Vascular Calcification In End-stage Renal Disease Research Articles

Metabolomics of clinical samples reveal the treatment mechanism of lanthanum hydroxide on vascular calcification in chronic kidney disease.

Previous studies showed that lanthanum hydroxide (LH) has a therapeutic effect on chronic kidney disease (CKD) and vascular calcification, which suggests that it might have clinical value. However, the target and mechanism of action of LH are unclear. Metabolomics of clinical samples can be used to predict the mechanism of drug action. In this study, metabolomic profiles in patients with end-stage renal disease (ESRD) were used to screen related signaling pathways, and we verified the influence of LH on the ROS-PI3K-AKT-mTOR-HIF-1α signaling pathway by western blotting and quantitative real-time RT-qPCR in vivo and in vitro. We found that ROS and SLC16A10 genes were activated in patients with ESRD. The SLC16A10 gene is associated with six significant metabolites (L-cysteine, L-cystine, L-isoleucine, L-arginine, L-aspartic acid, and L-phenylalanine) and the PI3K-AKT signaling pathway. The results showed that LH inhibits the ESRD process and its cardiovascular complications by inhibiting the ROS-PI3K-AKT-mTOR-HIF-1α signaling pathway. Collectively, LH may be a candidate phosphorus binder for the treatment of vascular calcification in ESRD.

POS-412 INHIBITING POST-TRANSLATIONAL CORE FUCOSYLATION PREVENTS VASCULARCALCIFICATION IN THE MODEL OF UREMIA

Vascular calcification (VC) is an independent risk factor for cardiovascular disease and mortality in uremia. Post-translational core fucosylation is implicated in a number of pathological processes. We investigated the role of core fucosylation and key TGF-β1 pathway receptors in calcified arteries in vivo. This study provides evidence to suggest core fucosylation plays a major role in the process of VC and appropriate blockade of core fucosylation may represent a potential therapeutic strategy for treating VC in end-stage renal disease.

EVALUATION OF MINERAL BONE DISEASE IN PATIENTS WITH ACUTE KIDNEY INJURY

IntroductionPatients with end‐stage renal disease (ESRD) develop various kinds of abnormalities in bone and mineral metabolism, widely known mineral bone disease (MBD). The MBD is one of the main cause of vascular calcification (VC) and mortality in this patients. This abnormalities are a consequence of the glomerular filtration rate declined and retention of a large number of compounds which under normal conditions are excreted by healthy kidneys. In the last years, Fibroblast Growth Factor 23 (FGF‐23) a phosphaturic hormone, Sclerostin (SOST) (a protein that inhibit bone formation ) and inflammation markers have been described as a important axis of the physiopathology of MBD and VC in ESRD. The early detection of MBD can reduced the VC and its complications. However, patients with acute kidney injury (AKI) which abruptly lose kidney function; have not been yet investigated to MBD. Thus, the objective of this study was to investigate markers of MBD in AKI patients.Material and MethodsWe included 77 severe patients without AKI and 83 severe AKI patients (ageing‐ 77 (60–84) all admitted to the Intensive Care Unit. Patients with AKI were characterized by AKIN criteria that used a 0.3 mg/dL increase in serum creatinine within seven days of admission in the hospital. Serum markers of MBD and inflammation investigated were: FGF‐23, SOST, Interleukin‐6 (IL‐6), Tumor Necrosis Factor Alpha (TNF‐α) and Interleukin‐10 (IL‐10) (by enzyme‐linked immunosorbent assay (ELISA). Results are expressed as median. Mann‐Whitney test was used to analyze the groups.ResultsAll AKI patients presented serum creatinine >3.1 mg/dL (reference value 0.8 – 1.3 mg/dL). We observed increased serum levels of SOST (pg/mL) [AKI 1.74 (1.74–46.40) vs. No‐AKI 1.74 (1.74–1.74); p=0.009)], IL‐6 (pg/mL) [AKI 21 (11–32) vs. No‐AKI 12 (7–19); p<0.001], TNF‐α (pg/mL) [AKI 8.2 (6.7–10.5) vs. No‐AKI 7.0 (6.2–7.9); p<0.001], IL‐10 (pg/mL) [AKI 1.1 (0.8–1.6) vs. No‐AKI 0.8 (0.7–1.0); p<0.001]. We did not observe difference in FGF‐23 (pg/mL) [AKI 48.3 (1.5–141.3) vs. No‐AKI 48.0 (1.5–188.5); p=0.35].ConclusionAKI patients presented higher inflammation state characterized by increased serum levels of IL‐6, TNF‐α and IL‐10. Additionally, as SOST was higher in AKI patients, is possible used it as a marker of early bone disease in this population. In summary, this is the first study that detected high levels of SOST in AKI patients.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Bone mineral density of extremities is associated with coronary calcification and biopsy-verified vascular calcification in living-donor renal transplant recipients.

