Development of CARRA/PReS-endorsed consensus Core and Expanded Datasets in childhood-onset systemic lupus erythematosus for international registry-based research.

OBJECTIVES: Childhood-onset systemic lupus erythematosus (cSLE), representing 15%-20% of individuals with SLE, has been difficult to study globally due to differences between registries. This initiative, supported by Childhood Arthritis Rheumatology Research Alliance (CARRA) and Paediatric Rheumatology European Society (PReS), aims to create Core and Expanded cSLE Datasets to standardise and enhance research worldwide. METHODS: 21 international cSLE experts and 4 patients participated in a Delphi process (questionnaires, 2 topic-specific focus groups and 3 virtual consensus meetings) to create 2 standardised cSLE datasets. The Core cSLE Dataset was designed to include data essential to meaningful clinical research across many settings. The Expanded cSLE Dataset was designed for centres able to consistently collect data to address broader research questions. Final data items for the Core and Expanded datasets were determined by consensus defined as >80% agreement) using an adapted nominal group technique and voting. RESULTS: The resulting Core cSLE Dataset contains 46 items, including demographics, clinical features, laboratory results, medications and significant adverse events. The Expanded cSLE Dataset adds 26 additional items and includes patient-reported outcomes. Consensus was also achieved regarding the frequency and time points for data collection: baseline, quarterly follow-up visits, annually and flare visits. CONCLUSION: Standardised Core and Expanded cSLE Datasets for registry-based international cSLE research were defined through the consensus of global experts and patient/caregiver representatives, endorsed by CARRA and PReS. These datasets incorporate disease-specific and patient-specific features, optimised for diverse settings to facilitate international collaborative research for children and adolescents with SLE worldwide.

Method to apply temporal graph analysis on electronic patient record data to explore healthcare professional-patient interaction intensity: a cohort study.

AIM: Interactions between patients and healthcare professionals (HCP) during hospital admissions are complex and difficult to interrogate using traditional analysis of electronic patient record (EPR) data. The objective of this study was to determine the feasibility of applying temporal network analytics to EPR data, focusing on HCP-patient interactions over time. METHOD: Network (graph) analysis was applied to routinely collected structured data from an EPR for HCP interactions with individual patients during admissions for patients undergoing renal transplantation between May 2019 and June 2023. Networks were constructed per day of admission within a session, defined by whether the patient was in the intensive care unit (ICU) or standard hospital ward. Connections between HCP were defined using a 60 min period. Reports were generated visualising daily interaction network structures, across individual admissions. RESULTS: 2300 individual networks were constructed from 127 hospital admissions for renal transplantation. The number of nodes or HCP per network varied from 2 to 45, and network metrics provided detail regarding variation in the density and transitivity, changes in structure with different diameters and radii, and variations in centralisation. Each network analysis metric has a contribution to play in describing the dynamics of a daily HCP network and the composite findings provide insights that cannot be determined with standard approaches. CONCLUSIONS: Network analysis provides a novel approach to investigate and visualise patterns of HCP-patient interactions which allow for a deeper understanding of the complex nature of hospital patient care and could have numerous practical operational applications.

The spectrum of co-existing disease in children with established kidney failure using registry and linked electronic health record data.

