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.

Use of a donor kidney with known autosomal dominant polycystic kidney disease in a highly sensitised paediatric recipient.

We report the use of an autosomal-dominant polycystic kidney disease (ADPKD) donor kidney in a paediatric recipient. A 14-year-old boy on haemodialysis for 4 years following loss of a first kidney transplant, highly sensitised, and with limited vascular options for ongoing dialysis access, was offered a deceased brain death donor transplant from a mid-30s donor with known ADPKD but normal kidney function and negligible proteinuria. After extensive discussion with the patient and family, discussing all alternative options and review of available literature, the kidney was accepted and implanted. Graft function was immediate. An early post-transplant creatinine rise was attributed to possible antibody-mediated rejection, treated with plasmapheresis and rituximab. Ten months post-transplant, the patient remains dialysis-free with stable function. Extended criteria kidneys are already considered for highly sensitised or long-waiting dialysis patients. Though the literature is limited, kidneys from patients with ADPKD could be considered within extended criteria offers on a case-by-case basis.

Fifteen-minute consultation: Empowering children, young people and families through shared decision-making: a practical guide.

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.

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.

Increasing SARS-CoV-2 seroprevalence among UK pediatric patients on dialysis and kidney transplantation between January 2020 and August 2021.

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.

UK experience of ofatumumab in recurrence of focal segmental glomerulosclerosis post-kidney transplant.

BACKGROUND: Steroid-resistant nephrotic syndrome (SRNS), commonly caused by focal segmental glomerulosclerosis (FSGS), is associated with progression to stage 5 chronic kidney disease, requirement for kidney replacement therapy and a risk of disease recurrence post-kidney transplantation. Ofatumumab (OFA) is a fully humanised monoclonal antibody to CD20, with similar mechanisms of action to rituximab (RTX). METHODS: We report a case series of seven UK patients (five paediatric, two adult), all of whom developed FSGS recurrence after kidney transplantation and received OFA as part of their therapeutic intervention. All also received concomitant plasmapheresis. The 2-year outcome of these seven patients is reported, describing clinical course, kidney function and proteinuria. RESULTS: Four patients (all paediatric) achieved complete urinary remission with minimal proteinuria 12 months post-treatment. Three of those four also had normal graft function. Two patients showed partial remission-brief improvement to non-nephrotic proteinuria (197 mg/mmol) in one patient, maintained improvement in kidney function (estimated glomerular filtration rate 76 ml/min/1.73 m2) in the other. One patient did not demonstrate any response. CONCLUSIONS: OFA may represent a useful addition to therapeutic options in the management of FSGS recurrence post-transplantation, including where RTX has shown no benefit. Concomitant plasmapheresis in all patients prevents any definitive conclusion that OFA was the beneficial intervention.

Thromboprophylaxis in congenital nephrotic syndrome: 15-year experience from a national cohort.

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.

Treatment and long-term outcome in primary nephrogenic diabetes insipidus.

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.

Direct venous pressure assessment pre-renal transplantation to optimise graft venous drainage.

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.

Low-dose rituximab is no less effective for nephrotic syndrome measured by 12-month outcome.

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/m2 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/m2. Later, patients received the current regimen of a single dose of 375 mg/m2. 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/m2 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.

Renal and Adrenal Ultrasonography: a valuable diagnostic tool in the salt-wasting infant.

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.

Exposure to inflammatory cytokines selectively limits GM-CSF production by induced T regulatory cells.

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-ß. 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-ß in combination, can mediate the selective loss of GM-CSF production by iTreg cells.

Domiciliary administration of intravenous albumin in congenital nephrotic syndrome.

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.

Bones, stones, moans and groans: hypercalcaemia revisited.

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.

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.

Silicon in the Earth's core.

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.

Clinical Experience of a Long-acting Pegylated Erythropoietin-Stimulating Agent in Pediatric Chronic Kidney Disease.

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.

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.