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Ben Christopher Reynolds,1 Robert James Alan Oswald2 1Department of Paediatric Nephrology, Royal Hospital for Children, Glasgow G51 4TF, UK; 2Tayside Children’s Hospital, Ninewells Hospital & Medical School, Dundee DD1 9SY, UKCorrespondence: Ben Christopher ReynoldsDepartment of Paediatric Nephrology, Royal Hospital for Children, 1345 Govan Road, Glasgow G51 4TF, UKEmail ben.reynolds@ggc.scot.nhs.ukAbstract: Congenital Nephrotic Syndrome (CNS) is defined as nephrotic range proteinuria, hypoalbuminaemia and edema in the first three months of life. CNS is most commonly genetic in cause, with international variance in the incidence of causative mutations. Initially defined by the histopathological appearance, increasingly sophisticated and accessible genetic analyses now provide a body of evidence to suggest that there is a disparity between the histological appearance, the genotype of individuals and the severity of the clinical disease. Through the evolution of management approaches CNS has changed from being an invariably fatal condition to one with appreciable ongoing morbidity and mortality but comparably good outcomes to other causes of paediatric end-stage renal disease, especially following transplantation. This review briefly summarises the more commonly recognised genetic mutations leading to CNS, addresses common management decisions, and concludes with potential therapies for the future.Keywords: nephrectomy, genetics, infantile nephrotic syndrome

Shared decision-making (SDM) is a collaborative approach to healthcare decision-making that involves patients and healthcare professionals working together to make decisions that are informed by the best available medical evidence, as well as the patient's values, preferences and goals. The importance of SDM and the intricate interplay among parents, children and young people (CYP), and healthcare professionals are increasingly acknowledged as the crucial aspects of delivering high-quality paediatric care. While there is a substantial evidence base for SDM improving knowledge and reducing decisional conflict, the evidence for long-term measures such as improved health outcomes is limited and mainly inconclusive. To support healthcare teams in implementing SDM, the authors offer a practical guide to enhance decision-making processes and empower CYP and their families., Competing Interests: Competing interests: All authors are part of the Ready Steady Go-TIER Collaborative. Information about the Collaborative can be found at www.readysteadygo.net., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Audience: This simulation is intended for 4 th year medical students., Introduction: Headache is the fifth most common chief complaint in the emergency room, and the vast majority are ultimately diagnosed as benign primary headaches.1,2 However, subarachnoid hemorrhage (SAH) is one of several critical diagnoses which can present as a headache. With a case fatality rate of up to 66.7% in some instances, SAH is considered a "can't miss" diagnosis.3Subarachnoid hemorrhage is classically associated with a thunderclap headache, one definition of which is a headache that reaches maximal intensity within one minute or less and reaches a seven out of ten in severity.1 Unfortunately, a thunderclap headache is not as sensitive nor specific for SAH as is often taught. In one study, only 50% of patients with an aneurysmal subarachnoid hemorrhage presented with a thunderclap headache and an additional 19% of SAH headache came on more gradually over the course of five minutes.4 A second study found that only 66% of SAH patients reported a thunderclap headache.2 Thunderclap headaches can also be associated with other intercranial pathology including intracerebral hemorrhage, cerebral venous thrombosis, cervical artery dissection, posterior reversible encephalopathy syndrome, meningitis, and temporal arteritis among others.1,2 In a large observational study, SAH accounted for 32% of the serious pathology cases identified in patients with a thunderclap headache. Even among the thunderclap headache cohort, however, 88% of patients ultimately had a benign diagnosis (compared to 93% of patients who did not report a thunderclap headache).2Additional signs and symptoms of SAH include seizures in 6-9% of patients, vomiting, neck pain and stiffness, visual disturbances, loss of consciousness, and focal cranial nerve or supratentorial deficits.1,5 A non-contrasted computer tomography (CT) of the head within six hours of headache onset can have a sensitivity of 98.7 to 100%; however, the sensitivity decreased to 86% at the 24-48 hour mark.1,6 A meta-analysis found a pooled six hour sensitivity of 1.0 and asserts that a head CT interpreted as negative by an attending radiologist effectively rules out SAH in neurologically intact patients with a defined onset of a thunderclap headache.6 Some guidelines in the United States still recommend shared decision making with the patient to choose between a Lumbar Puncture (LP), Computer Tomography Angiogram (CTA), or no further testing to rule out SAH in the case of a negative head CT.2 The more time that has elapsed between onset and CT imaging, the stronger the recommendation to pursue further testing. A negative head CT followed by a negative LP approaches 100% sensitivity for ruling out SAH, and a negative head CT with a negative CTA has a 99.4% probability of ruling out SAH.1,3 Thus it is an important learning point that if a headache has been ongoing for more than six hours and there is a high pre-test probability for an SAH, a negative head CT is not sufficient to rule out the diagnosis, and a secondary test should be ordered.Status epilepticus is defined as five minutes of continuous seizure activity or repeated seizures without return to baseline between seizures.7 The immediate priorities for a seizing patient include providing supplemental oxygen, considering intubation if patient is unable to protect airway, obtaining IV access if not previously established, and checking glucose.7 The main priority for a patient in status epilepticus is to stop the seizure with seizure abortive medications, typically benzodiazepines, and treat life-threatening causes of status epilepticus.7 This simulation will enable learners to diagnose SAH that is not the classical "worst headache of my life" and manage an actively seizing patient., Educational Objectives: At the conclusion of the simulation leaners will be able to:Efficiently take a history from the patient and perform a physical exam (including a complete neurological exam)Identify red flag symptoms in a patient complaining of a headacheOrder and interpret the results of a CT of the head and either a CT angiogram of the brain or a lumbar puncture to make the diagnosis of subarachnoid hemorrhageDemonstrate appropriate management of a seizureCheck a fingerstick glucoseProvide supplemental oxygenAdminister an IV or IM benzodiazepine to treat the seizureUtilize the I-PASS framework to communicate with the inpatient team during the transition of care., Educational Methods: This summative simulation was designed to assess competence in two of the core Entrustable Professional Activities (EPAs), as defined by the Association of American Medical Colleges (AAMC). These include EPA 8 (Give or Receive a Patient Handover to Transition Care Responsibility) and EPA 10 (Recognize a Patient Requiring Urgent or Emergent Care and Initiate Evaluation and Management). It was performed with 4th year medical students at the conclusion of their required month-long emergency medicine (EM) clerkship. This scenario joined eight other scenarios in our pool of potential cases. These sessions are conducted using a high-fidelity manikin as the patient and a confederate/actor in the nursing role. The students complete the assessment in groups of three or four with each student acting as the team lead for one scenario. After each scenario concludes, there is a post-simulation debriefing session on the presentation, differential diagnosis, physical exam findings, and management of the target pathology. A Gather-Analyze-Summarize technique was used for the debriefing session.8., Research Methods: Facilitators provided informal feedback to the scenario developers after the case was introduced into the assessment rotation. Learners completed a standard evaluation issued by the College of Medicine for the entire session rather than for individual scenarios. These evaluations were reviewed for the first year of implementation of this new case. Over the year, 209 students completed the summative simulation exercise, and 84 of those students completed this simulation as part of the overall exercise., Results: Overall, our facilitators felt the case fit well into our pool of simulation cases. They felt they were adequately able to assess the students' ability to respond to a seizing patient and thought the difficulty level was appropriate for fourth year medical students. Students are asked to assess the simulation session as a whole using a standard evaluation form from the College of Medicine. The simulation assessment exercise as a whole was highly rated by the students, with 93% of students rating the overall quality of the session as Very Good or Excellent. Of the students who completed the SAH scenario, 96% rated the overall quality of the session as Very Good or Excellent. None of the comments specifically mention the SAH case., Discussion: Our department has run formative simulations during the 4th year EM clerkship for over ten years. Our primary objective is to assess 4th year students' competence in EPA 10 (Recognize a Patient Requiring Urgent or Emergent Care and Initiate Evaluation and Management). This simulation case was written to replace another SAH case which was a more straightforward and typical presentation of a subarachnoid hemorrhage as "the worst headache of my life." The previous case also did not require seizure management. The inclusion of the seizure management better allowed faculty to assess the students' response to a patient's acute decompensation, which is more in line with EPA 10, than simply making a critical diagnosis.Our facilitators did notice that many groups initially work the patient up for meningitis but ultimately make the correct diagnosis with the lumbar puncture (LP) results. Because the students have correctly identified that the patient requires more extensive work up, and meningitis is certainly on the differential diagnoses, students are not penalized for following this line of clinical reasoning.This simulation proved to be highly engaging for 4th year medical students, and students seemed to perform at a similar level as previous summative simulations. Overall, we felt this simulation successfully achieved the objectives of the simulation session as whole, and it was integrated into our 4th year EM clerkship simulation curriculum., Topics: Medical simulation, Emergency Medicine, Subarachnoid Hemorrhage, Intracranial Hemorrhage, Seizure, Status Epilepticus., (© 2024 Ranier, et al.)

