Search

Background: Signal transducer and activator of transcription 3 (STAT3), a multifaceted transcription factor, modulates host immune responses by activating cellular response to signaling ligands. STAT3 has a pivotal role in the pathophysiology of kidney injury by counterbalancing resident macrophage phenotypes under inflammation conditions. However, STAT3's role in acute kidney injury (AKI), particularly in macrophage migration, and in chronic kidney disease (CKD) through fibrosis development, remains unclear., Methods: Stattic (a JAK2/STAT3 inhibitor, 5 mg/kg or 10 mg/kg) was administered to evaluate the therapeutic effect on LPS-induced AKI (L-AKI) and LPS-induced CKD (L-CKD), with animals sacrificed 6-24 h and 14 days post-LPS induction, respectively. The immune mechanisms of STAT3 blockade were determined by comparing the macrophage phenotypes and correlated with renal function parameters. Also, the transcriptomic analysis was used to confirm the anti-inflammatory effect of L-AKI, and the anti-fibrotic role was further evaluated in the L-CKD model., Results: In the L-AKI model, sequential increases in BUN and blood creatinine levels were time-dependent, with a marked elevation of 0-6 h after LPS injection. Notably, two newly identified macrophage subpopulations (CD11b high F4/80 low and CD11b low F4/80 high ), exhibited population changes, with an increase in the CD11b high F4/80 low population and a decrease in the CD11b low F4/80 high macrophages. Corresponding to the FACS results, the tubular injury score, NGAL, F4/80, and p-STAT3 expression in the tubular regions were elevated. STAT3 inhibitor injection in L-AKI and L-CKD mice reduced renal injury and fibrosis. M2-type subpopulation with CD206 in CD11b low F4/80 high population increased in the Stattic-treated group compared with that in the LPS-alone group in the L-AKI model. Additionally, STAT3 inhibitor reduced inflammation driven by LPS-stimulated macrophages and epithelial cells injury in the co-culture system. Transcriptomic profiling identified 3 common genes in the JAK-STAT, TLR, and TNF signaling pathways and 11 common genes in the LPS with macrophage response. The PI3K-AKT (IL-6, Akt3, and Pik3r1) and JAK-STAT pathways were determined as potential Stattic targets. Further confirmation through mRNA and protein expressions analyses showed that Stattic treatment reduced inflammation in the L-AKI and fibrosis in the L-CKD mice., Conclusions: STAT3 blockade effectively mitigated inflammation by retrieving the CD11b low F4/80 high population, further emphasizing the role of STAT3-associated macrophage-driven inflammation in kidney injury., (© 2024. The Author(s).)

Chronic kidney disease (CKD) progression involves tubulointerstitial fibrosis, a process characterized by excessive extracellular matrix accumulation. To identify potential biomarkers for kidney fibrosis, we performed mass spectrometry-based proteomic profiling of human kidney tubular epithelial cells and kidney tissue from a 5/6 nephrectomy rat model. Multidisciplinary analysis across kidney fibrosis models revealed 351 differentially expressed proteins associated with kidney fibrosis, and they were enriched in processes related to the extracellular matrix, kidney aging, and mitochondrial functions. Network analysis of the selected proteins revealed five crucial proteins, of which transgelin emerged as a candidate protein that interacts with known fibrosis-related proteins. Concordantly, the gene expression of transgelin in the kidney tissue from the 5/6 nephrectomy model was elevated. Transgelin expression in kidney tissue gradually increased from intermediate to advanced fibrosis stages in 5/6 Nx rats and mice with unilateral ureteral obstruction. Subsequent validation in kidney tissue and urine samples from patients with CKD confirmed the upregulation of transgelin, particularly under advanced disease stages. Moreover, we investigated whether blocking TAGLN ameliorated kidney fibrosis and reduced reactive oxygen species levels in cellular models. In conclusion, our proteomic approach identified TAGLN as a potential noninvasive biomarker and therapeutic target for CKD-associated kidney fibrosis, suggesting its role in modulating mitochondrial dysfunction and oxidative stress responses., (© 2024. The Author(s).)

Peritoneal dialysis is a common treatment for end-stage renal disease, but complications often force its discontinuation. Preventive treatments for peritoneal inflammation and fibrosis are currently lacking. Cyclo(His-Pro) (CHP), a naturally occurring cyclic dipeptide, has demonstrated protective effects in various fibrotic diseases, yet its potential role in peritoneal fibrosis (PF) remains uncertain. In a mouse model of induced PF, CHP was administered, and quantitative proteomic analysis using liquid chromatography-tandem mass spectrometry was employed to identify PF-related protein signaling pathways. The results were further validated using human primary cultured mesothelial cells. This analysis revealed the involvement of histone deacetylase 3 (HDAC3) in the PF signaling pathway. CHP administration effectively mitigated PF in both peritoneal tissue and human primary cultured mesothelial cells, concurrently regulating fibrosis-related markers and HDAC3 expression. Moreover, CHP enhanced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) while suppressing forkhead box protein M1 (FOXM1), known to inhibit Nrf2 transcription through its interaction with HDAC3. CHP also displayed an impact on spleen myeloid-derived suppressor cells, suggesting an immunomodulatory effect. Notably, CHP improved mitochondrial function in peritoneal tissue, resulting in increased mitochondrial membrane potential and adenosine triphosphate production. This study suggests that CHP can significantly prevent PF in peritoneal dialysis patients by modulating HDAC3 expression and associated signaling pathways, reducing fibrosis and inflammation markers, and improving mitochondrial function., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Inflammation, metabolic acidosis, renin-angiotensin system activation, insulin resistance, and impaired perfusion to skeletal muscles, among others, are possible causes of uremic sarcopenia. These conditions induce the activation of the nuclear factor-kappa B and mitogen-activated protein kinase pathways, adenosine triphosphate ubiquitin-proteasome system, and reactive oxygen species system, resulting in protein catabolism. Strategies for the prevention and treatment of sarcopenia in chronic kidney disease (CKD) are aerobic and resistance exercises along with nutritional interventions. Anabolic hormones have shown beneficial effects. Megestrol acetate increased weight, protein catabolic rate, and albumin concentration, and it increased intracellular water component and muscle mass. Vitamin D supplementation showed improvement in physical function, muscle strength, and muscle mass. Correction of metabolic acidosis showed an increase in protein intake, serum albumin levels, body weight, and mid-arm circumference. The kidney- gut-muscle axis indicates that dysbiosis and changes in gut-derived uremic toxins and short-chain fatty acids affect muscle mass, composition, strength, and functional capacity. Biotic supplements, AST-120 administration, hemodiafiltration, and preservation of residual renal function are alleged to reduce uremic toxins, including indoxyl sulfate (IS) and p-cresyl sulfate (PCS). Synbiotics reversed the microbiota change in CKD patients and decreased uremic toxins. AST-120 administration changed the overall gut microbiota composition in CKD. AST-120 prevented IS and PCS tissue accumulation, ameliorated muscle atrophy, improved exercise capacity and mitochondrial biogenesis, restored epithelial tight junction proteins, and reduced plasma endotoxin levels and markers of oxidative stress and inflammation. In a human study, the addition of AST-120 to standard treatment had modest beneficial effects on gait speed change and quality of life.

Background: Sarcopenia is common in hemodialysis patients. This study aimed to evaluate the effect of simultaneous nutritional support and intradialytic neuromuscular electrical stimulation (NMES) in hemodialysis patients., Methods: We performed a 12-week, multicenter, randomized controlled trial. The participants were randomly assigned to the control group, the protein group (25 g of protein at every dialysis session), the NMES group (intradialytic NMES to quadriceps femoris muscles), and the NMES + P group (NMES with protein supplementation). The primary outcome was the difference in hand grip strength (HGS) and leg muscle strength (LMS) among groups. Secondary outcomes included body composition, physical performance (the 10-m walk test and the timed up and go test [TUG]), and questionnaires about quality of life (QoL), physical activity, and depression. In addition, subgroup analysis was performed by dividing NMES and NMES + P groups into high- and low-intensity NMES groups., Results: Fifty-nine patients completed all the study outcomes. There was no difference in muscle strength (HGS and LMS) and muscle mass among groups. Gait speed improved in NMES and NMES + P groups. Subscale scores for QoL (kidney disease effect, role limitations due to physical or emotional problems, and overall health ratings) improved in the NMES + P group. In subgroup analysis, LMS and TUG improved only in the high-intensity NMES group., Conclusion: In this study, NMES and-/or- protein supplementation did not make a significant difference in HGS and LMS. However, NMES or NMES + P improved functional capacity and QoL. Furthermore, higher NMES was superior in improving LMS and functional capacity.

