Calcification In Chronic Kidney Disease Patients Research Articles

Eduardo Slatopolsky: A Pioneer in the Field of Mineral and Bone Disorders in Kidney Disease.

Eduardo Alberto Slatopolsky (1934-2024), Washington University Joseph Friedman Professor Emeritus of Medicine, a prominent physician-scientist, was born in Buenos Aires, Argentina. The impact of his research in the area of mineral and bone disorders in kidney disease has been profound for over 50 years starting in the 1960s. He was a global authority on secondary hyperparathyroidism. He was instrumental in illustrating the role of hyperphosphatemia in chronic kidney disease (CKD) and in developing the first reliable parathyroid hormone (PTH) assay. His research led to the utilization of calcium salts as phosphate binders replacing the toxic aluminum salts. Moreover, he illustrated the role of vascular calcifications in CKD patients, paving the way for non-calcium phosphate binders. He proposed the use of calcitriol and later vitamin D analogs in the management of secondary hyperparathyroidism, which is the current standard of care. He demonstrated the decreased expression of the calcium-sensing receptor in parathyroid tissue in CKD patients. Dr. Slatopolsky's global legacy will last for generations.

Indoxyl Sulfate-Induced Macrophage Toxicity and Therapeutic Strategies in Uremic Atherosclerosis.

Cardiovascular disease (CVD) frequently occurs in patients with chronic kidney disease (CKD), particularly those undergoing dialysis. The mechanisms behind this may be related to traditional risk factors and CKD-specific factors that accelerate atherosclerosis and vascular calcification in CKD patients. The accumulation of uremic toxins is a significant factor in CKD-related systemic disorders. Basic research suggests that indoxyl sulfate (IS), a small protein-bound uremic toxin, is associated with macrophage dysfunctions, including increased oxidative stress, exacerbation of chronic inflammation, and abnormalities in lipid metabolism. Strategies to mitigate the toxicity of IS include optimizing gut microbiota, intervening against the abnormality of intracellular signal transduction, and using blood purification therapy with higher efficiency. Further research is needed to examine whether lowering protein-bound uremic toxins through intervention leads to a reduction in CVD in patients with CKD.

Calcium isotopes as a biomarker for vascular calcification in chronic kidney disease.

Calcium balance is abnormal in adults with chronic kidney disease (CKD) and is associated with the development of vascular calcification. It is currently not routine to screen for vascular calcification in CKD patients. In this cross-sectional study, we investigate whether the ratio of naturally occurring calcium (Ca) isotopes, 44Ca and 42Ca, in serum could be used as a noninvasive marker of vascular calcification in CKD. We recruited 78 participants from a tertiary hospital renal center: 28 controls, 9 subjects with mild-moderate CKD, 22 undertaking dialysis and 19 who received a kidney transplant. For each participant, systolic blood pressure, ankle brachial index, pulse wave velocity, and estimated glomerular filtration rate were measured, along with serum markers. Calcium concentrations and isotope ratios were measured in urine and serum. While we found no significant association between urine Ca isotope composition (noted δ44/42Ca) between the different groups, δ44/42Ca values in serum were significantly different between healthy controls, subjects with mild-moderate CKD and those undertaking dialysis (P<0.01). Receiver operative characteristic curve analysis shows that the diagnostic utility of serum δ44/42Ca for detecting medial artery calcification is very good (AUC=0.818, sensitivity 81.8% and specificity 77.3%, P<0.01), and performs better than existing biomarkers. Although our results will need to be verified in prospective studies across different institutions, serum δ44/42Ca has the potential to be used as an early screening test for vascular calcification.

Hypoxia-inducible factor signaling in vascular calcification in chronic kidney disease patients.

