Influence of genetic polymorphism in renin-angiotensin system-candidate genes on urinary trefoil family factor 3 levels in children with congenital anomalies of kidney and urinary tract.

BACKGROUND: This cross-sectional study aimed to determine the influence of genetic polymorphism in two renin-angiotensin system (RAS)-candidate genes on urinary trefoil family factor 3 (TFF3) levels in children with congenital anomalies of kidney and urinary tract (CAKUT). METHODS: The study included fifty children with CAKUT (PUV, VUR, and PUJO) and twenty age-matched controls. Urinary TFF3 levels were measured by enzyme-linked immunosorbent assay. Detection of genetic polymorphisms in two genes, i.e., I/D polymorphism (SNP at rs4340) in angiotensin-converting enzyme (ACE) and A/T polymorphism in the angiotensin II receptor type-2 (AT2R) due to point mutation at rs3736556 was performed by polymerase chain reaction. Progressive deterioration in kidney function was defined as fall in GFR to < 60 ml/min/1.73 m2 and/or progressive scarring. RESULTS: In our cohort, the genotypic distribution of patients and controls showed no difference. Progressive functional deterioration was significantly associated with the presence of D allele (p = 0.0004), A allele (p = 0.005), and both (p < 0.0001) in patients. Significantly raised TFF3 levels were detected in the urine of children having D allele (D/D > I/D > I/I; p < 0.0001) and A allele (A/A > A/T > TT; p < 0.0001). Also, children with both D/D and A/A allelic genotypes had significantly elevated urinary TFF3 compared to those having either of them. CONCLUSIONS: The presence of D allele and/or A allele is significantly associated with progressive functional deterioration and elevated urinary TFF3 levels. These findings support the role of angiotensin II-AT2R-NF-κB interaction in progressive deterioration of kidney function and subsequent TFF3 expression in CAKUT.

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.

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.

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.

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.

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.

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).

The role of urinary TIMP1 and MMP9 levels in predicting vesicoureteral reflux in neonates with antenatal hydronephrosis.

BACKGROUND: Antenatal hydronephrosis (AH) is commonly found on evaluation of pregnant women and 20-30 % of neonates have vesicoureteral reflux (VUR). In order to diagnose VUR, we required invasive testing and exposure of the neonate to radiation. The concentrations of a matrix metalloproteinase, MMP9, and its inhibitor TIMP1, were analyzed in hydronephrotic newborns with VUR and were compared to those without reflux. METHODS: The neonates with a history of prenatal hydronephrosis were enrolled in two groups based on imaging study results, the neonates with VUR and without VUR. Neonates with a normal prenatal history and postnatal ultrasound were placed in a third group. We measured the random urinary levels of MMP9, TIMP1, and creatinine, their cut-off values and the MMP9/Cr and MMP9/TIMP1/Cr ratio was calculated, and an ROC curve was drawn. RESULTS: Sixty-nine neonates were enrolled in three groups; 27 patients (20 male, seven female) with AH and VUR were in group 1, 23 neonates (19 male, four female) without VUR were placed in group 2, and 19 (15 male, four female) acted as controls in group 3. The differences between the three groups and the normal and total hydronephrotic groups were statistically significant for MMP9, the MMP9/Cr, MMP9/TIMP1, and MMP9/TIMP1/Cr ratios. The urinary TIMP1 and TIMP1/Cr ratios were not significantly different between the groups. A cut-off value of MMP9 was measured as 358.5 ng/ml (sensitivity [sens] 74 %, specificity [spec] 78 %) and was used to compare groups 1 and 2. For groups 2 and 3, this cut-off was 181.00 pg/ml (sens 91 %, spec 89 %). The cut-off values measured for the MMP9/TIMP1 ratio were 30.32 (sens 70 %, spec 61 %) and 9.85 (sens 96 %, spec 89 %) to compare groups 1 and 2, and 2 and 3, respectively. We found no valuable cut-offs for the TIMP1 and TIMP1/Cr values. There was no difference between neonates with mild, moderate, and severe VUR according to urinary biomarker concentrations. CONCLUSIONS: Evaluation of urinary levels of MMP9, or the MMP9/Cr, MMP9/TIMP1, or MMP9/TIMP1/Cr ratios may help us to differentiate the newborns with hydronephrosis and VUR from those without reflux.

The predictive value of urinary UPIb mRNA levels in VUR and recurrent urinary tract infections.

