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Background: Elevated blood pressure and intrarenal renin-angiotensin system activity are closely related to chronic kidney disease (CKD) progression. However, interrelationship between blood pressure and intrarenal renin-angiotensin system activity on the risk of CKD progression is unknown., Methods: We analyzed 2076 participants from the Korean Cohort Study for Outcomes in Patients With CKD. The main exposure was systolic blood pressure (SBP). The urinary angiotensinogen-to-creatinine ratio was stratified according to the median value (3.65 μg/gCr). The primary outcome was a composite kidney outcome of a ≥50% decline in estimated glomerular filtration rate from baseline measurement or initiation of kidney replacement therapy., Results: During 10 550 person-years of follow-up (median, 5.2 years), the composite outcome occurred in 800 (38.5%) participants. In the multivariable cause-specific hazard model, higher SBP was associated with an increased risk of CKD progression. There was a significant interaction between SBP and urinary angiotensinogen-to-creatinine ratio on the risk of the primary outcome ( P value for interaction=0.019). In patients with urinary angiotensinogen-to-creatinine <3.65 μg/gCr, the hazard ratios (95% CIs) for SBP 120 to 129, 130 to 139, and ≥140 mmHg were 1.46 (1.07-1.99), 1.71 (1.25-2.35), and 2.40 (1.73-3.32), respectively, compared with SBP <120 mmHg. However, these associations were not observed in patients with urinary angiotensinogen-to-creatinine ≥3.65 μg/gCr., Conclusions: In this prospective CKD cohort, higher SBP was associated with CKD progression when urinary angiotensinogen levels were low, while this association was not seen when urinary angiotensinogen levels were high. This finding suggests that intrarenal renin-angiotensin system activity may modify the relationship between SBP and adverse kidney outcome.

Background: Many trials have attempted to slow the progression of chronic kidney disease (CKD) by modifying specific risk factors, but without achieving satisfactory results. We aimed to evaluate the association between the degree of improvement in multiple risk factors and adverse kidney outcomes., Methods: This was a prospective observational study of 839 patients with CKD G3-G4. The main predictors were the number of improved risk factors between baseline and year one as follows: a decrease in proteinuria, systolic blood pressure, phosphate, and uric acid, and an increase in hemoglobin and bicarbonate from the baseline status to out of the target range. The primary outcome was a composite one, including CKD progression (50% decline in eGFR or kidney replacement therapy) and all-cause death., Results: Patients whose risk factors eventually improved had more unfavorable baseline profiles of the six considered factors. During 3097.8 person-years of follow-up (median 3.5 years per patient), the composite outcome occurred in 48.0% of patients (incidence rate, 13.0 per 100 person-years). Compared with an improvement of no risk factors, the adjusted HRs (95% CI) for improvement of 1 and ≥ 2 risk factors were 0.96 (0.76-1.22) and 0.53 (0.37-0.75), respectively. The association was not affected by diabetic status or CKD severity. Among the risk factors, proteinuria accounted for the greatest contribution to CKD progression., Conclusions: In patients with CKD G3-G4, improvement in multiple factors was associated with a decreased risk of CKD progression, suggesting the importance of multifactorial risk management., (© 2022. The Author(s) under exclusive licence to Italian Society of Nephrology.)

Background: In East Asian countries, patients with chronic kidney disease (CKD) have lower cardiovascular risk profiles and experience fewer cardiovascular events (CVEs) than those in Western countries. Thus the clinical predictive performance of well-known risk factors warrants further testing in this population., Methods: The KoreaN cohort study for Outcome in patients With Chronic Kidney Disease (KNOW-CKD) is a multicenter, prospective observational study. We included 1579 participants with CKD G1-G5 without kidney replacement therapy between 2011 and 2016. The main predictor was the coronary artery calcium score (CACS). The primary outcome was a composite of nonfatal CVEs or all-cause mortality. Secondary outcomes included 3-point major adverse cardiovascular events (MACEs; the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke), all CVEs and all-cause mortality., Results: During a median follow-up of 5.1 years, a total of 123 primary outcome events occurred (incidence rate 1.6/100 person-years). In the multivariable Cox model, a 1-standard deviation log increase in the CACS was associated with a 1.67-fold [95% confidence interval (CI), 1.37-2.04] higher risk of the primary outcome. Compared with a CACS of 0, the hazard ratio associated with a CACS >400 was 4.89 (95% CI 2.68-8.93) for the primary outcome. This association was consistent for secondary outcomes. Moreover, inclusion of the CACS led to modest improvements in prediction indices of the primary outcome compared with well-known conventional risk factors., Conclusions: In Korean patients with CKD, the CACS was independently associated with adverse cardiovascular outcomes and all-cause death. The CACS also showed modest improvements in prediction performance over conventional cardiovascular risk factors., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Background: Recent advances in magnetic resonance imaging (MRI) may allow it to be an alternative emerging tool for the non-invasive evaluation of renal parenchymal disease., Purpose: To validate the usefulness of quantitative multiparametric MRI protocols and suggest the suitable quantitative MR sequence protocol to evaluate parenchymal fibrosis using an animal model of chronic kidney disease (CKD) by long-term adenine intake., Material and Methods: In this prospective animal study, 16 male Wistar rats were analyzed and categorized into three groups. Rats in the CKD groups underwent 0.25% adenine administration for three or six weeks. Quantitative MRI protocols, including diffusion-weighted imaging (DWI), T1ρ (T1 rho), and T2* mapping were performed using a 9.4-T animal MR scanner. A semi-quantitative histopathologic analysis for renal fibrosis was conducted. Quantitative MR values measured from anatomic regions of kidneys underwent intergroup comparative analyses., Results: The apparent diffusion coefficient (ADC) and T1 (T1 rho) values were significantly increased in all CKD groups. Values measured from the cortex and outer medulla showed significant intergroup differences. Total ADC values tended to increase according to periods, and T1ρ values increased in three weeks and decreased in six weeks., Conclusion: Quantitative MRI protocols could be a non-invasive assessment modality in the diagnosis and evaluation of CKD. Particularly, T1ρ may be a suitable MR sequence to quantitatively assess renal parenchymal fibrosis.

Background: An elevated coronary artery calcification score (CACS) is associated with increased cardiovascular disease risk in patients with CKD. However, the relationship between CACS and CKD progression has not been elucidated., Methods: We studied 1936 participants with CKD (stages G1-G5 without kidney replacement therapy) enrolled in the KoreaN Cohort Study for Outcome in Patients With CKD. The main predictor was Agatston CACS categories at baseline (0 AU, 1-100 AU, and >100 AU). The primary outcome was CKD progression, defined as a ≥50% decline in eGFR or the onset of kidney failure with replacement therapy., Results: During 8130 person-years of follow-up, the primary outcome occurred in 584 (30.2%) patients. In the adjusted cause-specific hazard model, CACS of 1-100 AU (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.04 to 1.61) and CACS >100 AU (HR, 1.42; 95% CI, 1.10 to 1.82) were associated with a significantly higher risk of the primary outcome. The HR associated with per 1-SD log of CACS was 1.13 (95% CI, 1.03 to 1.24). When nonfatal cardiovascular events were treated as a time-varying covariate, CACS of 1-100 AU (HR, 1.31; 95% CI, 1.07 to 1.60) and CACS >100 AU (HR, 1.46; 95% CI, 1.16 to 1.85) were also associated with a higher risk of CKD progression. The association was stronger in older patients, in those with type 2 diabetes, and in those not using antiplatelet drugs. Furthermore, patients with higher CACS had a significantly larger eGFR decline rate., Conclusion: Our findings suggest that a high CACS is associated with significantly increased risk of adverse kidney outcomes and CKD progression., (Copyright © 2022 by the American Society of Nephrology.)

