Survey of pediatric transplant center practices regarding COVID-19 vaccine mandates for transplant candidates and living donors and use of COVID-19-positive deceased organs.

BACKGROUND: COVID-19 vaccine is recommended for individuals ages ≥6 months; however, whether vaccination should be mandated for transplant candidates and living donors remains controversial. This study assessed COVID-19 policies at US pediatric solid organ transplant centers. METHODS: A 79-item survey was emailed between March and April 2022 to 200 UNOS Medical Directors detailing center COVID-19 vaccine policies for transplant candidates and living donors and use of grafts from COVID-19-positive deceased donors. RESULTS: The response rate was 77% (154/200). For children aged 5-15 years, 23% (35/154 centers) have a COVID-19 vaccine mandate, 27% (42/154) anticipate implementing a future mandate, and 47% (72/154) have not considered or do not anticipate implementing a mandate. For children ≥16 years, 32% (50/154 centers) have a COVID-19 vaccine mandate, 25% (39/154) anticipate implementing a future mandate, and 40% (62/154) have not considered or do not anticipate implementing a mandate. The top two reasons for not implementing a COVID-19 vaccine mandate were concerns about penalizing a child for their parent's decision and worsening inequities in transplant. Of 85 kidney and liver living donor centers, 32% (27/85) require vaccination of donors. Twenty percent (31/154) of centers accept organs from COVID-19-positive deceased donors. CONCLUSIONS: There is great variation among pediatric SOT centers in both the implementation and details of COVID-19 vaccine mandates for candidates and living donors. To guide more uniform policies, further data are needed on COVID-19 disease, vaccine efficacy, and use of grafts from donors positive for COVID-19 in the pediatric transplant population.

The learning health system for pediatric nephrology: building better systems to improve health.

Learning health systems (LHS) align science, informatics, incentives, and culture for continuous improvement and innovation. In this organizational system, best practices are seamlessly embedded in the delivery process, and new knowledge is captured as an integral byproduct of the care delivery experience aimed to transform clinical practice and improve patient outcomes. The objective of this review is to describe how building better health systems that integrate clinical care, improvement, and research as part of an LHS can improve care within pediatric nephrology. This review will provide real-world examples of how this system can be established in a single center and across multiple centers as learning health networks.

The ERN-LUNG Population Registry: Aims, Software-Implementation and First Results.

The ERN-LUNG Population Registry is a new European-wide collection of patients with rare lung diseases, allowing patients to register online in the registry. Medical experts can recruit patients in the registry for disease-specific registries and care options. The Population Registry was implemented on the basis of the open source software OSSE and extended by functions for the self-registration of patients. Patients were invited through patient organizations between May and November 2022. 115 patients registered online in the registry, whereas 60 of them provided full data in the registry form. After first months of usage, further dissemination of the registry is necessary to reach more patients, e.g. by recruiting them via medical centres directly. Improvements of the registry should be conducted to achieve a higher number of fully completed forms.

A Medication Adherence Promotion System to Reduce Late Kidney Allograft Rejection: A Quality Improvement Study.

RATIONALE & OBJECTIVE: Adolescent and young adult kidney transplant recipients have a high risk of rejection related to suboptimal adherence. Multicomponent interventions improve adherence in controlled trials, but clinical implementation is lacking. We describe an initiative to reduce allograft rejection using evidence-based adherence promotion strategies. STUDY DESIGN: Interrupted time series. SETTING & PARTICIPANTS: Kidney transplant recipients cared for at Cincinnati Children's Hospital ≥ 1 year after transplant and taking ≥1 immunosuppressive medication(s) from 2014 through 2017. QUALITY IMPROVEMENT ACTIVITIES: The following interventions, collectively called MAPS (Medication Adherence Promotion System), were implemented over 14 months: (1) adherence promotion training for clinical staff, 2) electronic health record-supported adherence risk screening, (3) systematic assessment of medication adherence barriers, (4) designation of specific staff to address adherence barriers, (5) shared decision-making with the patients to overcome adherence barriers, (6) follow-up evaluation to assess progress, and (7) optional electronic medication monitoring. OUTCOMES: Primary Outcome: Late acute rejection. Process measures were conducted to assess barriers, identify barriers, and perform interventions. The secondary outcomes/balancing measures were de novo donor-specific antibodies (DSA), biopsy rate, and rejections per biopsy. ANALYTICAL APPROACH: Time series analysis using statistical process control evaluated patient-days between acute rejections as well as monthly rejections per 100 patient-months before and after implementation. To control for known rejection risk factors including changes in treatment and case mix, multivariable analyses were performed. RESULTS: The monthly rejection rate fell from 1.61 rejections per 100 patient-months in the 26 months before implementation to 0.88 rejections per 100 patient-months in the 22 months after implementation. In the multivariable analysis, MAPS was associated with a 50% reduction in rejection incidence (incidence rate ratio, 0.50 [95% CI, 0.27-0.91]; P = 0.02). DSA and time since transplant (per each additional year) were also associated with rejection incidence (incidence rate ratio, 2.27 [P = 0.02] and 0.87 [P = 0.02], respectively). LIMITATIONS: Single-center study, and potential confounding by unmeasured variables. CONCLUSIONS: Clinical implementation of evidence-based adherence-promotion strategies was associated with a 50% reduction in acute rejection incidence over 2 years.

