Angels Betriu

Large Artery Calcification on Dialysis Patients Is Located in the Intima and Related to Atherosclerosis

BACKGROUND AND OBJECTIVES Vascular calcification (VC) has a significant effect in cardiovascular diseases on dialysis patients. However, VC is assessed with x-ray-based techniques, which do not inform about calcium localization (intima, media, atherosclerosis-related). The aim of this work is to study VC and its related factors using arterial ultrasound to report the exact location of calcium. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was an observational, cross-sectional, case-control study that included 232 patients in dialysis and 208 age- and sex-matched controls with normal kidney function. Demographic data and laboratory values were collated. Carotid, femoral, and brachial ultrasounds were performed to assess VC and atherosclerosis burden using a standardized protocol. RESULTS Cardiovascular risk factors were predominantly found in controls, although the burden of atherosclerosis was higher in the dialysis group. VC was significantly more prevalent in the group of patients on dialysis than control subjects, and in both groups the most prevalent pattern of VC was linear calcification located in the intima of the artery wall. Age and undergoing dialysis (with or without previous cardiovascular diseases) were positively and significantly associated with linear calcification. Conversely, the absence of atherosclerosis and low levels of C-reactive protein and phosphorus significantly impeded the development of linear calcification. CONCLUSIONS VC in large, conduit arteries is more prevalent in patients on dialysis than controls and is predominantly located in a linear fashion in the intima of the arteries.

Treatment with Sevelamer Decreases Bicarbonate Levels in Hemodialysis Patients

Accessible online at: www.karger.com/journals/nef Dear Sir, Until now, hyperparathyroidism has been among the most difficult chronic renal failure-associated conditions to treat. Hyperphosphatemia plays a key role in the development of hyperparathyroidism in hemodialysis patients. Although new membranes and high-flux dialyzers have improved hemodialysis quality in recent years, phosphate balance remains positive regardless of the type of hemodialysis [1]. Slow nocturnal daily hemodialysis is effective but is not applicable in most hemodialysis facilities [2]. The use of calcium-based salts is useful to bind phosphate but often results in hypercalcemia and increase of the calcium ! phosphate product, thus limiting the use of calcitriol and increasing soft-tissue calcifications [3]. Aluminum-based salts carry a risk of intoxication which also limits their use. Sevelamer is a new aluminum and calcium free molecule which has proven to be effective in lowering phosphate without raising calcium levels and consequently, decreasing the calcium ! phosphate product [4, 5]. However, although some studies have shown a decrease of bicarbonate levels during the first weeks of treatment with sevelamer [6, 7], this aspect has not been given much attention by investigators. We investigated the effects of sevelamer on bicarbonate levels in 18 stable chronic hemodialysis patients who were followed-up for 3 months. They were previously treated with calcium carbonate/acetate or alumiFig. 1. Ca ! P product (a) and bicarbonate (b) levels at baseline, 15 days and 3 months after the introduction of sevelamer.

Prevalence of subclinical atheromatosis and associated risk factors in chronic kidney disease: the NEFRONA study

BACKGROUND The causes of the high cardiovascular mortality observed in chronic kidney disease (CKD) are unknown. Here, we report data on prevalence of subclinical atherosclerosis in the NEFRONA population and a stratified multivariate logistic analysis of factors associated with the presence of plaque. METHODS We analysed 2445 patients with an estimated glomerular filtration rate (eGFR) <60 mL/min (CKD 3: 937; CKD 4-5: 820; CKD 5D: 688) and 559 non-CKD subjects (eGFR >60 mL/min), 18-75 years old, without previous cardiovascular events. An itinerant team of professionals performed carotid and femoral arterial ultrasound. RESULTS The already high prevalence of plaques in CKD 3 is even higher in more severe CKD. Multivariate logistic analysis showed that, at any CKD stage, age and being male are independently associated with the presence of plaques. In CKD 3, there was a significant interaction of the smoking status and triglycerides levels which were independently associated with the presence of plaque. Furthermore, being diabetic was also associated with the presence of subclinical atherosclerosis. In stage 4-5 there was a significant association with smoking, high phosphate and hsCRP levels. In dialysis patients, being diabetic, having low levels of 25(OH)-vitamin D3 and smoking status also showed a significant association with the presence of plaque. Furthermore, the association of phosphate levels with the presence of subclinical atheromatosis showed a U-shaped curve. CONCLUSIONS This analysis demonstrates the magnitude of subclinical atheromatous disease in a large CKD population. The patient characteristics associated with the presence of plaque differ in every CKD stage.

