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Introduction: We aimed to evaluate the efficacy, safety, and immunogenicity profile of Etanercept (ETA) and Adalimumab (ADA) biosimilars (BIOs) compared to their originators in children with juvenile idiopathic arthritis (JIA)., Method: Eighty-one JIA children treated with ETA or ADA originators or BIOs were examined at baseline (T0) and after 3- (T1), 6- (T2), 12- (T3), and 24-(T4) months after starting treatment., Results: Lower Juvenile Arthritis Disease Activity Score 10 (JADAS-10) scores were reported at T1, T2, T3, and T4 in JIA children treated with BIOs than originators (all p < 0.05). At T1 and T3, anti-drugs antibodies levels were lower in children receiving BIOs than originators (p = 0.04 and p = 0.0007, respectively), even after adjustments (both p < 0.05). Relapses were lower for BIOs compared to originators (p < 0.001). Safety profile was comparable between the groups (p > 0.05)., Discussion: A better overall profile of BIOs than originators was demonstrated in JIA children, but larger confirmatory studies are needed., Competing Interests: CONFLICT OF INTEREST None to report., (Copyright © 2024 National Association of Pediatric Nurse Practitioners. Published by Elsevier Inc. All rights reserved.)

Background: We aimed to evaluate the baseline performance and improvement of ChatGPT-4 "omni" (ChatGPT-4o) and Gemini 1.5 Flash (Gemini 1.5) in answering multiple-choice questions related to pediatric nephrology after specific training., Methods: Using questions from the "Educational Review" articles published by Pediatric Nephrology between January 2014 and April 2024, the models were tested both before and after specific training with Portable Data Format (PDF) and text (TXT) file formats of the Educational Review articles removing the last page containing the correct answers using a Python script. The number of correct answers was recorded., Results: Before training, ChatGPT-4o correctly answered 75.2% of the 1395 questions, outperforming Gemini 1.5, which answered 64.9% correctly (p < 0.001). After training with PDF files, ChatGPT-4o's accuracy increased to 77.8%, while Gemini 1.5 improved significantly to 84.7% (p < 0.001). Training with TXT files showed similar results, with ChatGPT-4o maintaining 77.8% accuracy and Gemini 1.5 further improving to 87.6% (p < 0.001)., Conclusions: The study highlights that while ChatGPT-4o has strong baseline performance, specific training does not significantly enhance its accuracy. Conversely, Gemini 1.5, despite its lower initial performance, shows substantial improvement with training, particularly with TXT files. These findings suggest Gemini 1.5's superior ability to store and retrieve information, making it potentially more effective in clinical applications, albeit with a dependency on additional data for optimal performance., Competing Interests: Declarations. Ethics approval: Not applicable. Consent to participate: Not applicable. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s).)

Nephrogenic diabetes insipidus (NDI) results from the kidneys' inability to concentrate urine. We describe a 6-month-old male with a history of poor weight gain who presented with an incidental finding of hypernatremia (155 mEq/L) during an episode of acute gastroenteritis. The arginine vasopressin (AVP) test, along with molecular analysis revealing the M272R mutation in the AVP receptor 2 (AVPR2) gene, confirmed the diagnosis of congenital NDI. Interestingly, this mutation was also identified in the patient's maternal grandfather, who had never been diagnosed or treated for NDI despite a history of polydipsia, polyuria, and evidence of chronic kidney disease (CKD), severe bilateral hydronephrosis, hypertension, and severe bladder dysfunction. Early intervention with hydrochlorothiazide in the infant resulted in a significant reduction in urinary output and improved growth. The untreated grandfather's case highlights the potential severity of untreated NDI and the benefits of timely therapeutic intervention. This report contributes to the limited long-term data on congenital NDI, emphasizing the critical role of early detection and consistent management in preventing severe complications such as CKD, hydronephrosis, and bladder dysfunction. Regular follow-up, including renal ultrasound and monitoring of renal function, is essential for effectively managing NDI and improving patient outcomes., Competing Interests: Declarations. Conflict of interest: The authors have no conflicts of interest to disclose. Ethical approval: This article does not contain any studies with human participants performed by any of the authors. Informed consent: Informed consent was obtained from all the patients described., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Background: The diagnosis of monogenic obesity is burdened by frequent variants of uncertain significance (VUS). We describe our real-life approach of variant reassessment over time and we assess whether inconclusive variants are decreasing in monogenic obesity., Methods: We tested for monogenic obesity (genes: LEPR, POMC, ADCY3, PCSK1, CARTPT, SIM1, MRAP2, LEP, NTRK2, BDNF, KSR2, MAGEL2, SH2B1, MC4R, MC3R) in 101 children/adolescents (11.7 [7.3-13.7] years, 3.6 [3.3-4.0] z-BMI) in Verona and 183 (11.3 [8.4-12.2] years, 3.2 [2.7-3.9] z-BMI) in Naples from January 2020 to February 2023. In March-July 2024 we reassessed the baseline variants by updated software interpretation and literature renavigation., Results: We initially found 20 VUS, 4 Likely Pathogenic (LP), 5 Likely Benign (LB) and 1 benign variant in 33 individuals. At follow-up, 6 VUS were reclassified as benign/LB, one LP as pathogenic and 3 LB as benign. Overall, 10/30 variants (6/18 in Verona, 3/11 in Naples and a variant found in both centres) were reclassified, leading to a less uncertain report for 13 of 33 variant-carrying patients. Monogenic obesity was diagnosed in 3 probands in Verona and 4 in Naples, carrying variants at MC4R or NTRK2., Conclusion: Our variant reassessment was effective to improve classification certainty for the 39% of patients and suggested that the molecular diagnosis of monogenic obesity is becoming more accurate over time., (© 2024 The Author(s). Pediatric Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Aim: To assess the prevalence and determinants of failure to thrive (FTT) among patients with vesico-ureteral reflux (VUR) and evaluating the effects of supplementation on growth in patients with urinary solute losses., Methods: We retrospectively enrolled 1277 patients with VUR (mean age at diagnosis = 6.5 months). Patients with FTT were screened for renal tubular function impairment (TFI). If fractional excretion of sodium (FENa) >2% or blood bicarbonate <20 mmol/L, supplementation was provided., Results: Among 1277 patients, 56 (4.4%) had FTT. Of these, 42 (75%) presented extrarenal causes of FTT, 3 (5.4%) had chronic kidney disease (CKD), 9 (16.1%) had TFI, and 2 (3.5%) had CKD and TFI. FTT occurred in 8/208 patients (3.8%) with and in 48/1069 patients (4.5%) without (p = 0.68) recurrent urinary tract infections (UTIs). At multiple logistic regression, birthweight <10th percentile, preterm birth, TFI, identified or suspected syndromes and other diseases were predictors of FTT. Eleven (19.6%) patients with FTT had TFI; five with increased FENa and/or acidosis received supplementation and showed catch-up growth. The remaining six patients exhibited spontaneous catch-up growth., Conclusion: FTT was found in <5% of children with VUR. It was not determined by recurrent UTIs and was mainly associated with extrarenal causes. Supplementation with sodium and bicarbonates could be useful in selected cases., (© 2024 The Author(s). Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Purpose: Omnitrope ® (a somatropin biosimilar), used to treat growth disturbances, is considered to have a good safety profile in children. Here, we present the analysis of final data of the Italian cohort of the PAtients TReated with Omnitrope ® (PATRO) Children study., Methods: This multicenter, open-label, longitudinal, post-marketing surveillance study enrolled eligible children during 2010-2018. The primary objective was to assess the long-term safety of Omnitrope ® by recording all adverse events (AEs), serious AEs, and adverse drug reactions (ADRs). A secondary objective was to evaluate the long-term effectiveness of Omnitrope ® using height measurements., Results: A total of 375 patients were included in the Italian cohort of the PATRO Children study. After a mean ± standard deviation (SD) follow-up duration of 40.9 ± 24.6 months, 607 AEs were reported in 58.4% of patients, mostly of mild (52.5%) or moderate (15.7%) severity. The most common AEs were headache (11.7%), elevated insulin-like growth factor (IGF)-1 (4.8%), abdominal pain (4.3%), and pyrexia (3.7%). Sixty-seven ADRs occurred in 52 patients (13.9%); the most common ADRs were elevated IGF-1 (3.5%) and insulin resistance (2.9%). Mean ± SD height standard deviation scores in treatment-naïve patients increased from -2.5 ± 0.7 at baseline (n = 318) to -1.3 ± 0.7 at 5 years (n = 56) and to -0.8 ± 0.7 at 7.5 years (n = 13)., Conclusions: This final analysis extends the interim analysis findings from the PATRO Children study and confirms the long-term safety and effectiveness of Omnitrope ® in Italian pediatric patients with growth disturbances., Competing Interests: Compliance with ethical standards. Conflict of interest: Lorenzo Iughetti has received fees for participation on advisory boards from Sandoz. Franco Antoniazzi has received research funding from Merck Serono and Sandoz, and fees for participation on advisory boards from BioMarin. Tommaso Aversa has consulted for Pfizer and Sandoz. Luca Persani has received fees for participation on advisory boards from Sandoz. Gabriella Pozzobon has received consulting fees and for participation on advisory boards from Sandoz, Merck Serono and Novo Nordisk. Emiliano Zecchi, Paolo Fedeli and Markus Zabransky are part of Sandoz Company Organization. Claudia Giavoli, Simonetta Bellone, Laura Guazzarotti, Maria Elisabeth Street, Emanuele Miraglia del Giudice, Stefano Stagi, Gianluca Tornese, Chiara Mameli, Laura Lucaccioni, Letizia Ragusa, Clara Zecchino, and Stefano Zucchini have no relevant financial or non-financial interests to disclose. Ethics approval: The study was reviewed and approved by each study site’s Independent Ethics Committee/Institutional Review Board. Research involving human participants: All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committees, with the 1964 Helsinki Declaration and its later amendments, and with the ethical principles outlined in the Oviedo Human Rights Convention. Consent to participate: All patients (or their parents/legal guardians) provided written informed consent before study inclusion., (© 2024. The Author(s).)

