Andrew Savage

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.

Treatment of BK viremia in a pediatric heart transplant recipient

A 9-year-old, 16-kg (body surface area 0.7 m2) girl, 8 years post-transplant, was referred to our heart transplant clinic after a family relocation. She had developed renal insufficiency, which was attributed to calcineurin-induced nephrotoxicity. Multiple months prior to her presentation to our clinic, she was switched to a lower dose of tacrolimus, and sirolimus was added to her anti-rejection regimen. Despite these changes, her renal function worsened with a peak serum creatinine of 1.9 mg/dl, and she developed hematuria. Further evaluation included urine and serum BK viral polymerase chain reaction tests, which were positive at 1.22e10 copies/ml and 7.13e5 copies/ml, respectively (SmartCycler; Cepheid, Sunnyvale, CA). Creatinine clearance at that time was measured by a 24-hour urine collection to be 20 ml/min/1.73 m2. Subsequent renal biopsy performed showed BK virus nephropathy (Figure 1). Figure 1 Immunohistochemical stain for big “T” antigen specific for polyoma virus replication. The tubule in the center of the figure is positive for big T antigen, as demonstrated by its dark brown color. The patient was initiated on leflunomide (Arava; Sanofi Aventis, Bridgewater, NJ) to aggressively treat BK virus nephropathy and to decrease the risk of rejection. Leflunomide was started 2 weeks after stopping the sirolimus. The tacrolimus goal level while on leflunomide was 8 to 10 ng/ml. Her leflunomide regimen consisted of 40 mg/day for 2 days, and then maintenance therapy at 10 mg/day.1 Teriflunomide (Mayo Medical Laboratories, St. Paul, MN) levels were checked monthly, with goal of 30 to 60 μg/ml. Liver chemistries, electrolytes and complete blood counts were checked bi-weekly. She was maintained on leflunomide 10 mg/day for the vast majority of treatment (range 7.5 to 15 mg/day). Therapy was withheld twice during the course of treatment due to mild rise in transaminases. After 10 months of therapy, serum BK viral load decreased to 1,176 copies/ml and creatinine was 1.1 mg/dl (Figure 2). Leflunomide treatment was stopped based on improved kidney function and reduced BK viremia. She was maintained on tacrolimus alone until teriflunomide levels were undetectable, and then sirolimus was restarted. The patient has maintained a serum creatinine of 1.2 mg/dl at 5 months after stopping leflunomide. Figure 2 Serum creatinine and serum BK viral load over time, with Week 0 being the time of biopsy. Therapy was held from Weeks 18 to 22 (influenza) and Weeks 36 to 38 (teriflunomide level 81 μg/ml). Leflunomide began at Week 4.

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.

Continuous-flow, implantable biventricular assist device as bridge to cardiac transplantation in a small child with restrictive cardiomyopathy

Continuous-flow, implantable biventricular assist device as bridge to cardiac transplantation in a small child with restrictive cardiomyopathy Lauren Glass, MD, Andrew Savage, MD, Osama Haddad, MD, and Minoo N. Kavarana, MD From the Department of Pediatrics, Division of Pediatric Cardiology, Medical University of South Carolina, Charleston, South Carolina, USA; and the Department of Surgery, Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina, USA

Decline in ventricular function as a result of general anesthesia in pediatric heart transplant recipients

Echocardiography is frequently performed under anesthesia during procedures such as cardiac catheterization with EMB in pediatric HTx recipients. Anesthetic agents may depress ventricular function, resulting in concern for rejection. The aim of this study was to compare ventricular function as measured by echocardiography before and during GA in 17 pediatric HTx recipients. Nearly all markers of ventricular systolic function were significantly decreased under GA, including EF (−4.2% ±1.2, P < .01) and RV FAC (−0.05 ± 0.02, P = .04). Subjects in the first post‐transplant year (n = 9) trended toward a more significant decrease in EF vs those beyond the first post‐transplant year (n = 8; −6.0% ±1.2 vs −2.1 ± 2.0, P = .1). This information quantifies a decline in biventricular function that should be expected in pediatric HTx recipients while under GA and can assist the transplant clinician in avoiding unnecessary treatment of transient GA‐induced ventricular dysfunction.

Effective mechanical cardiac support in a child in the absence of a mitral valve.

From the Pediatric Cardiothoracic Surgery Section, Division of Cardiothoracic Surgery, and Division of Pediatric Cardiology, Medical University of South Carolina, Charleston, SC. Disclosures: Authors have nothing to disclose with regard to commercial support. Received for publication July 10, 2013; revisions received July 28, 2013; accepted for publication Aug 1, 2013; available ahead of print Sept 25, 2013. Address for reprints: Minoo N. Kavarana, MD, Pediatric Cardiothoracic Surgery Section, Division of Cardiothoracic Surgery, Medical University of South Carolina, 96 Jonathan Lucas St, CSB 424/MSC 613, Charleston, SC 29425-6130 (E-mail: kavarana@musc.edu). J Thorac Cardiovasc Surg 2013;146:e61-2 0022-5223/

The impact of flow PRA on outcome in pediatric heart recipients in modern era: An analysis of the Pediatric Heart Transplant Study database

36.00 Copyright 2013 by The American Association for Thoracic Surgery http://dx.doi.org/10.1016/j.jtcvs.2013.08.002

Right Ventricular Function is Important for Pulmonary Artery Banding in Left Ventricular Dysfunction

Data from patients in the Pediatric Heart Transplant Study (PHTS) registry transplanted between 2010 and 2014 were analyzed to determine the association between HLA antibody (PRA) determined by SPA using Luminex or flow cytometry with a positive retrospective cross‐match and the post‐transplant outcomes of acute rejection and graft survival. A total of 1459 of 1596 (91%) recipients had a PRA reported pretransplant; 26% had a PRA > 20%. Patients with a PRA > 20% were more likely to have CHD, prior cardiac surgery, ECMO support at listing, and waited longer for transplantation than patients with a PRA <20%. Patients with higher PRA% determined by SPA were predictive of a positive retrospective cross‐match determined by flow cytometric method (P < .001). A PRA > 50% determined by SPA was independently associated with worse overall graft survival after first month of transplant in both unadjusted and adjusted for all other risk factors. In this large multicenter series of pediatric heart transplant recipients, an elevated PRA determined by SPA remains a significant risk factor in the modern era.

Autoimmune enteropathy and hepatitis in pediatric heart transplant recipient

Small infants with severe left ventricular dysfunction (LVD) carry a poor prognosis with limited therapeutic options. Although mechanical support and heart transplantation are definitive therapies, improvement of left ventricular function with reversible pulmonary artery banding (rPAB) has been described. We report two cases of LVD treated with rPAB. One was successfully temporized, and one progressed to requiring transplantation, indicating that appropriate patient selection is critical to this techniques success.