Pediatric Learning Health Networks in Solid Organ Transplantation-Engaging all Stakeholders to Achieve Health for Children Who Require Transplantation.

BACKGROUND: Learning Health Networks (LHN) have evolved within medicine over the past two decades, but their integration into transplantation has been more recent. OBJECTIVES AND METHODS: In this paper, we describe three LHNs in end-stage organ disease/transplantation, their common and unique features, and how their "actor-oriented" architecture allowed for rapid adaptation to meet the needs of their patients and practitioners during the recent COVID-19 pandemic. RESULT: The structure and focus of the Improving Renal Outcomes Collaborative (IROC), Starzl Network for Excellence in Pediatric Transplantation (SNEPT), and the Advanced Cardiac Therapies Improving Outcomes Network (ACTION) are reviewed. We discuss the critical role of patient and family engagement, focusing on collaboration with Transplant Families. Finally, we review challenges common to the LHN concept and potential common areas of alignment to achieve the goal of more rapid and sustained progress to improve health in pediatric transplantation. CONCLUSION: LHN in transplantation are essential to accelerate knowledge dissemination and improve outcomes.

Clinical Profile and Outcome of Patients Presenting With Acute-on-Chronic Liver Failure: A Single-Center Experience.

BACKGROUND AND AIM: We aimed to study the etiologies and clinical profile and to describe the factors associated with mortality in acute-on-chronic liver failure (ACLF) patients at our center. METHODS: Patients meeting the Asian Pacific Association for the Study of the Liver (APASL) definition of ACLF were included. We studied etiologies and clinical profile and analyzed the factors associated with mortality in patients with ACLF. We also analyzed the mortality rates based on the number of organ failures and the grade of ACLF. RESULTS: 114 patients were included. Alcohol (82, 71.9%), drugs (22, 19.3%), and viral hepatitis (17, 14.9%) were the commonest precipitating factors of ACLF. The commonest cause of chronic disease was alcohol (83, 72.8%). Fifty-three (46.5%), 60 (52.6%), 44 (38.6%), 32 (28.1%), and 24 (21.1%) experienced renal, coagulation, cerebral, respiratory, and circulation failures, respectively. Overall, the in-hospital mortality rate stood at 54 (48.6%), with a median stay of eight days. Advanced hepatic encephalopathy and ventilator support independently predicted mortality. The Sequential Organ Failure Assessment (SOFA) score outperformed all other prognostic scores in predicting mortality in ACLF. CONCLUSION: Alcohol was the most common precipitating factor for ACLF. The in-hospital mortality rate was 48.6%. Advanced hepatic encephalopathy and ventilator support independently predicted mortality. The SOFA score is a more accurate predictor of mortality in ACLF when compared to other prognostic scores.

BK polyomavirus DNAemia, allograft rejection, and de novo donor-specific antibodies after lowering target tacrolimus levels in pediatric kidney transplant recipients.

BACKGROUND: BK polyomavirus (BKV) DNAemia is a challenging infectious complication after kidney transplant (KT). Reduction of immunosuppression is the mainstay of management, and tacrolimus is often the first immunosuppressive medication adjusted upon the diagnosis of BKV DNAemia. This study aimed to evaluate the impact of a new institutional protocol with lower target tacrolimus levels on BKV DNAemia, allograft rejection, and de novo donor-specific antibodies (dnDSA) among pediatric KT recipients. METHODS: We conducted a retrospective chart review of all KT episodes between January 2013 and December 2018. The new protocol with lower target tacrolimus levels was implemented in March 2015. One hundred twenty-seven patients were included in primary analysis. All patients received induction with basiliximab and methylprednisolone and were maintained on a steroid-based immunosuppressive regimen. RESULTS: In the post-intervention cohort, cumulative incidence of BKV DNAemia at 100 days (13.4% vs. 17.8%, p = .605) and 18 months post-KT (34.1% vs. 26.7%, p = .504) was not significantly different from the pre-intervention cohort. Biopsy-proven rejection rate did not change. However, we observed a trend toward earlier development of dnDSA in the post-intervention cohort using the Kaplan-Meier survival analysis (log-rank p = .06). Younger recipient age at the time of transplant was found to slightly increase the risk of BKV DNAemia (OR: 1.09, 95% CI [1.01, 1.16], p = .024). There was an association between BKV DNAemia and biopsy-proven rejection of any type (adjustedOR: 2.77, 95% CI [1.26, 6.23], p = .012), especially acute T-cell-mediated rejection grade 1A and above (adjustedOR: 2.95, 95% CI [1.06, 8.30], p = .037), after adjusted for recipient age at the time of transplant. CONCLUSIONS: Targeting lower tacrolimus levels did not decrease the incidence of BKV DNAemia within 100 days or 18 months post-KT, nor did it increase the risk of biopsy-proven rejection among pediatric KT recipients in our center. However, there was a trend toward earlier development of dnDSA, which may portend worse long-term graft outcome post-KT. Our findings highlight the need for individualized immunosuppressive regimens based on immunologic and infectious risk factors and the importance of implementing innovative biomarkers to guide therapy and improve outcomes.

