Causal Effect of Chondroitin, Glucosamine, Vitamin, and Mineral Intake on Kidney Function: A Mendelian Randomization Study.

The causal effects of chondroitin, glucosamine, and vitamin/mineral supplement intake on kidney function remain unknown, despite being commonly used. We conducted a two-sample summary-level Mendelian randomization (MR) analysis to test for causal associations between regular dietary supplement intake and kidney function. Genetic instruments for chondroitin, glucosamine, and vitamin/mineral supplement intake were obtained from a genome-wide association study of European ancestry. Summary statistics for the log-transformed estimated glomerular filtration rate (log-eGFR) were provided by the CKDGen consortium. The multiplicative random-effects inverse-variance weighted method showed that genetically predicted chondroitin and glucosamine intake was causally associated with a lower eGFR (chondroitin, eGFR change beta = -0.113%, standard error (SE) = 0.03%, p-value = 2 × 10-4; glucosamine, eGFR change beta = -0.240%, SE = 0.035%, p-value = 6 × 10-12). However, a genetically predicted vitamin/mineral supplement intake was associated with a higher eGFR (eGFR change beta = 1.426%, SE = 0.136%, p-value = 1 × 10-25). Validation analyses and pleiotropy-robust MR results for chondroitin and vitamin/mineral supplement intake supported the main results. Our MR study suggests a potential causal effect of chondroitin and glucosamine intake on kidney function. Therefore, clinicians should carefully monitor their long-term effects.

Optimal target blood pressure for major adverse cardiovascular and cerebrovascular events in hypertensive patients: a nationwide population-based study.

BACKGROUND: Generalizing an 'optimal' blood pressure (BP) level for individuals with hypertension remains controversial due to the implementation of different medical guidelines. This study investigated the association of BP with major adverse cardiovascular and cerebrovascular events (MACCE) and determined the optimal BP for patients with hypertension. METHOD: A total of 934 179 individuals who received antihypertensive medications were selected from the National Health Insurance Service Examination Database between 2003 and 2011 in Korea. Their BP was measured at the index date, which was the first health examination. The study outcomes were MACCE, including acute myocardial infarction, heart failure, stroke, and all-cause mortality. The participants were monitored until in December, 2017. The hazard ratios were calculated using Cox proportional hazard models. The cumulative incidence of MACCE for each BP group was estimated using the Kaplan-Meier method. RESULTS: A lower risk of MACCE was observed at a SBP of 120-129 mmHg and a DBP of 80-89 mmHg. The endpoint-specific incidence rates and hazard ratios for acute myocardial infarction, heart failure, stroke, and all-cause mortality were the lowest at a SBP of 120-129 mmHg and a DBP of 80-89 mmHg. CONCLUSION: Even though this observational study did not support inference of a causal relationship, a SBP of 120-129 mmHg and a DBP of 80-89 mmHg may be safely recommended considering the possibility of MACCE in Korean patients with hypertension. In addition, the target BP should be tailored individually according to age, sex, and comorbidities.

Causal Effects of Serum Levels of n-3 or n-6 Polyunsaturated Fatty Acids on Coronary Artery Disease: Mendelian Randomization Study.

We aimed to investigate the causal effects of n-3 and n-6 polyunsaturated fatty acids (PUFAs) on the risk of coronary artery disease (CAD) through Mendelian randomization (MR) analysis. This MR study utilized a genetic instrument developed from previous genome-wide association studies for various serum n-3 and n-6 PUFA levels. First, we calculated the allele scores for genetic predisposition of PUFAs in individuals of European ancestry in the UK Biobank data (N = 337,129). The allele score-based MR was obtained by regressing the allele scores to CAD risks. Second, summary-level MR was performed with the CARDIoGRAMplusC4D data for CAD (N = 184,305). Higher genetically predicted eicosapentaenoic acid and dihomo-gamma-linolenic acid levels were significantly associated with a lower risk of CAD both in the allele-score-based and summary-level MR analyses. Higher allele scores for linoleic acid level were significantly associated with lower CAD risks, and in the summary-level MR, the causal estimates by the pleiotropy-robust MR methods also indicated that higher linoleic acid levels cause a lower risk of CAD. Arachidonic acid showed significant causal estimates for a higher risk of CAD. This study supports the causal effects of certain n-3 and n-6 PUFA types on the risk of CAD.

