Publications by authors named "Sehoon Park"

115 Publications

Association between early post-transplant hypertension or related antihypertensive use and prognosis of kidney transplant recipients: a nationwide observational study.

J Nephrol 2021 Sep 6. Epub 2021 Sep 6.

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

Background: Additional research is warranted for the clinical significance of post-transplant hypertension and related antihypertensive medication use in kidney transplant (KT) recipients.

Methods: This observational study included nationwide KT recipients who maintained a functioning graft for at least 1 year after KT in South Korea, observed between 2008 and 2017. The use of antihypertensive medications lasting between 6 months and 1 year was the main exposure, and those who had inconsistent/transient use of antihypertensive drugs were excluded. The prognostic outcome included death-censored graft failure (DCGF), death-with functioning graft (DWFG), and major adverse cerebrocardiovascular events (MACCEs).

Results: We included 8,014 patients without post-transplant hypertension and 6,114 recipients who received treatment for hypertension in the post-transplant period. Those with post-transplant hypertension had a significantly higher risk of DCGF than those without [adjusted hazard ratio (HR) 1.27 (1.09-1.48)]. Post-transplant hypertension patients who required multiple drugs showed a significantly higher risk of DWFG [HR 1.57 (1.17-2.10)] and MACCE [HR 1.35 (1.01-1.81)] than the controls. Among the single-agent users, those who received beta-blockers showed a significantly higher risk of DCGF, although the risks of DWFG or MACCE were similar between the types of antihypertensive agents. Among the multiple agent users, the prognosis was similar, regardless of the prescribed types of antihypertensive agents.

Conclusion: Post-transplant hypertension was associated with poor post-transplant prognosis, particularly when multiple types of medications were required for treatment. During initial prescription of antihypertensive medication, clinicians may consider that beta-blockers were associated with a higher risk of DCGF in the single-agent users.
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http://dx.doi.org/10.1007/s40620-021-01143-6DOI Listing
September 2021

Weak base-promoted selective rearrangement of oxaziridines to amides visible-light photoredox catalysis.

Chem Commun (Camb) 2021 Sep 6. Epub 2021 Sep 6.

Department of Chemistry, University of Ulsan, 93 Daehak-Ro, Nam-Gu, Ulsan 44610, Korea.

The selective rearrangement of oxaziridines to amides a single electron transfer (SET) pathway is unexplored. In this study, we present a weak base-promoted selective rearrangement of oxaziridines to amides visible-light photoredox catalysis. The developed method shows excellent functional group tolerance with a broad substrate scope and good to excellent yields. Furthermore, control experiments and density functional theory (DFT) calculations are performed to gain insight into the reactivity and selectivity.
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http://dx.doi.org/10.1039/d1cc03855aDOI Listing
September 2021

Statin initiation and all-cause mortality in incident statin-naïve dialysis patients.

Atherosclerosis 2021 Aug 17. Epub 2021 Aug 17.

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

Background And Aims: Cardiovascular disease is the main cause of death in end-stage kidney disease (ESKD) patients. We aimed to explore the association between statin initiation after starting dialysis and all-cause mortality in statin-naïve ESKD patients.

Methods: We analyzed nationwide claims data of incident dialysis patients from 2010 to 2017 in South Korea. Patients who had previous cardiovascular events or were administered statins before dialysis were excluded. The study group included dialysis patients receiving statins within 1 year after dialysis initiation. The control group was organized after propensity-score matching with age, sex, time of dialysis initiation, and underlying diabetes mellitus and hypertension. The main outcomes were all-cause mortality and major cardiovascular events.

Results: We included 1596 patients who started statin treatment and 1:1 matched statin-nonusers. During the 9438 person-year follow-up, 468 deaths and 264 major adverse cardiovascular events (MACEs) occurred. Statin initiation was associated with a reduced risk of all-cause mortality (adjusted hazard ratio (aHR) 0.72, 95% confidence interval (CI) 0.60-0.87, p = 0.001), but not with MACE incidence (aHR 1.06, 95% CI 0.83-1.36, p = 0.62). In particular, patients prescribed the recommended dosage of statins according to the Kidney Disease Improving Global Outcomes guidelines showed the lowest mortality risk (aHR 0.55, 95% CI 0.40-0.75, p < 0.001).

