CKAP4 contributes to the progression of vascular calcification (VC) in chronic kidney disease (CKD) by modulating YAP phosphorylation and MMP2 expression.

Chronic kidney disease (CKD) is an growing public health concern associated with high mortality rates. The occurrences of vascular calcification (VC) increase concordantly with the progression of CKD.With CKD, hyperphosphatemia promotes intermediate VC, a process that is further facilitated by vascular smooth muscle cells (VSMCs) initiating osteogenic transdifferentiation. The purpose of this study was to determine the involvement of CKAP4 in VC progression. Clinical investigations demonstrate that elevated blood CKAP4 and matrix metallopeptidase 2 (MMP2) levels are related with CKD in individuals. As an in vitro model, mouse VSMCs were extracted and treated with high levels of phosphates (2.5 mmol/L Pi). We also created an in vivo mice model of CKD induced by 5/6 nephrophrectomies and a high-protein diet (High Pi diet). The expression of CKAP4 and MMP2 in both in vitro and in vivo models was significantly higher in VSMCs and calcified aorta in both models. Additionally, in vitro tests indicated that CKAP4 modulates YAP phosphorylation. Simultaneous silencing of CKAP4 and calcium content assay revealed a significant reduction in the VSMCs and calcium content of the aorta. Alizarin red staining and calcium content assay reveled that silencing of CKAP4 reduced the VSMCs and aortic calcification, accompanied with reduced expression of YAP and MMP2. Overall, our study demonstrates for the first time that CKAP4 contributes to VC in CKD by modulating YAP phosphorylation and MMP2 expression.

High Mobility Group Box 1 Promotes Aortic Calcification in Chronic Kidney Disease via the Wnt/ß-Catenin Pathway.

Vascular calcification (VC) is common in chronic kidney disease (CKD), where cardiovascular mortality remains the leading cause of death. Here, we examined the role of high-mobility group box1 (HMGB1), a nuclear DNA-binding protein involved in inflammation, in aortic calcification and renal dysfunction induced by high phosphate in a mouse model of CKD induced by 5/6 nephrectomy. HMGB1 and kidney function markers were measured by ELISA in the serum of CKD patients and in CKD mice. Sections of the aortas of mice were analyzed by immunofluorescence and Alizarin red staining, and protein lysates were generated to analyze the expression of related proteins in response to silencing of HMGB1 or ß-catenin by western blotting. Our results showed that serum HMGB1 levels were significantly higher in CKD patients than in healthy controls and related to disease stage. High phosphate promoted the translocation of HMGB1 from the nucleus to the cytosol and aortic calcification in CKD mice in vivo, whereas HMGB1 knockdown ameliorated part of renal and vascular function. ß-catenin silencing reversed high phosphate-induced calcification and restored renal marker levels. Taken together, our results suggest that HMGB1 is involved in VC associated with CKD via a mechanism involving the ß-catenin.

Risk factors for heart valve calcification in chronic kidney disease.

Cardiovascular disease (CVD) is a common cause of death in patients with chronic kidney disease (CKD). Aortic and mitral valve calcification (AVC and MVC, respectively) are critical indicators of CVD and all-cause mortality in CKD patients.We conducted a single center retrospective study of Chinese inpatients with CKD to identify risk factors associated with valve calcification (VC).Of 288 enrolled CKD patients, 22.9% had VC, all of which exhibited AVC, while 21.2% exhibited MVC. The VC group were significantly older than the non-VC group (70.42 ±â€Š11.83 vs 56.47 ±â€Š15.00, P < .001), and contained more patients with history of coronary artery disease (12.1% vs 4.5%, P = .025) or stroke (18.2% vs 5.4%, P < .001). Subjective global assessment scoring indicated that more VC patients were mid/severely malnourished. Levels of prealbumin, cholesterol (Ch), triglycerides, low-density lipoprotein (LDL), apolipoprotein E, ejection fraction, and fraction shortening were significantly lower, and blood C reactive protein, IL-6, left ventricular internal end diastole diameter measured in end diastole, and interventricular septum thickness (IVST) levels were significantly higher in the VC group. Bone metabolism did not differ significantly between the 2 groups. Multivariable logistic regression analysis indicated that age, blood Ch, and LDL levels were significantly associated with VC.Advanced age, increased IVST, hypocholesterolemia, and hyper-LDL cholesterolemia were key risk factors for VC in Han patients with CKD.