BACKGROUND: Children with established kidney failure may have additional medical conditions influencing kidney care and outcomes. This cross-sectional study aimed to examine the prevalence of co-existing diseases captured in the electronic hospital record compared to UK Renal Registry (UKRR) data and differences in coding. METHODS: The study population comprised children aged < 18 years receiving kidney replacement therapy (KRT) in England and Wales on 31/12/2016. Comorbidity data at KRT start was examined in the hospital record and compared to UKRR data. Agreement was assessed by the kappa statistic. Associations between patient and clinical factors and likelihood of coding were examined using multivariable logistic regression. RESULTS: A total of 869 children (62.5% male) had data linkage for inclusion. UKRR records generally reported a higher prevalence of co-existing disease than electronic health records; congenital, non-kidney disease was most commonly reported across both datasets. The highest sensitivity in the hospital record was seen for congenital heart disease (odds ratio (OR) 0.65, 95% confidence interval (CI) 0.51, 0.78) and malignancy (OR 0.63, 95% CI 0.41, 0.85). At best, moderate agreement (kappa ≥ 0.41) was seen between the datasets. Factors associated with higher odds of coding in hospital records included age, while kidney disease and a higher number of comorbidities were associated with lower odds of coding. CONCLUSIONS: Health records generally under-reported co-existing disease compared to registry data with fair-moderate agreement between datasets. Electronic health records offer a non-selective overview of co-existing disease facilitating audit and research, but registry processes are still required to capture paediatric-specific variables pertinent to kidney disease.

International consensus statement on the diagnosis and management of phaeochromocytoma and paraganglioma in children and adolescents.

Phaeochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumours that arise not only in adulthood but also in childhood and adolescence. Up to 70-80% of childhood PPGL are hereditary, accounting for a higher incidence of metastatic and/or multifocal PPGL in paediatric patients than in adult patients. Key differences in the tumour biology and management, together with rare disease incidence and therapeutic challenges in paediatric compared with adult patients, mandate close expert cross-disciplinary teamwork. Teams should ideally include adult and paediatric endocrinologists, oncologists, cardiologists, surgeons, geneticists, pathologists, radiologists, clinical psychologists and nuclear medicine physicians. Provision of an international Consensus Statement should improve care and outcomes for children and adolescents with these tumours.

Protocol for a multicentre prospective exploratory mixed-methods study investigating the modifiable psychosocial variables influencing access to and outcomes after kidney transplantation in children and young people in the UK.

INTRODUCTION: Kidney transplantation is the preferred therapy for children with stage 5 chronic kidney disease (CKD-5). However, there is a wide variation in access to kidney transplantation across the UK for children. This study aims to explore the psychosocial factors that influence access to and outcomes after kidney transplantation in children in the UK using a mixed-methods prospective longitudinal design. METHODS: Qualitative data will be collected through semistructured interviews with children affected by CKD-5, their carers and paediatric renal multidisciplinary team. Recruitment for interviews will continue till data saturation. These interviews will inform the choice of existing validated questionnaires, which will be distributed to a larger national cohort of children with pretransplant CKD-5 (n=180) and their carers. Follow-up questionnaires will be sent at protocolised time points regardless of whether they receive a kidney transplant or not. Coexisting health data from hospital, UK renal registry and National Health Service Blood and Transplant registry records will be mapped to each questionnaire time point. An integrative analysis of the mixed qualitative and quantitative data will define psychosocial aspects of care for potential intervention to improve transplant access. ANALYSIS: Qualitative data will be analysed using thematic analysis. Quantitative data will be analysed using appropriate statistical methods to understand how these factors influence access to transplantation, as well as the distribution of psychosocial factors pretransplantation and post-transplantation. ETHICS AND DISSEMINATION: This study protocol has been reviewed by the National Institute for Health Research Academy and approved by the Wales Research Ethics Committee 4 (IRAS number 270493/ref: 20/WA/0285) and the Scotland A Research Ethics Committee (ref: 21/SS/0038). Results from this study will be disseminated across media platforms accessed by affected families, presented at conferences and published in peer-reviewed journals.

The IPTA Nashville consensus conference on post-transplant lymphoproliferative disorders after solid organ transplantation in children: IV-consensus guidelines for the management of post-transplant lymphoproliferative disorders in children and adolescents.

The International Pediatric Transplant Association convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post-transplant lymphoproliferative disorders (PTLD) after pediatric solid organ transplantation. This report addresses the outcomes of deliberations by the PTLD Management Working Group. A strong recommendation was made for reduction in immunosuppression as the first step in management. Similarly, strong recommendations were made for the use of the anti-CD20 monoclonal antibody (rituximab) as was the case for chemotherapy in selected scenarios. In some scenarios, there is uncoupling of the strength of the recommendations from the available evidence in situations where such evidence is lacking but collective clinical experiences drive decision-making. Of note, there are no large, randomized phase III trials of any treatment for PTLD in the pediatric age group. Current gaps and future research priorities are highlighted.

