Non-invasive markers in the management of pediatric neurogenic bladder over the last two decades - A review.

Neurogenic bladder (NB) is one of the most challenging problems in nephro-urological management in pediatrics. It is an important risk factor of secondary upper urinary tract damage. A complete clinical evaluation is necessary and requires life-long extensive medical attention including invasive procedures that affect patients' quality of life. Potential non-invasive biomarkers would be desirable, especially in the pediatric population. The aim of this review was to analyze two decades of data regarding potential non-invasive biomarkers in the assessment and follow-up of children with NB. This paper summarizes and appraises the knowledge about both biochemical and imaging-based markers in 3 aspects: markers of urinary tract infections (UTIs), bladder and renal function, and this paper looks at their prospective application in everyday clinical care.

Urodynamic Findings and Renal Function in Children with Neurogenic Bladder after Myelomeningocele.

INTRODUCTION: Myelomeningocele (MMC) is a congenital central nervous system malformation caused by a failure of the neurulation process in early pregnancy. Patients with MMC present many abnormalities and the nervous, skeletal and urinary systems are the most affected. The aim of this study was to clinically evaluate patients with MMC, estimate renal and lower urinary tract (LUT) function and to ascertain whether urodynamic findings can predict the deterioration of urinary tract function. MATERIALS AND METHODS: Medical records of 112 patients were gathered from a database and evaluated retrospectively. The data included age, sex, BMI Z-score WHO, physical activity, urodynamic parameters and diagnosis and renal function. RESULTS: A total of 112 patients with MMC were enrolled in the study. There were no differences in age, sex, BMI Z-score WHO, physical activity, renal function and urodynamic findings (apart from cystometric capacity) between boys and girls. Detrusor overactivity was the most frequent urodynamic diagnosis in all groups of physical activity, level of lesion and in catheterized and non-catheterized children. The correlations between urodynamic findings and renal function tests were found. CONCLUSIONS: Patients with neurogenic bladder after MMC most often present detrusor overactivity. LUT function is disturbed in all MMC patients independent of lesion level and physical activity.

Urinary MMP-9/NGAL ratio as a potential marker of FSGS in nephrotic children.

BACKGROUND: The study was undertaken to develop a potential new markers for distinguishing minimal change nephrotic syndrome (MCNS) and focal segmental glomerulosclerosis (FSGS) in children. We hypothesized that matrix metalloproteinase-9/neutrophil gelatinase-associated lipocalin (MMP-9/NGAL) is a better marker of focal sclerosis in the glomerulus then matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 (MMP-9/TIMP-1) and matrix metalloproteinase-2/tissue inhibitor of metalloproteinase-2 MMP2/TIMP-2. METHODS: The present study used a sample of 36 children and adolescents subdivided into two groups: I - 20 children with MCNS, subjected to examination twice: A - in relapse of nephrotic syndrome, before treatment and B - after regression of proteinuria; II - 16 children with FSGS. MMPs and TIMPs and NGAL levels were measured in the urine using ELISA kit. MMP-9/TIMP-1, MMP-2/TIMP-2 and MMP-9/NGAL ratios were calculated. RESULTS: Median NGAL/cr. was significantly higher in MCNS and FSGS patients when compared to healthy controls. Both, NGAL and MMP-9 urinary levels were significantly elevated in FSGS subjects, as compared with control subjects. Contrary to FSGS children, in MCNS group, before treatment only NGAL/cr., but not MMP-9/cr. was increased. Urinary concentrations of NGAL and MMP-9 were highly associated with each other (NGAL/cr. vs. MMP-9/cr., r=0.485, p<0.01). Median urine MMP-9/NGAL ratio in FSGS patients was significantly higher than in patients with MCNS. We also found that significant increase in MMP-9/NGAL was associated with FSGS [odds ratio (OR) - 9.0; confidence interval (CI) 1.97-41.07]. CONCLUSION: MMP-9/NGAL ratio may serve as differentiation marker between MCNS and FSGS in nephrotic children.

