Association between circulating ECM-associated molecules and cardiovascular outcomes in hemodialysis patients: a multicenter prospective cohort study.

Hemodialysis patients are susceptible to cardiovascular remodeling, which increases the risk of cardiovascular morbidity and mortality. Circulating extracellular matrix (ECM)-associated molecules increase during cardiovascular remodeling and can be potential biomarkers of adverse cardiovascular outcomes. However, their clinical significance in patients undergoing hemodialysis remain unclear. This study aimed to elucidate the association between circulating ECM-associated molecules and cardiovascular outcomes in patients undergoing hemodialysis. To this end, we measured levels of plasma matrix metalloproteinase (MMP)-2, MMP-9, tenascin-C, and thrombospondin-2 in 372 patients with hemodialysis. Plasma MMP-2 levels were significantly higher in patients with future cardiovascular events than in those without future cardiovascular events (P = 0.004). All measured molecules had significant correlations with amino-terminal pro-brain natriuretic peptide levels, but the correlation coefficient was the strongest for plasma MMP-2 (rho = 0.317, P < 0.001). High plasma MMP-2 levels were predictive of left ventricular (LV) diastolic dysfunction (adjusted odds ratio per a standard deviation increase = 1.48, 95% confidence interval [CI] = 1.05-2.08) and were independently associated with an increased risk of composite cardiovascular events (adjusted hazard ratio per a standard deviation increase = 1.30, 95% CI = 1.04-1.63). In conclusion, high plasma MMP-2 levels are associated with LV diastolic dysfunction and an increased risk of adverse cardiovascular outcomes in hemodialysis patients.

PTEN-induced kinase 1 exerts protective effects in diabetic kidney disease by attenuating mitochondrial dysfunction and necroptosis.

Mitochondrial dysfunction plays a pivotal role in diabetic kidney disease initiation and progression. PTEN-induced serine/threonine kinase 1 (PINK1) is a core organizer of mitochondrial quality control; however, its function in diabetic kidney disease remains controversial. Here, we aimed to investigate the pathophysiological roles of PINK1 in diabetic tubulopathy, focusing on its effects on mitochondrial homeostasis and tubular cell necroptosis, which is a specialized form of regulated cell death. PINK1-knockout mice showed more severe diabetes-induced tubular injury, interstitial fibrosis, and albuminuria. The expression of profibrotic cytokines significantly increased in the kidneys of diabetic Pink1-/- mice, which eventually culminated in aggravated interstitial fibrosis. Additionally, the knockdown of PINK1 in HKC-8 cells upregulated the fibrosis-associated proteins, and these effects were rescued by PINK1 overexpression. PINK1 deficiency was also associated with exaggerated hyperglycemia-induced mitochondrial dysfunction and defective mitophagic activity, whereas PINK1 overexpression ameliorated these negative effects and restored mitochondrial homeostasis. Mitochondrial reactive oxygen species triggered tubular cell necroptosis under hyperglycemic conditions, which was aggravated by PINK1 deficiency and improved by its overexpression. In conclusion, PINK1 plays a pivotal role in suppressing mitochondrial dysfunction and tubular cell necroptosis under high glucose conditions and exerts protective effects in diabetic kidney disease.

Prostaglandin F2α analogue, bimatoprost ameliorates colistin-induced nephrotoxicity.

Colistin (polymyxin E) is an antibiotic that is effective against multidrug-resistant gram-negative bacteria. However, the high incidence of nephrotoxicity caused by colistin limits its clinical use. To identify compounds that might ameliorate colistin-induced nephrotoxicity, we obtained 1707 compounds from the Korea Chemical Bank and used a high-content screening (HCS) imaging-based assay. In this way, we found that bimatoprost (one of prostaglandin F2α analogue) ameliorated colistin-induced nephrotoxicity. To further assess the effects of bimatoprost on colistin-induced nephrotoxicity, we used in vitro and in vivo models. In cultured human proximal tubular cells (HK-2), colistin induced dose-dependent cytotoxicity. The number of terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells, indicative of apoptosis, was higher in colistin-treated cells, but this effect of colistin was ameliorated by cotreatment with bimatoprost. The generation of reactive oxygen species, assessed using 2,7-dichlorodihydrofluorescein diacetate, was less marked in cells treated with both colistin and bimatoprost than in those treated with colistin alone. Female C57BL/6 mice (n = 10 per group) that were intraperitoneally injected with colistin (10 mg/kg/12 hr) for 14 days showed high blood urea nitrogen and serum creatinine concentrations that were reduced by the coadministration of bimatoprost (0.5 mg/kg/12 hr). In addition, kidney injury molecule-1 (KIM1) and Neutrophil gelatinase-associated lipocalin (NGAL) expression also reduced by bimatoprost administration. Further investigation in tubuloid and kidney organoids also showed that bimatoprost attenuated the nephrotoxicity by colistin, showing dose-dependent reducing effect of KIM1 expression. In this study, we have identified bimatoprost, prostaglandin F2α analogue as a drug that ameliorates colistin-induced nephrotoxicity.