The role of obesity as a risk factor for chronic kidney disease (CKD) in adulthood has been well established. Over the last years, kidney damage (KD) has emerged as a significant consequence of obesity since childhood. Indeed, a complex interplay of metabolic factors, including insulin resistance (IR), hypertension, oxidative stress, adipose tissue dysfunction, and systemic inflammation, might affect renal hemodynamics, contributing to CKD development over time in at-risk young patients. As the prevalence of pediatric obesity continues to rise globally, understanding the implications for kidney health in terms of early intervention is of paramount importance. Careful monitoring of kidney function within a multidisciplinary approach in children with obesity is crucial for detecting early KD, allowing for timely lifestyle modifications and treatment. In this framework, continued research is essential to further elucidate mechanisms linking obesity and KD and to explore not only effective preventive strategies but also the long-term impact of obesity on kidney health in children with obesity. Given the intimate link of KD with the metabolic milieu in children with obesity, we aimed to provide a comprehensive and insightful overview on KD and its implications in pediatric obesity by reviewing the most recent literature in the field.

Objectives: Evidence linked metabolic associated steatotic liver disease (MASLD) to kidney damage with the potential contribution of the I148M variant of the Patatin-like phospholipase containing domain 3 (PNPLA3) gene. We aimed at investigating the relationship of MASLD and of its genetics with kidney function in children with obesity., Methods: A comprehensive evaluation including genotyping for the I148M PNPLA3 polymorphism was performed in 1037 children with obesity. Fatty liver (FL) was assessed by liver ultrasound. According to MASLD criteria, subjects with obesity but without FL were included in group 1, while patients with obesity and FL (encompassing one MASLD criterion) were clustered into group 2. Group 3 included patients with obesity, FL, and metabolic dysregulation (encompassing >1 MASLD criterion)., Results: Alanine transaminase levels significantly increased while estimated glomerular filtration rate (eGFR) significantly reduced from group 1 to 3. Group 3 showed a higher percentage of carriers of the I148M allele of the PNPLA3 gene compared to other groups (p < 0.0001). Carriers of group 2 and of group 3 showed reduced eGFR levels than noncarriers of group 2 (p = 0.04) and of group 3 (p = 0.02), respectively. A general linear model for eGFR variance in the study population showed an inverse association of eGFR with both MASLD and PNPLA3 genotypes (p = 0.011 and p = 0.02, respectively). An inverse association of eGFR with MASLD was also confirmed only in carriers (p = 0.006)., Conclusions: The coexistence of more than 1 MASLD criterion in children with obesity seems to adversely affect kidney function. The PNPLA3 I148M allele further impacts on this association., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background/Objectives: The pediatric definition of severe obesity (OB) depends on the body mass index (BMI) references. We evaluated different BMI-derived metrics of the World Health Organization (WHO) system to define which cut-off is associated with the highest cardiometabolic risk (CMR); Methods: In this multicentric study, data were retrieved for 3727 youths (1937 boys; 2225 children, 1502 adolescents). OB was defined as BMI > 97th percentile (BMI 97th ), severe OB was defined as BMI > 99th percentile (BMI 99th ), BMI ≥ 120% of the 97th percentile (120% BMI 97th ), or BMI Z-score > 3 (WHO tables), or BMI ≥ the International Obesity Task Force (IOTF) value crossing a BMI of 35 kg/m 2 at the age of 18 (IOTF 35 ). The continuous CMR Z-score (sum of residual standardized for age and sex of waist-to-height ratio, systolic and diastolic blood pressure, triglycerides, and HDL-cholesterol x -1) and the cluster of at least two CMR factors (hypertension, high triglycerides, low HDL-cholesterol, and high waist-to-height ratio) were calculated. Results: Continuous CMR Z-score was significantly higher both in children or adolescents with severe OB defined by 120% BMI 97th compared to BMI 99th ( p < 0.0001), while it was lower only in adolescents with severe OB defined by 120% BMI 97th compared to BMI Z-score >3 ( p < 0.0001). Compared to 120% BMI 97th , BMI Z-score > 3 and IOTF 35 had higher specificity, but lower sensitivity in identifying children and adolescents with clustered CMR factors. Conclusions: The definition of severe OB based on 120% BMI 97th is superior to BMI 99th but it is inferior to BMI Z score > 3 as far as the association between severe OB and CMR factors is concerned. Pediatricians should take into consideration the implication of the use of different BMI metrics in those countries that recommend the WHO system. WHO BMI Z-score > 3 and IOTF 35 can be used interchangeably to predict cardiometabolic risk.

We previously developed and retrospectively validated the estimated percentage of heart rate variation (EHRV) as a predictor of the composite outcome of ≥ 5% dehydration and/or acute kidney injury (AKI) in non-febrile children. The current study aimed to prospectively validate EHRV as a predictor for dehydration or AKI in a different cohort of children attending the Pediatric Emergency Department. From July 2022 to August 2023, 256 pediatric patients aged 0-18 years attending the Pediatric Emergency Department were enrolled. EHRV was calculated as follows: [(HR at admission - 50th percentile of HR for age and sex)/HR at admission] × 100. Dehydration was categorized as < 5% or ≥ 5% fluid deficit. AKI was defined according to KDIGO creatinine criteria. Statistical analyses included receiver-operating characteristic (ROC) curves and logistic regression analysis. Among enrolled patients, 52 had ≥ 5% dehydration, 50 had AKI, and 16 had both conditions. EHRV demonstrated significant predictive ability for both ≥ 5% dehydration (AUROC = 0.71; 95% confidence interval (CI), 0.63-0.78; p < 0.001) and AKI (AUROC = 0.78; 95% CI, 0.71-0.84; p < 0.001). An EHRV > 24.5% was associated with an increased odds ratio (OR), adjusted for confounders, of ≥ 5% dehydration (OR = 3.5; 95% CI, 1.6-8.0; p = 0.003) and AKI (OR = 3.4; 95% CI, 1.6-7.3; p = 0.002). The sensitivity and specificity of this cut-off were 34% and 83% for ≥ 5% dehydration and 36% and 84% for AKI, respectively., Conclusions: This study prospectively validates the clinical utility of EHRV in predicting dehydration and AKI in a pediatric emergency care setting. An EHRV > 24.5% could serve as a marker for suspecting dehydration or AKI. Further validation across diverse patient populations and settings is needed., What Is Known: • An increased heart rate (HR) is a readily detectable sign of dehydration in children. • In a retrospective validation cohort, an estimated HR variation (EHRV) greater than 24.5% compared to the 50th percentile of HR was predictive of ≥ 5% dehydration and/or acute kidney injury (AKI) in non-febrile patients., What Is New: • We prospectively validated the clinical utility of EHRV in predicting dehydration and AKI in a pediatric emergency care setting. • We confirmed that an EHRV greater than 24.5% is associated with increased odds of ≥ 5% dehydration and AKI., (© 2024. The Author(s).)

