Publications by authors named "Chun Soo Lim"

174 Publications

cMet agonistic antibody prevents acute kidney injury to chronic kidney disease transition by suppressing Smurf1 and activating Smad7.

Clin Sci (Lond) 2021 Jun;135(11):1427-1444

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.

We aimed to investigate the role of cMet agonistic antibody (cMet Ab) in preventing kidney fibrosis during acute kidney injury (AKI) to chronic kidney disease (CKD) transition. Additionally, we explored the effect of cMet Ab on TGF-β1/Smad pathway during the pathogenesis of kidney fibrosis. A unilateral ischemia-reperfusion injury (UIRI) mouse model was established to induce AKI-to-CKD transition. Furthermore, we incubated human proximal tubular epithelial cells (hPTECs) under hypoxic conditions as in vitro model of kidney fibrosis. We analyzed the soluble plasma cMet level in patients with AKI requiring dialysis. Patients who did not recover kidney function and progressed to CKD presented a higher increase in the cMet level. The kidneys of mice treated with cMet Ab showed fewer contractions and weighed more than the controls. The mice in the cMet Ab-treated group showed reduced fibrosis and significantly decreased expression of fibronectin and α-smooth muscle actin. cMet Ab treatment decreased inflammatory markers (MCP-1, TNF-α, and IL-1β) expression, reduced Smurf1 and Smad2/3 level, and increased Smad7 expressions. cMet Ab treatment increased cMet expression and reduced the hypoxia-induced increase in collagen-1 and ICAM-1 expression, thereby reducing apoptosis in the in vitro cell model. After cMet Ab treatment, hypoxia-induced expression of Smurf1, Smad2/3, and TGF-β1 was reduced, and suppressed Smad7 was activated. Down-regulation of Smurf1 resulted in suppression of hypoxia-induced fibronectin expression, whereas treatment with cMet Ab showed synergistic effects. cMet Ab can successfully prevent fibrosis response in UIRI models of kidney fibrosis by decreasing inflammatory response and inhibiting the TGF-β1/Smad pathway.
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http://dx.doi.org/10.1042/CS20210013DOI Listing
June 2021

Causal effect of alcohol use on the risk of end-stage kidney disease and related comorbidities: a Mendelian randomization study.

Kidney Res Clin Pract 2021 Apr 20. Epub 2021 Apr 20.

Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.

Background: An inverse observational association between alcohol use and the risk of chronic kidney disease (CKD) or end-stage kidney disease (ESKD) has been reported. The causal effect of alcohol use on the risk of ESKD warrants additional investigation.

Methods: The study was an observational cohort study investigating the UK Biobank and performed Mendelian randomization (MR) analysis. Amounts of alcohol use were collected using a touchscreen questionnaire. In the observational analysis, 212,133 participants without prevalent ESKD were studied, and the association between alcohol use and the risk of prevalent CKD or incident ESKD was investigated. The genetic analysis included 337,138 participants of white British ancestry. For one-sample MR, an analysis based on a polygenic risk score (PRS) was conducted with genetically predicted alcohol intake. The MR analysis investigated ESKD outcome and related comorbidities.

Results: Lower alcohol use was observationally associated with a higher risk of prevalent CKD or incident ESKD. However, the genetic risk of CKD was significantly associated with lower alcohol use, suggesting reverse causation. A higher PRS for alcohol use was significantly associated with a higher risk of ESKD (per units of one phenotypical alcohol drink; adjusted odds ratio of 1.16 [95% confidence interval, 1.02-1.31]) and related comorbidities, including hypertension, diabetes mellitus, obesity, and central obesity.

Conclusion: The inverse observational association between alcohol use and the risk of CKD or ESKD may have been affected by reverse causation. Our study supports a causal effect of alcohol use on a higher risk of ESKD and related predisposing comorbidities.
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http://dx.doi.org/10.23876/j.krcp.20.186DOI Listing
April 2021

Atrial fibrillation and kidney function: a bidirectional Mendelian randomization study.

Eur Heart J 2021 May 23. Epub 2021 May 23.

Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Korea.

Aims: The aim of this study was to investigate the causal effects between atrial fibrillation (AF) and kidney function.

Methods And Results: We performed a bidirectional summary-level Mendelian randomization (MR) analysis implementing the results from a large-scale genome-wide association study for estimated glomerular filtration rate (eGFR) by the CKDGen (N = 765 348) and AF (N = 588 190) to identify genetic instruments. The inverse variance weighted method was the main MR method used. For replication, an allele score-based MR was performed by individual-level data within a UK Biobank cohort of white British ancestry individuals (N = 337 138). A genetic predisposition to AF was significantly associated with decreased eGFR [for log-eGFR, beta -0.003 (standard error, 0.0005), P < 0.001] and increased risk of chronic kidney disease [beta 0.059 (0.0126), P < 0.001]. The significance remained in MR sensitivity analyses and the causal estimates were consistent when we limited the analysis to individuals of European ancestry. Genetically predicted eGFR did not show a significant association with the risk of AF [beta -0.366 (0.275), P = 0.183]. The results were similar in allele score-based MR, as allele score for AF was significantly associated with reduced eGFR [for continuous eGFR, beta -0.079 (0.021), P < 0.001], but allele score for eGFR did not show a significant association with risk of AF [beta -0.005 (0.008), P = 0.530].

Conclusions: Our study supports that AF is a causal risk factor for kidney function impairment. However, an effect of kidney function on AF was not identified in this study.
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http://dx.doi.org/10.1093/eurheartj/ehab291DOI Listing
May 2021

Clinical outcomes associated with long-term exposure to airborne particulate pollution in kidney transplant recipients.

Environ Health 2021 May 15;20(1):61. Epub 2021 May 15.

Department of Public Health Science, Institute of Sustainable Development, Institute of Health and Environment, Graduate School of Public Health, Seoul National University, Room 708, Building 220, Gwanak-Ro Gwanak-Gu, Seoul, 08826, Republic of Korea.

Background: Researchers have yet to investigate the specific association between 10-μm particulate matter (PM10) levels and the risk of graft failure, kidney disease, or the functional decline of transplanted kidneys, in kidney transplant recipients (KTRs). Furthermore, we know very little about the association between PM10 levels and the development of allograft rejection in transplanted kidneys. Identification of air pollution as a potential contributor to kidney disease could help reduce future disease burden, stimulate policy discussions on the importance of reducing air pollution with respect to health and disease, and increase public awareness of the hazards of air pollution. We aimed to evaluate the relationship of PM10 with the risk of graft failure, mortality, and decline of graft function in KTRs.

Methods: Air pollutant data were obtained from the Korean National Institute of Environmental Research. We then investigated potential associations between these data and the clinical outcomes of 1532 KTRs who underwent kidney transplantation in a tertiary hospital between 2001 and 2015. Survival models were used to evaluate the association between PM10 concentrations and the risk of death-censored graft failure (DCGF), all-cause mortality, and biopsy-proven rejection (BPR), over a median follow-up period of 6.31 years.