Favorable Outcome After Single-kidney Transplantation From Small Donors in Children: A Match-controlled CERTAIN Registry Study.

BACKGROUND: Kidney transplantation (KTx) from small donors is associated with inferior graft survival in registry studies, whereas single-center studies show favorable results. METHODS: We compared 175 pediatric KTx from small donors ≤20 kg (SDKTx) with 170 age-matched recipients from adult donors (ADKTx) from 20 centers within the Cooperative European Paediatric Renal Transplant Initiative registry. Graft survival and estimated glomerular filtration rate (eGFR) were analyzed by Cox regression and mixed models. Detailed data on surgical and medical management were tested for association with graft survival. RESULTS: One-year graft survival was lower after SDKTx compared with ADKTx (90.9% versus 96.5%; odds ratio of graft loss, 2.92; 95% confidence interval [CI], 1.10-7.80; P  = 0.032), but 5-y graft survival was comparable (90.9% versus 92.7%; adjusted hazard ratio of graft loss 1.9; 95% CI, 0.85-4.25; P  = 0.119). SDKTx recipients had an annual eGFR increase of 8.7 ±â€…6.2 mL/min/1.73 m² compared with a decrease of 6.9 ±â€…5.7 mL/min/1.73 m² in ADKTx recipients resulting in a superior 5-y eGFR (80.5 ±â€…25.5 in SDKTx versus 65.7 ±â€…23.1 mL/min/1.73 m² in ADKTx; P  = 0.008). At 3 y posttransplant, eGFR after single SDKTx was lower than after en bloc SDKTx (86.6 ±â€…20.4 versus 104.6 ±â€…35.9; P  = 0.043) but superior to ADKTx (68.1 ±â€…23.9 mL/min/1.73 m²). Single-kidney SDKTx recipients had a lower rate of hypertension at 3 y than ADKTx recipients (40.0% versus 64.7%; P  = 0.008). CONCLUSIONS: Compared with ADKTx, 5-y graft function is superior in SDKTx and graft survival is similar, even when performed as single KTx. Utilizing small donor organs, preferably as single kidneys in experienced centers, is a viable option to increase the donor pool for pediatric recipients.

National study on the risks of COVID-19 infection for paediatric kidney transplant recipients: a retrospective, cross-sectional study.

INTRODUCTION: During the COVID-19 pandemic, evidence emerged that immunosuppressed children were less affected by COVID-19 infections compared with immunosuppressed adults. The aim of our study was to investigate how COVID-19 infections affected paediatric kidney transplant recipients (pKTR) in the UK. METHODS: Questionnaires regarding COVID-19 infection data and care of pKTR during the COVID-19 pandemic were sent to all 13 UK paediatric nephrology centres examining asymptomatic and symptomatic pKTR with positive COVID-19 PCR testing from 1 April 2020 to 1 December 2021. RESULTS: 63 pKTR who were 3.1 (range 0.1-15) years post-transplantation had COVID-19 infection with positive SARS-CoV-2 PCR RNA. Classical COVID-19 symptoms were present in half of the patients; with atypical presentations including diarrhoea (13%) and lethargy (13%) also noted, while a third of patients were asymptomatic. Eighteen patients (28%) were hospitalised including five asymptomatic patients admitted for other reasons. No patients needed ventilation or intensive care admission, and one patient received supplemental oxygen. There was evidence of acute kidney injury (AKI) in 71% of patients, but no patients needed kidney replacement therapy with haemofiltration or dialysis. CONCLUSION: We report 10.4% of the UK paediatric renal transplantation population had documented COVID-19 infections with positive SARS-CoV-2 PCR RNA with 28% of those affected requiring hospitalisation. The increased incidence of AKI, particularly after the first wave of the COVID-19 pandemic, was possibly due to increased testing. There was low morbidity and mortality compared with the adult population.

