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Background: Several studies have reported that depression is prevalent in patients with diabetes or chronic kidney disease. However, the relationship between weight changes and the risk of depression has not been elucidated in patients with diabetic kidney disease (DKD)., Methods: From the Korean National Health Insurance Service database, we selected 67,866 patients with DKD and body weight data from two consecutive health examinations with a 2-year interval between 2009 and 2012. Weight change over 2 years was categorized into five groups: ≥-10%, <-10% to ≥-5%, <-5% to <5%, ≥5% to <10%, and ≥10%. The occurrence of depression was monitored via the codes of International Statistical Classification of Diseases, 10th revision through the end of 2018., Results: During the 5.24-year follow-up, 17,023 patients with DKD developed depression. Weight change and the risk of depression had a U-shaped relationship: patients with ≥-10% weight change (hazard ratio [HR], 1.12) and those with ≥10% weight change (HR, 1.11) showed higher HRs for depression than those with <-5% to <5% weight change, even after adjusting for several confounding factors. In the subgroup analyses, the risk of depression tended to increase as weight gain or weight loss increased in all subgroups., Conclusion: Both weight loss and weight gain increased the risk of depression in patients with DKD.

To investigate whether high serum triglycerides (TG) level is associated with adverse renal outcomes in patients with non-dialysis chronic kidney disease (CKD), a total of 2,158 subjects from a prospective cohort study (Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease) were divided into the quartile by serum TG level. The primary outcomes were composite renal events, which is defined as a composite of decline of kidney function (the first occurrence of > 50% decline of estimated glomerular filtration rate or doubling of serum creatinine from the baseline) or onset of end-stage renal disease (initiation of dialysis or kidney transplantation). During the median follow-up of 6.940 years, the cumulative incidence of composite renal event was significantly differed by serum TG level in Kaplan-Meier curve analysis (P < 0.001, by Log-rank test). Cox regression analysis demonstrated that, compared to that of the 1st quartile, the risk of composite renal event was significantly higher in the 4th quartile (adjusted hazard ratio 1.433, 95% confidence interval 1.046 to 1.964). The association between high serum TG level and adverse renal outcome remained consistent in the cause-specific hazard model. Subgroup analyses revealed that the association is modified by age, estimated glomerular filtration rate, and spot urine albumin-to-creatinine ratio. In conclusion, high serum TG level is independently associated with adverse renal outcomes in patients with non-dialysis CKD. Interventional studies are warranted to determine whether lowering serum TG levels may alter the natural course of CKD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Suh, Oh, Choi, Kim, Bae, Oh, Han, Ma and Kim.)

Hollow-fiber membranes are widely used in various fields of membrane processes because of their numerous properties, e.g., large surface area, high packing density, mass production with uniform quality, obvious end-of-life indicators, and so on. However, it is difficult to control the pores and internal properties of hollow-fiber membranes due to their inherent structure: a hollow inside surrounded by a wall membrane. Herein, we aimed to control pores and the internal structure of hollow-fiber membranes by fabricating a dual layer using a dual nozzle. Two different pore formers, polyethylene glycol (PEG) and polyvinyl pyrrolidone (PVP), were separately prepared in the dope solutions and used for spinning the dual layer. Our results show that nanoscale pores could be formed on the lumen side (26.8-33.2 nm), and the open pores continuously increased in size toward the shell side. Due to robust pore structure, our fabricated membrane exhibited a remarkable water permeability of 296.2 ± 5.7 L/m 2 ·h·bar and an extremely low BSA loss rate of 0.06 ± 0.02%, i.e., a high BSA retention of 99.94%. In consideration of these properties, the studied membranes are well-suited for use in either water treatment or hemodialysis. Overall, our membranes could be considered for the latter application with a high urea clearance of 257.6 mL/min, which is comparable with commercial membranes.

As the relation between serum non-high-density lipoprotein cholesterol (nHDL) level and renal outcomes has never been investigated in patients with non-dialysis chronic kidney disease (CKD) yet, we here aimed to unveil the association of nHDL with CKD progression. A total of 2152 patients with non-dialysis CKD at stages 1 to 5 from the KNOW-CKD study were categorized into the tertile (i.e., 1st (T1), 2nd (T2), and 3rd (T3) tertiles) by nHDL, and were prospectively analyzed. The primary outcome was the composite renal event, defined as a composite of decline of kidney function or onset of end-stage renal disease. Kaplan-Meier survival curves analysis demonstrated that the cumulative incidence of the composite renal event was significantly increased in T1 and T3, compared to T2 ( p = 0.028, by Log-rank test). Cox regression analysis revealed that both T1 (adjusted hazard ratio 1.309, 95% confidence interval 1.074-1.595) and T3 (adjusted hazard ratio 1.272, 95% confidence interval 1.040-1.556) are associated with significantly increased risk of a composite renal event, compared to T2. The restricted cubic spline plot demonstrated a non-linear, U-shaped association between nHDL and the risk of a composite renal event. In conclusion, both low and high serum nHDL levels are associated with increased risk of CKD progression.

As non-high-density lipoprotein cholesterol (non-HDL-C) levels account for all atherogenic lipoproteins, serum non-HDL-C level has been suggested to be a marker for cardiovascular (CV) risk stratification. Therefore, to unveil the association of serum non-HDL-C levels with CV outcomes in patients with non-dialysis chronic kidney disease (ND-CKD), the patients at stages 1 to 5 ( n = 2152) from the Korean Cohort Study for Outcomes in Patients with Chronic Kidney Disease (KNOW-CKD) were prospectively analyzed. The subjects were divided into quintiles by serum non-HDL-C level. The primary outcome was a composite of all-cause death or non-fatal CV events. The median duration of follow-up was 6.940 years. The analysis using the Cox proportional hazard model unveiled that the composite CV event was significantly increased in the 5th quintile (adjusted hazard ratio 2.162, 95% confidence interval 1.174 to 3.981), compared to that of the 3rd quintile. A fully adjusted cubic spline model depicted a non-linear, J-shaped association between non-HDL-C and the risk of a composite CV event. The association remained robust in a series of sensitivity analyses, including the analysis of a cause-specific hazard model. Subgroup analyses reveled that the association is not significantly altered by clinical conditions, including age, gender, body mass index, estimated glomerular filtration rate, and albuminuria. In conclusion, high serum non-HDL-C level increased the risk of adverse CV outcomes among the patients with ND-CKD. Further studies are warranted to define the optimal target range of non-HDL-C levels in this population.

Background: Recent hypertension guidelines have recommended lower blood pressure (BP) targets in high-risk patients. However, there are no specific guidelines based on age or systolic and diastolic blood pressure (SBP and DBP, respectively). We aimed to assess the effects of age-related BP on development of end-stage renal disease (ESRD) in patients with diabetes., Methods: A total of 2 563 870 patients with diabetes aged >20 years were selected from the Korean National Health Screening Program from 2009 to 2012 and followed up until the end of 2019. Participants were categorized into age and BP groups, and the hazard ratios for ESRD were calculated., Results: During a median follow-up of 7.15 years, the incidence rates of ESRD increased with increasing SBP and DBP. The hazard ratio for ESRD was the highest in patients younger than 40 years of age with DBP≥100 mm Hg. The effect of SBP and DBP on ESRD development was attenuated with age (interaction P was <0.0001 for age and SBP, and 0.0022 for age and DBP). The subgroup analysis for sex, antihypertension medication, and history of chronic kidney disease showed higher hazard ratios for ESRD among males, younger than 40 years, not taking antihypertension medications and chronic kidney disease compared to those among females, older than 40 years, antihypertension medication, and nonchronic kidney disease groups., Conclusions: Higher SBP and DBP increase the risk of developing ESRD in patients with diabetes, and in particular, younger individuals face greater risk. Therefore, intensive BP management is warranted in younger patients to prevent ESRD.