Conclusions: Statin initiation was associated with lower risk of all-cause mortality in statin-naïve ESKD patients. As indication bias may be present in observational study setting, further prospective studies are warranted to validate the association of statin initiation with mortality in incident dialysis cases.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.08.026DOI Listing
August 2021

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

J Hypertens 2021 Aug 20. Epub 2021 Aug 20.

Department of Internal Medicine, Seoul National University Hospital, Seoul Department of Statistics, Daegu University, Gyeongsan-si Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul Department of Internal Medicine, Seoul National University College of Medicine, Seoul Department of Internal Medicine, Keimyung University School of Medicine, Daegu Department of Biomedical Science, Seoul National University College of Medicine, Seoul Department of Internal Medicine, Armed Forces Capital Hospital, Seongnam-si Division of Mathematics and Big Data Science, Daegu University, Gyeongsan-si Kidney Research Institute, Seoul National University College of Medicine, Seoul Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, South Korea Department of Nephrology, Sheikh Khalifa Specialty Hospital, Ras Al Khaimah, UAE.

Background: Generalizing an 'optimal' blood pressure (BP) level for individuals with hypertension remains controversial due to the implementation of different medical guidelines. This study investigated the association of BP with major adverse cardiovascular and cerebrovascular events (MACCE) and determined the optimal BP for patients with hypertension.

Method: A total of 934 179 individuals who received antihypertensive medications were selected from the National Health Insurance Service Examination Database between 2003 and 2011 in Korea. Their BP was measured at the index date, which was the first health examination. The study outcomes were MACCE, including acute myocardial infarction, heart failure, stroke, and all-cause mortality. The participants were monitored until in December, 2017. The hazard ratios were calculated using Cox proportional hazard models. The cumulative incidence of MACCE for each BP group was estimated using the Kaplan-Meier method.

Results: A lower risk of MACCE was observed at a SBP of 120-129 mmHg and a DBP of 80-89 mmHg. The endpoint-specific incidence rates and hazard ratios for acute myocardial infarction, heart failure, stroke, and all-cause mortality were the lowest at a SBP of 120-129 mmHg and a DBP of 80-89 mmHg.

Conclusion: Even though this observational study did not support inference of a causal relationship, a SBP of 120-129 mmHg and a DBP of 80-89 mmHg may be safely recommended considering the possibility of MACCE in Korean patients with hypertension. In addition, the target BP should be tailored individually according to age, sex, and comorbidities.
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http://dx.doi.org/10.1097/HJH.0000000000002980DOI Listing
August 2021

Economic Impact of Donating a Kidney on Living Donors: A Korean Cohort Study.

Am J Kidney Dis 2021 Aug 19. Epub 2021 Aug 19.

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

Rationale & Objective: Although existing studies have reported adverse health outcomes following kidney donation, its socioeconomic impact on living donors requires further study.

Study Design: A retrospective observational cohort study including a matched comparison group.

Setting & Participants: 1,285 living kidney donors from seven tertiary hospitals between 2003 and 2016, and a matched comparison group consisting of the same number of health screening examinees with similar baseline clinical characteristics and socioeconomic status. All participants were receiving Korean national health insurance.

Exposures: Kidney donation as reflected in the Korean National Health Insurance System (NHIS) database.

Outcomes: Changes in household economic status estimated by Korean national health insurance fees and changes in employment status reflected in the NHIS database.

Analytical Approach: The outcomes of the donor group and matched control group were compared annually using multivariable logistic regression analyses adjusted for clinical and demographic characteristics.

Results: The median ages of the donors and matched controls were 45 and 46 years, respectively; 44.6% of both groups were male. Compared to the comparison group, living donors were at higher risk of being unemployed or losing employment during the first two years after donation [e.g., first-year loss of employment, odds ratio (OR) 2.27 (1.55-3.33)]; however, this association did not persist. Donors also had a significantly lower odds of improvement in economic status [OR 0.57 (0.47-0.71)] and a higher odds of deterioration in financial status [OR 1.54 (1.23-1.93)] in the first year following transplantation and subsequently.

