Calcineurin-Inhibitor Minimization in Pediatric Heart Transplant Recipients

Calcineurin-Inhibitor Minimization in Pediatric Heart Transplant Recipients

S406 The Journal of Heart and Lung Transplantation, Vol 35, No 4S, April 2016 Purpose: Worsening renal function is a strong predictor of clinical o...

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The Journal of Heart and Lung Transplantation, Vol 35, No 4S, April 2016

Purpose: Worsening renal function is a strong predictor of clinical outcomes in children with heart failure. Venous congestion plays an important role in renal dysfunction in adults but has not been studied in children. We sought to determine the relationship between central venous pressure (CVP) and renal function in children with cardiovascular disease. Methods: Children age 1 week to 21 years with acyanotic, biventricular cardiac anatomy who underwent a right heart catheterization (RHC) from 1/2010-6/2014 were identified using a single institution’s cardiac database. Patients with primary kidney disease, liver disease or chronic lung disease were excluded. Estimated glomerular filtration rate (eGFR) was calculated using the modified Schwartz equation. Worsening renal function (WRF) was defined as an increase in serum creatinine ≥ 0.3 mg/dL within 1 year after RHC. Logistic regression was performed to determine associations between CVP and renal function at the time of RHC. Results: The study population included 322 unique patients. Heart failure was identified in 27% of patients. Indications for RHC included: biopsy post cardiac transplant (41%), balloon angioplasty/stent implant (12%), balloon valvuloplasty (5%), pulmonary hypertension study (6%), pre-transplant evaluation (7%), ASD closure (2%), PDA closure (8%), other (19%). Median age was 5.1 years (1.1, 13.7). Mean eGFR was 102.4 ± 32.0 ml/min/1.73 m2. Mean cardiac index (CI) was 3.8 ± 1.2 l/min/m2, arterial-venous oxygen difference (AV-O2) 27.4 ± 9.1, and CVP 7.4 ± 3.9 mmHg. In univariable analysis, CVP was associated with eGFR (r=  -0.24, p< 0.001) and AV-O2 (r= -0.13, p= 0.009), but not CI (r= 0.07, p= 0.217). In multivariable analysis, only high CVP remained associated with eGFR (p< 0.001); a 1 mm Hg increase in CVP was associated with a 1.7 ml/min/1.73 m2 decrease in eGFR (p< 0.001). When analyzing only non-transplant patients, CVP remained associated with eGFR (p< 0.001). Patients with heart failure and CVP ≥ 10 mm Hg were at increased risk of developing WRF than heart failure patients with CVP ≤ 10 mm Hg (OR= 3.4; p= 0.018). Conclusion: In children with cardiovascular disease, venous congestion is associated with impaired renal function, independent of cardiac output. Children with heart failure and venous congestion are at increased risk of developing WRF. 1( 138)

of Pittsburgh of UPMC, Pittsburgh, PA; 2Pediatric Cardiology, St. Louis Children’s Hospital, Washington University in St. Louis, St. Louis, MO; 3Biostatistics, Washington University School of Medicine, St. Louis, MO; 4Washington University School of Medicine, St. Louis, MO; 5Cardiothoracic Surgery, University of Alabama at Birmingham, Birmingham, AL. Purpose: No consensus exists among pediatric heart transplant (HT) centers on the optimal routine surveillance biopsy (RSB) protocol. Data is lacking on the utility of higher RSB intensity and intensity-specific outcomes. We hypothesized that higher RSB intensity is associated with greater detection of moderate to severe (ISHLT grade 2R/3R) cellular rejection (RSBMSR). Methods: Pediatric Heart Transplant Study (PHTS) data were analyzed from 2010-2013. In addition, 34/47 PHTS centers responded to a survey on RSB practices. Identical question sets queried the current era (2005-present, primarily tacrolimus era) and past era (1995-2004, mixed immunosuppression). PHTS and survey data were integrated and analyzed as a single data set. Results: RSB detected 280/343 (81.6%) episodes of MSR in all age groups even >  than 5 years after HT. In the current era, 21 centers have not replaced RSB with non-invasive imaging, 17 use BNP/NT-proBNP for routine monitoring, 7 use AlloMap or ImmuKnow, and 12 centers reduced RSB intensity without an increase in rejection. Centers were categorized as low, medium, or high intensity based on reported biopsy rate [Table 1]. In the past era, all centers were high intensity for all age groups until beyond the fifth year when the majority became medium intensity. Higher intensity was not associated with decreased 4 year mortality (p=  0.63) on proportional hazard regression, or with faster detection of first RSBMSR in the first year after HT (p= 0.87). First year RSBMSR incidence did not differ with intensity or age at HT. Conclusion: Significant variability exists in RSB intensity among pediatric HT centers, but with no impact on timing and incidence of RSBMSR or 4 year mortality. This data is reassuring that reduction of RSB intensity may be safe in certain populations, such as patients without RSBMSR in the first year after HT. Further studies are necessary to evaluate the long term effects of RSB reduction on morbidity and mortality.

