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.     

Cardiac valve calcifications and left ventricular hypertrophy in hemodialysis patients

Cardiac valve calcification (VC) is a common finding in end-stage renal disease patients. It was shown recently that VC is an independent predictor for all-cause and cardiovascular mortality in peritoneal dialysis patients. In hemodialysis (HD) patients, VC was associated with all-cause and cardiovascular mortality, but after adjusting for other cardiovascular risk factors and complications, as well as left ventricular mass index (LVMI), it lost significance. The aim of the study was to assess the relationship between VC and left ventricular hypertrophy in hemodialysis patients. Echocardiographic examination with mitral and aortic valves assessment and LVMI calculation was performed in 65 HD patients ages 49+/-12, with duration of HD therapy 38+/-32 months. VC were found in 32 of 65 patients (49%)-Group VC(+), mitral valve calcifications (MVC) in 10, aortic valve calcifications (AVC) in 9, and both valves calcifications (MVC+AVC) in 13 patients. Patients with VC were older, on HD therapy were longer, had higher systolic and pulse pressure, and had higher LVMI. Patients with both VCs had the highest LVMI. No significant differences were found with respect to Ca, P, PTH, and mean Ca x P product, but the incidence of Ca x P product above 4.43 mmol2/L2 was higher in VC(+) compared with those without VCs. VC coexists with left ventricular hypertrophy, particularly when both valves are calcified. Even short-lasting incidents of increased Ca x P product may lead to cardiac VC.     

The influence of cardiac valvular calcification on all-cause and cardiovascular mortality in maintenance hemodialysis patients

Objective

To investigate the effect of cardiac valve calcification (CVC) on all-cause and cardiovascular mortality in maintenance hemodialysis (MHD) patients.

Methods

A retrospective cohort study was conducted in 183 long-term hemodialysis patients with complete follow-up data from January 1, 2012, to December 30, 2015. The baseline data between CVC and non-CVC groups were compared. Kaplan–Meier method was used to analyze all-cause and cardiovascular mortality. The effect of CVC on prognosis was analyzed using the Cox proportional hazard regression model and subgroup analysis.

Results

Among 183 patients under hemodialysis, 104 (56.8%) were males, with an average age of 56.1?±?17.0 years and 68 (37.2%) were complicated with valvular calcification. The median follow-up period was 30.8 months. All-cause and cardiovascular mortality were 50% vs. 14.8% and 25% vs. 7.0% in the CVC and non-CVC groups, respectively (P?<?0.05). Kaplan–Meier indicated that differences in all-cause and cardiovascular mortality were statistically significant between the two groups (P?<?0.001). Cox regression analysis showed that CVC significantly increased all-cause (hazards ratio [HR] 2.161 [1.083–4.315]) and cardiovascular mortality (3.435 [1.222–9.651]) after adjusting for multiple factors. Meanwhile, CVC also increases the incidence of new-onset cardiovascular events. Subgroup analysis revealed that all-cause and cardiovascular mortality were significantly higher in patients with aortic valve calcification (AVC) than in patients with mitral valve calcification (MVC). Multivariate calibration showed that AVC increased the risk of cardiovascular death (HR 5.486 [1.802–16.702]) (P?<?0.05), whereas MVC did not. By further comparing the echocardiographic data of the two groups, the incidence of LVH and pulmonary hypertension in the AVC group was significantly higher than that in the MVC group.

Conclusion

Valve calcification increases the risk of all-cause and cardiovascular mortality in MHD patients, also new-onset cardiovascular events, and aortic valve calcification contributes more to the risk of cardiovascular mortality.

     

Cardiac Valve Calcifications and Left Ventricular Hypertrophy in Hemodialysis Patients