Limitations: Unmeasured differences between donors and matched controls creating residual selection bias and confounding.

Conclusions: Living kidney donors may suffer loss of employment and poor economic status after their voluntary donation. The socioeconomic impact on these donors should be considered in conjunction with the potential long-term adverse health outcomes following donation.
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http://dx.doi.org/10.1053/j.ajkd.2021.07.009DOI Listing
August 2021

The Prognostic Significance of Body Mass Index and Metabolic Parameter Variabilities in Predialysis CKD: A Nationwide Observational Cohort Study.

J Am Soc Nephrol 2021 Aug 12. Epub 2021 Aug 12.

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

Background: The association between variabilities in body mass index (BMI) or metabolic parameters and prognosis of patients with CKD has rarely been studied.

Methods: In this retrospective observational study on the basis of South Korea's national health screening database, we identified individuals who received ≥3 health screenings, including those with persistent predialysis CKD (eGFR <60 ml/min per 1.73 m or dipstick albuminuria ≥1). The study exposure was variability in BMI or metabolic parameters until baseline assessment, calculated as the variation independent of the mean and stratified into quartiles (with Q4 the highest quartile and Q1 the lowest). We used Cox regression adjusted for various clinical characteristics to analyze risks of all-cause mortality and incident myocardial infarction, stroke, and KRT.

Results: The study included 84,636 patients with predialysis CKD. Comparing Q4 versus Q1, higher BMI variability was significantly associated with higher risks of all-cause mortality (hazard ratio [HR], 1.66; 95% confidence interval [95% CI], 1.53 to 1.81), [for trend] <0.001), KRT (HR, 1.20; 95% CI, 1.09 to 1.33; <0.001), myocardial infarction (HR, 1.19; 95% CI, 1.05 to 1.36, =0.003), and stroke (HR, 1.19; 95% CI, 1.07 to 1.33, =0.01). The results were similar in the subgroups divided according to positive or negative trends in BMI during the exposure assessment period. Variabilities in certain metabolic syndrome components (., fasting blood glucose) also were significantly associated with prognosis of patients with predialysis CKD. Those with a higher number of metabolic syndrome components with high variability had a worse prognosis.

Conclusions: Higher variabilities in BMI and certain metabolic syndrome components are significantly associated with a worse prognosis in patients with predialysis CKD.
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http://dx.doi.org/10.1681/ASN.2020121694DOI Listing
August 2021

Predictive value of triglyceride/high-density lipoprotein cholesterol for major clinical outcomes in advanced chronic kidney disease: a nationwide population-based study.

Clin Kidney J 2021 Aug 25;14(8):1961-1968. Epub 2020 Dec 25.

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

Background: Dyslipidemia is an essential parameter in the prediction of cardiovascular disease (CVD). We aimed to explore whether lipid profiles could predict major outcomes in patients with advanced chronic kidney disease (CKD).

Methods: We retrospectively reviewed the National Health Insurance Service database for people who received nationwide health screening in 2009. All subjects exposed to a lipid-lowering agent before screening were excluded. The population was divided into control, early [estimated glomerular filtration rate (eGFR) 45-59 mL/min/1.73 m] and advanced (eGFR <45 mL/min/1.73 m) CKD groups. The hazard ratios (HRs) of outcomes were calculated using multivariate Cox regression models.

Results: A total of 3 634 873 participants were included in this study, with 404 298 (11.1%) and 66 805 (1.8%) having early and advanced CKD, respectively. For all populations, levels of triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) showed a linear association with major cardiovascular and cerebrovascular events (MACCEs) and all-cause mortality, while low-density lipoprotein cholesterol (LDL-C) showed a different pattern of association with MACCEs (linear association) from all-cause mortality (U-shaped association). The significance between the levels of LDL-C and outcomes was attenuated in the advanced CKD group. For TG/HDL-C, although the significance was decreased, the linear patterns with both MACCEs and all-cause mortality were maintained in the advanced CKD group.

