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. 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) in Taiwan, we identified adults with DKD, dividing them into those without and with different severities of frailty based on a modified 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, co‐morbidities, 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 1.18, 1.26 and 1.30, 95% confidence interval 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 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.
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.
Transforming growth factor beta (TGFβ) signalling regulates extracellular matrix accumulation known to be essential for the pathogenesis of renal fibrosis; latent transforming growth factor beta ...binding protein 4 (LTBP4) is an important regulator of TGFβ activity. To date, the regulation of LTBP4 in renal fibrosis remains unknown. Herein, we report that LTBP4 is upregulated in patients with chronic kidney disease and fibrotic mice kidneys created by unilateral ureteral obstruction (UUO). Mice lacking the short LTBP4 isoform (Ltbp4S
) exhibited aggravated tubular interstitial fibrosis (TIF) after UUO, indicating that LTBP4 potentially protects against TIF. Transcriptomic analysis of human proximal tubule cells overexpressing LTBP4 revealed that LTBP4 influences angiogenic pathways; moreover, these cells preserved better mitochondrial respiratory functions and expressed higher vascular endothelial growth factor A (VEGFA) compared to wild-type cells under hypoxia. Results of the tube formation assay revealed that additional LTBP4 in human umbilical vein endothelial cell supernatant stimulates angiogenesis with upregulated vascular endothelial growth factor receptors (VEGFRs). In vivo, aberrant angiogenesis, abnormal mitochondrial morphology and enhanced oxidative stress were observed in Ltbp4S
mice after UUO. These results reveal novel molecular functions of LTBP4 stimulating angiogenesis and potentially impacting mitochondrial structure and function. Collectively, our findings indicate that LTBP4 protects against disease progression and may be of therapeutic use in renal fibrosis.
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.
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;
=0.03). Furthermore, serum miR-125b levels on enrollment can predict VC progression years later (for high versus low, odds ratio, 0.14;
<0.01; for the highest versus lowest tertile and middle versus lowest tertile, odds ratio, 0.55 and 0.13;
=0.3 and <0.01, respectively). The uremic VC prediction efficacy using circulating miR-125b levels was also observed in an independent cohort (n=135).
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.
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.
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of end-stage kidney disease (ESKD) worldwide. Guidelines for the diagnosis and management of ADPKD in Taiwan ...remains unavailable. In this consensus statement, we summarize updated information on clinical features of international and domestic patients with ADPKD, followed by suggestions for optimal diagnosis and care in Taiwan. Specifically, counselling for at-risk minors and reproductive issues can be important, including ethical dilemmas surrounding prenatal diagnosis and pre-implantation genetic diagnosis. Studies reveal that ADPKD typically remains asymptomatic until the fourth decade of life, with symptoms resulting from cystic expansion with visceral compression, or rupture. The diagnosis can be made based on a detailed family history, followed by imaging studies (ultrasound, computed tomography, or magnetic resonance imaging). Genetic testing is reserved for atypical cases mostly. Common tools for prognosis prediction include total kidney volume, Mayo classification and PROPKD/genetic score. Screening and management of complications such as hypertension, proteinuria, urological infections, intracranial aneurysms, are also crucial for improving outcome. We suggest that the optimal management strategies of patients with ADPKD include general medical care, dietary recommendations and ADPKD-specific treatments. Key points include rigorous blood pressure control, dietary sodium restriction and Tolvaptan use, whereas the evidence for somatostatin analogues and mammalian target of rapamycin (mTOR) inhibitors remains limited. In summary, we outline an individualized care plan emphasizing careful monitoring of disease progression and highlight the need for shared decision-making among these patients.
Context:
Studies addressing the association of metabolic syndrome and insulin resistance with the risks of incident chronic kidney disease (CKD) and the progression of renal function were either ...lacking or inconclusive.
Objective:
The aim of this study was to define the effect of metabolic syndrome and insulin resistance on the development of new CKD and the decline in renal function.
Design and Setting:
A prospective cohort study was conducted at a tertiary university-based hospital in Taiwan.
Patients and Other Participants:
We studied a total of 1456 Asians 65 or older who were followed for an average of 3.15 yr. Within the cohort, we measured insulin resistance using the homeostasis model assessment formula in 652 nondiabetic participants.
Interventions:
There were no interventions.
Main Outcome Measures:
We measured the prevalence and incidence of CKD and the annual decline of the estimated glomerular filtration rate.
Results:
We found that the adjusted odds ratio for prevalent CKD in association with metabolic syndrome was 1.778 (95% confidence interval, 1.188 to 2.465), the hazard ratio for rapid decline in renal function was 1.042 (0.802–1.355), and the hazard ratio for incident CKD was 1.931 (1.175–3.174). With each one-unit increment of insulin resistance, the odds ratio of prevalent CKD and proteinuria were raised 1.312-fold (1.114 to 1.545) and 1.278-fold (1.098 to 1.488), respectively. Insulin resistance was not associated with incident CKD. Increment of insulin resistance per unit was associated with 1.16-fold (1.06 to 1.26) elevation in the hazard ratios of the decline in renal function.
Conclusions:
Metabolic syndrome predicts the risks of prevalent and incident CKD, whereas insulin resistance is associated with prevalent CKD and rapid decline in renal function in elderly individuals.
Background Micro RNA ‐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.
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.
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