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Julita Szulimowska,1 Anna Zalewska,1 Katarzyna Taranta-Janusz,2 Grażyna Marczuk-Kolada,3 Małgorzata Żendzian-Piotrowska,4 Mateusz Maciejczyk4 1Department of Restorative Dentistry, Medical University of Bialystok, Bialystok, Poland; 2Department of Pediatrics and Nephrology, Medical University of Bialystok, Bialystok, Poland; 3Department of Pedodontics, Medical University of Bialystok, Bialystok, Poland; 4Department of Hygiene, Epidemiology and Ergonomics, Medical University of Bialystok, Bialystok, PolandCorrespondence: Mateusz Maciejczyk, Department of Hygiene, Epidemiology and Ergonomics, Medical University of Bialystok, Bialystok, 2c Mickiewicza Street, Bialystok, 15-233, Poland, Email mat.maciejczyk@gmail.comIntroduction: Chronic kidney disease (CKD) is a systemic inflammatory disease that leads to multiple organ complications not only in the kidneys and the cardiovascular system, but also in the oral cavity. CKD children experience reduced saliva secretion (hyposalivation), which leads to increased incidence of dental caries and significant impairment of patients’ quality of life. However, the causes of salivary gland dysfunction in children with CKD are unknown. The present study is the first to evaluate the inflammatory and anti-inflammatory profile in the saliva of children with CKD at different stages of renal failure with normal and reduced salivary gland function.Methods: Thirty children with CKD (age 9– 16) and thirty age- and gender-matched healthy children were classified for the study. Salivary inflammatory and anti-inflammatory profile were assayed using the multiplex ELISA assay.Results: We demonstrated statistically significant changes in salivary pro-inflammatory (↑TNF-α, ↓IL-7), anti-inflammatory (↑IL-10), Th1 (↑INF-γ, ↑IL-15), Th2 (↑IL-4, ↑IL-5, ↑IL-6, ↑IL-9) and Th17 (IL-17) cytokines as well as chemokines (↑MCP-1/CCL-2, ↑MIP-1α/CCL3, ↓MIP-1β/CCL4, ↓EOTAXIN/CCL11) and growth factors (↑G-CSF, ↑FGF) in unstimulated saliva of children with CKD compared to the controls. Although the evaluation of the salivary inflammatory profile does not indicate a particular dominance of any of the branches of the immune system, we observed a statistically significant increase in the concentration of all Th2 cytokines assayed. The multivariate regression analysis showed that the content of salivary cytokines, chemokines and growth factors depends on the secretory function of the salivary glands, ie, salivary flow, total protein concentration and amylase activity in the saliva. Salivary MIP-1α/CCL3 was the most effective to differentiate children with CKD and hyposalivation from patients with normal saliva secretion.Discussion: Inflammation is involved in salivary gland dysfunction in children with CKD, although further studies on in vitro and in vivo models are necessary to confirm this hypothesis.Keywords: chronic kidney disease, saliva, inflammation, salivary gland dysfunction, hyposalivation

Pediatric chronic kidney disease (CKD) is a clinical condition characterized by progressive renal function deterioration. CKD diagnosis is based on glomerular filtration rate, but its reliability is limited, especially at the early stages. New potential biomarkers (citrulline (CIT), symmetric dimethylarginine (SDMA), S-adenosylmethionine (SAM), n-butyrylcarnitine (nC4), cis-4-decenoylcarnitine, sphingosine-1-phosphate and bilirubin) in addition to creatinine (CNN) have been proposed for early diagnosis. To verify the clinical value of these biomarkers we performed a comprehensive targeted metabolomics study on a representative cohort of CKD and healthy pediatric patients. Sixty-seven children with CKD and forty-five healthy children have been enrolled in the study. Targeted metabolomics based on liquid chromatography-triple quadrupole mass spectrometry has been used for serum and plasma samples analysis. Univariate data analysis showed statistically significant differences (p < 0.05) in the concentration of CNN, CIT, SDMA, and nC4 among healthy and CKD pediatric patients. The predictive ability of the proposed biomarkers was also confirmed through specificity and sensitivity expressed in Receiver Operating Characteristic curves (AUC = 0.909). In the group of early CKD pediatric patients, AUC of 0.831 was obtained, improving the diagnostic reliability of CNN alone. Moreover, the models built on combined CIT, nC4, SDMA, and CNN allowed to distinguish CKD patients from healthy control regardless of blood matrix type (serum or plasma). Our data demonstrate potential biomarkers in the diagnosis of early CKD stages., (© 2024. The Author(s).)

Background/Objectives: The survival rate among pediatric cancer patients has reached 80%; however, these childhood cancer survivors (CCSs) are at a heightened risk of developing chronic conditions in adulthood, particularly kidney and cardiovascular diseases. The aims of this study were to assess the serum α-Klotho and FGF23 levels in CCSs and to determine their association with nephro- and cardiotoxicity. Methods: This study evaluated a cohort of 66 CCSs who remained in continuous remission, with a mean follow-up of 8.41 ± 3.76 years. Results: The results of this study revealed that CCSs exhibited significantly higher levels of soluble α-Klotho compared to healthy peers (1331.4 ± 735.5 pg/mL vs. 566.43 ± 157.7 pg/mL, p < 0.0001), while no significant difference was observed in their FGF23 levels. Within the participant cohort, eight individuals (12%) demonstrated a reduced estimated glomerular filtration rate (eGFR) below 90 mL/min/1.73 m 2 . The relationship between treatment with abdominal radiotherapy and reduced eGFR was confirmed ( p < 0.05). No correlations were found between potential treatment-related risk factors, such as chemotherapy or radiation therapy, serum levels of α-Klotho and FGF23, and nephro- and cardiotoxicity. Conclusions: In conclusion, this preliminary cross-sectional study revealed elevated levels of α-Klotho among childhood cancer survivors but did not establish a direct association with anticancer treatment. The significance of elevated α-Klotho protein levels among CCSs warrants further investigation., Competing Interests: The authors declare no conflicts of interest.

