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1.  Control of fluid balance guided by body composition monitoring in patients on peritoneal dialysis (COMPASS): study protocol for a randomized controlled trial 
Trials  2014;15(1):432.
Background
The clinical benefits of bioimpedance spectroscopy (BIS)-guided fluid management in patients on hemodialysis have been widely demonstrated. However, no previous reports have evaluated the effect of regular and serial BIS-guided fluid management on the residual renal function (RRF) in patients on peritoneal dialysis (PD). Therefore, we will evaluate the clinical efficacy of BIS-guided fluid management for preserving RRF and protecting cardiovascular events in patients on PD.
Methods/design
This is a multicenter, prospective, randomized controlled trial. A total of 138 participants on PD will be enrolled and randomly assigned to receive either BIS-guided fluid management or fluid management based only on the clinical information for 1 year. The primary outcome is the change in the glomerular filtration rate (GFR) between months 0 and 12 after starting treatment. The secondary outcomes will include GFR at month 12, time to the anuric state (urine volume <100 ml/day), and fatal and nonfatal cardiovascular events during treatment.
Discussion
This is the first clinical trial to investigate the effect of BIS-guided fluid management on RRF and for protecting against cardiovascular events in patients on PD.
Trial registration
Clinical Trials.gov number NCT01887262, June 24, 2013.
doi:10.1186/1745-6215-15-432
PMCID: PMC4233087  PMID: 25376940
Fluid balance; Bioimpedance spectroscopy; Peritoneal dialysis
2.  Administration of TSG-6 improves memory after traumatic brain injury in mice 
Neurobiology of disease  2013;59:86-99.
Traumatic brain injury (TBI) causes multiple long-term defects including a loss of working memory that is frequently incapacitating. Administrations of mesenchymal stem/stromal cells (MSCs) previously produced beneficial effects in models of TBI as well as other disease models. In several models, the beneficial effects were explained by the MSCs being activated to express TSG-6, a multifunctional protein that modulates inflammation. In a mouse model of TBI, we found the initial mild phase of the inflammatory response persisted for at least 24 hour and was followed by secondary severe response that peaked at 3 days. Intravenous human MSCs or TSG-6 during initial mild phase decreased neutrophil extravasation, expression of matrix metalloproteinase 9 by endothelial cells and neutrophils, and the subsequent blood brain barrier leakage in secondary phase. Administration of TSG-6 also decreased the lesion size at 2 weeks. Importantly, the acute administration of TSG-6 within 24 hour of TBI was followed 6 to 10 weeks later by improvements in memory, depressive-like behavior and the number of newly born-neurons. The data suggested that acute administration of TSG-6 may be an effective therapy for decreasing some of the long-term consequences of TBI.
doi:10.1016/j.nbd.2013.06.017
PMCID: PMC3790317  PMID: 23851308
TSG-6; mesenchymal stem cells; traumatic brain injury; blood brain barrier; neutrophils; matrix metalloproteinase
3.  Urinary Sodium Excretion Has Positive Correlation with Activation of Urinary Renin Angiotensin System and Reactive Oxygen Species in Hypertensive Chronic Kidney Disease 
Journal of Korean Medical Science  2014;29(Suppl 2):S123-S130.
It is not well described the pathophysiology of renal injuries caused by a high salt intake in humans. The authors analyzed the relationship between the 24-hr urine sodium-to-creatinine ratio (24HUna/cr) and renal injury parameters such as urine angiotensinogen (uAGT/cr), monocyte chemoattractant peptide-1 (uMCP1/cr), and malondialdehyde-to-creatinine ratio (uMDA/cr) by using the data derived from 226 hypertensive chronic kidney disease patients. At baseline, the 24HUna/cr group or levels had a positive correlation with uAGT/cr and uMDA/cr adjusted for related factors (P<0.001 for each analysis). When we estimated uAGT/cr in the 24HUna/cr groups by ANCOVA, the uAGT/cr in patients with ≥200 mEq/g cr was higher than in patients with <100 mEq/g cr (708 [95% CI, 448-967] vs. 334 [95% CI, 184-483] pg/mg cr, P=0.014). Similarly, uMDA/cr was estimated as 0.17 (95% CI, 0.14-0.21) pM/mg cr in patients with <100 mEq/g cr and 0.27 (95% CI, 0.20-0.33) pM/mg cr in patients with ≥200 mEq/g cr (P=0.016). During the 16-week follow-up period, an increase in urinary sodium excretion predicted an increase in urinary angiotensinogen excretion. In conclusion, high salt intake increases renal renin-angiotensin-system (RAS) activation, primarily, and directly or indirectly affects the production of reactive oxygen species through renal RAS activation.
doi:10.3346/jkms.2014.29.S2.S123
PMCID: PMC4194282  PMID: 25317016
Chronic Renal Insufficiency; Sodium Chloride; Renin; Angiotensinogen
4.  Circulating TNF Receptors Are Significant Prognostic Biomarkers for Idiopathic Membranous Nephropathy 
PLoS ONE  2014;9(8):e104354.