Nutritional Status of Children Undergoing Heart Transplantation at the Heart Institute of São Paulo (Incor) between 2013-2015 C.V. Campos , A.W. Siqueira, N. Myura, M.B. Jatene, E. Azeka.  Incor HCFMUSP, Sao Paulo, Brazil. Purpose: Congestive heart failure in children presents as an increased risk for malnutrition, due to cardiac cachexia and increased metabolic demand. The effect of malnutrition on adults undergoing heart transplantation (HTx) has been well-studied; however there are few data on pediatric population. The goal of our study was to analyse the nutritional status of children undergoing HTx at the Heart Institute of Sao Paulo (Incor), Brazil. Methods: We conducted a retrospective analysis of the medical records of all pediatric patients who underwent HTx between 2013 and 2015. Results: Fifty-five patients were submitted to heart transplantation (28 girls and 27 boys), with an average age of 10 years. The average height was 127 cm ( median 131 cm, standard deviation (stdev) 32 cm), and the average Z-score according to world health organization (WHO) growth charts was -1,12 (median -0,97; stdev 2,01). The average body mass index Z-score according to world health organization (WHO) growth charts was -1,75 (median -0,8; stdev 1,7). We used the WHO definition for thinness, which is BMI Zscore< -2. There were 15 patients (27%) with diagnosis of thinness, of whom 7 had severe thinness (BMI Zscore< -3). There were no obese patients. Wasting was present in 18% of patients with congenital heart disease and 35% of patients with cardiomyopathy. There were 6 boys whose BMI Zscore was below -2, and 9 girls were under the same condition. Among the patients who died after heart transplantation, 31% were thin or severely thin before the procedure, while among those who survived heart transplantation, 28% were thin or severely thin. Conclusion: The data shows a tendency towards malnutrition at the time of HTx, which may impact on the outcome of the procedure. 1( 139) Impact of Routine Surveillance Biopsy Intensity on the Diagnosis of Moderate to Severe Cellular Rejection and Survival After Pediatric Heart Transplantation M.D. Zinn ,1 K.E. Simpson,2 M.J. Wallendorf,3 A.D. Osborne,4 J.K. Kirklin,5 C.E. Canter.2  1Pediatric Cardiology, Children’s Hospital

1( 140) Calcineurin-Inhibitor Minimization in Pediatric Heart Transplant Recipients M.J. Bock ,1 T. Shankel,2 J. Fitts,3 R. Tan,4 R.E. Chinnock.2  1Pediatric Cardiology, Loma Linda University Children’s Hospital, Loma Linda, CA; 2Pediatrics, Loma Linda University Children’s Hospital, Loma Linda, CA; 3Transplant Institute, Loma Linda University Medical Center, Loma Linda, CA; 4Pharmacy, Loma Linda University Medical Center, Loma Linda, CA. Purpose: A Calcineurin-inhibitor (CNI) minimization strategy has been applied to all pediatric heart transplant (HTx) recipients since 03/11 at our institution. Initiation of mTOR inhibitors (everolimus or sirolimus) at 4mo post-HTx with reduction in the CNI target by 40% has been used since that time. We hypothesize that a CNI minimization immunosuppression (IS) protocol leads to improved renal function at 1 & 2y post-HTx without a significant difference in graft survival or major complications.

