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Endothelial cell injury is a hallmark of IgA vasculitis (IgAV), possibly associated with various factors, including oxidative stress. Certain single nucleotide polymorphisms (SNPs) of glutathione S-transferases ( GST ) genes have been shown to increase susceptibility to oxidative stress. The objective of our study was to evaluate the gene polymorphisms of GSTM1 , GSTT1, GSTP1 , and GSTA1 in patients with IgAV. DNA was extracted from the blood of 124 children with IgAV and 168 age-matched healthy controls. A higher frequency of the GSTM1 null genotype was observed in patients with gastrointestinal (GI) system involvement compared to those without GI system involvement (51.5% vs. 28.6%, p = 0.011). Additionally, the GSTM1 null genotype was less prevalent (30.8% vs. 69.2%, p = 0.032), while the GSTP1 Val/Val genotype was significantly more prevalent in patients who developed urogenital complications (scrotal swelling) during the course of the disease (60% vs. 40%, p = 0.039). This study is the first to suggest an association between GSTM1 and GSTP1 polymorphisms and various phenotypes observed during the clinical course of IgAV in the pediatric population. However, it was performed on a national and likely single ethnic cohort, too small for definitive conclusions, so larger studies are needed to confirm this association.

The pathogenesis of IgAV, the most common systemic vasculitis in childhood, appears to be complex and requires further elucidation. We aimed to investigate the potential role of galactose-deficient immunoglobulin A1 (Gd-IgA1), high-mobility group box 1 (HMGB1), receptor for advanced glycation end products (RAGE) and protocadherin 1 (PCDH1) in the pathogenesis of IgAV. Our prospective study enrolled 86 patients with IgAV and 70 controls. HMGB1, RAGE, Gd-IgA1 and PCDH1 in serum and urine were determined by the enzyme-linked immunosorbent assay (ELISA) method at the onset of the disease and after a six-month interval in patients and once in the control group. Serum concentrations of HMGB1, RAGE and PCDH1 and urinary concentrations of HMGB1, RAGE, Gd-IgA1 and PCDH1 were significantly higher in patients with IgAV than in the control group ( p < 0.001). Concentrations of HMGB1 (5573 pg/mL vs. 3477 pg/mL vs. 1088 pg/mL, p < 0.001) and RAGE (309 pg/mL vs. 302.4 pg/mL vs. 201.3 pg/mL, p = 0.012) in the serum of patients remained significantly elevated when the disease onset was compared with the six-month follow-up interval, and thus could be a potential marker of disease activity. Urinary concentration of HMGB1 measured in the follow-up period was higher in patients with nephritis compared to IgAV without nephritis (270.9 (146.7-542.7) ng/mmol vs. 133.2 (85.9-318.6) ng/mmol, p = 0.049) and significantly positively correlated with the urine albumine to creatinine ratio (τ = 0.184, p < 0.05), the number of erythrocytes in urine samples (τ = 0.193, p < 0.05) and with the outcome of nephritis (τ = 0.287, p < 0.05); therefore, HMGB1 could be a potential tool for monitoring patients with IgAV who develop nephritis. Taken together, our results imply a possible interplay of Gd-IgA1, HMGB1, RAGE and PCDH1 in the development of IgAV. The identification of sensitive biomarkers in IgAV may provide disease prevention and future therapeutics.

Introduction: This cross-sectional study enrolled a group of 271 children with microcytic anemia in order to test the performance of 41 single and 2 composite formulas andindices in distinguishing between β-thalassemia (β-thal) and iron deficiency anemia (IDA) in the pediatric population., Methods: Optimal pediatric cut-off values from the previously published formulas and indices were generated using ROC analysis. Logistic regression in R using generalized linear models (GLM) generated two new indices., Results: Formulas and indices with optimal cut-offvalues in children with accuracy ≥90% were (in descending order): Matos & Carvalho index, MDHL(Telmissani) formula, England and Fraser formula, Pornprasert index, Sirachainan index, Telmissani (MCHD) formula, CRUISE index, Hameed index, Sargolzaie formula and Zaghloul II index. The CroThalDD-LM1 index has an accuracy of 93.36% (AUC 0.986, 95% CI 0.975-0.997), while the second CroThalDD-LM2 index utilizes absolute reticulocyte count alongside CBC variables, with an accuracy of 96.77% (AUC 0.985, 95% CI 0.988-0.999)., Discussion and Conclusion: We recommend using aforementioned formulas and indices with corrected cut-off values and accuracy >90% alongside two new proposed indices. A comparison of both native and these new indices is encouraged. These are the first discrimination indices generated and designed precisely for the pediatric population, which includes preschool children., 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., (© 2024 Turudic, Vucak, Kocheva, Milosevic and Bilic.)

