Urine soluble TLR4 levels may contribute to predict urinary tract infection in children: the UTILISE Study.

BACKGROUND: One of the most common bacterial infections in childhood is urinary tract infection (UTI). Toll-like receptors (TLRs) contribute to immune response against UTI recognizing specific pathogenic agents. Our aim was to determine whether soluble TLR4 (sTLR4), soluble TLR5 (sTLR5) and interleukin 8 (IL-8) can be used as biomarkers to diagnose UTI. We also aimed to reveal the relationship between urine Heat Shock Protein 70 (uHSP70) and those biomarkers investigated in this study. METHODS: A total of 802 children from 37 centers participated in the study. The participants (n = 282) who did not meet the inclusion criteria were excluded from the study. The remaining 520 children, including 191 patients with UTI, 178 patients with non-UTI infections, 50 children with contaminated urine samples, 26 participants with asymptomatic bacteriuria and 75 healthy controls were included in the study. Urine and serum levels of sTLR4, sTLR5 and IL-8 were measured at presentation in all patients and after antibiotic treatment in patients with UTI. RESULTS: Urine sTLR4 was higher in the UTI group than in the other groups. UTI may be predicted using 1.28 ng/mL as cut-off for urine sTLR4 with 68% sensitivity and 65% specificity (AUC = 0.682). In the UTI group, urine sTLR4 levels were significantly higher in pyelonephritis than in cystitis (p < 0.0001). Post-treatment urine sTLR4 levels in the UTI group were significantly lower than pre-treatment values (p < 0.0001). CONCLUSIONS: Urine sTLR4 may be used as a useful biomarker in predicting UTI and subsequent pyelonephritis in children with UTI. A higher resolution version of the Graphical abstract is available as Supplementary information.

Characteristics and predictors of chronic kidney disease in children with myelomeningocele: a nationwide cohort study.

BACKGROUND: Myelomeningocele (MMC) is highly prevalent in developing countries, and MMC-related neurogenic bladder is an important cause of childhood chronic kidney disease (CKD). This nationwide study aimed to evaluate demographic and clinical features of pediatric patients with MMC in Turkey and risk factors associated with CKD stage 5. METHODS: Data from children aged 0-19 years old, living with MMC in 2022, were retrospectively collected from 27 pediatric nephrology centers. Patients > 1 year of age without pre-existing kidney abnormalities were divided into five groups according to eGFR; CKD stages 1-5. Patients on dialysis, kidney transplant recipients, and those with eGFR < 15 ml/min/1.73 m2 but not on kidney replacement therapy at time of study constituted the CKD stage 5 group. RESULTS: A total of 911 (57.8% female) patients were enrolled, most of whom were expectantly managed. Stages 1-4 CKD were found in 34.3%, 4.2%, 4.1%, and 2.4%, respectively. CKD stage 5 was observed in 5.3% of patients at median 13 years old (range 2-18 years). Current age, age at first abnormal DMSA scan, moderate-to-severe trabeculated bladder on US and/or VCUG, and VUR history were independent risk factors for development of CKD stage 5 (OR 0.752; 95%; CI 0.658-0.859; p < 0.001; OR 1.187; 95% CI 1.031-1.367; p = 0.017; OR 10.031; 95% CI 2.210-45.544; p = 0.003; OR 2.722; 95% CI 1.215-6.102; p = 0.015, respectively). Only eight CKD stage 5 patients underwent surgery related to a hostile bladder between 1 and 15 years old. CONCLUSION: MMC-related CKD is common in childhood in Turkey. A proactive approach to neurogenic bladder management and early protective surgery in selected cases where conservative treatment has failed should be implemented to prevent progressive kidney failure in the pediatric MMC population in our country.

Urinary HSP70 improves diagnostic accuracy for urinary tract infection in children: UTILISE study.