Conclusions: The pattern and significance of lipid profiles were different according to the grade of kidney function. TG/HDL-C should be additionally considered as a predictive marker for CVD and mortality along with LDL-C in patients with CKD.
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http://dx.doi.org/10.1093/ckj/sfaa252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323149PMC
August 2021

Causal effects of education on chronic kidney disease: a Mendelian randomization study.

Clin Kidney J 2021 Aug 22;14(8):1932-1938. Epub 2020 Dec 22.

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

Background: Poor socio-economic status, including low education attainment, has been reported in chronic kidney disease (CKD) patients. We aimed to investigate the causal effects of education attainment on the risk of CKD.

Methods: The study was an observational cohort study including Mendelian randomization (MR) analysis. First, the clinical association between education attainment years as the exposure and prevalent CKD Stages 3-5 as the outcome was investigated by multivariable logistic regression in 308 741 individuals 40-69 years of age from the UK Biobank. MR analysis was performed with a previously reported genetic instrument from a genome-wide association meta-analysis of education attainment. Two-sample MR was performed with summary statistics for CKD in 567 460 individuals with European ancestry in the CKDGen genome-wide association meta-analysis. The findings were replicated by allele score-based MR in 321 260 individuals of white British ancestry in the UK Biobank with quality-controlled genetic data.

Results: Higher education attainment was significantly associated with lower adjusted odds for CKD in the clinical analysis {>17 years versus <16 years, adjusted odds ratio [OR] 0.910 [95% confidence interval (CI) 0.849-0.975]}. The causal estimates obtained by the inverse variance method in the two-sample MR indicated that higher genetically predicted education attainment causally reduced the risk of CKD [OR 0.934 (95% CI 0.873-0.999)]. Allele score-based MR also supported that higher education attainment was causally linked to a decreased risk of CKD [adjusted OR 0.944 (95% CI 0.922-0.966)].

Conclusion: The study suggests that higher education attainment causally reduces the risk of CKD development in the general population.
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http://dx.doi.org/10.1093/ckj/sfaa240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323131PMC
August 2021

A Mendelian randomization study found causal linkage between telomere attrition and chronic kidney disease.

Kidney Int 2021 Jul 30. Epub 2021 Jul 30.

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

Chronic kidney disease (CKD) is highly prevalent in the elderly population. However, it is rarely investigated whether kidney function is causally linked to biological aging itself. In this Mendelian randomization study, genetic instruments for telomere attrition were applied to a CKDGen genome wide association study results for 41,395 cases of CKD among 480,698 individuals as summary-level Mendelian randomization. A replicative analysis was performed by polygenic score analysis using independent United Kingdom Biobank data for 8,118 cases of CKD among 321,024 white individuals of British ancestry. Reverse-direction Mendelian randomization analysis was performed utilizing genetic instruments for log-estimated glomerular filtration rate change with Z-standardized telomere length outcome data for 326,075 participants in the UK Biobank. Genetic predisposition toward telomere attrition (one Z score decrease in length) was found to be a causative factor for a higher CKD risk [Odds Ratio 1.20 (95% confidence interval 1.08‒1.33)], as supported by pleiotropy-robust Mendelian randomization sensitivity analyses implemented using the CKDGen data. Based on United Kingdom Biobank data, the polygenic score for telomere attrition was significantly associated with a higher risk of CKD [1.20 (1.04‒1.39)]. In reverse-direction Mendelian randomization, the genetically predicted kidney function decrease was significantly associated with a higher degree of telomere attrition [beta 0.039 (0.009‒0.069)]. Thus, our study supports the causal linkage between telomere attrition and kidney function impairment.
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http://dx.doi.org/10.1016/j.kint.2021.06.041DOI Listing
July 2021

Causal linkage between adult height and kidney function: An integrated population-scale observational analysis and Mendelian randomization study.

PLoS One 2021 29;16(7):e0254649. Epub 2021 Jul 29.