Chronic kidney disease (CKD) mineral and bone disorders (CKD-MBD) may lead to low bone mineral density (BMD) and vascular calcification (VC), but links to the latter are unclear. Here we investigated associations between BMD, coronary artery calcium (CAC) scores, and histological signs of VC in end-stage renal disease (ESRD) patients undergoing living-donor kidney transplantation (LD-Rtx). In 66 ESRD patients (median age 45years, 68% males), BMD (by dual-energy X-ray absorptiometry, DXA), CAC score (by computed tomography, CT; n=54), and degree of VC score (graded by histological examination of epigastric artery specimens collected at LD-Rtx; n=55) were assessed at the time of LD-Rtx. Of the patients, 26% had osteopenia and 7% had osteoporosis. Of those undergoing artery biopsy, 16% had extensive VC, and of those undergoing CT 28% had high CAC score (>100 Agatston units). CAC scores correlated with BMD of legs and pelvis. BMDs of leg and pelvic sub-regions were significantly lower in patients with extensive VC. In multivariate regression analysis adjusted for age and gender, lower BMD of leg sub-region was associated with CAC score >100 AUs and extensive VC, and patients with extensive VC had significantly higher CAC score. Both high CAC and extensive VC were independently predicted by low BMD of legs. Low BMD has the potential to identify ESRD patients at risk of vascular calcification.

Resveratrol Ameliorated Vascular Calcification by Regulating Sirt-1 and Nrf2

Pathologic vascular calcification is a significant reason for mortality and morbidity in patients who suffer from end-stage renal disease (ESRD). Resveratrol, a scavenger for many free radicals, is a crucial compound for biomedicine. However, the role and mechanism of resveratrol in vascular calcification is still unknown. In this study, to mimic vascular calcification in ESRD, we used β-glyceophosphate to stimulate the rat vascular smooth muscle cells (RASMCs). We investigate the therapeutic role of resveratrol pretreatment in vascular calcification. In the current in vitro study, we observe the effects of resveratrol on improving intracellular calcium deposition and protecting against mitochondria dysfunction in calcific RASMCs. Resveratrol decreased the mRNA level of fibroblast growth factor-23, then increased the mRNA level of klotho and the nuclear transcription factor NF-E2–related factor 2 (nuclear factor-erythroid 2–related factor 2 [Nrf2]) in RASMCs after calcification. Further, resveratrol activated the expression of sirtuin-1 and Nrf2, and inhibited the expression of osteopontin, runt-related transcription factor 2, and heme oxygenase-1. Our study shows that resveratrol could ameliorate oxidative injury of RASMCs by preventing vascular calcification–induced calcium deposition and mitochondria dysfunction through involving sirtuin-1 and Nrf2. These results might indicate a novel role for resveratrol in resistance to oxidative stress for ESRD patients suffering from vascular calcification.

Inhibiting post-translational core fucosylation prevents vascular calcification in the model of uremia

Vascular calcification (VC) is an independent risk factor for cardiovascular disease and mortality in uremia. Post-translational core fucosylation is implicated in a number of pathological processes. First, we investigated the role of core fucosylation and key TGF-β1 pathway receptors in calcified arteries in vivo. To determine whether blocking core fucosylation effectively inhibited VC and TGF-β/Smad signaling pathway, we established an in vitro model of phosphate-induced calcification in rat vascular smooth muscle cells (VSMCs) to assess the role of core fucosylation in VC. Core fucose could be detected at markedly higher levels in calcified VSMCs than control cells. Fut8 (α-1,6 fucosyltransferase), the only enzyme responsible for core fucosylation in humans, was significantly upregulated by high phosphate. Exposed to high phosphate media and blocking core fucosylation in VSMCs by knocking down Fut8 using a siRNA markedly reduced calcium and phosphorus deposition and Cbfα1 expression (osteoblast-specific transcription factor), and increased α-Sma expression (smooth muscle cell marker). Fut8 siRNA significantly inhibited TGF-β/Smad2/3 signaling activation in VSMCs cultured in high phosphate media. In conclusion, this study provides evidence to suggest core fucosylation plays a major role in the process of VC and appropriate blockade of core fucosylation may represent a potential therapeutic strategy for treating VC in end-stage renal disease.