Dietary potassium intake is a dilemma in patients with chronic kidney disease (CKD). We investigated the association of urine potassium excretion, a surrogate for dietary potassium intake, with blood pressure variability (BPV) and cardiovascular (CV) outcomes in patients with pre-dialysis CKD. A total of 1860 participants from a cohort of pre-dialysis CKD (KNOW-CKD) patients were divided into the quartiles by spot urine potassium-to-creatinine ratio. The first quartile (26.423 ± 5.731 mmol/gCr) was defined as low urine potassium excretion. Multivariate linear regression analyses revealed an independent association of low urine potassium excretion with high BPV (adjusted β coefficient 1.163, 95% confidence interval 0.424 to 1.901). Cox regression analyses demonstrated that, compared to high urine potassium excretion, low urine potassium excretion is associated with increased risk of CV events (adjusted hazard ratio 2.502, 95% confidence interval 1.162 to 5.387) but not with all-cause mortality. In conclusion, low urine potassium excretion is associated with high BPV and increased risk of CV events in patients with pre-dialysis CKD. The restriction of dietary potassium intake should be individualized in patients with pre-dialysis CKD.

Background: The transtubular potassium gradient which reflects potassium secretion by the kidney through the cortical collecting duct, has not yet been tested as a surrogate marker of kidney function decline. Here, we investigate the relationship between the transtubular potassium gradient and chronic kidney disease (CKD) progression., Methods: We studied 1672 patients from the KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD) cohort. The transtubular potassium gradient was calculated using a standard equation. The study endpoint was CKD progression, defined as a composite of a ≥ 50% decrease in estimated glomerular filtration rate (eGFR) from baseline values or end-stage kidney disease., Results: During a median follow-up of 4.1 years (7149 person-years), 441 participants reached the endpoint. In cause-specific competing risk analysis, the highest tertile was associated with a significantly lower risk of an adverse kidney outcome compared with the lowest tertile [hazard ratio (HR), 0.73; 95% confidence interval (CI), 0.55-0.97]. When the transtubular potassium gradient was treated as a continuous variable, an increase of 1 in the transtubular potassium gradient was associated with a 6% lower risk of CKD progression (95% CI, 0.90-0.99). This association was particularly evident in patients with an eGFR ≥ 45 mL/min/1.73 m 2 . A time-updated transtubular potassium gradient model showed similar results. The predictive performance of the transtubular potassium gradient was significantly less than that of the eGFR, but similar to that of proteinuria, serum bicarbonate, and urine osmolality., Conclusions: A higher transtubular potassium gradient is associated with a significantly lower risk of CKD progression, suggesting that it may offer insights into the prognosis of CKD., (© 2021. Italian Society of Nephrology.)

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Background and Aims: Decreased kidney function is an important risk factor for cardiovascular disease (CVD). However, assessing risk of CVD may be difficult when there is a gap between creatinine- and cystatin C-based estimated glomerular filtration rate (eGFR). We studied the association of the difference in eGFRs with major adverse cardiovascular events (MACE) in patients with chronic kidney disease (CKD)., Methods: This prospective cohort study was conducted in 2076 patients with CKD stages based on the KDIGO guideline (eGFR categories of G1: ≥90; G 2: 60-89; G3: 30-59; G4: 15-29; G5: <15 mL/min/1.73 m 2 without kidney replacement therapy). The difference in eGFR (eGFR diff ) was calculated by subtracting the cystatin C-based eGFR (eGFR cys ) from the creatinine-based eGFR (eGFR creat ). The primary outcome was MACE, defined as non-fatal acute myocardial infarction and unstable angina, stroke, congestive heart failure, symptomatic arrhythmia, and cardiac death., Results: During a median follow-up of 4.1 years, MACE occurred in 147 patients (incidence rate, 15.0 per 1000 patient-years). When patients were categorized into baseline eGFR diff tertiles, the highest tertile was associated with a significantly higher risk of MACE (hazard ratio, 2.12; 95% confidence interval [CI], 1.28-3.51) than the lowest tertile when adjusted for eGFR creat , eGFR cys , or eGFR based on both creatinine and cystatin C. Patients in the highest tertile had more baseline coronary artery calcification (CAC) than those in the lowest tertile (odds ratio [OR], 1.38; 95% CI, 1.03-1.86). In addition, 978 patients had data for both baseline and follow-up CAC at year 4. In this subgroup, baseline eGFR diff was significantly associated with accelerated CAC progression (≥50/year) (OR, 1.03; 95% CI, 1.01-1.05)., Conclusions: A large positive difference between eGFR creat and eGFR cys was associated with a higher risk of MACE and faster CAC progression in patients with CKD. Therefore, careful monitoring of CVD is needed for patients with a higher eGFR diff ., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Anemia is a common complication of chronic kidney disease (CKD). Blood urea nitrogen (BUN) in CKD represents nitrogenous uremic toxin accumulation which could be involved in anemia of CKD. We investigated the effects of BUN independent of estimated glomerular filtration rate (eGFR) on anemia in non-dialysis CKD (NDCKD)., Methods: This prospective study included 2,196 subjects enrolled in the KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD) cohort with BUN and hemoglobin level data. Initially, we investigated the association between BUN and hemoglobin level. To examine the impact of baseline BUN on the incident anemia, a longitudinal study was performed on 1,169 patients without anemia at study enrollment. BUN residuals were obtained from the fitted curve between BUN and eGFR. Anemia was defined as a hemoglobin level of <13.0 g/dL for men and <12.0 g/dL for women., Results: BUN residuals were not related to eGFR but to daily protein intake (DPI), while BUN was related to both eGFR and DPI. BUN was inversely associated with hemoglobin level (β -0.03; 95% confidence interval [CI] -0.04, -0.03; P <0.001) in the multivariable linear regression analysis adjusted for multiple confounders including eGFR, and BUN residual used instead of BUN was also inversely associated with hemoglobin level (β -0.03; 95% CI -0.04, -0.02; P <0.001). Among the 1,169 subjects without anemia at baseline, 414 (35.4%) subjects newly developed anemia during the follow-up period of 37.5 ± 22.1 months. In the multivariable Cox regression analysis with adjustment, both high BUN level (Hazard ratio [HR] 1.02; 95% CI 1.01, 1.04; P = 0.002) and BUN residual used instead of BUN (HR 1.02; 95% CI 1.00, 1.04; P = 0.031) increased the risk of anemia development. Moreover, BUN, rather than eGFR, increased the risk of anemia development in patients with CKD stage 3 in the multivariable Cox regression., Conclusion: Higher BUN levels derived from inappropriately high protein intake relative to renal function were associated with low hemoglobin levels and the increased risk of anemia independent of eGFR in NDCKD patients., Competing Interests: The authors have declared that no competing interests exist.

Background The function of high-density lipoprotein can change from protective to proatherosclerotic under inflammatory conditions. Herein, we studied whether inflammation could modify the relationship between high-density lipoprotein level and risk of adverse outcomes in patients with chronic kidney disease . Methods and Results In total, 1864 patients from the prospective KNOW-CKD (Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease) were enrolled. The main predictor was high-density lipoprotein cholesterol (HDL-C) level. Presence of inflammation was defined by hs-CRP (high-sensitivity C-reactive protein) level of ≥1.0 mg/L. The primary outcome was extended major adverse cardiovascular events. During 9231.2 person-years of follow-up, overall incidence of the primary outcome was 15.8 per 1000 person-years. In multivariable Cox analysis after adjusting for confounders, HDL-C level was not associated with the primary outcome. There was a significant interaction between the inflammatory status and HDL-C for risk of extended major adverse cardiovascular events ( P =0.003). In patients without inflammation, the hazard ratios (HRs) (95% CIs) for HDL-C levels <40, 50 to 59, and ≥60 mg/dL were 1.10 (0.50-1.82), 0.95 (0.50-1.82), and 0.42 (0.19-0.95), respectively, compared with HDL-C of 40 to 49 mg/dL. However, the significant association for HDL-C ≥60 mg/dL was not seen after Bonferroni correction. In patients with inflammation, we observed a trend toward increased risk of extended major adverse cardiovascular events in higher HDL-C groups (HRs [95% CIs], 0.73 [0.37-1.43], 1.24 [0.59-2.61], and 1.56 [0.71-3.45], respectively), but without statistical significance. Conclusions The association between HDL-C level and adverse cardiovascular outcomes showed reverse trends based on inflammation status in Korean patients with chronic kidney disease. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01630486.