Idiopathic membranous nephropathy (iMN) is a common cause of nephrotic syndrome in adults. A biomarker to accurately indicate the severity of iMN and predict long-term prognosis is insufficient. Here, we evaluated the clinical significance of circulating tumor necrosis factor receptors (cTNFRs) as prognostic biomarkers of iMN with nephrotic syndrome. A total of 113 patients with biopsy-proven iMN and 43 healthy volunteers were enrolled in this study. Ninety patients with iMN had nephrotic range proteinuria. Levels of cTNFRs were measured by using serum samples collected at the time of initial diagnosis. Levels of cTNFRs were higher in the patients with nephrotic syndrome than in those with subnephrotic range proteinuria or in the healthy volunteers (P for trend <0.001). Estimated glomerular filtration rate and proteinuria tended to worsen as the cTNFRs levels increased. Having a cTNFR1 level within the highest tertile was a significant risk factor for renal progression after adjustment, in comparison with the other tertiles (hazard ratio [HR], 3.39; 95% confidence interval [95% CI], 1.48–7.78; P = 0.004). The cTNFR2 level within the highest tertile also significantly increased the risk of renal progression (HR, 3.29; 95% CI, 1.43–7.54; P = 0.005). Renal tubular TNFRs expression was associated with cTNFRs level. However, the cTNFRs levels were not associated with autoantibody against phospholipase A2 receptor reactivity/levels or treatment response. This study demonstrated that cTNFRs levels at the time of initial diagnosis could predict renal progression in patients with iMN.
doi:10.1371/journal.pone.0104354
PMCID: PMC4123977  PMID: 25098821
5.  The Clinical Association of the Blood Pressure Variability with the Target Organ Damage in Hypertensive Patients with Chronic Kidney Disease 
Journal of Korean Medical Science  2014;29(7):957-964.
It is known that blood pressure variability (BPV) can independently affect target organ damage (TOD), even with normal blood pressure. There have been few studieson chronic kidney disease (CKD) patients. We evaluated the relationship between BPV and TOD in a cross-sectional, multicenter study on hypertensive CKD patients. We evaluated 1,173 patients using 24-hr ambulatory blood pressure monitoring. BPV was defined as the average real variability, with a mean value of the absolute differences between consecutive readings of systolic blood pressure. TOD was defined as left ventricular hypertrophy (LVH) (by the Romhilt-Estes score ≥4 in electrocardiography) and kidney injury (as determined from an estimated glomerular filtration rate [eGFR]<30 mL/min/1.73 m2 and proteinuria).The mean BPV of the subjects was 15.9±4.63 mmHg. BPV displayed a positive relationship with LVH in a univariate analysis and after adjustment for multi-variables (odds ratio per 1 mmHg increase in BPV: 1.053, P=0.006). In contrast, BPV had no relationship with kidney injury. These data suggest that BPV may be positively associated with LVH in hypertensive CKD patients.
Graphical Abstract
doi:10.3346/jkms.2014.29.7.957
PMCID: PMC4101784  PMID: 25045228
Blood Pressure Variability; Kidney Failure, Chronic; Hypertension; Hypertrophy, Left Ventricular; Target Organ Damage
6.  Non-linear association of serum 25-hydroxyvitamin D with urinary albumin excretion rate in normoalbuminuric subjects 
BMC Nephrology  2014;15:97.
Background
Vitamin D deficiencies and increases in urinary albumin excretion (UAE) are both important and potentially related health problems; however, the nature of their relationship has not been established in normoalbuminuric subjects.
Methods
We obtained data from 14,594 normoalbuminuric Korean adults who underwent voluntary health screenings. We used a generalized additive model to examine the threshold level for relationship between serum 25-hydroxyvitamin D [25(OH)D] and urinary-albumin creatinine ratio (UACR) levels. We conducted multivariate logistic regression for high-normal UAE (UACR, 10–29 mg/g), according to various categories of vitamin D status.
Results
The generalized additive model confirmed a non-linear relationship between serum 25(OH)D and UACR levels, and the threshold concentration of 25(OH)D was 8.0 ng/mL after multivariate adjustment. Comparing subjects who fell into the lowest category of serum 25(OH)D levels with subjects who were in the reference range (the highest category), we observed that the multivariate adjusted odds ratio (OR) for high-normal UAE was significantly increased, regardless of the criteria used to categorize vitamin D levels: OR of the 1st quartile over the 4th quartile, 1.20 (95% CI, 1.04-1.39); OR of the 1.0-4.9th percentile over the 50-100th percentile, 1.56 (95% CI, 1.25-1.93); and OR of vitamin D deficiency group over vitamin D sufficiency group, 1.28 (95% CI, 1.08-1.52).
Conclusions
We demonstrated that there was an inverse relationship between serum 25(OH)D less than 8.0 ng/mL and UACR in normoalbuminuric subjects, suggesting that severe vitamin D deficiency could cause an increase in UAE in subjects with normoalbuminuria.
doi:10.1186/1471-2369-15-97
PMCID: PMC4079922  PMID: 24957097
Epidemiology; Low-grade albuminuria; Threshold; Vitamin D deficiency
7.  Long-term prognosis of clinically early IgA nephropathy is not always favorable 
BMC Nephrology  2014;15:94.