Hydrogen peroxide prevents vascular calcification induced ROS production by regulating Nrf-2 pathway

Background: Although vascular calcification in end-stage renal disease (ESRD) represents a ubiquitous human health problem, effective therapies with limited side effects are still lacking, and the precise mechanisms are not fully understood. The Nrf-2/ARE pathway is a pivotal to regulate anti-oxidative responses in vascular calcification upon ESRD. Although Nrf-2 plays a crucial role in atherosclerosis, pulmonary fibrosis, and brain ischemia, the effect of Nrf-2 and oxidative stress on vascular calcification in ESRD patients is still unclear. The aim of this research was to study the protective role of hydrogen peroxide in vascular calcification and the mechanism of Nrf-2 and oxidative stress on vascular calcification.Materials and methods: Here we used the rat vascular smooth muscle cell model of β-glycerophosphate-induced calcification resembling vascular calcification in ESRD to investigate the therapeutic effect of 0.01 mM hydrogen peroxide on vascular calcification and further explores the possible underlying mechanisms.Results: Our current report shows the in vitro role of 0.01 mM hydrogen peroxide in protecting against intracellular ROS accumulation upon vascular calcification. Both hydrogen peroxide and sulforaphane pretreatment reduced ROS production, increased the expression of Nrf-2, and decreased the expression of Runx2 following calcification.Conclusion: Our study demonstrates that 0.01 mM hydrogen peroxide can effectively protect rat aortic vascular smooth muscle cells against oxidative stress by preventing vascular calcification induced ROS production through Nrf-2 pathway. These data might define an antioxidant role of hydrogen peroxide in vascular calcification upon ESRD.

Low serum intact parathyroid hormone level is an independent risk factor for overall mortality and major adverse cardiac and cerebrovascular events in incident dialysis patients.

Abnormal bone dynamics is a major risk factor for cardiovascular disease in patients with chronic kidney disease. The level of serum intact parathyroid hormone (iPTH) is widely used as a bone dynamic marker. We investigated the effect of the mean level of serum iPTH on overall mortality and cardiovascular outcomes in incident dialysis patients. Chronic kidney disease-mineral bone disorder (CKD-MBD) is a major risk factor for cardiovascular disease (CVD) in patients with end-stage renal disease (ESRD). CKD-MBD is classified as low- or high-turnover bone disease according to the bone dynamics; both are related to vascular calcification in ESRD. To evaluate the prognostic value of abnormal serum parathyroid hormone (PTH) levels on ESRD patients, we investigated the effects of time-averaged serum intact PTH (TA-iPTH) levels on overall mortality and major adverse cardiac and cerebrovascular events (MACCEs) in incident dialysis patients. Four hundred thirteen patients who started dialysis between January 2009 and September 2013 at Yonsei University Health System were enrolled. The patients were divided into three groups according to TA-iPTH levels during the 12months after the initiation of dialysis: group 1, <65pg/ml; group 2, 65-300pg/ml; and group 3, >300pg/ml. Cox regression analyses were performed to determine the prognostic value of TA-iPTH for overall mortality and MACCEs. The mean age of the patients was 57 ± 15years, and 222 patients (54%) were men. During the median follow-up of 40.8 ± 29.3months, 49 patients (12%) died, and MACCEs occurred in 55 patients (13%). The multivariate Cox regression analyses demonstrated that a low TA-iPTH level was an independent risk factor for both overall mortality (group 2 as reference; group 1: hazard ratio (HR) = 2.06, 95% confidence interval (CI) = 1.11-3.83, P = 0.023) and MACCEs (HR = 1.82, 95% CI = 1.04-3.20, P = 0.036) in incident dialysis patients after adjustment for confounding factors. Low serum TA-iPTH is a useful clinical marker of both overall mortality and MACCEs in patients undergoing incident dialysis, mediated by vascular calcification.

