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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 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 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.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) attacks pulmonary alveolar cells via angiotensin-converting enzyme 2 (ACE2) receptors and causes pulmonary infections that result in coronavirus disease (COVID-19), inducing immune responses that can result in severe pneumonia. We reviewed the clinical experiences of lung diseases during the COVID-19 pandemic to offer insights into the adaptations made by experts in the diagnosis and treatment of these comorbidities. Various lung comorbidities increase the severity of COVID-19 and associated mortality by amplifying ACE2 expression. Additionally, the COVID-19 pandemic has changed the use of routine diagnostic pulmonary imaging methods, making chest sonography scoring the most convenient, as it can be conducted bedside. Treatment protocols for SARS-CoV-2 infection and the underlying lung diseases are also affected owing to potential interactions. The optimal diagnostic methods and treatment protocols for lung diseases have been adapted worldwide to increase survival rates and attenuate acute lung injuries during the COVID-19 pandemic.

This study investigated whether oncogenic and tumor-suppressive gene mutations are involved in the differential outcomes of patients with rectal carcinoma receiving neoadjuvant chemoradiotherapy (nCRT). Genomic DNA was obtained from formalin-fixed paraffin-embedded (FFPE) specimens of patients with rectal carcinoma who received a complete nCRT course. Gene mutation status was examined in specimens from patients before and after nCRT by using the AmpliSeq platform. Our data revealed that the nonsynonymous p53, APC, KRAS, CDKN2A, and EGFR mutations were observed in 93.1%, 65.5%, 48.6%, and 31% of the patients with rectal adenocarcinoma, respectively. BRAF, FBXW7, PTEN, and SMAD4 mutations were observed in 20.7% of patients with rectal carcinoma. The following 12 gene mutations were observed more frequently in the patients exhibiting a complete response than in those demonstrating a poor response before nCRT: ATM, BRAF, CDKN2A, EGFR, FLT3, GNA11, KDR, KIT, PIK3CA, PTEN, PTPN11, SMAD4, and TP53. In addition, APC, BRAF, FBXW7, KRAS, SMAD4, and TP53 mutations were retained after nCRT. Our results indicate a complex mutational profile in rectal carcinoma, suggesting the involvement of BRAF, SMAD4, and TP53 genetic variants in the outcomes of patients with nCRT.

The coronavirus disease 2019 (COVID-19) pandemic has claimed the lives of millions of people around the world. Severe vitamin D deficiency can increase the risk of death in people with COVID-19. There is growing evidence that acute kidney injury (AKI) is common in COVID-19 patients and is associated with poorer clinical outcomes. The kidney effects of SARS-CoV-2 are directly mediated by angiotensin 2-converting enzyme (ACE2) receptors. AKI is also caused by indirect causes such as the hypercoagulable state and microvascular thrombosis. The increased release of soluble urokinase-type plasminogen activator receptor (suPAR) from immature myeloid cells reduces plasminogen activation by the competitive inhibition of urokinase-type plasminogen activator, which results in low plasmin levels and a fibrinolytic state in COVID-19. Frequent hypercoagulability in critically ill patients with COVID-19 may exacerbate the severity of thrombosis. Versican expression in proximal tubular cells leads to the proliferation of interstitial fibroblasts through the C3a and suPAR pathways. Vitamin D attenuates the local expression of podocyte uPAR and decreases elevated circulating suPAR levels caused by systemic inflammation. This decrease preserves the function and structure of the glomerular barrier, thereby maintaining renal function. The attenuated hyperinflammatory state reduces complement activation, resulting in lower serum C3a levels. Vitamin D can also protect against COVID-19 by modulating innate and adaptive immunity, increasing ACE2 expression, and inhibiting the renin–angiotensin–aldosterone system. We hypothesized that by reducing suPAR levels, appropriate vitamin D supplementation could prevent the progression and reduce the severity of AKI in COVID-19 patients, although the data available require further elucidation.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has become a global pandemic since December 2019. Most of the patients are mild or asymptomatic and recovered well as those suffered from other respiratory viruses. SARS-CoV-2 infection is supposed to demonstrate more sequelae. Acute kidney injury (AKI) is common among COVID-19 patients and is associated with disease severity and outcomes. Only a few studies focused on a detailed analysis of kidney damage in asymptomatic or mildly symptomatic COVID-19 patients. Whether any minor viral infection is likely to exhibit similar minor effect on renal function as COVID-19 is still unclear, and the definite pathophysiology of viral invasion is not fully understood. Currently, the proposed mechanisms of AKI include direct effects of virus on kidney, dysregulated immune response, or as a result of multi-organs failure have been proposed. This study will discuss the difference between COVID-19 and other viruses, focusing on proposed mechanisms, biomarkers and whether it matters with clinical significance.

The coronavirus disease 2019 (COVID-19) pandemic is the largest health crisis ever faced worldwide. It has resulted in great health and economic costs because no effective treatment is currently available. Since infected persons vary in presentation from healthy asymptomatic mild symptoms to those who need intensive care support and eventually succumb to the disease, this illness is considered to depend primarily on individual immunity. Demographic distribution and disease severity in several regions of the world vary; therefore, it is believed that natural inherent immunity provided through dietary sources and traditional medicines could play an important role in infection prevention and disease progression. People can boost their immunity to prevent them from infection after COVID-19 exposure and can reduce their inflammatory reactions to protect their organ deterioration in case suffering from the disease. Some drugs with in-situ immunomodulatory and anti-inflammatory activity are also identified as adjunctive therapy in the COVID-19 era. This review discusses the importance of COVID-19 interactions with immune cells and inflammatory cells; and further emphasizes the possible pathways related with traditional herbs, medications and nutritional products. We believe that such pathophysiological pathway approach treatment is rational and important for future development of new therapeutic agents for prevention or cure of COVID-19 infection.

Life does not sustain without water. For water, there is a natural abundance of stable isotope hydrogen and oxygen. Water molecules get across cell membranes through a plasma membrane protein, named aquaporin. Moreover, the kidney is the main organ to maintain water homeostasis. Here, we study the stable isotopic ratios of hydrogen and oxygen in human blood plasma and erythrocyte corresponding to kidney functions. We extract waters from human plasma and erythrocyte, collected from 110 participants, including 51 clinically stable outpatients with end-stage renal disease (ESRD) and 59 subjects with normal renal function (NRF). We observed that (i) both extracellular (blood plasma) and intracellular (erythrocyte) biology waters are isotopic differences between the ESRD and NRF participants, (ii) the natural abundance of isotopic waters of ESRD is hypo-isotopic, and (iii) the isotopic enrichment of water between erythrocyte and blood plasma are distinct. In addition, we introduce an empirical formula using entropy transformation to describe isotopic water enrichment for biology. Accordingly, the natural abundance of stable isotope water of blood plasma and erythrocyte may be possibly put in practice a new sign for assessments of kidney dysfunctions.