Mitochondrial quality control and its emerging role in the pathogenesis of diabetic kidney disease.

Most eukaryotic cells have mitochondrial networks that can change in shape, distribution, and size depending on cellular metabolic demands and environments. Mitochondrial quality control is critical for various mitochondrial functions including energy production, redox homeostasis, intracellular calcium handling, cell differentiation, proliferation, and cell death. Quality control mechanisms within mitochondria consist of antioxidant defenses, protein quality control, DNA damage repair systems, mitochondrial fusion and fission, mitophagy, and mitochondrial biogenesis. Defects in mitochondrial quality control and disruption of mitochondrial homeostasis are common characteristics of various kidney cell types under hyperglycemic conditions. Such defects contribute to diabetes-induced pathologies in renal tubular cells, podocytes, endothelial cells, and immune cells. In this review, we focus on the roles of mitochondrial quality control in diabetic kidney disease pathogenesis and discuss current research evidence and future directions.

Corrigendum: Development and validation of urinary exosomal microRNA biomarkers for the diagnosis of acute rejection in kidney transplant recipients.

[This corrects the article DOI: 10.3389/fimmu.2023.1190576.].

PTEN-induced kinase 1 is associated with renal aging, via the cGAS-STING pathway.

Mitochondrial dysfunction is considered to be an important mediator of the pro-aging process in chronic kidney disease, which is continuously increasing worldwide. Although PTEN-induced kinase 1 (PINK1) regulates mitochondrial function, its role in renal aging remains unclear. We investigated the association between PINK1 and renal aging, especially through the cGAS-STING pathway, which is known to result in an inflammatory phenotype. Pink1 knockout (Pink1-/- ) C57BL/6 mice and senescence-induced renal tubular epithelial cells (HKC-8) treated with H2 O2 were used as the renal aging models. Extensive analyses at transcriptomic-metabolic levels have explored changes in mitochondrial function in PINK1 deficiency. To investigate whether PINK1 deficiency affects renal aging through the cGAS-STING pathway, we explored their expression levels in PINK1 knockout mice and senescence-induced HKC-8 cells. PINK1 deficiency enhances kidney fibrosis and tubular injury, and increases senescence and the senescence-associated secretory phenotype (SASP). These phenomena were most apparent in the 24-month-old Pink1-/- mice and HKC-8 cells treated with PINK1 siRNA and H2 O2 . Gene expression analysis using RNA sequencing showed that PINK1 deficiency is associated with increased inflammatory responses, and transcriptomic and metabolomic analyses suggested that PINK1 deficiency is related to mitochondrial metabolic dysregulation. Activation of cGAS-STING was prominent in the 24-month-old Pink1-/- mice. The expression of SASPs was most noticeable in senescence-induced HKC-8 cells and was attenuated by the STING inhibitor, H151. PINK1 is associated with renal aging, and mitochondrial dysregulation by PINK1 deficiency might stimulate the cGAS-STING pathway, eventually leading to senescence-related inflammatory responses.

Development and validation of urinary exosomal microRNA biomarkers for the diagnosis of acute rejection in kidney transplant recipients.

