Comparing the prognostic performance of iBOX and biopsy-proven acute rejection for long-term kidney graft survival.

Biopsy-proven acute rejection (BPAR) occurs in approximately 10% of kidney transplant recipients in the first year, making superiority trials unfeasible. iBOX, a quantitative composite of estimated glomerular filtration rate, proteinuria, antihuman leukocyte antigen donor-specific antibody, and + full/- abbreviated kidney histopathology, is a new proposed surrogate endpoint. BPAR's prognostic ability was compared with iBOX in a pooled cohort of 1534 kidney transplant recipients from 4 data sets, including 2 prospective randomized controlled trials.

Qualifying a novel clinical trial endpoint (iBOX) predictive of long-term kidney transplant outcomes.

New immunosuppressive therapies that improve long-term graft survival are needed in kidney transplant. Critical Path Institute's Transplant Therapeutics Consortium received a qualification opinion for the iBOX Scoring System as a novel secondary efficacy endpoint for kidney transplant clinical trials through European Medicines Agency's qualification of novel methodologies for drug development. This is the first qualified endpoint for any transplant indication and is now available for use in kidney transplant clinical trials.

Posttransplant reduction in preexisting donor-specific antibody levels after belatacept- versus cyclosporine-based immunosuppression: Post hoc analyses of BENEFIT and BENEFIT-EXT.

BENEFIT and BENEFIT-EXT were phase III studies of cytotoxic T-cell crossmatch-negative kidney transplant recipients randomized to belatacept more intense (MI)-based, belatacept less intense (LI)-based, or cyclosporine-based immunosuppression. Following study completion, presence/absence of HLA-specific antibodies was determined centrally via solid-phase flow cytometry screening. Stored sera from anti-HLA-positive patients were further tested with a single-antigen bead assay to determine antibody specificities, presence/absence of donor-specific antibodies (DSAs), and mean fluorescent intensity (MFI) of any DSAs present.

De novo donor-specific antibodies in belatacept-treated vs cyclosporine-treated kidney-transplant recipients: Post hoc analyses of the randomized phase III BENEFIT and BENEFIT-EXT studies.

Donor-specific antibodies (DSAs) are associated with an increased risk of antibody-mediated rejection and graft failure. In BENEFIT and BENEFIT-EXT, kidney-transplant recipients were randomized to receive belatacept more intense (MI)-based, belatacept less intense (LI)-based, or cyclosporine-based immunosuppression for up to 7 years (84 months). The presence/absence of HLA-specific antibodies was determined at baseline, at months 6, 12, 24, 36, 48, 60, and 84, and at the time of clinically suspected episodes of acute rejection, using solid-phase flow-cytometry screening.

Ten-year outcomes in a randomized phase II study of kidney transplant recipients administered belatacept 4-weekly or 8-weekly.

In the phase II IM103-100 study, kidney transplant recipients were first randomized to belatacept more-intensive-based (n = 74), belatacept less-intensive-based (n = 71), or cyclosporine-based (n = 73) immunosuppression. At 3-6 months posttransplant, belatacept-treated patients were re-randomized to receive belatacept every 4 weeks (4-weekly, n = 62) or every 8 weeks (8-weekly, n = 60). Patients initially randomized to cyclosporine continued to receive cyclosporine-based immunosuppression.

Efficacy and Safety Outcomes of Extended Criteria Donor Kidneys by Subtype: Subgroup Analysis of BENEFIT-EXT at 7 Years After Transplant.

The phase III Belatacept Evaluation of Nephroprotection and Efficacy as First-Line Immunosuppression Trial-Extended Criteria Donors Trial (BENEFIT-EXT) study compared more or less intensive belatacept-based immunosuppression with cyclosporine (CsA)-based immunosuppression in recipients of extended criteria donor kidneys. In this post hoc analysis, patient outcomes were assessed according to donor kidney subtype. In total, 68.

Long-Term Outcomes in Belatacept- Versus Cyclosporine-Treated Recipients of Extended Criteria Donor Kidneys: Final Results From BENEFIT-EXT, a Phase III Randomized Study.

