Vascular Calcification Heterogeneity from Bench to Bedside: Implications for Manifestations, Pathogenesis, and Treatment Considerations.

Vascular calcification (VC) is the ectopic deposition of calcium-containing apatite within vascular walls, exhibiting a high prevalence in older adults, and those with diabetes or chronic kidney disease. VC is a subclinical cardiovascular risk trait that increases mortality and functional deterioration. However, effective treatments for VC remain largely unavailable despite multiple attempts. Part of this therapeutic nihilism results from the failure to appreciate the diversity of VC as a pathological complex, with unforeseeable variations in morphology, risk associates, and anatomical and molecular pathogenesis, affecting clinical management strategies. VC should not be considered a homogeneous pathology because accumulating evidence refutes its conceptual and content uniformity. Here, we summarize the pathophysiological sources of VC heterogeneity from the intersecting pathways and networks of cellular, subcellular, and molecular crosstalk. Part of these pathological connections are synergistic or mutually antagonistic. We then introduce clinical implications related to the VC heterogeneity concept. Even within the same individual, a specific artery may exhibit the strongest tendency for calcification compared with other arteries. The prognostic value of VC may only be detectable with a detailed characterization of calcification morphology and features. VC heterogeneity is also evident, as VC risk factors vary between different arterial segments and layers. Therefore, diagnostic and screening strategies for VC may be improved based on VC heterogeneity, including the use of radiomics. Finally, pursuing a homogeneous treatment strategy is discouraged and we suggest a more rational approach by diversifying the treatment spectrum. This may greatly benefit subsequent efforts to identify effective VC therapeutics.

Sleep Duration and Kidney Function - Does Weekend Sleep Matter?

Objective: Weekend sleep duration is linked to health issues, including mortality. However, how weekend sleep duration can impact chronic kidney disease (CKD) still needs to be understood. Therefore, we aimed to analyze how weekend sleep duration is associated with kidney function. Methods: This is a cross-sectional study. Data were obtained from the 2017-2018 National Health and Nutrition Examination Survey. We included 5362 study participants and categorized them into nine subgroups by sleep duration (short: ≤6 hours, normal: 6-9 hours, and long: ≥9 hours) on weekdays and weekends and analyzed for the respective association with renal function using stratified multivariable linear regression. Results: Weekend sleep duration for 9 hours or more was associated with decreasing estimated glomerular filtration rate (eGFR) levels by 2.8 to 6.4 mL/min/1.73 m2 among people with long to short weekday sleep duration compared with short weekday and weekend sleep durations (control group) after adjusting for demographic characteristics, body measurement, sleep quality, smoking, and comorbidities. The study population with short weekday sleep duration (sWK) and long weekend sleep duration (lWD) had the most significant decline in eGFR. For the study population with sWK, eGFR level significantly decreased by 1.1 mL/min/1.73 m2 as sleep duration on weekends increased by one hour. Conclusion: The underlying mediators of lWD and CKD could be the dysregulation of human behaviors, metabolism, or biological functions. Longer weekend sleep duration was linked to a decrease in eGFR levels. It warrants further study to clarify the mediators.

AST-120 improved uremic pruritus by lowering indoxyl sulfate and inflammatory cytokines in hemodialysis patients.

BACKGROUND AND HYPOTHESIS: Pruritus is a common and distressing symptom that affects patients with chronic kidney disease. The concentration of protein bounded uremic toxin was associated with the uremic pruritus. The aim is to assess the efficacy of AST-120 for uremic pruritus in hemodialysis patients. MATERIALS AND METHODS: The participants were enrolled and then divided into the AST-120 treatment group and control group with a ratio of 2:1. All participants underwent pre-observation screenings two weeks before the study with three visits. In the treatment phase (week 1 to week 4), the treatment group added 6g/day of AST-120 along with routine anti-pruritic treatment. Visual analog scale (VAS) and biochemical parameters were measured. RESULTS: The VAS score began to be lower in the AST-120 treatment group after the 5th visiting (p < 0.05). The reduction in indoxyl sulfate (IS) at 5th week along with TNF-alpha. The reduction ratio of indoxyl sulfate correlated with reduction of parathyroid hormone. CONCLUSION: This study has demonstrated that the four-week treatment of AST-120 decreased the severity of uremic pruritus in patients with ESRD. The concentration of IS and TNF-alpha decreased in the AST-120 treatment group. The reduction of iPTH correlated with the reduction of IS in the AST-120 treatment.

