Critical roles of tubular mitochondrial ATP synthase dysfunction in maleic acid-induced acute kidney injury.

Maleic acid (MA) induces renal tubular cell dysfunction directed to acute kidney injury (AKI). AKI is an increasing global health burden due to its association with mortality and morbidity. However, targeted therapy for AKI is lacking. Previously, we determined mitochondrial-associated proteins are MA-induced AKI affinity proteins. We hypothesized that mitochondrial dysfunction in tubular epithelial cells plays a critical role in AKI. In vivo and in vitro systems have been used to test this hypothesis. For the in vivo model, C57BL/6 mice were intraperitoneally injected with 400 mg/kg body weight MA. For the in vitro model, HK-2 human proximal tubular epithelial cells were treated with 2 mM or 5 mM MA for 24 h. AKI can be induced by administration of MA. In the mice injected with MA, the levels of blood urea nitrogen (BUN) and creatinine in the sera were significantly increased (p < 0.005). From the pathological analysis, MA-induced AKI aggravated renal tubular injuries, increased kidney injury molecule-1 (KIM-1) expression and caused renal tubular cell apoptosis. At the cellular level, mitochondrial dysfunction was found with increasing mitochondrial reactive oxygen species (ROS) (p < 0.001), uncoupled mitochondrial respiration with decreasing electron transfer system activity (p < 0.001), and decreasing ATP production (p < 0.05). Under transmission electron microscope (TEM) examination, the cristae formation of mitochondria was defective in MA-induced AKI. To unveil the potential target in mitochondria, gene expression analysis revealed a significantly lower level of ATPase6 (p < 0.001). Renal mitochondrial protein levels of ATP subunits 5A1 and 5C1 (p < 0.05) were significantly decreased, as confirmed by protein analysis. Our study demonstrated that dysfunction of mitochondria resulting from altered expression of ATP synthase in renal tubular cells is associated with MA-induced AKI. This finding provides a potential novel target to develop new strategies for better prevention and treatment of MA-induced AKI.

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

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of end-stage kidney disease (ESKD) worldwide. Guidelines for the diagnosis and management of ADPKD in Taiwan remains unavailable. In this consensus statement, we summarize updated information on clinical features of international and domestic patients with ADPKD, followed by suggestions for optimal diagnosis and care in Taiwan. Specifically, counselling for at-risk minors and reproductive issues can be important, including ethical dilemmas surrounding prenatal diagnosis and pre-implantation genetic diagnosis. Studies reveal that ADPKD typically remains asymptomatic until the fourth decade of life, with symptoms resulting from cystic expansion with visceral compression, or rupture. The diagnosis can be made based on a detailed family history, followed by imaging studies (ultrasound, computed tomography, or magnetic resonance imaging). Genetic testing is reserved for atypical cases mostly. Common tools for prognosis prediction include total kidney volume, Mayo classification and PROPKD/genetic score. Screening and management of complications such as hypertension, proteinuria, urological infections, intracranial aneurysms, are also crucial for improving outcome. We suggest that the optimal management strategies of patients with ADPKD include general medical care, dietary recommendations and ADPKD-specific treatments. Key points include rigorous blood pressure control, dietary sodium restriction and Tolvaptan use, whereas the evidence for somatostatin analogues and mammalian target of rapamycin (mTOR) inhibitors remains limited. In summary, we outline an individualized care plan emphasizing careful monitoring of disease progression and highlight the need for shared decision-making among these patients.

The Impact of Thallium Exposure in Public Health and Molecular Toxicology: A Comprehensive Review.

This review offers a synthesis of the current understanding of the impact of low-dose thallium (Tl) on public health, specifically emphasizing its diverse effects on various populations and organs. The article integrates insights into the cytotoxic effects, genotoxic potential, and molecular mechanisms of thallium in mammalian cells. Thallium, a non-essential heavy metal present in up to 89 different minerals, has garnered attention due to its adverse effects on human health. As technology and metallurgical industries advance, various forms of thallium, including dust, vapor, and wastewater, can contaminate the environment, extending to the surrounding air, water sources, and soil. Moreover, the metal has been identified in beverages, tobacco, and vegetables, highlighting its pervasive presence in a wide array of food sources. Epidemiological findings underscore associations between thallium exposure and critical health aspects such as kidney function, pregnancy outcomes, smoking-related implications, and potential links to autism spectrum disorder. Thallium primarily exerts cellular toxicity on various tissues through mitochondria-mediated oxidative stress and endoplasmic reticulum stress. This synthesis aims to shed light on the intricate web of thallium exposure and its potential implications for public health, emphasizing the need for vigilant consideration of its risks.

