A. Burnette

Association of Human Leukocyte Antigen Donor–Recipient Matching and Pediatric Heart Transplant Graft Survival

Background—The effect of donor–recipient human leukocyte antigen (HLA) matching on outcomes remains relatively unexplored in pediatric patients. The objective of this study was to investigate the effects of donor–recipient HLA matching on graft survival in pediatric heart transplantation. Methods and Results—The UNOS (United Network for Organ Sharing) database was queried for heart transplants occurring between October 31, 1987, and December 31, 2012, in a recipient aged ⩽17 years with ≥1 postoperative follow-up visit. Retransplants were excluded. Transplants were divided into 3 donor–recipient matching groups: no HLA matches (HLA-no), 1 or 2 HLA matches (HLA-low), and 3 to 6 HLA matches (HLA-high). Primary outcome was graft loss. Four thousand four hundred seventy-one heart transplants met the study inclusion criteria. High degree of donor–recipient HLA matching occurred infrequently: HLA-high (n=269; 6%) versus HLA-low (n=2683; 60%) versus HLA-no (n=1495; 34%). There were no differences between HLA matching groups in the frequency of coronary vasculopathy (P=0.19) or rejection in the first post-transplant year (P=0.76). Improved graft survival was associated with a greater degree of HLA donor–recipient matching: HLA-high median survival, 17.1 (95% confidence interval, 14.0–20.2) years; HLA-low median survival, 14.2 (13.1–15.4) years; and HLA-no median survival, 12.1 (10.9–13.3 years) years; P<0.01, log-rank test. In Cox-regression analysis, HLA matching was independently associated with decreased graft loss: HLA-low versus HLA-no hazard ratio, 0.86 (95% confidence interval, 0.74–0.99), P=0.04; HLA-high versus HLA-no, 0.62 (95% confidence interval, 0.43–0.90), P<0.01. Conclusions—Decreased graft loss in pediatric heart transplantation was associated with a higher degree of donor–recipient HLA matching, although a difference in the frequency of early rejection or development of coronary artery vasculopathy was not seen.

Effect of Induction Therapy on Graft Survival in Primary Pediatric Heart Transplantation: A Propensity Score Analysis of the Unos Database

Background The use of induction therapy in pediatric heart transplantation has increased. The aim of this study was to investigate the effects of induction therapy on graft survival. Methods The United Network for Organ Sharing database was queried for isolated pediatric heart transplants from January 1, 1994, to December 31, 2013. Propensity scores for induction treatment were calculated by estimating probability of induction using a logistic regression model. Transplants were then matched between induction treatment groups based on the propensity score, reducing potential biases. Using only propensity score matched transplants, the effect of induction therapy on graft survival was investigated using Cox-proportional hazards. Subgroup analyses were performed based on age, race, recipient cardiac diagnosis, HLA, and recipient panel-reactive antibody (PRA). Results Of 4565 pediatric primary heart transplants from 1994 to 2013, 3741 had complete data for the propensity score calculation. There were 2792 transplants successfully matched (induction, n = 1396; no induction, n = 1396). There were no significant differences in transplant and pretransplant covariates between induction and no induction groups. In the Cox-proportional hazards model, the use of induction of was not associated with graft loss (hazard ratio [HR], 0.88; 95% confidence interval [95% CI], 0.75-1.01; P = 0.07). In subgroup analyses, induction therapy may be associated with improved survival in patients with PRA greater than 50% (HR, 0.57; 95% CI, 0.34-0.97) and congenital heart disease (HR, 0.78; 95% CI, 0.64-0.96). Conclusions Induction therapy is not associated with improved graft survival in primary pediatric heart transplantation. However, in pediatric heart transplant recipients with PRA greater than 50% or congenital heart disease, induction therapy is associated with improved survival.

Effect of human leukocyte antigen-C and -DQ matching on pediatric heart transplant graft survival