The influence of uremic toxins on low bone turnover disease in chronic kidney disease.

Uremic toxins play a crucial role in the development of low bone turnover disease in chronic kidney disease (CKD) through the induction of oxidative stress. This oxidative stress disrupts the delicate balance between bone formation and resorption, resulting in a decline in both bone quantity and quality. Reactive oxygen species (ROS) activate nuclear factor kappa-B and mitogen-activated protein kinase signaling pathways, promoting osteoclastogenesis. Conversely, ROS hinder osteoblast differentiation by facilitating the binding of Forkhead box O proteins (FoxOs) to ß-catenin, triggering apoptosis through FoxOs-activating kinase phosphorylation. This results in increased osteoblastic receptor activator of nuclear factor kappa-B ligand (RANKL) expression and decreased nuclear factor erythroid 2-related factor 2 levels, compromising antioxidant defenses against oxidative damage. As CKD progresses, the accumulation of protein-bound uremic toxins such as indoxyl sulfate (IS) and p-cresyl sulfate (PCS) intensifies oxidative stress, primarily affecting osteoblasts. IS and PCS directly inhibit osteoblast viability, induce apoptosis, decrease alkaline phosphatase activity, and impair collagen 1 and osteonectin, impeding bone formation. They also reduce cyclic adenosine 3',5'-monophosphate (cAMP) production and lower parathyroid hormone (PTH) receptor expression in osteoblasts, resulting in PTH hyporesponsiveness. In summary, excessive production of ROS by uremic toxins not only reduces the number and function of osteoblasts but also induces PTH hyporesponsiveness, contributing to the initiation and progression of low bone turnover disease in CKD.

The Ratio of Plasma Amyloid-ß 1-42 over Serum Albumin Can Be a Novel Biomarker Signature for Diagnosing End-Stage Renal Disease-Associated Cognitive Impairment.

BACKGROUND: Cognitive impairment (CI) is one of the major complications in chronic kidney disease patients, especially those with end-stage renal disease (ESRD). Limited biomarkers have been found that can significantly predict ESRD-associated cognitive decline. OBJECTIVE: This cohort study aimed to investigate de novo biomarkers for diagnosis of the ESRD-associated CI. METHODS: In this cohort study, qualified samples were divided into control (with an estimated glomerular filtration rate (eGFR) of≥60 mL/min and a Mini-Mental State Examination (MMSE) score of > 27), ESRD without CI (eGFR < 15 and MMSE > 27), and ESRD with CI (eGFR < 15 and MMSE < 27) groups. Levels of plasma amyloid-ß (Aß)1 - 42, serum indoxyl sulfate, and hematologic and biochemical parameters were measured. RESULTS: Compared to the control group, levels of blood urea nitrogen, creatinine, and indoxyl sulfate were elevated in ESRD patients both without and with CI. Interestingly, ESRD patients with CI had the lowest levels of serum albumin. In contrast, levels of plasma Aß1 - 42 were significantly higher in the ESRD with CI group than in the control and ESRD without CI groups. In addition, the ratio of plasma Aß1 - 42 over serum albumin was significantly higher in the ESRD with CI group than in the control or ESRD without CI groups. Importantly, the area under the receiver operating characteristic curve (AUROC) for CI in the total population by the ratio of Aß1 - 42 over albumin was 0.785 and significant (p < 0.05). CONCLUSIONS: This cohort study has shown that the ratio of plasma Aß1 - 42 over serum albumin can be a de novo biomarker for the diagnosis and prognosis of ESRD-associated cognitive decline.