Cardiovascular risk factors underestimate atherosclerotic burden in chronic kidney disease: usefulness of non-invasive tests in cardiovascular assessment

BACKGROUND Cardiovascular risk scoring (Score) does not specifically address chronic kidney disease (CKD) patients. The aim of our study is to quantify atherosclerosis using carotid ultrasound and ankle-brachial index (ABI) and to assess its additional value in risk scoring. METHODS In this cross-sectional, observational study, patients were studied according to a standardized protocol including carotid ultrasound and ABI to determine the atherosclerosis score (AS), ranging from absence of to severe atherosclerosis (AS 0 to AS 3). RESULTS We included 409 CKD-affected patients (231 on dialysis, 99 in CKD Stages IV-V and 79 in CKD Stages I-III) and 851 subjects with normal renal function. The presence and severity of atherosclerosis was significantly higher in the CKD group than in the controls at every decade of age studied. Among the CKD-affected subjects, the prevalence of carotid plaques was significantly higher in the dialysis group (78.3%) than in the group in CKD Stages I-III (55.6%, P < 0.001). We identified 174 patients at low-intermediate risk. Among them, 110 (63.2%) presented either moderate (AS 2) or severe (AS 3) atherosclerosis. Variables significantly (P < 0.05) and positively related to atherosclerosis were being on dialysis [OR = 3.40, 95% CI (1.73, 6.78) vs CKD Stages I-III], age [OR = 1.08, 95% CI (1.06-1.11)] and C-reactive protein [OR = 1.04, 95% CI (1.01-1.08)]. Conversely, female sex was negatively related to atherosclerosis [OR = 0.40, 95% CI (0.23-0.71), P = 0.002]. CONCLUSION The use of carotid ultrasound and ABI identifies atherosclerosis in a population of CKD patients in which risk scoring underestimates atherosclerosis burden.

Evidence for Both Abnormal Set Point of PTH Stimulation by Calcium and Adaptation to Serum Calcium in Hemodialysis Patients with Hyperparathyroidism

In vitro studies of parathyroid glands removed from dialysis patients with secondary hyperparathyroidism and hypercalcemia have demonstrated the presence of an increased set point of parathyroid hormone (PTH) stimulation by calcium (set point [PTHstim]), suggesting an intrinsic abnormality of the hyperplastic parathyroid cell. However, clinical studies on dialysis patients have not observed a correlation between the set point (PTHstim) and the magnitude of hyperparathyroidism. In the present study, 58 hemodialysis patients with moderate to severe hyperparathyroidism (mean PTH 780 ± 377 pg/ml) were evaluated both before and after calcitriol treatment to establish the relationship among PTH, serum calcium, and the set point (PTHstim) and to determine whether changes in the serum calcium, as induced by calcitriol treatment, modified these relationships. Calcitriol treatment decreased serum PTH levels and increased the serum calcium and the setpoint (PTHstim); however, the increase in serum calcium was greater than the increase in the setpoint (PTHstim). Before treatment with calcitriol, the correlation between the set point (PTHstim) and the serum calcium was r = 0.82, p < 0.001, and between the set point (PTHstim) and PTH was r = 0.39, p = 0.002. After treatment with calcitriol, the correlation between the set point (PTHstim) and the serum calcium remained significant (r = 0.70, p < 0.001), but the correlation between the set point (PTHstim) and PTH was no longer significant (r = 0.09); moreover, a significant correlation was present between the change in the set point (PTHstim) and the change in serum calcium that resulted from calcitriol treatment (r = 0.73, p < 0.001). The correlation between the residual values (deviation from the regression line) of the set point (PTHstim), derived from the correlation between PTH and the set point (PTHstim), and serum calcium was r = 0.77, p < 0.001 before calcitriol and r = 0.72, p < 0.001 after calcitriol. In conclusion, the set point (PTHstim) increased after a sustained increase in the serum calcium, suggesting an adaptation of the set point to the existing serum calcium; the increase in serum calcium resulting from calcitriol treatment was greater than the increase in the set point (PTHstim); the set point (PTHstim) was greater in hemodialysis patients with higher serum PTH levels; and the correlation between PTH and the set point (PTHstim) may be obscured because the serum calcium directly modifies the set point (PTHstim).