BACKGROUND A higher degree of human leukocyte antigen (HLA) matching at the A, B, and DR loci has been associated with improved long-term survival after pediatric heart transplantation in multiple International Society for Heart and Lung Transplantation registry reports. The aim of this study was to investigate the association of HLA matching at the C and DQ loci with pediatric graft survival. METHODS The United Network of Organ Sharing database was queried for isolated heart transplants that occurred from 1988 to 2012 with a recipient age of 17 or younger and at least 1 postoperative follow-up encounter. When HLA matching at the C or DQ loci were analyzed, only transplants with complete typing of donor and recipient at the respective loci were included. Transplants were divided into patients with at least 1 match at the C locus (C-match) vs no match (C-no), and at least 1 match at the DQ (DQ-match) locus vs no match (DQ-no). Primary outcome was graft loss. Univariate analysis was performed with the log-rank test. Cox regression analysis was performed with the following patient factors included in the model: recipient age, ischemic time; recipient on ventilator, extracorporeal membrane oxygenation, ventricular assist device, or inotropes at transplant; recipient serum bilirubin and creatinine closest to transplant, ratio of donor weight to recipient weight, underlying cardiac diagnosis, crossmatch results, transplant year, and HLA matching at the A, B, and DR loci. RESULTS Complete typing at the C locus occurred in 2,429 of 4,731 transplants (51%), and complete typing at the DQ locus occurred in 3,498 of 4,731 transplants (74%). Patient factors were similar in C-match and C-no, except for year of transplant (median year, 2007 [interquartile range, 1997-2010] vs year 2005 [interquartile range, 1996-2009], respectively; p = 0.03) and the degree of HLA matching at the A, B, and DR loci (high level of HLA matching in 11.9% vs 3%, respectively; p < 0.01). Matching at the C locus was not associated with a decreased risk of graft loss (median graft survival: 13.1 years [95% confidence interval {CI}, 11.5-14.8] in C-no vs 15.1 years [95% CI, 13.5-16.6) in C-match, p = 0.44 log-rank; hazard ratio, 0.93; 95% CI, 0.76-1.15; p = 0.52). DQ-match did not differ from DQ-no in any of the analyzed patient factors, except DQ-match was more likely to have high degree of matching at the A, B, and DR loci vs DQ-no (9.8% vs 3.2%, p < 0.01). Matching at the DQ locus was not associated with decreased risk of graft loss (median graft survival: DQ-no, 13.1 years [95% CI, 11.7-14.6) vs DQ-match, 13.0 years [95% CI, 11.4-14.6], p = 0.80, log-rank; hazard ratio, 0.95; 95% CI, 0.81-1.1; p = 0.51. CONCLUSIONS Complete typing at the C locus of both donor and recipient occurs less often then typing at the DQ locus. A higher degree of donor-recipient HLA matching at the C locus or the DQ locus appears not to confer any graft survival advantage.

Autoimmune enteropathy and hepatitis in pediatric heart transplant recipient

AIE is a rare disorder in children that presents with severe diarrhea and malabsorption, caused by immune‐mediated damage to intestinal mucosa. AIE is often associated with various syndromes of immunodeficiency including IPEX syndrome (immune dysregulation, polyendocrinopathy and enteropathy, X‐linked). Dysfunctional T regulatory cells are the source of pathology in both IPEX syndrome and AIE as they are essential in maintaining tolerance to self‐antigens and eliminating autoreactive B cells. This case report describes a 10‐year‐old cardiac transplant and total thymectomy patient on chronic immunosuppression with tacrolimus that presented with AIE and extraintestinal manifestations of cyclical hepatitis. Transition from tacrolimus to sirolimus successfully increased T regulatory cells and resolved enteritis and hepatitis symptoms. Data support that thymectomy at <1 year of age increases risk of autoimmune disease due to abnormal immune maturation. Studies suggest that the sirolimus promotes the upregulation of the FoxP3 protein that is classically associated with Tregs. In turn, Tregs prevent the maturation of autoreactive B cells that lead to autoimmune reactions.

Pre-Solid Organ Transplantation Vaccination Status: Opportunities Revealed!.: Abstract# A364

