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1.  Prevalence of chronic kidney disease defined by using CKD-EPI equation and albumin-to-creatinine ratio in the Korean adult population 
Background/Aims
An updated chronic kidney disease (CKD) definition and classification were proposed by Kidney Disease: Improving Global Outcomes (KDIGO), with adoption of a new equation to estimate glomerular filtration rate (GFR) and albuminuria to evaluate kidney structural damage. This study was performed to estimate the prevalence of CKD in the Korean adult population as defined and classified by the KDIGO guidelines.
Methods
Cross-sectional samples of the fifth Korean National Health and Nutrition Examination Survey for 2011 to 2012 were examined for adults aged ≥ 19 years. CKD prevalence was determined based on decreased GFR and albuminuria. The GFR was estimated using the CKD Epidemiology Collaboration creatinine equation, and albuminuria was evaluated using the albumin-to-creatinine ratio (ACR) in spot urine.
Results
Of the 16,576 subjects participating in the survey, 10,636 (4,758 men, 5,878 women) were included in the present study. The prevalence of CKD was estimated as 7.9% (7.8% in 2011 and 8.0% in 2012, p = 0.770). The prevalence of low, moderately increased, high, and very high CKD risk prognosis was 92.0%, 6.3%, 1.1%, and 0.6%, respectively. The prevalence of albuminuria (ACR ≥ 30 mg/g) in individuals with GFR ≥ 60 mL/min/1.73 m2 has reached 5.7%. The odds ratios of hypertension and diabetes to CKD were 3.4 and 3.1 in men, and 2.9 and 2.0 in women (all p < 0.001), respectively.
Conclusions
A large percentage of CKD patients had albuminuria prior to a decrease in GFR. Regular laboratory tests for albuminuria for the high-risk group, and especially for hypertensive or diabetic patients, might improve detection of CKD at an early stage.
doi:10.3904/kjim.2015.193
PMCID: PMC5094925  PMID: 27017386
Renal insufficiency, chronic; Kidney Disease Improving Global Outcomes; Glomerular filtration rate; Albuminuria; Korea
2.  A Case Report of a Middle East Respiratory Syndrome Survivor with Kidney Biopsy Results 
Journal of Korean Medical Science  2016;31(4):635-640.
A 68-year old man diagnosed with Middle East Respiratory Syndrome-Coronavirus (MERS-CoV) presented with multiple pneumonic infiltrations on his chest X-ray, and the patient was placed on a mechanical ventilator because of progressive respiratory failure. Urinary protein excretion steadily increased for a microalbumin to creatinine ratio of 538.4 mg/g Cr and a protein to creatinine ratio of 3,025.8 mg/g Cr. The isotope dilution mass spectrometry traceable serum creatinine level increased to 3.0 mg/dL. We performed a kidney biopsy 8 weeks after the onset of symptoms. Acute tubular necrosis was the main finding, and proteinaceous cast formation and acute tubulointerstitial nephritis were found. There were no electron dense deposits observed with electron microscopy. We could not verify the virus itself by in situ hybridization and confocal microscopy (MERS-CoV co-stained with dipeptidyl peptidase 4). The viremic status, urinary virus excretion, and timely kidney biopsy results should be investigated with thorough precautions to reveal the direct effects of MERS-CoV with respect to renal complications.
doi:10.3346/jkms.2016.31.4.635
PMCID: PMC4810350  PMID: 27051251
Acute Tubulointerstitial Nephritis; Kidney Tubular Necrosis, Acute; Middle East Respiratory Syndrome-Coronavirus; Renal Pathology
3.  Validation of the Korean coefficient for the modification of diet in renal disease study equation 
Background/Aims:
Race and ethnicity are important determinants when estimatingglomerular filtration rate (GFR). The Korean coefficients for the isotope dilution mass spectrometry (IDMS) Modification of Diet in Renal Disease (MDRD) Study equations were developed in 2010. However, the coefficients have not been validated. The aim of this study was to validate the performance of the Korean coefficients for the IDMS MDRD Study equations.
Methods:
Equation development and validation were performed in separate groups (development group, n = 147 from 2008 to 2009; validation group, n = 125 from 2010 to 2012). We compared the performance of the original IDMS MDRD equations and modified equations with Korean coefficients. Performance was assessed by comparing correlation coefficients, bias, and accuracy between estimated GFR and measured GFR, with systemic inulin clearance using a single injection method.
Results:
The Korean coefficients for the IDMS MDRD equations developed previously showed good performance in the validation group. The new Korean coefficients for the four- and six-variable IDMS MDRD equations using both the development and validation cohorts were 1.02046 and 0.97300, respectively. No significant difference was detected for the new Korean coefficients, in terms of estimating GFR, between the original and modified IDMS MDRD Study equations.
Conclusions:
The modified equations with Korean coefficients for the IDMS MDRD Study equations were not superior to the original equations for estimating GFR. Therefore, we recommend using the original IDMS MDRD Study equation without ethnic adjustment in the Korean population.
doi:10.3904/kjim.2015.227
PMCID: PMC4773731  PMID: 26759158
Coefficients; Glomerular filtration rate; Equation; Inulin clearance
4.  Change in Body Compositions of Asian Recipients after Kidney Transplantation 
Journal of Korean Medical Science  2012;27(10):1182-1187.
