Peritoneal Dialysis Is an Independent Factor Associated to Lower Intima Media Thickness in Dialysis Patients Free From Previous Cardiovascular Disease.

Carotid intima media thickness (cIMT) displays prognostic value as a marker of cardiovascular risk in dialysis patients. However, few data are available regarding the impact of dialysis modality on cIMT. The aim of this study is to determine whether the modality of dialysis influences cIMT values. We compared 237 peritoneal dialysis (PD) and 451 hemodialysis (HD) patients without previous cardiovascular disease included in NEFRONA, a prospective, observational and multicenter study. This cross sectional study included the determination of cIMT in 6 carotid territories by arterial ultrasound. cIMT was determined in territories without atheroma plaque and averaged. A second analysis was performed using all territories, giving a truncated cIMT value of 1,5 mm to territories presenting with atheroma plaque. Age and plaque presence at baseline were the clinical variables more closely associated to cIMT in dialysis patients. The evaluation of the impact of the modality of dialysis on cIMT showed that PD patients had lower cIMT than HD patients, both in territories with no plaques and when using truncated cIMT values. No differences were found between right and left sides, neither in cIMT or truncated cIMT values. Lineal multivariate analysis adjusted by several clinical variables showed a statistically significant association of PD with a lower cIMT (slope -0.036; SD 0.010). These results were also confirmed when truncated cIMT values were used. We conclude that the modality of dialysis has an impact on cITM. HD patients have greater global cIMT than PD patients, and PD is and independent factor associated with a lower cIMT.

High Levels of Hemoglobin Promote Carotid Adventitial Vasa Vasorum Neoangiogenesis in Chronic Kidney Disease.

Chronic kidney disease (CKD) patients, characterized by traditional and nontraditional risk factors, are prone to develop atheromatosis and thus cardiovascular events and mortality. The angiogenesis of the adventitial vasa vasorum (aVV) surrounding the carotid has been described as the atheromatosis initiator. Therefore, the aim of the study was to (1) evaluate if the carotid aVV in CKD patients increases in comparison to its physiological value of healthy patients; (2) explore which traditional or nontraditional risk factor including inflammation, bone and mineral metabolism, and anemia could be related to the aVV angiogenesis. CKD patients without previous cardiovascular events (44, stages 3-4; 37, stage 5D) and 65 healthy subjects were compared. The carotid aVV and the intima-media thickness (cIMT) were evaluated by ultrasound. CKD patients at stages 3-4 showed higher aVV of the right carotid artery even after adjusting for age. Importantly, a multiple linear regression model showed hemoglobin levels > 12.5 g/dL as the factor for an estimated higher aVV of the right carotid artery. In conclusion, the association of hemoglobin with higher aVV could suggest the role of high hemoglobin in the higher incidence of adverse cardiovascular outcomes in CKD patients.

Left carotid adventitial vasa vasorum signal correlates directly with age and with left carotid intima-media thickness in individuals without atheromatous risk factors.

OBJECTIVE: The early identification of the onset of subclinical atheromatosis is essential in reducing the high mortality risk from cardiovascular disease (CVD) worldwide. Although carotid intima-media thickness (cIMT) is the most commonly used early predictor of ongoing atherosclerosis, an experimental model of atherosclerosis, demonstrated that increases in adventitial microvessels (vasa vasorum (VV)) precede endothelial dysfunction. Using the reported accuracy of contrast-enhanced ultrasound (CEU) to measure carotid adventitial VV, this study assessed whether measurements of carotid adventitial VV serve as a marker of subclinical atherosclerotic lesions in a control population with none of the classical risk factors for CVD. METHODS AND RESULTS: Measurements of cIMT (B-mode ultrasound) and adventitial VV (CEU) were conducted in 65 subjects, 30-70 years old, 48% men, with none of the classical risk factors for CVD. Adventitial VV strongly correlated with its own cIMT only in the left carotid artery. Importantly, the left carotid adventitial VV directly correlated with age. CONCLUSIONS: The increases with age in left carotid adventitial VV in individuals with zero risk for atheromatosis suggest that the measurement of carotid adventitial VV could be an accurate and sensitive marker for the diagnosis of subclinical atheromatosis and therefore a prominent tool for monitoring the efficacy of anti-atheromatous therapies.

