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Personalization of maintenance immunosuppression in kidney transplant recipients has long remained a goal in the transplant community. The recent addition of donor-derived cell-free DNA assays to detect allograft rejection and monitor allograft health may permit for reductions in maintenance immunosuppression in recipients with stable levels. Herein, we described 5 patients with stable donor-derived cell-free DNA levels who underwent reduction in maintenance immunosuppression without precipitation of clinical rejection, proteinuria, or de novo donor specific antibody formation., Competing Interests: DISCLOSURE S.B. receives grant funding from Natera, CareDx. E.L. received grant funding from Natera., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: One of the most commonly used immunosuppressants in organ transplant, tacrolimus exhibits wide interpatient and intrapatient variability and narrow therapeutic index that necessitates routine concentration monitoring and dosage adjustments. Availability of modified -release tacrolimus products offer once-daily dosing options. The objective of this review is to highlight and compare available pharmacokinetic (PK) data of extended-release tacrolimus tablets (LCP-TAC) to immediate-release tacrolimus (IR-TAC) in kidney transplant recipients., Areas Covered: A review of the literature was performed using PubMed and Embase search to identify relevant articles evaluating PK data for LCP-TAC compared to IR-TAC in kidney transplant patients including special populations., Expert Opinion: LCP-TAC's unique PK profile may be more favorable than IR-TAC. While the clinical impact of these PK differences have not been established, several outcomes are being evaluated in ongoing studies. Results of these studies will add information incrementally to care for kidney transplant patients. Larger prospective studies evaluating kidney and patient survival differences are needed but it is unlikely that they will be conducted. Given that the patent exclusivity of LCP-TAC for the next several years and imminent loss of exclusivity of PR-TAC, our opinion is the use of LCP-TAC will be increasing, especially in Europe.

BACKGROUND The pharmacokinetics and metabolism of tacrolimus, an immunosuppressant commonly used to prevent transplant rejection, can differ in specific subpopulations. This analysis examined treatment outcomes and safety of immediate-release tacrolimus (IR-Tac) and LCP-tacrolimus (LCPT) in stable Hispanic kidney transplant recipients. MATERIAL AND METHODS This was a post hoc analysis of clinical trial data from Hispanic adult stable kidney transplant recipients randomized to remain on IR-Tac or convert from IR-Tac to a reduced dose of LCPT (NCT00817206). Composite treatment failure was evaluated at 12 months. Estimated glomerular filtration rate and tacrolimus trough concentrations were evaluated over 12 months. RESULTS Fifty-five stable (LCPT n=26, IR-Tac n=29) kidney transplant recipients who self-identified as Hispanic or Latino were included in this analysis. Composite treatment failure occurred in 1 patient (4%) who converted to LCPT and 1 (3%) who remained on IR-Tac. The estimated glomerular filtration rate was stable over time and similar in the 2 treatment groups (P=0.08). Tacrolimus trough levels for both groups were similar over time in the 2 treatment groups (P=0.98). Treatment-emergent adverse events were similar in patients who converted to LCPT and in those who remained on IR-Tac. CONCLUSIONS Efficacy and safety were similar in Hispanic kidney transplant recipients who converted from IR-Tac to LCPT and in those remaining on IR-Tac.

BACKGROUND A previous phase 3 clinical trial in de novo adult kidney transplant recipients (NCT01187953) compared the efficacy and safety of once-daily LCP-tacrolimus (LCPT) and twice-daily immediate-release tacrolimus (IR-Tac). However, whether the rate of tacrolimus metabolism affects outcomes between LCPT and IR-Tac was not examined. MATERIAL AND METHODS Patients were initiated on 0.17 mg/kg/day LCPT or 0.1 mg/kg/day IR-Tac, with doses adjusted over time to maintain target therapeutic trough concentrations. This post hoc analysis examined dosing trends, relative efficacy, and safety of LCPT (n=247) and IR-Tac (n=249) in slow, intermediate, and rapid metabolizers as defined by concentration/dose ratios at day 30. RESULTS For all metabolizer subgroups, minimum target tacrolimus trough concentrations were obtained more rapidly with LCPT than with IR-Tac. Slow metabolizers were more likely to exceed target trough concentrations with LCPT, while rapid metabolizers were more likely to fall below target trough concentrations with IR-Tac. Regardless of metabolizer status, significant differences were not detected between LCPT and IR-Tac for treatment failure, death, graft failure, biopsy-proven acute rejection, estimated glomerular filtration rate, or other clinical outcomes. CONCLUSIONS Although within metabolizer subgroups, attainment of target trough concentrations in the first week differed between LCPT and IR-Tac, these results suggest that, regardless of metabolizer phenotype, clinical outcomes do not differ between these formulations when dose adjustments are made.