Kidney transplantation and accompanying medical conditions may result in changes in body composition. Such changes have been evaluated in Caucasian recipients, but not in Asian recipients. Herein, we conducted a study on Asian recipients because Asians have a different body composition from Caucasians. A total of 50 Asian recipients was enrolled as a prospective cohort. Using bioelectrical impedance analysis, body composition (muscle and fat mass) was assessed after 2 weeks (baseline), and at 1, 3, 6, 9, and 12 months following kidney transplantation. To find predictors related to changes, the data were analyzed by multivariate analysis using forward selection. All of the patients had good graft function during the study period. Patients gained approximately 3 kg within 1 yr of kidney transplantation. The proportion of muscle mass significantly decreased (Ptrend = 0.001) and the proportion of fat mass significantly increased over time (Ptrend = 0.002). The multivariate results revealed that male recipients, deceased donor type, and low protein intake were associated with an increase in fat mass and a decrease in muscle mass. The results from this study may help to investigate differences in body composition changes between races, as well as the factors related to these changes.
doi:10.3346/jkms.2012.27.10.1182
PMCID: PMC3468754  PMID: 23091315
Asian; Body Composition; Fat; Kidney Transplantation; Muscle
5.  Induction of Donor-Specific Tolerance: Is This Achievable? 
doi:10.3904/kjim.2012.27.1.114
PMCID: PMC3295979  PMID: 22403511
Donor-specific tolerance; Antigen-presenting cells; Intercellular adhesion molecule 1
6.  The impact of blood flow rate during hemodialysis on all-cause mortality 
Background/Aims
Inadequacy of dialysis is associated with morbidity and mortality in chronic hemodialysis (HD) patients. Blood flow rate (BFR) during HD is one of the important determinants of increasing dialysis dose. However, the optimal BFR is unclear. In this study, we investigated the impact of the BFR on all-cause mortality in chronic HD patients.
Methods
Prevalent HD patients were selected from Clinical Research Center registry for end-stage renal disease cohort in Korea. We categorized patients into two groups by BFR < 250 and ≥ 250 mL/min according to the median value of BFR 250 mL/min in this study. The primary outcome was all-cause mortality.
Results
A total of 1,129 prevalent HD patients were included. The number of patients in the BFR < 250 mL/min was 271 (24%) and in the BFR ≥ 250 mL/min was 858 (76%). The median follow-up period was 30 months. Kaplan-Meier analysis showed that the mortality rate was significantly higher in patients with BFR < 250 mL/min than those with BFR ≥ 250 mL/min (p = 0.042, log-rank). In the multivariate Cox regression analyses, patients with BFR < 250 mL/min had higher all-cause mortality than those with BFR ≥ 250 mL/min (hazard ratio, 1.66; 95% confidence interval, 1.00 to 2.73; p = 0.048).
Conclusions
Our data showed that BFR < 250 mL/min during HD was associated with higher all-cause mortality in chronic HD patients.
doi:10.3904/kjim.2015.111
PMCID: PMC5094923  PMID: 26898596
Mortality; Renal dialysis; Blood flow rate; Dialysis adequacy
7.  Ethnic Coefficients for Glomerular Filtration Rate Estimation by the Modification of Diet in Renal Disease Study Equations in the Korean Population 
Journal of Korean Medical Science  2010;25(11):1616-1625.
Race and ethnicity are influential in estimating glomerular filtration rate (GFR). We aimed to find the Korean coefficients for the Modification of Diet in Renal Disease (MDRD) study equations and to obtain novel proper estimation equations. Reference GFR was measured by systemic inulin clearance. Serum creatinine (SCr) values were measured by the alkaline picrate Jaffé kinetic method, then, recalibrated to CX3 analyzer and to isotope dilution mass spectrometry (IDMS). The Korean coefficients for the 4 and 6 variable MDRD and IDMS MDRD study equations based on the SCr recalibrated to CX3 and to IDMS were 0.73989/0.74254 and 0.99096/0.9554, respectively. Coefficients for the 4 and 6 variable MDRD equations based on the SCr measured by Jaffé method were 1.09825 and 1.04334, respectively. The modified equations showed better performances than the original equations. The novel 4 variable equations for Korean based on the SCr measured and recalibrated to IDMS were 107.904×SCr-1.009×age-0.02 (×0.667, if woman) and 87.832×SCr-0.882×age0.01 (×0.653, if woman), respectively. Modified estimations of the MDRD and IDMS MDRD study equations with ethnic coefficients and the novel equations improve the performance of GFR estimation for the overall renal function.
doi:10.3346/jkms.2010.25.11.1616
PMCID: PMC2966999  PMID: 21060751
Coefficient; Glomerular Filtration Rate; Inulin Clearance; Modification of Diet in Renal Disease Study
8.  Kidney Transplantation in Sensitized Recipients; A Single Center Experience 
Journal of Korean Medical Science  2009;24(Suppl 1):S143-S147.
