Kee Hwan Yoo

Utility of Rapid B-Type Natriuretic Peptide Assay for Diagnosis of Symptomatic Patent Ductus Arteriosus in Preterm Infants

Objective. In preterm infants, the rapid and accurate determination of the presence of a hemodynamically significant patent ductus arteriosus (PDA) is extremely important, but this is often difficult. Plasma B-type natriuretic peptide (BNP) measurement has been reported to be a helpful aid in the diagnosis of hemodynamically significant PDA in preterm infants. The aim of our study was to investigate the usefulness of a rapid BNP assay as a diagnostic marker of symptomatic PDA (sPDA) in preterm infants. Methods. Sixty-six preterm infants, ranging from 25 to 34 gestational weeks of age, underwent clinical and echocardiographic examinations for PDA every other day from the third day of life until the disappearance of ductal flow. Blood samples were collected and plasma BNP concentrations were measured simultaneously using a commercial kit, (Triage BNP test kit; Biosite Diagnositics, San Diego, CA). When ≥2 clinically significant features of PDA were noted, and a large ductal flow was confirmed by color Doppler echocardiography, sPDA was diagnosed and treated with indomethacin. Results. On the third day after birth, the mean BNP concentration in the sPDA group (n = 23) was significantly higher than in the control group (n = 43) (2896 ± 1627 vs 208 ± 313 pg/mL). Seventeen infants (74%) in the sPDA group became asymptomatic after an initial course of indomethacin and their BNP levels concomitantly decreased. Moreover, BNP concentrations were significantly correlated with the magnitudes of the ductal shunt, such as the ratio of left atrial to aortic root diameter and the diastolic flow velocity of the left pulmonary artery (r = 0.726 and 0.877). The area under the receiver operator characteristic curve for the detection of sPDA was high: 0.997 (95% confidence interval: 0.991–1.004). The best cutoff of BNP concentration for the diagnosis of sPDA was determined to be 1110 pg/mL (sensitivity: 100%; specificity: 95.3%). Conclusion. In preterm infants, the circulating BNP levels correlated well with the clinical and echocardiographic assessments of PDA. Although not a stand-alone test, the rapid BNP assay provides valuable information for the detection of infants with sPDA that require treatment. Moreover, serial BNP measurements may be of value in determining the clinical course of PDA in preterm infants.

Genetic control of VEGF and TGF-β1 gene polymorphisms in childhood urinary tract infection and vesicoureteral reflux

We investigated whether genetic polymorphisms of vascular endothelial growth factor (VEGF) and transforming growth factor-β1 (TGF-β1), potential candidate genes in the pathogenesis of urinary tract infection (UTI) and vesicoureteral reflux (VUR), are associated with the susceptibility to UTI and VUR, and renal scarring. We recruited 89 controls and 86 UTI and 58 VUR children. The UTI group was subdivided into two groups according to renal scarring. Two polymorphisms of VEGF and three of TGF-β1 genes were investigated by using PCR-restriction fragment length polymorphism analysis. In both UTI and VUR groups, there was an increase in frequency of the VEGF –460 CC (control, 4.3; UTI, 15.9; VUR, 17.8%; p < 0.05), TGF-β1 –509 CC (control, 8.7; UTI, 34.6; VUR, 35.1%; p < 0.001), and TGF-β1 –800 GG genotypes (control, 19.1; UTI, 40.5; VUR, 40.4%; p < 0.05). An increase in the TGF-β1 +869 CC (scar-positive, 35.4; scar-negative, 10.3%; p < 0.05) and a decrease in the +869 TC genotype (scar-positive, 29.2; scar-negative, 55.2%; p < 0.05) were observed in the scar-positive subjects. There were no differences in +405 VEGF genotype frequencies. The VEGF T-460C and the TGF-β1 C-509T, G-800A, and T869C polymorphisms could be genetic markers of the process of UTI and VUR.

Angiotensin-converting enzyme inhibition decreases growth factor expression in the neonatal rat kidney

The renin-angiotensin system plays an important role in renal growth and development: exposure of the fetus or neonate to angiotensin-converting enzyme (ACE) inhibitors increases mortality and results in growth retardation and abnormal renal development. This study was designed to investigate the effects of ACE inhibition in the neonatal rat on the expression of genes known to modulate renal cellular proliferation, cell interactions, and extracellular matrix. Newborn rat pups were treated with enalapril (30 mg/kg/d) or vehicle for 14 d, and kidneys were removed for Northern analysis of mRNA for transforming growth factor-β1 (TGF-β1), prepro epidermal growth factor (EGF), clusterin, and renin. Distribution of TGF-β1, EGF, and clusterin was also determined by immunohistochemistry. Enalapril treatment resulted in 40% mortality by d 14, reduced body and kidney weight, decreased glomerular area, and caused tubular dilatation (p < 0.05 versus vehicle group). Enalapril decreased renal TGF-β1 and EGF mRNA expression, and increased renal clusterin and renin expression (p < 0.05). Renal tubular immunoreactive EGF was decreased, and clusterin was increased by enalapril treatment. These results indicate that ACE inhibition in the developing kidney reduces the renal expression of critical growth factors, which may account for renal growth impairment. Clusterin expression may increase either due to blockade of tonic angiotensin-mediated inhibition, or as an adaptive response to renal ischemia.

