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Introduction: Activation of the focal adhesion kinase (FAK) in podocytes is involved in the pathogenesis of minimal change disease (MCD), but the pathway leading to its activation in this disease is unknown. Here, we tested whether podocyte β1 integrin is the upstream modulator of FAK activation and podocyte injury in experimental models of MCD-like injury., Methods: We used lipopolysaccharide (LPS) and MCD sera to induce MCD-like changes in vivo and in cultured human podocytes, respectively. We performed functional studies using specific β1 integrin inhibitors in vivo and in vitro, and integrated histological analysis, western blotting, and immunofluorescence to assess for morphological and molecular changes in podocytes. By ELISA, we measured serum LPS levels in 35 children with MCD or presumed MCD (idiopathic nephrotic syndrome [INS]) and in 18 healthy controls., Results: LPS-injected mice showed morphological (foot process effacement, and normal appearing glomeruli on light microscopy) and molecular features (synaptopodin loss, nephrin mislocalization, FAK phosphorylation) characteristic of human MCD. Administration of a β1 integrin inhibitor to mice abrogated FAK phosphorylation, and ameliorated proteinuria and podocyte injury following LPS. Children with MCD/INS in relapse had higher serum LPS levels than controls. In cultured human podocytes, β1 integrin blockade prevented cytoskeletal rearrangements following exposure to MCD sera in relapse., Conclusions: Podocyte β1 integrin activation is an upstream mediator of FAK phosphorylation and podocyte injury in models of MCD-like injury., (Copyright © 2022 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

Autosomal dominant loss-of-function (LoF) variants in cytotoxic T-lymphocyte associated protein 4 ( CTLA4 ) cause immune dysregulation with autoimmunity, immunodeficiency and lymphoproliferation (IDAIL). Incomplete penetrance and variable expressivity are characteristic of IDAIL caused by CTLA-4 haploinsufficiency (CTLA-4h), pointing to a role for genetic modifiers. Here, we describe an IDAIL proband carrying a maternally inherited pathogenic CTLA4 variant and a paternally inherited rare LoF missense variant in CLEC7A, which encodes for the β-glucan pattern recognition receptor DECTIN-1. The CLEC7A variant led to a loss of DECTIN-1 dimerization and surface expression. Notably, DECTIN-1 stimulation promoted human and mouse regulatory T cell (T reg ) differentiation from naïve αβ and γδ T cells, even in the absence of transforming growth factor-β. Consistent with DECTIN-1's T reg -boosting ability, partial DECTIN-1 deficiency exacerbated the T reg defect conferred by CTL4-4h. DECTIN-1/ CLEC7A emerges as a modifier gene in CTLA-4h, increasing expressivity of CTLA4 variants and acting in functional epistasis with CTLA-4 to maintain immune homeostasis and tolerance.

Purpose: To determine whether hypercapnia is associated with risk of hospital readmission related to anorexia nervosa (AN) in children and adolescents., Methods: We performed a prospective study of patients ≤ 18 years old admitted due to AN decompensation from November 2018 to October 2019. Both subtypes of AN, restricting subtype (AN-R) and binge-eating/purging subtype (AN-BP), were included. Study participants were evaluated upon admission, at discharge and six months after discharge. T-tests or Mann-Whitney U tests was used to compare means values. Pearson or Spearman correlations were used to measure the association between two variables. Logistic regression models were developed to evaluate the relationship between scoring methods and readmission., Results: Of the 154 persons admitted during the study period, 131 met the inclusion criteria. Median age was 15.1 years. At admission, 71% of participants were malnourished and 33 (25%) had been previously admitted. We observed a marked decrease in venous pH and stable pCO 2 elevation during follow-up period. Hypercapnia at discharge was associated with a twofold increased likelihood of readmission and the odds of readmission increased as discharge pCO 2 rose. These findings did not depend on AN subtype or participant sex. Electrolytes persisted within the normal range., Conclusion: Hypercapnia and respiratory acidosis are common alterations in children and adolescents hospitalized due to AN decompensation. Hypercapnia persists for at least 6 months after discharge despite clinical improvement and is associated with higher odds of readmission. This is the first study to identify an abnormal laboratory finding as a potential predictor of readmission in AN., Level of Evidence: IV: Multiple time series without intervention., (© 2023. The Author(s).)

