Perceived barriers to adherence have previously been investigated in SOT to identify plausible intervention targets to improve adherence and transplant outcomes. Fifteen centers in CTOTC enrolled patients longitudinally. Patients >8 years completed Adolescent Scale(AMBS) at two visits at least 6 months apart in the first 17 months post-transplant while their guardians completed PMBS. Differences over time for pre-identified AMBS/PMBS factors were analyzed. Perceived barrier reporting impact on subsequent TAC levels was assessed. A total of 123 patients or their guardians completed PMBS or AMBS. Twenty-six were 6-11 years and 97 were >= 12. The final cohort consisted of kidney (66%), lung (19%), liver (8%), and heart (7%) recipients. Unadjusted analysis showed no statistically significant change in reported barriers from visit 1 (median 2.6 months, range 1.2-3.7 post-transplant) to visit 2 (median 12, range 8.9-16.5). Of 102 patients with TAC levels, 74 had a single level reported at both visits. The factor of "Disease frustration" was identified through the PMBS/AMBS questions about fatigue around medication and disease. Each point increase in "disease frustration" at visit 1 on the AMBS/PMBS doubled the odds of a lower-than-threshold TAC level at visit 2. No clear change in overall level of perceived barriers to medication adherence in the first year post-transplant was seen in pediatric SOT. However, disease frustration early post-transplant was associated with a single subtherapeutic TAC levels at 12 months. A brief screening measure may allow for early self-identification of risk.

Staging of heart failure represents a major issue in clinical practice. In this setting, the MOGE(S) classi fi cation was designed to be similar to the TNM classi fi cation used in oncology. Nevertheless, MOGE(S) nosology differs greatly from the key elements of the TNM classi fi cation, as well as its simplicity and clinical applicability. In fact, MOGE(S) acronym stands for morphofunctional characteristics (M), organ involvement (O), genetic or familial inheritance pattern (G), etiological information (E), and functional status (S). Recently, a new TNM-like classi fi cation for heart failure was proposed. This classi fi cation, named HLM, refers to heart damage arising from an initial stage of impaired systolic or diastolic function, without structural injury, to an advanced stage of biventricular dysfunction (H), different stages of lung involvement (L), and malfunction of peripheral organs such as the kidney, liver, and brain (M). HLM classi fi cation was in fl uenced by the key elements of TNM staging: simplicity, clinical usefulness, ef fi cacy for planning a therapeutic strategy, and ability to determine patient prognosis. HLM classi fi cation seems to be easily applied in the real world and valuable for balancing economic resources with the clinical complexity of patients. (J Am Coll Cardiol 2014;63:1959 – 60) ª 2014 by the American College of Cardiology Foundation

Twenty percent of pediatric patients experience an acute rejection (AR) episode in the first year post-kidney transplantation (KT). We aimed to identify mRNA signature in non-invasive specimens—peripheral blood cells (PBC) and urinary cells (UC)—to diagnose AR without the need for biopsy. Living donor KT patients (N=34) were enrolled in a NIAID sponsored multicenter calcineurin inhibitor avoidance (CN01) study. Biopsies, PBC, and UC were collected on month 3, 6, 12, and at the time of for-cause biopsy collection. Using real-time PCR, levels of FOXP3, GZMB, IP10, TGF-b1 and BKV mRNA, and 18S rRNA in UC, PBC, and biopsies, along with several other immune related genes in PBC and biopsies, were quantified. Gene expression levels were normalized by 18S rRNA expression and log10-transformed for statistical analysis. Univariate and multivariable logistic regression using step-wise variable selection (p<0.10 for inclusion) was used to identify mRNA signatures diagnostic of AR in concurrent UC, PBC and biopsies. Model accuracy and reliability were assessed using bootstrap resampling to estimate adjusted AUC of the final models by ROC analysis. Although expression of tested genes in UC (N=48 (AR=11 (Protocol-biopsies (P)=8; Suspected rejection (SR)=3, BKV-VP1 mRNA positive=2); Non rejection (NR)=37 (P=36; SR=1, BKV-VP1 mRNA positive=3)) was not diagnostic of AR, expression of GATA3, OR=3.55 (0.87, 14.52), and HO-1, OR=0.56 (0.31, 1.02), in PBC (N=45 (AR=7 (P=6; SR=1); NR=38 (P=36; SR=2))) was associated with AR (adjusted AUC=0.70, sensitivity=71.4% and specificity=71.1%). Similarly, expression of CXCR3, OR=0.27 (0.07, 0.99), and MIG, OR=21.48 (2.54, 181.5), in biopsies (N=50 (AR=12 (P=7; SR=5); NR=38 (P=33; SR=5))) was associated with AR (adjusted AUC=0.82, sensitivity=83.3% and specificity=71.1%). This study shows potential for development of molecular profiling of select targets using PBC specimens to diagnose AR.

