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Five preventable causes of kidney graft loss in the 1990s: A single-center analysis. Background Despite improvements in immunosuppressive protocols and patient care, kidney allografts continue to fail. We studied causes of graft loss for primary kidney transplants in the 1990s to determine major causes and potential interventions. Methods Causes of graft loss were reviewed for 1467 primary kidney transplants done at our institution between January 1, 1990, and December 31, 1999. Graft loss for that entire population was studied and then the causes of loss selectively examined at 5 years post-transplant. Finally, causes of loss in the 1990s versus the 1980s were compared. Results Five major causes of graft loss were noted in the 1990s: thrombosis, acute rejection (either alone or combined with delayed graft function or infection), chronic rejection, death with function, and noncompliance. In the first year post-transplant, thrombosis (25%) and death with function (41%) were the major causes of graft loss. After the first year, chronic rejection and death with function predominated. For recipients dying with graft function, cardiovascular disease was the major cause of death. Conclusions This study identified the five major causes of kidney graft loss in the 1990s. Different interventions are required to decrease loss from each of these causes. Future research needs to be directed at such interventions.

The Organ Procurement Transplant Network (OPTN) listing criteria for simultaneous liver-kidney transplant (SLK) are not well defined. Concerns remain about rising numbers of SLKs, which divert quality kidneys from candidates awaiting kidney transplants (KT). We performed a retrospective review of liver transplants (LTs) at our center from 2004 to 2014; 127 recipients (liver transplant alone; 102 LTA, 25 SLK) were identified with short-term preoperative kidney dysfunction (creatinine >4 mg/dL or preoperative hemodialysis [HD] for

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.

Compared with enteric drainage, bladder-drained solitary pancreas transplants can be monitored for rejection by measuring urine amylase levels. However, bladder drainage is associated with a higher risk of infection and metabolic complications, necessitating enteric conversion in about one third of patients. We hypothesized that hypersecreting pancreata with high urine amylase levels have a higher propensity for enteric conversion from an antecedent elevated enzymatic effect on the urinary tract and increased fluid losses.We analyzed the risk for enteric conversion in 312 bladder-drained solitary pancreas transplant recipients. Urine amylase levels at 30 days were used to identify those at risk for enteric conversion. Time-to-event analysis was used to evaluate the risk of enteric conversion at 10 years, adjusting for urine amylase level and other confounding factors. Confounding risk factors statistically related to enteric conversion were incorporated into the multivariable analysis by using Cox proportional hazards regression at 3 years' posttransplant.During the median follow-up of 184.6 months, 31% of recipients underwent duct conversion. A majority of recipients (84.5%) who required duct conversion were primary transplants. The 30-day median urine amylase level was 1749 IU/h (quartile 1, 777 IU/h; quartile 3, ≥3272 IU/h). Using receiver operating characteristic analysis, it was determined that urine amylase levels3272 IU/h had the greatest specificity for predicting risk of enteric conversion. In the multivariate analysis, high urine amylase levels increased the risk of enteric conversion only in repeated pancreas transplants.Primary transplants are more likely to undergo enteric conversion than retransplants. High urine amylase levels increase the risk of enteric conversion in retransplants only, and therefore this enzyme alone cannot serve as the sole predictor for conversion in primary transplants. Other factors, such as fluid and bicarbonate losses, increased bladder pressure, and a pre-existing lower urinary tract pathologic condition may be also responsible for the development of complications; these factors warrant additional study.

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.

Given the constant flux in caseload and the number of personnel available in the OR, waiting for a final XM often prolongs organ preservation time (a room available at the time a XM is started is not available when the XM is completed). Longer preservation is associated with increased DGF and decreased graft survival. We have shown in a retrospective analysis that final XMs on 0% PRA recipients were always negative (Transplantation, 1999). We now describe a policy of: a) not doing screening XM and b) proceeding to the OR without a XM, in situations where the recipients's PRA has been documented to be 0% and when there have not been any interim transfusions (and the OR is ready before XM completion). Final XM is completed after the transplant. All patients send sera every 6 weeks for PRA (antiglobulin technique). If > o r=3 consecutive PRAs are 0%, no donor-specific screening XM is done prior to calling the patient in for tx (UNOS allocation algorithm used). If there have not been any interim transfusions, we have proceeded to tx prior to completion of the final XM. Between 1/1/98-12/31/99, we did 109 CAD kidney (K) and 79 simultaneous kidney pancreas (SPK) tx; 67 (61%) K and 56 (71%) SPK had 0% PRA. Of the 0% PRA, 25/67 (37%) K and 28/56 (50%) SPK had no pre-tx XM. For K with no XM, cold ischemia was shorter (13.2+/-0.2 vs. 18+/-0.9 hrs, p=0.01) and DGF less (12% vs. 24%, p=0.3); for SPK with no XM, cold ischemia was shorter (15.2+/-2 vs. 18+/-0.9 hrs, p=0.1); no diff in DGF. All post-XM were negative and there were no hyperacute rejections; there was no diff in acute rejection episodes. Actuarial 1 yr graft survival: no XM-K=87.5%, SKP=82%; Yes XM-K=88%, SKP=86% (NS). Our data suggests it is safe, in select circumstances, to proceed to the OR without a XM. Elimination of the screening XM for 0% PRA candidates saves money. Proceeding of the OR (if available) without a final XM shortens cold ischemia time.