Background: X-linked hypophosphatemia (XLH) is a rare, hereditary, progressive, renal phosphate-wasting disorder characterized by a pathological increase in FGF23 concentration and activity. Due to its rarity, diagnosis may be delayed, which can adversely affect outcomes. As a chronic disease resulting in progressive accumulation of musculoskeletal manifestations, it is important to understand the natural history of XLH over the patient's lifetime and the impact of drug treatments and other interventions. This multicentre, international patient registry (International XLH Registry) was established to address the paucity of these data. Here we present the findings of the first interim analysis of the registry., Results: The International XLH Registry was initiated in August 2017 and includes participants of all ages diagnosed with XLH, regardless of their treatment and management. At the database lock for this first interim analysis (29 March 2021), 579 participants had entered the registry before 30 November 2020 and are included in the analysis (360 children [62.2%], 217 adults [37.5%] and 2 whose ages were not recorded [0.3%]; 64.2% were female). Family history data were available for 319/345 (92.5%) children and 145/187 (77.5%) adults; 62.1% had biological parents affected by XLH. Genetic testing data were available for 341 (94.7%) children and 203 (93.5%) adults; 370/546 (67.8%) had genetic test results; 331/370 (89.5%) had a confirmed PHEX mutation. A notably longer time to diagnosis was observed in adults ≥ 50 years of age (mean [median] duration 9.4 [2.0] years) versus all adults (3.7 [0.1] years) and children (1.0 [0.2] years). Participants presented with normal weight, shorter length or height and elevated body mass index (approximately - 2 and + 2 Z-scores, respectively) versus the general population. Clinical histories were collected for 349 participants (239 children and 110 adults). General data trends for prevalence of bone, dental, renal and joint conditions in all participants were aligned with expectations for a typical population of people with XLH., Conclusion: The data collected within the International XLH Registry, the largest XLH registry to date, provide substantial information to address the paucity of natural history data, starting with demographic, family history, genetic testing, diagnosis, auxology and baseline data on clinical presentation., (© 2023. Institut National de la Santé et de la Recherche Médicale (INSERM).)

Given the relatively recent introduction of burosumab in the management of X-linked hypophosphatemia (XLH), there is limited real-world data to guide its use in clinical practice. As a group of European physicians experienced with burosumab treatment in clinical practice, we convened with the objective of sharing these practice-based insights on the use of burosumab in children and adolescents with XLH. We attended two virtual meetings, then discussed key questions via Within3, a virtual online platform. Points of discussion related to patient selection criteria, burosumab starting dose, dose titration and treatment monitoring. Our discussions revealed that criteria for selecting children with XLH varied across Europe from all children above 1 year to only children with overt rickets despite conventional treatment being eligible. We initiated burosumab dosing according to guidance in the Summary of Product Characteristics, an international consensus statement from 2019 and local country guidelines. Dose titration was primarily guided by serum phosphate levels, with some centers also using the ratio of tubular maximum reabsorption of phosphate to glomerular filtration rate (TmP/GFR). We monitored response to burosumab treatment clinically (growth, deformities, bone pain and physical functioning), radiologically (rickets and deformities) and biochemically (serum phosphate, alkaline phosphatase, 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D, urine calcium-creatinine ratio and TmP/GFR). Key suggestions made by our group were initiation of burosumab treatment in children as early as possible, from the age of 1 year, particularly in those with profound rickets, and a need for clinical studies on continuation of burosumab throughout adolescence and into adulthood., Competing Interests: MZM, received honoraria from Kyowa Kirin International for attending advisory boards and for educational lectures/webinars. GIB, received honoraria from Kyowa Kirin International for attending advisory boards and webinars. CdLC, received honoraria from Kyowa Kirin International for attending advisory boards and for educational lectures. AL, an investigator for clinical trials for Kyowa Kirin International and has received research grant support from Kyowa Kirin International. AM, received an honorarium from Kyowa Kirin International for participation in the Expert Practice Exchange meeting. AR, received honoraria from Kyowa Kirin International for consultancy and for lectures. FS, received honoraria from Kyowa Kirin International for teaching activities and scientific consultancy. DS, received honoraria from Kyowa Kirin Germany for scientific consultancy. NS, received an honorarium from Kyowa Kirin International for participation in the Expert Practice Exchange meeting. ON, received honoraria from Kyowa Kirin International for attending advisory boards and for educational lectures/webinars, as well as speakers’ honoraria from Abbott and Biomarin. The authors declare that this study received funding from Kyowa Kirin International. The funder had a role in organising meetings upon which this manuscript is based. The medical writing support was also funded by Kyowa Kirin International., (Copyright © 2023 Mughal, Baroncelli, de Lucas-Collantes, Linglart, Magnolato, Raimann, Santos, Schnabel, Shaw and Nilsson.)