Chronic kidney disease (CKD) affects approximately 15% of the adult population in high-income countries and is associated with significant comorbidities, including increased vascular calcifications which is associated with a higher risk for cardiovascular events. Even though the underlying pathophysiology is unclear, hypoxia-inducible factor (HIF) signaling appears to play a central role in inflammation, angiogenesis, fibrosis, cellular proliferation, apoptosis and vascular calcifications which is influenced by multiple variables such as iron deficiency anemia, serum phosphorus and calcium levels, fibroblast growth factor-23 (FGF-23) and Klotho. Along with the growing understanding of the pathology, potential therapeutic alternatives have emerged including HIF stabilizers and SGLT-2 inhibitors. The aim of this review is to discuss the role of HIF signaling in the pathophysiology of vascular calcification in CKD patients and to identify potential therapeutic approaches.

Periostin Augments Vascular Smooth Muscle Cell Calcification via β-Catenin Signaling.

Medial vascular calcification is common in chronic kidney disease (CKD) and is closely linked to hyperphosphatemia. Vascular smooth muscle cells (VSMCs) can take up pro-calcific properties and actively augment vascular calcification. Various pro-inflammatory mediators are able to promote VSMC calcification. In this study, we investigated the effects and mechanisms of periostin, a matricellular signaling protein, in calcifying human VSMCs and human serum samples. As a result, periostin induced the mRNA expression of pro-calcific markers in VSMCs. Furthermore, periostin augmented the effects of β-glycerophosphate on the expression of pro-calcific markers and aggravated the calcification of VSMCs. A periostin treatment was associated with an increased β-catenin abundance as well as the expression of target genes. The pro-calcific effects of periostin were ameliorated by WNT/β-catenin pathway inhibitors. Moreover, a co-treatment with an integrin αvβ3-blocking antibody blunted the pro-calcific effects of periostin. The silencing of periostin reduced the effects of β-glycerophosphate on the expression of pro-calcific markers and the calcification of VSMCs. Elevated serum periostin levels were observed in hemodialysis patients compared with healthy controls. These observations identified periostin as an augmentative factor in VSMC calcification. The pro-calcific effects of periostin involve integrin αvβ3 and the activation of the WNT/β-catenin pathway. Thus, the inhibition of periostin may be beneficial to reduce the burden of vascular calcification in CKD patients.

Endoplasmic reticulum stress mediates parathyroid hormone-induced apoptosis in vascular smooth muscle cells

Vascular calcification is one of the most common complications of chronic kidney disease (CKD), which is closely associated with increased mortality and morbidity rates of CKD patients. It has been reported that increased parathyroid hormone (PTH) aggravates vascular calcification in CKD patients. However, the direct role of PTH in vascular smooth muscle cells (VSMCs) is less elucidated. Here, we present evidence that PTH promotes apoptosis of VSMCs and endoplasmic reticulum (ER) stress participates in this process. Human aorta vascular smooth muscle cells (HASMCs) were treated with different concentrations of PTH for various time. HASMC apoptosis was detected by flow cytometry. Expression of phosphorylated (p)-PERK, CHOP, IRE1, p-JNK, and cleaved caspase 3 was determined by Western blotting. We found that PTH induced HASMC apoptosis and increased the expression of cleaved caspase 3. Furthermore, PTH activated PERK-CHOP and IRE1-JNK ER stress pathways. Either inhibition of JNK by SP600125 or CHOP by siRNA ameliorated PTH-induced apoptosis in HASMCs. We therefore suggest that ER stress participates in PTH-induced apoptosis of VSMCs, which may be a possible mechanism of PTH-promoted vascular calcification in CKD patients.

Daprodustat Accelerates High Phosphate-Induced Calcification Through the Activation of HIF-1 Signaling.