Cardiac valve calcification (VC) is a common finding in end-stage renal disease patients. It was shown recently that VC is an independent predictor for all-cause and cardiovascular mortality in peritoneal dialysis patients. In hemodialysis (HD) patients, VC was associated with all-cause and cardiovascular mortality, but after adjusting for other cardiovascular risk factors and complications, as well as left ventricular mass index (LVMI), it lost significance. The aim of the study was to assess the relationship between VC and left ventricular hypertrophy in hemodialysis patients. Echocardiographic examination with mitral and aortic valves assessment and LVMI calculation was performed in 65 HD patients ages 49 ± 12, with duration of HD therapy 38 ± 32 months. VC were found in 32 of 65 patients (49%)—Group VC(+), mitral valve calcifications (MVC) in 10, aortic valve calcifications (AVC) in 9, and both valves calcifications (MVC + AVC) in 13 patients. Patients with VC were older, on HD therapy were longer, had higher systolic and pulse pressure, and had higher LVMI. Patients with both VCs had the highest LVMI. No significant differences were found with respect to Ca, P, PTH, and mean Ca × P product, but the incidence of Ca × P product above 4.43 mmol²/L² was higher in VC(+) compared with those without VCs. VC coexists with left ventricular hypertrophy, particularly when both valves are calcified. Even short-lasting incidents of increased Ca × P product may lead to cardiac VC.     

Impact of carotid atherosclerosis on long-term mortality in chronic hemodialysis patients

BACKGROUND: Cardiovascular event is the major cause of mortality in patients on maintenance hemodialysis. We prospectively tested the predictive values of atherosclerotic parameters for all-cause and cardiovascular outcomes in 219 hemodialysis patients (age, 58 +/- 13 years; time on hemodialysis, 13 +/- 7 years; male/female, 144/75). METHODS: We measured blood homocysteine (Hcy), ultrasound carotid artery intima media thickness (IMT) and % aortic wall calcification at L2/3 region [% of calcification index in the abdominal aortic wall (%ACI)] by computed tomography (CT) scan, and followed all patients for 5 years. RESULTS: During the follow-up periods, 54 patients (25%) died, 40 (74%) of them of cardiovascular causes. IMT was significantly higher in patients who expired (0.75 +/- 0.02 mm) than in those who survived (0.62 +/- 0.01 mm). IMT was significantly correlated with age (r = 0.47, P < 0.01) and %ACI (r = 0.27, P < 0.01). The survival rate during the observation was significantly lower in the final IMT third (58%) than in the first (90%) and the middle IMT third (80%) (P < 0.01). Multivariate Cox proportional hazards analysis revealed that diabetes and IMT became independent determinants of all-cause and cardiovascular death. Adjusted hazards ratios of all-cause and cardiovascular mortality for an increase of 0.1 mm in IMT were 1.31 (95% CI, 1.07 to 1.59) and 1.41 (95% CI, 1.12 to 1.76). In contrast, %ACI at abdominal aorta and blood Hcy did not affect their 5-year mortality. CONCLUSION: These findings suggested that measurement of carotid artery IMT is useful for predicting long-term mortality in patients receiving maintenance hemodialysis.     

Circulating nonphosphorylated carboxylated matrix gla protein predicts survival in ESRD

The mechanisms for vascular calcification and its associated cardiovascular mortality in patients with ESRD are not completely understood. Dialysis patients exhibit profound vitamin K deficiency, which may impair carboxylation of the calcification inhibitor matrix gla protein (MGP). Here, we tested whether distinct circulating inactive vitamin K-dependent proteins associate with all-cause or cardiovascular mortality. We observed higher levels of both desphospho-uncarboxylated MGP (dp-ucMGP) and desphospho-carboxylated MGP (dp-cMGP) among 188 hemodialysis patients compared with 98 age-matched subjects with normal renal function. Levels of dp-ucMGP correlated with those of protein induced by vitamin K absence II (PIVKA-II; r = 0.62, P < 0.0001). We found increased PIVKA-II levels in 121 (64%) dialysis patients, indicating pronounced vitamin K deficiency. Kaplan-Meier analysis showed that patients with low levels of dp-cMGP had an increased risk for all-cause and cardiovascular mortality. Multivariable Cox regression confirmed that low levels of dp-cMGP increase mortality risk (all-cause: HR, 2.2; 95% CI, 1.1 to 4.3; cardiovascular: HR, 2.7; 95% CI, 1.2 to 6.2). Furthermore, patients with higher vascular calcification scores showed lower levels of dp-cMGP. In 17 hemodialysis patients, daily supplementation with vitamin K2 for 6 weeks reduced dp-ucMGP levels by 27% (P = 0.003) but did not affect dp-cMGP levels. In conclusion, the majority of dialysis patients exhibit pronounced vitamin K deficiency. Lower levels of circulating dp-cMGP may serve as a predictor of mortality in dialysis patients. Whether vitamin K supplementation improves outcomes requires further study.     