Background
The long-term prognosis of clinically early IgA nephropathy (IgAN) patients remains to be clarified. We investigated the long-term outcomes of IgAN patients with an apparently benign presentation and evaluated prognostic factors for renal survival.
Methods
We included patients with biopsy-proven IgAN who had estimated glomerular filtration rates (eGFR) ≥60 mL/min/1.73 m2, normal blood pressure, and proteinuria <0.5 g/day at the time of biopsy. The primary outcome was progression to end-stage renal disease (ESRD). The secondary outcome was a 50% increase in serum creatinine level or an increase in proteinuria to >1 g/day.
Results
The analysis included 153 patients who met the inclusion criteria. At diagnosis, their median systolic blood pressure was 120 (110–130) mmHg, eGFR was 85.9 (74.9–100.1) mL/min/1.73 m2, and proteinuria was 0.25 (0.13–0.38) g/day. Of these, 4 patients died and 6 reached ESRD. The 30-year renal survival rate was 85.5%. Three patients had increased serum creatinine levels and 11 developed proteinuria. Remission was observed in 35 (22.9%) patients. A moderate or severe degree of interstitial fibrosis (adjusted odd ratio [OR] 5.93, 95% confidence interval [CI] 1.44–24.45, P = 0.014) and hypoalbuminemia (adjusted OR 6.18, 95% CI 1.20–31.79, P = 0.029) were independent predictors of the secondary outcome.
Conclusions
This study showed that the prognosis of early IgAN was not always favorable, even resulting in progression to ESRD in some cases. Hypoalbuminemia and interstitial fibrosis should also be considered important prognostic factors in clinically early IgAN patients.
doi:10.1186/1471-2369-15-94
PMCID: PMC4070337  PMID: 24946688
IgA nephropathy; Interstitial fibrosis; Progression of renal failure
8.  Dose selection method for pharmacokinetic study in hemodialysis patients using a subpharmacological dose: oseltamivir as a model drug 
BMC Nephrology  2014;15:46.
Background
Dose selection is an important step in pharmacokinetic (PK) studies of hemodialysis patients. We propose a simulation-based dose-selection method for PK studies of hemodialysis patients using a subpharmacological dose of oseltamivir as a model drug.
Methods
The concentrations of oseltamivir and its active metabolite, oseltamivir carboxylate (OC), were measured by liquid chromatography-tandem mass spectrometry. To determine a low oseltamivir dose exhibiting PK linearity, a pilot low dose determination investigation (n = 4) was performed using a single administration dose-escalation study. After the dose was determined, a low dose study (n = 10) was performed, and the optimal dose required to reach the hypothetical target OC exposure (area under the concentration-time curve [AUC] of 60,000 ng · hr/mL) was simulated using a nonparametric superposition method. Finally, observed PKs at the optimal dose were compared to the simulated PKs to verify PK predictability.
Results
In the pilot low dose determination study, 2.5 mg of oseltamivir was determined to be the low dose. Subsequently, we performed a single-dose PK study with the low oseltamivir dose in an additional group of 10 hemodialysis patients. The predicted AUClast of OC following continuous oseltamivir doses was simulated, and 35 mg of oseltamivir corresponded to the hypothetical target AUClast of OC. The observed PK profiles of OC at a 35-mg oseltamivir dose and the simulated data based on the low dose study were in close alignment.
Conclusion
The results indicate that the proposed method provides a rational approach to determine the proper PK dose in hemodialysis patients.
doi:10.1186/1471-2369-15-46
PMCID: PMC3995549  PMID: 24636040
Hemodialysis; Pharmacokinetics; Drug; Dosage
9.  Renal adverse effects of sunitinib and its clinical significance: a single-center experience in Korea 
Background/Aims
Sunitinib is an oral multitargeted tyrosine kinase inhibitor used mainly for the treatment of metastatic renal cell carcinoma. The renal adverse effects (RAEs) of sunitinib have not been investigated. The aim of this study was to determine the incidence and risk factors of RAEs (proteinuria [PU] and renal insufficiency [RI]) and to investigate the relationship between PU and antitumor efficacy.
Methods
We performed a retrospective review of medical records of patients who had received sunitinib for more than 3 months.
Results
One hundred and fifty-five patients (mean age, 58.7 ± 12.6 years) were enrolled, and the mean baseline creatinine level was 1.24 mg/dL. PU developed in 15 of 111 patients, and preexisting PU was aggravated in six of 111 patients. Only one patient developed typical nephrotic syndrome. Following discontinuation of sunitinib, PU was improved in 12 of 17 patients but persisted in five of 17 patients. RI occurred in 12 of 155 patients, and the maximum creatinine level was 3.31 mg/dL. RI improved in two of 12 patients but persisted in 10 of 12 patients. Risk factors for PU were hypertension, dyslipidemia, and chronic kidney disease. Older age was a risk factor for RI. The median progression-free survival was significantly better for patients who showed PU.