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., Competing Interests: Competing interests: SDM had unpaid roles during COVID-19 pandemic with national COVID-19 working groups of the UK Kidney Association, UK Renal Registry, The British Association for Paediatric Nephrology, National Health Service Blood and Transplant and National Institute for Health and Care Research., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Coronavirus disease 2019 (COVID-19) was officially declared a pandemic by the World Health Organisation (WHO) on 11 March 2020, as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread rapidly across the world. We investigated the seroprevalence of anti-SARS-CoV-2 antibodies in pediatric patients on dialysis or kidney transplantation in the UK., Methods: Excess sera samples were obtained prospectively during outpatient visits or haemodialysis sessions and analysed using a custom immunoassay calibrated with population age-matched healthy controls. Two large pediatric centres contributed samples., Results: In total, 520 sera from 145 patients (16 peritoneal dialysis, 16 haemodialysis, 113 transplantation) were analysed cross-sectionally from January 2020 until August 2021. No anti-SARS-CoV-2 antibody positive samples were detected in 2020 when lockdown and enhanced social distancing measures were enacted. Thereafter, the proportion of positive samples increased from 5% (January 2021) to 32% (August 2021) following the emergence of the Alpha variant. Taking all patients, 32/145 (22%) were seropositive, including 8/32 (25%) with prior laboratory-confirmed SARS-CoV-2 infection and 12/32 (38%) post-vaccination (one of whom was also infected after vaccination). The remaining 13 (41%) seropositive patients had no known stimulus, representing subclinical cases. Antibody binding signals were comparable across patient ages and dialysis versus transplantation and highest against full-length spike protein versus spike subunit-1 and nucleocapsid protein., Conclusions: Anti-SARS-CoV-2 seroprevalence was low in 2020 and increased in early 2021. Serological surveillance complements nucleic acid detection and antigen testing to build a greater picture of the epidemiology of COVID-19 and is therefore important to guide public health responses. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2023. The Author(s).)