We present eight cases of the homozygous MCPggaac haplotype, which is considered to increase the likelihood and severity of atypical hemolytic uremic syndrome (aHUS), especially in combination with additional risk aHUS mutations. Complement blockade (CBT) was applied at a median age of 92 months (IQR 36-252 months). The median number of relapses before CBT initiation (Eculizumab) was two. Relapses occurred within an average of 22.16 months (median 17.5, minimum 8 months, and maximum 48 months) from the first subsequent onset of the disease (6/8 patients). All cases were treated with PI/PEX, and rarely with renal replacement therapy (RRT). When complement blockade was applied, children had no further disease relapses. Children with MCPggaac haplotype with/without additional gene mutations can achieve remission through renal replacement therapy without an immediate need for complement blockade. If relapse of aHUS occurs soon after disease onset or relapses are repeated frequently, a permanent complement blockade is required. However, the duration of such a blockade remains uncertain. If complement inhibition is not applied within 4-5 relapses, proteinuria and chronic renal failure will eventually occur.

Background: GIGER MD device applies a biofeedback method through stimulated coordinated rhythmic and dynamic movements of the trunk and extremities in an anti-gravity position, thus helping to regain lost motor functions., Methods: In this article, the performance of the GIGER MD device was evaluated in 36 children with neurogenic bladder measuring gait speed, voiding bladder capacity, deviation from the age-adjusted bladder capacity (measured using the Koff scale), and urinary incontinence., Results: Children using the GIGER MD device had an increase in voiding bladder capacity (33.79%, median volume increase of 50 ml) with a subsequent median decrease in median age-adjusted bladder capacity by 45.50% (median deviation before was 36% vs. 16% after treatment). The number of urinary incontinence episodes also reduced by 55.57% (7-3 episodes per day), and the 20-meter motor gait speed increased by 14.26% (from 23 to 19 s)., Conclusion: Children who follow the GIGER MD therapy regularly for a period of 6 months show that CNS functional damage can be significantly improved., 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 Cvitkovic-Roic, Mikulic, Turudic, Milosevic, Roic and Matijevic.)

Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II region and three additional independent risk loci. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. Here, we conduct a multi-population GWAS meta-analysis in 38,463 participants (2440 cases). We then conduct conditional analyses and population specific GWAS. We discover twelve significant associations-eight from the multi-population meta-analysis (four novel), two from the multi-population conditional analysis (one novel), and two additional novel loci from the European meta-analysis. Fine-mapping implicates specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk locus. Non-HLA loci colocalize with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs is lacking but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associates with earlier disease onset. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cell-specific insights into its molecular drivers. Evaluating these associations in additional cohorts will refine our understanding of population specificity, heterogeneity, and clinical and molecular associations., (© 2023. The Author(s).)

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.

Background: Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most common cause of chronic kidney disease among children and adults younger than 30 yr. In our previous study, whole-exome sequencing (WES) identified a known monogenic cause of isolated or syndromic CAKUT in 13% of families with CAKUT. However, WES has limitations and detection of copy number variations (CNV) is technically challenging, and CNVs causative of CAKUT have previously been detected in up to 16% of cases., Objective: To detect CNVs causing CAKUT in this WES cohort and increase the diagnostic yield., Design Setting and Participants: We performed a genome-wide single nucleotide polymorphism (SNP)-based CNV analysis on the same CAKUT cohort for whom WES was previously conducted., Outcome Measurements and Statistical Analysis: We evaluated and classified the CNVs using previously published predefined criteria., Results and Limitations: In a cohort of 170 CAKUT families, we detected a pathogenic CNV known to cause CAKUT in nine families (5.29%, 9/170). There were no competing variants on genome-wide CNV analysis or WES analysis. In addition, we identified novel likely pathogenic CNVs that may cause a CAKUT phenotype in three of the 170 families (1.76%)., Conclusions: CNV analysis in this cohort of 170 CAKUT families previously examined via WES increased the rate of diagnosis of genetic causes of CAKUT from 13% on WES to 18% on WES + CNV analysis combined. We also identified three candidate loci that may potentially cause CAKUT., Patient Summary: We conducted a genetics study on families with congenital anomalies of the kidney and urinary tract (CAKUT). We identified gene mutations that can explain CAKUT symptoms in 5.29% of the families, which increased the percentage of genetic causes of CAKUT to 18% from a previous study, so roughly one in five of our patients with CAKUT had a genetic cause. These analyses can help patients with CAKUT and their families in identifying a possible genetic cause., (© 2022 The Authors.)