Conclusions
The incidence of RAEs associated with sunitinib was lower than those of previous reports. The severity of RAEs was mild to moderate, and partially reversible after cessation of sunitinib. We suggest that blood pressure, urinalysis, and renal function in patients receiving sunitinib should be monitored closely.
doi:10.3904/kjim.2014.29.1.40
PMCID: PMC3932394  PMID: 24574832
Acute kidney injury; Proteinuria; Sunitinib
10.  Effect of beraprost sodium on arterial stiffness in patients with type 2 diabetic nephropathy 
Trials  2013;14:275.
Background
Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD). Cardiovascular (CV) complications are the most common cause of death among ESRD patients. Beraprost sodium (BPS) is a prostacyclin analog with vasodilatory and antiplatelet effects.
Methods
This is a multicenter prospective, randomized, double-blind, placebo-controlled trial to determine whether treatment with BPS improves arterial stiffness in patients with type 2 diabetic nephropathy. A total of 102 participants with type 2 diabetic nephropathy will be screened, enrolled, and randomly assigned to receive either 80 μg BPS or placebo daily for 12 weeks. The primary outcome is the change in brachial-ankle pulse wave velocity between baseline and after 12 weeks of medication use. The secondary outcomes will include changes in the ankle-brachial index, the urine albumin to creatinine ratio, the estimated glomerular filtration rate, lipid profiles, and blood pressure from baseline to after treatment.
Discussion
This clinical trial is the first to investigate the effects of BPS on changes in CV biomarkers, albuminuria, renal function, and lipid profiles in patients with diabetic nephropathy.
Trial registration
ClinicalTrials.gov number NCT01796418
doi:10.1186/1745-6215-14-275
PMCID: PMC3765998  PMID: 24066672
Beraprost sodium; Arterial stiffness; Diabetic nephropathy; Cardiovascular; Pulse wave velocity
11.  Non-Linear Relationship between Serum 25-Hydroxyvitamin D and Hemoglobin in Korean Females: The Korean National Health and Nutrition Examination Survey 2010–2011 
PLoS ONE  2013;8(8):e72605.
Background
Anemia and vitamin D deficiency are both important health issues; however, the nature of the association between vitamin D and either hemoglobin or anemia remains unresolved in the general population.
Methods
Data on 11,206 adults were obtained from the fifth Korean National Health and Nutritional Examination Survey. A generalized additive model was used to examine the threshold level for relationship between serum 25-hydroxyvitamin D [25(OH)D] and hemoglobin levels. A multivariate logistic regression for anemia was conducted according to 25(OH)D quintiles. All analyses were stratified according to sex and menstrual status.
Results
The generalized additive model confirmed a threshold 25(OH)D level of 26.4 ng/mL (male, 27.4 ng/mL; premenopausal females, 11.8 ng/mL; postmenopausal females, 13.4 ng/mL). The threshold level affected the pattern of association between 25(OH)D and anemia risk: the odds ratio of the 1st quintile but not the 2nd, 3rd, and 4th quintiles were significantly different from the 5th quintile in both premenopausal and postmenopausal females, however there was no obvious trend in males.
Conclusions
This population-based study demonstrated a non-linear relationship with a threshold effect between serum 25(OH)D and hemoglobin levels in females. Further interventional studies are warranted to determine whether the appropriate level of hemoglobin can be achieved by the correction of vitamin D deficiency.
doi:10.1371/journal.pone.0072605
PMCID: PMC3755993  PMID: 24015265
12.  Duration of acute kidney injury and mortality in critically ill patients: a retrospective observational study 
BMC Nephrology  2013;14:133.
Background
The addition of relevant parameters to acute kidney injury (AKI) criteria might allow better prediction of patient mortality than AKI criteria alone. Here, we evaluated whether inclusion of AKI duration could address this issue.
Methods
AKI was defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines in 2,143 critically ill patients, within 15 days of patient admission. AKI cases were categorized according to tertiles of AKI duration: 1st tertile, 1–2 days; 2nd tertile, 3–5 days; and 3rd tertile, ≥6 days. The hazard ratios (HRs) for overall survival rates in three groups were calculated after adjustment for multiple covariates compared with ICU patients without AKI as the reference group. The predictive ability for mortality was assessed by calculating the area under the curve (AUC) of the receiver operating characteristic curve.
Results
AKI increased the HRs for overall mortality, and the mortality rate increased with AKI duration: the adjusted HRs were 1.99 (1st tertile), 2.67 (2nd tertile), and 2.85 (3rd tertile) compared with the non-AKI group (all Ps < 0.001). The AUC of the ROC curve for overall mortality based on the AKI duration groups (0.716) was higher than the AUC of AKI staging using the KDIGO guidelines (0.696) (P = 0.001). When considering KDIGO stage and AKI duration together, the AUC (0.717) was also significantly higher than that using the KDIGO stage alone (P < 0.001).