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., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Objective: Management of anemia of chronic kidney disease (CKD) often includes subcutaneous or intravenous administration of erythropoietin-stimulating agents (ESAs). Mircera, a pegylated continuous erythropoietin receptor agonist, has a longer duration of action and requires less frequent administration than other ESAs. Pediatric experience with Mircera is limited. We retrospectively reviewed our long-term experience of Mircera in a national pediatric nephrology center., Methods: Patients were identified via an electronic patient record database. Data collected included demographics (sex, age, etiology of CKD, CKD stage, dialysis modality), dosing information, and laboratory data-hemoglobin (Hb), parathormone (PTH), ferritin, hematinics prior to commencing Mircera and all subsequent values associated with dose adjustments., Results: Seventy-seven patients aged 2 to 18 years, with CKD stages 2 to 5T had received at least 1 dose of Mircera, with 75 patients having sufficient data and a total of 1473 doses. No patients discontinued Mircera owing to adverse effects. One patient experienced a potential severe adverse drug reaction. Mircera was effective in improving or maintaining Hb ≥10.0 g/dL in most (58/75, 77.3%) patients. The median dose to achieve Hb ≥10.0 g/dL was 2.1 µg/kg/4 wk. Most doses (1039, 71.5%) were administered 4-weekly. The doses (161, 11.1%) that were administered 6-weekly remained efficacious. Thirty-two patients started Mircera with Hb <10.0 g/dL; 26 (81%) achieved Hb ≥10.0 g/dL within a median time of 4 months. Mircera was less effective if given every 8 weeks, or in the presence of hyperparathyroidism or hyperferritinemia., Conclusion: Mircera appears safe and effective in pediatric patients with CKD., Competing Interests: Disclosures. The authors declare no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. The authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis., (Copyright. Pediatric Pharmacy Association. All rights reserved. For permissions, email: membership@pediatricpharmacy.org.)

The UK Renal Registry currently collects information on UK children with kidney failure requiring long-term kidney replacement therapy (KRT), which supports disease surveillance and auditing of care and outcomes; however, data are limited on children with chronic kidney disease (CKD) not on KRT., Methods: In March 2020, all UK Paediatric Nephrology centres submitted data on children aged <16 years with severely reduced kidney function as of December 2019, defined as an estimated glomerular filtration rate <30 mL/min/1.73 m 2 ., Results: In total, 1031 children had severe CKD, the majority of whom (80.7%) were on KRT. The overall prevalence was 81.2 (95% CI 76.3 to 86.3) per million of the age-related population., Conclusions: The prevalence of severe CKD among UK children is largely due to a high proportion of children on long-term KRT. Expanding data capture to include children with CKD before reaching failure will provide greater understanding of the CKD burden in childhood., Competing Interests: Competing interests: LP declares funding from the National Institute for Health Research (NIHR) and Kidney Research UK (KRUK). BCR declares funding from KRUK, honoraria from Alexion Pharmaceuticals and Magnolia Innovation, and consultancy payment from Chiesi. MM reports previous honoraria and travel expenses from Alexion. SM declares a role as head of the UK Renal Registry Audit and Informatics group. KT declares a role as clinical lead of the National Institute for Health and Care Excellence Medical Technologies Advisory Committee during the study period. DN declares funding/payment from the Health Foundation, UK Kidney Association, Chiang Mai University and GSK., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Erythropoiesis-stimulating agents (ESAs) revolutionized the management of anaemia in chronic kidney disease (CKD) when introduced in the late 1980s. A range of ESA types, preparations and administration modalities now exist, with newer agents requiring less frequent administration. Although systematic reviews and meta-analyses have been published in adults, no systematic review has been conducted investigating ESAs in children., Methods: The Preferred Reporting Items for Systematic Reviews and Meta-analyses statement for the conduct of systematic reviews was used. All available literature on outcomes relating to ESAs in children with CKD was sought. A search of the MEDLINE, CINAHL and Embase databases was conducted by two independent reviewers. Inclusion criteria were published trials in English, children with chronic and end-stage kidney disease and use of any ESA studied against any outcome measure. An assessment of risk of bias was carried out in all included randomized trials using the criteria from the Cochrane Handbook for Systematic Reviews of Interventions. Two tables were used for data extraction for randomized and observational studies. Study type, participants, inclusion criteria, case characteristics, follow-up duration, ESA type and dosage, interventions and outcomes were extracted by one author., Results: Of 965 identified articles, 58 were included covering 54 cohorts. Six were randomized trials and 48 were observational studies. A total of 38 studies assessed the efficacy of recombinant human erythropoietin (rHuEPO), 11 of darbepoetin alpha (DA) and 3 of continuous erythropoietin receptor activator (CERA), with 6 studies appraising secondary outcome measures exclusively. Recruitment to studies was a consistent challenge. The most common adverse effect was hypertension, although confounding effects often limited direct correlation. Two large cohort studies demonstrated a greater hazard of death independently associated with high ESA dose. Secondary outcome measures included quality of life measures, growth and nutrition, exercise capacity, injection site pain, cardiovascular function, intelligent quotient, evoked potentials and platelet function., Conclusions: All ESA preparations and modes of administration were efficacious, with evidence of harm at higher doses. Evidence supports individualizing treatments, with strong consideration given to alternate treatments in patients who appear resistant to ESA therapy. Further research should focus on randomized trials comparing the efficacy of different preparations, treatment options in apparently ESA-resistant cohorts and clarification of meaningful secondary outcomes to consolidate patient-relevant indices., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Monogenic causes of paediatric nephrocalcinosis are associated with extensive phenotypic variability. We report a 14-year-old male who presented at 8 years of age with incidentally identified nephrocalcinosis alongside growth impairment and dental anomalies. Extensive genetic investigation confirmed a molecular diagnosis of Bartter syndrome type II. This is exceptional in both late presentation and the presence of amelogenesis imperfecta, a very rare association of inherited tubulopathies. Details of the nephrocalcinosis gene panel analysed and associated phenotypes are presented to highlight the utility of a phenotype-driven genetic panel in resolving an atypical presentation of nephrocalcinosis, allowing precise diagnosis, tailored therapy and prognostication., (© The Author(s) 2021. Published by Oxford University Press on behalf of the ERA.)

