A quantitative assessment of renal function utilizing albuminuria in pediatric heart transplant recipients.

INTRODUCTION: Kidney disease is common after pediatric heart transplantation. Serum creatinine-based glomerular filtration rate is the most frequently reported measure of kidney function. Albuminuria is an additional marker of kidney dysfunction and is not well described in this population. In this study, we evaluate the prevalence and degree of albuminuria and describe clinical factors associated with albuminuria in a cohort of pediatric heart transplant recipients. METHODS: This was a cross-sectional study of pediatric heart transplant recipients. Albuminuria was assessed using spot urine albumin-to-creatinine ratio collected at the most recent annual screening cardiac catheterization through August 2019. RESULTS: In 115 patients at a median duration of 10.2 years post-transplant, 39% had albuminuria. Stage 3 or greater chronic kidney disease was present in 6%. The immunosuppressive regimen at the time of measurement contained a calcineurin inhibitor (CNI) in 88% and a proliferation signal inhibitor (PSI) in 62%. In multivariable modeling, lower eGFR, PSI use, and younger age at transplant were associated with higher levels of albuminuria, whereas CNI use was associated with lower levels of albuminuria. CONCLUSION: Albuminuria is a prevalent finding in medium-term follow up of pediatric heart transplant recipients, reflecting kidney injury, and is associated with other markers of kidney dysfunction, such as low eGFR. Younger age at transplant, lower eGFR, and PSI use were among the associations with albuminuria.

Applying the Hybrid Concept as a Bridge to Transplantation in Infants Without Hypoplastic Left Heart Syndrome.

Therapies to support small infants in decompensated heart failure that are failing medical management are limited. We have used the hybrid approach, classically reserved for high-risk infants with single ventricle physiology, in patients with biventricular physiology with left ventricular failure. This approach secures systemic circulation, relieves left atrial hypertension, protects the pulmonary vasculature, and allows the right ventricle to support cardiac output. This approach can be used as a bridge to transplantation in select individuals. Infants without single ventricle congenital heart disease who were treated with the hybrid approach between 2008 and 2021 were included in analysis. Eight patients were identified. At the time of hybrid procedure, the median weight was 3.2 kg (range 2.4-3.6 kg) and the median age was 18 days (range 1-153 days). Seventy five percent were mechanically ventilated and 88% were on inotropic support. The median duration from hybrid procedure to transplant was 63 days (range 4-116 days). All patients experienced a good outcome (delisted for improvement or transplanted). The hybrid procedure is an appropriate therapeutic bridge to transplantation in a carefully selected subset of critically ill infants without single ventricle congenital heart disease in whom alternate therapies may confer increased risk for morbidity and mortality.

Contemporary outcomes of pediatric cardiac transplantation with a positive retrospective crossmatch.

BACKGROUND: A positive crossmatch (+ XM) has traditionally been associated with adverse outcomes following pediatric heart transplantation. However, more recent studies suggest that favorable intermediate-term outcomes may be achieved despite a + XM. This study's hypothesis is that children with a + XM have similar long-term survival, but higher rate of complications such as rejection, coronary allograft vasculopathy (CAV), and infection, compared to patients with a negative (-) XM. METHODS: The Pediatric Heart Transplant Society Registry (PHTS) database was queried from 2010-2021 for all patients <18 years of age with a known XM. Baseline demographics were compared between + XM and - XM groups using appropriate parametric and non-parametric group comparisons. Cox Proportional Hazards Modeling was used to identify risk factors for post-transplant graft loss, rejection, and CAV. RESULTS: Of 4599 pediatric heart transplants during the study period, XM results were available for 3914 (85%), of which 373 (9.5%) had a + XM. Univariate analysis showed lower 10-year survival for patients with + XM (HR = 1.3, p = .04). Multivariate analyses revealed no significant difference in 10-year survival in the 2 groups; however, time to first rejection (p = .0001) remained significantly shorter in the + XM group. CONCLUSIONS: Pediatric patients transplanted across a + XM experience earlier rejection; however, after multivariate adjustment, + XM is not independently associated with intermediate-term graft loss. The risk of heart transplantation against a + XM must be balanced with the ongoing risk of waitlist mortality.

Takotsubo cardiomyopathy in a 4-year-old female with pneumococcal meningitis.

A previously healthy 4-year-old female presented in cardiogenic shock with pneumococcal meningitis. Findings on echocardiogram raised suspicion for takotsubo cardiomyopathy. With supportive care, left ventricular systolic function normalised. Findings on cardiac imaging helped determine the aetiology and avoid further invasive studies or unnecessary treatment.

Waitlist and posttransplant outcomes of critically ill infants awaiting heart transplantation managed without ventricular assist device support.