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., (© 2016 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.)

Background: 1-year data from this trial showed the noninferiority of a novel once-daily extended-release tacrolimus (LCPT; Envarsus XR) to immediate-release tacrolimus (IR-Tac) twice daily after kidney transplantation., Study Design: Final 24-month analysis of a 2-armed, parallel-group, randomized, double-blind, double-dummy, multicenter, phase 3 trial., Setting & Participants: 543 de novo kidney recipients randomly assigned to LCPT (n=268) or IR-Tac (n=275); 507 (93.4%) completed the 24-month study., Intervention: LCPT tablets once daily at 0.17 mg/kg/d or IR-Tac twice daily at 0.1 mg/kg/d; subsequent doses were adjusted to maintain target trough ranges (first 30 days, 6-11 ng/mL; thereafter, 4-11 ng/mL). The intervention was 24 months; the study was double blinded for the entirety., Outcomes & Measurements: Treatment failure (death, transplant failure, biopsy-proven acute rejection, or loss to follow up) within 24 months. Safety end points included adverse events, serious adverse events, new-onset diabetes, kidney function, opportunistic infections, and malignancies. Pharmacokinetic measures included total daily dose (TDD) of study drugs and tacrolimus trough levels., Results: 24-month treatment failure was LCPT, 23.1%; IR-Tac, 27.3% (treatment difference, -4.14% [95% CI, -11.38% to +3.17%], well below the +10% noninferiority criterion defined for the primary 12-month end point). Subgroup analyses showed fewer treatment failures for LCPT versus IR-Tac among black, older, and female recipients. Safety was similar between groups. From month 1, TDD was lower for LCPT; the difference increased over time. At month 24, mean TDD for LCPT was 24% lower than for the IR-Tac group (P<0.001), but troughs were similar (means at 24 months: LCPT, 5.47 ± 0.17 ng/mL; IR-Tac, 5.8 ± 0.30 ng/mL; P=0.4)., Limitations: Trial participant eligibility criteria may limit the generalizability of results to the global population of de novo kidney transplant recipients., Conclusions: Results suggest that once-daily LCPT in de novo kidney transplantation has comparable efficacy and safety profile to that of IR-Tac. Lower TDD reflects LCPT's improved bioavailability and absorption., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