Effect of Liver Cirrhosis on the Outcomes of Peritoneal Dialysis.

Background:Peritoneal dialysis (PD) has become an increasingly important treatment modality for end-stage renal disease. However, application of PD in patients with liver cirrhosis (LC) and subsequent outcomes have not been thoroughly evaluated.Methods:A total of 1,366 patients (≥ 18 years old) who started PD at 4 tertiary referral centers between January 2000 and December 2015 were initially reviewed. Among them, 45 patients with LC were finally analyzed (LC-PD). Using the multivariate Cox hazard ratio (HR) model, outcomes such as technique failure, infection, and mortality in patients with LC-PD were compared with those in non-LC-PD patients (non-LC-PD) or patients with LC who received hemodialysis (LC-HD). All of the patients were selected by 1:1 matching of age, sex, catheter insertion date, and diabetes mellitus.Results:During the mean follow-up duration of 43 ± 35.8 months, 12 patients with LC-PD experienced technique failure, and this rate was similar to that of non-LC-PD patients. In evaluating infection episodes, the most common causes for peritonitis and exit-site infection were Escherichia coli (5.8%) and Staphylococcus aureus (19.3%), respectively; these event rates of LC-PD did not differ from those of non-LC-PD. The all-cause mortality rate of the LC-PD group was not different from that of the non-LC-PD and LC-HD groups.Conclusion:Dialysis outcomes such as technique failure, infection, and mortality are not affected by the presence of LC. Accordingly, PD therapy is a good option in patients with LC.

Early dialysis initiation does not improve clinical outcomes in elderly end-stage renal disease patients: A multicenter prospective cohort study.

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.

Development and Validation of the Modified Charlson Comorbidity Index in Incident Peritoneal Dialysis Patients: A National Population-Based Approach.

♦ BACKGROUND: The utility of applying the Charlson comorbidity index (CCI) to peritoneal dialysis (PD) patients is disputed because the relative weight of each comorbidity in PD patients may be different from those in other chronic diseases. We aimed to develop and validate a modified CCI in incident PD patients (mCCI-IPD) for better risk stratification and prediction of mortality. ♦ METHODS: The mCCI-IPD was developed using data from all Korean adult incident PD patients between 2005 and 2008 (n = 7,606). Multivariate Cox regression was used to determine new weights for the individual comorbidities in the CCI. The prognostic performance of the mCCI-IPD was validated in an independent cohort (n = 664) through c-statistics and continuous net reclassification improvement (cNRI). ♦ RESULTS: A total of 75.5% of the patients in the development cohort had 1 or more comorbidities. The Cox proportional hazards model provided reassigned severity weights for the 11 comorbidities that significantly predicted mortality. In the validation cohort, the CCI and mCCI-IPD scores were both correlated with survival and showed no differences in their c-statistics. However, multivariate analyses using cNRI revealed that the mCCI-IPD provided a 38.2% improvement in mortality risk assessment compared with the CCI (95% confidence interval [CI], 15.3 - 61.0; p < 0.001). These significant reclassification improvements were observed consistently in subjects with events (cNRIEvent, 28.2% [95% CI, 6.9 - 49.5; p = 0.009]) and without events (cNRINon-event, 10.0% [95% CI, 1.7 - 18.2; p = 0.019]). ♦ CONCLUSIONS: Compared with the CCI, the mCCI-IPD showed better performance in mortality prediction for incident PD patients. Therefore, this tool may be used as a preferred index for statistical analysis and clinical decision-making.

Early initiation of continuous renal replacement therapy improves survival of elderly patients with acute kidney injury: a multicenter prospective cohort study.

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.