BACKGROUND: Infants listed for heart transplant are at high risk for waitlist mortality. While waitlist mortality for children has decreased in the current era of increased ventricular assist device use, outcomes for small infants supported by ventricular assist device remain suboptimal. We evaluated morbidity and survival in critically ill infants listed for heart transplant and managed without ventricular assist device support. METHODS: Critically ill infants (requiring ≥1 inotrope and mechanical ventilation or ≥2 inotropes without mechanical ventilation) listed between 2008 and 2019 were included. During the study period, infants were managed primarily medically. Mechanical circulatory support, specifically extracorporeal membrane oxygenation, was utilized as "rescue therapy" for decompensating patients. RESULTS: Thirty-two infants were listed 1A, 66% with congenital heart disease. Median age and weight at listing were 2.2 months and 4.4 kg, with 69% weighing <5 kg. At listing, 97% were mechanically ventilated, 41% on ≥2 inotropes, and 25% under neuromuscular blockade. Five patients were supported by ECMO after listing. A favorable outcome (transplant or recovery) was observed in 84%. One-year posttransplant survival was 92%. Infection was the most common waitlist complication occurring in 75%. Stroke was rare, occurring in one patient who was supported on ECMO. Renal function improved from listing to transplant, death, or recovery (eGFR 70 vs 87 ml/min/1.73m2 , p = .001). CONCLUSION: A strategy incorporating a high threshold for mechanical circulatory support and acceptance of prolonged mechanical ventilation and neuromuscular blockade can achieve good survival and morbidity outcomes for critically ill infants listed for heart transplant.

A Quality Initiative to Improve Appropriate Use of Initial Outpatient Echocardiography Among Pediatric Cardiologists.

INTRODUCTION: Appropriate use criteria (AUC) guide initial transthoracic echocardiogram (TTE) use in outpatient pediatrics. We sought to improve pediatric cardiologist TTE ordering appropriateness (mean AUC score) with a quality improvement initiative. METHODS: The outcome of interest was the prospective AUC score for all initial outpatient TTEs ordered between November 2016 and August 2017, categorized per the AUC: "appropriate" (score 7-9), "may be appropriate" (4-6), "rarely appropriate" (1-3). Interventions included a didactic review of 2014 AUC and participant documentation of AUC criteria for each TTE. Participants met quarterly to evaluate outcome, process, and balancing measures, intervention effectiveness, and to identify and mitigate barriers. RESULTS: Twenty-two pediatric cardiologists participated. TTE appropriateness level before (n = 216) and after (n = 557) intervention was high. There was no significant difference in mean baseline and post-intervention AUC score (7.42 ± 1.87 versus 7.16 ± 2.87, P = 0.1), nor in TTE sensitivity (27% versus 25%, P > 0.1) as a balancing measure. Among baseline studies, 81% were "appropriate," and 6% "rarely appropriate." Among post-intervention studies, 76% were "appropriate," and 11% "rarely appropriate." Barriers identified to implementing AUC include TTE indications not specified by current AUC, expectations of referring provider or parent to perform TTE, consistent provider application of AUC, and ability of AUC to capture comprehensive clinical judgment. CONCLUSIONS: Although the mean AUC appropriateness level was high, we were able to identify significant barriers to the implementation of AUC. Future efforts should focus on the reduction of "rarely appropriate" TTE ordering.

A fatal case of bortezomib-induced lung toxicity in a young adult heart transplant recipient.

Bortezomib is approved for the treatment of multiple myeloma but increasingly used in heart transplant (HTx) recipients with antibody-mediated rejection (AMR). Severe pulmonary toxicity is a rare complication in multiple myeloma patients treated with bortezomib, but has not been described in a solid organ transplant recipient. A 20-year-old man 7 years post-HTx presented with acute rejection with hemodynamic compromise. Endomyocardial biopsy showed mixed rejection (ISHLT grade 2R-3R acute cellular rejection (ACR) and pAMR 1 (I+) with diffuse C4d staining). Two new high MFI circulating MHC class-II donor-specific antibodies (DSA) were detected. Treatment included corticosteroids, antithymocyte globulin, plasmapheresis, IVIG, rituximab, and bortezomib (1.3 mg/m2 ). Due to rebound in DSA, a second course of bortezomib was started. Thrombocytopenia and peripheral neuropathy prompted a 50% dose reduction during the 2nd course. Shortly after the 3rd reduced dose, the patient developed hypoxemic respiratory failure. Bronchoscopy revealed pulmonary hemorrhage with negative infectious studies. Chest CT showed bilateral parenchymal disease with bronchiectasis and alveolar bleeding. Despite treatment with high-dose steroids, severe ARDS ensued with multisystem organ failure. The patient expired 23 days after the final dose of bortezomib. Post-mortem lung histology revealed diffuse alveolar damage, pulmonary fibrosis, and hemorrhage. Cardiac histology showed resolving/residual ACR 1R and pAMR 1 (I+). While rare, bortezomib-induced lung toxicity (BILT) can occur in HTx recipients and can carry a high risk of mortality. Drug reaction and immediate drug withdrawal should be considered in patients who develop respiratory symptoms, though optimal management of BILT is unclear.

