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Abstract Background Collaborative learning is an essential pedagogy in medical education, within which small group learning constitutes an integral component. Online small group teaching has been widely applied and blended with in-person sessions in the aftermath of the Covid-19 pandemic. This study examined whether group metacognition was associated with teamwork satisfaction in an online small group teaching curriculum for medical students. Methods We enrolled medical students of the 2nd and 4th years during the 2021 fall semester after they participated in 3 consecutive sessions of online small group tutorials (SGTs), which have been implemented in our medical school for more than 20 years. The students completed a group metacognitive scale (GMS) and a teamwork satisfaction scale (TSS) after the sessions. We analyzed whether group metacognition in 4 dimensions (knowledge of cognition, planning, evaluating, and monitoring) could be connected with medical students’ teamwork satisfaction using partial least squares-structural equation modeling (PLS-SEM). Results A total of 263 medical students participated in this study. Both GMS and TSS exhibited good reliability and validity. Three of the 4 dimensions of group metacognition (cognition, planning, and evaluating) positively correlated with teamwork satisfaction (path coefficients 0.311, 0.279, and 0.21; p = 0.002, 0.002, and 0.043, respectively) following the online SGT curriculum, whereas the monitoring dimension did not (path coefficient 0.087; p = 0.357). The model achieved an adjusted R square of 0.683. Conclusion We discovered that group metacognition correlated positively with better teamwork satisfaction, supporting the importance of group metacognitive competency for online collaborative learning.

Background: Valvular calcification (VC) refers to the calcified valvular remodeling associated with kidney dysfunction, especially end-stage kidney disease (ESKD). ESKD patients with VC had significantly higher cardiovascular risk than those without. Factors interacted with VC regarding prognostic prediction in this population were seldom investigated. We aimed to examine the potential synergetic effects of VC and alkaline phosphatase (Alk-P) on ESKD patients’ cardiovascular risk and mortality. Methods: ESKD patients undergoing hemodialysis were prospectively enrolled from a medical center in 2018. We identified patients with echocardiography and available serum Alk-P levels. Cox proportional hazard regression was performed to analyze the risk of major adverse cardiovascular events (MACEs), cardiovascular and overall mortality among 4 participant groups (with or without VC versus low or high Alk-P levels). The models were further adjusted for age, sex, and clinical variables. Results: Of the 309 ESKD patients, 38, 46, 112, and 113 had no VC with low Alk-P, no VC with high Alk-P, VC with low Alk-P, and VC with high Alk-P, respectively. After adjusting for age and sex, patients with VC and high Alk-P had a higher risk of developing MACE, cardiovascular and overall mortality (HR, 3.07, 3.67, 3.65; 95% CI 1.38–6.84, 1.1–12.24, 1.29–10.36, respectively). Patients with VC and high Alk-P remained at higher risk of MACE (HR, 2.76; 95% CI 1.17–6.48) than did those without VC and with low Alk-P. Conclusion: Serum Alk-P could be used to identify a subgroup of ESKD patients with elevated cardiovascular risk among those with VC.

Summary: Protein-energy wasting (PEW) denotes the pathologic combination of undernutrition and excessive catabolism observed mainly in patients with chronic kidney disease (CKD). The risk of PEW increases progressively during the trajectory of renal function decline, so does that of another progeric syndrome “frailty” which describes the rising susceptibility to various insults during chronological or biological aging. Patients with CKD and PEW are at higher risk of having chronic uncontrolled pain, for which the treatment of choice is frequently limited. Under-treatment of pain is a common scenario in renal patients with PEW. Opioids and their derivatives carry therapeutic potential in these patients, but their use is associated with an increased probability of consciousness change, falls and fractures over time, followed by a surge in short- and long-term mortality due to pharmacokinetic issues. This condition poses an ethical dilemma for physicians who wish to optimize pain management for renal patients with PEW based on opioids. Our prior investigation showed that frailty assisted in stratifying patients into groups without or with opioid-related mortality risk. Opioid users with CKD may have progressively diminished mortality risk from opioid use compared to never-users following frail severity increases, and the risk disappeared among those with severe frailty. The use of frailty as a simple triaging approach may play a potential role in the shared decision making course, with regard to who will not be harmed by opioid use among patients with CKD and PEW.

Background: The factors affecting cardiovascular risk associated with vascular calcification in patients with chronic kidney disease are less well addressed. Distinct risk factors may contribute synergistically to this elevated cardiovascular risk in this population. Objectives: We aimed to determine whether echocardiographic left ventricular hypertrophy (LVH) affects the risk of major adverse cardiac events (MACE) associated with vascular calcification in end-stage kidney disease (ESKD) patients. Methods: In this retrospective cohort study, ESKD patients underwent chest radiography and echocardiography to assess aortic arch calcification (AoAC) and LVH, respectively, and were classified into three groups accordingly: non-to-mild AoAC without LVH, non-to-mild AoAC with LVH, and moderate-to-severe AoAC. The risks of MACE, cardiovascular mortality, and overall mortality were assessed using Cox proportional hazard analysis. Results: Of the 283 enrolled ESKD patients, 44 (15.5%) had non-to-mild AoAC without LVH, 117 (41.3%) had non-to-mild AoAC with LVH, and 122 (43.1%) had moderate-to-severe AoAC. After 34.1 months, 107 (37.8%) participants developed MACE, including 6 (13.6%), 40 (34.2%), and 61 (50%) from each respective group. Those with moderate-to-severe AoAC (Hazard ratio, 3.72; 95% confidence interval, 1.58–8.73) had a significantly higher risk of MACE than did those with non-to-mild AoAC without LVH or with non-to-mild AoAC and LVH (Hazard ratio, 2.73; 95% confidence interval, 1.16–6.46). A similar trend was observed for cardiovascular and overall mortality. Conclusion: Echocardiographic LVH could modify the risk of adverse cardiovascular events associated with vascular calcification in ESKD patients. Interventions aiming to ameliorate both morbidities might be translated into a lower MACE risk in this population.

Abstract Frailty is the incremental accumulation of minute defects that progressively impair health and performance. Frailty is commonly observed in older adults; however, secondary frailty may also occur in patients with metabolic disorders or major organ failure. In addition to physical frailty, several distinct types of frailty have been identified, including oral, cognitive, and social frailty, each of which is of practical importance. This nomenclature suggests that detailed descriptions of frailty can potentially advance relevant researches. In this narrative review, we first summarize the clinical value and plausible biological origin of frailty, as well as how to appropriately assess it using physical frailty phenotypes and frailty indexes. In the second part, we discuss the issue of vascular tissue as a relatively underappreciated organ whose pathologies contribute to the development of physical frailty. Moreover, when vascular tissue undergoes degeneration, it exhibits vulnerability to subtle injuries and manifests a unique phenotype amenable to clinical assessment prior to or accompanying physical frailty development. Finally, we propose that vascular frailty, based on an extensive set of experimental and clinical evidence, can be considered a new frailty type that requires our attention. We also outline potential methods for the operationalization of vascular frailty. Further studies are required to validate our claim and sharpen the spectrum of this degenerative phenotype.

