KoreaN Cohort Study For Outcome In Patients With Chronic Kidney Disease Research Articles

Association between urine creatinine excretion and bone mineral density in chronic kidney disease: Results from the KNOW-CKD study.

Decreased lean body mass or muscle mass is associated with decreased bone mineral density in individuals with preserved renal function. However, the association between muscle mass and bone mineral density in chronic kidney disease (CKD) patients is not well known. The aim of this study was to assess the relationship between muscle mass estimated from urine creatinine (UCr) and bone mineral density in Korean CKD patients. This cross-sectional study analyzed 1872 participants from the Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD) cohort. Participants underwent UCr (g/day) and bone mineral density measurements, which were measured at the lumbar spine, total hip, and femoral neck by dual-energy X-ray absorptiometry. Patients were divided into three groups according to the tertiles of 24h UCr (T1-T3). The mean values for 24h urine creatinine of T1, T2, and T3 were 0.83 ± 0.23g, 1.18 ± 0.24g, and 1.55 ± 0.38g, respectively. A total of 172 patients were diagnosed withosteoporosis. The number of patients in each group was 92 (14.4%) in T1, 45 (7.3%) in T2, and 35 (5.7%) in T3. The odds ratio (95% confidence interval) for osteoporosis was 0.37 (0.20-0.69) for 1g/day increase of UCr. Compared with T1, the odds ratios (95% confidence interval) for osteoporosis were 0.58 (0.39-0.87) for T2 and 0.51 (0.32-0.80) for T3. Low 24-h UCr was associated with low bone mineral density. Low 24h UCr was significantly and independently associated with osteoporosis in Korean pre-dialysis CKD patients. Further research is warranted to verify the influence of muscle mass on bone health in CKD.

#1200 Coronary artery calcium modifies the relationship between blood pressure and adverse kidney outcome: results from KNOW-CKD

Abstract Background and Aims Previous studies evidenced that elevated coronary artery calcium (CAC) score is associated with higher chronic kidney disease (CKD) progression. However, the use of CAC score to guide CKD management has not been adequately evaluated. Here, we evaluated whether presence of CAC modify the association between systolic blood pressure (SBP) and CKD progression in patients with CKD. Method We analyzed 1693 participants with CKD stages G1 to G5 from the KoreaN cohort study for Outcome in patients With Chronic Kidney Disease (KNOW-CKD). Key exclusion criteria were kidney failure with replacement therapy (KFRT) and missing data for CAC and SBP information. We categorized participants according to baseline SBP and CAC score (Controlled BP, SBP < 120 mmHg; Elevated BP without CAC, SBP 120-140 mmHg and CAC score = 0; Elevated BP with CAC, SBP 120-140 mmHg and CAC score >0; Uncontrolled BP, SBP >140 mmHg) and compared the CKD progression. The CKD progression was defined as a composite of halving eGFR from baseline value or onset of KFRT. Results During 10,023 person-years of follow-up (median 6.2 years), the composite outcome occurred in 689 (40.7%) participants, and 108 (6.4%) participants died among the KNOW-CKD participants. There was significant interaction between CAC score and SBP for CKD progression (P < 0.001). There were 181/568 (31.9%), 167/424 (39.4%), 128/314 (40.8%) 213/387 (55.0%), composite outcomes in controlled BP, elevated BP without CAC, elevated BP with CAC, uncontrolled BP group, respectively. In crude Cox regression, compared to controlled BP, elevated BP with CAC group showed similar CKD progression risk (Hazard ratio [HR], 1.17; 95% confidence interval [CI], 0.95-1.44), whereas other strata group showed increased risk of CKD progression (elevated BP with CAC; HR, 1.59; 95% CI 1.31-1.94 and uncontrolled BP, HR, 1.94; 95% CI 1.56-2.41). Similar elevated risk in elevated BP with CAC was observed even after adjustment of age, sex, diabetes mellitus, estimated glomerular filtration ratio, and proteinuria (HR, 1.26; 95% CI, 1.02-1.56). However, the risk of CKD progression in elevated BP without CAC group was comparable to controlled BP group (HR, 1.20; 95% CI, 0.87-1.66). Conclusion Elevated SBP was more strongly associated with an increased risk of adverse kidney outcomes in patients with coronary calcification.

Measured sodium excretion is associated with cardiovascular outcomes in non-dialysis CKD patients: results from the KNOW-CKD study.