Comparison of the Oral Calcimimetics Evocalcet and Cinacalcet in East Asian Patients on Hemodialysis with Secondary Hyperparathyroidism.

Introduction: Evocalcet is an oral calcimimetic agent with proven efficacy and safety in treating secondary hyperparathyroidism (SHPT) in Japanese patients on dialysis. Methods: This randomized, double-blind, intrapatient dose-adjustment, parallel-group, international multicenter study compared the efficacy and safety of evocalcet versus cinacalcet for 52 weeks in East Asian hemodialysis patients with SHPT. Results: In total, 203 and 200 patients were randomized to receive evocalcet or cinacalcet, respectively (overall, 70.1% had baseline intact parathyroid hormone (PTH) levels ≥500 pg/ml, with no between-group difference). Mean percentage changes in intact PTH levels from baseline were -34.7% and -30.2% in the evocalcet and cinacalcet groups at 52 weeks (between-group difference -4.4%, 95% confidence interval [CI] -13.1%, 4.3%, below the predefined 15% noninferiority margin). Overall, 67.3% and 58.7% of patients in the evocalcet and cinacalcet groups, respectively, achieved ≥30% decrease in intact PTH levels from baseline (between-group difference 8.6%; 95% CI -1.8%, 19.1%). No major safety concerns were observed. Gastrointestinal adverse events (AEs) were significantly less frequent with evocalcet compared with cinacalcet (33.5% vs. 50.5%, P = 0.001), whereas the incidence of hypocalcemia did not differ. Conclusion: Evocalcet might be a better alternative to cinacalcet for East Asian patients on hemodialysis with SHPT.

Influenza vaccination is associated with lower risk of renal cell carcinoma among chronic kidney disease patients: a population-based cohort study.

Background: Chronic kidney disease (CKD) patients possess a higher risk for renal cell carcinoma (RCC) possibly because of related underlying inflammation and immune dysregulation. In the current population-based cohort study, we evaluate the effects of influenza vaccination on RCC among CKD patients. Methods: We analysed the vaccinated and unvaccinated CKD patients (≥55 years of age) identified from the Taiwan National Health Insurance Database. Propensity score matching was used to reduce the selection bias. Subgroup analyses based on comorbid conditions, dialysis status and vaccinated dosages were also conducted. Results: The incidence of RCC decreased significantly in the vaccinated compared with unvaccinated group {unadjusted hazard ratio [HR] 0.50 [95% confidence interval (CI) 0.31-0.81], P < .01; adjusted HR 0.46 [95% CI 0.28-0.75], P < .01}. Such protective effects of influenza vaccination were noted significantly among those ≥75 years of age [unadjusted HR 0.29 (95% CI 0.12-0.74), P < .01; adjusted HR 0.22 (95% CI 0.08-0.58), P < .01]. A reverse association was noted between the total number of vaccinations and RCC events in both unadjusted and adjusted models. The Kaplan-Meier estimates of the RCC events showed significantly higher free survival rates in the vaccinated as compared with the unvaccinated patients (logrank P = .005). Conclusion: This population-based cohort study found a significant inverse relationship between influenza vaccination and the risk of RCC in CKD patients and the protective effects were more prominent in patients >75 years of age. A possible relation exists between the total number of vaccinations and RCC events. Future randomized clinical and basic studies will be needed to prove these findings and underlying pathophysiological mechanisms.

Association of mono-2-ethylhexyl phthalate with adverse outcomes in chronic hemodialysis patients.