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.

The two-layer method [University of Wisconson solution (UW)/perfluorochemical plus O2] for pancreas preservation has been demonstrated to be superior to simple UW storage alone in the canine model. For the first time, we applied the two-layer method to clinical whole-pancreas transplantation.Pancreases were placed in the two-layer method in 10 cases and UW alone in 44 cases before transplant. The mean cold ischemic time was 16.5 hr in the two-layer group versus 18.1 hr in the UW group (P=NS). We compared the condition of graft at the time of reperfusion, and then 3 months posttransplant graft function and complications.At the time of reperfusion, no grafts in the two-layer group were edematous, compared with 10(23.3%) of 43 in the UW group (P=0.18). Seven (70%) of 10 grafts in the two-layer group obtained the best overall quality score, compared with 24(57.1%) of 42 in the UW group (P=0.72). Nine (90%) of 10 recipients in the two-layer group became insulin-independent during hospitalization, compared with 31(70.5%) of 44 in the UW group (P=0.26). Time to insulin independence was no different between the two groups. No pancreas grafts preserved by the two-layer method suffered acute rejection. Conclusions. The two-layer preservation method is feasible in human clinical transplantation. It was at least equivalent and may be superior to UW alone in both morphologic and functional assessment of the transplanted pancreas.

Prolonged preservation of the donor organ may result in delayed graft function or nonfunction after most organ transplants. We studied whether or not prolonged preservation increases surgical complications after pancreas transplants.Between January 1, 1994, and September 30, 1998, a total of 294 recipients underwent cadaver pancreas transplants at our institution. Recipients were analyzed in 2 groups: those with pancreas preservation timeor = 20 hours (n = 211) versus20 hours (n = 83).Demographic data were similar between the 2 groups, except that mean donor age in the prolonged preservation group was significantly lower. Despite use of younger donors, prolonged preservation was associated with an increased incidence of surgical complications, most notably leaks, thrombosis, and wound infections. Grafts with prolonged preservation were more often noted by the transplant surgeon to be edematous after reperfusion, although the incidence of hyperamylasemia posttransplant did not differ between the 2 groups. Graft and patient survival rates also did not differ between the 2 groups. The incidence of early graft loss (3 months) was, however, higher in the prolonged preservation group (20.5% versus 9.0%, P = .04).Prolonged preservation of the donor organ increases the incidence of surgical complications after pancreas transplants. All attempts should be made to minimize preservation time, keeping it below 20 hours, if possible.

BACKGROUND Numerous studies of steroid withdrawal have been carried out in kidney and liver transplant recipients, but only a few in pancreas transplant recipients. Yet, pancreas transplant recipients could have significant long-term benefits from steroid withdrawal. METHODS We performed a retrospective analysis to determine the feasibility of steroid withdrawal in pancreas transplant recipients. RESULTS Of 360 recipients who underwent a pancreas transplant between January 1, 1994 and June 30, 1998, 14 attempted steroid withdrawal (12 simultaneous pancreas-kidney [SPK]; 2 pancreas transplant alone [PTA]). Reasons for steroid withdrawal were bone fractures (n = 3), psychiatric disorders (n = 2), severe acne (n = 1), recurrent infections (n = 4), and problems with hypercholesterolemia or hypertension (n = 4). All 14 were maintained on tacrolimus and mycophenolate mofetil (MMF) immunosuppression, except for 1 who was on tacrolimus and azathioprine (AZA). Of the 14 recipients, 11 had no episodes of acute rejection before steroid withdrawal. The remaining 3 had one or more acute rejection episodes. Of the 14 recipients, 10 (72%) currently remain off steroids (mean follow-up 18 months, range 5-51 months). However, 4 recipients have resumed steroids: 2 after an acute rejection episode (at 2 and 21 months post-withdrawal) and 2 because of leukopenia (WBC < 3000) and an inability to tolerate full-dose MMF. Steroid withdrawal was unsuccessful in both PTA recipients and in 2 of the 12 SPK recipients. All 14 recipients currently have a functioning pancreas graft. However, 1 of the SPK recipients, in whom steroid withdrawal failed, has developed chronic kidney rejection and is now back on hemodialysis awaiting a retransplant. CONCLUSION Steroid withdrawal is possible in up to 70% of pancreas transplant recipients. Further studies are necessary to define ideal candidates for steroid withdrawal. Based on the results of this analysis, we have launched a prospective, randomized trial of steroid withdrawal in pancreas transplant recipients.