Cross-sectional association of kidney function with valvular and annular calcification: the Framingham heart study

Valvular calcification is common in the setting of end-stage kidney disease and is associated with increased risks for cardiovascular disease events. It is unknown whether the prevalence of valvular calcification is increased in milder kidney disease after accounting for cardiovascular risk factors. Participants who attended the sixth examination of the Framingham Offspring Study (1995 to 1998) were eligible. Kidney function was estimated by GFR using the simplified Modification of Diet in Renal Disease Study equation. Mitral annular calcification (MAC), aortic sclerosis, and aortic annular calcification were assessed by two-dimensional echocardiography. Logistic regression was used to examine the odds of valvular calcification among participants with chronic kidney disease (CKD; GFR < 60 ml/min per 1.73 m(2)). A total of 3047 participants (52% women; mean age 59 +/- 10 yr) were available for analysis. CKD was present in 8.6% (n = 262) of the sample. Among participants with valve/annular calcification (n = 284; 9.3%), 20% had CKD, compared with 7% in patients without valvular calcification. After adjustment for age, gender, systolic and diastolic BP, hypertension treatment, total/HDL cholesterol, body mass index, diabetes, smoking status, and cardiovascular disease, participants with CKD had a 60% increased odds of MAC (odds ratio 1.6; 95% confidence interval 1.03 to 2.5). There was no significant association between CKD and either aortic sclerosis or aortic annular calcification (odds ratio 1.1 and 1.1, respectively). After age and gender adjustment, the combination of both CKD and MAC was associated with a three-fold increased risk for death compared with those with neither condition (P = 0.0004). In the community, CKD is associated with presence of MAC before the onset of ESRD. Further research is warranted to understand whether traditional and novel vascular risk factor burden, as well as metabolic derangements found in early kidney disease, can account for the CKD-MAC association.     

Low fetuin-A levels are associated with cardiovascular death: Impact of variations in the gene encoding fetuin

BACKGROUND: Vascular calcification is common among end-stage renal disease (ESRD) patients and a central characteristic of the atherosclerotic cardiovascular disease observed in dialysis patients. Fetuin-A, a circulating calcium-regulatory glycoprotein that inhibits vascular calcification, is associated with inflammation and outcome in dialysis patients. In the present study, we evaluated the association between fetuin-A, clinical phenotype, and outcome, as well as the impact of fetuin gene (AHSG) polymorphisms on the protein product and outcome. METHODS: In a cohort of 258 (161 males) ESRD patients starting renal replacement therapy [glomerular filtration rate (GFR) 6.8 +/- 0.2 mL/min] aged 52 +/- 1 years the following parameters were studied: presence of malnutrition (subjective global assessment), comorbidity [diabetes mellitus and clinical manifest cardiovascular disease (CVD)], carotid plaques (N= 101), hs-CRP, fetuin-A, S-albumin, interleukin (IL)-6, and single nucleotide polymorphisms (SNPs) in the AHSG gene (N= 215) at amino acid positions Thr248Met (C-->T), Thr256Ser (C-->G), Asp276Asn (G-->A), and Arg317Cys (C-->T). RESULTS: Both all-cause (P < 0.001) and cardiovascular (P < 0.001) mortality were associated with low fetuin-A levels independently of age, smoking, diabetes, S-albumin, CVD, and inflammation (CRP > or =10 mg/L). Inflamed (0.199 vs. 0.247 g/L; P < 0.01) and malnourished (0.207 vs. 0.262 g/L; P < 0.05) patients had significantly lower median fetuin-A than noninflamed and well-nourished ESRD patients, respectively. In a logistic regression model (N= 101), fetuin-A was significantly (P < 0.05) associated with the presence of carotid plaques independently of age, CVD, diabetes, S-albumin, gender, and inflammation. Significant correlations were observed between fetuin-A and both S-albumin (Rho = 0.30; P < 0.0001) and IL-6 (Rho =-0.21; P < 0.01). Patients with the AHSG 256Ser allele had lower serum fetuin-A levels, and higher all-cause and cardiovascular mortality rate if they were inflamed. CONCLUSION: The present study shows that a low fetuin-A level is associated with malnutrition, inflammation, and atherosclerosis (carotid plaques), as well as with increased cardiovascular and all-cause mortality. Because the present study demonstrates an effect of variations in the AHSG gene on both circulating fetuin-A levels and outcome, this indicates that ESRD patients with the AHSG 256Ser allele are at risk of accelerated vascular calcification.     

