Role of calcification inhibitors in the pathogenesis of vascular calcification in chronic kidney disease (CKD)

BACKGROUND: The majority of patients with chronic kidney disease (CKD) have excessive vascular calcification; however, most studies demonstrate that a subset of CKD patients do not have, nor develop, vascular calcification despite similar exposure to the uremic environment. This suggests protective mechanisms, or naturally occurring inhibitors, of calcification may be important. METHODS: In order to determine the role of three inhibitors, fetuin-A, matrix gla protein (MGP), and osteoprotegerin (OPG) in the vascular calcification observed in patients with CKD-5, we (1) measured serum levels of these inhibitors and compared the levels to calcification assessed by computed tomography (CT); (2) examined arteries from CKD-5 patients by immunostaining for these inhibitors; and (3) examined the expression and effect of these inhibitors in cultured bovine vascular smooth muscle cells (BVSMCs) incubated in serum pooled from uremic patients compared to healthy controls. RESULTS: There was a negative correlation of coronary artery calcification scores with serum fetuin-A levels (r=-0.30, P= 0.034) and a positive association with OPG levels (r= 0.29, P= 0.045). There was increasing immunostaining for both fetuin-A and MGP in arteries with increasing calcification graded semiquantitatively (P < 0.003). In vitro, fetuin-A added to mineralizing BVSMCs inhibited mineralization (P < 0.001). Compared to normal serum, BVSMCs incubated with uremic serum had a progressive increase in MGP expression with mineralization (P < 0.001) and increased expression of OPG in BVSMCs (P < 0.04). CONCLUSION: These data demonstrate that fetuin-A, OPG, and MGP play an important role in the pathogenesis of uremic vascular calcification.     

Fetuin-A Protects against Atherosclerotic Calcification in CKD

Reduced serum levels of the calcification inhibitor fetuin-A associate with increased cardiovascular mortality in dialysis patients. Fetuin-A–deficient mice display calcification of various tissues but notably not of the vasculature. This absence of vascular calcification may result from the protection of an intact endothelium, which becomes severely compromised in the setting of atherosclerosis. To test this hypothesis, we generated fetuin-A/apolipoprotein E (ApoE)-deficient mice and compared them with ApoE-deficient and wild-type mice with regard to atheroma formation and extraosseous calcification. We assigned mice to three treatment groups for 9 wk: (1) Standard diet, (2) high-phosphate diet, or (3) unilateral nephrectomy (causing chronic kidney disease [CKD]) plus high-phosphate diet. Serum urea, phosphate, and parathyroid hormone levels were similar in all genotypes after the interventions. Fetuin-A deficiency did not affect the extent of aortic lipid deposition, neointima formation, and coronary sclerosis observed with ApoE deficiency, but the combination of fetuin-A deficiency, hyperphosphatemia, and CKD led to a 15-fold increase in vascular calcification in this model of atherosclerosis. Fetuin-A deficiency almost exclusively promoted intimal rather than medial calcification of atheromatous lesions. High-phosphate diet and CKD also led to an increase in valvular calcification and aorta-associated apoptosis, with wild-type mice having the least, ApoE-deficient mice intermediate, and fetuin-A/ApoE-deficient mice the most. In addition, the combination of fetuin-A deficiency, high-phosphate diet, and CKD in ApoE-deficient mice greatly enhanced myocardial calcification, whereas the absence of fetuin-A did not affect the incidence of renal calcification. In conclusion, fetuin-A inhibits pathologic calcification in both the soft tissue and vasculature, even in the setting of atherosclerosis.Hemodialysis (HD) patients experience a cardiovascular mortality of up to 20% per year, and vascular calcification is a strong independent risk factor of cardiovascular death.^1,2 Pathologic calcification is driven both by an elevated serum calcium phosphate product and by differentiation of vascular or mesenchymal cells into osteoblast-like cells, becoming mineralization competent.Serum is a metastable solution with respect to calcium phosphate precipitation. Once started, calcification proceeds rapidly in the presence of calcifiable templates such as collagen, elastin, and cell debris.^3–5 Fetuin-A accounts for approximately 50% of the capacity of serum to inhibit the spontaneous apatite formation from solutions supersaturated in calcium and phosphate.⁶ The inhibition is achieved by rapid formation of soluble colloidal fetuin-A calcium phosphate complexes, termed calciprotein particles (CPPs).^7–9We previously showed that HD and calciphylaxis patients have depressed fetuin-A serum levels accompanied by a reduced capacity of their serum to inhibit calcium phosphate precipitation.⁵ In cross-sectional studies in HD patients, fetuin-A deficiency was identified as an inflammation-related predictor of cardiovascular and all-cause mortality, respectively.^10,11 In patients without chronic kidney disease (CKD), fetuin-A levels correlated inversely with advanced coronary calcification.^12,13 Fetuin-A–deficient (Ahsg−/−) mice maintained on the DBA/2 background exhibit a fully penetrating phenotype with extensive soft tissue calcification, whereas C57BL/6 Ahsg−/− mice represent “borderline calcifying” mice whereby rapid calcification can be induced by additional metabolic challenges or induction of CKD.^5,14Calcification of the aorta or larger vessels is conspicuously absent in Ahsg−/− mice; therefore, the role for fetuin-A as an inhibitor of vascular calcification was uncertain.^15,16 Absent vascular calcification in Ahsg−/− mice may be related to the protective mechanisms by an intact endothelium, which is severely compromised in humans with atherosclerosis and thus may serve as a nidus for subsequent calcification. To test this hypothesis, we created Ahsg−/−/apolipoprotein E double-deficient (ApoE−/−) mice maintained on the C57BL/6 genetic background to dissect the contribution of fetuin-A, CKD, and an elevated calcium-phosphorus product (Ca × P) to the development of atheroma formation and vascular calcification in an established murine model of atherosclerosis.     

