examined by transmission electron microscopy. The number of insulin granules and insulin-labeled immunogold particles were counted. The in vivo effect of proteases on islet function was studied by transplanting acinar cells adjacent to islet grafts in diabetic mice. The effects of A1AT culture supplementation on protease activity, insulin levels, and islet function were assessed in pure and impure islets.Islet loss after culture was significantly higher in impure relative to pure preparations (30% vs. 14%, P0.04). Lower islet purity was associated with increased protease activity and decreased insulin levels in culture supernatants. Reduced β-cell insulin granules and insulin degradation by proteases were confirmed by transmission electron microscopy. Transplantations in mice showed delayed islet graft function when acinar cells were transplanted adjacent to the islets under the kidney capsule. Supplementation of A1AT to impure islet cultures maintained islet cell mass, restored insulin levels, and preserved islet functional integrity.Culture of impure human islet fractions in the presence of A1AT prevents insulin degradation and improves islet recovery.

Total pancreatectomy (TP) and islet autotransplant (IAT) have been used to treat patients with painful chronic pancreatitis. Initial studies indicated that most patients experienced significant pain relief, but there were few validated measures of quality of life. We investigated whether health-related quality of life improved among pediatric patients undergoing TP/IAT.Nineteen consecutive children (aged 5-18 years) undergoing TP/IAT from December 2006 to December 2009 at the University of Minnesota completed the Medical Outcomes Study 36-item Short Form (SF-36) health questionnaire before and after surgery. Insulin requirements were recorded.Before TP/IAT, patients had below average health-related quality of life, based on data from the Medical Outcomes Study SF-36; they had a mean physical component summary (PCS) score of 30 and mental component summary (MCS) score of 34 (2 and 1.5 standard deviations, respectively, below the mean for the US population). By 1 year after surgery, PCS and MCS scores improved to 50 and 46, respectively (global effect, PCS P.001, MCS P = .06). Mean scores improved for all 8 component subscales. More than 60% of IAT recipients were insulin independent or required minimal insulin. Patients with prior surgical drainage procedures (Puestow) had lower yields of islets (P = .01) and greater incidence of insulin dependence (P = .04).Quality of life (physical and emotional components) significantly improve after TP/IAT in subsets of pediatric patients with severe chronic pancreatitis. Minimal or no insulin was required for most patients, although islet yield was reduced in patients with previous surgical drainage operations.

Islet autotransplantation (IAT) is performed at the time of total pancreatectomy (TP) to prevent or minimize post-surgical diabetes. Corticosteroids induce insulin resistance and present a risk to islet autografts, through glucotoxicity and increased metabolic demand on a marginal islet mass. We present four IAT recipients treated with oral or injected corticosteroids after transplant for medical conditions unrelated to chronic pancreatitis or TPIAT. Hyperglycemia or insulin resistance was evident in all four patients, including reversion to long-term insulin therapy in two patients. One patient receiving corticosteroid injections had a transient increase in hemoglobin A1c (+0.6% above baseline), and one patient given a one time dose of oral dexamethasone exhibited hyperglycemia despite high insulin (>200 mU/L) and C-peptide (15.3 ng/mL) production on an oral glucose tolerance test. IAT recipients have insufficient islet mass to compensate for the insulin resistance induced by corticosteroids. Caution should be given to using these agents in IAT recipients. When corticosteroids are medically necessary, insulin therapy should be administered temporarily to compensate for the increased metabolic demand and minimize long-term risks on the islet graft.

Previously, recurrence of insulin-dependent diabetes mellitus after pancreas transplants was only sporadically reported. Newer data, however, indicate recurrence rates as high as 5%. After identical-twin pancreas transplants, diabetes recurs in the absence of immunosuppressive therapy - strong evidence that it is an autoimmune disease. After deceased donor pancreas transplants, immunologic markers (autoantibodies, autoreactive T cells) herald recurrence. Selective destruction of β cells, still relatively uncommon, is not restricted to MHC compatibility. The development of diabetes in living pancreas donors is rare; it can be largely avoided by meticulous metabolic evaluation before donation and prevention of obesity after donation.

Background Using standard density gradient (SDG) ranges for human islet purification frequently results in islet loss and transplantation of lower islet mass. Measuring the densities of islet and acinar tissue beforehand to customize the gradient range for the actual COBE 2991 cell processor (COBE) purification is likely to maximize the recovery of islets. We developed an analytical test gradient system (ATGS) for predicting pancreatic tissue densities before COBE purification to minimize islet loss during purification. Methods Human islets were isolated from deceased donor (n=30) and chronic pancreatitis pancreata (n=30). Pancreatic tissue densities were measured before purification by the ATGS, and the density gradient range for islet purification in a COBE was customized based on density profiles determined by the ATGS. The efficiency of custom density gradients (CDGs) to recover high islet yield was compared with predefined SDGs. Results Pancreatic tissue densities from autografts were significantly higher than in allograft preparations. In allograft purifications, a higher proportion of islets were recovered using ATGS-guided CDGs (85.9%±18.0%) compared with the SDG method (69.2%±27.0%; P=0.048). Acinar contamination at 60%, 70%, and 80% cumulative islet yield for allografts was significantly lower in the CDG group. In autograft purifications, more islets were recovered with CDGs (81.9%±28.0%) than SDGs (55.8%±22.8%; P=0.03). CDGs effectively reduced islet loss by minimizing islet sedimentation in the COBE bag. Conclusions Using ATGS-guided CDGs maximizes the islet recovery for successful transplantations by reducing acinar contamination in allograft preparations and by reducing sedimentation of islets in the COBE bag in autograft preparations.