Abstract Background Small group tutorials (SGT) promotes self-directed learning and is widely used in medical education. The coronavirus pandemic (COVID-19) has accelerated the trend toward SGT digitalization, with unclear effect. We hypothesize that team dynamics and facilitator support influence SGT satisfaction in digital versus conventional SGT. Methods During the spring semester of year 2021, medical students (the second, third, and fourth year; n = 433) participating in conventional face-to-face and digital SGT curricula were enrolled. Participating students completed the collaborative learning attitude scale (including team dynamics, team acquaintance, and facilitator support dimensions) and teamwork satisfaction scale, previously validated for small-group collaborative learning, and chose preference between conventional or digital SGT in future curricula. Exploratory factor analysis (EFA) was performed to extract the essential structural factors of these scales. Paired t-tests were conducted to compare differences in different dimensions and satisfaction between the conventional and digital SGT settings. Two sets of multiple regression analyses were done; one with team satisfaction scale results and the other with preference for digital SGT as the dependent variable were used to evaluate determinants of these two variables. Results The EFA results revealed that the original collaborative learning attitude scale was concentrated on two dimensions: team dynamics and facilitator support. No significant differences were noted between the SGT settings for the two dimensions and teamwork satisfaction. Regression analyses showed that teamwork dynamics was independently correlated with teamwork satisfaction in both conventional and digital SGT. Facilitator support was positively correlated with teamwork satisfaction in conventional, but not digital SGT. Higher teamwork satisfaction was an important determinant of preference for digital SGT among medical students. Conclusions Team dynamics were closely linked to teamwork satisfaction among medical students in both conventional and digital SGT, while the role of facilitator support became less obvious during digital SGT.

Digital problem-based learning (PBL) was originally introduced as a means to improve student engagement and increase flexibility. However, its use becomes mandatory during the coronavirus disease 2019 (COVID-19) period, accelerating changes in medical education. Few elaborated on the implementation details of digital PBL curricula. Technical guidance can be important but under-recognized prerequisite of a successful digital PBL session. In National Taiwan University College of Medicine, we established a digital PBL curriculum and previously validated a confidence questionnaire for surveying undergraduate students receiving digital PBL sessions. In this opinion piece, we gleaned multiple procedural details from our experiences based on students'/tutors' feedback, which we summarized in a 5″W″ recommendations (Who), timing/duration (When), location (Where), software/hardware/topics (What), and evaluation aspects (Why). Suggestions on how to optimally prepare for digital PBL session are also provided. We believe that these tips can further facilitate the wide adoption of digital PBL.

Abstract Background To enhance tutors’ teaching skills, tutor shadowing for novice tutors of problem-based learning (PBL) in addition to conventional faculty development (FD) was applied. This study aimed to develop a tutoring-skill scale (TS-scale) and evaluate the effect of shadowing on PBL tutors. Methods This study employed a before-and-after study design with three phases. In phase 1, a TS-scale was elaborated. A validity examination was performed in phase 2. Phase 3 was a study of the effectiveness using a TS-scale survey of novice PBL tutors before and after the FD course. The FD course for novice PBL tutors included an FD workshop and PBL shadowing activities. Results A TS-scale with a 32-item questionnaire of self-rated confidence for PBL tutors was identified in phase 1. In phase 2, 7 experienced specialists in medical education were invited to evaluate the content validity of the scale. The item content validity index (I-CVI) ranged from 0.86 to 1, and the scale-CVI (S-CVI) was 0.95. A total of 85 novice PBL tutors completed the TS-scale before the FD course, yielding a Cronbach’s alpha of 0.98. An exploratory factor analysis with varimax rotation was performed. The twenty-four items with significant loadings greater than 0.5 were incorporated into a new TS-scale and were grouped into three factors: student contact, medical expertise, and teaching expertise. In phase 3, 76 novice PBL tutors completed the 24-item TS-scale before (pretest) and after (posttest) the FD course. Their self-rated confidence improved significantly across the three factors after the FD course. The pretest and posttest scores did not differ according to the tutors’ gender, the grades they taught, or their specialty background. Conclusions Novice PBL tutors benefit from FD that incorporates tutor shadowing in the 3 key domains of tutoring competencies. The TS-scale developed in this study can be applied in future research on FD design.

Abstract Background The activation of the unfolded protein response (UPR) is closely linked to the pathogenesis of renal injuries. However, the role of XBP1, a crucial regulator of adaptive UPR, remains unclear during the transition from acute kidney injury (AKI) to chronic kidney disease (CKD). Methods We characterized XBP1 expressions in different mouse models of kidney injuries, including unilateral ischemia–reperfusion injury (UIRI), unilateral ureteral obstruction, and adenine-induced CKD, followed by generating proximal tubular XBP1 conditional knockout (XBP1cKO) mice for examining the influences of XBP1. Human proximal tubular epithelial cells (HK-2) were silenced of XBP1 to conduct proteomic analysis and investigate the underlying mechanism. Results We showed a tripartite activation of UPR in injured kidneys. XBP1 expressions were attenuated after AKI and inversely correlated with the severity of post-AKI renal fibrosis. XBP1cKO mice exhibited more severe renal fibrosis in the UIRI model than wide-type littermates. Silencing XBP1 induced HK-2 cell cycle arrest in G2M phase, inhibited cell proliferation, and promoted TGF-β1 secretion. Proteomic analysis identified TNF receptor associated protein 1 (Trap1) as the potential downstream target transcriptionally regulated by XBP1s. Trap1 overexpression can alleviate silencing XBP1 induced profibrotic factor expressions and cell cycle arrest. Conclusion The loss of XBP1 in kidney injury was profibrotic, and the process was mediated by autocrine and paracrine regulations in combination. The present study identified the XBP1-Trap1 axis as an instrumental mechanism responsible for post-AKI fibrosis, which is a novel regulatory pathway.

Summary: Earlier detection of aortic calcification can facilitate subsequent cardiovascular care planning. Opportunistic screening based on plain chest radiography is potentially feasible in various population. We used multiple deep convolutional neural network (CNN) transfer learning by fine-tuning pre-trained models followed by ensemble technique for aortic arch calcification on chest radiographs from a derivation and two external databases with distinct features. Our ensemble approach achieved 84.12% precision, 84.70% recall, and an area under the receiver-operating-characteristic curve (AUC) of 0.85 in the general population/older adult’s dataset. We also obtained 87.5% precision, 85.56% recall, and an AUC of 0.86 in the pre-end-stage kidney disease (pre-ESKD) cohort. We identified discriminative regions for identifying aortic arch calcification between patients without and with pre-ESKD. These findings are expected to optimize cardiovascular risk prediction if our model is incorporated into the process of routine care.

IntroductionThis study aimed to investigate the association of aortic arch calcification (AoAC) and aortic valve calcification (AVC) with major adverse cardiovascular events (MACE) and cardiovascular and all-cause mortality in patients on maintenance hemodialysis (MHD).MethodsThis study enrolled 297 adult patients with end-stage kidney disease who were on MHD. They were divided into those with an AoAC score

Abstract Background Patients with diabetic mellitus (DM) and chronic kidney disease (CKD) are at an increased risk of urinary tract infection (UTI) due to their altered immunological integrity. These patients are similarly prone to developing frailty, a state of cumulative health deficits involving multiple domains and leading to adverse outcomes. Whether frailty predisposes affected individuals to UTI among patients with DM and CKD remains unclear. Methods A population-based cohort of patients with DM and CKD (n = 79,887) were assembled from the Longitudinal Cohort of Diabetes Patients, with their baseline frailty status measured by a modified FRAIL scale. We analyzed their risk of developing UTI depending on their severity of frailty, after accounting demographic profiles, lifestyle factors, comorbidities, concurrent medications, and major interventions. A secondary analysis focused on the risk of urosepsis related to frailty. Results Among all participants, 36.1 %, 50.3 %, 12.8 %, and 0.8 % did not have or had 1, 2, and ≥ 3 FRAIL items, respectively, at baseline. After 3.51 years, 11,175 UTI events occurred. Kaplan-Meier analysis showed that participants with DM, CKD and an increasing number of FRAIL items had successively higher incidence of UTI than those without any FRAIL items (log rank p