Introduction: Acute rejection (AR) continues to be a significant obstacle for short- and long-term graft survival in kidney transplant recipients. Herein, we aimed to examine urinary exosomal microRNAs with the objective of identifying novel biomarkers of AR. Materials and methods: Candidate microRNAs were selected using NanoString-based urinary exosomal microRNA profiling, meta-analysis of web-based, public microRNA database, and literature review. The expression levels of these selected microRNAs were measured in the urinary exosomes of 108 recipients of the discovery cohort using quantitative real-time polymerase chain reaction (qPCR). Based on the differential microRNA expressions, AR signatures were generated, and their diagnostic powers were determined by assessing the urinary exosomes of 260 recipients in an independent validation cohort. Results: We identified 29 urinary exosomal microRNAs as candidate biomarkers of AR, of which 7 microRNAs were differentially expressed in recipients with AR, as confirmed by qPCR analysis. A three-microRNA AR signature, composed of hsa-miR-21-5p, hsa-miR-31-5p, and hsa-miR-4532, could discriminate recipients with AR from those maintaining stable graft function (area under the curve [AUC] = 0.85). This signature exhibited a fair discriminative power in the identification of AR in the validation cohort (AUC = 0.77). Conclusion: We have successfully demonstrated that urinary exosomal microRNA signatures may form potential biomarkers for the diagnosis of AR in kidney transplantation recipients.

Cortical thickness of the rostral anterior cingulate gyrus is associated with frailty in patients with end-stage renal disease undergoing hemodialysis in Korea: a cross-sectional study.

BACKGROUND: Frailty is defined as a condition of being weak and delicate, and it represents a state of high vulnerability to adverse health outcomes. Recent studies have suggested that the cingulate gyrus is associated with frailty in the elderly population. However, few imaging studies have explored the relationship between frailty and the cingulate gyrus in patients with end-stage renal disease (ESRD) undergoing hemodialysis. METHODS: Eighteen right-handed patients with ESRD undergoing hemodialysis were enrolled in the study. We used the FreeSurfer software package to estimate the cortical thickness of the regions of interest, including the rostral anterior, caudal anterior, isthmus, and posterior cingulate gyri. The Beck Depression Inventory, Beck Anxiety Inventory, and laboratory tests were also conducted. RESULTS: The cortical thickness of the right rostral anterior cingulate gyrus (ACG) was significantly correlated with the Fried frailty index, age, and creatinine level. Multiple regression analysis indicated that the cortical thickness of the right rostral ACG was associated with frailty after controlling for age and creatinine level. CONCLUSION: Our results indicate that the cortical thickness of the rostral ACG may be associated with frailty in patients with ESRD on hemodialysis and that the rostral ACG may play a role in the frailty mechanism of this population.

Proteomic profiling of protein expression changes after 3 months-exercise in ESRD patients on hemodialysis.

The prevalence of chronic kidney disease (CKD) is steadily increasing, and it is a global health burden. Exercise has been suggested to improve physical activity and the quality of life in patients with CKD, eventually reducing mortality. This study investigated the change in physical performance after exercise in dialysis-dependent patients with CKD and analyzed differentially expressed proteins before and after the exercise. Plasma samples were collected at enrollment and after 3 months of exercise. Liquid chromatography with tandem mass spectrometry analysis and data-independent acquisition results were analyzed to determine the significantly regulated proteins. A total of 37 patients on dialysis were recruited, and 16 were randomized to exercise for 3 months. The hand grip strength and the walking speed significantly improved in the exercise group. Proteome analysis revealed 60 significantly expressed proteins after 3 months of exercise. In the protein functional analysis, the significantly expressed proteins were involved in the immune response. Also, some of the key significantly expressed proteins [(M Matrix metallopeptidase 9 (MMP-9), Activin A Receptor Type 1B (ACVR1B), Fetuin B (FETUB)] were validated via an enzyme-linked immunosorbent assay. Our results showed that exercise in dialysis-dependent patients with CKD could improve their physical performance. These results indicated that this beneficial effect of exercise in these populations could be associated with immune response.

Plasma Interleukin-6 Level Predicts the Risk of Arteriovenous Fistula Dysfunction in Patients Undergoing Maintenance Hemodialysis.

Systemic inflammation has been proposed as a relevant factor of vascular remodeling and dysfunction. We aimed to identify circulating inflammatory biomarkers that could predict future arteriovenous fistula (AVF) dysfunction in patients undergoing hemodialysis. A total of 282 hemodialysis patients were enrolled in this prospective multicenter cohort study. Plasma cytokine levels were measured at the time of data collection. The primary outcome was the occurrence of AVF stenosis and/or thrombosis requiring percutaneous transluminal angioplasty or surgery within the first year of enrollment. AVF dysfunction occurred in 38 (13.5%) patients during the study period. Plasma interleukin-6 (IL-6) levels were significantly higher in patients with AVF dysfunction than those without. Diabetes mellitus, low systolic blood pressure, and statin use were also associated with AVF dysfunction. The cumulative event rate of AVF dysfunction was the highest in IL-6 tertile 3 (p = 0.05), and patients in tertile 3 were independently associated with an increased risk of AVF dysfunction after multivariable adjustments (adjusted hazard ratio = 3.06, p = 0.015). In conclusion, circulating IL-6 levels are positively associated with the occurrence of incident AVF dysfunction in hemodialysis patients. Our data suggest that IL-6 may help clinicians identify those at high risk of impending AVF failure.