A successful transplantation, across a positive crossmatch barrier, is one of the most persistent long-standing problems in the field of kidney transplant medicine. The aim of this study was to describe seven consecutive living renal transplantations in recipients with positive crossmatch for donors or positive for donor specific antibodies (DSAs). A preconditioning regimen including plasmapheresis and intravenous immunoglobulin was delivered three times a week until the crossmatch and/or DSAs became negative. Mycophenolate mofetil and tacrolimus were started two days before the plasmapheresis. The protocol was modified to include administration of anti-CD 20 antibody (rituximab, 375 mg/m2) from the patient number 3 through the patient number 7. All seven patients achieved negative conversion of the crossmatch or DSAs, and the kidney transplantations were successfully performed in all cases. Acute cellular rejection occurred in two patients, which were subclinical and controlled with high dose steroid treatment. Antibody-mediated rejection occurred in one patient, which was easily reversed with plasmapheresis. All recipients attained normal graft function during the 7-24 months of follow up. Our study suggests that sensitized patients can be transplanted successfully with desensitization pretreatment.
doi:10.3346/jkms.2009.24.S1.S143
PMCID: PMC2633205  PMID: 19194544
Desensitization, Immunologic; Immunoglobulins, Intravenous; Kidney Transplantation; Plasmapheresis; Rituximab
9.  The Mildly Elevated Serum Bilirubin Level is Negatively Associated with the Incidence of End Stage Renal Disease in Patients with IgA Nephropathy 
Journal of Korean Medical Science  2009;24(Suppl 1):S22-S29.
Oxidative stress plays various roles in the development and progression of IgA nephropathy, while bilirubin is known as a potent antioxidant. We therefore hypothesized that serum bilirubin would be associated with renal prognosis in IgA nephropathy. The study subjects comprised 1,458 adult patients with primary IgA nephropathy in Korea. We grouped patients according to the following quartile levels of bilirubin: <0.4 mg/dL (Q1), 0.4-0.5 mg/dL (Q2), 0.6-0.7 mg/dL (Q3), and >0.8 mg/dL (Q4). The outcome data were obtained from the Korean Registry of end-stage renal disease (ESRD). Eighty patients (5.5%) contracted ESRD during a mean follow-up period of 44.9 months. The ESRD incidences were 10.7% in Q1, 8.2% in Q2, 2.8% in Q3, and 2.8% in Q4 (p<0.001). The relative risk of ESRD compared to that in Q1 was 0.307 (95% confidence interval [CI], 0.126-0.751) in Q3 and 0.315 (95% CI, 0.130-0.765) in Q4. The differences of ESRD incidence were greater in subgroups of males and of patients aged 35 yr or more, with serum albumin 4.0 g/dL or more, with normotension, with eGFR 60 mL/min/1.73 m2 or more, and with proteinuria less then 3+ by dipstick test. In conclusion, higher bilirubin level was negatively associated with ESRD incidence in IgA nephropathy.
doi:10.3346/jkms.2009.24.S1.S22
PMCID: PMC2633177  PMID: 19194557
Bilirubin; Glomerulonephritis, IGA; Kidney Failure, Chronic
10.  The role of local IL6/JAK2/STAT3 signaling in high glucose–induced podocyte hypertrophy 
Background
Interleukin-6 (IL6) is an important regulator of cellular hypertrophy through the gp130/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway. We tested the hypothesis that IL6 and its downstream gp130/JAK2/STAT3 pathway participated in high glucose (HG)–induced podocyte hypertrophy.
Methods
IL6 levels in the media and lysates of podocytes were measured by enzyme-linked immunosorbent assay. Western blots were performed to determine the protein expression levels of gp130/JAK2/STAT3 among podocytes cultured with normal glucose (NG), NG + mannitol, NG + recombinant IL6, HG, and HG + IL6-neutralizing antibodies (IL6NAb). Immunoprecipitation was examined to determine whether gp130 interacted with JAK2 in response to HG or IL6. Podocyte hypertrophy was verified using protein/cell counts and flow cytometry.
Results
IL6 levels were significantly increased in the media and lysates of podocytes cultured in HG compared with the NG groups. The nuclear phospho-STAT3/STAT3 ratio was increased by HG and NG + IL6 and was attenuated in the HG + IL6NAb groups, indicating that nuclear STAT3 was activated following JAK2 and cytosolic STAT3 activation in response to IL6 secreted by HG-stimulated podocytes. Immunoprecipitation showed increased phospho-JAK2 recruitment to gp130 in the HG and NG + IL6 groups, and the addition of IL6NAb in the HG group significantly abrogated these increases. Podocyte hypertrophy was significantly increased in the HG and NG + IL6 compared with the NG condition and was diminished by the addition of IL6NAbs to the HG group.
Conclusion
IL6 might play a prominent role in the local activation of JAK2/STAT3 in podocyte hypertrophy under HG conditions. In vivo studies examining this pathway are warranted.
doi:10.1016/j.krcp.2016.09.003
PMCID: PMC5143438  PMID: 27957415
Diabetic nephropathy; Hypertrophy; Interleukin-6; JAK2/STAT3; Podocytes
11.  Early initiation of continuous renal replacement therapy improves survival of elderly patients with acute kidney injury: a multicenter prospective cohort study 
Critical Care  2016;20:260.
Background
Continuous renal replacement therapy (CRRT) is essential in the management of critically ill patients with acute kidney injury (AKI). However, the optimal timing for initiating CRRT remains controversial, especially in elderly patients. Therefore, we investigated the outcomes of early CRRT initiation in elderly patients with AKI.
Methods
A total of 607 patients ≥65 years of age who started CRRT due to AKI between August 2009 and December 2013 were prospectively enrolled. They were divided into two groups based on the median 6-hour urine output immediately before CRRT initiation. Propensity score matching was used to compare the overall survival rate, CRRT duration, and hospitalization duration.