Rationale & Objective: Optimal blood pressure (BP) control is a major therapeutic strategy in the management of chronic kidney disease (CKD). We studied the association between BP and adverse kidney outcomes within a diverse cohort of Koreans with CKD., Study Design: Prospective observational cohort study., Setting & Participants: 2,044 participants from the Korean Cohort Study for Outcomes in Patients With CKD (KNOW-CKD)., Exposures: Baseline and time-updated systolic BP (SBP) and diastolic BP (DBP)., Outcome: A composite kidney outcome of a≥50% decline in estimated glomerular filtration rate (eGFR) from the baseline value or incident kidney replacement therapy., Analytical Approach: Multivariate cause-specific hazards models and marginal structural models were fitted for baseline and time-updated BP, respectively., Results: During 7,472 person-years of follow-up, the primary composite kidney outcome occurred in 473 participants (23.1%), an incidence rate of 63.3 per 1,000 patient-years. Compared with baseline SBP<120mm Hg, the hazard ratios (HRs) for 120-129, 130-139, and≥140mm Hg were 1.10 (95% CI, 0.83-1.44), 1.20 (95% CI, 0.93-1.59), and 1.43 (95% CI, 1.07-1.91), respectively. This association was more evident in the model with time-updated SBP, for which the corresponding HRs were 1.31 (95% CI, 0.98-1.75), 1.59 (95% CI, 1.16-2.16), and 2.29 (95% CI, 1.69-3.11), respectively. In the analyses of DBP, we observed that time-updated DBP but not baseline DBP was significantly associated with the composite kidney outcome. Compared to patients with SBP<120mm Hg, patients with higher SBP had steeper slopes of eGFR decline. In the model including both SBP and DBP, only SBP was significantly associated with the composite kidney outcome., Limitations: Observational design, unmeasured confounders, and use of office BPs only., Conclusions: In patients with CKD, higher SBP and DBP levels were associated with a higher risk of a composite kidney outcome reflecting CKD progression. SBP had a greater association with adverse kidney outcomes than DBP., (Copyright © 2021 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Aims: Longitudinal studies of the association between sex and adverse clinical outcomes in patients with chronic kidney disease (CKD) are scarce. We assessed whether major outcomes may differ by sex among CKD patients., Methods: We analyzed a total of 1780 participants with non-dialysis CKD G1-5 from the KoreaN cohort study for Outcome in patients with Chronic Kidney Disease (KNOW-CKD). The primary outcome was a composite of non-fatal cardiovascular events or all-cause mortality. Secondary outcomes included fatal and non-fatal cardiovascular events, all-cause mortality, and a composite kidney outcome of ≥ 50% decline in estimated glomerular filtration rate from baseline or the onset of end-stage kidney disease., Results: There were 1088 (61%) men and 692 (39%) women in the study cohort. The proportion of smokers was significantly higher in men (24% vs. 3%). During 8430 person-years of follow-up, 201 primary outcome events occurred: 144 (13%) in men and 57 (8%) in women, with corresponding incidence rates of 2.9 and 1.7 per 100 person-years, respectively. In multivariable Cox models, men were associated with a 1.58-fold (95% CI 1.06-2.35) higher risk of composite outcome. Propensity score matching analysis revealed similar findings (HR 1.81; 95% CI 1.14-2.91). Risk of all-cause mortality was significantly higher in men of the matched cohort. However, there was no difference in the risk of CKD progression. In the subgroup with coronary artery calcium (CAC) measurements, men had a higher likelihood of CAC progression., Conclusions: In Korean CKD patients, men were more likely to experience adverse cardiovascular events and death than women.

Background: Urinary chloride is regulated by kidney transport channels, and high urinary chloride concentration in the distal tubules can trigger tubuloglomerular feedback. However, little attention has been paid to urinary chloride as a biomarker of clinical outcomes. Here, we studied the relationship between urinary chloride concentration and chronic kidney disease (CKD) progression., Methods: We included 2086 participants with CKD from the KoreaN cohort study for Outcomes in patients With Chronic Kidney Disease. Patients were categorized into three groups, according to baseline urinary chloride concentration tertiles. The study endpoint was a composite of ≥50% decrease in estimated glomerular filtration rate from baseline values, or end-stage kidney disease., Results: During a median follow-up period of 3.4 years (7452 person-years), 565 participants reached the primary endpoint. There was a higher rate of CKD progression events in the lowest and middle tertiles than in the highest tertile. Compared with the lowest tertile, the highest tertile was associated with 33% [95% confidence interval (CI) 0.49-0.90] lower risk for the primary outcome in a cause-specific hazard model after adjustment for confounding variables. In addition, for every 25 mEq/L increase in urinary chloride concentration, there was 11% (95% CI 0.83-0.96) lower risk for CKD progression. This association was consistent in a time-varying model. Urinary chloride concentration correlated well with tubule function and kidney injury markers, and its predictive performance for CKD progression was comparable to that of these markers., Conclusions: In this hypothesis-generating study, low urinary chloride concentration was associated with a higher risk for CKD progression., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

The benefits and risks of aspirin therapy for patients with chronic kidney disease (CKD) who have a high burden of cardiovascular events (CVE) are controversial. To examine the effects of low-dose aspirin on major clinical outcomes in patients with CKD. As a prospective observational cohort study, using propensity score matching, 531 aspirin recipients and non-recipients were paired for analysis from 2070 patients and fulfilled the inclusion criteria among 2238 patients with CKD. The primary outcome was the first occurrence of major CVE. The secondary outcomes were kidney events defined as a > 50% reduction of estimated glomerular filtration rate from baseline, doubling of serum creatinine, or onset of kidney failure with replacement therapy, the all-cause mortality, and bleeding event. The incidence of CVE was significantly greater in low-dose aspirin users than in non-users (HR 1.798; P = 0.011). A significant association between aspirin use and an increased risk of CVE was observed only in the lowest quartile of body weight (HR 4.014; P = 0.019) (Q1 < 60.0 kg). Secondary outcomes were not significantly different between aspirin users and non-users. It needs to be individualized of prescribing low-dose aspirin for the prevention of cardiovascular events in patients with chronic kidney disease, particularly patients with low bodyweight (< 60 kg).

Few studies have investigated the incidence of cardiovascular disease (CVD) in the Asian chronic kidney disease (CKD) population. This study assessed the incidence of CVD, death, and a composite outcome of CVD and death in a prospective Korean predialysis CKD cohort. From a total of 2179 patients, incidence rates were analyzed, and competing risk analyses were conducted according to CKD stage. Additionally, incidence was compared to the general population. During a median 4.1 years of follow-up, the incidence of CVD, all-cause death, and the composite outcome was 17.2, 9.6, and 24.5 per 1000 person-years, respectively. These values were higher in diabetic vs. non-diabetic subjects (P < 0.001). For all outcomes, incidence rates increased with increasing CKD stage (CVD, P = 0.001; death, P < 0.001; and composite, P < 0.001). Additionally, CKD stage G4 [hazard ratio (HR) 2.8, P = 0.008] and G5 (HR 5.0, P < 0.001) were significant risk factors for the composite outcome compared to stage G1 after adjustment. Compared to the general population, the total cohort population (stages G1-G5) showed significantly higher risk of CVD (HR 2.4, P < 0.001) and the composite outcome (HR 1.7, P < 0.001). The results clearly demonstrate that CKD is a risk factor for CVD in an Asian population.

