Comparison of diagnostic accuracy of models combining the renal biomarkers in predicting renal scarring in pediatric population with vesicoureteral reflux (VUR).

INTRODUCTION: Renal scarring is prominently observed in children with vesicoureteral reflux (VUR) and can lead to complicated renal outcomes. Although biopsy is the gold standard to detect renal scarring, it is an invasive procedure. There are established renal biomarkers which can help detect renal scarring. Individual biomarkers have not shown to have extensively good discriminatory ability for this. AIM: This paper aims at combining the values of multiple biomarkers in models to detect renal scarring. METHODOLOGY: Secondary data with the values of renal biomarkers like kidney injury molecule-1, neutrophil gelatinase-associated lipocalin (NGAL), and urinary creatinine along with the renal scarring status was considered. Logistic regression, discriminant analysis, Bayesian logistic regression, Naïve Bayes, and decision tree models were developed with these markers. The discriminatory ability of individual biomarkers along with the models was assessed using the area under the curve from ROC curve. Sensitivity, specificity, and misclassification rates were estimated and compared. RESULTS: NGAL was the most predominant renal biomarker in classifying the patients with renal scarring (AUC: 0.77 (0.67, 0.87); p value < 0.001). Each of the model performed better than individual biomarkers. Decision tree (AUC: 0.83 (0.74, 0.91); p value < 0.001) and Naïve Bayes model (misclassification rate = 20.2%) performed the best amongst the models. CONCLUSION: Combining the values of renal biomarkers through a statistical or machine learning model to detect renal scarring is a better approach as compared to considering individual renal biomarkers.

Characterizing Patients with Recurrent Urinary Tract Infections in Vesicoureteral Reflux: A Pilot Study of the Urinary Proteome.

Recurrent urinary tract infections (UTIs) pose a significant burden on the health care system. Underlying mechanisms predisposing children to UTIs and associated changes in the urinary proteome are not well understood. We aimed to investigate the urinary proteome of a subset of children who have vesicoureteral reflux (VUR) and recurrent UTIs because of their risk of developing infection-related renal damage. Improving diagnostic modalities to identify UTI risk factors would significantly alter the clinical management of children with VUR. We profiled the urinary proteomes of 22 VUR patients with low grade VUR (1-3 out of 5), a history of recurrent UTIs, and renal scarring, comparing them to those obtained from 22 age-matched controls. Urinary proteins were analyzed by mass spectrometry followed by protein quantitation based on spectral counting. Of the 2,551 proteins identified across both cohorts, 964 were robustly quantified, as defined by meeting criteria with spectral count (SC) ≥2 in at least 7 patients in either VUR or control cohort. Eighty proteins had differential expression between the two cohorts, with 44 proteins significantly up-regulated and 36 downregulated (q <0.075, FC ≥1.2). Urinary proteins involved in inflammation, acute phase response (APR), modulation of extracellular matrix (ECM), and carbohydrate metabolism were altered among the study cohort.

Validity of urine neutrophile gelatinase-associated lipocalin in children with primary vesicoureteral reflux.

BACKGROUND: Vesicoureteral reflux (VUR) is the most common congenital urinary tract abnormality in children. The objective of this study was to evaluate the diagnostic value of urine neutrophil gelatinase-associated lipocalin (NGAL) in children with primary vesicoureteral reflux (VUR). MATERIALS AND METHODS: A total of 69 patients were evaluated in 2 groups with (32) and without (37) VUR. Patients with secondary VUR, infectious or inflammatory disorders, obstructive uropathies, and acute or chronic kidney disease were excluded. Urine NGAL level was measured by ELISA kit. RESULTS: Mean age of children with VUR was 36.84 ± 28.16, compared to those without VUR 32.32 ± 29.08, with no significant difference (p = 0.51). Mean urine NGAL (p = 0.012) and urine NGAL/Cr (p = 0.003) were higher in patients with VUR. In addition, urine NGAL/Cr increased significantly in patients with decreased parenchymal function, compared to those with normal DMSA scan. Using the cutoff value of 0.888, urine NGAL had 84% sensitivity and 81% specificity for diagnosis of VUR. Based on AUC (0.86), urine NGAL had acceptable diagnostic accuracy in children with VUR. CONCLUSION: The results of this study support the evidence that urine NGAL/Cr is a sensitive, specific and accurate biomarker for diagnosis of children with primary VUR.