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

As adult height is linked to various health outcomes, further investigation of its causal effects on kidney function later in life is warranted. This study involved a cross-sectional observational analysis and summary-level Mendelian randomization (MR) analysis. First, the observational association between height and estimated GFR determined by creatinine (eGFRcreatinine) or cystatin C (eGFRcystatinC) was investigated in 467,182 individuals aged 40-69 using UK Biobank. Second, the genetic instrument for adult height, as reported by the GIANT consortium, was implemented, and summary-level MR of eGFRcreatinine and CKDcreatinine in a CKDGen genome-wide association study was performed (N = 567,460), with multivariable MR being adjusted for the effects of genetic predisposition on body mass index. To replicate the findings, additional two-sample MR using the summary statistics of eGFRcystatinC and CKDcystatinC in UK Biobank was performed (N = 321,405). In observational analysis, adult height was inversely associated with both eGFRcreatinine (per 1 SD, adjusted beta -1.039, standard error 0.129, P < 0.001) and eGFRcystatinC (adjusted beta -1.769, standard error 0.161, P < 0.001) in a multivariable model adjusted for clinicodemographic, anthropometric, metabolic, and social factors. Moreover, multivariable summary-level MR showed that a taller genetically predicted adult height was causally linked to a lower log-eGFRcreatinine (adjusted beta -0.007, standard error 0.001, P < 0.001) and a higher risk of CKDcreatinine (adjusted beta 0.083, standard error 0.019, P < 0.001). Other pleiotropy-robust sensitivity MR analysis results supported the findings. In addition, similar results were obtained by two-sample MR of eGFRcystatinC (adjusted beta -1.303, standard error 0.140, P < 0.001) and CKDcystatinC (adjusted beta 0.153, standard error 0.025, P < 0.001) in UK Biobank. In conclusion, the results of this study suggest that a taller adult height is causally linked to worse kidney function in middle-aged to elderly individuals, independent of the effect of body mass index.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0254649PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321232PMC
July 2021

Detection of Aberrant Glycosylation of Serum Haptoglobin for Gastric Cancer Diagnosis Using a Middle-Up-Down Glycoproteome Platform.

J Pers Med 2021 Jun 18;11(6). Epub 2021 Jun 18.

Asia-Pacific Glycomics Reference Site, Chungnam National University, Daejeon 34134, Korea.

Gastric cancer is a frequently occurring cancer and is the leading cause of cancer-related deaths. Recent studies have shown that aberrant glycosylation of serum haptoglobin is closely related to gastric cancer and has enormous potential for use in diagnosis. However, there is no platform with high reliability and high reproducibility to comprehensively analyze haptoglobin glycosylation covering microheterogeneity to macroheterogeneity for clinical applications. In this study, we developed a middle-up-down glycoproteome platform for fast and accurate monitoring of haptoglobin glycosylation. This platform utilizes an online purification of LC for sample desalting, and an in silico haptoglobin glycopeptide library constructed by combining peptides and N-glycans to readily identify glycopeptides. In addition, site-specific glycosylation with glycan heterogeneity can be obtained through only a single MS analysis. Haptoglobin glycosylation in clinical samples consisting of healthy controls ( = 47) and gastric cancer patients ( = 43) was extensively investigated using three groups of tryptic glycopeptides: GP1 (including Asn184), GP2 (including Asn207 and Asn211), and GP3 (including Asn241). A total of 23 individual glycopeptides were determined as potential biomarkers ( < 0.00001). In addition, to improve diagnostic efficacy, we derived representative group biomarkers with high AUC values (0.929 to 0.977) through logistic regression analysis for each GP group. It has been found that glycosylation of haptoglobin is highly associated with gastric cancer, especially the glycosite Asn241. Our assay not only allows to quickly and easily obtain information on glycosylation heterogeneity of a target glycoprotein but also makes it an efficient tool for biomarker discovery and clinical diagnosis.
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http://dx.doi.org/10.3390/jpm11060575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235735PMC
June 2021

reversible tuning of chemical interface damping in single gold nanorod-based recyclable platforms through manipulation of supramolecular host-guest interactions.