Implementing Entrustable Professional Activities in Pediatric Fellowships: Facilitating the Process.

BACKGROUND AND OBJECTIVES: Entrustable professional activities (EPAs) will be used for initial certification by the American Board of Pediatrics by 2028. Less than half of pediatric fellowships currently use EPAs for assessment, yet all will need to adopt them. Our objectives were to identify facilitators and barriers to the implementation of EPAs to assess pediatric fellows and to determine fellowship program directors' (FPD) perceptions of EPAs and Milestones. METHODS: We conducted a survey of FPDs from 15 pediatric subspecialties. EPA users were asked about their implementation of EPAs, barriers encountered, and perceptions of EPAs. Nonusers were queried about deterrents to using EPAs. Both groups were asked about potential facilitators of implementation and their perceptions of Milestones. RESULTS: The response rate was 65% (575/883). Of these, 344 (59.8%) were EPA users and 231 (40.2%) were nonusers. Both groups indicated work burden as a barrier to implementation. Nonusers reported more barriers than users (mean [SD]: 7 [3.8] vs 5.8 [3.4], P < .001). Both groups identified training materials and premade assessment forms as facilitators to implementation. Users felt that EPAs were easier to understand than Milestones (89%) and better reflected what it meant to be a practicing subspecialty physician (90%). In contrast, nonusers felt that Milestones were easy to understand (57%) and reflected what it meant to be a practicing subspecialist (58%). CONCLUSIONS: Implementing EPA-based assessment will require a substantial investment by FPDs, facilitated by guidance and easily accessible resources provided by multiple organizations. Perceived barriers to be addressed include FPD time constraints, a need for additional assessment tools, and outcomes data.

Distinguishing Clinical Features of Cannabinoid Hyperemesis Syndrome and Cyclic Vomiting Syndrome: A Retrospective Cohort Study.

OBJECTIVE: To identify clinical characteristics that distinguish cannabinoid hyperemesis syndrome (CHS) from cyclic vomiting syndrome (CVS), 2 conditions marked by episodes of nausea, vomiting, and abdominal pain. STUDY DESIGN: We performed a retrospective chart review of patients admitted to a large children's health care system from 2015 through 2022. Patients with CHS and CVS were identified by the electronic medical record using International Classification of Diseases, Ninth and Tenth Revision codes. RESULTS: Of 201 patients screened, 125 were included. Patients with CHS were older than those with CVS (mean [SD] 18.06 [1.41] vs 14.50 [2.91] years, P < .001). There were no significant differences in sex, race, ethnicity, or hospital length of stay between groups. Patients with CHS were more likely to have a positive urine drug screen (86% vs 2.9%, P < .001), lower mean (SD) serum potassium (3.62 [0.77] vs 3.88 [0.49], P < .001), and greater mean (SD) serum creatinine (0.83 (0.41) vs 0.63 (0.17), P < .001). The average (SD) systolic blood pressure was significantly greater in patients with CHS (systolic blood pressure 124.46 [10.66] vs 118.55 [10.99], P = .032) compared with children of comparable age range with CVS. Imaging was obtained in 36% of all patients, and only 2.4% had abnormalities. CONCLUSIONS: Clinical features including older age, greater systolic blood pressure, positive urine drug screen, and select electrolyte findings might distinguish CHS from CVS. Abdominal imaging in both conditions is of low yield. These findings may allow for early recognition and appropriate therapy in CHS patients.