Background Inflammation levels are lower in East Asians than in Western people. We studied the association between high-sensitivity hs-CRP (C-reactive protein) and adverse outcomes in Korean patients with chronic kidney disease. Methods and Results We included 2018 participants from the KNOW-CKD (Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease) between April 2011 and February 2016. The primary outcome was a composite of extended major cardiovascular events (eMACE) or all-cause mortality. The secondary end points were separate outcomes of eMACE, all-cause death, and adverse kidney outcome. We also evaluated predictive ability of hs-CRP for the primary outcome. The median hs-CRP level was 0.60 mg/L. During the mean follow-up of 3.9 years, there were 125 (6.2%) eMACEs and 80 (4.0%) deaths. In multivariable Cox analysis after adjustment of confounders, there was a graded association of hs-CRP with the primary outcome. The hazard ratios for hs-CRPs of 1.0 to 2.99 and ≥3.0 mg/L were 1.33 (95% CI, 0.87-2.03) and 2.08 (95% CI, 1.30-3.33) compared with the hs-CRP of <1.0 mg/L. In secondary outcomes, this association was consistent for eMACE and all-cause death; however, hs-CRP was not associated with adverse kidney outcomes. Finally, prediction models failed to show improvement of predictive performance of hs-CRP compared with conventional factors. Conclusions In Korean patients with chronic kidney disease, the hs-CRP level was low and significantly associated with higher risks of eMACEs and mortality. However, hs-CRP did not associate with adverse kidney outcome, and the predictive performance of hs-CRP was not strong. Registration URL: http://www.clinicaltrials.gov; Unique identifier: NCT01630486.

Background: Intrarenal renin-angiotensin system (RAS) is known to play the major role in the development of hypertension and renal progression in autosomal dominant polycystic kidney disease (ADPKD). Urinary angiotensinogen to creatinine ratio (AGT/Cr) was suggested as a novel biomarker to reflect intrarenal RAS activity. This study was performed to evaluate urinary AGT/Cr as a predictive biomarker for renal function decline in addition to imaging classification in a prospective ADPKD cohort., Methods: From 2011 to 2016, a total of 364 ADPKD patients were enrolled in the prospective cohort called the KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD). Among them, a total of 207 subjects in chronic kidney disease stage 1-4 with baseline urinary AGT and total kidney volume and subsequent renal function follow-up data over more than 1 year were included in the analysis. Patients were defined as slow progressors (SP) if they are classified as 1A or 1B by imaging classification whereas rapid progressors (RP) if they are classified as 1C-1E. Patients were divided according to AGT/Cr quartiles and annual estimated glomerular filtration rate (eGFR) slope was compared among highest quartile (hAGT group) and the rest of quartiles (lAGT group). Patients were divided into 4 groups to evaluate the predictive value of urinary AGT/Cr in addition to imaging classification: SP/lAGT, SP/hAGT, RP/lAGT, and RP/hAGT. The Cox regression model was used to evaluate the hazard ratio (HR) between groups., Results: The mean age was 45.9 years and 88.9% had hypertension. Baseline eGFR was 79.0 ± 28.4 mL/min/1.73 m² and median height-adjusted total kidney volume was 788.2 (471.2; 1,205.2) mL/m. The patients in the hAGT group showed lower eGFR (72.4 ± 24.8 vs. 81.1 ± 29.2 mL/min/1.73 m², P = 0.039), lower plasma hemoglobin (13.0 ± 1.4 vs. 13.7 ± 1.6 g/dL, P = 0.007), higher urinary protein to creatinine ratio (0.14 [0.09, 0.38] vs. 0.07 [0.04, 0.12] g/g, P = 0.007) compared to the lAGT group. The hAGT group was an independent risk factor for faster eGFR decline after adjusting for gender, RP, baseline eGFR, and other known risk factors. During median follow-up duration of 4.6 years, a total of 29 renal events (14.0%) occurred. The SP/hAGT group showed significantly higher risk of developing renal outcome compared to SP/lAGT group (HR, 13.4; 95% confidence interval, 1.282-139.324; P = 0.03)., Conclusion: Urinary AGT/Cr can be a useful predictive marker in the patients with relatively small ADPKD. Various biomarkers should be considered to define RP when implementing novel treatment in the patients with ADPKD., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2020 The Korean Academy of Medical Sciences.)

Background: No study has compared the clinical impact of indexation of left ventricular mass (LVM) on adverse clinical outcomes in pre-dialysis patients with chronic kidney disease (CKD)., Methods: We reviewed 2,101 patients from a large-scale multi-center prospective study that gathered anthropometric and echocardiographic measurements and clinical outcomes. The LVM was indexed as body surface area (LVMI-BSA) and height raised to the power of 2.7 (LVMI-H2.7). The main outcomes were composite renal and cardiovascular events and all-cause mortality. Left ventricular hypertrophy (LVH) was defined as the highest sex-specific quartile of LVMI-BSA or LVMI-H2.7., Results: During a mean period of 3.5 years, 692 patients developed composite outcomes (32.9%). The area under the curve at 5 year of LVM (60.6%) for composite outcome was smaller than that for LVMI-BSA (63.2%, P <0.001) and LVMI-H2.7 (63.4%, P <0.001). The hazard ratio (HR) and 95% confidence interval (CI) per one unit increase in LVM (g), LVMI-BSA (g/m2), and LVMI-H2.7 (g/m2.7) for composite outcomes were 1.004 (1.002-1.005, P <0.001), 1.011 (1.006-1.016, P <0.001), and 1.023 (1.012-1.035, P <0.001), respectively. Patients with LVH determined by LVMI-BSA and LVMI-H2.7 (HR 1.352, 95% CI 1.123-1.626, P = 0.001) and LVH determined by only LVMI-BSA (HR 1.908, 95% CI 1.233-2.953, P = 0.004) showed an independent increase in the risk of composite-outcome development, when compared with patients without LVH, according to LVMI-BSA and LVMI-H2.7., Conclusion: Indexation of LVM improved the prediction of adverse outcomes. BSA may be as useful as height2.7 in indexing of LVM for predicting adverse outcomes in pre-dialysis patients with CKD., Competing Interests: The authors have declared that no competing interests exist.

Objective: To assess the association of alcohol consumption with chronic kidney disease (CKD) progression in patients with CKD., Patients and Methods: The KoreaN cohort study for Outcome in patients with CKD (KNOW-CKD) is a prospective observational study that included detailed questionnaires regarding alcohol consumption. The 1883 individuals with CKD were enrolled from April 1, 2011, through February 28, 2016, and followed until May 31, 2017. Using a questionnaire, alcohol consumption pattern was classified according to the amount of alcohol per occasion (none, moderate, or binge) or drinking frequency (none, occasional, or regular). The primary endpoint was a composite of 50% or greater decline in estimated glomerular filtration rate (eGFR) from the baseline level or end-stage renal disease., Results: During a follow-up of 5555 person-years (median, 2.95 years), the primary outcome occurred in 419 patients. Unadjusted cause-specific hazards model showed that the risk of the primary outcome was lower in drinkers than in non-drinkers. However, a fully adjusted model including eGFR and proteinuria yielded a reverse association. Compared with non-drinking, regular and occasional binge drinking were associated with a 2.2-fold (95% CI, 1.38-3.46) and a 2.0-fold (95% CI, 1.33-2.98) higher risk of CKD progression, respectively. This association was particularly evident in patients who had decreased kidney function and proteinuria. There was a significant interaction between alcohol consumption and eGFR for CKD progression. The slopes of eGFR decline were steeper in binge drinkers among patients with eGFR less than 60 mL/min/1.73 m 2 ., Conclusions: Heavy alcohol consumption was associated with faster progression of CKD., (Copyright © 2019 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Background It is unclear whether high-sensitivity troponin T (hs-TnT) is associated with subclinical cardiac changes in chronic kidney disease (CKD). We evaluated the relationship between hs-TnT and left ventricular structure and function in a CKD population, according to estimated glomerular filtration rate. Methods and Results We analyzed 2017 patients with CKD stages 1 to 5 (predialysis) in the KNOW-CKD (Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease) cohort. The predictor was hs-TnT level measured at baseline, and the outcomes were left ventricular hypertrophy (LVH) and systolic and diastolic dysfunction shown by echocardiography at baseline and after 4 years. Participants were categorized into quartiles according to hs-TnT levels. The associations between quartiles of hs-TnT and outcomes were assessed using multivariable logistic regression analysis with confounders including demographics, medical history, and laboratory findings. A receiver operating characteristic curve was used to assess the diagnostic power of hs-TnT for the outcomes as a continuous variable. For subgroup analysis, patients were stratified based on an estimated glomerular filtration rate of 60 mL/min per 1.73 m 2 . Elevated hs-TnT was associated with LVH and diastolic dysfunction at baseline in an adjusted model but was not associated with systolic dysfunction. These associations remained significant for both estimated glomerular filtration rate subgroups. Receiver operating characteristic curve analysis showed that hs-TnT as a continuous variable exhibited fair significance for detection of LVH (area under the curve: 0.689) and diastolic dysfunction (area under the curve: 0.744). Multivariable analysis showed that higher hs-TnT levels at baseline were related to development of LVH but not diastolic dysfunction (n=864). Conclusions In CKD patients, hs-TnT is strongly associated with alterations of left ventricular structure and diastolic dysfunction for both estimated glomerular filtration rate strata. Baseline hs-TnT levels are predictive of new LVH on follow-up.