Chylous ascites as a result of laparoscopic donor nephrectomy (LDN) is a rare complication which carries significant morbidity, including severe protein-calorie malnutrition and an associated immunocompromised state. We report a patient who underwent hand-assisted left LDN and subsequently developed chylous ascites. He failed conservative therapy including low-fat diet with medium-chain triglycerides (LFD/MCT) and oral protein supplementation as well as strict NPO status with intravenous (IV) total parenteral nutrition (TPN) and subcutaneous (SQ) somatostatin analogue administration. Laparoscopic re-exploration and intracorporeal suture ligation and clipping of leaking lymph channels successfully sealed the chyle leak. We review the literature to date including diagnosis, incidence, management options, psychosocial aspects and clinical outcomes of chylous ascites after LDN.

OBJECTIVES: The probability of insulin independence after intraportal islet autotransplantation (IAT) for chronic pancreatitis (CP) treated by total pancreatectomy (TP) relates to the number of islets isolated from the excised pancreas. Our goal was to correlate the islet yield with the histopathologic findings and the clinical parameters in pediatric (age

Bellin MD, Blondet JJ, Beilman GJ, Dunn TyB, Balamurugan AN, Thomas W, Sutherland DER, Moran A. Predicting islet yield in pediatric patients undergoing pancreatectomy and autoislet transplantation for chronic pancreatitis. Background/Objective: Chronic pancreatitis (CP) in children is associated with significant morbidity and can lead to narcotic dependence. Total pancreatectomy (TP) may be indicated in refractory CP to relieve pain; simultaneous islet autotransplant (IAT) may prevent postsurgical diabetes. About half of pediatric patients are insulin independent 1 yr after IAT. Insulin independence correlates best with the number of islets available for transplantation (islet yield). Currently there is no known method to predict islet yield in a given patient. We assessed the ability of preoperative metabolic tests to predict islet yields in 10 children undergoing TP/IAT. Design/Methods: Hemoglobin A1c (HbA1c) and mixed meal tolerance tests (MMTT) were obtained prior to surgery in 10 patients age ≤ 18 yr. Fasting glucose, C-peptide, and creatinine were used to calculate the C-peptide to glucose* creatinine ratio (CPGCR). C-peptide peak and area under the curve (AUC) were determined from 2 h MMTT. Linear regressions were performed to predict islet yield from baseline test results. Results: Islet yield ranged from 7000 to 434 000 islet equivalents (IE) (mean 222 452 ± 148 697 IE). Islet yield was well predicted from body weight and fasting plasma glucose (R 2 = 57%, adjusted for overfitting by bootstrap). Islet yield was positively associated with CPGCR, peak C-peptide, and AUC C-peptide and negatively associated with HbA1c. Conclusions: Pilot data from 10 pediatric patients suggest that simple preoperative measurement of fasting plasma glucose may give a useful prediction of islet yield. Islet yield correlates with HbA1c and C-peptide levels. This information allows individual candidates to weigh the specific risk of becoming diabetic against the benefit of pain relief should they undergo TP-IAT.

The advantages of living donor pancreas transplants for the recipient include good HLA matching, lower immunologic risk, less immunosuppression, lower risk of infection and of posttransplant malignancies, and shorter pancreas graft preservation time. In 2008, a total of 155 segmental pancreas transplants using living donors were reported to the International Pancreas Transplant Registry from six countries. Pancreas living donors need to undergo a thorough pretransplant endocrinologic workup in order to minimize the risk of metabolic complications. The pretransplant workup has evolved over time, after initial reports showed that up to 25% of living donors had elevated hemoglobin A(1c) levels after donation. Avoiding obesity after donation diminishes the risk of long-term metabolic complications. The risk of surgical complications for the donor (such as pancreatitis, pancreatic leak or fistula, pancreatic abscess, and pancreatic pseudocyst) is less than 5%. If both the donor and recipient operations are technically successful, the long-term graft survival rate is significantly higher for living (versus deceased) donor pancreas transplant recipients. Future long-term studies of metabolic function in living donors are warranted to determine whether living donor pancreas transplants can safely be applied more widely and whether living donors can be used for islet transplants.