Despite the implementation of preventive measures to counteract the obesity epidemics, the prevalence of childhood obesity is still alarming all over the world. Childhood obesity is the most common risk factor for both cardiovascular and metabolic diseases. In fact, an earlier onset of obesity can cause a greater risk of adiposity tracking across the lifespan and consequently a longer exposure to cardiometabolic risk factors. Accumulating evidence provided by prospective and intervention studies demonstrated the link between pediatric obesity and selected subclinical signs of cardiovascular damage (atherosclerosis and left ventricular hypertrophy), or fatal and not fatal cardiovascular events as early as 40 years of age.The numerous guidelines and scientific documents published in the last years demonstrate the relevance of assessing cardiometabolic risk factors in children and adolescents with OB.This Position paper, released by experts of the "Childhood Obesity study group" within the Italian Society for Pediatric Endocrinology and Diabetology, aims to review the assessment of cardiometabolic risk factors and comorbidities in children and adolescents with OW/OB on the light of the most recent scientific evidence.The main recommendations are: (a) early detection of comorbidities, including hypertension, dyslipidemia, prediabetes/type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, polycystic ovary syndrome, inactivity, obstructive sleep apnea and decline in kidney function; (b) weight loss treatment, which is associated with a reduction of all cardiometabolic risk factors; (c) specific treatment of comorbidities, through lifestyle modifications or pharmacological treatment added to lifestyle for suitable individuals; d). monitoring comorbidities for mitigating future morbidity and mortality., (© 2024. The Author(s).)

Objectives: To compare characteristics and outcomes of vesicoureteral reflux (VUR) detected solely on isotopic cystography (IC) ("occult" VUR) with voiding cystourethrography (VCUG)-detected VUR., Materials and Methods: Between 2015 and 2020, we retrospectively enrolled all male children first undergoing VCUG and, if negative, IC in the same session. Kidney injury (KI) was defined by abnormal estimated glomerular filtration rate and/or blood pressure and/or proteinuria., Results: We enrolled 421 males with a median age of 3 months and a follow-up of 5.3 years. None exhibited KI initially, but 10% of those with VUR developed KI during follow-up. Two hundred and twenty-two patients (52.7%) did not show VUR, 152 (36.1%) had VCUG-diagnosed VUR, and 47 (11.2%) had occult VUR. Therefore, 47/199 patients (23.6%) with VUR had occult VUR. Among these, 34/47 (72.3%) had dilated VUR, and 22/47 (46.8%) exhibited split renal function < 45% and/or scar (scintigraphic damage). Compared to patients with occult VUR, those with VCUG-diagnosed VUR showed a similar prevalence of febrile urinary tract infection (fUTI) before and after VUR diagnostics and KI at the last follow-up but a higher prevalence of dilated VUR, of scintigraphic damage, and underwent surgery more frequently. At multiple logistic regression analysis, patients with VCUG-diagnosed VUR presented an increased risk of fUTI either before or after VUR diagnosis and of KI, while patients with occult VUR presented an increased risk of fUTI before (and among patients with dilated VUR also after) VUR diagnosis and of KI., Conclusion: Occult VUR affects 23.6% of male children with VUR with a non-negligible risk of VUR-associated KI and fUTI. IC could select, among males with recurrent fUTIs and negative VCUG, those requiring surgery for a possible dilated occult VUR., Clinical Relevance Statement: Vesicoureteral reflux may be overlooked in 25% of boys during VCUG, yet they are at risk of fUTIs and KI. In case of recurrent infections post-negative cystourethrography, IC could detect occult reflux, guiding surgical intervention., (© 2024. The Author(s).)

Competing Interests: The authors declare no conflict of interest.

Background: Pediatric obesity treatment is based on high-intensity lifestyle counseling. However, high dropout rates and low effectiveness have been reported, even in specialized centers. Mobile health technologies have been used to overcome these limits with contrasting results. This study aims at evaluating the effectiveness of a six-month intervention with a mobile app for the treatment of pediatric obesity at 6 and 12 months of follow-up., Methods: Seventy-five patients were randomly assigned to standard care or standard care plus mobile app (2:1) using an online randomizer system. The mobile app delivered high-intensity lifestyle counseling for diet and physical activity., Results: At six months of follow-up, the M-App group showed significantly lower dropout rates compared to standard care ( p = 0.01). The risk of dropout was significantly higher in controls compared to the intervention group (OR 3.86, 95% C.I. 1.39-10.42, p = 0.01). After one year, we observed lower albeit non-statistically significant dropout rates in the M-App compared to the standard care group ( p = 0.24). No differences were observed in z-score BMI and percentage of BMI reduction between the two groups., Conclusions: Our findings suggest that the mobile app might help in the clinical management of children and adolescents with obesity in terms of dropout reduction.

Background and Aim: To assess the performance of Friedewald's and Sampson's formulas in relation to high or borderline-high levels of measured LDL-Cholesterol (LDL-C) in youths with overweight/obesity (OW/OB)., Methods and Results: A cross-sectional study was performed in 1694 youths (age 5-17 years) with OW/OB observed in Italian centers of Messina (group 1) and Naples (group 2). LDL-C levels were both measured and calculated using Friedewald's (LDL-C F ) and Sampson's (LDL-C S ) formulas. The two groups were similar for sex, age, BMI, BMI Z-score, and measured LDL-C. Levels of LDL-C F and LDL-C S were higher in group 1 than group 2. In the overall sample, 9.9 % youths had measured LDL-C ≥130 mg/dL and 27.8 % ≥ 110 mg/dL, without differences between centers. The two formulas showed comparable high sensitivity and specificity in relation to levels of measured LDL-C ≥130 mg/dL or ≥110 mg/dL. However, LDL-C F showed a higher positive predictive value than LDL-C S ., Conclusions: Both formulas estimate with high accuracy measured LDL-C levels in youths with OW/OB. Therefore, calculated LDL-C can be a useful tool for universal screening when direct LDL-C measurement is not available. The Friedewald's formula is more feasible in clinical practice for simplicity of calculation., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2024 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Objective: To investigate fear of hypoglycemia (FoH) in parents of children with type 1 diabetes (T1D) before and after undergoing training to learn intranasal (IN) glucagon administration., Method: In this pre-test/post-test uncontrolled study 364 caregivers of patients with T1D (6-18 years) completed questionnaires measuring sociodemographic characteristics, diabetes-related factors (e.g., type of insulin therapy, glycemic control), and parents' trait anxiety. Parents' FoH was assessed at baseline (T0, training) and after nine months (T1). Two repeated-measure mixed analyses of covariance (ANCOVA) compared the FoH at T0 and at T1 and analyzed the moderating roles of anxiety proneness and type of insulin therapy, as well as of anxiety proneness and use of sensor. Age, T1D duration, HbA1c values, and SES were included as covariates., Results: Parental FoH at T1 (M = 1.72; SE = 0.06/M = 1.57; SE = 0.09) was significantly lower than parental FoH at T0 (M = 1.89; SE = 0.06/M = 1.77; SE = 0.09). The group with high trait-anxiety had a higher level of FoH (M = 2.05; SE = 0.08/M = 1.89; SE = 0.12) than the group with low trait-anxiety (M = 1.57; SE = 0.08/M = 1.46; SE = 0.09) at both time points. SES was negatively associated with FoH at T0 (t = -2.87; p = .004/t = -2.87; p = .005). No other significant effects were found., Conclusions: Training and educating parents on IN glucagon use can help them effectively manage hypoglycemic episodes and alleviate the fear that generally accompany such events., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The role of obesity as risk factor for chronic kidney disease (CKD) has been well-recognized. As previously demonstrated in adults, emerging data highlighted the relevant impact of obesity on renal function since childhood. As a matter of fact, obesity also affects renal health through a complex pathogenic mechanism in which insulin resistance (IR) plays a pivotal role. Worthy of note, the vicious interplay among obesity, IR, and renal hemodynamics clinically translates into a plethora of kidney function impairments potentially leading to CKD development. Therefore, renal injury needs to be added to the well-known spectrum of cardiometabolic obesity comorbidities (e.g., type 2 diabetes, IR, metabolic syndrome, cardiovascular disease)., Conclusion: Taking this into account, a careful and timely monitoring of kidney function should not be neglected in the global assessment of children with obesity. We aimed to provide a comprehensive overview on the relevance of kidney evaluation in children with obesity by shedding lights on the intriguing relationship of obesity with renal health in this at-risk population., What Is Known: • Obesity has been found to be a risk factor for chronic kidney disease. • Unlike adults, pediatric data supporting the association between obesity and renal function are still limited., What Is New: • As observed in adults, obesity might affect renal function since childhood. • Kidney function should be carefully evaluated in children with obesity., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Acute kidney injury (AKI) presents significant challenges in pediatric care, often remaining underrecognized. This paper provides an overview of pediatric AKI, highlighting its epidemiology, pathophysiology, diagnosis, predisposing conditions, and treatment. AKI in children stems from diverse causes, including renal tubular damage, vasoconstriction, and inflammation. Diagnosis relies on traditional markers such as serum creatinine and urine output, alongside emerging biomarkers such as Cystatin C, NGAL, KIM-1, IL-18, TIMP-2 and IGFBP7, urinary calprotectin, URBP4, L-FABP, and clusterin. Various pediatric conditions predispose to AKI, including type 1 diabetes, pneumonia, bronchiolitis, appendicitis, gastroenteritis, COVID-19, multisystem inflammatory syndrome, sickle cell disease, and malignancies. Treatment entails supportive care with fluid management and, in severe cases, renal replacement therapy. Timely recognition and management are essential to mitigating adverse outcomes. Enhanced awareness and integration of novel biomarkers could improve pediatric AKI care, warranting further research for better diagnosis and management.