Background: Metabolic syndrome (MS) is prevalent in chronic kidney disease (CKD). Klotho, a protein linked to aging, is closely associated with CKD. Each component of MS and klotho has an association. However, little is known about the association between klotho and MS per se. We investigated the association between serum klotho levels and MS using baseline cross-sectional data obtained from a large Korean CKD cohort., Methods: Of the 2238 subjects recruited in the KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD) between 2011 and 2016, 484 patients with missing data on serum klotho and extreme klotho values (values lower than the detectable range or > 6000 pg/mL) or with autosomal dominant polycystic kidney disease patients were excluded. The data of the remaining 1754 subjects were included in the present study. MS was defined using the revised National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP) III criteria. Serum klotho levels were measured using an enzyme-linked immunosorbent assay., Results: Mean patient age was 54.9 ± 12.1 years and 1110 (63.3%) were male. The prevalence of MS among all study subjects was 63.7% (n = 1118). The median serum klotho level was 527 pg/mL (interquartile range [IQR]: 418-656 pg/mL). Serum klotho level was significantly lower in MS patients than patients without MS (Median [IQR]; 521 pg/mL [413, 651] vs. 541 pg/mL [427, 676], respectively; P = 0.012). After adjusting for age, sex, estimated glomerular filtration rate, and overt proteinuria, serum klotho was independently associated with MS (adjusted odds ratio [OR], 0.44; 95% confidence interval, 0.23-0.82; P = 0.010). Furthermore, the adjusted OR for MS was found to be significantly increased at serum klotho levels of < 518 pg/mL (receiver operating characteristic curve cut-off value)., Conclusions: Serum klotho was inversely associated with the presence of MS in patients with CKD., Trial Registration: This trial was registered on ClinicalTrials.gov on 26 June 2012 ( https://clinicaltrials.gov;NCT01630486 ).

Background High-density lipoprotein cholesterol ( HDL -C) levels are generally decreased in patients with chronic kidney disease ( CKD ). However, studies on the relationship between HDL -C and CKD progression are scarce. Methods and Results We studied the association between serum HDL -C levels and the risk of CKD progression in 2168 participants of the KNOW - CKD (Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease). The primary outcome was the composite of a 50% decline in estimated glomerular filtration rate from baseline or end-stage renal disease. The secondary outcome was the onset of end-stage renal disease. During a median follow-up of 3.1 (interquartile range, 1.6-4.5) years, the primary outcome occurred in 335 patients (15.5%). In a fully adjusted Cox model, the lowest category with HDL -C of <30 mg/dL (hazard ratio, 2.21; 95% CI, 1.30-3.77) and the highest category with HDL -C of ≥60 mg/dL (hazard ratio, 2.05; 95% CI , 1.35-3.10) were associated with a significantly higher risk of the composite renal outcome, compared with the reference category with HDL -C of 50 to 59 mg/dL. This association remained unaltered in a time-varying Cox analysis. In addition, a fully adjusted cubic spline model with HDL -C being treated as a continuous variable yielded similar results. Furthermore, consistent findings were obtained in a secondary outcome analysis for the development of end-stage renal disease. Conclusions A U-shaped association was observed between serum HDL -C levels and adverse renal outcomes in this large cohort of patients with CKD . Our findings suggest that both low and high serum HDL -C levels may be detrimental to patients with nondialysis CKD .

Background and Objectives: Data on whether low or high urinary potassium excretion is associated with poor kidney outcome have been conflicting. The aim of this study was to clarify the association between urinary potassium excretion and CKD progression., Design, Setting, Participants, & Measurements: We investigated the relationship between lower urinary potassium excretion and CKD progression and compared three urinary potassium indices among 1821 patients from the Korean Cohort Study for Outcome in Patients with CKD. Urinary potassium excretion was determined using spot urinary potassium-to-creatinine ratio, spot urinary potassium concentration, and 24-hour urinary potassium excretion. Patients were categorized into four groups according to quartiles of each urinary potassium excretion metric. The study end point was a composite of a ≥50% decrease in eGFR from baseline values and ESKD., Results: During 5326 person-years of follow-up, the primary outcome occurred in 392 (22%) patients. In a multivariable cause-specific hazard model, lower urinary potassium-to-creatinine ratio was associated with higher risk of CKD progression (adjusted hazard ratio, 1.47; 95% confidence interval, 1.01 to 2.12) comparing the lowest quartile with the highest quartile. Sensitivity analyses with other potassium metrics also showed consistent results in 855 patients who completed 24-hour urinary collections: adjusted hazard ratios comparing the lowest quartile with the highest quartile were 3.05 (95% confidence interval, 1.54 to 6.04) for 24-hour urinary potassium excretion, 1.95 (95% confidence interval, 1.05 to 3.62) for spot urinary potassium-to-creatinine ratio, and 3.79 (95% confidence interval, 1.51 to 9.51) for spot urinary potassium concentration., Conclusions: Low urinary potassium excretion is associated with progression of CKD., (Copyright © 2019 by the American Society of Nephrology.)

Background: Urine osmolality indicates the ability of the kidney to concentrate the urine and reflects the antidiuretic action of vasopressin. However, results about the association between urine osmolality and adverse renal outcomes in chronic kidney disease (CKD) are conflicting. We investigated the association between urine osmolality and adverse renal outcomes in a nationwide prospective CKD cohort., Methods: A total of 1,999 CKD patients were categorized into 3 groups according to their urine osmolality tertiles. Primary outcome was a composite of 50% decline in the estimated glomerular filtration rate (eGFR), initiation of dialysis, or kidney transplantation., Results: During a mean follow-up of 35.2 ± 19.0 months, primary outcome occurred in 432 (21.6%) patients; 240 (36.4%), 162 (24.3%), and 30 (4.5%) in the lowest, middle, and highest tertiles, respectively. Low urine osmolality was independently associated with a greater risk of CKD progression (hazard ratio [HR], 1.71; 95% confidence interval [CI], 1.12-2.59). This association was particularly evident in patients with CKD stages 3-4 (per 10 mosm/kg decrease; HR, 1.02; 95% CI, 1.00-1.03). Adding urine osmolality to a base model with conventional factors significantly increased the ability to predict CKD progression (C-statistics, 0.86; integrated discrimination improvement [IDI], 0.021; both p < 0.001). However, adding both urine osmolality and eGFR did not further improve the predictive ability compared with the addition of eGFR only (C-statistics, p = 0.29; IDI, p = 0.09)., Conclusions: Low urine osmolality was an independent risk factor for adverse renal outcomes in CKD patients, but its predictive ability did not surpass eGFR. Thus, kidney function should be considered while interpreting the clinical significance of urine osmolality., (© 2019 The Author(s) Published by S. Karger AG, Basel.)

