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.).

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.

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.

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.

Basal knowledge in the field of pediatric nephrology and its enhancement following specific training of ChatGPT-4 "omni" and Gemini 1.5 Flash.

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.

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.

Heart rate to identify non-febrile children with dehydration and acute kidney injury in emergency department: a prospective validation study.

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.

Kidney function evaluation in children and adolescents with obesity: a not-negligible need.

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.

Prevalence of and factors associated with Na + /K + imbalances in a population of children hospitalized with febrile urinary tract infection.

We aimed to assess the prevalence of and factors associated with Na + /K + imbalances in children hospitalized for febrile urinary tract infection (fUTI). This retrospective Italian multicenter study included children aged 18 years or younger (median age = 0.5 years) who were discharged with a primary diagnosis of fUTI. Na + /K + imbalances were classified as hyponatremia (sodium < 135 mEq/L), hypernatremia (sodium > 145 mEq/L), hypokalemia (potassium < 3.5 mEq/L), hyperkalemia (potassium > 5.5 mEq/L), and concurrent hyponatremia and hyperkalemia, in the absence of evidence of hemolyzed blood samples. Among the 849 enrolled children, 23% had hyponatremia, 6.4% had hyperkalemia, 2.9% had concurrent hyponatremia and hyperkalemia, 0.7% had hypokalemia, and 0.4% had hypernatremia. In the multiple logistic regression analysis, after applying the Bonferroni correction, only C-reactive protein (C-RP) levels were significantly associated with hyponatremia (OR = 1.04; 95% CI: 1.02-1.06; p < 0.001), only age was significantly associated with hyperkalemia (OR = 1.7; 95% CI: 1.1-2.7; p = 0.01), and only CAKUT was significantly associated with concurrent hyponatremia and hyperkalemia (OR = 4.3; 95% CI: 1.7-10.8; p = 0.002). Even after adjusting for the presence of kidney hypoplasia, abnormal renal echogenicity, pelvi-caliceal dilation, ureteral dilation, uroepithelial thickening of the renal pelvis, bladder abnormalities, pathogen other than E. coli, concurrent hyponatremia and hyperkalemia persisted significantly associated with CAKUT (OR = 3.6; 95% CI: 1.2-10.9; p = 0.02). CONCLUSION: Hyponatremia was the most common Na + /K + imbalance in children hospitalized for fUTI, followed by hyperkalemia and concurrent hyponatremia and hyperkalemia. C-RP levels were most strongly associated with hyponatremia, age with hyperkalemia, and CAKUT with concurrent hyponatremia and hyperkalemia (suggestive of transient secondary pseudo-hypoaldosteronism). Therefore, in children who develop concurrent hyponatremia and hyperkalemia during the course of a fUTI, an underlying CAKUT could be suspected. WHAT IS KNOWN: • Na+ and K+ abnormalities can occur in patients hospitalized for febrile urinary tract infection (fUTI). • Concurrent hyponatremia and hyperkalemia during fUTI may suggest transient secondary pseudo-hypoaldosteronism (TPHA), for which limited data on prevalence are available. WHAT IS NEW: • The most common Na+/K+ imbalance in children hospitalized with fUTI was hyponatremia (23%), followed by hyperkalemia (6.4%), concurrent hyponatremia and hyperkalemia (2.9%), hypokalemia (0.7%), and hypernatremia (0.4%). • Concurrent hyponatremia and hyperkalemia were mainly associated with CAKUT, while hyponatremia alone correlated with high C-reactive protein and hyperkalemia alone with younger age. In cases of concurrent hyponatremia and hyperkalemia during fUTI, an underlying CAKUT should be suspected.

Prevalence and determinants of failure to thrive in children with vesico-ureteral reflux.

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.

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.

Rare Single Nucleotide and Copy Number Variants and the Etiology of Congenital Obstructive Uropathy: Implications for Genetic Diagnosis.