Phthalate exposure is widespread and has a global impact. Growing evidence shows that mono-2-ethylhexyl phthalate (MEHP) exposure has a negative impact on human health. However, whether MEHP exposure is associated with mortality and other adverse outcomes in hemodialysis patients remains unknown. This study prospectively enrolled 217 patients on maintenance hemodialysis from June 30, 2021, to August 16, 2022. Baseline serum MEHP, di-2-ethylhexyl phthalate (DEHP), and indoxyl sulfate (IS) concentrations were measured. Primary endpoints were all-cause mortality or composite adverse outcomes, including all-cause death plus hospitalization due to cardiovascular disease, heart failure, stroke, infection, or cancer. Serum MEHP concentrations were positively associated with DEHP but not indoxyl sulfate concentrations in hemodialysis patients. Additionally, serum MEHP concentrations were significantly and independently associated with all-cause mortality and composite adverse outcomes (adjusted hazard ratios [HRs], 1.04 and 1.03 per ng/mL, 95% confidence intervals [CIs], 1.01-1.07 and 1.00-1.05; p = 0.016 and 0.015, respectively). We found a cutoff value of MEHP for predicting both endpoints. Patients with serum MEHP concentrations of ≥ 41.8 ng/mL had much higher risks for all-cause mortality and composite adverse outcomes (adjusted HRs, 39.2 and 13; 95% CIs, 2.44-65.7 and 2.74-61.4; p = 0.011 and 0.001, respectively). MEHP exposure is significantly associated with higher risks for all-cause mortality and composite adverse outcomes. Hemodialysis patients with serum MEHP concentrations above 41.8 ng/mL had much poorer prognoses regarding both outcomes.

Indoxyl sulfate induced frailty in patients with end-stage renal disease by disrupting the PGC-1α-FNDC5 axis.

OBJECTIVE: Sarcopenia or frailty is common among patients with chronic kidney disease (CKD). The protein-bound uremic toxin indoxyl sulfate (IS) is associated with frailty. IS induces apoptosis and disruption of mitochondrial activity in skeletal muscle. However, the association of IS with anabolic myokines such as irisin in patients with CKD or end-stage renal disease (ESRD) is unclear. This study aims to elucidate whether IS induces frailty by dysregulating irisin in patients with CKD. MATERIALS AND METHODS: The handgrip strength of 53 patients, including 28 patients with ESRD, was examined. Serum concentrations of IS and irisin were analyzed. CKD was established in BALB/c mice through 5/6 nephrectomy. Pathologic analysis of skeletal muscle was assessed through haematoxylin and eosin and Masson's trichrome staining. Expression of peroxisome proliferator-activated receptor-gamma coactivator PGC-1α and irisin were analyzed using real-time polymerase chain reaction and Western blotting. RESULTS: Handgrip strength was lower among patients with ESRD than among those without ESRD. In total, 64.3% and 24% of the patients in the ESRD and control groups had low handgrip strength, respectively (p < 0.05). Serum concentrations of IS were significantly higher in the ESRD group than in the control group (222.81 ± 90.67 µM and 23.19 ± 33.28 µM, respectively, p < 0.05). Concentrations of irisin were lower in the ESRD group than in the control group (64.62 ± 32.64 pg/mL vs. 99.77 ± 93.29 pg/mL, respectively, p < 0.05). ROC curves for low handgrip strength by irisin and IS were 0.298 (95% confidence interval (CI): 0.139-0.457, p < 0.05) and 0.733 (95% CI: 0.575-0.890, p < 0.05), respectively. The percentage of collagen was significantly higher in mice with 5/6 nephrectomy than in the control group. After resveratrol (RSV) treatment, the percentage of collagen significantly decreased. RSV modulates TGF-ß signaling. In vitro analysis revealed that IS treatment suppressed expression of PGC-1α and FNDC5 in a dose-dependent manner, whereas RSV treatment attenuated IS-induced phenomena in C2C12 cells. CONCLUSION: IS was positively correlated with frailty in patients with ESRD through the modulation of the PGC-1α-FNDC5 axis. RSV may be a potential drug for reversing IS-induced suppression of the PGC-1α-FNDC5 axis in skeletal muscle.

Interplay of Chemokines Receptors, Toll-like Receptors, and Host Immunological Pathways.