A365 Donor-Specific Anti-HLA Antibodies at the Time of Kidney Transplant Biopsy Associates With Late Graft Failure in Pediatric Renal Transplant Recipients. A. Fichtner,1 B. Hoecker,1 S. Rieger,1 R. Waldherr,2 G. Opelz,3 C. Suesal,3 B. Toenshoff.1 1University Children’s Hospital, Heidelberg, Germany; 2Institute for Clinical Pathology, Heidelberg, Germany; 3Institute of Immunology, Heidelberg, Germany. Purpose: The role of antibody-mediated rejection (AMR) for late kidney transplant failure in pediatric renal transplant (RTx) recipients is poorly defi ned. We therefore investigated the frequency of anti-HLA donor-specifi c antibodies (DSA) in patients requiring a late (>1 year post-transplant) indication graft biopsy, and the association of these fi ndings with graft outcome. Methods: 54 patients undergoing a late biopsy between January 2005 and June 2012 at our institution were investigated. Inclusion criteria were 1st RTx and a transplant date after December 1998. Patients were tested for DSA using the LABScreen Luminex kit (One Lambda, Canoga Park, CA, USA) at the time of biopsy and pre-transplant. A mean fl uorescence intensity (MFI) of >500 was used to defi ne the cutoff for antibody positivity. Results: 21/54 (39%) of the tested patient sera were DSA positive at the time of biopsy. In 20/54 patients (37%) the DSA were directed against HLA class II antigens; class II DQ and DR DSA occurred with the same frequency (12/20 and 13/20). In 10/54 patients (19%), the DSA were directed against class I and in 9/54 patients (17%) against both class I and II. 60% of these antibodies were de novo DSA. The DSA+ cohort showed signifi cantly (p=0.02) more often proteinuria than the DSAcohort. Median follow-up was 44 months. The 4-year graft survival was signifi cantly inferior in the DSA+ (42%) compared to the DSAcohort (89%; p=0.002, log-rank test). Patients with DSA and positive C4d staining in the graft biopsy showed the worst outcome (24% graft survival at 4 years). Overall 13 grafts failed; 10/13 (77%) patients were DSA positive, 2/13 were DSA negative, but C4d positive, and 1 graft was lost due to treatment-resistant acute T-cell mediated rejection. Maximal MFI of class II DSA was signifi cantly (p=0.01) higher in the group with graft failure. eGFR <30 ml/min·1.73 m2 (hazard ratio (HR) 3.8), DSA positivity (HR 5.4) and positive C4d staining (HR 3.4) were signifi cant factors associated with graft loss. Conclusions: Anti-HLA DSA at the time of a late graft biopsy for clinical indication in pediatric RTx recipients is primarily against class II antigens and associates with subsequent graft failure. As many as 92% of the graft failures in this cohort could be attributed to AMR. Abstract# A366 Is Vitamin D Insuffi ciency Common in Pediatric Kidney Transplant Patients With Rejection? K. Twombley,2 O. Moussa.1 1Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC; 2Pediatrics, Medical University of South Carolina, Charleston, SC. Background It is estimated that as many as 74% of children are 25-hydroxyvitamin D [25(OH)D] defi cient post kidney transplantation. Most of the immune system cells express vitamin D receptors, and active 25(OH)D is well-known to have immunomodulatory activities. The mechanisms of how alterations in 25(OH)D levels infl uence the clinical outcomes of pediatric kidney transplant patients are not known, and there has been debate regarding the optimal target level of 25(OH)D. Objective Study 25(OH)D serum levels in pediatric kidney transplant pts that experienced rejection episode(S) and compare to pts without episodes of rejection. Design/MethodsA retrospective chart review was conducted of pediatric kidney transplant pts (<18yr) who had 25(OH)D levels checked between 2012-2013. Data were collected using medical records. Patients were excluded if they did not have a 25(OH)D level drawn. Results 37 kidney transplant recipients were eligible for review. 7 patients had a rejection during that time. The mean 25(OH)D level in the rejection group was 23.8ng/ml (+/14.9) and the mean 25(OH)D in the group that did not have a rejection was 35.6ng/ml (+/12.3) p=0.034. 57% (4/7) of the pts with rejection had 25(OH)D<30ng/ml. A366 Is Vitamin D Insuffi ciency Common in Pediatric Kidney Transplant Patients With Rejection? K. Twombley,2 O. Moussa.1 1Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC; 2Pediatrics, Medical University of South Carolina, Charleston, SC. Background It is estimated that as many as 74% of children are 25-hydroxyvitamin D [25(OH)D] defi cient post kidney transplantation. Most of the immune system cells express vitamin D receptors, and active 25(OH)D is well-known to have immunomodulatory activities. The mechanisms of how alterations in 25(OH)D levels infl uence the clinical outcomes of pediatric kidney transplant patients are not known, and there has been debate regarding the optimal target level of 25(OH)D. Objective Study 25(OH)D serum levels in pediatric kidney transplant pts that experienced rejection episode(S) and compare to pts without episodes of rejection. Design/MethodsA retrospective chart review was conducted of pediatric kidney transplant pts (<18yr) who had 25(OH)D levels checked between 2012-2013. Data were collected using medical records. Patients were excluded if they did not have a 25(OH)D level drawn. Results 37 kidney transplant recipients were eligible for review. 7 patients had a rejection during that time. The mean 25(OH)D level in the rejection group was 23.8ng/ml (+/14.9) and the mean 25(OH)D in the group that did not have a rejection was 35.6ng/ml (+/12.3) p=0.034. 57% (4/7) of the pts with rejection had 25(OH)D<30ng/ml. Table 1 All n=37 Rjx n=7 No Rjx n= 30 P Age 12.6 15.3±2.9 11.2±4.7 NS Sex, F 17(46%) 1 (14%) 15 (50%) 0.12 Race AA W H 18 (48.5%)