There are insufficient studies on the effect of dietary salt intake on cardiovascular (CV) outcomes in chronic kidney disease (CKD) patients, and there is no consensus on the sodium (Na) intake level that increases the risk of CV disease in CKD patients. Therefore, we investigated the association between dietary salt intake and CV outcomes in CKD patients. In the Korean cohort study for Outcome in patients with CKD (KNOW-CKD), 1,937 patients were eligible for the study, and their dietary Na intake was estimated using measured 24h urinary Na excretion. The primary outcome was a composite of CV events and/or all-cause death. The secondary outcome was a major adverse cardiac event (MACE). Among 1,937 subjects, there were 205 (10.5%) events for the composite outcome and 110 (5.6%) events for MACE. Compared to the reference group (urinary Na excretion< 2.0g/day), the group with the highest measured 24h urinary Na excretion (urinary Na excretion ≥ 8.0g/day) was associated with increased risk of both the composite outcome (hazard ratio 3.29 [95% confidence interval 1.00-10.81]; P = 0.049) and MACE (hazard ratio 6.28 [95% confidence interval 1.45-27.20]; P = 0.013) in a cause-specific hazard model. Subgroup analysis also showed a pronounced association between dietary salt intake and the composite outcome in subgroups of patients with abdominal obesity, female, lower estimated glomerular filtration rate (< 60 ml/min per 1.73m2), no overt proteinuria, or a lower urinary potassium-to-creatinine ratio (< 46 mmol/g). A high-salt diet is associated with CV outcomes in non-dialysis CKD patients.

#3537 RAPID DECLINE IN KIDNEY FUNCTION IS ASSOCIATED WITH HIGHER HEMOGLOBIN VARIABILITY IN CHRONIC KIDNEY DISEASE

Abstract Background and Aims Hemoglobin decrease and anemia are common in chronic kidney disease (CKD). This study aimed to evaluate hemoglobin variability in patients with CKD according to decline in kidney function. Method We analyzed patients from the KoreaN cohort study for Outcome in patients With CKD (KNOW-CKD). The rates of renal function decline per year were determined using the slope of estimated glomerular filtration rate (eGFR) analyzed using a generalized linear mixed model. Rapid decline in kidney function was defined as a decline in the eGFR of &amp;gt;3 mL/min/1.73 m2/year. Hemoglobin value was measured at 0, 6, and 12 month and annually for up to 8 years. Hemoglobin variability was calculated by standard deviation. Higher hemoglobin variability was defined as a hemoglobin variability value greater than the median. Results Among 1895 patients, 736 patients (38.8%) were in the rapid kidney function decline group. In 1472 patients who were 1:1 propensity score-matched, the baseline eGFR was not significantly different between the non-rapid and rapid kidney function decline groups (48.2 ± 26.9 vs 46.9 ± 26.2 ml/min/1.73m2, P = 0.345). The use of iron supplements (P = 0.536) or erythropoiesis stimulating agents (P = 0.699) was similar in both groups. In multivariable logistic regression analysis, rapid decline in kidney function was significantly associated with higher hemoglobin variability (odds ratio [OR]: 1.81; 95% confidence interval [CI]: 1.43–2.28; P &amp;lt; 0.001). This association was prominent in the group without anemia at baseline (OR: 2.82; 95% CI: 1.99–4.01; P &amp;lt; 0.001). Conclusion Rapid decline in kidney function is associated with higher hemoglobin variability in patients with CKD. Attention should be paid to hemoglobin variability in patients with a rapid decline in kidney function.

#4356 DYNAMIC EFFECT OF PROTEINURIA ON ADVERSE KIDNEY OUTCOMES WITH TARGETED MAXIMUM LIKELIHOOD ESTIMATION METHOD: RESULT FROM THE KNOW-CKD STUDY