This Phase III randomized trial examined efficacy and safety of a novel once-daily extended-release tacrolimus formulation (LCP-Tacro [LCPT]) versus twice-daily tacrolimus in de novo kidney transplantation. Primary efficacy end point was proportion of patients with treatment failure (death, graft failure, biopsy-proven acute rejection or lost to follow-up) within 12 months. Starting doses were, LCPT: 0.17 mg/kg/day and tacrolimus twice-daily: 0.1 mg/kg/day; 543 patients were randomized, LCPT: n = 268; tacrolimus twice-daily: n = 275. At 12 months treatment failure was LCPT: 18.3% and tacrolimus twice-daily: 19.6%; the upper 95% CI of the treatment difference was +5.27%, below the predefined +10% noninferiority criteria. There were no significant differences in the incidence of individual efficacy events or adverse events. Target tacrolimus trough levels were more rapidly achieved in the LCPT group. Following initial dose, 36.6% of patients in the LCPT group had rapidly attained trough levels within 6-11 ng/mL versus 18.5% of tacrolimus twice-daily patients; majority of tacrolimus twice-daily patients (74.7%) had troughs <6 ng/mL compared with 33.5% in the LCPT group. Overall, cumulative study dose was 14% lower for LCPT. Results suggest that use of once-daily LCPT in de novo kidney transplantation is efficacious and safe. Lower LCPT dose reflects the improved absorption provided by the novel formulation., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background/aims: Gastrointestinal (GI) symptoms in renal transplant recipients may be caused due to mycophenolic acid (MPA) toxicity. Using small bowel capsule endoscopy (SBCE) we examined the impact of conversion from Mycophenolate Mofetil (MMF) to enteric-coated formulation of Mycophenolate Sodium (EC-MPS) given to treat GI mucosal lesions., Methods: Adult kidney-only recipients at least 30 days after transplant, presenting with GI symptoms while receiving MMF completed a Gastrointestinal Symptom Rating Scale (GSRS) questionnaire, underwent SBCE, and had MMF substituted by EC-MPS. After 30 days, GSRS and SBCE were repeated and findings were compared to baseline values. Patients who were still on EC-MPS 6-24 months post-conversion were contacted for completing a follow-up GSRS questionnaire and SBCE., Results: Eighteen out of 23 subjects completed the first part of the study. Subjects' median ages and post-transplant time were 47.5 years old and 4.5 months, respectively. Tacrolimus, MMF and prednisone was the main regimen (94%), with a median MMF dose of 750 mg BID. The average baseline GSRS was 2.99 ± 0.81; it significantly decreased to 2.19 ± 0.8 at 30 days post-conversion. At baseline, 50 had gastric and 89% had small bowel lesions. At 30 days, 29 and 62% of the SBCE were still showing gastric and small bowel lesions, respectively. Of 5 patients in the study extension, 4 had abnormal SBCE findings but have been reporting improvement in their symptoms., Conclusion: Stomach and small bowel mucosal lesions are common in kidney recipients with GI symptoms when treated with MMF. Conversion to EC-MPS for 30 days significantly alleviated the GI symptoms; however, no evident correlation with SBCE findings was found., (© 2014 S. Karger AG, Basel.)

Background: LCP-Tacro is an extended-release formulation of tacrolimus designed for once-daily dosing. Phase 1 studies demonstrated greater bioavailability to twice-daily tacrolimus capsules and no new safety concerns., Methods: In this phase 2 study, adult stable kidney 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 to 21; trough levels were to be maintained between 5 and 15 ng/mL; 24-hr pharmacokinetic assessments were done on days 7 (baseline pre-switch), 14, and 21., Results: Forty-seven patients completed LCP-Tacro dosing per protocol. The mean conversion ratio was 0.71. Pharmacokinetic data demonstrated consistent exposure (AUC) at the lower conversion dose. C(max) (P = 0.0001), C(max)/C(min) ratio (P < 0.001), percent fluctuation (P < 0.0001), and swing (P = 0.0004) were significantly lower and T(max) significantly (P < 0.001) longer for LCP-Tacro versus Prograf. AUC24 and C(min) correlation coefficients after 7 and 14 days of therapy were 0.86 or more, demonstrating a robust correlation between LCP-Tacro tacrolimus exposure and trough levels. There were three serious adverse events; none were related to study drug and all were resolved., Conclusions: Stable kidney transplant patients can be safely converted from Prograf twice-daily to LCP-Tacro. The greater bioavailability of LCP-Tacro allows for once-daily dosing and similar (AUC) exposure at a dose approximately 30% less than the total daily dose of Prograf. LCP-Tacro displays flatter kinetics characterized by significantly lower peak-trough fluctuations.