Results
The median age of both groups was 73.0 years, and 60 % of the patients were male. The most common cause of AKI was sepsis. In the early CRRT group, the mean arterial pressure was higher, but the prothrombin time and total bilirubin, aspartate aminotransferase, and alanine aminotransferase levels were lower. The overall cumulative survival rate was higher in the early CRRT group (log-rank P < 0.01). Late CRRT initiation was associated with a higher mortality rate than early initiation after adjusting for age, sex, the Charlson comorbidity index, systolic arterial pressure, prothrombin time, the total bilirubin, aspartate aminotransferase, and alanine aminotransferase levels, cumulative fluid balance and diuretic use (hazard ratio, 1.35; 95 % confidence interval 1.06, 1.71, P = 0.02). Following propensity score matching, patient survival was significantly better in the early CRRT group than in the late CRRT group (P < 0.01). The total duration of hospitalization from the start of CRRT was shorter among the survivors when CRRT was started earlier (26.7 versus 39.1 days, P = 0.04).
Conclusion
A better prognosis can be expected if CRRT is applied early in the course of AKI in critically ill, elderly patients.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-016-1437-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s13054-016-1437-8
PMCID: PMC4986348  PMID: 27526933
Elderly patients; Survival; Continuous renal replacement therapy; Acute kidney injury; Propensity score matching
12.  Open the black box; is urine valuable for screening BK virus-associated nephropathy? 
doi:10.1016/j.krcp.2016.08.003
PMCID: PMC5025459  PMID: 27668154
13.  Pre-Transplant Cardiovascular Risk Factors Affect Kidney Allograft Survival: A Multi-Center Study in Korea 
PLoS ONE  2016;11(8):e0160607.
Background
Pre-transplant cardiovascular (CV) risk factors affect the development of CV events even after successful kidney transplantation (KT). However, the impact of pre-transplant CV risk factors on allograft failure (GF) has not been reported.
Methods and Findings
We analyzed the graft outcomes of 2,902 KT recipients who were enrolled in a multi-center cohort from 1997 to 2012. We calculated the pre-transplant CV risk scores based on the Framingham risk model using age, gender, total cholesterol level, smoking status, and history of hypertension. Vascular disease (a composite of ischemic heart disease, peripheral vascular disease, and cerebrovascular disease) was noted in 6.5% of the patients. During the median follow-up of 6.4 years, 286 (9.9%) patients had developed GF. In the multivariable-adjusted Cox proportional hazard model, pre-transplant vascular disease was associated with an increased risk of GF (HR 2.51; 95% CI 1.66–3.80). The HR for GF (comparing the highest with the lowest tertile regarding the pre-transplant CV risk scores) was 1.65 (95% CI 1.22–2.23). In the competing risk model, both pre-transplant vascular disease and CV risk score were independent risk factors for GF. Moreover, the addition of the CV risk score, the pre-transplant vascular disease, or both had a better predictability for GF compared to the traditional GF risk factors.
Conclusions
In conclusion, both vascular disease and pre-transplant CV risk score were independently associated with GF in this multi-center study. Pre-transplant CV risk assessments could be useful in predicting GF in KT recipients.
doi:10.1371/journal.pone.0160607
PMCID: PMC4976895  PMID: 27501048
14.  Factors associated with the specialty choice of Korean medical students: a cross-sectional survey 
Background
An imbalance of physician supply by medical specialty has been observed in most countries. In Korea, there is a greater tendency to avoid surgical specialties and specialty choices in nonclinical medicine, such as the basic science of medicine. In this study, we identified factors affecting the specialty choice of physicians in order to provide a basis for policies to address this problem.
Methods
We used the results of a 2013 nationwide survey of 12 709 medical students (82.7 % responded) to analyze the data of 9499 students after excluding missing data. Descriptive analyses of all students’ specialty choice were performed. Logistic regression was performed by selecting gender, age, grade level, type of medical school, hometown, and the location of the medical school as the independent variables. Medical specialty was the dependent variable. The dependent variable, or specialty of medicine, was categorized into three groups: nonclinical/clinical medicine, surgical-medical specialty, and controllable lifestyle specialty.
Results
The order of preferred medical specialties was internal medicine, psychiatry, and pediatrics; for surgical specialties, the order was orthopedic surgery, general surgery, and ophthalmology. Medical specialties were most favored by women and students in the third (men) and second (women) year of the medical program, whereas surgical specialties were most preferred by men and students in the first year of the program. Students in the third year mostly favored nonclinical medicine. Medical college students had a stronger preference for nonclinical medicine (odds ratio [OR] 1.625, 95 % confidence interval [CI] 1.139–2.318) than graduate medical school students. Surgical specialties were more favored by men (OR 2.537, 95 % CI 2.296–2.804) than by women. However, they were favored less by medical college students (OR 0.885, 95 % CI 0.790–0.991) than by graduate medical school students and by medical students in metropolitan areas (OR 0.892, 95 % CI 0.806–0.988) than by medical students in nonmetropolitan areas. A controllable lifestyle specialty was less favored by men (OR 0.802, 95 % CI 0.730–0.881) than by women.