The downregulation of melatonin receptor 1A (MTNR1A) is associated with a range of pathological conditions, including membranous nephropathy. Knowledge of the mechanism underlying MTNR1A expression has been limited to the transcriptional regulation level. Here, RNA interference screening in human kidney cells revealed that heterogeneous nuclear ribonucleoprotein L (hnRNPL) upregulated MTNR1A RNA post-transcriptionally. hnRNPL knockdown or overexpression led to increased or decreased levels of cyclic adenosine monophosphate-responsive element-binding protein phosphorylation, respectively. Molecular studies showed that cytoplasmic hnRNPL exerts a stabilizing effect on the MTNR1A transcript through CA-repeat elements in its coding region. Further studies revealed that the interaction between hnRNPL and MTNR1A serves to protect MNTR1A RNA degradation by the exosome component 10 protein. MTNR1A, but not hnRNPL, displays a diurnal rhythm in mouse kidneys. Enhanced levels of MTNR1A recorded at midnight correlated with robust binding activity between cytoplasmic hnRNPL and the MTNR1A transcript. Both hnRNPL and MTNR1A were decreased in the cytoplasm of tubular epithelial cells from experimental membranous nephropathy kidneys, supporting their clinical relevance. Collectively, our data identified cytoplasmic hnRNPL as a novel player in the upregulation of MTNR1A expression in renal tubular epithelial cells, and as a potential therapeutic target.

Background: The recommended target low-density lipoprotein cholesterol (LDL-C) level for coronary artery disease (CAD) patients has been lowered from 100 to 70 mg/dL in several clinical guidelines for secondary prevention. We aimed to assess whether initiating statin treatment in CAD patients with baseline LDL-C 70–100 mg/dL in Taiwan could be cost-effective. Methods: A Markov model was developed to simulate a hypothetical cohort of CAD patients with a baseline LDL-C level of 90 mg/dL. The incidence and recurrence of MI and stroke related to specific LDL-C levels as well as the statin effect, mortality rate, and health state utilities were obtained from the literature. The direct medical costs and rate of fatal events were derived from the national claims database. The incremental cost-effectiveness ratio (ICER) per quality-adjusted life years (QALYs) was calculated, and sensitivity analyses were performed. Results: Moderate-intensity statin use, a treatment regimen expected to achieve LDL

This longitudinal study with a randomized controlled trial evaluated the long-term effectiveness of the patient-centered self-management intervention program on the control of blood pressure and renal function, as well as the quality of life of patients with hypertensive nephropathy. The control group ( n = 38) received usual care while the experimental group ( n = 38) participated in a patient-centered self-management program. After the pre-test, the intervention was performed with the experimental group once a week for a total of 4 weeks. Then, the post-test was performed 1, 3, and 6 months later. A questionnaire was used to collect the demographic data and disease characteristics, laboratory data, and quality of life scale. This study tracked three time points (i.e., 1, 3, and 6 months) after the intervention and found that the experimental group achieved significant results in controlling systolic blood pressure ( p < 0.001), diastolic blood pressure ( p = 0.007), and eGFR ( p = 0.013). Significant results were achieved in the overall quality of life ( p < 0.001) and the quality of life in the physical (PHC; p < 0.001) and mental health components (MHC; p < 0.001). Furthermore, the effects in the experimental group lasted for as long as 6 months and were better than those in the control group. Moreover, this program can provide nursing staff with a reference different from traditional health education methods.

The human host immune responses to parasitic infections are complex. They can be categorized into four immunological pathways mounted against four types of parasitic infections. For intracellular protozoa, the eradicable host immunological pathway is TH1 immunity involving macrophages (M1), interferon gamma (IFNγ) CD4 T cells, innate lymphoid cells 1 (NKp44+ ILC1), CD8 T cells (Effector-Memory4, EM4), invariant natural killer T cells 1 (iNKT1) cells, and immunoglobulin G3 (IgG3) B cells. For intracellular protozoa, the tolerable host immunological pathway is TH1-like immunity involving macrophages (M2), interferon gamma (IFNγ)/TGFβ CD4 T cells, innate lymphoid cells 1 (NKp44- ILC1), CD8 T cells (EM3), invariant natural killer T 1 (iNKT1) cells, and immunoglobulin A1 (IgA1) B cells. For free-living extracellular protozoa, the eradicable host immunological pathway is TH22 immunity involving neutrophils (N1), interleukin-22 CD4 T cells, innate lymphoid cells 3 (NCR+ ILC3), iNKT17 cells, and IgG2 B cells. For free-living extracellular protozoa, the tolerable host immunological pathway is TH17 immunity involving neutrophils (N2), interleukin-17 CD4 T cells, innate lymphoid cells 3 (NCR- ILC3), iNKT17 cells, and IgA2 B cells. For endoparasites (helminths), the eradicable host immunological pathway is TH2a immunity with inflammatory eosinophils (iEOS), interleukin-5/interleukin-4 CD4 T cells, interleukin-25 induced inflammatory innate lymphoid cells 2 (iILC2), tryptase-positive mast cells (MCt), iNKT2 cells, and IgG4 B cells. For ectoparasites (parasitic insects and arachnids), the eradicable host immunological pathway is TH2b immunity with inflammatory basophils, chymase- and tryptase-positive mast cells (MCct), interleukin-3/interleukin-4 CD4 T cells, interleukin-33 induced nature innate lymphoid cells 2 (nILC2), iNKT2 cells, and immunoglobulin E (IgE) B cells. The tolerable host immunity against ectoparasites and endoparasites is TH9 immunity with regulatory eosinophils, regulatory basophils, interleukin-9 mast cells (MMC9), thymic stromal lymphopoietin induced innate lymphoid cells 2, interleukin-9 CD4 T cells, iNKT2 cells, and IgA2 B cells. In addition, specific transcription factors important for specific immune responses were listed. This JAK/STAT signaling is key to controlling or inducing different immunological pathways. In sum, Tfh is related to STAT5β, and BCL6 expression. Treg is related to STAT5α, STAT5β, and FOXP3. TH1 immunity is related to STAT1α, STAT4, and T-bet. TH2a immunity is related to STAT6, STAT1α, GATA1, and GATA3. TH2b immunity is related to STAT6, STAT3, GATA2, and GATA3. TH22 immunity is associated with both STAT3α and AHR. THαβ immunity is related to STAT1α, STAT1β, STAT2, STAT3β, and ISGF. TH1-like immunity is related to STAT1α, STAT4, STAT5α, and STAT5β. TH9 immunity is related to STAT6, STAT5α, STAT5β, and PU.1. TH17 immunity is related to STAT3α, STAT5α, STAT5β, and RORG. TH3 immunity is related to STAT1α, STAT1β, STAT2, STAT3β, STAT5α, STAT5β, and ISGF. This categorization provides a complete framework of immunological pathways against four types of parasitic infections. This framework as well as relevant JAK/STAT signaling can provide useful knowledge to control allergic hypersensitivities and parasitic infections via development of vaccines or drugs in the near future.

Background Several meta-analyses of the relationship between endothelial nitric oxide synthase (eNOS) T-786C gene polymorphism and chronic kidney disease (CKD) have been published. However, the results of these studies were inconsistent, and it is undetermined whether sample sizes are sufficient to reach a definite conclusion. Objective To elucidate the relationship between T-786C and CKD by combining previous studies with our case-control sample and incorporate trial sequential analysis (TSA) to verify whether the sample size is adequate to draw a definite conclusion. Methods PubMed and Embase databases were searched for relevant articles on eNOS T-786C and CKD before February 28, 2021. TSA was also incorporated to ascertain a conclusion. A total of 558 hemodialysis cases in the case-control study was recruited from nine dialysis centers in the northern area of Taiwan in 2020. Additionally, 640 healthy subjects of the control group, with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2, were selected from participants of the annual elderly health examination program at the Tri-Service General Hospital. The functional analysis was based on eQTL data from GTExPortal. Results After screening with eligibility criteria, 15 papers were included and eventually combined in a meta-analysis. The result of the TSA showed that the sample size for Caucasians was adequate to ascertain the correlation between eNOS T-786C and CKD but was insufficient for Asians. Therefore, we added our case-control samples (n = 1198), though not associated with CKD (odds ratio [OR] = 1.01, 95% confidence interval [CI] = 0.69–1.46), into a meta-analysis, which supported that eNOS T-786C was significantly associated with CKD in Asians (OR = 1.39, 95% CI = 1.04–1.85) by using an adequate cumulative sample size (n = 4572) analyzed by TSA. Data of eQTL from GTEx showed that T-786C with the C minor allele exhibited relatively lower eNOS mRNA expression in whole blood, indicating the hazardous role of eNOS T-786C in CKD. Conclusions eNOS T-786C genetic polymorphism was of conclusive significance in the association with CKD among Asians in our meta-analysis. Our case-control samples play a decisive role in changing conclusions from indefinite to definite.