Abstract Background and Aims Proteinuria is a risk factor for the progression of chronic kidney disease (CKD), but its causal inference may be challenging due to time varying exposure and confounding, the changing its degree, and loss to follow up. Method A total of 1,223 patients enrolled as part of The Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD) were analyzed at 3 observational points (baseline, 3-year; early, and 7-year; late) at which spot urine protein creatinine ratio (UPCR) was measured. We used longitudinal targeted minimum loss-based estimation (TMLE) and marginal structural models (MSM) to estimate the cumulative incidence of adverse kidney outcomes (eGFR halving and kidney failure requiring replacement therapy) of dynamic exposure to high proteinuria (UPCR≥1g/g) comparing counterfactuals (UPCR&amp;lt;1g/g) adjusted for time varying confounding (systolic blood pressure, estimated glomerular filtration rate, and renin-angiotensin-aldosterone blockers) and baseline covariates (age, sex, diabetes, cardiovascular disease, and smoking). Results Patients with sustained high proteinuria throughout 7-year follow-up had significant higher risk of renal events than those with counterfactuals (relative risk [RR], 3.120; 95% confidence interval, 2.150-4.528; P &amp;lt; 0.001). The RR were 0.168 (0.055-0.517; P = 0.002) and 0.613 (0.337-1.114; P = 0.108) for early and late proteinuria reduction comparing sustained high proteinuria, respectively. In MSM, hazard ratio (HR) of accumulative high proteinuria frequency were 1.612 (1.463-1.844; P &amp;lt;0.001) up to 3 years and 1.102 (0.877-1.387; P = 0.404) up to 7 years, respectively. Conclusion In CKD patients, sustained higher proteinuria is the main risk factor during the entire observation period. However, considering dynamic exposure, proteinuria reduction from the beginning has a protective effect on renal progression, but the effect weakens as the observation period becomes longer.

Glycemic Control and Adverse Clinical Outcomes in Patients with Chronic Kidney Disease and Type 2 Diabetes Mellitus: Results from KNOW-CKD.

The optimal level of glycosylated hemoglobin (HbA1c) to prevent adverse clinical outcomes is unknown in patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). We analyzed 707 patients with CKD G1-G5 without kidney replacement therapy and T2DM from the KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD), a nationwide prospective cohort study. The main predictor was time-varying HbA1c level at each visit. The primary outcome was a composite of development of major adverse cardiovascular events (MACEs) or all-cause mortality. Secondary outcomes included the individual endpoint of MACEs, all-cause mortality, and CKD progression. CKD progression was defined as a ≥50% decline in the estimated glomerular filtration rate from baseline or the onset of end-stage kidney disease. During a median follow-up of 4.8 years, the primary outcome occurred in 129 (18.2%) patients. In time-varying Cox model, the adjusted hazard ratios (aHRs) for the primary outcome were 1.59 (95% confidence interval [CI], 1.01 to 2.49) and 1.99 (95% CI, 1.24 to 3.19) for HbA1c levels of 7.0%-7.9% and ≥8.0%, respectively, compared with <7.0%. Additional analysis of baseline HbA1c levels yielded a similar graded association. In secondary outcome analyses, the aHRs for the corresponding HbA1c categories were 2.17 (95% CI, 1.20 to 3.95) and 2.26 (95% CI, 1.17 to 4.37) for MACE, and 1.36 (95% CI, 0.68 to 2.72) and 2.08 (95% CI, 1.06 to 4.05) for all-cause mortality. However, the risk of CKD progression did not differ between the three groups. This study showed that higher HbA1c levels were associated with an increased risk of MACE and mortality in patients with CKD and T2DM.

Predictive performance of the new race-free Chronic Kidney Disease Epidemiology Collaboration equations for kidney outcome in Korean patients with chronic kidney disease.

The new Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations without a race coefficient have gained recognition across the United States. We aimed to test whether these new equations performed well in Korean patients with chronic kidney disease (CKD). This study included 2,149 patients with CKD G1-G5 without kidney replacement therapy from the Korean Cohort Study for Outcome in Patients with CKD (KNOW-CKD). The estimated glomerular filtration rate (eGFR) was calculated using the new CKD-EPI equations with serum creatinine and cystatin C. The primary outcome was 5-year risk of kidney failure with replacement therapy (KFRT). When we adopted the new creatinine equation [eGFRcr (NEW)], 81 patients (23.1%) with CKD G3a based on the current creatinine equation (eGFRcr) were reclassified as CKD G2. Accordingly, the number of patients with eGFR of &lt;60 mL/min/1.73 m2 decreased from 1,393 (64.8%) to 1,312 (61.1%). The time-dependent area under the receiver operating characteristic curve for 5-year KFRT risk was comparable between the eGFRcr (NEW) (0.941; 95% confidence interval [CI], 0.922-0.960) and eGFRcr (0.941; 95% CI, 0.922-0.961). The eGFRcr (NEW) showed slightly better discrimination and reclassification than the eGFRcr. However, the new creatinine and cystatin C equation [eGFRcr-cys (NEW)] performed similarly to the current creatinine and cystatin C equation. Furthermore, eGFRcr-cys (NEW) did not show better performance for KFRT risk than eGFRcr (NEW). Both the current and the new CKD-EPI equations showed excellent predictive performance for 5-year KFRT risk in Korean patients with CKD. These new equations need to be further tested for other clinical outcomes in Koreans.