Impact of once-daily ER-Tac on trough concentration variability in a stable AYA renal transplant recipient cohort.

BACKGROUND: Successful renal transplantation requires complex medication regimens that rely on strict adherence to be effective. Variability in immunosuppression exposure, specifically tacrolimus, is associated with poor allograft outcomes. Wide intra-patient variability of tacrolimus trough concentrations (Vtac) is likely, in part, attributable to regimen complexity and poor medication adherence. Once-daily tacrolimus formulations create opportunity to simplify therapeutic regimens, and this study aims to evaluate their impact on Vtac and ultimately transplant outcomes. METHODS: This retrospective cohort study investigated stable (AYA) renal transplant recipients converted from (IR-Tac) to (ER-Tac). Subjects served as their own controls. Vtac was assessed by measuring the (SD) of serial tacrolimus trough concentrations prior to and at four time points post-conversion to ER-Tac over 24-month follow-up. Secondary outcome measures included graft function, infection rates, and effect on modifiable treatment-related factors. RESULTS: Twenty-eight AYA subjects were converted from IR-Tac to ER-Tac. Vtac significantly improved following conversion and was sustained for 24 months (Vtac0 2.32 vs. Vtac24 1.11, p .017). Renal function remained stable, and (BPAR) rates were modest (14%). Mean pill burden was reduced by 15%, and 42.9% of subjects achieved a once-daily medication regimen. CONCLUSIONS: Conversion from IR-Tac to ER-Tac in this AYA population significantly improved Vtac with sustained effect over 2 years. This effect is likely attributable in part to simplification of the medication regimen and presumably improved medication adherence. Such conversion does not appear to compromise graft function for at least 2 years post-conversion.

COVID-19 in pediatric kidney transplantation: The Improving Renal Outcomes Collaborative.

There are limited data on the impact of COVID-19 in children with a kidney transplant (KT). We conducted a prospective cohort study through the Improving Renal Outcomes Collaborative (IROC) to collect clinical outcome data about COVID-19 in pediatric KT patients. Twenty-two IROC centers that care for 2732 patients submitted testing and outcomes data for 281 patients tested for SARS-CoV-2 by PCR. Testing indications included symptoms and/or potential exposures to COVID-19 (N = 134, 47.7%) and/or testing per hospital policy (N = 154, 54.8%). Overall, 24 (8.5%) patients tested positive, of which 15 (63%) were symptomatic. Of the COVID-19-positive patients, 16 were managed as outpatients, six received non-ICU inpatient care and two were admitted to the ICU. There were no episodes of respiratory failure, allograft loss, or death associated with COVID-19. To estimate incidence, subanalysis was performed for 13 centers that care for 1686 patients that submitted all negative and positive COVID-19 results. Of the 229 tested patients at these 13 centers, 10 (5 asymptomatic) patients tested positive, yielding an overall incidence of 0.6% and an incidence among tested patients of 4.4%. Pediatric KT patients in the United States had a low estimated incidence of COVID-19 disease and excellent short-term outcomes.

Management of dyslipidemia in pediatric renal transplant recipients.

Dyslipidemia after kidney transplantation is a common complication that has historically been underappreciated, especially in pediatric recipients. It is also a major modifiable risk factor for cardiovascular disease, a top cause of morbidity and mortality of transplant patients. While most knowledge about post-transplant dyslipidemia has been generated in adults, recommendations and treatment strategies also exist for children and are presented in this review. Awareness of these applicable guidelines and approaches is required, but not sufficient, for the reliable management of dyslipidemia in our patients, and additional needs and opportunities for comprehensive care in this area (e.g., quality improvement) are outlined.

Clinical Outcomes of Allogeneic Ocular Surface Stem Cell Transplantation in Pediatric Patients.