Conclusions
Based on these results, we can evaluate the effectiveness of the government’s educational policies for solving the imbalance of physician supply and provide empirical evidence to understand and solve this problem.
doi:10.1186/s12960-016-0141-8
PMCID: PMC4957410  PMID: 27443277
Health manpower; Medical education; Medical specialties; Specialty choice
15.  Lower serum uric acid level predicts mortality in dialysis patients 
Medicine  2016;95(24):e3701.
Supplemental Digital Content is available in the text
Abstract
We evaluated the impact of serum uric acid (SUA) on mortality in patients with chronic dialysis. A total of 4132 adult patients on dialysis were enrolled prospectively between August 2008 and September 2014. Among them, we included 1738 patients who maintained dialysis for at least 3 months and had available SUA in the database. We categorized the time averaged-SUA (TA-SUA) into 5 groups: <5.5, 5.5–6.4, 6.5–7.4, 7.5–8.4, and ≥8.5 mg/dL. Cox regression analysis was used to calculate the hazard ratio (HR) of all-cause mortality according to SUA group. The mean TA-SUA level was slightly higher in men than in women. Patients with lower TA-SUA level tended to have lower body mass index (BMI), phosphorus, serum albumin level, higher proportion of diabetes mellitus (DM), and higher proportion of malnourishment on the subjective global assessment (SGA). During a median follow-up of 43.9 months, 206 patients died. Patients with the highest SUA had a similar risk to the middle 3 TA-SUA groups, but the lowest TA-SUA group had a significantly elevated HR for mortality. The lowest TA-SUA group was significantly associated with increased all-cause mortality (adjusted HR, 1.720; 95% confidence interval, 1.007–2.937; P = 0.047) even after adjusting for demographic, comorbid, nutritional covariables, and medication use that could affect SUA levels. This association was prominent in patients with well nourishment on the SGA, a preserved serum albumin level, a higher BMI, and concomitant DM although these parameters had no significant interaction in the TA-SUA-mortality relationship except DM. In conclusion, a lower TA-SUA level <5.5 mg/dL predicted all-cause mortality in patients with chronic dialysis.
doi:10.1097/MD.0000000000003701
PMCID: PMC4998435  PMID: 27310949
end-stage renal disease; mortality; time-averaged serum uric acid
16.  Serum Alkaline Phosphatase Levels Predict Infection-Related Mortality and Hospitalization in Peritoneal Dialysis Patients 
PLoS ONE  2016;11(6):e0157361.
Background
Serum alkaline phosphatase (ALP) levels have been reported to be associated with all-cause and cardiovascular mortality in peritoneal dialysis (PD) patients. However, it is unclear whether serum ALP levels predict infection-related clinical outcomes in PD patients. The aim of this study was to determine the relationships between serum ALP levels, infection-related mortality and hospitalization in PD patients.
Methods
PD patients from the Clinical Research Center registry for end-stage renal disease, a multicenter prospective observational cohort study in Korea, were included in the present study. Patients were categorized into three groups by serum ALP tertiles as follows: Tertile 1, ALP <78 U/L; Tertile 2, ALP = 78–155 U/L; Tertile 3, ALP >155 U/L. Tertile 1 was used as the reference category. The primary outcomes were infection-related mortality and hospitalization.
Results
A total of 1,455 PD patients were included. The median follow-up period was 32 months. The most common cause of infection-related mortality and hospitalization was PD-related peritonitis. Multivariate Cox regression analyses showed that patients in the highest tertiles of serum ALP levels were at higher risk of infection-related mortality (HR 2.29, 95% CI, 1.42–5.21, P = 0.008) after adjustment for clinical variables. Higher tertiles of serum ALP levels were associated with higher risk of infection-related hospitalization (Tertile 2: HR 1.56, 95% CI, 1.18–2.19, P = 0.009, tertile 3: HR 1.34, 95% CI, 1.03–2.62, P = 0.031).
Conclusions
Our data showed that elevated serum ALP levels were independently associated with a higher risk of infection-related mortality and hospitalization in PD patients.
doi:10.1371/journal.pone.0157361
PMCID: PMC4911047  PMID: 27310428
17.  Serum Anion Gap Predicts All-Cause Mortality in Patients with Advanced Chronic Kidney Disease: A Retrospective Analysis of a Randomized Controlled Study 
PLoS ONE  2016;11(6):e0156381.
Background and Objectives
Cardiovascular outcomes and mortality rates are poor in advanced chronic kidney disease (CKD) patients. Novel risk factors related to clinical outcomes should be identified.
Methods
A retrospective analysis of data from a randomized controlled study was performed in 440 CKD patients aged > 18 years, with estimated glomerular filtration rate 15–60 mL/min/1.73m2. Clinical data were available, and the albumin-adjusted serum anion gap (A-SAG) could be calculated. The outcome analyzed was all-cause mortality.
Results
Of 440 participants, the median (interquartile range, IQR) follow-up duration was 5.1 (3.0–5.5) years. During the follow-up duration, 29 participants died (all-cause mortality 6.6%). The area under the receiver operating characteristic curve of A-SAG for all-cause mortality was 0.616 (95% CI 0.520–0.712, P = 0.037). The best threshold of A-SAG for all-cause mortality was 9.48 mmol/L, with sensitivity 0.793 and specificity 0.431. After adjusting for confounders, A-SAG above 9.48 mmol/L was independently associated with increased risk of all-cause mortality, with hazard ratio 2.968 (95% CI 1.143–7.708, P = 0.025). In our study, serum levels of beta-2 microglobulin and blood urea nitrogen (BUN) were positively associated with A-SAG.
