Crosstalk between Renal and Vascular Calcium Signaling: The Link between Nephrolithiasis and Vascular Calcification

Calcium (Ca²⁺) is an important mediator of multicellular homeostasis and is involved in several diseases. The interplay among the kidney, bone, intestine, and parathyroid gland in Ca²⁺ homeostasis is strictly modulated by numerous hormones and signaling pathways. The calcium-sensing receptor (CaSR) is a G protein–coupled receptor, that is expressed in calcitropic tissues such as the parathyroid gland and the kidney, plays a pivotal role in Ca²⁺ regulation. CaSR is important for renal Ca²⁺, as a mutation in this receptor leads to hypercalciuria and calcium nephrolithiasis. In addition, CaSR is also widely expressed in the vascular system, including vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) and participates in the process of vascular calcification. Aberrant Ca²⁺ sensing by the kidney and VSMCs, owing to altered CaSR expression or function, is associated with the formation of nephrolithiasis and vascular calcification. Based on emerging epidemiological evidence, patients with nephrolithiasis have a higher risk of vascular calcification, but the exact mechanism linking the two conditions is unclear. However, a dysregulation in Ca²⁺ homeostasis and dysfunction in CaSR might be the connection between the two. This review summarizes renal calcium handling and calcium signaling in the vascular system, with a special focus on the link between nephrolithiasis and vascular calcification.     

COX-2 Is Downregulated in Human Stenotic Aortic Valves and Its Inhibition Promotes Dystrophic Calcification

Calcific aortic valve disease (CAVD) is the result of maladaptive fibrocalcific processes leading to a progressive thickening and stiffening of aortic valve (AV) leaflets. CAVD is the most common cause of aortic stenosis (AS). At present, there is no effective pharmacotherapy in reducing CAVD progression; when CAVD becomes symptomatic it can only be treated with valve replacement. Inflammation has a key role in AV pathological remodeling; hence, anti-inflammatory therapy has been proposed as a strategy to prevent CAVD. Cyclooxygenase 2 (COX-2) is a key mediator of the inflammation and it is the target of widely used anti-inflammatory drugs. COX-2-inhibitor celecoxib was initially shown to reduce AV calcification in a murine model. However, in contrast to these findings, a recent retrospective clinical analysis found an association between AS and celecoxib use. In the present study, we investigated whether variations in COX-2 expression levels in human AVs may be linked to CAVD. We extracted total RNA from surgically explanted AVs from patients without CAVD or with CAVD. We found that COX-2 mRNA was higher in non-calcific AVs compared to calcific AVs (0.013 ± 0.002 vs. 0.006 ± 0.0004; p < 0.0001). Moreover, we isolated human aortic valve interstitial cells (AVICs) from AVs and found that COX-2 expression is decreased in AVICs from calcific valves compared to AVICs from non-calcific AVs. Furthermore, we observed that COX-2 inhibition with celecoxib induces AVICs trans-differentiation towards a myofibroblast phenotype, and increases the levels of TGF-β-induced apoptosis, both processes able to promote the formation of calcific nodules. We conclude that reduced COX-2 expression is a characteristic of human AVICs prone to calcification and that COX-2 inhibition may promote aortic valve calcification. Our findings support the notion that celecoxib may facilitate CAVD progression.     

Role of sodium thiosulfate therapy in the treatment of digital necrosis due to Mönckeberg sclerosis

Accelerated vascular calcification is a well‐described complication of chronic kidney disease often affecting large and small vessels alike through a variety of mechanisms. Accordingly, dysregulation of calcium and phosphate balance, vitamin D metabolism, hyperparathyroidism, and endothelial injury can lead to both macrovascular and microvascular complications. We describe a 56‐year‐old Hispanic male with a history of end‐stage renal disease, diabetes mellitus type 2, and medical noncompliance who developed sequential digital ischemia and necrosis involving both hands as well as right foot as a result of Mönckeberg sclerosis. An extensive metabolic and serologic workup was unrevealing but radiographic studies and histopathology revealed the diagnosis. A multifaceted approach was instituted including wound debridement and amputations along with intensive medical support. In addition to improving hypertensive control and striving for improved calcium and phosphate balance, sodium thiosulfate solution was administered for more than 1 year. This aggressive approach allowed his wounds to heal and has arrested further digital ischemia from occurring.     

Diabetes and Hypertension Consistently Predict the Presence and Extent of Coronary Artery Calcification in Symptomatic Patients: A Systematic Review and Meta-Analysis

Background: The relationship of conventional cardiovascular risk factors (age, gender, ethnicity, diabetes, dyslipidaemia, hypertension, obesity, exercise, and the number of risk factors) to coronary artery calcification (CAC) presence and extent has never before been assessed in a systematic review and meta-analysis. Methods: We included only English language studies that assessed at least three conventional risk factors apart from age, gender, and ethnicity, but excluded studies in which all patients had another confirmed condition such as renal disease. Results: In total, 10 studies, comprising 15,769 patients, were investigated in the systematic review and seven studies, comprising 12,682 patients, were included in the meta-analysis, which demonstrated the importance of diabetes and hypertension as predictors of CAC presence and extent, with age also predicting CAC presence. Male gender, dyslipidaemia, family history of coronary artery disease, obesity, and smoking were overall not predictive of either CAC presence or extent, despite dyslipidaemia being a key risk factor for coronary artery disease (CAD). Conclusion: Diabetes and hypertension consistently predict the presence and extent of CAC in symptomatic patients.     