Background: Osteoprotegerin (OPG) plays protective roles against the development of vascular calcification (VC) which greatly contributes to the increased cardiovascular events in patients with chronic kidney disease (CKD). The present study aimed to find the non-traditional, kidney-related cardiovascular risk factors correlated to serum OPG and the effect of serum OPG on the arterial stiffness measured by brachial ankle pulse wave velocity (baPWV) in patients with the pre-dialysis CKD., Methods: We cross-sectionally analyzed the data from the patients in whom baPWV and the serum OPG were measured at the time of enrollment in a prospective pre-dialysis CKD cohort study in Korea., Results: Along with traditional cardiovascular risk factors such as age, diabetes mellitus, pulse pressure, and baPWV, non-traditional, kidney-related factors such as albuminuria, plasma level of hemoglobin, total CO 2 content, alkaline phosphatase, and corrected calcium were independent variables for serum OPG in multivariate linear regression. Reciprocally, the serum OPG was positively associated with baPWV in multivariate linear regression. The baPWV in the 3rd and 4th quartile groups of serum OPG were higher than that in the 1st quartile group after adjustments by age, sex and other significant factors for baPWV in linear mixed model., Conclusion: Non-traditional, kidney-related cardiovascular risk factors in addition to traditional cardiovascular risk factors were related to serum level of OPG in CKD. Serum OPG level was significantly related to baPWV. Our study suggests that kidney-related factors involved in CKD-specific pathways for VC play a role in the increased secretion of OPG into circulation in patients with CKD., Trial Registration: ClinicalTrials.gov Identifier: NCT01630486., Competing Interests: Disclosure: The authors have no potential conflicts of interest to disclose.

Rationale & Objective: Recent studies have yielded conflicting findings on the association between obesity and progression of chronic kidney disease (CKD). Few studies have evaluated whether metabolic abnormalities may accelerate the rate of progression of CKD., Study Design: Prospective observational cohort study., Setting & Participants: 1,940 participants from the Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD) PREDICTORS: Obesity and metabolic abnormality. Obesity was defined as body mass index ≥ 25kg/m 2 . Metabolic abnormality was defined as the presence of 3 or more of the following 5 components: hypertension, fasting glucose level > 125mg/dL or the presence of type 2 diabetes, triglyceride level > 150mg/dL or use of lipid-lowering drugs, high-density lipoprotein cholesterol level ≤ 40mg/dL in men and ≤ 50mg/dL in women, and high-sensitivity C-reactive protein level > 1mg/L., Outcome: A composite of a 50% decline in estimated glomerular filtration rate from the baseline value or end-stage kidney disease., Analytic Approach: Multivariable cause-specific hazards models implemented to assess the association between obesity, metabolic abnormality, and CKD progression., Results: During a mean follow-up of 3.1 years, the primary outcome occurred in 395 (20.4%) patients. In multivariable analyses, after adjustment for confounding factors, obesity and metabolic abnormality were significantly associated with 1.41-fold (95% CI, 1.08-1.83; P=0.01) and 1.38-fold (95% CI, 1.03-1.85; P=0.03) increased risk for adverse renal outcomes, respectively. Patients were categorized into 4 groups depending on the presence of obesity and metabolic abnormality. Compared with those with neither obesity nor metabolic abnormality, those with obesity and metabolic abnormality had a greater risk for CKD progression (HR, 1.53; P=0.03). Those with obesity without metabolic abnormality also had a higher rate of CKD progression (HR, 1.97; P=0.01)., Limitations: Observational study, limited power to detect cardiovascular disease outcomes, unmeasured confounders., Conclusions: Both metabolic abnormality and obesity are associated with a significantly increased risk for CKD progression. Notably, obese patients without metabolic abnormality also have an elevated risk for CKD progression., (Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Left ventricular hypertrophy (LVH) is one of the risk factors for cardiovascular (CV) disease and mortality. However, the relationship between socioeconomic status (SES) and LVH in chronic kidney disease remains unclear., Methods: Data were collected from the KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD, NCT01630486 at http://www.clinicaltrials.gov ). Subjects with CKD and aged ≥50 were included. SES was characterized based on monthly income and educational attainment, each of which was divided into three strata. LVH was defined as LV mass/height 2.7  ≥ 47 g/m 2.7 in female and ≥ 50 g/m 2.7 in male. Age, sex, diabetes, CKD stage, body mass index, blood pressure and physical activity were included as covariates., Results: A total of 1361 patients were included. Mean age was 60.9 ± 6.9 years, and 63.2% were men. Higher education level was associated with higher monthly income (P for trend < 0.001). The lowest education level was independently associated with LVH (lower than high school, adjusted odds ratio [OR] 1.485, 95% CI 1.069-2.063, P = 0.018; completed high school, adjusted OR 1.150, 95% confidence interval [CI] 0.834-1.584, P = 0.394; highest education level as the reference). Monthly income level was marginally associated with LVH after adjusting for covariates ($1500-4500, adjusted OR 1.230, 95% CI 0.866-1.748, P = 0.247; < $1500, adjusted OR 1.471, 95% CI 1.002-2.158, P = 0.049; > $4500; reference)., Conclusions: In the CKD population, lower SES, defined by educational attainment and low income level exhibited a significant association with LVH, respectively. Longitudinal follow-up will reveal whether lower SES is associated with poor CKD outcomes.

Fibroblast growth factor-23 (FGF23) is an established biomarker of adverse outcomes in patients with chronic kidney disease (CKD). Several cross-sectional studies have suggested a possible association between FGF23 and anemia in these patients. In this large-scale prospective cohort study, we investigated this relationship and examined whether high FGF23 levels increase the risk of incident anemia. This prospective longitudinal study included 2,089 patients from the KoreaN cohort study for Outcome in patients With CKD. Anemia was defined as hemoglobin level <13.0 g/dl (men) and <12.0 g/dl (women). Log-transformed FGF23 significantly correlated with hepcidin but inversely correlated with iron profiles and hemoglobin. Multivariate logistic regression showed that log-transformed FGF23 was independently associated with anemia (odds ratio [OR], 1.14; 95% confidence interval [CI], 1.04-1.24, P = 0.01). Among 1,164 patients without anemia at baseline, 295 (25.3%) developed anemia during a median follow-up of 21 months. In fully adjusted multivariable Cox models, the risk of anemia development was significantly higher in the third (hazard ratio [HR], 1.66; 95% CI, 1.11-2.47; P = 0.01) and fourth (HR, 1.84; 95% CI, 1.23-2.76; P = 0.001) than in the first FGF23 quartile. In conclusion, high serum FGF23 levels were associated with an increased risk for anemia in patients with nondialysis CKD.

Background: Klotho, a protein linked to aging, has emerged as a pivotal player in mineral bone metabolism and might explain the relationship between chronic kidney disease (CKD) and cardiovascular disease (CVD). The present study aimed to investigate the association between serum klotho and cardiac parameters from a large-scale Korean CKD cohort., Methods: We analyzed 2101 participants from KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD) cohort who had been measured for serum klotho levels. Left ventricular hypertrophy evaluated by left ventricular mass index (LVMI) and arterial stiffness measured by brachial-to-ankle pulse wave velocity (baPWV) were explored as cardiovascular parameters., Results: Patients were 53.6 ± 12.2 years old and 61.1% were male. The mean estimated glomerular filtration rate (eGFR) was 53.0 ± 30.7 mL/min/1.73m 2 . The median serum klotho level was 536 (interquartile range [IQR]: 420-667) pg/mL. Advanced CKD stages were associated with lower serum klotho levels (P < 0.001, P for linear trend < 0.001). Ascending quartiles of klotho were significantly associated with decreased LMVI (P < 0.001, P for linear trend< 0.001). A multivariable linear regression model showed serum klotho had a significant inverse association with LVMI (β - 0.04; 95% CI [confidence interval] -0.004, - 0.00007; P = 0.041). However, there was no significant association between serum klotho and baPWV after adjustment (β 0.003; 95% CI -0.04, 0.05; P = 0.876)., Trial Registration: This trial was registered on ClinicalTrials.gov on 28 June 2012 ( NCT01630486 )., Conclusions: Serum klotho was an independent biomarker of LVMI, but not arterial stiffness.