Background. Both antigen-dependent (immunologic) and non-antigen-dependent (nonimmunologic) factors have been implicated in long-term renal allograft loss. Differentiating between these two factors is important because prevention strategies differ. Methods. To isolate the importance of these 2 factors, we studied long-term actuarial graft survival in a cohort of adult kidney recipients who underwent transplants at a single institution between January 1, 1984 and October 31, 1998. Excluded were recipients with graft loss as a result of death with function, technical failure, primary nonfunction, and recurrent disease, leaving 1587 recipients (757 cadaver [CAD], 830 living donor [LD]) who would be at risk for graft loss secondary to both immunologic and nonimmunologic factors. These recipients were analyzed in the following 2 groups: those treated for a previous episode of acute rejection (AR) (Group1; n=588; 328 CAD, 260 LD) and those with no AR (Group 2: n=999; 429 CAD, 570 LD). Actuarial graft survival and causes of graft loss were determined for each group. Presumably, graft loss in Group 1 would be caused by immunologic and nonimmunologic factors; graft loss in Group 2 would be caused primarily by nonimmunologic factors. Results. The 10-year graft survival rate (censored for death with function, technical failure, primary non-function, and recurrent disease) in Group 2 was 91%. In contrast, the 10-year graft survival rate in Group 1 was 45% (P

Background This international multicenter trial explores the feasibility and reproducibility of islet transplantation using a single common protocol (Edmonton Protocol ) for islet manufacture and post-transplant management. Methods A total of 36 subjects underwent islet transplantation at 9 international sites (6 in North America, 3 in Europe). Islets were prepared from cadaveric donors, purified, and transplanted within two hours, without culture. The primary endpoint was defined as the proportion of subjects that remained insulin independent with adequate glycemic control at one year following their final transplant. Results 16/36 (44%, CI 30% - 61%) subjects achieved the primary endpoint, 10 (28%) demonstrated partial islet function, and 10 had complete graft loss before one year. 22/36 (61%) derived benefit at one year post final transplant as demonstrated by insulin independence or reduced insulin requirement, HbA1C 0.3ng/mL and protection from severe hypoglycemia. Of 21/36 (58%) subjects attaining primary endpoint criteria at any point throughout the trial, 15/21 (71%) became dependent on insulin again by two years. Conclusions This multicenter trial confirms that islet transplantation successfully restores long-term endogenous insulin production and glycemic stability in T1DM subjects with unstable baseline control, but insulin independence is usually evanescent over time. Persistent islet function despite loss of insulin independence provided complete protection from severe hypoglycemia and improved HbA1C. Islet transplantation is an appropriate therapy for highly selected subjects with severe hypoglycemia or labile diabetes, provided all other attempts to stabilize glycemic control have been exhausted.

Phytobezoars associated with diabetic gastroparesis are often sources of diminished quality of life for patients. Poor blood sugar control has been associated with increasing gastroparesis. For recipients of pancreas transplants to correct diabetes, phytobezoar treatment post-transplant can typically be limited to invasive procedures and prokinetic agents. We present the case of an alternative treatment to phytobezoar, cola libation, i.e., "cola-lysis."

The number of pancreas transplants has decreased over the past decade, most notably numbers of pancreas after kidney (pak) and pancreas transplant alone (pta) procedures. This decrease may be mitigated in the future when changes to national pancreas allocation policy approved by the Organ Procurement and Transplantation Network Board of Directors in 2010 are implemented. The new policy will combine waiting lists for pak, pta, and simultaneous pancreas-kidney (spk) transplants), and give equal priority to candidates for all three procedures. This policy change may also eliminate geographic variation in waiting times caused by geographic differences in allocation policy. Deceased donor pancreas donation rates have been declining since 2005, and the donation rate remains low. The outcomes of pancreas grafts are difficult to describe due to lack of a uniform definition of graft failure in the transplant community. However long-term survival is better for spk versus pak and pta transplants. This may represent the difficulty of detecting rejection in the absence of a simultaneously transplanted kidney. The challenges of pancreas transplant are reflected in high rates of rehospitalization, most occurring within the first 6 months posttransplant. Pancreas transplant is associated with higher incidence of rejection compared with kidney transplant.