Dialysis unit blood pressure two hours after hemodialysis is useful for predicting home blood pressure and ambulatory blood pressure in maintenance hemodialysis patients.

This study aimed to determine which BP measurement obtained in the HD unit correlated best with home BP and ambulatory BP monitoring (ABPM). We retrospectively analyzed data from 40 patients that received maintenance HD who had available home BP and ABPM data. Dialysis unit BPs were the averages of pre-, 2hr- (2 h after starting HD), and post-HD BP during a 9-month study. Home BP was defined as the average of morning and evening home BPs. Dialysis unit BP and home BP were compared over the 9-month study period. ABPM was performed once for 24 h in the absence of dialysis during the final 2 weeks of the study period and was compared to the 2-week dialysis unit BP and home BP. There was a significant difference between dialysis unit systolic blood pressure (SBP) and home SBP over the 9-month period. No significant difference was observed between the 2hr-HD SBP and home SBP. When analyzing 2 weeks of dialysis unit BP and home BP, including ABPM, SBPs were significantly different (dialysis unit BP > home BP > ABPM; P = 0.009). Consistent with the 9-month study period, no significant difference was observed between 2hr-HD SBP and home SBP (P = 0.809). The difference between 2hr-HD SBP and ambulatory SBP was not significant (P = 0.113). In conclusion, the 2hr-HD SBP might be useful for predicting home BP and ABPM in HD patients.

PINK1 deficiency impairs osteoblast differentiation through aberrant mitochondrial homeostasis.

BACKGROUND: PTEN-induced kinase 1 (PINK1) is a serine/threonine-protein kinase in mitochondria that is critical for mitochondrial quality control. PINK1 triggers mitophagy, a selective autophagy of mitochondria, and is involved in mitochondrial regeneration. Although increments of mitochondrial biogenesis and activity are known to be crucial during differentiation, data regarding the specific role of PINK1 in osteogenic maturation and bone remodeling are limited. METHODS: We adopted an ovariectomy model in female wildtype and Pink1-/- mice. Ovariectomized mice were analyzed using micro-CT, H&E staining, Masson's trichrome staining. RT-PCR, western blot, immunofluorescence, alkaline phosphatase, and alizarin red staining were performed to assess the expression of PINK1 and osteogenic markers in silencing of PINK1 MC3T3-E1 cells. Clinical relevance of PINK1 expression levels was determined via qRT-PCR analysis in normal and osteoporosis patients. RESULTS: A significant decrease in bone mass and collagen deposition was observed in the femurs of Pink1-/- mice after ovariectomy. Ex vivo, differentiation of osteoblasts was inhibited upon Pink1 downregulation, accompanied by impaired mitochondrial homeostasis, increased mitochondrial reactive oxygen species production, and defects in mitochondrial calcium handling. Furthermore, PINK1 expression was reduced in bones from patients with osteoporosis, which supports the practical role of PINK1 in human bone disease. CONCLUSIONS: In this study, we demonstrated that activation of PINK1 is a requisite in osteoblasts during differentiation, which is related to mitochondrial quality control and low reactive oxygen species production. Enhancing PINK1 activity might be a possible treatment target in bone diseases as it can promote a healthy pool of functional mitochondria in osteoblasts.

The adipokine Retnla deficiency increases responsiveness to cardiac repair through adiponectin-rich bone marrow cells.

Resistin-like alpha (Retnla) is a member of the resistin family and known to modulate fibrosis and inflammation. Here, we investigated the role of Retnla in the cardiac injury model. Myocardial infarction (MI) was induced in wild type (WT), Retnla knockout (KO), and Retnla transgenic (TG) mice. Cardiac function was assessed by echocardiography and was significantly preserved in the KO mice, while worsened in the TG group. Angiogenesis was substantially increased in the KO mice, and cardiomyocyte apoptosis was markedly suppressed in the KO mice. By Retnla treatment, the expression of p21 and the ratio of Bax to Bcl2 were increased in cardiomyocytes, while decreased in cardiac fibroblasts. Interestingly, the numbers of cardiac macrophages and unsorted bone marrow cells (UBCs) were higher in the KO mice than in the WT mice. Besides, phosphorylated histone H3(+) cells were more frequent in bone marrow of KO mice. Moreover, adiponectin in UBCs was notably higher in the KO mice compared with WT mice. In an adoptive transfer study, UBCs were isolated from KO mice to transplant to the WT infarcted heart. Cardiac function was better in the KO-UBCs transplanted group in the WT-UBCs transplanted group. Taken together, proliferative and adiponectin-rich bone marrow niche was associated with substantial cardiac recovery by suppression of cardiac apoptosis and proliferation of cardiac fibroblast.

