Genotype–Phenotype Analysis in Pediatric Patients with Distal Renal Tubular Acidosis

Park, Eujin,Cho, Myung Hyun,Hyun, Hye Sun,Shin, Jae Il,Lee, Joo Hoon,Park, Young Seo,Choi, Hyun Jin,Kang, Hee Gyung,Cheong, Hae Il Karger Medical and Scientific Publishers 2018 Kidney & blood pressure research Vol. No.

<P>Background/Aims: Primary distal renal tubular acidosis (dRTA) in children is a rare genetic disorder, and three causative mutated genes have been identified: SLC4A1, ATP6V1B1, and ATP6V0A4. We analyzed the prevalence and phenotypic differences of genetic mutations in children with dRTA. Methods: A total of 17 children with dRTA were enrolled in the study. All patients underwent genetic testing for all three candidate genes. Results: Pathogenic mutations, including six novel mutations, were detected in 15 (88.2%) patients: dominant SLC4A1 mutations in ten (58.8%) patients, recessive ATP6V0A4 mutations in three (17.6%) patients, and recessive ATP6V1B1 mutations in two (11.8%) patients. Compared to other patients, patients with SLC4A1 mutations showed an older age of onset (3.7 +/- 2.6 years) and less severe metabolic acidosis at initial presentation. All patients developed nephrocalcinosis, and sensorineural hearing loss was observed in two patients with ATP6V1B1 mutations. Three (17.6%) patients had decreased renal function (chronic kidney disease stage 2), and five (29.4%) patients had persistent growth retardation at the last follow-up. Long-term prognosis showed no genotype-phenotype correlation. Conclusions: SLC4A1 is the most common defective gene in Korean children with dRTA. Patients with SLC4A1 mutations show later onset and milder disease severity. Long-term follow-up of hearing ability, renal function, and growth is necessary for patients with (C) 2018 The Author(s) Published by S. Karger AG, Basel.</P>

Association of Age and BP Variability with Long-term Mortality in Hemodialysis Patients

Kim, Ha Yeon,Kang, Yong Un,Kim, Chang Seong,Choi, Joon Seok,Bae, Eun Hui,Ma, Seong Kwon,Kim, Soo Wan Karger Medical and Scientific Publishers 2014 Kidney & blood pressure research Vol.38 No.2

<P>Abstract</P><P><B><I>Background/Aims: </I></B>Blood pressure (BP) variability is known as a poor prognostic factor for cardiovascular outcomes. This study assessed the prognostic significance of BP variability in association with increasing age in hemodialysis patients. <B><I>Methods</I></B><B><I>: </I></B>We retrospectively analyzed 2,174 patients on hemodialysis from March 2005 to December 2012. The impact of intradialytic and interdialytic BP variability on all-cause mortality according to age groups was analyzed. <B><I>Results: </I></B>Kaplan-Meier survival curves for 5-year cumulative mortality showed higher mortality in patients with higher intradialytic systolic and diastolic BP variability as well as interdialytic systolic and diastolic BP variability (log-rank p=0.006, <0.001, 0.018 and < 0.001) in patients aged <55 years, but not in older age groups. Cox proportional analysis revealed that 5-year mortality was associated with intradialytic diastolic BP variability in patients aged <55 years (HR, 2.03 CI, 1.24-3.32). <B><I>Conclusion: </I></B>The overall mortality was associated with BP variability in patients aged <55 years, but not in older ages. This result suggests that younger hemodialysis patients with BP variability require further medical attention and intervention to reduce BP variability.</P><P>© 2014 S. Karger AG, Basel</P>

Renoprotective Effects of Sildenafil in DOCA-Salt Hypertensive Rats

Bae, Eun Hui,Kim, In Jin,Joo, Soo Yeon,Kim, Eun Young,Kim, Chang Seong,Choi, Joon Seok,Ma, Seong Kwon,Kim, Suhn Hee,Lee, Jong Un,Kim, Soo Wan Karger Medical and Scientific Publishers 2013 Kidney & blood pressure research Vol.36 No.1