Abstracts S407 Methods: All pediatric HTx recipients surviving to 4mo post-HTx at our institution between 03/11-07/14 were included in the study. Age and sex matched subjects were selected from the preceding era (09/07-02/11) for comparison (1:1). IS regimen, renal function (eGFR), graft survival, and conditional freedom from rejection, infection, malignancy, and CAV were compared between the groups. Results: Twenty-seven subjects in each era were included. Basic demographic data (age, sex, race, blood type, pre-HTx diagnosis, and listing status) were similar between groups. At 1y post-HTx, 70% in the current era were taking mTOR inhibitors (58% sirolimus; 12% everolimus) vs. 48% in the prior era (all sirolimus). No CAV was seen in either group. There was a small, though not significant, improvement in renal function with the new protocol at 2y post-HTx (p= 0.11; Fig a), while freedom from rejection was higher in the current era (96% vs. 86% at 1y post-HTx) (p= 0.04; Fig b). Graft survival (both 100% at 1y post-HTx) (p= 0.65; Fig c) and freedom from infection (p= 0.34; Fig d) and malignancy (p= 0.99) were similar between groups. Conclusion: CNI minimization by early transition to mTOR inhibitors in pediatric heart transplant recipients appears safe, though it only trended toward improvement in renal function in short-term follow-up (1 & 2y postHTx). Freedom from rejection was improved, while survival and other shortterm complications were similar. Longer-term follow-up is needed to assess for late differences in renal function.

1( 141) Pre-Clinical Testing Results for a New Infant-Sized VAD W.J. Weiss ,1 J.B. Clark,2 J.M. Izer,3 B. Lukic,4 T.K. Cooper.5  1Penn State Hershey Medical Center, Hershey, PA; 2Pediatrics and Surgery, Penn State Hershey Medical Center, Hershey, PA; 3Comparative Medicine, Penn State Hershey Medical Center, Hershey, PA; 4Surgery, Penn State Hershey Medical Center, Hershey, PA; 5Comparative Medicine and Pathology, Penn State Hershey Medical Center, Hershey, PA. Purpose: Ventricular assist devices (VADs) are used as a bridge in approximately 30% of pediatric heart transplantations. For small children and infants requiring support longer than 2 weeks, the only available VAD is the Berlin Heart EXCOR. Although the EXCOR provides a needed option, its use is associated with higher rates of thromboembolism, pump thrombosis, and bleeding compared to the adult VAD experience. To address the need for a safer device, we have developed an Infant VAD based on the Pierce-Donachy VAD (Thoratec PVAD). Methods: The Infant VAD has a stroke volume of 12-14 ml and an output of 0.6 to 1.5 liters/min. It includes custom tilting disk valves, a unique ventricular apical connection, precision-fit pump connectors, and coated, reinforced 6 mm ePTFE cannulae. The VAD has been tested in 33 chronic studies (60 day duration) in lambs (18-29 kg). To provide a challenging test of thrombogenicity, heparin anticoagulation was intentionally reduced and no platelet inhibitors were used. Heparin was titrated to achieve a TEG R-time of either twice normal (2R group) or normal (1R group). In the 1R group, heparin was given only during the early postoperative acute phase which is associated with hypercoagulability. Separate long-term in vitro durability studies continue to test pump reliability. Results: Heparin dose was 15.0 +/-8.3 U/kg/h in the 2R group (n= 7) and 1.8 +/- 2.8 U/kg/h in the 1R group (n= 4). In both groups, anti-factor Xa (heparin activity) levels were below detectable levels (< 0.1 U/ml) and aPTT