Introduction: Congenital nephrotic syndrome (CNS) is an ultra-rare disease associated with a pro-thrombotic state and venous thromboembolisms (VTE). There is very limited evidence evaluating thromboprophylaxis in patients with CNS. This study aimed to determine the doses and duration of treatment required to achieve adequate thromboprophylaxis in patients with CNS., Methods: From 2005 to 2018 children in Scotland with a confirmed genetic or histological diagnosis of CNS were included if commenced on thromboprophylaxis. The primary study endpoint was stable drug monitoring. Secondary outcomes included VTE or significant haemorrhage., Results: Eight patients were included; all initially were commenced on low-molecular weight heparin (enoxaparin). Four patients maintained therapeutic anti-Factor Xa levels (time 3-26 weeks, dose 3.2-5.07 mg/kg/day), and one patient developed a thrombosis (Anti-Factor Xa: 0.27 IU/ml). Four patients were subsequently treated with warfarin. Two patients maintained therapeutic INRs (time 6-11 weeks, dose 0.22-0.25 mg/kg/day), and one patient had two bleeding events (Bleed 1: INR 6, Bleed 2: INR 5.5)., Conclusions: Achieving thromboprophylaxis in CNS is challenging. Similar numbers of patients achieved stable anticoagulation on warfarin and enoxaparin. Enoxaparin dosing was nearly double the recommended starting doses for secondary thromboprophylaxis. Bleeding events were all associated with supra-therapeutic anticoagulation.

Aims: To investigate access to paediatric renal transplantation and examine potential barriers within the process., Methods: Cross-sectional, multicentre, observational study where paediatric nephrology centres in the UK were requested to provide data on transplantation plans for all children (<18 years) with end-stage kidney disease (ESKD)., Results: 308 children with ESKD were included in this study from 12 out of 13 UK paediatric nephrology centres. 139 (45%) were being prepared for living donor transplantation and 82 (27%) were listed for deceased donor transplantation. The most common cited factors delaying transplantation from occurring in children were disease factors (36%), donor availability (27%) and size of the child (20%). Psychosocial factors were listed as a barrier in 19% of children., Conclusions: In this study we have documented the main barriers to renal transplantation in children. Some identified factors may be modifiable through local or national intervention, including donor availability and patient psychosocial factors., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Primary nephrogenic diabetes insipidus (NDI) is a rare disorder and little is known about treatment practices and long-term outcome., Methods: Paediatric and adult nephrologists contacted through European professional organizations entered data in an online form., Results: Data were collected on 315 patients (22 countries, male 84%, adults 35%). Mutation testing had been performed in 270 (86%); pathogenic variants were identified in 258 (96%). The median (range) age at diagnosis was 0.6 (0.0-60) years and at last follow-up 14.0 (0.1-70) years. In adults, height was normal with a mean (standard deviation) score of -0.39 (±1.0), yet there was increased prevalence of obesity (body mass index >30 kg/m2; 41% versus 16% European average; P < 0.001). There was also increased prevalence of chronic kidney disease (CKD) Stage ≥2 in children (32%) and adults (48%). Evidence of flow uropathy was present in 38%. A higher proportion of children than adults (85% versus 54%; P < 0.001) received medications to reduce urine output. Patients ≥25 years were less likely to have a university degree than the European average (21% versus 35%; P = 0.003) but full-time employment was similar. Mental health problems, predominantly attention-deficit hyperactivity disorder (16%), were reported in 36% of patients., Conclusion: This large NDI cohort shows an overall favourable outcome with normal adult height and only mild to moderate CKD in most. Yet, while full-time employment was similar to the European average, educational achievement was lower, and more than half had urological and/or mental health problems., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Renal transplantation is the modality of choice in the treatment of end-stage kidney disease. Surgically challenging aspects of renal transplantation may include creation of vascular anastomoses where there is complex vascular anatomy. We present a paediatric case of living-related donor (LRD) renal transplantation in whom direct intravenous pressure measurement guided the management of the vascular anastomoses in the context of inferior vena cava (IVC) obstruction., Case-Diagnosis/treatment: During venography for transplant assessment, 150 mL of 0.9% sodium chloride was infused for over 20 s into well-developed collateral paravertebral veins to simulate the anticipated high-volume venous return from an implanted kidney. Direct venous pressure measurements were 20 mmHg in the right paravertebral vein and 19 mmHg in the left paravertebral vein. We were reassured by this result that the collateralised venous system could sustain the high venous drainage and maintain the arteriovenous (AV) gradient required for adequate graft perfusion. Intra-operative measurement at the time of transplantation, following release of venous clamps, of 22 mmHg supported the validity of this approach., Conclusions: In children with complex venous anatomy pre-transplant, direct intravenous pressure measurement may provide a useful adjunct in deciding which vessel is most suitable for transplant anastomosis.