Abstract Background Chronic kidney disease (CKD) introduces an increased cardiovascular risk among patients with diabetes mellitus (DM). The risk and tempo of cardiovascular diseases may differ depending upon their type. Whether CKD differentially influences the risk of developing each cardiovascular morbidity in patients with newly diagnosed DM remains unexplored. Methods We identified patients with incident DM from the Longitudinal Cohort of Diabetes Patients (LCDP) cohort (n = 429,616), and uncovered those developing CKD after DM and their propensity score-matched counterparts without. After follow-up, we examined the cardiovascular morbidity-free rates of patients with and without CKD after DM, followed by Cox proportional hazard regression analyses. We further evaluated the cumulative risk of developing each outcome consecutively during the study period. Results From LCDP, we identified 55,961 diabetic patients with CKD and matched controls without CKD. After 4.2 years, patients with incident DM and CKD afterward had a significantly higher risk of mortality (hazard ratio [HR] 1.1, 95% confidence interval [CI] 1.06–1.14), heart failure (HF) (HR 1.282, 95% CI 1.19–1.38), acute myocardial infarction (AMI) (HR 1.16, 95% CI 1.04–1.3), and peripheral vascular disease (PVD) (HR 1.277, 95% CI 1.08–1.52) compared to those without CKD. The CKD-associated risk of mortality, HF and AMI became significant soon after DM occurred and remained significant throughout follow-up, while the risk of PVD conferred by CKD did not emerge until 4 years later. The CKD-associated risk of ischemic, hemorrhagic stroke and atrial fibrillation remained insignificant. Conclusions The cardiovascular risk profile among incident DM patients differs depending on disease type. These findings can facilitate the selection of an optimal strategy for early cardiovascular care for newly diagnosed diabetic patients.

BackgroundDepression confers substantial disease burden globally, especially among those with chronic kidney disease (CKD). The presence of depression significantly impairs one's quality of life. Risk factors for depression in patients with CKD remain under-appreciated, and whether frailty, a geriatric phenotype, constitutes a risk factor for depression in this population is unknown.MethodsWe prospectively enrolled patients with end-stage renal disease (ESRD) undergoing hemodialysis for >3 months from National Taiwan University Hospital Yunlin Branch between 2019 and 2021. Clinical, physical, functional, and performance parameters were recorded, followed by frailty/sarcopenia assessment. Depression was screened for using the Geriatric Depression Scale. We analyzed the independent relationship between frailty and depression in these patients, using multiple regression analyses.ResultsTotally 151 patients with ESRD were enrolled (mean 61.1 years, 66.9% male), among whom 16.6% had screening-identified depression. ESRD participants with depression did not differ from those without regarding most parameters except serum creatinine, functional indices, and sarcopenia/frailty status. We found that having greater frail severities was independently associated with a higher probability of depression; having FRAIL- (odds ratio [OR] 5.418) and SOF-based (OR 2.858) frailty independently correlated with a higher depression probability. A linear relation exists between a greater frail severity and the probability of depression. Using a more relaxed criterion for detecting depression, higher SOF scores remained significantly associated with an increased depression risk.ConclusionsIn patients with CKD, frailty independently correlated with a higher probability of having depression. Strategies aiming to attenuate frailty may be able to benefit those with depression simultaneously in this population.

Background: Patients with diabetic kidney disease (DKD) are at an increased risk of frailty. The exposure to muscle relaxants frequently leads to adverse effects despite their modest therapeutic efficacy, but whether muscle relaxants predispose users to frailty remains unclear. Methods: Patients with DKD from a population-based cohort, the Longitudinal Cohort of Diabetes Patients, were identified between 2004 and 2011 ( N = 840,000). Muscle relaxant users were propensity score-matched to never-users in a 1:1 ratio based on demographic features, comorbidities, outcome-relevant medications, and prior major interventions. Incident frailty, the study endpoint, was measured according to a modified FRAIL scale. We used Kaplan–Meier analyses and Cox proportional hazard regression to analyze the association between cumulative muscle relaxant use (⩾ 28 days) and the risk of incident frailty. Results: Totally, 11,637 users and matched never-users were enrolled, without significant differences regarding baseline clinical features. Cox proportional hazard regression showed that patients with DKD and received muscle relaxants had a significantly higher risk of incident frailty than never-users [hazard ratio (HR) 1.26, 95% confidence interval (CI) 1.04–1.53]. This increase in frailty risk paralleled that in cumulative muscle relaxant dosages (quartile 1 versus 2 versus 3 versus 4, HR 0.91 versus 1.22 versus 1.38 versus 1.45, p = 0.0013 for trend) and in exposure durations (quartile 1 versus 2 versus 3 versus 4, HR 1.12 versus 1.33 versus 1.23 versus 1.34, p = 0.0145 for trend) of muscle relaxants. Conclusion: We found that cumulative muscle relaxant exposure might increase frailty risk. It is prudent to limit muscle relaxant prescription in patients with DKD. Plain language summary Does cumulative muscle relaxant exposure increase the risk of incident frailty among patients with diabetic kidney disease? Background: Frailty denotes a degenerative feature that adversely influences one’s survival and daily function. Patients with diabetes and chronic kidney disease are at a higher risk of developing frailty, but whether concurrent medications, especially muscle relaxants, aggravate this risk remains undefined. Methods: In this population-based study including 11,637 muscle relaxant users and matched never-users with diabetic kidney disease, we used a renowned frailty-assessing tool, FRAIL scale, to assess frailty severity and examined the incidence of frailty brought by muscle relaxant exposure. Results: We found that users exhibited a 26% higher risk of developing incident frailty compared with never-users, and the probability increased further if users were prescribed higher doses or longer durations of muscle relaxants. Conclusion: We concluded that in those with diabetic kidney disease, cumulative muscle relaxant use was associated with a higher risk of incident frailty, suggesting that moderation of muscle relaxant use in this population can be of potential importance.

Background/Aims: Awareness of chronic kidney disease (CKD) has been low among affected patients, particularly the older ones. However, whether such awareness is synonymous with the presence of laboratory-diagnosed CKD among older adults is currently unclear. Methods: We enrolled community-dwelling old adults (≥ 65 years) who received health examinations between 2013 and 2016 from a regional metropolitan hospital. Clinical information and geriatric syndromes including depression, cognitive impairment, fall, quality of life, and visual disturbance were evaluated during the medical interview. We compared the differences in clinical features between those with and without self-reported or estimated glomerular filtration rate (eGFR)-based CKD and investigated their influences and interactions on the risk of CKD complications and geriatric syndromes. Results: Among the 2932 enrolled older adults (mean 73.4 ± 7 years), 93 (3%) reported that they had CKD by history, while 306 (10%) had an eGFR < 60 mL/min/1.73m2 persisted for over 3 months. The prevalence of hyperlipidemia, body mass index, waist circumference, leukocyte count, and the incidence of fall differed only between those with and without eGFR-based CKD, but not between those with and without self-reported CKD. A synergistic effect was found between self-reported and eGFR-based CKD regarding the CKD complication severity, including malnutrition (albumin), anemia (hemoglobin), dyslipidemia (serum cholesterol), and geriatric syndromes (cognitive and quality of life impairment). Multivariate regression analyses showed that self-reported CKD exhibited better predictive efficacy for lower serum albumin and hemoglobin than eGFR-based CKD, while the latter outperformed the former for predicting lower serum cholesterol and a higher risk of cognitive impairment. Conclusion: Among older adults, self-reported CKD may not be a surrogate for laboratory-diagnosed CKD and has an independent effect on CKD-related complications.