Conclusions
AKI duration is an additional parameter for the prediction of mortality in critically ill patients. The inclusion of AKI duration could be considered as a refinement of the AKI criteria.
doi:10.1186/1471-2369-14-133
PMCID: PMC3697999  PMID: 23802916
Acute kidney injury; Acute renal failure; Duration; Mortality; Survival
13.  Successfully Treated Escherichia coli-Induced Emphysematous Cyst Infection with Combination of Intravenous Antibiotics and Intracystic Antibiotics Irrigation in a Patient with Autosomal Dominant Polycystic Kidney Disease 
Journal of Korean Medical Science  2013;28(6):955-958.
A 62-yr-old woman with an autosomal dominant polycystic kidney disease (ADPKD) was admitted to our hospital for further evaluation of intermittent fever, nausea and left flank discomfort. The computed tomography (CT) scan revealed a gas-forming, infectious cyst of approximately 8.1 cm in size in left kidney lower pole. Escherichia coli was identified from the cyst fluid culture examination. Her symptoms improved only after the concomitant use of intravenous ciprofloxacin and an intracystic irrigation of ciprofloxacin through a percutaneous cystostomy drainage. Our case presents the successfully treated emphysematous cyst infection with combination of intravenous antibiotics and intracystic antibiotic therapy instead of surgical management.
doi:10.3346/jkms.2013.28.6.955
PMCID: PMC3678017  PMID: 23772165
Autosomal Dominant Polycystic Kidney Disease; Escherichia coli; Emphysematous
14.  Mortality of IgA Nephropathy Patients: A Single Center Experience over 30 Years 
PLoS ONE  2012;7(12):e51225.
Research on the prognosis of IgA nephropathy (IgAN) has focused on renal survival, with little information being available on patient survival. Hence, this investigation aimed to explore long-term patient outcome in IgAN patients. Clinical and pathological characteristics at the time of renal biopsy were reviewed in 1,364 IgAN patients from 1979 to 2008. The outcomes were patient death and end stage renal disease (ESRD) progression. Overall, 71 deaths (5.3%) and 277 cases of ESRD (20.6%) occurred during 13,916 person-years. Ten-, 20-, and 30-year patient survival rates were 96.3%, 91.8%, and 82.7%, respectively. More than 50% patient deaths occurred without ESRD progression. Overall mortality was elevated by 43% from an age/sex-matched general population (GP) (standardized mortality ratio [SMR], 1.43; 95% confidence interval [CI], 1.04–1.92). Men had comparable mortality to GP (SMR, 1.22; 95% CI, 0.82–1.75), but, in women, the mortality rate was double (SMR, 2.17; 95% CI, 1.21–3.57). Patients with renal risk factors such as initial renal dysfunction (estimated glomerular filgration rate <60 ml/min per 1.73m2; SMR, 1.70; 95% CI, 1.13–2.46), systolic blood pressure ≥140 mmHg (SMR, 1.88; 95% CI, 1.19–2.82) or proteinuria ≥1 g/day (SMR, 1.66; 95% CI, 1.16–2.29) had an elevated mortality rate. Patients with preserved renal function, normotension, and proteinuria <1 g/day, however, had a similar mortality rate to GP. When risk stratification was performed by counting the number of major risk factors present at diagnosis, low-risk IgAN patients had a mortality rate equal to that of GP, whereas high-risk patients had a mortality rate higher than that of GP. This investigation demonstrated that overall mortality in IgAN patients was higher than that of GP. Women and patients with renal risk factors had a higher mortality than that of GP, Therefore, strategies optimized to alleviate major renal risk factors are warranted to reduce patient mortality.
doi:10.1371/journal.pone.0051225
PMCID: PMC3514188  PMID: 23226568
15.  Early Start of Dialysis Has No Survival Benefit in End-Stage Renal Disease Patients 
Journal of Korean Medical Science  2012;27(10):1177-1181.
The timing for dialysis initiationis still debated. The aim of this study was to compare mortality rates, using a propensity-score approach, in dialysis patients with early or late starts. From January 2000 to June 2009, incident adult patients (n = 836) starting dialysis for end-stage renal disease (ESRD) were enrolled. The patients were assigned to either an early- or late-start group depending on the initiation time of the dialysis. After propensity-score-basedmatching, 450 patients remained. At the initiation of dialysis, the mean estimated glomerular filtration rate (eGFR) was 11.1 mL/min/1.73 m2 in the early-start group compared with 6.1 mL/min/1.73 m2 in the late-start group. There were no significant differences in survival between the patients in the early- and late-start groups (Log rank tests P = 0.172). A higher overall mortality risk was observed in the early-start group than in the late-start group for the patients aged ≥ 70 yr (hazard ratio [HR]: 3.29; P = 0.048) and/or who had albumin levels ≥ 3.5 g/dL (HR: 2.53; P = 0.046). The survival of the ESRD patients was comparable between the patients in the early and late-start groups. The time to initiate dialysis should be determined based on clinical findings as well as the eGFR.
doi:10.3346/jkms.2012.27.10.1177
PMCID: PMC3468753  PMID: 23091314
End Stage Renal Disease; Glomerular Filtration Rate; Renal Dialysis; Mortality; Peritoneal Dialysis
16.  Soluble Epoxide Hydrolase Activity Determines the Severity of Ischemia-Reperfusion Injury in Kidney 
PLoS ONE  2012;7(5):e37075.
