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Frailty denotes the increased vulnerability to stressors/insults associated with aging or diseases, and has high incidence in patients with diabetes mellitus (DM). We hypothesized that chronic kidney disease (CKD) and non-kidney morbidities in patients with newly diagnosed DM might modulate their risk of developing incident frailty.From the Longitudinal Cohort of Diabetes Patients, we identified 322,109 patients with newly diagnosed DM, and classified them into those without CKD, with CKD before and after DM. We used Kaplan-Meier analyses and Cox proportional hazard regression to analyze associations between CKD or non-kidney morbidities and the risk of incident frailty. We further analyzed the year-to-year trend of frailty risk brought by CKD or non-kidney morbidities.Patients with DM but without CKD (n = 249,752; 77.5%), with CKD prior to (n = 23,829; 7.4%), and after DM (n = 48,528; 15.1%) were enrolled. Those with CKD, regardless of onset timing, had a significantly higher risk of developing frailty than those without (for onset prior to DM, hazard ratio (HR) 1.235, 95% confidence interval (CI) 1.11-1.38; for onset after DM, HR 1.386, 95% CI 1.21-1.59). The risk was more prominent early after the diagnosis of DM was made. Patients with chronic obstructive pulmonary disease, liver, and cardiovascular morbidities all had a significantly higher risk of frailty than those without, with cerebrovascular accident carrying the most prominent risk elevation (HR 4.059, 95% CI 3.73-4.42).CKD regardless of onset timing relative to DM predicted a higher risk of incident frailty, while non-kidney morbidities including cardiovascular morbidities, similarly increased frailty risk among incident diabetic patients.

Background/Purpose: We evaluated whether the results of the computed tomography (CT)-based sarcopenia assessment were correlated with edema-free lean soft tissue (LST) and were associated with the prognosis of patients receiving peritoneal dialysis (PD). Methods: We conducted a prospective cohort study and enrolled patients aged >20 years who started to undergo PD between February 2009 and February 2012. All patients underwent LST evaluation and non-contrast abdominal CT for assessing the total skeletal muscle (TSM) and psoas muscle (PM) indices at the level of the third lumbar vertebra. We analyzed the correlation between LST and CT assessment of muscle mass. Then we determined optimal sex-specific cutoff values for TSM-defined and PM-defined sarcopenia to predict mortality, aided by the maximally selected rank statistics. Results: A total of 158 patients were enrolled, of whom 41 (25.9%) and 65 (41.1%) had sarcopenia based on the TSM and PM indices, respectively. LST was significantly strong correlated with TSM and PM indices (r = 0.517, p

Background. Vascular calcification (VC) constitutes subclinical vascular burden and increases cardiovascular mortality. Effective therapeutics for VC remains to be procured. We aimed to use a deep learning-based strategy to screen and uncover plant compounds that potentially can be repurposed for managing VC. Methods. We integrated drugome, interactome, and diseasome information from Comparative Toxicogenomic Database (CTD), DrugBank, PubChem, Gene Ontology (GO), and BioGrid to analyze drug-disease associations. A deep representation learning was done using a high-level description of the local network architecture and features of the entities, followed by learning the global embeddings of nodes derived from a heterogeneous network using the graph neural network architecture and a random forest classifier established for prediction. Predicted results were tested in an in vitro VC model for validity based on the probability scores. Results. We collected 6,790 compounds with available Simplified Molecular-Input Line-Entry System (SMILES) data, 11,958 GO terms, 7,238 diseases, and 25,482 proteins, followed by local embedding vectors using an end-to-end transformer network and a node2vec algorithm and global embedding vectors learned from heterogeneous network via the graph neural network. Our algorithm conferred a good distinction between potential compounds, presenting as higher prediction scores for the compound categories with a higher potential but lower scores for other categories. Probability score-dependent selection revealed that antioxidants such as sulforaphane and daidzein were potentially effective compounds against VC, while catechin had low probability. All three compounds were validated in vitro. Conclusions. Our findings exemplify the utility of deep learning in identifying promising VC-treating plant compounds. Our model can be a quick and comprehensive computational screening tool to assist in the early drug discovery process.