Background: Vascular calcification (VC) is a subclinical manifestation of vascular disease burden among older adults, conferring an elevated mortality risk. Biomarkers capable of detecting and risk-stratifying VC associated with advanced age remains unavailable, impeding our effort to provide optimal care to geriatric patients.Objectives: In this study, we aimed to investigate whether circulating miR-125b served as a potential indicator for VC in relatively healthy older adults.Methods: Community-dwelling older adults (age ≥65) were prospectively recruited during 2017, followed by clinical features documentation and VC rating based on aortic arch calcification (AAC) and abdominal aortic calcification (AbAC). Multiple logistic regression was done to evaluate the relationship between circulating miR-125b levels, VC presence and severity, followed by selecting the optimal cutoff point for VC diagnosis.Results: A total of 343 relatively healthy older adults (median age, 73.8 years; 40% male; 59.8% having AAC) were enrolled, with a median circulating miR-125b level of 0.012 (interquartile range, 0.003–0.037). Those with more severe AAC had progressively decreasing miR-125b levels (p

Background Vascular calcification (VC) is associated with high morbidity and mortality among older adults, a population that exhibits a higher tendency for developing frailty at the same time. Whether VC serves as a risk factor for the development of frailty in this population remains unclear. Methods and Results We analyzed a prospectively assembled cohort of community‐dwelling older adults between 2014 and 2017 (n=1783). Frailty and prefrailty were determined on the basis of the Study of Osteoporotic Fractures criteria, and VC was measured using semiquantitative aortic arch calcification (AAC) and abdominal aortic calcification scoring. We conducted multiple logistic regression with prefrailty or frailty as the dependent variable, incorporating sociodemographic profiles, comorbidities, medications, laboratory data, AAC status/severity, and other geriatric phenotypes. Among all participants, 327 (18.3%) exhibited either prefrailty (15.3%) or frailty (3.1%), and 648 (36.3%) exhibited AAC. After adjusting for multiple confounders, we found that AAC incidence was associated with a substantially higher probability of prefrailty or frailty (odds ratio [OR], 11.9; 95% CI, 7.9–15.4), with a dose‐responsive relationship (OR for older adults with AAC categories 1, 2, and 3 was 9.3, 13.6, and 52.5, respectively). Similar association was observed for older adults with abdominal aortic calcification (OR, 5.0; 95% CI, 1.3–19.5), and might be replicable in another cohort of patients with end‐stage renal disease. Conclusions Severity of VC exhibited a linear positive relationship with frailty in older adults. Our findings suggest that a prompt diagnosis and potential management of VC may assist in risk mitigation for patients with frailty.

Background: Older adults are at an increased risk of frailty, but laboratory surrogates for identifying frailty in this population remain controversial and clinicians frequently encounter difficulty during frailty screening. We examined whether having a high red cell distribution width (RDW) was associated with an increased probability of frailty in older adults.Methods: We prospectively included community-dwelling older adults between 2013 and 2016 from a single institute, with their clinical features/laboratory parameters documented. We used the Study of Osteoporotic Fractures index (malnutrition, poor physical performance, and fatigue) to delineate frailty, and harnessed multiple logistic regression to investigate whether having a high RDW (≥ 15.7%) was associated with an increased risk of having frailty among these participants.Results: A total of 2,932 older adults (mean 73.5 ± 6.7 years; 44.6% male) were included, among whom 113 (3.9%) and 76 (2.6%) had a high RDW and presented frailty, respectively. Older adults with a high RDW were more likely to be frail (p = 0.002) and had more positive SOF items than those with normal RDW levels (p = 0.013). Those with a high RDW exhibited a significantly higher risk of having frailty (odds ratio [OR] 2.689, 95% confidence interval [CI] 1.184–6.109) compared to those without. Sensitivity analyses using RDW as a continuous variable similarly showed that RDW levels were positively associated with frailty risk (OR 1.223 per 1% RDW higher).Conclusions: In older adults, higher RDW can be regarded as a frailty indicator, and the readiness in RDW assessment supports its screening utility.

ObjectivePatients with diabetes have an increased risk for urolithiasis, but the associated risk factors remain an active area of research. We investigated whether frailty influenced the probability of patients with diabetes developing urolithiasis.Research design and methodsUsing data from the Longitudinal Cohort of Diabetic Patients from 2004 to 2010, we identified those without and with frailty based on a validated, modified FRAIL scale. Patients were followed until they developed urolithiasis, and we used Kaplan-Meier and Cox proportional hazard regression analyses to examine the relationship between frailty, its severity, and the risk of urolithiasis, accounting for demographic profiles, comorbidities, frailty status changes over follow-up, and medications, with risk competition by mortality.ResultsAmong 525 368 patients with diabetes, 64.4% were not frail, while 28.5%, 6.6%, and 0.6% had 1, 2, and ≥3 FRAIL items at baseline. After 4.2 years of follow-up, 13.4% experienced incident urolithiasis. Cox proportional hazard regression analysis showed that patients with diabetes having at least one FRAIL criterion exhibited a significantly higher risk for urolithiasis compared with non-frail patients (for 1, 2, and ≥3 items, hazard ratio (HR)s: 1.04, 1.23, and 1.46; 95% confidence intervals (CIs) 0.99 to 1.09, 1.12 to 1.35, and 1.12 to 1.91, respectively). This increase in urolithiasis risk remained significant if we restricted analyses to renal stones or recurrent urolithiasis as the study outcomes.ConclusionsFrailty may pose a risk for incident urolithiasis in patients with diabetes. Treating frailty may potentially reduce their risk for urolithiasis.

Chronic kidney disease (CKD) refers to the phenomenon of progressive decline in the glomerular filtration rate accompanied by adverse consequences, including fluid retention, electrolyte imbalance, and an increased cardiovascular risk compared to those with normal renal function. The triggers for the irreversible renal function deterioration are multifactorial, and diabetes mellitus serves as a major contributor to the development of CKD, namely diabetic kidney disease (DKD). Recently, epigenetic dysregulation emerged as a pivotal player steering the progression of DKD, partly resulting from hyperglycemia-associated metabolic disturbances, rising oxidative stress, and/or uncontrolled inflammation. In this review, we describe the major epigenetic molecular mechanisms, followed by summarizing current understandings of the epigenetic alterations pertaining to DKD. We highlight the epigenetic regulatory processes involved in several crucial renal cell types: Mesangial cells, podocytes, tubular epithelia, and glomerular endothelial cells. Finally, we highlight epigenetic biomarkers and related therapeutic candidates that hold promising potential for the early detection of DKD and the amelioration of its progression.

Abstract Background Diabetes mellitus (DM) correlates with accelerated aging and earlier appearance of geriatric phenotypes, including frailty. However, whether pre-frailty or frailty predicts greater healthcare utilization in diabetes patients is unclear. Methods From the Longitudinal Cohort of Diabetes Patients in Taiwan (n = 840,000) between 2004 and 2010, we identified 560,795 patients with incident type 2 DM, categorized into patients without frailty, or with 1, 2 (pre-frail) and ≥ 3 frailty components, based on FRAIL scale (Fatigue, Resistance, Ambulation, Illness, and body weight Loss). We examined their long-term mortality, cardiovascular risk, all-cause hospitalization, and intensive care unit (ICU) admission. Results Among all participants (56.4 ± 13.8 year-old, 46.1% female, and 84.8% community-dwelling), 77.8% (n = 436,521), 19.2% (n = 107,757), 2.7% (n = 15,101), and 0.3% (n = 1416) patients did not have or had 1, 2 (pre-frail), and ≥ 3 frailty components (frail), respectively, with Fatigue and Illness being the most common components. After 3.14 years of follow-up, 7.8% patients died, whereas 36.6% and 9.1% experienced hospitalization and ICU stay, respectively. Cox proportional hazard modeling discovered that patients with 1, 2 (pre-frail), and ≥ 3 frailty components (frail) had an increased risk of mortality (for 1, 2, and ≥ 3 components, hazard ratio [HR] 1.05, 1.13, and 1.25; 95% confidence interval [CI] 1.02–1.07, 1.08–1.17, and 1.15–1.36, respectively), cardiovascular events (HR 1.05, 1.15, and 1.13; 95% CI 1.02–1.07, 1.1–1.2, and 1.01–1.25, respectively), hospitalization (HR 1.06, 1.16, and 1.25; 95% CI 1.05–1.07, 1.14–1.19, and 1.18–1.33, respectively), and ICU admission (HR 1.05, 1.13, and 1.17; 95% CI 1.03–1.07, 1.08–1.14, and 1.06–1.28, respectively) compared to non-frail ones. Approximately 6–7% risk elevation in mortality and healthcare utilization was noted for every frailty component increase. Conclusion Pre-frailty and frailty increased the risk of mortality and cardiovascular events, and entailed greater healthcare utilization in patients with type 2 DM.