BACKGROUND Ischemia-modified albumin (IMA) is a secreted biomarker for ischemic oxidative stress. This case-control study aimed to evaluate the association of ischemia-modified albumin (IMA) in saliva, serum, and urine with diagnosis of chronic kidney disease (CKD) in 24 children. MATERIAL AND METHODS The study involved 24 children with CKD. CKD was defined according to the Kidney Disease Improving Global Outcomes (KDIGO) diagnostic criteria. The control group consisted of 24 healthy children who were matched for age and gender to the experimental group. The concentration of IMA was determined by the colorimetric method in non-stimulated whole saliva (NWS), stimulated whole saliva (SWS), serum, and urine of children with CKD. The Mann-Whitney U test was used for inter-group comparisons. RESULTS IMA levels were significantly higher in NWS (P=0.0082) and SWS (P=0.0014) of children with CKD than in the control group. The concentration of IMA in NWS was correlated with standard indicators of kidney function, including the estimated glomerular filtration rate (r=-0.798, P≤0.0001), stage of CKD (r=0.814, P≤0.0001), and serum creatinine (r=0.711, P≤0.0001) and urea levels (r=0.738, P≤0.0001). CONCLUSIONS Salivary IMA concentration depends on renal function in children. Salivary IMA discriminates children with end-stage kidney disease from children with mild and moderate CKD and healthy children with high sensitivity and specificity. Further research is required, including assessment of the diagnostic usefulness and validation of the biomarker in a clinical diagnostic study.

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.)., (Copyright © 2023 Massachusetts Medical Society.)

Congenital lower urinary tract obstructions (LUTO) are most often caused by posterior urethral valves (PUV), a male limited anatomical obstruction of the urethra affecting 1 in 4,000 male live births. Little is known about the genetic background of PUV. Here, we report the largest genome-wide association study (GWAS) for PUV in 4 cohorts of patients and controls. The final meta-analysis included 756 patients and 4,823 ethnicity matched controls and comprised 5,754,208 variants that were genotyped or imputed and passed quality control in all 4 cohorts. No genome-wide significant locus was identified, but 33 variants showed suggestive significance ( P < 1 × 10 -5 ). When considering only loci with multiple variants residing within < 10 kB of each other showing suggestive significance and with the same effect direction in all 4 cohorts, 3 loci comprising a total of 9 variants remained. These loci resided on chromosomes 13, 16, and 20. The present GWAS and meta-analysis is the largest genetic study on PUV performed to date. The fact that no genome-wide significant locus was identified, can be explained by lack of power or may indicate that common variants do not play a major role in the etiology of PUV. Nevertheless, future studies are warranted to replicate and validate the 3 loci that yielded suggestive associations., Competing Interests: Author SH was employed by Life&Brain GmbH. The remaining 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 van der Zanden, Maj, Borisov, van Rooij, Quaedackers, Steffens, Schierbaum, Schneider, Waffenschmidt, Kiemeney, de Wall, Heilmann, Hofmann, Gehlen, Schumacher, Szczepanska, Taranta-Janusz, Kroll, Krzemien, Szmigielska, Schreuder, Weber, Zaniew, Roeleveld, Reutter, Feitz and Hilger.)

Obesity rates among children are growing rapidly worldwide, placing massive pressure on healthcare systems. Untargeted metabolomics can expand our understanding of the pathogenesis of obesity and elucidate mechanisms related to its symptoms. However, the metabolic signatures of obesity in children have not been thoroughly investigated. Herein, we explored metabolites associated with obesity development in childhood. Untargeted metabolomic profiling was performed on fasting serum samples from 27 obese Caucasian children and adolescents and 15 sex- and age-matched normal-weight children. Three metabolomic assays were combined and yielded 726 unique identified metabolites: gas chromatography-mass spectrometry (GC-MS), hydrophilic interaction liquid chromatography coupled to mass spectrometry (HILIC LC-MS/MS), and lipidomics. Univariate and multivariate analyses showed clear discrimination between the untargeted metabolomes of obese and normal-weight children, with 162 significantly differentially expressed metabolites between groups. Children with obesity had higher concentrations of branch-chained amino acids and various lipid metabolites, including phosphatidylcholines, cholesteryl esters, triglycerides. Thus, an early manifestation of obesity pathogenesis and its metabolic consequences in the serum metabolome are correlated with altered lipid metabolism. Obesity metabolite patterns in the adult population were very similar to the metabolic signature of childhood obesity. Identified metabolites could be potential biomarkers and used to study obesity pathomechanisms.

Introduction: Drug-induced diabetes mellitus (DIDM) could be defined as a heterogenic group of diabetes caused by pharmacotherapy. The DIDM is considered to be reversible after discontinuation of diabetogenic treatment, but there is a risk of persistence, which is related to the duration of treatment, prescribed medication, and body mass index., Case Presentation: A 13-year-old boy treated for nephrotic syndrome with the use of tacrolimus and prednisone was diagnosed with diabetes during a check-up visit. On admission, he showed a cushingoid appearance and complained of dry mouth, which was not accompanied by polyuria or polydipsia. Blood tests showed elevated levels of glucose, and glycated A1c fraction of haemoglobin (HbA1c = 10.2%). Pancreatic islet autoantibodies were negative. The fasting and postprandial C-peptide levels were within the normal range. Diabetic ketoacidosis was excluded. Intensive insulin therapy was initially introduced; the daily dose of insulin per kilogram was low (TDD/kg = 0.31 U/kg). Those findings prompted us to consider diabetes mellitus type 2 or DIDM. Moreover, the TDD/kg and HbA1c additionally decreased after the steroid withdrawal. Because he was constantly on diabetogenic therapy and experienced periodical hyperglycaemia, DIDM could not be excluded. Therefore, our patient remained on insulin treatment., Conclusions: DIDM in children is challenging for all specialists. Diabetologists need to remember about this rare subtype of diabetes, and other specialist should perform screening on their patients who are at risk of DIDM. There is a great need for guidelines that would provide a standardized approach for diagnosing and treating DIDM in the paediatric population.

