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This study assesses the impact of a telemedicine-based home management program (THMP) on patient adherence, hospital readmissions, and quality of life (QOL) after liver transplantation (LT).Telemedicine interventions represent an opportunity to personalize care and can lead to improved adherence and patient satisfaction. However, there is limited data on impact of these interventions on outcomes after LT. Therefore, we conducted the first randomized controlled trial (RCT) of a THMP compared to standard of care (SOC) after LT.One hundred six consecutive LT recipients were randomized (1:1) to 1 of 2 posttransplant care strategies: SOC or THMP. The THMP included an electronic tablet and bluetooth devices to support daily text messages, education videos, and video FaceTime capability; data was cyber-delivered into our electronic medical record daily. Endpoints were THMP participation, 90-day hospital readmission rate, and QOL.One hundred patients completed the study with 50 enrolled in each arm. Participation and adherence with telemedicine was 86% for basic health sessions (vital sign recording), but only 45% for using messaging or FaceTime. The THMP group had a lower 90-day readmission rate compared to SOC (28% vs 58%; P = 0.004). The THMP cohort also showed improved QOL in regards to physical function (P = 0.02) and general health (P = 0.05) at 90 days.To our knowledge, this is the first RCT demonstrating the impact of THMP after LT. The magnitude of effect on LT outcomes, hospital readmissions, and QOL suggests that the adoption of telemedicine has great potential for other major operations.

Currently trials of immunosuppression in transplantation are in decline because their objectives remain focused on improving acute rejection rates and graft survival in the first 12 months. With 1 year renal graft survival rates of greater than 90% the best that can be hoped for is noninferiority trial outcomes compared with current standard of care. Current trial design is not leading to novel therapies improving long-term outcomes and safety, and hence important unmet clinical needs in transplantation remain unanswered. Issues that need to be addressed include but are not limited to: prevention of subclinical rejection in the first year, better 5- and 10-year graft outcomes, more effective treatment for high immunological risk and sensitized (including donor-specific antibody) patients, immunosuppressive combinations that are better tolerated by patients with fewer side effects and less morbidity and mortality. In September 2015, the Transplantation Society convened a group of transplant clinical trial experts to address these problems. The aims were to substantially realign the priorities of clinical trials for renal transplant immunosuppression with the current unmet needs and to propose new designs for clinical trials for transplant immunosuppression. Moving forward, the transplant community needs to provide trial data that will identify superior treatment options for patient subgroups and allow new agents to be evaluated for efficacy and safety and achieve timely regulatory approval. Trial designs for new transplant immunosuppression must be intelligently restructured to ensure that short- and long-term clinical outcomes continue to improve.

Importance The complications of corticosteroids make the inclusion of these drugs in immunosuppressive protocols for kidney transplant patients undesirable. However, cessation of corticosteroids is associated with a higher risk of short-term rejection, and the long-term outcomes of patients withdrawn from corticosteroids remain uncertain. Objective To compare long-term kidney transplant outcomes of patients randomized to continue or withdraw corticosteroids. Design, Setting, and Participants This prospective multicenter randomized double-blind placebo-controlled trial was conducted between November 1999 and December 2002 with linkage to a mandatory national registry with validated outcome ascertainment until June 8, 2018. The study included 28 kidney transplant centers in the United States, including 386 low– to moderate–immune risk adult recipients of a living or deceased donor kidney transplant without delayed graft function or short-term rejection in the first week after transplant. Analyses were intention to treat. Analysis began September 2018 and ended June 2019. Interventions Patients were randomized to receive tacrolimus and mycophenolate mofetil with or without corticosteroids 7 days after transplant. Main Outcomes and Measures Kidney allograft failure from any cause including death and allograft failure censored for patient death defined by the requirement for long-term dialysis or repeat transplant. Results Of 385 patients, 191 were assigned to withdraw from corticosteroids (mean [SD] age, 46.5 [12.1] years), and 194 patients were assigned to continued corticosteroids (mean [SD] age, 46.3 [12.6] years). The median (interquartile range) follow-up time was 15.8 (12.0-16.3) years after transplant. The adjusted hazard ratios of allograft failure from any cause including death was 0.83 (95% CI, 0.62-1.10;P = .19) and for allograft failure censored for patient death was 0.78 (95% CI, 0.52-1.19;P = .25) and did not differ between the patients assigned to withdraw from corticosteroids vs assigned to continued corticosteroids. Results were consistent in a per-protocol analysis among 223 patients who continued the trial-assigned treatment of corticosteroid withdrawal (n = 114) or corticosteroids (n = 109) through at least 5 years after transplant. The outcomes of trial participants in either treatment group did not differ from similarly treated contemporary registry patients who met trial eligibility criteria and were treated with the same immunosuppressive drugs. Conclusions and Relevance Long-term corticosteroids may not be necessary as part of a calcineurin-based multiple drug immunosuppressive regimen in low– to moderate–immune risk kidney transplant recipients.

Background Atypical hemolytic uremic syndrome (aHUS) is associated with significant morbidity and mortality and occurs due to genetic or acquired abnormalities that result in the dysregulation of the alternative complement pathway. Case Report We report a case of post-living kidney transplantation de novo aHUS in a setting of heterozygous deletion in the complement factor H-related protein (CFHR)3-CFHR1 gene. The aHUS episode was possibly triggered by antibody-mediated rejection or tacrolimus. The patient responded well to eculizumab and substituting belatacept for tacrolimus. Her serum creatinine level was stable at 1.5 mg/dL after 2.5 years of follow-up. Conclusion This case highlights the success of using a strategy that combines eculizumab and belatacept, as an alternative to calcineurin inhibitors, in treating aHUS in a patient with heterozygous deletion in the CFHR3-CFHR1 gene.

Background Highly sensitized patients, who produce antibodies against multiple anti-human leukocyte antigens, have significantly reduced chances for renal transplantation. Traditionally, desensitization protocols to reduce the levels of antibodies have relied on the use of intravenous immunoglobulin and plasmapheresis. Results Here we report the case of a patient with a calculated panel-reactive antibody level of 100% who was desensitized using multiple courses of bortezomib, a proteasome inhibitor, in an intravenous immunoglobulin-free regimen. The patient underwent a successful transplantation with an allograft from a living donor and has continued to do well post-transplantation. Conclusions The expression of anti-human leukocyte antigen antibodies decreases the likelihood of transplantation for patients by restricting the available donor pool. New protocols that reduce antibody expression in these patients and allow for renal transplantation are needed. Bortezomib, as used in the patient reported here, represents a promising new medication for successful desensitization and transplantation.

Background Post-transplantation recurrence of primary focal and segmental glomerulosclerosis (FSGS) is estimated to occur in 30%–50% of cases and doubles the risk of allograft failure. Treatment of recurrent FSGS is challenging because specific pathogenic targets are unknown and available therapeutic options have limited efficacy. Case Report We report a case of recurrent FSGS with nephrotic-range proteinuria (urine protein creatinine ratio [UPCR], >50) and debilitating edema that was resistant to rituximab and plasmapheresis. The patient had a remarkable response to adrenocorticotropic hormone (ACTH) gel and achieved complete remission (UPCR, 0.5; serum albumin, 4.1 g/dL; serum creatinine, 1.0 mg/dL) which was maintained over 10 months on this treatment. Conclusions We conclude that ACTH gel is a potential therapeutic option for post-transplantation recurrence of FSGS and warrants further evaluation.