A comprehensive framework has been established for understanding immunological pathways, which can be categorized into eradicated and tolerable immune responses. Toll-like receptors (TLRs) are associated with specific immune responses. TH1 immunity is related to TLR7, TLR8, and TLR9, while TH2 immunity is associated with TLR1, TLR2, and TLR6. TH22 immunity is linked to TLR2, TLR4, and TLR5, and THαß (Tr1) immunity is related to TLR3, TLR7, and TLR9. The chemokine receptor CXCR5 is a marker of follicular helper T cells, and other chemokine receptors can also be classified within a framework based on host immunological pathways. On the basis of a literature review on chemokines and immunological pathways, the following associations were identified: CCR5 with TH1 responses, CCR1 with TH1-like responses, CCR4 (basophils) and CCR3 (eosinophils) with TH2 and TH9 responses, CCR10 with TH22 responses, CCR6 with TH17 responses, CXCR3 with THαß responses, CCR8 with regulatory T cells (Treg), and CCR2 with TH3 responses. These findings contribute to the identification of biomarkers for immune cells and provide insights into host immunological pathways. Understanding the chemokine and Toll-like receptor system is crucial for comprehending the function of the innate immune system, as well as adaptive immune responses.

Coronavirus disease 2019 and cardiovascular disease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus behind the coronavirus disease 2019 (COVID-19) pandemic, is a type of RNA virus that is nonsegmented. Cardiovascular diseases (CVDs) increase the mortality risk of patients. In this review article, we overview the existing evidence regarding the potential mechanisms of myocardial damage in coronavirus disease 2019 (COVID-19) patients. Having a comprehensive knowledge of the cardiovascular damage caused by SARS-CoV-2 and its underlying mechanisms is essential for providing prompt and efficient treatment, ultimately leading to a reduction in mortality rates. Severe COVID-19 causes acute respiratory distress syndrome and shock in patients. In addition, awareness regarding COVID-19 cardiovascular manifestations has increased, including the adverse impact on prognosis with cardiovascular involvement. Angiotensin-converting enzyme 2 receptor may play a role in acute myocardial injury caused by SARS-CoV-2 infection. COVID-19 patients experiencing heart failure may have their condition exacerbated by various contributing factors and mechanisms. Increased oxygen demand, myocarditis, stress cardiomyopathy, elevated pulmonary pressures, and venous thrombosis are potential health issues. The combination of these factors may lead to COVID-19-related cardiogenic shock, resulting in acute systolic heart failure. Extracorporeal membrane oxygenation (ECMO) and left ventricular assist devices (LVADs) are treatment options when inotropic support fails for effective circulatory support. To ensure effective COVID-19-related cardiovascular disease (CVD) surveillance, it is crucial to closely monitor the future host adaptation, viral evolution, and transmissibility of SARS-CoV-2, given the virus's pandemic potential.

The Potential Influence of Uremic Toxins on the Homeostasis of Bones and Muscles in Chronic Kidney Disease.

Patients with chronic kidney disease (CKD) often experience a high accumulation of protein-bound uremic toxins (PBUTs), specifically indoxyl sulfate (IS) and p-cresyl sulfate (pCS). In the early stages of CKD, the buildup of PBUTs inhibits bone and muscle function. As CKD progresses, elevated PBUT levels further hinder bone turnover and exacerbate muscle wasting. In the late stage of CKD, hyperparathyroidism worsens PBUT-induced muscle damage but can improve low bone turnover. PBUTs play a significant role in reducing both the quantity and quality of bone by affecting osteoblast and osteoclast lineage. IS, in particular, interferes with osteoblastogenesis by activating aryl hydrocarbon receptor (AhR) signaling, which reduces the expression of Runx2 and impedes osteoblast differentiation. High PBUT levels can also reduce calcitriol production, increase the expression of Wnt antagonists (SOST, DKK1), and decrease klotho expression, all of which contribute to low bone turnover disorders. Furthermore, PBUT accumulation leads to continuous muscle protein breakdown through the excessive production of reactive oxygen species (ROS) and inflammatory cytokines. Interactions between muscles and bones, mediated by various factors released from individual tissues, play a crucial role in the mutual modulation of bone and muscle in CKD. Exercise and nutritional therapy have the potential to yield favorable outcomes. Understanding the underlying mechanisms of bone and muscle loss in CKD can aid in developing new therapies for musculoskeletal diseases, particularly those related to bone loss and muscle wasting.