Importance: Optimal blood pressure (BP) management in children with chronic kidney disease (CKD) slows progression to end-stage renal disease. Studies often base progression risk on a single baseline BP measurement, which may underestimate risk., Objective: To determine whether time-varying BP measurements are associated with a higher risk of progression of CKD than baseline BP measurements., Design, Setting, and Participants: The ongoing longitudinal, prospective cohort study Chronic Kidney Disease in Children (CKID) recruited children from January 19, 2005, through March 19, 2014, from pediatric nephrology centers across North America, with data collected at annual study visits. Participants included children aged 1 to 16 years with a diagnosis of CKD and a glomerular filtration rate (GFR) of 30 to 90 mL/min/1.73 m2. Data were analyzed from February 11, 2005, through February 13, 2018., Exposures: Office BP measurement classified as less than 50th percentile, 50th to less than 90th percentile, or at least 90th percentile. Blood pressure categories were treated as time fixed (baseline) or time varying (updated at each visit) in models., Main Outcomes and Measures: A composite renal outcome (50% GFR reduction from baseline, estimated GFR less than 15 mL/min/1.73 m2, or dialysis or transplant). Pooled logistic models using inverse probability weighting estimated the hazard odds ratio (HOR) of the composite outcome associated with each BP category stratified by CKD diagnosis., Results: A total of 844 children (524 [62.1%] male; median age, 11 [interquartile range, 8-15] years; 151 [17.9%] black; 580 [68.7%] with nonglomerular CKD; and 264 [31.3%] with glomerular CKD) with complete baseline data and median follow-up of 4 (interquartile range, 2-6) years were included. One hundred ninety-six participants with nonglomerular diagnoses (33.8%) and 99 with glomerular diagnoses (37.5%) reached the composite outcome. Baseline systolic BP in at least the 90th percentile was associated with a higher risk of the composite outcome (HOR for nonglomerular disease, 1.58 [95% CI, 1.07-2.32]; HOR for glomerular disease, 2.85 [95% CI, 1.64-4.94]) compared with baseline systolic BP in less than the 50th percentile. Time-fixed estimates were substantially lower compared with time-varying systolic BP percentile categories (HOR among those with nonglomerular CKD, 3.75 [95% CI, 2.53-5.57]; HOR among those with glomerular diagnoses, 5.96 [95% CI, 3.37-10.54]) comparing those at or above the 90th percentile vs below the 50th percentile. Adjusted models (adjusted for proteinuria and use of antihypertensives) attenuated the risk in nonglomerular CKD (adjusted HOR for baseline measurement, 1.52 [95% CI, 0.98-2.36]; adjusted HOR for time-varying measurement, 2.25 [95% CI, 1.36-3.72]) and in glomerular CKD (adjusted HOR for baseline, 0.97 [95% CI, 0.39-2.36]; adjusted HOR for time-varying measurement, 1.41 [95% CI, 0.65-3.03]). Similar results were observed for diastolic BP., Conclusions and Relevance: Among children with nonglomerular CKD included in this study, elevated time-varying BP measurements were associated with a greater risk of CKD progression compared with baseline BP measurement. This finding suggests that previous studies using only baseline BP likely underestimated the association between BP and CKD progression.

Background: Congenital diaphragmatic hernia (CDH) often presents with severe cardio-respiratory impairment in the neonatal period. Affected infants may be exposed to multiple nephrotoxic insults, predisposing them to acute kidney injury (AKI). The prevalence of AKI in a CDH cohort has not previously been described., Objectives: The primary aim of this study was to quantify the prevalence of AKI in patients with CDH treated in a single national centre. Secondarily, we investigated the association between AKI, select neonatal outcomes, and recognised AKI risk factors., Methods: This was a retrospective analysis of all patients with CDH treated at our regional neonatal surgical centre between September 2011 and December 2017. Data was collected on demographics, CDH Study Group stage (size), laboratory and physiological parameters, medications, mortality, and duration of hospitalisation. AKI severity was stratified using the modified paediatric RIFLE criteria, determined by comparing the percentage increase in serum creatinine from baseline. Statistical analysis was performed using Fisher's exact and Pearson's χ2 tests for parametric analysis and Mann-Whitney U testing for non-parametric analysis., Results: Fifty-four CDH patients met the inclusion criteria, 37% of whom developed AKI. The development of AKI was significantly associated with larger CDH defect (type C/D; p = 0.014), extracorporeal membranous oxygenation support (p = 0.003), patch repair (p = 0.004), and exposure to vancomycin, corticosteroids and diuretics (p = 0.004, p = 0.007, and p ≤ 0.001, respectively). There was no statistical association between AKI and gentamicin administration, umbilical arterial catheter insertion, or significant infection. Prolonged hospitalisation and patient mortality were significantly associated with AKI (p = 0.01 and p = 0.001, respectively)., Conclusions: AKI is common in CDH cases treated in our centre and is associated with adverse outcomes. Potentially modifiable risk factors include nephrotoxic medication exposure. Prevention and early recognition of contributory factors for AKI may improve outcomes in CDH., (© 2019 S. Karger AG, Basel.)