Morbid obesity is a barrier to kidney transplantation due to inferior outcomes, including higher rates of new-onset diabetes after transplantation (NODAT), delayed graft function (DGF), and graft failure. Laparoscopic sleeve gastrectomy (LSG) increases transplant eligibility by reducing BMI in kidney transplant candidates, but the effect of surgical weight loss on posttransplantation outcomes is unknown. Reviewing single-center medical records, we identified all patients who underwent LSG before kidney transplantation from 2011-2016 (n = 20). Post-LSG kidney recipients were compared with similar-BMI recipients who did not undergo LSG, using 2:1 direct matching for patient factors. McNemar's test and signed-rank test were used to compare groups. Among post-LSG patients, mean BMI ± standard deviation (SD) was 41.5 ± 4.4 kg/m2 at initial encounter, which decreased to 32.3 ± 2.9 kg/m2 prior to transplantation (P

Background Contrast-induced nephropathy (CIN) in native kidneys is associated with a significant increase in mortality and morbidity. Data regarding CIN in renal allografts are limited, however. We retrospectively studied CIN in renal allografts at our institution: its incidence, risk factors, and effect on long-term outcomes including allograft loss and death. Methods One hundred thirty-five renal transplant recipients undergoing 161 contrast-enhanced computed tomography (CT) scans or coronary angiograms (Cath) between years 2000 and 2014 were identified. Contrast agents were iso- or low osmolar. CIN was defined as a rise in serum creatinine (SCr) by >0.3 mg/dl or 25% from baseline within 4 days of contrast exposure. After excluding 85 contrast exposures where patients had no SCr within 4 days of contrast administration, 76 exposures (CT: n = 45; Cath: n = 31) in 50 eligible patients were analyzed. Risk factors assessed included demographics, comorbid conditions, type/volume of contrast agent used, IV fluids, N-acetylcysteine administration, and calcineurin inhibitor use. Bivariate and multivariable analyses were used to assess the risk of CIN. Results Incidence of CIN was 13% following both, CT (6 out of 45) and Cath (4 out of 31). Significant bivariate predictors of CIN were IV fluid administration (p = 0.05), lower hemoglobin (p = 0.03), and lower albumin (p = 0.02). In a multivariable model, CIN was predicted by N-acetylcysteine (p = 0.03) and lower hemoglobin (p = 0.01). Calcineurin inhibitor use was not associated with CIN. At last follow-up, CIN did not affect allograft or patient survival. Conclusion CIN is common in kidney transplant recipients, and there is room for quality improvement with regards to careful renal function monitoring post-contrast exposure. In our study, N-acetylcysteine exposure and lower hemoglobin were associated with CIN. Calcineurin inhibitor use was not associated with CIN. Our sample size is small, however, and larger prospective studies of CIN in renal allografts are needed.

LCP-Tacro is an extended-release formulation of tacrolimus designed for once-daily dosing. Studies in renal transplantation demonstrate greater bioavailability with similar safety and efficacy vs. twice-daily tacrolimus capsules. In this phase 2 study, adult stable liver transplant patients on tacrolimus capsules (Prograf) twice-daily were converted to tacrolimus tablets (LCP-Tacro) once-daily; patients continued on LCP-Tacro once-daily for days 8-21; target trough levels were 5-15 ng/mL; 24-hour pharmacokinetic (PK) assessments were done on days 7 (baseline pre-switch), 14, and 21. A 6 month extension study phase evaluated PK and safety following a total of 52 weeks of LCP-Tacro. Fifty-seven patients completed LCP-Tacro dosing in the core study; 43 completed the extension phase. The mean conversion ratio was 0.71 (Prograf:LCP-Tacro). PK data demonstrated consistent exposure (AUC) at the lower conversion dose. Cmax , Cmax /Cmin ratio, percent fluctuation and swing were significantly (P

Background A prolonged-release formulation of tacrolimus for once-daily administration (tacrolimus QD) has been developed. This phase II, open-label, multicenter, prospective single-arm study compared the pharmacokinetics (PK) of tacrolimus in stable heart transplant patients before and after conversion from twice-daily tacrolimus (tacrolimus BID) to tacrolimus QD. Methods Heart transplant recipients (≥6 months after transplant), previously maintained on tacrolimus BID–based therapy, received tacrolimus BID from Days 1 to 7 and were converted on a 1:1 (mg/mg) basis to tacrolimus QD. Five 24-hour PK profiles were collected (Days 1, 7, 8, 14, 21). Safety parameters were also evaluated. Results Of 85 patients, 45 (50.6%) completed all 5 evaluable PK profiles. Steady-state tacrolimus area under the curve, 0 to 24 hours (AUC 0–24 ) and minimum concentration (C min ) were comparable for both formulations, with treatment ratio means of 90.5% (90% confidence intervals [CI], 86.4%–94.6%) and 87.4% (95% CI, 82.9%–92.0%), respectively (acceptance interval, 80%–125%). There was good correlation between AUC 0–24 and C min for tacrolimus QD ( r = 0.94) and BID ( r = 0.91). The relationship between these 2 parameters was also similar. Conclusions This study provides evidence for successful conversion from tacrolimus BID to QD on a 1:1 (mg/mg) total daily dose basis. Approximately one-third of patients may require dose adjustments. Both formulations were well tolerated, with stable renal function during the study. Adverse events were reported by approximately one-tenth of patients receiving tacrolimus BID and a quarter of those who received QD.

This study assessed the long-term effects of prolonged-release tacrolimus (Advagraf(®) [Tacrolimus QD]), which has been developed to provide similar efficacy and safety to twice-daily tacrolimus (Prograf(®) [Tacrolimus BID]) with the added benefit of once-daily dosing.

Gaber AO, Mulgaonkar S, Kahan BD, Woodle ES, Alloway R, Bajjoka I, Jensik S, Klintmalm GB, Patton PR, Wiseman A, Lipshutz G, Kupiec-Weglinski J, Gaber LW, Katz E, Irish W, Squiers EC, Hemmerich S. YSPSL (rPSGL-Ig) for improvement of early renal allograft function: A double-blind, placebo-controlled, multi-center Phase IIa study. Clin Transplant 2011: 25: 523–533. © 2010 John Wiley & Sons A/S. Abstract: Introduction: Recombinant P-selectin glycoprotein ligand IgG fusion protein, rPSGL-Ig (YSPSL), a fusion protein of human P-selectin ligand and IgG1-Fc, blocks leukocyte adhesion and protects against ischemia reperfusion injury (IRI) in animal models. Patients and Methods: This randomized 15-center, double-blind, 59-patient Ph2a study assessed YSPSL’s safety in recipients of deceased-donor kidney allografts and its potential efficacy in improving early graft function. Two doses and two dosing modalities were evaluated. Results: No drug-specific toxicities or increased adverse event rates were noted. Two YSPSL-treated patients died of causes determined as unrelated to study drug. YSPSL did not reduce the incidence of dialysis within the first week post-transplant (41% in treated vs. 20% in placebo patients). Renal function endpoints scored at post-operative days 1 & 2 were also not impacted by YSPSL. However, at day 5, the fraction of patients with serum creatinine above 6 mg/dL was lower in the YSPSL vs. placebo group (26% vs. 55%, p = 0.043). Large variations in the dialysis-delayed graft function (DGF) rates were observed between centers, independently of treatment assignment, indicating subjectivity of this endpoint. Conclusion: In this first Ph2a study in kidney transplantation, YSPSL was safe but did not impact the dialysis-DGF rate. Further studies with more objective efficacy endpoints are required to define the impact of YSPSL on early renal allograft function.

Background Rapid and complete elimination of donor-specific anti-human leukocyte antigen antibodies (DSA) during antibody-mediated rejection (AMR) is rarely achieved with traditional antihumoral therapies. Proteasome inhibitor-based therapy has been shown to effectively treat refractory AMR, but its use as a primary therapy for AMR has not been presented. Our initial experience with proteasome inhibition as a first-line therapy for AMR is presented. Methods Adult kidney transplant recipients with AMR, diagnosed by Banff criteria, received a bortezomib-based regimen as the primary therapy. Bortezomib therapy was administered per package insert with plasmapheresis performed immediately before each bortezomib dose, and a single rituximab dose (375 mg/m2) given with the first bortezomib dose. DSA were quantitated using single-antigen beads on a Luminex platform. Results Two patients underwent bortezomib-based therapy for acute AMR occurring within the first 2 weeks after transplantation. High DSA levels and positive C4d staining of peritubular or glomerular capillaries were present at the time of diagnosis. Both patients experienced prompt AMR reversal and elimination of detectable DSA within 14 days of bortezomib-based therapy. Renal function remains excellent with normal urinary protein excretion at 5 and 6 months after AMR diagnosis. One patient experienced a repeated elevation of DSA (including two new human leukocyte antigen specificities) 2 months after initial bortezomib therapy, but without C4d deposition or histologic evidence of AMR. Retreatment with bortezomib provided prompt, complete, and durable DSA elimination. Conclusions Proteasome inhibitor-based combination therapy provides a potential means for rapid DSA elimination in early acute AMR in renal transplant recipients.