Background: Adiponectin is an adipokine secreted by adipocytes. A low adiponectin level is a significant risk factor of diabetes mellitus and cardiovascular disease. Recent studies have shown that adiponectin is negatively associated with hematopoiesis and predicts the development of anemia in the general population. In chronic kidney disease (CKD) patients, circulating adiponectin level is paradoxically elevated and the role of adiponectin is complex. Therefore, we evaluated the relationship between adiponectin and anemia in these patients., Methods: This prospective longitudinal study included 2113 patients from the KNOW-CKD study (KoreaN cohort study for Outcome in patients With CKD), after excluding 125 without data on adiponectin levels. Hemoglobin levels were measured yearly during a mean follow-up period of 23.7 months. Anemia was defined as hemoglobin levels of <13.0 and 12.0 g/dL for men and women, respectively., Results: Mean patient age was 53.6 ± 12.2 years, and 1289 (61%) were men. The mean estimated glomerular filtration rate (eGFR) was 50.4 ± 30.2 mL min -1  1.73 m -2 . Serum adiponectin level was inversely associated with body mass index, eGFR, log-transformed C-reactive protein, and positively with Charlson comorbidity index, urine protein to creatinine ratio, and high density lipoprotein cholesterol. In addition, serum adiponectin level was also negatively correlated with hemoglobin level and reticulocyte production index in both men and women. In multivariable linear regression analysis after adjustment of multiple confounders, adiponectin was negatively associated with hemoglobin (men, β = -0.219, P < .001; women, β = -0.09, P = .025). Among 1227 patients without anemia at baseline, 307 newly developed anemia during the follow-up period. In multivariable Cox regression analysis after adjustment of confounders, high adiponectin level was significantly associated with an increased risk of incident anemia (per 1 µg/mL increase, hazard ratio, 1.02; 95% confidence interval 1.01-1.04; P = .001)., Conclusions: A high serum adiponectin level is independently associated with a low hemoglobin level and predicts the development of anemia in patients with CKD. These findings reveal the potential role of adiponectin in CKD-related anemia., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: The goal of this study was to evaluate the quality of life (QOL) of Asian children with pre-dialysis chronic kidney disease (CKD) and to reveal the factors influencing the QOL of children with CKD., Methods: We performed a cross-sectional study of the PedsQL 4.0 Generic Core Scale Module in the KNOW-PedCKD (KoreaN cohort study for Outcome in patients with Pediatric Chronic Kidney Disease) cohort, and compared the child self-reported and parent proxy-reported QOL of the pediatric cohort. From 2011 through 2016, a total of 376 children with CKD were enrolled after informed consent was obtained from parents or caregivers in seven pediatric nephrology centers., Results: In parent proxy-reports, male patients had a better QOL than female patients in the Physical Functioning category. In child self-reports, male patients had better QOL than female patients in the Physical, Emotional, and School Functioning categories. According to CKD stage, there were significant differences in the QOL score in all categories of parent proxy-reports, and patients with higher CKD stage (lower glomerular filtration rate) had a worse QOL. Growth parameters showed a significantly positive correlation with the QOL score in all categories., Conclusions: The QOL of children with predialysis CKD is affected by various factors, including sex, glomerular filtration rate (GFR), socio-economic status, existence of co-morbidities, anemia, growth retardation, and behavioral disorders. To improve their QOL, it is important to objectively understand the respective effects of these factors and attempt early intervention.

Purpose: Recent studies have reported that loss of bone mass is associated with renal function decline and increased fracture risks in chronic kidney disease (CKD) patients. The aim of this study was to investigate the best estimated glomerular filtration rate (eGFR) equation to detect osteopenia in CKD patients., Materials and Methods: This was a cross-sectional study, and 780 patients aged 50 years or above were classified into normal bone mass or osteopenia groups according to the -1.0 of T-scores at total hip and femur neck. Comparisons of area under the receiver operating characteristic (ROC) curves (AUC) were performed to investigate significant differences among three eGFR formulas: Modification of Diet in Renal Disease, CKD-Epidemiology Collaboration (EPI) creatinine, and CKD-EPI cystatin C (CKD-EPI-Cys)., Results: The mean age was 61 years old and the proportion of females was 37.3%. The total hip osteopenia group showed lower CKD-EPI-Cys eGFR levels (osteopenia group, 33.3±19.0 mL/min/1.73 m²; normal group, 48.1±26.2 mL/min/1.73 m², p<0.001). In multiple logistic regression analysis, CKD-EPI-Cys eGFR was independently associated with osteopenia at the total hip (per 1 mL/min/1.73 m² increase, odds ratio 0.98, 95% confidence interval 0.97-0.99, p=0.004) after adjusting for confounding variables. ROC curve analyses indicated that CKD-EPI-Cys shows the largest AUC for osteopenia at the total hip (AUC=0.678, all p<0.01) and the femur neck (AUC=0.665, all p<0.05)., Conclusion: Decreased renal function assessed by CKD-EPI-Cys equation correlates with osteopenia better than creatinine-based methods in CKD patients, and the CKD-EPI-Cys formula might be a useful tool to assess skeletal-related event risks., Competing Interests: The authors have no financial conflicts of interest.

This study examined the characteristics of biochemical parameters, bone diseases, and vascular calcification in Korean patients with chronic kidney disease (CKD) not yet on dialysis. Serum levels of fibroblast growth factor 23 (FGF23), intact parathyroid hormone (iPTH), 25-hydroxyvitamin D3 (25D), and 1,25-dihydroxyvitamin D3 (1,25D); lumbar spine, total hip, and femur neck bone mineral densities; and brachial-to-ankle pulse wave velocity (baPWV) representing vascular calcification were measured at baseline for 2,238 CKD patients in the KoreaN Cohort Study for Outcomes in Patients With CKD (KNOW-CKD). Increases in serum FGF23 and iPTH preceded changes in serum calcium and phosphate, similar to Western populations. However, the 25D and 1,25D levels decreased earlier than serum FGF23 or iPTH increased, with a decreased estimated glomerular filtration rate (eGFR) in Korean CKD patients. Vitamin D deficiency occurred in 76.7% of patients with CKD stage 1. Bone mineral densities were lowest in CKD stage 5 (lumbar spine, -0.64 ± 1.67; total hip, -0.49 ± 1.21; femur neck, -1.02 ± 1.25). Osteoporosis was more prevalent in patients with higher CKD stages. The mean baPWV, abdominal aortic calcification (AAC), and coronary calcium score also increased, with declined eGFR. In conclusion, a decline in serum vitamin D levels was observed in early CKD stages before significant increases of FGF23 and iPTH in the Korean CKD population compared with that in Western populations. Increased bone disease and vascular calcification occurred in early-stage CKD., Competing Interests: The authors have no potential conflicts of interest to disclose.

The KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD) was developed to investigate various clinical courses and risk factors for progression of Korean chronic kidney disease (CKD). The KNOW-CKD study consists of nine clinical centers in Korea, and patients aged between 20 and 75 years with CKD from stage 1 to 5 (predialysis) were recruited. At baseline, blood and urine samples were obtained and demographic data including comorbidities, drugs, quality of life, and health behaviors were collected. Estimated glomerular filtration rate (eGFR) was calculated by 4-variable Modification of Diet in Renal Disease (MDRD) equation using isotope dilution mass spectrometry (IDMS)-calibrated serum creatinine measured at a central laboratory. As a dynamic cohort, a total of 2,341 patients were enrolled during the enrollment period from 2011 until 2015, among whom 2,238 subjects were finally analyzed for baseline profiles. The mean age of the cohort was 53.7 ± 12.2 year and 61.2% were men. Mean eGFR was 50.5 ± 30.3 mL/min/1.73 m². The participants with lower eGFR had a tendency to be older, with more comorbidities, to have higher systolic blood pressure (BP) and pulse pressure, with lower income level and education attainment. The patients categorized as glomerulonephritis (GN) were 36.2% followed by diabetic nephropathy (DN, 23.2%), hypertensive nephropathy (HTN, 18.3%), polycystic kidney disease (PKD, 16.3%), and other unclassified disease (6.1%). The KNOW-CKD participants will be longitudinally followed for 10 years. The study will provide better understanding for physicians regarding clinical outcomes, especially renal and cardiovascular outcomes in CKD patients., Competing Interests: The authors have no potential conflicts of interest to disclose.