The ultimate goal of clinical transplantation is for the recipients to achieve long-term survival, with continuing graft function, that is equivalent to that of the age-matched general population. We studied subsequent outcome in kidney transplant recipients with 10 years of graft function. In all, 2202 kidney transplant recipients survived with graft function10 years. For 10-year survivors, the actuarial 25-year patient survival rate for primary transplant living donor (LD) recipients was 57%; graft survival, 43%. For primary transplant deceased donor (DD) recipients, the actuarial 25-year patient survival rate was 39%; graft survival, 27%. The two major causes of late graft loss were death (with graft function) and chronic allograft nephropathy (tubular atrophy and interstitial fibrosis). The two major causes of death with function were cardiovascular disease (CVD) and malignancy. For nondiabetic recipients, the mean age at death with function from CVD was 54 +/- 13 years; for diabetic recipients, 53 +/- 7 years. By 20 years posttransplant, morbidity was common:40% recipients had skin cancer (mean age for nondiabetic recipients, 53 +/- 13 years; for diabetics, 49 +/- 8 years),10% had non-skin cancer (mean age for nondiabetic recipients, 53 +/- 16 years; for diabetics, 46 +/- 9 years), and30% had CVD (mean age for nondiabetic recipients, 53 +/- 15 years; for diabetics, 47 +/- 9 years). We conclude that long-term transplant recipients have a high rate of morbidity and early mortality. As short-term results have improved, more focus is needed on long-term outcome.

Background A total pancreatectomy is the last resort in the treatment of chronic pancreatitis because it results in complete endocrine and exocrine pancreatic insufficiency. More than 50% of total pancreatectomy patients experience severe glucose control problems, which cause up to 50% of late deaths. Study Design Between June 1, 1986, and May 15, 2007, we performed 26 pancreas allotransplants (18 primary, 8 retransplants) in 18 patients who had previously undergone a total pancreatectomy for chronic pancreatitis. All patients had a history of labile diabetes mellitus with hypoglycemic unawareness; secondary diabetic complications developed in 12. The median time interval from the total pancreatectomy to the pancreas allotransplant was 5 years (range 9 months to 22 years). Of the 26 transplants, 6 were performed in the cyclosporine (CSA) era, 15 in the tacrolimus (TAC) era, and 5 in the calcineurin inhibitor (CNI)-free era. Results Patient survival rates at 1 and 3 years in both the CSA and TAC eras were 100% and 100%; in the CNI-free era, at 1 year, the survival rate was 40%. Pancreas graft survival rates in the CSA era were 67% and 50% at 1 and 3 years, respectively; in the TAC era, 73% and 51%, respectively; and in the CNI-free era, at 1 year, 40% (p=0.13). The mean number of rejection episodes in the CSA era was 2.1; in the TAC era, 1.4; and in the CNI-free era, 0.6. Conclusions Our series of pancreas allotransplants in patients with a previous total pancreatectomy for chronic pancreatitis showed that pancreas graft survival rates of more than 70% can be achieved with TAC-based immunosuppression; pancreas transplants can successfully treat both endocrine and exocrine insufficiency; and sequential pancreas allotransplants should be considered a treatment option in patients with pancreatectomy-induced brittle diabetes mellitus or with progression of secondary complications of diabetes mellitus.

Background. A pancreas transplant alone (PTA) in a nonuremic patient with brittle diabetes mellitus remains a rare procedure because the tradeoff for insulin independence is lifelong immunosuppression. Methods. Herein we report our results at the University of Minnesota of 513 PTAs from December 17, 1966, through December 31, 2006. Of these recipients, 87% had previously experienced hypoglycemic unawareness and 23% experienced coma and/or seizures. These transplants spanned four immunosuppressive eras: pre-cyclosporine A (pre-CsA) era (16%), CsA era (23%), tacrolimus (TAC) era (47%), and calcineurin-inhibitor (CNI)-free era (14%). Results. The overall patient survival rate at 1 year posttransplant was about 95%; at 5 years, it was 90%. The pancreas graft survival rate at 1 year increased significantly from the pre-CsA era (31%) to the TAC era (75%), thanks to a significant decline in immunologic and technical failures. The CNI-free protocol, because of its high infection and hematologic infection rate, did not further improve outcome. Risk factors for subsequent kidney failure (13% at 5 years posttransplant) were serum creatinine levels > 1.5 mg/dl at the time of the pancreas transplant and recipient age

Background and Objectives Acquired red cell aplasia (RCA) is a rare disorder and can be either idiopathic or associated with certain diseases, pregnancy, or drugs. In exceptionally rare cases, it has been reported to co-exist with other autoimmune cytopenias. We report a high incidence of RCA and autoimmune hemolytic anemia (AIHA) in pancreas transplant recipients on alemtuzumab-based maintenance therapy. Design and Methods Between February 2003 and July 2005, 357 pancreas transplant recipients were treated with immunosuppressive regimens containing the lymphocyte-depleting antibody alemtuzumab, the T-cell activation inhibitor daclizumab, and the anti-metabolite mycophenolate mofetil (MMF). We retrospectively reviewed medical records, blood bank data and bone marrow biopsy specimens of patients with a Transplant Information Services database diagnosis of RCA and AIHA from February 2003 to November 2005. Results Severe RCA, AIHA, and idiopathic thrombocytopenic purpura (ITP) occurred independently or in combination, in 20 out of 357 (5.6%) pancreas transplant recipients, 12 to 24 months following the initiation of the aforementioned immunosuppressive regimens. Severe opportunistic infections developed late in 14/20 (70%) of these patients. Atypical morphologic features, including variable dysgranulopoiesis, variable megakaryocytic hyperplasia with normal or low peripheral platelet counts, and atypical lymphoid aggregates were found in bone marrow trephine sections of 11 patients in whom the diagnosis of RCA was made. Interpretation and Conclusions We hypothesize that the combination of alemtuzumab, daclizumab and MMF can result in immune dysregulation thereby permitting autoantibody formation. Because the use of these three immune suppressants is becoming increasingly common, it is important to recognize the severe hematologic complications that can arise.