Results: The annual mean PM10 exposure after kidney transplantation was 27.1 ± 8.0 μg/m. Based on 1-year baseline exposure, 1 μg/m increase in PM10 concentration was associated with an increased risk of DCGF (hazard ratio (HR): 1.049; 95% confidence interval (CI): 1.014-1.084) and BPR (HR: 1.053; 95% CI: 1.042-1.063). Fully adjusted models showed that all-cause mortality was significantly associated with 1-year average PM10 concentrations (HR, 1.09; 95% CI, 1.043 to 1.140).

Conclusions: Long-term PM10 exposure is significantly associated with BPR, DCGF, and all-cause mortality in KTRs.
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http://dx.doi.org/10.1186/s12940-021-00741-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126074PMC
May 2021

The minimum-mortality estimated glomerular filtration rate percentile shifts upward in the aged population: a nationwide population-based study.

Clin Kidney J 2021 May 29;14(5):1356-1363. Epub 2020 Dec 29.

Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.

Background: The estimated glomerular filtration rate (eGFR) is a biomarker not only for kidney function, but also for major clinical outcomes. We aimed to evaluate the patterns of mortality across the entire eGFR percentile spectrum using a population-based dataset.

Methods: We retrospectively reviewed the National Health Insurance Service (NHIS) database for people who received nationwide health check-ups from 2009 to 2012. Subjects who were ≥45 years old and had one or more serum creatinine values available were included in the study. The primary outcome was all-cause mortality as a function of eGFR percentile.

Results: The middle-aged group (45-64 years) showed a U-shaped pattern of association between eGFR percentile and all-cause mortality. The minimum-mortality eGFR percentile was shifted upward in the elderly group (≥65 years). Specifically, the minimum-mortality eGFR percentiles were the 28th percentile (83.8 mL/min/1.73 m) for middle-aged males, the 63rd percentile (86.2 mL/min/1.73 m) for elderly males, the 42nd percentile (102.8 mL/min/1.73 m) for middle-aged females and the 75th percentile (90.1 mL/min/1.73 m) for elderly females. Diabetes and hypertension shifted the minimum-mortality eGFR percentile upward in the middle-aged group. This pattern was attenuated in the elderly group.

Conclusions: The eGFR percentile showing minimum mortality moves upward in the aged population as well as patients with diabetes and hypertension, which might reduce the clinical significance of hyperfiltration. Risk stratification for mortality should be approached differently according to the specific conditions of the patient group.
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http://dx.doi.org/10.1093/ckj/sfaa238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087142PMC
May 2021

Kidney function and obstructive lung disease: a bidirectional Mendelian randomisation study.

Eur Respir J 2021 May 6. Epub 2021 May 6.

Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea

Background: Additional study is warranted to investigate the causal effects between kidney function and obstructive lung disease.

Methods: This study was a bidirectional two-sample Mendelian randomisation (MR) analysis. The CKDGen genome-wide association study (GWAS) meta-analysis for estimated glomerular filtration rate (eGFR) including individuals of European ancestry (N=567 460) provided the genetic instrument for kidney function and outcome summary statistics. A GWAS for FEV1/FVC including individuals of European ancestry from the UK Biobank (N=321 047) provided the genetic instrument for FEV1/FVC and outcome data. A polygenic score (PGS) analysis was performed to test the causal estimates from kidney function to binary obstructive lung disease outcomes, including chronic obstructive pulmonary disease (COPD), asthma, and FEV1/FVC<70%, and to perform non-linear MR with individual-level UK Biobank data.

Results: The causal estimates by summary-level MR indicated that genetically predicted increased kidney function was significantly associated with increased FEV1/FVC Z scores [10% increase in eGFR, beta 0.055 (0.024, 0.086)]. The PGS for increased eGFR showed a significant association with a reduced risk of FEV1/FVC<70% [OR 0.93 (0.87, 0.99)], COPD [OR 0.93 (0.87, 0.99)] and late-onset (≥50 years old) asthma [OR 0.93 (0.88, 0.99)]. The non-linear MR demonstrated that the causal effect from eGFR to FEV1/FVC was apparent in eGFR ranges lower than 60 mL/min/1.73 m. On the other hand, genetically predicted FEV1/FVC showed nonsignificant causal estimates of eGFR change [beta 0.568% (-0.458, 1.605%)].

Conclusion: This study supports kidney function impairment would be a causative factor for obstructive lung disease.
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http://dx.doi.org/10.1183/13993003.00848-2021DOI Listing
May 2021

Comprehensive metabolomic profiling in early IgA nephropathy patients reveals urine glycine as a prognostic biomarker.

J Cell Mol Med 2021 Jun 3;25(11):5177-5190. Epub 2021 May 3.

Kidney Research Institute, Seoul National University, Seoul, Korea.

Identification of a urinary metabolite biomarker with diagnostic or prognostic significance for early immunoglobulin A nephropathy (IgAN) is needed. We performed nuclear magnetic resonance-based metabolomic profiling and identified 26 metabolites in urine samples. We collected urine samples from 201, 77, 47, 36 and 136 patients with IgAN, patients with membranous nephropathy, patients with minimal change disease, patients with lupus nephritis and healthy controls, respectively. We determined whether a metabolite level is associated with the prognosis of IgAN through Cox regression and continuous net reclassification improvement (cNRI). Finally, in vitro experiments with human kidney tubular epithelial cells (hTECs) were performed for experimental validation. As the results, the urinary glycine level was higher in the IgAN group than the control groups. A higher urinary glycine level was associated with lower risk of eGFR 30% decline in IgAN patients. The addition of glycine to a predictive model including clinicopathologic information significantly improved the predictive power for the prognosis of IgAN [cNRI 0.72 (0.28-0.82)]. In hTECs, the addition of glycine ameliorated inflammatory signals induced by tumour necrosis factor-α. Our study demonstrates that urinary glycine may have diagnostic and prognostic value for IgAN and indicates that urinary glycine is a protective biomarker for IgAN.
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http://dx.doi.org/10.1111/jcmm.16520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178259PMC
June 2021

Causal effects of physical activity or sedentary behaviors on kidney function: an integrated population-scale observational analysis and Mendelian randomization study.

Nephrol Dial Transplant 2021 Apr 7. Epub 2021 Apr 7.

Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.

Background: An investigation for the causality of the effects of physical activity and specific sedentary activities on kidney function in the general population is warranted.

Methods: In this observational cohort study, first, the clinical associations of the prevalence of stages 3-5 chronic kidney disease (CKD) and the eGFR with physical activity, determined by self-report or objective wrist-band accelerometer results, and sedentary activities (watching television, using a computer, and driving) were investigated in 329,758 UK Biobank participants. To assess causality, a two-sample Mendelian randomization (MR) analysis was performed to investigate the associations of a genetic predisposition to physical activity and a sedentary lifestyle with the risk of kidney function impairment in an independent CKDGen genome-wide association study (N = 567,460). The findings were replicated with the 321,024 UK white British Biobank participants in the allele-score-based one-sample MR.