Implementation of artificial intelligence Chatbot in peritoneal dialysis nursing care: Experience from a Taiwan medical center.

PURPOSE: Coronavirus disease pandemic makes high requirements in delivering remote and efficient communication, and patient education. Because of the increases of digital and social media applications in Taiwan, we aim to apply Artificial Intelligence of LINE Chatbot to improve the self-care ability of patients undergoing peritoneal dialysis. MATERIALS AND METHODS: We conducted the project since 1 May 2021 to 30 April 2022. We designed an automatically replied Chatbot system, and divided into six scopes of interaction interfaces, including peritoneal dialysis technique operation video, clinical reminder, home caring, hospital registration service, dietary guideline, and Automatic Peritoneal dialysis guidance. We surveyed patients' satisfaction with the LINE Chatbot 3 months later by the Likert 1-5 score-based questionnaire and the higher score indicated higher satisfaction. RESULTS: There were 440 patients who joined the PD AI Chatbot study and use the Chatbot, but the satisfaction questionnaire recovery rate was only 297 patients. We found that 91.7% of participants agreed 'Overall satisfaction with patient intelligent Chatbot application'. More than 4 points accounted for 86.6%. We traced every click in each section of the Chatbot and explored the potential scenario patients face. The Chatbot statistically significant reduced infection rate of exit site and tunnel infection before using (p = .049 and .024). Furthermore, peritonitis rate decreased from 0.93 to 0.8/100 patient month after using Artificial Intelligence technique. Peritoneal dialysis Artificial Intelligence Chatbot had similar effect with face-to-face education. CONCLUSION: The innovative Chatbot allowed delivering remote and digital information's to improve patients' self-care ability. Peritoneal dialysis patients were highly recognized and satisfied with the tools. It deserves to further explore the long-term impact of Artificial Intelligence Chatbot in peritoneal dialysis care.

Angiopoietin-2 inhibition attenuates kidney fibrosis by hindering chemokine C-C motif ligand 2 expression and apoptosis of endothelial cells.

Plasma levels of angiopoietin-2 are increased in patients with chronic kidney disease (CKD). Moreover, mouse models of progressive kidney disease also demonstrate increased angiopoietin-2 in both plasmas and kidneys. The role of dysregulated angiopoietins in the progression of kidney disease has not been thoroughly investigated. Here, we found in a cohort of 319 patients with CKD that plasma angiopoietin-2 and angiopoietin-2/angiopoietin-1 ratios were positively associated with the development of kidney failure. In mice with progressive kidney disease induced by either ureteral obstruction or ischemia-reperfusion injury, overexpression of human angiopoietin-1 in the kidney tubules not only reduced macrophage infiltration in the initial stage post-injury but also attenuated endothelial cell apoptosis, microvascular rarefaction, and fibrosis in the advanced disease stage. Notably, angiopoietin-1 attenuated chemokine C-C motif ligand 2 (CCL2) expression in the endothelial cells of the fibrosing kidneys, and these protective effects led to attenuation of functional impairment. Mechanistically, angiopoietin-1 reduced CCL2-activated macrophage migration and protected endothelial cells against cell apoptosis induced by angiopoietin-2 and Wnt ligands. Based on this, we applied L1-10, an angiopoietin-2 inhibitor, to the mouse models of progressive kidney disease and found inhibitory effects on macrophage infiltration, microvascular rarefaction, and fibrosis. Thus, we defined the detrimental impact of increased angiopoietin-2 on kidney survival of patients with CKD which appears highlighted by angiopoietin-2 induced endothelial CCL2-activated macrophage infiltration and endothelial cell apoptosis in their kidneys undergoing fibrosis.

Therapeutic effect of quercetin polymeric nanoparticles on ischemia/reperfusion-induced acute kidney injury in mice.