Aim: To determine (i) prevalence and the risk factors for acute kidney injury (AKI) in children hospitalised for febrile urinary tract infection (fUTI) and (ii) role of AKI as indicator of an underlying VUR. AKI, in fact, is favoured by a reduced nephron mass, often associated to VUR., Methods: This retrospective Italian multicentre study enrolled children aged 18 years or younger (median age = 0.5 years) discharged with a primary diagnosis of fUTI. AKI was defined using Kidney Disease/Improving Global Outcomes serum creatinine criteria., Results: Of 849 children hospitalised for fUTI (44.2% females, median age 0.5 years; IQR = 1.8), 124 (14.6%) developed AKI. AKI prevalence rose to 30% in the presence of underlying congenital anomalies of the kidney and urinary tract (CAKUT). The strongest AKI predictors were presence of CAKUT (OR = 7.5; 95%CI: 3.8-15.2; p = 9.4e-09) and neutrophils levels (OR = 1.13; 95%CI: 1.08-1.2; p = 6.8e-07). At multiple logistic regression analysis, AKI during fUTI episode was a significant indicator of VUR (OR = 3.4; 95%CI: 1.7-6.9; p = 0.001) despite correction for the diagnostic covariates usually used to assess the risk of VUR after the first fUTI episode. Moreover, AKI showed the best positive likelihood ratio, positive predictive value, negative predictive value and specificity for VUR., Conclusion: AKI occurs in 14.6% of children hospitalised for fUTI and is a significant indicator of VUR., (© 2024 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Background: Genetic and environmental factors are implicated in many developmental processes. Recent evidence, however, has suggested that epigenetic changes may also influence the onset of puberty or the susceptibility to a wide range of diseases later in life. The present study aims to investigate changes in genomic DNA methylation profiles associated with pubertal onset analyzing human peripheral blood leukocytes from three different groups of subjects: 19 girls with central precocious puberty (CPP), 14 healthy prepubertal girls matched by age and 13 healthy pubertal girls matched by pubertal stage. For this purpose, the comparisons were performed between pre- and pubertal controls to identify changes in normal pubertal transition and CPP versus pre- and pubertal controls., Results: Analysis of methylation changes associated with normal pubertal transition identified 1006 differentially methylated CpG sites, 86% of them were found to be hypermethylated in prepubertal controls. Some of these CpG sites reside in genes associated with the age of menarche or transcription factors involved in the process of pubertal development. Analysis of methylome profiles in CPP patients showed 65% and 55% hypomethylated CpG sites compared with prepubertal and pubertal controls, respectively. In addition, interestingly, our results revealed the presence of 43 differentially methylated genes coding for zinc finger (ZNF) proteins. Gene ontology and IPA analysis performed in the three groups studied revealed significant enrichment of them in some pathways related to neuronal communication (semaphorin and gustation pathways), estrogens action, some cancers (particularly breast and ovarian) or metabolism (particularly sirtuin)., Conclusions: The different methylation profiles of girls with normal and precocious puberty indicate that regulation of the pubertal process in humans is associated with specific epigenetic changes. Differentially methylated genes include ZNF genes that may play a role in developmental control. In addition, our data highlight changes in the methylation status of genes involved in signaling pathways that determine the migration and function of GnRH neurons and the onset of metabolic and neoplastic diseases that may be associated with CPP in later life., (© 2024. The Author(s).)

Background: Pediatric obesity is closely associated with cardiometabolic comorbidities, but the role of sex in this relationship is less investigated. We aimed to evaluate sex-related differences on cardiometabolic risk factors and preclinical signs of target organ damage in adolescents with overweight/obesity (OW/OB)., Methods: The main cross-sectional study included 988 adolescents (510 boys and 478 girls) with OW/OB aged 10-18 years. In all youths clinical and biochemical variables were evaluated and an abdominal echography was performed. Echocardiographic data for the assessment of left ventricular mass (LVM) and relative wall thickness (RWT) were available in an independent sample of 142 youths (67 boys and 75 girls), while echographic data of carotid intima media thickness (cIMT) were available in 107 youths (59 boys and 48 girls)., Results: The three samples did not differ for age, body mass index, and sex distribution. In the main sample, boys showed higher waist-to-height ratio (WHtR) values ( p < 0.0001) and fasting glucose levels ( p = 0.002) than girls. Lower levels of estimates glomerular filtration rate (eGFR) were found in girls vs boys ( p < 0.0001). No sex-related differences for prediabetes and hyperlipidemia were observed. A higher prevalence of WHtR ≥ 0.60 (57.3% vs 49.6%, p = 0.016) and fatty liver disease (FLD) (54.5% vs 38.3%, p < 0.0001) as well as a trend for high prevalence of hypertension (40.4 vs 34.7%, p = 0.06) were observed in boys vs girls. More, a higher prevalence of mild reduced eGFR (MReGFR) ( < 90 mL/min/1.73 m 2 ) was observed in girls vs boys (14.6% vs 9.6 %, p < 0.0001). In the sample with echocardiographic evaluation, boys showed higher levels of LVM ( p = 0.046), and RWT ( p = 0.003) than girls. Again, in the sample with carotid echography, boys showed higher levels of cIMT as compared to girls ( p = 0.011)., Conclusions: Adolescent boys with OW/OB showed higher risk of abdominal adiposity, FLD, and increased cardiac and vascular impairment than girls, whereas the latter had a higher risk of MReGFR. Risk stratification by sex for cardiometabolic risk factors or preclinical signs of target organ damage should be considered in youths with OW/OB., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2024 The Author(s). Published by IMR Press.)

Importance: Induced hypothermia, the standard treatment for hypoxic-ischemic encephalopathy (HIE) in high-income countries (HICs), is less effective in the low-income populations in South Asia, who have the highest disease burden., Objective: To investigate the differences in blood genome expression profiles of neonates with HIE from an HIC vs neonates with HIE from South Asia., Design, Setting, and Participants: This case-control study analyzed data from (1) a prospective observational study involving neonates with moderate or severe HIE who underwent whole-body hypothermia between January 2017 and June 2019 and age-matched term healthy controls in Italy and (2) a randomized clinical trial involving neonates with moderate or severe HIE in India, Sri Lanka, and Bangladesh recruited between August 2015 and February 2019. Data were analyzed between October 2020 and August 2023., Exposure: Whole-blood RNA that underwent next-generation sequencing., Main Outcome and Measures: The primary outcomes were whole-blood genome expression profile at birth associated with adverse outcome (death or disability at 18 months) after HIE in the HIC and South Asia cohorts and changes in whole-genome expression profile during the first 72 hours after birth in neonates with HIE and healthy controls from the HIC cohort. Blood samples for RNA extraction were collected before whole-body hypothermia at 4 time points (6, 24, 48, and 72 hours after birth) for the HIC cohort. Only 1 blood sample was drawn within 6 hours after birth for the South Asia cohort., Results: The HIC cohort was composed of 35 neonates (21 females [60.0%]) with a median (IQR) birth weight of 3.3 (3.0-3.6) kg and gestational age of 40.0 (39.0-40.6) weeks. The South Asia cohort consisted of 99 neonates (57 males [57.6%]) with a median (IQR) birth weight of 2.9 (2.7-3.3) kg and gestational age of 39.0 (38.0-40.0) weeks. Healthy controls included 14 neonates (9 females [64.3%]) with a median (IQR) birth weight of 3.4 (3.2-3.7) kg and gestational age of 39.2 (38.9-40.4) weeks. A total of 1793 significant genes in the HIC cohort and 99 significant genes in the South Asia cohort were associated with adverse outcome (false discovery rate <0.05). Only 11 of these genes were in common, and all had opposite direction in fold change. The most significant pathways associated with adverse outcome were downregulation of eukaryotic translation initiation factor 2 signaling in the HIC cohort (z score = -4.56; P < .001) and aldosterone signaling in epithelial cells in the South Asia cohort (z score = null; P < .001). The genome expression profile of neonates with HIE (n = 35) at birth, 24 hours, 48 hours, and 72 hours remained significantly different from that of age-matched healthy controls in the HIC cohort (n = 14)., Conclusions and Relevance: This case-control study found that disease mechanisms underlying HIE were primarily associated with acute hypoxia in the HIC cohort and nonacute hypoxia in the South Asia cohort. This finding might explain the lack of hypothermic neuroprotection.