An important call: Suggestion of using IL-10 as therapeutic agent for COVID-19 with ARDS and other complications.

The global coronavirus disease 2019 (COVID-19) pandemic has a detrimental impact on public health. COVID-19 usually manifests as pneumonia, which can progress into acute respiratory distress syndrome (ARDS) related to uncontrolled TH17 immune reaction. Currently, there is no effective therapeutic agent to manage COVID-19 with complications. The currently available anti-viral drug remdesivir has an effectiveness of 30% in SARS-CoV-2-induced severe complications. Thus, there is a need to identify effective agents to treat COVID-19 and the associated acute lung injury and other complications. The host immunological pathway against this virus typically involves the THαß immune response. THαß immunity is triggered by type 1 interferon and interleukin-27 (IL-27), and the main effector cells of the THαß immune response are IL10-CD4 T cells, CD8 T cells, NK cells, and IgG1-producing B cells. In particular, IL-10 exerts a potent immunomodulatory or anti-inflammatory effect and is an anti-fibrotic agent for pulmonary fibrosis. Concurrently, IL-10 can ameliorate acute lung injury or ARDS, especially those caused by viruses. Owing to its anti-viral activity and anti-pro-inflammatory effects, in this review, IL-10 is suggested as a possible treatment agent for COVID-19.

Indoxyl sulfate mediates low handgrip strength and is predictive of high hospitalization rates in patients with end-stage renal disease.

Background and aims: Sarcopenia has a higher occurrence rate in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) than in the general population. Low handgrip strength-and not sarcopenia per se-is associated with clinical outcomes in patients with CKD, including cardiovascular mortality and hospitalization. The factors contributing to low handgrip strength are still unknown. Accordingly, this study aimed to determine whether uremic toxins influence low handgrip strength in patients with CKD. Materials and methods: This cohort study lasted from August 2018 to January 2020. The participants were divided into three groups: the control group [estimated glomerular filtration rate (eGFR) ≥ 60 ml/min], an advanced CKD group (eGFR = 15-60 ml/min), and an ESRD group (under maintenance renal replacement therapy). All participants underwent handgrip strength measurement, dual-energy X-ray absorptiometry, and blood sampling for myokines (irisin, myostatin, and interleukin 6) and indoxyl sulfate. Sarcopenia was defined according to the Asian Working Group for Sarcopenia consensus as low appendicular skeletal muscle index (appendicular skeletal muscle/height2 of < 7.0 kg/m2 in men and < 5.4 kg/m2 in women) and low handgrip strength (< 28 kg in men and < 18 kg in women). Results: Among the study participants (control: n = 16; CKD: n = 17; and ESRD: n = 42), the ESRD group had the highest prevalence of low handgrip strength (41.6 vs. 25% and 5.85% in the control and CKD groups, respectively; p < 0.05). The sarcopenia rate was similar among the groups (12.5, 17.6, and 19.5% for the control, CKD, and ESRD groups, respectively; p = 0.864). Low handgrip strength was associated with high hospitalization rates within the total study population during the 600-day follow-up period (p = 0.02). The predictions for cardiovascular mortality and hospitalization were similar among patients with and without sarcopenia (p = 0.190 and p = 0.094). The serum concentrations of indoxyl sulfate were higher in the ESRD group (227.29 ± 92.65 µM vs. 41.97 ± 43.96 µM and 6.54 ± 3.45 µM for the CKD and control groups, respectively; p < 0.05). Myokine concentrations were similar among groups. Indoxyl sulfate was associated with low handgrip strength in univariate and multivariate logistic regression models [univariate odds ratio (OR): 3.485, 95% confidence interval (CI): 1.372-8.852, p = 0.001; multivariate OR: 8.525, 95% CI: 1.807-40.207, p = 0.007]. Conclusion: Handgrip strength was lower in the patients with ESRD, and low handgrip strength was predictive of hospitalization in the total study population. Indoxyl sulfate contributed to low handgrip strength and counteracted the benefits of myokines in patients with CKD.