Background: A race-free glomerular filtration rate (GFR) estimation equation has recently been developed. However, the performance of the new Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations needs to be evaluated in Asian populations., Methods: We performed a cross-sectional study at a single center in South Korea. The measured GFR (mGFR) was determined based on systemic inulin clearance. The GFR was estimated using the five CKD-EPI equations: 2009 CKD-EPIcr, 2012 CKD-EPIcr-cys, 2012 CKD-EPIcys, 2021 CKD-EPIcr, and 2021 CKD-EPIcr-cys. The performances of five estimated GFR (eGFR) equations were assessed by bias, precision, and accuracy (percentage of estimates within 30% of mGFR)., Results: The median mGFR and interquartile range (IQR) was 53.5 (32.4-80.0) mL/min/1.73 m2. The mGFR better correlated with 2009 CKD-EPIcr (ρ = 0.628) and 2021 CKD-EPIcr-cys (ρ = 0.806) than with 2021 CKD-EPIcr (ρ = 0.623) and 2012 CKD-EPIcr-cys (ρ = 0.801). The median bias of 2009 CKD-EPIcr and 2012 CKD-EPIcr-cys were lower than those of 2021 CKD-EPI equations (2009 CKD-EPIcr, 2.24 [IQR, -8.83 to 17.39] vs. 2021 CKD-EPIcr, 5.40 [IQR, -6.04 to 20.40]; 2012 CKD-EPIcr-cys, 6.74 [IQR, -2.81 to 20.80] vs. 2021 CKD-EPIcr-cys, 10.54 [IQR, 0.30-24.37]; all in mL/min/1.73 m2). The percentage of eGFR values within 30% of mGFR was higher in 2009 CKD-EPIcr and 2012 CKD-EPIcr-cys equations than 2021 CKD-EPI equations. The CKD prevalence in 2009 CKD-EPIcr, 2021 CKD-EPIcr, 2012 CKD-EPIcr-cys, and 2021 CKD-EPIcr-cys was 54.8%, 51.0%, 47.7%, and 44.8%, respectively., Conclusion: Our study demonstrated better performance of the original CKD-EPIcr and CKD-EPIcr-cys equations than the 2021 new CKD-EPI equations. We do not recommend the adoption of the new CKD-EPI equations in Korea.

Introduction: Major depressive disorder (MDD) is a common and debilitating mental illness. Postpartum depression (PPD) impacts women globally and is one of the most common complications of childbirth that is underdiagnosed and undertreated, adversely impacting the mental health of women, children, and partners.Available antidepressant medications require weeks to months before showing effect. In this setting, zuranolone, an oral neuroactive steroid and a positive allosteric modulator of GABA A receptors, is an attractive alternative as a rapid-acting antidepressant treatment., Areas Covered: This article reviews zuranolone (SAGE217), focusing on available clinical studies in individuals with PPD and MDD. This paper adds to the extant literature by presenting the efficacy data as Number Needed to Treat (NNT) to facilitate indirect comparisons with other antidepressants., Expert Opinion: Zuranolone is a novel rapid-acting (i.e. two week course) oral antidepressant for the treatment of adults with PPD with ongoing clinical trials evaluating its efficacy in adults with MDD. Zuranolone is well tolerated with no significant safety concerns in any clinical trials completed to date. Zuranolone will be scheduled by the Drug Enforcement Agency (DEA).

Background: Gait speed is an important measure of functional ability. This study aimed to investigate the factors associated with gait speed in patients with chronic kidney disease. The study focused on sarcopenic components, plasma uremic or inflammatory marker levels, and quality of life effects., Methods: The RolE of AST120 (Renamezin) in sarCOpenia preVEntion in pRe-dialYsis chronic kidney disease patients is a 48-week, randomized controlled, parallel-group, open-label, multicenter trial to determine the role of Renamezin (Daewon Pharmaceutical Co., Ltd.) in patients with chronic kidney disease. The participants were classified into four groups according to gait speed: ≤0.8, 0.8-1.0, ≤1.0-1.3, and ≥1.3 m/sec. Linear regression analysis was performed to identify the factors associated with gait speed., Results: The group with a gait speed of ≤0.8 m/sec was the oldest and had the highest proportion of participants with low education level and medical aid. Participants with a gait speed of ≤0.8 m/sec showed the lowest physical and mental component scale scores. The interleukin-6 (IL-6) level tended to be the higher trend in the lowest gait speed group. In the multivariate linear regression analysis adjusted for age, sex, diabetes mellitus, and estimated glomerular filtration rate, insurance status, handgrip strength, IL-6 level, hemoglobin level, mental component scale score, and physical component scale score were significantly associated with gait speed., Conclusion: In conclusion, gait speed is associated with handgrip strength, IL-6 level, and various components of quality of life in predialysis chronic kidney disease patients.

There were few data regarding the association of volume status with sarcopenia using muscle mass, strength, and physical performance in non-dialysis chronic kidney disease (ND-CKD) patients. We aimed to evaluate the association between volume status and sarcopenia in ND-CKD patients. Our retrospective study analyzed data from a previous study which included ND-CKD patients who had stable renal function. Our study used its baseline data alone. The edema index and muscle mass were measured using a multi-frequency bioimpedance analysis machine. The edema index was calculated using extracellular water/total body water ratio. The skeletal muscle index (SMI, kg/m 2 ) was calculated using appendicular muscle mass per height squared. Handgrip strength (HGS, kg) was measured during the standing position in all patients. Dynamic gait speed (GS, m/s) was evaluated using 6-m walking speed. Patients with both low muscle mass (SMI < 7.0 kg/m 2 for men and < 5.7 kg/m 2 for women using bioimpedance analysis) and low HGS (< 28 kg for men and < 18 kg for women) or low GS (< 1.0 m/s) were classified as having sarcopenia. The patients (n = 147) were divided into tertiles based on the edema index level. The mean edema index in the low, middle, and high tertiles was 0.377 ± 0.006, 0.390 ± 0.003, and 0.402 ± 0.006, respectively. The edema index was significantly correlated with SMI, HGS, and GS (r = - 0.343 for SMI, - 0.492 for HGS, and - 0.331 for GS; P < 0.001 for three indicators). The SMI, HGS, and GS values were 8.1 ± 1.0 kg/m 2 , 33.0 ± 9.4 kg, and 1.2 ± 0.2 m/s in the low tertile,7.8 ± 1.2 kg/m 2 , 30.0 ± 7.5 kg, and 1.0 ± 0.3 m/s in the middle tertile, and 7.2 ± 1.4 kg/m 2 , 23.7 ± 7.4 kg, and 1.0 ± 0.3 m/s in the high tertile, respectively. Univariate analyses revealed that SMI was lower in patients in the high tertile than in those in the low tertile. HGS was lowest in high tertile, and GS was greatest in the low tertile. The high tertile for predicting sarcopenia had an odds ratio of 6.03 (95% CI, 1.78-20.37; P = 0.004) compared to low or middle tertiles. The results of multivariate analyses were similar to those of the univariate analyses. The subgroup analyses showed that statistical significance was greater in < 65 years and men than ≥ 65 years and women. The present study showed that the edema index is inversely associated with sarcopenia, muscle mass index, strength, and physical performance in ND-CKD patients. However, considering the limitations of our study such as its small sample size, this association was not strong. Further studies that include volume-independent measurements, data on physical activity and diet, and a larger number of patients are warranted to overcome these limitations., (© 2022. The Author(s).)

Serum myostatin and indoxyl sulfate (IS) levels increase with kidney function decline and may function as uremic toxins in chronic kidney disease (CKD)-related sarcopenia. Herein, we analyzed the association between serum myostatin and IS levels and sarcopenia in patients with CKD, by performing a post hoc analysis of baseline data extracted from the RECOVERY study (clinicaltrials.gov: NCT03788252) of 150 patients with CKD. We stratified patients into two groups according to the median value of myostatin (cutoff 4.5 ng/mL) and IS levels (cutoff 0.365 mg/dL). The proportion of patients with sarcopenia was higher in those with high IS levels but lower in those with high myostatin levels. The skeletal muscle mass index (SMI) and handgrip strength (HGS) were significantly lower in patients with high IS levels but significantly higher in patients with high myostatin levels. IS levels showed a negative correlation with glomerular filtration rate (GFR), SMI, and HGS. However, myostatin levels were positively correlated with SMI and HGS, but not with GFR. Sarcopenia was independently associated with age and IS level after adjustment. Increased levels of serum total IS might play a role in sarcopenia, while increased levels of serum myostatin are associated with muscle mass in patients with CKD.