BACKGROUND: The accuracy of conventional urinalysis in diagnosing urinary tract infection (UTI) in children is limited, leading to unnecessary antibiotic exposure in a large fraction of patients. Urinary heat shock protein 70 (uHSP70) is a novel marker of acute urinary tract inflammation. We explored the added value of uHSP70 in discriminating UTI from other infections and conditions confused with UTI. METHODS: A total of 802 children from 37 pediatric centers in seven countries participated in the study. Patients diagnosed with UTI (n = 191), non-UTI infections (n = 178), contaminated urine samples (n = 50), asymptomatic bacteriuria (n = 26), and healthy controls (n = 75) were enrolled. Urine and serum levels of HSP70 were measured at presentation in all patients and after resolution of the infection in patients with confirmed UTI. RESULTS: Urinary (u)HSP70 was selectively elevated in children with UTI as compared to all other conditions (p < 0.0001). uHSP70 predicted UTI with 89% sensitivity and 82% specificity (AUC = 0.934). Among the 265 patients with suspected UTI, the uHSP70 > 48 ng/mL criterion identified the 172 children with subsequently confirmed UTI with 90% sensitivity and 82% specificity (AUC = 0.862), exceeding the individual diagnostic accuracy of leukocyturia, nitrite, and leukocyte esterase positivity. uHSP70 had completely normalized by the end of antibiotic therapy in the UTI patients. Serum HSP70 was not predictive. CONCLUSIONS: Urine HSP70 is a novel non-invasive marker of UTI that improves the diagnostic accuracy of conventional urinalysis. We estimate that rapid urine HSP70 screening could spare empiric antibiotic administration in up to 80% of children with suspected UTI. A higher resolution version of the Graphical abstract is available as Supplementary information.

PROGRESS STUDY: Progression of chronic kidney disease in children and heat shock proteins.

Various molecular and cellular processes are involved in renal fibrosis, such as oxidative stress, inflammation, endothelial cell injury, and apoptosis. Heat shock proteins (HSPs) are implicated in the progression of chronic kidney disease (CKD). Our aim was to evaluate changes in urine and serum HSP levels over time and their relationships with the clinical parameters of CKD in children. In total, 117 children with CKD and 56 healthy children were examined. The CKD group was followed up prospectively for 24 months. Serum and urine HSP27, HSP40, HSP47, HSP60, HSP70, HSP72, and HSP90 levels and serum anti-HSP60 and anti-HSP70 levels were measured by ELISA at baseline, 12 months, and 24 months. The urine levels of all HSPs and the serum levels of HSP40, HSP47, HSP60, HSP70, anti-HSP60, and anti-HSP70 were higher at baseline in the CKD group than in the control group. Over the months, serum HSP47 and HSP60 levels steadily decreased, whereas HSP90 and anti-HSP60 levels steadily increased. Urine HSP levels were elevated in children with CKD; however, with the exception of HSP90, they decreased over time. In conclusion, our study demonstrates that CKD progression is a complicated process that involves HSPs, but they do not predict CKD progression. The protective role of HSPs against CKD may weaken over time, and HSP90 may have a detrimental effect on the disease course.

Parvovirus Infection in a Child Presenting with Erythema Multiforme and Vasculitis after a Yellow Jacket Bee Sting.

Parvovirus B19 has a wide spectrum of clinical manifestations. Erythema multiforme and vasculitis are rarely reported with parvovirus B19 infections. Reactions to insect stings can range from local swelling to life-threatening systemic reactions. There have been rare reports of unusual reactions, such as vasculitis, occurring in a temporal relationship with insect stings. We report an 8-year-old patient having Parvovirus B-19-related erythema multiforme and vasculitis after a yellow jacket bee sting.

Evaluation of health-related quality of life and affecting factors in child with enuresis.