PS-BPC11-4: LOW SOLUBLE KLOTHO IS ASSOCIATED WITH RESISTANT HYPERTENSION IN CKD: FROM THE KNOW-CKD STUDY

Objective: Apparent treatment-resistant hypertension (ATRH) is highly prevalent in chronic kidney disease (CKD) and is a risk factor for rapid progression of CKD. Soluble klotho is an extracellular domain of klotho released into the circulation. Although soluble klotho is known to be a risk factor for hypertension, the association between soluble klotho and ATRH is unknown. The aim of this study is to evaluate the association of soluble klotho with ATRH in CKD. Design and method: In this cross-sectional study, we analyzed 1,737 predialysis CKD patients enrolled in the prospective Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD). Apparent treatment-resistant hypertension was defined as systolic blood pressure &gt; = 140 mm Hg or diastolic blood pressure &gt; = 90 mm Hg with concurrent use of three antihypertensive medication classes or use of four or more antihypertensive medication classes regardless of blood pressure level. Serum klotho levels were measured using an enzyme-linked immunosorbent assay. Participants were divided into quartiles. Results: Among study subjects, 303 patients (17.4%) had ATRH. Prevalence of ATRH were 21.9%, 18.9%, 18.2% and 10.8% for the 1st to 4th quartiles of soluble klotho, respectively (p for trend &lt; 0.001). The adjusted OR [95% CI] of 1st to 3th quartile of soluble klotho in reference to 4th quartile were 2.01 (1.32–3.06), 1.59 (1.04–2.42) and 1.69 (1.11–2.57). Conclusions: Soluble klotho level was inversely associated with the presence of ATRH in Korean predialysis CKD patients. This relationship was independent of various cardiovascular risk factors.

Urine creatinine concentration influences the prognostic value of proteinuria for MACE prediction from the findings of the KNOW-CKD study

Proteinuria is typically quantified according to the spot urine protein–creatinine ratio (UPCR) and an association with cardiovascular events has not been thoroughly investigated in chronic kidney disease (CKD) patients. We investigated whether the severity of proteinuria assessed by spot UPCR is associated with an increased risk for cardiovascular outcomes in the CKD population, and whether the relationship is influenced by urine creatinine concentration. We analyzed 1746 patients enrolled as part of The KoreaN cohort study for Outcome in patients With Chronic Kidney Disease (KNOW-CKD). Multivariable Cox proportional hazard analysis was performed to evaluate models with proteinuria as a predictor of renal events and extended major adverse cardiovascular events (eMACEs). Risk for renal events was significantly associated with proteinuria across all eGFR and UPCR categories. By contrast, risk for eMACEs increased significantly with UPCR in patients with eGFR ≥ 60 mL/min/1.73 m2 (hazard ratio [HR] 2.109; 95% confidence interval [CI] 1.375–3.235; P = 0.001), but not in patients with eGFR < 60 mL/min/1.73 m2 (HR 1.086; 95% CI 0.910–1.296; P = 0.358). However, in those with the lower eGFR, risk for eMACEs increased significantly with UPCR in participants with urine creatinine concentration ≥ 95 mg/dL (HR 1.503; 95% CI 1.047–2.159; P = 0.027). In non-dialysis CKD patients, the prognostic value of UPCR for eMACEs is weakened in patients with reduced eGFR levels, for whom it has prognostic significance only in patients with high urine creatinine concentration.

Left Ventricular Diastolic Dysfunction and Progression of Chronic Kidney Disease: Analysis of KNOW-CKD Data.

