The screening, diagnosis, and management of patients with autosomal dominant polycystic kidney disease: A national consensus statement from Taiwan.

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.

A combined circulating microRNA panel predicts the risk of vascular calcification in community-dwelling older adults with age strata differences.

BACKGROUND: Older adults have a higher risk of developing vascular calcification (VC). Circulating miRNAs can be potential risk indicators. However, prior studies used single miRNA mostly, whereas miRNA panels were rarely evaluated. We aimed to examine whether a miRNA panel outperformed each miRNA alone, and analyzed whether advanced age affected VC risk predictive performance offered by the miRNA panel. METHODS: We prospectively enrolled older adults (age ≥65 years) during their annual health checkup in 2017, and examined their VC severity followed by analyzing sera for VC regulatory miRNAs (miR-125b-5p, miR-125b-3p, and miR-378a-3p). We used multiple regression analyses to determine associations between each miRNA or a 3-combind panel and VC risk, followed by area under the receiver-operating-characteristics curve (AUROC) analysis. Participants were further divided to those of 65-75 and ≥75 years for comparison. RESULTS: From 199 older adults screened, 169 (median age, 73.3 years) with available calcification assessment were analyzed, among whom 74.6 % having VC. Those with VC had significantly lower circulating miR-125b-5p, miR-125b-3p, and miR-378a-3p levels than those without. Regression analyses showed that the 3-combined miRNA panel exhibited significant associations with VC risk, with significantly higher AUROC than those of models based on individual miRNA. Importantly, in those ≥75 years, the miRNA-predicted risk of VC was more prominent than that in the 65-75 years group. CONCLUSION: A miRNA panel for VC risk prediction might outperform individual miRNA alone in older adults, and advanced age modified the association between circulating miRNAs and the risk of VC.

Aortic arch calcification increases major adverse cardiac event risk, modifiable by echocardiographic left ventricular hypertrophy, in end-stage kidney disease patients.

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.

Literacy for Frailty among Undergraduate Medical Education: An Under-Recognized Opportunity to Improve Geriatric Care.

Our society is aging much faster than it was before, and this phenomenon demands concerted action to optimize geriatric care. Presentations, clinical features, and management decision making are distinct between older adults and general population, and to enhance care quality, there remains unmet needs for undergraduate geriatric education. Among all geriatric syndromes that clinically matter, frailty is particularly instrumental, serving as the overarching phenotype that connects other geriatric conditions and predisposes individuals to adverse outcomes. However, understandings for frailty, or "literacy for frailty" is often poor among healthcare professionals, and misidentification, terminology confusion, and uncertainty surrounding the care of frail older adults, are not uncommon. This lack of frailty literacy undoubtedly contributes to the suboptimal geriatric care patients receive. We therefore propose a rationally designed, concise, and structured program for eliciting medical students' motivation for understanding frailty during their undergraduate period. Our increasing-frailty-literacy program includes 7 modules, accommodating the terminology, integrative pathogenesis, epidemiology of frailty, appropriate screening and identification tool selection, prognostication and patient communication, and individualization of treatment strategies. In combination with digital technologies and hands-on practice opportunities, we believe that our curriculum can promote medical students' learning efficacy for frailty and improve geriatric care for the current generation.

Extracellular MicroRNAs as Potential Biomarkers for Frail Kidney Phenotype: Progresses and Precautions.

Frailty describes the cumulative subtle health deficits leading to an increased vulnerability to insults among older individuals or disease-laden ones. The prevalence of frailty increases substantially and relentlessly over declining renal function. Frailty in patients with chronic kidney disease (CKD) carries kidney-specific risk factors, clinical correlates and outcomes associations, hence alternatively termed frail kidney phenotype by researchers. Pathogenetically, miRNAs participate extensively in the development and aggravation of frailty, including the occurrence of frail kidney phenotype in CKD patients. These understandings spark profound interest in discovering biomarkers for identifying this detrimental phenotype, and extracellular miRNAs emerge as potentially useful ones. Pilot studies identify promising miRNA candidates for evaluating intermediates and surrogates of frail kidney phenotype, and more are underway. Several potential miRNA species in biologic fluids, such as circulating miR-29b and miR-223 (as inflammatory markers), exosomal miR-16-5p, miR-17/92 cluster members, and miR-106-5p (for uremic vasculopathy), serum exosomal miR-203a-3p (for uremic sarcopenia) have been examined and can be promising choices. Nonetheless, there remains research gap in affirming the direct connections between specific miRNAs and frail kidney phenotype. This stems partially from multiple limitations less well acknowledged before. From this perspective, we further outline the limitations and precautions prior to validating specific extracellular miRNA(s) for this purpose, from the definition of frailty definition, the functional and tissue specificity of miRNAs, the severity of CKD, and various technical considerations. It is expected that more affirmative studies can be produced for extending the utility of extracellular miRNAs in predicting frail kidney phenotype.

The Impact of Glucose-Lowering Strategy on the Risk of Increasing Frailty Severity among 49,519 Patients with Diabetes Mellitus: A Longitudinal Cohort Study.