Background and Aim: To evaluate the relationship between HDL-Cholesterol (HDL-C), hypertension, and left ventricular hypertrophy (LVH) in a large sample of Caucasian youths with overweight/obesity (OW/OB)., Methods and Results: A cross-sectional multicenter study was performed in 1469 youths (age 6-16 years) with OW/OB observed in the period 2016-2020. An additional independent sample of 244 youths with an echocardiographic evaluation, observed in a single center was analyzed. The sample was divided in six quantiles (Q) of HDL-C: Q1: >56, Q2: ≤56 > 51, Q3: ≤51 > 45, Q4: ≤45 > 41, Q5: ≤41 > 39, Q6: <39 mg/dL. The nadir of the relationship was identified in youths in the first quantile. Among HDL-Cholesterol quantiles the distribution of hypertension was non-linear with a percentage of 25.0%, 40.1%, 33.6%, 31.3%, 35.2% and 39.7% in the six quantiles, respectively. The percentage of LVH was 21.8%, 43.6%, 48.8%, 35.5%, 38.5% and 52.0% in the six quantiles, respectively. The highest odds [95%Cl] of hypertension were 2.05 (1.33-3.16) (P < 0.01) in Q2, 1.67 (1.10-2.55) (P < 0.05) in Q3 and 1.59 (1.05-2.41) (P < 0.05) in Q6 vs Q1. The odds of LVH were 3.86 (1.15-10.24) (P < 0.05) in Q2, 4.16 (1.58-10.91) (P < 0.05) in Q3 and 3.60 (1.44-9.02) (P < 0.05) in Q6 vs Q1, independently by centers, age, sex, prepubertal stage, and body mass index., Conclusion: Contrary to the common belief, the present study shows that high levels of HDL-C may be not considered a negative predictor of hypertension and LVH, two risk factors for future CV disease., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: To identify the diagnostic performance of clinical and radiological signs (on voiding cystourethrography [VCUG]) to detect posterior urethral valves (PUV) in the post-neonatal period., Materials and Methods: One hundred eighteen males (median age = 0.8 years, range = 1 month-14 years, 48 toilet-trained) undergoing VCUG in a 2-year period were prospectively enrolled. Direct (dilated posterior urethra) and indirect (hypertrophied bladder neck, musculus interuretericus hypertrophy, and trabeculated appearance of the bladder wall) PUV signs on VCUG were assessed. Uroflowmetry was defined pathological by patterns suggesting infravesical obstruction., Results: Twenty-two patients with direct, 28 with indirect PUV signs on VCUG, and one with normal VCUG but persisting micturition symptoms with pathological uroflowmetry underwent urethrocystoscopy and in 43/51 a PUV diagnosis was made (n = 22, 51.2%, with direct PUV signs). In 8/28 patients with indirect signs, PUV were not confirmed. Among non-toilet-trained patients, none of the clinical signs/symptoms was associated with PUV while among toilet-trained patients only pathological uroflowmetry (odds ratio, OR = 4.0 [95% confidence interval:1.2-13.2; p = 0.02]) and pathological uroflowmetry with history of urinary tract infection (OR = infinity) were significantly associated with PUV. Significant associations with PUV of direct and indirect signs on VCUG were found both in toilet-trained and non-toilet trained patients. Direct PUV sign had 100% specificity and sensitivity while indirect PUV signs showed sensitivity = 58.1% and specificity = 89.3%. The absence of any radiological sign had a negative predictive value = 98.5%., Conclusion: Only half of patients with endoscopy-confirmed PUV presents with direct sign of PUV on VCUG. Accounting for indirect PUV signs on VCUG and pathological uroflowmetry (in toilet-trained children) could improve the PUV detection rate., Clinical Relevance Statement: Indirect radiological PUV signs should be valorized when interpreting VCUG to improve the PUV detection rate. The absence of any radiological PUV (direct and indirect) sign on VCUG excludes PUV with a very high negative predictive value., Key Points: • Worldwide agreement is that a non-dilated urethra on voiding cystourethrography excludes obstruction. • Half of patients with posterior urethral valves have non-dilated urethra on voiding cystourethrography. • Accounting for indirect signs of posterior urethral valves on voiding cystourethrography improves the diagnostic performance., (© 2023. The Author(s).)