Melatonin is a hormone majorly secreted by the pineal gland and contributes to a various type of physiological functions in mammals. The melatonin production is tightly limited to the AANAT level, yet the most known molecular mechanisms underlying AANAT gene transcription is limited in the pinealocyte. Here, we find that c-Fos and cAMP-response element-binding protein (CREB) decreases and increases the AANAT transcriptional activity in renal tubular epithelial cell, respectively. Notably, c-Fos knockdown significantly upregulates melatonin levels in renal tubular cells. Functional results indicate that AANAT expression is decreased by c-Fos and resulted in enhancement of cell damage in albumin-injury cell model. We further find an inverse correlation between c-Fos and AANAT levels in renal tubular cells from experimental membranous nephropathy (MN) samples and clinical MN specimens. Our finding provides the molecular basis of c-Fos in transcriptionally downregulating expression of AANAT and melatonin, and elucidate the protective role of AANAT in preventing renal tubular cells death in albumin-injury cell model and MN progression.

Severe acute respiratory syndrome coronavirus 2 is a new, highly pathogenic virus that has recently elicited a global pandemic called the 2019 coronavirus disease (COVID-19). COVID-19 is characterized by significant immune dysfunction, which is caused by strong but unregulated innate immunity with depressed adaptive immunity. Reduced and delayed responses to interferons (IFN-I/IFN-III) can increase the synthesis of proinflammatory cytokines and extensive immune cell infiltration into the airways, leading to pulmonary disease. The development of effective treatments for severe COVID-19 patients relies on our knowledge of the pathophysiological components of this imbalanced innate immune response. Strategies to address innate response factors will be essential. Significant efforts are currently underway to develop vaccines against SARS-CoV-2. COVID-19 vaccines, such as inactivated DNA, mRNA, and protein subunit vaccines, have already been applied in clinical use. Various vaccines display different levels of effectiveness, and it is important to continue to optimize and update their composition in order to increase their effectiveness. However, due to the continuous emergence of variant viruses, improving the immunity of the general public may also increase the effectiveness of the vaccines. Many observational studies have demonstrated that serum levels of vitamin D are inversely correlated with the incidence or severity of COVID-19. Extensive evidence has shown that vitamin D supplementation could be vital in mitigating the progression of COVID-19 to reduce its severity. Vitamin D defends against SARS-CoV-2 through a complex mechanism through interactions between the modulation of innate and adaptive immune reactions, ACE2 expression, and inhibition of the renin-angiotensin system (RAS). However, it remains unclear whether Vit-D also plays an important role in the effectiveness of different COVID-19 vaccines. Based on analysis of the molecular mechanism involved, we speculated that vit-D, via various immune signaling pathways, plays a complementary role in the development of vaccine efficacy.

Renal osteodystrophy (ROD) represents bone disorders related to chronic kidney disease (CKD) and several bone biomarkers are used clinically to predict ROD in CKD and hemodialysis (HD) patients. Serum albumin associates with inflammation other than nutritional status in these patients. Chronic inflammation is proved to relate with bone loss, however, the influence of hypoalbuminemia on bone biomarkers is still unclear. In this study, we evaluated the pattern of bone biomarker changes and further studied the influence of hypoalbuminemia on these biomarkers. A total of 300 maintenance HD patients were evaluated and 223 HD patients were included in the study. The patients were grouped according to serum parathyroid hormone (PTH) levels (PTH ≤150 pg/mL, PTH 150-300 pg/mL, PTH 300-600 pg/mL and PTH >600 pg/mL). Bone biomarkers and inflammatory markers were measured and their relation with PTH levels was determined. Significantly increased interleukin-6 (IL-6) and lower albumin levels were noted among PTH>600 pg/mL group. Bone turnover markers were significantly higher in PTH >600 pg/mL group (p< 0.05). Hypoalbuminemia significantly increased the fibroblast growth factor-23 (FGF-23) and procollagen type 1N-terminal propeptide (P1NP) in PTH ≤150 pg/mL, PTH 150-300 pg/mL, PTH 300-600 pg/mL groups, whereas no such relation was noted among PTH> 600 ng/dL group. In conclusion, hypoalbuminemia represents a chronic inflammation which differently relates to bone turnover markers according to serum PTH levels in SHPT patients. Thus, serum albumin measurement should be considered in determining bone disorders among these patients.

Vitamin D has been described as an essential nutrient and hormone, which can cause nuclear, non-genomic, and mitochondrial effects. Vitamin D not only controls the transcription of thousands of genes, directly or indirectly through the modulation of calcium fluxes, but it also influences the cell metabolism and maintenance specific nuclear programs. Given its broad spectrum of activity and multiple molecular targets, a deficiency of vitamin D can be involved in many pathologies. Vitamin D deficiency also influences mortality and multiple outcomes in chronic kidney disease (CKD). Active and native vitamin D serum levels are also decreased in critically ill patients and are associated with acute kidney injury (AKI) and in-hospital mortality. In addition to regulating calcium and phosphate homeostasis, vitamin D-related mechanisms regulate adaptive and innate immunity. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have a role in excessive proinflammatory cell recruitment and cytokine release, which contribute to alveolar and full-body endothelial damage. AKI is one of the most common extrapulmonary manifestations of severe coronavirus disease 2019 (COVID-19). There are also some correlations between the vitamin D level and COVID-19 severity via several pathways. Proper vitamin D supplementation may be an attractive therapeutic strategy for AKI and has the benefits of low cost and low risk of toxicity and side effects.