[Serum and urinary concentration of selected metalloproteinases and their tissue inhibitors in children with vesicoureteral reflux]. / Stezenie wybranych metaloproteinaz i ich tkankowych inhibitorów w surowicy i moczu dzieci z odplywami pecherzowo-moczowodowymi.

UNLABELLED: Vesicoureteral reflux (VUR) in children may lead to the renal fibrosis and scarring due to the overproduction and accumulation of extracellular matrix proteins (ECM) in interstitial tissue. Metalloproteinases produced in the kidneys are called biological markers of fibrosis. THE AIM OF THE STUDY was to assess if the presence of VUR in children disturb the balance between the serum and urinary concentrations of matrix metalloproteinases 2 and 9 and their tissue inhibitors 1 (TIMP-1) and 2 (TIMP-2) and predispose to excessive renal fibrosis. MATERIAL AND METHODS. The study was performed in 88 children, median aged 5.5 years (0.08-16 yrs) with VUR confirmed by voiding cystouretrography (VCUG). In 95% of estimated children the pyelonephritis indicated for VCUG performance. Control group consisted of 30 healthy children at similar age. Concentrations of MMP-2, MMP-9, TIMP-1 and TIMP-2 were estimated using immunoenzymatic ELISA method in urine of all examined children, additionally all the mentioned parameters in children with high (ll-V) grade of VUR were assessed in serum. RESULTS revealed that the urinary and serum concentrations of TIMP-1 and TIMP-2 were higher in healthy controls (p < 0.05). MMP-9 levels were higher only in the urine (p < 0.05) and MMP-2 in serum (p < 0.05). Increase in TIMP concentrations was connected with parallel increase in MMP levels in children with I-V grades of VUR, what was confirmed by the normal values of MMP-2/TIMP-2 and MMP-9/TIMP-1 ratios (p > 0.05). Only children with Ill-rd grade of VUR revealed reduced values of MMP/TIMP ratios (p < 0.05). Children's with Ill-V grade VUR revealed higher increase in serum concentrations of TIMP than in MMP, it was also seen in decrease in MMP/TIMP ratios (p < 0.05). No correlation was found between serum and urinary results of estimated parameters (p > 0.05). CONCLUSION: MMP-2 and MMP-9 and TIMP-1 and TIMP-2 play role in pathogenesis of VUR disturbances, what was confirmed by the change in their serum and urinary concentrations. In serum and urine of children with high (Ill-V) grade VUR the biggest disturbances were observed in MMPs: TIMPs system with the TIMP levels higher than MMP values, what indirectly indicated ECM degradation disturbances and increase in renal fibrosis.

[Urinary laminin and fibronectin level in children with nephritic syndrome]. / Stezenie lamininy i fibronektyny w moczu dzieci z zespolem nerczycowym.

UNLABELLED: Laminin (LN) and fibronectin (FN) are important extra cellular matrix (ECM) proteins. Disturbance between production and degradation of ECM proteins contributes to renal scarring. The aim of the study was evaluation the levels of urinary LN and FN in children with proteinuria in nephrotic syndrome (NS). MATERIALS AND METHODS: Examinations were conducted on 71 children, 3-15 years old: (A)--44 children with NS (proteinuria above 50 mg/kg b.v./24 hours); (B)--27 children without proteinuria (remission NS). Control group (K)--30 healthy children. Concentration of LN and FN were determined by EIA. RESULTS: In urine of children with NS (A) urinary concentration of LN significantly increased, in comparison to control (K) (p<0.05), but FN was normal (p>0.05). In children with remission of NS (B) urinary concentration of LN was unchanged (p>0.05), but concentration of FN significantly decreased (p<0.05). In renal biopsies majority children of A group presented minimal changes, but majority children of B group presented hyalinization of renal tubules. CONCLUSION: Nephrotic proteinuria disturbs production of LN and increases its urinary excretion, but did not influence on urinary excretion of FN.

[The evaluation of urinary tract dysfunction in children with monosymptomatic primary nocturnal enuresis]. / Ocena czynnosci dolnych dróg moczowych u dzieci z pierwotnym izolowanym moczeniem nocnym (PIMN).