Beneficial Effect of Chloroquine and Amodiaquine on Type 1 Diabetic Tubulopathy by Attenuating Mitochondrial Nox4 and Endoplasmic Reticulum Stress.

BACKGROUND: Oxidative stress induced by chronic hyperglycemia is recognized as a significant mechanistic contributor to the development of diabetic kidney disease (DKD). Nonphagocytic nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) is a major source of reactive oxygen species (ROS) in many cell types and in the kidney tissue of diabetic animals. We designed this study to explore the therapeutic potential of chloroquine (CQ) and amodiaquine (AQ) for inhibiting mitochondrial Nox4 and diabetic tubular injury. METHODS: Human renal proximal tubular epithelial cells (hRPTCs) were cultured in high-glucose media (30 mM D-glucose), and diabetes was induced with streptozotocin (STZ, 50 mg/kg i.p. for 5 days) in male C57BL/6J mice. CQ and AQ were administered to the mice via intraperitoneal injection for 14 weeks. RESULTS: CQ and AQ inhibited mitochondrial Nox4 and increased mitochondrial mass in hRPTCs under high-glucose conditions. Reduced mitochondrial ROS production after treatment with the drugs resulted in decreased endoplasmic reticulum (ER) stress, suppressed inflammatory protein expression and reduced cell apoptosis in hRPTCs under high-glucose conditions. Notably, CQ and AQ treatment diminished Nox4 activation and ER stress in the kidneys of STZ-induced diabetic mice. In addition, we observed attenuated inflammatory protein expression and albuminuria in STZ-induced diabetic mice after CQ and AQ treatment. CONCLUSION: We substantiated the protective actions of CQ and AQ in diabetic tubulopathy associated with reduced mitochondrial Nox4 activation and ER stress alleviation. Further studies exploring the roles of mitochondrial Nox4 in the pathogenesis of DKD could suggest new therapeutic targets for patients with DKD.

Genome-wide RNA interference screening reveals a COPI-MAP2K3 pathway required for YAP regulation.

The transcriptional regulator YAP, which plays important roles in the development, regeneration, and tumorigenesis, is activated when released from inhibition by the Hippo kinase cascade. The regulatory mechanism of YAP in Hippo-low contexts is poorly understood. Here, we performed a genome-wide RNA interference screen to identify genes whose loss of function in a Hippo-null background affects YAP activity. We discovered that the coatomer protein complex I (COPI) is required for YAP nuclear enrichment and that COPI dependency of YAP confers an intrinsic vulnerability to COPI disruption in YAP-driven cancer cells. We identified MAP2K3 as a YAP regulator involved in inhibitory YAP phosphorylation induced by COPI subunit depletion. The endoplasmic reticulum stress response pathway activated by COPI malfunction appears to connect COPI and MAP2K3. In addition, we provide evidence that YAP inhibition by COPI disruption may contribute to transcriptional up-regulation of PTGS2 and proinflammatory cytokines. Our study offers a resource for investigating Hippo-independent YAP regulation as a therapeutic target for cancers and suggests a link between YAP and COPI-associated inflammatory diseases.

Anti-microbial and anti-inflammatory effects of Cheonwangbosim-dan against Helicobacter pylori-induced gastritis.