Phase III noninferiority trial examining efficacy and safety of converting stable renal transplant recipients from twice-daily tacrolimus to a novel extended-release once-daily tacrolimus formulation (LCPT) with a controlled agglomeration technology. Controls maintained tacrolimus twice daily. The primary efficacy endpoint was proportion of patients with efficacy failures (death, graft failure, locally read biopsy-proven acute rejection [BPAR], or loss to follow-up) within 12 months. Starting LCPT dose was 30% lower (15% for blacks) than preconversion tacrolimus dose; target trough levels were 4-15 ng/mL. A total of 326 patients were randomized; the mITT population (n = 162 each group) was similar demographically in the two groups. Mean daily dose of LCPT was significantly (p < 0.0001) lower than preconversion tacrolimus dose at each visit; mean trough levels between groups were similar. There were four efficacy failures in each group; safety outcomes were similar between groups. Frequency of premature study drug discontinuation was LCPT: 12% versus tacrolimus twice daily: 5% (p = 0.028). LCPT demonstrated noninferiority to tacrolimus twice daily in efficacy failure rates. LCPT may offer a safe and effective alternative for converting patients to a once-daily formulation. Compared to currently available tacrolimus formulation, LCPT requires lower doses to achieve target trough levels., (© Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The majority of kidney transplant recipients in the United States receive antibody induction, but its impact on outcomes in living donor transplant is not well-described. We used Organ Procurement and Transplant Network/United Network for Organ Sharing (OPTN/UNOS) data as of November 2009 to compare acute rejection (AR) and graft survival among all primary adult living donor kidney recipients of no antibody induction, antithymocyte globulin (ATG) and interleukin-2 receptor antagonists (IL-2RA) in an earlier era (1998-2002; n=21,919) and a later era (2003-2008, n=26,837). The incidence of AR in the overall cohort decreased from 18.5% in 1998 to 8% in 2008. From 1998 to 2002, antibody induction was associated with a decreased risk of acute rejection at six months (RR 0.67, 95% CI 0.62-0.72) and one yr (RR 0.71, 0.65-0.76), while in the recent era, induction was not associated with acute rejection at six months (RR 0.97, 0.88-1.07) or one yr (RR 1.01, 0.91-1.10). There was no difference in graft survival over five yr with antibody induction in either era. Although antibody induction was associated with a decreased risk of AR from 1998 to 2002, it was not associated with a decreased risk of acute rejection from 2003 to 2008, nor was it associated with a difference in graft survival in either era., (© 2011 John Wiley & Sons A/S.)

Background: The association of immunosuppressive regimens (ISRs) with posttransplant lymphoproliferative disorder (PTLD) may be related with the Epstein-Barr virus (EBV) recipient serostatus., Methods: We selected primary kidney transplant recipients from Organ Procurement Transplant Network/United Network for Organ Sharing database (2000-2009) who were discharged with a functioning graft and were receiving an ISR including an antiproliferative drug and a calcineurin inhibitor as follows: mycophenolate mofetil (MMF)/mycophenolate sodium+tacrolimus (TAC), MMF+cyclosporine A (CsA); mammalian target of rapamycin inhibitor (mTORi)+TAC; and mTORi+CsA. Adjusted risks of PTLD, rejection, death, and graft failure were examined in all recipients and compared between EBV+ and EBV- recipients., Results: Of 114,025 recipients, 754 developed PTLD (5-year incidence of 0.84%). Adjusted hazard ratio for PTLD was 4.39 (95% CI: 3.60-5.37) for EBV- versus EBV+ recipients; and 1.40 (95% CI: 1.03-1.90) for mTORi+TAC, 0.80 (95% CI: 0.65-0.99) for MMF+CsA, and 0.90 (95% CI: 0.57-1.42) for mTORi+CsA, versus MMF+TAC users. In EBV- recipients, hazard ratio for PTLD was 1.98 (95% CI: 1.28-3.07) for mTORi+TAC, 0.45 (95% CI: 0.28-0.72) for MMF+CsA, and 0.84 (95% CI: 0.39-1.80) for mTORi+CsA users versus MMF+TAC. No difference was seen in EBV+ recipient groups. Rejection rates were higher among MMF+CsA recipients in both EBV groups. Death and graft failure risk were increased in all EBV+ISR groups, while in EBV- these risks were only increased in mTORi+TAC group versus MMF+TAC., Conclusions: In EBV- recipients, immunosuppression with mTORi+TAC was associated with increased risk of PTLD, death, and graft failure, while MMF+CsA use was associated with a trend to increased risk of rejection, lower PTLD risk, and similar risk for graft failure when compared with MMF+TAC.

The objectives of this study are to examine the incidence of new-onset diabetes mellitus after transplant (NODAT) and to identify its risk factors in adult lung transplant recipients using the Organ Procurement and Transplant Network/United Network of Organ Sharing database. Between July 2004 and December 2007, a total of 3540 adults (≥18 yr old) received their first single- or double-lung transplant alone and had at least one follow-up report of post-transplant diabetic status. Among these, 2991 recipients were identified as not having diabetes mellitus (DM) pre-transplant. Risk factors for NODAT were examined. DM was newly reported in 33.4% of the 2991 recipients over the median follow-up time of 670 d. Significant independent risk factors for the development of NODAT included male gender (HR = 1.15), recipient age ≥50 (1.46), African American (1.39), higher body mass index (1.51 for ≥30 vs. 18-25), cystic fibrosis (3.30), and tacrolimus use at discharge (1.67). NODAT occurred in a third of adult lung transplant recipients during the median follow-up period. Some of the risk factors for NODAT after lung transplant are similar to those reported in other solid-organ transplants. Cystic fibrosis is a strong risk factor for development of NODAT after lung transplant., (© 2010 John Wiley & Sons A/S.)