Patients with chronic kidney disease (CKD), especially those undergoing hemodialysis, are at a considerably high risk of bone fracture events. Experimental data indicate that uremic toxins intricately involved in bone-related proteins exert multi-faced toxicity on bone cells and tissues, leading to chronic kidney disease–mineral and bone disorder (CKD-MBD). Nonetheless, information regarding the association between p-cresyl sulfate (PCS), non-hepatic alkaline phosphatase (NHALP) and skeletal events remains elusive. We aim to explore the association between PCS, NHALP and risk of bone fracture (BF) in patients with hemodialysis. Plasma concentrations of PCS and NHALP were ascertained at study entry. Cox proportional hazard regression analyses were used to determine unadjusted and adjusted hazard ratios (aHRs) of PCS for BF risk. In multivariable analysis, NHALP was associated with incremental risks of BFs [aHR: 1.06 (95% CI: 1.01–1.11)]. The association between the highest PCS tertile and BF risk remained robust [aHR: 2.87 (95% CI: 1.02–8.09)]. With respect to BF events, the interaction between NHALP and PCS was statistically significant (p value for the interaction term < 0.05). In addition to mineral dysregulation and hyperparathyroidism in hemodialysis patients, higher circulating levels of PCS and NHALP are intricately associated with incremental risk of BF events, indicating that a joint evaluation is more comprehensive than single marker. In light of the extremely high prevalence of CKD-MBD in the hemodialysis population, PCS may act as a pro-osteoporotic toxin and serve as a potential surrogate marker for skeletal events.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is still an ongoing global health crisis. Immediately after the inhalation of SARS-CoV-2 viral particles, alveolar type II epithelial cells harbor and initiate local innate immunity. These particles can infect circulating macrophages, which then present the coronavirus antigens to T cells. Subsequently, the activation and differentiation of various types of T cells, as well as uncontrollable cytokine release (also known as cytokine storms), result in tissue destruction and amplification of the immune response. Vitamin D enhances the innate immunity required for combating COVID-19 by activating toll-like receptor 2. It also enhances antimicrobial peptide synthesis, such as through the promotion of the expression and secretion of cathelicidin and β-defensin; promotes autophagy through autophagosome formation; and increases the synthesis of lysosomal degradation enzymes within macrophages. Regarding adaptive immunity, vitamin D enhances CD4+ T cells, suppresses T helper 17 cells, and promotes the production of virus-specific antibodies by activating T cell-dependent B cells. Moreover, vitamin D attenuates the release of pro-inflammatory cytokines by CD4+ T cells through nuclear factor κB signaling, thereby inhibiting the development of a cytokine storm. SARS-CoV-2 enters cells after its spike proteins are bound to angiotensin-converting enzyme 2 (ACE2) receptors. Vitamin D increases the bioavailability and expression of ACE2, which may be responsible for trapping and inactivating the virus. Activation of the renin–angiotensin–aldosterone system (RAS) is responsible for tissue destruction, inflammation, and organ failure related to SARS-CoV-2. Vitamin D inhibits renin expression and serves as a negative RAS regulator. In conclusion, vitamin D defends the body against SARS-CoV-2 through a novel complex mechanism that operates through interactions between the activation of both innate and adaptive immunity, ACE2 expression, and inhibition of the RAS system. Multiple observation studies have shown that serum concentrations of 25 hydroxyvitamin D are inversely correlated with the incidence or severity of COVID-19. The evidence gathered thus far, generally meets Hill’s causality criteria in a biological system, although experimental verification is not sufficient. We speculated that adequate vitamin D supplementation may be essential for mitigating the progression and severity of COVID-19. Future studies are warranted to determine the dosage and effectiveness of vitamin D supplementation among different populations of individuals with COVID-19.

Aim and objectives To evaluate the effect of patient-centred self-management programme on mental health, self-efficacy and self-management of patients with hypertensive nephropathy. Background If the symptoms of hypertension are not well-controlled, deterioration of renal function will accelerate and evolve into hypertensive nephropathy. Design A randomised single-blind trial. This article follows the requirements of CONSORT statement. Methods The experimental group (n = 35) after pre-test used patient-centred self-management programme once a week for a total of 4 weeks and the intervention effect was measured after 3 months for post-test. Contrarily, the traditional care was employed for the control group (n = 35). The measuring outcomes included mental health, self-efficacy and self-management. Trial registry is listed under https://clinicaltrials.gov/ with Identifier No. NCT04633993. Results After the intervention, the average score of mental health for the experimental group was 20.79 (SD = 0.82) which was higher than the 19.27 points for the control group (SD = 0.77) and showed a significant difference (F = 8.31, p = .005, partial eta2 = 0.133). In terms of self-efficacy, the average score for the experimental group was 214.13 (SD = 6.40), which was higher than the 189.58 points for the control group (SD = 6.03) and exhibited a significant difference (F = 11.82, p = .001, partial eta2 = 0.197). Regarding self-management, the average score of the experimental group was 75.12 (SD = 2.29) which was significantly higher than the 68.80 points of the control group (SD = 2.43) (F = 11.17, p = .001, partial eta2 = 0.190). Conclusions In addition to promoting mental health of individual cases, this intervention also increases their self-confidence in disease control and improves their self-management on diseases. Relevance to clinical practice The intervention provides an effective option for clinical care workers as a replacement for or supplement to the traditional care.

Introduction: Patients with carbon monoxide poisoning (COP) commonly have long-term morbidities. However, it is not known whether patients with COP exhibit an increased risk of developing chronic kidney disease (CKD) and whether hyperbaric oxygen therapy (HBOT) alters this risk. Methods: This study identified 8,618 patients who survived COP and 34,464 propensity score-matched non-COP patients from 2000 to 2013 in a nationwide administrative registry. The primary outcome was the development of CKD. The association between COP and the risk of developing CKD was estimated using a Cox proportional hazards regression model; the cumulated incidence of CKD among patients stratified by HBOT was evaluated using a Kaplan-Meier analysis. Results: After adjusting for covariates, the risk of CKD was 6.15-fold higher in COP patients than in non-COP controls. Based on the subgroup analyses, regardless of demographic characteristics, environmental factors, and comorbidities, the COP cohort exhibited an increased risk of developing CKD compared with the controls. The cumulative incidence of CKD in COP patients did not differ between the HBOT and non-HBOT groups (p = 0.188). Conclusions: COP might be an independent risk factor for developing CKD. Thus, clinicians should enhance the postdischarge follow-up of kidney function among COP patients.

Background Arteriovenous access (AV) thrombosis is an important and preventable problem amongst chronic hemodialysis (HD) patients. Systolic blood pressure (SBP) fluctuation relates to higher cardiovascular mortality amongst these patients. We proposed there is a close relation between SBP changes and arteriovenous (AV) access thrombosis. We also determined other risk factors and biochemical parameters related to AV access failure. Methods 50 HD patients with thrombosis and 50 HD patients without thrombosis were included in the study. Odds ratios and 95% confidence intervals were estimated with multivariate-adjusted logistic regression models to determine the association between potential thrombosis-related risk factors and thrombosis risk. Results Elder adults, women, and patients with AV grafts, lower intradialytic SBP and higher SBP variations during HD sessions had higher incidence of AV access thrombosis. AV access infection and decreased blood flow (BF) velocity were associated with an increased incidence of thrombotic events, whereas the use of anti-thrombotic agents was associated with a decreased incidence of thrombotic events. Further, anaemia, hypoalbuminemia, hyperlipidemia, and impaired mineral metabolism parameters were also found to be associated with AV access thrombosis. Conclusions Close monitoring and management of intradialytic hypotension and SBP fluctuation in every HD session are important. Some important and novel modifiable risk factors related to AV access thrombosis were identified in this study (eg, AV access infection, decreased BF and abnormal biochemical parameters, etc). Earlier surveillance and modification of these risk factors is crucial to prevent AV access failure in HD patients.