The objectives of this study were to evaluate urinary beta-2-microglobulin (β2M) levels in long-term childhood cancer survivors and to establish its association with anticancer drug-induced nephrotoxicity. The study consisted of 165 childhood cancer survivors (CCS) who were in continuous complete remission. We reported that CCS had a significantly higher level of β2M ( p < 0.001) and β2M/Cr. ratio ( p < 0.05) than healthy peers. Among all participants, 24 (14.5%) had decreased eGFR (<90 mL/min/1.73 m 2 ). A significant positive correlation between β2M/Cr. ratio and body mass index (coef. 14.48, p = 0.046) was found. Furthermore, higher levels of urinary β2M were detected among CCS with a longer follow-up time (over 5 years) after treatment. Subjects with decreased eGFR showed statistically higher urinary β2M levels (20.06 ± 21.56 ng/mL vs. 8.55 ± 3.65 ng/mL, p = 0.007) compared with the healthy peers. Twelve survivors (7.2%) presented hyperfiltration and they had higher urinary β2M levels than CCS with normal glomerular filtration (46.33 ± 93.11 vs. 8.55 ± 3.65 ng/mL, p = 0.029). This study did not reveal an association between potential treatment-related risk factors such as chemotherapy, surgery, radiotherapy, and the urinary β2M level. The relationship between treatment with abdominal radiotherapy and reduced eGFR was confirmed ( p < 0.05). We demonstrated that urinary beta-2-microglobulin may play a role in the subtle kidney injury in childhood cancer survivors; however, the treatment-related factors affecting the β2M level remain unknown. Further prospective studies with a longer follow-up time are needed to confirm the utility of urinary β2M and its role as a non-invasive biomarker of renal dysfunction.

The study was conducted to analyze urinary tract infections (UTI) in children by considering epidemiology and antibiotic resistance patterns of pathogens in accordance with inflammatory parameters. The research included 525 patients who demonstrated 627 episodes of UTI. The increasing resistance of bacteria was observed over the years covered by the study ( p < 0.001). There was a significant increase of resistance to amoxicillin with clavulanic acid ( p = 0.001), gentamicin ( p = 0.017) and ceftazidime ( p = 0.0005). According to the CART method, we managed to estimate C-reactive protein (CRP), procalcitonin (PCT) and white blood cell (WBC) values, in which antibiotic sensitivity was observed. In children with CRP > 97.91 mg/L, there was a high percentage of sensitive cases to amoxicillin with clavulanic acid (87.5%). Values of WBC above 14.45 K/µL were associated with E. coli more sensitivity to ampicillin. 100% of children with CRP > 0.42 mg/L and PCT ≤ 6.92 ng/mL had confirmed sensitivity to cefuroxime. Concerning sensitivity to gentamicin, the most optimal cut-off point of WBC was >7.80 K/µL, while in the case of nitrofurantoin, it was CRP value > 0.11 mg/L (which was presented in 98.50% of children). These results may guide us with antibiotic therapy and help to inhibit increasing antibiotic resistance.

Lower urinary tract obstruction (LUTO) is, in most cases, caused by anatomical blockage of the bladder outlet. The most common form are posterior urethral valves (PUVs), a male-limited phenotype. Here, we surveyed the genome of 155 LUTO patients to identify disease-causing CNVs. Raw intensity data were collected for CNVs detected in LUTO patients and 4.392 healthy controls using CNVPartition, QuantiSNP and PennCNV. Overlapping CNVs between patients and controls were discarded. Additional filtering implicated CNV frequency in the database of genomic variants, gene content and final visual inspection detecting 37 ultra-rare CNVs. After, prioritization qPCR analysis confirmed 3 microduplications, all detected in PUV patients. One microduplication (5q23.2) occurred de novo in the two remaining microduplications found on chromosome 1p36.21 and 10q23.31. Parental DNA was not available for segregation analysis. All three duplications comprised 11 coding genes: four human specific lncRNA and one microRNA. Three coding genes ( FBLIM1 , SLC16A12 , SNCAIP ) and the microRNA MIR107 have previously been shown to be expressed in the developing urinary tract of mouse embryos. We propose that duplications, rare or de novo, contribute to PUV formation, a male-limited phenotype., Competing Interests: The authors declare no conflicts of interest.

Background and Objectives: Maturation of the gut microbiota (GM) in infants is critically affected by environmental factors, with potential long-lasting clinical consequences. Continuous low-dose antibiotic prophylaxis (CAP) is the standard of care for children with vesicoureteral reflux (VUR), in order to prevent recurrent urinary tract infections. We aimed to assess short-term GM modifications induced by CAP in infants. Methods: We analyzed the GM structure in 87 infants (aged 1-5 months) with high-grade VUR, previously exposed or naïve to CAP. Microbial DNA was extracted from stool samples. GM profiling was achieved by 16S rRNA gene-based next-generation sequencing. Fecal levels of short- and branched-chain fatty acids were also assessed. Results: 36/87 patients had been taking daily CAP for a median time of 47 days, while 51/87 had not. In all patients, the GM was predominantly composed by Bifidobacteriaceae and Enterobacteriaceae . Subgroup comparative analysis revealed alterations in the GM composition of CAP-exposed infants at phylum, family and genus level. CAP-exposed GM was enriched in members of Enterobacteriaceae and Bacteroidetes, especially in the genera Bacteroides and Parabacteroides , and showed a trend toward increased Klebsiella , often associated with antibiotic resistance. In contrast, the GM of non-CAP children was mostly enriched in Bifidobacterium . No differences were found in fatty acid levels. Conclusions: In infants with VUR, even a short exposure to CAP definitely alters the GM composition, with increased relative abundance of opportunistic pathogens and decreased proportions of health-promoting taxa. Early low-dose antibiotic exposure might bear potential long-term clinical risks., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Morello, D'Amico, Serafinelli, Turroni, Abati, Fiori, Baskin, Yalcinkaya, Jankauskiene, Pennesi, Zurowska, Becherucci, Drozdz, Mekahli, Krzemien, La Scola, Taranta-Janusz, Mehls, Schaefer, Candela and Montini.)