Aims: Chronic kidney disease (CKD) is frequently associated with other chronic diseases including anemia. Daprodustat (DPD) is a prolyl hydroxylase inhibitor, a member of a family of those new generation drugs that increase erythropoiesis via activation of the hypoxia-inducible factor 1 (HIF-1) pathway. Previous studies showed that HIF-1 activation is ultimately linked to acceleration of vascular calcification. We aimed to investigate the effect of DPD on high phosphate-induced calcification. Methods and Results: We investigated the effect of DPD on calcification in primary human aortic vascular smooth muscle cells (VSMCs), in mouse aorta rings, and an adenine and high phosphate-induced CKD murine model. DPD stabilized HIF-1α and HIF-2α and activated the HIF-1 pathway in VSMCs. Treatment with DPD increased phosphate-induced calcification in cultured VSMCs and murine aorta rings. Oral administration of DPD to adenine and high phosphate-induced CKD mice corrected anemia but increased aortic calcification as assessed by osteosense staining. The inhibition of the transcriptional activity of HIF-1 by chetomin or silencing of HIF-1α attenuated the effect of DPD on VSMC calcification. Conclusion: Clinical studies with a long follow-up period are needed to evaluate the possible risk of sustained activation of HIF-1 by DPD in accelerating medial calcification in CKD patients with hyperphosphatemia.

Fibroblast growth factor 23 and carotid intima media thickness in non-diabetic chronic kidney disease patients

ObjectivesTo clarify the relationship between fibroblast growth factor-23 (FGF23) and carotid intima-media thickness (CIMT) in nondiabetic chronic kidney disease (CKD) patients on conservative treatment.BackgroundCIMT is a reliable marker of subclinical atherosclerosis, and it has been associated with increased risk of cardiovascular events among CKD. Vascular calcification in CKD patients was independently correlated with FGF23.Patients and methodsThe study included 75 nondiabetic CKD patients on conservative treatment aged from 20 to 65 years as group 1 and 15 healthy individuals aged from 28 to 61 years, who have no medical history as a control group (group 2). Group 1 was subdivided into two groups: patients with increased CMIT and patients with normal CMIT. The study was conducted from October 2018 to May 2019. The patients were excluded if they have any of the following criteria: acute illness, CKD on dialysis, and patients with diabetes mellitus. The study was a case–control study. All patients and healthy individuals were subjected to the following: full history taking, general demographic data, including age, sex, height, weight, drug history, clinical examination, and laboratory investigations in the form of complete blood count, serum creatinine, and fasting and postprandial blood glucose. Estimated glomerular filtration rate (eGFR) was calculated by the Cockcroft–Gault formula as follows: eGFR=[140 − age (years)]×weight (kg)/serum creatinine (mg/dl)×72 [×0.85 if female], liver function tests (alanine transferase, aspartate transferase, serum albumin level), corrected serum calcium, serum phosphorus, lipid profile, carotid ultrasound, and intact FGF23.ResultsFGF23 levels and CIMT were significantly increasing across all the stages of CKD. The CIMT is significantly increasing in nondiabetic CKD patients with FGF23 levels of above 190 pg/ml. FGF23 levels positively correlated with the levels of creatinine, calcium, phosphrous, eGFR, hemoglobin, and albumin in nondiabetic CKD patients.ConclusionNondiabetic CKD patients had higher levels of FGF23 than controls. Nondiabetic CKD patients with increased CIMT had significantly higher phosphorus, creatinine, and FGF23 levels than those with normal CIMT. CIMT and FGF23 were significantly increased across all the stages of CKD. Increasing FGF23 concentrations across the stages of CKD reflect increasing CIMT and progression in CKD nondiabetic patients on conservative treatment.