Level of Supervision for the Entrustable Professional Activities Common to General Pediatrics and the Subspecialties Decreases from Residency to Fellowship.

OBJECTIVES: To compare level of supervision (LOS) ratings of graduating pediatric residents with their assessments as fellows for the five Entrustable Professional Activities (EPAs) common to general pediatrics and the subspecialties and to determine if the difference between ratings from residency to fellowship is less for the QI and Practice Management EPAs, since the skills needed to perform these may be less context-dependent. METHODS: We compared ratings of graduating residents with their assessments as fellows using LOS data from two sequential EPA studies. RESULTS: There were 65 ratings from 41 residents at the first fellow assessment. At graduation, most residents needed little to no supervision for all EPAs with 94% (61/65) of ratings level four or five. In contrast, only 5/65 (8%) of the first fellow assessments were level four or five. The ratings difference for the QI and Practice Management EPAs was similar to the others. CONCLUSIONS: LOS ratings for the EPAs common to generalists and subspecialists reset as residents become fellows. There was no evidence that the QI and Practice Management EPAs are less context-dependent. This study provides additional validity evidence for using these LOS scales to assess trainees in pediatric residency and fellowship.

Arginine Dysregulation and Myocardial Dysfunction in a Mouse Model and Children with Chronic Kidney Disease.

Cardiovascular disease is the leading cause of death in chronic kidney disease (CKD). Arginine, the endogenous precursor for nitric oxide synthesis, is produced in the kidneys. Arginine bioavailability contributes to endothelial and myocardial dysfunction in CKD. Plasma from 129X1/SvJ mice with and without CKD (5/6th nephrectomy), and banked plasma from children with and without CKD were analyzed for amino acids involved in arginine metabolism, ADMA, and arginase activity. Echocardiographic measures of myocardial function were compared with plasma analytes. In a separate experiment, a non-specific arginase inhibitor was administered to mice with and without CKD. Plasma citrulline and glutamine concentrations correlated with multiple measures of myocardial dysfunction. Plasma arginase activity was significantly increased in CKD mice at 16 weeks vs. 8 weeks (p = 0.002) and ventricular strain improved after arginase inhibition in mice with CKD (p = 0.03). In children on dialysis, arginase activity was significantly increased vs. healthy controls (p = 0.04). Increasing ADMA correlated with increasing RWT in children with CKD (r = 0.54; p = 0.003). In a mouse model, and children, with CKD, arginine dysregulation correlates with myocardial dysfunction.

Multidisciplinary and multidimensional approaches to transplantation in children with rare genetic kidney diseases.

In this review, we describe the multidisciplinary, multidimensional care required to optimize outcomes for pediatric transplant recipients with rare genetic kidney diseases. Transplant success, recipient survival, and improvement in quality of life depend on collaboration between patients, families, and a team of specialists with medical, as well as nonmedical expertise. A multidisciplinary transplant team composed of experts from medicine, surgery, nursing, nutrition, social services, transplant coordination, psychology, and pharmacology, is now standard in most transplant centers and is critical to the success of a transplant. In addition to these professionals, other specialists, such as cardiologists, urologists, geneticists, metabolic disease specialists, occupational therapists, case management, child life, chaplain, and palliative care services, have a crucial role to play in the preparation, surgery, and follow-up care, especially when a pediatric patient has a rare genetic disorder leading to renal involvement, and the need for transplantation. In order to describe this multidisciplinary care, we divide the genetic renal diseases into five subgroups-metabolic and tubular disorders, glomerular diseases, congenital anomalies of the kidney and urinary tract, ciliopathies including cystic diseases, and miscellaneous renal conditions; and describe for each, the need for care beyond that provided by the standard transplant team members.

Transition of Care in Children with Chronic Kidney Disease, Dialysis, and Transplantation.