A study of 269 children enrolled into a National Registry for children with persistent glomerular hematuria identified 131 individuals with genetically confirmed X-linked Alport Syndrome. A single variant c.1871G>A p.Gly624Asp (G624D) in COL4A5 was predominant and accounted for 39% of X-linked Alport Syndrome in unrelated Polish families (44 of 113). To evaluate its origins, the genetic variation in a 2.79 Mb segment encompassing the COL4A5 locus on chromosome X was assessed. All G624D alleles were found on the same rare haplotype background, indicating a founder effect dating back to the 12-13th century. The phenotypic data of 131 children with X-linked Alport Syndrome and their 195 affected adult relatives revealed that the G624D variant was associated with a significantly milder clinical course in comparison to other pathogenic COL4A5 variants. Furthermore the clinical course of this genetically uniform cohort was milder than that observed in individuals with other COL4A5 missense mutations. In spite of the benign clinical manifestation throughout childhood and early adulthood, the G624D variant confers significant risk for both kidney failure and deafness in males, albeit 20-30 years later than that observed in individuals with other COL4A5 pathogenic variants (50% cumulative risk of starting dialysis at 54 years (95% confidence interval: 50-62) v. 26 years (95% confidence interval: 22-30)). Thus, males with G624D are candidates for existing and emerging therapies for Alport Syndrome., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

The aim of this study was to evaluate the galectin-3 (Gal-3) level in children with a congenital solitary functioning kidney (cSFK) and determine its association with common renal function parameters. The study consisted of 68 children (49 males) with cSFK. We demonstrated that children with cSFK had a lower level of galectin-3 than that of healthy subjects ( p < 0.001). No significant differences in serum cystatin C (Cys C) levels between the cSFK children and the reference group were found. The subjects with cSFK and reduced estimated glomerular filtration rate (eGFR) had significantly higher levels of Gal-3 and Cys C compared to those with normal eGFR ( p < 0.05). Children with eGFR <60 mL/min/1.73 m 2 showed significant statistical differences between the values of area under ROC curve (AUC) for Gal-3 (AUC 0.91) and Cys C (AUC 0.96) compared to that for creatinine level (AUC 0.76). Similar analyses carried out among cSFK children with eGFR <90 mL/min/1.73 m 2 revealed an AUC value of 0.69 for Gal-3, 0.74 for Cys C, and 0.64 for creatinine; however, no significant superiority was shown for any of them. The receiver operating characteristic (ROC) analyses for identifying the SFK children among all participants based on the serum levels of Gal-3 and Cys C did not show any diagnostic profile (AUCs for Gal-3 and Cys C were 0.22 and 0.59, respectively). A positive correlation between the Gal-3 and Cys C concentrations was found ( r = 0.39, p = 0.001). We demonstrated for the first time that Gal-3 might play an important role in the subtle kidney damage in children with cSFK. However, further prospective studies are required to confirm the potential applicability of Gal-3 as an early biomarker for kidney injury and possible progression to CKD.

This study was performed to explore serum tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its dependent cytokines urinary excretion: monocyte chemoattractant protein- 1 (MCP-1) and regulated on activation, normal T cell expressed and secreted chemokine (RANTES) with their relation to the kidney function parameters in children with solitary functioning kidney (SFK). The study included 80 children and adolescents (median age 9.75 year) with congenital and acquired (after surgical removal) SFK. Serum TWEAK and urinary MCP-1 and RANTES levels were significantly higher in SFK patients ( p < 0.05). The serum TWEAK was positively related to serum creatinine ( r = 0.356; p < 0.001). Moreover, in SFK the receiver operating characteristic analyses revealed good diagnostic profile for serum TWEAK with AUC (Area Under The Curve)-0.853, uRANTES-0.757, and for RANTES/cr.: AUC-0.816. Analysis carried out to identify children with impaired renal function (albuminuria and/or decreased estimated glomerular filtration rate < 90 mL/min/1.73 m 2 and/or hypertension) showed good profile for TWEAK (AUC-0.79) and quite good profile for uRANTES and RANTES/cr. (AUC 0.66 and 0.631, respectively). This is the first study investigating serum TWEAK and urinary excretion of MCP-1 and RANTES together in children with SFK. Obtained results indicate that TWEAK and RANTES may serve as potential markers of renal impairment.

The deterioration of renal function after childhood solid tumors treatment is the result of using the intensive multimodal therapy. In recent years, urinary kidney injury molecule-1 (KIM-1) and urinary neutrophil gelatinase-associated lipocalin (NGAL) have been introduced as potential promising biomarkers of early kidney damage. The aim of the present study was to determine whether anticancer treatment has any effect on the concentration of KIM-1 and NGAL and its association with renal impairment in survivors of childhood solid tumors. Sixty patients previously treated for solid tumors were involved in this study. The median time after end of treatment was 8.35 years. Urine KIM-1 and NGAL levels were measured using immunoenzymatic ELISA commercial kits. Higher levels of urine NGAL, KIM-1/cr. (creatinine), and NGAL/cr. ratios were found in comparison with healthy controls ( p < 0.0001). Among all subjects, 23% were found to have decreased estimated glomerular filtration rate (eGFR). A strong correlation between KIM-1/cr. and a cumulative dose of ifosfamide was observed (r = 0.865, p < 0.05). In addition, a moderate correlation between NGAL/cr. and a cumulative dose of cisplatin was identified (r = 0.534, p < 0.05). The AUC for KIM-1/cr. was 0.52, whereas NGAL/cr. showed a diagnostic profile describing the AUC of 0.67. Univariable regression showed significant associations between NGAL/cr. ratio and subjects after unilateral nephrectomy (coeff. 63.8, p = 0.007), cumulative dose of cisplatin (coeff. 0.111, p = 0.033), and age at diagnosis (coeff. 3.75, p = 0.023). The multivariable model demonstrated only cumulative dose of cisplatin as an independent factor influence on NGAL/cr. ratio. The results of our study showed increased levels of urine KIM-1 and NGAL many years after completion of the childhood solid tumors treatment, which correlated positively with a cumulative dose of ifosfamide and cisplatin. This study also suggests that unilateral nephrectomy could affect the concentration of the studied biomarkers.