We have previously demonstrated calcimimetics optimize the balance between osteoclastic bone resorption and osteoblastic mineralization through upregulating Wingless and int-1 (Wnt) signaling pathways in the mouse and cell model. Nonetheless, definitive human data are unavailable concerning therapeutic effects of Cinacalcet on chronic kidney disease and mineral bone disease (CKD-MBD) and osteoclast&ndash, osteoblast interaction. We aim to investigate whether Cinacalcet therapy improves bone mineral density (BMD) through optimizing osteocytic homeostasis in a human model. Hemodialysis patients with persistently high intact parathyroid hormone (iPTH) levels &gt, 300 pg/mL for more than 3 months were included and received fixed dose Cinacalcet (25 mg/day, orally) for 6 months. Bone markers presenting osteoclast&ndash, osteoblast communication were evaluated at baseline, the 3rd and the 6th month. Eighty percent of study patients were responding to Cinacalcet treatment, capable of improving BMD, T score and Z score (16.4%, 20.7% and 11.1%, respectively). A significant correlation between BMD improvement and iPTH changes was noted (r = &minus, 0.26, p &lt, 0.01). Nonetheless, baseline lower iPTH level was associated with better responsiveness to Cinacalcet therapy. Sclerostin, an inhibitor of canonical Wnt/&beta, catenin signaling, was decreased from 127.3 &plusmn, 102.3 pg/mL to 57.9 &plusmn, 33.6 pg/mL. Furthermore, Wnt-10b/Wnt 16 expressions were increased from 12.4 &plusmn, 24.2/166.6 &plusmn, 73.3 pg/mL to 33.8 &plusmn, 2.1/217.3 &plusmn, 62.6 pg/mL. Notably, procollagen type I amino-terminal propeptide (PINP), a marker of bone formation and osteoblastic activity, was increased from baseline 0.9 &plusmn, 0.4 pg/mL to 91.4 &plusmn, 42.3 pg/mL. In contrast, tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), a marker of osteoclast activity, was decreased from baseline 16.5 &plusmn, 0.4 mIU/mL to 7.7 &plusmn, 2.2 mIU/mL. Moreover, C-reactive protein levels were suppressed from 2.5 &plusmn, 0.6 to 0.8 &plusmn, 0.5 mg/L, suggesting the systemic inflammatory burden may be benefited after optimizing the parathyroid&ndash, bone axis. In conclusion, beyond iPTH suppression, our human model suggests Cinacalcet intensifies BMD through inhibiting sclerostin expression and upregulating Wnt-10b/Wnt 16 signaling that activates osteoblastic bone formation and inhibits osteoclastic bone resorption and inflammation. From the perspective of translation to humans, this research trial brings a meaningful insight into the osteoblast&ndash, osteoclast homeostasis in Cinacalcet therapy for CKD-MBD.

Indoxyl sulfate (IS), a uremic toxin, causes chronic kidney disease (CKD) progression via its tubulotoxicity. After cellular uptake, IS directly induces apoptotic and necrotic cell death of tubular cells. Additionally, IS increases oxidative stress and decreases antioxidant capacity, which are associated with tubulointerstitial injury. Injured tubular cells are a major source of transforming growth factor-β1 (TGF-β1), which induces myofibroblast transition from residual renal cells in damaged kidney, recruits inflammatory cells and thereby promotes extracellular matrix deposition in renal fibrosis. Moreover, IS upregulates signal transducers and activators of transcription 3 phosphorylation, followed by increases in TGF-β1, monocyte chemotactic protein-1 and α-smooth muscle actin production, which participate in interstitial inflammation, renal fibrosis and, consequently, CKD progression. Clinically, higher serum IS levels are independently associated with renal function decline and predict all-cause mortality in CKD. The poor removal of serum IS in conventional hemodialysis is also significantly associated with all-cause mortality and heart failure incidence in end-stage renal disease patients. Scavenging the IS precursor by AST-120 can markedly reduce tubular IS staining that attenuates renal tubular injury, ameliorates IS-induced oxidative stress and rescues antioxidant glutathione activity in tubular epithelial cells, thereby providing a protective role against tubular injury and ultimately retarding renal function decline.

The development of sodium-glucose transporter 2 inhibitor (SGLT2i) broadens the therapeutic strategies in treating diabetes mellitus. By inhibiting sodium and glucose reabsorption from the proximal tubules, the improvement in insulin resistance and natriuresis improved the cardiovascular mortality in diabetes mellitus (DM) patients. It has been known that SGLT2i also provided renoprotection by lowering the intraglomerular hypertension by modulating the pre- and post- glomerular vascular tone. The application of SGLT2i also provided metabolic and hemodynamic benefits in molecular aspects. The recent DAPA-CKD trial and EMPEROR-Reduced trial provided clinical evidence of renal and cardiac protection, even in non-DM patients. Therefore, the aim of the review is to clarify the hemodynamic and metabolic modulation of SGLT2i from the molecular mechanism.

The association between regional economic status and the probability of renal recovery among patients with dialysis-requiring AKI (AKI-D) is unknown. The nationwide prospective multicenter study enrolled critically ill adult patients with AKI-D in four sampled months (October 2014, along with January, April, and July 2015) in Taiwan. The regional economic status was defined by annual disposable income per capita (ADIPC) of the cities the hospitals located. Among the 1,322 enrolled patients (67.1 ± 15.5 years, 36.2% female), 833 patients (63.1%) died, and 306 (23.1%) experienced renal recovery within 90 days following discharge. We categorized all patients into high (n = 992) and low economic status groups (n = 330) by the best cut-point of ADIPC determined by the generalized additive model plot. By using the Fine and Gray competing risk regression model with mortality as a competing risk factor, we found that the independent association between regional economic status and renal recovery persisted from model 1 (no adjustment), model 2 (adjustment to basic variables), to model 3 (adjustment to basic and clinical variables; subdistribution hazard ratio, 1.422; 95% confidence interval, 1.022–1.977; p = 0.037). In conclusion, high regional economic status was an independent factor for renal recovery among critically ill patients with AKI-D.

Cardiovascular disease (CVD) is closely related to chronic kidney disease (CKD), and patients with CKD have a high risk of CVD-related mortality. Traditional CVD risk factors cannot account for the higher cardiovascular risk of patients with CKD, and standard CVD interventions cannot reduce the mortality rates among patients with CKD. Nontraditional factors related to mineral and vitamin-D metabolic disorders provide some explanation for the increased CVD risk. Non-dialyzable toxins, indoxyl sulfate (IS) and p-cresol sulfate (PCS)—produced in the liver by colonic microorganisms—cause kidney and vascular dysfunction. Plasma trimethylamine-N-oxide (TMAO)—a gut microbe-dependent metabolite of dietary L-carnitine and choline—is elevated in CKD and related to vascular disease, resulting in poorer long-term survival. Therefore, the modulation of colonic flora can improve prospects for patients with CKD. Managing metabolic syndrome, anemia, and abnormal mineral metabolism is recommended for the prevention of CVD in patients with CKD. Considering nontraditional risk factors, the use of resveratrol (RSV), a nutraceutical, can be helpful for patients with CVD and CKD. This paper discusses the beneficial effects of RSV on biologic, pathophysiological and clinical responses, including improvements in intestinal epithelial integrity, modulation of the intestinal microbiota and reduction in hepatic synthesis of IS, PCS and TMAO in patients with CVD and CKD.

BACKGROUND Taiwan has the world's highest prevalence of end-stage kidney disease, as well as the world's third highest incidence. The study investigated the effectiveness of a self-management program for enhancing health-related quality of life, self-care behaviors, and self-efficacy in patients with end-stage kidney disease undergoing hemodialysis. METHODS This was a quasi-experimental design with convenient sampling, and allocated 32 participants in the control group (conventional program) and 32 participants in the experimental group (self-management program). The self-management program intervention lasted 4 weeks, and a posttest was administered 3 months later. The questionnaire included the 36-Item Short Form Health Survey, a Chronic Kidney Disease Self-Care Instrument, and a Chronic Kidney Disease Self-Efficacy Instrument. RESULTS Three months after the intervention, the self-management program had improved patients' health-related quality of life in the mental health components (p