Vascular calcification in chronic kidney disease

Vascular calcification is often encountered in advanced atherosclerotic lesions and is a common consequence of aging. Calcification of the coronary arteries has been positively correlated with coronary atherosclerotic plaque burden, increased risk of myocardial infarction, and plaque instability. Chronic kidney disease (CKD) patients have two to five times more coronary artery calcification than healthy age-matched individuals. Vascular calcification is a strong prognostic marker of cardiovascular disease mortality in CKD patients. Vascular calcification has long been considered to be a passive, degenerative, and end-stage process of atherosclerosis and inflammation. However, recent evidence indicates that bone matrix proteins such as osteopontin, matrix Gla protein (MGP), and osteocalcin are expressed in calcified atherosclerotic lesions, and that calcium-regulating hormones such as vitamin D₃ and parathyroid hormone-related protein regulate vascular calcification in in vitro vascular calcification models based on cultured aortic smooth muscle cells. These findings suggest that vascular calcification is an actively regulated process similar to osteogenesis, and that bone-associated proteins may be involved in the development of vascular calcification. The pathogenesis of vascular calcification in CKD is not well understood and is almost multifactorial. In CKD patients, several studies have found associations of both traditional risk factors, such as hypertension, hyperlipidemia, and diabetes, and uremic-specific risk factors with vascular calcification. Most patients with progressive CKD develop hyperphosphatemia. An elevated phosphate level is an important risk factor for the development of calcification and cardiovascular mortality in CKD patients. Thus, it is hypothesized that an important regulator of vascular calcification is the level of inorganic phosphate. In order to test this hypothesis, we characterized the response of human smooth muscle cell (HSMC) cultures to inorganic phosphate levels. Our findings indicate that inorganic phosphate directly regulates HSMC calcification through a sodium-dependent phosphate transporter mechanism. After treatment with elevated phosphate, there is a loss of smooth muscle lineage markers, such as α-actin and SM-22α, and a simultaneous gain of osteogenic markers such as cbfa-1 and osteocalcin. Elevated phosphate may directly stimulate HSMC to undergo phenotypic changes that predispose to calcification, and offer a novel explanation of the phenomenon of vascular calcification under hyperphosphatemic conditions. Furthermore, putative calcification inhibitory molecules have been identified using mouse mutational analyses, including MGP, β-glucosidase, fetuin-A, and osteoprotegerin. Mutant mice deficient in these molecules present with enhanced cardiovascular calcification, demonstrating that specific molecules are normally important in suppressing vascular calcification. These findings suggest that the balance of inducers, such as phosphate, and inhibitors, such as MGP, fetuin-A, and others, are likely to control whether or not calcification occurs under pathological conditions.     