UNLABELLED: The reason for our search was various investigations about urinary tract dysfunctions in enuretic children. AIM: The aim of our study was estimation of lover urinary tract function in children with monosymptomatic primary nocturnal enuresis without positive reaction for a long non pharmacological therapy. MATERIAL AND METHODS: 54 children after 9-12 months behavioral therapy and short pharmacological treatment (desmopresin) was undergoing urodynamic investigation (uroflowmetry and cystometry). RESULTS: Urodynamic disorders was found in 44/54 of estimated children. In 34 of children it was overactive bladder, in 6 patients we found detrusor-sphincter discoordination. Five children had decreased bladder capacity. Next to non pharmacological treatment we used anticholinergic or Baclofen depending on the results of urodynamic tests. The response to the treatment (non bedwetting at all) we observed in 34 children (in 9 of them after 3 months of therapy, in 16 after 6 months of therapy and in 12 after 12 months of therapy). The rest of children had decreased number of wet night per month. CONCLUSION: The pharmacological treatment of urodynamic disorders helps to children with monosymptomatic primary nocturnal enuresis to lost this symptom.

[Analysis of vesicoureteral reflux (VUR) course in children]. / Analiza przebiegu odplywów pecherzowo-moczowodowych (OPM) u dzieci.

UNLABELLED: A small number of reports evaluating early effects of vesicoureteral reflux conservative therapy in children, based on antibacterial prophylaxis combined with correction of the of lower urinary tract function inspired us to perform the study. THE AIM OF THE STUDY was to assess the effects of vesicoureteral reflux (VUR) management in children according to grade, sex and way of treatment. MATERIAL AND METHODS: The study group consisted of 108 children, who were treated in 2000-2007 due to VUR. There were 162 refluxing ureters (grades I-V) diagnosed by voiding cystourethrography (VCU). In 82 children cystometry and (or) uroflowmetry were additionally performed, which revealed lower urinary tract disorders in 41 (60 refluxing ureters), mostly detrusor hyperactivity or detrusor-sphincter dyscoordination. All children had conservative treatment, A - in 67 (102 refluxing ureters) only antibacterial prophylaxis, B - in 41 of children (60 refluxing ureters) in combination with pharmacological treatment of urodynamic abnormalities. RESULTS: The check-up VCU was performed after 23+/-15 months on average. VUR was observed to subside in 44/162 (28%) of refluxing ureters, including 22/108 (22%) of those treated managed with method A and 22/60 (37%) with method B. Fifty three of refluxing ureters were qualified for further conservative therapy and 65/162 (40%) for surgery (especially endoscopic). Following 2-3 years medical and surgical treatment, 87/162 (54%) refluxing ureters resolved. CONCLUSION: In the diagnostics of VUR in children we should take into consideration the assessment of lower urinary tract function, as treatment of these abnormalities increases the effects of VUR conservative management. However it should be confirmed on a larger group of patients.

[Evaluation of inflammatory and renal injury markers in youngest children with pyelonephritis]. / Ocena wskazników zapalenia i uszkodzenia nerek u najmlodszych dzieci chorych na odmiedniczkowe zapalenie nerek.