We evaluated the effectiveness of induction therapy on transplant outcomes during 2004-2007 in the United States. We retrospectively reviewed OPTN/UNOS registry and selected kidney pediatric (<21-yr) recipients that received no induction (NoIND), IL-2RA, or rabbit anti-THY and were discharged with a triple drug immunosuppressive maintenance regimen, including steroids. Of 2932 recipients, 20%, 36%, and 43% were in NoIND, THY, and IL-2RA groups, respectively. The majority received tacrolimus (88%) and MMF (89%) at discharge. There was no association of induction with the risk of acute rejection even after adjusting for known cofounders. Compared to NoIND, IL2-RA, but not THY, had a modest decrease (3%) in absolute rate of graft loss and was associated with a risk reduction ratio of 0.51 (95% CI, 0.31-0.84) in one-yr graft loss. At three yr, no induction agent was associated with decreased graft loss. In conclusion, induction agents were used in 80% of pediatric kidney recipients discharged with a triple drug immunosuppressive maintenance regimen between 2004-2007 in the United States. Neither THY nor IL-2RA was associated with reduced rejection episodes. The use of induction therapy was not associated with improvement in three-yr graft survival.

New classes of agents have sequentially increased the specificity of post-transplant immunosuppression, leading to profound improvements in success rates after renal transplantation. The next era will focus on increased long-term survival rates through optimal use of existing agents and the rational development of drugs based on prior identification of specific immunologic targets. Conventionally, long-term outcomes after kidney transplantation have been assessed by surrogate markers, notably acute rejection, but graft-threatening complications such as development of new-onset diabetes mellitus and polyomavirus nephropathy must be addressed if long-term survival rates are to be improved. Mycophenolic acid therapy must be administered optimally to ensure that adequate exposure is achieved in the immediate post-transplant period and, subsequently, by avoiding underdosing due to gastrointestinal events. Chronic allograft nephropathy remains a major concern, and protocol-led, reliable monitoring strategies are essential to enable early intervention, for example, through introduction of proliferation signal inhibitor therapy with concomitant calcineurin inhibitor reduction or withdrawal. The range of immunosuppressive regimens now available and in development, together with improved assessment of patients' risk profiles for immunologic events and comorbid disease, offers the opportunity for further individualization of immunosuppression after renal transplantation.

We describe factors associated with poor compliance and dose reductions and examine the relative impact of compliance, dose reduction and discontinuation on graft outcome. Medicare claims for MMF in 7062 deceased donor renal recipients with at least 1 year of graft function were used to calculate compliance and dose reductions. Compliance was modeled using medication possession ratio to define quartiles for poor, low, medium and high compliance. The relative impact of compliance, dose reduction and discontinuation on graft outcome was assessed with Cox proportional hazards. Pediatric (Age 0-18, Odds ratio = 1.71, 95% CI 1.11-2.63, p = 0.014) and adolescent recipients (19-24, 1.57, 1.23-2.00, p < 0.001) were more likely poorly compliant compared to adults age 25-44. Poor compliance was also associated with physical limitations, hypertension, delayed graft function, rejection, infection and GI conditions. Poor (1.43, 1.11-1.84, p = 0.005) and low (1.46, 1.13-1.88, p = 0.004) compliance was associated with an increased hazard of graft loss as was >50% dose reduction (1.69, 1.15-2.50, p = 0.008) and discontinuation (8.34, 6.85-10.2, p < 0.001). Medication possession ratios lower than the 3-year mean were associated with an increased risk of graft loss. These results may indicate that interventions to improve compliance among kidney transplant recipients should strive for high rather than discourage low compliance.

