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Background: The association of a higher body mass index (BMI) with better survival is a well-known “obesity paradox” in patients on hemodialysis (HD). However, men and women have different body compositions, which could impact the effect of BMI on mortality. We investigated the effect of gender on the obesity-mortality relationship in Korean patients on HD. Methods: This study included 2,833 maintenance patients on HD from a multicenter prospective cohort study in Korea (NCT00931970). The relationship between categorized BMI and gender-specific mortality was evaluated by an adjusted Cox proportional hazard model with restricted cubic spline analyses and the Competing risk analysis. We also investigated the effect of changes in BMI over 12 months and serum creatinine level on survival in male and female patients on HD. Results: The mean BMI was 22.6 ± 3.3 kg/m2 and the mean follow up duration was 24.2 ± 3.4 months. The patients with the highest quintile of BMI (≥25.1 kg/m2) showed lower mortality (subdistributional hazard ratio [SHR] = 0.63, 95% confidence interval [CI] = 0.43–0.93, P = 0.019) compared with those with the reference BMI quintile. When analyzed by gender, male patients with a BMI over 25.1 kg/m2 had lower mortality risk (HR = 0.43, 95% CI = 0.25–0.75, P = 0.003); however, no significant difference was found in female patients. Increased BMI after 12 months and high serum creatinine were associated with better survival only in male patients on HD. Conclusions: BMI could be used as a risk factor for mortality in male patients on HD. However, the mortality of female patients on HD was not related with baseline and follow-up BMI. This suggests that BMI is a good surrogate marker of lean body composition, especially in male patients on HD. [ABSTRACT FROM AUTHOR]

Prevalent anuric peritoneal dialysis (PD) patients usually have higher mortality than PD patients with residual urine volume. We aimed to evaluate the predictors of survival in anuric PD patients. Anuric PD patients (n = 505, <100 mL of daily urine) enrolled in Korean nationwide prospective cohort were analyzed. Survived and non-survived anuric PD patients were compared by propensity score matching analysis with a ratio of two to one. The propensity method was used to adjust for patient age, dialysis duration, and presence of diabetes. Among the total anuric PD patients, non-survived patients showed a significantly older age, higher incidence of diabetes, coronary artery disease, and arrhythmia, and lower serum creatinine and albumin. After propensity score matching, multivariate Cox regression analysis for patient survival showed a decreasing risk as serum albumin increased (HR = 0.347, p = 0.0094). Analysis using the receiver-operating-characteristic (ROC) curve showed that survival could be predicted with a sensitivity of 59.4% and a specificity of 63.2% using a cutoff value of 3.6 g/dL of serum albumin in unmatched total PD patients. The beneficial impact of high albumin level on death was significantly greater for patients with older age (≥50 years), no diabetes, low ultrafiltration (UF) volume (<1000 mL/day), and low levels of serum creatinine (<10 mg/dL), total cholesterol (<177.5 mg/dL), ferritin (<100 ng/mL), and high-sensitivity C-reactive protein (hs-CRP) (<0.1 mg/dL). Survival in anuric PD patients was associated with age, comorbidities, and nutritional factors such as creatinine and albumin. After adjustment by propensity score matching, serum albumin level was an independent predictor for survival in anuric PD patients. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate whether the combination of inflammatory markers could provide predictive powers for mortality in individual patients on dialysis and develop a predictive model for mortality according to dialysis modality. Data for inflammatory markers were obtained at the time of enrollment from 3,309 patients on dialysis from a prospective multicenter cohort. Net reclassification index (NRI) and integrated discrimination improvement (IDI) were calculated. Cox proportional hazards regression analysis was used to derive a prediction model of mortality and the integrated area under the curve (iAUC) was calculated to compare the predictive accuracy of the models. The incremental additions of albumin, high-sensitive C-reactive protein (hsCRP), white blood count (WBC), and ferritin to the conventional risk factors showed the highest predictive powers for all-cause mortality in the entire population (NRI, 21.0; IDI, 0.045) and patients on peritoneal dialysis (NRI, 25.7; IDI, 0.061). The addition of albumin and hsCRP to the conventional risk factors markedly increased predictive powers for all-cause mortality in HD patients (NRI, 19.0; IDI, 0.035). The prediction model for all-cause mortality using conventional risk factors and combination of inflammatory markers with highest NRI value (iAUC, 0.741; 95% CI, 0.722–0.761) was the most accurate in the entire population compared with a model including conventional risk factors alone (iAUC, 0.719; 95% CI, 0.700–0.738) or model including only significant conventional risk factors and inflammatory markers (iAUC, 0.734; 95% CI, 0.714–0.754). Using multiple inflammatory markers practically available in a clinic can provide higher predictive power for all-cause mortality in patients on dialysis. The predictive model for mortality based on combinations of inflammatory markers enables a stratified risk assessment. However, the optimal combination for the predictive model was different in each dialysis modality. [ABSTRACT FROM AUTHOR]