Cardiovascular disease (CVD) is the most common cause of death in patients with chronic kidney disease (CKD). We report the baseline cardiovascular characteristics of 2,238 participants by using the data of the KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD) study. The cohort comprises 5 subcohorts according to the cause of CKD: glomerulonephritis (GN), diabetic nephropathy (DN), hypertensive nephropathy (HTN), polycystic kidney disease (PKD), and unclassified. The average estimated glomerular filtration rate (eGFR) was 50.5 ± 30.3 mL/min⁻¹/1.73 m⁻² and lowest in the DN subcohort. The overall prevalence of previous CVD was 14.4% in all patients, and was highest in the DN followed by that in the HTN subcohort. The DN subcohort had more adverse cardiovascular risk profiles (higher systolic blood pressure [SBP], and higher levels of cardiac troponin T, left ventricular mass index [LVMI], coronary calcium score, and brachial-ankle pulse wave velocity [baPWV]) than the other subcohorts. The HTN subcohort exhibited less severe cardiovascular risk profiles than the DN subcohort, but had more severe cardiovascular risk features than the GN and PKD subcohorts. All these cardiovascular risk profiles were inversely correlated with eGFR. In conclusion, this study shows that the KNOW-CKD cohort exhibits high cardiovascular burden, as other CKD cohorts in previous studies. Among the subcohorts, the DN subcohort had the highest risk for CVD. The ongoing long-term follow-up study up to 10 years will further delineate cardiovascular characteristics and outcomes of each subcohort exposed to different risk profiles., Competing Interests: The authors have no potential conflicts of interest to disclose.

In chronic kidney disease (CKD), overweight and mild obesity have shown the lowest cardiovascular (CV) risk. However, central obesity has been directly associated with CV risk in these patients. This bidirectional relationship of body mass index (BMI) and central obesity prompted us to evaluate CV risk based on a combination of BMI and waist-to-hip ratio (WHR) in nondialysis CKD patients. We included 1078 patients with CKD stage 2 through 5 (nondialysis) enrolled in a nationwide prospective cohort of Korea. Patients were divided into 3 groups by BMI (normal BMI, 18.5-22.9; overweight, 23.0-27.4; and obese, 27.5 and over kg/m 2 ) and were dichotomized by a sex-specific median WHR (0.92 in males and 0.88 in females). Coronary artery calcification (CAC) was determined by multislice computed tomography. CAC (score above 10 Agatston units) was found in 477 patients. Multivariate logistic regression analysis indicated that BMI was not independently associated with CAC. However, WHR showed an independent linear and significant association with CAC (odds ratio, 1.036; 95% confidence interval, 1.007-1.065 per 0.01 increase). Furthermore, when patients were categorized into 6 groups according to a combination of BMI and WHR, normal BMI but higher WHR had the highest risk of CAC compared with the normal BMI with lower WHR group (2.104; 1.074-4.121). Thus, a normal BMI with central obesity was associated with the highest risk of CAC, suggesting that considering BMI and WHR, 2 surrogates of obesity, can help to discriminate CV risk in Korean nondialysis CKD patients., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Osteoprotegerin, a potent osteoclast activation inhibitor, decreases bone resorption and positively affects bone mineral density. This study examined the association between serum osteoprotegerin levels and bone loss in patients with chronic kidney disease, a condition associated with increased risk of mineral and bone disorders. The bone mineral densities of the lumbar spine, total hip, and femur neck were assessed by dual-energy X-ray absorptiometry; serum osteoprotegerin levels were measured at baseline for 1,423 patients enrolled in the prospective KoreaN cohort study for Outcome in patients With Chronic Kidney Disease (KNOW-CKD). Patients aged ≥50 years and with a T-score ≤ -2.5 were diagnosed as having osteoporosis. Multivariable linear regression analysis indicated independent association between serum osteoprotegerin levels and decreased bone mineral density in the lumbar spine (B: -0.489, 95% confidence interval [CI]: -0.883 to -0.095, P = 0.015), and total hip (B: -0.349, 95% CI: -0.672 to -0.027, P = 0.027). However, bone mineral density of the femur neck was not associated with serum osteoprotegerin levels in women. After adjustments, no independent association was found between serum osteoprotegerin levels and bone mineral density in men. In multivariable logistic regression analysis, serum osteoprotegerin levels were associated with increased risk of osteoporosis in women (odds ratio [OR]: 4.72, 95% CI: 1.35 to 16.52, P = 0.015), but not in men (OR: 0.21; 95% CI: 0.04 to 1.31, P = 0.095). To summarize, in female patients with chronic kidney disease, increased serum osteoprotegerin levels were independently associated with decreased bone mineral density in the lumbar spine and total hip, and with increased risk of osteoporosis. Therefore, the measurement of serum osteoprotegerin concentration might be useful as a surrogate marker for determining bone loss in patients with chronic kidney disease, especially for women, although not so much for men., Competing Interests: The authors have declared that no competing interests exist.

Background: The global prevalence of chronic kidney disease (CKD) is increasing. In children, CKD exhibits unique etiologies and can have serious impacts on children's growth and development. Therefore, an aggressive approach to preventing the progression of CKD and its complications is imperative. To improve the understanding and management of Asian pediatric patients with CKD, we designed and launched KNOW-Ped CKD (KoreaN cohort study for Outcome in patients With Pediatric Chronic Kidney Disease), a nationwide, prospective, and observational cohort study of pediatric CKD with funding from the Korean government., Methods/design: From seven major centers, 450 patients <20 years of age with CKD stages I to V are recruited for the comprehensive assessment of clinical findings, structured follow-up, and bio-specimen collection. The primary endpoints include CKD progression, defined as a decline of estimated glomerular filtration rate by 50 %, and a requirement for renal replacement therapy or death. The secondary outcomes include the development of left ventricular hypertrophy or hypertension, impairment of growth, neuropsychological status, behavioral status, kidney growth, and quality of life., Discussion: With this study, we expect to obtain more information on pediatric CKD, which can be translated to better management for the patients., Trial Registration: NCT02165878 (ClinicalTrials.gov), submitted on June 11, 2014.

Background: The progression and complications of chronic kidney disease should differ depending on the cause (C), glomerular filtration rate category (G), and albuminuria (A). The KNOW-CKD (KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease), which is a prospective cohort study, enrolls subjects with chronic kidney disease stages 1 to 5 (predialysis)., Methods/design: Nine nephrology centers in major university hospitals throughout Korea will enroll approximately 2,450 adults with chronic kidney disease over a 5-year period from 2011 to 2015. The participating individuals will be monitored for approximately 10 years until death or until end-stage renal disease occurs. The subjects will be classified into subgroups based on the following specific causes of chronic kidney disease: glomerulonephritis, diabetic nephropathy, hypertensive nephropathy, polycystic kidney disease, and others. The eligible subjects will be evaluated at baseline for socio-demographic information, detailed personal/family history, office BP, quality of life, and health behaviors. After enrollment in the study, thorough assessments, including laboratory tests, cardiac evaluation and radiologic imaging, will be performed according to the standardized protocol. The biospecimen samples will be collected regularly. A renal event is defined by >50% decrease in estimated GFR (eGFR) from the baseline values, doubling of serum creatinine, or end-stage renal disease. The primary composite outcome consists of renal events, cardiovascular events, and death. As of September 2013, 1,470 adult chronic kidney disease subjects were enrolled in the study, including 543 subjects with glomerulonephritis, 317 with diabetic nephropathy, 294 with hypertensive nephropathy and 249 with polycystic kidney disease., Discussion: As the first large-scale chronic kidney disease cohort study to be established and maintained longitudinally for up to 10 years, the KNOW-CKD will help to clarify the natural course, complication profiles, and risk factors of Asian populations with chronic kidney disease., Trial Registration: No. NCT01630486 at http://www.clinicaltrials.gov.