Background: X-linked hypophosphataemia (XLH) is a rare, inherited, phosphate-wasting disorder that elevates fibroblast growth factor 23 (FGF23), causing renal phosphate-wasting and impaired active vitamin D (1,25(OH) 2 D) synthesis. Disease characteristics include rickets, osteomalacia, odontomalacia, and short stature. Historically, treatment has been oral phosphate and 1,25(OH) 2 D supplements. However, these treatments do not correct the primary pathogenic mechanism or treat all symptoms and can be associated with adverse effects. Burosumab is a recombinant human immunoglobulin G1 monoclonal antibody against FGF23, approved for treating XLH in several geographical regions, including Europe and Israel. Burosumab restores normal serum phosphate levels, minimising the clinical consequences of XLH. Safety data on long-term treatment with burosumab are lacking owing to the rarity of XLH. This post-authorisation safety study (PASS) aims to evaluate the safety outcomes in patients aged >1 year., Methods: The PASS is a 10-year retrospective and prospective cohort study utilising data from the International XLH Registry (NCT03193476), which includes standard diagnostic and monitoring practice data at participating centres. The PASS aims to evaluate frequency and severity of safety outcomes, frequency and outcomes of pregnancies in female patients, and safety outcomes in patients with mild to moderate kidney disease at baseline, in children, adolescents and adults treated with burosumab for XLH. It is expected that there will be at least 400 patients who will be administered burosumab., Results: Data collection started on 24 April 2019. The expected date of the final study report is 31 December 2028, with two interim reports., Conclusion: This PASS will provide data on the long-term safety of burosumab treatment for XLH patients and describe safety outcomes for patients receiving burosumab contrasted with those patients receiving other XLH treatments, to help inform the future management of XLH patients. The PASS will be the largest real-world safety study of burosumab., Registry Identification: The International XLH Registry is registered with clinicaltrials.gov as NCT03193476 (https://clinicaltrials.gov/ct2/show/NCT03193476), and the PASS is registered with the European Union electronic Register of Post-Authorisation Studies as EUPAS32190 (http://www.encepp.eu/encepp/viewResource.htm?id=32191)., Competing Interests: Competing interests: AB has received research grants and received honoraria as a consultant and speaker, paid to her institution, from Kyowa Kirin and Ultragenyx. CLC has received honoraria as a consultant for Kyowa Kirin. MCZ reports that her institution has received a research grant from Kyowa Kirin. DH has received a research grant or honoraria as a consultant and speaker from Amgen, Chiesi and Kyowa Kirin. DS has received honoraria as a consultant from BioMarin, Kyowa Kirin, Novo Nordisk and Sandoz. EL has received honoraria as a consultant from Advicenne, Chiesi, Kyowa Kirin, Novartis and Recordati. FE declares competing interests with Avrobio, Chiesi, Kyowa Kirin, Otsuka and Recordati Rare Diseases. GA has received personal fees and non-financial support from Advicenne, Alexion, Kyowa Kirin, Recordati Rare Diseases and received personal fees from Alnylam and Dicerna, and received personal fees and other from Chiesi. KB has received honoraria as a consultant from Amgen, Kyowa Kirin, Theramex and UCB. LTS has received honoraria as a consultant from Amgen and Kyowa Kirin. MB has received research grants or honoraria as a consultant or speaker from Abiogen, Alexion, Amgen, Bruno Farmaceutici, Calilytix, Echolight, Eli Lilly, Kyowa Kirin, SPA, Theramex and UCB. ON has received honoraria as a consultant from BioMarin and Kyowa Kirin. OM has received honoraria as a consultant from BridgeBio, Kyowa Kirin and Ultragenyx. RK has received honoraria as a consultant or for advisory boards from Kyowa Kirin. SBN and ZM have received honoraria as a consultant or speaker from Inozyme Pharma and Kyowa Kirin. JL and AT are employees of Kyowa Kirin International plc. SG declares no conflict of interests., (© The Author(s), 2022.)

Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease 1-7 , evidence of lupus-causing TLR7 gene variants is lacking. Here we describe human systemic lupus erythematosus caused by a TLR7 gain-of-function variant. TLR7 is a sensor of viral RNA 8 , 9 and binds to guanosine 10 - 12 . We identified a de novo, previously undescribed missense TLR7 Y264H variant in a child with severe lupus and additional variants in other patients with lupus. The TLR7 Y264H variant selectively increased sensing of guanosine and 2',3'-cGMP 10-12 , and was sufficient to cause lupus when introduced into mice. We show that enhanced TLR7 signalling drives aberrant survival of B cell receptor (BCR)-activated B cells, and in a cell-intrinsic manner, accumulation of CD11c + age-associated B cells and germinal centre B cells. Follicular and extrafollicular helper T cells were also increased but these phenotypes were cell-extrinsic. Deficiency of MyD88 (an adaptor protein downstream of TLR7) rescued autoimmunity, aberrant B cell survival, and all cellular and serological phenotypes. Despite prominent spontaneous germinal-centre formation in Tlr7 Y264H mice, autoimmunity was not ameliorated by germinal-centre deficiency, suggesting an extrafollicular origin of pathogenic B cells. We establish the importance of TLR7 and guanosine-containing self-ligands for human lupus pathogenesis, which paves the way for therapeutic TLR7 or MyD88 inhibition., (© 2022. The Author(s).)