Osteogenesis in human arterial smooth muscle cell (HASMC) is a key feature of uremic vascular calcification (UVC). Concerning pro-oxidant properties of p-cresyl sulfate (PCS), the therapeutic effect of reactive oxygen species (ROS) scavenger on PCS triggered inflammatory signaling transduction in osteogenesis was investigated in this translational research. Based on severity level of chronic kidney disease (CKD), arterial specimens with immunohistochemistry stain were quantitatively analyzed for UVC, oxidative injury and osteogenesis along with PCS concentrations. To mimic human UVC, HASMC model was used to explore whether PCS-induced ROS could trigger mitogen-activated protein kinase (MAPK) pathways with nuclear factor-κB (NF-κB) translocation that drive context-specific gene/protein expression, including Runt-related transcription factor 2 (Runx2) and alkaline phosphatase (ALP). In parallel with PCS accumulation, CKD arteries corresponded with UVC severity, oxidative DNA damage (8-hydroxy-2′-deoxyguanosine), Runx2 and ALP. PCS directly phosphorylated extracellular signal-regulated kinase (ERK)/c-Jun N-terminal kinase (JNK)/P38 (pERK/pJNK/pP38) and modulated NF-κB translocation to promote expressions of Runx2 and ALP in HASMC. Notably, intracellular ROS scavenger attenuated pERK signaling cascade and downstream osteogenic differentiation. Collectively, our data demonstrate PCS induces osteogenesis through triggering intracellular ROS, pERK/pJNK/pP38 MAPK pathways and NF-κB translocation to drive Runx2 and ALP expressions, culminating in UVC. Beyond mineral dysregulation, osteocytic conversion in HASMC could be the stimulation of PCS. Thus PCS may act as a pro-osteogenic and pro-calcific toxin. From the perspective of translational medicine, PCS and intracellular ROS could serve as potential therapeutic targets for UVC in CKD patients.

AIMS OF THE STUDY A high prevalence of protein-energy wasting and malnutrition among uremic patients is associated with an increase in morbidity and mortality. We aimed to investigate the modulating effect of daily dietary protein intake (DPI) evaluated by normalised protein catabolic rate (nPCR) on mortality in long-term haemodialysis (HD) patient from a nationwide population-based study. METHODS USED TO CONDUCT THE STUDY By Taiwan Renal Registry Data System between 2005 and 2012, we divided the long-term HD patients into average nPCR

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

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

Prion diseases, including Creutzfeldt–Jakob disease, are mediated by transmissible proteinaceous pathogens. Pathological changes indicative of neuro-degeneration have been observed in the brains of affected patients. Simultaneously, microglial activation, along with the upregulation of pro-inflammatory cytokines, including IL-1 or TNF-α, have also been observed in brain tissue of these patients. Consequently, pro-inflammatory cytokines are thought to be involved in the pathogenesis of these diseases. Accelerated prion infections have been seen in interleukin-10 knockout mice, and type 1 interferons have been found to be protective against these diseases. Since interleukin-10 and type 1 interferons are key mediators of the antiviral THαβ immunological pathway, protective host immunity against prion diseases may be regulated via THαβ immunity. Currently no effective treatment strategies exist for prion disease; however, drugs that target the regulation of IL-10, IFN-alpha, or IFN-β, and consequently modulate the THαβ immunological pathway, may prove to be effective therapeutic options.

Background Post‐transplantation malignancy influenced graft survival and overall survival in the patients receiving renal transplantation. Immunosuppressants influenced the immune surveillance, but whether immunosuppressive agents have impact for incidence of post‐transplantation malignancy is still elusive in Taiwan. Method We conducted a nationwide population‐based study. Patients who did not have malignancy history and received kidney transplantation between 2000 and 2010 were enrolled. Specific immunosuppressive users are defined as sustained use (more than 12 months) after renal transplantation. The primary outcome is the development of cancer after kidney transplantation. A Cox proportional hazards model was used to determine the risk of cancer development. Result Among 4438 recipients, 559 of them were diagnosed with malignancy after 1 year of transplantation. A total of 742 of recipients were as user of mechanistic target of rapamycin (mTOR) inhibitors. The mTOR users had higher rate of receiving pulse therapy. The hazard ratios (HR) for mTOR inhibitor users with exposure more than 5 years for overall malignancy and urothelial malignancy were 0.68 (95% CI: 0.48‐0.95, P = 0.02) and 0.60 (95% CI: 0.36‐0.99, P = 0.02), respectively. For the overall mortality and reentry of dialysis, the probability of both groups was similar (overall mortality: P = 0.53; reentry of dialysis: P = 0.77). Conclusion Among the recipients of renal transplantation in Taiwan, mTOR inhibitors with exposure more than 5 years provided a protective role in reducing the risk of overall neoplasm and urothelial malignancy. The probability of reentry of dialysis and overall mortality was similar between the mTORi users and nonusers.

Chronic kidney disease-mineral bone disorders (CKD-MBD) exhibit abnormalities in the circulating mineral levels, vitamin D metabolism, and parathyroid function that contribute to the formation of a bone lesion. The uremic toxin, indoxyl sulfate (IS), accumulates in the blood in cases of renal failure and leads to bone loss. The bone and renal responses to the action of the parathyroid hormone (PTH) are progressively decreased in CKD in spite of increasing PTH levels, a condition commonly called PTH resistance. There is a high prevalence of low bone turnover or adynamic bone disease in the early stages of CKD. This could be due to the inhibition of bone turnover, such as in PTH resistance, reduced active vitamin D levels, diabetes, aluminum, and, increased IS. With an increase in IS, there is a decrease in the osteoblast Wnt/b-catenin signaling and increase in the expression of Wnt signaling inhibitors, such as sclerostin and Dickkopf-1 (DKK1). Thus, a majority of early CKD patients exhibit deterioration of bone quality owing to the action of IS, this scenario could be termed uremic osteoporosis. However, this mechanism is complicated and not fully understood. With progressive deterioration in the renal function, IS accumulates along with persistent PTH secretion, potentially leading to high-turnover bone disease because high serum PTH levels have the ability of overriding peripheral PTH resistance and other inhibitory factors of bone formation. Finally, it leads to deterioration in bone quantity with prominent bone resorption in end stage renal disease. Uremic toxins adsorbents may decelerate oxidative stress and improve bone health in CKD patients. This review article focuses on IS and bone loss in CKD patients.

Uremic toxins, such as indoxyl sulfate (IS) and kynurenine, accumulate in the blood in the event of kidney failure and contribute to further bone damage. To maintain the homeostasis of the skeletal system, bone remodeling is a persistent process of bone formation and bone resorption that depends on a dynamic balance of osteoblasts and osteoclasts. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates the toxic effects of uremic toxins. IS is an endogenous AhR ligand and is metabolized from tryptophan. In osteoclastogenesis, IS affects the expression of the osteoclast precursor nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) through AhR signaling. It is possible to increase osteoclast differentiation with short-term and low-dose IS exposure and to decrease differentiation with long-term and/or high-dose IS exposure. Coincidentally, during osteoblastogenesis, through the AhR signaling pathway, IS inhibits the phosphorylation of ERK, and p38 reduces the expression of the transcription factor 2 (Runx2), disturbing osteoblastogenesis. The AhR antagonist resveratrol has a protective effect on the IS/AhR pathway. Therefore, it is necessary to understand the multifaceted role of AhR in CKD, as knowledge of these transcription signals could provide a safe and effective method to prevent and treat CKD mineral bone disease.