Our objective was to analyze factors predicting outcomes after a total pancreatectomy and islet autotransplantation (TP-IAT).Chronic pancreatitis (CP) is increasingly treated by a TP-IAT. Postoperative outcomes are generally favorable, but a minority of patients fare poorly.In our single-centered study, we analyzed the records of 581 patients with CP who underwent a TP-IAT. Endpoints included persistent postoperative "pancreatic pain" similar to preoperative levels, narcotic use for any reason, and islet graft failure at 1 year.In our patients, the duration (mean ± SD) of CP before their TP-IAT was 7.1 ± 0.3 years and narcotic usage of 3.3 ± 0.2 years. Pediatric patients had better postoperative outcomes. Among adult patients, the odds of narcotic use at 1 year were increased by previous endoscopic retrograde cholangiopancreatography (ERCP) and stent placement, and a high number of previous stents (3). Independent risk factors for pancreatic pain at 1 year were pancreas divisum, previous body mass index30, and a high number of previous stents (3). The strongest independent risk factor for islet graft failure was a low islet yield-in islet equivalents (IEQ)-per kilogram of body weight. We noted a strong dose-response relationship between the lowest-yield category (2000 IEQ) and the highest (≥5000 IEQ or more). Islet graft failure was 25-fold more likely in the lowest-yield category.This article represents the largest study of factors predicting outcomes after a TP-IAT. Preoperatively, the patient subgroups we identified warrant further attention.

A total pancreatectomy and islet autotransplant (TPIAT) offers substantial pain relief and improved quality of life for children who are severely affected by chronic or recurrent acute pancreatitis and for whom the usual medical and endoscopic therapies have failed. The pancreas is entirely resected, and the pancreatic islets are isolated from the pancreas and infused back into the patient’s liver. Because this is an autologous transplant, no immunosuppression is required. Over several months, the islets engraft in the liver; the patient is then slowly weaned off insulin therapy. Slightly more than 40 % of patients become and remain insulin independent, yet even among patients who remain on insulin, most have some islet function, permitting easier diabetes control. The majority of patients experience pain relief, with significant improvements in health-related quality of life. A TPIAT should be considered for children who are significantly disabled by chronic pancreatitis.

Chronic pancreatitis is a painful and often debilitating disease. Total pancreatectomy with intra-portal islet autotransplantation (TP-IAT) is a treatment option that allows for pain relief and preservation of beta-cell mass, thereby minimizing the complication of diabetes mellitus. Cultures of harvested islets are often positive for bacteria, possibly due to frequent procedures prior to TP-IAT, such as endoscopic retrograde cholangiopancreatography (ERCP), stenting, or other operative drainage procedures. It is unclear if these positive cultures contribute to post-operative infections.We hypothesized that positive cultures of transplant solutions will not be associated with increased infection risk.We reviewed retrospectively the sterility cultures from both the pancreas preservation solution used to transport the pancreas and the final islet preparation for intra-portal infusion of patients who underwent TP-IAT between April 2006 and November 2012. Two hundred fifty-one patients underwent total, near-total, or completion pancreatectomy with IAT and had complete sterility cultures. All patients received prophylactic peri-operative antibiotics. Patients with positive pancreas preservation solution or islet sterility cultures received further antibiotics for 5-7 d. Patients' medical records were reviewed for post-operative infections and causative organisms.Of the 251 patients included, 151 (61%) had one or more positive bacterial cultures from the pancreas preservation solution or final islet product. Seventy-three of the 251 patients (29%) had an infectious complication. Thirty-four of the 73 (22%) patients with a post-operative infectious complication also had positive cultures. Only seven of 151 patients with positive cultures (4.7%) had an infectious complication caused by the same organism as that isolated from their pancreas or islet cell preparation.In autologous islet preparations, isolation solutions frequently have positive cultures, but this finding is associated infrequently with clinical infection.