High-Dose Versus Conventional-Dose Continuous Venovenous Hemodiafiltration and Patient and Kidney Survival and Cytokine Removal in Sepsis-Associated Acute Kidney Injury: A Randomized Controlled Trial.

BACKGROUND: Soluble inflammatory mediators are known to exacerbate sepsis-induced acute kidney injury (AKI). Continuous renal replacement therapy (CRRT) has been suggested to play a part in immunomodulation by cytokine removal. However, the effect of continuous venovenous hemodiafiltration (CVVHDF) dose on inflammatory cytokine removal and its influence on patient outcomes are not yet clear. STUDY DESIGN: Prospective, randomized, controlled, open-label trial. SETTING & PARTICIPANTS: Septic patients with AKI receiving CVVHDF for AKI. INTERVENTION: Conventional (40mL/kg/h) and high (80mL/kg/h) doses of CVVHDF for the duration of CRRT. OUTCOMES: Patient and kidney survival at 28 and 90 days, circulating cytokine levels. RESULTS: 212 patients were randomly assigned into 2 groups. Mean age was 62.1 years, and 138 (65.1%) were men. Mean intervention durations were 5.4 and 6.2 days for the conventional- and high-dose groups, respectively. There were no differences in 28-day mortality (HR, 1.02; 95% CI, 0.73-1.43; P=0.9) or 28-day kidney survival (HR, 0.96; 95% CI, 0.48-1.93; P=0.9) between groups. High-dose CVVHDF, but not the conventional dose, significantly reduced interleukin 6 (IL-6), IL-8, IL-1b, and IL-10 levels. There were no differences in the development of electrolyte disturbances between the conventional- and high-dose groups. LIMITATIONS: Small sample size. Only the predilution CVVHDF method was used and initiation criteria were not controlled. CONCLUSIONS: High CVVHDF dose did not improve patient outcomes despite its significant influence on inflammatory cytokine removal. CRRT-induced immunomodulation may not be sufficient to influence clinical end points.

Recalibration and validation of the Charlson comorbidity index in Korean incident hemodialysis patients.

BACKGROUND: Weights assigned to comorbidities to predict mortality may vary based on the type of index disease and advances in the management of comorbidities. We aimed to develop a modified Charlson comorbidity index (CCI) in incident hemodialysis patients (mCCI-IHD), thereby improving risk stratification for mortality. METHODS: Data on 24,738 Koreans who received their first hemodialysis treatment between 2005 and 2008 were obtained from the Korean Health Insurance dataset. The mCCI-IHD score were calculated by summing up the weights which were assigned to individual comorbidities according to their relative prognostic significance determined by multivariate Cox proportional hazards model. The modified index was validated in an independent nationwide prospective cohort (n=1,100). RESULTS: The Cox proportional hazards model revealed that all comorbidities in the CCI except ulcers significantly predicted mortality. Thus, the mCCI-IHD included 14 comorbidities with re-assigned severity weights. In the validation cohort, both the CCI and the mCCI-IHD were correlated with mortality. However, the mCCI-IHD showed modest but significant increases in c statistics compared with the CCI at 6 months and 1 year. The analyses using continuous net reclassification improvement revealed that the mCCI-IHD improved net mortality risk reclassification by 24.6% (95% CI, 2.5-46.7; P=0.03), 26.2% (95% CI, 1.0-51.4; P=0.04) and 42.8% (95% CI, 4.9-80.8; P=0.03) with respect to the CCI at 6 months and 1 and 2 years, respectively. CONCLUSIONS: The mCCI-IHD facilitates better risk stratification for mortality in incident hemodialysis patients compared with the CCI, suggesting that it may be a preferred index for use in clinical practice and the statistical analysis of epidemiological studies.

Non-linear association of serum 25-hydroxyvitamin D with urinary albumin excretion rate in normoalbuminuric subjects.

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.

Dose selection method for pharmacokinetic study in hemodialysis patients using a subpharmacological dose: oseltamivir as a model drug.

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 AUC last of OC following continuous oseltamivir doses was simulated, and 35 mg of oseltamivir corresponded to the hypothetical target AUC last 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.