The side effects of cisplatin, a widely used chemotherapeutic agent, include nephrotoxicity. Previous studies have reported that cisplatin induces ferroptosis and lipid peroxide accumulation. Ferroptosis, a type of regulated cell death, is characterized by iron-dependent lipid peroxidation. Although previous studies have examined the regulation of ferroptosis in acute kidney injury (AKI), the regulatory mechanism of ferroptosis has not been elucidated. Here, the ability of activated farnesoid X receptor (FXR) to attenuate cisplatin-induced AKI through the regulation of ferroptosis was examined. FXR deficiency exhibited more ferroptosis responses, such as increase in lipid peroxidation, iron content and heme oxygenase 1 protein, and a decrease in glutathione/glutathione disulfide ratio and glutathione peroxidase 4 levels in HK2 cells and mice. Increased blood urea nitrogen, serum creatinine, and ferroptotic responses in the cisplatin-induced AKI mouse model were mitigated upon treatment with the FXR agonist GW4064 but were exacerbated in FXR knockout mice. RNA sequencing analysis revealed that ferroptosis-associated genes were novel targets of FXR. FXR agonist upregulated the expression of lipid and glutathione metabolism-related genes and downregulated cell death-related genes. Additionally, chromatin immunoprecipitation assays, using mice renal tissues, revealed that agonist-activated FXR could bind to its known target genes (Slc51a, Slc51b, Osgin1, and Mafg) and ferroptosis-related genes (Aifm2, Ggt6, and Gsta4). Furthermore, activated FXR-dependent MAFG, a transcriptional repressor, could bind to Hmox1, Nqo1, and Tf in the renal tissues of FXR agonist-treated mice. These findings indicate that activated FXR regulates the transcription of ferroptosis-related genes and protects against cisplatin-induced AKI., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The increased risk of fracture has been associated with weight loss in patients with diabetes or chronic kidney disease. However, the relationship between weight changes over time and fracture risk in patients with diabetic kidney disease is still unknown., Methods: A total number of 78,922 patients with diabetic kidney disease, aged ≥ 40 years, were selected using the Korean National Health Insurance Service database, between 2009 and 2012. They were followed up until the end of 2018. Weight change was defined as the difference in body weight from the index year to 2 years later. Weight changes were then divided into five categories, ranging from weight loss of ≥10% to weight gain of ≥10%., Results: Fractures were identified in 9,847 patients with diabetic kidney disease, over a median follow-up of 5.2 years. The risk of composite fracture of the vertebral, hip, or other sites increased as the weight change increased. Specifically, patients with ≥10% weight loss (hazard ratio [HR], 1.286; 95% confidence interval [CI], 1.184-1.398) and ≥10% weight gain (HR, 1.198; 95% CI, 1.080-1.330) showed a higher HR compared to those with ≤ 5% weight change after adjusting for several confounding factors. Higher HR of vertebral and hip fractures was also seen with increased weight loss or gain. In particular, patients with ≥10% weight loss showed the highest HR for hip fractures (HR, 1.738; 95% CI, 1.489-2.028)., Conclusions: Both weight loss and weight gain increase the risk of fracture in patients with diabetic kidney disease. Therefore, patients with diabetic kidney disease who experience weight changes should be made aware of the risk of fracture., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kim, Choi, Bae, Ma, Kim, Han and Kim.)

Background/aims: The obesity paradox has been known in end-stage renal disease (ESRD). However, the effect of body mass index (BMI) or waist circumference (WC) prior to percutaneous coronary intervention (PCI) on the development of ESRD is not clear., Methods: Using nationally representative data from the Korean National Health Insurance System, we enrolled 140,164 subjects without ESRD at enrolment who underwent PCI between 2010 and 2015, and were followed-up until 2017. Patients were stratified into five levels based on their baseline BMI and six levels based on their WC with 5-cm increments. BMI and WC were measured at least 2 years prior to PCI. The primary outcome was the development of ESRD., Results: During a median follow-up of 5.4 years, 2,082 (1.49%) participants developed ESRD. The underweight group (hazard ratio [HR], 1.331; 95% confidence interval [CI], 0.955 to 1.856) and low WC (< 80/< 75) (HR, 1.589; 95% CI, 1.379 to 1.831) showed the highest ESRD risk and the BMI 25 to 30 group showed the lowest ESRD risk (HR, 0.604; 95% CI, 0542 to 0.673) in all participants after adjusting for all covariates. In the subgroup analysis for diabetes mellitus (DM) duration, WC < 85/80 cm (men/women) increased ESRD risk in only the DM group (DM < 5 years and DM ≥ 5 years) compared to the reference group (85-90/80-85 of WC), but not the normal or impaired fasting glucose group., Conclusion: Low WC prior to PCI showed an increased ESRD risk in patients with DM undergoing PCI as compared to those without DM.

Background: The impact of left ventricular (LV) geometry on the renal outcomes in patients with chronic kidney disease (CKD) has not been established yet. We aimed to investigate the association of LV geometry with renal outcomes and all-cause mortality in patients with pre-dialysis CKD., Methods: A total of 2,144 subjects from the Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD) were categorized by LV geometry, which was defined by LV mass index and relative wall thickness [normal geometry, concentric remodeling, eccentric hypertrophy (eLVH), and concentric hypertrophy (cLVH)]. Study outcomes were composite renal events [decline of kidney function (the first occurrence of > 50% decline of eGFR or doubling of serum creatinine from the baseline) and onset of ESRD (initiation of dialysis or kidney transplantation) during follow-up periods)] and all-cause mortality., Results: Cox regression analysis revealed that eLVH [adjusted hazard ratio (HR) 1.498, 95% confidence interval (CI) 1.197-1.873] and cLVH (adjusted HR 1.289, 95% CI 1.011-1.643) were associated with increased risk of composite renal events, whereas concentric remodeling (adjusted HR 1.881, 95% CI 1.135-3.118) and cLVH (adjusted HR 2.216, 95% CI 1.341-3.664) were associated with increased risk of all-cause mortality. Sensitivity analyses confirmed that concentric remodeling (adjusted HR 1.993, 95% CI 1.197-3.368) and eLVH (adjusted HR 1.588, 95% CI 1.261-2.001) are independently associated with all-cause mortality and composite renal events, respectively., Conclusion: In conclusion, we report that LV geometry is significantly associated with adverse renal outcomes and all-cause mortality in patients with pre-dialysis CKD. Echocardiographic determination of LV geometry may help the early identification for the patients with high risk of CKD progression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Suh, Oh, Choi, Kim, Bae, Oh, Lee, Jung, Lee, Ma and Kim.)