Conclusions
A-SAG is an independent risk factor for all-cause mortality in advanced CKD patients. The positive correlation between A-SAG and serum beta-2 microglobulin or BUN might be a potential reason. Future study is needed.
Trial Registration
Clinicaltrials.gov NCT 00860431
doi:10.1371/journal.pone.0156381
PMCID: PMC4889106  PMID: 27249416
18.  Pretransplant Hepatitis B Viral Infection Increases Risk of Death After Kidney Transplantation 
Medicine  2016;95(21):e3671.
Supplemental Digital Content is available in the text
Abstract
Clinical outcomes in kidney transplant recipients (KTRs) with hepatitis B virus (HBV) have not been thoroughly evaluated. Here, we investigated recent posttransplant clinical outcomes of KTRs with HBV and compared them with KTRs with hepatitis C virus (HCV) and seronegative KTRs.
Of 3855 KTRs from April 1999 to December 2011, we enrolled 3482 KTRs who had viral hepatitis serology data; the patients were followed up for 89.1 ± 54.1 months. The numbers of recipients with HBV and HCV were 160 (4.6%) and 55 (1.6%), respectively. We analyzed the clinical outcomes, including overall mortality and graft failure, among patients who had undergone kidney transplantation.
Patients with HBV showed poorer survival (P = 0.019; adjusted hazard ratio [HR] = 2.370; 95% confidence interval [CI]: 1.155–4.865) than KTRs without HBV. However, the graft survival of patients with chronic hepatitis B did not differ from that of patients without HBV. Hepatic complications were the primary causes of mortality of KTRs with HBV. Mortality significantly correlated with a higher grade of inflammation (P = 0.002) and with the use of lamivudine or adefovir antiviral treatment (P = 0.016). HBV-positive KTRs treated with the new-generation antiviral agent entecavir showed improved patient survival compared with KTRs receiving lamivudine (log-rank P = 0.050). HCV did not affect patient survival; however, it increased the incidence of graft failure (P = 0.010; adjusted HR = 2.899; 95% CI: 1.289–6.519). KTRs with HCV had an increased incidence of acute rejection (log-rank P = 0.005, crude HR = 2.144; 95% CI: 1.341–3.426; P = 0.001).
KTRs with chronic hepatitis B may exhibit poor survival due to post-transplantation hepatic complications. Pretransplant histological liver evaluations and adequate antiviral management with potent nucleoside/nucleotide analogues are needed to improve the survival of KTRs with chronic hepatitis B even when liver function is within the normal range.
doi:10.1097/MD.0000000000003671
PMCID: PMC4902351  PMID: 27227927
19.  Posttransplant Hyponatremia Predicts Graft Failure and Mortality in Kidney Transplantation Recipients: A Multicenter Cohort Study in Korea 
PLoS ONE  2016;11(5):e0156050.
Although hyponatremia is related to poorer outcomes in several clinical settings, its significance remains unresolved in kidney transplantation. Data on 1,786 patients who received kidney transplantations between January 2000 and December 2011 were analyzed. The patients were divided into two groups according to the corrected sodium values for serum glucose 3 months after their transplantations (<135 mmol/L vs. ≥135 mmol/L). Subsequently, the hazard ratios (HRs) for biopsy-proven acute rejection, graft failure, and all-cause mortality were calculated after adjustments for several immunological and non-immunological covariates. 4.0% of patients had hyponatremia. Patients with hyponatremia had higher risks for graft failure and all-cause mortality than did the counterpart normonatremia group; the adjusted HRs for graft failure and mortality were 3.21 (1.47–6.99) and 3.03 (1.21–7.54), respectively. These relationships remained consistent irrespective of heart function. However, hyponatremia was not associated with the risk of acute rejection. The present study addressed the association between hyponatremia and graft and patient outcomes in kidney transplant recipients. Based on the study results, our recommendation is to monitor serum sodium levels after kidney transplantations.
doi:10.1371/journal.pone.0156050
PMCID: PMC4877062  PMID: 27214138
20.  The Association of Visual Impairment With Clinical Outcomes in Hemodialysis Patients 
Medicine  2016;95(19):e3591.
Supplemental Digital Content is available in the text
Abstract
Visual impairment limits people's ability to perform daily tasks and affects their quality of life. We evaluated the impact of visual impairment on clinical outcomes in hemodialysis (HD) patients.
HD patients were selected from the Clinical Research Center registry a prospective cohort study on dialysis patients in Korea. Visual impairment was defined as difficulty in daily life due to decreased visual acuity or blindness. The primary outcome was all-cause mortality and the secondary outcomes were cardiovascular and infection-related hospitalization.
A total of 3250 patients were included. Seven hundred thirty (22.5%) of the enrolled patients had visual impairment. The median follow-up period was 30 months. The Kaplan–Meier curve and log-rank test showed that all-cause mortality rates (P < 0.001) as well as cardiovascular and infection-related hospitalization rates (P < 0.001 and P < 0.001) were significantly higher in patients with visual impairment than in patients without visual impairment. In the multivariable analysis, visual impairment had significant predictive power for all-cause mortality (Hazard ratio [HR], 1.77, 95% confidence interval [CI], 1.21–2.61, P = 0.004) and cardiovascular hospitalization (HR 1.45 [1.00–1.90], P = 0.008) after adjusting for confounding variables. Of these 3250 patients, 634 patients from each group were matched by propensity scores. In the propensity score matched analysis, patients with visual impairment had independently significant associations with increased all-cause mortality (HR 1.69 [1.12–2.54], P = 0.01) and cardiovascular hospitalization (HR 1.48 [1.08–2.02], P = 0.01) compared with patients without visual impairment after adjustment for confounding variables.