BACKGROUND: Enuresis is a common problem in children and distressing condition that can have an impact on the child's behavior and on their emotional and social life. Health-related quality of life (HRQoL) is defined as an individual's perception of the impact of the disease and treatment. OBJECTIVE: The aim of this study was to evaluate the HRQoL in Turkish children with enuresis and to investigate the effect of independent sociodemographic and clinical variables on HRQoL in children with enuresis. STUDY DESING: 110 children with enuresis and their mothers and 120 healthy children and their mothers were included in the study. The German quality of life questionnaire (KINDL®) scales were used to assess the children's HRQoL. For comparing the data of children with enuresis and healthy children, a two-sided unpaired t-test and linear regression model were used. RESULT: The total HRQoL score for the children with enuresis group was 63.14 ± 21.98 and for the children in the control group was 75.6 ± 10.1 (P < 0.001). After adjusting for sex and age using the unstandardized coefficient of regression model, HRQoL score for the children with enuresis still remained statistically significant lower than that for healthy peers (64.21 ± vs 75.11 ± P < 0.001). The HRQoL subscale scores showed that children with enuresis had lower emotional well-being scores (64.23 ± 14.2 vs 78.9 ± 11.4, P < 0.001), self-esteem score (62.23 ± 11 vs 68.6 ± 17.4, P = 0.001), family relationship score (76.23 ± 2 vs 83.4 ± 12.2, P = 0.042), and friendship score (62.4 ± 13.2 vs 68.8 ± 15.3, P = 0.023) compared to the control group. When the effects of independent sociodemographic factors and clinical variables on HRQoL were evaluated, it was seen that the presence of lower urinary tract symptoms (LUTS) negatively affected total HRQoL score (59.89 ± 11.2 vs 69.29 ± 10.9 P = 0.028). Also the total HRQoL score was higher in treated children with enuresis than in nontreated children (65.96 ± 12.1 vs 55.27 ± 10.1 P = 0.032). Among the treated children, complete treatment response group had higher total HRQoL score compared to partial treatment response group and nonresponse group (respectively, 70.98 ± 9.7, 65.25 ± 10.1, 60.45 ± 10.9, P = 0.034, P = 0.01) (Summary Figure). Family income level affected total HRQoL score, low-income group had lower total HRQoL score compared to high-income group (62.17 ± 11.9 vs 69.25 ± 10 P = 0.039). DISCUSSION: This study demonstrated that enuresis negatively affects the HRQoL of children and most affected domains in HRQoL were self-esteem, emotional well-being, and their relationship for family and friends. Our presented study showed that HRQoL was lower in non-primary monosymptomatic nocturnal enuresis (non-PMNE) children, nontreated patients. Also there were higher HRQoL scores in patients who had a total or partial response to treatment. CONCLUSION: Our study may indicate that, low-income children with enuresis, nontreated enuretic children, and presence of LUTS should be considered as a risk group for low HRQoL.

Assessment of Ten-Year-Long Results of Kidney Biopsies Performed on Children in the Thrace Region of Turkey.

BACKGROUND: Many children with kidney diseases can be diagnosed and treated without a biopsy. However, biopsy is a valuable method for the diagnostic and prognostic evaluation of children with kidney diseases. AIMS: To evaluate the clinical and pathological profiles of the kidney biopsies in our department to provide epidemiological data for clinical practice. STUDY DESIGN: Retrospective cross-sectional study. METHODS: Kidney biopsies and patient's charts in pediatric patients performed between May 2005 and February 2015 at the Pediatric Nephrology Department, Trakya University School of Medicine were assessed retrospectively. RESULTS: A total of 100 patients were examined. Their mean age was 9.62±4.26 years (range: 1-17 years); 54% of the patients were girls and 46% were boys. The most frequent indication for kidney biopsy was nephrotic syndrome (33%). The most common kidney disease was primary glomerulonephritis, which was observed in 65% of cases. IgA nephropathy (24%) was the most frequently observed subtype in primary glomerulonephritis groups. Secondary glomerulonephritis was diagnosed in 35% of cases. Systemic lupus erythematosus (51%) was the most frequently observed subtype in the secondary glomerulonephritis groups. CONCLUSION: IgA nephropathy and systemic lupus erythematosus were the most frequent primary and secondary glomerulonephritis in our region among children, respectively.

