Racial disparities persist in access to renal transplantation in the United States, but the degree to which patient and neighborhood socioeconomic status (SES) impacts racial disparities in deceased donor renal transplantation access has not been examined in the pediatric and adolescent end-stage renal disease (ESRD) population. We examined the interplay of race and SES in a population-based cohort of all incident pediatric ESRD patients <21 years from the United States Renal Data System from 2000 to 2008, followed through September 2009. Of 8 452 patients included, 30.8%were black, 27.6% white-Hispanic, 44.3% female and 28.0% lived in poor neighborhoods. A total of 63.4% of the study population was placed on the waiting list and 32.5% received a deceased donor transplant. Racial disparities persisted in transplant even after adjustment for SES, where minorities were less likely to receive a transplant compared to whites, and this disparity was more pronounced among patients 18–20 years. Disparities in access to the waiting list were mitigated in Hispanic patients with private health insurance. Our study suggests that racial disparities in transplant access worsen as pediatric patients transition into young adulthood, and that SES does not explain all of the racial differences in access to kidney transplantation.
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Ali H. Charafeddine;
Eugenia J. Kim;
Dawn M. Maynard;
Hong Yi;
Timothy A. Weaver;
Meral Gunay-Aygun;
Maria C. Russell;
William A. Gahl;
Allan D Kirk
CD154 is an immunostimulatory ligand for CD40 that markedly influences alloimmunity. Its presence in platelets suggests that its release and subsequent immune effects are driven by trauma and thus could be relevant following organ transplantation. However, the release of platelet derived CD154 and its consequences have not been investigated in a clinical transplant setting. To better characterize the relationship between platelet activation and CD154 release, we investigated CD154 release by platelets obtained from normal individuals, and patients with two genetic defects that influence platelet granule development. Using these unique patient populations and immune-electron microscopy, we confirmed that CD154 was an alpha granule and not a cell surface protein, and thereafter optimized the methods for its in vivo measurement in humans. We then investigated plasma CD154 levels in kidney and liver transplant recipients and found no evidence that CD154 levels fluctuated systemically as a result of kidney or liver transplant procedures. Paradoxically, we found that kidney transplant patients had significantly lower systemic CD154 levels during episodes of rejection. These data suggest that the immune effects of CD154 are likely mediated through local and not systemic mechanisms, and discourage the use of CD154 as a peripheral biomarker in organ transplantation.
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Asha Moudgil;
Vikas R. Dharnidharka;
Daniel I. Feig;
Barry Warshaw;
Vidya Perera;
Bindu Murthy;
Mustimbo Roberts;
Martin S. Polinsky;
Robert B. Ettenger
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.
Allosensitized children who require a negative prospective crossmatch have a high risk of death awaiting heart transplantation. Accepting the first suitable organ offer, regardless of the possibility of a positive crossmatch, would improve waitlist outcomes but it is unclear whether it would result in improved survival at all times after listing, including posttransplant. We created a Markov decision model to compare survival after listing with a requirement for a negative prospective donor cell crossmatch (WAIT) versus acceptance of the first suitable offer (TAKE). Model parameters were derived from registry data on status 1A (highest urgency) pediatric heart transplant listings. We assumed no possibility of a positive crossmatch in the WAIT strategy and a base-case probability of a positive crossmatch in the TAKE strategy of 47%, as estimated from cohort data. Under base-case assumptions, TAKE showed an incremental survival benefit of 1.4 years over WAIT. In multiple sensitivity analyses, including variation of the probability of a positive crossmatch from 10% to 100%, TAKE was consistently favored. While model input data were less well suited to comparing survival when awaiting transplantation across a negative virtual crossmatch, our analysis suggests that taking the first suitable organ offer under these circumstances is also favored.
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Robert Ettenger;
Hyunsook Chin;
Karen Kesler;
Nancy Bridges;
Paul Grimm;
Elaine F. Reed;
Minnie Sarwal;
Richard Sibley;
Eileen Tsai;
Barry L Warshaw;
Allan D Kirk
The Immune Development in Pediatric Transplantation (IMPACT) study was conducted to evaluate relationships among alloimmunity, protective immunity, immune development, physical parameters, and clinical outcome in children undergoing kidney transplantation. We prospectively evaluated biopsy-proven acute rejection (BPAR), de novo donor-specific antibody (dnDSA) formation, viremia, viral infection, T cell immunophenotyping, and body mass index (BMI)/weight Z scores in the first year posttransplantation in 106 pediatric kidney transplant recipients. Outcomes were excellent with no deaths and 98% graft survival. Rejection and dnDSAs occurred in 24% and 22%, respectively. Pretransplant cytomegalovirus (CMV) and Epstein–Barr virus (EBV) serologies and subsequent viremia were unrelated to BPAR or dnDSA. Viremia occurred in 73% of children (EBV, 34%; CMV, 23%; BMK viremia, 23%; and JC virus, 21%). Memory lymphocyte phenotype at baseline was not predictive of alloimmune complications. Patients who developed viral infection had lower weight (−2.1) (p = 0.028) and BMI (−1.2) (p = 0.048) Z scores at transplantation. The weight difference persisted to 12 months compared with patients without infection (p = 0.038). These data indicate that there is a high prevalence of viral disease after pediatric kidney transplantation, and underweight status at transplantation appears to be a risk factor for subsequent viral infection. The occurrence of viremia/viral infection is not associated with alloimmune events.