BackgroundFew studies have examined the association between the early diastolic mitral inflow velocity/early diastolic mitral annulus velocity ratio (E/e’) and chronic kidney disease progression.Methods and ResultsWe reviewed data from 2238 patients with nondialysis chronic kidney disease from the KNOW‐CKD (Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease); data from 163 patients were excluded because of missing content. A >50% decrease in estimated glomerular filtration rate from baseline, doubling of serum creatinine, or dialysis initiation and/or kidney transplantation were considered renal events. At baseline, median (interquartile range) ejection fraction and E/e’ were 64.0% (60.0%–68.0%) and 9.1 (7.4–11.9), respectively. Proportions of ejection fraction <50% and E/e’ ≥15 were 1.3% and 9.6%, respectively. More than one quarter of patients (27.2%) had an estimated glomerular filtration rate <30 mL/min per 1.73 m2. During the mean 59.1‐month follow‐up period, 724 patients (34.9%) experienced renal events. In multivariable Cox proportional hazard regression analysis, the hazard ratio with 95% CI per 1‐unit increase in E/e’ was 1.027 (1.005–1.050; P=0.016). Penalized spline curve analysis yielded a suggested threshold of E/e’ for renal events of 12; in our data set, the proportion of E/e’ ≥12 was 4.1%.ConclusionsIncreased E/e’ was associated with an increased hazard of renal events, suggesting that diastolic heart dysfunction is a novel risk factor for chronic kidney disease progression.

Association Between Systolic Blood Pressure Variability and Major Adverse Cardiovascular Events in Korean Patients With Chronic Kidney Disease: Findings From KNOW-CKD.

BackgroundWhether visit‐to‐visit systolic blood pressure (SBP) variability can predict major adverse cardiovascular events (MACE) in patients with chronic kidney disease is unclear.Methods and ResultsWe investigated the relationship between SDs of visit‐to‐visit SBP variability during the first year of enrollment and MACE among 1575 participants from KNOW‐CKD (Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease). Participants were categorized into 3 groups according to tertiles of visit‐to‐visit SBP variability (SD). The study end point was MACE, defined as a composite of nonfatal myocardial infarction, unstable angina, revascularization, nonfatal stroke, hospitalization for heart failure, or cardiac death. During 6748 patient‐years of follow‐up (median, 4.2 years), MACE occurred in 64 participants (4.1%). Compared with the lowest tertile of visit‐to‐visit SBP variability (SD), the hazard ratios (HRs) for the middle and the highest tertile were 1.64 (95% CI, 0.80–3.36) and 2.23 (95% CI, 1.12–4.44), respectively, in a multivariable cause‐specific hazard model. In addition, the HR associated with each 5‐mm Hg increase in visit‐to‐visit SBP variability (SD) was 1.21 (95% CI, 1.01–1.45). This association was consistent in sensitivity analyses with 2 additional definitions of SBP variability determined by the coefficient of variation and variation independent of the mean. The corresponding HRs for the middle and highest tertiles were 2.11 (95% CI, 1.03–4.35) and 2.28 (95% CI, 1.12–4.63), respectively, in the analysis with the coefficient of variation and 1.76 (95% CI, 0.87–3.57) and 2.04 (95% CI, 1.03–4.03), respectively, with the variation independent of the mean.ConclusionsHigher visit‐to‐visit SBP variability is associated with an increased risk of MACE in patients with chronic kidney disease.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT01630486.

Association Between Left Ventricular Geometry and Renal Outcomes in Patients With Chronic Kidney Disease: Findings From Korean Cohort Study for Outcomes in Patients With Chronic Kidney Disease Study.

BackgroundThe impact of left ventricular (LV) geometry on the renal outcomes in patients with chronic kidney disease (CKD) has not been established yet. We aimed to investigate the association of LV geometry with renal outcomes and all-cause mortality in patients with pre-dialysis CKD.MethodsA total of 2,144 subjects from the Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD) were categorized by LV geometry, which was defined by LV mass index and relative wall thickness [normal geometry, concentric remodeling, eccentric hypertrophy (eLVH), and concentric hypertrophy (cLVH)]. Study outcomes were composite renal events [decline of kidney function (the first occurrence of > 50% decline of eGFR or doubling of serum creatinine from the baseline) and onset of ESRD (initiation of dialysis or kidney transplantation) during follow-up periods)] and all-cause mortality.ResultsCox regression analysis revealed that eLVH [adjusted hazard ratio (HR) 1.498, 95% confidence interval (CI) 1.197–1.873] and cLVH (adjusted HR 1.289, 95% CI 1.011–1.643) were associated with increased risk of composite renal events, whereas concentric remodeling (adjusted HR 1.881, 95% CI 1.135–3.118) and cLVH (adjusted HR 2.216, 95% CI 1.341–3.664) were associated with increased risk of all-cause mortality. Sensitivity analyses confirmed that concentric remodeling (adjusted HR 1.993, 95% CI 1.197–3.368) and eLVH (adjusted HR 1.588, 95% CI 1.261–2.001) are independently associated with all-cause mortality and composite renal events, respectively.ConclusionIn conclusion, we report that LV geometry is significantly associated with adverse renal outcomes and all-cause mortality in patients with pre-dialysis CKD. Echocardiographic determination of LV geometry may help the early identification for the patients with high risk of CKD progression.