Preliminary Evaluation of Virtual Touch Tissue Imaging Quantification for Differential Diagnosis of Metastatic and Nonmetastatic Cervical Lymph Nodes.

OBJECTIVES: Virtual Touch tissue imaging quantification (VTIQ; Siemens Medical Solutions, Mountain View, CA) is useful for assessing tissue hardness. This study aimed to investigate the value of VTIQ in differential diagnosis of cervical lymph nodes. METHODS: We retrospectively analyzed conventional sonograms and VTIQ images of 85 pathologically confirmed patients with superficial lymph node lesions. Conventional sonography was first performed, with 2-dimensional images described. Then VTIQ shear wave velocity (SWV) values of superficial lymph nodes were measured. With pathologic diagnosis as the reference standard, a receiver operating characteristic curve was generated to evaluate VTIQ efficacy in differential diagnosis of metastatic and nonmetastatic cervical lymph nodes. RESULTS: Of the 85 nodes, 44 and 41 were metastatic and nonmetastatic, respectively. The latter group included 24 and 17 hematologic/lymphatic system disease and reactive hyperplastic nodes, respectively. Shear wave velocity values of metastatic nodes were significantly higher than those of their nonmetastatic counterparts (P < .001). With an area under the curve (AUC) of 0.953 and SWV cutoff of 3.27 m/s, accuracy, sensitivity, and specificity were 89.4%, 88.6%, and 90.2%, respectively, for distinguishing metastatic and nonmetastatic nodes. An AUC of 0.943 and SWV cutoff of 3.23 m/s yielded accuracy, sensitivity, and specificity of 88.2%, 88.6%, and 87.5% for differentiating metastatic from hematologic/lymphatic system disease nodes. Finally, an AUC of 0.968 and SWV cutoff of 3.27 m/s yielded accuracy, sensitivity, and specificity of 90.2%, 88.6%, and 94.1% for differentiating metastatic from reactive hyperplastic nodes. CONCLUSIONS: Virtual Touch tissue imaging quantification is efficient in differential diagnosis of metastatic and nonmetastatic cervical lymph nodes.

Transcatheter Closure of Intracristal Ventricular Septal Defect With Mild Aortic Cusp Prolapse Using Zero Eccentricity Ventricular Septal Defect Occluder.

BACKGROUND: Transcatheter closure is a well-established therapy for patients with perimembranous ventricular septal defects (VSDs), but with limited experience in intracristal VSDs (IVSDs) with aortic cusp prolapse (ACP). METHODS AND RESULTS: From 2012 to 2014, we reviewed 38 patients with IVSDs complicated with mild ACP who underwent device closure, and, in light of the findings, assessed the effect of transcatheter intervention on preoperative mild ACP. The zero eccentric VSD occluder was chosen for closure (Shanghai Shape Memory Alloy Ltd, Shanghai, China). The mean defect was 4.8±1.6 mm (range, 2-8) as measured by transthoracic echocardiography and the mean device size was 10.1±2.1 mm (range, 4-14). Placement of the device was successful in 35 patients (92.1%). In the remaining 3 patients (7.9%), major complications occurred and they were converted to surgical intervention: severe aortic regurgitation (AR) in 2 patients and occluder dislodgement in 1 patient. During the follow-up (median 14.2 months; range, 3-24), no deaths, residual shunt, late-onset AR, heart block, or device failure occurred. CONCLUSIONS: The mid-term prognostic results of high success rate and low complications rate in this study are inspiring. Transcatheter closure of IVSD with mild ACP can be performed safely and effectively as an alternative to surgery in selected patients.

Vascular calcification in chronic kidney disease is induced by bone morphogenetic protein-2 via a mechanism involving the Wnt/ß-catenin pathway.