As of December 31, 2004, more than 23,000 pancreas transplant had been reported to the IPTR,17,000 in the US and almost 6000 from outside the US. An analysis of US pancreas transplants performed between 1988 and 2003 showed a progressive improvement in outcome, with pancreas transplant graft survival rates (GSRs) going from 75% at 1 yr for 1988/1989 to 85% for 2002/2003 simultaneous pancreas-kidney (SPK) cases, from 55 to 78% for pancreas after kidney (PAK) cases, and from 45 to 77% for pancreas transplants alone (PTA) cases. The improvements were due both to decreases in technical failure (TF) rates (from 12 to 6% in SPK, 13-8% in PAK, and 24-7% in PTA) and immunological failure rates (going from 7 to 2% for SPK, from 28 to 7% for PAK, and from 38 to 8% for PTA cases). These results are even more impressive under the aspect that during the same time the rate of potential risk factors increased and the duct management techniques changed from bladder to enteric drainage. The improvement in outcome allowed also an increase in the number of solitary pancreas transplants from initially 12% to now 35%. Contemporary primary deceased donor pancreas transplant outcomes were calculated separately for 2000-2004 US and non-US cases. The US patient survival rates at 1 yr were95% in each recipient category, with 1 yr primary pancreas GSRs of 85% for SPK, 78% for PAK, and 76% for PTA (p0.0001). The immunological graft failure rates for 2000-2004 technically successful (TS) SPK, PAK, and PTA cases were 2, 8, and 10% at 1 yr (p = 0.0001). In the majority of all transplants ED was used for duct management (81% of SPK, 67% of PAK, and 56% for PTA cases). Of the ED transplants, venous drainage via the portal system was used for 20% of SPK, 23% of PAK, and 35% of PTA cases. Duct management technique did not have a significant impact on overall pancreas graft function in the univariate or the multivariate model. The outcomes of ED and BD transplants are comparable with 85 vs. 87% at 1 yr for SPK, 77 vs. 80% for PAK, and 72 vs. 79% for PTA. The overall TF rate was higher in ED pancreas transplants but this difference did reach significance only in SPK. In addition, in technically successful PTA the immunological graft loss rate was higher in ED vs. BD transplants (15 vs. 5% at 1 yr). The different vascular management techniques did not seem to have an impact on the outcome of the pancreas transplants. Kidney GSRs were not significantly different for ED vs. BD SPK cases, 93 and 91% at 1 yr (p = 0.24). The overall conversion rate from BD to ED was 9% at 1 yr and 17% at 3 yr post-transplant. The most influential factor for patient survival in SPK and PAK in the multivariate and the univariate models was the status of the transplanted organ. The hazard ratio (HR) for a failed kidney was 14.99 in SPK and 9.17 in PAK (p = 0.0001). The HR for a failed pancreas graft was 3.51 in SPK and 4.17 for PAK (p = 0.0001). In PTA a failed pancreas graft did not have a direct impact on patient survival. SPK and PAK patients older than 44 yr at the time of transplants also showed an increased mortality risk, but at the same time the risk of immunological graft loss was significantly decreased for those patients. TACMMF remained the dominant maintenance immunosuppressant for 2000-2004 US cases (approximately two-third) in all three categories and with this regime 1-year GSRs wereor =80% in all three recipient categories. The results were comparable (or =83% 1-year GSR) for patients (approximately 10%) treated with Sirolimus (SIR) under various protocols. In regard to non-US pancreas transplants, even for 2000-2004 the overwhelming majority continued to be in the SPK category (91%), with 1-year patient, kidney and pancreas survival rates of 94, 92, and 87%. Solitary transplants are still very rarely done outside the US. Non-US PAK GSR at 1 yr was 85%, non-US PTA GSR at 1 yr was 76%. In summary, with the new advancements in immunosuppression and changes in surgical techniques the outcomes in patient survival and pancreas transplant graft function continue to improve even with an increasing proportion of high risk patients in all three categories.

With the proliferation and expanding applications of laparoscopic techniques, we determined the applicability of the laparoscopic approach to living pancreas donation. We performed the first laparoscopic donor distal pancreatectomy in 1999. We herein present our initial experience with five hand-assisted laparoscopic donor pancreatectomies. Three donors underwent distal pancreatectomy alone; two underwent a simultaneous left nephrectomy. The mean donor age was 48.4 ± 8.7 years with a body mass index of 23.7 kg/m 2 . The donor and recipient survival rate was 100% at up to 3 years of follow-up. There were no episodes of pancreatitis, leaks, or pseudocysts. All donors returned to their preoperative state of health and to work. None of the donors have required oral anti-diabetic medications or insulin. We conclude that laparoscopic donor distal pancreatectomy is a safe and efficient procedure; hand-assisted laparoscopic distal pancreatectomy appears to be preferable, because of the added margin of safety from increased tactile feedback and ease of pancreatic dissection. The procedure can be accomplished with a single 6-cm periumbilical incision and only two 12-mm ports, resulting in excellent cosmesis and high donor satisfaction.

We compared three maintenance immunosuppressive regimens in a rapid discontinuation of prednisone protocol. From March 1, 2001, through December 31, 2003, 239 first and second kidney transplant recipients (166 LD; 73 DD) were randomized. All recipients were treated with Thymoglobulin; all received steroids intraoperatively and for 5 days postoperatively. Randomization was to cyclosporine–mycophenolate mofetil (n = 85); high-level tacrolimus (TAC) (8–12 ng/mL)–low-level sirolimus (SRL) (3–7 ng/mL) (n = 72); or low-level TAC (3–7 ng/mL)–high-level SRL (8–12 ng/mL) (n = 82). We found no difference at 24 months between groups in patient, graft, death-censored graft, or acute rejection-free graft survival, or in kidney function. Wound complications were more common in SRL-treated recipients (p = 0.02); we found no other differences between groups in complication rates. Our data suggest that excellent patient and graft survival and low rejection rates can be obtained using a variety of maintenance protocols without prednisone.