Soluble epoxide hydrolase (sEH) in endothelial cells determines the plasma concentrations of epoxyeicosatrienoic acids (EETs), which may act as vasoactive agents to control vascular tone. We hypothesized that the regulation of sEH activity may have a therapeutic value in preventing acute kidney injury by controlling the concentration of EETs. In this study, we therefore induced ischemia-reperfusion injury (IRI) in C57BL/6 mice and controlled sEH activity by intraperitoneal administration of the sEH inhibitor 12-(3-adamantan-1-ylureido)-dodecanoic acid (AUDA). The deterioration of kidney function induced by IRI was partially moderated and prevented by AUDA treatment. In addition, AUDA treatment significantly attenuated tubular necrosis induced by IRI. Ischemic injury induced the down-regulation of sEH, and AUDA administration had no effect on the expression pattern of sEH induced by IRI. In vivo sEH activity was assessed by measuring the substrate epoxyoctadecenoic acid (EpOME) and its metabolite dihydroxyoctadec-12-enoic acid (DHOME). Ischemic injury had no effects on the plasma concentrations of EpOME and DHOME, but inhibition of sEH by AUDA significantly increased plasma EpOME and the EpOME/DHOME ratio. The protective effect of the sEH inhibitor was achieved by suppression of proinflammatory cytokines and up-regulation of regulatory cytokines. AUDA treatment prevented the intrarenal infiltration of inflammatory cells, but promoted endothelial cell migration and neovascularization. The results of this study suggest that treatment with sEH inhibitors can reduce acute kidney injury.
doi:10.1371/journal.pone.0037075
PMCID: PMC3349654  PMID: 22590647
17.  The association of moderate renal dysfunction with impaired preference-based health-related quality of life: 3rd Korean national health and nutritional examination survey 
BMC Nephrology  2012;13:19.
Background
Only a few large-scale studies have investigated the association between health-related quality of life (HRQOL) and renal function. Moreover, the HRQOL of patients with moderate renal dysfunction is frequently underestimated by healthcare providers. This study assessed the impact of renal function on preference-based HRQOL in Korean adult population.
Methods
We analyzed data for 5,555 adults from the 3rd Korean National Health and Nutritional Examination Survey 2005. The EuroQol-5D (EQ-5D) utility score was used to evaluate HRQOL. The study subjects were stratified into three groups based on their estimated glomerular filtration rates (eGFRs): ≥ 90.0, 60.0-89.9 and 30.0-59.9 mL/min/1.73 m2. Individuals with advanced renal dysfunction were excluded from the analysis.
Results
The proportions of participants who reported problems in each of the five EQ-5D dimensions increased significantly with decreasing eGFR. However, a significant decrease in the EQ-5D utility score was observed among participants with an eGFR of 30.0-59.9 mL/min/1.73 m2. Participants with an eGFR of 30.0-59.9 mL/min/1.73 m2 had an almost 1.5-fold higher risk of impaired health utility (the lowest quartile of EQ-5D utility score) compared with those participants with eGFRs ≥ 90.0 mL/min/1.73 m2, after adjustment for age, gender, health-related behaviors, socioeconomic and psychological variables, and other comorbidities. Among the five dimensions of the EQ-5D, an eGFR of 30.0-59.9 mL/min/1.73 m2 was an independent determinant of self-reported problems in the mobility and pain/discomfort dimensions.
Conclusions
Although age affects the association between renal dysfunction and the EQ-5D, moderate renal dysfunction seems to be an important determinant of impaired health utility in a general population and may affect the mobility and pain/discomfort dimensions of health utility.
doi:10.1186/1471-2369-13-19
PMCID: PMC3404912  PMID: 22530944
Chronic kidney disease; EuroQol-5D; Preference-based health utility
18.  Low Resistin Level is Associated with Poor Hospitalization-Free Survival in Hemodialysis Patients 
Journal of Korean Medical Science  2012;27(4):377-381.
Malnutrition and inflammation are related to high rates of morbidity and mortality in hemodialysis patients. Resistin is associated with nutrition and inflammation. We attempted to determine whether resistin levels may predict clinical outcomes in hemodialysis patients. We conducted a prospective evaluation of 100 outpatients on hemodialysis in a single dialysis center (male, 46%; mean age, 53.7 ± 16.4 yr). We stratified the patients into 4 groups according to quartiles of serum resistin levels. During the 18-month observational period, patients with the lowest quartile of serum resistin levels had poor hospitalization-free survival (log rank test, P = 0.016). After adjustment of all co-variables, patients with the lowest quartile of serum resistin levels had poor hospitalization-free survival, compared with reference resistin levels. Higher levels of interleukin-6 were an independent predictor of poor hospitalization-free survival. In contrast, serum resistin levels were not correlated with interleukin-6 levels. The current data showed that low resistin levels may independently predict poor hospitalization free survival in hemodialysis patients.
doi:10.3346/jkms.2012.27.4.377
PMCID: PMC3314849  PMID: 22468100
Renal Dialysis; Resistin; Hospitalization
19.  Outcome of Early Initiation of Peritoneal Dialysis in Patients with End-Stage Renal Failure 
Journal of Korean Medical Science  2012;27(2):170-176.