SIGNIFICANCE STATEMENT: Congenital obstructive uropathy (COU) is a prevalent human developmental defect with highly heterogeneous clinical presentations and outcomes. Genetics may refine diagnosis, prognosis, and treatment, but the genomic architecture of COU is largely unknown. Comprehensive genomic screening study of 733 cases with three distinct COU subphenotypes revealed disease etiology in 10.0% of them. We detected no significant differences in the overall diagnostic yield among COU subphenotypes, with characteristic variable expressivity of several mutant genes. Our findings therefore may legitimize a genetic first diagnostic approach for COU, especially when burdening clinical and imaging characterization is not complete or available. BACKGROUND: Congenital obstructive uropathy (COU) is a common cause of developmental defects of the urinary tract, with heterogeneous clinical presentation and outcome. Genetic analysis has the potential to elucidate the underlying diagnosis and help risk stratification. METHODS: We performed a comprehensive genomic screen of 733 independent COU cases, which consisted of individuals with ureteropelvic junction obstruction ( n =321), ureterovesical junction obstruction/congenital megaureter ( n =178), and COU not otherwise specified (COU-NOS; n =234). RESULTS: We identified pathogenic single nucleotide variants (SNVs) in 53 (7.2%) cases and genomic disorders (GDs) in 23 (3.1%) cases. We detected no significant differences in the overall diagnostic yield between COU sub-phenotypes, and pathogenic SNVs in several genes were associated to any of the three categories. Hence, although COU may appear phenotypically heterogeneous, COU phenotypes are likely to share common molecular bases. On the other hand, mutations in TNXB were more often identified in COU-NOS cases, demonstrating the diagnostic challenge in discriminating COU from hydronephrosis secondary to vesicoureteral reflux, particularly when diagnostic imaging is incomplete. Pathogenic SNVs in only six genes were found in more than one individual, supporting high genetic heterogeneity. Finally, convergence between data on SNVs and GDs suggest MYH11 as a dosage-sensitive gene possibly correlating with severity of COU. CONCLUSIONS: We established a genomic diagnosis in 10.0% of COU individuals. The findings underscore the urgent need to identify novel genetic susceptibility factors to COU to better define the natural history of the remaining 90% of cases without a molecular diagnosis.

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.

Euthyroid sick syndrome and its association with complications of type 1 diabetes mellitus onset.

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.

Body surface area-based kidney length percentiles misdiagnose small kidneys in children with overweight/obesity.

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 < 3rd) 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.

Combination therapy (desmopressin plus oxybutynin) improves the response rate compared with desmopressin alone in patients with monosymptomatic nocturnal enuresis and nocturnal polyuria and absence of constipation predict the response to this treatment.

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.

Acute kidney injury in infants hospitalized for viral bronchiolitis.

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.

Uric acid could be a marker of cardiometabolic risk and disease severity in children with juvenile idiopathic arthritis.

In addition to disease-specific complications, juvenile idiopathic arthritis (JIA) has been linked to metabolic impairments in adults. Recent data supported the usefulness of uric acid (UA) as risk factor for cardiometabolic derangements. Given the lack of pediatric evidence in this field, we aimed to explore this association in a cohort of children diagnosed with JIA. We retrospectively evaluated 113 children diagnosed with JIA classified according to the International League of Association for Rheumatology (ILAR) criteria attending our Rheumatology Clinic. Both clinical and biochemical assessments were performed. Participants were stratified in four groups according to quartiles of serum UA. Disease activity was calculated by the Juvenile Arthritis Disease Activity Score 10 (JADAS-10) joint reduced count, and cut-offs for disease states were applied. Patients belonging to the highest UA quartile showed higher serum triglycerides, total cholesterol, creatinine, and glucose levels (p = 0.01, p = 0.025, p = 0.04, and p = 0.005, respectively) and lower HDL cholesterol values (p < 0.0001) than subjects belonging to the lowest quartiles. Ferritin, erythrocyte sedimentation rate levels, and age at disease onset did not significantly differ across UA quartiles (all p > 0.05). As activity disease index, JADAS-10 score significantly increased across UA quartiles (p = 0.009). CONCLUSION: Children with JIA presented with a worse cardiometabolic profile and a greater disease severity across UA quartiles. Our findings suggest that in clinical practice, UA might represent a useful marker of cardiometabolic risk and disease severity in children with JIA. WHAT IS KNOWN: • JIA has been linked to metabolic derangements in adulthood. • UA has been recognized as a marker of cardiometabolic risk both in adults and children. WHAT IS NEW: • Children with JIA belonging to the highest UA quartile showed a worse cardiometabolic profile and a greater disease severity. • UA might represent a helpful marker not only of cardiometabolic risk but also of disease severity in children with JIA.