Background Few prospective trials in human leukocyte antigen (HLA) identical living donor (LD) renal transplantation exist. This prospective study evaluated a corticosteroid (CS)-free, calcineurin inhibitor (CNI) minimization immunosuppressive regimen in HLA-identical LD renal transplant recipients. Methods Twenty HLA-identical LD recipients were prospectively enrolled. Immunosuppression included mycophenolate mofetil (MMF) (2 g/day), tacrolimus (target trough 4-8 ng/mL), sirolimus (target trough 6-10 ng/mL), and no pre- or postoperative steroids. In the absence of prior rejection, tacrolimus was discontinued at posttransplant day 120 and sirolimus at 1 year, leaving patients on MMF monotherapy. Results Tacrolimus was successfully withdrawn in 94% of patients (16/17). One hundred percent (15/15) of patients who reached 1-year posttransplant had sirolimus discontinued. Ninety-four percent (17/18) of patients remain off CSs. Mean serum creatinine at 6, 12, and 24 months were 1.38+/-0.32, 1.35+/-0.37, and 1.25+/-0.29 mg/dL; corresponding mean calculated creatinine clearance estimates were 70+/-18, 73+/-17, and 72+/-15 mL/min. Acute cellular rejection, chronic allograft nephropathy, and CNI toxicity were not observed. Death-censored graft survival was 100% at last follow-up. Conclusions A CS-free, CNI minimization immunosuppressive regimen with weaning to MMF monotherapy provides excellent renal function, graft survival, and patient survival in HLA-identical LD renal transplant recipients.

Background: A great deal of ethical debate has accompanied the introduction of facial tissue allotransplantation into the clinical arena. Critics contend that the risks of lifelong immunosuppression do not justify the benefits of this new non-life-saving reconstructive procedure, whereas proponents argue that they do. Absent from this debate are the opinions of individuals with real-life experiences with the risks and benefits associated with this new treatment. Methods: In this study, the authors question facially disfigured individuals (n = 33) and the reconstructive surgeons who treat them (n = 45), organ transplant recipients (n = 42) and the professionals who manage their immunosuppression medication (n = 37), and healthy volunteer controls (n = 148) to determine the amount of risk they are willing to accept to receive facial tissue allotransplantation. A survey with psychometrically reliable and validated questions was administered to the above five groups, and appropriate statistical analysis was used to analyze and compare the data within and between groups. Results: Of the five groups studied, reconstructive surgeons would accept the least amount of risk for a facial tissue allotransplant, followed by transplant specialists, then kidney transplant recipients, then facially disfigured individuals, and finally healthy control volunteers, who would accept the most amount of risk. Conclusions: The authors' data indicate that reconstructive surgeons are the least tolerant of risks compared with the other groups studied concerning facial tissue allotransplantation. This is particularly important because they are the primary caregivers to facially disfigured patients and, as such, will be the ones to lead the effort to move this new reconstructive treatment into the clinical arena.

Background: Promising data regarding the safety and efficacy of gastric bypass surgery (GBS) as an option to address obesity in the transplant population are emerging. The data lack on how GBS may alter the pharmacokinetics (PK) of modern immunosuppression. The objective of this study was to describe the alterations in the PK of modern immunosuppressants and the GBS population. Methods: Data are presented on six subjects who participated in this trial – four were on dialysis and two were renal transplant recipients. Dialysis-dependent bypass subjects received a single dose of 6 mg of sirolimus, two 4-mg doses of tacrolimus and two 1000-mg doses of mycophenolate mofetil (MMF) over the 24-h study period. Transplant recipients continued their current regimen. Maximum plasma concentration (Cmax), time to reach the maximum plasma concentration (Tmax) and the area under the plasma concentration vs. time curve (AUC0–12 and AUC0–∞ where appropriate) were calculated for tacrolimus, sirolimus, mycophenolic acid (MPA) and mycophenolic acid glucuronide (MPAG). Results: Significant inter-patient variability in the Cmax, Tmax and AUC of tacrolimus, sirolimus MPA and MPAG was observed. A notable difference in the AUC:dose ratio for tacrolimus was seen when comparing data with published data in the non-bypass population. Similar differences in PK were seen with sirolimus, MPA and MPAG. Conclusions: When comparing the PK of sirolimus, tacrolimus, MPA and MPAG to published PK data in the non-bypass population, significant differences are observed. It is likely that transplant recipients with GBS would need higher doses of tacrolimus, sirolimus and MMF to provide similar exposure to a non-bypass patient.

Background: Cardiovascular disease (CVD) is the leading cause of death with a functioning graft in renal transplant recipients. The purpose of this study was to compare Framingham Risk Score (FRS), metabolic syndrome (MS), and cardiovascular events (CVE) in patients receiving early corticosteroid withdrawal (ECSWD), or chronic corticosteroid therapy (CCS). Methods: In all, 251 ECSWD and 146 CCS patients were evaluated. FRS and MS were identified at baseline, six, 12, and 24 months post-transplant. A total of 124 patients with diabetes mellitus prior to transplantation were excluded from MS analysis. CVE were defined as sudden-death, MI, angina, or CVA/TIA. Repeat-measure logistic regression was used for statistical analysis. Results: Fifty-four patients experienced 72 CVE. Mean follow-up was 755 ± 312 d and time to CVE was 14.8 ± 8.3 months. Demographics were similar between groups. FRS was not different between groups. CVE were significantly greater in CCS patients then ECSWD (20% vs. 10%, p = 0.024). New-onset MS occurred more frequently in patients receiving CCS then ECSWD (45% vs. 22%, p

Tacrolimus extended-release (XL) is a once-daily formulation recently developed to reduce the frequency of dosing for patients currently using the twice-a-day formulation of tacrolimus (TAC). As reported previously, 67 kidney transplant recipients were safely converted (1:1 mg basis, total daily dose) from TAC twice-a-day to XL once-daily in the morning and were maintained on an am dosing regimen of XL using the same therapeutic monitoring and patient care techniques currently employed with TAC. The 2-year postconversion patient (100%) and graft (98.5%) survival, incidence of biopsy-confirmed acute rejection (6.0%), incidence of multiple rejections (1.5%), and safety profile (posttransplant diabetes, hyperlipidemia, hypertension, infections, renal dysfunction, hepatic dysfunction, and malignancies) were consistent with or more favorable than those previously reported for TAC twice-a-day.

Renal transplantation in high-risk patients is a growing phenomenon. More patients are progressing to endstage renal failure, in the setting of an increased incidence of diabetes mellitus and cardiovascular disease. Current organ shortages and the use of more marginal donors have affected both patient and graft survival. Acute rejection has been minimised under modern immunosuppression; however, patient and long-term allograft outcomes have not improved concurrently. Specific understanding of donor, recipient and allograft variables associated with stratification of patients as 'high risk for renal transplantation' is necessary to facilitate appropriate peri- and post-transplant pharmacotherapy. Induction and maintenance immunosuppression choices are different for high-risk patients and must be made to ensure optimal immunosuppression, while limiting patient and allograft toxicity.

African-American and elderly kidney transplant recipients (KTR) have increased risk for poor clinical outcomes post-transplant. Management of immunosuppression may be challenging in these patients and contribute to worse outcomes. A novel once-daily formulation of tacrolimus (LCPT) has demonstrated noninferiority, similar safety, improved bioavailability, a consistent concentration time profile, and less peak and peak-trough fluctuations vs. tacrolimus twice-daily (Tac BID). This pooled analysis of two phase 3 randomized, controlled trials, including 861 (LCPT N = 428; Tac BID N = 433; 38% of patients were stable KTR, and 62% were de novo KTR) patients, examined the efficacy of LCPT in KTR subgroups (blacks, females, and age ≥65). Overall, treatment failure [death, graft failure, centrally read biopsy-proven acute rejection (BPAR), or lost to follow-up] at 12 months was as follows: LCPT: 11.9%, BID Tac: 13.4% [-1.48% (-5.95%, 2.99%)]. BPAR rates were as follows: LCPT: 8.2%, Tac BID: 9.5% [-1.29% (-5.14%, 2.55%)]. Numerically, fewer treatment failure events with LCPT were found in the majority of subgroups, with significantly less treatment failure associated with LCPT among black KTR [-13.82% (-27.22%, -0.31%)] and KTR ≥65 [-13.46% (-25.27%, -0.78%)]. This pooled analysis suggests numerically lower efficacy failure rates associated with LCPT among high-risk subgroups, in particular black KTR and KTR ≥65 years old.

Background Long-term outcomes of kidney transplantation with organs from donors with disseminated intravascular coagulation (DIC) are comparable with those from other deceased donors. The use of tranexamic acid to impair fibrinolysis in the treatment of DIC is becoming increasingly frequent, particularly in the trauma setting. However, the effects of tranexamic acid on a transplanted kidney allograft are unknown. Results We report 2 cases of kidney transplantation following administration of tranexamic acid to the donor prior to organ donation. Microthrombi were present in the renal allografts. Both recipients experienced clinically significant hemolytic anemia, which typically occurs at a very low frequency. Conclusions These cases illustrate a potential concern for the use of tranexamic acid in deceased kidney donors with DIC.