Adult cancers often arise from premalignant clonal expansions. Whether the same is true of childhood tumors has been unclear. To investigate whether Wilms tumor (nephroblastoma; a childhood kidney cancer) develops from a premalignant background, we examined the phylogenetic relationship between tumors and corresponding normal tissues. In 14 of 23 cases studied (61%), we found premalignant clonal expansions in morphologically normal kidney tissues that preceded tumor development. These clonal expansions were defined by somatic mutations shared between tumor and normal tissues but absent from blood cells. We also found hypermethylation of the H19 locus, a known driver of Wilms tumor development, in 58% of the expansions. Phylogenetic analyses of bilateral tumors indicated that clonal expansions can evolve before the divergence of left and right kidney primordia. These findings reveal embryonal precursors from which unilateral and multifocal cancers develop., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Objective: Rituximab is an effective treatment for children with steroid dependent or frequently relapsing nephrotic syndrome. The optimum dosing schedule for rituximab has not been established. We hypothesized that a single low dose of 375 mg/m 2 would have comparable outcomes to higher doses in reducing the frequency of relapse and time to B cell reconstitution., Methods: We conducted a multicenter retrospective observational cohort study of children with steroid-sensitive frequently relapsing nephrotic syndrome. Data were extracted from clinical records including the dates of diagnosis, treatment, relapses, the use of concomitant immunosuppression, and lymphocyte subset profiling. Patients treated earlier received variable doses of rituximab, although typically two doses of 750 mg/m 2 . Later, patients received the current regimen of a single dose of 375 mg/m 2 . The primary outcome was an absence of clinically confirmed relapse 12 months following rituximab administration. Secondary outcomes were median time to relapse, probability of being relapse-free at 6 and 24 months and time to reconstitution of CD19 + B cells., Results: Sixty patients received 143 courses of rituximab. Seven different dosing regimen strategies were used, ranging between 375 and 750 mg/m 2 per dose, with administration of 1-4 doses. There was no significant difference in event-free survival at 12 months between dosing strategies. The median time to reconstitution of B cells was not significantly different between groups., Conclusions: Use of a single low-dose regimen of rituximab in the management of frequently relapsing nephrotic syndrome does not affect the probability of relapse at 12 months or time to B cell reconstitution compared to a conventional higher dose.

Acute pancreatitis is a well-recognised complication of hypertriglyceridaemia. High serum triglycerides may develop in the autosomal recessive disorder glycogen storage disease (GSD). Plasmapheresis has been effective in reducing triglyceride levels in pancreatitis secondary to other conditions but not previously described in GSD. We describe a 16-year-old male with type 1a GSD who presented with severe abdominal pain, tachycardia and tachypnoea. Abdominal computed tomography (CT) demonstrated acute pancreatitis. Serum triglycerides were 91.8 mM. Despite intravenous fluids and morphine sulphate, he remained seriously ill, and plasmapheresis was therefore started. After daily plasma exchange for 6 days, triglyceride levels dropped to 5 mM. This was associated with a rapid resolution of pancreatitis. Plasmapheresis is effective in rapidly reducing hypertriglyceridaemia from numerous causes, including glycogen storage disease, and may facilitate recovery from acute pancreatitis.

Kidney transplantation is the treatment of choice for patients with end stage renal disease to optimize survival, freedom from morbidity and quality of life. A fundamental aspect of the pre-transplant assessment is a thorough understanding of their immunological history and prior exposures, so that the immunological risk from a given donor can be estimated, if not quantified, in order to guide interventions to optimize transplant access and success. The methodologies available to complete this assessment have evolved rapidly, with flow cytometric based analyses now standard in many laboratories, availability of comprehensive molecular methods for HLA typing of both donors and recipients, and an increasing recognition of the vital dialogue that must occur between the HLA laboratory and transplant clinicians. This review considers the pre-transplant histocompatibility assessment journey that a recipient undertakes, from initial referral through transplantation, discussing the methodologies used, the benefits and limitations offered by current technologies, and reviewing the basics of interpretation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The Asiatic oak weevil, Cyrtepistomus castaneus Roelofs (Coleoptera: Curculionidae), is a nonnative defoliator of trees in the Fagaceae family in the United States but has not been studied on Castanea species in the southern Appalachian Mountains. Planted trees of Castanea dentata (Marsh.) Borkh. (Fagales: Fagaceae), Castanea mollissima Blume (Fagales: Fagaceae), and four hybrid breeding generations were evaluated in 2012 for insect defoliation and C. castaneus abundance and frequency. Defoliation was visually assessed throughout the growing season at two sites in the southern Appalachian Mountains (western North Carolina and eastern Tennessee). C. castaneus abundance and frequency were monitored on trees using beat sheets and emergence was recorded from ground traps. Asiatic oak weevils were more abundant and more frequently collected on American chestnut (Ca. dentata) and its most closely related BC3F3 hybrid generation than on the Asian species Ca. mollissima. In most months, C. castaneus colonization of hybrid generations was not significantly different than colonization of parental species. Frequency data for C. castaneus suggested that adults were distributed relatively evenly throughout the study sites rather than in dense clusters. Emergence of C. castaneus was significantly higher under a canopy dominated by Quercus species than under non-Quercus species or open sky. C. castaneus emergence began in May and peaked in late June and early July. These results may be useful for resource managers trying to restore blight-resistant chestnut to the Southern Appalachians while minimizing herbivory by insect pests., (Published by Oxford University Press on behalf of the Entomological Society of America 2016. This work is written by US Government employees and is in the public domain in the United States.)