Successful clinical allotransplants only became possible with the development of immunosuppression. Initially, 6-mercaptopurine, or its derivative azathioprine (AZA), was used.1–3 Shortly thereafter, Starzl et al4 reported improved graft survival when AZA was combined with prednisone. Since that time, transplant clinical research has focused on improving short- and long-term graft survival while simultaneously minimizing immunosuppression-related complications. Prednisone has a well-defined side effect profile, which includes hypertension, osteoporosis (and fractures), avascular necrosis, cataracts, mood alterations, posttransplant diabetes, easy bruisability, and skin changes. Some of these side effects are related to the cumulative steroid dose.5 Others develop rapidly posttransplant6 and can occur early, even with use of relatively low-dose steroids.7–9 Consequently, even early in the history of transplantation, attempts were made to minimize the daily prednisone dose.10 In general, however, kidney transplant recipients who began prednisone at the time of their transplant tended to have better long-term graft survival than those who did not take prednisone. Throughout the 1980s and 1990s, many transplant centers studied whether selected, clinically well, immunologically low-risk kidney transplant recipients, without a previous acute rejection episode, could undergo prednisone withdrawal. Those studies showed that, even in carefully selected recipients, prednisone withdrawal was associated with an increased risk of acute rejection11,12 and of graft loss.12 Of particular concern was a Canadian multicenter, prospective, randomized study in which recipients on cyclosporine (CSA) and prednisone, without active rejection, were randomized at 90 days posttransplant to continue on CSA and either low-dose prednisone or placebo. The Canadian study found no difference in graft survival for the first 3 years posttransplant, but thereafter the steroid-free group had significantly worse graft survival (P = 0.03 versus the low-dose prednisone group).13 More recently, with the introduction of new, more potent immunosuppressive agents, interest in steroid-sparing protocols has resurged. Two prospective randomized studies of steroid withdrawal in recipients on CSA, mycophenolate mofetil (MMF), and prednisone showed an increased incidence of acute rejection episodes in the steroid withdrawal arm.14,15 In contrast, numerous other studies have now shown a low acute rejection rate when steroids are completely avoided or discontinued in the first week after kidney or simultaneous kidney-pancreas transplants.16–24 Outcome at 1 year posttransplant has been excellent with protocols incorporating prednisone avoidance or rapid discontinuation. Yet concern remains, fueled by the results of the Canadian study, that long-term outcome will be worse in prednisone-free recipients. We herein report 4-year outcome in a cohort of kidney transplant recipients who discontinued their prednisone in the first posttransplant week.

Historically, late steroid withdrawal after kidney transplants has been associated with an increased rejection rate. Recently, low rejection rates have been reported for recipients treated with complete avoidance or rapid elimination of steroids. However, follow-up has been short. We herein report on 3-year outcome in recipients whose prednisone was rapidly eliminated and who were maintained on a steroid-free regimen. From 10/1/1999 through 5/1/2003, 349 recipients (254 LD, 95 CAD; 319 in first 30 s) were immunosuppressed with polyclonal antibody (Thymoglobulin), a calcineurin inhibitor, either mycophenolate mofetil or sirolimus, and rapid discontinuation of prednisone. Actuarial 3-year patient survival was 95%; graft survival, 93%. Acute rejection-free graft survival at 1 year was 94%; at 3 years, 92%. There was no difference between LD and CAD. At 2 years, the mean (± SE) serum creatinine level for LDs was 1.6 ± 0.5 mg/dL; for CAD, 1.6 ± 0.4 mg/dL. We have no new cases of PTLD or avascular necrosis; 22 recipients (6%) developed CMV. Currently, 84% of recipients remain prednisone-free. We conclude that excellent 3-year patient and graft survival can be achieved without maintenance prednisone. With such a protocol, steroid-related side-effects are minimal.

We sought to determine whether or not optimizing pancreas preservation, islet processing, and induction immunosuppression would facilitate sustained diabetes reversal after single-donor islet transplants. Islets were isolated from two-layer preserved pancreata, purified, cultured for 2 days; and transplanted into six C-peptide-negative, nonuremic, type 1 diabetic patients with hypoglycemia unawareness. Induction immunosuppression, which began 2 days pretransplant, included the Fc receptor nonbinding humanized anti-CD3 monoclonal antibody hOKT3gamma1 (Ala-Ala) and sirolimus. Immunosuppression was maintained with sirolimus and reduced-dose tacrolimus. Of our six recipients, four achieved and maintained insulin independence with normal HbA1c levels and freedom from hypoglycemia; one had partial islet graft function; and one lost islet graft function 2 weeks post-transplant. The four insulin-independent patients showed prolonged CD4+ T-cell lymphocytopenia; inverted CD4:CD8 ratios; and increases in the percentage of CD4+CD25+ T cells. These cells suppressed the in-vitro proliferative response to donor cells and, to a lesser extent, to third-party cells. Severe adverse events were limited to a transient rash in one recipient and to temporary neutropenia in three. Our preliminary results thus suggest that a combination of maximized viable islet yield, pretransplant islet culture, and preemptive immunosuppression can result in successful single-donor islet transplants.