Here we retrospectively examine the efficacy of two antibody induction regimens using Zenapax or Thymoglobulin in patients with positive complement-dependent cytotoxicity crossmatches (CDC-CMXs) desensitized with IVIG (intravenous immunoglobulin). Between January 1999 and March 2005, 97 patients with (+) CDC-CMXs received kidney transplants (43 deceased donors/54 living donors). All patients received at least 2 g/kg IVIG (maximum four doses) until an acceptable CMX was obtained. Patients were divided into two groups: 1. IVIG + Zenapax (n = 58), 2. IVIG + Thymoglobulin (n = 39). A total of 94% of patients in Group 1 and 84% in G2 have at least 2 years of follow up. Patient and graft survival was 96%/84% in Group 1 and 100%/90% in Group 2, p = NS. The number and severity of AR episodes were similar (36% Group 1 vs. 31% Group 2, p = NS) as was the incidence of C4d (+) antibody-mediated rejection (AMR) (Banff Grade II/III) (22% Group 1 vs. 21% Group 2). Mean serum creatinines (SCrs) at 24 months were similar (Group 1: 1.4 +/- 0.7 vs. G2: 1.5 +/- 0.7 mg/dL). Induction therapy with Zenapax or Thymoglobulin results in excellent patient, graft survival and graft function at 2 years. There was no increased risk of viral infections or malignancies with either agent. Neither agent was effective in reducing the incidence of AMR.

Background: Mycophenolate mofetil (MMF) use in renal transplantation has steadily increased since 1995 because of its ability to lower the risks of rejection and chronic allograft nephropathy. However, significant gastrointestinal (GI) complications may lead to MMF dose reductions and discontinuations. Little is known of the association between MMF dose reductions and discontinuations following GI complications and graft survival., Methods: Using the United States Renal Data System, we identified 3,675 adult recipients (age >or=18) with a diagnosed GI complication who were prescribed MMF at the time of first GI diagnosis and had Medicare as their primary insurer. MMF doses were ascertained from Medicare payment records. We estimated risk of graft loss associated with MMF dose adjustments after GI diagnosis: dosage unchanged (reference), reduced <50%, reduced >or=50%, and MMF discontinued. Patients were followed until graft loss, death, last recorded immunosuppression prescription, or 3 years posttransplant., Results: Compared to those with no MMF dose reductions or discontinuations, the risk of graft failure increased with MMF doses reduction >or=50% (HR=2.36, 95% CI 1.23-4.54) and those with MMF discontinuation (2.72, CI 1.60-4.64)., Conclusion: Renal transplant recipients who underwent MMF dose reduction or withdrawal following GI diagnosis are associated with increased risk of graft failure.

Aims: The aims of this study were to describe factors associated with the use of overall induction, classes of induction agents, and to evaluate the incidence of acute rejection, short-term graft survival, and patient survival., Methods: Of 24,901 transplants reported to the United Network for Organ Sharing (UNOS) between 1999 and 2001, 51% received induction therapy including Thymoglobulin (T; n = 3090), Simulect (S; n = 6063), or Zenapax (Z; n = 3755). Propensity scores (PS) were calculated to indicate factors associated with use of induction and for each induction agent. Outcome parameters included graft survival (GS), hazard ratio (HR) for graft loss (GL), and odds ratio (OR) for first-year acute rejection (AR)., Results: Pediatric (PS = 1.29; 95% confidence interval [CI] 1.12-1.49, vs adults) and retransplanted recipients (PS = 1.36; 1.23-1.49, vs first) were more likely to receive induction. One-year GS (90.1 vs 88.0%; P < .001), GL = 0.92% (0.86-0.98; P = .01), and AR free = 0.74 (P < .001) were superior in patients receiving induction. Using multivariate analysis, the odds of rejection 0.73 (0.68-0.78), GL 0.91 (0.85-0.97), and death 0.90 (0.82-0.98) were lower in those receiving induction. Among patients given induction, those receiving T were more likely sensitized (PS = 1.50%; 1.31-1.71), retransplanted (PS = 1.51; 1.31-1.75), or had delayed graft function (PS = 1.75; 1.58-1.93). T decreased the odds of rejection compared with S or Z (OR = 0.74; 0.69-0.79), but the type of induction agent did not have an impact on graft outcome HR for T = 1.07 (0.96-1.19)., Conclusions: The use of antibody induction was associated with lower risk of rejection and better GS. There were no differences in GS among individual regimens. Comparative safety data were not analyzed but should be taken into consideration when choosing antibody preparations.