Abdominal Aortic Calcification and Cardiovascular Outcomes in Chronic Kidney Disease: Findings from KNOW-CKD Study.

To investigate the association between abdominal aortic calcification score (AACS) assessed by plain radiograph of the lateral abdomen and the risk of cardiovascular (CV) events in patients with pre-dialysis chronic kidney disease (CKD), a total of 2090 pre-dialysis CKD patients from the Korean Cohort Study for Outcome in Patients with Chronic Kidney Disease (KNOW-CKD) were categorized by AACS into 0, 1–2, 3–4, 5–6, and ≥7. The primary outcome of the study was the composite CV events, defined as a composite of non-fatal CV events and all-cause death. The risk of composite CV events was significantly higher in the subjects with AACS ≥ 7 (adjusted hazard ratio (HR) 1.888, 95% confidence interval (CI) 1.219 to 2.923), compared to that of the subjects with AACS 0. The risks of fatal and non-fatal CV events (adjusted HR 1.052, 95% CI 1.030 to 1.073) and all-cause death (adjusted HR 1.949, 95% CI 1.073 to 3.539) were also significantly higher in the subjects with AACS ≥ 7. In conclusion, AACS assessed by plain radiograph is independently associated with adverse CV outcomes in patients with pre-dialysis CKD. A simple radiographic examination of the lateral abdomen may help CV risk stratification in this population.

The Association between Health-Enhancing Physical Activity and Quality of Life in Patients with Chronic Kidney Disease: Propensity Score Matching Analysis.

We investigate the association between health-enhancing physical activity and the quality of life in patients with non-dialysis chronic kidney disease. We performed data analysis on 1618 of 2238 patients from 2011 to 2016, obtained from the KoreaN Cohort Study for Outcome in Patients with Chronic Kidney Disease (KNOW-CKD). Health-related quality of life was measured using the Korean version 1.3 of Kidney Disease Quality of Life short-form questionnaire. Health-enhancing physical activity was defined as 150 min of moderate-intensity or 75 min of vigorous-intensity aerobic physical activity throughout the week. Propensity score matching analysis and linear regression was performed to estimate the effect of health-enhancing physical activity on health-related quality of life. The estimate of average treatment effects was 2.60 in the kidney component summary score, 4.45 in the physical component summary score, and 4.24 in the mental component summary score. In all component summary scores and most of their subscales, health-enhancing physical activity showed a significant association with health-related quality of life. Subgroup and sensitivity analyses also showed robust results. This study suggests that health-enhancing physical activity elevated quality of life in patients with non-dialysis chronic kidney disease. The results can contribute to encourage physical activity in patients with chronic kidney disease.

Low-density lipoprotein cholesterol levels and adverse clinical outcomes in chronic kidney disease: Results from the KNOW-CKD

Background and aimsThe optimal low-density lipoprotein cholesterol (LDL-C) level to prevent cardiovascular disease in chronic kidney disease (CKD) patients remains unknown. This study aimed to explore the association of LDL-C levels with adverse cardiovascular and kidney outcomes in Korean CKD patients and determine the validity of “the lower, the better” strategy for statin intake. Methods and resultsA total of 1886 patients from the KoreaN cohort study for Outcome in patients With CKD (KNOW-CKD) were included. Patients were classified into four LDL-C categories: <70, 70–99, 100–129, and ≥130 mg/dL. The primary outcome was extended major adverse cardiovascular events (eMACEs). Secondary outcomes included all-cause mortality, and CKD progression.During the follow-up period, the primary outcome events occurred in 136 (7.2%) patients (16.9 per 1000 person-years). There was a graded association between LDL-C and the risk of eMACEs. The hazard ratios (95% confidence intervals) for LDL-C categories of 70–99, 100–129, and ≥130 mg/dL were 2.06 (1.14–3.73), 2.79 (1.18–6.58), and 4.10 (1.17–14.3), respectively, compared to LDL-C <70 mg/dL. Time-varying analysis showed consistent findings. The predictive performance of LDL-C for eMACEs was affected by kidney function. Higher LDL-C levels were also associated with significantly higher risks of CKD progression. However, LDL-C level was not associated with all-cause mortality. ConclusionsThis study showed a graded relationship between LDL-C and the risk of adverse cardiovascular outcome in CKD patients. The lowest risk was observed with LDL-C <70 mg/dL, suggesting that a lower LDL-C target may be acceptable.