Rapid discontinuation of prednisone (RDP) has minimized steroid-related complications following kidney transplant (KT). This trial compares long-term (10-year) outcomes with three different maintenance immunosuppressive protocols following RDP in adult KT. Recipients (n = 440; 73% living donor) from March 2001 to April 2006 were randomized into one of three arms: cyclosporine (CSA) and mycophenolate mofetil (MMF) (CSA/MMF, n = 151); high-level tacrolimus (TAC, 8–12 μg/L) and low-level sirolimus (SIR, 3–7 μg/L) (TACH/SIRL, n = 149) or low-level TAC (3–7 μg/L) and high-level SIR (8–12 μg/L) (TACL/SIRH, n = 140). Median follow-up was ∼7 years. There were no differences between arms in 10-year actuarial patient, graft and death-censored graft survival or in allograft function. There were no differences in the 10-year actuarial rates of biopsy-proven acute rejection (30%, 26% and 20% in CSA/MMF, TACH/SIRL and TACL/SIRH) and chronic rejection (38%, 35% and 31% in CSA/MMF, TACH/SIRL and TACL/SIRH). Rates of new-onset diabetes mellitus were higher with TACH/SIRL (p = 0.04), and rates of anemia were higher with TACH/SIRL and TACL/SIRH (p = 0.04). No differences were found in the overall rates of 16 other post-KT complications. These data indicate that RDP-based protocol yield acceptable 10-year outcomes, but side effects differ based on the maintenance regimen used and should be considered when optimizing immunosuppression following RDP.

Prednisone-minimization protocols have been successful in low-risk recipients. We report on the use of a protocol incorporating rapid discontinuation of prednisone in a cohort of kidney transplant recipients (n = 79) at increased immunologic risk. Our data suggests that such recipients should not be excluded from prednisone-minimization protocols.

Numbers of pancreas transplants have been decreasing over the past decade, but outcomes continue to improve for all types: simultaneous pancreas-kidney transplant, pancreas after kidney transplant (PAK), and pancreas transplant alone (PTA). The most notable decrease occurred for PAK transplants, possibly due in part to decreases in numbers of living donor kidney transplants. The number of new candidates on the pancreas transplant waiting list has decreased steadily since 2000; only 1005 active candidates were added in 2011. Transplant rates for all pancreas transplant types reached a low in 2011 of 34.9 transplants per 100 wait-list years. Deceased donation rates have also been decreasing since 2005, but use of donation after circulatory death has been gradually increasing. The discard rate in 2011 was 27.7%, and higher for pancreata recovered from older donors. Improved outcomes during the early posttransplant period largely reflect improved donor and recipient selection and improved technical strategies. Inconsistent definitions of graft failure across reporting centers creates an ongoing challenge in the interpretation of outcome data for pancreas transplants. Rates of posttransplant re-hospitalization are high, most occurring in the first 6 months. Rejection rates are highest for PTA recipients, who also experience higher incidence of posttransplant lymphoproliferative disorder.

Kidney transplant and liver transplant are the treatments of choice for patients with end-stage renal disease and end-stage liver disease, respectively. Pancreas transplant is most commonly performed along with kidney transplant in diabetic end-stage renal disease patients. Despite a steady increase in the numbers of kidney and liver transplants performed each year in the United States, a significant shortage of kidneys and livers available for transplant remains. Organ allocation is the process the Organ Procurement and Transplantation Network (OPTN) uses to determine which candidates are offered which deceased donor organs. OPTN is charged with ensuring the effectiveness, efficiency and equity of organ sharing in the national system of organ allocation. The policy has changed incrementally over time in efforts to optimize allocation to meet these often competing goals. This review describes the history, current status and future direction of policies regarding the allocation of abdominal organs for transplant, namely the kidney, liver and pancreas, in the United States.

Desensitization therapies have been used with modest success in kidney transplantation. Some candidates, however, have such great breadth and depth of anti-HLA antibodies that they remain incompatible with potential donors. Bortezomib has been used without much success in desensitization regimens, but we hypothesized that its use during induction may be helpful in targeting antibody production by long-lived plasma cells. This report describes a high-risk positive crossmatch son-to-mother transplant that was performed after desensitization. The induction immunosuppression was supplemented with bortezomib. Pre- and post-transplant immunosuppression, antibody monitoring, biopsy data, and the clinical course are described in detail. Following transplant, the patient had excellent early graft function. Serial biopsies did not reveal acute antibody mediated rejection. Despite excellent graft function, the patient underwent withdrawal of care and died due to complications of calciphylaxis and deconditioning. This case details the first report of bortezomib used as part of induction therapy in solid organ transplant. Donor specific antibody production remained stable after transplant, with near complete abrogation of class I specificities. There were no bortezomib-related complications.

The shortage of deceased donor organs for solid organ transplantation continues to be an ongoing dilemma. One approach to increase the number of pancreas transplants is to share organs between procurement regions. To assess for the effects of organ importation, we reviewed the outcomes of 1014 patients undergoing deceased donor pancreas transplant at a single center. We performed univariate and multivariate analyses of the association of donor, recipient and surgical characteristics with patient outcomes. Organ importation had no effect on graft or recipient survival for recipients of solitary pancreas transplants. Similarly, there was no effect on technical failure rate, graft survival or long-term patient survival for simultaneous kidney-pancreas (SPK) recipients. In contrast, there was a significant and independent increased risk of death in the first year in SPK recipients of imported organs. SPK recipients had longer hospitalizations and increased hospital costs. This increased medical complexity may make these patients more susceptible to short-term complications resulting from the longer preservation times of import transplants. These findings support the continued use of organ sharing to reduce transplant wait times but highlight the importance of strategies to reduce organ preservation times.