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 n = 70, 23.6%), those with an AoAC score n = 96, 32.3%), and those with an AoAC score ≥2 regardless of AVC status (n = 131, 44.1%). We analyzed the risks of MACE, cardiovascular and overall mortality among the three groups using Cox proportional hazard analyses. Survival probabilities were estimated using the log-rank test via the Kaplan–Meier method.ResultsKaplan–Meier analysis revealed that the MACE-free rate and the survival rates of cardiovascular and overall mortality were significantly higher in adult chronic hemodialysis patients with AoAC score p < 0.01). The grade of AoAC is a significant risk factor for MACE, cardiovascular mortality, and overall mortality after adjusting for age and gender Relative to AoAC score p = 0.023) after adjusting for age, sex, and all significant variables in baseline characteristics.ConclusionAoAC grade was positively correlated with a higher risk of MACE and cardiovascular and overall mortality. Furthermore, the presence of AVC modified the adverse cardiovascular risk associated with AoAC in patients on MHD.

Chronic kidney disease (CKD) and its complications, including vascular senescence and progressive renal fibrosis, are associated with inflammation. Vascular senescence, in particular, has emerged as an instrumental mediator of vascular inflammation that potentially worsens renal function. Epigenetically regulated inflammation involving histone modification, DNA methylation, actions of microRNAs and other non-coding RNAs, and their reciprocal reactions during vascular senescence and inflammaging are underappreciated. Their synergistic effects can contribute to CKD progression. Vascular senotherapeutics or pharmacological anti-senescent therapies based on epigenetic machineries can therefore be plausible options for ameliorating vascular aging and even halting the worsening of renal fibrosis. These include histone deacetylase modulators, histone methyltransferase modulators, other histone modification effectors, DNA methyltransferase inhibitors, telomerase reverse transcriptase enhancers, microRNA mimic delivery, and small molecules with microRNA-regulating potentials. Some of these molecules have already been tested and have shown anecdotal evidence for treating uremic vasculopathy and renal fibrosis, supporting the feasibility of this approach.

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.

The prevalence of chronic pain in patients with chronic kidney disease (CKD) and diabetes mellitus is high and correlates with higher frailty risk, but satisfactory pain control frequently fails, necessitating opioid initiation. We aimed to examine whether opioid use affected their outcomes and whether such a relationship was modified by frailty. From the longitudinal cohort of diabetes patients (n = 840,000), we identified opioid users with CKD (n = 26,029) and propensity score-matched them to opioid-naïve patients in a 1:1 ratio. We analyzed the associations between opioid use and long-term mortality according to baseline frailty status, defined by the modified FRAIL scale. Among all, 20.3% did not have any FRAIL items, while 57.2%, 20.6%, and 1.9% had 1, 2, and at least 3 positive FRAIL items, respectively. After 4.2 years, 16.4% died. Cox proportional hazard regression showed that opioid users exhibited an 18% higher mortality risk (HR 1.183, 95% CI 1.13-1.24) with a dose- and duration-responsive relationship, compared to opioid-naive ones. Furthermore, the mortality risk posed by opioids was observed only in CKD patients without frailty but not in those with frailty. In conclusion, opioid use increased mortality among patients with CKD, while this negative outcome influence was not observed among frail ones.

Metabolic syndrome (MetS) predisposes older adults to the development of frailty. However, previous studies have not explored factors that may influence the association between MetS and the risk of frailty in this population. Community-dwelling older adults (≥65 years of age) were prospectively identified and enrolled between 2013 and 2016. MetS and frailty were defined based on the American Association of Clinical Endocrinologists and Study of Osteoporotic Fractures criteria, respectively. Multiple logistic regression with frailty/prefrailty as the dependent variable was used to examine the relationship between MetS and frailty/prefrailty, supplemented by subgroup analyses of the influence of aging and chronic kidney disease (CKD). Among 2862 elderly (73.4 ± 6.7 years), 17.5% and 17.3%, respectively, had MetS and frailty/prefrailty, among whom 74 (2.6%) and 420 (14.7%) had frailty and prefrailty. The presence of MetS (odds ratio [OR] 2.53

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.