Predictors of Subclinical Atheromatosis Progression over 2 Years in Patients with Different Stages of CKD

BACKGROUND AND OBJECTIVES Ultrasonographic detection of subclinical atheromatosis is a noninvasive method predicting cardiovascular events. Risk factors predicting atheromatosis progression in CKD are unknown. Predictors of atheromatosis progression were evaluated in patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Our multicenter, prospective, observational study included 1553 patients with CKD (2009-2011). Carotid and femoral ultrasounds were performed at baseline and after 24 months. A subgroup of 476 patients with CKD was also randomized to undergo ultrasound examination at 12 months. Progression of atheromatosis was defined as an increase in the number of plaque territories analyzed by multivariate logistic regression. RESULTS Prevalence of atheromatosis was 68.7% and progressed in 59.8% of patients after 24 months. CKD progression was associated with atheromatosis progression, suggesting a close association between pathologies. Variables significantly predicting atheromatosis progression, independent from CKD stages, were diabetes and two interactions of age with ferritin and plaque at baseline. Given that multiple interactions were found between CKD stage and age, phosphate, smoking, dyslipidemia, body mass index, systolic BP (SBP), carotid intima-media thickness, plaque at baseline, uric acid, cholesterol, 25-hydroxy vitamin D (25OH vitamin D), and antiplatelet and phosphate binders use, the analysis was stratified by CKD stages. In stage 3, two interactions (age with phosphate and plaque at baseline) were found, and smoking, diabetes, SBP, low levels of 25OH vitamin D, and no treatment with phosphate binders were positively associated with atheromatosis progression. In stages 4 and 5, three interactions (age with ferritin and plaque and plaque with smoking) were found, and SBP was positively associated with atheromatosis progression. In dialysis, an interaction between body mass index and 25OH vitamin D was found, and age, dyslipidemia, carotid intima-media thickness, low cholesterol, ferritin, and uric acid were positively associated with atheromatosis progression. CONCLUSIONS Atheromatosis progression affects more than one half of patients with CKD, and predictive factors differ depending on CKD stage.

Association of serum phosphorus with subclinical atherosclerosis in chronic kidney disease. Sex makes a difference

BACKGROUND Cardiovascular disease is the leading cause of mortality in chronic kidney disease (CKD). Serum phosphate has been associated to cardiovascular disease in the general population and this effect seems to be different according to sex. In the present study we analyze the effect of phosphate on subclinical atherosclerosis in the NEFRONA population and its effect depending on sex. DESIGN Carotid ultrasound assessing the presence of plaques was performed by an itinerant team in 1687 CKD patients not in dialysis without previous cardiovascular events. Standard blood test and anthropometrical parameters were also recorded. RESULTS Multivariate linear regression to model phosphate levels in patients with CKD showed an interaction of sex with age. Thus, among men, serum phosphate levels declined significantly with age almost linearly. Serum phosphate levels in women under the age of 40-45 years overlapped with those in men and then stayed above, showing and overall constant relationship. Multivariate logistic regression analysis showed that higher phosphate levels associated with a higher risk of presenting atheromatous plaque. This risk however was different according to sex. In men, phosphate levels within the normal range associated with an increased risk of subclinical atheromatosis whereas in women this risk only increased with serum levels over the normal range. CONCLUSIONS This study demonstrates that phosphate levels are associated with the presence of subclinical atheromatosis in a large CKD population. This effect of phosphate on subclinical atheromatosis was different according to sex, suggesting that a recommended serum phosphate levels could be different for male than for female CKD patients.

Circulating angiotensin-converting enzyme 2 activity in patients with chronic kidney disease without previous history of cardiovascular disease

Abstract Background Patients with cardiovascular (CV) disease have an increased circulating angiotensin-converting enzyme 2 (ACE2) activity, but there is little information about changes in ACE2 in chronic kidney disease (CKD) patients without history of CV disease. We examined circulating ACE2 activity in CKD patients at stages 3–5 (CKD3-5) and in dialysis (CKD5D) without any history of CV disease. Methods Circulating ACE2 activity was measured in human ethylenediamine-tetraacetic acid (EDTA)-plasma samples from the NEFRONA study (n = 2572): control group (CONT) (n = 568), CKD3-5 (n = 1458) and CKD5D (n = 546). Different clinical and analytical variables such as gender; age; history of diabetes mellitus (DM), dyslipidemia and hypertension; glycaemic, renal, lipid and anaemia profiles; vitamin D analogues treatment and antihypertensive treatments (angiotensin-converting enzyme inhibitor and angiotensin receptor blockade) were analysed. Circulating ACE2 and ACE activities were measured using modified fluorimetric assay for EDTA-plasma samples, where zinc chloride was added to recover enzymatic activity. Results In CKD3-5 and CKD5D, significant decrease in circulating ACE2 activity was observed when compared with CONT, but no differences were found between CKD3-5 and CKD5 when performing paired case-control studies. By multivariate linear regression analysis, male gender and advanced age were identified as independent predictors of ACE2 activity in all groups. Diabetes was identified as independent predictor of ACE2 activity in CKD3-5. Significant increase in the activity of circulating ACE was found in CKD3-5 and CKD5D when compared with CONT and in CKD5D when compared with CKD3-5. By multiple regression analysis, female gender and younger age were identified as independent predictors of ACE activity in CONT and CKD3-5. Diabetes was also identified as an independent predictor of ACE activity in CKD3-5 patients. Conclusions Circulating ACE2 and ACE activities can be measured in human EDTA-plasma samples with zinc added to recover enzymatic activity. In a CKD population without previous history of CV disease, ACE2 activity from human EDTA-plasma samples directly correlated with the classical CV risk factors namely older age, diabetes and male gender. Our data suggest that circulating ACE2 is altered in CKD patients at risk for CV event.