Circulating calcification inhibitors and vascular properties in children after renal transplantation

Pediatric transplant patients are known to have vascular abnormalities. The calcification inhibitors matrix Gla protein (MGP) and fetuin-A play an important role in the pathophysiology of vascular calcification. In the cross-sectional study reported here, we examined the circulating levels of fetuin-A and MGP in children after renal transplantation compared to healthy children and the association of these factors with vascular properties of the carotid artery. Levels of MGP and fetuin-A together with vascular properties of the carotid artery were determined in 29 pediatric renal transplant recipients and 54 healthy controls. The level of fetuin-A was decreased in the transplant group relative to the control group (P = 0.005), whereas the level of MGP (both non-phosphorylated MGP and non-carboxylated MGP) did not differ between groups. The intima-media thickness (P < 0.001) and the elasticity (P = 0.002) of the carotid artery were significantly increased in children after renal transplantation compared to healthy children. No associations between vascular parameters and calcification inhibitors were found in either group. Circulating levels of MGP and fetuin-A could not be identified as independent predictors of vascular stiffness or other carotid artery parameters in pediatric renal transplant recipients. Future prospective studies in pediatric ESRD and transplant patients are needed to learn more about the role of calcification inhibitors in relation to the prevention of vascular damage.     

Associations of serum fetuin-A with malnutrition, inflammation, atherosclerosis and valvular calcification syndrome and outcome in peritoneal dialysis patients.

BACKGROUND: Fetuin-A (alpha2-Heremans Schmid glycoprotein) has recently been identified as a circulating inhibitor of calcification and is regulated as a negative acute phase protein. However, its relationships with cardiac valvular calcification and atherosclerosis and outcome have not been evaluated in peritoneal dialysis (PD) patients. METHOD: We performed a prospective follow-up study in 238 PD patients with echocardiography done at baseline to detect cardiac valvular calcification and biochemical analysis performed for serum fetuin-A, albumin and C-reactive protein (CRP). RESULTS: Baseline serum fetuin-A concentration was (mean+/-SD) 0.309+/-0.068 g/l (normal range 0.4-0.95). Across the three tertiles of increasing serum fetuin-A, a significant trend effect was observed for age (P = 0.023), diabetes (P = 0.008), background atherosclerotic vascular disease (P = 0.010), cardiac valvular calcification (P = 0.002), serum albumin (P<0.001), subjective global assessment (P = 0.005) and CRP (P<0.001). Adjusting for CRP and calcium x phosphorus product, every 0.01 g/l increase in serum fetuin-A remained independently associated with a 6% decrease in the risk of valvular calcification (95% confidence intervals, 0.90-0.99; P = 0.028). Furthermore, serum fetuin-A showed a significant decrease across the four groups of patients with increasing components of the malnutrition, inflammation, atherosclerosis/calcification (MIAC) syndrome (P<0.001) and was the lowest among patients with all components of the MIAC syndrome (0.263+/-0.055 g/l) and highest among those who do not have the MIAC syndrome at all (0.338+/-0.063 g/l). Lower serum fetuin-A was associated with greater all-cause mortality (P = 0.0011) and fatal and non-fatal cardiovascular events (P = 0.0017), but its significance was lost when atherosclerotic vascular disease, valvular calcification, inflammation and malnutrition were included in the model. CONCLUSIONS: Serum fetuin-A showed important associations with valvular calcification, atherosclerosis, malnutrition and inflammation, and was linked to mortality and cardiovascular events in PD patients via its close relationships with the MIAC syndrome.     