Resting energy expenditure and subsequent mortality risk in peritoneal dialysis patients

Cardiovascular disease is the leading cause of death in ESRD patients and is strongly associated with malnutrition. The mechanism of malnutrition is not clear, but hypermetabolism is suggested to contribute to cardiac cachexia. This study examined resting energy expenditure (REE) in relation to the clinical outcomes of ESRD patients who receive continuous ambulatory peritoneal dialysis (CAPD) treatment. A prospective observational cohort study was performed in 251 CAPD patients. REE was measured at study baseline using indirect calorimetry together with other clinical, nutritional, and dialysis parameters. Patients were followed up for a mean +/- SD duration of 28.7 +/- 14.3 mo. REE was 39.1 +/- 9.6 and 40.1 +/- 9.0 kcal/kg fat-free edema-free body mass per day for men and women, respectively (P = 0.391). Using multiple regression analysis, fat-free edema-free body mass-adjusted REE was negatively associated with residual GFR (P < 0.001) and serum albumin (P = 0.046) and positively associated with diabetes (P = 0.002), cardiovascular disease (P = 0.009), and C-reactive protein (P = 0.009). At 2 yr, the overall survival was 63.3, 73.6, and 95.9% (P < 0.0001), and cardiovascular event-free survival was 72.3, 84.6, and 97.2% (P = 0.0003), respectively, for patients in the upper, middle, and lower tertiles of REE. Adjusting for age, gender, diabetes, and cardiovascular disease, patients in the upper and middle tertiles showed a 4.19-fold (95% confidence interval, 2.15 to 8.16; P < 0.001) and a 2.90-fold (95% confidence interval, 1.49, 5.63; P = 0.002) respective increase in the risk of all-cause mortality compared with those in the lower tertile. However, the significance of REE in predicting mortality was gradually reduced when additional adjustment was made for C-reactive protein, serum albumin, and residual GFR in a stepwise manner. In conclusion, a higher REE is associated with increased mortality and cardiovascular death in CAPD patients and is partly related to its close correlations with residual kidney function, cardiovascular disease, inflammation, and malnutrition in these patients.     

Inflammation, residual kidney function, and cardiac hypertrophy are interrelated and combine adversely to enhance mortality and cardiovascular death risk of peritoneal dialysis patients

C-reactive protein (CRP), the prototype marker of inflammation, and cardiac hypertrophy are important prognostic indicators in dialysis patients. Residual renal function (RRF) has also been shown to influence survival of peritoneal dialysis (PD) patients. This study examined the relations between inflammation, RRF, and left ventricular hypertrophy (LVH) and determined whether inflammation, RRF, and LVH combine adversely to predict the outcomes of PD patients. A prospective observational study was performed in 231 chronic PD patients. Left ventricular mass index (LVMi), residual glomerular filtration rate (GFR), CRP, hemoglobin, serum albumin, and BP were determined at study baseline and related to outcomes. On univariate analysis, age (P = 0.002), dialysis duration (P = 0.004), coronary artery disease (P < 0.001), pulse pressure (P < 0.001), hemoglobin (P < 0.001), serum albumin (P = 0.032), log-CRP (P < 0.001), and GFR (P < 0.001) were significantly associated with log-LVMi. Log-CRP was positively correlated with pulse pressure (R = 0.218, P = 0.001) and negatively correlated with GFR (R = -0.272, P < 0.001). Multivariate analysis showed that log-CRP (P = 0.008) and RRF (P = 0.003) remained associated with log-LVMi independent of hemoglobin, serum albumin, arterial pulse pressure, and coronary artery disease. After follow-up for 30 +/- 14 mo, 34.2% patients had died. CRP, RRF, and LVMi each were significantly predictive of all-cause mortality and cardiovascular death. Kaplan-Meier analysis showed a significant increase in all-cause (P < 0.0001) and cardiovascular mortality (P < 0.0001) as the number of risk factors, namely CRP >/=50th percentile, no RRF, and LVMi>/= 50th percentile increased with the 2-yr all-cause mortality and cardiovascular death reaching as high as 61% and 46%, respectively, for patients who had all three risk factors. Compared with patients with none of the three risk factors, those with all three risk factors had an adjusted hazards ratio of 6.94 (P < 0.001) and 5.43 (P = 0.001) for all-cause mortality and cardiovascular mortality, respectively. In conclusion, inflammation, RRF, and LVH are interrelated and combine adversely to increase mortality and cardiovascular death risk of PD patients.     

Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality.

BACKGROUND: Cross-sectional and follow-up studies on end-stage renal disease patients showed that arterial calcifications are associated with cardiovascular (CV) morbidity and are an independent predictor of all-cause and CV mortality. However, these studies did not examine the impact on prognosis according to the type of calcification, i.e. intimal vs medial. Arterial media calcification (AMC), a non-occlusive condition, affects haemodynamics differently from arterial intima calcification (AIC), which occurs in atherosclerotic plaques. The aim of this study was to investigate the prognostic value of AMC in relationship to all-cause or CV mortality for stable haemodialysis (HD) patients. METHODS: We included 202 such patients in the present study. At baseline, soft-tissue native radiograms of the pelvis and the thigh were analysed for the presence and type (AMC vs AIC) of arterial calcifications. All patients underwent B-mode ultrasonography of the common carotid artery to determine the presence of atherosclerotic calcified plaques, measurement of aortic pulse wave velocity and echocardiography. RESULTS: AIC was usually observed in older patients with a clinical history of atherosclerosis before starting HD treatment and typical risk factors associated with atherosclerotic disease. AMC was observed in young and middle-aged patients without conventional atherosclerotic risk factors. AMC was closely associated with the duration of HD and calcium-phosphate disorders, including the oral dose of elemental calcium prescribed as phosphate binder (CaCO(3)). Compared to patients with AIC, patients with AMC had a longer survival, but in turn their survival was significantly shorter than that of patients without calcifications. CONCLUSIONS: AMC is a strong prognostic marker of all-cause and CV mortality in HD patients, independently of classical atherogenic factors. The principal effect of AMC on arterial function is increased arterial stiffness.     

Clinical study on the relationship between calcium and phosphorus metabolism with aortic arch calcification in maintenance peritoneal dialysis patients

Objective To retrospectively study the risk factors of aortic arch calcificationand its influence on the survival prognosis of maintenance peritoneal dialysis patients. Methods One hundred seventy-seven cases of maintenance peritoneal dialysis patients were enrolled, including 66 cases of aortic arch calcification cases. Their general dialysis data were collected for the evaluation of dialysis adequacy and residual renal function, and their chest X-rays were recorded to assess the degree of aortic arch calcification. The two variables Logistics regression was used to analyze independent risk factors of aortic arch calcification; Kaplan-Meier analysis was used to analyze the influence on prognosis of dialysis patients; and multivariate COX regression was employed to analyze independent risk factors of death in dialysis patients. Results Among the 177 selected cases of peritoneal dialysis patients, 66 cases (37.29%) presented with aortic arch calcification. Elevated serum phosphorus was an independent risk factor of aortic arch calcification (OR=54.69，95%CI: 10.01-298.65, P＜0.01). The probability of survival in patients with mild and moderate (severe) calcification of aortic arch was less than those without calcification. Moderate (severe) calcification of aortic arch was the independent risk factor of all-cause mortality and cardiovascular disease mortality, whose hazard ratios in patients with calcification were 3.779 times and 5.636 times of those in patients without calcification respectively. Conclusions Hyperphosphatemia is an independent risk factor promoting the development of calcification of aortic arch. The probability of survival in patients with mild and moderate (severe) calcification of aortic arch is less than those without calcification; moderate (severe) calcification of aortic arch is the independent risk factor of all-cause mortality and cardiovascular disease mortality.     

Vascular calcification and cardiovascular function in chronic kidney disease.