Introduction: Nephrotoxicity is a potential adverse effect of anticancer treatment in childhood. Cytostatics, abdominal radiotherapy, total body irradiation (TBI) and some agents used in supportive care may induce acute kidney injury (AKI) or lead to chronic kidney disease (CKD). The aim of this study was to test the hypothesis whether urinary kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) are increased in acute lymphoblastic leukemia (ALL) survivors., Method: The study cohort consisted of 86 patients (42 females) previously treated for ALL. The median time after cessation of treatment was 6.55 (IQR: 1.96-9.93) years and median age at the time of study: 12 (IQR: 6.76-16.00). The control group included 53 healthy peers. Immunoenzymatic ELISA commercial kits were used to measure urine KIM-1 and NGAL levels., Results: The median levels of urine uNGAL (p < 0.05), uNGAL/creatinine (cr.) ratio (p < 0.0001) and uKIM-1/creatinine ratio (p < 0.0001) were significantly higher in ALL survivors in comparison with healthy controls. Female patients had significantly higher levels of NGAL and NGAL/cr. than males (mean 8.42 ± 7.1 vs. 4.59 ± 4.5 ng/mL and 86.57 ± 77 vs. 37.7 ± 37 ng/mg, respectively; p < 0.01). Of all the study participants, 11 (13%) presented eGFR below 90 mL/min/1.73 m 2 . The NGAL/cr. ratio seemed to be the best predictor of decreased eGFR (AUC = 0.65). The cumulative dose of methotrexate and cyclophosphamide did not predict the values of the urine NGAL, NGAL/cr., KIM-1/cr. and eGFR. Five years after the end of treatment, the patients had higher levels of uKIM-1 (1.02 ± 0.8 vs. 0.62 ± 0.6 ng/mL, p < 0.01), uNGAL (7.9 ± 6.7 vs. 4.6 ± 5 ng/mL, p < 0.01) and lower eGFR (114 ± 29 vs. 134 ± 35 mL/min/1.73 m 2 , p < 0.01) in comparison with ALL survivors with the observation period of less than 5 years., Conclusion: We demonstrated that ALL survivors have higher levels of urine NGAL, NGAL/cr. and uKIM-1/cr. ratio as compared to the control group. Further long-term follow-up studies are necessary to assess the significance of the NGAL and KIM-1 and their relationship to kidney damage after anticancer treatment in childhood.

To test the association between bilateral nephrectomies in patients with autosomal recessive polycystic kidney disease (ARPKD) and long-term clinical outcome and to identify risk factors for severe outcomes, a dataset comprising 504 patients from the international registry study ARegPKD was analyzed for characteristics and complications of patients with very early (≤ 3 months; VEBNE) and early (4-15 months; EBNE) bilateral nephrectomies. Patients with very early dialysis (VED, onset ≤ 3 months) without bilateral nephrectomies and patients with total kidney volumes (TKV) comparable to VEBNE infants served as additional control groups. We identified 19 children with VEBNE, 9 with EBNE, 12 with VED and 11 in the TKV control group. VEBNE patients suffered more frequently from severe neurological complications in comparison to all control patients. Very early bilateral nephrectomies and documentation of severe hypotensive episodes were independent risk factors for severe neurological complications. Bilateral nephrectomies within the first 3 months of life are associated with a risk of severe neurological complications later in life. Our data support a very cautious indication of very early bilateral nephrectomies in ARPKD, especially in patients with residual kidney function, and emphasize the importance of avoiding severe hypotensive episodes in this at-risk cohort.

This study is the first to evaluate protein glycooxidation products, lipid oxidative damage and nitrosative stress in non-stimulated (NWS) and stimulated whole saliva (SWS) of children with chronic kidney disease (CKD) divided into two subgroups: normal salivary secretion ( n = 18) and hyposalivation (NWS flow < 0.2 mL min -1 ; n = 12). Hyposalivation was observed in all patients with severe renal failure (4-5 stage CKD), while saliva secretion > 0.2 mL/min in children with mild-moderate CKD (1-3 stage) and controls. Salivary amylase activity and total protein content were significantly lower in CKD children with hyposalivation compared to CKD patients with normal saliva secretion and control group. The fluorescence of protein glycooxidation products (kynurenine, N-formylkynurenine, advanced glycation end products), the content of oxidative damage to lipids (4-hydroxynonneal, 8-isoprostanes) and nitrosative stress (peroxynitrite, nitrotyrosine) were significantly higher in NWS, SWS, and plasma of CKD children with hyposalivation compared to patients with normal salivary secretion and healthy controls. In CKD group, salivary oxidation products correlated negatively with salivary flow rate, -amylase activity and total protein content; however, salivary oxidation products do not reflect their plasma level. In conclusion, children with CKD suffer from salivary gland dysfunction. Oxidation of salivary proteins and lipids increases with CKD progression and deterioration of salivary gland function.

Oxidative stress plays a critical role in the pathogenesis of hypertension; however, there are no data on salivary redox homeostasis and salivary gland function in children with hypertension. A total of 53 children with hypertension and age- and sex-matched controls were classified for the study. The antioxidant barrier and oxidative/nitrosative stress were evaluated in non-stimulated (NWS) and stimulated (SWS) whole saliva, plasma, and erythrocytes, with Student's t-test and Mann-Whitney U-test used for statistical analysis. We demonstrated that the activities of superoxide dismutase, catalase, and peroxidase were significantly higher in NWS, SWS, and erythrocytes of children with hypertension, similar to oxidative damage in proteins (advanced glycation end products) and lipids (malondialdehyde) as well as nitrosative stress markers (peroxynitrite and nitrotyrosine). The level of uric acid (UA) was significantly higher in NWS, SWS, and plasma of children with hypertension. UA concentration in SWS correlated positively with systolic and diastolic blood pressure and UA content in plasma. This parameter differentiates children with hypertension from healthy controls (AUC = 0.98) with a high degree of sensitivity (94%) and specificity (94%). Stimulated salivary flow was significantly lower in the hypertension group, similar to total protein content and salivary amylase activity. In summary, childhood hypertension is associated with hyposalivation as well as disturbances in antioxidant defense and enhanced oxidative/nitrosative damage both in the plasma/erythrocytes as well as saliva. Salivary UA may be a potential biomarker of hypertension in children.