Effectiveness of treatment with oral paricalcitol in patients on peritoneal dialysis: a Spanish multicenter study.

AIMS: Recently, oral form of paricalcitol has allowed extension of treatment to ambulatory patients on peritoneal dialysis but few data have been published about the benefits of paricalcitol in this subgroup. A multicenter, retrospective study was carried out to increase current knowledge on the effectiveness and safety of paricalcitol in 162 peritoneal dialyzed patients with secondary hyperparathyroidism. METHODS: Case histories of patients treated with paricalcitol for at least 6 months were reviewed to extract data on 12 biochemical parameters related to bone disease and health status. Changes in these parameters were described. Doses of paricalcitol and other concomitant treatments were evaluated at least every 3 months. RESULTS: 99 men (61.1%) and 63 women (38.9%) with an average age of 62.07 years were included. PTH levels showed an acute decrease in the three first months (35.88%) and a global decrease at month 6 of 42.39%. A slight increase in calcium was observed (p < 0.001) but it remained between normal range values. Only 5 patients presented serum calcium over 10.2 in two consecutive measurements. No changes were found in phosphorus, calcium-phosphorus product, hemoglobin, alkaline phosphatase, GGT, albumin, PCR inflammatory markers, pH and bicarbonate. The decrease in proteinuria levels was nearly statistically significant (p = 0.061). Only 6 patients (0.36%) abandoned the treatment. CONCLUSIONS: Paricalcitol therapy was well tolerated with a high effectiveness in patients on peritoneal dialysis. A slight increase in serum calcium levels was observed, although within normal ranges. No changes in other biochemical parameters related to bone disease could be associated to paricalcitol with data compiled in our study. Paricalcitol seems to have a protective effect on proteinuria levels.

Assessment of the potential role of active vitamin D treatment in telomere length: a case-control study in hemodialysis patients.

BACKGROUND: Telomeres are special chromatin sequences located at the end of eukaryotic chromosomes, protecting these regions from recombination and degradation. Previous studies have reported a decrease in telomere length on white blood cells from hemodialysis (HD) patients, which suggests premature senescence. Active vitamin D treatment has been reported to have an effect on telomere length and beneficial effects on HD patients, but the mechanisms are unknown. OBJECTIVE: Our aim was to assess the potential protective role of active vitamin D treatment on telomere length in peripheral mononuclear cells (PBMC) from HD patients. METHODS: A retrospective case-control study of 62 stable HD patients and 60 healthy sex-matched controls was undertaken. Telomere length was measured in PBMC by Southern blot. After telomere length measurement, 5 control samples that did not reach quality-control standards were excluded. Standard epidemiological and biochemical parameters were recorded. Blood biochemistries were performed at the Biochemistry Department of the University Hospital Arnau de Vilanova in Lleida, Spain, using standard routine techniques. Differences in telomere length were analyzed using Student's t test. Multiple regression analysis examined the independent contribution of the factors that significantly affected telomere length in the bivariate analysis. RESULTS: HD patients presented shorter telomere length in PBMC, independent of age and sex (mean [SD] 8.8 [1.5] kbp vs 10.5 [2.9] kbp; P = 0.0001). Multivariate regression analysis of the HD subgroup suggested that patients under active vitamin D treatment have greater telomere length in PBMC than untreated patients (9.5 [0.2] kbp vs 8.4 [0.2] kbp; P = 0.003). CONCLUSIONS: HD patients were observed to have decreased PBMC telomere length compared with healthy controls. HD patients treated with active vitamin D compounds had greater PBMC telomere length than untreated patients. Prospective studies are required to assess the potential role of active vitamin D treatment in PBMC telomere length.

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.

Serum levels of matrix metalloproteinase-10 are associated with the severity of atherosclerosis in patients with chronic kidney disease.