We examined the long-term outcome of transplantation for alpha 1-antitrypsin deficiency (A1ATD).Data were reviewed on 42 transplants in 35 children with A1ATD over 42 yr and compared with 129 transplants in 116 children with biliary atresia (BA).Over 50% of patients were followed up for10 yr. A1ATD were older than BA at transplantation, median age, 6.0 vs. 1.0 yr (p 0.0001), and transplanted earlier in the course of liver failure (total bilirubin, 2.7 mg/dL [1.4-6.9] vs. 9.7 mg/dL [2.9-15.4], p = 0.005). Patient survival was greater in A1ATD than BA: one-yr post-transplant, 82.7% vs. 67.9%; five yr, 76.5% vs. 60.2%; and 10 yr, 76.5% vs. 55.9% (p = 0.03). Death-censored graft survival was similar: one-yr post-transplant, 68.4% vs. 66.2%; five yr, 68.4% vs. 55.8%; and 10 yr, 68.4% vs. 52.5% (p = 0.2). Deaths were from infection, hemorrhage, and graft failure6 months post-transplant. Patient survival improved at five yr from 33.3% pre-cyclosporine (CSA) (1969-1984) (n = 6) to 76.5% in the CSA era (1985-1994) (n = 17) and 100% with tacrolimus (1995-2006) (n = 12) (p = 0.007).The age at transplantation and the degree of liver dysfunction were related to the differences in graft and patient survival between A1AT and BA.

Background Calcineurin inhibitors (CNI) are the basis of contemporary immunosuppression in clinical pancreas transplantation (PT). Nevertheless, CNI toxicities, especially nephrotoxicity, have stimulated the search for CNI-sparing protocols. We performed a retrospective analysis of 25 PT patients with progressive CNI toxicities that were switched to a daclizumab (DAC)–based maintenance regimen. Methods From 2003 to 2007, 25 PT patients with progressive CNI toxicity (predominantly nephrotoxicity) were identified and switched from CNI to monthly DAC maintenance therapy. The DAC group was compared with matched control subjects (1:1) by transplant type and number, age, year of transplant, and duct management. Results and conclusions Results showed improved graft survival rates and decreased immunologic loss rates at 1, 3, and 5 years in the DAC group compared with the control group. There was no difference in patient survival rate between the 2 groups. Analysis demonstrates that DAC maintenance therapy is safe and effective for PT patients experiencing CNI toxicities. A randomized trial to compare DAC- and CNI-based regimens is needed in CNI-intolerant patients, with particular attention to the impact on renal function and patient morbidity (eg, infection rates).

Background Current ex vivo quality assessment of donor kidneys is limited to vascular resistance measurements and histological analysis. New techniques for the assessment of organ quality before transplantation may further improve clinical outcomes while expanding the depleted deceased-donor pool. We propose the measurement of whole organ oxygen consumption rate (WOOCR) as a method to assess the quality of kidneys in real time before transplantation. Methods Five porcine kidneys were procured using a donation after cardiac death (DCD) model. The renal artery and renal vein were cannulated and the kidney connected to a custom-made hypothermic machine perfusion (HMP) system equipped with an inline oxygenator and fiber-optic oxygen sensors. Kidneys were perfused at 8°C, and the perfusion parameters and partial oxygen pressures (pO2) were measured to calculate WOOCR. Results Without an inline oxygenator, the pO2 of the perfusion solution at the arterial inlet and venous outlet diminished to near 0 within minutes. However, once adequate oxygenation was provided, a significant pO2 difference was observed and used to calculate the WOOCR. The WOOCR was consistently measured from presumably healthy kidneys, and results suggest that it can be used to differentiate between healthy and purposely damaged organs. Conclusions Custom-made HMP systems equipped with an oxygenator and inline oxygen sensors can be applied for WOOCR measurements. We suggest that WOOCR is a promising approach for the real-time quality assessment of kidneys and other organs during preservation before transplantation.