Improvement in management of pediatric renal disorders has led to patient survival rates of 85-90%, increasing the number of adolescent and young adult (AYA) patients with childhood onset chronic kidney disease (CKD) transitioning to adult care settings. Pediatric CKD patients differ from adults with CKD in view of early onset of disease (sometimes with fetal onset), different disease spectrum, the potential effect of CKD on neurodevelopment, and substantial involvement of parents in medical decision making. In addition to the usual challenges of emerging adulthood (graduation from school to work, independent living, peak in impulsivity and risk-taking behaviors), young adults with pediatric CKD need to learn to manage a serious medical condition independently. In kidney transplant patients, regardless of the age at transplantation, graft failure rates are higher during adolescence and young adulthood than at any other age. All pediatric CKD patients must move from a pediatric to adult-focused settings and this transition is a longitudinal process requiring collaboration and interactions of AYA patients, their families, providers, health care environment and agencies. Consensus guidelines have provided recommendations to pediatric and adult renal teams to enable successful transition. Suboptimal transition is a risk factor for poor adherence to treatment and unfavorable health outcomes. The authors discuss the process of transition as it applies to pediatric CKD patients and review challenges faced by patients/families, pediatric and adult nephrology teams. They provide some suggestions and available tools to optimize the transition of pediatric CKD patients to adult-oriented care.

Successful Use of Fosmanogepix for Treatment of Rare Highly Resistant Cutaneous Fusariosis in a Pediatric Patient With STAT3 Hyper-Immunoglobulin E Syndrome and End-Stage Kidney Disease.

We describe the successful use of the novel antifungal drug fosmanogepix to treat a chronic case of multidrug-resistant cutaneous Fusarium suttonianum infection in a pediatric patient with STAT3 hyper-IgE syndrome and end-stage kidney disease on peritoneal dialysis.

Diagnostic utility of urine neutrophil gelatinase-associated lipocalin and renal resistive index in patients of decompensated cirrhosis with acute kidney injury.

BACKGROUND: The differentiation between types of acute kidney injury(AKI) in decompensated cirrhosis(DC) patients in clinical practice is done by clinical adjudication. Biomarkers have good diagnostic accuracy for predicting acute tubular necrosis(ATN), however they are not available routinely. AIMS: We compared the diagnostic accuracy of urine neutrophil gelatinase-associated lipocalin(UNGAL) and renal resistive index(RRI) in predicting type of AKI among DC patients. METHODS: Consecutive DC patients with AKI stage≥1B seen between June/2020 to May/2021 were evaluated. UNGAL levels and RRI were measured at diagnosis of AKI(Day 0) and 48hrs(Day 3) after volume expansion. Diagnostic accuracy of UGNAL and RRI was compared for differentiating ATN and non-ATN AKI by area under receiver operating characteristic curve(AUROC), using clinical adjudication as gold standard. RESULTS: 388 DC patients were screened, 86 patients(Pre-renal AKI[PRA] n=47,55%; Hepatorenal syndrome[HRS] n=25,29%;ATN n= 14,16%) were included. The AUROC of UNGAL for differentiating ATN-AKI and non-ATN AKI at day 0 was 0.97(95%CI, 0.95-1.0) and on day 3 was 0.97(95%CI, 0.94-1.0). The AUROC of RRI for differentiating ATN and non-ATN AKI at day 0 was 0.68(95%CI, 0.55-0.80) and on day 3 was 0.74(95%CI, 0.63-0.84). CONCLUSION: UNGAL has an excellent diagnostic accuracy in predicting ATN-AKI in DC patients both at day 0 and 3.

Incidence of cytomegalovirus DNAemia in pediatric kidney, liver, and heart transplant recipients: Efficacy and risk factors associated with failure of weight-based dosed valganciclovir prophylaxis.