Common clinical markers predict end-stage renal disease in children with obstructive uropathy.

BACKGROUND: Obstructive uropathy (OU) is a common cause of end-stage renal disease (ESRD) in children. Children who escape the newborn period with mild-to-moderate chronic kidney disease (CKD) continue to be at increased risk. The predictive ability of clinically available markers throughout childhood is poorly defined. METHODS: Patients with OU were identified in the Chronic Kidney Disease in Children Study. The primary outcome of interest was renal replacement therapy (RRT) (cases). Controls were age matched and defined as patients within the OU cohort who did not require RRT during study follow-up. RESULTS: In total, 27 cases and 41 age-matched controls were identified. Median age at baseline and age at outcome measurement were 10 vs. 16 years, respectively. First available glomerular filtration rate (GFR) (36.9 vs. 53.5 mL/min per 1.73 m2), urine protein/creatinine (Cr) (0.40 vs. 0.22 mg/mg) and microalbumin/Cr (0.58 vs. 0.03 mg/mg), and serum CO2 (20 vs. 22 mmol/L) and hemoglobin (12.4 vs. 13.2 g/dL) differed significantly between cases and controls, respectively. GFR declined 3.07 mL/min per 1.73 m2/year faster in cases compared to that in controls (p < 0.0001). Urine protein/Cr and microalbumin/Cr increased by 0.16 and 0.11 per year more in cases compared to those in controls, respectively (p ≤ 0.001 for both). Serum phosphate increased by 0.11 mg/dL and serum albumin and hemoglobin decreased by 0.04 (g/dL) and 0.14 (g/dL) per year more for cases compared to those for controls, respectively (p < 0.05 for all). CONCLUSIONS: Age-specific baseline and longitudinal measures of readily available clinical measures predict progression to ESRD in children with mild-to-moderate CKD from OU.

Ureteral dilatation detected in magnetic resonance imaging predicts vesicoureteral reflux in children with urinary tract infection.

OBJECTIVE: Urinary tract infection (UTI), one of the most common bacterial infections occurring during infancy and early childhood, is frequently associated with vesicoureteral reflux (VUR). Although several guidelines recommend performing ultrasonography as a screening test, its utility is not adequate and appropriate screening tests are strongly desirable. In this study, we evaluate the use of magnetic resonance imaging (MRI) as a screening test for VUR in children with UTI. METHODS: We prospectively studied 108 patients with suspected UTI between April 2014 and March 2016. UTI was diagnosed on the basis of diffusion-weighted MRI (DW-MRI) and urine culture findings. We measured ureteral dilatation using MRI in 96 patients with UTI and assessed the relationship between ureteral dilatation in MRI and VUR in 46 patients who underwent voiding cystourethrography (VCUG). RESULTS: Among 108 patients, 88 and 8 were diagnosed with upper and lower UTI, respectively. Among 46 patients who underwent VCUG, 23 had VUR (14 low grade and 9 high grade). Patients with ureteral dilatation detected on MRI had VUR more frequently than those without ureteral dilatation (any grades VUR, 71% vs. 32%; P = 0.02; high-grade VUR, 38% vs. 2%, P = 0.007). Overall, ureteral dilatation findings on MRI achieved sensitivity 65.2% and specificity 73.9% as a screening test for VUR. In addition, DW-MRI achieved sensitivity 100% and specificity 81.8% in the diagnosis of upper UTI. CONCLUSION: These findings suggested that MRI is a valuable tool for screening of VUR as well as diagnosis of upper UTI.

Imaging studies and biomarkers to detect clinically meaningful vesicoureteral reflux.

The work-up of a febrile urinary tract infection is generally performed to detect vesicoureteral reflux (VUR) and its possible complications. The imaging modalities most commonly used for this purpose are renal-bladder ultrasound, voiding cystourethrogram and dimercapto-succinic acid scan. These studies each contribute valuable information, but carry individual benefits and limitations that may impact their efficacy. Biochemical markers are not commonly used in pediatric urology to diagnose or differentiate high-risk disease, but this is the emerging frontier, which will hopefully change our approach to VUR in the future. As it becomes more apparent that there is tremendous clinical variation within grades of VUR, the need to distinguish clinically significant from insignificant disease grows. The unfortunate truth about VUR is that recommendations for treatment may be inconsistent. Nuances in clinical decision-making will always exist, but opinions for medical versus surgical intervention should be more standardized, based on risk of injury to the kidney.