The risk of cardiovascular death is 10 times higher in patients with CKD (chronic kidney disease) than in those without CKD. Vascular calcification, common in patients with CKD, is a predictor of cardiovascular mortality. Vitamin D deficiency, another complication of CKD, is associated with vascular calcification in patients with CKD. GFR decline, proteinuria, tubulointerstitial injury, and the therapeutic dose of active form vitamin D aggravate vitamin D deficiency and reduce its pleiotropic effect on the cardiovascular system. Vitamin D supplement for CKD patients provides a protective role in vascular calcification on the endothelium by (1) renin-angiotensin-aldosterone system inactivation, (2) alleviating insulin resistance, (3) reduction of cholesterol and inhibition of foam cell and cholesterol efflux in macrophages, and (4) modulating vascular regeneration. For the arterial calcification, vitamin D supplement provides adjunctive role in regressing proteinuria, reverse renal osteodystrophy, and restoring calcification inhibitors. Recently, adventitial progenitor cell has been linked to be involved in the vascular calcification. Vitamin D may provide a role in modulating adventitial progenitor cells. In summary, vitamin D supplement may provide an ancillary role for ameliorating uremic vascular calcification.

AIM This study was designed to investigate the longitudinal effect of participating in a self-management program (SMP) on renal function control in patients receiving hemodialysis. METHODS This randomized controlled trial enrolled a total of 58 patients at the hemodialysis center of a teaching hospital in Taiwan. The control group (n = 30) received the usual care and the experimental group (n = 28) received a 4-week SMP intervention. The results of the follow-up on the longitudinal data at 3, 6, and 9 months showed that the renal function indices, potassium and phosphorus levels, and interdialytic weight gain were significantly better than at the pre-test for the experimental group. RESULTS In terms of the interaction between group and time, the potassium level dropped significantly below the pre-test value only after 3 months (B = -0.31, SE = 0.15, p = .044), suggesting that the post-test potassium level had significantly decreased after 3 months. In terms of the interaction between group and time, the phosphorus level dropped significantly below the pre-test value only after 6 months (B = -0.53, SE = 0.28, p = .050), suggesting that the post-test phosphorus level significantly decreased after 6 months. Finally, the intervention could effectively control the weight change between dialysis sessions for up to 9 months (B = -1.34, SE = 0.30, p

Vitamin D has been demonstrated to lessen proteinuria severity in chronic kidney disease (CKD). Compared with healthy populations, patients with CKD may have lower serum levels of 1,25-dihydroxy vitamin D (1,25-(OH)2 D) and 25-hydroxy vitamin D (25-(OH) D). We investigated the effect of oral low-dose active vitamin D (calcitriol at 0.25 μg, 3 times weekly) on urinary protein excretion.We conducted a nonblinded and non-placebo-controlled study. In total, 60 patients with CKD (average estimated glomerular filtration rate of15 mL/min) who received a stable dose of angiotensin receptor blocker (ARB) or angiotensin-converting enzyme inhibitor (ACEI) were enrolled in this 24-week study. We randomly assigned these patients to the vitamin D group (oral calcitriol at 0.25 μg 3 times weekly with an ACEI or ARB) or the control group (ACEI or ARB). Change in the urine protein/creatinine ratio (uPCR) was the primary endpoint in this study.The mean baseline uPCRs of the 2 groups were comparable (1.84 ± 0.83 g/g vs. 2.02 ± 0.97 g/g, control vs. vitamin D group; P = .46). After the 24-week treatment, the uPCRs were significantly lower than the baseline values in the vitamin D group (1.35 ± 0.64 g/g; P .05) but not in the control group. The values of uPCR decreased significantly at 8, 16, and 24 weeks (P .05 vs. baseline) in the vitamin D group. The values of uPCRs were significantly lower in the vitamin D group than in the control group at 8, 16, and 24 weeks (P .05). A positive correlation was discovered between reduction in uPCRs at 24-week and baseline 25-(OH) D serum level in the vitamin D group (r = 0.738, P .001).Supplementary low-dose active vitamin D could reduce proteinuria in CKD patients with low serum 25-(OH) D levels.

It remains unclear how different uses of angiotensin-converting inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) influence the progression of chronic kidney disease (CKD). This study explored CKD progression in a multicentre, longitudinal cohort study that included 2639 patients with CKD stage 1–5 and hypertension. Patients treated with ACEI or ARB for ≥90 days during a 6-mo period comprised the study group, or no treatment, comprised the control group. The study group was subdivided on the basis of treatment: ACEI monotherapy or ARB monotherapy. Progression of renal deterioration was defined by an average eGFR decline of more than 5 mL/min/1.73 m2/yr or the commencement of dialysis. With at least 1-year follow up, a progression of renal deterioration was demonstrated in 29.70% of the control group and 25.09% of the study group. Patients in the study group had significantly reduced progression of CKD with adjusted odds ratio 0.79 (95% confidence interval: 0.63–0.99). However, when ACEI monotherapy and ARB monotherapy were analyzed separately, none of their associations with CKD progression was statistically significant. In conclusion, ACEI or ARB monotherapy may retard the deterioration of renal function among patients with CKD and hypertension.

Vascular calcification is a critical complication in patients with chronic kidney disease (CKD) because it is predictive of cardiovascular events and mortality. In addition to the traditional mechanisms associated with endothelial dysfunction and the osteoblastic transformation of vascular smooth muscle cells (VSMCs), the regulation of calcification inhibitors, such as calciprotein particles (CPPs) and matrix vesicles plays a vital role in uremic vascular calcification in CKD patients because of the high prevalence of vitamin K deficiency. Vitamin K governs the gamma-carboxylation of matrix Gla protein (MGP) for inhibiting vascular calcification, and the vitamin D binding protein receptor is related to vitamin K gene expression. For patients with chronic kidney disease, adequate use of vitamin D supplements may play a role in vascular calcification through modulation of the calciprotein particles and matrix vesicles (MVs).

Background: The endothelial progenitor cells (EPCs) dysfunction is a critical event in the initiation of atherosclerotic plaque development and the level of circulating EPCs can be considered a biomarker of cardiovascular events. The level and functional change in EPCs has been investigated in hemodialysis patients, but the effect of absolute number of EPCs on risk of death has not yet been explored. We hypothesized that the number of EPCs predicted death from cardiovascular and all-cause mortality in hemodialysis patients. Methods: We evaluate the association between endothelial progenitor cells and clinical outcome in 154 patients on maintenance hemodialysis. The blood sample was drawn at the time of patient enrollment and EPCs were identified by flow cytometry using triple staining for CD34/CD133/KDR. Results: The median duration of follow-up was 4.19 years. There were 79 (51.3%) deaths during the follow-up period, 41 of whom died due to a confirmed cardiovascular cause. The cumulative survival was greater in the high-EPC group than the low-EPC group for all-cause and cardiovascular mortality. Decreased EPCs levels were associated with a significant increase in the risk of cardiovascular and all-cause mortality after adjusting for age, gender, current smokers, diabetes mellitus, and hypertension. Conclusions: The level of circulating EPCs independently predicts the clinical outcome in patients on maintenance hemodialysis. Thus, the EPCs levels may be a useful predictive tool for evaluating the risk of death in maintenance hemodialysis patients.

Indoxyl sulfate (IS), a uremic toxin derived from dietary tryptophan metabolism by the gut microbiota, is an endogenous aryl hydrocarbon receptor (AhR) agonist and a key player in bone remodeling. Resveratrol (RSV), an AhR antagonist, plays a protective role in shielding against AhR ligands. Our study explored the impact of IS on osteoblast differentiation and examined the possible mechanism of IS in controlling the expression of osteoblastogenesis markers through an in-depth investigation of AhR signaling. In vivo, we found histological architectural disruption of the femoral bones in 5/6 nephrectomies of young adult IS exposed mice, including reduced Runx2 antigen expression. RSV improved the diaphysis architecture, Runx2 expression, and trabecular quality. In vitro data suggest that IS at 500 and 1000 &mu, M disturbed osteoblastogenesis through suppression of the ERK and p38 mitogen-activated protein kinase (MAPK) pathways, which were found to be downstream of AhR. RSV proved to ameliorate the anti-osteoblastogenic effects of IS through the inhibition of AhR and downstream signaling. Taken together, we demonstrated that the IS/AhR/MAPK signaling pathway plays a crucial role in the inhibition of osteoblastogenesis, and RSV has a potential therapeutic role in reversing the IS-induced decline in osteoblast development and suppressing abnormal bone turnover in chronic kidney disease patients.

