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.

Un pequeño paso para el cirujano, un gran salto para la cirugía / A small step for the surgeon, a big jump for the surgery

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Antenatal hydronephrosis and fetal urine sampling.

The aim of this study is to evaluate the significance of renal pelvis aspiration (RPA) in the management of antenatal hydronephrosis (AHN). This study enrolled 15 AHN cases (one twin pregnancy) that necessitated RPA for AHN. Chromosomal abnormalities, gene disorders, and additional life-threatening congenital abnormalities were eliminated prior to intrauterine interventions. Urine analysis were performed for the evaluation of renal function. Normal renal function was observed in six neonates/infants (40%) (group 1), whereas impaired renal function and various type of urinary system anomalies were observed in 9 neonates/infants (60%) (group 2) during the short-term and longitudinal follow-up periods. There were statistically significant differences in the oligohydroamniosis rate, mean fetal urine sodium value, mean fetal urine ß2-microglobulin, mean gestational week at birth, and mean birthweight values between the groups (P = 0.007, P < 0.001, P = 0.035, P < 0.001, and P = 0.001, respectively). Renal pelvis aspiration and urine analysis were substantial for the management of AHN in necessary cases. ß2-microglobulin and sodium are clinically useful markers to detect the presence of severe renal damage due to obstructive uropathy and thus, important adjuvants in the proper selection of fetuses for further antenatal interventions.

Myocardial function in fetuses with lower urinary tract obstruction: Is there a cardiac remodeling effect due to renal damage?

OBJECTIVES: Cardiac remodeling due to renal dysfunction may have an impact on myocardial function (MF) of fetuses with lower urinary tract obstruction (LUTO). The aim was to identify possible differences in MF in LUTO fetuses compared with healthy controls and to look for interactions between urine biochemistry and MF indices. METHODS: This is a cohort study consisting of 31 LUTO fetuses and 45 healthy controls. Subgroups were generated according to intrauterine therapy (group 1: LUTO after therapy, group 2: LUTO without therapy at the time of examination, and group 3: controls). MF indices were measured using pulsed wave tissue Doppler imaging and M-mode. Furthermore, results of fetal urine biochemistry were gathered retrospectively. RESULTS: Among other findings, right ventricular (RV) e'/a' ratio was lower in group 1 compared with group 3 (p = .050). According to gestational age (GA) level-dependent analysis, RV isovolumetric relaxation time was significantly longer in group 2 compared with group 1 and group 3 at GA level 1 (19 wk of gestation). A significant positive correlation between RV e'/a' ratio and ß-2-microglobulin as well as α-1-microglobulin and potassium could be observed. CONCLUSION: We observed differences in MF and an association between ventricular filling pattern and renal protein secretion in LUTO fetuses. This can be interpreted as a sign of intrauterine cardiac remodeling.

Prospective Study on Several Urinary Biomarkers as Indicators of Renal Damage in Children with CAKUT.

PURPOSE: The aim of the study was to investigate urinary levels of monocyte chemotactic protein-1 (MCP-1), epidermal growth factor (EGF), ß-2-microglobulin (ß2M), and FAS-ligand (FAS-L) in children with congenital anomalies of kidney and urinary tract (CAKUT) disease at risk of developing glomerular hyperfiltration syndrome. For this reason, we selected patients with multicystic kidney, renal agenesia and renal hypodysplasia, or underwent single nephrectomy. MATERIALS AND METHODS: This prospective, multicentric study was conducted in collaboration between the Pediatric Surgery Unit in Foggia and the Pediatric Nephrology Unit in Bari, Italy. We enrolled 80 children with CAKUT (40 hypodysplasia, 22 agenetic; 10 multicystic; 8 nephrectomy) who underwent extensive urological and nephrological workup. Exclusion criteria were recent urinary tract infections or pyelonephritis, age > 14 years, presence of systemic disease, or hypertension. A single urine sample was collected in a noninvasive way and processed for measuring by enzyme-linked immunosorbent assay urine levels of MCP-1, EGF, ß2M, and FAS-L. As control, urine samples were taken from 30 healthy children.Furthermore, we evaluated the urinary ratios uEGF/uMCP-1 (indicator of regenerative vs inflammatory response) and uEGF/uß2M (indicator of regenerative response vs. tubular damage). RESULTS: These results suggest that urinary levels of MCP-1 are overexpressed in CAKUT patients. Furthermore, our findings clearly demonstrated that both uEGF/uMCP-1 and uEGF/uß2M ratios were significantly downregulated in all patient groups when compared with the control group. CONCLUSION: These findings further support that CAKUT patients may, eventually, experience progressive renal damage and poor regenerative response. The increased urinary levels of MCP-1 in all groups of CAKUT patients suggested that the main factor responsible for the above effects is chronic renal inflammation mediated by local monocytes.

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.

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.

New tubular injury markers in children with a solitary functioning kidney.

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

Foetal serum but not urinary ß2-microglobulin correlates with histological injury to the kidney.