Malignancy is a well defined complication of chronic immunosuppression. Post transplant malignancies appear to be related to cumulative doses of immunosuppression, and in pediatric patients, acute infection of previously naive patients. The most commonly encountered malignancy in this age population is Post Transplant Lymphoproliferative Disorder (PTLD). PTLD is not a single entity but rather represents a continuum of disease. Treatment of PTLD should be initiated with immunosuppression reduction. Standard dose chemotherapy leads to significant morbidity. With the introduction of anti-CD20 antibody treatment with rituximab, chemotherapy has become second line therapy. The occurrence of solid malignancy appears to be associated with chronic immunosuppression. These cancers include those of skin, gynecologic organs, and the rectum, all of which appear to have the strongest association with viral mediators. Several strategies have been postulated to minimize the occurrence of malignancy. These include ganciclovir prophylaxis for the prevention of PTLD and the use of mychophenolic acid and TOR inhibitor maintenance to diminish the incidence of PTLD and solid malignancies. This leaves transplant physicians with several new and novel immunosuppressive agents with uncertain oncologic potentials that will need to be examined over the next decade.

Summary Steroids and calcineurin inhibitors (CNI) have been mainstays of immunosuppression but both have numerous side effects that are associated with substantial morbidity and mortality. This study was carried out to determine if steroids can be eliminated with early discontinuation of cyclosporine A (CsA) and later discontinuation of mycophenolate mofetil (MMF). Ninety-six patients with kidney transplants were entered into four subgroups of two pilot studies. All patients received Thymoglobulin® induction, rapamycin (RAPA), and the immunonutrients arginine and an oil containing ω-3 fatty acids. Mycophenolate mofetil was started in standard doses and discontinued by 2 years. CsA was given in reduced doses for either 4, 6, or 12 months. Follow-up was 12–36 months. Thirteen first rejection episodes occurred during the first year (14%). Combining all patients, 86% were rejection-free at 1 year, 80% at 2 years and 79% at 3 years. No kidney has been lost to acute rejection. Ninety percent of the 84 patients at risk at the end of the study were steroid-free and 87% were off CNI. Fifty-seven percent of 54 patients with a functioning kidney at 3 years were receiving monotherapy with RAPA. We conclude that this therapeutic strategy is worthy of a prospective multi-center clinical trial.

This is a report of outcomes at 36 months of a prospective, multicenter study comparing the safety and efficacy of two dosing regimens of daclizumab with no antibody induction in simultaneous kidney–pancreas transplant (SKPT) patients receiving tacrolimus, mycophenolate mofetil, and prednisone. A total of 298 SKPT patients were randomized into one of three groups: daclizumab 1 mg/kg/dose every 14 days for 5 doses (group 1, n = 107); daclizumab 2 mg/kg/dose for 2 doses (group 2, n = 113); and no antibody induction (group 3, n = 78). There were no differences in baseline characteristics among the three groups, and results were analyzed by an intent-to-treat analysis. The incidence of composite events (acute rejection [AR], any allograft lost, or death) at 3 years was 49%, 43%, and 55% in groups 1, 2, and 3, respectively (P = .278). The cumulative incidences of AR were not statistically different among the three groups (P = .178). The mean time to first AR was delayed in groups 2 (288 days) and 1 (245 days) compared to group 3 (145 days, P = .07). There were no differences in patient or allograft survival rates among the three groups, and the rates of serious adverse events, infections, and hospital readmissions were also comparable. Excellent dual graft function in patients with surviving grafts was observed in all three groups at 3 years. Conclusions The alternative 2-dose regimen of daclizumab was as safe and effective as the conventional 5-dose regimen compared to no antibody induction in SKPT patients, but no long-term benefits were noted.

Significant mortality is associated with post-transplant lymphoproliferative disorder (PTLD) in kidney transplant recipients (KTX). Univariate/multivariate risk factor survival analysis of US PTLD KTX reported to Israel Penn International Transplant Tumor Registry from November 1968 to January 2000 was performed. PTLD presented 18 (median) (range 1-310) months in 402 KTX. Death rates were greater for those diagnosed within 6 months (64%) versus beyond 6 months (54%, p = 0.04). No differences in death risk for gender, race, immunosuppression, EBV, B or T cell positivity were identified. Death risk increased for multiple versus single sites (73% vs. 53%, hazards ratio (HR) 1.4). A 1-year increase in age increased HR for death by 2%. Surgery was associated with increased survival (55% vs. 0% without surgery) (p < 0.0001). Patients with allograft involvement, treated with transplant nephrectomy alone (n = 20), had 80% survival versus 53% without allograft removal (n = 15) (p < 0.001). Overall survival was 69% for allograft involvement alone versus 36% for other organ involvement plus allograft (n = 19 alive) (p < 0.0001). Death risk was greater for multiple site PTLD and increasing age, and risks were additive. Univariate analysis identified increased death risk for those not receiving surgery, particularly allograft involvement alone.

Background. Posttransplant lymphoproliferative disorder (PTLD) is a life-threatening complication that occurs in a small but significant minority of solid organ transplant recipients. Published experiences with PTLD in cardiac transplant recipients are limited to relatively small single-center reports. Methods. This report presents experience with 274 cases of PTLD in cardiac transplant recipients reported to the Israel Penn International Transplant Tumor Registry (IPITTR). Results. PTLD carried an ominous prognosis: Kaplan Meier survival after PTLD diagnosis was 45%, 33%, 30%, and 13%, respectively, at 1, 3, 5, and 10 years. Common causes of death included: PTLD, cardiovascular collapse, and infection; all occurred at a median of less than 6 months. Risk of death from cardiovascular collapse secondary to immunosuppression withdrawal was substantial (28%), indicating that a fine balance exists between death from PTLD and from sudden cardiac death due to acute rejection. PTLD therapy in the majority of patients consisted of combination therapy (49%). Survival in patients receiving immunosuppression minimization (ISM) alone was 32%, with ISM plus other therapy was 27%, and with other therapies not containing ISM was 11% (P Conclusion. PTLD in cardiac transplant recipients is associated with low long-term survival rates. Analysis of PTLD therapies and outcomes suggest that immunosuppression minimization, when applied, improves survival. However, risk of sudden death may mitigate the positive effect of ISM. This observation has important implications for ISM in PTLD therapy in cardiac transplant recipients. Carefully designed prospective studies are needed to evaluate the positive and negative effects of ISM in cardiac transplant recipients with PTLD.

This study defines the incidence and recurrence risk of Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL) after organ transplant. Patients from the United States with a history of HD or NHL before organ transplantation reported to the Israel Penn International Transplant Tumor Registry from 1968 to 2001 were analyzed. A total of 91 patients underwent organ transplantation with a lymphoma history: HD (38 patients) and NHL (53 patients). Median disease-free interval pretransplant was 99 (range 0-459.1) months, and median follow-up posttransplant was 25.7 (0.4-131.1) months. Ten patients were excluded from further analysis because of lack of follow-up information (n=9) or they never achieved remission (n=1). Recurrence incidence was 8 of 81 patients (10%) (HD=3/34 [9%] vs. NHL=5/47 [11%]). Gender, race, allograft type and source, age at lymphoma diagnosis, and immunosuppression did not influence recurrence. Patients with less than a 2-year period between diagnosis and transplant seem to be at increased risk of relapse. Median disease-free interval before transplant was longer for patients without recurrence (115 vs. 30.2 months, P=0.24), but was not statistically significant. Median time to recurrence posttransplant was 18.7 (range 1.9-82.2) months (HD=3.7 vs. NHL 23.6 months, P=0.10). Survival after recurrence was poor (HD [1/3] and NHL [1/5], median survival 6.8 [range 0-22.1] months). There is no difference in recurrence rates for HD and NHL. The outcome for recurrent lymphoma is poor. The low risk of recurrence (10%) indicates that preexisting HD and NHL need not be an absolute contraindication to transplantation.