Background: Fanconi syndrome (FS) can be of primary or secondary origin. Some cases of FS secondary to the use of sodium valproate (VPA) have been described, mostly in children with severe psychomotor retardation who are fed by feeding device. The objetive of this study was to describe patients treated for this entity in our center, comparing them against the published literature., Methods: Descriptive study of our patients and those found in the literature. Epidemiologic and clinical data were collected., Results: We describe seven patients (three to 17 years old) with severe psychomotor retardation and undergoing treatment with VPA. Four presented pathologic fractures before the diagnosis of FS, and in three patients the diagnosis was reached due to abnormal laboratory findings. A review of the published cases was carried out and, including our sample, a total of 42 patients were studied: 51.3% were male, and the median age at diagnosis of FS was 6 years. Severe psychomotor retardation was found in 92.8% of patients, 78% carried a feeding device, and 77.5% received treatment with several antiepileptic drugs. The mean duration of VPA treatment was 5.7 years (range 2 to 7.5 years). Fifteen patients (37.5%) had bone complications. The resolution time of FS after discontinuation of drug therapy ranged from two to 19 months (median 4 months)., Conclusions: FS related to VPA is a rare complication, but it should be considered in patients with epilepsy, especially if they have severe psychomotor retardation, are users of feeding devices, and receive other antiepileptic treatments in addition to VPA., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Minimal change disease (MCD) is the most common type of idiopathic nephrotic syndrome in childhood and represents about 15% cases in adults. It is characterized by massive proteinuria, edema, hypoalbuminemia, and podocyte foot process effacement on electron microscopy. Clinical and experimental studies have shown an association between MCD and immune dysregulation. Given the lack of inflammatory changes or immunocomplex deposits in the kidney tissue, MCD has been traditionally thought to be mediated by an unknown circulating factor(s), probably released by T cells that directly target podocytes leading to podocyte ultrastructural changes and proteinuria. Not surprisingly, research efforts have focused on the role of T cells and podocytes in the disease process. Nevertheless, the pathogenesis of the disease remains a mystery. More recently, B cells have been postulated as an important player in the disease either by activating T cells or by releasing circulating autoantibodies against podocyte targets. There are also few reports of endothelial injury in MCD, but whether glomerular endothelial cells play a role in the disease remains unexplored. Genome-wide association studies are providing insights into the genetic susceptibility to develop the disease and found a link between MCD and certain human haplotype antigen variants. Altogether, these findings emphasize the complex interplay between the immune system, glomerular cells, and the genome, raising the possibility of distinct underlying triggers and/or mechanisms of proteinuria among patients with MCD. The heterogeneity of the disease and the lack of good animal models of MCD remain major obstacles in the understanding of MCD. In this study, we will review the most relevant candidate mediators and mechanisms of proteinuria involved in MCD and the current models of MCD-like injury., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Purohit, Piani, Ordoñez, de Lucas-Collantes, Bauer and Cara-Fuentes.)

Introduction: Minimal change disease (MCD) is considered a podocyte disorder triggered by unknown circulating factors. Here, we hypothesized that the endothelial cell (EC) is also involved in MCD., Methods: We studied 45 children with idiopathic nephrotic syndrome (44 had steroid sensitive nephrotic syndrome [SSNS], and 12 had biopsy-proven MCD), 21 adults with MCD, and 38 healthy controls (30 children, 8 adults). In circulation, we measured products of endothelial glycocalyx (EG) degradation (syndecan-1, heparan sulfate [HS] fragments), HS proteoglycan cleaving enzymes (matrix metalloprotease-2 [MMP-2], heparanase activity), and markers of endothelial activation (von Willebrand factor [vWF], thrombomodulin) by enzyme-linked immunosorbent assay (ELISA) and mass spectrometry. In human kidney tissue, we assessed glomerular EC (GEnC) activation by immunofluorescence of caveolin-1 ( n = 11 MCD, n = 5 controls). In vitro , we cultured immortalized human GEnC with sera from control subjects and patients with MCD/SSNS sera in relapse ( n = 5 per group) and performed Western blotting of thrombomodulin of cell lysates as surrogate marker of endothelial activation., Results: In circulation, median concentrations of all endothelial markers were higher in patients with active disease compared with controls and remained high in some patients during remission. In the MCD glomerulus, caveolin-1 expression was higher, in an endothelial-specific pattern, compared with controls. In cultured human GEnC, sera from children with MCD/SSNS in relapse increased thrombomodulin expression compared with control sera., Conclusion: Our data show that alterations involving the systemic and glomerular endothelium are nearly universal in patients with MCD and SSNS, and that GEnC can be directly activated by circulating factors present in the MCD/SSNS sera during relapse., (© 2021 International Society of Nephrology. Published by Elsevier Inc.)