Urinary excretion of EGF and MCP-1 in children with vesico-ureteral reflux

ABSTRACT Purpose The aim of this study was to investigate the urinary concentration of epidermal growth factor (EGF) and monocyte chemotactic protein-1 (MCP-1) as reflux nephropathy (RN) biomarkers before and after endoscopic treatment of moderate to severe vesico-ureteral reflux (VUR). Materials and methods A prospective study was carried out on 72 children with moderate to severe VUR. All patients underwent endoscopic treatment using Macroplastique® or Deflux®. Vesico-ureteral reflux resolution was tested by post-operative voiding cystourethrography after 3 months and 2 years. Follow-up urinary samples were collected at that time. Control samples were taken from healthy children with no clinical evidence of renal and bladder disease and no history of UTI. Results In VUR patients, pre-operative urinary EGF levels had a down-regulation when compared to controls. Following successful VUR repair, urinary EGF levels of VUR children progressively increased only at long term follow-up but without returning to normal levels. Urinary MCP-1 levels were highly expressed in pre-operative samples and decreased markedly during early post-operative measurements. Urinary MCP-1 levels did not further decreased in late post-operative follow-up. In fact, these levels remained significantly higher when compared to controls. Conclusions Urinary levels of EGF and MCP-1 may become useful markers for monitoring the response to surgical treatment in VUR patients. Although endoscopic VUR treatment is effective in reducing the inflammatory response, the persistence of significant abnormal levels of inflammatory cytokines (such as urinary MCP-1) at long term follow-up suggests that surgery alone may not completely treat the chronic renal inflammation evidenced in these children.

Urinary albumin excretion and chronic kidney disease in children with vesicoureteral reflux.

BACKGROUND: Albuminuria is a potential biomarker of chronic kidney disease (CKD) in various glomerular diseases. Vesicoureteral reflux (VUR) often progresses to CKD, and study is required of use of albuminuria as a biomarker for this condition. The aim of this study was to evaluate the association between albuminuria and glomerular filtration rate (GFR) or filtration fraction (FF) in children with VUR. STUDY DESIGN: In this retrospective study, renal parameters of 141 children with VUR were investigated, using inulin clearance, FF, and albuminuria. The association between urinary albumin to creatinine ratio (ACR), GFR, and FF was analyzed in a continuous manner by calculating the ß coefficient, and also in a binary manner by calculating the OR. RESULTS: Using both continuous and binary analyses, ACR values were negatively and significantly associated to GFR values in patients with low, normal, or high FF values (Table). It was also positively and significantly associated with FF values in patients with low, normal or high GFR values (Table). No association was found between ACR and gender, VUR stages or laterality, number of urinary tract infection, presence of a single functional kidney, history of reflux surgery, or renal scars or hypertension. DISCUSSION: ACR is associated with CKD in patients with VUR. In addition, increased urinary albumin excretion cannot be completely and solely explained by decreased GFR and/or increased FF values. The two main limitations of this study are the crude assessment of renal scarring, which prevented finer analysis between albuminuria and renal scarring surface area, and that the study cohort may not be representative of the true VUR population. CONCLUSION: This study shows that albuminuria is associated with decreased renal function in patients with VUR and that it could be used to monitor renal function in this condition.

Urinary excretion of EGF and MCP-1 in children with vesicoureteral reflux.

PURPOSE: The aim of this study was to investigate the urinary concentration of epidermal growth factor (EGF) and monocyte chemotactic protein-1 (MCP-1) as reflux nephropathy (RN) biomarkers before and after endoscopic treatment of moderate to severe vesico-ureteral reflux (VUR). MATERIALS AND METHODS: A prospective study was carried out on 72 children with moderate to severe VUR. All patients underwent endoscopic treatment using Macroplastique ® or Deflux®. Vesico-ureteral reflux resolution was tested by post-operative voiding cystourethrography after 3 months and 2 years. Follow-up urinary samples were collected at that time. Control samples were taken from healthy children with no clinical evidence of renal and bladder disease and no history of UTI. RESULTS: In VUR patients, pre-operative urinary EGF levels had a down-regulation when compared to controls. Following successful VUR repair, urinary EGF levels of VUR children progressively increased only at long term follow-up but without returning to normal levels. Urinary MCP-1 levels were highly expressed in pre-operative samples and decreased markedly during early post-operative measurements. Urinary MCP-1 levels did not further decreased in late post-operative follow-up. In fact, these levels remained significantly higher when compared to controls. CONCLUSIONS: Urinary levels of EGF and MCP-1 may become useful markers for monitoring the response to surgical treatment in VUR patients. Although endoscopic VUR treatment is effective in reducing the inflammatory response, the persistence of significant abnormal levels of inflammatory cytokines (such as urinary MCP-1) at long term follow-up suggests that surgery alone may not completely treat the chronic renal inflammation evidenced in these children.