Despite the well-known role of obesity as risk factor for Juvenile Idiopathic Arthritis (JIA) severity, emerging but limited evidence suggested a similar role for underweight. We investigated the role of body mass index (BMI) across its full spectrum in a cohort of children with JIA.We retrospectively studied 113 children with JIA classified according to the International League of Association for Rheumatology (ILAR) criteria attending our Rheumatology Clinic. The patients underwent a comprehensive evaluation including both clinical and biochemical assessments. According to BMI Z-score, the cohort was divided into five groups as underweight, normal weight, overweight (OW), obesity (OB), and severe OB. Disease activity was calculated by Juvenile Arthritis Disease Activity Score 10 (JADAS-10) joint reduced count and relapses were defined according to Wallace criteria.The mean age of the cohort was 7.43 ± 4.03 years. The prevalence of underweight, normal weight, OW, OB, and severe OB was 7.2%, 54.1%, 10.8%, 17.1%, and 10.8%, respectively. Significant higher ferritin levels and erythrocyte sedimentation rate values were found in patients with severe OB and underweight compared to subjects belonging to normal weight, OW, and OB groups. A greater JADAS-10 score was observed in underweight patients and in those with severe OB than other groups. The relapse rate was higher in patients with severe OB and underweight compared to other groups.          Conclusions: Both underweight and OB might negatively affect JIA course. Weight control is fundamental in children with JIA to avoid a more unfavourable course of the disease. What is Known: • Obesity represents a well-known risk factor for JIA severity. • The role of underweight in children with JIA is still poorly explored. What is New: • As observed in children with obesity, underweight young patients with JIA seem to experience a more severe JIA course. • Healthy lifestyle promotion in children with JIA is a crucial step in the management of the disease., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Importance: Although hypoglycaemia and hyperglycaemia represent the most common metabolic problem in neonates, there is still uncertainty regarding the effects of glucose homoeostasis on the neurological outcomes of infants with neonatal encephalopathy (NE)., Objective: To systematically investigate the association between neonatal hypoglycaemia and hyperglycaemia with adverse outcome in children who suffered from NE., Study Selection: We searched Pubmed, Embase and Web of Science databases to identify studies which reported prespecified outcomes and compared infants with NE who had been exposed to neonatal hypoglycaemia or hyperglycaemia with infants not exposed., Data Analysis: We assessed the risk of bias (ROBINS-I), quality of evidence (Grading of Recommendations, Assessment, Development and Evaluation (GRADE)) for each of the studies. RevMan was used for meta-analysis (inverse variance, fixed effects)., Main Outcome: Death or neurodevelopmental outcomes at 18 months of age or later., Results: 82 studies were screened, 28 reviewed in full and 12 included. Children who were exposed to neonatal hypoglycaemia had higher odds of neurodevelopmental impairment or death (6 studies, 685 infants; 40.6% vs 25.4%; OR=2.17, 95% CI 1.46 to 3.25; p=0.0001). Neonatal exposure to hyperglycaemia was associated with death or neurodisability at 18 months or later (7 studies, 807 infants; 46.1% vs 28.0%; OR=3.07, 95% CI 2.17 to 4.35; p<0.00001). These findings were confirmed in the subgroup analysis, which included only the infants who underwent therapeutic hypothermia., Conclusions: These data suggest that neonatal hypoglycaemia and hyperglycaemia may be associated with the neurodevelopmental outcome later on in infants with NE. Further studies with long-term follow-up are needed to optimise the metabolic management of these high-risk infants., Prospero Registration Number: CRD42022368870., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Obesity and kidney damage have been closely linked in adults, but little is still known in childhood., Objective: To identify predictors of kidney damage in children with metabolically healthy (MHO) and metabolically unhealthy (MUO) obesity phenotypes., Methods: We retrospectively examined 396 children with obesity (mean age 10.72 ± 2.71 years, body mass index-standard deviation score, BMI-SDS, 2.23 ± 0.57) stratified according to metabolic phenotypes. Kidney damage was defined as the presence of reduced estimated glomerular filtration rate (eGFR < 90 mL/min/1.73m2) and/or albuminuria (≥ 30 mg/g urinary creatinine)., Results: Kidney damage was found in 20.9% of the study population. Children with kidney damage had higher BMI-SDS, homeostasis model assessment of insulin resistance (HOMA-IR), and inflammation markers levels and increased prevalence of non-alcoholic fatty liver disease (NAFLD) than those without kidney damage (all p < 0.005). MUO and MHO subjects had respectively an odds ratio (OR) to show kidney damage of of 1.92 (95%CI:1.22-3.01; p = 0.005) and 1.05 (95%CI:1.00-1.09; p = 0.028) after adjustments. Moreover, we found that only HOMA-IR was closely associated to kidney damage in MUO group (OR = 2.07;95%CI:1.20-3.57; p = 0.007), while HOMA-IR (OR = 1.15;95%CI:1.02-1.29; p = 0.011) and uric acid (OR = 1.15;95% CI:1.02-1.30; p = 0.010) were the only significant risk factors for kidney damage in MHO group., Conclusion: An increased risk of kidney damage has been observed in children with obesity and in particular in those with MUO phenotype. As their role on kidney function, HOMA-IR should be monitored in MUO children and both HOMA-IR and uric acid in MHO children., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: Leptin plays a key role in the regulation of body weight and other endocrine systems. Recently, impairment of leptin gene transcription due to genetic variations in a long noncoding RNA (lncOb) has been described. This retrospective study aims to characterize the clinical and metabolic phenotype of children and adolescents with obesity who were homozygous for the lncOb rs10487505 leptin lowering allele., Methods: Enrolled children underwent an anthropometrical evaluation, biochemical assessment, and genotyping for lncOb rs10487505. Plasma leptin levels were assessed in 150 participants. A total of 434 patients were included and divided into two groups according to rs10487505 recessive inheritance (CC vs. GG/GC)., Results: Children who were homozygous for the C allele showed higher fasting insulin (p = 0.01), homeostasis model assessment of insulin resistance (p = 0.01), lower whole-body insulin sensitivity index (p = 0.02), and lower disposition index (p = 0.03). Moreover, CC patients presented with a higher prevalence of prediabetes (9.3% vs. 3.4%, p = 0.04) and a 2.9-fold (95% CI: 1.1-7.9, p = 0.04) higher risk of prediabetes compared with G-carriers independently from confounders. Leptin plasma levels were significantly lower in the CC group (p = 0.002). Hormone levels correlated with BMI z score (r = 0.19, p = 0.04), fasting insulin (r = -0.34, p < 0.0001), homeostasis model assessment of insulin resistance (r = -0.33, p < 0.0001), and disposition index (r = 0.20, p = 0.04)., Conclusions: The lncOb rs10487505 polymorphism affects leptin circulating levels, worsens insulin resistance, and heightens the risk of prediabetes in children and adolescents with obesity., (© 2023 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Childhood obesity and its related comorbidities have become major health issues over the last century. Among these comorbidities, cardiovascular diseases, especially hypertension, are the most significant. Recently, a polymorphism affecting the activity of lanosterol synthase has been associated with an increased risk of hypertension in adolescents. In this study, we aimed to investigate the effect of LSS rs2254524 polymorphism on blood pressure in children and adolescents with obesity. We enrolled 828 obese children aged 6-17 years. Subjects carrying the A allele showed higher rates of systolic and diastolic stage I hypertension and stage II hypertension. Carriers of the A allele showed a 2.4-fold (95% C.I. 1.5-4.7, p = 0.01) higher risk for stage II hypertension and a 1.9-fold higher risk for stage I hypertension (95% C.I. 1.4-2.6, p < 0.0001). The risk was independent of confounding factors. In conclusion, LSS rs2254524 worsens the cardiovascular health of children and adolescents with obesity, increasing their blood pressure.

We investigated prevalence of and factors associated with acute kidney injury (AKI) in a group of patients hospitalized with viral bronchiolitis. We retrospectively enrolled 139 children (mean age = 3.2 ± 2.1 months; males = 58.9%) hospitalized for viral bronchiolitis in a non-pediatric intensive care unit (PICU) setting. The Kidney Disease/Improving Global Outcomes creatinine criterion was used to diagnose AKI. We estimated basal serum creatinine by back-calculating it by Hoste (age) equation assuming that basal eGFR were the median age-based eGFR normative values. Univariate and multivariate logistic regression models were used to explore associations with AKI. Out of 139 patients, AKI was found in 15 (10.8%). AKI was found in 13 out of 74 (17.6%) patients with and in 2 out of 65 (3.1%) without respiratory syncytial virus (RSV) infection (p = 0.006). No patient required renal replacement therapies, while 1 out of 15 (6.7%) developed AKI stage 3, 1 (6.7%) developed AKI stage 2, and 13 (86.6%) developed AKI stage 1. Among the 15 patients with AKI, 13 (86.6%) reached the maximum AKI stage at admission, 1 (6.7%) at 48 h, and 1 (6.7%) at 96 h. At multivariate analysis, birth weight < 10th percentile (odds ratio, OR = 34.1; 95% confidence interval, CI = 3.6-329.4; p = 0.002), preterm birth (OR = 20.3; 95% CI = 3.1-129.5; p = 0.002), RSV infection (OR = 27.0; 95% CI = 2.6-279.9; p = 0.006), and hematocrit levels > 2 standard deviation score (SDS) (OR = 22.4; 95% CI = 2.8-183.6; p = 0.001) were significantly associated with AKI., Conclusion: About 11% of patients hospitalized with viral bronchiolitis in a non-PICU setting develop an AKI (frequently mild in degree). Preterm birth, birth weight < 10th percentile, hematocrit levels > 2SDS, and RSV infection are significantly associated with AKI in the setting of viral bronchiolitis., What Is Known: • Viral bronchiolitis affects children in the first months of life and in 7.5% of cases it can be complicated by acute kidney injury (AKI). • No studies investigated associations with AKI in infants hospitalized for viral bronchiolitis., What Is New: • About 11% of patients hospitalized with viral bronchiolitis can develop an AKI (frequently mild in degree). • Preterm birth, birth weight <10th percentile, hematocrit levels > 2 standard deviation score, and respiratory syncytial virus infection are associated with AKI development in infants with viral bronchiolitis., (© 2023. The Author(s).)

Objective: To evaluate (i) the prevalence and association of euthyroid sick syndrome (ESS) [decreased FT3 and/or FT4 and normal/decreased TSH] with severity indexes of type 1 diabetes mellitus (T1DM) onset such as diabetic ketoacidosis (DKA) and kidney damage [acute kidney injury (AKI) based on KDIGO criteria, acute tubular necrosis (ATN), renal tubular damage (RTD)], (ii) relationship between clinical/metabolic parameters at T1DM onset and thyroid hormones, and (iii) ESS as a prognostic indicator of delayed recovery from kidney damage., Methods: A total of 161 children with T1DM onset were included. RTD was defined by abnormal urinary beta-2-microglobulin and/or neutrophil gelatinase-associated lipocalin (NGAL) and/or tubular reabsorption of phosphate <85% and/or fractional excretion of Na>2%. ATN was defined by RTD+AKI., Results: Of 161 participants, 60 (37.3%) presented ESS. It was more prevalent in case of more severe T1DM presentation both in terms of metabolic derangement (DKA) and kidney function impairment (AKI, RTD and ATN). Only ATN, however, was associated with ESS at adjusted analysis. FT3 inversely correlated with serum triglycerides and creatinine, and urinary calcium/creatinine ratio and NGAL. Participants with euthyroidism showed earlier recovery from AKI than those with ESS. ESS spontaneously disappeared., Conclusions: ESS is associated with T1DM onset severity and spontaneously disappears. ESS delayed the recovery from AKI., Impact: This is the first longitudinal study describing in detail the relationship between clinical/metabolic factors at type 1 diabetes mellitus (T1DM) onset and thyroid hormones, with particular attention to the relationship between diabetic ketoacidosis (DKA)-related kidney function impairment and euthyroid sick syndrome (ESS). Participants with more severe T1DM onset presentation both in terms of metabolic derangement and kidney function impairment had an increased prevalence of ESS. Children with ESS had a slower recovery from acute kidney injury compared with those without ESS. ESS spontaneously disappeared in all participants., (© 2023. The Author(s).)