MO740EFFECT OF DIPHOSPHONATES FOR VASCULAR CALCIFICATION IN CHRONIC KIDNEY DISEASE: A META-ANALYSIS

Abstract Background and Aims Vascular calcification is an independent predict factor of cardiovascular mortality and all-cause mortality in chronic kidney disease (CKD) patients. Animals experiments and clinical studies showed the inhibition effect of diphosphonates in vascular calcification, but the results of the studies remains controversial. This meta-analysis aims to evaluate the effects of diphosphonates on vascular calcification in patients with CKD. Method Randomized controlled trials (RCT) and non-RCTs of diphosphonates for the treatment of vascular calcification in CKD patients until September 2020 were searched in the database of PubMed, Embase, Cochrane library, CNKI and Wanfang. Literatures were screened according to the inclusion and exclusion criteria and quality was evaluated by two investigators independently. The standard deviation from mean (SMD) and 95% confidence interval (CI) were used to representthe counting data. Data extracted from the literatures were analyzed with Stata software (version 15.0). Results A total of 6 RCTs and 1 non-RCT with 272 patients were included, characteristics of the studies included are shown in Table 1. Meta-analysis indicated that diphosphonates inhibit vascular calcification in CKD [SMD =-0.297, 95% CI = (-0.591, -0.002), P = 0.049] (Figure 1). Etidronate is the most effective one in treating with vascular calcification (P = 0.020) (Figure 2). But there isn’t significant difference in aortic artery calcification and coronary artery calcification compared with the control group (P&amp;gt;0.05). There was no statistically significant difference in the change of blood calcium, blood phosphate, and serum parathyroid hormone between two groups (all P&amp;gt;0.05). Conclusion Diphosphonates can inhibit the progression of vascular calcification in CKD patients, and it hasn’t obvious effect on blood calcium, blood phosphate, and serum parathyroid hormone. Etidronate is the most promising therapeutic agent.

A Cross-sectional Study of Osteoporosis and Cardiovascular Calcification in Patients with Chronic Kidney Disease at Different CKD Stages

To investigate the status of osteoporosis and cardiovascular calcification in patients with chronic kidney disease (CKD) with different stages, and analyze the correlation between the stages and markers of bone metabolism To correlation. A total of 368 CKD patients at stage 3-5 who were treated in First Affiliated Hospital Affiliate to Chongqing Medical University and Chongqing Fuling Central Hospital from July 2017 to January 2018 were enrolled. A total of 60 healthy people who underwent physical examination in the hospital during the same period were enrolled as control group. Age, gender and body mass index (BMI) of all study objects at enrollment time were collected. The levels of estimate glomerular filtration rate (eGFR), serum calcium (Ca), phosphorus (P), albumin (ALB), intact parathyroid hormone (iPTH), bone alkaline phosphatase (BALP), procollagen Ⅰ N-terminal peptide (PINP) and β-crosslaps (β-CTX) were detected. The occurrence of osteoporosis, vascular calcification and heart valve calcification was detected. Pearson correlation analysis was applied to analyze correlation between eGFR, serum bone metabolism markers and osteoporosis, cardiovascular calcification. Compared with control group, levels of serum P, iPTH, BALP, PINP and β-CTX were significantly increased in CKD stage 3-5 group ( P<0.05), while levels of eGFR and serum Ca were decreased ( P<0.05). With the increase of CKD staging, changes of their levels were more significant ( P<0.05). The incidence of vascular calcification and heart valve calcification in CKD stage 5 hemodialysis group was higher than that in CKD stage 3-4 group and CKD stage 5 without dialysis group ( P<0.05). eGFR was positively correlated with serum Ca in CKD patients at stage 3-5 ( P<0.05), while negatively correlated with serum P, iPTH, BALP, PINP and β-CTX ( P<0.05). The occurrence of osteoporosis, vascular calcification and heart valve calcification was negatively correlated with increase of eGFR and serum Ca levels in CKD patients at stage 3-5 ( P<0.05), while positively correlated with increase of levels of serum P, iPTH, BALP, PINP and β-CTX ( P<0.05). The levels of serum bone metabolism markers and eGFR are closely related to occurrence of osteoporosis and cardiovascular calcification in CKD patients at stage 3-5.

MGP T-138C Polymorphism (TT Genotype) is Associated with Vascular Calcification Incidence in Indonesian Regular Hemodialysis Patients