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.

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.

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.

Acute kidney injury (AKI)-related fibrosis is emerging as a major driver of chronic kidney disease (CKD) development. Aberrant kidney recovery after AKI is multifactorial and still poorly understood. The accumulation of indoxyl sulfate (IS), a protein-bound uremic toxin, has been identified as a detrimental factor of renal fibrosis. However, the mechanisms underlying IS-related aberrant kidney recovery after AKI is still unknown. The present study aims to elucidate the effects of IS on tubular damage and its involvement in the pathogenesis of AKI-to-CKD transition. Our results showed that serum IS started to accumulate associated with the downregulation of tubular organic anion transporter but not observed in the small-molecule uremic toxins of the unilateral ischemia–reperfusion injury (UIRI) without a contralateral nephrectomy model. Serum IS is positively correlated with renal fibrosis and binding immunoglobulin protein (BiP) and CAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) expression induction in the UIRI with a contralateral nephrectomy model (UIRI+Nx). To evaluate the effects of IS in the AKI-to-CKD transition, we administered indole, a precursor of IS, at the early stage of UIRI. Our results demonstrated IS potentiates renal fibrosis, senescence-associated secretory phenotype (SASP), and activation of endoplasmic reticulum (ER) stress, which is attenuated by synergistic AST-120 administration. Furthermore, we clearly demonstrated that IS exposure potentiated hypoxia–reperfusion (H/R) induced G2/M cell cycle arrest, epithelial–mesenchymal transition (EMT) and aggravated ER stress induction in vitro. Finally, the ER chemical chaperon, 4-phenylbutyric acid (4-PBA), successfully reversed the above-mentioned AKI-to-CKD transition. Taken together, early IS elimination in the early stage of AKI is likely to be a useful strategy in the prevention and/or treatment of the AKI-to-CKD transition.

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) is highly prevalent in patients with advanced age, or those with chronic kidney disease and diabetes, accounting for substantial global cardiovascular burden. The pathophysiology of VC involves active mineral deposition by transdifferentiated vascular smooth muscle cells exhibiting osteoblast-like behavior, building upon cores with or without apoptotic bodies. Oxidative stress drives the progression of the cellular phenotypic switch and calcium deposition in the vascular wall. In this review, we discuss potential compounds that shield these cells from the detrimental influences of reactive oxygen species as promising treatment options for VC. A comprehensive summary of the current literature regarding antioxidants for VC is important, as no effective therapy is currently available for this disease. We systematically searched through the existing literature to identify original articles investigating traditional antioxidants and novel compounds with antioxidant properties with regard to their effectiveness against VC in experimental or clinical settings. We uncovered 36 compounds with antioxidant properties against VC pathology, involving mechanisms such as suppression of NADPH oxidase, BMP-2, and Wnt/β-catenin; anti-inflammation; and activation of Nrf2 pathways. Only two compounds have been tested clinically. These findings suggest that a considerable opportunity exists to harness these antioxidants for therapeutic use for VC. In order to achieve this goal, more translational studies are needed.