In a context of foetal obstructive uropathies, biochemical markers can be helpful to assess the renal function, but most studies to date have focused on their correlation with ultrasound findings and neonatal outcome. Our aim was to evaluate foetal ß2-microglobulin as an index of histological injury to the kidney. ß2-microglobulin was measured in serum and/or urine from 27 foetuses with bilateral obstructive uropathy, and compared to the findings of kidney examination following the termination of pregnancy. In serum, increased ß2-microglobulin levels correlated to a decreased number of glomeruli, a reduction in the blastema and the presence of primitive ducts reflecting renal hypoplasia and dysplasia. However, elevated ß2-microglobulin levels in the urine correlated only to a decreased number of glomeruli.

Diagnostic efficiency and quality indexes of several markers of renal function for detecting the loss of parenchyma in paediatric patients.

INTRODUCTION: We analysed a large sample of children diagnosed with urinary tract malformations and/or infections and calculated diagnostic efficiency and quality indexes for five different functional markers, with the goal of testing which is the most sensitive for detecting a loss of renal parenchyma. PATIENTS AND METHOD: Ours was a cross-sectional retrospective study in which the clinical histories of 179 paediatric patients (91 male and 88 female) were evaluated. In 102 of these patients (57%), a scintigraphy revealed loss of parenchyma. The most commonly observed morphological type of damage was renal scarring. All patients had undergone at least one desmopressin urine concentration test. We also analysed albumin/creatinine and N-acetyl-glucosaminidase (NAG)/creatinine ratios, glomerular filtration rate (GFR), and urine volume. RESULTS: By distributing patients according to normal/abnormal scintigraphy, we observed statistically significant differences between the two groups in maximum urine osmolality and GFR. Urine volume was elevated in 31.3% of cases (sensitivity: 37.9%; specificity: 81.8%) and 24% had a defect in renal concentrating ability (sensitivity: 30.4%; specificity: 84.8%). Urinary albumin excretion was high in 12.2% of patients, and 7.2% had a high NAG/creatinine ratio. GFR was low in only 5.7% of patients. These last two markers were the least sensitive but most specific for detecting a loss of renal parenchyma (100%). CONCLUSIONS: In our study, the most sensitive functional tests for detecting the loss of renal parenchyma were the two that take into account the ability of the kidney to manage water, i.e. urine volume and maximum urine osmolality. These two tests had specificity >80%. However, the maximum specificity was obtained by the NAG/creatinine ratio and GFR, which were, conversely, the least sensitive tests. A normal GFR does not necessarily show normal renal function.

Urinary transforming growth factor beta1 in children and adolescents with congenital solitary kidney.

The aim of the study was to assess urinary transforming growth factor beta1 (TGF beta1) level in children and adolescents with congenital solitary kidney (CSK), depending on estimated glomerular filtration rate (eGFR) and compensatory overgrowth of the kidney. The study group (I) consisted of 65 children and young adults, 0.5-22 years of age (median 10.0 years) with CSK and no other urinary defects. The control group (C) contained 44 healthy children and adolescents, 0.25-21 years old (median 10.3 years). We used an enzyme-linked immunosorbent assay (ELISA) to determine the urinary level of TGF beta1, the Jaffe method to assess creatinine concentration, and the Schwartz formula to estimate GFR. Kidney length was measured while the patient was in a supine position, and overgrowth (O%) was calculated with reference to the charts. Urinary TGF beta1 level in CSK patients was more than twice as high as that in controls (P < 0.05). Also, eGFR in patients with CSK exceeded the values in the control group (P < 0.01). Compensatory overgrowth of the solitary kidney was found (median 19.44%). Urinary TGF beta1 concentration was positively correlated with eGFR (r = 0.247, P < 0.05), uric acid concentration (r = 0.333, P < 0.01), and percentage of overgrowth (r = 0.338, P < 0.01) and body mass index (BMI) centile (r = 0.274, P < 0.05). We concluded that, although proteinuria and progressive renal insufficiency is not observed in patients with CSK during childhood, the renal haemodynamic changes are present and may be a risk factor for impairment of renal function and hypertension in future life.

Beta-ureidopropionase deficiency presenting with congenital anomalies of the urogenital and colorectal systems.

Beta-ureidopropionase deficiency (McKusick 606673) is an autosomal recessive condition caused by mutations in the UPB1 gene. To date, five patients have been reported, including one putative case detected through newborn screening. Clinical presentation includes neurological and developmental problems. Here, we report another case of beta-ureidopropionase deficiency who presented with congenital anomalies of the urogenital and colorectal systems and with normal neurodevelopmental milestones. Analysis of a urine sample, because of the suspicion of renal stones on ultrasound, showed strongly elevated levels of the characteristic metabolites, N-carbamyl-beta-amino acids. Subsequent analysis of UPB1 identified a novel mutation 209 G>C (R70P) in exon 2 and a previously reported splice receptor mutation IVS1-2A>G. Expression studies of the R70P mutant enzyme showed that the mutant enzyme did not possess any residual activity. Long-term follow-up is required to determine the clinical significance of the beta-ureidopropionase deficiency in our patient.

Fetal uropathy.

Our understanding of the causes, mechanisms, and prenatal management of fetal obstructive uropathy has increased significantly. Improved methods of prenatal evaluation have allowed the better selection of fetuses for invasive therapy, and studies indicate better survival and renal outcomes in carefully selected cases. New biological markers in fetal urine may provide a better understanding of the pathological processes of renal damage, additional prognostic markers, and lead to non-surgical approaches to preventing renal damage.