Background: Diabetic kidney disease (DKD) is the main cause of end-stage renal disease in patients with diabetes mellitus type I (DM-T1). Microalbuminuria and estimated glomerular filtration rate (eGFR) are standard predictors of DKD. However, these predictors have serious weaknesses. Our study aimed to analyze cystatin C, renal resistance index, and urinary kidney injury molecule-1 (KIM-1) as predictors of DKD., Methods: We conducted a cross-sectional study in 2019 on a consecutive sample of children and adolescents (10-18 years) diagnosed with DM-T1. The outcome was a risk for DKD estimated using standard predictors: age, urinary albumin, eGFR, serum creatinine, DM-T1 duration, HbA1c, blood pressure, and body mass index (BMI). We conducted the analysis using structural equation modeling., Results: We enrolled 75 children, 36 girls and 39 boys with the median interquartile range (IQR) age of 14 (11-16) years and a median (IQR) duration of DM-T1 of 6 (4-9) years. The three focal predictors (cystatin C, resistance index, and urinary KIM-1) were significantly associated with the estimated risk for DKD. Raw path coefficients for cystatin C were 3.16 [95% CI 0.78; 5.53; p = 0.009, false discovery rate (FDR) < 5%], for renal resistance index were -8.14 (95% CI -15.36; -0.92; p = 0.027; FDR < 5%), and for urinary KIM-1 were 0.47 (95% CI 0.02; 0.93; p = 0.040; FDR < 5%)., Conclusion: Cystatin C, renal resistance index, and KIM-1 may be associated with the risk for DKD in children and adolescents diagnosed with DM-T1. We encourage further prospective cohort studies to test our results., 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 © 2022 Trutin, Bajic, Turudic, Cvitkovic-Roic and Milosevic.)

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.

Purpose: Although contrast-enhanced urosonography (ceVUS) has shown capable diagnostic accuracy for the diagnosis of vesicoureteral reflux (VUR) in children, the ability of ceVUS to detect intrarenal reflux (IRR) is considered limited. The purpose of our study is to assess the ability of ceVUS to detect IRR as well as its association with age, gender, and the grade of VUR., Methods: This study included 5153 children who were referred to our clinic for ceVUS. All children underwent sonographic examinations, which were performed on a LOGIQ S8 machine equipped with dedicated software for contrast-enhanced studies with harmonic imaging. Standard ultrasound of the urinary tract was followed by bladder catheterisation and instillation of physiological normal saline and the US contrast medium (SonoVue ® , Bracco)., Results: VUR was diagnosed by ceVUS in 1959 out of 5153 children (38%), of whom IRR was found in 233 of 1959 children (11.9%). A total of 285 ureteral units showing IRR were found. High grades of VUR (IV + V) with IRR were found in a total of 235 of 285 (82.81%) renal units. Bilateral IRR was found in 53 patients, usually with a high-grade VUR on both sides. Most children had VUR grade IV, predominantly those < 12 months. The younger the child, the higher the likelihood of higher-grade VUR (p = 0.02)., Conclusion: ceVUS, combined with harmonic imaging and second-generation ultrasound contrast media, enabled IRR detection in almost 12% of our patients with VUR. IRR is most commonly found in children under 1 year of age with VUR grades IV and V., (© 2021. Società Italiana di Ultrasonologia in Medicina e Biologia (SIUMB).)