PURPOSE: To describe the outcomes of allograft ocular surface stem cell transplantation (OSST) and the complication profile of systemic immunosuppression (SI) in pediatric patients with limbal stem cell deficiency. METHODS: This was a retrospective interventional case series from a single tertiary referral institution of 20 eyes from 13 patients who 1) underwent allograft OSST surgery, 2) were 18 years or less at time of OSST, and 3) received SI with 4) a minimum of 12-months follow-up. The main outcome measures were ocular surface stability, visual acuity, and SI adverse events. RESULTS: The mean age of patients was 15.1 ± 3.2 years (range 9-18 years). The mean follow-up was 5.6 ± 5.0 years after OSST. At the last follow-up, 15 eyes (75%) had a stable ocular surface, 1 eye (5%) developed partial failure, and 4 eyes (20%) developed total surface failure. Preoperative mean logarithm of the minimum angle of resolution visual acuity 1.5 improved to 1.1 at the last follow-up (P = 0.1); when 4 eyes of 3 nonadherent patients were excluded, the results were more pronounced and statistically significant (1.5 improved to 1.0, P = 0.002). SI was tolerated well by all patients with minimal adverse events. CONCLUSIONS: OSST provides a stable ocular surface and is a successful treatment option for pediatric patients with limbal stem cell deficiency. SI is well-tolerated with a minimal complication profile.

Pediatric trichodysplasia spinulosa: A report of 2 cases and review of the literature.

Trichodysplasia spinulosa is a rare disorder caused by the ubiquitous trichodysplasia spinulosa-associated polyomavirus (TSPyV) and characterized clinically by predominately centrofacial, but often generalized, folliculocentric papules with protuberant keratinaceous spines. Although seroprevalence reaches up to 70% in adult populations, TSPyV causes clinical manifestations in a small percentage of patients who are immunosuppressed. Diagnosis can be made using typical clinical and histologic features, SV40T antibody immunostaining, and PCR of various tissues including the keratinaceous spine, skin, serum, urine, and CSF. Various topical and systemic medications have demonstrated variable success. Decreasing or discontinuing immunosuppression has also been shown to improve or alleviate clinical manifestations.

The Improving Renal Outcomes Collaborative: Blood Pressure Measurement in Transplant Recipients.

BACKGROUND AND OBJECTIVES: Hypertension is highly prevalent in pediatric kidney transplant recipients and contributes to cardiovascular death and graft loss. Improper blood pressure (BP) measurement limits the ability to control hypertension in this population. Here, we report multicenter efforts from the Improving Renal Outcomes Collaborative (IROC) to standardize and improve appropriate BP measurement in transplant patients. METHODS: Seventeen centers participated in structured quality improvement activities facilitated by IROC, including formal training in quality improvement methods. The primary outcome measure was the proportion of transplant clinic visits with appropriate BP measurement according to published guidelines. Prospective data were analyzed over a 12-week pre-intervention period and a 20-week active intervention period for each center and then aggregated as of the program-specific start date. We used control charts to quantify improvements across IROC centers. We applied thematic analysis to identify patterns and common themes of successful interventions. RESULTS: We analyzed data from 5392 clinic visits. At baseline, BP was measured and documented appropriately at 11% of visits. Center-specific interventions for improving BP measurement included educating clinic staff, assigning specific team member roles, and creating BP tracking tools and alerts. Appropriate BP measurement improved throughout the 20-week active intervention period to 78% of visits. CONCLUSIONS: We standardized appropriate BP measurement across 17 pediatric transplant centers using the infrastructure of the IROC learning health system and substantially improved the rate of appropriate measurement over 20 weeks. Accurate BP assessment will allow further interventions to reduce complications of hypertension in pediatric kidney transplant recipients.

Donor-specific antibodies in a pediatric kidney transplant population-Prevalence and association with antiproliferative drug dosing.

Prevalence and implications of anti-HLA class I and class II antibodies are beginning to be better characterized in pediatric kidney transplant recipients. dnDSA formation is predictive of AMR and downstream diminished graft function and survival. However, risk factors for the development of dnDSA are not well defined in this patient population. After introducing DSA surveillance into our pediatric kidney transplant program, we are reporting the prevalence of class I and class II DSA in 67 otherwise stable recipients. Secondary end-points included risk factors for DSA development and assessment of graft function. Significantly, lower median daily MMF doses were observed in patients with DSAs compared to patients without DSAs (371 vs 617 mg/m2 /d, respectively; P = 0.035). Class II DSA formation was more common, with a prevalence of 17.9%, as compared to 10.4% for class I DSA. Estimated glomerular filtration rate was also decreased in patients with positive DSA vs those with negative titers (71, SD 25 vs 78, SD 29 mL/min/1.73 m2 , respectively; P = 0.034). We conclude that reduced-dose MMF is associated with dnDSA and DSA is associated with diminished graft function in stable pediatric kidney transplant recipients.