Cardiovascular disease is the leading cause of mortality in chronic kidney disease (CKD). As matrix metalloproteinases have a major role in atherosclerosis, we hypothesized that alterations in metalloproteinases-8, -10 and their tissue inhibitor-1 can be associated with the severity of atherosclerosis in patients with kidney disease. This was evaluated in a cross-sectional, observational study of 111 patients with stages I-V kidney disease, 217 patients on dialysis and 50 healthy controls. The severity of atherosclerosis was estimated with the atherosclerosis score (AS), combining the results of ankle-brachial index and carotid ultrasound. Serum levels of the two metalloproteinases and tissue inhibitor-1 were measured by enzyme-linked immunosorbent assay and were significantly increased in patients with kidney disease compared with the healthy controls, and higher in patients on dialysis than in earlier stages of CKD. The severity of the AS was also more prevalent in the dialysis group, in which serum levels of both metalloproteinases and tissue inhibitor-1 were significantly higher. After multivariate analysis, metalloproteinase-10, dialysis, C-reactive protein, age, and male gender were associated with increased risk of atherosclerosis. Thus, patients with CKD exhibit elevated levels of circulating metalloproteinase-10, and this was independently associated with the severity of atherosclerosis and may represent a new biomarker of atherosclerotic diseases.

Predicting cardiovascular disease morbidity and mortality in chronic kidney disease in Spain. The rationale and design of NEFRONA: a prospective, multicenter, observational cohort study.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD). Cardiovascular risk assessment in this population is hampered by the failure of traditional risk factors to fully account for the elevated CVD risk (reverse epidemiology effect) and the presence of emerging risk factors specifically related to kidney failure. Therefore, diagnostic tools capable of improving cardiovascular risk assessment beyond traditional risk factors are currently warranted. We present the protocol of a 4-year prospective study aimed to assess the predictive value of non-invasive imaging techniques and biomarkers for CVD events and mortality in patients with CKD. METHODS: From November 2009 to October 2010, 4137 asymptomatic adult patients with stages 2 to 5 CKD will be recruited from nephrology services and dialysis units throughout Spain. During the same period, 843 participants without CKD (control group) will be recruited from lists of primary care physicians, only at baseline. During the follow-up, CVD events and mortality will be recorded from all CKD patients. Clinical and laboratory characteristics will be collected in a medical documentation sheet. Three trained itinerant teams will carry out a carotid ultrasound to assess intima-media thickness and presence of plaques. A composite atherosclerosis score will be constructed based on carotid ultrasound data and measurement of ankle-brachial index. In CKD patients, presence and type of calcifications will be assessed in the wall of carotid, femoral and brachial arteries, and in cardiac valves, by ultrasound. From all participants, blood samples will be collected and stored in a biobank to study novel biomarkers. CONCLUSIONS: The NEFRONA study is the first large, prospective study to examine the predictive value of several non-invasive imaging techniques and novel biomarkers in CKD patients throughout Spain. Hereby, we present the protocol of this study aimed to explore the most effective way in which these tests can be integrated with traditional risk factors to maximize CVD detection in this population.

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.

Sevelamer hydrochloride in peritoneal dialysis patients: results of a multicenter cross-sectional study.