The clearance time of infused hematopoietic stem cell from the blood circulation.

There is no detailed information about the clearance time of infused hematopoietic stem cell (HSC) from the blood circulation in humans. In this prospective study, peripheral blood CD34+ cell counts were detected during the 4days period following autologous HSC transplantation in 20 patients by means of flow cytometry. The median CD34+ cells were at the highest level in the first hour and decreased below pre-infusion values on the first day after HSC infusion. By nonparametric analysis, positive correlation was found between CD34+ cell levels at the first hour and the post-thaw CD34+ cell dose (r=0.57, p=0.01). An inverse correlation was determined between CD34+ cell levels at the first hour and neutrophil engraftment (r=-0.54, p=0.01). Compared with the patients having CD34+ cell count of ⩾2µL(-1) in the first hour following HSC infusion, the patients having CD34+ cell count of <2µL(-1) had delayed both neutrophil (20 vs. 12, p=0.008) and platelet (47 vs. 11, p=0.01) engraftments. Our results indicated that infused HSCs were removed from the blood circulation within 1day. In addition, CD34+ cell levels at the first hour may be used as an important indicator to predict the delay of neutrophil and platelet engraftments.

Risk factors for renal scarring in children with primary vesicoureteral reflux disease.

To determine the incidence of renal scarring among patients with primary vesicoureteral reflux (VUR) and the possible risk factor(s), we studied 90 children (60 girls and 30 boys) with VUR followed in the Pediatric Nephrology Unit at the Ege University Hospital from 1998 to 2003. All the patients were assessed for VUR grade by voiding cystoureterography and for presence of renal scarring by (99 m) technetium dimercapto-succinic acid scintigraphy. All infants with VUR were given low-dose prophylactic antibiotics and followed-up until resolution of the reflux. Grade of reflux and number of urinary tract infection (UTI) episodes (≥3) were found to be statistically significant risk factors for renal scarring (P <0.05). However, gender, familial history and laterality of the disease were not found to be statistically significant risk factors (P >0.05). Similarly, there was no statistically significant difference of frequency of renal scarring among the different age groups (P >0.05). We conclude that recurrences of UTI and VUR severity are significant risk factors for renal scarring in children with VUR. Therefore, identification of VUR at an early age may offer the opportunity to prevent episodes of UTI and possible formation of renal scars that may result in end-stage renal failure.

Association of FAS -670A/G and FASL -843C/T Gene Polymorphisms on Allograft Nephropathy in Pediatric Renal Transplant Patients.

OBJECTIVE: FAS and FASL polymorphisms are suggested to play an important role in tubulitis that is a major component of acute rejection. The aim of this study was to investigate the role of FAS-670A/G and FASL-843C/T gene polymorphisms on allograft nephropathy in pediatric renal transplant patients METHODS: Fifty three patients (22 males 31 females) aged 2 to 20 years (mean 12.3±0.6) who had renal transplantation and fifty healthy control subjects (25 males 25 females) were enrolled in the study. Pearson's Chi Square test was used for the statistical analysis. Survival rates were estimated with the Kaplan Meier method. Age, sex, chronic renal failure etiology, treatment modality and duration and donor type were recorded. FAS-670A/G and FASL-843C/T gene polymorphisms were compared between renal transplant patients and normal healthy population as well as between renal transplant patients with and without acute rejection. FINDINGS: FAS-670A/G genotypes or alleles were not significantly different between control and transplant patients and among transplant patients with and without acute rejection (P>0.05 for all). FASL-843C/T genotypes and alleles were not different between transplantation and control groups (P>0.05 for all). However, FASL-843C/T alleles were significantly different between patients with and without AR (P=0.02). The percentages of C allele were higher in children with acute rejection (68.8% vs 44.6%). CONCLUSION: FASL gene polymorphisms may play a major role in acute rejection while FAS polymorphisms have not been found to be different between patients with and without acute renal graft rejection.

Association of macrophage migration inhibitory factor -173C allele polymorphism with steroid resistance in children with nephrotic syndrome.

