Clinical implications of primary "occult" vesicoureteral reflux in male children.

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.

Acute kidney injury in children hospitalised for febrile urinary tract infection.

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.

Interplay between metabolic dysfunction-associated fatty liver disease and renal function: An intriguing pediatric perspective.

Over recent years, the nomenclature of non-alcoholic fatty liver disease has undergone significant changes. Indeed, in 2020, an expert consensus panel proposed the term "Metabolic (dysfunction) associated fatty liver disease" (MAFLD) to underscore the close association of fatty liver with metabolic abnormalities, thereby highlighting the cardiometabolic risks (such as metabolic syndrome, type 2 diabetes, insulin resistance, and cardiovascular disease) faced by these patients since childhood. More recently, this term has been further replaced with metabolic associated steatotic liver disease. It is worth noting that emerging evidence not only supports a close and independent association of MAFLD with chronic kidney disease in adults but also indicates its interplay with metabolic impairments. However, comparable pediatric data remain limited. Given the progressive and chronic nature of both diseases and their prognostic cardiometabolic implications, this editorial aims to provide a pediatric perspective on the intriguing relationship between MAFLD and renal function in childhood.

Unusual position of pilonidal sinus in children may explain its malformative etiology: Case report and review of the literature.

INTRODUCTION: Pilonidal sinus is a condition that causes inflammation and abscesses in the sacral region and affects adolescents and young adults. The etiology of this condition remains controversial. CASE PRESENTATION: A six year old boy was observed to have an orifice in the frontonasal region which contained hair. He had two previous infections which were treated with antibiotics. Magnetic Resonance Imaging showed no cranial malformations. Surgery was performed under general anesthesia and the pilonidal sinus was completely excised. At follow-up the child was in good health. CLINICAL DISCUSSION: This case in a child with a frontonasal skin anomaly highlights that skin anomalies may be a cause of pilonidal sinus. CONCLUSION: Skin malformations can be the underlying cause of pilonidal sinus in some cases.

Primary non-refluxing megaureter: Natural history, follow-up and treatment.

Primary non-refluxing megaureter (PMU) is a congenital dilation of the ureter which is not related to vesicoureteral reflux, duplicated collecting systems, ureterocele, ectopic ureter, or posterior urethral valves and accounts for 5 to 10% of all prenatal hydronephrosis (HN) cases. The etiology is a dysfunction or stenosis of the distal ureter. Most often PMU remains asymptomatic with spontaneous resolution allowing for non-operative management. Nevertheless, in selective cases such as the development of febrile urinary tract infections, worsening of the ureteral dilatation, or reduction in relative renal function, surgery should be considered. CONCLUSION: Ureteral replantation with excision of the dysfunctional ureteral segment and often ureteral tapering is the gold-standard procedure for PMU, although endoscopic treatment has been shown to have a fair success rate in many studies. In this review, we discuss the natural history, follow-up, and treatment of PMU. WHAT IS KNOWN: • PMU is the result of an atonic or stenotic segment of the distal ureter, resulting in congenital dilation of the ureter, and is frequently diagnosed on routine antenatal ultrasound. WHAT IS NEW: • Most often, PMU remains asymptomatic and clinically stable, allowing for non-operative management. • Nevertheless, since symptoms can appear even after years of observation, long-term ultrasound follow-up is recommended, even up to young adulthood, if hydroureteronephrosis persists. • Ureteral replantation is the gold standard in case surgery is needed. In selected cases, however, HPBD could be a reasonable alternative.

Editorial on the Special Issue "Advances in Pediatric Acute Kidney Injury".

Acute kidney injury (AKI) refers to a swift decline in kidney function, marked by the reduced excretion of waste products and disturbances in fluid and electrolyte balance [...].

The dual role of body mass index on Juvenile Idiopathic Arthritis course: a pediatric experience.

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.

Indirect signs of infravesical obstruction on voiding cystourethrography improve post-neonatal posterior urethral valves detection rate.

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.

Failure to thrive in children with tubulopathies increases the risk of overweight later in life.