BACKGROUND: Sevelamer hydrochloride is a phosphate binder widely employed in hemodialysis patients. Until now, information about its efficacy and safety in peritoneal dialysis patients has been scarce. PATIENTS AND METHODS: In September 2005 a cross-sectional study of demographic, biochemical, and therapeutic data of patients from 10 peritoneal dialysis units in Catalonia and the Balearic Islands, Spain, was conducted. RESULTS: We analyzed data from 228 patients. At the time of the study, 128 patients (56%) were receiving sevelamer. Patients receiving sevelamer were younger (p < 0.01), showed a longer period of time on dialysis (p < 0.01), and had a lower Charlson Comorbidity Index (p < 0.01). Serum calcium and intact parathyroid hormone levels were not different between the two groups, while phosphate levels <5.5 mg/dL were observed more frequently in patients not receiving sevelamer (79% vs 61%, p < 0.01). Serum total cholesterol (167 +/- 41 vs 189 +/- 42 mg/dL, p < 0.01) and low density lipoprotein (LDL) cholesterol (90 +/- 34 vs 109 +/- 34 mg/dL, p < 0.01), but not high density lipoprotein cholesterol or triglycerides, were lower in sevelamer-treated patients. Moreover, sevelamer-treated patients displayed a higher serum albumin (38 +/- 5 vs 36 +/- 4 g/L, p < 0.01) and a lower C-reactive protein (4.9 +/- 12.8 vs 8.8 +/- 15.7 mg/L, p < 0.01). Blood bicarbonate levels <22 mmol/L were observed more frequently in patients receiving sevelamer (22% vs 5%, p < 0.01). Logistic regression analysis adjusting by confounding variables confirmed that sevelamer therapy was associated with serum total cholesterol <200 mg/dL [relative risk (RR): 2.77, 95% confidence interval (CI): 1.44 - 5.26, p = 0.002] and blood bicarbonate <22 mmol/L (RR: 8.5, 95% CI: 2.6 - 27.0, p < 0.001), but not with serum phosphate >5.5 mg/dL, calcium-phosphate product >55 mg(2)/dL(2), serum albumin <35 g/L, or C-reactive protein >5 mg/L. CONCLUSIONS: This uncontrolled cross-sectional study in peritoneal dialysis patients showed that sevelamer hydrochloride treatment allows an adequate serum phosphate level in about 60% of patients and significantly reduces total and LDL-cholesterol levels. Since this treatment is associated with metabolic acidosis in 22% of patients, we recommend close monitoring of bicarbonate levels in this group of patients until the clinical significance of this result is clarified.

Mineral metabolism parameters throughout chronic kidney disease stages 1-5--achievement of K/DOQI target ranges.

BACKGROUND: Dialysis Outcomes and Practice Patterns Study has shown that the proportion of haemodialysis patients with adequate mineral metabolism parameters according to the Kidney Disease Outcome Quality Initiative (K/DOQI) guidelines is very low. The adequacy of such parameters in relation to the recommended ranges in patients with different chronic kidney disease (CKD) stages has not been reported. The objective of this study is to provide an in-depth description of mineral metabolism in the early stages of CKD in a European population, and to compare it with current recommendations for stages 3-5 (K/DOQI guidelines). METHODS: A total of 1836 patients were classified into stages 1-5 according to K/DOQI guidelines. The following clinical and biochemical data were recorded: age, gender, CKD aetiology, presence of diabetes, serum creatinine, creatinine clearance, serum phosphate, calcium, CaxP product and intact parathyroid hormone (PTH). RESULTS: A decrease in 1,25-dihydroxyvitamin D and an increase in PTH are the earliest mineral metabolism alterations in CKD, while serum calcium and phosphate are altered later in the course of CKD. The percentages of patients with serum levels within the recommended K/DOQI guidelines for stages 3, 4 and 5 were as follows: serum calcium: 90.7, 85.6 and 55; serum phosphate: 90.9, 77.1 and 70.3; iPTH 42.4, 24.6 and 46.8 and Ca x P product 99.9, 99.6 and 83.8, respectively. The percentages of patients who had all four parameters within the recommended ranges were 34.9, 18.4 and 21.6 for stages 3, 4 and 5, respectively. CONCLUSION: Mineral metabolism disturbances start early in the course of CKD. The first alterations to take place are a 1,25-dihydroxyvitamin D decrease, a 24 h urine phosphate decrease and a PTH elevation, which show significant level variation when the glomerular filtration rate falls below 60 ml/min. K/DOQI recommended levels for mineral metabolism parameters are difficult to accomplish, in particular for PTH levels.

Patients with learning difficulties: outcome on peritoneal dialysis.

In the present study, we identified patients who had difficulties learning the minimum knowledge and skills required to carry out peritoneal dialysis (PD), and we compared the outcomes in this subgroup of patients with outcomes in the general PD population. We calculated the mean learning sessions needed by our total PD population during the training period. We then assigned patients to one of two groups according to the number of learning sessions they needed. Patients who required a number of sessions equal to or less than the mean were placed in the "standard learning" group; patients who required more sessions but who reached the minimum knowledge and skills were placed in the "learning difficulties " group. We compared these two groups in terms of age, sex, diabetes status, autonomy to perform PD, family support, education level, residual renal function, and Charlson comorbidity index. Outcomes on PD included time to first peritonitis episode, peritonitis rate, percentage of patients free of peritonitis during follow-up, survival time on PD, and transfer to hemodialysis. Patients with learning difficulties were older and had more comorbidities. Outcomes on PD in the learning difficulties group were similar to those in the standard learning group, except for time to first peritonitis.