BACKGROUND: Vascular calcification (VC), in which vascular smooth muscle cells (VSMCs) undergo a phenotypic transformation into osteoblast-like cells, is one of the emergent risk factors for the accelerated atherosclerosis process characteristic of chronic kidney disease (CKD). Phosphate is an important regulator of VC. METHODS: The expression of different smooth muscle cell or osteogenesis markers in response to high concentrations of phosphate or exogenous bone morphogenetic protein 2 (BMP-2) was examined by qRT-PCR and western blotting in rat VSMCs. Osteocalcin secretion was measured by radioimmunoassay. Differentiation and calcification of VSMCs were examined by alkaline phosphatase (ALP) activity assay and Alizarin staining. Short hairpin RNA-mediated silencing of ß-catenin was performed to examine the involvement of Wnt/ß-catenin signaling in VSMC calcification and osteoblastic differentiation induced by high phosphate or BMP-2. Apoptosis was determined by TUNEL assay and immunofluorescence imaging. RESULTS: BMP-2 serum levels were significantly higher in CKD patients than in controls. High phosphate concentrations and BMP-2 induced VSMC apoptosis and upregulated the expression of ß-catenin, Msx2, Runx2 and the phosphate cotransporter Pit1, whereas a BMP-2 neutralization antibody reversed these effects. Knockdown of ß-catenin abolished the effect of high phosphate and BMP-2 on VSMC apoptosis and calcification. CONCLUSIONS: BMP-2 plays a crucial role in calcium deposition in VSMCs and VC in CKD patients via a mechanism involving the Wnt/ß-catenin pathway.

Effects of in-center nocturnal versus conventional hemodialysis on endothelial dysfunction.

Cardiovascular disease is the leading cause of morbidity and mortality in patients with end-stage renal disease who undergo hemodialysis and endothelial dysfunction is an early key step in the development of atherosclerosis. The aim of this study was to investigate the effect of thrice-weekly in-center nocturnal hemodialysis (INHD, 8 h per session and three sessions per week) and conventional hemodialysis (CHD, 4 h per session and three sessions per week) on endothelial dysfunction in patients with end-stage renal disease. 32 INHD and 58 matched CHD patients were enrolled, baseline and 12-month measures of blood pressure (BP), serum calcium and phosphorus, serum intact PTH (iPTH) and brachial artery flow-mediated dilation (FMD) were collected and analyzed. Baseline characteristics were similar between groups except that serum phosphorus and calcium × phosphorus were higher in the INHD group. At the 12-month follow-up, there was a significant increase in FMD (6.0 ± 1.5% to 7.1 ± 1.8%, P < 0.01) in INHD patients. Multivariate analysis showed that FMD was inversely correlated with systolic BP (SBP) (ß = -0.485, P < 0.01), diastolic BP (DBP) (ß = -0.428, P < 0.01), iPTH (ß = -0.405, P < 0.01) and serum phosphorus level (ß = -0.375, P < 0.01). There was no significant change in FMD in the CHD group. Compared with CHD, INHD improves endothelial function, and control of serum phosphorus is associated with the improvement of endothelial function.

Effects of thrice-weekly in-center nocturnal vs. conventional hemodialysis on integrated backscatter of myocardial tissue.

Ultrasonic tissue characterization with integrated backscatter (IBS) offers a promising method for the noninvasive assessment of myocardial fibrosis and contractile performance. The aim of this study was to investigate the effect of thrice-weekly in-center nocturnal hemodialysis (INHD) and conventional hemodialysis (CHD) on myocardial fibrosis and left ventricular function in end-stage renal disease patients. Thirty-two INHD and 58 matched CHD patients were enrolled; baseline and 12-month measures of blood pressure (BP), serum calcium and phosphorus, echocardiographic left ventricular mass index (LVMI) and left ventricular function, the myocardial calibrated IBS (C-IBS), and systodiastolic cyclical variations in IBS (CV-IBS) were collected. The baseline characteristics were similar between groups, except that serum phosphorus and calcium × phosphorus were higher in the INHD group. At 12-month follow-up, there was a significant decrease in the mean C-IBS (-20.2 ± 3.7 to -28.1 ± 4.0 dB, P<0.01) and a significant increase in CV-IBS (5.0 ± 1.5 to 7.1 ± 1.6 dB, P<0.01) in INHD patients. Multivariate analysis showed that the mean C-IBS was positively related to SBP, DBP, LVMI, serum phosphorus, and left atrial volume index and inversely related to midwall fractional shortening, transmitral E/A ratio, and E(m) . The mean CV-IBS was positively correlated with left ventricular midwall fractional shortening, E/A ratio, E(m) and inversely correlated with SBP, DBP, LVMI, serum phosphorus, E/E(m) , and left atrial volume index. There was no significant change in the mean C-IBS, mean CV-IBS, and LVMI in the CHD group. Compared with CHD, INHD improves myocardial fibrosis and left ventricular function, and control of serum phosphorus is associated with the improvement of myocardial fibrosis. Improvement of myocardial fibrosis contributes to the reduction of left ventricle hypertrophy.

