Outcomes in patients with chronic kidney disease not on dialysis receiving extended dosing regimens of darbepoetin alfa: long-term results of the EXTEND observational cohort study.

BACKGROUND: Extended dosing of the erythropoiesis-stimulating agent (ESA) darbepoetin alfa (DA) once biweekly or monthly reduces anaemia treatment burden. This observational study assessed outcomes and dosing patterns in patients with chronic kidney disease not on dialysis (CKD-NoD) commencing extended dosing of DA. METHODS: Adult CKD-NoD patients starting extended dosing of DA in Europe or Australia in June 2006 or later were followed up until December 2012. Outcomes included haemoglobin (Hb) concentration, ESA dosing, mortality rates and receipt of dialysis and renal transplantation. Subgroup analyses were conducted for selected outcomes. RESULTS: Of 6035 enrolled subjects, 5723 (94.8%) met analysis criteria; 1795 (29.7%) received dialysis and 238 (3.9%) underwent renal transplantation. Mean (standard deviation) Hb concentration at commencement of extended dosing was 11.0 (1.5) g/dL. Mean [95% confidence interval (CI)] Hb 12 months after commencement of extended dosing (primary outcome) was 11.6 g/dL (11.5, 11.6) overall and was similar across countries, with no differences between subjects previously treated with an ESA versus ESA-naïve subjects, subjects with versus without prior renal transplant or diabetics versus non-diabetics. Weekly ESA dose gradually decreased following commencement of extended DA dosing and was similar across subgroups. The decrease in weekly DA dose was accompanied by an increase in the proportion of patients receiving iron therapy. Hb concentrations declined following changes in ESA labels and treatment guidelines. The mortality rate (95% CI) was 7.06 (6.68, 7.46) deaths per 100 years of follow-up. Subjects alive at study end had stable Hb concentrations in the preceding year, while those who died had lower and declining Hb concentrations in their last year. CONCLUSIONS: Long-term, extended dosing of DA maintained Hb concentrations in patients already treated with an ESA and corrected and maintained Hb in ESA-naïve patients.

[Cardiovascular calcification inhibitors]. / Inhibiteurs des calcifications cardiovasculaires.

Vascular calcification is a marker of cardiovascular risk increase. Age and specific disease such as diabetes or chronic kidney disease are important factors for calcification genesis. Vascular calcification process is a complex phenomenon, involving several activators and inhibitors factors. Indeed, recent works related to in vitro and in vivo experimental studies have led to a better understanding of calcification process and identification of molecules able to modulate this system. This revue will summarize some of these molecules with a particular interest of those with therapeutic relevance. We will present: i) calcium sensing receptor and its modulation by cinacalcet; ii) pyrophosphate supplementation; iii) fetuin A and overall propensity serum test for calcification and finally; iv) matrix-Gla-protein and the use of vitamin K to prevent vascular calcification progression.

Ankle-brachial index and bone turnover in patients on dialysis.

An association between atherosclerosis and osteoporosis has been reported in several studies. This association could result from local intraosseous atherosclerosis and ischemia, which is shown by limb osteoporosis in patients with peripheral artery disease (PAD), but also could result from bidirectional communication between the skeleton and blood vessels. Systemic bone disorders and PAD are frequent in ESRD. Here, we investigated the possible interaction of these disorders. For 65 prevalent nondiabetic patients on hemodialysis, we measured ankle-brachial pressure index (ABix) and evaluated mineral and bone disorders with bone histomorphometry. In prevalent patients on hemodialysis, PAD (ABix<0.9 or >1.4/incompressible) was associated with low bone turnover and pronounced osteoblast resistance to parathyroid hormone (PTH), which is indicated by decreased double-labeled surface and osteoblast surface (P<0.001). Higher osteoblast resistance to PTH in patients with PAD was characterized by weaker correlation coefficients (slopes) between serum PTH and double-labeled surface (P=0.02) or osteoblast surface (P=0.03). The correlations between osteoclast number or eroded surface and serum mineral parameters, including PTH, did not differ for subjects with normal ABix and PAD. Common vascular risk factors (dyslipidemia, smoking, and sex) were similar for normal, low, and incompressible ABix. Patients with PAD were older and had high C-reactive protein levels and longer hemodialysis vintage. These results indicate that, in prevalent nondiabetic patients with ESRD, PAD associates with low bone turnover and pronounced osteoblast resistance to PTH.

[Intravenous iron during predialysis period improves anemia management and cardiovascular parameters in incident hemodialysis patients]. / La prise en charge de l'anémie et de ses conséquences chez les patients débutant l'hémodialyse : importance du fer intraveineux en prédialyse.