Our data demonstrated that visual impairment was an independent risk factor for clinical adverse outcomes in HD patients.
doi:10.1097/MD.0000000000003591
PMCID: PMC4902503  PMID: 27175661
21.  Factors Affecting the Referral Time to Nephrologists in Patients With Chronic Kidney Disease 
Medicine  2016;95(19):e3648.
Supplemental Digital Content is available in the text
Abstract
Timely referral to nephrologists is important for improving clinical outcomes and reducing costs during transition periods. We evaluated the impact of patients’ demographic, clinical, and social health characteristics on referral time.
A total of 1744 CKD patients who started maintaining dialysis were enrolled in a Korean prospective cohort. The early referral (ER) and late referral group (LR) were defined as patients who were referred to a nephrologist more than or less than 1 year prior to dialysis initiation, respectively.
A total of 1088 patients (62.3%) were in the ER, and 656 patients (37.6%) were in the LR. Among the patients in the LR, 398 patients (60.7%) were referred within the 3 months prior to the start of dialysis (ultralate referral group [ULR]). The ER was younger at the time of referral than the LR; however, the ER was older at the start of dialysis. Patients with diabetes or hypertension as the cause of kidney disease were more common in the LR, whereas patients with glomerulonephritis, females, and nonsmokers were more common in the ER. The ER had more well-controlled blood pressure, lower phosphorus levels, and higher hemoglobin levels at the start of dialysis. Congestive heart failure (CHF) was more common in the LR. In the multivariate analysis, male sex (odds ratio [OR] 1.465, 95% confidence interval [CI] 1.034–2.076), underlying kidney disease (diabetes mellitus [OR 1.507, 95% CI 1.057–2.148] and hypertension [OR 1.995, 95% CI 1.305–3.051]), occupation (mechanician [OR 2.975, 95% CI 1.445–6.125], laborer [OR 3.209, 95% CI 1.405–7.327], and farmer [OR 5.147, 95% CI 2.217–11.953]), CHF (OR 2.152, 95% CI 1.543–3.000), and ambulatory status (assisted-walks, OR 2.072, 95% CI 1.381–3.111) were proved as the independent risk factor for late referral.
Patients with hypertensive or diabetic kidney disease are referred later than those with glomerulonephritis. Male patients with physically active occupations exhibiting CHF and restricted ambulation were associated with a late referral. Considering the various factors associated with late referral, efforts to increase early referrals should be emphasized, particularly in patients with hypertension, diabetes, or congestive heart failure.
doi:10.1097/MD.0000000000003648
PMCID: PMC4902530  PMID: 27175688
22.  Contrast-Induced Nephropathy After Computed Tomography in Stable CKD Patients With Proper Prophylaxis 
Medicine  2016;95(18):e3560.
Abstract
Conflicting data have been reported on the clinical significance of contrast-induced nephropathy after CT scan (CT-CIN). In addition, the epidemiologic characteristics and clinical outcomes of CT-CIN following proper prophylactic intervention remain elusive.
We examined the incidence, risk factors, and outcomes of CT-CIN in stable chronic kidney disease (CKD) patients using data collected from our outpatient CT-CIN prophylaxis program conducted between 2007 and 2014. The program recruited patients with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 using an electronic health record-based pop-up alert system and provided an identical protocol of CIN prophylaxis to all patients.
A total of 1666 subjects were included in this study, and 61 of the 1666 subjects (3.7%) developed CT-CIN. Multivariate analysis showed that baseline eGFR, diabetes mellitus, and low serum albumin were significant risk factors for CT-CIN. The generalized additive model analysis revealed a nonlinear relationship between the baseline eGFR and the risk of CT-CIN. In this analysis, the risk of CT-CIN began to increase below an eGFR threshold of 36.8 mL/min/1.73 m2. To assess the outcomes of CT-CIN, patients with and without CT-CIN were compared after propensity score-based 1:2 matching. CT-CIN did not increase the mortality rate of patients. However, patients with CT-CIN were significantly more likely to start dialysis within 6 months of follow-up, but not after those initial 6 months.
CT-CIN developed in only a small number of stable CKD patients who received proper prophylactic intervention, and the risk of CT-CIN was increased in patients with more advanced CKD. Despite the low incidence, CT-CIN conferred a non-negligible risk for the initiation of dialysis in the acute period, even after prophylaxis.
doi:10.1097/MD.0000000000003560
PMCID: PMC4863791  PMID: 27149474
23.  Monitoring the Intracellular Tacrolimus Concentration in Kidney Transplant Recipients with Stable Graft Function 
PLoS ONE  2016;11(4):e0153491.