BACKGROUND: Vascular calcification contributes greatly to the incidence of cardiovascular disease. Previously, vascular calcification was considered as a passive process caused by the mineral deposition from the circulation. Nowadays, researchers have found inhibitors and promoter factors from vascular calcification, one of which is the matrix gla protein (MGP). MGP levels depend on the gene that encodes them. The MGP T-138C polymorphism is one of the most common causes of vascular calcification.METHODS: This was a case-control study involving 86 chronic kidney disease (CKD) patients who underwent regular hemodialysis in Rasyida Kidney Hospital, Medan, Indonesia. Vascular calcification was determined from lateral and posteroanterior abdominal X-ray. The MGP T-138 C polymorphism was analyzed using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP).RESULTS: The TT/TC genotype associates with the incidence of vascular calcification with OR of 3.52, 95% CI: 1.23-10.106 (p-value&lt;0.001).CONCLUSION: There is an association between MGP T-138C polymorphism, particularly on T Allele with the incidence of vascular calcification in CKD patients undergoing regular hemodialysis.KEYWORDS: hemodialysis, T-138 C polymorphism, vascular calcification, matrix GLA protein

Mitoquinone attenuates vascular calcification by suppressing oxidative stress and reducing apoptosis of vascular smooth muscle cells via the Keap1/Nrf2 pathway

Oxidative stress and apoptosis of vascular smooth muscle cells (VSMCs) are key to vascular calcification in patients with chronic kidney disease (CKD). The mitochondria-targeted antioxidant, mitoquinone (MitoQ), which reduces oxidative stress and apoptosis, has a protective effect in acute models of renal injury but whether MitoQ can attenuate vascular calcification in CKD patients is unknown. This study was conducted to investigate whether MitoQ can prevent calcification, both in vitro and in vivo. Adenine was used to induce calcification in rats, and inorganic phosphate was used to induce calcification in VSMCs. To elucidate the underlying molecular mechanism, a specific inhibitor of Nrf2, ML385, was used 1 h before MitoQ administration. Histological staining, ELISA, flow cytometry, alizarin red staining and western blotting were used to test this hypothesis. Administration of MitoQ alleviated calcification and oxidative stress. The anti-apoptotic effect of MitoQ was associated with upregulation of Bcl-2, downregulation of Bax, and increased Nrf2 expression. The effects of MitoQ were reversed by treatment with ML385. This study offers evidence that MitoQ attenuates vascular calcification by suppressing oxidative stress and apoptosis of VSMCs through the Keap1/Nrf2 pathway. MitoQ should be further investigated as a potential therapy to prevent vascular calcification in CKD patients.

Farnesoid X receptor activation inhibits TGFBR1/TAK1-mediated vascular inflammation and calcification via miR-135a-5p

Chronic inflammation plays a crucial role in vascular calcification. However, only a few studies have revealed the mechanisms underlying the development of inflammation under high-phosphate conditions in chronic kidney disease (CKD) patients. Here, we show that inflammation resulting from the activation of the TGFBR1/TAK1 pathway is involved in calcification in CKD rats or osteogenic medium-cultured human aortic smooth muscle cells (HASMCs). Moreover, miR-135a-5p is demonstrated to be a key regulator of the TGFBR1/TAK1 pathway, which has been reported to be decreased in CKD rats. We further reveal that farnesoid X receptor (FXR) activation increases miR-135a-5p expression, thereby inhibiting the activation of the TGFBR1/TAK1 pathway, ultimately resulting in the attenuation of vascular inflammation and calcification in CKD rats. Our findings provide advanced insights into the mechanisms underlying the development of inflammation in vascular calcification, and evidence that FXR activation could serve as a therapeutic strategy for retarding vascular calcification in CKD patients.

MO036SINGLE NUCLEOTIDE POLYMORPHISMS OF THE CYP24A1 AND KL GENES ARE ASSOCIATED WITH THE EXTENT OF ARTERIAL CALCIFICATION IN PATIENTS WITH CHRONIC KIDNEY DISEASE