Holistic care and symptom management for pediatric kidney transplant recipients.

While many aspects of life may improve substantially for children and young people undergoing kidney transplant, there may be new challenges including symptoms that can be detrimental to health-related quality of life. Addressing symptoms requires attention to patient and family perspectives and a holistic approach grounded in symptom management. The interdisciplinary pediatric nephrology transplant team should be attuned to the prevalence of common symptoms including fatigue, anxiety, depression, post-traumatic stress, pain, and sleep disturbances, as well as poor body image and sexual health. These common symptoms require regular assessment with a focus on appropriate interventions and how care may be impacted by transplant status.

A pragmatic, open-label, randomized controlled trial of Plasma-Lyte-148 versus standard intravenous fluids in children receiving kidney transplants (PLUTO).

Acute electrolyte and acid-base imbalance is experienced by many children following kidney transplant. This is partly because doctors give very large volumes of artificial fluids to keep the new kidney working. When severe, fluid imbalance can lead to seizures, cerebral edema and death. In this pragmatic, open-label, randomized controlled trial, we randomly assigned (1:1) pediatric kidney transplant recipients to Plasma-Lyte-148 or standard of care perioperative intravenous fluids (predominantly 0.45% sodium chloride and 0.9% sodium chloride solutions). We then compared clinically significant electrolyte and acid-base abnormalities in the first 72 hours post-transplant. The primary outcome, acute hyponatremia, was experienced by 53% of 68 participants in the Plasma-Lyte-148 group and 58% of 69 participants in the standard fluids group (odds ratio 0·77 (0·34 - 1·75)). Five of 16 secondary outcomes differed with Plasma-Lyte-148: hypernatremia was significantly more frequent (odds ratio 3·5 (1·1 - 10·8)), significantly fewer changes to fluid prescriptions were made (rate ratio 0·52 (0·40-0·67)), and significantly fewer participants experienced hyperchloremia (odds ratio 0·17 (0·07 - 0·40)), acidosis (odds ratio 0·09 (0·04 - 0·22)) and hypomagnesemia (odds ratio 0·21 (0·08 - 0·50)). No other secondary outcomes differed between groups. Serious adverse events were reported in 9% of participants randomized to Plasma-Lyte-148 and 7% of participants randomized to standard fluids. Thus, perioperative Plasma-Lyte-148 did not change the proportion of children who experienced acute hyponatremia compared to standard fluids. However fewer fluid prescription changes were made with Plasma-Lyte-148, while hyperchloremia and acidosis were less common.

The IPTA Nashville Consensus Conference on Post-Transplant lymphoproliferative disorders after solid organ transplantation in children: III - Consensus guidelines for Epstein-Barr virus load and other biomarker monitoring.

The International Pediatric Transplant Association convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post-transplant lymphoproliferative disorders after solid organ transplantation in children. In this report from the Viral Load and Biomarker Monitoring Working Group, we reviewed the existing literature regarding the role of Epstein-Barr viral load and other biomarkers in peripheral blood for predicting the development of PTLD, for PTLD diagnosis, and for monitoring of response to treatment. Key recommendations from the group highlighted the strong recommendation for use of the term EBV DNAemia instead of "viremia" to describe EBV DNA levels in peripheral blood as well as concerns with comparison of EBV DNAemia measurement results performed at different institutions even when tests are calibrated using the WHO international standard. The working group concluded that either whole blood or plasma could be used as matrices for EBV DNA measurement; optimal specimen type may be clinical context dependent. Whole blood testing has some advantages for surveillance to inform pre-emptive interventions while plasma testing may be preferred in the setting of clinical symptoms and treatment monitoring. However, EBV DNAemia testing alone was not recommended for PTLD diagnosis. Quantitative EBV DNAemia surveillance to identify patients at risk for PTLD and to inform pre-emptive interventions in patients who are EBV seronegative pre-transplant was recommended. In contrast, with the exception of intestinal transplant recipients or those with recent primary EBV infection prior to SOT, surveillance was not recommended in pediatric SOT recipients EBV seropositive pre-transplant. Implications of viral load kinetic parameters including peak load and viral set point on pre-emptive PTLD prevention monitoring algorithms were discussed. Use of additional markers, including measurements of EBV specific cell mediated immunity was discussed but not recommended though the importance of obtaining additional data from prospective multicenter studies was highlighted as a key research priority.