Endoplasmic Reticulum Stress in Elderly Patients with COVID-19: Potential of Melatonin Treatment.

Aging processes, including immunosenescence, inflammation, inflammasome formation, genomic instability, telomeric attrition, and altered autophagy, are involved in viral infections and they may contribute to increased pathophysiological responses to the SARS-CoV-2 infection in the elderly; this poses additional risks of accelerated aging, which could be found even after recovery. Aging is associated with oxidative damage. Moreover, SARS-CoV-2 infections may increase the production of reactive oxygen species and such infections will disturb the Ca++ balance via an endoplasmic reticulum (ER) stress-mediated unfolded protein response. Although vaccine development and anti-inflammation therapy lower the severity of COVID-19, the prevalence and mortality rates are still alarming in some countries worldwide. In this review, we describe the involvement of viral proteins in activating ER stress transducers and their downstream signals and in inducing inflammation and inflammasome formation. Furthermore, we propose the potential of melatonin as an ER stress modulator, owing to its antioxidant, anti-inflammatory, and immunoregulatory effects in viral infections. Considering its strong safety profile, we suggest that additive melatonin supplementation in the elderly could be beneficial in treating COVID-19.

Immunothrombosis biomarkers as potential predictive factors of acute respiratory distress syndrome in moderate-to-critical COVID-19: A single-center, retrospective cohort study.

BACKGROUND: Immunothrombosis, a process of inflammation and coagulation, is involved in sepsis-induced acute respiratory distress syndrome formation (ARDS). However, the clinical correlation between immunothrombosis biomarkers (including tissue factor [TF] and von Willebrand factor [vWF]) and coronavirus disease 2019 (COVID-19)-related ARDS is unknown. This study investigated ARDS development following moderate-to-critical COVID-19 and examined immunothrombosis biomarkers as ARDS predictors. METHODS: This retrospective cohort study included patients with moderate-to-critical COVID-19 (n = 165) admitted to a northern teaching hospital during the 2021 pandemic in Taiwan, who had no COVID-19 vaccinations. Immunothrombosis biomarkers were compared between COVID-19 patients with and without ARDS (no-ARDS) and a control group consisting of 100 healthy individuals. RESULTS: The study included 58 ARDS and 107 no-ARDS patients. In multivariable analysis, TF (aOR=1.031, 95% CI: 1.009-1.053, p = 0.006); and vWF (aOR=1.053, 95% CI: 1.002-1.105, p = 0.041) were significantly associated with ARDS episodes, after adjusting for other confounding factors. vWF and TF predicted ARDS with the area under the curve of 0.870 (95% CI: 0.796-0.945). Further mechanical ventilation analysis found TF to be correlated significantly with pCO2 and ventilatory ratio. CONCLUSIONS: TF and vWF levels potentially predicted ARDS development within 7 days of admission for COVID-19 after adjusting for traditional risk factors. TF correlated with ventilation impairment in COVID-19 ARDS but further prospective studies are needed.

The von Hippel-Lindau Tumor Suppressor Gene Mutations Modulate Lipocalin-2 Expression in Ferroptotic-Inflammatory Pathways.