Inflammation and apoptosis are the major contributors to the mechanisms of acute kidney injury (AKI) due to renal ischemia-reperfusion injury (IRI). Maslinic acid (MA), a pentacyclic triterpene acid mostly found in dietary plants, the current study was to demonstrate the renoprotective effect of MA on IRI-induced AKI, and to investigate the role of inflammation and apoptosis-related signaling pathways as a molecular mechanism. C57BL/6J mice were subjected to IRI for 72 h, and MA was daily administered by intraperitoneal injection during this period. In parallel, rat renal proximal tubule cells (NRK52E) were prophylactically treated with MA and then exposed to hydrogen peroxide (H 2 O 2 ). MA treatment significantly inhibited the mRNA expression of interleukin (IL-1β), tumor necrosis factor-α (TGF-α), monocyte chemoattractant protein-1 (MCP-1), and intercellular adhesion molecule-1(ICAM-1). Also, MA reduced the expression of Bax/Bcl2 ratio and cleaved caspase-3. In NRK52 cells, MA inhibited the IκBα degradation, blocked NF-κB/p65 phosphorylation, and nuclear translocation. The phosphorylation of ERK, JNK, and p38 was attenuated by MA in IRI-induced kidney injury and H 2 O 2 -stimulated NRK52 cells. The expression levels of IL-1β, MCP-1, and ICAM-1 were upregulated in H 2 O 2 -stimulated NRK52E cells, which was attenuated by NF-κB inhibitor. H 2 O 2 treatment increased the Bax/Bcl2 ratio and cleaved caspase-3 in NRK52E cells, which was counteracted by MAPK inhibitors. Together, our data demonstrate that MA suppresses IR-induced AKI injury through NF-κB and MAPK signaling pathways and that MA is a promising agent in the treatment of kidney diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sun, Choi, Kim, Bae, Ma and Kim.)

Rationale & Objective: Reduced kidney function is associated with an increased risk of cancer; however, it is unclear if cancer increases the risk of kidney failure with replacement therapy (KFRT). We assessed the risk of KFRT among patients with various types of cancer collectively and with specific types of cancer., Study Design: Retrospective population-based cohort study., Setting & Participants: A total of 2,473,095 participants with (n = 824,365) or without (n = 1,648,730) cancer registered in the Korean National Health Insurance Service database., Predictors: Cancer and cancer subtypes defined using International Classification of Diseases, 10th Revision, Clinical Modification, codes., Outcomes: Primary outcome was KFRT defined as the initiation of hemodialysis or peritoneal dialysis or kidney transplantation., Analytical Approach: For each patient with cancer, 2 controls matched for age, sex, estimated glomerular filtration rate, diabetes, and hypertension were included. To address the competing risk of death, a competing risk survival analysis was conducted using the Fine and Gray method., Results: Occurrence of KFRT was higher in patients with cancer than in controls without cancer (incidence rates of 1.07 vs 0.51 cases per 1,000 person-years). Competing risk analysis showed that cancer was significantly associated with an increased risk of KFRT after adjusting for other potential predictors (adjusted hazard ratio, 2.29 [95% CI, 2.20-2.39]). Multiple myeloma, leukemia, lymphoma, and kidney, ovarian, and liver cancer were most significantly associated with an increased KFRT risk, with multiple myeloma conferring the highest risk across age and sex groups. All subgroups of patients with cancer (based on age, sex, smoking, alcohol, exercise, obesity, and comorbid conditions) exhibited a higher risk of KFRT., Limitations: Causal association between cancer and kidney outcomes could not be confirmed., Conclusions: Patients with cancer, particularly those with multiple myeloma, exhibited an increased risk of KFRT after accounting for the competing risk of death., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The impact of left ventricular diastolic dysfunction (LVDD) on cardiovascular (CV) outcomes in patients with pre-dialysis chronic kidney disease (CKD) has been rarely unveiled. We here investigated the association of LVDD with CV outcomes and all-cause mortality in patients with pre-dialysis CKD., Methods: A total of 2,135 patients with pre-dialysis CKD from the Korean Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD) cohort were dichotomized by the absence or presence of LVDD, which was defined as the ratio of the early transmitral blood flow velocity to early diastolic velocity of the mitral annulus ( E / e ') > 14., Results: Cox regression analysis revealed that LVDD was significantly associated with increased risk of composite CV events [adjusted hazard ratio (HR) 2.194, 95% confidence interval (CI) 1.486-3.240] and all-cause mortality (adjusted HR 1.830, 95% CI 1.168-2.869). Restricted cubic splines visualized stringent linear correlations of E / e ' with both composite CV events and all-cause mortality. In the sensitivity analysis only including the subjects with left ventricular ejection fraction ≥ 50%, LVDD was still significantly associated with adverse CV outcomes (adjusted HR 1.984, 95% CI 1.325-3.000) and all-cause mortality (adjusted HR 1.727, 95% CI 1.083-2.754), suggesting that the impact of LVDD on the outcomes in patients with CKD is independent of LV systolic function. Subgroup analyses revealed that the associations were not modified by various clinical contexts, such as age, sex, burden of comorbid conditions, body mass index, estimated glomerular filtration rate, and albuminuria., Conclusion: LVDD is independently associated with adverse CV outcomes and all-cause mortality in patients with pre-dialysis CKD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Suh, Oh, Choi, Kim, Bae, Oh, Choi, Oh, Ma and Kim.)

Background: Osteoprotegerin is an important regulator of bone metabolism and vascular calcification. The association between serum osteoprotegerin level and chronic kidney disease (CKD) progression has not been elucidated. We investigated the prognostic value of serum osteoprotegerin levels in nondialysis CKD patients., Methods: We analyzed 2,082 patients enrolled in the Korean Cohort Study for Outcomes in Patients with CKD between 2011 and 2016. Patients were divided into quartiles by their serum osteoprotegerin levels. The primary outcome was the occurrence of ≥1 of the following: dialysis initiation, kidney transplantation, a two-fold increase in serum creatinine level from baseline, or a 50% decrease in the estimated glomerular filtration rate (eGFR). Cox proportional hazard regression models were used to investigate the prognostic value of the serum osteoprotegerin level to CKD progression., Results: The median follow-up period was 48.9 months, and 641 patients (30.8%) experienced the primary outcome. The hazard ratio of serum osteoprotegerin for renal progression in the full extended Cox proportional hazard model was 1.064 (95% confidence interval, 1.041-1.088). Subgroup analyses by age, presence of diabetes, and eGFR showed significant results consistent with the overall analysis results., Conclusion: Serum osteoprotegerin level is independently associated with renal prognosis and could have prognostic importance in CKD progression.

Background: We investigated whether high body weight variability (BWV) is associated with a higher prevalence of coronary artery calcification (CAC) or more rapid progression of CAC in patients with predialysis chronic kidney disease (CKD)., Methods: A total of 1,162 subjects from a nationwide prospective cohort of predialysis CKD were analyzed. The subjects were divided into the tertile (T1, T2, and T3) by BWV. CAC was assessed at the baseline and a 4-year follow-up by CT scan. Rapid progression of coronary artery calcification was defined as an increase in coronary artery calcium score (CACS) more than 200 Agatston units during a 4-year follow-up., Results: One-way ANOVA revealed that CACS change during the follow-up period is significantly higher in the subjects with high BWV, although CACS at the baseline and 4-year follow-up was not different among the tertile groups by BWV. Logistic regression analysis revealed that compared to low BWV (T1), both moderate (T2, adjusted odds ratio (OR) 2.118, 95% CI 1.075-4.175) and high (T3, adjusted OR 2.602, 95% CI 1.304-5.191) BWV was associated with significantly increased risk of rapid progression of CAC. Importantly, the association between BWV and progression of CAC remained robust even among the subjects without significant BW gain or loss during follow-up periods (T2, adjusted OR 2.007, 95% CI 1.011-3.984; T3, adjusted OR 2.054, 95% CI 1.003-4.207)., Conclusion: High BWV is independently associated with rapid progression of CAC in patients with predialysis CKD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Suh, Oh, Choi, Kim, Bae, Oh, Lee, Han, Sung, Ma and Kim.)