Urinary biomarkers for renal tract malformations.

INTRODUCTION: Renal tract malformations (RTMs) are congenital anomalies of the kidneys and urinary tract, which are the major cause of end-stage renal disease in children. Using immunoassay-based approaches (ELISA, western blot), individual urinary proteins including transforming growth factor ß, tumor necrosis factor and monocyte attractant proteins 1 were found to be associated to RTMs. However, only mass spectrometry (MS) based methods leading to the identification of panels of protein-based markers composed of fragments of the extracellular matrix allowed the prediction of progression of RTMs and its complications. Areas covered: In this review, we summarized relevant studies identified in "Pubmed" using the keywords "urinary biomarkers" and "proteomics" and "renal tract malformations" or "hydronephrosis" or "ureteropelvic junction obstruction" or "posterior urethral valves" or "vesicoureteral reflux". These publications represent studies on potential protein-based biomarkers, either individually or combined in panels, of RTMs in human and animal models. Expert commentary: Successful use in the clinic of these protein-based biomarkers will need to involve larger scale studies to reach sufficient power. Improved performance will potentially come from combining immunoassay- and MS-based markers.

Emphysematous pyelitis and cystitis associated with vesicoureteral reflux in a diabetic dog.

A 12-year-old female dog with a 3-month history of poor response to diabetes treatment had an acute worsening of symptoms, including weakness and blindness. The dog had elevated blood glucose, alkaline phosphatase and urea concentration, hyposthenuria, glycosuria, hematuria, and pyuria. Escherichia coli was isolated from the urine. Radiographs and ultrasound examination showed that the dog had unilateral emphysematous pyelitis and concurrent cystitis associated with vesicoureteral reflux.

Pyélite emphysémateuse et cystite associées au reflux vésico-urétéral chez une chienne diabétique. Une chienne âgée de 12 ans avec une anamnèse de 3 mois de mauvaise réponse au traitement du diabète a présenté un aggravement aigu des symptômes, y compris de la faiblesse et de la cécité. La chienne avait une glycémie élevée, ainsi que des concentrations sériques élevées de la phosphatase alcaline et d'urée, de l'hyposthénurie, de la glycosurie, de l'hématurie et de la pyurie. Escherichia coli a été isolé de l'urine. Des radiographies et des échographies ont montré que la chienne était atteinte de pyélite emphysémateuse unilatérale et de cystite concomitante associées au reflux vésico-urétéral.(Traduit par Isabelle Vallières).

Urinary microprotein concentrations in the long-term follow-up of dilating vesicoureteral reflux patients who underwent medical or surgical treatment.

PURPOSE: This study examined the relationship between urinary microprotein concentrations and renal functional parameters in children with dilating (grade III-V) vesicoureteral reflux (VUR) who underwent either medical or surgical treatment. METHODS: All 44 dilating VUR patients who were followed for 4 years were screened for inclusion in this study. The patients' clinical features and clinical outcomes, as well as the urinary activities of albumin (ALB), transferrin (TRF), immunoglobulin G (IgG), alpha-1-microglobulin (α1-MG), and N-acetyl-ß-glucosaminidase (NAG), were retrospectively analyzed. RESULTS: High values of NAG, α1-MG, IgG, TRF, and ALB were noted in 73.33, 58.33, 43.33, 24.14, and 53.33 % of patients, respectively, at the first examination. Cystatin C, eGFR, and urinary microprotein levels were associated with a good prognosis after 4 years of follow-up. No differences in recurrent UTI, cystatin C concentration, most microprotein/creatinine (Cr) ratios, eGFR, or ΔGFR4 % were found between the groups. High levels of urinary proteins were found in 2.38-9.52 % of cases after 4 years of follow-up. ALB/Cr, IgG/Cr, and α1-MG/Cr levels were positively correlated with 99mTc-dimercaptosuccinic acid (DMSA) grade, and α1-MG excretion was inversely correlated with eGFR. CONCLUSIONS: The levels of microprotein were elevated at diagnosis in a higher proportion of patients than for the other markers examined. At long-term follow-up, the reflux level had decreased or completely resolved in all patients, and the proportions of microproteins that were elevated were significantly reduced. Renal impairment measured by eGFR and DMSA grade was related to increased urinary α1-MG levels.