Background & Aims: Sarcopenia is associated with adverse health outcomes in individuals with chronic kidney disease (CKD); hence, a convenient and reliable method for monitoring muscle health is required. This study investigated the utility of the phase angle (PhA) to estimate muscle health and health-related quality of life (HRQoL) in patients with CKD., Methods: Data were obtained from a multicenter randomized trial that examined the effect of AST-120 on sarcopenia and HRQoL. The PhA and skeletal muscle mass index (SMI) were derived from bioelectrical impedance analyses at baseline, 24-week, and 48-week. In addition, handgrip strength (HGS), 6 m gait speed (GS), and HRQoL were obtained simultaneously., Results: In total, 149 participants were included. PhA was linearly related to SMI, HGS, and GS (r = 0.616, 0.619, and 0.290, respectively; all P < 0.001). Moreover, PhA was associated with the criteria for low muscle mass and low muscle strength (both P < 0.001), and it predicted the presence of sarcopenia (P = 0.001). Substantial agreement was observed in the diagnosis of sarcopenia (κ = 0.510; P < 0.001). In addition, PhA was related to various aspects of HRQoL, including physical functioning, general health, mental health, physical component scale, mental component scale, work status, quality of social interaction, sexual function, and social support. In the longitudinal analysis, SMI increased in the increasing PhA group (a PhA slope ≥ 0.2° per year), and HGS was reduced in the decreasing PhA group (a PhA slope of < -0.2° per year) as compared to the constant PhA group (a PhA slope of -0.2 to 0.2° per year; both P = 0.054). The GS pattern did not differ among the three groups. In addition, the prevalence of sarcopenia was comparable at baseline (P = 0.220); however, its proportion rose in the decreasing PhA group and reduced in the increasing PhA group (P at 48-week = 0.058). With regards to aspects of HRQoL, role limitations due to physical health problems worsened in the decreasing PhA group., Conclusions: PhA appears to be a reliable marker for estimating muscle health and HRQoL in patients with CKD. In addition, monitoring PhA may help estimate the longitudinal patterns of muscle health and HRQoL., Competing Interests: Conflict of Interest The authors have no conflicts of interest to disclose., (Copyright © 2022 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: The prevalence of sarcopenia is increased with declining renal function. Elevated serum indoxyl sulfate levels are associated with poor skeletal muscle conditions. We aimed to determine the effects of AST-120, the oral adsorbent of indoxyl sulfate, on sarcopenia and sarcopenia-associated factors in chronic kidney disease patients., Methods: This was a 48 week, randomized controlled, parallel group, open-label, multicentre trial (n = 150). The participants were randomly assigned in a 1:1 ratio to the control (CON) and AST-120 (Renamezin®, REN) groups. Outcome measurements were performed at baseline and every 24 weeks for 48 weeks. The primary outcome was gait speed difference ≥0.1 m/s between the two groups, and secondary outcomes included hand grip strength, muscle mass, and health-related quality of life., Results: A difference of gait speed ≥0.1 m/s was not observed during the study period. The mean dynamic-start gait speed in the REN group increased from baseline to 48 weeks (1.04 ± 0.31 to 1.08 ± 0.32 m/s, P = 0.019). The static-start gait speed changed by -0.024 and 0.04 m/s (P = 0.049) in the CON and REN groups over 48 weeks, respectively. Hand grip strength decreased during the first 24 weeks and did not significantly change over the next 24 weeks in either group. The proportion of low muscle mass or sarcopenia at baseline was larger in the REN group than in the CON group, but the difference attenuated over the study period [low muscle mass and sarcopenia in the CON and REN groups at baseline, 4.0% vs. 18.9% (P = 0.004) and 2.7% vs. 13.5% (P = 0.017); at 24 weeks, 2.9% vs. 13.6% (P = 0.021) and 1.4% vs. 10.5% (P = 0.029); and at 48 weeks, 7.6% vs. 12.9% (P = 0.319) and 4.5% vs. 8.1% (P = 0.482), respectively]. Bodily pain, vitality, symptoms/problems, and cognitive function in the REN group improved, while the quality of social interactions and the kidney disease effects in the CON group aggravated from baseline to 48 weeks. Interaction between time and group was evident only in symptoms/problems, cognitive function, and kidney disease effects., Conclusions: The addition of AST-120 to standard treatment in chronic kidney disease patients did not make a significant difference in gait speed, although AST-120 modestly had beneficial effects on gait speed change and quality of life and showed the potential to improve sarcopenia. (clinicaltrials.gov: NCT03788252)., (© 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Sarcopenia due to chronic inflammation and biochemical disturbances in chronic kidney disease is severer and more prevalent in hemodialysis (HD) patients. We longitudinally evaluated the hand grip strength (HGS) and leg muscle strength (LMS) and evaluated the role of exercise in muscle strength in HD patients. We screened (January, n=127) and followed up (June, n=110 and December 2020, n=104). HGS and LMS at single center by using digital hand and leg dynamometer. HGS (24.2 kg vs. 15.5 kg) and LMS (32.8 kg vs. 22.5 kg) were better in men ( P <0.001 and P <0.001, respectively). Older patients (≥60 years) showed decreased LMS than others in women ( P =0.01). Patients who performed steady home- or hospital-based exercise showed marginally higher HGS (23.1 kg vs. 19.8 kg, P =0.07) and significantly higher LMS (33.7 kg vs. 25.9 kg, P =0.004). Steady exercise improved LMS throughout the study period (30.3 kg vs. 33.2 kg from Jan to Jun 2020, P =0.004; 30.3 kg vs. 34.2 kg from Jan to Dec 2020, P =0.014). Multiple linear regression analysis proved steady exercise was independently associated with better HGS and LMS. Steady exercise showed greater impact on LMS in male patients with longer HD vintage (≥44 months) and on HGS in younger male patients with shorter HD vintage (<44 months). Steady exercise was an important determinant of muscle strength in HD patients. We need to encourage patients to steadily perform regular home- or group-exercise before sarcopenia develops., Competing Interests: CONFLICT OF INTEREST No potential conflict of interest relevant to this article was reported., (Copyright © 2021 Korean Society of Exercise Rehabilitation.)

Background: The prevalence of sarcopenia increases as renal function decreases, and a considerable number of hemodialysis (HD) patients have sarcopenia. Exercise and nutritional support are established interventions to prevent and treat sarcopenia. Recently, many studies evaluating intradialytic neuromuscular electrical stimulation (NMES) showed improvement of muscular strength and mass, functional capacity, and quality of life (QOL). However, there has been no research about the effect of simultaneous nutritional support and NMES in HD patients., Methods: This is a 12-week, randomized controlled, parallel-group, multicenter trial of intradialytic NMES and protein supplementation for HD patients. Seventy-two patients receiving HD will be randomly assigned in a 1:1:1:1 ratio to control, intradialytic NMES only, protein supplementation only, and intradialytic NMES combined with protein supplementation groups. NMES will be delivered to a total of four areas of the bilateral vastus medialis and vastus lateralis using a 4-channel NMES instrument. A total of 25 g of protein supplements will be provided at the beginning of every dialysis session or after the NMES. The primary endpoint is the difference of hand grip and leg muscle strength at 12 weeks among 4 treatment groups. Secondary endpoints include muscle mass, physical performances, and questionnaires about QOL and physical activity., Discussion: In this study, we will evaluate the differential effectiveness of nutritional support and NMES during HD on muscle strength, muscle mass, physical function, and QOL. We expect that this study can provide guidelines for a new therapeutic option for HD patients who are unable or hesitant to exercise. Furthermore, this option can offer an opportunity to improve the physical function, QOL, and prognosis of HD patients., Trial Registration: Clinical Research Information Service (CRIS), Korea, KCT0005573 . Retrospectively registered on 03 November 2020., (© 2021. The Author(s).)

Background: Chronic kidney disease is associated with chronic inflammation and progressive loss of peripheral muscle strength and the ability to exercise, and these changes are highly pronounced in patients receiving hemodialysis (HD). We evaluated hand grip strength (HGS) and leg muscle strength (LMS) in patients receiving HD and attempted to identify factors associated with muscle strength., Methods: We screened HGS (opposite the fistula side) and LMS (both sides) in HD patients at a single center (n = 112) by using digital hand and leg dynamometers (T.K.K. 5401 and 5710e/5715, Takei Scientific Instruments Co. Ltd., Niigata, Japan)., Results: The mean age of patients was 62.6 years, and 73.2% of the patients were male. Diabetes was the cause of kidney failure in 50% of the patients, and the median HD vintage was 34 months. A total of 77.7% of patients reported that they participated in regular home-based exercise, and 29.5% of patients regularly participated in hospital-based resistance exercise. HGS and LMS showed good correlation ( r = 0.715, P < 0.001). HGS (25.1 vs. 17.0 kg) and LMS (30.1 vs. 20.4 kg) were greater in males ( P < 0.001 and P < 0.001, respectively) than in females. Older patients (≥ 60 years) showed less LMS than younger patients in both males and females ( P = 0.012 and P = 0.037, respectively), but HGS did not differ according to age. Patients performing regular home- or hospital-based exercise showed higher HGS than those who did not exercise (24.2 vs. 18.6 kg, P = 0.011), but LMS was not significantly different (29.3 vs. 23.6 kg, P = 0.185). Multiple linear regression analysis proved that male sex, younger age, and any type of exercise were factors associated with improved HGS and LMS. Groups of older age (≥ 60 years), male sex, and shorter duration of HD (< median) benefitted more from exercise., Conclusion: Sex, age, and exercise were the most important determinants of muscle strength in HD patients. We need to encourage patients to engage in regular home or group exercise from the beginning of dialysis and introduce new feasible forms of exercise for HD patients., Competing Interests: The authors have no conflicts of interest to disclose., (© 2021 The Korean Academy of Medical Sciences.)