Acute kidney injury (AKI) is known as a sudden episode of kidney injury, which happens suddenly within a few hours or a few days. Quercetin (3,3',4',5,7-pentahydroxyflavone) is a flavonoid found in plants. Quercetin is known to have several biological activities, such as anti-oxidant, anti-inflammatory, and anti-carcinogenic effects. However, low water solubility and bioavailability are the limitations of quercetin for its clinical applications. Moreover, ischemia/reperfusion (I/R) injury is a common cause of AKI. There are no satisfactory strategies for I/R-induced AKI. Developing suitable preventive or therapeutic intervention for AKI is an important and urgent issue. We investigated the benefit effect of synthesized polyethylene glycol (PEG) conjugated polyethyleneimine (PEI) nanoparticles for targeted delivery of quercetin on AKI in a mouse model. An I/R-induced AKI mouse model was used to evaluate the therapeutic effect of quercetin polymeric nanoparticles by intravenous injection. Biochemical changes for renal function in blood samples were analyzed. Histological and immunohistochemical changes were also analyzed. The biochemical changes of blood urea nitrogen (BUN), creatinine, and cystatin C were significantly increased in I/R-induced AKI mice, which could be significantly reversed by quercetin polymeric nanoparticles. Quercetin polymeric nanoparticles could also significantly decrease the histological lesions, positive staining for 3-nitrotyrosine and cyclooxygenase-2, and lipid peroxidation in the kidneys of I/R-induced AKI mice. These results demonstrate for the first time that quercetin polymeric nanoparticles possess therapeutic potential for the treatment of I/R-induced AKI in vivo.

The down-regulation of XBP1, an unfolded protein response effector, promotes acute kidney injury to chronic kidney disease transition.

BACKGROUND: The activation of the unfolded protein response (UPR) is closely linked to the pathogenesis of renal injuries. However, the role of XBP1, a crucial regulator of adaptive UPR, remains unclear during the transition from acute kidney injury (AKI) to chronic kidney disease (CKD). METHODS: We characterized XBP1 expressions in different mouse models of kidney injuries, including unilateral ischemia-reperfusion injury (UIRI), unilateral ureteral obstruction, and adenine-induced CKD, followed by generating proximal tubular XBP1 conditional knockout (XBP1cKO) mice for examining the influences of XBP1. Human proximal tubular epithelial cells (HK-2) were silenced of XBP1 to conduct proteomic analysis and investigate the underlying mechanism. RESULTS: We showed a tripartite activation of UPR in injured kidneys. XBP1 expressions were attenuated after AKI and inversely correlated with the severity of post-AKI renal fibrosis. XBP1cKO mice exhibited more severe renal fibrosis in the UIRI model than wide-type littermates. Silencing XBP1 induced HK-2 cell cycle arrest in G2M phase, inhibited cell proliferation, and promoted TGF-ß1 secretion. Proteomic analysis identified TNF receptor associated protein 1 (Trap1) as the potential downstream target transcriptionally regulated by XBP1s. Trap1 overexpression can alleviate silencing XBP1 induced profibrotic factor expressions and cell cycle arrest. CONCLUSION: The loss of XBP1 in kidney injury was profibrotic, and the process was mediated by autocrine and paracrine regulations in combination. The present study identified the XBP1-Trap1 axis as an instrumental mechanism responsible for post-AKI fibrosis, which is a novel regulatory pathway.

Therapeutic Ultrasound Halts Progression of Chronic Kidney Disease In Vivo via the Regulation of Markers Associated with Renal Epithelial-Mesenchymal Transition and Senescence.

Low-intensity pulsed ultrasound (LIPUS), a therapeutic type of ultrasound, is known to enhance bone fracture repair processes and help some tissues to heal. Here, we investigated the therapeutic potential of LIPUS for the treatment of chronic kidney disease (CKD) in two CKD mouse models. CKD mice were induced using both unilateral renal ischemia/reperfusion injury (IRI) with nephrectomy and adenine administration. The left kidneys of the CKD mice were treated using LIPUS with the parameters of 3 MHz, 100 mW/cm2, and 20 min/day, based on the preliminary experiments. The mice were euthanized 14 days after IRI or 28 days after the end of adenine administration. LIPUS treatment effectively alleviated the decreases in the body weight and albumin/globulin ratio and the increases in the serum renal functional markers, fibroblast growth factor-23, renal pathological changes, and renal fibrosis in the CKD mice. The parameters for epithelial-mesenchymal transition (EMT), senescence-related signal induction, and the inhibition of α-Klotho and endogenous antioxidant enzyme protein expression in the kidneys of the CKD mice were also significantly alleviated by LIPUS. These results suggest that LIPUS treatment reduces CKD progression through the inhibition of EMT and senescence-related signals. The application of LIPUS may be an alternative non-invasive therapeutic intervention for CKD therapy.