Ultrasonic characterization (integrated backscatter) of myocardial tissue in patients with autosomal dominant polycystic kidney disease.

OBJECTIVE: To study changes in myocardial wall texture in autosomal dominant polycystic kidney disease (ADPKD) patients by ultrasonic integrated backscatter (IBS) analysis. METHODS: Hypertensive and normotensive ADPKD patients, essential hypertension (EHP) patients and healthy volunteers were included in the study. All the subjects underwent conventional echocardiography and ultrasonic IBS of the myocardial wall. Both the calibrated IBS (C-IBS) and the systolic-diastolic cyclical variations in IBS (CV-IBS) were evaluated. RESULTS: Mean C-IBS in hypertensive ADPKD patients was significantly higher than that in EHP patients and normotensive ADPKD patients. Mean C-IBS in normotensive ADPKD patients was significantly higher than that in healthy subjects. Mean CV-IBS in hypertensive ADPKD patients was significantly lower than that in EHP patients and normotensive ADPKD patients. Mean CV-IBS in normotensive ADPKD patients was significantly lower than that in healthy subjects. Multivariate analysis showed that the mean C-IBS was positively related to the systolic and diastolic blood pressure (SBP, DBP) and left ventricular mass index (LVMI); mean CV-IBS was positively correlated with contractile performance and transmitral E/A ratio and inversely correlated with SBP, DBP and LVMI. CONCLUSIONS: ADPKD patients experienced myocardial interstitial collagen deposition and impairment to myocardial contractile performance, which were both aggravated by hypertension. IBS seems to be a useful tool for the assessment of myocardial changes in ADPKD patients.

Carotid vascular remodelling in patients with autosomal dominant polycystic kidney disease.

AIM: To study carotid vascular wall remodelling in patients with autosomal dominant polycystic kidney disease (ADPKD) using integrated backscatter signal (IBS) analysis. METHODS: Included in the study were: 60 ADPKD patients with preserved renal function, including 32 patient with hypertension and 28 with normotension; 25 patients with essential hypertension; and 30 healthy volunteers. Carotid intima-media thickness (IMT) was measured by 2-D conventional ultrasonography. Acoustic tissue characterization of the carotid wall was assessed by IBS analysis, and the percentage of regions considered as fibromatosis was calculated in all groups. RESULTS: Carotid IMT in hypertensive ADPKD patients (0.8 +/- 0.05 vs 0.68 +/- 0.02 mm, P < 0.01 and 0.8 +/- 0.05 vs 0.56 +/- 0.04 mm, P < 0.01 respectively) and patients with essential hypertension (0.79 +/- 0.03 vs 0.68 +/- 0.02 mm, P < 0.01 and 0.79 +/- 0.03 vs 0.56 +/- 0.0 4 mm, P < 0.01 respectively) was significantly greater than that of normotensive patients and healthy subjects. Carotid IMT in normotensive ADPKD patients was also significantly greater than that in healthy subjects (0.68 +/- 0.02 vs 0.56 +/- 0.04 mm, P < 0.01). Calibrated IBS (C-IBS) in hypertensive ADPKD patients was significantly greater than that in patients with essential hypertension and normotensive ADPKD patients (-21.2 +/- 1.51 dB vs -23.1 +/- 1.61 dB, P < 0.05; -21.2 +/- 1.51 dB vs -24.5 +/- 1.34 dB, P < 0.01). C-IBS in normotensive ADPKD patients was significantly greater than that in healthy subjects (-24.5 +/- 1.34 dB vs -26.2 +/- 1.69 dB, P < 0.01). The percentage of regions that could be considered as fibromatosis in hypertensive ADPKD patients was significantly greater than that in patients with essential hypertension and normotensive ADPKD patients (30.0% vs 22.4%, P < 0.05; 30.0% vs 17.9%, P < 0.01). The percentage of regions that could be considered as fibromatosis in normotensive ADPKD patients was significantly greater than that in healthy subjects (15.2% vs 10.3%, P < 0.01). CONCLUSION: Carotid remodelling occurs in the early stage of ADPKD and can be aggravated by hypertension. Fibrosis contributes to the vascular rearrangement.