Fetuin-mineral complex reflects extraosseous calcification stress in CKD

Fetuin-A is an important inhibitor of extraosseous calcification, but some of the studies that used ELISAs did not identify a significant relationship between serum fetuin-A levels and vascular calcification in patients with chronic kidney disease (CKD). Here, we used centrifugation to separate a fetuin-mineral complex (FMC) composed of fetuin-A, fibrinogen, fibronectin-1, and calcium from the serum of hemodialysis patients. In addition, we analyzed serum fetuin-A levels of 73 patients with diabetes and CKD (predialysis) after centrifugation. Fetuin-A concentrations were significantly lower in supernatants than in serum from patients at any stage of CKD, indicating systemic circulation of FMC in these patients. With greater severity of CKD, the contribution of FMC to total fetuin-A increased. Despite the absence of a correlation between serum fetuin-A and coronary artery calcification scores (CACS), supernatant fetuin-A negatively correlated with CACS and the extent to which centrifugation reduced fetuin-A (reduction ratio [RR]) positively correlated with CACS. In a longitudinal study of 12 hemodialysis patients with secondary hyperparathyroidism, parathyroidectomy and cinacalcet therapy each significantly reduced the RR without changing supernatant fetuin-A levels after 1 month, suggesting a reduction in FMC. Moreover, the magnitude of cinacalcet-induced reduction in parathyroid hormone correlated with the decrease in RR but not with changes in serum or supernatant fetuin-A. These data suggest that a quantitative measure of FMC, not supernatant or serum fetuin-A as measured in previous studies, reflects extraosseous calcification stress.     

Association between biomarkers of inflammation and left ventricular hypertrophy in moderate chronic kidney disease

AIMS: Left ventricular hypertrophy (LVH) is a predictor for cardiovascular mortality, and it is considered to be a surrogate marker of preclinical cardiovascular disease. This study aimed at evaluating whether fetuin-A plasma levels are decreased in patients with moderate chronic kidney disease (CKD) and their linkage to plasma concentrations of hs-C-reactive protein (CRP), cardiotrophyn-1 (CT-1), tumor necrosis factor-ac (TNF-alpha), propeptide of collagen Type I (PIP) and to LVH. MATERIAL AND METHODS: We enrolled 64 moderate CKD and 55 essential hypertensives (EH) with normal renal function as controls. All the patients underwent an echocardiographic examination; plasma samples were obtained to measure routine clinical parameters and the molecules listed above (measured by ELISA). RESULTS: Among CKD there were 30/64 patients with LVH, and in EH group 14/55 subjects had LVH. Fetuin A was reduced in CKD when compared with EH (p < 0.0001). The comparison between CKD having LVH with those without LVH showed significant differences in plasma levels of fetuin-A (p < 0.002), TNF-alpha (p < 0.01) and hs-CRP (p < 0.001), CT-1 and PIP (p < 0.002). CKD with LVH had lower values of fetuin-A (p < 0.001), and higher values of hs-CRP (p < 0.001) TNF-alpha (p < 0.001), CT-1 (p < 0.001) and PIP (p < 0.001) than EH with LVH. The multivariate analysis of correlation demonstrated that in CKD patients hs-CRP (beta 0.42, p < 0.00006), and systolic blood pressure (beta 0.29, p < 0.02) were independent predictors of LV mass index. The relationship between LV mass index and fetuin-A did not reach statistical significance. CONCLUSIONS: For the first time in moderate CKD patients, we demonstrate that fetuin-A is decreased and relates to LVH depending on C-reactive protein.     

