Sutherland, Scott M.

ImportanceStudies suggest that everolimus may reduce the risk of rejection, cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD), and cytomegalovirus (CMV) after heart transplant. Everolimus use is controversial because of data demonstrating higher infection deaths when everolimus is introduced de novo after transplant. It is unclear whether everolimus is safe and effective when initiated at 6 months posttransplant in children, a population in which median graft survival is limited to 15 years and randomized clinical trials are lacking.ObjectiveTo evaluate the safety and efficacy of everolimus combined with low-dose tacrolimus to prevent major adverse transplant events (MATEs) in children after heart transplant.Design, Setting, and ParticipantsMulticenter, randomized, open-label, clinical trial enrolling 211 patients who were alive 6 months after pediatric heart transplant at 25 US sites from February 2018 to August 2020. The last date of follow-up was April 17, 2023.InterventionsParticipants were randomized to receive everolimus and low-dose tacrolimus (n = 107) or standard-dose tacrolimus and mycophenolate mofetil (n = 104) for 30 months.Main Outcomes and MeasuresThe primary efficacy end point was the MATE-3 score at 30 months, a validated composite ordinal end point including acute cellular rejection, CAV, and CKD. The primary safety end point was the MATE-6 score, encompassing the MATE-3 score plus antibody-mediated rejection, infection, and posttransplant lymphoproliferative disorder.ResultsAmong 211 children randomized, the mean age was 8.2 (SD, 6.3) years, 97 (46%) underwent transplant for congenital heart disease, and 49 (23%) were treated for rejection before 6 months. At 30 months, the mean MATE-3 score did not differ between the 2 treatment groups (mean difference, −0.32; 95% CI, −0.90 to 0.20; P = .16). The mean MATE-6 score was no higher in the everolimus group than in the mycophenolate group (baseline-adjusted mean difference, −0.40; 95% CI, −1.81 to 0.93), meeting the success criterion for safety (noninferiority margin <3). There were no differences in graft survival, MATE-free survival, or freedom from any individual MATE. Everolimus was associated with greater improvement in estimated glomerular filtration rate at 12 months (mean difference, 10.5 mL/min/1.73 m2; 95% CI, 1.09-19.91 mL/min/1.73 m2) and a lower incidence of CMV infection (hazard ratio, 0.50; 95% CI, 0.26-0.93).Conclusions and RelevanceAmong 6-month pediatric heart transplant survivors, everolimus and low-dose tacrolimus did not differ from tacrolimus and mycophenolate in preventing the composite of cellular rejection, CAV, and CKD at 30 months. However, everolimus and low-dose tacrolimus appear to be safe based on the total burden of 6 MATEs and may be associated with improved kidney function and less CMV infection.Trial RegistrationClinicalTrials.gov Identifier: NCT03386539

Importance Increasing evidence indicates that acute kidney injury (AKI) occurs frequently in children and young adults and is associated with poor short-term and long-term outcomes. Guidance is required to focus efforts related to expansion of pediatric AKI knowledge. Objective To develop expert-driven pediatric specific recommendations on needed AKI research, education, practice, and advocacy. Evidence Review At the 26th Acute Disease Quality Initiative meeting conducted in November 2021 by 47 multiprofessional international experts in general pediatrics, nephrology, and critical care, the panel focused on 6 areas: (1) epidemiology; (2) diagnostics; (3) fluid overload; (4) kidney support therapies; (5) biology, pharmacology, and nutrition; and (6) education and advocacy. An objective scientific review and distillation of literature through September 2021 was performed of (1) epidemiology, (2) risk assessment and diagnosis, (3) fluid assessment, (4) kidney support and extracorporeal therapies, (5) pathobiology, nutrition, and pharmacology, and (6) education and advocacy. Using an established modified Delphi process based on existing data, workgroups derived consensus statements with recommendations. Findings The meeting developed 12 consensus statements and 29 research recommendations. Principal suggestions were to address gaps of knowledge by including data from varying socioeconomic groups, broadening definition of AKI phenotypes, adjudicating fluid balance by disease severity, integrating biopathology of child growth and development, and partnering with families and communities in AKI advocacy. Conclusions and Relevance Existing evidence across observational study supports further efforts to increase knowledge related to AKI in childhood. Significant gaps of knowledge may be addressed by focused efforts.