Effect of Intrauterine Growth Retardation on the Progression of Nephrotic Syndrome

Background/Aim: Neonates with intrauterine growth retardation (IUGR) experience higher morbidity and mortality rates than appropriate-for-gestational-age (AGA) neonates. The purpose of our study was to clarify whether IUGR has any influences on the progression of nephrotic syndrome in children. Methods: We performed a retrospective review of 56 children with nephrotic syndrome. IUGR was defined as a birth weight less than the tenth percentile for gestational age. Among 56 patients having nephrotic syndrome, 8 had IUGR, and 48 were AGA. Results: The 24-hour urinary protein level in children with IUGR was significantly higher than that in children who were AGA (7.61 ± 6.75 vs. 3.92 ± 3.70 g/day, p < 0.05). There was a statistically significant difference in the incidence of steroid resistance (62.5 vs. 10.4%, p < 0.05) and in the time to remission (median 60 vs. 13 days, p < 0.05) between the children with IUGR and those being AGA. Also, there was a significant difference in the incidences of treatment with cytotoxic agents (75 vs. 29.2%, p < 0.05) and complications such as hypertension. Conclusions: Our report indicates that IUGR predicts an unfavorable progression of nephrotic syndrome. So, it is important for nephrologists to pay attention to the clinical course of nephrotic syndrome in neonates with IUGR.

Utility of the Rapid B-Type Natriuretic Peptide Assay for Detection of Cardiovascular Problems in Newborn Infants with Respiratory Difficulties

Background: Because the major problems of respiratory difficulties in newborn infants are due to cardiopulmonary problems, improving the early detection and referral of newborn infants with cardiovascular problems has been considered one of the primary goals of care in the neonatal intensive care unit. Objective: To evaluate whether rapid plasma B-type natriuretic peptide (BNP) assay could be used as a screening test to detect the cardiovascular problems in newborn infants with respiratory difficulties. Methods: We studied 73 newborn infants ≧34 weeks gestational age presenting with respiratory difficulties during the first few days after birth; they were divided into a cardiovascular problem group (CP group, n = 32) and a noncardiac problem group (NP group, n = 41) according to the presence of cardiovascular problems by clinical and/or echocardiographic studies in newborn infants with respiratory difficulties. Results: On admission, the median (25–75%) BNP concentration of the CP group was significantly higher than that of the NP group [1,038 (578–1,435) vs. 240 (118–388) pg/ml, p < 0.001]. The best cutoff BNP values for differentiating the CP group were 346.0, 421.0, 570.5 and 191.5 pg/ml within 18 h, at 18–36 h, at 36–60 h and after 60 h of life, respectively. Although the plasma BNP measurement was not a single confirmative test, it was found to have a high sensitivity and a high negative predictive value for rapidly ruling out serious cardiovascular problems in neonatal respiratory difficulties. Conclusion: A rapid plasma BNP assay may be useful for detection of cardiovascular problems in newborn infants with respiratory difficulties during the first few days after birth.

Indomethacin Treatment Decreases Renal Blood Flow Velocity in Human Neonates

This study was designed to evaluate the effect of indomethacin (ID) on renal perfusion in 13 neonates with symptomatic patent ductus arteriosus (PDA). Serial blood flow velocity in the left renal artery was measured just before and at 10, 30, 45, 60, 75 and 90 min after ID administration. Serum creatinine (Cr), sodium (Na), and osmolarity were measured just before, at 12 and 24 h, and at 3 days after ID administration. Timed urine also was collected for measurement of amount, fractional excretion of Na (FENa), and creatinine clearance (CCr). ID decreased end-diastolic flow velocity of renal artery and increased Pourcelot’s index, starting at 10 min and lasting for 75 min (p < 0.05). Serum Cr significantly increased at 12 h, and hourly urine output and CCr decreased for 24 h. Serum Na and osmolarity decreased for a period of at least 3 days (p < 0.05). FENa decreased at 12–24 h (p < 0.05). We conclude that ID treatment can induce significant renal dysfunction due to diminution of renal perfusion in human neonates.