We analyzed children with urolithiasis with age- and gender-matched healthy children. Calcium (mmol/mmol creatinine) and the calcium/citrate ratio (mol/mmol) are the only variables that differentiate children before puberty from healthy children (ROC analysis confirmed only calcium/citrate as a significant variable with cut-off value > 0.84). Peri-pubertal children are distinguished from age- and gender-matched healthy children by the following variables: citrate (mmol/mol creatinine), calcium/citrate (mol/mmol), oxalate/glycosaminoglycans (mmol/g), oxalate/citrate ratios (mmol/mmol) and oxalate/(citrate × glycosaminoglycans) (mol oxalate × mol creatinine)/(mol citrate × g glycosaminoglycans). All variables were confirmed by ROC analysis with cut-off values ≤ 327.87, >1.02, >11.24, >0.12 and >0.03, respectively. These results indicate a different risk of urinary stones development before puberty vs. pubertal/postpubertal children and increasing importance (deficiency) of citrate and glycosaminoglycans in such children. J48 classifier confirmed the importance of the oxalate/(citrate × glycosaminoglycans) and the calcium/citrate ratios (Ox/Cit × GAG 0.22 and Cit/GAG 0.612) with the practically applicable classification tree for distinguishing between pubertal/postpubertal children with urolithiasis with age- and gender-matched healthy children.

Rationale: This article describes a child with a life-threatening multiorgan failure with disseminated intravascular coagulation (DIC) and massive complement consumption. To our knowledge this therapeutic approach was for the first time effectively applied in a pediatric patient., Patient Concerns: A 14-month-old boy was presented with a severe, rapidly progressing, life-threatening disease because of sudden onset of fever, hemathemesis, hematuria, and bloody diarrhoea alongside fast spreading hematomas and general corporeal edema., Diagnosis: The most plausible diagnosis in our patient is Clostridium difficile sepsis-induced thrombotic microangiopathy alongside with DIC and consumption coagulopathy. The diagnosis was confirmed by positive C difficile bacteria strain in coproculture, clinical, and laboratory tests affirming DIC and global complement activation and consumption., Interventions: The patient was treated with antibiotics (Metronidazole, Vancomycin), plasmapheresis, dialysis, methylprednisolone, mycophenolate mofetil, and Eculizumab., Outcomes: The child is in fair overall condition in a 2 year follow-up with no complications save chronic renal failure., Lessons: In rare cases of sepsis with massive complement consumption, a case-sensitive Eculizumab therapy may be at least considered after the resolution of life-threatening multiorgan failure. The application of this drug can be performed only after sepsis induced disease is put under control. A fast withdrawal of Eculizumab after control of massive complement consumption is recommended to prevent triggering of second sepsis reactivation.

An analysis of genotype-phenotype correlation was performed for 14 patients with beta-thalassemia who had been registered in Referral Centre for hematology and oncology of the University Hospital Centre, Zagreb, Croatia. HBB gene mutations were determined using a gene-specific Q5 High-Fidelity PCR analysis with direct DNA sequencing of amplified transcripts. Mahidol score index used for classification of thalassemia severity was found to be low for all the patients enrolled in the study, indicating a mild β-thalassemia phenotype with no signs of disease progression. Most of the patients have already described gene mutations: IVS-II-666 C>T (HBB:c.316-185C>T) and IVS-II-16 G>C (HBB:c.315+16G>C). Each of the aforementioned mutations was found in (11/14; 78,57%) and (10/14; 71,43%) of our patients, respectively. Recently published HBB:c.9T>C mutation was found in 8 of 14 (57,14%) in our study group. IVSII-74 T>G (HBB:c.315+74T>G) is a worldwide mutation found in 6 of 14 (42.86%) of our patients. All these mutations occur among Croatian children with no obvious Indian/Near Eastern/Iranian ancestry. We also identified 7 de novo mutations (c.316-135het&#95;dupT, c.316-133A>G, c.93-54G>A, c.316-68&#95;316-67het&#95;insCGG, c.316-342delA, c.316-312delT, c.316-209delT) of mild severity phenotype according to Mahidol classification score index. We did not find children or adults with thalassemia major severity phenotype.