Chemokine receptor 5 (CCR5) is a pivotal regulator of macrophage trafficking in the kidneys in response to an inflammatory cascade. We investigated the role of CCR5 in experimental ischaemic-reperfusion injury (IRI) pathogenesis. To establish IRI, we clamped the bilateral renal artery pedicle for 30 min and then reperfused the kidney. We performed adoptive transfer of lipopolysaccharide (LPS)-treated RAW 264.7 macrophages following macrophage depletion in mice. B6.CCR5 -/- mice showed less severe IRI based on tubular epithelial cell apoptosis than did wild-type mice. CXCR3 expression in CD11b + cells and inducible nitric oxide synthase levels were more attenuated in B6.CCR5 -/- mice. B6.CCR5 -/- mice showed increased arginase-1 and CD206 expression. Macrophage-depleted wild-type mice showed more injury than B6.CCR5 -/- mice after M1 macrophage transfer. Adoptive transfer of LPS-treated RAW 264.7 macrophages reversed the protection against IRI in wild-type, but not B6.CCR5 -/- mice. Upon knocking out CCR5 in macrophages, migration of bone marrow-derived macrophages from wild-type mice towards primary tubular epithelial cells with recombinant CCR5 increased. Phospho-CCR5 expression in renal tissues of patients with acute tubular necrosis was increased, showing a positive correlation with tubular inflammation. In conclusion, CCR5 deficiency favours M2 macrophage activation, and blocking CCR5 might aid in treating acute kidney injury., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Rationale & Objective: We aimed to elucidate whether a balanced salt solution decreases the occurrence of contrast-induced acute kidney injury (CI-AKI) after contrast-enhanced computed tomography (CE-CT) as compared to 0.9% saline solution., Study Design: A randomized clinical trial., Setting & Participants: The study was performed in 14 tertiary hospitals in South Korea. Patients with estimated glomerular filtration rates (eGFRs) < 45 or <60 mL/min/1.73 m 2 and additional risk factors (age ≥ 60 years or diabetes) who were undergoing scheduled CE-CT were included from December 2016 to December 2018., Intervention: An open-label intervention was performed. The study group received a balanced salt solution and the control group received 0.9% saline solution as prophylactic fluids for CE-CT., Outcomes: The primary outcome was CI-AKI, defined by creatinine level elevation ≥ 0.5 mg/dL or 25% from baseline within 48 to 72 hours after CE-CT. Secondary outcomes included AKI defined based on the KDIGO (Kidney Disease: Improving Global Outcomes) guideline, eGFR changes, death, or requiring dialysis within 6 months after CE-CT., Results: 493 patients received the study fluids. The control and study groups included 251 and 242 patients, respectively. The occurrence of CI-AKI in the study (10 [4.2%]) and control (17 [6.8%]) groups was not significantly different ( P  = 0.27). No significant difference was present for the secondary outcomes; AKI by the KDIGO definition (study: 19 [7.9%], control: 27 [10.8%]; P  = 0.33), death/dialysis (study: 11 [4.7%], control: 9 [3.7%]; P  = 0.74), and eGFR changes (study: 0.1 ± 0.2 mg/dL, control: 0.3 ± 2.8 mg/dL; P  = 0.69)., Limitations: This study failed to meet target enrollment., Conclusions: The risk for CI-AKI was similar after administration of a balanced salt solution and after use of 0.9% saline solution during CE-CT in higher-risk patients., Funding: This study was funded by CJ Healthcare (CS2015&#95;0046)., Trial Registration: Registered at ClinicalTrials.gov with study number NCT02799368., (© 2020 The Authors.)

Blood pressure (BP) control is the most established practice for preventing the progression and complications of chronic kidney disease (CKD). We examined the influence of BP patterns on target organ damage in hypertensive patients with CKD by using long-term follow-up data of the APrODiTe-2 study.We collected 5 years of data of APrODiTe-2 study (1 year longitudinal study) participants after the enrollment on the progression of estimated glomerular filtration (eGFR), renal outcomes (doubling of serum creatinine, 50% decrease of eGFR, maintenance dialysis, and kidney transplantation), cerebro-cardiovascular (CCV) accidents, and all-cause mortality (n=378) to evaluate the long-term influence of BP patterns on target organ damages.Initially, more than 2/3 of patients showed masked (50.0%) and sustained uncontrolled (30.6%) BP control states as well as non- (31.3%) and reverse-dipping (35.0%) states. Only 18.8% and 20.8% of participants showed a better change in BP control patterns and a dipping pattern change to dippers over 1 year, respectively. Composite of new CCV accidents occurred in 43 patients (11.4%), and no BP patterns were associated with the occurrence of new CCV accidents. A worse change in BP control categories over 1 year was associated with increased occurrence of composites of renal outcomes after adjustment for age, sex, and the cause of CKD (HR 5.997 [1.454-24.742], P = .013 and HR 4.331 [1.347-13.927], P = .014, respectively). Patients with a worse initial BP control category, a worse change in BP control categories over 1 year, and higher clinic systolic BP and pulse pressure (PP) (> median level) were more likely to have faster eGFR progression (absolute eGFR and eGFR ratio).Higher BP burden (a worse change in BP control categories, higher initial clinic systolic BP and PP) was associated with faster eGFR progression and increased occurrence of renal outcomes.

Krüppel-like factor 15 (KLF15) is a well-known transcription factor associated with podocyte injury and fibrosis. Recently, hypertensive nephropathy was discovered to be closely related to podocyte injury and fibrosis. However, methods to stimulate hypertension in vitro are lacking. Here, we constructed an in vitro model mimicking hypertension using a rotational force device to identify the role of KLF15 in fibrosis due to mechanically induced hypertensive injury. First, we found that KLF15 expression was decreased in patients with hypertensive nephropathy. Then, an in vitro study of hypertension due to rotational force was conducted, and an increase in fibrosis markers and decrease in KLF15 levels were determined after application of 4 mmHg pressure in primary cultured human podocytes. KLF15 and tight junction protein levels increased with retinoic acid treatment. siRNA-mediated inhibition of KLF15 exacerbated pressure-induced fibrosis injury, and KLF15 expression after treatment with angiotensin II was similar to that observed after treatment with the blood pressure modeling device. Furthermore, the reduced KLF15 levels after mechanical pressure application were restored after the administration of an antihypertensive drug. KLF15 expression was also low in vivo. We confirmed the protective role of KLF15 in fibrosis using a mechanically induced in vitro model of hypertensive injury., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The 24-hour mean blood pressure (mBP) is the best predictor of organ damage; however, it is not easily applicable in clinical practice. The APrODiTe study suggested that systolic blood pressure (SBP) values at 7:00 AM and 9:30 PM were associated with the 24-hour mSBP in patients with chronic kidney disease (CKD). We investigated the association of the SBP values at these time-points with the renal outcomes in patients with diabetic CKD during 1-year follow-up., Methods: Ninety-six patients with diabetic CKD were included at 1-year follow-up. The renal outcomes were an increase in the random urine protein/creatinine ratio or estimated glomerular filtration rate (eGFR) deterioration, which means a decrease in eGFR ≥5 mL/min/1.73 m 2 compared to the baseline values., Results: The baseline SBP values at 7:00 AM, and 9:30 PM, and the 24-hour mSBP were 135.6±24.9 mmHg, 141.7±25.6 mmHg, and 136.4±20.7 mmHg, respectively. The SBP values measured at the same time-points after 1 year were similar to those at baseline. The SBP at 7:00 AM was significantly associated with eGFR deterioration in the univariate and multivariate analyses (odds ratio [OR]: 1.032; 95% confidence interval [CI]: 1.006-1.059; p=0.016). The SBP at 7:00AM and 24-hour mSBP did not show a concordant association with sustained proteinuria in the linear and logistic analyses. In the subgroup analysis, the association between the SBP at 7:00 AM and eGFR deterioration persisted in patients with CKD stage 3-5 (OR: 1.041; 95% CI: 1.010-1.073; p=0.010)., Conclusion: The SBP at 7:00 AM, in addition to the 24-hour mSBP, is also associated with eGFR deterioration in patients with diabetic CKD, particularly in those with CKD stage 3-5., Competing Interests: Conflict of interest: The authors have no conflicts of interested to disclose. This manuscript has not been published or presented elsewhere in part or in entirety., (Copyright © 2019 The Korean Society of Electrolyte Metabolism.)