Results: A higher degree of self-reported or accelerometer-determined moderate-to-vigorous physical activity was associated with a higher eGFR, while a longer time spent watching television was significantly associated with a lower eGFR and a higher prevalence of CKD. The two-sample MR demonstrated that the genetic predisposition to a higher degree of physical activity was associated with a lower risk of CKD and a higher eGFR, while the genetically predicted television watching duration was associated with a higher risk of CKD and a lower eGFR. The other sedentary behaviors yielded inconsistent results. The findings were similarly replicated in the one-sample MR.

Conclusion: Physical activity and television watching causally affect kidney function in the general population.
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http://dx.doi.org/10.1093/ndt/gfab153DOI Listing
April 2021

Causal Effects of Homocysteine, Folate, and Cobalamin on Kidney Function: A Mendelian Randomization Study.

Nutrients 2021 Mar 11;13(3). Epub 2021 Mar 11.

Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Korea.

Blood homocysteine level and related vitamin levels are associated with various health outcomes. We aimed to assess causal effects of blood homocysteine, folate, and cobalamin on kidney function in the general population by performing Mendelian randomization (MR) analysis. Genetic instruments for blood homocysteine, folate, and cobalamin levels were introduced from a previous genome-wide association (GWAS) meta-analysis of European individuals. Summary-level MR analysis was performed for the estimated glomerular filtration rate (eGFR) from the CKDGen consortium GWAS that included 567,460 European ancestry individuals. For replication, allele-score-based MR was performed with an independent U.K. Biobank cohort of 337,138 individuals of white British ancestry. In summary-level MR for the CKDGen data, high genetically predicted homocysteine levels were significantly associated with low eGFR (per 1 standard deviation, beta for eGFR change -0.95 (-1.21, -0.69) %), supported by pleiotropy-robust MR sensitivity analysis. Genetically predicted high folate levels were significantly associated with high eGFR change (0.86 (0.30, 1.42) %); however, causal estimates from cobalamin were nonsignificant (-0.11 (-0.33, 0.11) %). In the U.K. Biobank data, the results were consistently identified. Therefore, a high blood homocysteine level causally decreases eGFR. Future trials with appropriate homocysteine-lowering interventions may be helpful for the primary prevention of kidney function impairment.
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http://dx.doi.org/10.3390/nu13030906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001564PMC
March 2021

Causal Effects of Positive Affect, Life Satisfaction, Depressive Symptoms, and Neuroticism on Kidney Function: A Mendelian Randomization Study.

J Am Soc Nephrol 2021 Jun 30;32(6):1484-1496. Epub 2021 Mar 30.

Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea

Background: Further investigation of the causal effects of psychologic wellbeing on kidney function is warranted.

Methods: In this Mendelian randomization (MR) study, genetic instruments for positive affect, life satisfaction, depressive symptoms, and neuroticism were introduced from a previous genome-wide association study meta-analysis of European individuals. Summary-level MR was performed using the CKDGen data of European ancestry (=567,460), and additional allele score-based MR was performed in the individual-level data of White British UK Biobank participants (=321,024).

Results: In summary-level MR with the CKDGen data, depressive symptoms were a significant causative factor for kidney function impairment (CKD OR, 1.45; 95% confidence interval, 1.07 to 1.96; eGFR change [%] beta -2.18; 95% confidence interval, -3.61 to -0.72) and pleiotropy-robust sensitivity analysis results supported the causal estimates. A genetic predisposition for positive affect was significantly associated with better kidney function (CKD OR, 0.69; 95% confidence interval, 0.52 to 0.91), eGFR change [%] beta 1.50; 95% confidence interval, 0.09 to 2.93) and sensitivity MR analysis results supported the finding for CKD outcome, but was nonsignificant for eGFR. Life satisfaction and neuroticism exposures showed nonsignificant causal estimates. In the UK Biobank with covariate-adjusted allele score MR analysis, allele scores for positive affect and life satisfaction were causally associated with reduced risk of CKD and higher eGFR. In contrast, neuroticism allele score was associated with increased risk of CKD and lower eGFR, and depressive symptoms allele score was associated with lower eGFR, but showed nonsignificant association with CKD.

Conclusions: Health care providers in the nephrology field should be aware of the causal linkage between psychologic wellbeing and kidney function.
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http://dx.doi.org/10.1681/ASN.2020071086DOI Listing
June 2021

Observational or Genetically Predicted Higher Vegetable Intake and Kidney Function Impairment: An Integrated Population-Scale Cross-Sectional Analysis and Mendelian Randomization Study.

J Nutr 2021 May;151(5):1167-1174

Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.

Background: Further exploration of the possible effects of vegetable intake on kidney function is warranted.

Objective: We aimed to study the causality of the association between vegetable intake and kidney function by implementing Mendelian randomization (MR) analysis.

Methods: This study comprised a cross-sectional dietary investigation using UK Biobank data and MR analysis. For the cross-sectional investigation, 432,732 participants aged 40-69 y from the UK Biobank cohort were included. Self-reported vegetable intake was the exposure, and the outcomes were the estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD). Next, we included 337,138 participants of white British ancestry in the UK Biobank, and a genome-wide association study (GWAS) was performed to generate a genetic instrument. For MR, we first performed polygenic score (PGS)-based 1-sample MR. In addition, 2-sample MR was performed with CKDGen GWAS for kidney function traits, and the inverse variance weighted method was the main MR method.

Results: Higher vegetable intake was cross-sectionally associated with a higher eGFR (per heaped tablespoon increase; β: 0.154; 95% CI: 0.144, 0.165) and lower odds of CKD (OR: 0.975; 95% CI: 0.968, 0.982). A PGS for vegetable intake was significantly associated with a higher eGFR [per ordinal category increase (0, 1-3, 4-6, ≥7 tablespoons per day); β: 4.435; 95% CI: 2.337, 6.533], but the association with CKD remained nonsignificant (OR: 0.468; 95% CI: 0.143, 1.535). In the 2-sample MR, the causal estimates indicated that a higher genetically predicted vegetable intake was associated with a higher eGFR (percent change; β: 3.071; 95% CI: 0.602, 0.560) but nonsignificantly associated with the risk of CKD (OR: 0.560; 95% CI: 0.289, 1.083) in the European ancestry data from the CKDGen.

Conclusions: This study suggests that higher vegetable intake may have a causal effect on higher eGFRs in the European population.
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http://dx.doi.org/10.1093/jn/nxaa452DOI Listing
May 2021

Apolipoprotein B is a risk factor for end-stage renal disease.

Clin Kidney J 2021 Feb 11;14(2):617-623. Epub 2020 Feb 11.

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

Background: Apolipoprotein B (ApoB), a constituent of lipid particles, is known to increase the risk of cardiovascular diseases. However, the association between ApoB and end-stage renal disease (ESRD) remains to be resolved. Our objective was to determine whether the ApoB concentration has an association with the risk of ESRD.