Abstract Background and Aims Individuals with chronic kidney disease (CKD) constitute a population with an exceptionally high cardiovascular risk. Vascular calcification, a common finding in these patients, is a known contributor to cardiovascular disease and several studies suggest it has a certain genetic component. Single nucleotide polymorphisms (SNPs) associated with the extent of calcification in CKD patients could therefore be used to predict individual susceptibility to calcification and subsequent increased cardiovascular risk. We consequently searched for associations of SNPs from candidate genes of known implication in the pathogenesis of vascular calcification (encoding cytokines, extracellular matrix proteins, members of the RANK/RANKL/OPG axis and vitamin D metabolism proteins) with the extent of arterial calcium deposits in order to improve the risk prediction of cardiovascular events in CKD patients. Method The study was performed in 1439 individuals from the NEFRONA population, which include CKD patients (stages 2-3, 4-5, and dialysis) as well as healthy controls recruited from 81 Spanish hospitals. Individuals were genotyped with the iPLEXGOLD MassARRAY technology and Assay Design v4 software for 61 SNPs from 22 genes. A continuous vascular calcification score was calculated from the echogenicity of atherosclerotic plaques detected by ultrasonography in the carotid and femoral arteries. Among several other clinical variables, the presence of cardiovascular events during a 4-year follow up was collected. Association of SNPs with calcification extent was identified by univariate linear regression models. Multiple linear regression with backward elimination was used for the selection of an appropriate SNP-based model adjusted by age, sex and CKD stages. Finally, a Cox proportional hazard regression model was applied for the prediction of cardiovascular risk. Results Arterial calcification scores were higher with increasing age, male sex, and advanced CKD stages (all p&amp;lt;0.001), as expected. Univariate linear regression analyses of all SNPs with the arterial calcification score as dependent variable retrieved p-values &amp;lt;0.05 for 6 six of them (rs11568820, rs2248359, rs2296241, rs3102735, rs385564 and rs495392), which were selected for subsequent analyses. These polymorphisms were next included in a multivariate linear regression model with CKD stage, age and sex as additional independent variables. Only rs2296241 of CYP24A1 (estimate 0.36, 95% CI 0.14 to 0.58, p=0.001 for homocygous GG) and rs495392 of KL (estimate -0.39, 95% CI -0.69 to -0.09, p=0.011 for homocygous TT) remained independently associated with the extent of calcium deposits. Finally, using Cox regression models, it was determined that both the CKD stage (HR [for dialysis stage]=8.34, 95% CI 4.59 to 15.15, p&amp;lt;0.001) and the calcification score (HR=2.05, 95% CI 1.67 to 2.54, p&amp;lt;0.001) predicted the development of cardiovascular events. Considering all possible risk factors, no differences were found in the rate of development of cardiovascular events according to the genotype for the two associated polymorphisms: rs2296241 HR=1.13, 95% CI 0.87 to 1.48, p=0.36; rs495392 HR=0.80 95% CI 0.63 to 1.03, p=0.08. Conclusions Polymorphisms of KL and CYP24A1 genes are associated with the extent of calcification in CKD individuals although they lack the capacity to predict cardiovascular events. However, the echogenic determination of the extent of arterial calcium deposits in CKD patients seems a promising non-invasive, non-irradiating method for the scoring of calcification and even the prediction of cardiovascular events. Further genetic association studies using this technique could therefore yield valuable results.

Cardiovascular Calcification in Chronic Kidney Disease-Therapeutic Opportunities.

Patients with chronic kidney disease (CKD) are highly susceptible to cardiovascular (CV) complications, thus suffering from clinical manifestations such as heart failure and stroke. CV calcification greatly contributes to the increased CV risk in CKD patients. However, no clinically viable therapies towards treatment and prevention of CV calcification or early biomarkers have been approved to date, which is largely attributed to the asymptomatic progression of calcification and the dearth of high-resolution imaging techniques to detect early calcification prior to the ‘point of no return’. Clearly, new intervention and management strategies are essential to reduce CV risk factors in CKD patients. In experimental rodent models, novel promising therapeutic interventions demonstrate decreased CKD-induced calcification and prevent CV complications. Potential diagnostic markers such as the serum T50 assay, which demonstrates an association of serum calcification propensity with all-cause mortality and CV death in CKD patients, have been developed. This review provides an overview of the latest observations and evaluates the potential of these new interventions in relation to CV calcification in CKD patients. To this end, potential therapeutics have been analyzed, and their properties compared via experimental rodent models, human clinical trials, and meta-analyses.

