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Belatacept is an intravenously infused selective T cell costimulation blocker approved for preventing organ rejection in renal transplant recipients aged ≥18 years. This phase I trial examined the pharmacokinetics and pharmacodynamics (percentage CD86 receptor occupancy [%CD86RO]) of a single dose of belatacept (7.5 mg/kg) administered to kidney transplant recipients aged 12‐17 years receiving a stable calcineurin inhibitor–based immunosuppressive regimen. Nine adolescents (mean age 15.1 years) who were seropositive for Epstein‐Barr virus were enrolled; all completed the 6‐month study. Pharmacokinetics suggested relatively low variability of exposure (coefficients of variation for maximum observed serum concentration [C max] and area under the serum concentration‐time curve from time zero extrapolated to infinity [AUC 0‐ INF] were 20% and 25%, respectively). Mean half‐life (T 1/2) occurred 7.2 days postinfusion. Belatacept total body clearance was 0.48 mL/h/kg, and volume of distribution at steady‐state (V ss) was low at 0.09 L/kg. Compared with historical data from healthy adult volunteers administered a single dose of belatacept 10 mg/kg and adult kidney transplant recipients administered multiple doses of belatacept 5 mg/kg, pharmacokinetic values for adolescents were similar, indicating consistency across adolescent and adult populations. Mean %CD86RO increased with increasing belatacept concentration, indicating a direct relationship between pharmacokinetics and pharmacodynamics. Four patients reported 7 serious adverse events; none was considered related to belatacept. These data will inform belatacept dose selection in future studies of adolescent kidney transplant recipients., Results from a phase I study of adolescent renal transplant recipients administered a single intravenous infusion of belatacept at 7.5 mg/kg show comparable pharmacokinetic and pharmacodynamic values to those obtained historically from healthy adult volunteers given a single dose of belatacept (10 mg/kg) and adult kidney transplant recipients administered multiple doses of belatacept (5mg/kg/dose).

Evolving literature suggests that the epidemic of prescription opioid use affects the transplant population. We examined a novel database wherein national U.S. transplant registry records were linked to a large pharmaceutical claims warehouse (2007 to 2015) to characterize prescription opioid use before and after kidney transplant, and associations (adjusted hazard ratio, (95% LCL)aHR(95% UCL)) with death and graft loss. Among 75,430 eligible patients, 43.1% filled opioids in the year before transplant. Use was more common among recipients who were women, white, unemployed, publicly insured, and with longer pre-transplant dialysis. Of those with the highest level of pre-transplant opioid use, 60% continued high-level use post-transplant. Pre-transplant opioid use had graded associations with 1-year post-transplant outcomes; the highest-level use predicted 46% increased risk of death (aHR (1.28)1.46(1.66)) and 28% increased risk of all-cause graft failure (aHR (1.17)1.28(1.41)). Effects of high-level opioid use in the first year after transplant were stronger, predicting twice the risk of death (aHR (1.93)2.24(2.60)) and 68% higher all-cause graft loss risk (aHR (1.50)1.68(1.89)) over the subsequent year; increased risk persisted over 5 years. While associations may, in part, reflect underlying conditions or behaviors, opioid use history is relevant in assessing and providing care to transplant candidates and recipients.

A higher risk for a variety of cancers is among the major complications of posttransplantation immunosuppression. In this part of a continuing series on cancers posttransplantation, this review focuses on the hematologic cancers after solid organ transplantation. Posttransplantation lymphoproliferative disorders (PTLDs), which comprise the great majority of hematologic cancers, represent a spectrum of conditions that include, but are not limited to, the Hodgkin and non-Hodgkin lymphomas. The oncogenic Epstein-Barr virus is a key pathogenic driver in many PTLD cases, through known and unknown mechanisms. The other hematologic cancers include leukemias and plasma cell neoplasms (multiple myeloma and plasmacytoma). Clinical features vary across malignancies and location. Preventive screening strategies have been attempted mainly for PTLDs. Treatments include the chemotherapy regimens for the specific cancers, but also include reduction of immunosuppression, rituximab, and other therapies.