Early elimination of uremic toxin ameliorates AKI-to-CKD transition.

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

Gustatory Dysfunction Is Closely Associated With Frailty in Patients With Chronic Kidney Disease.

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

Angiopoietin-2 is associated with metabolic syndrome in chronic kidney disease.

BACKGROUNDS: Metabolic syndrome is a subclinical status in promoting atherosclerotic cardiovascular disease and type 2 diabetes mellitus. The significance of metabolic syndrome and pathophysiology in chronic kidney disease is not investigated. METHODS: We enrolled adult patients with CKD stages 3 to 5 from December 2006 to December 2007. Metabolic syndrome was defined by the US National Cholesterol Education Programme Adult Treatment Panel III guidelines. Plasma levels of angiogenic growth factors were measured. Univariate and multivariate logistic regression analyses were used. RESULTS: Total 451 patients were analyzed with median estimated glomerular filtration rate of 27.0 ml/min per 1.73m2 (interquartile range 14.3-41.3). Patients with metabolic syndrome were older (P = 0.002), had higher percentage using diuretics (P = 0.002) but lower percentage using pentoxifylline (P = 0.017). Patients with metabolic syndrome had higher levels of high-sensitivity C-reactive protein (P < 0.0001), uric acid (P = 0.009) and angiopoietin-2 (P = 0.001). Multivariate logistic regression analyses revealed significant association between plasma levels of angiopoietin-2 and metabolic syndrome (P = 0.042). CONCLUSION: The prevalence of metabolic syndrome in advanced CKD was higher than general population. CKD patients with metabolic syndrome had higher levels of high-sensitivity C-reactive protein, uric acid and angiopoietin-2. Plasma levels of angiopoietin-2 were significantly associated with metabolic syndrome in patients with CKD. Metabolic syndrome in CKD may be not only a prognostic factor but also an interventional target, possibly through ameliorating inflammation. Prospective and interventional studies are necessary to establish the pathophysiology.

Therapeutic Approaches Targeting Proteostasis in Kidney Disease and Fibrosis.

Pathological insults usually disturb the folding capacity of cellular proteins and lead to the accumulation of misfolded proteins in the endoplasmic reticulum (ER), which leads to so-called "ER stress". Increasing evidence indicates that ER stress acts as a trigger factor for the development and progression of many kidney diseases. The unfolded protein responses (UPRs), a set of molecular signals that resume proteostasis under ER stress, are thought to restore the adaptive process in chronic kidney disease (CKD) and renal fibrosis. Furthermore, the idea of targeting UPRs for CKD treatment has been well discussed in the past decade. This review summarizes the up-to-date literature regarding studies on the relationship between the UPRs, systemic fibrosis, and renal diseases. We also address the potential therapeutic possibilities of renal diseases based on the modulation of UPRs and ER proteostasis. Finally, we list some of the current UPR modulators and their therapeutic potentials.

Ochratoxin A-Induced Nephrotoxicity: Up-to-Date Evidence.

Ochratoxin A (OTA) is a mycotoxin widely found in various foods and feeds that have a deleterious effect on humans and animals. It has been shown that OTA causes multiorgan toxicity, and the kidney is the main target of OTA among them. This present article aims to review recent and latest intracellular molecular interactions and signaling pathways of OTA-induced nephrotoxicity. Pyroptosis, lipotoxicity, organic anionic membrane transporter, autophagy, the ubiquitin-proteasome system, and histone acetyltransferase have been involved in the renal toxicity caused by OTA. Meanwhile, the literature reviewed the alternative or method against OTA toxicity by reducing ROS production, oxidative stress, activating the Nrf2 pathway, through using nanoparticles, a natural flavonoid, and metal supplement. The present review discloses the molecular mechanism of OTA-induced nephrotoxicity, providing opinions and strategies against OTA toxicity.

Selective Activation of Endoplasmic Reticulum Stress by Reactive-Oxygen-Species-Mediated Ochratoxin A-Induced Apoptosis in Tubular Epithelial Cells.