Background: Many pediatric transplant (TX) centers routinely monitor Epstein-Barr (EB) viral load (VL) by real time quantitative PCR and intervene to prevent post-transplant lymphoproliferative disorder (PTLD). Some children develop asymptomatic persistent VL (PVL). Outcome of different interventions in preventing PTLD and other undesired effects on acute rejection (AR), graft failure (GF) and function amongst children with asymptomatic PVL is not known. Methods: NAPRTCS centers invited to enter data on children with asymptomatic PVL (≥ 6 months) into the EB VL registry. Comparison group included children into the NAPRTCS TX arm during the same period without PVL or VL monitoring. EB VL were arbitrarily divided into low (1-10), medium (>10-100) and high (>100times detection limit for the center) ratio. Results: Of 645 children (18 centers), 85 (13.2%) developed onset of PVL at a mean of 6.4 ± 6.3 months post-TX. PVL children were more likely to be younger (< 5 years) at TX and less likely to be African-American and majority (75.3%) was mismatched for EBV (donor EBV IgG positive and recipient negative). Thymoglobulin induction was used in 29.4% children with PVL versus 37% in controls (p=ns). PTLD developed in 7/85 (8.2%) children with PVL versus 5/560 (0.9%) controls (p < 0.0001). EB VL ratios were not different in those with and without PTLD. EB PVL as time varying covariate did not affect patient survival, GF and AR (HR, 0.85, 0.53 and 0.99). The change in GFR overtime in children with PVL was comparable to controls. Conclusion: Children with PVL (actual load not predictive) are at increased risk for PTLD, but not for AR, death, GF or loss of graft function.

Chapter 113 Pediatric Kidney Transplantation William Harmon, William Harmon Boston Children's Hospital, Boston, MA, USASearch for more papers by this author William Harmon, William Harmon Boston Children's Hospital, Boston, MA, USASearch for more papers by this author Book Editor(s):Allan D. Kirk MD, PhD, FACS, Allan D. Kirk MD, PhD, FACS Professor and Chairman, Department of Surgery, Duke University School of Medicine;, Surgeon-in-Chief for Duke University Health System, Duke University Medical Center, Durham, NC, USASearch for more papers by this authorStuart J. Knechtle MD, Stuart J. Knechtle MD Professor of Surgery, Emory University School of Medicine, Atlanta, GA, USASearch for more papers by this authorChristian P. Larsen MD, DPhil, Christian P. Larsen MD, DPhil Dean – Emory School of Medicine, Surgeon-in-Chief Emory Healthcare, Emory University, Atlanta, GA, USASearch for more papers by this authorJoren C. Madsen MD, DPhil, Joren C. Madsen MD, DPhil Professor of Surgery, W. Gerald and Patricia R. Austen, Distinguished Scholar in Cardiac Surgery, Massachusetts General Hospital, Boston, MA, USASearch for more papers by this authorThomas C. Pearson MD, Thomas C. Pearson MD Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USASearch for more papers by this authorSteven A. Webber MBChB, MRCP, Steven A. Webber MBChB, MRCP James C. Overall Professor and Chair, Department of Pediatrics, Monroe Carell Jr. Children's Hospital at Vanderbilt, Vanderbilt University School of Medicine, Nashville, TN, USASearch for more papers by this author First published: 25 July 2014 https://doi.org/10.1002/9781118873434.ch113 AboutPDFPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShareShare a linkShare onEmailFacebookTwitterLinkedInRedditWechat Summary Kidney transplantation is in children, as in adults, the preferred treatment for most causes of end stage renal disease. However, the indications bringing children to require transplantation differ from those of adults, as do the co-morbidities. Additionally, the pediatric population offers unique technical challenges related to congenital anomalies, social support concerns and issues of non-adherence, and nuances of immune, physical and emotional maturity that clearly distinguishes the practice of pediatric transplantation from adult transplantation. This chapter will provide an overview of pediatric kidney transplantation with particular attention directed toward those aspects of the patient population served that define the field. References Gaston RS, Danovitch GM, Adams PL, et al. The report of a national conference on the wait list for kidney transplantation. American Journal of Transplantation. 2003; 3(7): 775–785. 10.1034/j.1600-6143.2003.00146.x PubMedGoogle Scholar Fine RN. Renal transplantation for children-the only realistic choice. Kidney International. Supplement. 1985; 17(7): S15–S17. 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This review discusses unique aspects of kidney transplantation in children that necessitate specialized approaches and have resulted in clinical advances so that kidney transplantations in young children have higher success rates than in any other age group.