Assessment of kidney function in children by enzymatic determination of 2- or 24-h creatinine clearance: comparison with inulin clearance.

BACKGROUND: Although renal inulin clearance (Cin) is the gold standard for evaluation of kidney function, it cannot be measured easily. Therefore, creatinine clearance (Ccr) is often used clinically to evaluate kidney function. Enzymatically measured Ccr was recently found to be much higher than Cin because of the tubular secretion of creatinine (Cr). This study compared three measures of renal clearance, inulin, 2-h Ccr, and 24-h Ccr, in children. METHODS: Kidney function was evaluated in 76 children (51 males and 25 females) aged 1 month to 18 years with chronic kidney disease (CKD) by three renal clearance methods at almost the same time. RESULTS: Correlations between each pair of three renal clearance measurements were determined. Approximate glomerular filtration rate (GFR) was equal to 62 % of 2-h Ccr or 76 % of 24-h Ccr. CONCLUSION: Cr secretion by renal tubules was approximately 50 % of the GFR. In this study, we indicate that the measurements of 2-h Ccr or 24-h Ccr do not show true GFR but we could infer approximate GFR from the values. The use of 2- or 24-h Ccr might contribute to the treatment of pediatric CKD patients.

Role of new biomarkers for predicting renal scarring in vesicoureteral reflux: NGAL, KIM-1, and L-FABP.

BACKGROUND: Reflux nephropathy is the most serious complication of vesicoureteral reflux (VUR). The aim of this study was to assess the role of urinary levels of neutrophil-gelatinase-associated lipocalin (NGAL),kidney injury molecule-1 (KIM-1), and liver-type fatty-acid-binding protein (L-FABP) in the early diagnosis of reflux nephropathy in patients with VUR. METHODS: This study assessed 123 patients with primary VUR and 30 healthy children as a control group. The children were divided into five groups: Group A, patients with VUR and renal parenchymal scarring (RPS); Group B, patients with VUR and without RPS; Group C, patients with RPS and resolved VUR; Group D, patients with resolved VUR and without RPS; Group E, healthy reference group. RESULTS: Median urinary NGAL (uNGAL)/Creatinine (Cr) was significantly higher in patients with than those without RPS and the control group (p = 0.0001). Median uKIM-1/Cr was similar in all groups (p = 0.417). Median uL-FABP/Cr was significantly higher in patients with RPS than in the reference group (p < 0.05). CONCLUSIONS: Urinary NGAL levels may be used as a noninvasive diagnostic marker for predicting renal scarring in reflux nephropathy.

Urinary albumin and interleukin-8 levels are not good indicators of ongoing vesicoureteral reflux in children who have no active urinary tract infection.

INTRODUCTION: Vesicoureteral reflux (VUR) is a risk factor for kidney scarring, hypertension and declining renal function. Standard diagnostic methods are invasive and can cause exposure to radiation and urinary tract infections (UTIs). We aimed to investigate urine albumin and interleukin-8 levels as markers of ongoing VUR and renal damage in children without UTIs. METHODS: Random urine samples were collected from 51 children, including 16 children with VUR (group A), 17 children with resolved VUR (group B) and 18 normal children (group C). The diagnosis of VUR or resolved VUR was confirmed by voiding cystourethrogram (VCUG) or direct radionuclide cystography (DRNC). All children had normal kidney function and had no evidence of UTI in the preceding three months. Random urine specimens were assayed for albumin (Alb), creatinine (Cr) and interleukin-8 (IL-8) and mean values were compared by one way ANOVA. RESULTS: In groups A and B, the mean age at first UTI was 31.7 ± 2.4 and 27 ± 2.0 months respectively. In group A, the mean duration between VUR diagnosis and study entrance was 30 ± 9.1 months. In group B, the mean duration between VUR diagnosis and recovery was 19.9 ± 1.3 months. Overall, 76.4% of affected children had bilateral VUR and 41.2% had severe VUR. There were no significant differences in urinary Alb, IL-8, Alb/Cr and IL-8/Cr between the three groups. CONCLUSION: The current study does not support the hypothesis that microalbuminuria or urinary IL-8 are good indicators of ongoing VUR and renal injury in children.