<P> Abstract</P><P><B><I>Background/Aims: </I></B>Sildenafil, the first selective phosphodiesterase-5 (PDE5) inhibitor to be widely used for treating erectile dysfunction, has been investigated with regard to its cardioand renoprotective effects in animal models. This study further investigated the renoprotective effects of sildenafil and their molecular mechanisms in deoxycorticosterone acetate (DOCA)-salt hypertensive (DSH) rats. <B><I>Methods: </I></B>DOCA strips (200 mg/kg) were implanted in rats 1 week after unilateral nephrectomy. These rats were fed on a control diet, with or without sildenafil (50 mg·kg<SUP>–1</SUP>day<SUP>–1</SUP>), for 2 weeks. Systolic blood pressure (SBP) was measured by the tail cuff method, and the urinary albumin-to-creatinine ratio (ACR) was calculated. The extent of glomerulosclerosis and tubulointerstitial fibrosis was determined by Masson’s trichrome stain. Renal expression of ED-1, transforming growth factor-β1 (TGF-β1), Bax, and Bcl-2 were determined by semiquantitative immunoblotting, polymerase chain reaction (PCR), and immunohistochemistry. TUNEL staining was used for detecting apoptotic cells. <B><I>Results: </I></B>The increased SBP in DSH rats was not attenuated by sildenafil treatment. The decreased creatinine clearance and increased ACR in DSH rats, compared with control animals, were attenuated by sildenafil treatment. Further, sildenafil treatment attenuated glomerulosclerosis and tubulointerstitial fibrosis in DSH rats and counteracted the increased expression of ED-1, TGF-β1, and Bax and the decreased expression of Bcl-2 in the kidneys of these rats. The increase in the number of apoptotic cells in DSH rats was attenuated by sildenafil treatment. <B><I>Conclusion: </I></B>Sildenafil effectively prevented the progression of renal injury in DSH rats via its anti-inflammatory, antifibrotic, and antiapoptotic effects.</P><P>Copyright © 2012 S. Karger AG, Basel</P>

Gentamicin Decreases Guanylyl Cyclase Activity in Rat Glomerulus

Bae, Eun Hui,Oh, Yoon Wha,Park, Jeong Woo,Ma, Seong Kwon,Choi, Ki Chul,Lee, JongUn,Kim, Suhn Hee,Kim, Soo Wan Karger Medical and Scientific Publishers 2007 Kidney & blood pressure research Vol.30 No.2

<P><I>Background:</I> Effects of gentamicin (GM) on the local natriuretic peptide (NP) and nitric oxide (NO) systems in the kidney were investigated. <I>Methods:</I> Male Sprague-Dawley rats (180-200 g) were intramuscularly injected with GM (100 mg/kg/day) for 5 days. The expression of NO synthase (NOS) isoforms was determined by Western blot analysis, and that of NPs by real-time polymerase chain reaction. The activity of guanylyl cyclase was also determined by the amount of guanosine 3′,5′-cyclic monophosphate (cGMP) generated in responses to atrial natriuretic peptide (ANP) or sodium nitroprusside (SNP). <I>Results:</I> GM treatment resulted in renal failure in association with increases in urinary flow and the fractional excretion of sodium. Accordingly, the expression of inducible NOS was increased in the cortex, while that of endothelial NOS remained unchanged. The urinary excretion of NO metabolites was increased. The expression of ANP, brain natriuretic peptide and C-type natriuretic peptide mRNA was increased in the kidney. The cGMP production provoked by either ANP or SNP was decreased in the glomerulus, but not in the papilla. <I>Conclusion:</I> GM-induced nephropathy may be causally related with decreased guanylyl cyclase activities in the glomerulus.</P><P>Copyright © 2007 S. Karger AG, Basel</P>

Renal manifestations and visceral adiposity in apparently healthy Korean women.

Lee, Ji-Won,Bae, Urhee,Lee, Duk-Chul,Lee, Hye-Ree,Shim, Jae-Yong,Linton, John A Karger Medical and Scientific Publishers ; OCLC 2009 Kidney & blood pressure research Vol.31 No.6

<P>AIMS: It was the aim of this study to investigate the relationship between normal renal function--estimated glomerular filtration rate (GFR)--and visceral adiposity measured by CT in apparently healthy Korean women. METHODS: A total of 425 apparently healthy women were recruited. We assessed body composition with CT and divided the study population into 2 groups based on fat distribution: the visceral fat dominant group and the subcutaneous fat dominant group. GFR was estimated using the abbreviated Modification of Diet in Renal Disease and quadratic equation. RESULTS: After adjustment for age, mean blood pressure, body mass index, fasting glucose, homeostasis model assessment of the insulin resistance index, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, high-sensitivity C-reactive protein levels, and mean brachial-ankle pulse wave velocity, the visceral fat dominant group showed significantly lower GFR levels compared with the subcutaneous fat dominant group. The GFR level was negatively correlated with visceral fat areas after adjustment for age. By stepwise multiple regression analysis, age, triglyceride and visceral fat areas independently affected GFR levels. CONCLUSION: Our study shows that even in apparently healthy women, visceral fat seems to be an important contributor to renal impairment. Further studies on the causality between visceral adiposity and renal function are warranted.</P>

Alteration of Tight Junction Protein Expression in Dahl Salt-Sensitive Rat Kidney

Jo, Chor Ho,Kim, Sua,Oh, Il Hwan,Park, Joon-Sung,Kim, Gheun-Ho Karger Medical and Scientific Publishers 2018 Kidney & blood pressure research Vol. No.