UNLABELLED: Pyelonephritis (PN) is frequent bacterial infections in young infants and very important because may cause parenchymal scarring. Early confirmation of bacterial infection and application the appropriate treatment before obtaining result of urine culture, reduce probability of parenchymal scarring. THE AIM OF THE STUDY: To evaluate the useful of inflammatory and renal injury markers: serum procalcitonin (PCT), tumor necrosis factor alpha (TNF-alpha) and injury renal marker alpha1--microglobulin (A1M) measurement, in comparison with C-reactive protein concentration and abnormal urinary tract, in neonates and young infants with pyelonephritis. MATERIAL AND METHODS: Investigation was performed in two groups: I group--23 children with PN (1 to 24 weeks of age), and K group--30 healthy children aged from 1 to 24 weeks. Serum concentration of CRP was measured by immunonephelometric assay, PCT by immunoluminometric assay, TNF alpha by ELISA method, and urinary A1M by nephelometric assay. RESULTS: In control group (K) medians of all investigated markers were below minimum of detection. PN patients (I) had the highest PCT TNF-alpha, A1M and CRP concentration before treatment and normal results after antibiotic treatment. Using a cut-off: of 0.5 mg/dl for CRP, 0.5 ng/ml for PCT 15 pg/ml for TNF-alpha and 10 mg/g cr for A1M, sensitivity and specificity in children with pyelonephritis were: for CRP 100% and 62.5%, for PCT 81.8% and 87.2%, for TNF alpha 77.1% and 93.1% and A1M 70.4% and 56.1%, respectively. A positive correlation between serum PCT and CRP and TNF alpha was found. Very high concentration all markers were in patients with vesicoureteral reflux and 1 patient with hydronephrosis. CONCLUSION: In early diagnostics of PN (before obtaining results of urine culture) in youngest children, determination of concentration PCT and TNF alpha, has higher value than determination of CRP, taking into concentration high sensitivity and specificity for bacterial infection.

Assessment of serum cystatin C in children with congenital solitary kidney.

The aim of the study was to assess serum cystatin C level in children with a congenital solitary kidney, depending on their age and compensatory overgrowth of the kidney. The study group (I) consisted of 36 children, 3-21 years of age (median 10.8 years), with a congenital solitary kidney and no other urinary defects. The control group (C) contained 36 healthy children, 5-21 years old (median 10.9 years). Nephelometric methods were used to determine serum cystatin C level, the Jaffe method to assess creatinine concentration and the Schwartz formula to estimate glomerular filtration rate. Kidney length was measured with the patient in a supine position, and overgrowth was estimated (O%) in comparison with the respective kidney in the control group. Serum cystatin C level in group I was higher than that in the control group (P<0.05). Increased values, above 0.95 mg/l, were found in 16/36 (44%) children aged 12-21 years. Glomerular filtration rate (GFR, estimated by the Schwartz formula) and creatinine level in group I were similar to those of the control group (P>0.05). Increased kidney length was found (median 18.2%). Cystatin C concentration was positively correlated with O% (r=0.406, P<0.01) and kidney length to child height ratio (L/H) (r=0.376, P<0.05). We conclude that Increased serum cystatin C concentration in patients with a unilateral congenital solitary kidney occurs after 12 years of age and correlates with compensatory overgrowth of the kidney.

Evaluation of bladder instability in children with recurrent urinary tract infections.

BACKGROUND: Impairment in the functions of the lower urinary tract can be the cause of recurrent urinary tract infections (UTI) and vesicoureteral reflux (VUR) in children. The purpose of our research was to evaluate the frequency of occurrence of bladder instability in children with UTI. MATERIAL/METHODS: The research involved 114 children (21 boys, 93 girls), ranging in age from 5 to 16. Group I consisted of 61 children with a history of recurrent UTI, while Group II included 53 children with recurrent UTI and VUR. Urodynamic tests (uroflowmetry and cystometry) were done on all the children, while in selected cases profilometry was also performed, using a Duet apparatus (Dantec Medical A/S). RESULTS: Abnormal functioning of the lower urinary tract was found in 45 children (74%) from Group I and 44 children (84%) from Group II. The most common dysfunction was instability of the detrusor muscle, which was found in 52 children (45%), including 23 (38%) from Group I and 29 (55%) from Group II. In 19 children detrusor instability was accompanied by reduced bladder volume, and in 8 cases there was a lack of detrusor-sphincter coordination. In both groups ca. 20% of the children did not present with symptoms indicating urination dysfunctions. Ca. 80% reported various symptoms, of which the most common were nocturnal wetting and urinary urgency. In half of the children from Group I and one-fourth of the children from Group II there were several co-occurring symptoms: nocturnal and diurnal wetting, pollakiruria, and urinary urgency, or all three symptoms simultaneously. CONCLUSIONS: The most common disturbance of lower urinary tract functioning in these children with recurrent UTI was instability of the detrusor muscle, which occurred more often in children with VUR.