Ochratoxin A (OTA), one of the major food-borne mycotoxins, impacts the health of humans and livestock by contaminating food and feed. However, the underlying mechanism of OTA nephrotoxicity remains unknown. This study demonstrated that OTA induced apoptosis through selective endoplasmic reticulum (ER) stress activation in human renal proximal tubular cells (HK-2). OTA increased ER-stress-related JNK and precursor caspase-4 cleavage apoptotic pathways. Further study revealed that OTA increased reactive oxygen species (ROS) levels, and N-acetyl cysteine (NAC) could reduce OTA-induced JNK-related apoptosis and ROS levels in HK-2 cells. Our results demonstrate that OTA induced ER stress-related apoptosis through an ROS-mediated pathway. This study provides new evidence to clarify the mechanism of OTA-induced nephrotoxicity.

Applicability of laboratory deficit-based frailty index in predominantly older patients with end-stage renal disease under chronic dialysis: A pilot test of its correlation with survival and self-reported instruments.

AIM: Laboratory deficit-based frailty index (LFI) exhibited outcome-prediction ability in the elderly, but not in those with end-stage renal disease (ESRD). We hypothesized that LFI results might have outcome correlation and correlate closely with other instruments in ESRD patients. METHODS: We prospectively enroled ESRD patients between 2014 and 2015 and administered self-report frailty instruments (Strawbridge questionnaire, Edmonton frail scale (EFS), Groningen frailty indicator (GFI), Tilburg frailty indicator, G8 questionnaire and FRAIL scale), and Cardiovascular Health Study (CHS) scale, with two types of LFI calculated. They were followed up until June 30, 2017. Correlations between the results of six instruments, CHS scale, and those of LFI were identified, followed by Kaplan-Meier survival analyses and logistic regression analyses to compare those with high and low LFI. RESULTS: The frailty prevalence was 33.3% (CHS), 78.8% Strawbridge questionnaire, 45.5% (EFS), 57.6% (GFI), 27.3% (Tilburg frailty indicator), 84.8% (G8) and 18.2% (FRAIL) among ESRD participants. LFI-1 results were significantly correlated with those of LFI-2 (P < 0.01), EFS (P = 0.04) and GFI (P < 0.01), while LFI-2 results were not. Those with CHS or GFI-identified frailty had significantly lower 1,25-(OH)2 -D levels than those without. After 32.3 ± 5.4 months, patients with high LFI-1 scores, but not LFI-2, had a significantly higher mortality than those with lower scores. GFI and EFS scores were also independently associated with LFI-1, while CHS scores exhibited borderline association only. CONCLUSION: Among a group of predominantly older ESRD patients, LFI differentiates patients with good and poor outcomes, supporting its applicability in these patients.

MicroRNA-125b in vascular diseases: An updated systematic review of pathogenetic implications and clinical applications.

Epigenetic changes, particularly non-coding RNAs, have been implicated extensively in the pathogenesis of vascular diseases. Specific miRNAs are involved in the differentiation, phenotypic switch, proliferation, apoptosis, cytokine production and matrix deposition of endothelial cells and/or vascular smooth muscle cells. MicroRNA-125b has been studied in depth for its role in carcinogenesis with a double-edged role; that is, it can act as an oncogene in some cancer types and as a tumour suppressor gene in others. However, cumulative evidence from the use of advanced miRNA profiling techniques and bioinformatics analysis suggests that miR-125b can be a potential mediator and useful marker of vascular diseases. Currently, the exact role of miR-125b in vascular diseases is not known. In this systematic review, we intend to provide an updated compilation of all the recent findings of miR-125b in vascular diseases, using a systematic approach of retrieving data from all available reports followed by data summarization. MiR-125b serves as a pathogenic player in multiple vascular pathologies involving endothelia and vascular smooth muscle cells and also serves as a diagnostic marker for vascular diseases. We further provide a computational biologic presentation of the complex network of miR-125b and its target genes within the scope of vascular diseases.

Circulating MicroRNA-125b Predicts the Presence and Progression of Uremic Vascular Calcification.