Chem Sci 2021 Apr 15;12(20):7115-7124. Epub 2021 Apr 15.

Department of Chemistry, University of Ulsan 93 Daehak-ro, Nam-gu Ulsan 44610 Republic of Korea +82 52 712 8002 +82 52 712 8012.

Recently, chemical interface damping (CID) has been proposed as a new plasmon damping pathway based on interfacial hot-electron transfer from metal to adsorbate molecules. It has been considered essential, owing to its potential implications in efficient photochemical processes and sensing experiments. However, thus far, studies focusing on controlling CID in single gold nanoparticles have been very limited, and reversible tuning has remained a considerable challenge. In these scanning electron microscopy-correlated dark-field spectroscopic measurements and density functional theory calculations, cucurbit[7]uril (CB[7])-based host-guest supramolecular interactions were employed to examine and control the CID process using monoamine-functionalized CB[7] (CB[7]-NH) attached to single gold nanorods (AuNRs). tuning of CID through the CB[7]-oxaliplatin complexation, which can result in the variation of the chemical nature and electronic properties of adsorbates, was presented. In addition, tuning of CID was demonstrated through the competitive release of the oxaliplatin guest from the [email protected][7] complex, which was then replaced by a competitor guest of spermine in sufficient amounts. Furthermore, nuclear magnetic resonance experiments confirmed that the release of the guest is the consequence of adding salt (NaCl). Thus, reversible tuning of CID in single AuNRs was achieved through successive steps of encapsulation and release of the guest on the same AuNR in a flow cell. Finally, single CB[7][email protected] were presented as a recyclable platform for CID investigations after the complete release of guest molecules from their host-guest inclusion complexes. Therefore, this study has paved a new route to achieve reversible tuning of CID in the same AuNR and to investigate the CID process using CB-based host-guest chemistry with various guest molecules in single AuNRs for efficient hot-electron photochemistry and biosensing applications.
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http://dx.doi.org/10.1039/d1sc01204eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157306PMC
April 2021

Increasing prescription of renin-angiotensin-aldosterone system blockers associated with improved kidney prognosis in Korean IgA nephropathy patients.

Clin Kidney J 2021 Jun 11;14(6):1673-1680. Epub 2020 Dec 11.

Korean GlomeruloNEphritis sTudy (KoGNET) Group, Korean Society of Nephrology, Seoul, Korea.

Background: We aimed to describe the characteristics of immunoglobulin A nephropathy (IgAN) in Korea with assessment for time trends.

Methods: We performed a multicenter retrospective observational cohort study including biopsy-confirmed native IgAN cases from four tertiary hospitals in Korea. Time eras of diagnosis were stratified into 1979-2003, 2004-9 and 2010-17. The prognostic variable was progression to end-stage kidney disease (ESKD) analyzed by multivariable Cox regression analysis.

Results: We included 1366 (from 1979 to 2003), 1636 (from 2004 to 2009) and 1442 (from 2010 to 2017) IgAN patients in this study. In the recent periods, IgAN had relatively better clinical characteristics, as patients had higher estimated glomerular filtration rates and lower baseline blood pressures than before. The use of renin-angiotensin-aldosterone system (RAAS) blockers increased from 57.7% in 1979-2003 to 80.0% in 2010-17. During a median follow-up duration of 11.3 years, 722 patients progressed to ESKD with an incidence rate of 12.5 per 1000 person-years. The 10-year risk of progression to ESKD was lower in 2010-17 compared with that of 1979-2003 [adjusted hazard ratio 0.692 (95% confidence interval 0.523-0.915)], even after adjustment for multiple clinicopathologic characteristics. The use of RAAS blockers was a significant mediator (P < 0.001) for the association between time trends and lower 10-year ESKD risk.