Failure to thrive (FTT) is an inadequate growth in young children. It can increase the risk of overweight or obesity later in life. Patients with renal tubulopathies can present FTT due to solute losses in the urine. We aimed to test our hypothesis that children with tubulopathies have an increased risk of overweight and obesity due to rebound following FTT that could complicate these conditions. We enrolled 26 patients with tubulopathies and evaluated for the first time within the first 12 months of life (mean age: 4.8 months ± 2.6 SDS). FTT was evident in 17 out of 26 patients (65.4%). The mean age at the last follow-up was 14.1 years ± 5.5 SDS. The mean age at overweight/obesity onset was 9.0 years ± 3.6 SDS. The prevalence of overweight/obesity was 73.1% (19/26). Among the patients with FTT, 15 (88.2%) developed overweight/obesity compared to 4 out of the 9 patients (44.4%) without FFT (p = 0.028). The presence of FTT determined an OR for obesity/overweight of 9.4 (95% CI: 1.3-67.6; p = 0.026). FTT continued to be significantly associated with obesity/overweight also after adjustment for preterm birth and birth weight <10th percentile (OR = 23.3; 95% CI: 1.95-279.4; p = 0.01). In conclusion, in our series, patients with tubulopathies presented an increased risk of overweight/obesity due to the FTT that can complicate these conditions.

A Multicenter ICET-A Study on Age at Menarche and Menstrual Cycles in Patients with Transfusion-Dependent Thalassemia (TDT) who Started Early Chelation Therapy with Different Chelating Agents.

Introduction: To evaluate the effect of early chelation therapy (≤ 3 years) with a variety of chelating agents on age at menarche and menstrual characteristics in patients with transfusion-dependent thalassemia (TDT). Design: A retrospective multicenter study promoted by the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A). Setting: Eight of 13 International Thalassemia Centers (61.5%) in the ICET-A Network participated. Patients: Fifty-seven female TDT patients, aged 11 to 26 years, and with early iron chelation therapy, were eligible for the present study. They were enrolled from one center from Iran (33 patients), 3 centers from Bulgaria (9), 1 from Greece (8), one from Oman (4), 1 from Cyprus (2), and 1 from Italy (1). Seven patients were excluded, four still prepubertal (age 12-14 years) and 3 with primary amenorrhea. Therefore 50 patients were finally enrolled. Results: All fifty TDT patients developed spontaneous menarche at a mean age of 14.2 ± 2.24 years (range 9 - 20). A significant positive correlation was observed between age at menarche and serum ferritin levels (r: 0. 41, p=0.005). Regular menstrual cycles were reported from 32 (64%) patients, of whom 28 (83.3%) get menarche at age ≤ 14 years. Complications were more frequent in patients older than 14 years at menarche and in those with secondary amenorrhea. Conclusions: Age at menarche greater than 14 years was a forerunner of menstrual irregularities and associated complications in 36% of patients despite precocious chelation therapy. The poor adherence to treatment, to be demonstrated in future studies, could explain the finding.

Sensitivity to thyroid hormones and reduced glomerular filtration in children and adolescents with overweight or obesity.

BACKGROUND: Reduced central sensitivity to thyroid hormones (TH) has been observed in euthyroid adults with reduced renal function. This topic is unexplored in young people with overweight or obesity (OW/OB). OBJECTIVE: To evaluate the association between sensitivity to TH and mild reduced estimated glomerular filtration rate (MReGFR) in euthyroid children and adolescents with OW/OB. METHODS: Data of 788 euthyroid children and adolescents with OW/OB (aged 6-16 years), recruited from seven Italian centers for the care of OW/OB, were evaluated. Peripheral sensitivity to TH was estimated through the FT3/FT4 ratio, while central sensitivity was assessed by estimating TSH index (TSHI), Thyrotroph T4 Resistance Index (TT4RI), Thyroid Feedback Quantile-based Index (TFQI), Parametric Thyroid Feedback Quantile-based Index (PTFQI). MReGFR was defined by an eGFR value ≥60 and ≤90 mL/min/1.73 m2. RESULTS: Subjects with MReGFR had significantly lower levels of FT3/FT4 ratio (0.43±0.09 vs 0.44±0.10; p=0.028) and higher levels of TSH (2.89±1.00 vs 2.68±0.99; p=0.019), TSH Index (2.95±0.45 vs 2.85±0.55; p=0.031), TFQI [1.00 (0.98-1.00) vs 1.00 (0.97-1.00); p=0.046] and PTFQI (0.66±0.17 vs 0.60±0.23; p=0.006) compared with individuals with normal eGFR. Odds ratio of MReGFR raised of 1.2-3.2-fold for each increase of 1 mIU/L in TSH, 1 unit in TSHI, and PTFQI, but not for FT3/FT4 ratio. CONCLUSION: MReGFR is associated with reduced indices of central sensitivity to TH in euthyroid children and adolescents with OW/OB. This preliminary observation should be confirmed in prospective studies.