Composite Health Outcomes in Pediatric and Young Adult Kidney Transplant Recipients.

OBJECTIVE: To assess composite health outcomes in pediatric and young adult kidney transplant recipients following kidney transplantation. STUDY DESIGN: We conducted a cross-sectional study of all recipients at our center who had a 1-, 3-, 5-, and/or 10-year transplant anniversary visit between October 2008 and February 2015. The kidney transplant recipients were assessed at each time point according to an outcome measure consisting of 15 pass/fail criteria in 5 domains: allograft health, rejection and immunology, infection, cardiovascular health, and growth. RESULTS: We analyzed 148 patients at 231 transplantation anniversary visit time points; 52 of 82 (63%) patients assessed at 1 year had an ideal outcome, meeting at least 13 of the 15 criteria. This decreased to 37% at year 3, 40% at year 5, and 26% at year 10 (P < .01). The most common failures across all time points occurred in the domains of growth (43%-52% passing) and cardiovascular health (33%-51% passing). Allograft health declined significantly, decreasing from 74% at year 1 to 33% at year 10 (P < .01). The percentage of patients with graft failure increased from 2.4% at 1 year to 39.5% at 10 years (P < .01), and patient deaths increased from 0 to 11% (P < .01) in the same time frame. CONCLUSIONS: Ideal outcomes for pediatric kidney transplant recipients decrease over time with growth, cardiovascular health, and allograft health as the primary failure modes. Understanding the composite health of young recipients will allow primary care providers and nephrologists alike to evaluate the overall health of kidney transplant recipients and focus clinical care on the most common sequelae.

Increase in chloride from baseline is independently associated with mortality in critically ill children.

PURPOSE: To determine if there is an association between mortality and admission chloride levels and/or increases in the chloride level in critically ill children. METHODS: We performed a retrospective cohort study of all patients admitted to the paediatric intensive care unit (PICU) from January 2014 to December 2015. Patients were excluded for the following reasons: (1) age < 90 days or > 18 years, (2) admission to the cardiac intensive care unit, (3) no laboratory values upon admission to the PICU, (4) history of end-stage renal disease, (5) a disorder of chloride transport, and (6) admission for diabetic ketoacidosis. The patients were stratified on the basis of admission chloride levels (hypochloraemia, < 96 mEq/L; normochloraemia, 96-109 mEq/L; and hyperchloraemia, ≥ 110 mEq/L) and dichotomised on the basis of an increase in chloride in the first day (< 5 mEq/L, ≥ 5 mEq/L). Our primary outcome was in-hospital mortality. RESULTS: A total of 1935 patients [55% female, median age 6.3 years IQR (1.9-13.4)] were included. The overall mortality was 4% (n = 71) and day 2 AKI occurred in 17% (n = 333. Hypochloraemia, hyperchloraemia, and an increase in serum chloride ≥ 5 mEq/L occurred in 2%, 21%, and 12%, respectively. After adjusting for confounders, increase in chloride ≥ 5 mEq/L was associated with a 2.3 (95% CI 1.03-5.21) greater odds of mortality. CONCLUSIONS: An increase in serum chloride level in the first day of admission is common and an independent risk factor for mortality in critically ill children. Further studies are warranted to identify how chloride disturbances contribute to mortality risk in critically ill children.

OSSE Goes FAIR - Implementation of the FAIR Data Principles for an Open-Source Registry for Rare Diseases.

The Open Source Registry for Rare Diseases (OSSE) provides a concept and a software for the management of registries for patients with rare diseases. A disease is defined as rare if less than 5 out of 10,000 people are affected. Up to date, approximately 6,000 rare diseases are catalogued. Networking and data exchange for research purposes remains challenging due to the paucity of interoperability and due to the fact that small data stocks are stored locally. The so called "Findable, Accessible, Interoperable, Reusable" (FAIR) Data Principles have been developed to improve research in the field of rare diseases. Subsequently, the OSSE architecture was adapted to implement the FAIR Data Principles. Therefore, the so-called FAIR Data Point was integrated into OSSE to provide a description of metadata in a FAIR manner. OSSE relies on the existing metadata repository (MDR), which is used in to define data elements in the system. This is an important step towards unified documentation across multiple registries. The integration and use of new procedures to improve interoperability plays an important role in the context of registries for rare diseases.