BACKGROUND: Cytomegalovirus (CMV) is associated with morbidity and mortality in solid organ transplant recipients (SOTR). Valganciclovir (VGC) is extensively used for prophylaxis. Optimal dosing in children, risk factors for failure, and the impact of dose adjustments on CMV DNAemia is not well established. METHODS: This retrospective cohort study of pediatric SOTR transplanted between 2010-2018 evaluated the epidemiology of CMV DNAemia and used Cox-regression to assess the risk factors for CMV DNAemia within one-year following SOTR. RESULTS: In 393 pediatric SOTR (heart [96, 24.4%], kidney [180, 45.6%], liver [117, 29.8%]; median age 9.5 ± 0.3 years), overall CMV DNAemia incidence was 6.6/10 000 days (95%CI 5.1/10 000-7.9/10 000) and varied by organ groups: heart 8.2/10 000 days (95%CI 4.9/10 000-11.4/10 000), kidney 5.8/10 000 days (95%CI 3.9/10 000-7.8/10 000), liver 6.2/10 000 days (95%CI 3.7/10 000-8.7/10 000). CMV DNAemia was detected in 75 of 275 (27.2%) patients who received prophylaxis (40 cases occurred during prophylaxis and 35 occurred after completion of prophylaxis). The median VGC dose given according to institutional weight-based algorithm was approximately 1.5-fold lower than the manufacturer-recommended dose. This discordance was more prominent at younger age groups (3.2-fold lower in <2-year-old [100 mg versus 325 mg], 2.5-fold lower in <6-year-old [200 mg versus 447 mg]). Dose reduction due to adverse events was an independent risk factor for breakthrough CMV DNAemia (hazard ratio 2.2, 95%CI 1.2-3.8) among patients with similar age, CMV risk stratification, starting VGC dose, immunosuppressive therapy, and organ group. CONCLUSION: CMV events occurred while on VGC prophylaxis. Weight-based VGC may prevent supratherapeutic VGC exposure especially in younger children. Dose reduction of VGC prophylaxis for adverse event management places patients at an increased risk for CMV DNAemia suggesting other agents with fewer adverse effects should be considered and need to be studied in children.

A viewpoint describing the American Society of Transplantation rationale to conduct a comprehensive patient survey assessing unmet immunosuppressive therapy needs.

This viewpoint aims to "set the stage" and provide the rationale for the proposed development of a large-scale, comprehensive survey assessing transplant patients' perceived unmet immunosuppressive therapy needs. Research in organ transplantation has historically focused on reducing the incidence and impact of rejection on allograft survival and minimizing or eliminating the need for chronic immunosuppressive therapies. There has been less emphasis and investment in therapies to improve patient-reported outcomes including health-related quality of life and side-effects. Patient-focused drug development (PFDD) is a new and important emphasis of the Food and Drug Administration (FDA) that provides a guiding philosophy for incorporating the patient experience into drug development and evaluation. The American Society of Transplantation (AST) Board of Directors commissioned this working group to prepare for the conduct of a comprehensive patient survey assessing unmet immunosuppressive therapy needs. This paper aims to describe the basis for why it is important to conduct this survey and briefly outline the plan for broad stakeholder engagement to ensure the information gained is diverse, inclusive, and relevant for advancing PFDD in organ transplant recipients.

Ethical analysis examining the prioritisation of living donor transplantation in times of healthcare rationing.

The transplant community has faced unprecedented challenges balancing risks of performing living donor transplants during the COVID-19 pandemic with harms of temporarily suspending these procedures. Decisions regarding postponement of living donation stem from its designation as an elective procedure, this despite that the Centers for Medicare and Medicaid Services categorise transplant procedures as tier 3b (high medical urgency-do not postpone). In times of severe resource constraints, health systems may be operating under crisis or contingency standards of care. In this manuscript, the United Network for Organ Sharing Ethics Workgroup explores prioritisation of living donation where health systems operate under contingency standards of care and provide a framework with recommendations to the transplant community on how to approach living donation in these circumstances.To guide the transplant community in future decisions, this analysis suggests that: (1) living donor transplants represent an important option for individuals with end-stage liver and kidney disease and should not be suspended uniformly under contingency standards, (2) exposure risk to SARS-CoV-2 should be balanced with other risks, such as exposure risks at dialysis centres. Because many of these risks are not quantifiable, donors and recipients should be included in discussions on what constitutes acceptable risk, (3) transplant hospitals should strive to maintain a critical transplant workforce and avoid diverting expertise, which could negatively impact patient preparedness for transplant, (4) transplant hospitals should consider implementing protocols to ensure early detection of SARS-CoV-2 infections and discuss these measures with donors and recipients in a process of shared decision-making.

Vaccine Attitudes and COVID-19 Vaccine Intention Among Parents of Children With Kidney Disease or Primary Hypertension.