Introduction: Congenital anomalies of the kidney and urinary tract (CAKUT) can be associated with proteinuria, possibly leading to a decline in kidney function. The aim of this review is to evaluate evidence on the efficacy of renin-angiotensin-aldosterone system inhibitors (RAASi) in children affected by CAKUT with proteinuria or chronic kidney disease (CKD)., Areas Covered: We conducted a bibliographic search between 1 December 2022 and 20 February 2023, including randomized controlled trials, case-control studies, observational studies, meta-analyses, and systematic reviews dealing with the efficacy of RAASi in reducing proteinuria and slowing the decline of kidney function in children., Expert Opinion: RAASi are effective in reducing proteinuria and slowing CKD progression in many renal conditions; however, the efficacy of these drugs in patients affected by CAKUT with proteinuria is still unknown. While waiting for more evidence, when facing a child with CAKUT with isolated proteinuria or with proteinuria and CKD, a 6-12-month trial with RAASi with gradual increase to the maximal tolerated dose should be considered. If no improvement of proteinuria is obtained, the RAASi should be discontinued.

Introduction: As the pediatric obesity epidemic, nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in childhood. Pediatric NAFLD pathophysiology is tangled and still unclear, but insulin resistance (IR), genetics, epigenetics, oxidative stress, and inflammation act as key players. Due to the increased cardiometabolic risk of these patients, several biomarkers have been proposed for early NAFLD identification, but their clinical utility is poor. Recently, hepatic dysregulation of microRNAs (miRNAs) has been linked to metabolic dysfunction, which in turn implied in NAFLD development. Evidence on the intriguing role of miRNAs in NAFLD pathogenesis has emerging especially in at-risk children such as those with obesity. However, pediatric evidence supporting their potential use as early noninvasive NAFLD tools is still limited but promising., Areas Covered: We provided an overview on the emerging role of miRNAs in pediatric NAFLD by addressing some issues regarding their pathophysiological link with the metabolic milieu and their role as reliable NAFLD markers in children with obesity., Expert Opinion: Strong evidence supports a potential role of miRNAs as early biomarkers of NAFLD in children with obesity. They might represent a valid diagnostic and targeted therapeutic tool due to its close pathogenic link with the metabolic milieu.

This Position Statement updates the different components of the therapy of obesity (lifestyle intervention, drugs, and surgery) in children and adolescents, previously reported in the consensus position statement on pediatric obesity of the Italian Society of Pediatric Endocrinology and Diabetology and the Italian Society of Pediatrics. Lifestyle intervention is the first step of treatment. In children older than 12 years, pharmacotherapy is the second step, and bariatric surgery is the third one, in selected cases. Novelties are available in the field of the medical treatment of obesity. In particular, new drugs demonstrated their efficacy and safety and have been approved in adolescents. Moreover, several randomized control trials with other drugs are in process and it is likely that some of them will become available in the future. The increase of the portfolio of treatment options for obesity in children and adolescents is promising for a more effective treatment of this disorder., (© 2023. The Author(s).)

In youths, two cut-offs (133 and 155 mg/dL) have been proposed to identify high glucose levels at the 1 h (G 60 ) mark during an oral glucose tolerance test (OGTT). We evaluated which cut-off was more closely associated with isolated impaired glucose tolerance (IGT) and cardiometabolic risk (CMR) in 1199 youth with overweight/obesity (OW/OB) and normal fasting glucose and/or HbA1c. The disposition index (DI) was available in 724 youths. The sample was divided by two cut-offs of G 60 : <133 mg/dL (n = 853) and ≥133 mg/dL (n = 346), or G 60 < 155 mg/dL (n = 1050) and ≥155 mg/dL (n = 149). Independent of the cut-off, youths with high levels of G 60 showed higher levels of G 120 , insulin resistance (IR), triglycerides to HDL ratio (TG/HDL), alanine aminotransferase (ALT), and lower insulin sensitivity (IS) and DI than youths with lower levels of G 60 . The percentage of youths showing IGT, IR, low IS, high TG/HDL ratio, high ALT, and low DI was 50% higher in the G 60 ≥ 133 mg/dL group than in the G 60 ≥ 155 mg/dL one. In youths with OW/OB and IGT, a cut-off of G 60 ≥ 133 mg/dL is more useful than G 60 ≥ 155 mg/dL to identify those at high risk of IGT and altered CMR profile.

Background: We evaluated the diagnostic performance of height-, age- and body surface area (BSA)-based kidney length (KL) percentiles in the identification of at least one small kidney (KL < 3 rd ) and in the prediction of reduced estimated glomerular filtration rate (eGFR) and/or elevated blood pressure (BP) in children with and without overweight (OW)/obesity(OB)., Methods: In this cross-sectional study, 744 apparently healthy children (mean age 8.3 years) were recruited in a primary care setting. Clinical data were collected, and serum creatinine and KL were measured. Height-, age- and BSA-based percentiles of KL were calculated and the association of at least one small kidney per subject with reduced eGFR and/or elevated BP was explored by logistic regression., Results: Two hundred fifty-seven out of seven hundred forty-four (34.5%) subjects were OW/OB and 127 (17.1%) had reduced eGFR or elevated BP. In separate analyses in children with OW/OB, the KL percentiles calculated on the basis of BSA were lower compared with height- and age-based KL percentiles. Consequently, the prevalence of a small kidney was significantly higher when evaluating percentiles of KL based on BSA compared with other percentiles. In logistic regression analysis, a small kidney was significantly associated with reduced eGFR and/or elevated BP only when using height-based KL percentiles. The KL percentiles according to BSA for the ideal weight (iBSA) showed similar performance compared with height-based percentiles. No differences in the diagnostic performance of different percentiles were found in children with normal weight., Conclusions: BSA-based percentiles underestimate KL in children with OW/OB. In these subjects, the use of height-based or iBSA-based percentiles should be preferred. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2022. The Author(s).)

Children with type 1 diabetes mellitus (T1DM) have an increased risk of developing kidney involvement. Part of the risk establishes at the beginning of T1DM. In fact, up to 65% of children during T1DM onset may experience an acute kidney injury (AKI) which predisposes to the development of a later chronic kidney disease (CKD). The other part of the risk establishes during the following course of T1DM and could be related to a poor glycemic control and the subsequent development of diabetic kidney disease. In this review, we discuss the acute and chronic effects of T1DM on the kidneys, and the implications of these events on the long-term prognosis of kidney function., (© 2022. The Author(s).)

Lower urinary tract symptoms (LUTS) are a relevant problem in the pediatric population, having a very high prevalence. Diurnal incontinence and nocturnal enuresis are surely the most frequent symptoms, presenting, respectively, in up to 30% of school-age children and up to 10% of children between 6 and 7 years. Stypsis is the most common comorbidity, and it must be considered in the management of LUTS; indeed, the treatment of constipation is curative in most cases for both incontinence and enuresis. The presence or absence of diurnal symptoms in nocturnal enuresis and urgency in diurnal incontinence helps in the differential diagnosis. Urotherapy is always the first-line treatment, while oxybutynin and desmopressin (where appropriate) may help if the first-line treatment is unsuccessful. It is essential to identify conditions that are potentially dangerous for kidney and urinary tract well-being, for which LUTS can be the first manifestation. Starting from a series of clinical scenarios, we will underline the diagnostic clues behind LUTS in children and we will summarize clinical and surgical approaches for the proper management of these conditions.