IGG3 anti-HLA donor-specific antibodies and graft function in pediatric kidney transplant recipients.

Anti-HLA DSAs are associated with ABMR and graft loss in KT recipients, yet the influence of DSA IgG subclass on outcomes in pediatric KT recipients is not completely understood. We performed a single-center retrospective chart review of pediatric KT recipients with anti-HLA DSAs, aiming to study the association between specific DSA IgG subclasses and graft outcomes, including ABMR and significant graft dysfunction (graft loss or 50% decrease in eGFR). Thirty-six patients (mean age 15.4y) with DSAs initially detected 1 month-14.3 years post-transplantation were followed for a median of 2.8 years. Rates of IgG1, 2, 3, and 4 subclass detection were 92%, 33%, 58%, and 25%, respectively. Twenty-two patients (61%) had clinical ABMR, whereas 19% had subclinical ABMR, and 13 (36%) experienced significant graft dysfunction. Patients with IgG3+ DSAs had a higher risk of graft dysfunction compared with IgG3- patients (52% vs 13%, P = .03). In a multiple Cox proportional regression analysis, the presence of IgG3+ DSA was independently associated with significant graft dysfunction (HR 10.45, 95% CI 1.97-55.55, P = .006). In conclusion, IgG3 subclass DSAs are associated with graft dysfunction and may be useful for risk stratification and treatment decisions in DSA-positive pediatric KT recipients.

COQ2 nephropathy: a treatable cause of nephrotic syndrome in children.

BACKGROUND: Nephrotic syndrome can be caused by a subgroup of mitochondrial diseases classified as primary coenzyme Q10 (CoQ10) deficiency. Pathogenic COQ2 variants are a cause of primary CoQ10 deficiency and present with phenotypes ranging from isolated nephrotic syndrome to fatal multisystem disease. CASE-DIAGNOSIS/TREATMENT: We report three pediatric patients with COQ2 variants presenting with nephrotic syndrome. Two of these patients had normal leukocyte CoQ10 levels prior to treatment. Pathologic findings varied from mesangial sclerosis to focal segmental glomerulosclerosis, with all patients having abnormal appearing mitochondria on kidney biopsy. In two of the three patients treated with CoQ10 supplementation, the nephrotic syndrome resolved; and at follow-up, both have normal renal function and stable proteinuria. CONCLUSIONS: COQ2 nephropathy should be suspected in patients presenting with nephrotic syndrome, although less common than disease due to mutations in NPHS1, NPHS2, and WT1. The index of suspicion should remain high, and we suggest that providers consider genetic evaluation even in patients with normal leukocyte CoQ10 levels, as levels may be within normal range even with significant clinical disease. Early molecular diagnosis and specific treatment are essential in the management of this severe yet treatable condition.

Hyperchloremia is independently associated with mortality in critically ill children who ultimately require continuous renal replacement therapy.

BACKGROUND: The optimal fluid management in critically ill children is currently under investigation with several studies suggesting that hyperchloremia, chloride load, and the use of chloride-rich fluids contribute to worse outcomes. METHODS: This is a single-center retrospective cohort study of Pediatric Intensive Care Unit patients from 2008 to 2016 requiring continuous renal replacement therapy (CRRT). Patients were excluded if they had end-stage renal disease, a disorder of chloride transport, or concurrent provision of extracorporeal membrane oxygenation therapy. RESULTS: Patients (n = 66) were dichotomized into two groups (peak chloride (Cl) ≥ 110 mmol/L vs. peak Cl < 110 mmol/L prior to CRRT initiation). Hyperchloremia was present in 39 (59%) children. Baseline characteristics were similar between groups. Fluid overload at CRRT initiation was more common in patients with hyperchloremia (11.5% IQR 3.8-22.4) compared to those without (5.5% IQR 0.9-13.9) (p = 0.04). Mortality was significantly higher in patients with hyperchloremia (n = 26, 67%) compared to those without (n = 8, 29%) (p = 0.006). Patients with hyperchloremia had 10.9 times greater odds of death compared to those without hyperchloremia, after adjusting for percent fluid overload, PRISM III score, time to initiation of CRRT, height, and weight (95% CI 2.4 to 49.5, p = 0.002). CONCLUSIONS: Hyperchloremia is common among critically ill children prior to CRRT initiation. In this population, hyperchloremia is independently associated with mortality. Further studies are needed to determine the impact of hyperchloremia on all critically ill children and the impact of chloride load on outcomes.