was not higher than baseline preoperative levels. Further, in the 1R group, no heparin was used after 21.3 +/- 10.3 days. VAD flow in both groups was 1.2 +/- 0.2 liters/min. There were no clinical signs of thromboembolism in any animals. Comparing post-op values (> 2 weeks) to pre-op normal and surgical shams, there were no statistical differences (p <  .05 level) in plasma free hemoglobin or blood chemistry. Whole blood platelet aggregometry (ADP, collagen) returned to normal after 2-3 weeks. At necropsy, the number and size of renal ischemic lesions were consistent with findings in surgical shams (n= 5). In vitro durability testing has achieved 621, 689, and 409 days without failure, with tests at 198 and 187 days ongoing. Conclusion: In animal testing of the Infant VAD, thromboembolism was not detectable, despite a challenging anticoagulation protocol, and pump life in excess of 1 year with no failures has been demonstrated. 1( 142) Posterior Reversible Encephalopathy Syndrome after Pediatric Heart Transplantation B. Eilers ,1 E.L. Albers,2 Y.M. Law,2 M.S. Kemna.2  1University of Washington, School of Medicine, Seattle, WA; 2Pediatric Cardiology, Seattle Children’s Hospital/ University of Washington, Seattle, WA. Purpose: Identification of risk factors for posterior reversible encephalopathy syndrome (PRES) after organ transplant can improve early detection and avoid permanent neurologic injury. High calcineurin-inhibitor levels and hypertension are recognized risk factors for PRES in adult transplant recipients. Limited data exist regarding PRES after pediatric heart transplant (HTx), with studies limited to case reports. Our aim was to determine the prevalence and clinical features of PRES in pediatric HTx recipients. Based on our own clinical experience, we hypothesized a priori that recipients with Glenn or Fontan physiology (G/F) at time of transplant are at higher risk for PRES. Methods: We performed a retrospective review of 128 pediatric HTx recipients <  21 yo, who received their transplant at our institution between 19942014. Demographic and clinical risk factors were analyzed and Fisher’s exact test was used to estimate relative risk (RR) of PRES in recipients. Results: Seven of 128 (5.5%) recipients developed PRES at a median of 10 days (5-57) after HTx. The median age of recipients with PRES was 10.0 years (5.7-19.0), compared to 1.4 years (0.0-19.8) for recipients without PRES (p= 0.010). Recipients with PRES did not differ from those without PRES when comparing gender, BMI, total allograft ischemic time, aortic cross-clamp time, or cardiopulmonary bypass time. Fewer than half of recipients with PRES had elevated post-transplant calcineurin-inhibitor levels (n= 3) and/or preceding severe hypertension (n= 3), both considered traditional risk factors for PRES. Four of seven who developed PRES (57%) had pre-transplant G/F. G/F was a significant risk factor for PRES (RR 4.99, 95% CI: 1.19-21.0, p= 0.036). Five (71.0%) recipients returned to their neurological baseline. Two recipients (29%), both with severe PRES, have residual ongoing neurological symptoms. Conclusion: In summary, PRES occurred in 5.5% of pediatric HTx recipients, a higher prevalence than reported in adults. It presented early after HTx, and in older children: all recipients with PRES were >  5 yo. Patients with pretransplant G/F were at increased risk, a risk factor not previously described. 1( 143) Genetics of Pediatric Cardiomyopathy C. Ellepola ,1 L.M. Knight,2 S.R. Deshpande.3  1Emory University Children’s Healthcare of Atlanta, Atlanta, GA; 2Sibley Heart Center Cardiology, Atlanta, GA; 3Pediatric Cardiology, Emory University Children’s Healthcare of Atlanta, Atlanta, GA. Purpose: Genetic testing is strongly recommended in patients with dilated cardiomyopathy (DCM), however, there is extremely sparse genotype-phenotype data in pediatric DCM patients. Goal of this study was to describe genetics of pediatric DCM along with their clinical phenotype. Methods: Retrospective review of cardiomyopathy patients with genetic testing. Results: 47 consecutive patients with cardiomyopathy (non HCM) underwent genetic testing. Mean age at presentation was 5.83 year (range 0-18 years). Gender ratio was M:F of 27:20, with White race (21/47) and African American (20/47) accounting for majority of cases. Most common