Coronary calcification in hemodialysis patients: the contribution of traditional and uremia-related risk factors

BACKGROUND: Coronary artery calcification is a common feature of atherosclerosis, occurring in 90% of angiographically significant lesions. There is recent evidence that coronary artery calcification is frequent in hemodialysis patients and it has been suggested that this increased incidence may be associated to uremia-related factors. The development and progression of coronary artery calcification is similar to osteogenesis. The aim of this study was to evaluate the relationship between coronary artery calcification, uremia-related factors, and bone histomorphometry in hemodialysis patients. METHODS: A total of 101 hemodialysis patients were assessed for biochemical markers of inflammation, oxidative stress, and bone metabolism. Subsequently, they were submitted to multislice coronary tomography (MSCT) and transiliac bone biopsy. RESULTS: The median calcium score was 116.2 (range 0 to 5547). Fifty-two percent of the patients showed moderate and severe coronary artery calcification, 20% had calcium scores greater than 1000. In univariate analysis, age (r= 0.57, P < 0.000001), osteoprotegerin (OPG) (r= 0.44, P= 0.00002), and body mass index (BMI) (r= 0.24, P= 0.01) correlated positively with calcium score. Bone trabecular volume and trabecular thickness correlated negatively with calcium score (r=-0.24, P= 0.02; r=-0.22, P= 0.03). There was a correlation of borderline significance between calcium score and C-reactive protein (CRP) (r= 0.18, P= 0.062). The multiple linear regression analysis identified OPG as the only variable independently associated with coronary artery calcification. CONCLUSION: Coronary artery calcification is highly prevalent in the hemodialysis population and is associated with older age, higher BMI, inflammation and reduced trabecular bone volume. Higher OPG is independently associated with coronary artery calcification and may represent an incomplete self-defensive response to the progression of atherosclerosis in hemodialysis patients.     

Self-reported snoring is associated with chronic kidney disease in obese but not in normal-weight Chinese adults

BackgroundThe relationship between sleeping disorders and chronic kidney disease (CKD) has already been reported. Snoring, a common clinical manifestation of obstructive sleep apnea–hypopnea syndrome, is of clinical value in assessing sleeping disorder severity. However, investigations of the connection between snoring and CKD are limited, especially in normal-weight populations. This study assessed the relationship between snoring frequency and CKD in obese and normal-weight people in China.MethodsA community-based retrospective cross-sectional study of 3250 participants was performed. Study participants were divided into three groups – the regularly snoring group, occasionally snoring group, and never snoring group – based on their self-reported snoring frequency. CKD was defined as an estimated glomerular filtration rate of less than 60 mL/min/1.73 m². Multiple logistic regression analysis was used to explore the relevance between snoring frequency and CKD prevalence.ResultsThe CKD prevalence in obese participants was higher than that in normal-weight participants. Frequent snorers had a higher prevalence of CKD than those who were not frequent snorers in the obese group. Snoring frequency was correlated with CKD prevalence in obese participants independent of age, sex, smoking and drinking status, systolic blood pressure, triglyceride level, high-density lipoprotein, and homeostasis model assessment of insulin resistance (odds ratio: 2.66; 95% CI: 1.36–5.19; p=.004), while the same relationships did not exist in normal-weight participants (odds ratio: 0.79; 95% CI: 0.32–1.98; p=.614).ConclusionsSnoring appears to be independently associated with CKD in obese but not in normal-weight Chinese adults.     

Serum Trimethylamine-N-Oxide is Elevated in CKD and Correlates with Coronary Atherosclerosis Burden

Trimethlyamine-N-oxide (TMAO) was recently identified as a promoter of atherosclerosis. Patients with CKD exhibit accelerated development of atherosclerosis; however, no studies have explored the relationship between TMAO and atherosclerosis formation in this group. This study measured serum concentrations and urinary excretion of TMAO in a CKD cohort (n=104), identified the effect of renal transplant on serum TMAO concentration in a subset of these patients (n=6), and explored the cross-sectional relationship between serum TMAO and coronary atherosclerosis burden in a separate CKD cohort (n=220) undergoing coronary angiography. Additional exploratory analyses examined the relationship between baseline serum TMAO and long-term survival after coronary angiography. Serum TMAO concentrations demonstrated a strong inverse association with eGFR (r²=0.31, P<0.001). TMAO concentrations were markedly higher in patients receiving dialysis (median [interquartile range], 94.4 μM [54.8–133.0 μM] for dialysis-dependent patients versus 3.3 μM [3.1–6.0 μM] for healthy controls; P<0.001); whereas renal transplantation resulted in substantial reductions in TMAO concentrations (median [min–max] 71.2 μM [29.2–189.7 μM] pretransplant versus 11.4 μM [8.9–20.2 μM] post-transplant; P=0.03). TMAO concentration was an independent predictor for coronary atherosclerosis burden (P=0.02) and predicted long-term mortality independent of traditional cardiac risk factors (hazard ratio, 1.26 per 10 μM increment in TMAO concentration; 95% confidence interval, 1.13 to 1.40; P<0.001). In conclusion, serum TMAO concentrations substantially increase with decrements in kidney function, and this effect is reversed by renal transplantation. Increased TMAO concentrations correlate with coronary atherosclerosis burden and may associate with long-term mortality in patients with CKD undergoing coronary angiography.     