Mammalian target of rapamycin (mTOR) inhibitors were previously considered a potential therapy for autosomal dominant polycystic kidney disease (ADPKD), but prior studies remained controversial about their efficacy. We performed an updated meta-analysis regarding the therapeutic and adverse effects of mTOR inhibitors in patients with ADPKD. We systematically searched Cochrane Library, PubMed, EMBASE, and Medline for randomized controlled trials (RCTs) comparing mTOR inhibitors to placebo in ADPKD patients up to August 2019. We calculated weighted mean differences (WMDs) for total kidney volume (TKV), estimated glomerular filtration rates (eGFRs), and weighted odds ratios (ORs) for treatment-related complications between the treatment and the placebo groups, using the random effects model. We retrieved a total of 9 RCTs enrolling 784 ADPKD patients receiving rapamycin, sirolimus, or everolimus between 2009 and 2016. The WMDs of TKV and eGFR from baseline to the last measurement were − 31.54 mL (95% confidence interval [CI] − 76.79 to 13.71 mL) and 2.81 mL/min/1.73 m2 (95% CI − 1.85 to 7.46 mL/min/1.73 m2), respectively. Patients receiving mTOR inhibitors had a significantly increased risk of any adverse effects (OR 5.92, 95% CI 3.53–9.94), with the most common ones being aphthous stomatitis (OR 15.45, 95% CI 9.68–24.66) and peripheral edema (OR 3.49, 95% CI 1.31–9.27) compared to placebo users. mTOR inhibitors did not significantly influence renal progression in patients with ADPKD, but were associated with a higher risk of complications. Whether mTOR inhibitors can be an add-on option or second-line agents remain undetermined.

AIM Laboratory deficit-based frailty index (LFI) exhibited outcome-prediction ability in the elderly, but not in those with end-stage renal disease (ESRD). We hypothesized that LFI results might have outcome correlation and correlate closely with other instruments in ESRD patients. METHODS We prospectively enroled ESRD patients between 2014 and 2015 and administered self-report frailty instruments (Strawbridge questionnaire, Edmonton frail scale (EFS), Groningen frailty indicator (GFI), Tilburg frailty indicator, G8 questionnaire and FRAIL scale), and Cardiovascular Health Study (CHS) scale, with two types of LFI calculated. They were followed up until June 30, 2017. Correlations between the results of six instruments, CHS scale, and those of LFI were identified, followed by Kaplan-Meier survival analyses and logistic regression analyses to compare those with high and low LFI. RESULTS The frailty prevalence was 33.3% (CHS), 78.8% Strawbridge questionnaire, 45.5% (EFS), 57.6% (GFI), 27.3% (Tilburg frailty indicator), 84.8% (G8) and 18.2% (FRAIL) among ESRD participants. LFI-1 results were significantly correlated with those of LFI-2 (P

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.

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 p Conclusions Having frailty predicted a higher risk of developing UTI in the future in patients with DM and CKD. It would be prudent to screen for frailty in these patients and provide optimal frailty-directed management to attenuate their risk of UTI and improve their outcomes.

AIM The prevalence of chronic kidney disease (CKD) is on the rise due to population aging and multimorbidity. Taiwan is particularly afflicted by this prevailing ailment. Although multidisciplinary pre-dialysis care has been implemented to halt CKD progression and reduce health-care utilization in Taiwan, more is needed to reduce the local burden of CKD. METHODS The Taiwan Joint Commission initiated a kidney-care disease-specific care (DSC) certification program since 2017, aiming to improve participating hospitals' quality of care for kidney disease and to synchronize the quality of kidney care across Taiwan. We analysed the trend of changes over time among the kidney DSC certification program participating institutes during the period before, during, and after DSC certification program implementation, using the Generalized Estimating Equation methods. RESULTS A total of 20 institutes participated in the DSC certification program focusing on kidney diseases between January 2018 and March 2020, among which 70% were medical centres. DSC certification program was shown to significantly reduce the annual incidence of arteriovenous fistula reconstruction while increase the levels of serum albumin and haemoglobin among patients with end-stage renal disease (ESRD) under haemodialysis over time. For parameters related to peritoneal dialysis (PD), participating in the kidney-care DSC certification program significantly increased serum albumin levels among these patients with ESRD over time. CONCLUSION In this study, we discovered that a kidney-care DSC certification program significantly improved multiple performance indicators of participating institutes including patients' haemoglobin, albumin, and shunt re-creation probability among patients with end-stage renal disease.