BACKGROUND: Vascular calcification and arterial stiffening are independent predictors of all causes and cardiovascular mortality in chronic kidney disease (CKD). Few data are currently available comparing vascular calcification and its attendant functional cardiovascular consequences between CKD stage 4 patients and both peritoneal dialysis (PD) and haemodialysis (HD) (CKD stage 5) patients. METHOD: We studied 134 subjects (60 HD, 28 PD and 46 CKD 4). Vascular calcification was quantified using multi-slice spiral CT scanning of a 5 cm standardized segment of superficial femoral artery. Pulse wave analysis and pulse wave velocity were assessed using applanation tonometry, to determine arterial compliance. Further digital arterial pulse wave analysis was used to measure systemic haemodynamic variables. All medications were recorded and biochemical variables were time averaged for the 6 months prior to entering the study. RESULTS: Forty-seven percent of CKD 4 patients demonstrated vascular calcification as compared with CKD 5 (71% PD and 73% HD, P = 0.02). HD patients had higher calcification scores (median 121) than either PD (median 21) or CKD 4 (median 0) (P = 0.008). There were no significant differences in baseline characteristics between the groups. Comparing tertiles of patients (based on calcification score), increased calcification score was associated with a reduction in arterial compliance (mean PWV 8.9 +/- 1.1, 11 +/- 3.6, 11.3 +/- 3.7 m/s, P = 0.005). The degree of calcification did not influence systolic blood pressure (BP), diastolic BP or heart rate. However, more heavily calcified patients demonstrated significantly higher mean pulse pressures (58 +/- 19, 74 +/- 22 and 72 +/- 25 mmHg, P = 0.001), lower total peripheral resistance (1.5 +/- 1, 1.3 +/- 0.8, 0.9 +/- 0.4, P = 0.01) and higher stroke volume (84 +/- 25, 95 +/- 29, 106 +/- 39 ml, P = 0.01). More heavily calcified patients were significantly older and predominantly male. CONCLUSION: This study has successfully utilized a novel technique for the quantification of calcification. We have demonstrated vascular calcification and associated cardiovascular dysfunction in CKD 4, PD and HD with significant differences between the groups. Thirty percent of individuals show no calcification, even those established on renal replacement therapy for a prolonged period of time. Further work is required to identify factors which promote progression of arterial calcification in those who are susceptible.     

Vascular calcification and disordered mineral metabolism in dialysis patients

Vascular calcification is an active, cell-mediated process that can involve either the intima or media of the blood vessels. The current methods used to clinically measure vascular calcification cannot distinguish between intimal (invariably atherosclerotic) and medial calcification. The high calcification scores seen in patients with end-stage renal disease likely represent a composite of high calcification burden in both sites. The severity of vascular calcification has been associated with a variety of findings including left ventricular hypertrophy and angiographic vascular stenosis as well as with all-cause and cardiovascular mortality. There is increasing evidence that disordered mineral metabolism participates in the process of vascular calcification and is one of the mechanisms whereby hyperphosphatemia, hypercalcemia, and hyperparathyroidism enhance cardiovascular and all-cause mortality of end-stage renal disease patients. There are no studies showing improved outcomes of ESRD patients with aggressive control of disordered mineral metabolism. However, the preponderance of evidence argues strongly in favor of aggressive management of these abnormalities from starting early in the course of chronic kidney disease in the hope of improving patient outcomes.     

Fetuin-A and extraosseous calcification in uremia

PURPOSE OF REVIEW: It has become increasingly clear that vascular calcification, as part of accelerated uremic atherosclerosis, may powerfully predict mortality in the dialysis population. Secondary hyperparathyroidism and its consequences explain part of this phenomenon; however, serum concentrations of calcium and phosphate ions exceed their solubility product in an aqueous solution and must be prevented from precipitation by additional mechanisms. Fetuin-A is an inflammation-related calcium-regulatory glycoprotein acting as a systemic calcification inhibitor. The emerging role of fetuin-A deficiency as a risk factor in dialysis patients was documented in a cross-sectional study demonstrating a significant correlation with all-cause and cardiovascular mortality. RECENT FINDINGS: In-vitro studies in vascular smooth muscle cells revealed that fetuin-A interacts directly with matrix vesicle release and may thus modulate vascular calcification processes locally and at early stages. Accordingly, prominent fetuin-A staining of calcified vessel segments obtained from uremic patients, in the absence of local expression, emphasizes its potential role as a circulating defense against overwhelming calcification. While increased fetuin-A levels positively correlated with vascular calcification in patients with diabetes and mild to moderate renal impairment, an inverse relationship was observed in dialysis patients. Both chronic inflammation and uremia may thus contribute to exhausting fetuin-A release in the late stages of kidney disease. Specific polymorphisms of the fetuin-A gene may be additional determinants of fetuin-A deficiency. SUMMARY: Deficiencies of calcification inhibitors such as fetuin-A are relevant pathomechanisms in the progression of uncontrolled vascular calcification and may offer potential for future therapeutic approaches.     