<P>Background/Aims: Altered pressure natriuresis is an important mechanism of hypertension, but it remains elusive at the molecular level. We hypothesized that in the kidney, tight junctions (TJs) may have a role in pressure natriuresis because paracellular NaCl transport affects interstitial hydrostatic pressure. Methods: To assess the association of salt-sensitive hypertension with altered renal TJ protein expression, Dahl salt-sensitive (SS) and salt-resistant (SR) rats were put on an 8% NaCl-containing rodent diet for 4 weeks. Systolic blood pressure (SBP) and urine NaCl excretion were measured weekly, and kidneys were harvested for immunoblotting and quantitative PCR analysis at the end of the animal experiments. Results: SBP was significantly higher in SS rats than in SR rats during the first to fourth weeks of the animal experiments. During the first and second week, urinary NaCl excretion was significantly lower in SS rats as compared with SR rats. However, the difference between the two groups vanished at the third and fourth weeks. In the kidney, claudin-4 protein and mRNA were significantly increased in SS rats as compared with SR rats. On the other hand, occludin protein and mRNA were significantly decreased in SS rats as compared with SR rats. The expression of claudin-2, claudin-7, and claudin-8 did not vary significantly between the two groups. Conclusions: In SS rats, SS hypertension was associated with differential changes in renal TJ protein expression. Both upregulation of claudin-4 and downregulation of occludin might increase paracellular NaCl transport in the kidney, resulting in impaired pressure natriuresis in SS rats. (c) 2017 The Author(s) Published by S. Karger AG, Basel</P>

Long-Term Outcomes of Pediatric Renovascular Hypertension

Chung, Hyun,Lee, Jae Hwan,Park, Eujin,Hyun, Hyesun,Ahn, Yo Han,Jae, Hwan Jun,Kim, Gi Beom,Ha, Il Soo,Cheong, Hae Il,Kang, Hee Gyung Karger Medical and Scientific Publishers 2017 Kidney & blood pressure research Vol. No.

<P>Background/Aims: Renovascular hypertension (RVHT) is an important cause of childhood hypertension. This study evaluated the clinical characteristics and outcomes of Korean children with RVHT. Methods: Children treated for RVHT between 2000 and 2015 at our center were retrospectively reviewed. Results: Forty-six children were followed for a median of 6.5 (0.66-27.23) years. Forty-five percutaneous transluminal angioplasties (PTAs) were performed in 32 children. At the last visit, clinical benefit was observed in 53.3% of children. Patients with comorbid cerebrovascular disease (CVD) showed less favorable long-term outcomes after PTA (clinical benefit in 41.7% vs. 61.1% in others) and higher restenosis rates (50% vs. 31.6% in others). Surgical procedures (bypass or nephrectomy) were performed in 8 patients. After surgery, blood pressure was normalized in 2 patients, improved in 3 patients, and unchanged in the remaining patients. Between PTA group (n=21) and medication group (n=14), percentage of atrophic kidneys became higher after follow-up period in medication group than in PTA group (60.0% vs. 26.1%, P=0.037). Conclusion: Aggressive treatment of pediatric RVHT yielded fair outcomes in our cohort. CVD comorbidity was associated with relatively poor PTA outcomes. To confirm our findings, larger cohort studies with a longer follow-up period are warranted. (c) 2017 The Author(s) Published by S. Karger AG, Basel</P>

The Clinical Significance of Physical Activity in Maintenance Dialysis Patients

Kang, Seok Hui,Do, Jun Young,Jeong, Hye Yun,Lee, So-Young,Kim, Jun Chul Karger Medical and Scientific Publishers 2017 Kidney & blood pressure research Vol. No.