BACKGROUND: Vesicoureteral reflux (VUR) is a risk factor for progressive kidney damage especially when it is accompanied by urinary tract infections (UTIs). Uroplakins (UPs) are integral proteins found in the structure of urothelium. In the present study, we evaluated the usefulness of urinary UPIb messenger ribonucleic acid (mRNA) levels as an early and noninvasive diagnostic tool for VUR and as an indicator for predisposition to UTI. METHODS: Urinary UPIb mRNA levels were determined in patients experiencing their first UTI episode (n = 28) or recurrent UTI (n = 31) as well as patients having UTI with VUR (n = 30). These results were compared to a control group (n = 26). RESULTS: The UPIb mRNA values among patients diagnosed with their first UTI were lower, but not statistically different, than those in the control group. The UPIb mRNA levels of patients with recurrent UTI and UTI with VUR were significantly lower than those observed in control individuals. CONCLUSION: Urine UPIb levels may be useful for predicting the risk of recurrent UTI in patients diagnosed with their first UTI and may also be considered as a noninvasive screening test for VUR.

Microalbuminuria and hyperfiltration in subjects with nephro-urological disorders.

BACKGROUND: Microalbuminuria (MA) has been shown to be an early biomarker of renal damage. It is postulated that MA is the early result of hyperfiltration, which could evolve into glomerular sclerosis and renal failure if hyperfiltration is left untreated. We hypothesized that MA is a good indicator of hyperfiltration in children with kidney disorders, obviating the need to calculate the filtration fraction (FF). METHODS: A total of 155 children or young adults were prospectively included [42 single kidney (SK), 61 vesico-ureteral reflux, 23 obstructive uropathies, 29 other kidney diseases]. We measured inulin, para-aminohippuric acid clearances, FF and MA. Prediction of hyperfiltration was explored by studying the association between the FF and other variables such as urinary albumin (Alb), urinary albumin-creatinine ratio (ACR) and creatinine clearance. RESULTS: A significant but weak association between urinary Alb or ACR and FF was found in subjects with an SK (Spearman correlation coefficients 0.32 and 0.19, respectively). Multivariate analysis also showed that urinary Alb and ACR significantly predict FF only in subjects with an SK (r(2) = 0.17, P = 0.01 and r(2) = 0.13, P = 0.02, respectively). This holds true only in subjects with an SK and inulin clearance >90 mL/min/1.73 m(2) (r(2) = 0.41, P < 0.001). There was no association between creatinine clearance and FF. CONCLUSIONS: MA is not associated with FF in our subjects with nephro-urological disorders, except in those with an SK, where the association is weak, indicating that MA is due to other mechanisms than high FF and cannot predict hyperfiltration in such groups.

Interleukin-18, CRP and procalcitonin levels in vesicoureteral reflux and reflux nephropathy.

BACKGROUND: Some patients with vesicoureteral reflux (VUR) develop reflux nephropathy (RN) and a number of them progress to chronic kidney disease (CKD). However, it is unclear to predict which patient will develop RN and/or CKD. The aim of this study is to evaluate the role of Interleukin-18 (IL-18), C-reactive protein (CRP) and procalcitonin (PCT) as an indicator of RN in VUR. METHODS: Ninety-three children aged 3.5-16 years with primary VUR were enrolled. Patients were divided into two groups according to the presence of renal scarring (RS). CRP, PCT, blood urea nitrogen (BUN), serum creatinine (Scr), urinary protein (Up), creatinine (Ucr) and microalbumin (Umalb), serum and urine IL-18 levels were determined during urinary tract infection (UTI) free episode. RESULTS: BUN, Scr, Up/Ucr and Umalb/Ucr concentrations were higher whereas calculated creatinine clearance (Ccr) values were lower in RS (+) group compared to RS (-) group. CRP, PCT, serum and urine IL-18 levels and mean urine IL-18/Cr concentrations were similar in both groups. Serum and urine IL-18 levels did not differ according to the grade of VUR. No significant correlation was found between CRP, PCT and IL-18. CONCLUSIONS: Proteinuria and microalbuminuria are valuable hallmarks of RN. CRP and PCT seem not to be reliable indicators of RN in VUR patients. Moreover, serum and urine IL-18 might not predict RN.

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.

Matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 in vesicoureteral reflux.