Management and treatment of children, young people and adults with systemic lupus erythematosus: British Society for Rheumatology guideline scope.

The objective of this guideline is to provide up-to-date, evidence-based recommendations for the management of SLE that builds upon the existing treatment guideline for adults living with SLE published in 2017. This will incorporate advances in the assessment, diagnosis, monitoring, non-pharmacological and pharmacological management of SLE. General approaches to management as well as organ-specific treatment, including lupus nephritis and cutaneous lupus, will be covered. This will be the first guideline in SLE using a whole life course approach from childhood through adolescence and adulthood. The guideline will be developed with people with SLE as an important target audience in addition to healthcare professionals. It will include guidance related to emerging approved therapies and account for National Institute for Health and Care Excellence Technology Appraisals, National Health Service England clinical commissioning policies and national guidance relevant to SLE. The guideline will be developed using the methods and rigorous processes outlined in 'Creating Clinical Guidelines: Our Protocol' by the British Society for Rheumatology.

Epidemiology of childhood acute kidney injury in England using e-alerts.

Background: Few studies describe the epidemiology of childhood acute kidney injury (AKI) nationally. Laboratories in England are required to issue electronic (e-)alerts for AKI based on serum creatinine changes. This study describes a national cohort of children who received an AKI alert and their clinical course. Methods: A cross-section of AKI episodes from 2017 are described. Hospital record linkage enabled description of AKI-associated hospitalizations including length of stay (LOS) and critical care requirement. Risk associations with critical care (hospitalized cohort) and 30-day mortality (total cohort) were examined using multivariable logistic regression. Results: In 2017, 7788 children (52% male, median age 4.4 years, interquartile range 0.9-11.5 years) experienced 8927 AKI episodes; 8% occurred during birth admissions. Of 5582 children with hospitalized AKI, 25% required critical care. In children experiencing an AKI episode unrelated to their birth admission, Asian ethnicity, young (<1 year) or old (16-<18 years) age (reference 1-<5 years), and high peak AKI stage had higher odds of critical care. LOS was higher with peak AKI stage, irrespective of critical care admission. Overall, 30-day mortality rate was 3% (n = 251); youngest and oldest age groups, hospital-acquired AKI, higher peak stage and critical care requirement had higher odds of death. For children experiencing AKI alerts during their birth admission, no association was seen between higher peak AKI stage and critical care admission. Conclusions: Risk associations for adverse AKI outcomes differed among children according to AKI type and whether hospitalization was related to birth. Understanding the factors driving AKI development and progression may help inform interventions to minimize morbidity.

A clinical review of antidepressants, their sexual side-effects, post-SSRI sexual dysfunction, and serotonin syndrome.

Depression and anxiety are common, with one in six people experiencing symptoms in any given week. Of these people, 8.32 million are prescribed antidepressants. People living with HIV are likely to experience psychiatric disorder, with one in three experiencing depression and anxiety, and being at greater risk of developing post-traumatic stress disorder. Sexual side-effects of psychotropic medication are very common, cause distress, and can persist even after the medication has been withdrawn. Antidepressants are powerful drugs and can have severe interactions with many other substances. This article seeks to raise awareness of sexual side-effects of psychotropic medications and draw attention to ethical issues related to post selective serotonin reuptake inhibitor sexual dysfunction (PSSD). Additional risk factors and interactions between psychotropic medications and recreational drugs are identified. Recommendations are made to improve care and clinical outcomes through the development of therapeutic alliances.