Background: Serum adiponectin level predicts cardiovascular (CV) outcomes and progression of coronary artery calcification (CAC) in the general population, although the association has not been validated in patients with chronic kidney disease (CKD). In this study, we investigated the association of high serum adiponectin level with the risk of adverse CV outcomes and progression of CAC in patients with pre-dialysis CKD. Methods: A total of 1,127 patients with pre-dialysis CKD from a nationwide prospective cohort of patients with pre-dialysis CKD in Korea were divided into the tertile by serum adiponectin level at the baseline. CV outcome of interest was fatal and non-fatal CV events and all-cause mortality. Progression of CAC was defined as coronary artery calcium score (CACS) change more than 200 during a 4-year follow-up. Results: Cox regression analysis revealed that high serum adiponectin is associated with increased risk of fatal and non-fatal CV events (adjusted hazard ratio 2.799, 95% CI 1.348-5.811). In contrast, high serum adiponectin level was not significantly associated with all-cause mortality (adjusted hazard ratio 0.655, 95% CI 0.203-2.113). Binary logistic regression analysis revealed that high serum adiponectin level is also associated with increased risk of progression of CAC (adjusted odds ratio [OR] 2.078, 95% CI 1.014-4.260). Subgroup analyses demonstrated that the association of high serum adiponectin with increased risk of fatal and non-fatal CV events is not modified by age, gender, history of diabetes, estimated glomerular filtration rate (eGFR), or spot urine albumin-to-creatinine ratio (ACR). Conclusions: High serum adiponectin level is associated with adverse CV outcomes and progression of CAC in patients with pre-dialysis CKD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Suh, Oh, Choi, Kim, Lee, Oh, Jung, Lee, Oh, Ma, Bae and Kim.)

Background/aims: Hypertension is considered a risk factor in immunoglobulin A nephropathy (IgAN). However, after IgAN diagnosis, the relationship between early blood pressure control and renal prognosis remains unclear. This study aimed to analyze the association between the prognosis of IgAN patients and a controlled status of hypertension within the first year of IgAN diagnosis., Methods: We retrospectively analyzed 2,945 patients diagnosed with IgAN by renal biopsy. The patients were divided into 'normal,' 'new-onset,' 'well-controlled,' and 'poorly-controlled' groups using blood pressure data from two consecutive measurements performed within a year. The Kaplan-Meier survival analysis and Cox proportional-hazards regression model were used to survey the independent association between recovery from hypertension and the risk of IgAN progression. The primary endpoint was IgAN progression defined as the initiation of dialysis or kidney transplantation., Results: Before IgAN diagnosis, 1,239 patients (42.1%) had been diagnosed with hypertension. In the fully adjusted Cox proportional-hazards models, the risk of IgAN progression increased by approximately 1.7-fold for the prevalence of hypertension. In the subgroup analyses, the 'well-controlled' group showed a statistically significant risk of IgAN progression (hazard ratio [HR], 3.19; 95% confidence interval [CI], 1.103 to 9.245; p = 0.032). Moreover, the 'new-onset' and 'poorly-controlled' groups had an increased risk of IgAN progression compared to the 'normal' group (HR, 2.58; 95% CI, 1.016 to 6.545; p = 0.046 and HR, 3.85;95% CI, 1.541 to 9.603; p = 0.004, respectively)., Conclusion: Although hypertension was well-controlled in the first year after IgAN diagnosis, it remained a risk factor for IgAN progression.

Circulating osteoprotegerin (OPG) is a biomarker for cardiovascular complications that are closely related to chronic kidney disease (CKD). To investigate the association between circulating OPG level with long-term visit-to-visit blood pressure variability (BPV) in patients with pre-dialysis CKD, a total of 1855 subjects with CKD from stage 1 to pre-dialysis stage 5 from a prospective cohort were analyzed. Long-term visit-to-visit BPV was determined by average real variability (ARV), standard deviation (SD), and coefficient of variation (CoV) of systolic and diastolic blood pressure (SBP and DBP). ARV of SBP (Adjusted β coefficient 0.143, 95% confidence interval 0.021 to 0.264) was significantly associated with serum OPG level. Although SD and CoV of SBP were not significantly associated with serum OPG level in multivariate linear regression analyses, restricted cubic spline visualized the linear correlation of serum OPG level with all of ARV, SD, and CoV. The association between serum OPG level and DBP variability was not significant. Subgroup analyses revealed that the association of serum OPG with BPV is more prominent in the subjects with Charlson comorbidity index ≤3 and in the subjects without history of diabetes mellitus. In conclusion, circulating OPG level is potentially associated with long-term visit-to-visit BPV in patients with pre-dialysis CKD.

Weight variability has known as a risk factor for cardiovascular events and mortality. However, its effect on end-stage renal disease (ESRD) development remains controversial. We investigated the relationship between weight change and ESRD risk. Overall, 97,029 patients with DM aged >20 years were selected from the Korean National Health Screening Program 2009-2012. Weight change was defined as differences in body weight from the index year to 2 years later. Newly diagnosed ESRD was observed until 2017 end. Over a 5.1-year median follow-up period, ESRD was newly diagnosed in 7932 (4.81%) DM patients. BMI < 18.5 kg/m 2 and waist circumferences <85/80 and >100/95 cm were ESRD risk factors. ESRD risk increased with increasing weight change; ≥10% weight loss (hazard ratio [HR], 1.247) followed by ≥10% weight gain (1.247) was associated with a higher HR than ≤5% weight change after adjusting for several confounding factors. The association between weight change and ESRD risk in a subgroup analysis was significantly stronger in patients aged <65 years, without proteinuria, with BMI ≥ 25, with DM duration <5 years, and prescribed less than 3 classes of DM medication. Underweight patients showed higher ESRD risks than overweight patients. Weight loss >10% was associated with the fastest decline in renal function.