Background. In an era of organ shortage, the use of expanded or marginal donors has been attempted to increase transplantation rates and diminish waiting list mortality. One strategy is the use of organs from patients with a history of or active central nervous system (CNS) tumor. Methods. Sixty-two recipients were identified as the recipients of organs from donors with a history of or active CNS malignancy. Patient demographics, donor tumor management, incidence of tumor transmission, and patient survival were examined. Results. Of the organs recovered and transplanted from donors with astrocytoma, 14 were associated with at least one risk factor including high-grade tumor (n=4), prior surgery (n=5), radiation therapy (n=4), and systemic chemotherapy (n=4). One tumor transmission was identified at 20 months posttransplant with the patient expiring from metastatic disease. Twenty-six organs were transplanted from glioblastoma patients with 15 demonstrating risk factors including high-grade tumor (n=9) and prior surgery (n=10). Eight transmissions were identified with a range of 2 to 15 months posttransplant, with seven patients dying as the result of metastatic disease. Seven organs were used from donors with a medulloblastoma. Three transmissions were identified at a range of 5 to 7 months, all associated with ventriculoperitoneal shunts. Two medulloblastoma recipients died as the result of metastatic disease, whereas the third is alive with diffuse disease. The rate of donor tumor transmission, in the absence of risk factors, was 7%, whereas in the presence of one or more risk factor this rate dramatically rose to 53% (P Conclusions. Organs from donors with CNS tumors can be used with a low risk of donor tumor transmission in the absence of the following risk factors: high-grade tumors, ventriculoperitoneal or ventriculoatrial shunts, prior craniotomy, and systemic chemotherapy.

Background. Controversy exists about the optimal immunosuppressive regimen in simultaneous kidney-pancreas transplant (SKPT) recipients. This study determined the safety and efficacy of two dosing regimens of daclizumab compared with no antibody induction in SKPT recipients receiving tacrolimus, mycophenolate mofetil, and steroids. Methods. A total of 297 SKPT patients were enrolled in this prospective, multicenter, randomized, open-label study. The patients were randomized into three groups: daclizumab 1 mg/kg per dose every 14 days for five doses (group I, n=107), daclizumab 2 mg/kg per dose every 14 days for two doses (group II, n=112), and no antibody induction (group III, n=78). All patients received tacrolimus, mycophenolate mofetil, and steroids as maintenance immunosuppression. Results. Demographic and transplant characteristics were similar among the groups. At 6 months, there were no differences in patient, kidney, and pancreas graft survival rates among the three groups. The probability of either kidney or pancreas allograft rejection at 6 months was 21%, 17%, and 32% in groups I, II, and III, respectively (P=0.042). The median time to first acute rejection of either the kidney or pancreas was 23 days in group I, 44 days in group II, and 20 days in group III (group I vs. II, P=0.078; group II vs. III, P=0.016). At 6 months, the actuarial event-free survival (no acute rejection, allograft loss, or death) rates were 66%, 77%, and 56% in groups I, II, and III, respectively (group I vs. III, P=0.119; group II vs. III, P=0.002). There were no differences in the incidence of serious adverse events including infectious complications among the groups. All three groups demonstrate excellent kidney and pancreas function at 6 months. Conclusions. Daclizumab is safe and effective in reducing the incidence of acute rejection in SKPT recipients compared with no antibody induction. Moreover, the two-dose regimen of daclizumab (2 mg/kg on days 0 and 14) compares favorably with the standard five-dose regimen.

Purpose. To report the incidence and clinical characteristics of polyomavirus (PV) nephritis in kidney (KTX) and kidney–pancreas transplant (KPTX) recipients. Methods. Single center retrospective analysis of all cases of PV nephritis in KTX and KPTX patients transplanted between 1994 and 1999. Results. Thirteen (5 KTX and 8 KPTX) patients (2.1%) had PV nephritis diagnosed on multiple biopsies (n = 22) among 504 KTX and 106 KPTX recipients. The incidence of PV nephritis was higher in cadaver donor transplants (2.6% cadaver vs. 0.7% living donors), after KPTX (1% KTX vs. 7.5% KPTX), in males (3.3% male vs. 0.7% female), and in diabetic patients (4.4% diabetic vs. 0.8% nondiabetic). The mean time to diagnosis of PV nephritis was 18 (range 6–48) months after KTX and 17 (range 9–31) months after KPTX. Three KTX patients and 5 KPTX patients had calcineurin inhibitor toxicity on biopsy prior to developing PV nephritis. Reduction in immunosuppression occurred in 100% of KTX and 63% of KPTX patients. Three patients (23%) developed rejection within 3 months of diagnosis of PV, 1 after a reduction in immunosuppression. Despite multiple antiviral treatment regimens, renal allograft failure requiring dialysis occurred in 60% of KTX and 50% of KPTX patients. All KPTX patients remain insulin independent and 2 were successfully retransplanted with living donor kidneys. 2 patients (15%) died but there was no mortality directly related to the virus. Conclusions. Polyomavirus nephritis may be increasing in incidence and appears to be unresponsive to either conventional antiviral agents or a reduction in immunosuppression. Most of our cases occurred in male diabetic patients undergoing cadaveric donor transplantation and were preceded by biopsy-proven nephrotoxicity. Further studies are needed to better define the pathogenesis of PV and effective antiviral treatment.

Purpose: To review the safety and efficacy of thymoglobulin in pancreas transplant patients receiving tacrolimus and mycophenolate mofetil. Methods: Retrospective, single centre analysis of 45 patients transplanted between 1995 and 2000 who received 54 courses of thymoglobulin, including 36 courses in 29 solitary pancreas transplant recipients (16 pancreas alone, 13 pancreas after kidney transplants) and 18 courses in 16 simultaneous kidney-pancreas transplant patients. Thirty-two patients (71%) were primary pancreas transplants, 10 (22%) were second transplants and three (7%) were third transplants. Of the 54 treatment courses, 19 (35%) were for induction, 27 (50%) were for primary rejection and eight (15%) were rescue therapy for rejection. All rejection episodes were biopsy-proven in at least one organ. Results: The median thymoglobulin dose was 1.5 mg/kg/d with a mean of six doses (range 3-10). Dose reduction or interruption was required in 28 courses (52%), most often due to leukopenia (n = 24), fever (n = 2) and thrombocytopenia (n = 2). Thymoglobulin was d in all but three patients, two with persistent fever and one with infection. Infectious complications (n = 25) occurred in 17 patients (38%) within 30 days and included bacterial (n = 16), cytomegalovirus (n = 4), polyoma (n = 1), fungal (Candida albicans, n = 1), toxoplasmosis (n = 1) and ehrlichiosis (n = 2). Post-transplant lymphoproliferative disease occurred in two patients (4%) at a mean of 70 d post-thymoglobulin treatment. In the 19 patients that received thymoglobulin induction, one simultaneous kidney-pancreas transplant, two pancreas alone and four pancreas after kidney transplant recipients developed rejection (37% incidence), while all remaining patients followed by surveillance protocol biopsies were rejection-free. In the 35 patients that received thymoglobulin for rejection, reversal occurred in 26 of the patients (74%). Rejection recurred within 30 d in five patients and post-treatment biopsies revealed persistent rejection in three of 20 pancreas and two of eight renal biopsies. After a mean follow-up of 6 months, the actual patient and pancreas graft survival rates were 93% and 71%, respectively. Conclusion: Thymoglobulin was effective as induction therapy in high-risk pancreas transplant recipients, and resulted in initial reversal of rejection in 74% of patients. Dose adjustments were required in over half the cases and were usually due to leukopenia. Infections occurring subsequent to thymoglobulin were not uncommon and reflected the immunosuppressive burden of the patient population.