Objective. With newer immunosuppressive agents, acute rejection and graft loss resulting from acute rejection have become less common for pancreas transplant recipients. As long-term graft survival rates have improved, an increasing number of grafts are being lost to chronic rejection (CR). We studied the incidence of CR and identified risk factors. Methods. We retrospectively analyzed all cadaver pancreas transplants performed at the University of Minnesota between June 19, 1994, and December 31, 2002. We determined the causes of graft loss, the incidence of graft loss to CR and, using multivariate techniques, the major risk factors for CR. Results. A total of 914 cadaver pancreas transplants were performed in the following three categories: simultaneous pancreas-kidney (SPK) (n=321), pancreas after kidney (PAK) (n=389), and pancreas transplant alone (PTA) (n=204). The mean recipient age was 41.3 years and the mean donor age was 30.1 years. Of the 914 pancreas grafts, 643 (70.3%) continue to function (mean length of follow-up, 39 months). The most common cause of graft loss was technical failure, accounting for 118 (12.9%) of the failed grafts. The second most common cause was CR, accounting for 80 (8.8%) of the failed grafts. The incidence of graft loss to CR was highest for PTA (n=23 [11.3%]) and PAK (n = 45 [11.6%]) recipients and lowest for SPK recipients (n=12 [3.7%]) (P=0.002). By multivariate analysis, the most significant risk factors for graft loss to CR were a previous episode of acute rejection (relative risk [RR]=4.41, P

Donors undergoing hemi-pancreatectomy to provide a pancreas segment for transplantation into a relative with type 1 diabetes acquire diminished insulin and glucagon responses to intravenous agonists. Some donors develop diabetes and require treatment for hyperglycemia. They become at risk for hypoglycemia when treatment includes sulfonylureas and insulin. However, no studies assessing the impact of hemi-pancreatectomy in humans on islet α-cell responses to hypoglycemia have been reported. Consequently, we performed stepped hypoglycemic clamps in 7 donors of varying glycemic control and compared their responses to 16 control subjects. Donors and control subjects reached similar nadirs of glycemia (45 ± 3 and 41 ± 1 mg/dl, respectively) during the clamp. The donors had significantly higher mean basal glucagon levels than control subjects (203 ± 27 vs. 135 ± 15 pg/ml; P < 0.03) but did not have significant differences in glucagon responses during the clamp. The donors also had significantly higher mean peak epinephrine responses during the clamp (1,231 ± 134 vs. 730 ± 68 pg/ml; P < 0.002), but there were no statistically significant differences in norepinephrine or symptom responses. The glucose thresholds at which hormonal and symptom responses began were not different. We conclude that although glucagon response to arginine and insulin response to glucose and arginine are diminished after hemi-pancreatectomy, no deficiency in glucagon responses were detected during hypoglycemia.

Recent changes to pancreas graft allocation policy have increased the number of organs available for regional and distant sharing, which results in a corresponding increase in preservation time. We sought to systematically assess the impact of cold ischemia time (CIT) on outcomes post-transplant. A retrospective review of 1253 pancreas transplants performed at a single transplant center was performed to correlate CIT to transplant outcomes. The rate of technical failure (TF) increased with 20+ hours of CIT, with a 2.7-fold to 6.2-fold increased rate of TF for pancreas after kidney (PAK), simultaneous pancreas and kidney (SPK), and pancreas transplants overall. Long-term graft survival was best with12 hours of CIT; graft failure increased 1.2-fold to 1.4-fold with 12-24 hours of CIT and 2.2-fold with 24+ hours. CIT had less influence on the pancreas transplant alone category than either SPK or PAK and had markedly more influence on grafts from older (age25 years) and overweight (body mass index25) donors. In the final analysis, grafts with12 hours of CIT performed the best overall, and strategies that reduce CIT (such as early allocation, pre-recovery cross-matching, and chartered flights for organs) should be considered whenever possible.

Pancreas after previous kidney (PAK) transplants are an attractive option for type 1 diabetic patients because of the short waiting time and use of living kidney donors. Factors associated with the increased success rate of PAK transplants in four immunosuppressive eras were analyzed. Between July 1, 1978, and April 30, 2000, 406 PAK transplants were performed in posturemic patients. Four immunosuppressive eras were analyzed: (1) the precyclosporine era, era 1 (n = 65; 16%); (2) the cyclosporine era, era 2 (n = 109; 27%); (3) the tacrolimus era with monoclonal or polyclonal antibody induction therapy, era 3 (n = 104; 26%); and (4) the tacrolimus era with monoclonal and polyclonal antibody induction therapy, era 4 (n = 128; 31%). Patient and graft survival, rejection, and technical failure rates were calculated. Patient survival rates have remained high over time, from 91% (era 1) to 96% (era 4) at 1 yr posttransplant. Pancreas graft survival rates with primary cadaver transplants have significantly increased, from 17% (era 1) to 81% (era 4) at 1 yr. The rate of graft loss from rejection has significantly decreased, from 78% (era 1) to 9% (era 4) at 1 yr. Results were best when donors and recipients were matched for at least one antigen per HLA locus. Kidney graft survival was higher in PAK transplant recipients compared with diabetic recipients of kidney transplants alone from the time of the kidney as well as the pancreas transplants. PAK recipients now enjoy >80% graft survival at 1 yr. This improvement in outcome results from better immunosuppression, good matching, and close posttransplant monitoring for rejection.