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. Cumulative rates of biopsy-proven acute rejection (BPAR) from first randomization to year 10 were 22.8%, 37.0%, and 25.8% for belatacept more-intensive, belatacept less-intensive, and cyclosporine, respectively (belatacept more-intensive vs cyclosporine: hazard ratio [HR] = 0.95; 95% confidence interval [CI] 0.47-1.92; P =.89; belatacept less-intensive vs cyclosporine: HR = 1.61; 95% CI 0.85-3.05; P =.15). Cumulative BPAR rates from second randomization to year 10 for belatacept 4-weekly, belatacept 8-weekly, and cyclosporine were 11.1%, 21.9%, and 13.9%, respectively (belatacept 4-weekly vs cyclosporine: HR = 1.06, 95% CI 0.35-3.17, P =.92; belatacept 8-weekly vs cyclosporine: HR = 2.00, 95% CI 0.75-5.35, P =.17). Renal function trends were estimated using a repeated-measures model. Estimated mean GFR values at year 10 for belatacept 4-weekly, belatacept 8-weekly, and cyclosporine were 67.0, 68.7, and 42.7 mL/min per 1.73 m 2 , respectively (P < .001 for overall treatment effect). Although not statistically significant, rates of BPAR were 2-fold higher in patients administered belatacept every 8 weeks vs every 4 weeks.
Pretransplant exposure to donor antigen is known to modulate recipient alloimmunity, and frequently results in sensitization. However, donor-specific transfusion (DST) can have a protolerant effect that is dependent on route, dose and coadministered immunosuppression. Rodent studies have shown in some strain combinations that portal venous (PV) DST alone can induce tolerance, and uncontrolled clinical use of PVDST has been reported. In order to determine if pretransplant PVDST has a clinically relevant salutary effect, we studied it and the influence of concomitant immunosuppression in rhesus monkeys undergoing renal allotransplantation. Animals received PVDST with unfractionated bone marrow and/or tacrolimus or sirolimus 1 week prior to transplantation. Graft survival was assessed without any posttransplant immunosuppression. PVDST alone or in combination with tacrolimus was ineffective. However, PVDST in combination with sirolimus significantly prolonged renal allograft survival to a mean of 24 days. Preoperative sirolimus alone had no effect, and peripheral DST with sirolimus prolonged graft survival in 2/4 animals, but resulted in accelerated rejection in 2/4 animals. These data demonstrate that PVDST in combination with sirolimus delays rejection in a modest but measurable way in a rigorous model. It may thus be a preferable method for donor antigen administration.
Preemptive kidney transplantation is the optimal treatment for pediatric End Stage Renal Disease (ESRD) patients to avoid increased morbidity and mortality associated with dialysis. It is unknown how race/ethnicity and poverty influence preemptive transplant access in pediatric ESRD. We examined the incidence of living donor (LD) or deceased donor (DD) preemptive transplantation among all black, white, and Hispanic children (< 18 years) in the United States Renal Data System from 2000–2009. Adjusted risk ratios for preemptive transplant were calculated using multivariable-adjusted models and examined across health insurance and neighborhood poverty levels. Among 8,053 patients, 1117 (13.9%) received a preemptive transplant (66.9% from LD, 33.1% from DD). In multivariable analyses, there were significant racial/ethnic disparities in access to LD preemptive transplant where blacks were 66% (RR=0.34; 95% CI: 0.28–0.43) and Hispanics 52% (RR=0.48; 95% CI: 0.35–0.67) less likely to receive a LD preemptive transplant vs. whites. Blacks were 22% less likely to receive a DD preemptive transplant vs. whites (RR=0.78, 95% CI: 0.57–1.05) although results were not statistically significant. Future efforts to promote equity in preemptive transplant should address the critical issues of improving access to pre-ESRD nephrology care and overcoming barriers in living donation, including obstacles partially driven by poverty.
Tacrolimus impairs allo- and viral-specific T cell responses. Belatacept, a costimulation-based alternative to tacrolimus, has emerged with a paradoxical picture of less complete control of alloimmunity with concomitant impaired viral immunity limited to viral-naïve patients. To reconcile these signatures, bulk population and purified memory and naïve lymphocytes from cytomegalovirus (CMV)-seropositive (n = 10) and CMV-seronegative (n = 10) volunteers were studied using flow cytometry, interrogating proliferation (carboxyfluorescein succinimidyl ester dilution) and function (intracellular cytokine staining) in response to alloantigens or CMV-pp-65 peptides. As anticipated, T cells from CMV-experienced, but not naïve, individuals responded to pp-65 with a small percentage of their repertoire (<2.5%) consisting predominantly of mature, polyfunctional (expressing interferon gamma, tumor necrosis factor alpha and IL-2) T effector memory cells. Both CMV naïve and experienced individuals responded similarly to alloantigen with a substantially larger percentage of the repertoire (up to 48.2%) containing proportionately fewer polyfunctional cells. Tacrolimus completely inhibited responses of CMV- and allo-specific T cells regardless of their maturation. However, belatacept's effects were decreasingly evident in increasingly matured cells, with minimal effect on viral-specific triple cytokine producers and CD28-negative allo-specific cells. These data indicate that belatacept's immunosuppressive effect, unlike tacrolimus's, wanes on progressively developed effector responses, and may explain the observed clinical effects of belatacept. The authors characterize CMV- and allo-specific memory T cells and show that belatacept has decreasing inhibitory effect on increasingly matured memory cells, and minimal effect on the most highly differentiated CMV- and allo-specific cells.