The association between gout and injury remains unclear. This study aimed to investigate the injury risk in patients with gout. Using the Longitudinal Health Insurance Database (LHID) from 2000 to 2010 in Taiwan, patients with gout (group CFG) and those without gout (group C) were enrolled for further analysis. The CFG group was separated into two subgroups (with and without medication) to determine whether the risk of injury was reduced with drug intervention. The follow-up period was defined as the time from the initial diagnosis of gout to the date of injury. A total of 257,442 individuals were enrolled in this study, with 85,814 people in group CFG and 171,628 people in group C. Using Cox regression analysis, group CFG showed a significant increase in the risk of injury. Traffic injuries, poisoning, falls, crushing/cutting/piercing injury, and suicides were prominent among these injuries. Furthermore, when urate-lowing drugs were used to treat the CFG group, there were no significant differences in the occurrence of injury. Patients with gout had an increased risk of injury overall, and drug intervention did not lower the risk of injury in these patients.

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

This study investigated the characteristics of patients with different chronic kidney disease (CKD) stages according to various body mass index (BMI) categories and determined the influence of BMI in renal function deterioration. We conducted a multicenter, longitudinal cohort study based on the Epidemiology and Risk Factors Surveillance of CKD project (2008-2013) and National Health Insurance Research Database (2001-2013). A total of 7357 patients with CKD aged 20-85 years from 14 hospitals were included in the study. A higher male sex, diabetes mellitus (DM) and hypertension were noted among overweight and obese CKD patients, while more cancer prevalence was noted among underweight CKD patients. Charlson comorbidity index was significantly higher and correlated with BMI among late CKD patients. Patients with BMI 18.5 kg/m

As the GFR loss aggravates, the disturbed mineral metabolism worsens the bone microstructure and remodelling - scenario, which is known as CKD-mineral bone disease (MBD). CKD-MBD is characterized by : (i) abnormal metabolism of calcium, phosphorus, parathyroid hormone (PTH), or vitamin D; (ii) abnormalities in bone turnover, mineralization, volume linear growth or strength; (iii) soft-tissue calcifications, either vascular or extra-osseous. Uremic vascular calcification and osteoporosis are the most common complications related to CKD-MBD. Disregulated bone turnover by uremic toxin or secondary hyperparathyroidism disturbed bone mineralization and makes it difficult for calcium and inorganic phosphate to enter into bone, resulting in increased serum calcium and inorganic phosphate. Vascular calcification worsens by hyperphosphatemia and systemic inflammation. Since vitamin D deficiency plays an important role in renal osteodystrophy, supplement of nutritional vitamin D is important in treating uremic osteoporosis and vascular calcification at the same time. Its pleotropic effect improves the bone remodeling initiated by osteoblast and alleviates the risk factors for vascular calcification with less hypercalcemia than vitamin D receptor analogs. Therefore, nutritional vitamin D should be considered in managing CKDMBD.

Canonical Wnt (Wingless/Integrated) signaling is crucial in bone development and the Wnt ligand can promote osteoblast differentiation from mesenchymal progenitor cells. Calcitriol, an active vitamin D3, is used clinically for treatment of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD) patients. The bone effects of calcitriol in SHPT remains uncertain. We hypothesized that calcitriol improves bone mass by suppressing osteoclast activity, and simultaneously promoting Wnt ligand secretion. We designed a cross-sectional study in maintenance hemodialysis patients to explore the effects of calcitriol on different bone turnover markers and specifically emphasized the Wnt 10b levels. Then, we explored the source of Wnt 10b secretion by using osteoclasts and osteoblasts treated with calcitriol in cell culture studies. Finally, we explored the effects of calcitriol on bone microarchitectures in CKD mice, using the 5/6 nephrectomy CKD animal model with analysis using micro-computed tomography. Calcitriol promoted the growth of both trabecular and cortical bones in the CKD mice. Wnt 10b and Procollagen 1 N-terminal Propeptide (P1NP) significantly increased, but Tartrate-resistant acid phosphatase 5b (Trap 5b) significantly decreased in the calcitriol-treated maintenance hemodialysis patients. Calcitriol enhanced Wnt 10b secretion from osteoclasts in a dose-dependent manner. Treatment of SHPT with calcitriol improved the bone anabolism by inhibiting osteoclasts and promoting osteoblasts that might be achieved by increasing the Wnt 10b level.

Osteoporosis is a systemic skeletal disorder characterized by a decrease in bone mass and microarchitectural deterioration of bone tissue. The World Health Organization has defined osteoporosis as a decrease in bone mass (50%) and bony quality (50%). Vitamin D, a steroid hormone, is crucial for skeletal health and in mineral metabolism. Its direct action on osteoblasts and osteoclasts and interaction with nonskeletal tissues help in maintaining a balance between bone turnover and bone growth. Vitamin D affects the activity of osteoblasts, osteoclasts, and osteocytes, suggesting that it affects bone formation, bone resorption, and bone quality. At physiological concentrations, active vitamin D maintains a normal rate of bone resorption and formation through the RANKL/OPG signal. However, active vitamin D at pharmacological concentration inhibits bone resorption at a higher rate than that of bone formation, which influences the bone quality and quantity. Nutritional vitamin D rather than active vitamin D activates osteoblasts and maintains serum 25(OH)D 3 concentration. Despite many unanswered questions, much data support nutritional vitamin D use in osteoporosis patients. This article emphasizes the role of nutritional vitamin D replacement in different turnover status (high or low bone turnover disorders) of osteoporosis together with either anti-resorptive (Bisphosphonate, Denosumab et.) or anabolic (Teriparatide) agents when osteoporosis persists.

Background Despite the development of biomarkers and noninvasive imaging tools, biopsy remains the only method for correctly diagnosing patients with unexplained hematuria, proteinuria and renal failure. Renal biopsy has been performed for several decades in Taiwan; however, a national data registry is still lacking until 2013. Methods The Renal Biopsy Registry Committee was established within the Taiwan Society of Nephrology in January 2013. A biopsy registry format, including basic demographic data, baseline clinical features, laboratory data, and clinical and pathological diagnosis was developed. Approval from the local institutional review board was obtained in each participating medical center. Results From January 2014 to September 2016, 1445 renal biopsies were identified from 17 medical centers. 53.8% cases were reported in men. After excluding renal transplantation, renal biopsies were commonly performed in patients with primary glomerulonephritis (48.1%), secondary glomerulonephritis (36.2%), followed by tubulointerstitial diseases (12.3%) and vascular nephropathy (3.4%). Among primary glomerulonephritis, IgA nephropathy (26.0%), focal segmental glomerulosclerosis (21.6%), and membranous nephropathy (20.6%) were most frequently diagnosed. Diabetic nephropathy (22.4%) and lupus nephritis (21.8%) were the most common among secondary glomerulonephritis. Patients with minimal change disease and membranous nephropathy had heavier proteinuria than those with focal segmental glomerulosclerosis and IgA nephropathy (P