Passive immunoprophylaxis with hepatitis B immunoglobulin (HBIG) is important to prevent recurrence of hepatitis B virus (HBV) after orthotopic liver transplantation (OLT) for chronic HBV cirrhosis. With availability of lamivudine (3TC), the use of combination prophylaxis with long-term HBIG/3TC has been shown to prevent short-term HBV recurrence. This report compares HBV recurrence rates between groups receiving no/short-term HBIG, long-term HBIG alone, or HBIG/3TC prophylaxis, and describes HBIG requirements during the first 6 and 12 months in the latter two groups. This study involved patients undergoing OLT at the University of Tennessee-Memphis between May 1990 and July 2001. During this period, 388 liver transplants were performed at our center. All hepatitis B surface antigen (HBsAg)-positive recipients (n = 27) were included in this retrospective analysis. The groups were similar with regard to pre-transplant demographic characteristics such as age, gender, weight, and pre-transplant diagnosis. Owing to the retrospective study design, median follow-up was longer for the no-prophylaxis (5.6 years) and the HBIG-alone (6.0 years) groups compared to the HBIG/3TC group (4.2 years). Patient survival was 50% in the no-prophylaxis and 71% in the HBIG-alone groups compared to 100% in the HBIG/3TC group (P = 0.09). When censored for death with a functioning graft, graft survival was 50% in the no-prophylaxis and 86% in the HBIG-alone group compared to 100% in the HBIG/3TC group (P = 0.07). The overall incidence of HBV recurrence in the no-prophylaxis era was 100% and 21% in the HBIG-alone era compared to 0% in the HBIG/3TC era (P < 0.001), despite similar mean and median HBIG trough titers in the HBIG-alone and HBIG/3TC groups. The incidence of HBV recurrence in HBV DNA-positive recipients was 100% in the no-prophylaxis era, 30% in the HBIG-alone era, and 0% in the HBIG/3TC era (P < 0.001). Recipients in the HBIG-alone group had a nearly two-fold increase in HBIG requirement at 6 and 12 months in order to maintain similar HBIG trough titers post-transplant compared to recipients in the HBIG/3TC group despite similar pre-transplant HBV serology. This increased HBIG requirement in the HBIG-alone group resulted in a marked increase in the mean overall cost of HBV prophylaxis in this group ($47,367 US dollars at 6 months; $84,280 US dollars at 12 months) compared to the HBIG/3TC group ($25,931 US dollars at 6 months; $49,599 US dollars at 12 months). These data demonstrate an improvement in patient and graft survival rates in the group receiving combination HBIG/3TC prophylaxis compared to the HBIG-alone and no-prophylaxis groups. There was a significant reduction in HBV recurrence in the group receiving combination HBIG/3TC when compared to the groups receiving HBIG alone or no prophylaxis. Furthermore, we demonstrated that the addition of 3TC to the long-term HBIG regimen led to elimination of the disparity previously described in HBV recurrence rates between HBV DNA-positive and HBV DNA-negative recipients. Importantly, our data demonstrates a complete lack of HBV recurrence in the HBIG/3TC group at a median follow-up of 4.2 years. Additionally, the data show that the addition of 3TC to the post-operative prophylaxis regimen resulted in a reduction in the requirement of HBIG at 6 and 12 months, which markedly reduced the overall cost of post-transplant HBV prophylaxis.

Available data suggest that hepatitis C virus positive (HCV+) renal transplant patients may be at an increased risk of morbidity and mortality compared with HCV- patients. Limited data are available regarding the impact of HCV status in pancreas transplant patients. We compared the outcomes of 10 HCV+ patients undergoing pancreas transplantation (seven simultaneous kidney-pancreas, one pancreas after kidney, two pancreas alone) between 1/96 and 10/99 with 20 HCV- recipients that were matched for age, race, gender, timing of transplant, type of pancreas transplant, and surgical technique. Length of follow-up was not significantly different between the HCV+ group compared with the HCV- group (24 +/- 14 vs. 20 +/- 13 months; p=0.45). There was a trend toward a higher incidence of all cause mortality in HCV+ recipients compared with HCV- recipients, 30 vs. 10%, respectively (p=0.17). Additionally, the HCV+ recipients had a trend toward a higher incidence of sepsis-related mortality compared with HCV- recipients, 20 vs. 5%, respectively (p=0.19). Renal allograft survival was 50% in the HCV+ group compared with 94% in the HCV- group (p=0.02). Pancreas allograft survival was not significantly different between the groups, 60 vs. 80%, respectively (p=0.24). At 3, 6, 12 months, and end of follow-up, there were no differences in serum creatinine, amylase, C-peptide, or fasting glucose levels. However, there was a significantly higher incidence of proteinuria at last follow-up in the HCV+ recipients with a renal allograft when compared with HCV- recipients, 50 vs. 12.5%, respectively (p=0.05). In order to maintain comparable glycemic control between the groups, there was a significant increase in oral hypoglycemic requirement in HCV+ recipients compared with HCV- recipients, 33 vs. 0%, respectively (p=0.01). These data suggest that HCV+ pancreas transplant patients may be at an increased risk of graft dysfunction and morbidity. Further studies with more patients and longer follow-up are needed to fully define the impact of HCV status on pancreas graft survival and function.

Background Severe obesity has been shown to limit access to renal transplantation in patients with end stage renal disease (ESRD). Laparoscopic sleeve gastrectomy (LSG) has been performed in the ESRD population to assist in achieving waitlist and transplant eligibility. Little is known about how LSG impacts the bioequivalence tacrolimus products and immunosuppression pharmacokinetics. Methods This was a prospective, open-label, single-dose, crossover, two-period pharmacokinetic (PK) study. The purpose of this study was to assess single-dose PK of immediate-release tacrolimus (IR-TAC), extended-release tacrolimus (ER-TAC), and mycophenolic acid (MPA) in adult ESRD patients post-LSG. Results Twenty-three subjects were included in the 24-hour PK assessments. The ratio of geometric means between ER-TAC and IR-TAC was 103.5% (90% CI 89.6 – 119.6%) for AUC0-24 and 92.5% (90% CI 80.4 – 106.4%) for Cmax. PK parameters were similar between ER-TAC and IR-TAC, except for Cmin (p=0.004) and Cmax (p=0.04). MPA AUC0-24 was similar when given with either ER-TAC or IR-TAC (p=0.32). Patients expressing CYP3A5*1 genotypes had lower tacrolimus AUC0-24 values versus those with CYP3A5*3/*3 (IR-TAC p

We report an experience with 71 simultaneous kidney-pancreas transplant (SKPT) recipients receiving daclizumab induction in combination with tacrolimus (TAC), mycophenolate mofetil (MMF), and steroids. The mean follow-up time was 5.9+/-2.5 (SD) months (range 0.5-11 months). The study population included 47 males (65%) and 24 females (35%) with a mean age of 40+/-8 years. The mean pretransplant duration of diabetes and dialysis were 25+/-8 and 1.5+/-0.9 years (34 hemodialysis, 16 peritoneal dialysis), respectively. Mean HLA match was 1.2+/-1.5, with one patient receiving a second transplant. The mean cold ischemic times for the kidney and the pancreas were 15+/-5 and 16+/-4 hr, respectively. Six-month patient, kidney, and pancreas graft survival and rejection rates were 97, 96, 93, and 35%, respectively. There were two deaths, one due to fungal infection and the other due to a cardiac event. There were three kidney graft losses, two immunological, and one death with function. Of the five pancreas graft losses, two were due to infection, one immunological, one thrombosis, and one death with function. The patient population was then stratified according to the number of daclizumab doses: 4-5 doses (n=45) or 1-3 doses (n=26). There were no differences in patient and kidney graft survival rates, 98 vs. 96%, and 92 vs. 92%, respectively. However, there was a trend toward improved pancreas graft survival in the group receiving 4-5 doses (96%) compared with 1-3 doses (85%), P=0.07. Although more patients receiving 1-3 doses had rejection (54%) than patients receiving 4-5 doses (24%), there was no dose response relationship between the total number of doses or the adjusted total mg/kg dose and time to rejection. All patients with functioning grafts have good renal and pancreas allograft function at 6 and 12 months. The overall incidence of major infection was 27% and there were no differences in the incidence of infection between the two groups. No major adverse events were attributed to daclizumab use. In conclusion, excellent short-term outcomes were noted in this retrospective, multicenter survey of initial experience with daclizumab induction in combination with TAC, MMF, and steroids in SKPT recipients. Optimal dosing strategies for SKPT recipients remain to be determined.

Transplantation has enhanced the quality of life of all transplant recipients, but concern remains regarding the side effects of immunosuppressant drugs. In order to respond to these concerns, a survey to ascertain the side effect profile of transplant recipients was undertaken to identify the impact of chronic immunosuppression on quality of life. A nationwide survey of solid organ transplant recipients was carried out using a newly developed immunosuppressant side effect survey. Kidney, kidney-pancreas, liver and heart recipients responded to the survey (n = 505) and reflect the national distribution based on the UNOS data for organ type, recipient race and gender. The survey had four subscales: emotional burden, life/role responsibilities, mobility and GI distress. A fifth subscale included miscellaneous side effects that are more prevalent during the first 2 years post-transplant. Frequency and severity of each side effect were coded on a scale of 0-4 from 'no problem' to 'always' a problem. The entire range of possible scores (0-160) was reported, reflecting adequate variability in the responses. The sample consisted of 51% males, 77% Caucasians, 15% African Americans, with the remaining 8% other races. There were 225 (44.5%) kidney, 147 (29.1%) liver, 101 (20%) heart and 32 (6.4%) pancreas included. Age ranged from 18-71 years with time since transplant 1-21 years. Overall frequency (12.1 +/- 6.08), severity (10.5 +/- 6.96) and weighted scores (25.4 +/- 19.9) were low suggesting that, as a whole, immunosuppressant side effects, while present, were not severe or troublesome for most patients. Side effect profiles appeared similar among organ types. Differences were detected in the GI distress subscale with the heart recipients reporting significantly less GI distress than liver recipients (13.8 vs. 19.2; P