Aims Delirium, a form of acute brain failure, exhibits a high incidence among older adults. Recent studies have implicated frailty as an under-recognized complication of diabetes mellitus (DM). Whether the presence of frailty increases the risk of delirium/cognitive impairment among patients with diabetic kidney disease (DKD) remains unclear. Methods From the longitudinal cohort of diabetes patients (LCDP) (n = 840,000), we identified adults with DKD, dividing them into those without and with different severities of frailty based on the FRAIL scale. Cox proportional hazard regression was utilized to examine the frailty-associated risk of delirium/cognitive impairment, identified using approaches validated by others. Results Totally 149,145 patients with DKD (mean 61.0 years, 44.2% female) were identified, among whom 31.0%, 51.7%, 16.0%, and 1.3% did not have or had 1, 2, and > 2 FRAIL items at baseline. After 3.68 years, 6613 (4.4%) developed episodes of delirium/cognitive impairment. After accounting for demographic/lifestyle factors, comorbidities, medications and interventions, patients with DKD and 1, 2, and > 2 FRAIL items had a progressively higher risk of developing delirium/cognitive impairment than those without (for those with 1, 2, and > 2 items, hazard ratio [HR] 1.18, 1.26, and 1.30, 95% confidence interval [CI] 1.08 - 1.28, 1.14 - 1.39, and 1.10 - 1.55, respectively). For every FRAIL item increase, the associated risk rose by 9%. Conclusions Frailty significantly increased the risk of delirium/cognitive impairment among patients with DKD. Frailty screening in these patients may assist in delirium risk stratification.

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.

The omission of outcomes that are of relevance to patients, clinicians, and regulators across trials in autosomal dominant polycystic kidney disease (ADPKD) limits shared decision making. The Standardized Outcomes in Nephrology-Polycystic Kidney Disease (SONG-PKD) Initiative convened an international consensus workshop on October 25, 2018, to discuss the identification and implementation of a potential core outcome set for all ADPKD trials. This article summarizes the discussion from the workshops and the SONG-PKD core outcome set. Key stakeholders including 11 patients/ caregivers and 47 health professionals (nephrologists, policy makers, industry, and researchers) attended the workshop. Four themes emerged: "Relevance of trajectory and impact of kidney function" included concerns about a patient's prognosis and uncertainty of when they may need to commence kidney replacement therapy and the lack of an early prognostic marker to inform long-term decisions; "Discerning and defining pain specific to ADPKD" highlighted the challenges in determining the origin of pain, adapting to the chronicity and repeated episodes of pain, the need to place emphasis on pain management, and to have a validated measure for pain; "Highlighting ADPKD consequences" encompassed cyst-related complications and reflected patient's knowledge because of family history and the hereditary nature of ADPKD; and "Risk for life-threatening but rare consequences" such as cerebral aneurysm meant considering both frequency and severity of the outcome. Kidney function, mortality, cardiovascular disease, and pain were established as the core outcomes for ADPKD.

Vascular calcification (VC) describes the pathophysiological phenotype of calcium apatite deposition within the vascular wall, leading to vascular stiffening and the loss of compliance. VC is never benign; the presence and severity of VC correlate closely with the risk of myocardial events and cardiovascular mortality in multiple at-risk populations such as patients with diabetes and chronic kidney disease. Mitochondrial dysfunction involving each of vascular wall constituents (endothelia and vascular smooth muscle cells (VSMCs)) aggravates various vascular pathologies, including atherosclerosis and VC. However, few studies address the pathogenic role of mitochondrial dysfunction during the course of VC, and mitochondrial reactive oxygen species (ROS) seem to lie in the pathophysiologic epicenter. Superoxide dismutase 2 (SOD2), through its preferential localization to the mitochondria, stands at the forefront against mitochondrial ROS in VSMCs and thus potentially modifies the probability of VC initiation or progression. In this review, we will provide a literature-based summary regarding the relationship between SOD2 and VC in the context of VSMCs. Apart from the conventional wisdom of attenuating mitochondrial ROS, SOD2 has been found to affect mitophagy and the formation of the autophagosome, suppress JAK/STAT as well as PI3K/Akt signaling, and retard vascular senescence, all of which underlie the beneficial influences on VC exerted by SOD2. More importantly, we outline the therapeutic potential of a novel SOD2-targeted strategy for the treatment of VC, including an ever-expanding list of pharmaceuticals and natural compounds. It is expected that VSMC SOD2 will become an important druggable target for treating VC in the future.