Obesity is inseparably connected with oxidative stress. This process may disturb the functioning of the oral cavity, although the effect of oxidative stress on salivary gland function and changes in the qualitative composition of saliva are still unknown. Our study is the first to evaluate salivary redox homeostasis in 40 overweight and obese adolescents and in the age- and gender-matched control group. We demonstrated strengthening of the antioxidant barrier (superoxide dismutase, catalase, peroxidase, uric acid, total antioxidant capacity (TAC)) with a simultaneous decrease in reduced glutathione concentration in saliva (non-stimulated/stimulated) in overweight and obese teenagers compared to the controls. The concentration of the products of oxidative damage to proteins (advanced glycation end products), lipids (malondialdehyde, 4-hydroxynonenal) and DNA (8-hydroxydeoxyguanosine) as well as total oxidative status were significantly higher in both non-stimulated and stimulated saliva as well as plasma of overweight and obese adolescents. Importantly, we observed more severe salivary and plasma redox alterations in obese adolescents compared to overweight individuals. In the study group, we also noted a drop in stimulated salivary secretion and a decrease in total protein content. Interestingly, dysfunction of parotid glands in overweight and obese teenagers intensified with the increase of BMI. We also showed that the measurement of salivary catalase and TAC could be used to assess the central antioxidant status of overweight and obese adolescents., Competing Interests: The authors declare no conflict of interest.

Chronic kidney disease (CKD) is one of the most common modern-age diseases in children. Kidney failure does not reveal any symptoms for a long time; therefore, new biomarkers are sought, preferably those reflecting an early stage of CKD. The aim of our study was to evaluate total antioxidant potential as a biomarker differentiating the degree of CKD advancement. The study included 30 children with CKD and a control group matched by age and gender. Non-stimulated saliva (NWS), stimulated saliva (SWS), plasma and urine were used as study material. Total antioxidant potential was determined spectrophotometrically using the FRAP method (ferric ion reducing antioxidant parameter) by measuring total FRAP and uric acid (UA)-independent FRAP (FRAP-UA). We demonstrated that total FRAP, FRAP-UA and UA were significantly higher in stimulated saliva, as well as urine of CKD patients compared to the controls. These biomarkers increase with the progression of chronic kidney disease and their concentration in SWS reflects their content in urine. Interestingly, salivary FRAP and uric acid clearly differentiate between various stages of CKD as well as between healthy and ill children. Special attention should be paid to total FRAP which-measured in SWS-distinguishes patients with mildly to moderately decreased kidney function from those with severe renal impairment (AUC = 1, sensitivity = 100%, specificity = 100%). Although salivary FRAP may be a potential CKD biomarker in children, further studies are needed in a larger group of patients.

Congenital lower urinary-tract obstruction (LUTO) is caused by anatomical blockage of the bladder outflow tract or by functional impairment of urinary voiding. About three out of 10,000 pregnancies are affected. Although several monogenic causes of functional obstruction have been defined, it is unknown whether congenital LUTO caused by anatomical blockage has a monogenic cause. Exome sequencing in a family with four affected individuals with anatomical blockage of the urethra identified a rare nonsense variant (c.2557C>T [p.Arg853 ∗ ]) in BNC2, encoding basonuclin 2, tracking with LUTO over three generations. Re-sequencing BNC2 in 697 individuals with LUTO revealed three further independent missense variants in three unrelated families. In human and mouse embryogenesis, basonuclin 2 was detected in lower urinary-tract rudiments. In zebrafish embryos, bnc2 was expressed in the pronephric duct and cloaca, analogs of the mammalian lower urinary tract. Experimental knockdown of Bnc2 in zebrafish caused pronephric-outlet obstruction and cloacal dilatation, phenocopying human congenital LUTO. Collectively, these results support the conclusion that variants in BNC2 are strongly implicated in LUTO etiology as a result of anatomical blockage., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: We investigated the relationship between blood pressure (BP) and the activity of lysosomal exoglycosidases: N-acetyl-β-hexosaminidase (HEX), its isoenzymes A (HEX A) and B (HEX B), α-fucosidase (FUC), β-galactosidase (GAL), β-glucuronidase (GLU) and α-mannosidase (MAN) in pre-hypertensive (high normal blood pressure - HNBP) and normal blood pressure (NBP) children., Material and Methods: The study was carried out with urine samples collected from 176 children, aged 6-17.9 years, divided into 2 groups: 42 HNBP and 134 NBP subjects. The children were stratified depending on systolic and diastolic BP (SBP; DBP): HNBP (SBP and/or DBP greater than or equal to the 90th percentile, but less than the 95th percentile) for sex, age, and height; and NBP (SBP and DBP less than the 90th centile). The activities of lysosomal exoglycosidases were determined by the colorimetric method, and expressed in pKat/mL and pKat/μgCr., Results: The activity of urinary HEX A in HNBP group was significantly higher than in NBP (p < 0.05). The HNBP group showed significant positive correlation between HEX, HEX A (pKat/mL) and SBP. AUC for HEX A was 0.616, cut-off value -29.351 pKat/mL (sensitivity 51.2%, specificity 71.8%), and 0.589, cut-off value -0.054 pKat/μgCr (sensitivity 31.7%, specificity 86.3%)., Conclusions: This is the first report of the relationship between BP and the activity of urinary lysosomal exoglycosidases: HEX, HEX A and HEX B, FUC, GAL, GLU, and MAN in healthy children and adolescents. It seems that HEX A (pKat/mL) can be used as a useful tool in identifying children with HNBP., (Copyright © 2018. Published by Elsevier B.V.)

Purpose: We aimed at evaluating urinary levels of procollagen III aminoterminal propeptide (PIIINP) and β-catenin and the relationship between these markers and clinical and laboratory variables in children with a solitary functioning kidney (SFK)., Patients and Methods: The study group consisted of 98 (M/F: 62/36) children with an SFK with a median age of 8 years. An age-matched control group contained 54 healthy peers. Urinary levels of procollagen III aminoterminal propeptide and β-catenin were measured using a commercially available immunoassay kit., Results: The urinary values of PIIINP (UPIIINP) were significantly increased in patients with SFK versus controls (p < 0.01). Our analysis revealed no significant differences in urinary β-catenin levels between the SFK patients and control subjects (p > 0.05). Only urinary PIIINP levels were correlated to renal function tests, such as serum creatinine, urea, uric acid, and estimated glomerular filtration rate (p<0.05)., Conclusions: An increased urinary level of PIIINP may indicate early kidney impairment in children with SFK. Urinary β-catenin does not seem to play any important role as a marker of renal function in children with SFK. Further long-term studies are required in order to evaluate the clinical usefulness of these markers and their predictive value of chronic kidney disease (CKD) progression., (Copyright © 2018 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.)

