Young Sook Hong

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.

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.

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.

Angiotensin-converting enzyme inhibition modulates mitogen-activated protein kinase family expressions in the neonatal rat kidney.

Among the mitogen-activated protein kinase (MAPK) family members, extracellular signal–regulated kinase (ERK) promotes cell proliferation or differentiation, whereas c-jun N terminal kinase (JNK) and p38 MAPK are thought to inhibit cell growth and induce apoptosis. The MAPK family may plays some role during kidney development, when large-scale proliferation and apoptosis have been observed to occur. Also, in this period, the renin-angiotensin system is markedly activated. We have demonstrated that angiotensin-converting enzyme inhibition in the developing rat kidney increases apoptosis and decreases cell proliferation, which may account for renal growth impairment. The aim of this study, therefore, was to examine the relationship between the MAPK family and renin-angiotensin system during neonatal renal development. Newborn rat pups were treated with enalapril (30 mg · kg−1 · d−1) or normal saline for 7 d. Right kidneys of both groups were selected for immunohistochemical stains of MAPKs and activating transcription factor-2 (ATF-2), and left kidneys were selected for reverse transcriptase–PCR and immunoblot analysis of MAPKs, phospho-MAPKs, and ATF-2. To determine whether apoptosis is involved in the same tubules that highly expressed JNK and p38, we performed terminal deoxynucleotide transferase-mediated nick-end labeling stain for apoptotic cells and immunohistochemical stains for JNK-2, p38, and ATF-2 expression in the serial sections from the same kidney of the enalapril-treated group. In the enalapril-treated group, JNK-2, p38, phospho-JNK-2, phospho-p38, and ATF-2 protein expressions were significantly increased, and their immunoactivities were strongly detected in the proximal tubular epithelial cells in the cortex, compared with the control group. Especially JNK-2 and p38 expressions were highly activated and were spatially in accordance with the occurrence of apoptosis. ERK1/2 and phospho-ERK expressions were not changed by enalapril. These results suggest that the expressions of the MAPK family are modulated by angiotensin-converting enzyme inhibition in the developing kidney. JNK and p38 may be implicated to participate in angiotensin II–related intracellular signaling pathways of renal apoptosis in the developing kidney.

Genetic polymorphism of the renin-angiotensin system on the development of primary vesicoureteral reflux

Background: The familial clustering of vesicoureteral reflux (VUR) has suggested a genetic basis. This study was designed to investigate the genetic polymorphism of the renin-angiotensin system (RAS) in Korean children. Methods: Genetic polymorphism of angiotensin-converting enzyme (ACE) and angiotensin II receptor genes was evaluated in 67 primary VUR patients and compared to 58 controls with no urological abnormalities. To detect the relation of the risk factors of primary VUR with the genetic polymorphism, the distribution of ACE, AT1 and AT2 genotypes after stratification by risk factors was also studied in the primary VUR patients. Results: The incidence of AT2 A-1332G transition was significantly lower in primary VUR patients (p = 0.047). Furthermore, in the case of combination of ACE and AT2 gene, a significantly lower incidence of primary VUR was seen with II genotype of ACE and A-1332G transition in the AT2 receptor gene (p = 0.003). Concerning the risk factors of primary VUR, there were no biologically significant results. Conclusions: These findings indicate that a lower incidence of AT2 A-1332G transition is seen in primary VUR patients, at least in the Korean population. Also, in the case of combination of ACE and AT2 gene, the combination of ACE II genotype and AT2 A-1332G transition occurs infrequently in primary VUR.

Postnatal early overnutrition causes long-term renal decline in aging male rats

Background:We evaluated the influence of postnatal early overnutrition on renal pathophysiological changes in aging rats.Methods:Three or 10 male pups per mother were assigned to either the small litter (SL) or normal litter (control) groups, respectively, during the first 21 d of life. The effects of early postnatal overnutrition were determined at 12 mo.Results:SL rats weighed more than controls between 4 d and 6 mo of age (P < 0.05). However, between 6 and 12 mo, body weights in both groups were not different. In the SL group, at 12 mo, systolic blood pressure was higher and creatinine clearance was lower than the same in controls (P < 0.05). Numbers of CD68 (ED1)-positive macrophages and apoptotic cells in renal cortex were higher in SL rats (P < 0.05). Furthermore, index scores for glomerulosclerosis and tubulointerstitial fibrosis were higher in the SL group (P < 0.05). Significantly less glomeruli per section area were found in aging SL rats (P < 0.05). Immunoblotting and immunohistochemistry showed decreased intrarenal renin expression in SL rats (P < 0.05).Conclusion:Early postnatal overnutrition can potentiate structural and functional abnormalities in the aging kidney and can lead to systolic hypertension with reduced intrarenal renin activity.

Primary Sjögren's syndrome with mesangial proliferative glomerulonephritis and IgA deposits in a child.