Arteriovenous fistula use is associated with lower cardiovascular mortality compared with catheter use among ESRD patients

The arteriovenous fistula (AVF) is the recommended form of dialysis vascular access, however, limited studies suggest that AVF creation may result in increased cardiovascular stress and remodeling. To explore the contribution of vascular access type to cardiovascular-related (CV) mortality, we analyzed USRDS Clinical Performance Measures data comprising 4854 patients that initiated dialysis between October 1, 1999-December 31, 2004. CV mortality included death from acute myocardial infarction, atherosclerotic heart disease, cardiomyopathy, arrhythmia, cardiac arrest or stroke. Risk of cardiovascular mortality during a 4-year observation was analyzed by Cox-regression methods with adjustments for demographic and co-morbid conditions. AVF use was strongly associated with lower all-cause and CV mortality. After adjustment for covariates, AVF use 90 days after dialysis initiation remained significantly associated with lower cardiovascular mortality [hazard ratio (HR) 0.69, p = 0.0004] compared with catheter use. These findings suggest that vascular access type influences cause-specific mortality beyond that of infection, and support existing guidelines recommending the use of an AVF early in the course of chronic end-stage renal disease therapy.     

Fetuin-A is not associated with mortality in chronic kidney disease

Fetuin-A is a serum protein that inhibits vascular calcification such that lower levels are associated with a higher prevalence of vascular calcification and mortality risk among end-stage renal disease populations. We analyzed data of 822 persons in the Modification of Diet in Renal Disease study, a randomized, controlled trial of persons with predominantly non-diabetic stage 3-4 chronic kidney disease (CKD). Serum fetuin-A levels were measured in baseline serum. Survival status and cause of death were determined by the National Death Index. Cox proportional hazard models evaluated the association of fetuin-A levels with all-cause and cardiovascular mortality. Glomerular filtration ranged from 13 to 55 ml per min per 1.73 m(2). During a median follow-up of 9.5 years, 25% of persons died from any cause and 12% died from a cardiovascular cause. Compared to the lowest tertile, no association was found between the highest fetuin-A tertile and all-cause or cardiovascular mortality. Similarly, no association was found between fetuin-A as a continuous variable and all-cause or cardiovascular mortality. Our study shows that serum fetuin-A levels are not related to all-cause or cardiovascular mortality among persons with predominantly non-diabetic stage 3 or 4 CKD.     

Inverse association between lipid levels and mortality in men with chronic kidney disease who are not yet on dialysis: effects of case mix and the malnutrition-inflammation-cachexia syndrome

High total cholesterol is associated with lower mortality in dialysis patients, but the relationship between lipid levels and mortality in patients who have chronic kidney disease (CKD) and are not yet on dialysis is poorly described. This study examined the association between lipid levels and all-cause and cardiovascular mortality in 986 male patients (age 67.4 +/- 10.9 yr; race 23.7% black) who had CKD and were not yet on dialysis. Associations were determined in fixed-covariate and time-dependent Cox models, before and after adjustment for components of case mix and surrogates for malnutrition-inflammation-cachexia syndrome (MICS). Lower total cholesterol quartiles were associated with higher all-cause mortality in a fixed-covariate model that was adjusted for age, race, and body mass index (hazard ratio [95% confidence interval] for cholesterol <153, 153 to 182, and 183 to 215 versus >215 mg/dl: 1.91 [1.35 to 2.69], 1.36 [0.96 to 1.92], 1.10 [0.78 to 1.57]; P < 0.001 for trend), but this association was attenuated after adjustment for case mix (P = 0.023 for trend) and abolished after additional adjustment for MICS (P = 0.14 for trend), with time-dependent Cox models showing similar results. Similar tendencies also were detected in the association between levels of LDL cholesterol with total and cardiovascular mortality and triglycerides with all-cause mortality in both fixed-covariate and time-dependent analyses. Lower lipid levels are associated with higher mortality in patients who have moderate and advanced CKD and are not yet on dialysis. This inverse association is explained in part by case-mix characteristics and the presence of surrogates for MICS.     