Background: The role of mineral metabolism in mortality among dialysis patients has received increased attention, but some aspects remain unclear. The aim of the present study was to investigate the prognostic value of serum calcium and phosphate levels for all-cause mortality and cause-specific mortality in dialysis patients. Methods: Patients on hemodialysis and peritoneal dialysis were enrolled from a multicenter prospective cohort study in Korea (NCT00931970). The patients were divided into low, normal, and high groups according to their baseline serum calcium or phosphate levels. Cox proportional analysis and a proportional hazards model for the subdistribution of a competing risk were used to calculate hazard ratios (HRs) for the association of serum calcium and phosphate levels with all-cause and cause-specific mortality. Time-dependent values of calcium and phosphate were also evaluated to assess the effect of longitudinal change in mineral metabolism parameters on mortality types. Results: A total of 3,226 dialysis patients were followed up for a mean of 19.8 ± 8.2 months. Infection was the most common cause of death. Low serum phosphate was significantly associated with all-cause and infection-related death using time-dependent values (HR, 1.43 [95% confidence interval (CI), 1.06–1.93], P = 0.02, and HR, 1.66 [95% CI, 1.02–2.70], P = 0.04, respectively). Low serum phosphate was associated with significantly higher infection-related mortality, especially in patients older than 65 years or on dialysis more than one year or with serum albumin lower than 3.9 g/dL (HR, 2.06 [95% CI, 1.13–3.75], P = 0.02, HR, 2.19 [95% CI, 1.20–4.01], P = 0.01, and HR, 1.77 [95% CI, 1.00–3.13], P = 0.05, respectively). Multinomial logistic regression analysis results suggested that low serum albumin, creatinine, and body mass index correlated with low serum phosphate. Conclusions: Low serum phosphate in dialysis patients was an independent risk factor for infection-related death, especially in elderly patients. Persistently low serum phosphate might be a nutritional biomarker to predict increased susceptibility to infection and in turn worse outcomes in dialysis patients. [ABSTRACT FROM AUTHOR]