Evolution of congenital anomalies of urinary tract in children with and without solitary kidney.

BACKGROUND: We hypothesized that children with congenital solitary functioning kidney (CSFK) present forms of congenital urinary tract anomalies (CUTA) with higher chance of spontaneous resolution compared with patients with two kidneys. METHODS: We retrospectively selected 75 consecutive children with CUTA of the CSFK and 75 matched patients with unilateral CUTA but without CSFK (controls) with prenatal suspicion of unilateral CUTA and early evaluation. We compared the spontaneous CUTA resolution and the prevalence of kidney injury between groups at last follow-up. Patients and controls were clustered under the categories of "severe" and "non-severe" CUTA. RESULTS: The mean age at first and last follow-up was 0.17 ± 0.07 and 8.5 ± 5.2 years. Compared with controls, patients with CSFK had lower prevalence of severe CUTA at first evaluation; lower prevalence of febrile urinary tract infections, need of surgical correction, and higher rate of spontaneous CUTA resolution during follow-up; and a similar prevalence of mild kidney injury at last follow-up. CSFK compared with controls presented higher cumulative proportion of spontaneous resolution from severe CUTA (100 vs 41.8%; p < 0.001) and from the single CUTA sub-categories (severe vesicoureteral reflux, non-obstructive hydronephrosis, and megaureter). CONCLUSIONS: CSFK patients had lower prevalence of severe forms and better outcomes of their CUTA compared with controls. IMPACT: One-third of patients with congenital solitary functioning kidney (CSFK) present congenital urinary tract anomalies (CUTA) and manifest poorer outcomes compared with CSFK without CUTA. CSFK patients had lower prevalence of severe forms and better outcomes of their CUTA in spite of similar prevalence of kidney injury compared with controls. This adds evidence about disturbed nephrogenesis in CSFK patients and emboldens conservative management of many of their non-obstructive CUTA.

Parathyroid hormone and phosphate homeostasis in patients with Bartter and Gitelman syndrome: an international cross-sectional study.

BACKGROUND: Small cohort studies have reported high parathyroid hormone (PTH) levels in patients with Bartter syndrome and lower serum phosphate levels have anecdotally been reported in patients with Gitelman syndrome. In this cross-sectional study, we assessed PTH and phosphate homeostasis in a large cohort of patients with salt-losing tubulopathies. METHODS: Clinical and laboratory data of 589 patients with Bartter and Gitelman syndrome were provided by members of the European Rare Kidney Diseases Reference Network (ERKNet) and the European Society for Paediatric Nephrology (ESPN). RESULTS: A total of 285 patients with Bartter syndrome and 304 patients with Gitelman syndrome were included for analysis. Patients with Bartter syndrome type I and II had the highest median PTH level (7.5 pmol/L) and 56% had hyperparathyroidism (PTH >7.0 pmol/L). Serum calcium was slightly lower in Bartter syndrome type I and II patients with hyperparathyroidism (2.42 versus 2.49 mmol/L; P = .038) compared to those with normal PTH levels and correlated inversely with PTH (rs -0.253; P = .009). Serum phosphate and urinary phosphate excretion did not correlate with PTH. Overall, 22% of patients had low serum phosphate levels (phosphate-standard deviation score < -2), with the highest prevalence in patients with Bartter syndrome type III (32%). Serum phosphate correlated with tubular maximum reabsorption of phosphate/glomerular filtration rate (TmP/GFR) (rs 0.699; P < .001), suggesting renal phosphate wasting. CONCLUSIONS: Hyperparathyroidism is frequent in patients with Bartter syndrome type I and II. Low serum phosphate is observed in a significant number of patients with Bartter and Gitelman syndrome and appears associated with renal phosphate wasting.