Additional file 1: Table S1. Diagnostic and procedure codes for identifying cardiovascular morbidities in this study. Table S2. Risk of developing each cardiovascular morbidity according to the presence of DKD or not, based on a specific diagnostic codes for DKD (n = 5441 per group).

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: 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 (pConclusions: We found that miR-125b serves as an independent indicator for VC in relatively healthy older adults, and may potentially be linked with VC pathophysiology.

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.

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.

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 &lt, 60 mL/min/1.73 m2), 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.

Background and Aims The prevalence of chronic pain in patients with chronic kidney disease (CKD) is high and is associated with higher frailty risk, but satisfactory pain control frequently fails to be achieved. Opioid remains instrumental regarding optimal pain management, but its influence on outcomes can be of concern in CKD patients. We examined whether opioid use affected patient outcome and whether such relationship was modified by frailty. Method From the longitudinal cohort of diabetic patients (n = 840,000), a well-maintained population-based cohort, we identified those with CKD who were opioid user (at least 7 days within any month; n = 26,029), followed by propensity score-matched to opioid never-users from the same cohort in a 1:1 ratio, based on demographic features, comorbidities, and other medications. We analysed the associations between opioid use and survival in these patients according to their baseline frailty status, defined by the modified FRAIL (Fatigue, Resistance, Ambulation, Illness, and Loss of weight) scale. Results Among the enrolled CKD participants (mean age 62.9 ± 13.5 years, 48.2% female), 20.3% did not have any FRAIL item satisfied, while 57.2%, 20.6%, and 1.9% had 1, 2, and at least 3 positive FRAIL items at baseline, respectively. After a median of 4.2 years, 16.4% participants died. Univariate analysis showed that opioid users had an elevated risk of morality compared to non-users (hazard ratio [HR] 1.124, 95% confidence interval [CI] 1.08 – 1.17) (Figure). Cox proportional hazard regression showed that opioid users exhibited an 18.3% higher risk of mortality compared to non-users (HR 1.183, 95% CI 1.13-1.24) among patients with CKD; furthermore, the mortality risk associated with opioid use was observed in CKD participants without frailty only (HR 1.18, 95% CI 1.13-1.24) but not in those with frailty (HR 1.08, 95% CI 0.83 – 1.4). Conclusion Opioid use might lead to a higher risk of mortality among CKD patients, but this relationship was observed among those without frailty only. Interestingly, frail CKD patients who were opioid users were not at an elevated risk of mortality compared to non-users.

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.

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.

Objective Gustatory function is frequently impaired in patients with chronic kidney disease (CKD), and the associated taste dysfunction contributes to compromised nutrition. Whether gustatory dysfunction is an underappreciated risk factor for frailty in patients with CKD remains unclear. The objective of this work was to examine the role of gustatory dysfunction as a risk factor for frailty in patients with CKD. Methods We prospectively enrolled patients with stage 3 or higher CKD from a single institute, with their gustatory function assessed using both objective (taste strip method) and subjective approaches, and frailty identified using the Edmonton frail scale, FRAIL scale, and Study of Osteoporotic Fracture (SOF) scale. Multiple regression analyses were performed to investigate whether results from gustatory function tests independently correlated with frailty. Results Among the enrolled patients with CKD, 14 (17.9%) were found to be frail. We discovered that higher taste strip scores, or better taste function, were significantly associated with a lower frail probability (odds ratio [OR] 0.74 per score, 95% confidence interval [CI] 0.57-0.97), independent of clinical features, while better subjective taste function (OR 0.84 per score, 95% CI 0.74-0.96) and better oral cavity intactness (OR, 0.94; 95% CI, 0.9-0.98) were similarly associated with a lower frail probability among patients with CKD. Conclusion Gustatory dysfunction may be an important risk factor for frailty in patients with CKD. It is tempting to presume that interventions aiming to ameliorate such deficits may bear the potential of reducing frailty severity in this population with a high frailty burden.