The Effect of Smoking on Endothelial Dysfunction in Autosomal Dominant Polycystic Kidney Disease Patients with Preserved Renal Function

BackgroundIn autosomal dominant polycystic kidney disease (ADPKD), endothelial dysfunction (ED) is common and occurs much earlier than kidney function impairment. The impact of smoking on ED in ADPKD patients has not been previously studied. The aim of this study was to investigate the potential contribution of smoking habits to ED and subclinical atherosclerosis in these patients.MethodsThis case-control study included 54 ADPKD patients with preserved renal function and 45 healthy control subjects. ED was assessed using ischemia-induced forearm flow-mediated dilatation (FMD). Carotid intima-media thickness (CIMT) was measured from 10 mm proximal to the right common carotid artery. Clinical demographic characteristics and laboratory data were recorded for the patients and control group. Regression analysis was used to determine independent associations of ED and CIMT.ResultsFMD was significantly lower in the ADPKD patients (19.5 ± 5.63 vs. 16.56 ± 6.41, p = .018). Compared with nonsmoker ADPKD patients, smoker patients had significantly lower FMD values (18.19 ± 6.52 vs. 13.79 ± 5.27, p = .013). In multiple regression analysis, age (β = –0.294, 95% CI: −0.392: −1.96, p = .001) for FMD and smoking (β  =  1.328, 95% CI: 0.251, 2.404, p = .017) for CIMT were independent predictors.ConclusionsPatients with ADPKD had more impaired endothelial function and subclinical atherosclerosis compared with control subjects. Smoking may increase the risk of subclinical atherosclerosis in ADPKD patients.     

Assessment of Matrix Gla Protein,Klotho Gene Polymorphisms,and Oxidative Stress in Chronic Kidney Disease

Abstract

Increased vascular calcification and oxidative stress are considered as extra renal risk factors at the pathogenesis cardiovascular events in chronic kidney disease (CKD). We investigated matrix Gla protein (MGP) (T-138C, Glu60X, Thr83Ala) and Klotho (Cys370Ser) gene polymorphisms, serum MGP levels, and oxidative stress status of 84 CKD patients and 37 healthy controls. The MGP gene Glu60X and Thr83Ala polymorphisms were significantly associated with CKD. The correlation between T-138C genotype of MGP gene, Cys370Ser genotype of Klotho gene, and CKD was not significant (p > 0.05). At the haplotype analysis, the combination of the X allele of Glu60X and the Thr allele of Thr83Ala showed a significantly increased risk of CKD (p < 0.05). X allele, Thr allele, and C allele of T-138C were associated with diabetes mellitus and CKD phenotypes occurring concurrently (p < 0.01). Serum zinc levels were significantly low in end-stage renal disease (ESRD) patients (p = 0.0001). The total comet score frequency of ESRD patients was higher than that of control group (p < 0.05). The urinary 8-hydroxy-2′-deoxyguanosine levels were significantly high in CKD patients (p < 0.05). According to this study, analyzing the distribution of MGP gene and oxidative stress status would be very informative in order to detect their role at CKD.     