Background: The atherogenic index of plasma (AIP), which is the logarithmic ratio of triglyceride (TG) to high-density lipoprotein cholesterol (HDL-C), had a linear relationship with clinical outcomes in the general population. However, the association of each lipid profile, TG and HDL-C, with survival was not straightforward in dialysis patients. This non-linear association led us to further investigate the prognostic impact of the AIP in these patients. Methods: From a nationwide prospective cohort, 1,174 incident dialysis patients were included. Patients were categorized into quintiles according to the AIP. An independent association of the AIP with all-cause and cardiovascular mortality was determined. Results: During a mean follow-up duration of 33.2 months, 170 patients (14.5%) died, and cardiovascular death was observed in 55 patients (4.7%). Multivariate Cox analyses revealed that the lowest (quintile 1, hazard ratio [HR] = 1.76, 95% confidence interval [CI] = 1.02–3.03) and the highest (quintile 5, HR = 2.15, 95% CI = 1.26–3.65) AIP groups were significantly associated with higher all-cause mortality compared to patients in quintile 3 (reference group). In terms of cardiovascular mortality, only the highest AIP group (quintile 5, HR = 2.59, 95% CI = 1.06–6.34) was significantly associated with increased risk of mortality. Sensitivity analyses showed that a U-shaped association between the AIP and all-cause mortality remained significant in non-diabetic and underweight to normal body mass index patients. Conclusions: Both the highest and the lowest AIP groups were independently associated with all-cause mortality, showing a U-shaped association. It suggested further studies are needed to identify targets and subgroups that can benefit from intervention of the AIP in incident dialysis patients. [ABSTRACT FROM AUTHOR]

Background: The optimal timing for initiating dialysis in end-stage renal disease (ESRD) is controversial, especially in the elderly. Methods: 665 patients ≥65 years old who began dialysis from August 2008 to February 2015 were prospectively enrolled in the Clinical Research Center for End-Stage Renal Disease cohort study. Participants were divided into 2 groups based on the median estimated glomerular filtration rate at the initiation of dialysis. Propensity score matching (PSM) was used to compare the overall survival rate, cardiovascular events, Kidney Disease Quality of Life Short Form 36 (KDQOL-36) results, Karnofsky performance scale values, Beck’s depression inventory values, and subjective global assessments. Results: The mean patient age was 72.0 years, and 61.7% of the patients were male. Overall, the cumulative survival rates were lower in the early initiation group, although the difference was not significant after PSM. Additionally, the survival rates of the 2 groups did not differ after adjusting for age, sex, Charlson comorbidity index and hemoglobin, serum albumin, serum calcium and phosphorus levels. Although the early initiation group showed a lower physical component summary score on the KDQOL-36 3 months after dialysis, the difference in scores was not significant 12 months after dialysis. Furthermore, the difference was not significant after PSM. The Karnofsky performance scale, Beck’s depression inventory, and subjective global assessments were not significantly different 3 and 12 months after dialysis initiation. Conclusions: The timing of dialysis initiation is not associated with clinical outcomes in elderly patients with ESRD. [ABSTRACT FROM AUTHOR]

Background: Abnormal serum potassium concentration has been suggested as a risk factor for mortality in patients undergoing dialysis patients. We investigated the impact of serum potassium levels on survival according to dialysis modality. Methods: A nationwide, prospective, observational cohort study for end stage renal disease patients has been ongoing in Korea since August 2008. Our analysis included patients whose records contained data regarding serum potassium levels. The relationship between serum potassium and mortality was analyzed using competing risk regression. Results: A total of 3,230 patients undergoing hemodialysis (HD, 64.3%) or peritoneal dialysis (PD, 35.7%) were included. The serum potassium level was significantly lower (P < 0.001) in PD (median, 4.5 mmol/L; interquartile range, 4.0–4.9 mmol/L) than in HD patients (median, 4.9 mmol/L; interquartile range, 4.5–5.4 mmol/L). During 4.4 ± 1.7 years of follow-up, 751 patients (23.3%) died, mainly from cardiovascular events (n = 179) and infection (n = 120). In overall, lower serum potassium level less than 4.5 mmol/L was an independent risk factor for mortality after adjusting for age, comorbidities, and nutritional status (sub-distribution hazard ratio, 1.30; 95% confidence interval 1.10–1.53; P = 0.002). HD patients showed a U-shaped survival pattern, suggesting that both lower and higher potassium levels were deleterious, although insignificant. However, in PD patients, only lower serum potassium level (<4.5 mmol/L) was an independent predictor of mortality (sub-distribution hazard ratio, 1.35; 95% confidence interval 1.00–1.80; P = 0.048). Conclusion: Lower serum potassium levels (<4.5 mmol/L) occur more commonly in PD than in HD patients. It represents an independent predictor of survival in overall dialysis, especially in PD patients. Therefore, management of dialysis patients should focus especially on reducing the risk of hypokalemia, not only that of hyperkalemia. [ABSTRACT FROM AUTHOR]