Individualized use of iron therapy (IT) and erythropoiesis-stimulating agents (ESA) may effectively correct anemia and its symptoms in CKD patients (Pts). The aim of this retrospective study was to precise the anemia management (AM) in incident HD Pts, and to compare Pts treated by intravenous (i.v.) IT and ESA during predialysis to those treated by oral IT and ESA on AM and cardiovascular parameters during the first year of HD. One hundred and two Pts performed their first dialysis in the unit, mean age 58.5 (15.9) years, 70% males, 27% diabetes. Ninety Pts started with a native arteriovenous fistula. Charlson comorbidity index was 7.3 (3.5). Mortality rate was 3% at one year. Hb level was at start 10.6 (1.7) and at one year 11.7 (1.1) g/dL (P<0.0001). DA injected every 2weeks was at the beginning at 107 (56) µg and then at 61 (46) (P<0.0001). i.v. IT injected every week was at the dosage of 87 (23) mg and then at 57 (40mg) per injection (P<0.001). Out of 102 Pts, 33 received i.v. IT during predialysis. These Pts started dialysis with a better Hb level: 11.1 (1.3) versus 10.4 (1.55) g/dL (P<0.01), had a TSAT at 50.0 (19.2) versus 30.1 (15.2) % (P<0.001), received less ESA 0.58 (0.28) versus 0.82 (0.37) µg/kg per week (P<0.01). More important were the changes on the cardiovascular functions: left ventricular mass at 116 (34) versus 134 (39) g/m(2) (P<0.02), left ventricular ejection fraction at 64.7 (4.4) versus 61.4 (8.7) % (P<0.02) and mean arterial pressure at 104.7 (80) versus 109 (13.2) mmHg (P<0.02). These Pts were also less hospitalized. This study revealed the importance of i.v. IT during predialysis care not only on AM but also on cardiovascular status in HD Pts starting dialysis.

Predictive value of circulating endothelial microparticles for cardiovascular mortality in end-stage renal failure: a pilot study.

BACKGROUND: Endothelial dysfunction in cardiovascular (CV) diseases is closely associated with increases in plasma level of shed membrane microparticles (MPs) of endothelial origin. As arterial damage is a major contributor to CV mortality, we examined whether or not increases in endothelial microparticles (EMPs) circulating levels could predict outcome in patients with end-stage renal disease (ESRD). METHODS: This prospective pilot study conducted in a community hospital (median follow-up: 50.5 months), included 81 stable haemodialysed ESRD patients (59 ± 14 years; 63% male). Platelet-free plasma obtained 72 h after last dialysis was analysed by flow cytometry, and MPs cellular origin identified as endothelial (CD31+CD41-MPs; EMPs), platelets (CD31+CD41+MPs) or erythrocyte (CD235a+MPs). The main outcome measures were global and CV mortality (fatal myocardial infarction, stroke, acute pulmonary oedema and sudden cardiac death). RESULTS: Non-survivors (n = 24) were older (P < 0.001) and characterized by higher levels of EMPs (P < 0.01) and high-sensitivity C-reactive protein (P < 0.05) and lower diastolic blood pressure (P < 0.001). Kaplan-Meier analysis demonstrated significantly higher probability of all-cause (P < 0.001) and CV mortality (P < 0.0001) between the lower and upper EMPs tertiles. Multivariate Cox regression analysis demonstrated that baseline EMP levels independently predicted all-cause [hazard ratio (HR) = 21.7, 95% confidence interval (CI): 4.23-111.18 per log EMPs/µL; P = 0.0002] and CV mortality (HR = 20.0, 95% CI: 3.86-103.5) per log EMPs/µL; P < 0.0004) after adjustment for confounding factors. EMPs baseline level was a stronger predictor of poor outcome than classical risk factors. CONCLUSION: This study demonstrates that increased plasma levels of EMPs is a robust independent predictor of severe CV outcome in end-stage renal failure patients.

An observational cohort study of extended dosing (once every 2 weeks or once monthly) regimens with darbepoetin alfa in patients with chronic kidney disease not on dialysis: the EXTEND study.