Diabetes mellitus is frequent in kidney transplant recipients and is commonly associated with gastrointestinal (GI) complications. Delayed gastric emptying affects 30% to 50% of patients with type 1 or 2 diabetes and can influence oral drug absorption. Time-to-peak concentration of mycophenolic acid (MPA) from mycophenolate mofetil (MMF) is longer in diabetic kidney transplant patients than patients without diabetes. By retaining gut contents in the stomach for longer, this could increase local GI toxicity in diabetic recipients due to an extended duration of exposure to MPA in the stomach. The enteric-coated mycophenolate sodium (EC-MPS) formulation delays the release of MPA until pH is higher than 5.5, such that absorption takes place more distally compared with MMF. Patient-reported outcomes data have been used to assess the effect of conversion to EC-MPS in maintenance kidney transplant patients with diabetes who were experiencing MMF-related GI symptoms. Results indicated that conversion leads to improved GI symptom burden despite higher MPA exposure under the EC-MPS regimen. Improved GI tolerance using EC-MPS has permitted maintenance of optimal MPA exposure in nondiabetic populations. Comparative trials to evaluate the GI symptom burden and maximum achieved MPA dosing using the EC-MPS and MMF formulations in de novo and maintenance diabetic kidney transplant recipients are merited.

Nonadherence (NA) is a difficult posttransplant problem that can lead to graft loss. A retransplant is controversial because of a fear of recurrent NA. We reviewed our center's data base and identified 114 kidney recipients who lost their graft to overt NA; of this group, 35 (31%) underwent a retransplant after a thorough reevaluation. We compared this NA retransplant group to a control group of second transplant recipients who did not lose their first graft to overt NA (non-NA) (n = 552). After 8 years of follow-up, we found no significant differences between the groups in actuarial graft or patient survival rates, renal function, or the incidence of biopsy-proven chronic rejection. However, 5 of 35 (14%) NA recipients versus 10 of 552 (2%) non-NA recipients lost their retransplant to NA (p = 0.0001). Twenty of 35 (57%) of the NA group exhibited repeat NA behavior after retransplant. We conclude that prior graft loss to NA is associated with increased graft loss to NA after retransplant. However, the majority of NA retransplant recipients did well-with overall long-term outcomes similar to those of the non-NA group. With careful patient selection and aggressive intervention, prior overt NA should not be an absolute contraindication to retransplantation.

Protocols incorporating rapid discontinuation of prednisone (RDP) after kidney transplantation have been associated with good short-term results. However, concern remains that RDP will be associated with decreased long-term graft survival rates. We compared kidney transplant half-life (t1/2) for recipients treated with antibody induction, calcineurin inhibitor, antimetabolite, and RDP versus historical controls treated with antibody induction, calcineurin inhibitor, antimetabolite, and maintenance prednisone. For both living and deceased donor recipients, we found no difference between groups. We also found no differences in rate of graft loss to acute rejection or to tubular atrophy and interstitial fibrosis. Our study suggests that long-term graft outcome is not decreased when using RDP protocols versus chronic maintenance prednisone.

International audience; In this single-institution study, we compared outcomes in diabetic recipients of living donor (LD) kidney transplants that did vs. did not undergo a subsequent pancreas transplant. Of 307 diabetic recipients who underwent LD kidney transplants from January 1, 1995, through December 31, 2003, a total of 175 underwent a subsequent pancreas after kidney (PAK) transplant; 75 were deemed eligible (E) for, but did not receive (for personal or financial reasons), a PAK, and thus had a kidney transplant alone (KTA); and 57 deemed ineligible (I) for a PAK because of comorbidity also had just a KTA. We analyzed the three groups (PAK, KTA-E, KTA-I) for differences in patient characteristics, glycemic control, renal function, patient and kidney graft survival rates, and causes of death. Kidney graft survival rates (actuarial) were similar in the PAK vs. KTA-E groups at one, five, and 10 yr post-transplant: 98%, 82%, and 67% (PAK) vs. 100%, 84%, and 62% (KTA-E) (p = 0.9). The long-term (greater than four yr post-transplant) estimated glomerular filtration rate (GFR) was higher in the PAK than in the KTA-E group: 53 +/- 20 mL/min (PAK) vs. 43 +/- 16 mL/min (KTA-E) (p = 0.016). The patient survival rates were also similar for the PAK and KTA-E groups. We conclude that the subsequent transplant of a pancreas after an LD kidney transplant does not adversely affect patient or kidney graft survival rates; in fact, it is associated with better long-term kidney graft function.