The UK kidney donor risk index poorly predicts long-term transplant survival in paediatric kidney transplant recipients.

Background: The UK kidney offering scheme introduced a kidney donor risk index (UK-KDRI) to improve the utility of deceased-donor kidney allocations. The UK-KDRI was derived using adult donor and recipient data. We assessed this in a paediatric cohort from the UK transplant registry. Methods: We performed Cox survival analysis on first kidney-only deceased brain-dead transplants in paediatric (<18 years) recipients from 2000-2014. The primary outcome was death-censored allograft survival >30 days post-transplant. The main study variable was UK-KDRI derived from seven donor risk-factors, categorised into four groups (D1-low risk, D2, D3 and D4-highest risk). Follow-up ended on 31-December-2021. Results: 319/908 patients experienced transplant loss with rejection as the main cause (55%). The majority of paediatric patients received donors from D1 donors (64%). There was an increase in D2-4 donors during the study period, whilst the level of HLA mismatching improved. The KDRI was not associated with allograft failure. In multi-variate analysis, increasing recipient age [adjusted HR and 95%CI: 1.05(1.03-1.08) per-year, p<0.001], recipient minority ethnic group [1.28(1.01-1.63), p<0.05), dialysis before transplant [1.38(1.04-1.81), p<0.005], donor height [0.99 (0.98-1.00) per centimetre, p<0.05] and level of HLA mismatch [Level 3: 1.92(1.19-3.11); Level 4: 2.40(1.26-4.58) versus Level 1, p<0.01] were associated with worse outcomes. Patients with Level 1 and 2 HLA mismatches (0 DR +0/1 B mismatch) had median graft survival >17 years regardless of UK-KDRI groups. Increasing donor age was marginally associated with worse allograft survival [1.01 (1.00-1.01) per year, p=0.05]. Summary: Adult donor risk scores were not associated with long-term allograft survival in paediatric patients. The level of HLA mismatch had the most profound effect on survival. Risk models based on adult data alone may not have the same validity for paediatric patients and therefore all age-groups should be included in future risk prediction models.

Long term outcomes following kidney transplantation in children who weighed less than 15 kg - report from the UK Transplant Registry.

BACKGROUND: Kidney transplantation is the treatment of choice in chronic kidney disease (CKD) stage 5. It is often delayed in younger children until a target weight is achieved due to technical feasibility and historic concerns about poorer outcomes. METHODS: Data on all first paediatric (aged < 18 years) kidney only transplants performed in the United Kingdom between 1 January 2006 and 31 December 2016 were extracted from the UK Transplant Registry (n = 1,340). Children were categorised by weight at the time of transplant into those < 15 kg and those ≥ 15 kg. Donor, recipient and transplant characteristics were compared between groups using chi-squared or Fisher's exact test for categorical variables and Kruskal-Wallis test for continuous variables. Thirty day, one-year, five-year and ten-year patient and kidney allograft survival were compared using the Kaplan-Meier method. RESULTS: There was no difference in patient survival following kidney transplantation when comparing children < 15 kg with those ≥ 15 kg. Ten-year kidney allograft survival was significantly better for children < 15 kg than children ≥ 15 kg (85.4% vs. 73.5% respectively, p = 0.002). For children < 15 kg, a greater proportion of kidney transplants were from living donors compared with children ≥ 15 kg (68.3% vs. 49.6% respectively, p < 0.001). There was no difference in immediate graft function between the groups (p = 0.54) and delayed graft function was seen in 4.8% and 6.8% of children < 15 kg and ≥ 15 kg respectively. CONCLUSIONS: Our study reports significantly better ten-year kidney allograft survival in children < 15 kg and supports consideration of earlier transplantation for children with CKD stage 5. A higher resolution version of the Graphical abstract is available as Supplementary information.