The development of anti-donor humoral responses after transplantation associates with higher risks for acute rejection and 1-year graft survival in adults, but the influence of humoral immunity on transplant outcomes in children is not well understood. Here, we studied the evolution of humoral immunity in low-risk pediatric patients during the first 2 years after renal transplantation. Using data from 130 pediatric renal transplant patients randomized to steroid-free (SF) or steroid-based (SB) immunosuppression in the NIH-SNSO1 trial, we correlated the presence of serum anti-HLA antibodies to donor HLA antigens (donor-specific antibodies) and serum MHC class 1-related chain A (MICA) antibody with both clinical outcomes and histology identified on protocol biopsies at 0, 6, 12, and 24 months. We detected de novo antibodies after transplant in 24% (23% of SF group and 25% of SB group), most often after the first year. Overall, 22% developed anti-HLA antibodies, of which 6% were donor-specific antibodies, and 6% developed anti-MICA antibody. Presence of these antibodies de novo associated with significantly higher risks for acute rejection (P=0.02), chronic graft injury (P=0.02), and decline in graft function (P=0.02). In summary, antibodies to HLA and MICA antigens appear in approximately 25% of unsensitized pediatric patients, placing them at greater risk for acute and chronic rejection with accelerated loss of graft function. Avoiding steroids does not seem to modify this incidence. Whether serial assessments of these antibodies after transplant could guide individual tailoring of immunosuppression requires additional study.

Kidney transplant recipients have an increased risk of cancer. Data on non-LPD malignancies (solid tumors) in pediatric renal transplant recipients are limited. We performed a cohort study using the NAPRTCS transplant registry to describe the incidence of non-LPD malignancy compared with the general pediatric population. The observed incidence rate of non-LPD malignancy in the NAPRTCS transplant registry was 72.1 per 100,000 person-years (SIR 6.7; 95% CI, 5.3, 8.5); a 6.7-fold increased risk compared with the general pediatric population (10.7 cases per 100,000 person-years). Non-LPD malignancy was diagnosed in 35 subjects at a median of 726 days post-transplant. The most common type of malignancy was renal cell carcinoma. The increased risk of non-LPD malignancy was seen in all patients regardless of age, gender, race, etiology of end-stage kidney disease, and transplant era. The specific type of immunosuppression was not identified as a risk factor. In this first large-scale study of North American pediatric renal transplant recipients, we observed a 6.7-fold increased risk of non-LPD malignancy compared with the general pediatric population. Further examination of this unique patient population may provide greater insight into the impact of transplant and immunosuppression on malignancy risk.