Patients with diabetes mellitus (DM) have a higher risk of incident and aggravating frailty over time. Frailty-initiating risk factors have been identified, but modulators of frail severity over time remain poorly defined. We aimed to explore the influences of glucose-lowering drug (GLD) strategy on DM patients' risk of increasing frail severity. We retrospectively identified type 2 DM patients between 2008 and 2016, dividing them into "no GLD", oral GLD (oGLD) monotherapy, oGLD combination, and those receiving insulin without or with oGLD at baseline. Increasing frail severity, defined as ≥1 FRAIL component increase, was the outcome of interest. Cox proportional hazard regression was utilized to analyze the risk of increasing frail severity associated with GLD strategy, accounting for demographic, physical data, comorbidities, medication, and laboratory panel. After screening 82,208 patients with DM, 49,519 (no GLD, 42.7%; monotherapy, 24.0%; combination, 28.5%; and insulin user, 4.8%) were enrolled for analysis. After 4 years, 12,295 (24.8%) had increasing frail severity. After multivariate adjustment, oGLD combination group exhibited a significantly lower risk of increasing frail severity (hazard ratio (HR) 0.90, 95% confidence interval (CI) 0.86 - 0.94), while the risk of insulin users increased (HR 1.11, 95% CI 1.02 - 1.21) than no GLD group. Users receiving more oGLD exhibited a trend of less risk reduction relative to others. In conclusion, we discovered that the strategy of oral glucose lowering drugs combination might reduce the risk of frail severity increase. Accordingly, medication reconciliation in frail diabetic older adults should take into account their GLD regimens.

Chest radiography deep radiomics-enabled aortic arch calcification interpretation across different populations.

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.

Vascular frailty, a proposal for new frailty type: A narrative review.

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.

The context-dependent role of transforming growth factor-ß/miR-378a-3p/connective tissue growth factor in vascular calcification: a translational study.

BACKGROUND: Vascular calcification (VC) constitutes an important vascular pathology with prognostic importance. The pathogenic role of transforming growth factor-ß (TGF-ß) in VC remains unclear, with heterogeneous findings that we aimed to evaluate using experimental models and clinical specimens. METHODS: Two approaches, exogenous administration and endogenous expression upon osteogenic media (OM) exposure, were adopted. Aortic smooth muscle cells (ASMCs) were subjected to TGF-ß1 alone, OM alone, or both, with calcification severity determined. We evaluated miR-378a-3p and TGF-ß1 effectors (connective tissue growth factor; CTGF) at different periods of calcification. Results were validated in an ex vivo model and further in sera from older adults without or with severe aortic arch calcification. RESULTS: TGF-ß1 treatment induced a significant dose-responsive increase in ASMC calcification without or with OM at the mature but not early or mid-term VC period. On the other hand, OM alone induced VC accompanied by suppressed TGF-ß1 expressions over time; this phenomenon paralleled the declining miR-378a-3p and CTGF expressions since early VC. TGF-ß1 treatment led to an upregulation of CTGF since early VC but not miR-378a-3p until mid-term VC, while miR-378a-3p overexpression suppressed CTGF expressions without altering TGF-ß1 levels. The OM-induced down-regulation of TGF-ß1 and CTGF was also observed in the ex vivo models, with compatible results identified from human sera. CONCLUSIONS: We showed that TGF-ß1 played a context-dependent role in VC, involving a time-dependent self-regulatory loop of TGF-ß1/miR-378a-3p/CTGF signaling. Our findings may assist subsequent studies in devising potential therapeutics against VC.

Left Ventricular Hypertrophy Geometry and Vascular Calcification Co-Modify the Risk of Cardiovascular Mortality in Patients with End-Stage Kidney Disease: A Retrospective Cohort Study.

AIM: Patients with end-stage kidney disease (ESKD) have an unparalleled risk of left ventricular hypertrophy (LVH) and vascular calcification (VC), both of which introduce excessive cardiovascular risk. However, it remains unclear whether LVH geometry co-modulates cardiovascular outcomes with VC in this population. METHODS: A retrospective cohort study was conducted. Patients with ESKD requiring chronic hemodialysis were identified from Shin Kong Wu Ho-Su Memorial Hospital between October and December 2018, with echocardiographic LVH geometry and aortic arch calcification (AoAC) determined. They were divided into four groups according to AoAC severity and eccentric or concentric LVH. We used Kaplan-Meier analysis and Cox proportional hazard regression to analyze their cardiovascular and all-cause mortality after multivariate adjustment. RESULTS: Overall, 223 patients with ESKD with LVH were analyzed, among whom 29.1%, 23.3%, 25.1%, and 22.4% had non-to-mild AoAC with eccentric and concentric LVH and moderate-to-severe AoAC with eccentric and concentric LVH, respectively. After 3.5 years of follow-up, patients with ESKD with moderate-to-severe AoAC and concentric LVH had a significantly higher risk of cardiovascular mortality than those with non-to-mild AoAC and eccentric LVH (hazard ratio 3.35, p=0.002). However, those with moderate-to-severe AoAC but eccentric LVH did not have higher cardiovascular mortality. Similarly, patients with ESKD with moderate-to-severe AoAC and concentric LVH had a significantly higher all-cause mortality than those with non-to-mild AoAC and eccentric LVH, whereas the other two groups did not have higher risk. CONCLUSION: LVH geometry could help stratify the risk of patients with ESKD when they had severe VC, and co-existing severe VC and concentric LVH aggravated cardiovascular risk.

Association of aortic arch and aortic valve calcifications with cardiovascular risk in patients on maintenance hemodialysis.

Introduction: This 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). Methods: This study enrolled 297 adult patients with end-stage kidney disease who were on MHD. They were divided into those with an AoAC score <2 without AVC (n = 70, 23.6%), those with an AoAC score <2 with AVC (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. Results: Kaplan-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 <2 without AVC, followed by those with AoAC score <2 with AVC, and then those with AoAC score ≥2 (log-rank test; all 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 <2 without AVC, adult chronic hemodialysis patients with AoAC score ≥2 remained an independently significantly risk factor of MACE (adjusted hazard ratio, 2.17; 95% confidence interval 1.11-4.20; p = 0.023) after adjusting for age, sex, and all significant variables in baseline characteristics. Conclusion: AoAC 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.

Moving from tangibility toward digitalization: investigating team dynamics and facilitator support among medical students in conventional and digital small-group tutorials.

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.