Introduction. Previous studies have suggested that African-American (AA) ethnicity is a risk factor for rejection and graft loss after kidney transplantation. However, little data is available regarding outcomes after simultaneous kidney-pancreas transplantation (SKPT) in AA recipients. The objective of this study was to compare the outcomes of SKPT in AA patients to matched Caucasian patients as controls. Methods. From January 1996 to September 1999, we performed 79 SKPTs, including 10 in AA recipients. Ten Caucasian controls were selected and matched for age, gender, weight, timing and technique of transplantation, and immunosuppressive regimen. Clinical outcomes were collected and compared between the two groups. Results. The two groups were well matched for donor and recipient demographic, immunologic and transplant characteristics, including 2 patients in each group with type 2 diabetes. All patients received tacrolimus (TAC). mycophenolate mofetil (MMF) and steroids, and about half in each group received antibody induction therapy. Patient survival was 100% in both groups with a mean follow-up of 18 months (range 6-47). Kidney and pancreas graft survival rates were both 80% in the AA and 100% in the Caucasian groups, respectively (p = 0.14). All but one kidney (in the AA group) and all pancreas grafts experienced immediate function. There were two immunologic kidney and two immunologic pancreas graft losses in the AA group. No grafts were lost due to technical problems. The mean length of initial hospital stay was 16 d in the AA group compared to 10 d in the Caucasian group (p = 0.07). The AA group had a slight increase in the number of readmissions (mean 2.2 AA vs. 1.6 Caucasian, p = 0.08). The incidence of biopsy-proven pancreas acute rejection was significantly higher in the AA group (50%) compared to the Caucasian group (10%) (p = 0.05). The incidence of either kidney or pancreas acute rejection was also higher in the AA group (60% AA vs. 20% Caucasian, p = 0.06). TAC levels were comparable at specific times after transplantation, although there was a trend toward higher doses of TAC in the AA group to achieve therapeutic levels. The incidences of relaparotomy (30% AA vs. 20% Caucassian) and major infection (40% AA vs. 60% Caucassian) were similar between groups. Renal and pancreas allograft functions were comparable between groups at specific times after transplantation. Conclusions. These results suggest that SKPT in AA recipients may be associated with a higher incidence of rejection and immunologic graft loss compared to matched Caucassian controls.

In an effort to ameliorate the problem of orthostatic hypotension in pancreas transplant patients, current medical management consists of maximizing the patient's hydration, altering antihypertensives, increasing sodium intake, initiation of fludrocortisone, compression stockings, and behavioral modifications. Despite these medical interventions, a subset of patients remains symptomatic. Midodrine (ProAmatine), an alpha-adrenergic agonist, was approved for the treatment of symptomatic orthostatic hypotension in the US. This preliminary report attempts to assess the safety and efficacy of midodrine use in kidney/pancreas (KP) or pancreas alone (PA) transplant recipients. A retrospective review was performed of 7 KP and 1 PA recipient experiencing symptomatic postural hypotension after maximizing other medical treatments. Blood pressure, serum creatinine (SrCr), and objective responses to postural hypotension were assessed at routine intervals. Pre-midodrine monitoring revealed a mean orthostatic change in systolic blood pressure from sitting to standing of 43 mmHg (range 20-100 mmHg). Patients received a mean starting midodrine dose of 18 mg/d, which was titrated to a maximum dose of 30 mg/d. Systolic blood pressure monitoring revealed a mean orthostatic change of 27 mmHg (range 0-81 mmHg) after initiation of treatment with midodrine and a mean follow-up of 3.2 months. All study patients reported improvement in symptoms of orthostatic hypotension. SrCr was not affected based upon comparison of pre-treatment and current SrCr values of 1.4 and 1.3 mg/dL, respectively. The most common side effect experienced was supine hypertension. These preliminary results suggest that midodrine is safe and effective in transplant recipients; however, the dosage should be titrated to symptomatic relief or a maximum dose of 30 mg. Careful monitoring for supine hypertension is necessary.

Background: Despite recent advances, surgical complications remain an important source of morbidity after pancreas transplantation (PTX). Several previous studies have delineated the surgical complications after PTX with systemic-bladder (S-B) drainage, but data are limited regarding the incidence and outcomes of surgical complications after PTX with portal-enteric (P-E) drainage. Study Design: We retrospectively studied surgical complications after 83 vascularized PTXs with P-E drainage in 79 patients (65 simultaneous kidney-PTXs [SKPT] and 18 solitary PTXs [SPT], 8 pancreas alone and 10 pancreas after kidney transplantation). Twelve (15%) were retransplants. A surgical complication was defined as the need for repeat laparotomy within the first 3 months after PTX. Results: A total of 53 surgical complications requiring repeat laparotomy occurred in 31 patients (37%). The incidence of surgical complications in SKPT and SPT was 38% and 33%, respectively. The most common indications for repeat laparotomy were: vascular thrombosis in 13% (SKPT 14% and SPT 11%), intraabdominal infection in 10% (SKPT 12% and SPT 0%), intraabdominal bleeding in 8% (SKPT 8% and SPT 11%), and duodenal allograft leak in 4% (SKPT 3% and SPT 6%). Patient survival rates at 1 and 3 years with versus without surgical complications were 84% and 80% versus 94% and 86%, respectively (p = NS). Pancreas graft survival rates at 1 and 3 years with versus without surgical complications were 48% and 44% versus 89% and 76%, respectively (p Conclusions: Surgical complications after PTX are common, and their incidence and outcomes with P-E drainage are similar to those with S-B drainage. The complication rate does not vary according to the type of transplant (SKPT versus SPT). Increasing experience with P-E drainage results in a decreased incidence of surgical complications.

Between 1966 and 1997, over 10 000 pancreas transplants were performed worldwide, 88% of these being simultaneous kidney-pancreas transplantations (SKPTs). The overall 1-year patient survival rate exceeds 90%, and the graft survival (complete insulin independence) rate is 80%. SKPT should be regarded as the treatment of choice in carefully selected patients with type 1 (insulin-dependent; IDDM) diabetes mellitus and advanced nephropathy, because of its ability to offer superior glycaemic control and an improved quality of life. Studies have shown that the addition of a pancreas transplant does not appear to jeopardise either the patient or the kidney transplant, as many centres report either similar or improved survival rates after SKPT compared with kidney transplantation alone. Indications for solitary pancreas transplantation are based on the presence of early, well defined diabetic complications or glucose hyperlability with poor quality of life. Improvements in quality of life and possible prevention of further morbidity associated with diabetes makes pancreas transplantation an important therapeutic option for selected diabetic patients. According to registry data from the United Network for Organ Sharing (UNOS) Registry, rejection accounts for 32% of graft failures in the first year after pancreas transplantation. Most pancreas transplant centres employ quadruple drug immunosuppression with antilymphocyte induction with either a monoclonal or polyclonal agent. Maintenance immunosuppression involves triple therapy, consisting of a calcineurin inhibitor (cyclosporin or tacrolimus), corticosteroids and an antimetabolite (azathioprine or mycophenolate mofetil). Before 1995, nearly all pancreas transplant recipients were managed with the original formulation of cyclosporin ('Sandimmun'). In the past 2 years, tacrolimus-based therapy has been used in approximately 20% of cases and a new microemulsion formulation of cyclosporin ('Neoral') has replaced the original formulation in contemporary post-transplant immunosuppression. In addition, mycophenolate mofetil is replacing azathioprine as part of the standard immunosuppressive regimen after pancreas transplantation. At present, a number of centres are conducting various trials with new drug combinations including either cyclosporin microemulsion or tacrolimus in combination with corticosteroids and mycophenolate mofetil with or without antibody induction therapy. The current array of new immunosuppressive agents is providing more effective control of rejection and permitting solitary pancreas transplantation to become an accepted treatment option in diabetic patients without advanced complications. Immunosuppressive strategies will continue to evolve to achieve effective control of rejection while minimising injury to the allograft and risk to the patient. In addition, new regimens must not only address the issue of specific drug toxicities but also long term economic, metabolic and quality-of-life outcomes.