Hypertension is the leading risk factor for end-stage renal disease (ESRD). However, the association between sustained exposure to increased blood pressure (BP) and ESRD is not well established. This study investigated whether the cumulative hypertension burden is a substantial risk factor for ESRD. The incidence of ESRD among 2,144,801 participants identified from the Korean National Health Insurance Service database who had documented BP assessment data in their annual health check-up data from between 2006 and 2010, was determined. Over a median follow-up of 7.2 years, ESRD was identified in 1758 participants. Hypertension burden was defined as the cumulative exposure to hypertension (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg) during four consecutive follow-up periods and ranged from 0 to 4. The hypertension burden was as follows: 0 (n = 1,164,488), 77.6%; 1 (n = 292,377), 13.6%; 2 (n = 114,397), 5.3%; 3 (n = 52,671), 2.5%; and 4 (n = 20,886), 1.0%. Compared to the hypertension burden of 0, the adjusted hazard ratio for ESRD was 1.35, 1.54, 1.51, and 2.28 for hypertension burdens of 1, 2, 3, and 4, respectively. A positive dose-dependent relationship between hypertension burden and ESRD was found (P for interaction < 0.001). This association was maintained for sustained exposure to both systolic and diastolic hypertension burden. In conclusion, hypertension burden increases the risk of ESRD. Our study underlines the usefulness of a new assessment of the hypertension burden over a certain period for predicting the risk of ESRD in a large population-based cohort., (© 2021. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Background: Minimal change disease (MCD) is one of the most common causes of nephrotic syndrome worldwide. Hyperuricemia increases the end-stage renal disease (ESRD) risk in glomerulonephritis. In this study, we aimed to determine the effect of high serum uric acid levels on the progression to ESRD in MCD., Methods: A total of 800 patients diagnosed with MCD by kidney biopsy were retrospectively analyzed. We determined the relationship of hyperuricemia with the progression to ESRD in MCD using the Cox proportional hazard model and Kaplan-Meier survival analysis. The primary outcome was defined as the initiation of dialysis or kidney transplantation., Results: A total of 42 patients (5.3%) progressed to ESRD during the follow-up period. In the restricted cubic spline curve, serum uric acid levels exhibited a positive correlation with ESRD progression in patients with MCD. In the fully adjusted model, the risk of MCD progression increased by 29% for every 1 mg/dL increase in the baseline serum uric acid level (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.09-1.54; p = 0.004). Falling into the high uric acid group (serum uric acid level > 7 mg/dL in men and > 6 mg/dL in women) was also a risk factor for progression of MCD to ESRD (HR, 3.40; 95% CI, 1.59-7.31; p < 0.001)., Conclusion: Our study shows that hyperuricemia is an independent risk factor for the progression to ESRD in patients with MCD.

Background: Hypertension is the most important modifiable risk factor for mortality and morbidity in chronic kidney disease and coronary artery syndrome. The effect of hypertension prior to percutaneous coronary intervention (PCI) on the development of end-stage renal disease (ESRD) is unknown., Methods: We used nationally representative data from the Korean National Health Insurance System-140,164 subjects were enrolled during 2010-2015; they were free of ESRD at enrolment, underwent PCI, and were followed up until 2017. Blood pressure (BP) was measured within at least 2 years prior to PCI. The primary outcome was the development of ESRD., Results: During a median follow-up of 5.4 years, 2,082 participants (1.5%) developed ESRD. The highest systolic BP group (>160 mmHg) showed a higher hazard ratio (3.69; 95% confidence interval, 2.61-5.23) than the reference group (110-119 mmHg). Similar results were observed in the highest diastolic BP group (>120 mmHg), which showed a higher hazard ratio than the reference group (70-79 mmHg). However, ESRD risk showed a J-shaped relationship with baseline systolic and diastolic BP at 113 and 74 mmHg in diabetes mellitus subgroup, respectively, after adjustment for potential confounders., Conclusion: Our study showed that a high systolic or diastolic BP prior to PCI was independently associated with an increased incidence of ESRD.

Background: Although anastomosing hemangiomas are very rare and benign vascular neoplasms, these tumors are more common among patients with end-stage kidney disease. Incidental finding of these tumors in the kidney or adrenal gland has been reported. Herein, we describe a case in which an anastomosing hemangioma was misdiagnosed as a renal cell carcinoma before kidney transplant., Case Presentation: A 35-year-old woman with lupus nephritis was admitted to our emergency department for suspected uremic symptoms of nausea and general weakness. She had received hemodialysis due to end-stage kidney disease, and a living-donor kidney transplantation from her father was planned. On pre-operative contrast-enhanced computed tomography and magnetic resonance imaging, a 1.7 cm renal cell carcinoma was observed in the right kidney. On staining after radical nephrectomy, irregularly shaped vascular spaces of various sizes were observed, with these spaces having an anastomosing pattern. As the findings of the anastomosing hemangioma are similar to those of a renal cell carcinoma on imaging, histology examination was necessary to confirm the diagnosis of anastomosing hemangioma and to prevent delay in listing for kidney transplantation. Good kidney function was achieved after transplantation, with no tumor recurrence., Conclusion: Our case underlines the importance for prompt surgical resection of an enhancing renal mass to confirm diagnosis in patients scheduled for kidney transplantation to avoid any delay., (© 2021. The Author(s).)

Background/aims: This study aimed to investigate whether urinary angiotensinogen (UAGT) excretion was associated with elevated blood pressure in patients with chronic kidney disease (CKD) and to evaluate the relationship among blood pressure, intra-renal renin-angiotensin system (RAS) activity, and dietary sodium in patients with CKD., Methods: Participants from the Korean Cohort Study for Outcome in Patients with Chronic Kidney Disease (KNOW-CKD) were included. Of the total cohort of 2,238 individuals with CKD, we included 1,955 participants who underwent complete 24-hour urinary sodium (24-hour UNa) analysis. They were categorized into three groups according to three tertiles of their 24-hour UNa, reflecting daily salt intake. To measure intra-renal RAS activity, the UAGT excretion was assayed with an enzyme-linked immunosorbent assay., Results: Elevated 24-hour UNa levels, logarithm of UAGT-to-creatinine ratio (UAGT/Cr), increased waist-to-hip ratio, and decreased estimated glomerular filtration rate were the risk factors for increased systolic blood pressure. Systolic blood pressure showed a positive correlation with 24-hour UNa levels and logarithm of UAGT/Cr., Conclusion: UAGT and urinary sodium excretion are independent determinants of systolic blood pressure in patients with CKD. These findings suggest that increased systolic blood pressure in CKD patients is associated with both increased dietary sodium levels and intra-renal RAS activity. The risk of elevated systolic blood pressure in the 3rd tertile of both the UAGT/Cr and 24-hour UNa groups was about 2.3 times higher than that in the reference group.

Background: Recently, we developed hydrophobically modified glycol chitosan (HGC) nanomicelles loaded with tacrolimus (TAC) (HGC-TAC) for the targeted renal delivery of TAC. Herein, we determined whether the administration of the HGC-TAC nanomicelles decreases kidney injury in a model of lupus nephritis. Lupus-prone female MRL/lpr mice were randomly assigned into three groups that received intravenous administration of either vehicle control, an equivalent dose of TAC, or HGC-TAC (0.5 mg/kg TAC) weekly for 8 weeks. Age-matched MRL/MpJ mice without Fas lpr mutation were also treated with HGC vehicle and used as healthy controls., Results: Weekly intravenous treatment with HGC-TAC significantly reduced genetically attributable lupus activity in lupus nephritis-positive mice. In addition, HGC-TAC treatment mitigated renal dysfunction, proteinuria, and histological injury, including glomerular proliferative lesions and tubulointerstitial infiltration. Furthermore, HGC-TAC treatment reduced renal inflammation and inflammatory gene expression and ameliorated increased apoptosis and glomerular fibrosis. Moreover, HGC-TAC administration regulated renal injury via the TGF-β1/MAPK/NF-κB signaling pathway. These renoprotective effects of HGC-TAC treatment were more potent in lupus mice compared to those of TAC treatment alone., Conclusion: Our study indicates that weekly treatment with the HGC-TAC nanomicelles reduces kidney injury resulting from lupus nephritis by preventing inflammation, fibrosis, and apoptosis. This advantage of a new therapeutic modality using kidney-targeted HGC-TAC nanocarriers may improve drug adherence and provide treatment efficacy in lupus nephritis mice.