Management of the sensitized pediatric heart transplant patient.

Despite advancements in transplant immunosuppression and techniques for managing critically ill patients awaiting heart transplantation, children who are immunologically sensitized to human leukocyte antigen remain at increased risk for morbidity and mortality, both while awaiting and after heart transplant. In this review we will discuss the epidemiology of sensitization, review the immunologic basis and methods of human leukocyte antigen antibody detection, describe outcomes for sensitized pediatric transplant candidates, and consider both pre- and post-transplant management options for sensitized patients.

Ascending aortic size in aortic coarctation depends on aortic valve morphology: Understanding the bicuspid valve phenotype.

BACKGROUND: In roughly half of patients with coarctation of the aorta (CoA), the aorta may be enlarged. It is uncertain whether enlargement is independent of aortic valve morphology. We sought to compare aortic size in CoA with a tricuspid valve (TAV) to those with bicuspid aortic valve (BAV). METHODS: Sixty-eight CoA patients and 20 healthy controls with prior cardiac magnetic resonance (CMR) imaging were included. CMR was retrospectively reanalyzed to measure aortic root and mid-ascending aorta. The maximum aortic diameter was compared between CoA with TAV, CoA with BAV, and control groups. RESULTS: CoA with TAV patients (n=27) had smaller aortic root diameters than CoA with BAV (n=41) (32±4.9 vs. 37±5.8mm, p=0.001), despite being older (40 vs. 32years, p=0.01). Similarly, TAV CoA patients had a smaller mid-ascending aortic diameter (28±4.5 vs. 33±6.9mm, p=0.019) than BAV patients. TAV CoA was similar to controls in all metrics. Twenty-four patients (35%) with CoA had dilated aortas (>37mm), of which 79% had BAV. A history of hypertension did not predict larger aortic root or mid-ascending aortic dimensions. CONCLUSIONS: In patients with CoA, TAV is associated with smaller aortic size compared to those with BAV, and similar to healthy controls. Aortic size in CoA is independent of hypertension. Therefore, aortopathy associated with BAV is likely a reflection of the BAV phenotype rather than CoA or its physiologic effects. This distinction may have implications for the frequency and types of monitoring and treatment of CoA patients.

Subspecialty surveillance of long-term course of small and moderate muscular ventricular septal defect: heterogenous practices, low yield.

BACKGROUND: No expert consensus guides practice for intensity of ongoing pediatric cardiology surveillance of hemodynamically insignificant small and moderate muscular ventricular septal defect (mVSD). Therefore, despite the well-established benign natural history of mVSD, there is potential for widely divergent follow up practices. The purpose of this investigation was to evaluate (1) variations in follow up of mVSD within an academic children's hospital based pediatric cardiology practice, and (2) the frequency of active medical or surgical management resulting from follow up of mVSD. METHODS: We retrospectively reviewed records of 600 patients with isolated mVSD echocardiographically diagnosed between 2006 and 2012. Large mVSD were excluded (n = 4). Patient age, gender, echocardiographic findings, provider, recommendations for follow up, and medical and surgical management were tabulated at initial and follow up visits. Independent associations with follow up recommendations were sought using multivariate analysis. RESULTS: Initial echocardiography showed small single mVSD in 509 (85%), multiple small mVSD in 60 (10%), and small-to-moderate or moderate single mVSD in 31 (5%). The mean age at diagnosis was 15.9 months (0-18.5 years) and 25.7 months (0-18.5 years) at last follow up. There was slight female predominance (56.3%). Fourteen pediatric cardiology providers recommended 316 follow up visits, 259 of which were actually accomplished. There were 37 other unplanned follow up visits. No medical or surgical management changes were associated with any of the follow up visits. The proportion of patients for whom follow up was advised varied among providers from 11 to 100%. Independent associations with recommendation for follow up were limited to the identity and clinical volume of the provider, age of the patient, and the presence of multiple, small-to-moderate, or moderate mVSD. CONCLUSIONS: In this large series of moderate or smaller mVSD, pediatric cardiology follow up was commonly recommended but resulted in no active medical or surgical management. Major provider based inconsistency in intensity of follow up of mVSD was identified, but is difficult to justify.