In the Belatacept Evaluation of Nephroprotection and Efficacy as First-Line Immunosuppression Trial-Extended Criteria Donors (BENEFIT-EXT), extended criteria donor kidney recipients were randomized to receive belatacept-based (more intense [MI] or less intense [LI]) or cyclosporine-based immunosuppression. In prior analyses, belatacept was associated with significantly better renal function compared with cyclosporine. In this prospective analysis of the intent-to-treat population, efficacy and safety were compared across regimens at 7 years after transplant.

Belatacept and Long-Term Outcomes in Kidney Transplantation.

Background: In previous analyses of BENEFIT, a phase 3 study, belatacept-based immunosuppression, as compared with cyclosporine-based immunosuppression, was associated with similar patient and graft survival and significantly improved renal function in kidney-transplant recipients. Here we present the final results from this study.

Methods: We randomly assigned kidney-transplant recipients to a more-intensive belatacept regimen, a less-intensive belatacept regimen, or a cyclosporine regimen.

Lack of significant improvements in long-term allograft survival in pediatric solid organ transplantation: A US national registry analysis.

Improvements across many facets of transplantation have led to better 1-yr outcomes of transplanted organs. In this study, we assessed whether longer-term attrition rates improved in pediatric kidney (KI), liver (LI), heart (HR) and lung (LU) transplant (TX) survival. We analyzed data between 1989 and 2008 from 5747 KI, 7348 LI, 5103 HR, and 715 LU TXs (under 18 yr of age at transplant, first solitary transplant only), from the National Scientific Registry of Transplant Recipients database in the USA.

Across all solid organs, adolescent age recipients have worse transplant organ survival than younger age children: A US national registry analysis.

Univariate analyses suggest that adolescents have worse long-term allograft survival versus younger children across different SOT. This study's objective was to determine whether multivariate analyses of a large national database recording all deceased SOT (KI; LI; HR; LU) also show worse adolescent allograft survival in the different organs. Using data from the national Scientific Registry for Transplant Recipients in the USA for pediatric primary SOT from 1989 to 2010, we calculated median half-lives and constructed K-M graft survival curves.

Prolonged immunosuppression preserves nonsensitization status after kidney transplant failure.

Background: When kidney transplants fail, transplant medications are discontinued to reduce immunosuppression-related risks. However, retransplant candidates are at risk for allosensitization which prolonging immunosuppression may minimize. We hypothesized that for these patients, a prolonged immunosuppression withdrawal after graft failure preserves nonsensitization status (PRA 0%) better than early immunosuppression withdrawal.

Clinical characteristics and outcomes in 303 HIV-infected patients with invasive fungal infections: data from the Prospective Antifungal Therapy Alliance registry, a multicenter, observational study.

This analysis aimed to characterize the epidemiology, diagnosis, treatment, and outcomes of invasive fungal infections (IFIs) in patients with human immunodeficiency virus (HIV). Data were examined for HIV patients enrolled in the Prospective Antifungal Therapy (PATH) Alliance registry, a multicenter, observational study of patients with IFIs in North America from 2004 to 2008. Patient demographics, clinical characteristics, comorbidities, antifungal therapies, and survival were assessed.

Long-term follow-up of a phase III clinical trial comparing tacrolimus extended-release/MMF, tacrolimus/MMF, and cyclosporine/MMF in de novo kidney transplant recipients.

Background: In a phase III, open-label, comparative, noninferiority study, 638 subjects receiving de novo kidney transplants were randomized to one of three treatment arms: tacrolimus extended-release (Astagraf XL) qd, tacrolimus (Prograf) bid, or cyclosporine (CsA) bid. All subjects received basiliximab induction, mycophenolate mofetil, and corticosteroids. Safety and efficacy follow-up data through 4 years are reported.

Obesity and kidney transplantation.

Obesity confers increased risk for graft loss and death among renal transplant recipients. However the relationship of changes in body weight and composition to outcome on the transplant waitlist and post-transplantation is not straightforward. Strategies to manage weight in the waitlisted patient and after kidney transplantation must be performed in the context of a multidisciplinary approach and individualized based on risk factors in particular patients.

Best allograft survival from share-35 kidney donors occurs in middle-aged adults and young children-an analysis of OPTN data.

Background: On October 2005, the Organ Procurement and Transplant Network implemented a new allocation policy for kidney transplants (KTX) from deceased donors (DD) ages <35 years to increase an access to transplantation from young donors for pediatric (ages <18 years) recipients, which is known as Share-35 (S35). However, many of these kidneys were allocated to adult recipients. The intent of this study was to analyze the graft outcomes from S35 kidneys in pediatric and adult recipients, stratified further by recipient age, to assess if recipient age affects the outcome from these presumably ideal kidneys.