Methods: Serum ApoB, ApoA1, conventional lipid parameters and lipid subfractions were analyzed in 9403 subjects. The hazard ratio (HR) for the risk of ESRD was calculated using tertiles of ApoB concentration.

Results: ESRD developed in 110 patients (1.2%) during 10 years of follow-up. Several lipid parameters were compared for their association with the risk of ESRD, of which ApoB was best and its relationship was also independent of other clinical parameters. Individuals in the second and third ApoB tertiles had a higher risk of ESRD than those in the first tertile, with HRs of 1.5 [95% confidence interval (CI) 0.89-2.61] and 2.6 (1.56-4.20), respectively. A high ApoB:ApoA1 ratio was associated with a higher risk of ESRD, but ApoA1 had no independent association. Even after adjusting the competing risk for all-cause death, high ApoB concentrations had an association with the risk of ESRD.

Conclusions: High ApoB concentration is associated with a higher risk of ESRD, despite adjustment for other lipid and clinical parameters. Accordingly, the monitoring of ApoB may be helpful for the prediction of ESRD.
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http://dx.doi.org/10.1093/ckj/sfz186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886579PMC
February 2021

Causal effects of relative fat, protein, and carbohydrate intake on chronic kidney disease: a Mendelian randomization study.

Am J Clin Nutr 2021 04;113(4):1023-1031

Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.

Background: The effects of specific macronutrients on kidney function independent of total calorie intake have rarely been studied, although the composition of macronutrient intake has been reported to affect health outcomes.

Objectives: We aimed to investigate the effects of macronutrient intake ratios on the risk of chronic kidney disease (CKD) by Mendelian randomization (MR) analysis.

Methods: The study was an observational cohort study mainly based on the UK Biobank and including MR analysis. First, we evaluated the relative baseline macronutrient composition-that is, the number of calories from each macronutrient divided by total calorie intake-of the diets of UK Biobank participants, and we used Cox regression to assess the incidence of end-stage kidney disease (ESKD) in 65,164 participants with normal kidney function [estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2]. We implemented a genetic instrument for relative fat, protein, and carbohydrate intake developed by a previous genome-wide association study (GWAS) and performed MR analysis. Two-sample MR was performed with the summary statistics from independent CKDGen GWAS for kidney function traits (n = 567,460), including CKD (eGFR <60 mL/min/1.73 m2) and log-transformed eGFR.

Results: The median relative macronutrient intake composition at baseline was 35% fats, 15% protein, and 50% carbohydrates. Higher relative protein intake in subjects with normal kidney function was significantly associated with a lower risk of incident ESKD (HR: 0.54; 95% CI: 0.30, 0.95) in the observational investigation. Two-sample MR indicated that increased relative fat intake causally increased the risk of kidney function impairment [CKD (OR: 1.94; 95% CI: 1.39, 2.71); log eGFR (β: -0.036; 95% CI: -0.048, -0.024)] and that higher relative protein intake was causally linked to a lower CKD risk [CKD (OR: 0.50; 95% CI: 0.35, 0.72); log eGFR (β: 0.044; 95% CI: 0.030, 0.058)].

Conclusions: A desirable macronutrient composition, including high relative protein intake and low relative fat intake, may causally reduce the risk of CKD in the general population.
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http://dx.doi.org/10.1093/ajcn/nqaa379DOI Listing
April 2021

Low serum total CO and its association with mortality in patients being followed up in the nephrology outpatients clinic.

Sci Rep 2021 Jan 18;11(1):1711. Epub 2021 Jan 18.

Department of Internal Medicine, Seoul National University Boramae Medical Center, 20, Boramae-ro 5-gil, Dongjak-gu, Seoul, 07061, Korea.

Large-scale studies have not been conducted to assess whether serum hypobicarbonatemia increases the risk for kidney function deterioration and mortality among East-Asians. We aimed to determine the association between serum total CO (TCO) concentrations measured at the first outpatient visit and clinical outcomes. In this multicenter cohort study, a total of 42,231 adult nephrology outpatients from 2001 to 2016 were included. End-stage renal disease (ESRD) patients on dialysis within 3 months of the first visit were excluded. Instrumental variable (IV) was used to define regions based on the proportion of patients with serum TCO < 22 mEq/L. The crude mortality rate was 12.2% during a median 77.0-month follow-up period. The Cox-proportional hazard regression model adjusted for initial kidney function, alkali supplementation, and the use of diuretics demonstrated that low TCO concentration was not associated with progression to ESRD, but significantly increased the risk of death. The IV analysis also confirmed a significant association between initial TCO concentration and mortality (HR 0.56; 95% CI 0.49-0.64). This result was consistently significant regardless of the underlying renal function. In conclusion, low TCO levels are significantly associated with mortality but not with progression to ESRD in patients with ambulatory care.
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http://dx.doi.org/10.1038/s41598-021-81332-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814051PMC
January 2021

Smoking, development of or recovery from metabolic syndrome, and major adverse cardiovascular events: A nationwide population-based cohort study including 6 million people.

PLoS One 2021 12;16(1):e0241623. Epub 2021 Jan 12.

Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.

Smoking, metabolic syndrome (MetS), and major adverse cardiovascular events (MACEs) are important global health problems. We aimed to investigate the association between smoking, alteration in MetS status, and the consequent risk of MACE. We performed a nationwide observational cohort study based on the claims database of Korea. We included people with ≥ 3 national health screenings from 2009 to 2013. Total 6,099,717 people, including 3,576,236 nonsmokers, 862,210 ex-smokers, 949,586 light-to-moderate smokers, and 711,685 heavy smokers, at the first health screening, were investigated. First, we performed a logistic regression analysis using smoking status at the first screening as the exposure variable and MetS development or recovery as the outcome variable. Second, we performed a Poisson regression using smoking status at the third screening as the exposure variable and the outcome was risk of incident MACEs. Among those previously free from MetS (N = 4,889,493), 347,678 people developed MetS, and among those who had previous MetS (N = 1,210,224), 347,627 people recovered from MetS. Smoking was related to a higher risk of MetS development [for heavy smokers: adjusted OR 1.71 (1.69 to 1.73)] and a lower probability of MetS recovery [for heavy smokers: adjusted OR 0.68 (0.67 to 0.69)]. Elevated triglycerides was the MetS component with the most prominent association with smoking. The risk for incident MACEs (78,640 events during a median follow-up of 4.28 years) was the highest for heavy smokers, followed in order by light-to-moderate, ex-smokers and nonsmokers, for every MetS status. Therefore, smoking may promote MetS or even hinder recovery from MetS. Smoking cessation should be emphasized to reduce MACE risk even for those without MetS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241623PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802921PMC
April 2021

Cardiovascular or mortality risk of controlled hypertension and importance of physical activity.

Heart 2021 Jan 5. Epub 2021 Jan 5.

Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea (the Republic of)

Objective: To investigate the risk of major adverse cardiac and cerebrovascular events (MACCEs) and all-cause death of patients with controlled hypertension and suggest the benefits of physical activity in their prognosis.

Methods: People aged 40-69 years from the prospective UK Biobank cohort (UKB, n=220 026) and the retrospective Korean National Health Insurance Service cohort (KNHIS, n=3 593 202) were included in this observational cohort study, excluding those with previous cerebrocardiovascular diseases or hypertension without treatment. The study groups were stratified into normotension, controlled hypertension (patients with hypertension with systolic blood pressure <140 mm Hg and diastolic blood pressure <90 mm Hg) and uncontrolled hypertension groups. The outcomes were MACCEs and all-cause mortality, analysed by Cox regression analysis.

Results: We included 161 405/18 844/39 777 and 3 122 890/383 828/86 484 individuals with normotension/controlled hypertension/uncontrolled hypertension state from the UKB and KNHIS cohorts, respectively. The controlled hypertension group showed significantly higher risk of MACCEs (UKB: adjusted HR 1.73 (95% CI 1.55 to 1.92); KNHIS: 1.46 (95% CI 1.43 to 1.49)) and all-cause mortality (UKB: adjusted HR 1.28 (95% CI 1.18 to 1.39); KNHIS: 1.29 (95% CI 1.26 to 1.32)) than individuals with normotension. The controlled hypertension group not involved in any moderate or moderate-to-vigorous physical activity showed high risk of adverse outcomes, which was comparable with or even higher than the risk of patients with uncontrolled hypertension who were engaged in physical activity.

Conclusions: Controlled hypertension is associated with residual risks of adverse outcomes. Clinicians may encourage physical activity for patients with controlled hypertension, not being reassured by their achieved target blood pressure values.
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http://dx.doi.org/10.1136/heartjnl-2020-318193DOI Listing
January 2021

Impact of variability in estimated glomerular filtration rate on major clinical outcomes: A nationwide population-based study.

PLoS One 2020 17;15(12):e0244156. Epub 2020 Dec 17.

Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.

Background: The estimated glomerular filtration rate (eGFR), commonly estimated using the serum creatinine value, often fluctuates throughout the serial measurement. The clinical significance of GFR variation among the general population with normal renal function has not yet been demonstrated. Thus, we explored the impact of GFR variability on adverse clinical outcomes.

Methods: A nationwide retrospective cohort study using the Korean National Health Insurance System database was performed. National health screening examinees who underwent creatinine measurement ≥3 times between 2012 and 2016 were considered. Those with eGFR under 60 mL/min/m2 were excluded. The fluctuation of eGFR was represented with variability independent of the mean (VIM) index; which was calculated by the standard deviation divided by the exponent of the regression coefficient of the mean. Then, the risks of myocardial infarction (MI), stroke and death were assessed according to the quartiles of the VIM.

Results: Of total 3,538,500 participants, 0.29% of myocardial infarction (MI), 0.14% of stroke, 0.36% of deaths were observed during the median follow up of 3.27 years. Participants with the highest VIM index, which represents the highest eGFR variability, were significantly associated with an increased risk of MI (hazard ratio [HR]; 1.10, 95% confidence interval [95% CI]; 1.04-1.16), stroke (HR: 1.16; 95% CI 1.09-1.23), and death (HR: 1.18; 95% CI 1.12-1.24). The elevated risk of adverse events was consistent after the multivariate adjustment with potential confounding factors, except the risk of MI (HR 1.06; 95% 1.00-1.06).

Conclusions: Increased eGFR variability exhibited an association with major clinical outcomes, indicating that monitoring eGFR variability might be a useful parameter for predicting the adverse outcomes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244156PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746294PMC
March 2021

Cumulative fluid balance and mortality in elderly patients with acute kidney injury requiring continuous renal-replacement therapy: a multicenter prospective cohort study.

Kidney Res Clin Pract 2020 Dec;39(4):414-425

Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul, Republic of Korea.

Background: The effect of fluid balance on outcomes in elderly patients with acute kidney injury (AKI) requiring continuous renal-replacement therapy (CRRT) is not explained well. We investigated outcomes according to cumulative fluid balance (CFB) in elderly patients with AKI undergoing CRRT.

Methods: A total of 607 patients aged 65 years or older who started CRRT due to AKI were enrolled and stratified into two groups (fluid overload [FO] vs. no fluid overload [NFO]) based on the median CFB value for 72 hours before CRRT initiation. Propensity score-matching analysis was performed.

Results: The median age of included patients was 73.0 years and 60.0% of the population was male. The median 72-hour CFB value was 2,839.0 mL. The overall cumulative survival and 28-day survival rates were lower in the FO group than in the NFO group (P < 0.001 for both) and remained so after propensity score-matching. Furthermore, patients in the FO group demonstrated a higher overall mortality risk after adjustment for age, sex, systolic blood pressure, Charlson comorbidity index, Acute Physiology and Chronic Health Evaluation II score, serum albumin, creatinine, diuretic use, and mechanical ventilation status (hazard ratio, 1.38; 95% confidence interval, 1.13 to 1.89; < 0.001). Among survivors, both the duration of CRRT and the total duration of hospitalization from CRRT initiation showed no difference between the FO and NFO groups.

Conclusion: A higher CFB value is associated with an increased risk of mortality in elderly patients with AKI requiring CRRT.
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http://dx.doi.org/10.23876/j.krcp.20.089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770993PMC
December 2020

Impact of health-related quality of life on survival after dialysis initiation: a prospective cohort study in Korea.

Kidney Res Clin Pract 2020 Dec;39(4):426-440

Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Republic of Korea.

Background: The effect of each health-related quality of life (HRQOL) component on hemodialysis prognosis has not been well studied. We aimed to investigate the clinical factors associated with HRQOL and the effect of HRQOL after dialysis initiation on long-term survival in an Asian population.

Methods: A total of 568 hemodialysis patients were included from a nationwide prospective cohort study. HRQOL was evaluated using the Kidney Disease Quality of Life (KDQOL) Short FormTM 1.3 at 3 months after dialysis initiation. The effect of each KDQOL item score on mortality was analyzed. Multivariable Cox analysis was performed after adjusting for age, sex, modified Charlson comorbidity index, and causes of primary kidney disease.

Results: Old age, diabetes mellitus, high comorbidities, and low serum albumin levels were associated with poor physical health status. Decreased urine output was associated with both poor physical and mental health status. The scores of 3 indices in the kidney disease domain (effect of kidney disease, social support, and dialysis staff encouragement) showed significant associations with mortality, as did the 3 indices (physical function, physical role limitation, and body pain) in the physical health domain. Neither the 4 indices in the mental health domain nor the mental composite score showed a significant association with mortality. However, a high physical composite score was associated with decreased overall patient mortality ( = 0.003). The effect of physical composite score on survival was prominent among young or middle-aged groups.