The overexpression of urokinase-type plasminogen activator receptor (uPAR) is associated with inflammation and virtually all human cancers. Despite the fact that docosahexaenoic acid (DHA) has been reported to possess anti-inflammatory and anti-tumor properties, the negative regulation of uPAR by DHA is still undefined. Here, we investigated the effect of DHA on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced uPAR expression and the underlying molecular mechanisms in ECV304 human endothelial cells. DHA concentration-dependently inhibited TPA-induced uPAR. Specific inhibitors and mutagenesis studies showed that PKCδ, JNK1/2, Erk1/2, NF-κB, and AP-1 were critical for TPA-induced uPAR expression. Application of DHA suppressed TPA-induced translocation of PKCδ, activation of the JNK1/2 and Erk1/2 signaling pathways, and subsequent AP-1 and NF-κB transactivation. In conclusion, these observations suggest a novel role for DHA in reducing uPAR expression and cell invasion by inhibition of PKCδ, JNK1/2, and Erk1/2, and the reduction of AP-1 and NF-κB activation in ECV304 human endothelial cells. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Previous studies have reported the relationship between thyroid hormone levels and mortality in dialysis patients. However, little is known about the association of free thyroxine (fT4) and mortality in patients on peritoneal dialysis (PD). This study investigated the association between basal and annual variation in fT4 level and mortality in PD patients. Methods: Patients on maintenance PD were enrolled from a prospective multicenter cohort study in Korea; their serum triiodothyronine, fT4, and thyroid-stimulating hormone levels were measured 12 months apart. Patients with overt thyroid disease and those receiving thyroid hormone replacement therapy were excluded from the analysis. Patients were divided into two groups based on the median levels of fT4. The differences of all-cause, infection-related, and cardiovascular mortalities were analyzed between the two groups. The association of basal levels and annual variation with mortality was investigated with Kaplan–Meier curves and Cox proportional hazard models. Results: Among 235 PD patients, 31 (13.2%) deaths occurred during the mean follow-up period of 24 months. Infection (38.7%) was the most common cause of death. Lower basal fT4 levels were an independent predictor of all-cause and infection-related death (hazard ratio [HR] = 2.74, 95% confidence interval [CI] 1.27–5.90, P = 0.01, and HR = 6.33, 95% CI 1.16–34.64, P = 0.03, respectively). Longitudinally, patients with persistently lower fT4 levels during the 12-month period had significantly higher all-cause mortality than those with persistently higher levels (HR = 3.30, 95% CI 1.15–9.41, P = 0.03). The area under the receiver operating characteristic curve of fT4 for predicting all-cause and infection-related mortality was 0.60 and 0.68, respectively. Conclusions: fT4 level is an independent predictor of mortality and is especially attributable to infection in PD patients. This predictor was consistent when considering both baseline measurements and annual variation patterns. Close attention to infection in PD patients with relatively lower fT4 levels should be considered. [ABSTRACT FROM AUTHOR]