Detection of cardiac calcinosis in hemodialysis patients by whole-body scintigraphy with 99m-technetium methylene diphosphonate

A noninvasive method for the diagnosis of cardiac calcinosis, a life-threatening complication in hemodialysis patients with end-stage renal disease (ESRD), has not, as yet, been firmly established. We tested whether whole body scanning with 99m-technetium methylene diphosphonate (MDP) might visualize cardiac calcinosis. In 19 consecutive chronic hemodialysis ESRD patients (13 males and 6 females, aged 40-81, mean 63 +/- 8 years) with cardiovascular disease [mitral annular calcinosis and/or calcified aortic valve (n = 4), hemodialysis cardiomyopathy (n = 1), coronary artery disease (n = 9) and peripheral artery atherosclerotic disease (n = 6)], MDP uptake in the heart was compared to that in 7 non-ESRD controls with hyperparathyroidism due to adenoma. Cardiac and lung field MDP uptake was confirmed in only 3 (16%) and 5 (26%) of the 19 ESRD subjects, respectively, but was absent in controls. Positive cardiac uptake was related to cardiac calcified complications (mobile intracardiac calcinosis, myocardial calcinosis and mitral annular calcification) and the duration of hemodialysis (p = 0.015). While it was statistically insignificant, subjects showing MDP uptake were elder and had higher serum Ca or Ca x P product and lower intact parathyroid hormone levels. These results suggest that cardiac calcinosis in ESRD patients can be detected noninvasively by myocardial scintigraphy with 99m-technetium MDP.     

Serum phosphorus variation is associated with mortality in maintenance hemodialysis patients

Objective To investigate the relationship between serum phosphorus variability and mortality in maintenance hemodialysis (MHD) patients. Methods A total of 502 MHD cases from Renji hospital hemodialysis center were registered in Shanghai Registry Network from January 2007 to April 2015. They were recruited with general information, laboratory results and outcomes. According to their median of coefficient of variation (CV) of blood phosphorus, the patients were divided into high variation group (CV≥0.226 mmol/L) and low variation group (CV＜0.226 mmol/L). The relationship of serum phosphorus CV with all-cause mortality and cardiovascular disease mortality was assessed respectively. Results The average age was (63.9±14.6) years, the median dialysis age was 82.0 (43.0, 139.0) months, 118 patients (23.5%) died for all cause and 64 patients (12.7%) died for cardiovascular disease. Compared with patients in low phosphorus variation group, patients had a higher all-cause mortality in high phosphorus variation group (27.7% vs 19.3%, P=0.028). Higher cardiovascular disease mortality was observed in high variation group as well, but this difference was no statistical significant (15.4% vs 10.0%, P=0.082). COX regression analysis showed that ＞60 years of age (HR=2.762, 95%CI 1.707-4.468, P＜0.001), low hemoglobin (HR=0.466, 95%CI 0.317-0.686, P＜0.001), low albumin (HR=0.555, 95%CI 0.366-0.840, P=0.005), high CV of phosphorus (HR=1.479, 95%CI 1.023-2.139, P=0.037) were independent risk factors for all-cause mortality. Moreover, ＞60 years of age (HR=2.666, 95%CI 1.469-4.837, P=0.001), low hemoglobin (HR=0.480, 95%CI 0.238-0.801, P=0.005), and high CV of phosphorus (HR=1.655, 95%CI 1.003-2.729, P=0.049) were independent risk factors for cardiovascular disease mortality. There was no significant statistical difference between patients phosphorus on target and patients phosphorus below target in all-cause disease mortality (P=0.065) and cardiovascular disease mortality (P=0.425). High variation group whose phosphorus on target had higher all-cause mortality and cardiovascular disease mortality than those in low variation group (29.2% vs 16.9%, P=0.047; 15.0% vs 6.0%, P=0.033). Kaplan-Meier method showed that patients with high phosphorus variation had higher all-cause (P=0.023) and cardiovascular disease mortality (P=0.047) than patients with low phosphorus variation. Conclusions The high CV of phosphorus is independently correlated with all-cause and cardiovascular disease mortality. Patients with standard-reaching phosphorus in the low variation group have a lower mortality. A serum phosphorus level sustainably reaching the standard may improve the survival in MHD patients.