Magnesium and calciprotein particles in vascular calcification: the good cop and the bad cop.

Vascular calcification is a major contributor to increased cardiovascular mortality in chronic kidney disease (CKD). Recently, calciprotein particles (CPP) were identified to drive the calcification process. CPP may explain the effects of high phosphate on vascular calcification. Magnesium is a promising novel therapeutic approach to halt vascular calcification, because it inhibits CPP maturation and is associated with reduced cardiovascular mortality in CKD. We aim to examine the current evidence for the role of CPP in the calcification process and to explain how magnesium prevents calcification. A recent meta-analysis concluded that reducing high phosphate levels in CKD patients does not associate with lowering cardiovascular mortality. Inhibition of CPP formation prevents phosphate-induced calcification in vitro. Consequently, delaying CPP formation and maturation may be a clinical approach to reduce calcification. Magnesium inhibits CPP maturation and vascular calcification. Clinical pilot studies suggest that magnesium is a promising intervention strategy against calcification in CKD patients. CPP induce vascular calcification and are modulated by serum phosphate and magnesium concentrations. Magnesium is a strong inhibitor of CPP maturation and therefore, a promising therapeutic approach to reduce vascular calcification in CKD. Currently, several studies are being performed to determine the clinical outcomes of magnesium supplementation in CKD.

SAT-266 EVALUATION OF AORTIC CALCIFICATION VOLUME AND SITES USING A NEWLY DEVELOPED THREE-DIMENSIONAL VISUALIZATION AND QUANTIFICATION METHOD IN CHRONIC KIDNEY DISEASE PATIENTS WITH AND WITHOUT DIABETES

Chronic kidney disease (CKD) and diabetes mellitus (DM) are both crucial risk factors for vascular calcification, CVD and mortality. There are a great number of studies regarding the severity of vascular calcification in CKD and DM. While Agatston scoring is often used evaluating coronary artery calcification, there are very few studies to evaluate both severity and site of aortic calcification. The purpose of our study was to examine the volume and site of aortic calcification in CKD patients with and without DM using a newly developed three-dimensional visualization and quantification method. Fifty patients who were hospitalized and started hemodialysis at our hospital were included in the present study. They were divided into the two groups depending on the presence of DM; those with CKD and without DM group (CKD group, n=31), those with CKD and DM group (CKD+DM group, n=19). The volume and site of aortic calcification were assessed by CT-scan using a three-dimensional visualization and quantification method according to a previous study (Figure). We compared the calcification volume in total aorta and each of the five sites between the two groups. Total calcification volume was significantly greater in the CKD+DM group than in the CKD group. As for calcification sites, calcification volume in the thoracic aorta and abdominal aorta was greater in CKD+DM group compared to the CKD group. There were no significant differences in calcification volume in the aortic root, ascending aorta, and aortic arch. Total calcification volume of the aorta, calcification volume of the thoracic aorta, and calcification volume of the abdominal aorta were each significantly correlated with age, diastolic blood pressure and pulse pressure. Using a newly developed three-dimensional visualization and quantification method, the present study demonstrated that aortic calcification was more severe in CKD patients with DM than in those without DM and that calcification seemed to be likely to occur especially in the abdominal aorta. To clarify the mechanisms, a future detailed study is needed.

Peroxisome Proliferator-Activated Receptor-γ Coactivator-1α Inhibits Vascular Calcification Through Sirtuin 3-Mediated Reduction of Mitochondrial Oxidative Stress.