Steroid avoidance is safe and effective in children receiving kidney transplants in terms of graft function and survival, but the effects on allograft histology are unknown. In this multicenter trial, 130 pediatric renal transplant recipients were randomized to steroid-free (SF; n = 60) or steroid-based (SB; n = 70) immunosuppression, and underwent renal allograft biopsies at the time of graft dysfunction and per protocol at implantation and 6, 12 and 24 months after transplantation. Clinical follow-up was 3 years posttransplant. Subclinical acute rejection was present in 10.6% SF versus 11.3% SB biopsies at 6 months (p = 0.91), 0% SF versus 4.3% SB biopsies at 1 year (p = 0.21) and 0% versus 4.8% at 2 years (p = 0.20). Clinical acute rejection was present in 13.3% SF and 11.4% SB patients by 1 year (p = 0.74) and in 16.7% SF and 17.1% SB patients by 3 years (p = 0.94) after transplantation. The cumulative incidence of antibody-mediated rejection was 6.7% in SF and 2.9% in SB by 3 years after transplantation (p = 0.30). There was a significant increase in chronic histological damage over time (p < 0.001), without difference between SF and SB patients. Smaller recipient size and higher donor age were the main risk factors for chronic histological injury in posttransplant biopsies.

To determine whether steroid avoidance in pediatric kidney transplantation is safe and efficacious, a randomized, multicenter trial was performed in 12 pediatric kidney transplant centers. One hundred thirty children receiving primary kidney transplants were randomized to steroid-free (SF) or steroid-based (SB) immunosuppression, with concomitant tacrolimus, mycophenolate and standard dose daclizumab (SB group) or extended dose daclizumab (SF group). Follow-up was 3 years posttransplant. Standardized height Z-score change after 3 years follow-up was -0.99 ± 2.20 in SF versus -0.93 ± 1.11 in SB; p = 0.825. In subgroup analysis, recipients under 5 years of age showed improved linear growth with SF compared to SB treatment (change in standardized height Z-score at 3 years -0.43 ± 1.15 vs. -1.07 ± 1.14; p = 0.019). There were no differences in the rates of biopsy-proven acute rejection at 3 years after transplantation (16.7% in SF vs. 17.1% in SB; p = 0.94). Patient survival was 100% in both arms; graft survival was 95% in the SF and 90% in the SB arms (p = 0.30) at 3 years follow-up. Over the 3 year follow-up period, the SF group showed lower systolic BP (p = 0.017) and lower cholesterol levels (p = 0.034). In conclusion, complete steroid avoidance is safe and effective in unsensitized children receiving primary kidney transplants.

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; 0.51%), 13 937 HTX (140 PTLDs; 1.0%) and 40 437 LTX (383 PTLDs; 0.95%) performed January 2003 onward. The unadjusted hazard ratio (HR) for PTLD if recipient EBV seronegative was 5.005 for KTX, 6.528 for HTX and 2.615 for LTX (p < 0.001 for all). In models adjusted for multiple covariates, the adjusted HR was 3.583 (p < 0.001) for KTX, 4.037 (p < 0.001) for HTX, 1.479 (p = 0.03) for LTX. Interaction models using EBV seropositive KTX as reference group showed significantly higher risk for all other EBV seronegative organ transplant groups and also for EBV seropositive LTX (AHR 2.053, p < 0.0001).Recipient EBV seronegativity is still significantly associated with risk for PTLD in LTX, though less so because of higher baseline risk in the EBV seropositive LTX group.

Post-transplant lymphoproliferative disorder (PTLD) has been associated with high mortality, but recent anecdotal survival appeared better. From 1988 to 2010, the NAPRTCS registry had 235 registered PTLD cases. We sent a special 25-point questionnaire study to the NAPRTCS centers with the most recent 150 cases to obtain additional follow-up data not collected in the master registry, our objective being to determine the recent outcomes after PTLD and determine prognostic factors. We received 92 completed responses, in which only 12 (13%) deaths were reported, 2 from nonmedical causes, 10 with a functioning graft. Kaplan-Meier-calculated patient survival was 90.6% at 1 year and 87.4% at 3, 4 and 5 years post-PTLD. Graft survival post-PTLD was 81.8% at 1 year, 68.0% at 3 years and 65.0% at 5 years. Seven patients received a retransplant after PTLD, with no PTLD recurrence reported. Using all 235 PTLD cases, the covariates associated with better patient survival were more recent year of PTLD diagnosis (adjusted hazard ratio AHR 0.86, p < 0.001), and with worse survival were late PTLD (AHR 1.98, p = 0.0176) and patient age above 13 at PTLD (AHR 3.43, p value 0.022). In children with kidney transplants, patient survival has improved with more recent PTLDs.