Aims Vascular calcification (VC) increases the future risk of cardiovascular events in uraemic patients, but effective therapies are still unavailable. Accurate identification of those at risk of developing VC using pathogenesis-based biomarkers is of particular interest and may facilitate individualized risk stratification. We aimed to uncover microRNA (miRNA)-target protein-based biomarker panels for evaluating uraemic VC probability and severity. Methods and results We created a three-tiered in vitro VC model and an in vivo uraemic rat model receiving high phosphate diet to mimic uraemic VC. RNAs from the three-tiered in vitro and in vivo uraemic VC models underwent miRNA and mRNA microarray, with results screened for differentially expressed miRNAs and their target genes as biomarkers. Findings were validated in original models and additionally in an ex vivo VC model and human cells, followed by functional assays of identified miRNAs and target proteins, and tests of sera from end-stage renal disease (ESRD) and non-dialysis-dependent chronic kidney disease (CKD) patients without and with VC. Totally 122 down-regulated and 119 up-regulated miRNAs during calcification progression were identified initially; further list narrowing based on miRNA–mRNA pairing, anti-correlation, and functional enrichment left 16 and 14 differentially expressed miRNAs and mRNAs. Levels of four miRNAs (miR-10b-5p, miR-195, miR-125b-2-3p, and miR-378a-3p) were shown to decrease throughout all models tested, while one mRNA (SULF1, a potential target of miR-378a-3p) exhibited the opposite trend concurrently. Among 96 ESRD (70.8% with VC) and 59 CKD patients (61% with VC), serum miR-125b2-3p and miR-378a-3p decreased with greater VC severity, while serum SULF1 levels increased. Adding serum miR-125b-2-3p, miR-378a-3p, and SULF1 into regression models for VC substantially improved performance compared to using clinical variables alone. Conclusion Using a translational approach, we discovered a novel panel of biomarkers for gauging the probability/severity of uraemic VC based on miRNAs/target proteins, which improved the diagnostic accuracy.

AIM Increased oxidative stress significantly modifies the outcome of patients with diabetes mellitus (DM) and end-stage renal disease (ESRD), and is counteracted by antioxidative capacity. We aimed to investigate whether antioxidant single nucleotide polymorphisms (SNPs) influence the outcome of ESRD individuals and the influences exerted by DM, which has not been tested before. METHODS We prospectively enrolled multi-centre ESRD patients of Han Chinese origin between 2002 and 2003, recording their antioxidant (superoxide dismutase [SOD2], glutathione peroxidase [GPX1]) and peroxisome proliferator activated receptor-γ (PPAR-γ) genotyping results, and stratified based on DM. They were followed up until 2008, with risk factors for mortality analyzed by Cox proportional hazard regression. RESULTS We discovered that diabetic ESRD carriers of CC genotype of SOD2 exon 2 had an increased risk of mortality compared to non-diabetic ones with other genotypes (hazard ratio [HR] 4.04, P = 0.04), while GPX1 SNPs had no influence. Interactions between SOD2 and PPAR-γ SNPs regarding the mortality influence were also detected (for SOD2 CC genotype x PPAR-γ exon 6 CT genotype, HR 3.19, P = 0.008), suggesting the importance of considering a combination panel of SNPs on patient survival. CONCLUSION This might be the largest study focusing on the relationship between antioxidant SNPs and the outcomes of diabetic ESRD patients of Han Chinese origin. More studies are needed to validate our findings.

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.