Abstract Background Frailty is prevalent among patients with end-stage renal disease (ESRD) and is associated with an increased risk of cognitive impairment. However, apart from its influence on cognition, it is currently unknown whether frailty affects subtler cerebral function in patients with ESRD. Methods Patients with ESRD were prospectively enrolled, with clinical features and laboratory data recorded. The severity of frailty among these patients with ESRD was ascertained using the previously validated simple FRAIL scale, and was categorized as none-to-mild and moderate-to-severe frailty. All participants underwent quantitative electroencephalography (EEG), with band powers documented following the generation of the delta to alpha ratio (DAR) and delta/theta to alpha/beta ratio (DTABR). EEG results were then compared between groups of different levels of frailty. Results In this cohort, (mean age: 68.9 ± 10.4 years, 37% male, 3.4 ± 3 years of dialysis), 20, 60, 40, 17, and 6% patients exhibited positivity in the fatigue, resistance, ambulation, illness, and loss-of-body-weight domains, respectively, with 45.7% being none to mildly frail and 54.3% being moderately to severely frail. Those with mild frailty had a significantly higher delta power compared to those with more severe frailty, involving all topographic sites. Patients with ESRD and severe frailty had significantly lower global, left frontal, left temporo-occipital, and right temporo-occipital DAR and DTABR, except in the right frontal area, and tended to have central accentuation of alpha, beta, and theta power, and more homogeneous DTABR and DAR distribution compared to the findings in those with mild frailty. Conclusions Frailty in patients with ESRD can have subtler neurophysiological influences, presenting as altered EEG findings, which warrant our attention.

Chronic kidney disease (CKD), defined as the presence of irreversible structural or functional kidney damages, increases the risk of poor outcomes due to its association with multiple complications, including altered mineral metabolism, anemia, metabolic acidosis, and increased cardiovascular events. The mainstay of treatments for CKD lies in the prevention of the development and progression of CKD as well as its complications. Due to the heterogeneous origins and the uncertainty in the pathogenesis of CKD, efficacious therapies for CKD remain challenging. In this review, we focus on the following four themes: first, a summary of the known factors that contribute to CKD development and progression, with an emphasis on avoiding acute kidney injury (AKI); second, an etiology-based treatment strategy for retarding CKD, including the approaches for the common and under-recognized ones; and third, the recommended approaches for ameliorating CKD complications, and the final section discusses the novel agents for counteracting CKD progression.

Vascular calcification (VC) involves the deposition of calcium apatite in vascular intima or media. Individuals of advanced age, having diabetes mellitus or chronic kidney disease (CKD) are particularly at risk. The pathogenesis of CKD-associated VC evolves considerably. The core driver is the phenotypic change involving vascular wall constituent cells toward manifestations similar to that undergone by osteoblasts. Gender-related differences are observed regarding the expressions of osteogenesis-regulating effectors, and presumably the prevalence/risk of CKD-associated VC exhibits gender-related differences as well. Despite the wealth of data focusing on gender-related differences in the risk of atherosclerosis, few report whether gender modifies the risk of VC, especially CKD-associated cases. We systematically identified studies of CKD-associated VC or its regulators/modifiers reporting data about gender distributions, and extracted results from 167 articles. A significantly higher risk of CKD-associated VC was observed in males among the majority of original investigations. However, substantial heterogeneity exists, since multiple large-scale studies yielded neutral findings. Differences in gender-related VC risk may result from variations in VC assessment methods, the anatomical segments of interest, study sample size, and even the ethnic origins of participants. From a biological perspective, plausible mediators of gender-related VC differences include body composition discrepancies, alterations involving lipid profiles, inflammatory severity, diversities in matrix Gla protein (MGP), soluble Klotho, vitamin D, sclerostin, parathyroid hormone (PTH), fibroblast growth factor-23 (FGF-23), and osteoprotegerin levels. Based on our findings, it may be inappropriate to monotonously assume that male patients with CKD are at risk of VC compared to females, and we should consider more background in context before result interpretation.

Protein-energy wasting (PEW) is an important complication resulting from chronic kidney disease (CKD). Appetite impairment contributes significantly to PEW in these patients, but risk factors associated with having appetite impairment in patients with CKD remain elusive. Patients with an estimated glomerular filtration rate 2 for ≥2 times at least three months apart were prospectively enrolled during 2017, with their demographic features, comorbidities, anthropometric parameters, physical and performance indices, functional status, frailty, sensory organ integrity, and laboratory data collected. Their appetite status was measured using the Council on Nutrition Appetite Questionnaire (CNAQ). We examined independent determinants of appetite impairment in these CKD patients using multiple regression analyses. Among 78 patients with CKD, 42.3% had CNAQ-identified impaired appetite. Those with an impaired appetite also had poorer physical performance, a higher degree of functional impairment, higher frail severities, lower serum sodium levels, less intact oral cavity, and a trend toward having less intact nasal structures than those without. Multiple regression analyses revealed that a higher frail severity, in the forms of increasing Study of Osteoporotic Fractures (SOF) scores (odds ratio (OR), 2.74; 95% confidence interval (CI), 1.15–6.57) and a less intact nasal structure (OR, 0.96; 95% CI, 0.92–0.995) were associated with a higher probability of having an impaired appetite, while higher serum sodium (OR, 0.76; 95% CI, 0.6–0.97) correlated with a lower probability. Based on our findings, in patients with CKD, the severity of frailty, serum sodium, and nasal structural integrity might modify appetite status. Therapies targeting these factors might be beneficial for appetite restoration in patients with CKD.

The accumulation of uremic toxins (UTs) is a prototypical manifestation of uremic milieu that follows renal function decline (chronic kidney disease, CKD). Frailty as a potential outcome-relevant indicator is also prevalent in CKD. The intertwined relationship between uremic toxins, including small/large solutes (phosphate, asymmetric dimethylarginine) and protein-bound ones like indoxyl sulfate (IS) and p-cresyl sulfate (pCS), and frailty pathogenesis has been documented recently. Uremic toxins were shown in vitro and in vivo to induce noxious effects on many organ systems and likely influenced frailty development through their effects on multiple preceding events and companions of frailty, such as sarcopenia/muscle wasting, cognitive impairment/cognitive frailty, osteoporosis/osteodystrophy, vascular calcification, and cardiopulmonary deconditioning. These organ-specific effects may be mediated through different molecular mechanisms or signal pathways such as peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α), mitogen-activated protein kinase (MAPK) signaling, aryl hydrocarbon receptor (AhR)/nuclear factor-κB (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), Runt-related transcription factor 2 (RUNX2), bone morphogenic protein 2 (BMP2), osterix, Notch signaling, autophagy effectors, microRNAs, and reactive oxygen species induction. Anecdotal clinical studies also suggest that frailty may further accelerate renal function decline, thereby augmenting the accumulation of UTs in affected individuals. Judging from these threads of evidence, management strategies aiming for uremic toxin reduction may be a promising approach for frailty amelioration in patients with CKD. Uremic toxin lowering strategies may bear the potential of improving patients’ outcomes and restoring their quality of life, through frailty attenuation. Pathogenic molecule-targeted therapeutics potentially disconnect the association between uremic toxins and frailty, additionally serving as an outcome-modifying approach in the future.