BACKGROUND: There are various Helicobacter species colonizing the stomachs of animals. Although Helicobacter species usually cause asymptomatic infection in the hosts, clinical signs can occur due to gastritis associated with Helicobacter in animals. Among them, Helicobacter pylori is strongly associated with chronic gastritis, gastric ulcers, and gastric cancers. As the standard therapies used to treat H. pylori have proven insufficient, alternative options are needed to prevent and eradicate the diseases associated with this bacterium. Cheonwangbosim-dan (CBD), a traditional herbal formula that is popular in East Asia, has been commonly used for arterial or auricular flutter, neurosis, insomnia, and cardiac malfunction-induced disease. OBJECTIVES: The present study investigated the antimicrobial effect of CBD on H. pylori-infected human gastric carcinoma AGS cells and model mice. METHODS: AGS cells were infected with H. pylori and treated with a variety of concentrations of CBD or antibiotics. Mice were given 3 oral inoculations with H. pylori and then dosed with CBD (100 or 500 mg/kg) for 4 weeks or with standard antibiotics for 1 week. One week after the last treatment, gastric samples were collected and examined by histopathological analysis, real-time quantitative polymerase chain reaction, and immunoblotting. RESULTS: Our results showed that CBD treatment of AGS cells significantly reduced the H. pylori-induced elevations of interleukin-8, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). In the animal model, CBD treatment inhibited the colonization of H. pylori and the levels of malondialdehyde, inflammation, proinflammatory cytokines, iNOS, and COX-2 in gastric tissues. CBD also decreased the phosphorylation levels of p38 mitogen-activated protein kinase family. CONCLUSIONS: This study suggests that CBD might be a prospective candidate for treating H. pylori-induced gastric injury.

Long-Term Benefit and Withdrawal Effect of Statins After Percutaneous Coronary Intervention: A Nationwide Population-Based Cohort Study.

PURPOSE: Despite indubitable evidence for the cardiovascular benefits of statins, there have been concerns that statin discontinuation may cause negative effects known as "statin withdrawal syndrome." This study aimed to assess the benefit and the withdrawal effect of statins after percutaneous coronary intervention (PCI). PATIENTS AND METHODS: We conducted a retrospective cohort study on 5218 patients who underwent PCI between 2002 and 2013 using the nationwide health insurance claim data in Korea. Based on the prescription data, the use of statins during follow-up was classified into three risk periods: "statin period" (period with statin cover), "statin withdrawal period" (withdrawal of statin within 30 days), and "no statin period" (no exposure to statin for longer than 30 days). The primary outcome was the composite outcome of myocardial infarction, coronary revascularization, stroke, and all-cause death. We performed multivariate Cox proportional regression analyses which treated the use of statins as a time-dependent variable. RESULTS: During the follow-up period of 3.54 ± 2.91 years (mean ± standard deviation), 1515 (29.0%) patients sustained a primary outcome. Compared with the "no statin period," the "statin period" was associated with lower risk of the primary outcome (adjusted hazard ratio [HR] 0.72, 95% confidence interval [CI, 0.63-0.81]). While the "statin withdrawal period" posed a significantly increased risk (adjusted HR 1.87, 95% CI [1.52-2.29]). With respect to the intensity of statins associated with withdrawal, dose-dependent increased risk was observed for withdrawal of low-, moderate-, and high-intensity statins; adjusted HR [95% CI] were 1.45 [0.74-2.86], 1.86 [1.49-2.32], and 2.61 [1.41-4.81], respectively. CONCLUSION: After PCI, there was an increased cardiovascular risk during the statin withdrawal period, especially with the use of high-intensity statins. To maximize the beneficial effect and to avoid the withdrawal effect of statins, high-risk patients need to adhere to taking statins without discontinuation.

Association between Vitamin D Level and Muscle Strength in Patients Undergoing Hemodialysis.

INTRODUCTION: Identification of the risk factors and treatment of the decrease in muscle mass or strength are important to improve the prognosis of patients undergoing hemodialysis (HD). Previous studies have investigated the association between vitamin D level and muscle mass or strength in patients undergoing HD. However, there are conflicting results regarding this association. OBJECTIVE: To evaluate the association between vitamin D level and muscle mass indices, strength, or physical performance in patients undergoing HD. METHODS: This study was performed in a tertiary medical center. We included patients undergoing HD aged ≥20 years. A total of 84 patients were enrolled. The patients were divided into tertiles based on the 25-hydroxy (25-OH) vitamin D level as follows: lowest tertile (Lowest T, n = 28), middle tertile (Middle T, n = 28), and highest tertile (Highest T, n = 28). We evaluated the association between the tertiles and clinical outcomes including nutritional status, muscle mass, muscle function, handgrip strength (HGS), physical performance, and health-related quality of life (HRQoL) scales. RESULTS: There were no significant differences in the muscle mass indices and nutritional markers according to tertiles of 25-OH vitamin D level. However, 25-OH vitamin D level as a continuous variable or the tertile of 25-OH vitamin D level as a categorical variable was positively associated with HGS. Logistic and linear regression analyses showed a consistent superiority of the Highest T in HGS compared with the Lowest or Middle T. Although the statistical significance was weak, the scores of various physical performance tests and the HRQoL scales were highest in the Highest T among the 3 tertiles. CONCLUSION: The present study demonstrated that serum vitamin D level is associated with HGS in patients undergoing HD regardless of muscle mass indices or nutritional status.