[Utility of urine levels of interleukins in the diagnosis of vesicoureteral reflux: a case-control study in children]. / Utilidad de los niveles urinarios de interleuquinas en el diagnóstico del reflujo vésico-ureteral: estudio de casos y controles en niños.

UNLABELLED: Invasive imaging methods that require catheterization are used for the diagnosis of vesicoureteral reflux. Our aim is to assess the usefulness of interleukin urinary levels for the diagnosis of reflux in children without urinary tract infection. METHODS: Case-control study in children who underwent a voiding cystourethrogram: forty cases diagnosed of reflux and 80 controls. Concentrations of IL-1beta, IL-6 and IL-8 related to creatinine levels (pg/micromol) were determined in urine samples in all. RESULTS: Sixty-two patients were males and fifty-eight females, with a mean age of 2.4 years. Indications for cystography were previous urinary tract infection in 78 cases (65%), prenatal diagnosis in 24 cases (20%) and postnatal diagnosis of uropathy or family history in 18 cases (15.1%). No significant differences were observed between cases and controls in IL-1beta/creatinine and IL-6/creatinine levels. However, IL-8/creatinine levels were almost significant higher in case group (median 3.5 pg/micromol; SD 9.2) than in control group (median 1.54 pg/micromol; SD 3) (P=0.001). The odds ratio was 5.57 (CI95%: 1.51 a 20.60) (X(MH)=2.80; p=0.005). CONCLUSIONS: Urinary levels of IL-8/creatinine are elevated in children with vesicoureteral reflux, even in absence of urinary tract infection. It could be used as a non-invasive marker for detection of subclinical cases of disease.

Urine interlukein-8 as a diagnostic test for vesicoureteral reflux in children.

BACKGROUND: Vesicoureteral reflux (VUR) is a common finding in children with urinary tract infection (UTI), mostly diagnosed by voiding retrograde cystogram (VCUG). Children with VUR are at higher risk of renal damage with recurrent infections. Detecting VUR and renal scarring currently depends on imaging modalities with interventional invasive diagnostic methods. Noninvasive methods would greatly facilitate diagnosis and also help in identifying VUR in siblings of index cases who should be screened. Various imaging and biochemical methods with different specificity and sensitivity have been presented as substitute diagnostic tool for VCUG to identify VUR. Interleukin-8 (IL-8), a chemokine produced by damaged epithelial cells of the renal tract in response to inflammation, has been shown to increase during acute UTI. We have scarce data considering the cut point of urine IL-8 as a diagnostic method of VUR in children. The objective of this study was to assess the urine levels of IL-8 as a noninvasive marker of VUR in infants in the absence of a recent UTI episode. METHODS: This cross sectional study was conducted on28 patients with UTI and VUR (group 1), 28 patients with VUR and without UTI (group 2), and 28 healthy children/infants(control group)in St. Alzahra hospital, Esfahan, from January 2009 until March 2010.. Urine IL-8 level was measured for all children. The data was analyzed by SPSS soft ware version 17. The t-student test, ?2, and ANOVA were used as statistical method. RESULTS: The mean age of group 1, group 2 and control group were 4.3 +/- 2.9, 4 +/- 2.6 and 4 +/- 2.1 years respectively, p > 0.05. The mean level of IL-8 in group 1 was significantly higher than group 2 and control group 10 +/- 14.8 versus 6.5 +/- 8.4, and 2.9 +/- 4.5 respectively (P = 0.039). CONCLUSIONS: Although urinary IL-8 may be helpful in determining high grade VUR, but the results of this study showed that the sensitivity, specificity, PPV, and NPV of this marker were not satisfactory in cutoff point of 5 pg/pmol and other variables must be controlled.

Interleukin-6 and interleukin-8 levels in the urine of children with renal scarring.