Recent studies reported that early initiation of hemodialysis may increase mortality. However, studies that assessed the influence of early initiation of peritoneal dialysis (PD) yielded controversial results. In the present study, we evaluated the prognosis of early initiation of PD on the various outcomes of end stage renal failure patients by using propensity-score matching methods. Incident PD patients (n = 491) who started PD at SNU Hospital were enrolled. The patients were divided into 'early starters (n = 244)' and 'late starters (n = 247)' on the basis of the estimated glomerular filtration rate (eGFR) at the start of dialysis. The calculated propensity-score was used for one-to-one matching. After propensity-score-based matching (n = 136, for each group), no significant differences were observed in terms of all-cause mortality (P = 0.17), technique failure (P = 0.62), cardiovascular event (P = 0.96) and composite event (P = 0.86) between the early and late starters. Stratification analysis in the propensity-score quartiles (n = 491) exhibited no trend toward better or poorer survival in terms of all-cause mortality. In conclusion, early commencement of PD does not reduce the mortality risk and other outcomes. Although the recent guidelines suggest that initiation of dialysis at higher eGFR, physicians should not determine the time to initiate PD therapy simply rely on the eGFR alone.
doi:10.3346/jkms.2012.27.2.170
PMCID: PMC3271290  PMID: 22323864
Peritoneal Dialysis; End Stage Renal Failure; Dialysis Initiation; Propensity Score Match; Outcome; Survival
20.  Lower Residual Renal Function is a Risk Factor for Depression and Impaired Health-Related Quality of Life in Korean Peritoneal Dialysis Patients 
We retrospectively evaluated demographic and biochemical parameters associated with depression and health-related quality of life (HRQOL) in maintenance peritoneal dialysis (PD) patients. This study included 105 patients maintaining PD at Seoul National University Hospital. Data were collected from electronic medical record. Korean Beck's Depression Inventory and Korean version of Kidney Disease Quality of Life short form, version 1.3 were used to evaluate depression and HRQOL, respectively. Moderate to severe depression was found in 24.8% of patients. Patients with lower normalized protein equivalent of nitrogen appearance (nPNA) (< 1.2 g/kg/day), lower weekly renal Kt/Vurea (< 0.2), and lower serum albumin level (≤ 4.0 g/dL) were associated with depression (P < 0.05). Among them, lower weekly renal Kt/Vurea was the only independent risk factor associated with depression (OR = 3.1, P = 0.007). Depressed patients showed significantly lower scores in every dimension of HRQOL (P < 0.001). Lower weekly renal Kt/Vurea (β = 0.24, P = 0.005) and lower nPNA (β = 0.15, P = 0.03) were the independent risk factors associated with lower kidney dialysis component summary, whereas lower plasma hemoglobin level was the consistent risk factor for lower physical component summary (β = 0.22, P = 0.03) and mental component summary (β = 0.22, P = 0.01). Depression is a prevalent psychological problem in PD population. Residual renal function is the most important factor associated with depression and impaired HRQOL in PD patients.
doi:10.3346/jkms.2012.27.1.64
PMCID: PMC3247777  PMID: 22219616
Peritoneal Dialysis; Depression; Health-Related Quality of Life; Residual Renal Function; Beck's Depression Inventory; KDQOL-SF
21.  Hyponatremia in Patients with Neurologic Disorders 
The kidney and the brain play a major role in maintaining normal homeostasis of the extracellular fluid by neuroendocrine regulation of sodium and water balance. Therefore, disturbances of sodium balance are common in patients with central nervous system (CNS) disorders and clinicians should focus not only on the CNS lesion, but also on the potentially deleterious complications. Hyponatremia is the most common and important electrolyte disorder affecting patients with critical neurologic diseases. In these patients, the maladaptation to hyponatremia by impaired osmoregulation in pathologic lesions of brain may cause more aggressive cerebral edema and increased intracranial pressure due to hypoosmolality induced by hyponatremia. Furthermore, hyponatremia accompanied by CNS disorders has shown to increase delayed cerebral ischemia and mortality rates. Two main pathophysiologies of hyponatremia, excluding iatrogenic causes, are inappropriate secretion of antidiuretic hormone (SIADH) and cerebral salt wasting (CSW) syndrome. Differential diagnosis between these two entities can be difficult due to considerable overlap in the laboratory findings and clinical situations. SIADH is in a volume expanded status due to inappropriately secreted arginine vasopressin (AVP) and requires water restriction. However, CSW syndrome is characterized by renal sodium wasting mainly due to increased natriuretic peptides resulting in volume depletion and follows appropriate secretion of AVP. Therefore, maintenance of volume status and sodium replacement is the mainstay of treatment in CSW syndrome. In this review, we aimed to describe the regulation of sodium and water balance, and pathophysiology, diagnosis and treatment of hyponatremia in neurologic patients, especially focusing on SIADH and CSW syndrome.
doi:10.5049/EBP.2009.7.2.51
PMCID: PMC3041486  PMID: 21468186
hyponatremia; inappropriate ADH syndrome; cerebral salt wasting syndrome; nervous system diseases
22.  Idiopathic Retroperitoneal Fibrosis Associated with Hashimoto's Thyroiditis in an Old-aged Man 
Yonsei Medical Journal  2008;49(6):1032-1035.