Unlabelled: The major differential diagnosis in 'salt-wasting' infants (characterised by hyponatraemia and hyperkalaemia) is that of an adrenal or renal disorder. Appropriate management relies on rapid diagnosis, but existing guidelines do not highlight the role of ultrasonography. We describe how ultrasound may lead to a more rapid diagnosis in disorders of sex development (DSD) and other potential 'salt-wasting' infants., Conclusion: Ultrasonography as a diagnostic tool in infants with salt-wasting or DSD needs to be more widely recognised., (©2015 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background: Early management of congenital nephrotic syndrome invariably includes the frequent administration of intravenous human albumin solution. The safety and feasibility of intravenous administration of albumin in the patients' home setting has not previously been reported., Case-Diagnosis/treatment: We report a series of seven paediatric patients whose parents were trained in the administration of albumin via a central venous catheter at home, with the aim of minimising hospital admission or attendances. We describe the clinical course of these patients and complication rates ascribed to this strategy., Conclusions: Our results demonstrate that home albumin infusion can be performed safely.

Disorders of calcium homeostasis are uncommon but important because of the broad spectrum of potential underlying causes that lie on a spectrum from the benign to the life-threatening. Paediatricians may find them challenging because they do not arise often enough for the investigative approach to be second nature. We report a 4-year-old with acute onset profound hypercalcaemia. We focus on an approach to the clinical problem that is based on the potential organ systems affected, namely the gut, bone and kidney. Key biochemical parameters that may help the paediatric team to reach a diagnosis are discussed, as well as important components of acute management., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Interest in manipulating the immunosuppressive powers of Foxp3-expressing T regulatory cells as an immunotherapy has been tempered by their reported ability to produce proinflammatory cytokines when manipulated in vitro, or in vivo. Understanding processes that can limit this potentially deleterious effect of Treg cells in a therapeutic setting is therefore important. Here, we have studied this using induced (i) Treg cells in which de novo Foxp3 expression is driven by TCR-stimulation in vitro in the presence of TGF-β. We show that iTreg cells can produce significant amounts of three proinflammatory cytokines (IFN-γ, GM-CSF and TNF-α) upon secondary TCR stimulation. GM-CSF is a critical T-cell derived cytokine for the induction of EAE in mice. Despite their apparent capacity to produce GM-CSF, myelin autoantigen-responsive iTreg cells were unable to provoke EAE. Instead, they maintained strong suppressive function in vivo, preventing EAE induction by their CD4+ Foxp3- counterparts. We identified that although iTreg cells maintained the ability to produce IFN-γ and TNF-α in vivo, their ability to produce GM-CSF was selectively degraded upon antigen stimulation under inflammatory conditions. Furthermore, we show that IL-6 and IL-27 individually, or IL-2 and TGF-β in combination, can mediate the selective loss of GM-CSF production by iTreg cells., (© 2014 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We report a 17-yr-old boy who developed a microangiopathic hemolytic anemia presumed secondary to tacrolimus shortly following a living-related donor renal transplant. This was initially managed by plasmapheresis. Reinstitution of calcineurin inhibition using cyclosporine led to recurrence of hemolysis, so an alternative agent was needed. He was commenced on monthly intravenous belatacept, with no further recurrence of the hemolysis, and subsequent stable graft function. Modulation via CTLA-4 offers an alternative immunosuppressive tactic if current regimens produce graft threatening adverse effects. The method of administration and frequency of dosage of belatacept also lends itself well to the high-risk period of adolescence and transition. We propose that belatacept may therefore also have utility in difficult cases complicated by poor concordance, common in the adolescent age group., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

In this paper, we analyze the use of the body-powered split-hook prosthetic terminal device, which is the most commonly used upper-limb prosthesis. We developed two taxonomies of split-hook use, one on grasp shape and one on force exertion, illustrating the functional capabilities and use cases of the device. Video captured from an amputee using a body-powered split-hook during a number of common activities was used to lend weight to the completeness of the classifications. These taxonomies serve to establish a common language and means of comparing the types of grasps achievable by simple terminal devices to those of advanced myoelectric terminal devices or even human hands. The first taxonomy categorizes the grasp type based on the contacts with the environment while the second is categorized by the method and limitation of force exertion. We discuss the difference between grasps capable of holding objects compared to those that are capable of acquiring objects and the importance of non-prehensile uses of the split-hook. The classification schemes lay the groundwork for further detailed study of split-hook use, and the discussion of the use cases described may help guide terminal device developers to create improved prostheses.

Imidacloprid is a systemic insecticide effective in controlling the exotic pest (hemlock woolly adelgid) in eastern hemlock () trees. Concerns over imidacloprid impacts on nontarget species have limited its application in southern Appalachian ecosystems. We quantified the movement and adsorption of imidacloprid in forest soils after soil injection in two sites at Coweeta Hydrologic Laboratory in western North Carolina. Soils differed in profile depth, total carbon and nitrogen content, and effective cation exchange capacity. We injected imidacloprid 5 cm into mineral soil, 1.5 m from infested trees, using a Kioritz soil injector. We tracked the horizontal and vertical movement of imidacloprid by collecting soil solution and soil samples at 1 m, 2 m, and at the drip line from each tree periodically for 1 yr. Soil solution was collected 20 cm below the surface and just above the saprolite, and acetonitrile-extractable imidacloprid was determined through the profile. Soil solution and extractable imidacloprid concentrations were determined by high-performance liquid chromatography. Soil solution and extractable imidacloprid concentrations were greater in the site with greater soil organic matter. Imidacloprid moved vertically and horizontally in both sites; concentrations generally declined downward in the soil profile, but preferential flow paths allowed rapid vertical movement. Horizontal movement was limited, and imidacloprid did not move to the tree drip line. We found a negative relationship between adsorbed imidacloprid concentrations and soil microarthropod populations largely in the low-organic-matter site; however, population counts were similar to other studies at Coweeta., (Copyright © by the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America, Inc.)