Sirs, Sjogren’s syndrome is very rare in children. Here, we introduce the reader to a case of primary Sjogren’s syndrome (pSS) with mesangial proliferative glomerulonephritis and IgA deposits, an uncommon renal manifestation in boys. Although we thought his prognosis was not good, his response to steroid therapy was good regarding renal problems of pSS. An 11-year-old boy was admitted to the hospital for intermittent gross hematuria and mild proteinuria, which he had had for the past year. He complained of dry eyes and dry mouth, and this had been aggravated 6 months previously. He had no family history of any kidney disease or autoimmune disease. The vital signs were stable and the physical examination revealed no abnormalities, including the lack of parotid gland swelling. Laboratory findings were as follows: hemoglobin 12.2 g/dL, white blood cell count 7,100/μL, platelet count 327,000/μL, blood urea nitrogen (BUN) 10 mg/dL, creatinine 0.7 mg/dL, C3 134 mg/dL, C4 15.4 mg/dL, C1q 15.5 mg/dL, CH50 46.2 U/mL, IgA 196 mg/dL, IgG 1,230 mg/dL, and IgM 71.9 mg/dL. The blood gas results showed mild metabolic acidosis. The electrolytes, liver function tests, protein, albumin, antineutrophil antibody, and the glomerular filtration rate were also unremarkable. The cryoglobulin and anti-Ro/ SSA Ab tests were remarkably positive. Urine analysis showed microscopic hematuria (RBC > 60/high power field) and the 24-h urine protein was 154.9 mg/day. The radiological findings, including abdominal ultrasound, a Tc-dimercaptosuccinic acid scan and intravenous pyelography, were unremarkable. Ophthalmological consultation showed a positive Schirmer’s test, and distal renal tubular acidosis (RTA) was detected by a bicarbonate loading test. A diagnosis of pSS was made on the basis of the xerostomia, the xerophthalmia, the positive Schirmer test and the positive tests for anti-RO/SSA Ab. He underwent a kidney biopsy under local anesthesia. On the conventional light microscopy biopsy, our patient’s specimen showed increased mesangial cellularity (Fig. 1). On immunofluorescence microscopy, IgA (1+) deposits were seen in the mesangial regions. He was started on oral steroid (Deflazacort 1 mg/kg) and artificial tears. After 4 months, the patient’s hematuria and cryoglobulinemia subsided, yet the anti-RO/SSA Ab was still positive. The characteristic histological features of the kidney in patients with pSS are chronic interstitial nephritis with a diffuse or focal plasmacytoid lymphocytic infiltration. In addition, it has been reported that a few patients with pSS display glomerulonephritis (GN), including membranous nephropathy, membranoproliferative GN or mesangial proliferative GN. It has been reported that the glomerular lesions in pSS are related to systemic lupus erythematosus or combined cryoglobulinemia [1]. The pathogenesis of glomerular lesions remains unclear, yet circulating immune complex deposits might be an important factor. Our patient also had cryoglobulinemia and we can strongly suggest that it might have been related to GN. Regarding the clinical and biochemical manifestations and the immune abnormalities between the interstitial S. K. Jung :K. H. Park :H. E. Yim :K. H. Yoo (*) : Y. S. Hong : J. W. Lee Department of Pediatrics, Guro Hospital, Korea University Medical Center, #80, Guro-Dong, Guro-Gu, Seoul 152-703, Korea e-mail: guroped@korea.ac.kr

Spironolactone and enalapril differentially up-regulate the expression of VEGF and heme oxygenase-1 in the neonatal rat kidney.

Both the renin-angiotensin-aldosterone system (RAAS) and hypoxia are vital physiological factors involved in the control of nephrogenesis and vascularization. We investigated the relationship between RAAS and hypoxia in the developing kidney. The expression of VEGF and heme oxygenase (HO)-1 related with the oxygen was analyzed in the enalapril- or spironolactone-treated neonatal rat kidneys. Enalapril (30 mg/kg/d) or spironolactone (200 mg/kg/d) was administered to newborn rat pups for 7 d. The newborn rats were injected i.p. with pimonidazole (200 mg/kg), a marker of severe tissue hypoxia, 1 h before killing. VEGF and HO-1 protein expression was significantly increased by immunoblots and immunohistochemistry in both the enalapril- and spironolactone-treated kidneys, compared with the controls (p < 0.05). HO-1 mRNA expression was increased in the spironolactone-treated group (p < 0.05). The immunoactivity of pimonidazole was not different from that of the controls in the enalapril-treated group, whereas it was increased in the spironolactone-treated group. The results of this study indicate that aldosterone blockade or angiotensin II inhibition in the developing rat kidney up-regulated renal VEGF and HO-1 expression regardless of the hypoxic conditions and may differentially modulate VEGF and HO-1 production.