Conclusion: Poor physical health status 3 months after hemodialysis start correlates significantly with overall mortality.
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http://dx.doi.org/10.23876/j.krcp.20.065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770988PMC
December 2020

Association Between Moderate-to-Vigorous Physical Activity and the Risk of Major Adverse Cardiovascular Events or Mortality in People With Various Metabolic Syndrome Status: A Nationwide Population-Based Cohort Study Including 6 Million People.

J Am Heart Assoc 2020 11 6;9(22):e016806. Epub 2020 Nov 6.

Department of Internal Medicine Seoul National University Hospital Seoul Korea.

Background A population-scale evidence for the association between moderate-to-vigorous physical activity (MV-PA) and risks of major adverse cardiovascular event (MACE) or all-cause mortality in people with various metabolic syndrome (MetS) status is warranted. Methods and Results We performed a nationwide retrospective cohort study based on the claims database of South Korea. We included people who received ≥3 national health screenings from 2009 to 2013 without a previous MACE history. We determined the MetS status of 6 108 077 people: MetS-chronic (N=864 063), MetS-developed (N=348 163), MetS-recovery (N=348 313), and MetS-free (N=4 547 538). The exposure was self-reported MV-PA frequencies. The outcome was incident MACEs or all-cause mortality. The incidence rate ratios (IRR) were calculated with adjustments for clinical/demographic characteristics. During the median follow-up of 4.28 years, 78 770 and 51 840 people experienced MACEs or died, respectively. Those who engaged in MV-PA had a significantly lower risk of MACEs or all-cause mortality than those not engaged in MV-PA in every spectrum of MetS. Even among those who were free from MetS (for MACEs, IRR 0.94 [0.92-0.97], for all-cause mortality, IRR 0.85 [0.82-0.87]) or who had already recovered from MetS (for MACEs, IRR 0.89 [0.84-0.95], for all-cause mortality, IRR 0.74 [0.68-0.81]), 1 to 2 days per week of MV-PA were significantly associated with lower risk of the adverse outcomes when compared with not being engaged in MV-PA. Those who were engaged in MV-PA more frequently also had significantly lower risks of MACEs or all-cause mortality. Conclusions This nationwide study suggests that MV-PA may be recommended to the general population regardless of recent MetS status.
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http://dx.doi.org/10.1161/JAHA.120.016806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763708PMC
November 2020

Clinical outcomes of prolonged dual antiplatelet therapy after coronary drug-eluting stent implantation in dialysis patients.

Clin Kidney J 2020 Oct 3;13(5):803-812. Epub 2020 May 3.

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

Background: End-stage renal disease yields susceptibility to both ischemia and bleeding. The optimal duration of dual antiplatelet therapy (DAPT) after drug-eluting stent (DES) implantation is not established in dialysis patients, who are usually excluded from randomized studies. Since recent studies implied the benefits of prolonged DAPT >12 months in chronic kidney disease, we investigated the effectiveness and safety of prolonged DAPT in dialysis patients with higher cardiovascular risks.

Methods: In this nationwide population-based study, we analyzed dialysis patients who underwent DES implantation from 2008 to 2015. Continued DAPT was compared with discontinued DAPT using landmark analyses, including free-of-event participants at 12 ( = 2246), 15 ( = 1925) and 18 months ( = 1692) after DES implantation. The primary outcome was major adverse cardiovascular events (MACEs): a composite of mortality, nonfatal myocardial infarction, coronary revascularization and stroke. Major bleeding was a safety outcome. Inverse probability of treatment weighting Cox regression was performed.

Results: Mean follow-up periods were 278.3-292.4 days, depending on landmarks. Overall, incidences of major bleeding were far lower than those of MACE. Continued DAPT groups showed lower incidences of MACE and higher incidences of major bleeding, compared with discontinued DAPT groups. In Cox analyses, continued DAPT reduced the hazards of MACE at the 12- [hazard ratio (HR) = 0.74, 95% confidence interval (CI) 0.61-0.90; P=0.003], 15- (HR = 0.78, 95% CI 0.64-0.96; P=0.019) and 18-month landmarks (HR = 0.79, 95% CI 0.63-0.99; P=0.041), but without a significant increase in major bleeding at 12 (HR = 1.39, 95% CI 0.90-2.16; P=0.14), 15 (HR = 1.13, 95% CI 0.75-1.70; P=0.55) or 18 months (HR = 1.27, 95% CI 0.83-1.95; P=0.27).

Conclusions: Prolonged DAPT reduced MACE without significantly increasing major bleeding in patients who were event-free at 12 months after DES implantation. In deciding on DAPT duration, prolonged DAPT should be considered in dialysis patients.
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http://dx.doi.org/10.1093/ckj/sfaa037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577762PMC
October 2020

Operation and Management of Seoul Metropolitan City Community Treatment Center for Mild Condition COVID-19 Patients.

J Korean Med Sci 2020 Oct 19;35(40):e367. Epub 2020 Oct 19.

Laboratory of Emergency Medical Services, Seoul National University Hospital Biomedical Research Institute, Seoul, Korea.

Background: In response to the disaster of coronavirus disease 2019 (COVID-19) pandemic, Seoul Metropolitan Government (SMG) established a patient facility for mild condition patients other than hospital. This study was conducted to investigate the operation and necessary resources of a community treatment center (CTC) operated in Seoul, a metropolitan city with a population of 10 million.

Methods: To respond COVID-19 epidemic, the SMG designated 5 municipal hospitals as dedicated COVID-19 hospitals and implemented one CTC cooperated with the Boramae Municipal Hospital for COVID-19 patients in Seoul. As a retrospective cross-sectional observational study, retrospective medical records review was conducted for patients admitted to the Seoul CTC. The admission and discharge route of CTC patients were investigated. The patient characteristics were compared according to route of discharge whether the patient was discharged to home or transferred to hospital. To report the operation of CTC, the daily mean number of tests (reverse transcription polymerase chain reaction and chest X-ray) and consultations by medical staffs were calculated per week. The list of frequent used medications and who used medication most frequently were investigated.

Results: Until May 27 when the Seoul CTC was closed, 26.5% (n = 213) of total 803 COVID-19 patients in Seoul were admitted to the CTC. It was 35.7% (n = 213) of 597 newly diagnosed patients in Seoul during the 11 weeks of operation. The median length of stay was 21 days (interquartile range, 12-29 days). A total of 191 patients (89.7%) were discharged to home after virologic remission and 22 (10.3%) were transferred to hospital for further treatment. Fifty percent of transferred patients were within a week since CTC admission. Daily 2.5-3.6 consultations by doctors or nurses and 0.4-0.9 tests were provided to one patient. The most frequently prescribed medication was symptomatic medication for COVID-19 (cough/sputum and rhinorrhea). The next ranking was psychiatric medication for sleep problem and depression/anxiety, which was prescribed more than digestive drug.

Conclusion: In the time of an infectious disease disaster, a metropolitan city can operate a temporary patient facility such as CTC to make a surge capacity and appropriately allocate scarce medical resource.
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http://dx.doi.org/10.3346/jkms.2020.35.e367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572227PMC
October 2020

Short or Long Sleep Duration and CKD: A Mendelian Randomization Study.