Background Hypertension among young adults is common. However, the effect of isolated systolic hypertension (ISH), isolated diastolic hypertension (IDH), or systolic and diastolic hypertension (SDH) among young adults on chronic kidney disease (CKD) development is unknown. Methods and Results From a nationwide health screening database, we included 3 030 884 participants aged 20 to 39 years who were not taking antihypertensives at baseline examination in 2009 to 2010. Participants were categorized as having normal blood pressure (BP), elevated BP, stage 1 IDH, stage 1 ISH, stage 1 SDH, stage 2 IDH, stage 2 ISH, and stage 2 SDH. The primary outcome was incident CKD. A total of 5853 (0.19%) CKD events occurred. With normal BP as the reference, multivariable-adjusted hazard ratios (HRs) (95% CIs) for CKD were 1.14 (95% CI, 1.04-1.26), elevated BP; 1.19 (95% CI, 1.10-1.28), stage 1 IDH; 1.24 (95% CI, 1.08-1.42), stage 1 ISH; 1.39 (95% CI, 1.28-1.51), stage 1 SDH; 1.88 (95% CI, 1.63-2.16), stage 2 IDH; 1.84 (95% CI, 1.54-2.19), stage 2 ISH; 2.70 (95% CI, 2.44-2.98), stage 2 SDH. The HRs for CKD were attenuated in the patients who were antihypertensive and began medication within 1 year of medical checkup than in those without antihypertensives. Conclusions Among Korean young adults, those with elevated BP, stage 1 IDH, stage 1 ISH, stage 1 SDH, stage 2 IDH, stage 2 ISH, and stage 2 SDH were associated with a higher CKD risk than those with normal BP. The CKD risk in ISH and IDH groups was similar but lower than that in the SDH group. Antihypertensives attenuated the risk of CKD in young adults with hypertension.

Abstract: Data on the overall epidemiology and temporal trends of end-stage renal disease (ESRD) requiring hemodialysis in Korea are scarce. We aimed to estimate the prevalence and incidence of ESRD requiring hemodialysis in Korea between 2002 and 2017.Using the National Health Insurance Service database, we analyzed data from the entire Korean population between 2002 and 2017. Hemodialysis patients were identified using rare incurable disease codes (V001) or prescription of medical fee codes of hemodialysis (O7020 and O7021). We only included patients who had been maintained on hemodialysis for more than 90 days from the date of dialysis initiation, to exclude patients who required short-term dialysis for acute kidney injury, conversion to peritoneal dialysis, or kidney transplantation.During the 16-year follow-up, the number of hemodialysis patients in Korea has steadily increased from 11,215 in 2002 to 67,486 in 2017. The mean age of these patients has gradually increased from 55.57 ± 13.31 years in 2002 to 62.13 ± 13.23 years in 2017. In 2017, the crude prevalence rate of hemodialysis was 1303.4 per million population. Overall, the number of men tended to be somewhat higher than that of women, and the proportion of men increased slightly from 55.56% in 2002 to 58.45% in 2017. The proportion of diabetic patients increased rapidly from 23.84% to 47.84%, and the percentage of dyslipidemic patients rose from 18.9% to 86.7%. The number of incident hemodialysis patients increased significantly from 4406 in 2003 to 12,134 in 2014, and then decreased to 8090 in 2017. In the incident cases of hemodialysis, the observed increase in the proportion of male patients and in diabetes and dyslipidemia were similar to that of prevalent patients. The more recent era of hemodialysis initiation, the better 5-year survival rates were observed.The prevalence and incidence of hemodialysis in Korea gradually increased between 2002 and 2017. The proportion of men, and patients with diabetes and dyslipidemia requiring hemodialysis also increased continuously. The survival rate of hemodialysis patients was gradually improving. These findings may serve as a reference for future epidemiological studies on hemodialysis in Korea., Competing Interests: The authors have no conflict of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Autophagy is important for cells to break down and recycle cellular proteins, remove damaged organelles, and especially, for recovery from acute kidney injury (AKI). Despite research on the role and cellular mechanism of autophagy in AKI, the role of autophagy in the progression to chronic kidney disease (CKD) remains poorly understood. Here, using farnesoid X receptor (FXR) knockout (KO) mice, we determined whether FXR prevents the progression of AKI to CKD after renal ischemic-reperfusion (such as I/R) injury through the regulation of renal autophagy and apoptosis. FXR regulated genes that participate in renal autophagy under feeding and fasting conditions, such as hepatic autophagy, and the activation of FXR by agonists, such as GW4064 and INT-747, attenuated the increased autophagy and apoptosis of hypoxia-induced human renal proximal tubule epithelial (HK2) cells. The expression levels of autophagy-related and apoptosis-related proteins in FXR KO mice were increased compared with those in wild-type (WT) mice. We also showed that the increase in reactive oxidative species (ROS) in hypoxia-treated HK2 cells was attenuated by treatment with FXR agonist or by FXR overexpression, and that the level of ROS was elevated in FXR-deficient cells and mice. At 28 days after I/R injury, the autophagy levels were still elevated in FXR KO mice, and the expression levels of fibrosis-related proteins and ROS deposits were higher than those in WT mice. In conclusion, the regulation of renal autophagy and apoptosis by FXR may be a therapeutic target for the early stages of kidney damage, and the progression of AKI to CKD.

Background/aims: Despite recent improvements in the quality of life of patients with systemic lupus erythematosus (SLE), osteoporosis, and osteoporotic fractures are one of the major complications of SLE. Furthermore, limited data are available on the incidence and predictor of osteoporotic fractures in Korean patients with SLE. Herein, we aimed to assess the incidence and risk factors for osteoporotic fractures in Korean SLE patients compared to those without SLE., Methods: SLE patients aged ≥ 40 years (n = 10,434; mean age, 51.3 ± 9.1 years; women, 89.7%) were selected from the Korean National Health Insurance Service database, spanning a period from 2008 to 2014. Age- and sex-matched controls (n = 52,170) were randomly sampled in a 5:1 ratio from non-SLE individuals. The primary outcome was the first occurrence of osteoporotic fracture., Results: The incidence of osteoporotic fractures was significantly higher in the SLE patients (19.085 per 1,000 person-years) than in matched controls (6.530 per 1,000 person-years). According to the multivariable Cox proportional analysis, patients with SLE exhibited a higher osteoporotic fracture rate than the control group (hazards ratio, 2.964; 95% confidence interval, 2.754 to 3.188), even after adjustment for confounding variables. In the subgroup analysis, male SLE patients or SLE patients aged 40 to 65 years were associated with a higher osteoporotic fracture rate than women SLE patients or SLE patients aged ≥ 65 years, respectively., Conclusion: We found a 2.964-fold increased risk of osteoporotic fracture in SLE patients compared to age- and sex-matched non-SLE controls. Male or middle-aged SLE patients had a relatively higher fracture risk among patients with SLE.