BACKGROUND: Acute pyelonephritis (APN) is one of the most significant bacterial infections in infancy and early childhood, and can lead to permanent kidney damage and chronic renal failure. OBJECTIVE: To evaluate interleukin-6 (IL-6) and interleukin-8 (IL-8) levels in the urine of children with renal scarring (RS), searching for clinical information about the immuno-inflammatory process that contributes to RS. METHODS: Urine concentrations of IL-6 and IL-8 were evaluated in 50 children, 33 with RS detected after an episode of acute pyelonephritis (group A) and 17 children with a history of acute pyelonephritis, but without RS (group B). These children were divided into four groups: group A(1), 23 children with RS and vesicoureteral reflux (VUR); group A(2), 10 children with RS without VUR; group B(1), 13 children without RS and without VUR; group B(2), 4 children without RS, but with VUR. None of them had had urinary tract infection for a minimum of 6 months. To avoid dilution effects, urinary levels of IL-6 and IL-8 were expressed as the ratio of cytokine to urinary creatinine (pg/mg). RESULTS: Urinary IL-8 levels were below the lower detection limit in all samples. IL-6 was detectable in the majority of children with RS and below the detection limits in the urine samples of children without RS. There were no statistically significant differences between urinary interleukin-6 levels in children with and those without VUR. There was a significant relationship between the grade of renal scars, the time passed since the last episode of acute pyelonephritis and the urinary levels of IL-6 (p < 0.0001 and p < 0.04 respectively). CONCLUSION: Further experimental studies are required to demonstrate the correlation between histopathology and urinary cytokine levels.

Urinary proteome analysis to exclude severe vesicoureteral reflux.

OBJECTIVES: High-grade vesicoureteral reflux (VUR, grade IV or V) is a risk factor for renal scarring, impaired renal function, and arterial hypertension. Voiding cystourethrography is the gold standard for detecting the severity of VUR. High-grade VUR is present in the minority of children with urinary tract infection (UTI), thus exposing the majority to invasive diagnostics that have no surgical consequence. We therefore aimed at establishing a noninvasive test to identify children with high-grade VUR. METHODS: In a case-control study, a specific urinary proteome pattern was established by capillary electrophoresis coupled to mass spectrometry in 18 patients with primary VUR grade IV or V, distinguishing these from 19 patients without VUR after UTI. This proteome pattern was independently validated in a blinded cohort of 17 patients with VUR grade IV or V and 19 patients without VUR. RESULTS: Sensitivity in detecting VUR grade IV or V in the blinded study was 88%, specificity was 79%. The test's accuracy was independent of age, gender, and grade of VUR in the contralateral kidney. The odds ratio of suffering from VUR grade IV or V when tested positive was 28 (95% confidence interval: 4.5 to 176.0). CONCLUSIONS: This noninvasive test is ready for prospective validation in large cohorts with the aim of identifying those children with UTI and hydronephrosis in need of further invasive diagnostics, such as voiding cystourethrography, thus sparing most children without pathologic urinary proteome patterns from additional diagnostics.

[Comparison of two protocols of febrile urinary tract infection management in children]. / Comparaison de deux protocoles de prise en charge des infections urinaires fébriles de l'enfant.

PURPOSE: To compare two first febrile urinary tract infection (UTI) management protocols with regards to the diagnosis of high-grade vesicoureteral reflux (VUR) and cost. METHODS: This study compared two cohorts of children under 16 years of age, admitted for a first episode of febrile UTI. The first group (in 2005) was managed according to previous recommendations (IV treatment and cystography performed for all children under 3 years of age). The second group (in 2006) was managed according to age and procalcitonin level. High-grade VUR frequency, UTI recurrence, hospitalization rate, and cost were compared between the two cohorts. RESULTS: A total of 225 children were included in 2005 and 116 in 2006. High-grade VUR was found in 6.2 and 9.5% of the patients in 2005 and 2006, respectively (P=0.274). There was no statistically significant difference in the UTI recurrence rate between the two cohorts (5.3% in 2005 and 8.6% in 2006; P=0.237). The mean cost of an episode of febrile UTI was not significantly different in 2005 and 2006 (€2235 in 2005, €2256 in 2006; P=0.902), but was lower for children older than 6 months in 2006 (€1292 versus €1882 in 2005; P=0.0042). CONCLUSION: Our management protocol for a first febrile UTI episode in children based on procalcitonin levels seems to be suitable for the diagnosis of high-grade VUR. The hospitalization rate and the mean cost of management for children older than 6 months of age was significantly reduced in 2006. The management guidelines for a first occurrence of febrile UTI in children should be reconsidered.