The incidence of developing circulating anti-human leukocyte antigen antibodies and the kinetics of T cell depletion and recovery among pediatric renal transplant recipients who receive alemtuzumab induction therapy are unknown. In a collaborative endeavor to minimize maintenance immunosuppression in pediatric renal transplant recipients, we enrolled 35 participants from four centers and treated them with alemtuzumab induction therapy and a steroid-free, calcineurin-inhibitor-withdrawal maintenance regimen. At 3 months after transplant, there was greater depletion of CD4(+) than CD8(+) T cells within the total, naive, memory, and effector memory subsets, although depletion of the central memory subset was similar for CD4(+) and CD8(+) cells. Although CD8(+) T cells recovered faster than CD4(+) subsets overall, they failed to return to pretransplant levels by 24 months after transplant. There was no evidence for greater recovery of either CD4(+) or CD8(+) memory cells than naïve cells. Alemtuzumab relatively spared CD4(+)CD25(+)FoxP3(+) regulatory T cells, resulting in a rise in their numbers relative to total CD4(+) cells and a ratio that remained at least at pretransplant levels throughout the study period. Seven participants (20%) developed anti-human leukocyte antigen antibodies without adversely affecting allograft function or histology on 2-year biopsies. Long-term follow-up is underway to assess the potential benefits of this regimen in children.

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.

Monitoring of renal graft status through peripheral blood (PB) rather than invasive biopsy is important as it will lessen the risk of infection and other stresses, while reducing the costs of rejection diagnosis. Blood gene biomarker panels were discovered by microarrays at a single center and subsequently validated and cross-validated by QPCR in the NIH SNSO1 randomized study from 12 US pediatric transplant programs. A total of 367 unique human PB samples, each paired with a graft biopsy for centralized, blinded phenotype classification, were analyzed (115 acute rejection (AR), 180 stable and 72 other causes of graft injury). Of the differentially expressed genes by microarray, Q-PCR analysis of a five gene-set (DUSP1, PBEF1, PSEN1, MAPK9 and NKTR) classified AR with high accuracy. A logistic regression model was built on independent training-set (n = 47) and validated on independent test-set (n = 198)samples, discriminating AR from STA with 91% sensitivity and 94% specificity and AR from all other non-AR phenotypes with 91% sensitivity and 90% specificity. The 5-gene set can diagnose AR potentially avoiding the need for invasive renal biopsy. These data support the conduct of a prospective study to validate the clinical predictive utility of this diagnostic tool.

Purpose: Belatacept is a novel co-stimulatory blocker approved for prophylaxis of organ rejection in adult recipients of kidney transplants. It is a fully-human fusion protein that binds to CD80 and CD86, and blocks the CD28 co-stimulation pathway to prevent T-cell activation. CD28 is a co-stimulatory molecule expressed on T cells that binds CD80 and CD86 on antigen presenting cells. In general, CD86 is constitutively expressed on APCs and upon stimulation is rapidly up-regulated, whereas CD80 requires stimulation for expression on the surface of most APCs. This study evaluated and compared CD80 and CD86 expression on monocytes, B cells and myeloid dendritic cells (mDC), as well as belatacept binding to CD86, in adult and pediatric whole blood. Methods: Blood samples were obtained from pediatric patients (age 4-17 yrs) with chronic kidney disease and normal adult volunteers. Expression of CD80 and CD86 was evaluated using a whole blood flow cytometry-based assay. CD86 binding was assessed using a receptor competition assay. Statistical significance was calculated with a twosample unequal variance t-test. Results: CD80 and CD86 expression patterns were comparable between pediatric and adult blood samples. CD86 was expressed at high levels on monocytes and mDC and at very low levels on B cells in both pediatric and adult samples. However, the mean percentage of CD86+ mDC was higher in pediatric patients (69.0±10.0% SD) compared to adults (51.8±12.0% SD, P< 0.001). CD80 was expressed at low levels on monocytes and mDCs, and at slightly higher levels on B cells in pediatric patients and adults. CD80 expression in all cells was much lower overall than expression of CD86.Table: [CD80 and CD86 receptor levels in whole blood]Belatacept-mediated CD86 receptor saturation on monocytes in whole blood was similar between pediatric patients (IC50 = 0.340±0.250 μg/mL) and adults (IC50 = 0.220±0.190 μg/mL). Conclusion: Expression patterns of CD86 and CD80 were comparable between pediatric and adult blood samples. Belatacept binding to CD86 was similar in pediatric and adult blood samples, thereby supporting the investigation of belatacept therapy for pediatric renal transplant recipients.

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.