The use of alemtuzumab for induction therapy is increasing. 7.6% of antibody induction recipients in 2003 and 9.3% of induction recipients in 2004 received alemtuzumab. Antibody induction, especially T-cell depleting agents, Thymoglobulin and alemtuzumab are very effective in preventing early acute rejection in the initial hospitalization for both deceased and living donor transplants. However, when examining the effect of antibody induction on acute rejection after the initial hospitalization during the first year, alemtuzumab induction was associated with increased odds of acute rejection in deceased donor transplants compared to no antibody induction, IL-2RA, and Thymoglobulin. There was no difference in acute rejection during the first year after initial hospitalization in living donor transplants among all 4 induction groups. Despite lower acute rejection rates with alemtuzumab induction, no difference in graft survival was observed compared to no antibody induction, IL-2RA, and Thymoglobulin over 24 months. We conclude that alemtuzumab is an effective induction agent in kidney transplantation. However, further studies are needed to assess its long-term efficacy and to establish the optimal immunosuppressive regimen that should be maintained when alemtuzumab is used as an induction agent.

Previous analyses of outcomes between immunosuppressive regimens included data from the early years of tacrolimus use and frequently included all Tacrolimus- or cyclosporine-based regimens. We now evaluate clinical outcomes associated with only the two most commonly prescribed regimens--Tacrolimus (Tac)-mycophenylate mofetil (MMF) and cyclosporine (CsA)-MMF--using recent data reported to the UNOS Scientific Renal Transplant Registry. Data from living donor kidney transplants was chosen to minimize selection bias between treatment groups. Outcomes are reported only for recent years (1998 to 1999 with 3-year follow-up) because acute rejection rates were markedly higher in 1995 to 1997 compared to 1998 to 2000 (38% to 68% vs 21% to 32%) and clinical practice has evolved since 1995, which would have biased results in favor of more recent immunosuppressive regimens. Three-year graft survival for patients transplanted from 1998 to 1999 was significantly higher in living donor kidney transplant patients receiving CsA-MMF (91.1%, n = 4686) versus Tac-MMF (88.1%, n = 2393) (P =.0006). After adjustment for potential confounding variables, risk of graft failure at 3 years was significantly higher in patients receiving Tac-MMF versus CsA-MMF for both all-cause graft failure (hazard ratio 1.28, 95%CI 1.09 to 1.49, P =.002) and death-censored graft failure (hazard ratio 1.25, 95%CI 1.05 to 1.49, P =.013). In view of the reduced rejection rate that has been reported using Tac-MMF versus CsA-MMF in clinical trials, it is possible that the nonimmunologic effects of calcineurin inhibitors may now play an increasingly important role in determining graft survival rates. In conclusion, this large-scale registry analysis demonstrates that graft survival in living donor kidney transplant patients is significantly improved using CsA-MMF compared to Tac-MMF.

Background: Registry databases offer the statistical power to analyze differences in graft survival rates that may not be detected in randomized clinical trials. This study analyses 2-year graft survival using tacrolimus (tac) or cyclosporine (CsA) with mycophenolate mofetil (MMF) and steroids., Methods: Data reported to the United Network for Organ Sharing Renal Transplant Registry for living-donor kidney patients receiving a transplant during 1998 to 1999 were included. The primary end point was graft survival after adjustment for confounding variables. A Cox model multivariate analysis was used to adjust for potential confounding factors., Results: Patients receiving CsA-MMF (n=4,686) and tac-MMF (n=2,393) were included. Unadjusted all-cause 2-year graft survival rate was significantly higher with CsA-MMF than tac-MMF (94.3% vs. 92.2%, P=0.0006). After adjustment for potential confounding factors, risk of graft failure at 2 years was significantly higher in patients receiving tac-MMF versus CsA-MMF for both all-cause graft failure (hazards ratio [HR] 1.28, 95% confidence interval [CI] 1.09-1.49, P=0.002) and death-censored graft failure (HR 1.25, 95% CI 1.05-1.49, P=0.013). Other independent risk factors for graft failure were recipient or donor age greater than 55 years, female sex, pretransplant blood transfusions, one or two haplotype mismatches compared with zero haplotype mismatch, and panel reactive antibody (PRA) greater than 30%., Conclusions: Our findings demonstrate that 2-year renal allograft survival is significantly higher in living-donor recipients receiving CsA compared with tac as initial immunosuppression in combination with MMF.