Peritoneal fibrosis (PF) is an intractable complication of peritoneal dialysis (PD) that leads to peritoneal membrane failure. This study investigated the role of suppression of tumorigenicity (ST)2 in PF using patient samples along with mouse and cell-based models. Baseline dialysate soluble (s)ST2 level in patients measured 1 month after PD initiation was 2063.4 ± 2457.8 pg/mL; patients who switched to haemodialysis had elevated sST2 levels in peritoneal effluent (1576.2 ± 199.9 pg/mL, P = .03), which was associated with PD failure (P = .04). Baseline sST2 showed good performance in predicting PD failure (area under the receiver operating characteristic curve = 0.780, P = .001). In mice with chlorhexidine gluconate-induced PF, ST2 was expressed in fibroblasts and mesothelial cells within submesothelial zones. In primary cultured human peritoneal mesothelial cells (HPMCs), transforming growth factor-β treatment increased ST2, fibronectin, β-galactosidase and Snail protein levels and decreased E-cadherin level. Anti-ST2 antibody administration reversed the up-regulation of ST2 and fibronectin expression; it also reduced fibrosis induced by high glucose (100 mmol/L) in HPMCs. Thus, high ST2 level in dialysate is a marker for fibrosis and inflammation during peritoneal injury, and blocking ST2 may be an effective therapeutic strategy for renal preservation., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Background: Hyperuricemia is associated with the development and progression of chronic kidney disease (CKD) as well as cardiovascular diseases. However, there is no consistent recommendation regarding the treatment of asymptomatic hyperuricemia (AHU) in CKD patients. Here, we surveyed Korean physicians' perceptions regarding the diagnosis and management of AHU in CKD patients., Methods: Questionnaires on the management of AHU in CKD patients were emailed to regular members registered with the Korean Society of Nephrology., Results: A total of 158 members answered the questionnaire. Among the respondents, 49.4%/41.1% were considered hyperuricemic in male CKD patients whereas 36.7%/20.9% were considered hyperuricemic in female CKD patients when defined by serum uric acid level over 7.0/8.0 mg/dL, respectively. A total of 80.4% reported treating AHU in CKD patients. The most important reasons to treat AHU in CKD patients were renal function preservation followed by cerebro-cardiac protection. Majority of respondents (59.5%) thought that uric acid-lowering agents (ULAs) were the most effective method for controlling serum uric acid levels. Approximately 80% chose febuxostat as the preferred medication. A total of 32.3% and 31.0%, respectively, initiated ULA treatment if the serum uric acid level was more than 8.0 or 9.0 mg/dL, respectively. In addition, 39.2% and 30.4% answered that target serum uric acid levels of less than 6.0 or 7.0 mg/dL, respectively, were appropriate. The two major hurdles to prescribing ULAs were concerns of adverse reactions and the existing lack of evidence (i.e., the absence of Korean guidelines)., Conclusion: Most Korean physicians treat AHU in CKD patients to prevent CKD progression and cerebro-cardiovascular complications.

Background: Signal transducer and activator of transcription 3 (STAT3) is a latent transcription factor critical for T-cell function. Although inhibition of the Janus kinase 2 (JAK2)/STAT3 pathway has been reported to be protective against ischemia-reperfusion injury (IRI), the role of T cell-associated STAT3 in the pathogenesis of renal IRI has not been specifically defined., Methods: We induced renal IRI in both mice with T cell-specific STAT3 knockout (Lck-Cre;STAT3flox/flox) and wild-type controls (C57BL/6) and assessed renal damage and inflammation at 48 h after IRI. Human proximal tubular epithelial cells grown under hypoxia were treated with a JAK2 inhibitor, caffeic acid 3,4-dihydroxy-phenylethyl ester, to determine the effect of JAK2/STAT3 inhibition on renal epithelia. Independently, we disrupted Cln 3-requiring 9 (Ctr9) to inhibit T helper 17 (Th17) activation via RNA interference and determined if Ctr9 inhibition aggravates renal injury through upregulated Th17 activation., Results: The Lck-Cre;STAT3flox/flox mice exhibited significantly reduced kidney damage compared with controls. This protective effect was associated with reduced intrarenal Th17 infiltration and proinflammatory cytokines. Human proximal tubular epithelial cells under hypoxia exhibited significant upregulation of interleukin 17 receptors, and pharmacologic inhibition of JAK2 significantly ameliorated this change. RNA interference with Ctr9 in splenocytes enhanced differentiation into Th17 cells. In vivo knockdown of Ctr9 in mice with renal IRI further aggravated Th17-associated inflammation and kidney injury., Conclusions: STAT3 in T cells contributes to renal IRI through Th17 activation. Inhibition of Ctr9 further enhances Th17 activation and aggravates kidney injury, further supporting the role of Th17 cells in renal IRI., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Introduction : Approximately 50% of adults with major depressive disorder (MDD) who receive a first-line antidepressant treatment, at an appropriate dose, do not achieve an adequate response. Brexpiprazole is a novel serotonin-dopamine activity modulator in the second generation/atypical antipsychotic class that was approved by the United States Food & Drug Administration in 2015 for use as an adjunctive agent in the treatment of MDD inadequately responsive to antidepressant treatment. In general, second generation/atypical antipsychotics are widely used in the treatment of treatment resistant depression with brexpiprazole providing preliminary evidence for broad-spectrum efficacy across multiple domains affected by MDD, providing a basis for further elucidating its mechanistic effects to inform novel drug discovery. Areas covered : The review herein presents the evidence base for the use of brexpiprazole as an augmentation agent to antidepressants in individuals with treatment resistant MDD, including its efficacy, safety, and tolerability profile. Expert opinion : Brexpiprazole has been demonstrated to be effective and safe to use as an augmentation agent to antidepressant treatment among individuals with treatment resistant MDD due to its considerably improved tolerability profile when compared to other second generation/atypical antipsychotics; however, it is important to exercise clinical judgment when selecting disparate augmentation agents on a case-by-case basis weighing individual risks versus benefits.

Background/aims: Patients with chronic kidney disease (CKD) have been found to show markedly increased rates of end-stage renal disease, major adverse cardiovascular and cerebrovascular events (MACCEs), and mortality. Therefore, new biomarkers are required for the early detection of such clinical outcomes in patients with CKD. We aimed to determine whether the level of circulating renalase was associated with CKD progression, MACCEs, and all-cause mortality, using data from a prospective randomized controlled study, Kremezin STudy Against Renal disease progression in Korea (K-STAR; NCT00860431)., Methods: A retrospective analysis of the K-STAR data was performed including 383 patients with CKD (mean age, 56.4 years; male/female, 252/131). We measured circulating renalase levels and examined the effects of these levels on clinical outcomes., Results: The mean level of serum renalase was 75.8 ± 34.8 μg/mL. In the multivariable analysis, lower hemoglobin levels, higher serum creatinine levels, and diabetes mellitus were significantly associated with a higher renalase levels. Over the course of a mean follow-up period of 56 months, 25 deaths and 61 MACCEs occurred. Among 322 patients in whom these outcomes were assessed, 137 adverse renal outcomes occurred after a mean follow-up period of 27.8 months. Each 10- μg/mL increase in serum renalase was associated with significantly greater hazards of all-cause mortality and adverse renal outcomes (hazard ratio [HR] = 1.112, p = 0.049; HR = 1.052, p = 0.045). However, serum renalase level was not associated with the rate of MACCEs in patients with CKD., Conclusion: Our results indicated that circulating renalase might be a predictor of mortality and adverse renal outcomes in patients with CKD.

Background: The aim of this study was to examine the role of perceived sleep quality in predicting subjective as well as objective cognitive function in adults with major depressive disorder (MDD)., Methods: Adults with recurrent MDD (n = 100) experiencing a major depressive episode of at least moderate severity and age-, sex-, and education-matched healthy controls (HC) (n = 100) were recruited to participate in a clinical trial validating the THINC-integrated tool (THINC-it; NCT02508493) for cognitive function. The THINC-it includes subjective and objective measures of cognitive function. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI)., Results: Compared with HC, individuals with MDD reported significantly poorer sleep quality, as assessed by domain and global PSQI scores (all P values <.05). Both perceived sleep quality ( P < .001) and depression severity (P = .002) were found to independently predict impairments in subjective cognitive performance. Only perceived sleep quality predicted objective cognitive impairments (P = .017). Exploratory mediation analysis revealed depression severity to be a partial mediator of the relationship between perceived sleep quality and subjective cognitive performance (95% confidence interval [CI]: -0.56, -0.33)., Conclusions: The results indicate that the subjective and objective cognitive impairments are differentially related to perceived sleep quality and depression severity and emphasize the importance of treating sleep disturbances in MDD.

Background and Objectives: This study evaluated the association between self-reported anxiety and objective/subjective measures of cognitive performance in adults with Major Depressive Disorder (MDD)., Methods: Acutely depressed subjects with recurrent MDD (n = 100) and age-, sex-, and education-matched healthy controls (HC; n = 100) between the ages of 18 and 65 completed the cross-sectional validation study of the THINC-integrated tool (THINC-it; ClinicalTrials.gov: NCT02508493). Objective cognitive performance was assessed using the THINC-it, and subjective cognitive impairment with the Perceived Deficits Questionnaire for Depression-5-item. Subjects also completed the Generalized Anxiety Disorder-7-item (GAD-7) questionnaire., Results: Subjects with MDD reported significantly more anxiety symptoms, as assessed by the GAD-7, compared to HC (p < 0.001). Linear regression analysis determined that anxiety symptoms significantly accounted for 70.4% of the variability in subjective cognitive impairment, adjusting for depression severity. Moreover, subjects' ratings of the difficulties caused by their anxiety were reported as significantly more severe among subjects with MDD when compared to HC (p < 0.001). Likewise, greater self-reported difficulties with anxiety significantly predicted 57.8% of the variability in subjective cognitive impairment, adjusting for depression severity. Neither anxiety symptoms nor impairment due to anxiety symptoms predicted objective cognitive performance., Limitations: Subjects were not prospectively verified to have a clinical diagnosis of GAD. Rather, this study examined the relationships between symptoms of generalized anxiety, assessed using a brief screening tool, and subjective and objective cognitive function., Conclusions: Results from the current study indicate that adults with MDD and high levels of self-reported anxiety are significantly more likely to report experiencing subjective cognitive dysfunction., (Copyright © 2018 Elsevier B.V. All rights reserved.)