As results after transplants continue to improve, the burden associated with long-term immunosuppression and the complications associated with these agents become more significant. Recent trends in immunosuppression minimization strategies show that prednisone minimization protocols are not associated with significantly increased acute rejection or chronic graft dysfunction. With long-term data now available, we can see that the majority of such recipients (80%) can remain prednisone free. There seems to be no compromise in terms of long-term results, and a definite improvement with regard to steroid-related and viral complications. These protocols can be used in minorities, children, and higher immunologic risk kidney transplant recipients, and in liver and pancreas recipients. The question of what is the ideal maintenance agent to couple with prednisone-free regimes remains unclear, and it may be that different agents may be better suited for different groups of recipients. Why is prednisone minimization now possible, when previous attempts were unsuccessful? Several explanations are possible. Early attempts concentrated on steroid withdrawal - removing prednisone once the patient had been on therapy for at least 3 months (18-20). Outcomes differ between studies reporting rapid prednisone withdrawal and those reporting prednisone withdrawal at a later time, but it is not clear why rapid prednisone withdrawal has succeeded and late prednisone withdrawal has failed. Other factors may include the routine use of polyclonal antibody for induction therapy and the use of newer immunosuppression agents such as MMF, TAC, and SRL. Finally, the newer trials of prednisone minimization have been performed in a different era, a time when results have improved as has our understanding of the risk factors associated with long-term graft survival. While ongoing follow-up of this group of patients will continue to be important, our experience suggests that maintenance prednisone is likely not required for the majority of kidney transplant recipients today.

Phytobezoars associated with diabetic gastroparesis are often sources of diminished quality of life for patients. Poor blood sugar control has been associated with increasing gastroparesis. For recipients of pancreas transplants to correct diabetes, phytobezoar treatment post-transplant can typically be limited to invasive procedures and prokinetic agents. We present the case of an alternative treatment to phytobezoar, cola libation, i.e., "cola-lysis."

We examined a group of SPK recipients that had early (90 d post-transplant) pancreas graft failure caused by a technical complication, and looked at outcomes of the kidney graft in these recipients. Of 289 SPK transplants, 36 (12.5%) had early pancreas graft failure because of a technical complication: thrombosis (n = 16), leak (n = 5), infection (n = 14), and pancreatitis (n = 1). Once the pancreas was lost, there was a high incidence of subsequent kidney graft failure. Kidney graft survival in these 36 recipients was 71.4% at one yr and 59.5% at three yr, significantly inferior compared to recipients that did not have early failure of the pancreas (86% at one yr and 82% at three yr, p0.001). Of the 36 recipients with early pancreas loss, 18 have gone on to failure of the kidney graft. Causes included thrombosis (n = 3), infection (n = 1), death with function (n = 6), chronic rejection (n = 4), ischemia (n = 1), and other (n = 3). Of the 18 kidney graft failures, nine occurred within three months after loss of the pancreas graft, usually either because of graft thrombosis, or patient death (usually from systemic sepsis). Multivariate analysis showed technical failure of the pancreas to be the most significant risk factor for kidney graft loss (HR = 2.08, p = 0.006).

The benefits (e.g., low acute rejection [AR] rate) vs. the long-term risk of each immunosuppressive protocol may determine the protocol's value.We studied the long-term impact of new-onset posttransplant diabetes (PTDM) and/or AR in 1,487 adult, primary transplant, nondiabetic recipients. Per Cox regression, donor source, AR, and PTDM were independent risk factors for graft loss (each, p.0001). Recipients were subdivided by donor source and into these 4 groups: no AR, no PTDM [n=857]; no AR, PTDM [n=134];or =1 AR, no PTDM [n=403];or =1 AR, PTDM [n=93].There was a significant difference between groups in 15-yr actuarial graft survival (GS) and death-censored (DC) GS (p.0001). Importantly,or =1 AR had more impact on 15-yr GS and DC GS than did PTDM; the worst outcome was for those having both AR and PTDM. In separate analyses, we censored those with1 AR; and then only compared those developing AR or PTDM in the first year. The results were similar--the AR (no PTDM) group did worse than the PTDM (no AR) group (p.001).Determining long-term risks associated with immunosuppressive protocols is important for treating future patients. Our data suggests that 15-year actuarial outcome (GS and DC GS) is worse for those developing AR than for those developing PTDM.

Background: Steroid minimization regimens have become increasingly popular for kidney transplant recipients. We studied outcomes for liver transplant recipients with a regimen using rapid discontinuation of prednisone (RDP). Results: The study group consisted of 83 recipients transplanted between June 2004 and January 2006. Immunosuppression consisted of tacrolimus, MMF, and two doses of basiliximab with six d of steroids. Patients with underlying autoimmune disorders (PSC, autoimmune hepatitis) were not included as they were maintained on steroids. The control group consisted of 83 recipients transplanted between January 2002 and May 2004. Immunosuppression consisted of tacrolimus, MMF and steroids, with no antibody induction. Mean MELD score at time of transplant was significantly higher in the steroid free group vs. the control group (28 vs. 23, p = 0.02); mean donor age was also higher (42 vs. 37 yr, p = 0.02). Other characteristics including recipient age, cold ischemic time, donor source, and cause of liver disease were similar (p = ns). Mean length of follow-up was 16.1 months in the RDP group and 32 months in the control group; a minimum of six months follow up was present for all patients. Patient and graft survival rates were not statistically different in the two groups (p = ns). Biopsy proven rejection was low in both groups and not significantly different (at one yr post-transplant 11% in the RDP group vs. 12% in control, p = 0.53). Based on protocol biopsy data, histologic recurrence of hepatitis C was demonstrated in 56% of the control group hepatitis C positive recipients vs. 39% in the RDP group (p = 0.05). There was a significantly lower incidence of post-transplant diabetes (PTDM) in the RDP vs. control group (at 6 months post-transplant 12% vs. 32%, p = 0.004). Conclusions: Rapid discontinuation of prednisone in liver transplant recipients is not associated with an increased risk of rejection, and may be associated with lower morbidity, especially PTDM and hepatitis C recurrence.