1. There was a dramatic shift in the type of induction therapy used between 1996-2000. In 2000, more than half of recipients received induction therapy. 2. The type of transplants strongly influenced the use of antibody induction. LD recipients were least likely to receive antibody induction followed by unsensitized, sensitized cadaveric and SPK recipients. 3. Pan-T antibody induction was used more frequently in patients with DGF and in high immunologic risk groups. 4. IL-2 receptor antagonists have become the dominant induction therapy; even for recipients with high immunologic risk or those with DGF. 5. We cannot demonstrate the effects of pan-T antibody induction on the resolution of DGF. Pan-T antibody induction did not improve graft survival in any cohorts, although it was associated with lower acute rejection rates in LD and unsensitized groups. 6. IL-2R antibody induction therapy was associated with lower acute rejection and graft failure at one year in LD and unsensitized groups. However, this trend cannot be demonstrated in higher immunologic risk groups ie., sensitized cadaveric and SPK.

BACKGROUND There is great interest in reducing exposure of renal transplant recipients to the nephrotoxic effects of calcineurin inhibitors. OBJECTIVE To establish whether minimization or withdrawal of ciclosporin improves outcome after renal transplantation in patients receiving daclizumab, mycophenolate mofetil and corticosteroids. DESIGN Recipients of a first renal transplant were prospectively recruited from sites in Australia, Europe and North America for the randomized, open-label Cyclosporine Avoidance Eliminates Serious Adverse Renal Toxicity (CAESAR) trial. Exclusion criteria included receipt of an HLA-identical living related graft, a panel-reactive antibody value >20% in the previous 6 months, and an expected need for antilymphocyte treatment for delayed graft function. INTERVENTION In addition to mycophenolate and corticosteroids, participants were randomly allocated (1:1:1) to receive standard-dose ciclosporin; daclizumab induction plus low-dose ciclosporin; or daclizumab induction plus a maximum of 6 months' treatment with low-dose ciclosporin. In the third group, ciclosporin withdrawal began at month 4. Target ciclosporin trough levels were 50-100 ng/ml for low-dose treatment and 150-300ng/ml for the first 4 months of standard-dose treatment (100-200 ng/ml subsequently). Follow-up continued for 12 months OUTCOME MEASURES Glomerular filtration rate (GFR) 12 months after transplantation, as determined by clearance of an exogenous substrate, was the primary end point. Secondary end points included biopsy-proven acute rejection, graft failure and patient mortality. RESULTS Between 12 January 2001 and 24 October 2002, the investigators recruited 536 patients. In the intention to treat analysis, mean GFR at 12 months after transplantation was 50.9 ml/min/1.73 m² in both the ciclosporin withdrawal group (n = 128) and low-dose ciclosporin group (n = 138); mean GFR was 48.6ml/min/1.73m² in the standard- dose ciclosporin group (n = 119). There was no significant difference between these values. In addition, GFR at 3 months after transplantation, and creatinine clearance at 12 months after transplantation (calculated using the Cockcroft-Gault equation), did not differ significantly between the groups. Compared with the low-dose and standard-dose ciclosporin groups, a higher proportion of patients in the ciclosporin withdrawal group experienced a first episode of biopsy-proven acute rejection during the 12 months of follow-up (38% vs 25.4% and 27.5%; P=0.027 and P=0.040, respectively). There were 12 graft losses in the ciclosporin withdrawal group, 6 in the low-dose ciclosporin group and 9 in the standard-dose ciclosporin group (P= NS); 8, 4 and 5 patients died, respectively. The incidences of serious and ciclosporin-related adverse events did not differ significantly between the three groups. CONCLUSION In renal transplant patients receiving daclizumab, mycophenolate and corticosteroids, low-dose ciclosporin (target trough levels 50-100 ng/ml) produces 1-year outcomes similar to those obtained with standard-dose ciclosporin. [ABSTRACT FROM AUTHOR]