The diagnostic and therapeutic challenge of atrial flutter in children: a case report.

BACKGROUND: Palpitations represent a common cause for consultation in the pediatric Emergency Department (ED). Unlike adults, palpitations in children are less frequently dependent from the heart, recognizing other causes. CASE PRESENTATION: A 11-year-old male came to our pediatric ED for epigastric pain, vomiting and palpitations. During the previous 6 month the patient was affected by SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus). Electrocardiogram (ECG) revealed supraventricular tachycardia. Therefore, adenosine was administered unsuccessfully. The administration of adenosine, however, allowed us to make diagnosis of atypical atrial flutter. Multiple attempts at both electrical cardioversion, transesophageal atrial overdrive, and drug monotherapy were unsuccessful in our patient. Consequently, a triple therapy with amiodarone, flecainide, and beta-blocker was gradually designed to control the arrhythmic pattern with the restoration of a left upper atrial rhythm. There was not any evidence of sinus rhythm in the patient clinical history. CONCLUSIONS: The present study underlines the rarity of this type of dysrhythmia in childhood and the difficulties in diagnosis and management, above all in a patient who has never showed sinus rhythm. Raising awareness of all available treatment options is essential for a better management of dysrhythmia in children.

Antibiotic Prophylaxis in Infants with Grade III, IV, or V Vesicoureteral Reflux.

BACKGROUND: The efficacy of continuous antibiotic prophylaxis in preventing urinary tract infection (UTI) in infants with grade III, IV, or V vesicoureteral reflux is controversial. METHODS: In this investigator-initiated, randomized, open-label trial performed in 39 European centers, we randomly assigned infants 1 to 5 months of age with grade III, IV, or V vesicoureteral reflux and no previous UTIs to receive continuous antibiotic prophylaxis (prophylaxis group) or no treatment (untreated group) for 24 months. The primary outcome was the occurrence of the first UTI during the trial period. Secondary outcomes included new kidney scarring and the estimated glomerular filtration rate (GFR) at 24 months. RESULTS: A total of 292 participants underwent randomization (146 per group). Approximately 75% of the participants were male; the median age was 3 months, and 235 participants (80.5%) had grade IV or V vesicoureteral reflux. In the intention-to-treat analysis, a first UTI occurred in 31 participants (21.2%) in the prophylaxis group and in 52 participants (35.6%) in the untreated group (hazard ratio, 0.55; 95% confidence interval [CI], 0.35 to 0.86; P = 0.008); the number needed to treat for 2 years to prevent one UTI was 7 children (95% CI, 4 to 29). Among untreated participants, 64.4% had no UTI during the trial. The incidence of new kidney scars and the estimated GFR at 24 months did not differ substantially between the two groups. Pseudomonas species, other non-Escherichia coli organisms, and antibiotic resistance were more common in UTI isolates obtained from participants in the prophylaxis group than in isolates obtained from those in the untreated group. Serious adverse events were similar in the two groups. CONCLUSIONS: In infants with grade III, IV, or V vesicoureteral reflux and no previous UTIs, continuous antibiotic prophylaxis provided a small but significant benefit in preventing a first UTI despite an increased occurrence of non-E. coli organisms and antibiotic resistance. (Funded by the Italian Ministry of Health and others; PREDICT ClinicalTrials.gov number, NCT02021006; EudraCT number, 2013-000309-21.).

Kidney damage predictors in children with metabolically healthy and metabolically unhealthy obesity phenotype.

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.

LSS rs2254524 Increases the Risk of Hypertension in Children and Adolescents with Obesity.

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.

Renin angiotensin aldosterone inhibitors in the treatment of proteinuria in children with congenital anomalies of the kidney and urinary tract: more evidence needed.

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.