[This corrects the article on p. 68 in vol. 36, PMID: 28392999.].

Competing Interests: CONFLICTS OF INTEREST: The authors have nothing to disclose.

Background: Blood pressure (BP) control is the most-established method for the prevention of chronic kidney disease (CKD) progression. However, the ideal BP target for CKD patients is still under debate., Methods: We performed a survey of regular registered members of the Korean Society of Nephrology to determine physician perceptions of BP control in patients with CKD. In addition, we evaluated the target BP achievement rate using data from the APrODiTe-2 study., Results: Two-thirds of physicians considered the target BP for CKD to be < 130/85 mmHg. The systolic BP (SBP) thresholds for diabetic CKD, proteinuria ≥ 300 mg/day, 30 ≤ glomerular filtration rate (GFR) < 60 mL/min/1.73 m 2 , age < 60 years, and the presence of atherosclerotic (ASO) complications were significantly lower than the SBP thresholds of the opposite parameters. The three major hurdles to controlling BP were non-compliance with lifestyle modification and medications, and self-report of well-controlled home BP. Most physicians prescribed home and ambulatory BP monitoring to less than 50% of their patients. The target BP achievement rates using the SBP thresholds in this survey were as follows: non-diabetic (69.3%); diabetic (29.5%); proteinuria < 300 mg/day (72.3%); proteinuria > 300 mg/day (33.7%); GFR ≥ 60 (76.4%); GFR < 30 (47.8%); no evidence of ASO (67.8%); and the presence of ASO (42.9%)., Conclusion: The target BP was lower in patients with higher cerebro-cardiovascular risks. These patient groups also showed lower target BP achievement rates. We also found a relatively lower application and clinical reflection rate of home or ambulatory BP monitoring., Competing Interests: Conflicts of interest All authors have no conflicts of interest to declare.

Background: Contrast-induced acute kidney injury (CI-AKI) is one of the most common causes of iatrogenic kidney injury and, therefore, its prevention is an important issue. However, whether the administration of 0.9% saline is the optimal prophylaxis method remains uncertain due to its supra-physiologic chloride component. In particular, recent studies suggest that chloride-restricted solutions showed superiority over 0.9% saline in several clinical settings., Methods/design: The investigators designed a multicenter randomized controlled trial to compare the efficacy of a balanced salt solution and 0.9% saline in CI-AKI prophylaxis. This study will recruit patients who are scheduled for contrast-enhanced computed tomography (CT) scans with CI-AKI prophylaxis. In this study, participants will be randomized into two study arms; the study group will receive a balanced salt solution, and the control group will receive 0.9% saline. Fluids will be administered as designated in the protocol before and after the CT scan, and an evaluation of baseline clinical status will be performed by obtaining blood and urine samples. During the follow-up visits, the incidence of CI-AKI and long-term outcomes, including the start of renal replacement therapy or all-cause mortality, will be assessed., Discussion: To our knowledge, this study will be the first study assessing the preventive value of a balanced salt solution over 0.9% saline for CI-AKI. If the trial shows that the balanced salt solution is as effective for CI-AKI prophylaxis as 0.9% saline, the use of the balanced salt solution could be promoted due to the reduced possibility of consequent metabolic acidosis compared to 0.9% saline., Trials Registration: ClinicalTrials.gov, ID: NCT02799368 . Registered on 14 June 2016.

Patients with chronic kidney disease (CKD) have markedly increased rates of major adverse cardiovascular and cerebrovascular events (MACCEs) and mortality. Therefore, identifying early biomarkers predicting clinical outcomes in patients with CKD is critical. We aimed to determine whether osteoglycin, a basic component of the vascular extracellular matrix, was associated with MACCEs or all-cause mortality, using data from a prospective randomized controlled study, K-STAR (Kremezin STudy Against Renal disease progression in Korea: NCT 00860431). A total of 383 patients (mean age: 56.4 years, men/women = 252/131) with CKD stage 3 to 4 from the original trial were enrolled in the present study. We measured serum osteoglycin level and examined the impact of osteoglycin on clinical outcomes. The mean value of osteoglycin levels was 13.3 ± 9.4 ng/mL (healthy control: 5.3 ± 2.1 ng/mL). In multivariable analysis, lower levels of proteinuria and hemoglobin and higher levels of C-reactive protein were significantly associated with higher osteoglycin levels. Estimated glomerular filtration rate was not related to osteoglycin level. During a mean follow-up period of 56 months, 25 deaths, 61 MACCEs, and 76 composite outcomes (all-cause mortality or MACCEs) occurred. In the non-diabetic group, each 1-ng/mL increase in serum osteoglycin was associated with all-cause mortality and composite outcome (hazard ratio [HR] = 1.058, P = 0.031; HR = 1.041, P = 0.036). However, osteoglycin levels were not associated with mortality, MACCEs, or composite outcome in the diabetic group. Our results indicate that serum osteoglycin is a potential predictor of adverse outcomes in patients with CKD.

Cardiovascular disease (CVD) is the main public health problem in patients with chronic kidney disease (CKD); however, there is no established biomarker for predicting CVD morbidity and mortality in CKD. The aim of this study was to evaluate the role of circulating tumor necrosis factor receptors (cTNFRs) in predicting CVD risk in CKD patients.We prospectively recruited 984 patients with CKD from 11 centers between 2006 and 2012. The levels of cTNFR1 and cTNFR2 were determined by performing an enzyme-linked immunosorbent assay. During the mean follow-up period of 4 years, 36 patients experienced a CVD event. The median serum concentrations of cTNFR1 and cTNFR2 were 2703.4 (225.6-13,057.7) and 5661.0 (634.9-30,599.6) pg/mL, respectively, and the cTNFR1 level was closely correlated with the cTNFR2 level (r = 0.86, P < .0001). The urinary protein-to-creatinine ratio (UPCR) and estimated glomerular filtration rate (eGFR) were significantly correlated with the cTNFR2 level (r = 0.21 for UPCR, r = -0.67 for eGFR; P < .001 for all). Similar correlations were observed for serum cTNFR1 (r = 0.21 for UPCR, r = -0.75 for eGFR; P < .001 for all). In the Cox proportional hazard analyses, cTNFR1 (hazard ratio [HR] 2.506, 95% confidence interval [CI] 1.186-5.295, P = .016) and cTNFR2 (HR 4.156, 95% CI 1.913-9.030, P < .001) predicted CVD risk even after adjustment for clinical covariates, such as UPCR, eGFR, and high-sensitivity C-reactive protein. cTNFR1 and 2 are associated with CVD and other risk factors in CKD, independently of eGFR and UPCR. Furthermore, cTNFRs could be relevant predictors of CVD in CKD patients.

Objective: Blood pressure (BP) control is the most established practice for preventing the progression of chronic kidney disease (CKD). We examined the BP control and nocturnal dipping pattern changes in hypertensive patients with CKD and their effects on target organ damages., Methods: We recruited 378 hypertensive CKD patients from four centers in Korea. The patients underwent clinic and ambulatory BP monitoring at the time of enrollment and 1 year later., Results: The BP control states at the two time points were as follows: true controlled (16.5, 17.5%), white-coat (2.9, 0.4%), masked (50.0, 53.3%), and sustained uncontrolled (30.6, 28.8%) hypertension. The dipping states at two time points were as follows: extreme-dipping (11.4, 10.8%), dipping (22.2, 20.5%), nondipping (31.3, 34.7%), and reverse-dipping (35.0, 34.0%). When we divided the patients according to the median estimated glomerular filtration rate (eGFR) and proteinuria changes, more stable changes in eGFR and proteinuria were associated with better (to true controlled and white-coat) initial and follow-up BP control statuses. Moreover, better BP control and dipping (to dipper) changes were also associated with more stable eGFR and proteinuria changes. Good initial and follow-up BP control statuses were associated with less left ventricular hypertrophy. Also, masked and sustained uncontrolled hypertension was associated with more cardio-cerebrovascular events in the univariate analysis., Conclusions: A large majority of Korean hypertensive CKD patients had uncontrolled BP and abnormal dipping patterns. Furthermore, better BP control and dipping status changes were associated with better renal function and proteinuria, and also less cardio-cerebrovascular damages.