Frailty exhibits diverse influences on health-related outcomes and represents a surrogate of increased susceptibility to harmful injuries. Patients with chronic kidney disease (CKD) are at a higher risk of accelerated biologic aging, and, in this population, the concept of frailty emerges as an instrumental measurement of physiologic reserves. However, a comprehensive description of known independent contributors to, and risk associates of, frailty in these patients remain unavailable. In the present review, original studies up to 28 February 2019 that assessed frailty in patients with all stages of CKD were retrieved and reviewed, with results extracted and summarized. By pooling 62 original investigations, 58.1% and 49.1% used cohort and cross-sectional designs, respectively. Dialysis-dependent end-stage renal disease patients ( n = 39; 62.9%) were the most commonly examined population, followed by those with nondialysis CKD ( n = 12; 19.4%) and those receiving renal transplantation ( n = 11; 17.7%). Contributors to frailty in CKD patients included sociodemographic factors, smoking, CKD severity, organ-specific comorbidities, depression, hypoalbuminemia, and low testosterone levels. Conversely, the development of frailty was potentially associated with the emergence of cardiometabolic, musculoskeletal, and cerebral complications; mental distress; and a higher risk of subsequent functional and quality-of-life impairment. Moreover, frailty in CKD patients increased healthcare utilization and consistently elevated mortality among affected ones. Based on the multitude of contributors to frailty and its diverse health influences, a multifaceted approach to manage CKD patients with frailty is needed, and its potential influences on outcomes besides mortality need to be considered.

Background MicroRNA‐125b (miR‐125b) has been shown to regulate vascular calcification (VC), and serum miR‐125b levels are a potential biomarker for estimating the risk of uremic VC status. However, it is unknown whether clinical features, including chronic kidney disease–mineral bone disorder molecules, affect serum miR‐125b levels. Methods and Results Patients receiving chronic dialysis for ≥3 months were recruited from different institutes. Serum miR‐125b and chronic kidney disease–mineral bone disorder effectors, including intact parathyroid hormone, 25‐OH‐D, fibroblast growth factor‐23, osteoprotegerin, and fetuin‐A, were quantified. We used multivariate regression analyses to identify factors associated with low serum miR‐125b levels and an area under receiver operating characteristic curve curve to derive optimal cutoffs for factors exhibiting close associations. Further regression analyses evaluated the influence of miR‐125b on VC risk. Among 223 patients receiving chronic dialysis (mean age, 67.3 years; mean years of dialysis, 5.2), 54 (24.2%) had high serum miR‐125b levels. Osteoprotegerin (P=0.013), fibroblast growth factor‐23 (P=0.006), and fetuin‐A (P=0.036) were linearly associated with serum miR‐125b levels. High osteoprotegerin levels independently correlated with high serum miR‐125 levels. Adding serum miR‐125b levels and serum osteoprotegerin levels (≥400 pg/mL) into models estimating the risk of uremic VC increased the area under receiver operating characteristic curve values (for models without miR‐125b/osteoprotegerin, with miR‐125b, and both: 0.74, 0.79, and 0.81, respectively). Conclusions Serum osteoprotegerin levels ≥400 pg/mL and serum miR‐125b levels synergistically increased the accuracy of estimating VC risk among patients receiving chronic dialysis. Taking miR‐125b and osteoprotegerin levels into consideration when estimating VC risk may be recommended.

Uremic vascular calcification (VC) commonly occurs during advanced chronic kidney disease (CKD) and significantly increases cardiovascular morbidity and mortality. Uremic toxins are integral within VC pathogenesis, as they exhibit adverse vascular influences ranging from atherosclerosis, vascular inflammation, to VC. Experimental removal of these toxins, including small molecular (phosphate, trimethylamine-N-oxide), large molecular (fibroblast growth factor-23, cytokines), and protein-bound ones (indoxyl sulfate, p-cresyl sulfate), ameliorates VC. As most uremic toxins share a gut origin, interventions through gastrointestinal tract are expected to demonstrate particular efficacy. The “gastrointestinal decontamination” through the removal of toxin in situ or impediment of toxin absorption within the gastrointestinal tract is a practical and potential strategy to reduce uremic toxins. First and foremost, the modulation of gut microbiota through optimizing dietary composition, the use of prebiotics or probiotics, can be implemented. Other promising strategies such as reducing calcium load, minimizing intestinal phosphate absorption through the optimization of phosphate binders and the inhibition of gut luminal phosphate transporters, the administration of magnesium, and the use of oral toxin adsorbent for protein-bound uremic toxins may potentially counteract uremic VC. Novel agents such as tenapanor have been actively tested in clinical trials for their potential vascular benefits. Further advanced studies are still warranted to validate the beneficial effects of gastrointestinal decontamination in the retardation and treatment of uremic VC.

Renal supportive care (RSC) denotes a care program dedicated for patients with acute, chronic renal failure, and end-stage renal disease (ESRD), aiming to offer maximal symptom relief and optimize patients' quality of life. The uncertainty of prognosis for patients with chronic kidney disease and ESRD, the sociocultural issues inherent to the Taiwanese society, and the void of structured and practical RSC pathway, contributes to the underrecognition and poor utilization of RSC. Taiwanese patients rarely receive information regarding RSC as part of a standardized care and are not commonly offered this option. In National Taiwan University Hospital Jinshan branch, we started a RSC subprogram, supported by the community-based palliative/hospice care main program. We focused on understanding the need and providing the choice of RSC to suitable candidates. A three-step and four-phase protocol was designed and implemented to identify appropriate patients and to enhance the applicability of the RSC. We harnessed family visit and home-based family meeting as a vehicle to understand the patients' preferences, to discover what ESRD patients and their family value most, and to introduce the option of RSC. In the current review, we described our pilot experience of establishing a RSC program in Taiwan, and discuss its potential advantage.

Vascular calcification (VC) is a critical contributor to the rising cardiovascular risk among at-risk populations such as those with diabetes or renal failure. The pathogenesis of VC involves an uprising of oxidative stress, for which antioxidants can be theoretically effective. However, astaxanthin, a potent antioxidant, has not been tested before for the purpose of managing VC. To answer this question, we tested the efficacy of astaxanthin against VC using the high phosphate (HP)-induced vascular smooth muscle cell (VSMC) calcification model. RNAs from treated groups underwent Affymetrix microarray screening, with intra-group consistency and inter-group differential expressions identified. Candidate hub genes were selected, followed by validation in experimental models and functional characterization. We showed that HP induced progressive calcification among treated VSMCs, while astaxanthin dose-responsively and time-dependently ameliorated calcification severities. Transcriptomic profiling revealed that 3491 genes exhibited significant early changes during VC progression, among which 26 potential hub genes were selected based on closeness ranking and biologic plausibility. SOD2 was validated in the VSMC model, shown to drive the deactivation of cellular senescence and enhance antioxidative defenses. Astaxanthin did not alter intracellular reactive oxygen species (ROS) levels without HP, but significantly lowered ROS production in HP-treated VSMCs. SOD2 knockdown prominently abolished the anti-calcification effect of astaxanthin on HP-treated VSMCs, lending support to our findings. In conclusion, we demonstrated for the first time that astaxanthin could be a potential candidate treatment for VC, through inducing the up-regulation of SOD2 early during calcification progression and potentially suppressing vascular senescence.

Patients with chronic kidney disease (CKD) have an increased risk of vascular calcification (VC), including aortic arch calcification (AAC). Few investigated the influence of gustatory function on the probability of having VC. We examined whether gustatory function results modulated the probability of having VC in patients with CKD. We prospectively enrolled adults with CKD (estimated glomerular filtration rate 2), with their AAC rated semi-quantitatively and gustatory function assessed by objective and subjective approaches. Multiple logistic regression was used to analyze the relationship between gustatory function results and AAC. Those with AAC had significantly better objective gustatory function in aggregate scores (p = 0.039) and categories (p = 0.022) and less defective bitter taste (p = 0.045) and scores (p = 0.037) than those without. Multiple regression analyses showed that higher aggregate scores (odds ratio (OR) 1.288, p = 0.032), or better gustatory function, and higher bitter taste scores (OR 2.558, p = 0.019) were each associated with a higher probability of having AAC among CKD patients; such an association was modulated by serum phosphate levels. In conclusion, better gustatory function was independently correlated with having AAC among CKD patients. A follow-up of VC severity may be an underrecognized component of care for CKD patients with a preserved gustatory function.