Idiopathic retroperitoneal fibrosis (IRPF) is a rare disease characterized by a retroperitoneal inflammatory proliferative fibrosing process. Hashimoto's thyroiditis is the most common inflammatory condition of the thyroid gland; and is a frequently-occurring autoimmune disorder manifesting predominantly in middle-aged women. We report a rare association of IRPF with Hashimoto's thyroiditis in a 67-year-old man demonstrating good response to steroid therapy.
doi:10.3349/ymj.2008.49.6.1032
PMCID: PMC2628029  PMID: 19108029
Idiopathic retroperitoneal fibrosis; Hashimoto's thyroiditis; steroid therapy
23.  Factors associated with Hypokalemia in Continuous Ambulatory Peritoneal Dialysis Patients 
Hypokalemia is a frequent problem in patients on continuous ambulatory peritoneal dialysis (CAPD) and is affected by multiple factors. To evaluate factors associated with hypokalemia, we studied 68 patients on maintenance CAPD treatment for at least six months. In univariate analysis, patients with hypokalemia were associated with older age and the presence of diabetes mellitus. Serum albumin, calcium-phosphate product, triglyceride, body mass index, protein nitrogen appearance, and lean body mass assessed by creatinine kinetics were significantly lower as compared to those without hypokalemia. Serum C-reactive protein was significantly higher in the patients with hypokalemia. Multivariate stepwise linear regression analysis revealed that the serum albumin level and the ultrafiltration volume at the peritoneal equilibration test were independent factors associated with hypokalemia. This suggests that the serum potassium level may be an important nutritional marker in CAPD patients. Further longitudinal investigation is needed to clarify this relationship.
doi:10.5049/EBP.2007.5.2.102
PMCID: PMC3894509  PMID: 24459508
Hypokalemia; Potassium; Continuous ambulatory peritoneal dialysis; Nutritional status
24.  Human Spt6 Stimulates Transcription Elongation by RNA Polymerase II In Vitro 
Molecular and Cellular Biology  2004;24(8):3324-3336.
Recent studies have suggested that Spt6 participates in the regulation of transcription by RNA polymerase II (RNAPII). However, its underlying mechanism remains largely unknown. One possibility, which is supported by genetic and biochemical studies of Saccharomyces cerevisiae, is that Spt6 affects chromatin structure. Alternatively, Spt6 directly controls transcription by binding to the transcription machinery. In this study, we establish that human Spt6 (hSpt6) is a classic transcription elongation factor that enhances the rate of RNAPII elongation. hSpt6 is capable of stimulating transcription elongation both individually and in concert with DRB sensitivity-inducing factor (DSIF), comprising human Spt5 and human Spt4. We also provide evidence showing that hSpt6 interacts with RNAPII and DSIF in human cells. Thus, in vivo, hSpt6 may regulate multiple steps of mRNA synthesis through its interaction with histones, elongating RNAPII, and possibly other components of the transcription machinery.
doi:10.1128/MCB.24.8.3324-3336.2004
PMCID: PMC381665  PMID: 15060154
25.  Initial dose cascade of TTS fentanyl with proper adjuvant medications in cancer pain. 
Journal of Korean Medical Science  2003;18(5):733-737.
According to the three step-ladder analgesics in patients with cancer pain, adjuvant drugs are required for pain relief according to the pain character and also to reduce side effects of opioids. Pain clinicians sometimes want to decide to jump directly from naive and mild opioid to transdermal therapeutic system (TTS) fentanyl with less side effects. We investigated the safety, efficacy, and satisfaction of the patients of TTS fentanyl converting from opioid-naive and mild-opioid with adjuvant drug medications in related to dose cascade of TTS fentanyl. Both opioid-naive (n=3) and opioid-using (n=34) patients started with TTS fentanyl in the lowest available delivery rate (25 microg/hr) with rescue medication. A numeric rating scale (NRS, from 0=no pain to 10=worst pain imaginable), satisfaction of the patients with the transdermal therapy and side effects were recorded everyday during 29 days. Average reductions of NRS scores were 1.79 and 2.77, and the mean doses were 35.14 and 44.12 microg/hr on the 15th and 29th day, respectively. Reported level of satisfaction with the transdermal patch and generalized pain management were 'completely satisfied' and 'satisfied'. Frequent side effects were nausea, vomiting, and constipation. In conclusion, initial application of TTS fentanyl with proper adjuvant medications is effective, safe, and well tolerated.
PMCID: PMC3055111  PMID: 14555829

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