Association between serum indoxyl sulfate levels with carotid-femoral pulse wave velocity in patients with chronic kidney disease

BackgroundThe role of indoxyl sulfate (IS), an important protein-bound uremic toxin, in arterial stiffness (AS) in patients with chronic kidney disease (CKD) is unclear.Materials and methodsWe investigated the association between serum IS levels and AS in a cross-sectional study of 155 patients with CKD. Patients in the AS group was defined as carotid-femoral pulse wave velocity (cfPWV) value >10 m/s measured by a validated tonometry system (SphygmoCor), while values ≤10 m/s were regarded as without AS group Serum IS was measured by liquid chromatography–mass spectrometry analysis.ResultsOf these CKD patients, AS was present in 51 (32.9%) patients, who were older, had a higher rate of diabetes, higher systolic blood pressure (SBP), and higher IS levels compared to those without AS. By multivariable logistic regression analysis, IS (adjusted odds ratio [aOR] 1.436, 95% confidence interval [CI] 1.085–1.901, p = 0.011), age (aOR 1.058, 95% CI 1.021–1.097, p = 0.002), and SBP (aOR 1.019, 95%CI 1.000–1.038, p = 0.049) were independent predictors of AS. By multivariable stepwise linear regression analysis, logarithmically transformed IS, age, DM, and SBP were significantly correlated with cfPWV. The area under the receiver-operating characteristic curve for serum log-IS was 0.677 (95%CI 0.598–0.750, p = 0.0001) to predict the development of AS in patients with CKD.ConclusionThese finding demonstrate that in addition to older and higher SBP, a high serum IS level is a significant biomarker associated with AS in patients with CKD.     

Fetuin-A and kidney function in persons with coronary artery disease--data from the Heart and Soul Study.

BACKGROUND: Fetuin-A is a serum protein that inhibits ectopic vascular calcification and is present in lower concentrations in end-stage renal disease than in healthy controls. Whether fetuin-A concentrations are also lower in the setting of mild-to-moderate chronic kidney disease (CKD) is unknown. METHODS: We evaluated the associations of several parameters of kidney function including measured 24 h urinary creatinine clearance (CrCl), estimated glomerular filtration rate (GFR) by the Mayo Clinic quadratic GFR equation (qGFR), serum cystatin-C concentrations, and urinary albumin-to-creatinine ratio with serum fetuin-A concentrations in 970 outpatients with coronary artery disease. We used general linear models to determine the adjusted mean fetuin-A concentrations within each kidney function category. RESULTS: The mean age of the study sample was 67 years, 82% were male, 71% had hypertension and 26% had diabetes mellitus. In adjusted analysis, we observed no significant differences in mean fetuin-A concentrations across groups defined by CrCl, qGFR, or albumin-to-creatinine ratio groups. For example, adjusted mean fetuin-A concentrations were 0.66 g/l in participants with CrCl > 90, 60-90 and 45-60 ml/min/1.73 m(2), and 0.65 g/l in participants with CrCl < 45 ml/min/1.73 m(2). Higher serum cystatin-C (indicating worse kidney function) was associated with higher adjusted mean serum fetuin-A concentrations (lowest quartile 0.62 g/l, highest quartile 0.68 g/l; P for trend <0.001). CONCLUSIONS: Among ambulatory patients with coronary artery disease, there is no evidence that mild-to-moderate CKD is associated with lower concentrations of serum fetuin-A compared with persons with normal renal function. The mechanisms explaining the association between CKD and vascular calcification remain elusive.     

Fibroblast Growth Factor–23 Levels Are Associated With Uric Acid But Not Carotid Intima Media Thickness in Renal Transplant Recipients