Effects of blood urea nitrogen independent of the estimated glomerular filtration rate on the development of anemia in non-dialysis chronic kidney disease: The results of the KNOW-CKD study.

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). 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. 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. 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.

Association of blood pressure with cardiovascular outcome and mortality: results from the KNOW-CKD study.

Optimal blood pressure (BP) control is a major therapeutic strategy to reduce adverse cardiovascular events (CVEs) and mortality in patients with chronic kidney disease (CKD). We studied the association of BP with adverse cardiovascular outcome and all-cause death in patients with CKD. Among 2238 participants from the KoreaN cohort study for Outcome in patients With CKD (KNOW-CKD), 2226 patients with baseline BP measurements were enrolled. The main predictor was systolic BP (SBP) categorized by five levels: <110, 110-119, 120-129, 130-139 and ≥140 mmHg. The primary endpoint was a composite outcome of all-cause death or incident CVEs. We primarily used marginal structural models (MSMs) using averaged and the most recent time-updated SBPs. During the follow-up of 10 233.79 person-years (median 4.60 years), the primary composite outcome occurred in 240 (10.8%) participants, with a corresponding incidence rate of 23.5 [95% confidence interval (CI) 20.7-26.6]/1000 patient-years. MSMs with averaged SBP showed a U-shaped relationship with the primary outcome. Compared with time-updated SBP of 110-119 mmHg, hazard ratios (95% CI) for <110, 120-129, 130-139 and ≥140 mmHg were 2.47 (1.48-4.11), 1.29 (0.80-2.08), 2.15 (1.26-3.69) and 2.19 (1.19-4.01), respectively. MSMs with the most recent SBP also showed similar findings. In Korean patients with CKD, there was a U-shaped association of SBP with the risk of adverse clinical outcomes. Our findings highlight the importance of BP control and suggest a potential hazard of SBP <110 mmHg.

Inflammation Alters Relationship Between High-Density Lipoprotein Cholesterol and Cardiovascular Risk in Patients With Chronic Kidney Disease: Results From KNOW-CKD.

BackgroundThe 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 ResultsIn 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.ConclusionsThe association between HDL‐C level and adverse cardiovascular outcomes showed reverse trends based on inflammation status in Korean patients with chronic kidney disease.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT01630486.

Low serum adiponectin level is associated with better physical health-related quality of life in chronic kidney disease

Hyperadiponectemia is paradoxically associated with renal disease progression and mortality in chronic kidney disease (CKD). Its association with health-related quality of life (HR-QOL) is unknown. This study aimed to verify the association between adiponectin and HR-QOL in Korean pre-dialysis CKD cohort. This cross-sectional study analyzed 1551 pre-dialysis CKD patients from KNOW-CKD (KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease). Participants were categorized into three tertiles (T1–T3) according to adiponectin levels. HR-QOL was assessed using SF-36. High physical component summary (PCS) and mental component summary (MCS) were defined as highest quartile of each score. Multivariate logistic regression was used to analyze odds ratio (OR) and 95% confidence interval (CI) for high PCS and MCS. Prevalence of high PCS were 33.3%, 27.5%, and 17.0% and that of high MCS were 31.7%, 24.8%, and 21.3% for T1, T2, and T3 (both p for trend < 0.001). The adjusted OR [95% CI] of T1 and T2 in reference to T3 were 1.56 [1.09–2.23] and 1.19 [0.85–1.68] for high PCS and 1.19 [0.85–1.68] and 0.94 [0.68–1.29] for high MCS. Serum adiponectin level was inversely associated with physical HR-QOL in Korean pre-dialysis CKD patients. This relationship was independent of various cardiovascular risk factors.

Sex disparities and adverse cardiovascular and kidney outcomes in patients with chronic kidney disease: results from the KNOW-CKD.

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. 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. 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. In Korean CKD patients, men were more likely to experience adverse cardiovascular events and death than women.