OBJECTIVE: Vascular calcification (VC) is a major cause of mortality in patients with end-stage renal diseases. Biomarkers to predict the progression of VC early are in urgent demand. APPROACH AND RESULTS: We identified circulating, cell-free microRNAs as potential biomarkers using in vitro VC models in which both rat and human aortic vascular smooth muscle cells were treated with high levels of phosphate to mimic uremic hyperphosphatemia. Using an Affymetrix microRNA array, we found that miR-125b and miR-382 expression levels declined significantly as biomineralization progressed, but this decline was only observed for miR-125b in the culture medium. A time-dependent decrease in aortic tissue and serum miR-125b levels was also found in both ex vivo and in vivo renal failure models. We examined the levels of circulating, cell-free miR-125b in sera from patients with end-stage renal diseases (n=88) and found an inverse association between the severity of VC and the circulating miR-125b level, irrespective of age or mineral-related hormones (odds ratio, 0.71; P=0.03). Furthermore, serum miR-125b levels on enrollment can predict VC progression years later (for high versus low, odds ratio, 0.14; P<0.01; for the highest versus lowest tertile and middle versus lowest tertile, odds ratio, 0.55 and 0.13; P=0.3 and <0.01, respectively). The uremic VC prediction efficacy using circulating miR-125b levels was also observed in an independent cohort (n=135). CONCLUSIONS: The results suggest that serum miR-125b levels are associated with VC severity and serve as a novel predictive marker for the risk of uremia-associated calcification progression.

Anti-cytomegalovirus IgG antibody titer is positively associated with advanced T cell differentiation and coronary artery disease in end-stage renal disease.

BACKGROUND: Accumulating evidence indicates that persistent human cytomegalovirus (HCMV) infection is associated with several health-related adverse outcomes including atherosclerosis and premature mortality in individuals with normal renal function. Patients with end-stage renal disease (ESRD) exhibit impaired immune function and thus may face higher risk of HCMV-related adverse outcomes. Whether the level of anti-HCMV immune response may be associated with the prognosis of hemodialysis patients is unknown. RESULTS: Among 412 of the immunity in ESRD study (iESRD study) participants, 408 were HCMV seropositive and were analyzed. Compared to 57 healthy individuals, ESRD patients had higher levels of anti-HCMV IgG. In a multivariate-adjusted logistic regression model, the log level of anti-HCMV IgG was independently associated with prevalent coronary artery disease (OR = 1.93, 95% CI = 1.2~ 3.2, p = 0.01) after adjusting for age, sex, hemoglobin, diabetes, calcium phosphate product and high sensitivity C-reactive protein. Levels of anti-HCMV IgG also positively correlated with both the percentage and absolute number of terminally differentiated CD8+ and CD4+ CD45RA+ CCR7- TEMRA cells, indicating that immunosenescence may participate in the development of coronary artery disease. CONCLUSION: This is the first study showing that the magnitude of anti-HCMV humoral immune response positively correlates with T cell immunosenescence and coronary artery disease in ESRD patients. The impact of persistent HCMV infection should be further investigated in this special patient population.

Diabetes mellitus, superoxide dismutase and peroxisome proliferator activated receptor gamma polymorphisms modify the outcome of end-stage renal disease patients of Han Chinese origin.

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

Latent transforming growth factor binding protein 4 regulates transforming growth factor beta receptor stability.

Mutations in the gene for the latent transforming growth factor beta binding protein 4 (LTBP4) cause autosomal recessive cutis laxa type 1C. To understand the molecular disease mechanisms of this disease, we investigated the impact of LTBP4 loss on transforming growth factor beta (TGFß) signaling. Despite elevated extracellular TGFß activity, downstream signaling molecules of the TGFß pathway, including pSMAD2 and pERK, were down-regulated in LTBP4 mutant human dermal fibroblasts. In addition, TGFß receptors 1 and 2 (TGFBR1 and TGFBR2) were reduced at the protein but not at the ribonucleic acid level. Treatment with exogenous TGFß1 led to an initially rapid increase in SMAD2 phosphorylation followed by a sustained depression of phosphorylation and receptor abundance. In mutant cells TGFBR1 was co-localized with lysosomes. Treatment with a TGFBR1 kinase inhibitor, endocytosis inhibitors or a lysosome inhibitor, normalized the levels of TGFBR1 and TGFBR2. Co-immunoprecipitation demonstrated a molecular interaction between LTBP4 and TGFBR2. Knockdown of LTBP4 reduced TGFß receptor abundance and signaling in normal cells and supplementation of recombinant LTBP4 enhanced these measures in mutant cells. In a mouse model of Ltbp4 deficiency, reduced TGFß signaling and receptor levels were normalized upon TGFBR1 kinase inhibitor treatment. Our results show that LTBP4 interacts with TGFBR2 and stabilizes TGFß receptors by preventing their endocytosis and lysosomal degradation in a ligand-dependent and receptor kinase activity-dependent manner. These findings identify LTBP4 as a key molecule required for the stability of the TGFß receptor complex, and a new mechanism by which the extracellular matrix regulates cytokine receptor signaling.