Diagnostic criteria for determination of inclination towards idiopathic calcium oxalate (CaOx) urolithiasis based on biochemical urine parameters are not sufficiently well defined in children. The aim of this study was to determine the risk of CaOx urolithiasis in children from concentrations of calcium, oxalate, citrate, and glycosaminoglycans in urine and their ratios, all standardized in respect to creatinine. We collected and analyzed 24-h urine samples of children with CaOx urolithiasis (n = 61) and compared with urine samples of matched control group of healthy children (n = 25). The study has showed that all stone formers have higher excretion of calcium (mmol/mmol creatinine), calcium/citrate (mol/mmol), and oxalate/(citrate × glycosaminoglycans) ratio (mol Ox × mol cr)/(mol Cit × g GAGs). ROC analysis of these variables gave criteria (>0.28, >1.07, and >0.08, respectively) for distinguishing stone formers from healthy children. Biochemical urine parameters and their ratios (calcium, calcium citrate, and oxalate/(citrate × glycosaminoglycans) enable one to discriminate idiopathic calcium oxalate stone formers from healthy children. Oxalate/(citrate × glycosaminoglycans) ratio per se can serve as an independent risk for stone formation., Conclusion: Using biochemical urine parameters and their ratios such as calcium, calcium/citrate, and oxalate/(citrate × glycosaminoglycans) enables one to determine diagnostic criteria towards idiopathic calcium oxalate urolithiasis in children. What is known: • The role of urine calcium as a promoter in calcium oxalate urolithiasis is well established. • Seldom used calcium/citrate ratio is acknowledged as a risk factor for calcium/oxalate urolithiasis. What is new: • The values of calcium and citrate in clinically and genetically proven idiopathic calcium oxalate urolithiasis make calcium/citrate ratio useful for diagnostic purposes in such stone formers. • Rarely used calcium independent oxalate/(citrate x glycosaminoglycans) ratio serves as the second best high specificity marker for idiopathic calcium oxalate urolithiasis.

Introduction: The concept of vesicoureteral reflux (VUR) as a consequence of congenital anomaly of vesicoureteral junction has undergone changes owing to the finding that such children may have lower urinary tract dysfunction, which produces high intravesical pressure and consequently a predisposition for VUR., Patients and Methods: The urodynamics was investigated by pressure-flow-EMG study in 132 children with VUR and 162 refluxing units., Results: Only 33 (25.0%) patients had normal urodynamic finding. The most frequent pathological finding was overactive bladder (OAB), found in 59 (44.7%) children, followed by dysfunctional voiding (DV) in 25 (18.9%) children. Children with VUR grades I and II had a higher percentage of pathological urodynamic findings than children with VUR grades III and IV. OAB was more frequent in children under 5 years of age with unilateral and lower grade VUR. It was found equally in children with and without uroinfections. DV was more frequent in children older than 5 years, with bilateral VUR, higher grade VUR and uroinfections., Conclusions: Children with VUR have a high incidence of urodynamic disorders. The results of the study indicate the possible role of urodynamic dysfunction in the pathogenesis of VUR, especially mild one., (Copyright © 2012 S. Karger AG, Basel.)

Recent data suggests increased incidence of focal segmental glomerulosclerosis (FSGS) among children with idiopathic nephrotic syndrome (INS). To determine the causes and possible longitudinal changes in the etiology of INS, 282 Croatian children diagnosed with INS between 1990 and 2009 were evaluated. In total, 122 children were assessed as having minimal change nephrotic syndrome (MCNS) based on their initial presentation, laboratory findings and clinical course. Kidney biopsy was performed in the remaining 160 children. MCNS was present in 18.1% of all biopsies performed. Total incidence of MCNS (assessed + biopsy proven) was only 53.5%. In contrast, FSGS was found in 40.6% of all biopsies and accounted for 23.1% of all cases. Mesangial proliferative glomerulonephritis (MesPGN) was the third most common diagnosis, present in 26.9% of the biopsies, and accounted for 15.2% of all cases. There were no significant longitudinal differences in the incidence of different causes of INS. The overall response to steroids at presentation was 71.6%. A higher proportion of initial steroid responders among children with FSGS (43.1%) and MesPGN (67.4%) than previously reported was noted. A longitudinal tendency of increasing steroid resistance in FSGS and MesPGN groups was observed.