Vascular calcification, which involves the deposition of calcifying particles within the arterial wall, is mediated by atherosclerosis, vascular smooth muscle cell osteoblastic changes, adventitial mesenchymal stem cell osteoblastic differentiation, and insufficiency of the calcification inhibitors. Recent observations implied a role for mesenchymal stem cells and endothelial progenitor cells in vascular calcification. Mesenchymal stem cells reside in the bone marrow and the adventitial layer of arteries. Endothelial progenitor cells that originate from the bone marrow are an important mechanism for repairing injured endothelial cells. Mesenchymal stem cells may differentiate osteogenically by inflammation or by specific stimuli, which can activate calcification. However, the bioactive substances secreted from mesenchymal stem cells have been shown to mitigate vascular calcification by suppressing inflammation, bone morphogenetic protein 2, and the Wingless-INT signal. Vitamin D deficiency may contribute to vascular calcification. Vitamin D supplement has been used to modulate the osteoblastic differentiation of mesenchymal stem cells and to lessen vascular injury by stimulating adhesion and migration of endothelial progenitor cells. This narrative review clarifies the role of mesenchymal stem cells and the possible role of vitamin D in the mechanisms of vascular calcification.

Vascular calcification (VC) is highly associated with cardiovascular disease and all-cause mortality in patients with chronic kidney disease. Dysregulation of endothelial cells and vascular smooth muscle cells (VSMCs) is related to VC. Sirtuin-1 (Sirt1) deacetylase encompasses a broad range of transcription factors that are linked to an extended lifespan. Sirt1 enhances endothelial NO synthase and upregulates FoxOs to activate its antioxidant properties and delay cell senescence. Sirt1 reverses osteogenic phenotypic transdifferentiation by influencing RUNX2 expression in VSMCs. Low Sirt1 hardly prevents acetylation by p300 and phosphorylation of β-catenin that, following the facilitation of β-catenin translocation, drives osteogenic phenotypic transdifferentiation. Hyperphosphatemia induces VC by osteogenic conversion, apoptosis, and senescence of VSMCs through the Pit-1 cotransporter, which can be retarded by the sirt1 activator resveratrol. Proinflammatory adipocytokines released from dysfunctional perivascular adipose tissue (PVAT) mediate medial calcification and arterial stiffness. Sirt1 ameliorates release of PVAT adipokines and increases adiponectin secretion, which interact with FoxO 1 against oxidative stress and inflammatory arterial insult. Conclusively, Sirt1 decelerates VC by means of influencing endothelial NO bioavailability, senescence of ECs and VSMCs, osteogenic phenotypic transdifferentiation, apoptosis of VSMCs, ECM deposition, and the inflammatory response of PVAT. Factors that aggravate VC include vitamin D deficiency-related macrophage recruitment and further inflammation responses. Supplementation with vitamin D to adequate levels is beneficial in improving PVAT macrophage infiltration and local inflammation, which further prevents VC.

Vascular calcification (VC) is an important complication among patients of advanced age, those with chronic kidney disease, and those with diabetes mellitus. The pathophysiology of VC encompasses passive occurrence of physico-chemical calcium deposition, active cellular secretion of osteoid matrix upon exposure to metabolically noxious stimuli, or a variable combination of both processes. Epigenetic alterations have been shown to participate in this complex environment, through mechanisms including DNA methylation, non-coding RNAs, histone modifications, and chromatin changes. Despite such importance, existing reviews fail to provide a comprehensive view of all relevant reports addressing epigenetic processes in VC, and cross-talk between different epigenetic machineries is rarely examined. We conducted a systematic review based on PUBMED and MEDLINE databases up to 30 September 2019, to identify clinical, translational, and experimental reports addressing epigenetic processes in VC; we retrieved 66 original studies, among which 60.6% looked into the pathogenic role of non-coding RNA, followed by DNA methylation (12.1%), histone modification (9.1%), and chromatin changes (4.5%). Nine (13.6%) reports examined the discrepancy of epigenetic signatures between subjects or tissues with and without VC, supporting their applicability as biomarkers. Assisted by bioinformatic analyses blending in each epigenetic component, we discovered prominent interactions between microRNAs, DNA methylation, and histone modification regarding potential influences on VC risk.

Background: Acarbose has been deemed contraindicated in diabetic patients with chronic kidney disease (CKD) or end-stage renal disease (ESRD), but such use is not uncommon. We tested whether this concept hold true in this population with different background hepatic diseases.Methods: All incident diabetic patients (n = 2,036,531) with stage 5 CKD/ESRD were enrolled from Taiwan between 2017 and 2013 and divided into those without chronic liver disease (CLD), with CLD but without cirrhosis, and those with cirrhosis. Among each group, acarbose users, defined as cumulative use >30 days within the preceding year, were propensity-score matched 1:2 to non-users. Our main outcome was the development of liver injury events during follow-up.Results: Acarbose users did not exhibit an increased incidence of liver injury during follow-up compared to non-users (hazard ratio and 95% confidence interval, 1.04 [0.88–1.25], 0.97 [0.61–1.56], and 0.71 [0.33–1.54] among those without CLD, with CLD but without cirrhosis, and those with cirrhosis, respectively), after adjusting for demographic profiles, comorbidities, potentially hepatotoxic medication use, and diabetic severity.Conclusions: The incidence of liver injury did not increase significantly among diabetic acarbose users with severe renal insufficiency than non-users, regardless of the presence or absence of chronic liver disease. Our findings support the renaissance of acarbose as a useful adjunct in diabetic patients with stage 5 and 5D chronic kidney disease.

Background Renal supportive care (RSC) is an important option for elderly individuals reaching end-stage renal disease; however, the frequency of RSC practice is very low among Asian countries. We evaluated the attitude, the knowledge, and the preference for specific topics concerning RSC among participants who worked in different medical professions in Taiwan. Methods A cross-sectional questionnaire-based survey was employed. Healthcare personnel (N = 598) who were involved in caring for end-stage renal disease patients at more than 40 facilities in Taiwan participated in this study. Participants were asked about their motivation for learning about RSC, the topics of RSC they were most and least interested in, their willingness to provide RSC, and to rate their knowledge and perceived importance of different topics. Results The vast majority of respondents (81.9%) were self-motivated about RSC, among whom nephrologists (96.8%) and care facilitators (administrators/volunteers) (45%) exhibited the highest and the least motivation, respectively (p

Background Frailty exhibits a high prevalence in end-stage renal disease (ESRD) patients and is associated with adverse health-related outcomes, including falls and fractures. Available studies do not address whether frailty is associated with temporal changes in BMD. We evaluated this issue by analyzing the follow-up dual energy X-ray absorptiometry (DXA) results in an ESRD cohort. Methods In 2015, we enrolled forty-three ESRD patients, divided into frail, pre-frail, and robust ones based on a validated simple FRAIL scale, all receiving DXA at baseline. After one year of follow-up, survivors received another DXA, and we calculated the absolute and percentage changes in area, bone mineral density (BMD), T-, and Z-scores of lumbar spine and femoral neck (FN) between baseline and follow-up examinations. Results Among all, frail individuals with ESRD had significantly lower average lumbar spine area, lower L4, FN, and total BMD and T-scores, lower FN and total Z-scores than non-frail ones, without differences in gender, body mass index, dialysis duration, and comorbidities. Furthermore, we discovered frail ESRD patients had significantly more prominent decrease in average lumbar spine area, percentage changes in L1 Z-scores and average lumbar spine area, and a trend toward more prominent decrease in L4 area than non-frail ones after one year of follow-up. Conclusions Baseline frailty might be associated with deteriorating bone health, including shrinking L-spine areas and a more rapid decrease in L-spine Z scores, among ESRD patients. This frailty-bone association should be highlighted during our care of frail individuals with ESRD.