Purpose: The purpose of the study was to determine the effect of age on lysosomal exoglycosidase activities: α-fucosidase, β-galactosidase, β-glucuronidase and α-mannosidase in healthy children and adolescents., Material and Methods: Urine samples were collected from 203 healthy children and adolescents (girls = 99, boys = 104), aged six months to 17.9 years. The activities of α-fucosidase, β-galactosidase, β-glucuronidase and α-mannosidase were determined by colorimetric method and expressed in pKat/μg of creatine (pKat/μg Cr.)., Results: Urinary α-fucosidase, β-galactosidase, β-glucuronidase and α-mannosidase activities (pKat/μg Cr.) were the highest in children below 3 years of age in comparison to the remaining age groups. There was a statistically significant negative correlation between urinary α-fucosidase, β-galactosidase, β-glucuronidase and α-mannosidase (pKat/μg Cr.) and age (r = -0.36; r = -0.36; r = -0.35; r = -0.35; at p < 0.0001, respectively). In addition, we constructed the reference values for urinary activity of α-fucosidase, β-galactosidase, β-glucuronidase and α-mannosidase (pKat/μg Cr.) in percentiles according to age in 3-year intervals., Conclusions: Our study is the first to show reference values for urinary α-fucosidase, β-galactosidase, β-glucuronidase and α-mannosidase in children and adolescents., (Copyright © 2018 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.)

There are still missing non-invasive biomarkers of chronic kidney disease (CKD) in children. Therefore, the aim of the study was to evaluate oxidative stress indicators in the non-stimulated (NWS) and stimulated saliva (SWS) of CKD children ( n = 25) and healthy controls ( n = 25). Salivary antioxidants (catalase (CAT), peroxidase (Px), superoxide dismutase (SOD), uric acid (UA), reduced glutathione (GSH), albumin), redox status (total antioxidant capacity (TAC), total oxidant status (TOS), oxidative stress index (OSI)), and oxidative damage products (advanced glycation end products (AGE), advanced oxidation protein products (AOPP), malondialdehyde (MDA)) were evaluated. We have demonstrated the significantly higher activity of SWS GPx and SOD, as well as elevated concentrations of UA and albumin in NWS and SWS of CKD children vs. the control group. TAC, TOS and OSI were significantly higher only in SWS, while oxidative damage products (AGE, AOPP and MDA) were significantly higher in both NWS and SWS of CKD children. ROC analysis showed a considerably high diagnostic value of AOPP in both NWS and SWS of CKD children compared to controls (AUC = 0.92; 0.98). CKD is responsible for disturbances in salivary antioxidant systems and oxidative damage to proteins and lipids. Salivary AOPP can be a potential biomarker of CKD in children.

The prevalence of hypertension in pediatric populations continues to rise. Recent studies suggest that renalase plays an important role in blood pressure regulation. The aim of this study was to evaluate serum renalase concentrations in hypertensive children. This study was a prospective cohort analysis of 88 adolescents (40 girls; 48 boys) aged 11-18 years, divided into two groups: HT-38 subjects with primary hypertension; and R (reference group)-50 subjects with normal blood pressure. Serum renalase concentration was measured using a commercial enzyme-linked immunosorbent assay kit. Hypertensive patients had higher serum renalase levels (median 29.8 µg/mL; Q1-Q3: 26.1-35.8) than the reference group (median 26.8; Q1-Q3: 22.96-29.4, p < 0.01). Serum renalase was strongly related to serum uric acid levels. In hypertensive patients, serum renalase was positively correlated with 24-h systolic blood pressure (SBP) and 24-h diastolic blood pressure (DBP) and with 24-h SBP and 24-h DBP Z-score (LMS). Our results allow us to conclude that serum renalase correlates with blood pressure elevation. Special attention should be drawn to the correlation between renalase and serum uric acid levels not only in hypertensive, but also in normotensive teenagers. Further studies are needed to answer the question of whether increased serum renalase may be a predisposing factor to hypertension in normotensive patients with hyperuricemia.

Objective: To identify prenatal, perinatal, and postnatal risk factors for dialysis within the first year of life in children with autosomal recessive polycystic kidney disease (ARPKD) as a basis for parental counseling after prenatal and perinatal diagnosis., Study Design: A dataset comprising 385 patients from the ARegPKD international registry study was analyzed for potential risk markers for dialysis during the first year of life., Results: Thirty-six out of 385 children (9.4%) commenced dialysis in the first year of life. According to multivariable Cox regression analysis, the presence of oligohydramnios or anhydramnios, prenatal kidney enlargement, a low Apgar score, and the need for postnatal breathing support were independently associated with an increased hazard ratio for requiring dialysis within the first year of life. The increased risk associated with Apgar score and perinatal assisted breathing was time-dependent and vanished after 5 and 8 months of life, respectively. The predicted probabilities for early dialysis varied from 1.5% (95% CI, 0.5%-4.1%) for patients with ARPKD with no prenatal sonographic abnormalities to 32.3% (95% CI, 22.2%-44.5%) in cases of documented oligohydramnios or anhydramnios, renal cysts, and enlarged kidneys., Conclusions: This study, which identified risk factors associated with onset of dialysis in ARPKD in the first year of life, may be helpful in prenatal parental counseling in cases of suspected ARPKD., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: The objective of the study was to establish age - dependent values of the urinary lysosomal exoglycosidases activities: N-acetyl-β-D-hexosaminidase (HEX) and its isoenzyme A (HEX A) as well as isoenzyme B (HEX B) in healthy children and adolescents., Material and Methods: The study was performed using a random sample of 203 healthy children and adolescents (girls=99, boys=104), aged six months to 17.9 years. The activities of HEX, HEX A and HEX B were determined by a colorimetric method. The activities of the urinary HEX and its isoenzymes were expressed in pKat/μg of creatinine (pKat/μg Cr)., Results: Median concentrations of urinary HEX, and its HEX A, HEX B isoenzymes in particular age groups were analyzed using ANOVA. Urinary HEX, HEX A and HEX B activities (pKat/μg Cr) were the highest in children below 3 years, in comparison to remaining age groups. There were statistically significant negative correlations between urinary HEX, HEX A as well as HEX B and age (r=-0.24, p<0.001 (HEX); r=-0.20, p<0.01 (HEX A); r=-0.26, p<0.001 (HEX B), respectively. We constructed the reference values for urinary activity of HEX, HEX A and HEX B (pKat/μg Cr) in centiles according to age, in three-year intervals., Conclusions: Reported data present, for the first time, reference values for urinary activities of HEX and its isoenzymes HEX A and HEX B in children and adolescent., (Copyright © 2017 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.)