J Am Soc Nephrol 2020 12 1;31(12):2937-2947. Epub 2020 Oct 1.

Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea

Background: Studies have found sleeping behaviors, such as sleep duration, to be associated with kidney function and cardiovascular disease risk. However, whether short or long sleep duration is a causative factor for kidney function impairment has been rarely studied.

Methods: We studied data from participants aged 40-69 years in the UK Biobank prospective cohort, including 25,605 self-reporting short-duration sleep (<6 hours per 24 hours), 404,550 reporting intermediate-duration sleep (6-8 hours), and 35,659 reporting long-duration sleep (≥9 hours) in the clinical analysis. Using logistic regression analysis, we investigated the observational association between the sleep duration group and prevalent CKD stages 3-5, analyzed by logistic regression analysis. We performed Mendelian randomization (MR) analysis involving 321,260 White British individuals using genetic instruments (genetic variants linked with short- or long-duration sleep behavior as instrumental variables). We performed genetic risk score analysis as a one-sample MR and extended the finding with a two-sample MR analysis with CKD outcome information from the independent CKDGen Consortium genome-wide association study meta-analysis.

Results: Short or long sleep duration clinically associated with higher prevalence of CKD compared with intermediate duration. The genetic risk score for short (but not long) sleep was significantly related to CKD (per unit reflecting a two-fold increase in the odds of the phenotype; adjusted odds ratio, 1.80; 95% confidence interval, 1.25 to 2.60). Two-sample MR analysis demonstrated causal effects of short sleep duration on CKD by the inverse variance weighted method, supported by causal estimates from MR-Egger regression.

Conclusions: These findings support an adverse effect of a short sleep duration on kidney function. Clinicians may encourage patients to avoid short-duration sleeping behavior to reduce CKD risk.
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http://dx.doi.org/10.1681/ASN.2020050666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790216PMC
December 2020

Urinary cMet as a prognostic marker in immunoglobulin A nephropathy.

J Cell Mol Med 2020 10 21;24(19):11158-11169. Epub 2020 Aug 21.

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

The prediction of prognosis in patients with immunoglobulin A nephropathy (IgAN) is challenging. We investigated the correlation between urinary cMet (ucMet) levels and clinical parameters and examined the effects of cMet agonistic antibody (cMet Ab) in an in vitro IgAN model. Patients diagnosed with IgAN (n = 194) were divided into three groups representing undetectable (Group 1), below-median (Group 2) and above-median (Group 3) levels of ucMet/creatinine (ucMet/Cr). Stained kidney biopsy samples were graded according to cMet intensity. Primary-cultured human mesangial cells were stimulated with recombinant tumour necrosis factor (TNF)-α and treated with cMet Ab. Our results showed that ucMet/Cr levels positively correlated with proteinuria (P < .001). During the follow-up, patients in Group 3 showed a significantly lower probability of complete remission (CR; uPCr < 300 mg/g) than those in groups 1 and 2, after adjusting for blood pressure, estimated glomerular filtration rate, and proteinuria, which influence clinical prognosis (HR 0.60, P = .038); moreover, ucMet/Cr levels were also associated with glomerular cMet expression. After TNF-α treatment, the proliferation of mesangial cells and increased interleukin-8 and intercellular adhesion molecule-1 expression were markedly reduced by cMet Ab in vitro. In conclusion, ucMet/Cr levels significantly correlated with proteinuria, glomerular cMet expression, and the probability of CR. Further, cMet Ab treatment alleviated the inflammation and proliferation of mesangial cells. Hence, ucMet could serve as a clinically significant marker for treating IgAN.
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http://dx.doi.org/10.1111/jcmm.15636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576300PMC
October 2020

An independent validation of the kidney failure risk equation in an Asian population.

Sci Rep 2020 07 31;10(1):12920. Epub 2020 Jul 31.

Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Korea.

Predicting the risk of end-stage renal disease (ESRD) progression facilitates appropriate nephrology care of patients with chronic kidney disease (CKD). Previously, the kidney failure risk equations (KFREs) were developed and validated in several cohorts. The purpose of this study is to validate the KFREs in a Korean population and to recalibrate the equations. A total of 38,905 adult patients, including 13,244 patients with CKD stages G3-G5, who were referred to nephrology were recruited. Using the original KFREs (4-, 6- and 8-variable equations) and recalibration equations, we predicted the risk of 2- and 5-year ESRD progression. All analyses were conducted in CKD stages G3-G5 patients as well as the total population. In CKD stages G3-G5 patients, All the original 4-, 6- and 8-variable equations showed excellent areas under the receiver operating characteristic curve of 0.87 and 0.83 for the 2- and 5-year risk of ESRD, respectively. The results of net reclassification improvement, integrated discrimination index and Brier score showed that recalibration improved the prediction models in some cases. The original KFREs showed high discrimination in both CKD stages G3-G5 patients and the total population referred to nephrology in this large Korean cohort. KFREs can be implemented in Korean health systems and can guide nephrology referrals and other CKD-related treatment decisions.
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http://dx.doi.org/10.1038/s41598-020-69715-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395750PMC
July 2020

Fumarate modulates phospholipase A2 receptor autoimmunity-induced podocyte injury in membranous nephropathy.

Kidney Int 2021 02 23;99(2):443-455. Epub 2020 Jul 23.

Department of Internal Medicine, College of Medicine, Seoul National University, Seoul, Korea; Kidney Research Institute, Seoul National University, Seoul, Korea; Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea. Electronic address:

Downstream mechanisms that lead to podocyte injury following phospholipase A2 receptor (PLA2R) autoimmunity remain elusive. To help define this we compared urinary metabolomic profiles of patients with PLA2R-associated membranous nephropathy (MN) at the time of kidney biopsy with those of patients with minimal change disease (MCD) and to healthy individuals. Among the metabolites differentially expressed in patients with PLA2R-associated MN compared to healthy individuals, fumarate was the only significant differentially expressed metabolite in PLA2R-associated MN compared to MCD [fold-difference vs. healthy controls and vs. MCD: 1.76 and 1.60, respectively]. High urinary fumarate levels could predict the composite outcome of PLA2R-associated MN. Fumarate hydratase, which hydrolyzes fumarate, colocalized with podocalyxin, and its expression was lower in glomerular sections from patients with PLA2R-associated MN than in those from healthy individuals, patients with non-PLA2R-associated MN or MCD. Podocytes stimulated with IgG purified from serum with a high anti-PLA2R titer (MN-IgG) decreased expression of fumarate hydratase and increased fumarate levels. These changes were coupled to alterations in the expression of molecules involved in the phenotypic profile of podocytes (WT1, ZO-1, Snail, and fibronectin), an increase in albumin flux across the podocyte layer and the production of reactive oxygen species in podocytes. However, overexpression of fumarate hydratase ameliorated these alterations. Furthermore, knockdown of fumarate hydratase exhibited synergistic effects with MN-IgG treatment. Thus, fumarate may promote changes in the phenotypic profiles of podocytes after the development of PLA2R autoimmunity. These findings suggest that fumarate could serve as a potential target for the treatment of PLA2R-associated MN.
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http://dx.doi.org/10.1016/j.kint.2020.06.031DOI Listing
February 2021

Glomerular Hyperfiltration and Cancer: A Nationwide Population-Based Study.