The aim of this study was to determine the impact of ethnicity on the major endpoints of a prospective, multi-center, randomized trial of 2 dosing regimens of daclizumab compared with no antibody induction in simultaneous kidney-pancreas transplantation (SKPT). A total of 298 patients were randomized into 3 groups: daclizumab 1 mg/kg/dose every 14 days for 5 doses (Group I, n = 107), daclizumab 2 mg/kg/dose every 14 days for 2 doses (Group II, n = 113), and no antibody induction (Group III, n = 78). All patients received tacrolimus (TAC), mycophenolate mofetil (MMF), and steroids. Thirty-seven patients (12.4%) were African American (AA) and 261 were non-African American (NAA). Demographic and transplant characteristics were comparable between AA and NAA patients. At 3 years, there were no differences in patient, kidney, or pancreas graft survival rates. Rejection rate was similar between AA and NAA. Although mean serum creatinine (SCr) levels at 1 year were comparable between AA and NAA patients (AA 1.5 mg/dL vs NAA 1.3 mg/dL; P = .23), by 3 years AA patients had higher mean SCr levels (AA 2.1 mg/dL vs NAA 1.5 mg/dL; P.0001) and lower calculated glomerular filtration rate (GFR) (AA 45 mL/min vs NAA 56 mL/min; P = .01). Mean HgbA1C, total cholesterol, and diastolic blood pressure (BP) were higher in AA patients at 3 years, compared with NAA patients. In conclusion, in this study, AA patients had worse late functional and metabolic outcomes after SKPT compared with NAA patients. Further longitudinal follow-up is needed to determine the ultimate impact of these findings on long-term patient and graft survival.

The metabolic syndrome (MS) has been implicated as an important nonimmunologic risk factor for chronic renal transplant dysfunction. The aim of this study was to determine the impact of the MS on outcomes in simultaneous kidney-pancreas transplantation (SKPT). Data were available on 241 patients enrolled in a prospective, multicenter randomized study of daclizumab compared with no antibody induction in SKPT. Presence of MS before and after SKPT was defined using NCEP-ATP III (National Cholesterol Education Program Adult Treatment Panel III) criteria. Body mass index (BMI) was used as a surrogate for waist circumference. MS was present in 59% of patients pretransplantation but only in 19% of patients 1 year after SKPT (P < .0001). Demographic and transplant characteristics were well matched for those with MS (MS+) and without MS (MS-) at 1 year. Presence of MS at 1 year was associated with the following changes at 3 years: increased serum creatinine level (1.65 mg/dL MS- vs 2.05 mg/dL MS+; P = .13); decreased modification of diet in renal disease calculated glomerular filtration rate (GFR; 58 mL/min MS- vs 48 mL/min MS+; P = .02); increased HgbA1C level (5.6% MS- vs 6.6% MS+; P < .001); and lower pancreas graft (PG) survival rate (88% MS- vs 71% MS+; P = .01). Linear regression analysis identified MS+ and the subgroup of MS+ without functioning PG at 1 year as independent risk factors for renal dysfunction, whereas MS+ with functioning PG at 1 year was not a risk factor for renal dysfunction. Presence of MS at 1 year is associated with long-term renal dysfunction after SKPT. Efforts to decrease early PG failure may help mitigate against MS-associated renal dysfunction.

Despite intensive traditional immunosuppressive therapy, rates of graft loss have approximated 15% to 20% at 1 year following antibody-mediated rejection (AMR) in solid organ transplant recipients. Therefore, the development of antihumoral therapies that provide prompt elimination of donor-specific anti-HLA antibodies and improve allograft survival is an important goal. Traditional treatment modalities for AMR deplete B-cell populations but not the cell at the source of antibody production, the mature plasma cell. Plasma cell-targeted therapies using proteasome inhibition is a novel approach to treating AMR. This review discusses current and emerging treatment modalities used for AMR.

The purpose of this study was to evaluate the safety, efficacy, and transplant outcomes associated with FK506 rescue and maintenance therapy in pancreas transplant recipients. A chart review was conducted on 10 patients receiving FK506 after pancreas transplantation. Transplant outcomes were compared with an equivalent group of patients receiving cyclosporine. Medication dose, side effects, infections, rejection episodes, glycemic control, and graft survival were recorded from 2 to 28 weeks after transplant. Rescue therapy was successful in the patients who were converted to FK506 prior to a significant decline in glycemic control, whereas those patients who were converted after a decline in glycemic control were required to return to exogenous insulin administration. Neurological complications, nephrotoxicity, incidence of infection, hypertension, rejection, and graft survival were similar for both groups. Use of FK506 is comparable to cyclosporine in pancreas allograft recipients and successful conversion from cyclosporine to FK506 can be undertaken for rescue therapy.

Correlation between Banff classification, acute renal rejection scores and reversal of rejection. The Banff classification of acute rejection is based on histologic grades and scores for borderline changes, glomerular, vascular, interstitial and tubular lesions. We reviewed 56 episodes of acute rejection occurring in 44 kidney allograft recipients (30 cadaveric and 14 living donor transplants), comparing Banff classification to degree of reversibility of rejection. Rejection reversal was defined as complete if serum creatinine returned ≤ 25% of baseline, partial if creatinine was > 25% to < 75% of baseline, and irreversible if creatinine was ≥ 75% of baseline or graft loss occurred. Eight biopsies were classified as borderline (SUM score 1.6 ± 0.5), 14 grade I (SUM score 3.3 ± 0.4), 19 grade II (SUM score 4.2 ± 0.3), and 15 grade III (SUM score 8.5 ± 0.4). SUM distinguished borderline and grade III rejections, but not grades I and II. Clinically, grade and SUM score correlated with rejection reversal. Complete reversal of rejection occurred in 93% of patients with grade I rejection, while 47% of patients with grade III had irreversible rejection. The mean SUM for complete reversal was 3.9 ± 0.34 and was different from SUM of partial (6.0 ± 0.86) and irreversible (8.5 ± 0.93), P < 0.006. Meanwhile, vascular scores were similar for rejections with complete (0.9 ± 0.2) or partial (1.0 ± 0.4) reversal, but significantly higher in those with irreversible rejection (3.0 ± 0.4, P < 0.000). Likewise, mean scores for tubulitis and interstitial inflammation were significantly higher for irreversible rejection. Resolution of rejection by steroids was correlated to low vascular score (steroid sensitive 0.65 ± 0.25 vs. steroid resistant 1.42 ± 0.18, P < 0.01), and low SUM score (steroid sensitive 3.7 ± 0.5 vs. steroid resistant 5.22 ± 0.43, P < 0.04). Neither scores for tubulitis nor interstitial cellular inflammation were predictive of steroid sensitivity. These data demonstrate that Banff scoring has clinical relevance in predicting rejection reversal and has implications to first-line therapy of rejection episodes.

Background A prospective intermediate-term evaluation of toxicities associated with bortezomib therapy for antibody-mediated rejection (AMR) and desensitization was conducted. Methods Patients were graded for bortezomib-related toxicities: hematologic and gastrointestinal toxicities by Common Terminology Criteria for Adverse Events and peripheral neuropathy by modified Functional Assessment of Cancer Therapy questionnaire and Common Terminology Criteria for Adverse Events. Results Fifty-one patients treated for AMR and 19 patients treated for desensitization received 96 bortezomib cycles (1.3 mg/m(2) ×4 doses); mean (SD) follow-up was 16.3 (9.0) months. Patients treated for AMR and patients treated for desensitization were similar in age, gender, ethnicity, and baseline peripheral neuropathy. Patients treated for AMR received a mean (SD) of 4.9 (2.0) bortezomib doses in 1.3 (0.5) cycles; and patients treated for desensitization, a mean of 7.3 (1.6) doses in 1.8 (0.4) cycles. Prevalence of diabetes and anemia were higher at baseline in patients treated for AMR. In the AMR cohort, two cases of cytomegalovirus infection, two cases of BK virus infection, and one case of Epstein-Barr virus infection were observed. No cases of viral infection were observed in the desensitization cohort. Malignancies were not observed. Significant bortezomib toxicities included anemia and peripheral neuropathy, which were manageable. Anemia was more common in patients treated for AMR; and peripheral neuropathy, more common in patients treated for desensitization. Conclusions Bortezomib-related toxicities in kidney transplant candidates and recipients are low in incidence and severity and vary based on treatment population.

Morbid obesity is a barrier to renal transplantation and is inadequately addressed by medical therapy. We present results of a prospective evaluation of laparoscopic sleeve gastrectomy (LSG) for patients failing to achieve significant weight loss with medical therapy. Over a 25-month period, 52 obese renal transplant candidates meeting NIH guidelines for metabolic surgery underwent LSG. Mean age was 50.0 ± 10.0 years with an average preoperative BMI of 43.0 ± 5.4 kg/m(2) (range 35.8-67.7 kg/m(2)). Follow-up after LSG was 220 ± 152 days (range 26-733 days) with last BMI of 36.3 ± 5.3 kg/m(2) (range 29.2-49.8 kg/m(2)) with 29 (55.8%) patients achieving goal BMI of