<P>Background: The aim of the present study was to evaluate the effects of physical activity on various aspects in Asian dialysis patients. Methods: This was a retrospective cohort study. Study participants were recruited from 27 hospitals or dialysis centers in Korea (n = 1611). The participants were divided into 3 groups according to the degree of regular exercise: Inactive group, Intermediate group, and Active group. Results: The proportions of patients with frailty and the presence of each component decreased as physical activity increased. The presence and numbers of disabilities decreased as physical activity increased. The number of participants with a history of fall during the last 12 months was 149 (20.5%) in the Inactive group, 88 (16.9%) in the Intermediate group, and 48 (13.2%) in the Active group. Physical component scale and mental component scale scores increased as physical activity increased. The survival rate for all-cause death at 500 days was 95.5% in the Active group, 95.2% in the Intermediate group, and 93.5% in the Inactive group. Conclusion: High physical activity was associated with favorable results for most health-related quality of life scale scores, including frailty, disability, and exhaustion, in Korean dialysis patients. (C) 2017 The Author(s) Published by S. Karger AG, Basel</P>

Characteristics of _L -citrulline transport through blood-brain barrier in the brain capillary endothelial cell line (TR-BBB cells)

Lee, Kyeong-Eun,Kang, Young-Sook S. Karger Medical and Scientific Publishers 2017 JOURNAL OF BIOMEDICAL SCIENCE -BASEL- Vol.24 No.1

<P><B>Background</B></P><P><SUB>L</SUB>-Citrulline is a neutral amino acid and a major precursor of <SUB>L</SUB>-arginine in the nitric oxide (NO) cycle. Recently it has been reported that <SUB>L</SUB>-citrulline prevents neuronal cell death and protects cerebrovascular injury, therefore, <SUB>L</SUB>-citrulline may have a neuroprotective effect to improve cerebrovascular dysfunction. Therefore, we aimed to clarify the brain transport mechanism of <SUB>L</SUB>-citrulline through blood-brain barrier (BBB) using the conditionally immortalized rat brain capillary endothelial cell line (TR-BBB cells), as an in vitro model of the BBB.</P><P><B>Methods</B></P><P>The uptake study of [<SUP>14</SUP>C] L-citrulline, quantitative real-time polymerase chain reaction (PCR) analysis, and rLAT1, system b<SUP>0,+</SUP>, and CAT1 small interfering RNA study were performed in TR-BBB cells.</P><P><B>Results</B></P><P>The uptake of [<SUP>14</SUP>C] <SUB>L</SUB>-citrulline was a time-dependent, but ion-independent manner in TR-BBB cells. The transport process involved two saturable components with a Michaelis–Menten constant of 30.9 ± 1.0 μM (Km<SUB>1</SUB>) and 1.69 ± 0.43 mM (Km<SUB>2</SUB>). The uptake of [<SUP>14</SUP>C] <SUB>L</SUB>-citrulline in TR-BBB cells was significantly inhibited by neutral and cationic amino acids, but not by anionic amino acids. In addition, [<SUP>14</SUP>C]<SUB>L</SUB>-citrulline uptake in the cells was markedly inhibited by 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), which is the inhibitor of the large neutral amino acid transporter 1 (LAT1), B<SUP>0</SUP>, B<SUP>0,+</SUP> and harmaline, the inhibitor of system b<SUP>0,+</SUP>. Gabapentin and <SUB>L</SUB>-dopa as the substrates of LAT1 competitively inhibited the uptake of [<SUP>14</SUP>C] <SUB>L</SUB>-citrulline. IC<SUB>50</SUB> values for <SUB>L</SUB>-dopa, gabapentin, <SUB>L</SUB>-phenylalanine and <SUB>L</SUB>-arginine were 501 μM, 223 μM, 68.9 μM and 33.4 mM, respectively. The expression of mRNA for LAT1 was predominantly increased 187-fold in comparison with that of system b<SUP>0,+</SUP> in TR-BBB cells. In the studies of LAT1, system b<SUP>0,+</SUP> and CAT1 knockdown via siRNA transfection into TR-BBB cells, the transcript level of LAT1 and [<SUP>14</SUP>C] <SUB>L</SUB>-citrulline uptake by LAT1 siRNA were significantly reduced compared with those by control siRNA in TR-BBB cells.</P><P><B>Conclusions</B></P><P>Our results suggest that transport of <SUB>L</SUB>-citrulline is mainly mediated by LAT1 in TR-BBB cells. Delivery strategy for LAT1-mediated transport and supply of L-citrulline to the brain may serve as therapeutic approaches to improve its neuroprotective effect in patients with cerebrovascular disease.</P>