Conclusions: Clinicopathologic characteristics of IgAN in Korea have changed over time. Although the limitation of a retrospective observational study remains, the result showed that the prognosis of IgAN has improved over the study period, possibly related to increased prescription of RAAS blockers.
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http://dx.doi.org/10.1093/ckj/sfaa204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162855PMC
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 Jun 20;40(2):282-293. 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237113PMC
June 2021

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

Eur Heart J 2021 07;42(29):2816-2823

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
July 2021

Incident Parkinson's disease in kidney transplantation recipients: a nationwide population-based cohort study in Korea.

Sci Rep 2021 May 18;11(1):10541. Epub 2021 May 18.

Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea.

This nation-wide population based retrospective cohort study evaluated risk of incident Parkinson' disease in kidney transplant (KT) recipients in Korea. From Korean National Health Insurance Service database, we identified incident KT recipients aged ≥ 40 years without any history of Parkinson's disease between 2007 and 2015. We established two control cohorts without a history of Parkinson' disease: (1) General population (GP) cohort of insured subjects without a history of kidney disease, (2) end-stage renal disease (ESRD) cohort of incident ESRD subjects, with frequency matched for age, sex, and inclusion year. Parkinson's disease data were obtained from baseline until December 2017. We followed 8372 KT recipients, ESRD patients, and GP for 45,723, 38,357, and 47,476 patient-years, respectively. Their mean age was 51.2 years and 60.1% were men. During follow-up period, 19 KT recipients, 53 ESRD patients, and 15 GP developed Parkinson' disease. Risk of incident Parkinson's disease in KT recipients was similar to that in GP (adjusted hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.35 to 2.13, P = 0.75) and significantly lower than that in ESRD patients (adjusted HR 0.31, 95% CI 0.18 to 0.52, P < 0.001). Older age was the strongest predictor for incident Parkinson's disease in KT recipients.
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http://dx.doi.org/10.1038/s41598-021-90130-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131700PMC
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 06 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

Risk of active tuberculosis infection in kidney transplantation recipients: A matched comparative nationwide cohort study.

Am J Transplant 2021 May 3. Epub 2021 May 3.

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

Large-scale evidence comparing the risk of Mycobacterium tuberculosis (TB) between kidney transplant (KT) recipients and dialysis patients is warranted. This is a nationwide retrospective cohort study based on the claims database of South Korea where a moderate prevalence of TB is reported. We included incident KT recipients from 2011 to 2015 and compared their active TB risks with 1:1 matched dialysis and general population control groups, respectively. The risk of incident active TB was assessed by multivariable Cox regression. Associations between active TB and posttransplant death or death-censored graft failure were investigated. The number of matched subjects included in each of the study groups was 7462. The KT group showed a significantly higher risk of active TB than the general population group (hazard ratio [HR] 3.39 [1.88-6.10]), whereas it showed a similar risk to that of the dialysis group (HR 0.98 [0.73-1.31]). In KT patients, active TB was a significant risk factor for both death (HR 2.33 [1.24-4.39]) and death-censored graft failure (HR 2.26 [1.39-3.67]). Although KT recipients may not have to burden the additional risk of active TB when compared with dialysis patients in recent medicine, active TB should not be overlooked as it is associated with a worse prognosis in posttransplant patients.
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http://dx.doi.org/10.1111/ajt.16627DOI Listing
May 2021

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

Nutrients 2021 Apr 28;13(5). Epub 2021 Apr 28.

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

We aimed to investigate the causal effects of n-3 and n-6 polyunsaturated fatty acids (PUFAs) on the risk of coronary artery disease (CAD) through Mendelian randomization (MR) analysis. This MR study utilized a genetic instrument developed from previous genome-wide association studies for various serum n-3 and n-6 PUFA levels. First, we calculated the allele scores for genetic predisposition of PUFAs in individuals of European ancestry in the UK Biobank data ( = 337,129). The allele score-based MR was obtained by regressing the allele scores to CAD risks. Second, summary-level MR was performed with the CARDIoGRAMplusC4D data for CAD ( = 184,305). Higher genetically predicted eicosapentaenoic acid and dihomo-gamma-linolenic acid levels were significantly associated with a lower risk of CAD both in the allele-score-based and summary-level MR analyses. Higher allele scores for linoleic acid level were significantly associated with lower CAD risks, and in the summary-level MR, the causal estimates by the pleiotropy-robust MR methods also indicated that higher linoleic acid levels cause a lower risk of CAD. Arachidonic acid showed significant causal estimates for a higher risk of CAD. This study supports the causal effects of certain n-3 and n-6 PUFA types on the risk of CAD.
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http://dx.doi.org/10.3390/nu13051490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145894PMC
April 2021