To review a single center's experience and outcome with living donor transplants.Outcome after living donor transplants is better than after cadaver donor transplants. Since the inception of the authors' program, they have performed 2,540 living donor transplants. For the most recent cohort of recipients, improvements in patient care and immunosuppressive protocols have improved outcome. In this review, the authors analyzed outcome in relation to protocol.The authors studied patient and graft survival by decade. For those transplanted in the 1990s, the impact of immunosuppressive protocol, donor source, diabetes, and preemptive transplantation was analyzed. The incidence of rejection, posttransplant steroid-related complications, and return to work was determined. Finally, multivariate analysis was used to study risk factors for worse 1-year graft survival and, for those with graft function at 1 year, to study risk factors for worse long-term survival.For each decade since 1960, outcome has improved after living donor transplants. Compared with patients transplanted in the 1960s, those transplanted in the 1990s have better 8-year actuarial patient and graft survival rates. Death with function and chronic rejection have continued to be a major cause of graft loss, whereas acute rejection has become a rare cause of graft loss. Cardiovascular deaths have become a more predominant cause of patient death; infection has decreased. Donor source (e.g., ideally HLA-identical sibling) continues to be important. For living donor transplants, rejection and graft survival rates are related to donor source. The authors show that patients who had preemptive transplants or less than 1 year of dialysis have better 5-year graft survival and more frequently return to full-time employment. Readmission and complications remain problems; of patients transplanted in the 1990s, only 36% never required readmission. Similarly, steroid-related complications remain common. The authors' multivariate analysis shows that the major risk factor for worse 1-year graft survival was delayed graft function. For recipients with 1-year graft survival, risk factors for worse long-term outcome were pretransplant smoking, pretransplant peripheral vascular disease, pretransplant dialysis for more than 1 year, one or more acute rejection episodes, and donor age older than 55.These data show that the outcome of living donor transplants has continued to improve. However, for living donors, donor source affects outcome. The authors also identify other major risk factors affecting both short- and long-term outcome.

To determine outcome in diabetic pancreas transplant recipients according to risk factors and the surgical techniques and immunosuppressive protocols that evolved during a 33-year period at a single institution.Insulin-dependent diabetes mellitus is associated with a high incidence of management problems and secondary complications. Clinical pancreas transplantation began at the University of Minnesota in 1966, initially with a high failure rate, but outcome improved in parallel with other organ transplants. The authors retrospectively analyzed the factors associated with the increased success rate of pancreas transplants.From December 16, 1966, to March 31, 2000, the authors performed 1,194 pancreas transplants (111 from living donors; 191 retransplants): 498 simultaneous pancreas-kidney (SPK) and 1 simultaneous pancreas-liver transplant; 404 pancreas after kidney (PAK) transplants; and 291 pancreas transplants alone (PTA). The analyses were divided into five eras: era 0, 1966 to 1973 (n = 14), historical; era 1, 1978 to 1986 (n = 148), transition to cyclosporine for immunosuppression, multiple duct management techniques, and only solitary (PAK and PTA) transplants; era 2, 1986 to 1994 (n = 461), all categories (SPK, PAK, and PTA), predominantly bladder drainage for graft duct management, and primarily triple therapy (cyclosporine, azathioprine, and prednisone) for maintenance immunosuppression; era 3, 1994 to 1998 (n = 286), tacrolimus and mycophenolate mofetil used; and era 4, 1998 to 2000 (n = 275), use of daclizumab for induction immunosuppression, primarily enteric drainage for SPK transplants, pretransplant immunosuppression in candidates awaiting PTA.Patient and primary cadaver pancreas graft functional (insulin-independence) survival rates at 1 year by category and era were as follows: SPK, era 2 (n = 214) versus eras 3 and 4 combined (n = 212), 85% and 64% versus 92% and 79%, respectively; PAK, era 1 (n = 36) versus 2 (n = 61) versus 3 (n = 84) versus 4 (n = 92), 86% and 17%, 98% and 59%, 98% and 76%, and 98% and 81%, respectively; in PTA, era 1 (n = 36) versus 2 (n = 72) versus 3 (n = 30) versus 4 (n = 40), 77% and 31%, 99% and 50%, 90% and 67%, and 100% and 88%, respectively. In eras 3 and 4 combined for primary cadaver SPK transplants, pancreas graft survival rates were significantly higher with bladder drainage (n = 136) than enteric drainage (n = 70), 82% versus 74% at 1 year (P =.03). Increasing recipient age had an adverse effect on outcome only in SPK recipients. Vascular disease was common (in eras 3 and 4, 27% of SPK recipients had a pretransplant myocardial infarction and 40% had a coronary artery bypass); those with no vascular disease had significantly higher patient and graft survival rates in the SPK and PAK categories. Living donor segmental pancreas transplants were associated with higher technically successful graft survival rates in each era, predominately solitary (PAK and PTA) in eras 1 and 2 and SPK in eras 3 and 4. Diabetic secondary complications were ameliorated in some recipients, and quality of life studies showed significant gains after the transplant in all recipient categories.Patient and graft survival rates have significantly improved over time as surgical techniques and immunosuppressive protocols have evolved. Eventually, islet transplants will replace pancreas transplants for suitable candidates, but currently pancreas transplants can be applied and should be an option at all stages of diabetes. Early transplants are preferable for labile diabetes, but even patients with advanced complications can benefit.