Angiotensin Converting Enzyme Inhibition Decreases Cell Turnover in the Neonatal Rat Heart

The renin angiotensin system plays an important role in growth and development. Exposure of the neonate to an ACE inhibitor increases mortality and results in growth retardation and abnormal development. We have demonstrated that ACE inhibition in the developing kidney increases apoptosis and decreases cell proliferation, which may account for renal growth impairment. To evaluate the role of endogenous angiotensin in cardiac development, the relationship between ACE inhibition, cell proliferation, apoptosis, several modulators of apoptosis (bcl-2, bcl-xl, and clusterin) was examined in the developing rat heart. Thirty-five newborn rat pups were treated with enalapril (30 mg/kg/d) or a vehicle (control group) for 7 d, and hearts were removed for rt-PCR and Western blotting of bcl-2, bcl-xl, and clusterin. An additional 10 rat pups were treated with hydralazine (10 mg/kg/d) or a vehicle, to serve as a hypotensive control. Cell proliferation was determined by PCNA immunostaining, and apoptosis was detected using the total TUNEL technique. Enalapril treatment resulted in a 24% mortality, reduced body weight, and decreased heart weight (p < 0.05). Enalapril decreased proliferating myocytes by 23%, and reduced proliferating cardiac interstitial cells by 8.1% (p < 0.05). Enalapril also decreased myocytes apoptosis by 60%, but the proportion of myocytes undergoing apoptosis was 10-fold less than that of proliferating cells. Cardiac bcl-2 mRNA, clusterin mRNA, bcl-2 protein, and bcl-xl protein content were not changed, but clusterin protein expression was decreased by enalapril treatment. Hydralazine did not alter cardiac cell proliferation or apoptosis. We conclude that ACE inhibition decreases cell turnover in the developing rat heart, which may contribute to cardiac growth impairment. The loss of myocytes may lead to greater myocyte hypertrophy and myocardial damage during later life.

Predictive value of urinary and serum biomarkers in young children with febrile urinary tract infections

BackgroundEarly predictive biomarkers for the diagnosis and management of febrile urinary tract infections (UTIs) can be valuable diagnostic tools in children.MethodsThe study cohort comprised 73 pediatric patients with febrile UTIs [46 with acute pyelonephritis (APN) and 27 with lower UTIs] and 56 healthy children. Urine neutrophil gelatinase-associated lipocalin (uNGAL) and kidney injury molecule-1 (uKIM-1) levels and serum cystatin C (sCysC) levels were measured.ResultsThe uNGAL/creatinine (Cr) and uKIM-1/Cr levels were higher in the UTI group than in the controls (P < 0.05). uNGAL/Cr and sCysC levels were higher in patients with APN than in those with lower UTIs (P < 0.05). uNGAL/Cr levels in both the APN and UTI groups decreased following the administration of antibiotics compared to those before treatment (P < 0.05). The uNGAL/Cr level was correlated with serum levels of white blood cells, C-reactive protein, CysC and with uKIM-1/Cr (P < 0.05). uKIM-1/Cr was also correlated with sCysC (P < 0.05). Receiver operating curve analyses showed good diagnostic profiles of uNGAL/Cr and uKIM-1/Cr for identifying UTIs [area under the curve (AUC) 0.9 and 0.66, respectively) and of uNGAL/Cr and sCysC for predicting APN (AUC 0.78 and 0.72, respectively).ConclusionsOur results suggest that uNGAL, uKIM-1 and sCysC levels may be useful for predicting and managing febrile UTIs in children.

Atypical hemolytic uremic syndrome: Korean pediatric series.

Atypical hemolytic uremic syndrome (aHUS) is a rare disease with a genetic predisposition. Few studies have evaluated the disease in the Asian population. We studied a Korean pediatric cohort to delineate the clinical characteristics and genotypes.

Aldosterone regulates cellular turnover and mitogen‐activated protein kinase family expression in the neonatal rat kidney

Growing evidence indicates that aldosterone is a potent mitogenic signal regulating genes involved in antiapoptosis, cell proliferation and growth. We investigated the role of endogenous aldosterone in renal development, cell proliferation and apoptosis, and mitogen‐activated protein kinase (MAPK) family expression. Newborn rats were treated with either spironolactone (200 mg/kg/d) in olive oil or only olive oil for 7 days. TUNEL assay and proliferating cell nuclear antigen (PCNA) stain were performed on kidney sections. Immunoblots, immunohistochemical (IHC) stain, and reverse transcriptase‐PCR for MAPKs were performed. PCNA‐positive proliferating cells decreased and apoptotic cells increased significantly with spironolactone (P < 0.05). In the spironolactone‐treated group, c‐jun N‐terminal kinase (JNK)‐2 expression increased, whereas extracellular signal regulated kinase (ERK)‐2 and p38 expressions decreased in immunoblots (P < 0.05) and IHC stain. ERK‐2 and p38 mRNA expressions increased in the spironolactone‐treated group (P < 0.05). This study demonstrates that aldosterone blockade in the developing kidney decreases cellular proliferation, increases apoptosis, and modulates the expressions of JNK‐2, ERK‐2, and p38. Aldosterone possibly participates in renal development and MAPK family may serve as, in part, the signaling intermediate through the mineralocorticoid receptor (MR) in the developing kidney. J. Cell. Physiol. 219: 724–733, 2009.