Chemical and immunological characterization of oxidative nonenzymatic protein modifications in dialysis fluids.

BACKGROUND: Glucose degradation products (GDP) in dialysis fluids may induce nonenzymatic protein modifications, the chemical nature and biological properties of which should be better defined. AIMS: To characterize nonenzymatic protein modifications present in glucose-based peritoneal dialysis fluids (PDF) and to evaluate the relationship between concentrations of GDP and the derived nonenzymatic modifications, and the potential of PDF for generating these modifications in vitro. METHODS: The presence, distribution, and content of several nonenzymatic protein modifications in PDF were evaluated by immunological methods, by HPLC, and by gas chromatography-mass spectrometry (GC/MS). Peritoneal dialysis fluid-induced oxidative stress in cells was evaluated by flow cytometry. The potential of PDF for generating oxidative and glycoxidative modifications was examined by immunological and cross-linking analyses. RESULTS: The albumin present in PDF is modified by carboxymethyllysine (CML). GC/MS analyses of PDF proteins confirmed the presence of CML and demonstrated the occurrence of carboxyethyllysine, malondialdehyde lysine, and oxidation-derived semialdehydes. Furthermore, their concentrations in PDF proteins were significantly higher than those in plasma proteins (in all cases, p < 0.02). The concentration of pyrraline, a non-oxidative advanced glycation end-product, increased with dwell time up to 6 hours (p < 0.03). The PDF induced cellular free-radical production, which was partially inhibited by the Maillard reaction inhibitor aminoguanidine (p < 0.001). The potential to generate oxidative and glycoxidative modifications demonstrated an inverse relationship with dwell time (p < 0.05). The PDF was able to induce collagen cross-linking in a close relationship with GDP concentration. CONCLUSIONS: (1) PDF contains non-oxidative and several oxidative nonenzymatic protein modifications in higher concentrations than plasma. (2) Peritoneal dialysis fluid induces oxidative stress in vitro, which can be partially inhibited by aminoguanidine. (3) These properties are directly related to GDP concentration. (4) Peritoneal dialysis fluid is able to generate glycoxidative and oxidative damage to proteins in vitro in a dwell-time dependent fashion.

BB genotype of the vitamin D receptor gene polymorphism postpones parathyroidectomy in hemodialysis patients.

BACKGROUND: Bsml vitamin D receptor (VDR) gene polymorphism has been reported to influence the progression of secondary hyperparathyroidism but it is not known how much the genetic background contributes to the need for parathyroidectomy (PTx). We investigated the influence of VDR gene polymorphism on PTx in patients with different dialysis vintage. METHODS: We studied 121 parathyroidectomized HD patients ("PTx " group). Patients who had required early parathyroidectomy ("early PTx" group) or late parathyroidectomy ("late PTx" group) were analyzed separately. The cut-off point between these two groups was 89 months (mean time on hemodialysis (HD) before parathyroidectomy). Serum intact parathyroid hormone, calcium, phosphorus and alkaline phosphatase were measured. Bsml genotypes were analyzed by polymerase chain reaction. Statistical analysis was done with univariant analysis of variance (ANOVA) to compare the genotype groups and general factorial ANOVA, entering time on HD as the dependent variable, with genotype, sex, age and chronic renal failure (CRF) etiology as factors. As a control group for the association studies we determined genotypic frequencies in 162 HD patients ("total HD" group), and in a healthy control population of 120 individuals ("healthy" group), tested by contingency table analysis and the chi-square test. RESULTS: No significant differences were found between the genotypes except for the time on HD. General factorial ANOVA showed that the adjusted means of the time on HD were significantly different for the various genotypes (p = 0.015). The BB genotype was significantly less frequent in the "early PTx " group than in the "total HD" and "late PTx" groups. CONCLUSIONS: Individuals with the BB genotype can remain longer on HD before they need parathyroidectomy.