RATIONALE & OBJECTIVE: Children with kidney disease and primary hypertension may be more vulnerable to COVID-19. We examined COVID-19 vaccine hesitancy among parents of children with chronic kidney disease or hypertension. STUDY DESIGN: Sequential explanatory mixed-methods design; survey followed by in-depth interviews. SETTING & PARTICIPANTS: Parents of children aged <18 years with kidney disease or primary hypertension within a large pediatric practice. EXPOSURE: Parental attitudes toward general childhood and influenza vaccines assessed by the Vaccine Hesitancy Scale. Kidney disease classification, demographic and socioeconomic factors, experiences with COVID-19, COVID-19 mitigation activities and self-efficacy, and sources of vaccine information. OUTCOME: Willingness to vaccinate child against COVID-19. ANALYTICAL APPROACH: Analysis of variance (ANOVA) test to compare parental attitudes toward general childhood and influenza vaccination with attitudes toward COVID-19 vaccination. Multinomial logistic regression to assess predictors of willingness to vaccinate against COVID-19. Thematic analysis of interview data to characterize influences on parental attitudes. RESULTS: Of the participants, 207 parents completed the survey (39% of approached): 75 (36%) were willing, 80 (39%) unsure, and 52 (25%) unwilling to vaccinate their child against COVID-19. Hesitancy toward general childhood and influenza vaccines was highest among the unwilling group (P < 0.001). More highly educated parents more likely to be willing to vaccinate their children, while Black race was associated with being more likely to be unwilling. Rushed COVID-19 vaccine development as well as fear of serious and unknown long-term side effects were themes that differed across the parental groups that were willing, unsure, or unwilling to vaccinate their children. Although doctors and health care teams are trusted sources of vaccine information, perceptions of benefit versus harm and experiences with doctors differed among these 3 groups. The need for additional information on COVID-19 vaccines was greatest among those unwilling or unsure about vaccinating. LIMITATIONS: Generalizability may be limited. CONCLUSIONS: Two-thirds of parents of children with kidney disease or hypertension were unsure or unwilling to vaccinate their child against COVID-19. Higher hesitancy toward routine childhood and influenza vaccination was associated with hesitancy toward COVID-19 vaccines. Enhanced communication of vaccine information relevant to kidney patients in an accessible manner should be examined as a means to reduce vaccine hesitancy. PLAIN-LANGUAGE SUMMARY: Children with kidney disease or hypertension may do worse with COVID-19. As there are now effective vaccines to protect children from COVID-19, we wanted to find out what parents think about COVID-19 vaccines and what influences their attitudes. We surveyed and then interviewed parents of children who had received a kidney transplant, were receiving maintenance dialysis, had chronic kidney disease, or had hypertension. We found that two-thirds of parents were hesitant to vaccinate their children. Their reasons varied, but the key issues included the need for information pertinent to their child and a consistent message from doctors and other health care providers. These findings may inform an effective vaccine campaign to protect children with kidney disease and hypertension.

INCREASED DISTANCE FROM THE CLINIC LEADS TO HIGHER LOSS TO FOLLOW-UP AFTER PARS PLANA VITRECTOMY IN DIABETIC PATIENTS.

PURPOSE: The importance of consistent outpatient follow-up for management of diabetic eye disease has been well-established. The objective of this study was to identify patient factors associated with being lost to follow-up in postsurgical patients after undergoing pars plana vitrectomy for diabetic eye disease. METHODS: The charts of diabetic patients undergoing pars plana vitrectomy for nonclearing vitreous hemorrhage at an academic medical center by a single surgeon between 2012 and 2019 were reviewed. The rates of loss to follow-up during the postoperative period were compared based on patient distance from the clinic and insurance status. RESULTS: A total of 144 patients met inclusion criteria. A total of 45 patients (31.25%) were lost to follow-up during the 3-month postoperative period. The rate of loss to follow-up increased with every postoperative visit and was significantly higher for patients living greater than 30 miles from the clinic versus patients living within 30 miles from the clinic. There was no statistically significant difference in loss to follow-up based on insurance status. CONCLUSION: Increased distance from the clinic presents a challenge to providing safe and effective postsurgical care to diabetic patients. This presents opportunities for comanagement or other creative strategies to improve postsurgical follow-up rates for at-risk patients.