The potential effects of macrophage migration inhibitory factor (MIF) on the natural immune response are due to the inhibition of immune cell activation, which is regulated by glucocorticoids. In this study, we investigated MIF -173G/C genotype and C allele frequency in 214 patients with idiopathic nephrotic syndrome (INS) and 103 healthy volunteers. We found significant increases in GC genotype (OR=3, p=0.0009) and C allele frequency (OR=2.5, p=0.0007) in INS. Upon classifying patients as steroid responsive (n=137) or resistant (n=77), a 20-fold over-expression of the CC-genotype was found in the steroid-resistant group (OR=20, p=0.0002). Moreover, a significant increase in C allele frequency in patients with focal segmental glomerulosclerosis (FSGS) has also been noted when compared with other histopathological groups (OR=3.2, p=0.0017). Furthermore, significant increases in the CC genotype (15.6% vs 3.3%) and C allele (75% vs 32%) frequencies have been found in patients with permanent renal function failure (p=0.013 and p=0.0002, respectively). Patients with the CC genotype were found to be at considerably increased risk of permanent renal failure (OR=5.43, p=0.013) and end-stage renal disease (OR=5.53, p=0.020). Additionally, there was a correlation between age of detection of proteinuria and CC genotype. We found an earlier age of onset of proteinuria in patients with the CC genotype (1.9+/-1.7 years) than in patients who were GC-heterozygous (3.7+/-3.1 years) and GG-homozygous (3.6+/-2.9 years, p=0.88). In summary, our results indicate that the MIF -173 C allele confers an increased risk of susceptibility to INS and plays a crucial role in glucocorticoid responsiveness.

Gene locus ambiguity in posterior urethral valves/prune-belly syndrome.

Lower urinary tract obstruction by posterior urethral valves (PUV) is an important cause of congenital renal failure in male infants. Though population-based studies point to a role of genetic factors in the etiology of PUV, no clear evidence for a specific gene defect for PUV has been observed so far. Here we present a consanguineous family with four male descendants affected by PUV and a healthy girl, suggestive of autosomal recessive inheritance. One boy presented with prune-belly syndrome (PBS) in addition to PUV. Using a DNA chip-based genome-wide linkage analysis, we identified a region of homozygosity for the affected boys in an interval of 35 cM on chromosome 1q41-44 with a maximum multipoint LOD score of Z(max) = 3.134 at theta = 0 for single nucleotide polymorphisms (SNPs) rs158724-rs720163. By applying a second genetic model based on the assumption of a male-limited phenotype and the girl being carrier of the genetic defect without expressing the phenotype, a second alternative locus of 9 cM on chromosome 11p11 was identified with a LOD score of Z(max) = 3.61 at theta = 0. Equal significance for both loci with a LOD score of Z(max) = 3.01 at theta = 0 was obtained after the affection status of the female descendant was set "unknown". We suppose that most probably, only one of the two identified loci harbours the disease-causing gene. As the interpretation of the girl's status remains uncertain, we are not able to exclude one of the two loci. Analyses of additional informative families will be important to exclude one of the two loci and to restrict the critical interval.

The role of keto acids in the supportive treatment of children with chronic renal failure.

According to the hyperfiltration theory of renal diseases characterized by a decrease in the number of functional nephrons, increased arterial blood pressure, excessive protein intake in the diet, high levels of calcium (Ca) and phosphorus (P), secondary hyperparathyroidism, hypertriglyceridemia and/or hypercholesterolemia, proteinuria and metabolic acidosis are some factors that impair the prognosis of the disease. The amount of protein in the diet is the most important of these factors. A protein-restricted diet administered to patients with chronic renal failure results in the risk of inadequate amino acid intake. To overcome this problem, the use of dysaminated alpha-keto analogues has been considered to reduce the risk of nitrogenemia resulting from the continuous intake of essential amino acids. Currently, the necessity of essential amino acids even in adult patients with chronic renal failure is controversial; besides, trials on the use of these amino acids in pediatric patients are scarce. The aim of this study is to investigate the efficacy and applicability of conservative therapy with a protein-restricted diet supplemented with keto acids in the management of chronic renal insufficiency or failure.