低温微生物诱导碳酸钙沉积及其在混凝土裂缝修复中的应用研究

近些年来,对于混凝土裂缝的修复,微生物诱导碳酸钙沉积(MICP)已成一种高效和环境友好的技术。本文选用一种可在低温环境下生长的矿化微生物,然后在碱性溶液中研究Ca²⁺浓度、pH值和钙化速率的变化,来揭示微生物诱导矿化的动态过程。随后,将此微生物应用到混凝土裂缝自修复中,同时采用裂缝愈合率和渗水系数来表征混凝土裂缝的自修复效果。试验结果表明,微生物能够快速降低溶液中的Ca²⁺浓度,并提高钙化速率,矿化产物主要是球状方解石CaCO₃。对于宽度小于0.50 mm的早期混凝土裂缝,在10 ℃的养护温度下,28 d修复后裂缝表面基本能被白色物质填充,渗水系数下降2个数量级,并且裂缝区修复产物主要是大小不一的球状方解石CaCO₃。     

Effect of serum FGF‐23, MGP and fetuin‐A on calcium‐phosphate metabolism in maintenance hemodialysis patients

This study was aimed to explore the role of serum fibroblast growth factor (FGF)‐23, matrix Gla protein (MGP) and fetuin‐A in the calcium‐phosphate metabolism and their predicting value in coronary artery calcification in maintenance hemodialysis (MHD) patients. This study included 64 patients who receive hemodialysis in our hospital. The serum FGF‐23, MGP and fetuin‐A were analyzed by enzyme‐linked immunosorbent assay (ELlSA). Coronary artery calcification score (CACS) was evaluated by coronary artery computed tomography scan. The 64 patients (30 males, 34 females, 60.6 ± 11.3 years of age) received an average dialysis vintage of 6.88 ± 2.94 years. We divided the CACS into three levels, and 13 (20.31%), 16 (25%), and 35 (54.69%) exhibited a CACS of 0–100, 100–400, and >400, respectively. Dialysis vintage, serum FGF‐23, fetuin‐A, phosphorus and high‐density lipoprotein‐C levels were identified as independent variables of CACS by stepwise multiple regression analysis. The area under receiver operating characteristic curve indicated that serum FGF‐23 and fetuin‐A were useful for identifying CAC in MHD patients. The cut‐off value corresponding to the highest Youden's index was serum FGF‐23 ≥ 256 pg/mL and fetuin‐A ≤ 85 μg/mL, which was defined as the optimal predictors of CAC. Different combinations of serum FGF‐23 and fetuin‐A in parallel or in series effectively boosted the identification of CAC. The incidence of CAC is high in MHD patients. Serum FGF‐23 and fetuin‐A levels are closely correlated with CAC.     

Does hemodiafiltration reduce vascular stiffness measured by aortic pulse wave velocity compared with high‐flux hemodialysis?

Hemodialfiltration (HDF) has been reported to reduce the frequency of intradialytic hypotension compared with hemodialysis (HD). We wished to determine whether HDF resulted in improvement of arterial stiffness compared with HD. We reviewed peripheral blood pressure and pulse wave velocity measurements in a cross‐sectional analysis of stable HDF and HD outpatients. One hundred forty‐one HDF patients were matched to 148 HD patients in terms of age, sex, prevalence of diabetes, peripheral blood pressure, and body mass. Pulse wave velocity was not different between the HD and HDF cohorts (median 9.1 [8.0–10.7] m/s vs. 9.7 [8.5–11.6] m/s). Similarly, there were no differences in central aortic pressure (149.2 ± 30.9 mmHg vs. 151.9 ± 35.2 mmHg), or aortic (39 [25.1–51.2]% vs. 38.6 [25.8–51.4]%) and brachial (3.8 [?24.3 to 26.9]% vs. 3 [?22.4 to 27.1]%) augmentation indices, respectively. Pulse wave velocity did not differ between adult patients treated by HD and HDF, and similarly, there were no differences in central aortic pressure, aortic or brachial augmentation indices, and cardiac diastolic perfusion. Our study suggests that HDF does not appear to offer any benefit over HD in terms of vascular stiffness.     

Reaction mechanisms of low-grade molybdenum concentrate during calcification roasting process

The effects of Ca-based additives on roasting properties of low-grade molybdenum concentrate were studied. The results show that calcium-based additives can react with molybdenum concentrate to form CaSO₄ and CaMoO₄. The initial oxidation temperature of MoS₂ is 450 °C, while the formation of CaMoO₄ and CaSO₄ occurs above 500 °C. The whole calcification reactions are nearly completed between 600 and 650 °C. However, raising the temperature further helps for the formation of CaMoO₄ but is disadvantageous to sulfur fixing rate and molybdenum retention rate. Calcification efficiency of Ca-based additives follows the order: Ca(OH)₂>CaO>CaCO₃. With increasing the dosage of Ca(OH)₂, the molybdenum retention rate and sulfur-fixing rate rise, but excessive dosages would consume more acid during leaching process. The appropriate mass ratio of Ca(OH)₂ to molybdenum concentrate is 1:1. When roasted at 650 °C for 90 min, the molybdenum retention rate and the sulfur-fixing rate of low-grade molybdenum concentrate reach 100% and 92.92%, respectively, and the dissolution rate of molybdenum achieves 99.12% with calcines being leached by sulphuric acid.