The aim of this study was to investigate whether urine levels of matrix metalloproteinase 9 (uMMP9) and tissue inhibitor of metalloproteinase 1 (uTIMP1) are novel biomarkers of vesicoureteral reflux (VUR) and to determine the optimal cut-off levels of these enzymes to predict VUR in children. The study group consisted of 67 children with VUR and 20 healthy children. Urine MMP9 and TIMP1 levels were measured by an enzyme-linked immunosorbent assay. Children with VUR had significantly higher uMMP9 (1,539.8 vs. 256.4 pg/mL; p = 0.0001) and uTIMP1 (182 vs. 32.6 pg/mL; p = 0.0001) levels than healthy children. For the prediction of VUR, the sensitivity of uMMP9 was 67%, with a specificity of 85% [cut-off value 1,054 pg/mL; area under the curve (AUC) 0.77], and the sensitivity of uTIMP1 was 74%, with a specificity of 65% (cut-off value 18.7 pg/mL; AUC 0.73). Both uMMP9 and uTIMP1 levels were significantly higher in patients with renal scar (uMMP9: 3,117.3 vs. 1,234.15 pg/mL; p = 0.0001; uTIMP1: 551.05 vs. 128.64 pg/mL; p = 0.0001). Urine MMP9 levels had a sensitivity of 81.2%, with a specificity of 85% to predict renal scar in the VUR group (cut-off 1,054 pg/mL; AUC 0.88). The sensitivity of uTIMP1 was 75%, with a specificity of 90% to predict renal scar (cut-off 243.7 pg/mL; AUC 0.82). Based on these results, we suggest that uTIMP1 may be a useful marker to predict renal scarring with a different cut-off value from VUR and a high specificity at this cut-off point. Although uMMP9 seemingly cannot distinguish renal scar from VUR, the simultaneous increase in the level of both markers may indicate ongoing renal injury due to VUR.

Urinary calcium and uric acid excretion in children with vesicoureteral reflux.

Urolithiasis is relatively common in children, and identifiable predisposing factors for stone formation, including metabolic and structural derangements, can be established in most cases. Vesicoureteral reflux (VUR) is a common cause of kidney stone formation. The pathophysiological mechanism of urolithiasis in reflux is related to urinary tract infection and urinary stasis, both of which promote urinary crystal formation, but metabolic causes, such as crystallurias (mostly hypercalciuria), may also be involved in this process. However, few studies on urinary calcium and uric acid excretion in children with VUR have been conducted. We have studied the frequency of hypercalciuria and hyperuricosuria in children with VUR and compared the results with those from a control group. The VUR group comprised 108 children with VUR (19 boys, 89 girls; age range 3 months to 12 years), and the control group comprised 110 healthy children without any history of reflux or urinary tract infection (30 boys, 80 girls; age range 2 months to 12 years). Fasting urine was analyzed for the calcium/creatinine (Ca/Cr) and uric acid/creatinine (UA/Cr) ratios. Hypercalciuria was more frequently diagnosed in the VUR patients than in the control group (21.3 vs. 3.6%; P = 0.0001). Significant differences between the two groups were also found for the mean Ca/Cr and UA/Cr ratios (P = 0.0001 and P = 0.0001, respectively). No differences were found in the urinary Ca/Cr or UA/Cr ratios related to VUR grading or unilateral/bilateral VUR in the patient group, with the exception of those for hypercalciuria and mild VUR (P = 0.03). The association of urinary stones and microlithiasis in the VUR group was 29.6%. Our results demonstrate that the frequency of hypercalciuria and hyperuricosuria was higher in pediatric patients with VUR than in healthy children. Knowing this relationship, preventive and therapeutic interventions for stone formation in VUR could be greatly expanded.

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.

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.

[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 IL-8 concentrations in infectious and non-infectious urinary tract conditions.

Urine IL-8 concentrations are known to be elevated in urinary tract infection (UTI), as well as in vesicoureteral reflux (VUR) even in the absence of infection. In this study we further investigated urine IL-8 in infants with congenital anomalies of the kidneys and urinary tract and with antenatally diagnosed isolated pelvic dilatation. Urine IL-8 was measured in 159 infants aged 1 month to 1 year with acute UTI (group A, n = 26), resolved UTI (group B, n = 16), VUR without recent UTI (group C, n = 44), non-VUR congenital urinary anomalies without recent UTI (group D, n = 30), isolated antenatal pelvic dilatation (group E, n = 14) and in infants without known urinary tract condition (control group F, n = 29). Median values of urine IL-8/creatinine levels were 61.5, 4.64, 15.5, 14.3, 1.06 and 4.19 pg/µmol in groups A, B, C, D, E and F respectively. Compared with the control group, urine IL-8 was elevated in infants with acute UTI, VUR without acute UTI and congenital anomalies without acute UTI (p < 0.0001; p < 0.005; and p = 0.027 respectively), but not in infants with resolved UTI or with antenatal pelvic dilatation. Urine IL-8 levels are elevated in a variety of infectious and non-infectious urinary tract conditions, and hence may serve as a sensitive but not specific screening biomarker of urinary tract diseases.