Epidemiology and outcomes of candidemia in 3648 patients: data from the Prospective Antifungal Therapy (PATH Alliance®) registry, 2004-2008.

This analysis describes the epidemiology and outcomes of candidemia in patients enrolled in the Prospective Antifungal Therapy Alliance (PATH Alliance®) registry from 2004 to 2008. Overall, 4067 Candida isolates were identified from 3648 patients. The most common Candida spp.

Clinical epidemiology of 960 patients with invasive aspergillosis from the PATH Alliance registry.

Objectives: The study investigated the epidemiology and outcome of invasive aspergillosis (IA), an important cause of morbidity and mortality in immunocompromised patients.

Methods: Cases of proven/probable IA from the Prospective Antifungal Therapy Alliance (PATH Alliance(®)) registry - a prospective surveillance network comprising 25 centers in the United States and Canada that collected data on invasive fungal infections from 2004 to 2008 - were analyzed with respect to clinical outcome.

Results: Nine hundred and sixty patients with IA were enrolled, the most frequent underlying disease being hematologic malignancy (n=464 [48.

Pulsatile pump decreases risk of delayed graft function in kidneys donated after cardiac death.

Organ storage techniques have been under scrutiny to determine the best preservation method, particularly in donation after cardiac death (DCD) kidneys. Conflicting literature on the benefit of pulsatile perfusion (PP) over cold storage (CS) warrants further investigation. We analyzed the risk of developing delayed graft function (DGF) in recipients of DCD and donation after brain death (DBD) kidneys undergoing PP or CS.

The PATH (Prospective Antifungal Therapy) Alliance® registry and invasive fungal infections: update 2012.

The Prospective Antifungal Therapy Alliance (PATH Alliance®) performed prospective surveillance of invasive fungal infections (IFIs) among patients hospitalized at 25 medical centers in North America between 2004 and 2008, collecting information on the epidemiology, diagnosis, treatment, and mortality rates of IFIs. In total, 7526 IFIs were identified in 6845 patients. Candida spp.

Associations between EBV serostatus and organ transplant type in PTLD risk: an analysis of the SRTR National Registry Data in the United States.

In a prior multiorgan transplant database study, recipient Epstein-Barr virus (EBV) seronegativity was not associated with increased risk for posttransplant lymphoproliferative disorders (PTLD) in liver transplants (LTX), at variance with prior single center reports and with data from kidney and heart transplants (KTX and HTX). The Scientific Registry of Transplant Recipients (SRTR) in the United States is the only other registry with data on the required variables for comparison.Our study set comprised 112 756 KTX (580 PTLDs; 0.

The PROMISE study: a phase 2b multicenter study of voclosporin (ISA247) versus tacrolimus in de novo kidney transplantation.

Voclosporin (VCS, ISA247) is a novel calcineurin inhibitor being developed for organ transplantation. PROMISE was a 6-month, multicenter, randomized, open-label study of three ascending concentration-controlled groups of VCS (low, medium and high) compared to tacrolimus (TAC) in 334 low-risk renal transplant recipients. The primary endpoint was demonstration of noninferiority of biopsy proven acute rejection (BPAR) rates.

Calcineurin inhibitors in kidney transplantation: friend or foe?

Purpose Of Review: The utilization of calcineurin inhibitors (CNI) in kidney transplantation has dramatically improved short-term outcomes but significant gains in long-term outcomes have proved elusive. Nephrotoxicity is the major problem associated with CNIs and is responsible for the disappointing progress seen in long-term graft survival. In this review, we assess CNI efficacy as well as the latest strategies employed to limit long-term CNI nephrotoxicity.

Blood transfusions in organ transplant patients: mechanisms of sensitization and implications for prevention.

Sensitization by previous pregnancies or transplants is considered unavoidable, but it is transfusions given to these patients that leads most often to broad sensitization. Both leukocytes and red cells carry a significant HLA antigen load, and residual leukocytes and/or red cell HLA may explain why leukocyte-reduced units are unable to prevent sensitization to any significant degree. Prevention of sensitization will require a more active effort to avoid blood transfusions, whenever possible.