Introduction: Although the adverse effects of cocaine use in pregnancy are well recognised, we believe this case highlights the importance of considering the route of administration, and suggests the possibility of multifocal damage relating to intravenous use., Case Presentation: A Caucasian female baby of 29-weeks' gestation was spontaneously delivered and subsequently developed multi-organ failure considered unrelated to simple prematurity. Intensive care was re-orientated following the development of massive intraventricular haemorrhage., Conclusion: This case illustrates the need for regular cranial ultrasound in babies of pregnancies at risk due to intravenous cocaine use and also the necessity of counselling women who misuse cocaine in the antenatal period. As such, this article will be of most interest to paediatric and obstetric staff.

The modern Eastern Equatorial Pacific (EEP) Ocean is a large oceanic source of carbon to the atmosphere. Primary productivity over large areas of the EEP is limited by silicic acid and iron availability, and because of this constraint the organic carbon export to the deep ocean is unable to compensate for the outgassing of carbon dioxide that occurs through upwelling of deep waters. It has been suggested that the delivery of dust-borne iron to the glacial ocean could have increased primary productivity and enhanced deep-sea carbon export in this region, lowering atmospheric carbon dioxide concentrations during glacial periods. Such a role for the EEP is supported by higher organic carbon burial rates documented in underlying glacial sediments, but lower opal accumulation rates cast doubts on the importance of the EEP as an oceanic region for significant glacial carbon dioxide drawdown. Here we present a new silicon isotope record that suggests the paradoxical decline in opal accumulation rate in the glacial EEP results from a decrease in the silicon to carbon uptake ratio of diatoms under conditions of increased iron availability from enhanced dust input. Consequently, our study supports the idea of an invigorated biological pump in this region during the last glacial period that could have contributed to glacial carbon dioxide drawdown. Additionally, using evidence from silicon and nitrogen isotope changes, we infer that, in contrast to the modern situation, the biological productivity in this region is not constrained by the availability of iron, silicon and nitrogen during the glacial period. We hypothesize that an invigorated biological carbon dioxide pump constrained perhaps only by phosphorus limitation was a more common occurrence in low-latitude areas of the glacial ocean.

We describe a case of chronic mineralizing pulmonary elastosis in a seven-yr-old boy following DD renal transplantation for Wilms tumour. Fourteen months post-transplantation he developed respiratory symptoms with lung biopsy demonstrating chronic mineralizing pulmonary elastosis thought to be secondary to immunosuppression with MMF. Symptomatic resolution occurred following MMF cessation.

Small isotopic differences between the silicate minerals in planets may have developed as a result of processes associated with core formation, or from evaporative losses during accretion as the planets were built up. Basalts from the Earth and the Moon do indeed appear to have iron isotopic compositions that are slightly heavy relative to those from Mars, Vesta and primitive undifferentiated meteorites (chondrites). Explanations for these differences have included evaporation during the 'giant impact' that created the Moon (when a Mars-sized body collided with the young Earth). However, lithium and magnesium, lighter elements with comparable volatility, reveal no such differences, rendering evaporation unlikely as an explanation. Here we show that the silicon isotopic compositions of basaltic rocks from the Earth and the Moon are also distinctly heavy. A likely cause is that silicon is one of the light elements in the Earth's core. We show that both the direction and magnitude of the silicon isotopic effect are in accord with current theory based on the stiffness of bonding in metal and silicate. The similar isotopic composition of the bulk silicate Earth and the Moon is consistent with the recent proposal that there was large-scale isotopic equilibration during the giant impact. We conclude that Si was already incorporated as a light element in the Earth's core before the Moon formed.

Background: Recent Scottish Intercollegiate Guidelines Network/British Thoracic Society guidelines have highlighted best practice for asthma management. This study examines asthma management in a paediatric emergency setting before and after the publication of these guidelines., Objectives: To assess the impact of Scottish Intercollegiate Guidelines Network/British Thoracic Society guidelines on asthma management., Methods: Retrospective review of patient notes over two equivalent 2-month periods in 2002 and 2003. Main outcomes were documentation of clinical history, examination, investigation, treatment and discharge; and also the use of various treatment modalities in each case., Results: One hundred and sixty-four children presented with asthma, 100 in 2002 and 64 in 2003. Documentation was adequate throughout, though better when nursing staff were responsible. Completeness of documentation was not related to seniority or discipline of medical staff. Measurement of peak flow was poor in both years. The 'doubling up' of inhaled steroid dose for acute episodes was the only aspect of management affected by publication of the guidelines, with significantly fewer patients receiving this in 2003 (P<0.0001)., Conclusions: Documentation within the centre is good but has potential for improvement. Guidelines have not impacted on this except when explicit statements are made regarding treatment.

We report a twin pregnancy complicated by fetal goitrous hypothyroidism secondary to dyshormonogenesis caused by thyroglobulin deficiency. Antenatal treatment with intra-amniotic thyroxine was considered but not performed, given the late gestational age at diagnosis and the multiple nature of the pregnancy. Both twins developed airway obstruction at delivery, requiring intubation and ventilation. We review the literature and describe the practical issues relating to the antenatal assessment and perinatal management of fetal goitre.

A high-precision iron isotope time series for a ferromanganese crust demonstrates that the iron isotope composition in North Atlantic Deep Water has changed substantially over the past 6 million years and that iron isotope variations in the crust are closely correlated to those of lead isotopes. The close correlation between the two isotope series indicates that the observed iron isotope variations predominantly reflect those of iron input from terrigenous sources and provides no evidence for biologically induced mass fractionation within North Atlantic Deep Water.