Background: Controversy persists regarding the appropriate initiation timing of renal replacement therapy for patients with end-stage renal disease. We evaluated the effect of dialysis initiation timing on clinical outcomes. Initiation times were classified according to glomerular filtration rate (GFR). Methods: We enrolled a total of 1691 adult patients who started dialysis between August 2008 and March 2013 in a multi-center, prospective cohort study at the Clinical Research Center for End Stage Renal Disease in the Republic of Korea. The patients were classified into the early-start group or the late-start group according to the mean estimated GFR value, which was 7.37 ml/min/1.73 m2. The primary outcome was patient survival, and the secondary outcomes were hospitalization, cardiovascular events, vascular access complications, change of dialysis modality, and peritonitis. The two groups were compared before and after matching with propensity scores. Results: Before propensity score matching, the early-start group had a poor survival rate (P<0.001). Hospitalization, cardiovascular events, vascular access complications, changes in dialysis modality, and peritonitis were not different between the groups. A total of 854 patients (427 in each group) were selected by propensity score matching. After matching, neither patient survival nor any of the other outcomes differed between groups. Conclusions: There was no clinical benefit after adjustment by propensity scores comparing early versus late initiation of dialysis. [ABSTRACT FROM AUTHOR]

Background: The nature of cost-saving effects of early referral to a nephrologist in patients with chronic kidney disease (CKD) is not fully evaluated. We evaluated the health care costs before and after dialysis according to the referral time. Methods: A total of 879 patients who were newly diagnosed as having end-stage renal disease from August 2008 to June 2011 were prospectively enrolled. The early referral (ER) group was defined as patients who were referred to a nephrologist more than a year before dialysis and had visited a nephrology clinic 2 or more times. Patients whose referral time was less than a year were considered the late referral (LR) group. Information about medical costs was acquired from the claim data of the Korea Health Insurance Review and Assessment Service. Results: The total medical costs during the first 12 months after the initiation of dialysis were not different between the 526 ER patients and the 353 LR patients. However, the costs of the ER patients during the first month were significantly lower than those of the LR patients (ER vs. LR: 3029±2219 vs. 3438±2821 US dollars [USD], P = 0.025). The total 12-month health care costs before the initiation of dialysis were significantly lower in the ER group (ER vs. LR: 6206±5873 vs. 8610±7820 USD, P<0.001). In the multivariate analysis, ER significantly lowered the health care costs during the 12 months before (2534.0±436.2 USD, P<0.001) and the first month (428.5±172.3 USD, P = 0.013) after the initiation of dialysis. Conclusions: The ER of patients with CKD to a nephrologist is associated with decreased medical costs during the pretreatment period of renal replacement therapy and the early period of dialysis initiation. [ABSTRACT FROM AUTHOR]

Background: The effect of flux membranes on mortality in hemodialysis (HD) patients is controversial. Residual renal function (RRF) has shown to not only be as a predictor of mortality but also a contributor to β2-microglobulin clearance in HD patients. Our study aimed to determine the interaction of residual renal function with dialyzer membrane flux on mortality in HD patients. Methods: HD Patients were included from the Clinical Research Center registry for End Stage Renal Disease, a prospective observational cohort study in Korea. Cox proportional hazards regression models were used to study the association between use of high-flux dialysis membranes and all-cause mortality with RRF and without RRF. The primary outcome was all-cause mortality. Results: This study included 893 patients with 24 h-residual urine volume ≥100 ml (569 and 324 dialyzed using low-flux and high-flux dialysis membranes, respectively) and 913 patients with 24 h-residual urine volume <100 ml (570 and 343 dialyzed using low-flux and high-flux dialysis membranes, respectively). After a median follow-up period of 31 months, mortality was not significantly different between the high and low-flux groups in patients with 24 h-residual urine volume ≥100 ml (HR 0.86, 95% CI, 0.38–1.95, P = 0.723). In patients with 24 h-residual urine volume <100 ml, HD using high-flux dialysis membrane was associated with decreased mortality compared to HD using low-flux dialysis membrane in multivariate analysis (HR 0.40, 95% CI, 0.21–0.78, P = 0.007). Conclusions: Our data showed that HD using high-flux dialysis membranes had a survival benefit in patients with 24 h-residual urine volume <100 ml, but not in patients with 24 h-residual urine volume ≥100 ml. These findings suggest that high-flux dialysis rather than low-flux dialysis might be considered in HD patients without RRF. [ABSTRACT FROM AUTHOR]