Although monitoring the intracellular concentration of immunosuppressive agents may be a promising approach to individualizing the therapy after organ transplantation, additional studies on this issue are needed prior to its clinical approval. We investigated the relationship between intracellular and whole blood concentrations of tacrolimus (IC-TAC and WB-TAC, respectively), the factors affecting this relationship, and the risk of rejection based upon IC-TAC in stable kidney recipients. Both IC-TAC and WB-TAC were measured simultaneously in 213 kidney recipients with stable graft function using LC-MS/MS. The tacrolimus ratio was defined as IC-TAC per WB-TAC. The genetic polymorphism of ABCB1 gene and flow cytometric analyses were conducted to probe the correlation between tacrolimus concentrations and the immunoreactivity status as a potential risk of rejection, respectively. The correlation between IC-TAC and WB-TAC was relatively linear (r = 0.67; P<0.001). The factors affecting the tacrolimus ratio were sex, hematocrit, and the transplant duration, as follows: a high tacrolimus ratio was noted in female patients, patients with a low hematocrit, and patients with a short transplant period. However, the tacrolimus ratio did not reflect the prior clinical outcomes (e.g., rejection) or the genetic polymorphism of ABCB1. After stimulation with phorbol-12-myristate 13-acetate and ionomycin, the proportion of T cells producing interferon-gamma or interleukin-2 was higher in the low-IC-TAC group than in the high-IC-TAC group. Further studies are required to evaluate the value of the intracellular tacrolimus concentrations in several clinical settings, such as rejection, infection, and drug toxicity.
doi:10.1371/journal.pone.0153491
PMCID: PMC4833335  PMID: 27082871
24.  Predictors of Relapse in Adult-Onset Nephrotic Minimal Change Disease 
Medicine  2016;95(12):e3179.
Abstract
Minimal change disease (MCD) is a well-known benign primary glomerulonephritis because of its distinct rare tendency to progress to end-stage renal disease. However, factors associated with relapse in adults are not well known. We aimed to identify predictors of relapse in adult-onset MCD patients.
A retrospective cohort of 195 patients with adult-onset primary MCD with nephritic syndrome and disease onset between 1979 and 2013 was followed up for >12 months. The number of relapses was counted and predictors of relapse were analyzed.
A total of 195 patients were included. Median age at diagnosis was 38 years (IQR, 23–53 years) and 113 (57.9%) were men. During 81 months (IQR, 44–153 months) of follow-up, 92% of patients achieved remission after initial treatment. However, only 60 (32.8%) did not experience a relapse and 11 patients failed to remit. Among the remaining 124 patients, 65 experienced a relapse once or twice and 59 experienced a relapse more than twice. Younger onset age, increased severity of nephrotic features such as lower serum albumin levels and higher cholesterol level were associated with relapse. Interestingly, the grade of mesangial proliferation was lower in patients who experienced a relapse. Initial combined treatment with corticosteroids (CS) and cyclophosphamide reduced the number of relapses. In addition, patients with shorter treatment duration tended to experience relapse more often. Multivariate analysis showed that younger onset age, combined mesangial proliferation, initial treatment regimen, and treatment duration were independent risk factors for relapse. Progression to end-stage renal disease was developed in only a patient.
In conclusion, more than two-thirds of adult-onset nephrotic MCD patients experienced relapse, although their renal progression was rare. Younger onset age, CS without cyclophosphamide treatment, and shorter treatment duration were independent risk factors for relapse in adult-onset MCD patients.
doi:10.1097/MD.0000000000003179
PMCID: PMC4998403  PMID: 27015208
25.  Glycemic Control Modifies Difference in Mortality Risk Between Hemodialysis and Peritoneal Dialysis in Incident Dialysis Patients With Diabetes 
Medicine  2016;95(11):e3118.
Supplemental Digital Content is available in the text
Abstract
Although numerous studies have tried to elucidate the best dialysis modality in end-stage renal disease patients with diabetes, results were inconsistent and varied with the baseline characteristics of patients. Furthermore, none of the previous studies on diabetic dialysis patients accounted for the impact of glycemic control. We explored whether glycemic control had modifying effect on mortality between hemodialysis (HD) and peritoneal dialysis (PD) in incident dialysis patients with diabetes.
A total of 902 diabetic patients who started dialysis between August 2008 and December 2013 were included from a nationwide prospective cohort in Korea. Based on the interaction analysis between hemoglobin A1c (HbA1c) and dialysis modalities for patient survival (P for interaction = 0.004), subjects were stratified into good and poor glycemic control groups (HbA1c< or ≥8.0%). Differences in survival rates according to dialysis modalities were ascertained in each glycemic control group after propensity score matching.
During a median follow-up duration of 28 months, the relative risk of death was significantly lower in PD compared with HD in the whole cohort and unmatched patients (whole cohort, hazard ratio [HR] = 0.65, 95% confidence interval [CI] = 0.47–0.90, P = 0.01; patients with available HbA1c [n = 773], HR = 0.64, 95% CI = 0.46–0.91, P = 0.01). In the good glycemic control group, there was a significant survival advantage of PD (HbA1c <8.0%, HR = 0.59, 95% CI = 0.37–0.94, P = 0.03). However, there was no significant difference in survival rates between PD and HD in the poor glycemic control group (HbA1c ≥8.0%, HR = 1.21, 95% CI = 0.46–2.76, P = 0.80).
This study demonstrated that the degree of glycemic control modified the mortality risk between dialysis modalities, suggesting that glycemic control might partly contribute to better survival of PD in incident dialysis patients with diabetes.
doi:10.1097/MD.0000000000003118
PMCID: PMC4839943  PMID: 26986162

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