Microangiopathy of large artery wall: A neglected complication of diabetes mellitus

OBJECTIVE To test the concept that diabetic patients with microangiopathy of the retinal microcirculation would also show an involvement of the carotid adventitial microcirculation, we aimed to assess the status of the vasa vasorum (VV) signal, measured by contrast-enhanced carotid ultrasound imaging, in type 2 diabetic patients with and without retinopathy. METHODS AND RESULTS Using contrast-enhanced ultrasound imaging, we quantified the signal of the VV of the common carotid artery. We investigated two subgroups of type 2 diabetic patients who did not have previous cardiovascular disease: 51 with retinopathy and 56 without retinopathy. The reference VV signal was measured in a group of 65 healthy volunteers as the ratio of the contrast agent signal of the VV and that of the lumen of the artery. Patients and volunteers also underwent a clinical evaluation. The reference VV signal in the group of 65 healthy volunteers was 0.562 (SD = 0.142). Patients with diabetic retinopathy showed a higher mean adventitial VV signal (0.700; SD = 0.150) than those without retinopathy (0.621; SD = 0.120) (P < 0.0039). This difference remained highly significant after adjusting for cardiovascular risk factors. Common carotid intima-media thickness and carotid plaque prevalence were not different between diabetic subgroups. CONCLUSIONS Type 2 diabetic patients with retinopathy show increased angiogenesis of the VV of the common carotid artery. This suggests the existence of a diabetic microangiopathic complication affecting the wall of the large arteries that may be an important contributor to the cardiovascular disease burden in diabetes mellitus.

Safety and Efficacy of Sevelamer in the Treatment of Uncontrolled Hyperphosphataemia of Haemodialysis Patients

Background/Aim: The treatment of hyperphosphataemia is of major importance in the management of patients on dialysis. Traditional phosphate binders can be associated with undesirable effects. Recently, a new non-absorbable phosphate-binding polymer, sevelamer hydrochloride, has been available. Clinical information is scarce, and its cost could be a limiting factor for its wider use. No studies have evaluated its usefulness in uncontrolled hyperphosphataemic patients. Methods: We identified 34 patients with a maintained serum phosphorus concentration >6.5 mg/dl and/or toxicity related to standard phosphorus-binding treatment (aluminium or calcium based). Sevelamer was added and titrated up fortnightly to achieve phosphorus control. Previous phosphate binders were decreased, whenever possible. The period of the study was 6 months. Results: Thirteen patients (38%) dropped out because of side effects, mainly related to the gastro-intestinal tract. The efficacy analysis disclosed that the phosphorus concentration decreased from 2.39 ± 0.48 to 1.84 ± 0.48 mmol/l (p < 0.001). The mean dose of sevelamer was stabilised at 3.4 ± 1.8 g/day. The amount of calcium- and aluminium-based phosphate binders could be decreased from 5.1 ± 3.5 to 3.1 ± 2.7 g/day (38% decrease) and from 2.4 ± 1.5 to 1.5 ± 1.7 g/day (36% decrease), respectively. The Ca × P product was significantly decreased from 5.83 ± 1.19 to 4.36 ± 1.12 mmol/l2 (p < 0.001). The total cholesterol concentration decreased from 4.34 ± 0.9 to 3.98 ± 0.9 mmol/l (p < 0.01) and the low-density lipoprotein cholesterol level from 2.61 ± 0.98 to 2.20 ± 0.77 mmol/l (p < 0.03). Conclusions: Sevelamer is an effective phosphate binder that allows a better serum phosphorus control, while allowing a decrease in the dose of calcium- and aluminium-based phosphate binders in these difficult patients. The drawbacks are the high intolerance rate and the price of the product.