Background: We investigated the long-term effect of AST-120, which has been proposed as a therapeutic option against renal disease progression, in patients with advanced chronic kidney disease (CKD)., Methods: We performed post-hoc analysis with a per-protocol group of the K-STAR study (Kremezin study against renal disease progression in Korea) that randomized participants into an AST-120 and a control arm. Patients in the AST-120 arm were given 6 g of AST-120 in three divided doses, and those in both arms received standard conventional treatment., Results: The two arms did not differ significantly in the occurrence of composite primary outcomes (log-rank P = 0.41). For AST-120 patients with higher compliance, there were fewer composite primary outcomes: intermediate tertile hazard ratio (HR) 0.62, 95% confidence interval (CI) 0.38 to 1.01, P = 0.05; highest tertile HR 0.436, 95% CI 0.25 to 0.76, P = 0.003. The estimated glomerular filtration rate level was more stable in the AST-120 arm, especially in diabetic patients. At one year, the AST-120-induced decrease in the serum indoxyl sulfate concentration inversely correlated with the occurrence of composite primary outcomes: second tertile HR 1.59, 95% CI 0.82 to 3.07, P = 0.17; third tertile HR 2.11, 95% CI 1.07 to 4.17, P = 0.031. Furthermore, AST-120 showed a protective effect against the major cardiovascular adverse events (HR 0.51, 95% CI 0.26 to 0.99, P = 0.046)., Conclusion: Long-term use of AST-120 has potential for renal protection, especially in diabetic patients, as well as cardiovascular benefits. Reduction of the serum indoxyl sulfate level may be used to identify patients who would benefit from AST-120 administration.

We evaluated the diagnostic and clinical usefulness of blood specimens to detect Middle East respiratory syndrome coronavirus infection in 21 patients from the 2015 outbreak in South Korea. Viral RNA was detected in blood from 33% of patients at initial diagnosis, and the detection preceded a worse clinical course.

Background and Objectives: Cardiovascular outcomes and mortality rates are poor in advanced chronic kidney disease (CKD) patients. Novel risk factors related to clinical outcomes should be identified., Methods: A retrospective analysis of data from a randomized controlled study was performed in 440 CKD patients aged > 18 years, with estimated glomerular filtration rate 15-60 mL/min/1.73m2. Clinical data were available, and the albumin-adjusted serum anion gap (A-SAG) could be calculated. The outcome analyzed was all-cause mortality., Results: Of 440 participants, the median (interquartile range, IQR) follow-up duration was 5.1 (3.0-5.5) years. During the follow-up duration, 29 participants died (all-cause mortality 6.6%). The area under the receiver operating characteristic curve of A-SAG for all-cause mortality was 0.616 (95% CI 0.520-0.712, P = 0.037). The best threshold of A-SAG for all-cause mortality was 9.48 mmol/L, with sensitivity 0.793 and specificity 0.431. After adjusting for confounders, A-SAG above 9.48 mmol/L was independently associated with increased risk of all-cause mortality, with hazard ratio 2.968 (95% CI 1.143-7.708, P = 0.025). In our study, serum levels of beta-2 microglobulin and blood urea nitrogen (BUN) were positively associated with A-SAG., Conclusions: A-SAG is an independent risk factor for all-cause mortality in advanced CKD patients. The positive correlation between A-SAG and serum beta-2 microglobulin or BUN might be a potential reason. Future study is needed., Trial Registration: Clinicaltrials.gov NCT 00860431.

Background and Objectives: The notion that oral intestinal sorbent AST-120 slows renal disease progression has not been evaluated thoroughly. In this study, we investigated the long-term effect of AST-120 on renal disease progression (doubling of serum creatinine, eGFR decrease >50%, or initiation of RRT) in patients with advanced CKD., Design, Setting, Participants, & Measurements: We prospectively recruited 579 patients (CKD stage 3 or 4) from 11 medical centers in Korea from March 4, 2009 to August 31, 2010 and randomized them into an AST-120 arm and a control arm. Patients in the AST-120 arm were given 6 g AST-120 in three divided doses per day, and those in the control arm received only standard conventional treatment (open-label design) for 36 months or until the occurrence of primary outcomes., Results: Levels of serum and urine indoxyl sulfate and β2-microglobulin decreased throughout the study period in both treatment arms; however, there was not a significant difference in change in uremic toxins in the AST-120 and control arms. The two arms were not different in the occurrence of composite primary outcomes (100 events in 272 individuals in the AST-120 arm and 100 events in 266 individuals in the control arm; hazard ratio, 1.12; 95% confidence interval, 0.85 to 1.48; log-rank P=0.45). The decline in eGFR and change in proteinuria were similar in the two treatment arms over time (Prandomization-time=0.64 and Prandomization-time=0.16, respectively). There was no difference in mortality (nine deaths in the AST-120 arm and 11 deaths in the control arm; log-rank P=0.73) or unplanned hospitalizations (102 in the AST-120 arm and 109 in the control arm; log-rank P=0.76) in the two treatment arms. There was no significant difference of the health-related quality of life score between the two arms., Conclusions: Long-term use of AST-120 added to standard treatment did not change renal disease progression, proteinuria, mortality, and health-related quality of life in patients with advanced renal dysfunction., (Copyright © 2016 by the American Society of Nephrology.)

A 68-year old man diagnosed with Middle East Respiratory Syndrome-Coronavirus (MERS-CoV) presented with multiple pneumonic infiltrations on his chest X-ray, and the patient was placed on a mechanical ventilator because of progressive respiratory failure. Urinary protein excretion steadily increased for a microalbumin to creatinine ratio of 538.4 mg/g Cr and a protein to creatinine ratio of 3,025.8 mg/g Cr. The isotope dilution mass spectrometry traceable serum creatinine level increased to 3.0 mg/dL. We performed a kidney biopsy 8 weeks after the onset of symptoms. Acute tubular necrosis was the main finding, and proteinaceous cast formation and acute tubulointerstitial nephritis were found. There were no electron dense deposits observed with electron microscopy. We could not verify the virus itself by in situ hybridization and confocal microscopy (MERS-CoV co-stained with dipeptidyl peptidase 4). The viremic status, urinary virus excretion, and timely kidney biopsy results should be investigated with thorough precautions to reveal the direct effects of MERS-CoV with respect to renal complications.

Introduction: The objective of our study was to investigate cross-sectional associations of atrial fibrillation with neuroimaging measures of cerebrovascular disease and Alzheimer's disease and their interactions with mild cognitive impairment (MCI)., Methods: Magnetic resonance imaging scans of individuals from a population-based study were analyzed for infarctions, total gray matter, and hippocampal and white matter hyperintensity volumes. A subsample underwent positron emission tomography imaging., Results: Atrial fibrillation was associated with infarctions and lower total gray matter volume. Compared with subjects with no atrial fibrillation and no infarction, the odds ratio (95% confidence intervals) for MCI was 2.99 (1.57-5.70; P = .001) among participants with atrial fibrillation and infarction, 0.90 (0.45-1.80; P = .77) for atrial fibrillation and no infarction, and 1.50 (0.96-2.34; P = .08) for no atrial fibrillation and any infarction., Discussion: Participants with both atrial fibrillation and infarction are more likely to have MCI than participants with either infarction or atrial fibrillation alone., (Copyright © 2016 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Background/aims: Race and ethnicity are important determinants when estimatingglomerular filtration rate (GFR). The Korean coefficients for the isotope dilution mass spectrometry (IDMS) Modification of Diet in Renal Disease (MDRD) Study equations were developed in 2010. However, the coefficients have not been validated. The aim of this study was to validate the performance of the Korean coefficients for the IDMS MDRD Study equations., Methods: Equation development and validation were performed in separate groups (development group, n = 147 from 2008 to 2009; validation group, n = 125 from 2010 to 2012). We compared the performance of the original IDMS MDRD equations and modified equations with Korean coefficients. Performance was assessed by comparing correlation coefficients, bias, and accuracy between estimated GFR and measured GFR, with systemic inulin clearance using a single injection method., Results: The Korean coefficients for the IDMS MDRD equations developed previously showed good performance in the validation group. The new Korean coefficients for the four- and six-variable IDMS MDRD equations using both the development and validation cohorts were 1.02046 and 0.97300, respectively. No significant difference was detected for the new Korean coefficients, in terms of estimating GFR, between the original and modified IDMS MDRD Study equations., Conclusions: The modified equations with Korean coefficients for the IDMS MDRD Study equations were not superior to the original equations for estimating GFR. Therefore, we recommend using the original IDMS MDRD Study equation without ethnic adjustment in the Korean population.