Asteris Radix et Rhizoma suppresses testosterone-induced benign prostatic hyperplasia in rats by regulating apoptosis and inflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Asteris Radix et Rhizoma (AR) refers to the roots and rhizomes of Aster tataricus L., which is widely distributed throughout East Asia. AR has been consumed as a traditional medicine in Korea, Japan and China for the treatment of urologic symptoms. To date, however, the therapeutic effect of AR on benign prostatic hyperplasia (BPH) has not been investigated. AIM OF THE STUDY: The present study evaluated the therapeutic effects of AR on a testosterone-induced BPH rats. MATERIALS AND METHODS: We induced BPH to rats by subcutaneous injections (s.c) of testosterone propionate (TP) daily for four weeks. Rats were also administered daily oral gavage of AR (150 mg/kg) or vehicle. After four weeks of induction, all animals were euthanized humanely and their prostate glands were removed, weighed and processed for further analysis, including histopathological examination, real-time PCR, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and Western blot analysis. RESULTS: Administration of AR to TP-induced BPH rats considerably reduced prostate weight and concentrations of serum testosterone and prostate dihydrotestosterone (DHT). Epithelial thickness and expression of proliferating cell nuclear antigen (PCNA) were markedly suppressed by AR-treatment in the rats. Furthermore, the expression of the B-cell lymphoma 2 (Bcl-2) were reduced and expression of the Bcl-2-associated X protein (Bax) increased, resulting in significant reduction in Bcl-2/Bax ratio. In addition, AR decreased the level of pro-inflammatory cytokines, including interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). The expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) were reduced by AR treatment in a TP-induced BPH rat model. CONCLUSIONS: AR alleviates BPH by promoting apoptosis and suppressing inflammation, indicating that AR may be used clinically to treat BPH accompanied by inflammation.

Effects of online hemodiafiltration on anemia and nutritional status in chronic hemodialysis patients.

BACKGROUND: Online hemodiafiltration (OL-HDF) offers considerable advantages in clearance of molecules of various sizes. However, evidence of clinical effects of OL-HDF is scarce in Korea. In this study, we investigated changes in laboratory values over more than 12 months after switching to OL-HDF. METHODS: Adult patients with end-stage renal disease undergoing hemodialysis (HD) were prospectively enrolled in a K-cohort (CRIS no. KCT0003281) from 6 tertiary hospitals in South Korea. We recruited 435 patients, 339 of whom were on HD at enrollment. One hundred eighty-two patients were followed for more than 24 months. Among them, 44 were switched to OL-HDF for more than 12 months without conversion to HD. We used a paired t test to compare baseline and 24-month follow-up results. RESULTS: The mean age of the subjects was 61.2 ± 12.2 years, and 62.6% were male. The baseline hemoglobin level was not significantly different between HD and OL-HDF group (10.61 ± 1.15 vs. 10.46 ± 1.03 g/dL, P = 0.437). However, the baseline serum protein and albumin levels were significantly lower in the OL-HDF group (6.82 ± 0.49 vs. 6.59 ± 0.48 g/dL, P = 0.006; 3.93 ± 0.28 vs. 3.73 ± 0.29 g/dL, P < 0.001). In patients switched to OL-HDF, levels of hemoglobin and serum albumin significantly increased (10.46 ± 1.03 vs. 11.08 ± 0.82 g/dL, P = 0.001; 3.73 ± 0.29 vs. 3.87 ± 0.30 g/dL, P = 0.001). The normalized protein catabolic rate decreased after 24 months, but the change was not significant (1.07 ± 0.25 vs. 1.03 ± 0.21 g/kg/day, P = 0.433). Although the dose of erythropoiesis-stimulating agent was lower in patients who converted to HDF, it was not significantly different (-115.7 ± 189.7 vs. -170.5 ± 257.1 P = 0.206). CONCLUSION: OL-HDF treatment over more than 12 months was associated with no harmful effects on anemia and nutritional status.