Continuous renal replacement therapy (CRRT) is one of the dialysis modalities for critically ill patients. Despite intensive dialysis care, a high mortality rate is found in these patients. Our objective was to investigate the factors associated with poor outcomes in these patients. We conducted a retrospective cohort study using the National Health Insurance Research Database. Records of critically ill patients who received CRRT between 2007 and 2011 were retrieved, and the patients were categorized into two groups: those with acute kidney injury (AKI) and those with history of end-stage renal disease (ESRD). Our primary and secondary outcomes were in-hospital mortality and long-term survival and non-renal recovery (long-term dialysis dependence), respectively, in the AKI group. We enrolled 15,453 patients, with 13,204 and 2249 in the AKI and ESRD groups, respectively. Overall, 66.5% patients died during hospitalization. In-hospital mortality did not differ significantly between groups (adjusted odds ratio, 0.93; 95% CI, 0.84-1.02). Age, chronic liver disease, and cancer history were identified as independent risk factors for in-hospital mortality in both groups. Hypertension was associated with higher risk of in-hospital mortality in patients with AKI. Age, coronary artery disease, and admission to the medical intensive care unit (MICU) were risk factors for long-term dialysis dependence in patients with AKI. Patients with AKI and ESRD have similarly poor outcomes after CRRT. Older age and presence of chronic liver disease and cancer were associated with higher mortality. Older age, presence of coronary artery disease, and admission to MICU were associated with lower renal recovery rate in patients with AKI.

Background. Geriatric syndromes (GS) exhibit high prevalence in patients with end-stage renal disease (ESRD) under chronic dialysis irrespective of age. We sought to determine whether GS influences medication adherence in ESRD patients. Methods. A prospective cohort of chronic dialysis patients was assembled. The presence of GS components, including frailty/prefrailty, polypharmacy, and malnutrition, were ascertained through a validated questionnaire, electronic records and chart abstraction, and laboratory tests. The severity of medication non-adherence was defined using the eight-item Morisky Medication Adherence Scale (MMAS). Multiple logistic regression analysis was performed targeting MMAS results and incorporating relevant clinical features and GS. Results. The prevalence of frailty/pre-frailty, polypharmacy, and hypoalbuminemia/ malnutrition among the enrolled participants was 66.7%, 94%, and 14%, respectively. The average MMAS scores in these dialysis patients were 2 ± 1.7 (range, 0–6), with only 15.7% exhibiting high medication adherence. Multiple regression analyses showed that the absence of frailty/pre-frailty (P = 0.01) were significantly associated with poorer medication adherence, while the presence of polypharmacy (P = 0.02) and lower serum albumin, a potential sign of malnutrition (P = 0.03), were associated with poor adherence in another model. Conclusion. This study is among the very few reports addressing GS and medication adherence, especially in ESRD patients. Interventions targeting frailty, polypharmacy, and malnutrition might potentially improve the medication non-adherence and symptom control in these pill-burdened patients.

Background. Patients with end-stage renal disease (ESRD) have a high symptom burden, among which fatigue is highly prevalent. Many fatigue-assessing instruments exist, but comparisons among instruments in this patient population have yet to be investigated. Methods. ESRD patients under chronic hemodialysis were prospectively enrolled and seven types of fatigue instruments were administered: Brief Fatigue Inventory (BFI), Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F), Fatigue Severity Scale (FSS), Lee Fatigue Scale (LFS), Fatigue Questionnaire (FQ), Fatigue Symptom Inventory (FSI), and Short-Form 36-Vitality (SF36-V). Using these instruments, we investigated the correlation between fatigue severity and clinical/biochemical parameters, including demographic/comorbidity profile, dialysis-related complications, and frailty severity. We used regression analysis with serum albumin and frailty severity as the dependent variables to investigate the independent correlations. Results. A total of 46 ESRD patients were enrolled (average age of 67 ± 11.6 years), and 50% of them had type 2 diabetes mellitus. Results from the seven tested instruments showed high correlation with each other. We found that the fatigue severity by FACIT-F was significantly associated with age (p = 0.03), serum albumin (p = 0.003) and creatinine (p = 0.02) levels, while SF36-V scores were also significantly associated with age (p = 0.02) and serum creatinine levels (p = 0.04). However, the fatigue severity measured by the FSS, FSI, FQ, BFI, and LFS did not exhibit these associations. Moreover, regression analysis showed that only FACIT-F scores were independently associated with serum albumin levels and frailty severity in ESRD patients. Conclusion. Among the seven fatigue-assessing instruments, only the FACIT-F yielded results that demonstrated significant and independent associations with important outcome-related features in ESRD patients.

End-stage renal disease (ESRD) patients are at increased risk of sudden cardiac death, the risk of which is presumably related to arrhythmia. Electrocardiographic (ECG) parameters have been found to correlate with arrhythmia and predict cardiovascular outcomes in ESRD patients. Frailty is also a common feature in this population. We investigate whether the severity of dialysis frailty is associated with ECG findings, including PR interval, QRS duration, and QTc interval. Presence and severity of frailty was ascertained using six different self-report questionnaires with proven construct validity. Correlation analysis between frailty severity and ECG was made, and those with significant association entered into multiple regression analysis for confirmation. Among a cohort of chronic hemodialysis patients, we found that frailty severity, assessed by the Edmonton frailty scale, is significantly associated with QRS duration (r = − 0.3, p < 0.05). Dialysis patients with QRS longer than 120 ms had significantly lower severity of frailty than those with QRS less than 120 ms (p = 0.01 for the Edmonton frailty scale and 0.05 for simple FRAIL scale). Regression analysis showed that frailty severity, assessed by the Edmonton frailty scale and simple FRAIL scale, was significantly associated with QRS duration independent of serum electrolyte levels. In conclusion, a significant relationship exists between the severity of frailty and QRS duration in ESRD patients. This might be an under-recognized link between frailty and its adverse cardiovascular impact in these patients.

Acinetobacter species are assuming an increasingly important role in modern medicine, with their persistent presence in health-care settings and antibiotic resistance. However, clinical reports addressing this issue in patients with peritoneal dialysis (PD) peritonitis are rare.All PD peritonitis episodes caused by Acinetobacter that occurred between 1985 and 2012 at a single centre were retrospectively reviewed. Clinical features, microbiological data, and outcomes were analysed, with stratifications based upon temporal periods (before and after 2000).Acinetobacter species were responsible for 26 PD peritonitis episodes (3.5% of all episodes) in 25 patients. A. baumannii was the most common pathogen (54%), followed by A. iwoffii (35%), with the former being predominant after 2000. Significantly more episodes resulted from breaks in exchange sterility after 2000, while those from exit site infections decreased (P = 0.01). The interval between the last and current peritonitis episodes lengthened significantly after 2000 (5 vs. 13.6 months; P = 0.05). All the isolates were susceptible to cefepime, fluoroquinolone, and aminoglycosides, with a low ceftazidime resistance rate (16%). Nearly half of the patients (46%) required hospitalisation for their Acinetobacter PD-associated peritonitis, and 27% required an antibiotic switch. The overall outcome was fair, with no mortality and a 12% technique failure rate, without obvious interval differences.The temporal change in the microbiology and origin of Acinetobacter PD-associated peritonitis in our cohort suggested an important evolutional trend. Appropriate measures, including technique re-education and sterility maintenance, should be taken to decrease the Acinetobacter peritonitis incidence in PD patients.