The elevated markers of hypercoagulability in children with Henoch-Schönlein purpura.

Twenty-eight children with HSP and 79 healthy children were entered into study. Activities of protein C, free-protein S and antithrombin, activated protein C resistance, levels of fibrinogen. D-dimer, thrombin-antithrombin complex (TAT), prothrombin fragments 1 + 2 (PF(1+2)), and von Willebrand factor antigen (vWAg) and its activity (RiCof) were investigated in acute and recovery phases of HSP and controls. Fibrinogen, D-dimer, TAT, PF(1+2), vWAg, and RiCof levels in patients with HSP during the acute phase were significantly higher than those of recovery phase and of the controls. A significant correlation was detected between severity of disease and TAT, PF(1+2), vWAg, and D-dimer levels.

Hypercoagulability risk factors in children with minimal change disease and the protective role of protein-C activity.

It is believed that thrombotic activity in nephrotic syndrome is due to an imbalance between procoagulant/thrombotic and anticoagulant/antithrombotic factors in plasma. The aim of this study was to investigate the hypercoagulability risk in childhood minimal change disease and to find possible protective mechanisms with respect to hemostasis. Twenty-six children with minimal change disease were enrolled in this study. All patients were evaluated during an attack and on remission. The control group consisted of 33 healthy children. During the attack period, prothrombosis parameters, total lipid, cholesterol, fibrinogen levels and platelet count increased significantly compared to levels in the remission period. This denotes that hyperviscosity increases thrombosis tendency. In the attack period, the significant increase of prothrombin fragments 1 + 2 which shows thrombin formation and thrombin-antithrombin complex which causes prothrombin activation, are an indication of increased thrombosis risk. Five patients with lupus anticoagulant present and 7 patients with, activated protein-C resistance ratios carried an increased thrombosis risk. D-dimer level of fibrinolytic factors significantly increased during the attack period. These findings emphasize the existence of thrombotic activity causing the activation of the fibrinolytic system. The significant increase in protein-C activity in these patients represents one of the protective mechanisms against thrombosis. The decrease in tissue plasminogen activator and antiplasmin indicates the protective role of fibrinolytic activity. Consequently, an increase in the protein-C activity is one of the protective mechanisms. The fibrinolytic system also plays an important role in preventing thrombotic activity in these patients.

Effect of sucking characteristics on breast milk creamatocrit.

One of the problems in the care of healthy children is that mothers often give infant formulae to their normally growing infants in the first 4 months of life because they believe that they are unable to satisfy them. However, the association of fat content in breast milk with the sucking pattern of the infant is not clearly known. In order to determine whether the fat concentration of human milk was associated with sucking characteristics of the infants, 80 healthy 2-month-old babies and their mothers were included in the study. Milk creamatocrit was assessed at the beginning, at the first, fifth and 10th minutes and at the end of breast feeding. The creamatocrit values increased as the time elapsed from the beginning of breast feeding. There was an inverse relationship between milk volume and creamatocrit at both the beginning and the end of breast feeding (P < 0.05). The mean milk volume was higher and the mean creamatocrit at the end of breast feeding was lower in the infants whose 2-month weight gain was higher than the 75th percentile (75P) compared with those whose 2-month weight gain was lower than the 25th percentile (25P) (for milk volume 105 +/- 36 mL vs. 76 +/- 30 mL, respectively, P < 0.05; and for creamatocrit value 11.4 +/- 4.0 vs. 14.3 +/- 3.8, respectively, P < 0.05). Milk volume is the most important factor affecting weight gain of exclusively breast-fed babies, and fat concentration of human milk is not a primary determining factor in individual differences in weight gain of the infants and appears to be secondary to factors such as number of feeds per day, duration of breast feeding and the volume of milk sucked.