Vascular Calcification and ESRD

End-stage renal disease (ESRD) is associated with both accelerated cardiovascular disease and alterations in vitamin D and mineral metabolism. Calcification of both coronary and extra-cardiac vessels is common in ESRD. Several studies suggest that vascular calcification is associated with coronary atherosclerosis, vascular wall stiffness, left ventricular hypertrophy, and subsequent increased mortality, but it is not yet clear if vascular calcification is a direct cause of these changes or merely a marker of disease. Reviewed here is the current state of research on the biology and the significance of vascular calcification in ESRD, the role of vitamin D therapy in its development, and options for management.

The emerging role of phosphate in vascular calcification

Vascular calcification is recognized as a major contributor to cardiovascular disease (CVD) in end stage renal disease (ESRD) patients. Susceptibility to vascular calcification is genetically determined and actively regulated by diverse inducers and inhibitors. One of these inducers, hyperphosphatemia, promotes vascular calcification and is a nontraditional risk factor for CVD mortality in ESRD patients. Vascular smooth muscle cells (SMCs) respond to elevated phosphate levels by undergoing an osteochondrogenic phenotype change and mineralizing their extracellular matrix through a mechanism requiring sodium-dependent phosphate cotransporters. Disease states and cytokines can increase expression of sodium-dependent phosphate cotransporters in SMCs, thereby increasing susceptibility to calcification even at phosphate concentrations that are in the normal range.

Ethiopathogenesis, Diagnosis and Prevention of Vascular Calcification in End Stage Renal Disease

Extensive atherosclerosis and heavy vascular and valvular calcifications are common complications of end stage renal disease (ESRD) and are very likely related to the high incidence of cardiovascular disease in these patients. The greatly increased incidence of cardiovascular disease is only partly explained by traditional risk factors for atherosclerosis. In ESRD, vascular calcification occurs both in the vascular intima layer and in the tunica media. Intimal calcification is disseminated and is characteristically associated with damaged and abnormally functioning endothelium, and macrophage and vascular smooth muscle cell (VSMC) infiltration typical of atherosclerosis. On the contrary, medial calcification occurs in patchy distribution and the most frequent cell types found in its vicinity are the VSMC and macrophage. The uremic state is associated with numerous metabolic abnormalities and endocrine disturbances primarily involving calcium and phosphorus metabolism. Furthermore, chronic kidney disease and dialysis are considered states of active and strong inflammatory response. These dysfunctions occur early in the course of renal failure and likely contribute to the development and progression of vascular calcification and atherosclerosis. For many years, vascular calcification was considered solely the result of a passive deposition of hydroxyapatite crystals in the arterial wall due to elevated calcium-phosphate ion product. However, a large body of evidence has now shown that this is a highly regulated process governed by factors that closely resemble calcium deposition in bone tissue. In fact, vascular calcification requires changes in the phenotype of VSMC and the expression of several proteins normally involved in bone metabolism. This review is centered on the etiopathogenesis of vascular calcification in ESRD, its detection with modern imaging modalities and the therapeutic approaches currently available to slow its progression.

Vascular calcification in end stage renal disease

Vascular calcification is thought to play a crucial role in the excessive cardiovascular mortality and morbidity in patients with end-stage renal disease (ESRD). Recent evidence suggests that uremic vascular calcification is an active cell-mediated process resembling osteogenesis in bone, rather than passive precipitation of calcium and phosphorus in the setting of deranged mineral metabolism. To date, several bone-associated proteins (osteopontin, bone sialoprotein, alkaline phosphatase, type I collagen) have been demonstrated in histological sections of vessels obtained from patients with ESRD or calcific uremic arteriolopathy. In in vitro experiments, addition of uremic serum upregulates osteopontin expression by cultured vascular smooth muscle cells. We are only beginning to understand the process by which vascular smooth muscle cells transform into osteoblast-like cells, although phosphorus may play a key role. Additional factors mediating or modulating development of vascular calcification in ESRD remain to be identified. Further understanding of the pathophysiology of uremic vascular calcification is needed to design effective therapeutic strategies to intervene with this devastating condition in ESRD population.