Combination therapy (CT) (desmopressin plus oxybutynin) has been considered for the treatment of monosymptomatic nocturnal enuresis (MNE). We designed our study with the aim to evaluate the response rate to CT compared with desmopressin alone (primary outcome) and to identify factors associated with the response to CT (secondary outcome). We prospectively enrolled children with MNE with absent/partial response after 3 months of evening treatment with 240 mcg of desmopressin. We defined the response rate to CT compared with desmopressin alone according to the standardization of terminology document of the International Children's Continence Society: no-response, < 50% reduction; partial response, 50 to 99% reduction; and complete response, 100% reduction of wet nights. Both partial response and complete response to CT were clustered for the analyses of this manuscript. The enrolled children treated with 240 mcg/evening of desmopressin had also an additional evening administration of 0.3 mg/kg oxybutynin. A follow-up was scheduled at 3 and 6 months after the beginning of CT. At 3 months, oxybutynin dose was augmented to 0.5 mg/kg in case of absent/partial response to CT. Nocturnal diuresis was measured in 5 wet nights prior the beginning of therapy with desmopressin. Nocturnal polyuria (NP) was defined as nocturnal urine production > 130% of the expected bladder capacity. All patients with constipation were treated with macrogol. We enrolled 81 children (35.8% females) with a mean age of 8.4 ± 2.3 years. Seventy-eight patients completed the follow-up. After the CT, 59/78 (75.6%) patients showed an improvement of the response with CT compared with desmopressin alone. At multivariate analysis, both NP in more than 1 night (OR = 8.5; 95% CI, 1.4-51.6; p = 0.02) and absence of constipation (OR = 7.1; 95% CI, 1.6-31.0; p = 0.009) resulted significant after Bonferroni correction., Conclusions: CT determines an improvement of response compared to therapy with desmopressin alone in 75.6% of patients. Significant predictive factors of response to CT were presence of NP and absence of constipation., What Is Known: • Combination therapy (CT) (desmopressin plus anticholinergic drug) has been described as a therapeutic option for patients with monosymptomatic nocturnal enuresis (MNE) not responding to desmopressin alone as first-line treatment. • Variable protocols and variable combination of drugs have been described with a response rate ranging from 44 to 76%., What Is New: • We found that 59 patients (75.6%) treated with evening administration of 240 mcg of sublingual desmopressin plus 0.3-0.5 mg/kg of oxybutynin had an improvement of response compared to treatment with desmopressin alone. • We add evidence that presence of frequently recurring nocturnal polyuria and absence of constipation are predictors of response to CT., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Aim: Recently, the European Society of Cardiology task force released a Consensus document (ESC-CD) on pediatric hypertension (HTN) supporting the use of normative tables (age range 6-16 years) for the diagnosis of HTN, while the Hypertension Canada Guidelines (HTN-CGs) proposed static cutoffs. We aimed to assess the prevalence of HTN by ESC-CD or HTN-CGs and their association with glomerular function and left ventricular (LV) geometry in youths with overweight/obesity (OW/OB)., Methods and Results: Data of 3446 youths were analyzed. HTN by was defined using normative tables (ESC-CD) or static cutoffs of BP ≥ 120/80 in children (age <12 years) and ≥130/85 mmHg in adolescents (age ≥12 years) (HTN-CGs). Mildly reduced glomerular filtration rate was defined by GFR <90 ≥ 60 mL/min/1.73 m 2 . Concentric LV hypertrophy (cLVH) was assessed in 500 youths and defined by LVH and high relative wall thickness as proposed by ESC-CD. Prevalence of HTN was 27.9% by ESC-CD and 22.7% by HTN-CGs. The association with mildly reduced glomerular filtration rate was significant only in hypertensive adolescents classified by HTN-CGs [Odds Ratio (OR), 95%Cl] 2.16 (1.44-3.24), whereas the association with cLVH was significant using both criteria: children OR 2.18 (1.29-3.67) by ESC-CD and 2.27 (1.32-3.89) by HTN-CGs; adolescents OR 2.62 (1.17-5.84) by ESC-CD and 2.83 (1.14-7.02) by HTN-CGs., Conclusion: Although static cutoffs may represent a simplification for HTN identification, tables by ESC-CD detect a higher number of hypertensive youths before a clear appearance of glomerular impairment, which offers advantages in terms of primary cardiovascular prevention., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2023 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: The main purpose of the study is to assess the association between obstructive sleep apnea (OSA) and insulin secretion in children with obesity., Methods: We enrolled children and adolescents who attended our pediatric clinic because of obesity and OSA. Glucose homeostasis was assessed through standard 2-h oral glucose tolerance test (OGTT). Nocturnal cardio-respiratory polygraphy was performed for OSA diagnosis. Twenty-two patients underwent a 3-h OGTT to investigate insulin secretion and sensitivity through the oral-minimal model., Results: seventy-seven children and adolescents were included in the study. Based on OSA severity, the cohort was divided into three groups (29 mild, 29 moderate, and 19 severe OSA). The group with mild OSA showed lower levels of 30-min glucose (p = 0.01) and 60-min glucose (p = 0.03), and lower prevalence of elevated 1-h glucose (10.4% versus 44.8% in moderate and 31.6% in severe OSA, p = 0.01). The odds for elevated 1-h plasma glucose was 6.2-fold (95%CI 1.6-23.4) higher in subjects with moderate and severe OSA compared to mild OSA (p = 0.007) independent of confounders. Spearman correlation test revealed a positive correlation between 30-min plasma glucose and apnea-hypopnea index (AHI, r = 0.31, p = 0.01), oxygen desaturation index (ODI, r = 0.31, p = 0.009), and mean desaturation (r = 0.25, p = 0.04). The 3-h OGTT study included 22 participants (7 mild, 9 moderate, and 6 severe OSA). The group with mild OSA showed a higher dynamic, static, and total insulin secretion compared to those with moderate and severe OSA (p < 0.0001, p = 0.007, p = 0.007, respectively). AHI was significantly correlated to dynamic insulin secretion (r = -0.48, p = 0.02)., Conclusions: OSA might impair beta-cell function reducing the pool of promptly releasable insulin in children and adolescents with obesity, in the absence of an effect on insulin sensitivity., (© 2023. The Author(s).)

Background: Thyroid hormones (TH) play multiple effects on glucose metabolism. Some recent studies carried out in adult patients suggested an association between altered sensitivity to TH and type 2 diabetes, obesity, and metabolic syndrome. No studies are currently available on the presence of altered sensitivity to the action of TH in youths with prediabetes., Objective: To evaluate the relationship between sensitivity to TH and impaired glucose tolerance (IGT), impaired fasting glucose (IFG), or glycosylated hemoglobin (HbA1c) ≥ 5.7% in youths with overweight/obesity (OW/OB)., Materials and Methods: This cross-sectional study included 805 Caucasian youths with OW or OB (aged 6-18 years) recruited at seven Italian centers for the care of OW/OB. Individuals with TH out of the normal range of TH in each center were excluded. The fT3/fT4 ratio was evaluated to assess peripheral sensitivity, while TSH index (TSHI), Thyrotroph T4 Resistance Index (TT4RI), Thyroid Feedback Quantile-based Index (TFQI) and Parametric TFQI were calculated to assess central sensitivity., Results: Youths with IGT (n =72) showed higher levels of TSH (3.08 ± 0.98 vs 2.68 ± 0.98 mIU/L, P =0.001), TSHI (3.06 ± 0.51 vs 2.85 ± 0.53, P =0.001), TT4RI (46.00 ± 17.87 vs 38.65 ± 16.27, P <0.0001), TFQI [1.00 (0.97-1.00) vs 1.00 (0.99-1.00)], P=0.034), PTFQI (0.67 ± 0.20 vs 0.60 ± 0.22, P =0.007) compared to youths without IGT (n =733), independently of centers and age. No differences were observed for fT3/fT4-ratio. The others phenotypes of prediabetes were not associated with altered sensitivity to TH. Odds ratio of IGT raised of 1-7-fold for each increase of 1 mIU/L in TSH (P =0.010), 1 unit in TSH Index (P =0.004), TT4RI (P =0.003) or PTFQI (P =0.018), independently of centers, age, and prepubertal stage., Conclusion: IGT was associated with a reduced central sensitivity to TH in youths with OW/OB. Our finding suggests that IGT phenotype, known to be associated with an altered cardiometabolic risk profile, might also be associated with an impaired TH homeostasis in youths with OW/OB., 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 © 2023 Di Bonito, Corica, Licenziati, Di Sessa, Miraglia del Giudice, Faienza, Calcaterra, Franco, Maltoni, Valerio and Wasniewska.)

Background: Both direct and indirect effects of COVID-19 have been found in all age groups. In particular, adult data demonstrated significant changes in patients with chronic and metabolic disease (e.g., obesity, diabetes, chronic kidney disease (CKD), and metabolic associated fatty liver dysfunction (MAFLD)), while similar pediatric evidence is still limited. We aimed at investigating the impact of the COVID-19 pandemic lockdown on the relationship between MAFLD and renal function in children with CKD due to congenital abnormalities of the kidney and urinary tract (CAKUT)., Methods: A total of 21 children with CAKUT and CKD ≥ stage 1 underwent a comprehensive evaluation within 3 months before and 6 months after the first Italian lockdown., Results: At follow-up, CKD patients with MAFLD presented higher BMI-SDS, serum uric acid, triglycerides, and microalbuminuria levels and lower eGFR levels than those without MAFLD (all p < 0.05). Higher ferritin and white blood cell concentrations were also found in patients with CKD diagnosed with MAFLD than peers without MAFLD (both p = 0.01). Compared to children without MAFLD, a higher delta of BMI-SDS, eGFR levels, and microalbuminuria levels was found in patients with MAFLD., Conclusions: Due to the negative influence of the COVID-19 lockdown on cardiometabolic health in childhood, a careful management of children with CKD is warranted.