Comparative DFT Study on Dehydrogenative C(sp)-H Elementation (E = Si, Ge, and Sn) of Terminal Alkynes Catalyzed by a Cationic Ruthenium(II) Thiolate Complex.

Inorg Chem 2021 May 14;60(9):6228-6238. Epub 2021 Apr 14.

Department of Chemistry and Key Laboratory for Preparation and Application of Ordered Structural Materials of Guangdong Province, Shantou University, Shantou, Guangdong 515063, P. R. China.

Described herein is a comparative theoretical study of dehydrogenative C(sp)-H functionalizations of a terminal alkyne with group-14-based hydrides (HEEt; E = Si, Ge, Sn) catalyzed by an Ohki-Tatsumi complex-a cationic Ru(II) complex with a tethered thiolate ligand ([Ru-S] = [(DmpS)Ru(PPr)][BAr]; Dmp = 2,6-(dimesityl)CH; Ar = 3,5-(CF)CH). The calculations indicate that the energy barriers for heterolytic cleavage of the H-EEt bonds at the Ru-S sites of the Ohki-Tatsumi complex highly vary depending on the group 14 elements from 3.8 kcal/mol (E = Sn) to 10.5 kcal/mol (E = Ge) and 18.5 kcal/mol (E = Si), where Ru and S elements cooperatively serve as the Lewis acid and base, respectively. Likewise, the transfer of the group 14 cation (EtE) to the C-C triple bond to generate the β-element-stabilized vinyl cations-the rate-determining step (RDS) of the overall reaction-is predicted to be susceptible to the element's identity [ = 36.8 for Sn < 42.9 and Ge < 50.7 for Si (kcal/mol)]. The key transition states involved in the RDS are compared in terms of energy and structure within each system of the group 14 hydrides. The distortion/interaction-activation strain (DIAS) model analysis of the transition states responsible for dehydrogenative stannylation and hydrostannation of a terminal alkyne sheds light on the origin of the experimentally observed kinetic preference toward dehydrogenative C-H stannylation over hydrostannation.
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http://dx.doi.org/10.1021/acs.inorgchem.0c03695DOI Listing
May 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259638PMC
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 05;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

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

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 Sep 5;107(18):1472-1479. 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
September 2021

Structural analysis of RIG-I-like receptors reveals ancient rules of engagement between diverse RNA helicases and TRIM ubiquitin ligases.

Mol Cell 2021 02 28;81(3):599-613.e8. Epub 2020 Dec 28.

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address:

RNA helicases and E3 ubiquitin ligases mediate many critical functions in cells, but their actions have largely been studied in distinct biological contexts. Here, we uncover evolutionarily conserved rules of engagement between RNA helicases and tripartite motif (TRIM) E3 ligases that lead to their functional coordination in vertebrate innate immunity. Using cryoelectron microscopy and biochemistry, we show that RIG-I-like receptors (RLRs), viral RNA receptors with helicase domains, interact with their cognate TRIM/TRIM-like E3 ligases through similar epitopes in the helicase domains. Their interactions are avidity driven, restricting the actions of TRIM/TRIM-like proteins and consequent immune activation to RLR multimers. Mass spectrometry and phylogeny-guided biochemical analyses further reveal that similar rules of engagement may apply to diverse RNA helicases and TRIM/TRIM-like proteins. Our analyses suggest not only conserved substrates for TRIM proteins but also, unexpectedly, deep evolutionary connections between TRIM proteins and RNA helicases, linking ubiquitin and RNA biology throughout animal evolution.
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http://dx.doi.org/10.1016/j.molcel.2020.11.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183676PMC
February 2021
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