Aim: This study determined the specific reference values for urinary phosphorus excretion in healthy children and adolescents aged 2-18 years and evaluated whether they changed with age during growth and were gender dependent., Methods: We enrolled 3913 healthy children and adolescents aged 2-18 years to this study. The study population was divided into age groups, and the analysis was performed in one-year periods, separately for boys and girls. Urinary phosphorus excretion was analysed using four categories: P1 in mmol/24 hour units, P2 in mmol/kg/24 hours, P3 in mmol/1.73 m 2 /24 hours and P4 in mmol/mmol creatinine., Results: Clear differences in urinary exertion for girls and boys were observed as well as systematic changes with age. The boys presented with significantly higher daily urinary phosphorus excretion independent of its manner of expression (p < 0.001). The median urinary phosphorus (P1) rose with age (p < 0.001). Percentile tables of phosphorous exertion are presented., Conclusion: This was the largest study of urinary phosphate excretion based on a randomly selected sample of girls and boys aged 2-18 years. It highlights the importance of determining phosphorus reference values for children of different ages to provide early diagnosis and treatment for urolithiasis., (©2017 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Aim: We aimed to investigate whether urine intercellular adhesion molecule-1 (ICAM-1) might serve as a marker of renal disorder in children with ureteropelvic junction obstruction., Material and Methods: Twenty-nine children with severe hydronephrosis (HN) were compared with 23 participants with mild HN and with 19 healthy peers., Results: Urine ICAM-1/uCre levels were significantly higher in HN children than healthy controls (P<0.01), and in severe HN when compared with mild HN (p<0.05)., Conclusions: It seemed to us that uICAM-1 is a biomarker of renal disorder, and might have the potential to predict which patients will require surgery.

Aim: Hydronephrosis caused by ureteropelvic junction obstruction (UPJO) is an important problem in children and young adults. The aim of this pilot study was to determine the urine profiles of a number of lysosomal exoglycosidases to see whether they indicated tubular renal damage in children with UPJO., Methods: We measured lysosomal exoglycosidases urine activities in 32 patients with UPJO, dividing them into three groups. The surgical group comprised 16 children with severe hydronephrosis who required surgery, the nonsurgical group comprised 16 patients with mild hydronephrosis, and the reference group comprised 42 healthy children. The following indicators were measured: N-acetyl-β-hexosaminidase and its A and B isoenzymes, α-fucosidase, β-galactosidase, α-mannosidase and β-glucuronidase., Results: The urine activities of all exoglycosidases were significantly higher in children with UPJO than children in the reference group (p < 0.01). A strong positive correlation was also found between most of the urine exoglycosidases and the urine albumin/creatinine ratio (p < 0.01)., Conclusion: Our findings demonstrated that children with UPJO showed increased renal activities of assessed exoglycosidases, which correlated positively with the urine albumin/creatinine ratio. A larger multicentre study is required to confirm the clinical applications of these observations., (©2015 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Introduction: The purpose of this work was to investigate the association of serum asymmetric dimethylarginine (ADMA) and high-sensitivity C-reactive protein (hs-CRP) levels with duration of breastfeeding and body composition in children., Patients and Methods: The study group consisted of 88 patients with a median age of 12 months (42 boys, 46 girls), classified as never breastfed or fully breastfed. ADMA and hs-CRP were measured by immunoenzymatic enzyme-linked immunosorbent assay commercial kits. Body composition analysis was performed by bioelectrical impedance., Results: We found significantly higher serum ADMA levels but not serum hs-CRP levels in never breastfed compared with the fully breastfed group (p<0.05). Serum ADMA was inversely associated with high-density lipoprotein-cholesterol levels and breastfeeding duration (p<0.05). Positive correlation was found between ADMA and body fat mass (p<0.05)., Conclusions: In never breastfed children, increased ADMA is observed; however, further studies are needed to assess whether breastfeeding duration affects body fat and body composition at older ages.

In recent years, a blooming period of genomics brings a window of opportunity to assess predispositions to some diseases in individuals, even before the first symptoms appear. However, a risk of becoming ill is more complex, as the gene expression is modified by epigenetic and environmental factors. Fetal development and first months of life are periods of dynamic growth and significant sensitivity to external factors. According to the theory of early-life metabolic programming, adaptive changes in these stages have lasting health effects. Among many environmental factors, the youngest children's diet plays an important role. Breastfeeding of newborns and infants is an essential part of lifestyle diseases prevention. Constantly increasing number of reports link natural nutrition of the youngest children with less risk of obesity, hypertension, dyslipidemia and insulin resistance in future life. However, further long-term studies taking into account number of bias factors, explaining protective mechanisms of human milk, are needed.

Background: The present study aimed to assess whether the urinary profiles of the lysosomal exoglycosidases N‑acetyl‑β‑hexosaminidase (HEX) and its isoenzymes A (HEX A) and B (HEX B), α-fucosidase (FUC), β-galactosidase (GAL), α-mannosidase (MAN), and β- glucuronidase (GLU) are useful biomarkers of tubular dysfunction in children with a solitary functioning kidney (SFK)., Methods: We measured the urinary activity of HEX, its isoenzymes HEX A, HEX B, and FUC, GAL, MAN, and GLU in 52 patients with SFK. Patients were subdivided into two groups: congenital SFK (cSFK)-unilateral renal agenesis and acquired SFK (aSFK)-unilateral nephrectomy. The reference group (RG) contained 60 healthy sex- and age-matched children., Results: Urinary activity of all exoglycosidases in SFK was significantly higher than in RG (p < 0.05). There were no differences in exoglycosidase activity between cSFK and aSFK (p > 0.05). HEX and its isoenzymes HEX A and HEX B correlated negatively with estimated glomerular filtration rate (eGFR), and all estimated parameters correlated positively with albumin/creatinine ratio (p < 0.001)., Conclusion: Urinary activity of HEX, its isoenzymes HEX A and HEX B, and FUC, GAL, MAN, and GLU is elevated in children with SFK. Long-term follow-up studies in larger groups of children with SFK may help us to better understand their clinical significance.