Aims: Vascular calcification is associated with cardiovascular death in patients with chronic kidney disease (CKD). Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) plays an important role in various cardiovascular diseases. However, its role in vascular calcification remains unknown. Results: Adenine-induced rat CKD model was used to induce arterial medial calcification. The level of PGC-1α decreased in abdominal aorta of CKD rats. Overexpression of PGC-1α significantly ameliorated calcium deposition in rat abdominal aorta, isolated carotid rings, and cultured vascular smooth muscle cells (VSMCs). Mitochondrial reactive oxygen species (mtROS) increased in calcifying aorta and VSMCs. Upregulation of PGC-1α inhibited, whereas PGC-1α depletion promoted β-glycerophosphate-induced mtROS production and calcium deposition. Moreover, PGC-1α increased superoxide dismutase 1 (SOD1) and SOD2 contents in vivo and in vitro, whereas SOD2 deletion eliminated PGC-1α-mediated mtROS change and promoted calcium deposition. Mechanistically, sirtuin 3 (SIRT3) expression declined in calcifying aorta and VSMCs, while PGC-1α overexpression restored SIRT3 expression. Inhibition of SIRT3 by 3-TYP or siRNA (small interfering RNA) reduced PGC-1α-induced upregulation of SOD1 and SOD2, and abolished the protective effect of PGC-1α on calcification of VSMCs. Importantly, PGC-1α was reduced in calcified femoral arteries in CKD patients. In phosphate-induced human umbilical arterial calcification, upregulation of PGC-1α attenuated calcium nodule formation, while this protective effect was abolished by SIRT3 inhibitor. Innovation: We showed for the first time that PGC-1α is an important endogenous regulator against vascular calcification. Induction of PGC-1α could be a potential strategy to treat vascular calcification in CKD patients. Conclusions: PGC-1α protected against vascular calcification by SIRT3-mediated mtROS reduction.

Emerging Role of Vitamins D and K in Modulating Uremic Vascular Calcification: The Aspect of Passive Calcification.

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).

Serum sclerostin as a potential novel biomarker for heart valve calcification in patients with chronic kidney disease.

To explore the correlation between change in sclerostin level and heart valve calcification in patients with chronic kidney disease (CKD) in stages 3-5, as well as the possible underlying mechanism, which could provide a clinical reference for the diagnosis and treatment of cardiovascular disease (CVD). 110 patients were divided into a healthy control group and three groups of patients with CKD stages 3, 4, and 5 according to CKD staging guidelines. Scr, BUN, AKP, TC, TG, HDL, LDL, Ca, Pi, and CRP were measured, and calcium-phosphate product (Ca×Pi) calculated. ELISA was used to measure the sclerostin level, and the estimated glomerular filtration rate (eGFR) was calculated by MDRD. Heart valve calcification was measured by a physician in the Cardiac Department of our hospital. The correlations between sclerostin-level change and heart valve calcification, as well as each index in CKD patients in stages 3-5, were analyzed. Compared with the healthy control group, the serum Ca in CKD stage-3, stage-4, and stage-5 groups (p < 0.05) was reduced, and PTH was increased (p < 0.05). Blood Pi and Ca×Pi in the stage-4 and stage-5 groups were increased (p < 0.05). The serum sclerostin level increased with renal hypofunction in stage-3 CKD patients, and was significantly increased compared with that of the control group, reaching the highest level in the terminal stage (p < 0.01). Pearson correlation analysis indicated that serum sclerostin was negatively correlated with eGFR (r = -0.91, p < 0.001) and blood Ca (r= -0.271, p < 0.001), and positively correlated with SCr (r = 0.608, p < 0.001), blood Pi level (r = 0.295, p < 0.001), PTH (r = 0.334, p < 0.001), and Ca×Pi (r = 0.275, p < 0.001). The rate of heart valve calcification in the CKD patients in stage 5 was relatively high (11/30, 36.67%), and significantly higher than that in healthy controls (1/20, 5%; p < 0.01). Logistic regression analysis of heart valve calcification indicated that sclerostin was a risk factor for heart valve calcification in CKD patients in stages 3-5. The sclerostin level gradually increased with renal hypofunction in CKD patients in stages 3-5, and the increase in serum sclerostin level in the CKD patients occurred earlier than the change in Pi and Ca×Pi. The risk of heart valve calcification in stage-5 CKD patients was significantly increased. Sclerostin is an independent risk factor for heart valve calcification in CKD patients.