A previous study of an animal model with tumor suppressor gene von Hippel-Lindau (VHL) conditional knockdown suggested that tissue inflammation and fibrosis play important roles in the development of clear-cell renal cell carcinoma (ccRCC), which is consistent with the epidemiological evidence linking inflammatory kidney disease and renal cancer. Ferroptosis and inflammation have been linked in a recent study, but the exact mechanism remains unclear. This study is aimed at investigating the mechanism of lipocalin-2- (LCN-2-) mediated ferroptosis and inflammation in vhl-mutated HK-2 cells and mouse primary proximal tubule cells (mRTCs) and the polarization of macrophage RAW 264.7 cells. Based on the levels of lipid reactive oxygen species (ROS) and the expression of glutathione peroxidase 4 (GPX4) in HK-2 cells, we observed that a VHL mutation increased ROS production and depressed GPX4 expression, whereas LCN-2 knockdown reversed these effects. Accordingly, VHL appears to affect ferroptosis in an LCN-2-dependent manner. We also revealed that LCN-2 sensitizes HK-2 cells to inflammation and macrophage RAW 264.7 cells to M1-like polarization. This study provides novel insights into the potential therapeutic target and strategy for attenuating the progression of ccRCC by revealing the role of VHL in regulating chronic inflammation within the LCN-2-ferroptosis pathway.

Association between heme oxygenase one and sepsis development in patients with moderate-to-critical COVID-19: a single-center, retrospective observational study.

BACKGROUND: Heme oxygenase one (HO-1) is considered a poor prognostic factor for survival in patients with severe-to-critical coronavirus disease (COVID-19), but the clinical correlation between heme catabolism biomarkers and COVID-19-related sepsis is unknown. The etiopathogenetic hypothesis of HO-1 response during sepsis in patients with poor prognosis should be clarified. This study aimed to investigate sepsis development within 48 h following moderate-to-critical COVID-19 and examined heme/HO-1 catabolism biomarkers associated with sepsis. We also studied the HO-1 and traditional prognostic factors for predicting survival in patients with COVID-19. METHODS: This retrospective observational study included patients unvaccinated for COVID-19 with moderate-to-critical COVID-19 (n = 156) who had been admitted to Taipei Tzu Chi Hospital in 2021. All COVID-19 patients were diagnosed by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcriptase polymerase chain reaction. For analysis of heme catabolism in SARS-CoV-2-induced sepsis, we excluded patients with co-infection and severe anemia. Heme catabolism biomarkers were compared between groups of patients with COVID-19 and sepsis (sepsis) and those with COVID-19 without sepsis (no sepsis), and a control group comprising 100 healthy individuals. All clinical and laboratory data were collected retrospectively and blood specimens were collected from Biobank. Multivariable logistic regression analysis was used to compare all variables between the sepsis and no-sepsis groups. Cox regression analysis was used to determine predictors of survival in patients with COVID-19. RESULTS: There were 71 and 85 patients with and without sepsis, respectively. Heme and HO-1 levels differed significantly between the sepsis, no sepsis, and control groups. In multivariate analysis, confusion, blood urea nitrogen, respiration, blood pressure in patients aged > 65 years (CURB-65) (adjusted odds ratio [aOR] 5.331, 95% confidence interval [CI] 2.587-10.987; p < 0.001), albumin (aOR 0.139, 95% CI 0.003-0.636; p = 0.01), D-dimer (aOR 1.001, 95% CI 1.000-1.002; p = 0.032), and HO-1 (aOR 1.116, 95% CI 1.055-1.180; p < 0.001) were significantly associated with 48-h sepsis episodes after adjusting for other confounding factors. HO-1 levels were also significantly associated with 48-h Sequential Organ Failure Assessment Score (SOFA) scores. However, HO-1 did not significantly increase the hazard of in-hospital mortality in moderate-to-critical COVID-19 by Cox regression analysis. CONCLUSIONS: HO-1 levels increased with sepsis development within 48 h of admission for COVID-19 after adjusting for other risk factors, but no significant association was observed between HO-1 and COVID-19 mortality. We suppose that HO-1 may have protective effect in early sepsis, but further clinical multicenter prospective studies are needed.