Morning hypertension (HTN) and nocturnal non-dipping (ND) are closely associated with target organ damage and cardiovascular events. However, their importance in diabetics with advanced renal disease is unclear. We evaluated the relationships of morning HTN and ND with estimated glomerular filtration rate (eGFR) and proteinuria, and determined the risk of morning HTN and ND according to presence of diabetes mellitus (DM) and chronic kidney disease (CKD) stage. A total of 1312 patients, including 439 with diabetes, were prospectively recruited at 21 centers in Korea. All patients had HTN and an eGFR of 15-89 ml min(-1) per 1.73 m(2). Ambulatory 24-h blood pressure was assessed. The rates of morning HTN (25.2% vs. 13.6%, P<0.001) and ND (58.2% vs. 48.2%, P=0.002) were higher in diabetics than in non-diabetics. eGFR was correlated with ND in all patients (P<0.05) and with morning HTN only in non-diabetics (P=0.005). Proteinuria was related to ND in all patients (P<0.05) and to morning HTN only in diabetics (P=0.001). In a regression analysis, the risk of morning HTN was 2.093 (95% confidence interval (95% CI): 1.070-4.094) for the DMCKD2 group, 1.634 (95% CI: 1.044-2.557) for the CKD3-4-only group and 2.236 (95% CI: 1.401-3.570) for the DMCKD3-4 group compared with the CKD2-only group. The risk of ND was high for stage 3-4 CKD: 1.581 (95% CI: 1.180-2.120) for non-diabetics and 1.842 (95% CI: 1.348-2.601) for diabetics. Diabetics showed higher rates of morning HTN, ND and uncontrolled sustained HTN compared with non-diabetics with CKD of the same stages.

Some cases of Middle East Respiratory Syndrome-Coronavirus (MERS-CoV) infection presented renal function impairment after the first MERS-CoV patient died of progressive respiratory and renal failure. Thus, MERS-CoV may include kidney tropism. However, reports about the natural courses of MERS-CoV infection in terms of renal complications are scarce. We examined 30 MERS-CoV patients admitted to National Medical Center, Korea. We conducted a retrospective analysis of the serum creatinine (SCr), estimated glomerular filtration rate (eGFR), urine dipstick tests, urinary protein quantitation (ACR or PCR), and other clinical parameters in all patients. Two consecutive results of more than trace (or 1+) of albumin and blood on dipstick test occurred in 18 (60%) (12 [40%]) and 22 (73.3%) (19 [63.3%]) patients, respectively. Fifteen (50.0%) patients showed a random urine ACR or PCR more than 100 mg/g Cr. Eight (26.7%) patients showed acute kidney injury (AKI), and the mean and median durations to the occurrence of AKI from symptom onset were 18 and 16 days, respectively. Old age was associated with a higher occurrence of AKI in the univariate analysis (HR [95% CI]: 1.069 [1.013-1.128], P = 0.016) and remained a significant predictor of the occurrence of AKI after adjustment for comorbidities and the application of a mechanical ventilator. Diabetes, AKI, and the application of a continuous renal replacement therapy (CRRT) were risk factors for mortality in the univariate analysis (HR [95% CI]: diabetes; 10.133 [1.692-60.697], AKI; 12.744 [1.418-114.565], CRRT; 10.254 [1.626-64.666], respectively). Here, we report renal complications and their prognosis in 30 Korean patients with MERS-CoV.

Objective: To understand the neuropsychological basis of dementia risk among persons in the spectrum including cognitive normality and mild cognitive impairment., Methods: We quantitated risk of progression to dementia in elderly persons without dementia from 2 population-based studies, the Framingham Heart Study (FHS) and Mayo Clinic Study of Aging (MCSA), aged 70 to 89 years at enrollment. Baseline cognitive status was defined by performance in 4 domains derived from batteries of neuropsychological tests (that were similar but not identical for FHS and MCSA) at cut scores corresponding to SDs of ≤-0.5, -1, -1.5, and -2 from normative means. Participants were characterized as having no cognitive impairment (reference group), or single or multiple amnestic or nonamnestic profiles at each cut score. Incident dementia over the following 6 years was determined by consensus committee at each study separately., Results: The pattern of hazard ratios for incident dementia, rates of incident dementia and positive predictive values across cognitive test cut scores, and number of affected domains was similar although not identical across the FHS and MCSA. Dementia risks were higher for amnestic profiles than for nonamnestic profiles, and for multidomain compared with single-domain profiles., Conclusions: Cognitive domain subtypes, defined by neuropsychologically derived cut scores and number of low-performing domains, differ substantially in prognosis in a conceptually logical manner that was consistent between FHS and MCSA. Neuropsychological characterization of elderly persons without dementia provides valuable information about prognosis. The heterogeneity of risk of dementia cannot be captured concisely with one test or a single definition or cutpoint., (© 2015 American Academy of Neurology.)

We conducted a preliminary case-control investigation of the association of pancreatic polypeptide (PP) with mild cognitive impairment (MCI) in 202 MCI cases (mean age, 81.6 years) and 202 age- and sex-matched cognitively normal controls in the Mayo Clinic Study of Aging. Plasma PP was measured and examined as the natural logarithm (continuous) and dichotomized at the median. The OR (95% CI) of MCI increased with increasing PP [1.46 (1.04-2.05)]. There was a negative interaction of PP with apolipoprotein E (APOE) ε4 allele; compared to the reference group (no APOE ε4 allele and low PP), the OR (95% CI) for combinations of ε4 and PP were: 2.64 (1.39-5.04) for APOE ε4 plus low PP; 2.09 (1.27-3.45) for no APOE ε4 plus high PP; and 1.91 (1.04-3.53) for no APOE ε4 plus high PP (P for interaction = 0.017). There was also a trend toward a negative interaction with type 2 diabetes (P for interaction = 0.058). Compared to no diabetes and low PP, the OR (95% CI) was 3.02 (1.22-7.46) for low PP plus diabetes but 1.80 (1.01-3.22) for high PP plus diabetes. Participants with high PP had a greater mean (SD) weight loss (kilograms per decade) than persons with low PP [-2.27 (4.07) vs. -1.61 (5.24); P = 0.016]. MCI cases had a non-significantly greater weight loss per decade compared to controls. These findings suggest that high PP alone or jointly with APOE ε4 allele or type 2 diabetes is associated with MCI, and that high PP may mitigate some effects of APOE ε4 allele and type 2 diabetes on cognition. Potential mechanisms may involve PP-related weight loss and centrally mediated effects of PP on cognition. These findings remain to be validated in other studies.

Background/aims: Ambulatory blood pressure (BP) monitoring has been widely recommended for evaluating the status of BP, but is lacking in practicality. Determination of the specific time points for BP measurement that are representative of 24-hour mean BP could be useful and convenient in hypertensive patients with chronic kidney disease (CKD)., Methods: A total of 1,317 patients for whom 24-hour ambulatory BP monitoring was performed were enrolled in a multicenter study on hypertensive CKD. We analyzed the time points at which systolic blood pressure (SBP) values exhibited the smallest differences from 24-hour mean SBP (mSBP). We included office mSBP and analyzed the relationships between SBPs at the office and the time points with the smallest differences from 24-hour mSBP using several methods., Results: The time points with the smallest differences from 24-hour mSBP were 7:00 AM, 2:00 PM, and 9:30 PM. In regression analysis, SBPs at 7:00 AM and 9:30 PM were better correlated with 24-hour mSBP than SBPs at 2:00 PM and the office. The proportions of patients with SBPs within 30% of 24-hour mSBP were higher at 7:00 AM and 9:30 PM. The best consistency between the uncontrolled hypertensive groups, defined as ≥ 135 mmHg of 24-hour mSBP and higher values of SBPs corresponding to 135 mmHg of 24-hour mSBP, were observed at the 7:00 AM and 9:30 PM time points., Conclusions: The specific time points for SBPs that correlated well with 24-hour mSBP in hypertensive CKD patients were 7:00 AM and 9:30 PM.

Objectives: To determine the association between multiple chronic conditions and risk of incident mild cognitive impairment (MCI) and dementia., Design: Prospective cohort study., Setting: Olmsted County, Minnesota., Participants: Cognitively normal individuals (N = 2,176) enrolled in the Mayo Clinic Study of Aging (MCSA)., Measurements: Participants were randomly selected from the community, evaluated by a physician, and underwent neuropsychometric testing at baseline and at 15-month intervals to assess diagnoses of MCI and dementia. Information on International Classification of Diseases, Ninth Revision codes for chronic conditions in the 5 years before enrollment was electronically captured using the Rochester Epidemiology Project medical records linkage system. Multimorbidity was defined as having two or more chronic conditions, and the association between multimorbidity and MCI and dementia was examined using Cox proportional hazards models., Results: Of 2,176 cognitively normal participants (mean age ± standard deviation 78.5 ± 5.2; 50.6% male), 1,884 (86.6%) had multimorbidity. The risk of MCI or dementia was higher in persons with multimorbidity (hazard ratio (HR) = 1.38, 95% confidence interval (CI) = 1.05-1.82) than in those with one or no chronic condition. The HR was of greater magnitude in persons with four or more conditions (HR = 1.61, 95% CI = 1.21-2.13) than in those with two or three conditions (HR = 1.03, 95% CI = 0.76-1.39) and for men with multimorbidity(HR = 1.53, 95% CI = 1.01-2.31) than for women with multimorbidity (HR = 1.20, 95% CI = 0.83-1.74), compared to those with one or no chronic condition., Conclusion: In older adults, having multiple chronic conditions is associated with greater risk of MCI and dementia. This is consistent with the hypothesis that multiple etiologies may contribute to MCI and late-life dementia. Preventing chronic diseases may be beneficial in delaying or preventing MCI and dementia., (© 2015, Copyright the Authors Journal compilation © 2015, The American Geriatrics Society.)