We report the case of a patient with nephrotic syndrome and toxic epidermal necrolysis (TEN) caused by statin use. The associated hyperlipidemia was controlled using proprotein convertase subtilisin/ kexin type 9 (PCSK9) inhibitors. This is a unique case of treating hyperlipidemia with PCSK9 inhibitor in patient with nephrotic syndrome with TEN. A 54-year-old woman was admitted owing to generalized edema. She had massive proteinuria and was diagnosed with minimal change disease through kidney biopsy. Statins were used for treatment of hyperlipidemia associated with nephrotic syndrome; however, she developed a skin rash, which progressed to TEN. After discontinuation of statins, her skin symptoms improved; however, hyperlipidemia persisted. Because statins could not be administered, we injected evolocumab, a PCSK9 inhibitor, every 2 weeks. Since then, hyperlipidemia has been well controlled without any side effects. Thus, PCSK9 inhibitors may be a good alternative to control hyperlipidemia in patients with statin intolerance or serious side effects.

Data regarding health behavior-related factors and systolic or diastolic blood pressure to evaluate the association between blood pressure and kidney cancer are lacking. Using nationally representative data from the Korean National Health Insurance System, 9 746 445 participants without kidney cancer between January 1, 2006 and December 31, 2009 were followed up until December 31, 2017 to obtain data regarding cancer incidence. Participants were categorized, according to blood pressure, as normal (<120/80 mm Hg), elevated (120-129/<80 mm Hg), and hypertensive (≥130/80 mm Hg) with or without antihypertensive medication, according to the 2017 American College of Cardiology and American Heart Association blood pressure guidelines. Kidney cancer was noted in 11 083 participants during the 8-year follow-up. Participants with hypertension were at higher risk for kidney cancer than those without hypertension. Participants with hypertension using medication had a higher cancer risk than those not using medication and those with elevated blood pressure. The risk of kidney cancer significantly increased with higher systolic or diastolic blood pressure, in a dose-dependent manner, even after adjusting for antihypertensive medication use. Therefore, hypertension and high systolic or diastolic blood pressure, compared with normal blood pressure, were associated with an increased risk of kidney cancer.

Prolongation of the QT interval by antiarrhythmic drugs is the primary cause of torsade de pointes. Although there are previous reports of drug-induced torsade de pointes in patients undergoing hemodialysis, torsade de pointes caused by a sudden decrease of potassium levels in patients initiating hemodialysis has not been well described. A 70-year-old woman with recurrent bilateral gluteal abscesses visited the hospital for antibiotic treatment. Twenty-eight days after admission, atrial fibrillation with rapid ventricular rhythm was newly detected and was controlled with intravenous amiodarone treatment. After developing pulmonary edema that did not improve with diuretic treatment, she underwent emergency hemodialysis. During hemodialysis, serum potassium and magnesium levels decreased to 3.1 and 1.7 mg/dL, respectively. The electrocardiogram showed torsade de pointes. Amiodarone treatment was stopped, and magnesium sulfate was infused. A higher concentration of potassium dialysate was used in continuous renal replacement therapy. Torsade de pointes episodes halted, and QT interval prolongation normalized. We describe a case with a rare complication of torsade de pointes upon initiating hemodialysis in a patient with QT prolongation. When initiating hemodialysis, serum potassium levels as well as electrocardiograms should be monitored in patients with a prolonged QT interval.

Background/aims: The aim of this study was to evaluate the trend of incidence and prevalence of systemic lupus erythematosus (SLE) in South Korea from 2005 to 2015., Methods: From 2005 to 2015, individuals with SLE were identified from the National Health Insurance database, which records information on almost all Koreans. SLE was defined according to the International Classification of Diseases, 10th revision (ICD-10), code M32. The incidence was calculated per 100,000 person-years. The prevalence was calculated per 100,000 people and stratified by year, age group, sex, region, and income., Results: The annual prevalence of SLE increased slightly from 21.25/100,000 people in 2005 to 35.45/100,000 people in 2015. In contrast, the annual incidence of SLE decreased slightly from 5.42/100,000 person-years in 2005 to 3.6/100,000 person-years in 2015. The prevalence and incidence of SLE were 10- and 6-fold higher in women than in men, respectively. The peak age of prevalence and incidence was 30 to 39 years in 2005; in 2015, the peak age of prevalence was 30 to 49 years and of incidence was 20 to 49 years. Regional variation was observed in both incidence and prevalence of SLE. Jeju province showed the highest prevalence of SLE (44.54/100,000 person-years), and Gwangju province showed the highest incidence of SLE (6.98/100,000 person-years) in 2015. The income status did not affect the prevalence or incidence of SLE except in patients without income who received medical aid., Conclusion: The incidence of SLE has declined, but the prevalence has increased in Korea in recent years. Peak age of SLE trend to right shift in Korea.

Angiotensin-[1-7] (Ang-[1-7]) antagonize the actions of the renin-angiotensin-system via the Mas receptor and thereby exert renoprotective effects. Murine recombinant angiotensin-converting enzyme (ACE)2 was reported to show renoprotective effects in an experimental Alport syndrome model; however, the protective effect of direct administration of Ang-[1-7] is unknown. Here, we used Col4a3 -/- mice as a model of Alport syndrome, which were treated with saline or Ang- [1-7]; saline-treated wild-type mice were used as a control group. The mice were continuously infused with saline or Ang-[1-7] (25 μg/kg/h) using osmotic mini-pumps. Col4a3 -/- mice showed increased α-smooth muscle actin (SMA), collagen, and fibronectin expression levels, which were attenuated by Ang-[1-7] treatment. Moreover, Ang-[1-7] alleviated activation of transforming growth factor-β/Smad signaling, and attenuated the protein expression of ED-1 and heme oxygenase-1, indicating reduction of renal inflammation. Ang-[1-7] treatment further reduced the expression levels of inflammatory cytokines and adhesion molecules and attenuated apoptosis in human kidney cells. Finally, Ang-[1-7] downregulated TNF-α converting enzyme and upregulated ACE2 expression. Thus, treatment with Ang-[1-7] altered the ACE2-Ang-[1-7]-Mas receptor axis in the kidneys of Col4a3 -/- mice to attenuate the nephropathy progression of Alport syndrome.

Objective: The predictors of poor prognosis in heat stroke (HS) remain unknown. This study investigated the predictive factors of poor prognosis in patients with HS., Methods: Data were obtained and analyzed from the health records of patients diagnosed with heat illness at Ajou university hospital between January 2008 and December 2017. Univariate and multivariate analyses were performed to identify the independent predictors of poor prognosis., Results: Thirty-six patients (median age, 54.5 years; 33 men) were included in the study. Poor prognosis was identified in 27.8% of the study population (10 patients). The levels of S100B protein, troponin I, creatinine, alanine aminotransferase, and serum lactate were statistically significant in the univariate analysis. Multiple regression analysis revealed that poor prognosis was significantly associated with an increased S100B protein level (odds ratio, 177.37; 95% confidence interval, 2.59 to 12,143.80; P=0.016). The S100B protein cut-off level for predicting poor prognosis was 0.610 μg/L (area under the curve, 0.906; 95% confidence interval, 0.00 to 1.00), with 86% sensitivity and 86% specificity., Conclusion: An increased S100B protein level on emergency department admission is an independent prognostic factor of poor prognosis in patients with HS. Elevation of the S100B protein level represents a potential target for specific and prompt therapies in these patients.