BK virus (BKV) has emerged as a major complication of kidney transplantation. Since June 30, 2004, the OPTN in the USA collects BKV as a primary or secondary cause of graft loss and also if treatment for BK virus (TBKV) is administered. In this study, we determined characteristics of those recipients of repeat kidney transplants from the OPTN database, where either (a) a graft loss occurred between June 30, 2004 and December 31, 2008 and database recorded prior TBKV in that allograft or (b) a graft loss between June 30, 2004 and December 31, 2008 was attributed primarily or secondarily due to BKV. In the study time period, 823 graft losses have occurred where TBKV or graft failure attributable to BKV was reported in prior transplant; of these, 126 have received a retransplant as of June 5, 2009. Induction and maintenance immunosuppression usage mirrored current trends. As of June 5, 2009, 118/126 grafts are still functioning, one graft failure attributed to BKV. TBKV was reported in 17.5% of the retransplants. In the retransplants performed through December 31, 2007, 1-year acute rejection rate was 7%, 1-year and 3-year Kaplan-Meier graft survival rates and median GFR were 98.5%, 93.6%, 65.5 and 68.4 mL/min, respectively. Retransplantation after BKV appears to be associated with good results.

Transition of care from pediatric to adult-oriented health care providers is difficult for children with special health care needs. Children who have received solid organ transplants and their providers experience the same difficulties and frustrations as children with other major illnesses. A consensus conference was organized by several transplant organizations to identify major issues in this area and recommend possible approaches to easing the process of transition for solid organ transplant recipients. This report summarizes the discussions and recommendations.

Transplant patients are at the risk for posttransplant lymphoproliferative disease (PTLD), a virally-driven malignancy. Induction with the depleting antibody preparations Thymoglobulin and OKT3 is associated with PTLD suggesting that the T-cell depletion increases PTLD risk. We therefore studied 59 560 kidney recipients from the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) database for a relationship between induction agent use and PTLD. Two agents with comparable T-cell depletional effects, alemtuzumab and Thymoglobulin, were compared to nondepletional induction agents or no induction. The overall incidence of PTLD was 0.46% and differed significantly by induction strategy (p < 0.01): without induction (0.43%), basiliximab (0.38%), daclizumab (0.33%), Thymoglobulin (0.67%) and alemtuzumab (0.37%). Thymoglobulin was associated with significantly increased PTLD risk (p = 0.0025), but alemtuzumab (p = 0.74), basiliximab (p = 0.33) and daclizumab, which trended toward a protective effect (p = 0.06), were not. Alemtuzumab and Thymoglobulin treated patients did not differ in any established parameter affecting PTLD risk although alemtuzumab is known to have a more pronounced B-cell depleting effect. Interestingly, maintenance therapy with an mTOR inhibitor was strongly associated with PTLD (0.71%, p < 0.0001). Thus, depletional induction is not an independent risk factor for PTLD. Rather, maintenance drug selection or perhaps the balance between B- and T-cell depletion may be more relevant determinants of PTLD risk.

We previously showed that children are more likely to develop viral infections post-kidney transplant while adults are more likely to develop bacterial infections. In this study we determined the overall risk factors for hospitalization with either a bacterial (HBI) or a viral infection (HVI). We analyzed data from 28 924 United States Renal Data System (USRDS) Medicare primary renal transplant recipients from January 1996 to July 2000, for adjusted hazard ratio (AHR) for HBI or HVI in the first 3 years posttransplant. For HVI, significantly higher AHR was seen with (a) recipient age

With increasing donor organ shortages, en-bloc kidney (EBK) transplantation is an alternative to utilize very young or very old donor age cadaver kidneys for transplantation. Several single-center series have reported excellent graft survival (GS). We sought to determine national level registry-based patterns for GS and determine adjusted hazard ratios (AHR) for graft loss after EBK versus single kidney (SK) cadaver transplants. Data reported to UNOS from 1987 to 2003 were analyzed using PHREG (SAS version 8.1) statistical procedures. Proportional hazards models were constructed that included multiple donor, recipient and surgical variables. Of the 2160 EBK transplants reported, 77% were from donors < 5 years of age. EBK transplants had superior GS to SK transplants, when donor age was restricted to < 5 years (AHR 0.708, p < 0.001). GS at 1, 3 and 5 years post-transplant was superior with EBK (85%, 76% and 71%) versus SK (81%, 68%, 63% and p < 0.001 at all time points). EBK transplants from very young donors were associated with a significantly lower rate of delayed graft function than SK transplants (17.9% versus 23.4%, p < 0.001). National registry data suggest that EBK transplants present a viable option for transplantation of very young donor kidneys.