Disease-related malnutrition is highly prevalent, and has prognostic implications for patients with chronic kidney disease (CKD); however, few studies have investigated the impact of malnutrition, or protein-energy wasting (PEW), on healthcare utilization and medical expenditure among CKD patients.Using claim data from the National Health Insurance in Taiwan, this study identified patients with CKD between 2009-2013 and categorized them into those with mild, moderate, or severe CKD. Cases with PEW after CKD was diagnosed were propensity-score matched with controls in a 1:4 ratio. Healthcare resource utilization metrics were compared, including outpatient and emergency department visits, frequency and duration of hospitalization, and the cumulative costs associated with different CKD severity.From among 347,501 CKD patients, eligible cohorts of 66,872 with mild CKD (49.2%), 27,122 with moderate CKD (19.9%), and 42,013 with severe CKD (30.9%) were selected. Malnourished CKD patients had significantly higher rates of hospitalization (p .001 for all severities) and re-admission (p = .015 for mild CKD, p = .002 for severe CKD) than non-malnourished controls. Cumulative medical costs for outpatient and emergency visits, and hospitalization, were significantly higher among all malnourished CKD patients than non-malnourished ones (p .001); total medical costs were also higher among malnourished patients with mild (62.9%), moderate (59.6%), or severe (43.6%) CKD compared to non-malnourished patients (p .001).In a nationally-representative cohort, CKD patients with PEW had significantly more healthcare resource utilization and higher aggregate medical costs than those without, across the spectrum of CKD: preventing PEW in CKD patients should receive high priority if we would like to reduce medical costs.

Objective— Vascular calcification (VC) is a major cause of mortality in patients with end-stage renal diseases. Biomarkers to predict the progression of VC early are in urgent demand. Approach and Results— We identified circulating, cell-free microRNAs as potential biomarkers using in vitro VC models in which both rat and human aortic vascular smooth muscle cells were treated with high levels of phosphate to mimic uremic hyperphosphatemia. Using an Affymetrix microRNA array, we found that miR-125b and miR-382 expression levels declined significantly as biomineralization progressed, but this decline was only observed for miR-125b in the culture medium. A time-dependent decrease in aortic tissue and serum miR-125b levels was also found in both ex vivo and in vivo renal failure models. We examined the levels of circulating, cell-free miR-125b in sera from patients with end-stage renal diseases (n=88) and found an inverse association between the severity of VC and the circulating miR-125b level, irrespective of age or mineral-related hormones (odds ratio, 0.71; P =0.03). Furthermore, serum miR-125b levels on enrollment can predict VC progression years later (for high versus low, odds ratio, 0.14; P P =0.3 and Conclusions— The results suggest that serum miR-125b levels are associated with VC severity and serve as a novel predictive marker for the risk of uremia-associated calcification progression.

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.

Aims Patients with diabetes mellitus (DM) are at risk for developing frailty due to the complex interplay between different cardiometabolic factors. We examined whether hypoglycemia could independently increase frailty risk besides these factors. Methods From the Longitudinal Cohort of Diabetic Patients, 210,254 patients with new onset DM between 2004 and 2011 were identified, among whom 2119 non-frail patients had at least 1 hypoglycemic episode within 3 years of DM diagnosis. They were propensity score-matched to 8432 non-frail ones without hypoglycemia throughout the study period. Both groups were followed up longitudinally for incident physical frailty according to a modified FRAIL scale (Fatigue, Resistance, Ambulation, Illness, and Loss of weight). We analyzed the risk of frailty (primary) and mortality (secondary outcome) introduced by hypoglycemia, adjusted for known risk factors of frailty. Results The mean age of patients (46.2% male) was 65.9 ± 14 years; diabetic patients with hypoglycemia had significantly higher comorbidity burden than those without. After 2.68 years, 172 (1.6%) patients with hypoglycemia developed incident frailty, representing a 60% higher risk (hazard ratio [HR] 1.599, 95% confidence interval [CI] 1.14–2.42). After adjusting for other risk factors, those with hypoglycemia had a significantly higher risk of frailty than those without (HR 1.443, 95% CI 1.01–2.05). Additionally, the mortality of those with hypoglycemia was 2-fold higher than those without, and the risk persisted despite confounder adjustment (HR 1.462, 95% CI 1.3–1.65). Conclusion In this population-based cohort, hypoglycemic episodes among diabetic patients increased the risk of incident frailty and mortality.

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.