Objectives: Cardiac involvement is present in more than half of the patients with systemic lupus erythematosus (SLE). However, large-scale studies on the prevalence of atrial fibrillation (AF) in this disease do not exist. We aimed to investigate the incidence and clinical significance of AF in SLE., Methods: Patients with SLE (n=21,143; mean age, 41.8±13.13 years; female, 90.38%) without previous AF were selected from the Korean National Health Insurance Service National Sample Cohort database between 2008 and 2014. Age-and sex-matched controls (n=105,715) were randomly sampled in a 5:1 ratio from the population of individuals without SLE from the same database. Both cohorts were followed-up for incidental AF and death until 2015., Results: AF was newly detected in 481 (2.27%) patients with SLE and 619 (0.59%) controls (incidence: 3.692 and 0.941 per 1000 person-years, respectively). After multivariate adjustment, SLE was found to be a risk factor for developing AF [hazard ratio (HR), 2.84; 95% confidence interval (CI), 2.50-3.23]. On subgroup analysis, younger (age <40) patients showed a higher incidence of AF. SLE patients with incidental AF had a higher mortality rate compared with patients without SLE with AF (HR, 2.35; 95% CI 1.73-3.20) and those with SLE without AF (HR, 3.53; 95% CI 2.84-4.39) after adjustment., Conclusions: SLE was an independent risk factor for AF development, especially in younger patients without previous AF, stressing the importance of cardiac assessment in this population. Development of AF in patients with SLE was associated with increased mortality.

The prevalence rates of hypertension and chronic kidney disease (CKD) are increasing with the aging of the population. Hypertension and CKD are closely related, and hypertension with accompanying CKD is difficult to control. This difficulty controlling blood pressure (BP) can be explained by changes in diurnal variation in BP, such as non-dipping and reverse dipping patterns, increased pulse pressure, and BP variability in CKD patients resulting in a high frequency of nocturnal hypertension or masked hypertension. CKD patients with uncontrolled or nocturnal hypertension are at increased risk for cardiovascular disease, progression of CKD, and all-cause death. Recent studies have shown that intensive reduction of systolic BP below 120 mmHg is seems to favor in CKD patients regardless of the presence or absence of diabetes. As BP control is difficult in patients with CKD, appropriate measurement of BP is important. Automated BP monitoring could reduce the so-called "white coat effect" (spike in BP) that may be triggered by measurement in a clinical setting. Moreover, out-of-office BP monitoring at home or ambulatory BP monitoring for 24 hours may provide critical information regarding diurnal BP variability and nocturnal BP in patients with CKD.

Renal fibrosis is the common pathway of chronic kidney disease progression. The nuclear receptor farnesoid X receptor [FXR, NR1H4 (nuclear receptor subfamily 1 group member 4)], a multifunctional transcription factor, plays a pivotal role in protecting against fibrosis. However, the mechanisms underlying these antifibrotic actions of FXR in kidney disease are largely unknown. Here, we show that agonist GW4064-mediated FXR activation inhibits the activity of the nonreceptor tyrosine kinase Src (proto-oncogene tyrosine-protein kinase), which is critical for regulation of yes-associated protein (YAP) phosphorylation and nuclear localization in renal fibrosis. Activation of FXR suppressed renal fibrosis and Tyr416-Src phosphorylation in TGF-β-treated human renal proximal tubule epithelial (HK2) cells. Moreover, GW4064 treatment in HK2 cells increased Ser127 phosphorylation, cytosolic accumulation of YAP, and interaction of the hippo core kinases (Ste20-like kinase 1, large tumor suppressor kinase 1, and salvador homolog 1). Inhibition of Src using PP2 (Src kinase inhibitor) prevented renal fibrosis and increased Ser127 phosphorylation and cytosolic accumulation of YAP. The expression of fibrosis markers, inflammatory genes, and YAP target genes was increased in the kidneys of FXR knockout mice compared with those of wild-type mice. In addition, GW4064 or WAY-362450 (turofexorate isopropyl) treatment protected against unilateral ureteral obstruction-induced renal fibrosis. Collectively, our data support the novel conclusion that Src-mediated crosstalk between FXR and YAP protects against renal fibrosis, making this pathway a possible therapeutic target for chronic kidney disease.-Kim, D.-H., Choi, H.-I., Park, J. S., Kim, C. S., Bae, E. H., Ma, S. K., Kim, S. W. Src-mediated crosstalk between FXR and YAP protects against renal fibrosis.

Recent data suggest that visit-to-visit variability of blood pressure (BP) is associated with cardiovascular events. We evaluated the role of BP variability as a determinant of end-stage renal disease (ESRD). Using nationally representative data from the Korean National Health Insurance System, 8 199 089 subjects had been enrolled during 2009 to 2010 who were free of ESRD and underwent ≥3 health examinations during 2005 to 2010 were followed to the end of 2017. BP variability was measured using the coefficient of variation, SD, and variability independent of the mean. The primary outcome was the development of ESRD, defined as a combination of the relevant disease code and the initiation of renal replacement therapy. The χ 2 test, t test, and log-rank test were used in the statistical analysis. There were 16 567 cases of ESRD during a median follow-up of 7.89±0.88 years. The highest quartile of systolic or diastolic BP showed a higher incident rate of ESRD compared with the other 3 quartiles. It was augmented in patients with the highest quartile of both systolic and diastolic BP variabilities. Among patients with the highest quartile of systolic and diastolic BP variabilities, the uncontrolled hypertension group (>140/90 mm Hg) taking antihypertensive medication showed the highest incidence rate of ESRD. These results were consistent when modeling variability of BP using coefficient of variation, SD, and variability independent of the mean and in various sensitivity analyses. Systolic and diastolic BP variabilities were independently associated with an increased incidence of ESRD, and it was augmented when both variabilities were present together.

We present electrophysiological (EP) signals correlated with cellular cell activities in the adrenal cortex and medulla using an adrenal gland implantable flexible EP probe. With such a probe, we could observe the EP signals from the adrenal cortex and medulla in response to various stress stimuli, such as enhanced hormone activity with adrenocorticotropic hormone, a biomarker for chronic stress response, and an actual stress environment, like a forced swimming test. This technique could be useful to continuously monitor the elevation of cortisol level, a useful indicator of chronic stress that potentially causes various diseases., Competing Interests: The authors declare no conflict of interest.

Background: High serum adiponectin levels predict all-cause and cardiovascular mortality in chronic kidney disease (CKD). However, the relationship between serum adiponectin concentration and arterial stiffness in CKD is not well established. The aim of this study was to assess this relationship by measuring pulse wave velocity (PWV) in CKD patients., Methods: Serum adiponectin concentration was measured in 716 CKD patients in the prospective KoreaN cohort study for Outcome in patients With Chronic Kidney Disease. The study group consisted of 415 men and 301 women; mean age was 53.1 years, and baseline estimated glomerular filtration rate (eGFR) was 51 ± 29 ml/min per 1.73 m 2 . Heart to femoral PWV (hfPWV) and mean brachial to ankle PWV (baPWV) served as indicators of aortic artery stiffness and arterial stiffness, respectively., Results: Increasing quartiles of serum adiponectin levels were associated with women, lower eGFRs and body mass indices, and higher urinary albumin-creatinine ratios. Serum adiponectin concentration also correlated with hfPWV and mean baPWV, even after adjusting for age and sex. It independently associated with hfPWV (B 0.028; 95 % confidence interval, 0.004-0.051; P = 0.020) but not mean baPWV in a multivariable linear regression analysis. In a multivariable logistic regression analysis, it correlated significantly with the highest quartile of hfPWVs but not mean baPWVs., Conclusion: The independent and significant correlation of serum adiponectin concentration with hfPWV in CKD patients implicates adiponectin in CKD-associated aortic stiffness.