IntroductionCardiovascular disease (CVD) is the leading cause of mortality in chronic kidney disease (CKD) patients. Fibroblast growth factor–23 (FGF-23) is associated with atherosclerosis and cardiovascular mortality in CKD patients and healthy subjects. However, data in renal transplant recipients (RTR) are scarce. We aimed to determine factors associated with FGF-23 and to explore its relationship to atherosclerosis.MethodsForty-six patients and 44 controls were included. FGF-23 was measured from plasma. Carotid intima media thickness (CIMT) was evaluated ultrasonographically.ResultsPatients had higher waist circumference (WC; 92.2 ± 14.9 vs 85.3 ± 11.0 cm; P < .05), glucose (99.8 ± 17.2 vs 90.3 ± 6.5 mg/dL; P < .01), creatinine (1.43 ± 0.6 vs 0.86 ± 0.1 mg/dL; P < .01), triglyceride (160.4 ± 58.9 vs 135.6 ± 59.8 mg/dL; P < .05), white blood cells (WBC; 7938.6 ± 2105.2 vs 6715.7 ± 1807.5 WBC/mm³; P < .01), ferritin (217.0 ± 255.8 vs 108.3 ± 142.4 ng/mL; P < .05), uric acid (6.5 ± 1.6 vs 4.7 ± 1.3 mg/dL; P < .01), C-reactive protein (CRP; 8.2 ± 18.2 vs 5.3 ± 7.9 mg/L; P < .01), parathyroid hormone (PTH; 89.7 ± 59.2 vs 44.1 ± 16.7 pg/mL; P < .01), and alkaline phosphatase (ALP; 162.5 ± 86.6 vs 74.2 ± 21.9 U/L; P < .01). FGF-23 was higher in patients (11.7 ± 7.2 vs 9.6 ± 6.8 pg/mL; P < .05). CIMT was similar (0.58 ± 0.09 vs 0.57 ± 0.1 mm; P > .05). WC, creatinine, and uric acid were positively correlated with FGF-23, whereas albumin showed negative correlation. On multivariate analysis only creatinine and uric acid were determinants of FGF-23.ConclusionFGF-23 levels are associated with uric acid in RTR. Larger studies are needed to confirm this finding.     

Comparison of serum paraoxonase and arylesterase activities between iron deficiency anemia patients and chronic kidney disease patients with anemia

Objective: Altered paraoxonase (PON) and arylesterase (ARE) activities have been shown in anemic chronic kidney disease (CKD) patients and in iron deficiency anemia (IDA) patients. Whether accompanying anemia alone is responsible for this diminished PON and ARE activities in CKD patients or an additive factor for this is not well studied. Therefore, we tried to clarify this issue here. Methods: A total of 82 subjects that consisted of 19 patients with IDA (group 1), 23 anemic CKD patients (group 2), and 40 age and sex matched healthy subjects (group 3) were enrolled. Carotid intima media thickness (CIMT), serum total thiol (–SH), PON, and ARE activities of the participants were analyzed. Results: Group 2 patients had significantly lowest serum levels of Total –SH, PON and ARE. Further comparison showed that total –SH, PON and ARE levels were lower in group 1 than group 3 (p?=?0.0001 in both). Regarding comparison of group 1 and 2, only serum ARE levels were significantly lower in group 2 (p?=?0.001). PON activity was not different between group 1 and group 2 whereas ARE activity was lower in group 2 than groups 1 and 3. In addition, correlation analysis showed that CIMT was negatively correlated with PON and ARE. Conclusions: This markedly decreased ARE activity in CKD patients, which could not be explained by the anemia alone, may have a role in the pathogenesis of increased atherosclerosis in such patients. Still further studies are needed to certain this.     

Vascular Calcification: An Update on Mechanisms and Challenges in Treatment

Vascular calcification is highly associated with cardiovascular disease mortality, particularly in high-risk patients with diabetes and chronic kidney diseases (CKD). In blood vessels, intimal calcification is associated with atherosclerosis, whereas medial calcification is a nonocclusive process which leads to increased vascular stiffness and reduced vascular compliance. In the valves, calcification of the leaflets can change the mechanical properties of the tissue and result in stenosis. For many decades, vascular calcification has been noted as a consequence of aging. Studies now confirm that vascular calcification is an actively regulated process and shares many features with bone development and metabolism. This review provides an update on the mechanisms of vascular calcification including the emerging roles of the RANK/RANKL/OPG triad, osteoclasts, and microRNAs. Potential treatments adapted from osteoporosis and CKD treatments that are under investigation for preventing and/or regressing vascular calcification are also reviewed.