Cancer Epidemiol Biomarkers Prev 2020 10 22;29(10):2070-2077. Epub 2020 Jul 22.

Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.

Background: Glomerular hyperfiltration is associated with all-cause mortality. Herein, we evaluated the association between glomerular hyperfiltration and the development of cancer, the most common cause of death, in an Asian population.

Methods: We retrospectively reviewed the National Health Insurance Service database of Korea for people who received national health screenings from 2012 to 2013. Glomerular hyperfiltration was defined as the 95th percentile and greater after stratification by sex and age decile. We performed a multivariate Cox regression analysis using glomerular hyperfiltration at the first health screening as the exposure variable and cancer development as the outcome variable to evaluate the impact of glomerular hyperfiltration on the development of cancer.

Results: A total of 1,953,123 examinations for patients with a median follow-up time of 4.4 years were included in this study. Among the 8 different site-specific cancer categories, digestive organs showed significant associations between glomerular hyperfiltration and cancer. The population with glomerular hyperfiltration showed an increased risk for stomach cancer [adjusted hazard ratio (aHR) = 1.22], colorectal cancer (aHR = 1.16), and liver or intrahepatic malignancy (aHR = 1.35).

Conclusions: Glomerular hyperfiltration was associated with an increased risk for the development of cancer in specific organs, such as the stomach, colorectum, and liver and intrahepatic organ.

Impact: Glomerular hyperfiltration needs to be considered a significant sign of the need to evaluate the possibility of hidden adverse health conditions, including malignancies.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0078DOI Listing
October 2020

Environment-Wide Association Study of CKD.

Clin J Am Soc Nephrol 2020 06 22;15(6):766-775. Epub 2020 May 22.

Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea

Background And Objectives: Exposure to environmental chemicals has been recognized as one of the possible contributors to CKD. We aimed to identify environmental chemicals that are associated with CKD.

Design, Setting, Participants, & Measurements: We analyzed the data obtained from a total of 46,748 adults who participated in the National Health and Nutrition Examination Survey (1999-2016). Associations of chemicals measured in urine or blood (=262) with albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g), reduced eGFR (<60 ml/min per 1.73 m), and a composite of albuminuria or reduced eGFR were tested and validated using the environment-wide association study approach.

Results: Among 262 environmental chemicals, seven (3%) chemicals showed significant associations with increased risk of albuminuria, reduced eGFR, or the composite outcome. These chemicals included metals and other chemicals that have not previously been associated with CKD. Serum and urine cotinines, blood 2,5-dimethylfuran (a volatile organic compound), and blood cadmium were associated with albuminuria. Blood lead and cadmium were associated with reduced eGFR. Blood cadmium and lead and three volatile compounds (blood 2,5-dimethylfuran, blood furan, and urinary phenylglyoxylic acid) were associated with the composite outcome. A total of 23 chemicals, including serum perfluorooctanoic acid, seven urinary metals, three urinary arsenics, urinary nitrate and thiocyanate, three urinary polycyclic aromatic hydrocarbons, and seven volatile organic compounds, were associated with lower risks of one or more manifestations of CKD.

Conclusions: A number of chemicals were identified as potential risk factors for CKD among the general population.
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http://dx.doi.org/10.2215/CJN.06780619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274289PMC
June 2020

Prediction of the Mortality Risk in Peritoneal Dialysis Patients using Machine Learning Models: A Nation-wide Prospective Cohort in Korea.

Sci Rep 2020 05 4;10(1):7470. Epub 2020 May 4.

Department of Internal Medicine Seoul National University College of Medicine, Seoul, South Korea.

Herein, we aim to assess mortality risk prediction in peritoneal dialysis patients using machine-learning algorithms for proper prognosis prediction. A total of 1,730 peritoneal dialysis patients in the CRC for ESRD prospective cohort from 2008 to 2014 were enrolled in this study. Classification algorithms were used for prediction of N-year mortality including neural network. The survival hazard ratio was presented by machine-learning algorithms using survival statistics and was compared to conventional algorithms. A survival-tree algorithm presented the most accurate prediction model and outperformed a conventional method such as Cox regression (concordance index 0.769 vs 0.745). Among various survival decision-tree models, the modified Charlson Comorbidity index (mCCI) was selected as the best predictor of mortality. If peritoneal dialysis patients with high mCCI (>4) were aged ≥70.5 years old, the survival hazard ratio was predicted as 4.61 compared to the overall study population. Among the various algorithm using longitudinal data, the AUC value of logistic regression was augmented at 0.804. In addition, the deep neural network significantly improved performance to 0.841. We propose machine learning-based final model, mCCI and age were interrelated as notable risk factors for mortality in Korean peritoneal dialysis patients.
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http://dx.doi.org/10.1038/s41598-020-64184-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198502PMC
May 2020

Reduced risk for chronic kidney disease after recovery from metabolic syndrome: A nationwide population-based study.

Kidney Res Clin Pract 2020 Jun;39(2):180-191

Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.

Background: Metabolic syndrome (MetS) is linked to various chronic comorbidities, including chronic kidney disease (CKD). However, few large studies have addressed whether recovery from MetS is associated with reduction in the risks of such comorbidities.

Methods: This nationwide population-based study in Korea screened 10,664,268 people who received national health screening ≥ 3 times between 2012 and 2016. Those with a history of major cardiovascular events or preexisting CKD were excluded. We classified study groups into four, according to the course of MetS state, as defined by the harmonizing criteria. The main study outcome was incidental CKD (estimated glomerular filtration rate < 60 mL/min/1.73 m which was persistent until the last health exams). The study outcomes were investigated using multivariable logistic regression analysis, which was adjusted for clinical variables and the previous severity of MetS.

Results: Four study groups included 6,315,301 subjects: 4,537,869 people without MetS, 1,034,605 with chronic MetS, 438,287 who developed MetS, and 304,540 who recovered from preexisting MetS. Those who developed MetS demonstrated higher risk of CKD (adjusted odds ratio [OR], 1.26 [1.23-1.29]) than did those who did not develop MetS. In contrast, MetS-recovery was associated with decreased risk of CKD (adjusted OR, 0.84 [0.82-0.86]) than that in people with chronic MetS. Among the MetS components, change in hypertension was associated with the largest difference in CKD risk.

Conclusion: Reducing or preventing MetS may reduce the burden of CKD on a population-scale. Clinicians should consider the clinical importance of altering MetS status for risk of CKD.
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http://dx.doi.org/10.23876/j.krcp.20.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321670PMC
June 2020