Roughly 15% of kidney transplant recipients on a rapid discontinuation of prednisone (RDP) protocol have > or =1 episode of acute rejection (AR). One clinically important question is whether long-term maintenance steroids should be introduced in those recipients having AR. Of 842 adult kidney transplant recipients on an RDP protocol, 149 (17.7%) have had at least 1 AR episode. Of these, 51 (34%) started on maintenance prednisone (5 mg/day) after treatment of the AR, while 98 (66%) remained steroid free. Demographics for the two groups were similar. With mean follow-up of 26 months, 48 (32%) of the recipients have had a 2nd AR episode: 15 (29.4%) in those on maintenance steroids vs. 33 (33.7%) in those remaining steroid free (p = 0.12). Graft survival was not significantly different between the two groups. Multivariate analysis of risk factors for a 2nd episode found the histologic appearance of the initial AR episode to be the most significant risk factor. But, whether steroids were added to the maintenance regimen or not, also seemed to have an impact (RR = 2.1, p = 0.07). At present there is evidence to suggest that some SA patients should start on maintenance steroids after AR. However, longer follow-up with more patients is necessary.

Background Calcineurin inhibitors (CNIs) have been the mainstay of immunosuppressive protocols in kidney transplantation over the past 20 years. However, in some recipients, the adverse effects of CNIs contribute to chronic allograft nephropathy and death with function--the two leading causes of late graft loss. Other recipients maintain stable graft function. Methods We studied the impact of continuing CNI-based immunosuppression in the second decade after kidney transplantation. From 1984 through 1996, a total of 1,263 patients underwent a primary kidney transplant at the University of Minnesota and received cyclosporine-based immunosuppression. Antibody induction was used only in deceased donor recipients. Results The actuarial 20-year patient survival rate was 38%; graft survival, 30%; and death-censored graft survival, 60%. The annual mean serum creatinine level for recipients whose grafts survived > or =1 year remained stable, although recipients with a history of > or =1 acute rejection episode had a higher serum creatinine level vs. recipients who were rejection-free. The annual mean calculated creatinine clearance was also stable over time. In addition, for recipients who were acute rejection-free, chronic allograft nephropathy/chronic rejection was only responsible for 9% of graft losses. Conclusions Our study suggests that some kidney transplant recipients tolerate long-term CNI-based immunosuppression with stable creatinine levels. Identifying certain recipients' predisposition to CNI toxicity and individualizing immunosuppressive therapy may be important in order to improve long-term kidney function, while simultaneously preserving low short-term acute rejection rates.

Background: Pancreas graft thrombosis remains the leading non-immunologic cause of graft loss after pancreas transplantation. We studied the role of hypercoagulable states (HCS) in pancreas graft thrombosis (pthx). Methods: Between January 1, 1994, and January 1, 2003, 131 pancreas transplant recipients experienced a pthx (n = 67) or other thrombotic events. Fifty-six recipients consented to have their blood drawn and tested for the HCS. These results were compared with a control group of pancreas transplant recipients who did not experience a thrombotic event. Fisher's exact test was used to compare the groups. Results: We found 18% of the recipients with pancreas thrombosis to have a HCS. Factor V Leiden (FVL) was found in 15% vs. 4% in the control group (p = ns) vs. 3–5% in the general white population. We found 3% of the pancreas thrombosis patients to have a prothrombin gene mutation (PGM) vs. 0% in the control group (p = ns) vs. 1–2% in the general white population. Conclusions: Of pancreas transplant recipients with thrombosis, 18% had one or more of the most common factors associated with a HCS (FVL or PGM). This can be compared with 4% in a control group and 4–7% in the general white population, respectively. Although the differences are not statistically significant due to small numbers, we feel that the findings may be clinically relevant. While this is only a pilot study, it may be reasonable to screen select pancreas transplant candidates for HCS, especially FVL and PGM, until more data become available.

It is important to determine when to use and when to avoid calcineurin inhibitors (CNIs). CNIs are associated with kidney dysfunction in some, but not all, transplant recipients. CNI-sparing protocols have their own drug-specific limitations. Two major clinical series suggest the benefit of routine CNI-sparing approaches, but our review suggests weaknesses in both. Ongoing studies are needed to determine which subgroups of recipients will benefit from CNIs.