BACKGROUND: Darbepoetin alfa (DA) has been shown to be an effective treatment of anaemia in patients with chronic kidney disease (CKD) not on dialysis (NoD). EXTEND is an observational study assessing the effectiveness of DA administered once biweekly (Q2W) or monthly (QM) in a general CKD-NoD population. METHODS: Adult CKD-NoD patients starting DA Q2W/QM treatment in June 2006 or later were eligible. Retrospective and/or prospective data including haemoglobin levels and erythropoiesis-stimulating agent (ESA) dosing were collected for 6 months before and 12 months after DA initiation. Mean Hb levels were calculated every 3 months, and ESA dose was converted to a geometric mean weekly DA equivalent dose and summarized monthly. RESULTS: Data from 4278 patients showed that patients receiving ESA treatment before DA Q2W/QM initiation had a mean (95% confidence interval) Hb level of 11.9 g/dL (11.8-12.0 g/dL) at initiation and 11.6 g/dL (11.6-11.7 g/dL) at Months 10-12, with mean ESA dose of 22 µg/week (21-23 µg/week) prior to initiation, 16 µg/week (15-16 µg/week) at initiation and 16 µg/week (15-16 µg/week) at Month 12. In ESA-naive patients, Hb levels increased from 10.3 g/dL (10.2-10.3 g/dL) at initiation to 11.7 g/dL at Months 4-6 and were maintained at a mean level of 11.7 g/dL (11.7-11.8 g/dL) at Months 10-12, with mean ESA dose of 16 µg/week (16-17 µg/week) at initiation and 16 µg/week (16-17 µg/week) at Month 12. In the 85% of patients receiving DA at extended intervals (Q2W or less frequently) at Month 12, 12 patients (0.3%) experienced DA-related adverse reactions. CONCLUSION: DA Q2W/QM was an effective treatment of anaemia in the general CKD-NoD patient population and a dose increase was not required in patients switching from a previous ESA regimen.

Flow-mediated vasodilation in end-stage renal disease.

BACKGROUND AND OBJECTIVES: An intact endothelium is essential for adaptations between arterial vasomotor tone and shear stress (SS), i.e., flow-mediated vasodilation (FMD). Endothelial dysfunction occurs in hypertension, cardiac insufficiency, diabetes, atherosclerosis, and in end-stage renal disease (ESRD) patients, whose renal failure is associated with many of those cardiovascular diseases (CVD). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using a progressive hand-warming protocol and repeated measures ANOVA, we analyzed SS-mediated increase of brachial artery diameter (ΔBA) in 22 healthy controls, 18 CVD-negative ESRD patients (ESRD-CVD(-)), and 17 CVD-positive ESRD patients (ESRD-CVD(+)) to analyze the role of uremia versus CVD on FMD. RESULTS: Hand-warming increased SS (P < 0.001) and ΔBA (P < 0.001). Negative interactions were observed between ΔBA and ESRD (P < 0.001), and between ΔBA and CVD(+) (P < 0.02), but there was no interaction between ESRD and CVD(+) (P = 0.69). For low and mild SS increases, ESRD-CVD(-) patients were characterized by similar ΔBA as controls, but it was lower than controls at higher SS (P < 0.01). In ESRD-CVD(+) patients, brachial artery diameter did not respond to mild and moderate SS increases, and showed "paradoxical" vasoconstriction at higher SS (P < 0.05). In ESRD, a positive and independent interaction was observed between ΔBA and 25(OH) vitamin D(3) insufficiency (≤15 µg/L; P < 0.02). CONCLUSIONS: These observations indicate that, independently of each other, ESRD and CVD(+) history are associated with endothelial dysfunction. They also suggest the importance of considering the relationships between SS and endothelial function in different clinical conditions.

Vitamin D and musculoskeletal health, cardiovascular disease, autoimmunity and cancer: Recommendations for clinical practice.

BACKGROUND: There is increasing evidence that, in addition to the well-known effects on musculoskeletal health, vitamin D status may be related to a number of non-skeletal diseases. An international expert panel formulated recommendations on vitamin D for clinical practice, taking into consideration the best evidence available based on published literature today. In addition, where data were limited to smaller clinical trials or epidemiologic studies, the panel made expert-opinion based recommendations. METHODS: Twenty-five experts from various disciplines (classical clinical applications, cardiology, autoimmunity, and cancer) established draft recommendations during a 2-day meeting. Thereafter, representatives of all disciplines refined the recommendations and related texts, subsequently reviewed by all panelists. For all recommendations, panelists expressed the extent of agreement using a 5-point scale. RESULTS AND CONCLUSION: Recommendations were restricted to clinical practice and concern adult patients with or at risk for fractures, falls, cardiovascular or autoimmune diseases, and cancer. The panel reached substantial agreement about the need for vitamin D supplementation in specific groups of patients in these clinical areas and the need for assessing their 25-hydroxyvitamin D (25(OH)D) serum levels for optimal clinical care. A target range of at least 30 to 40 ng/mL was recommended. As response to treatment varies by environmental factors and starting levels of 25(OH)D, testing may be warranted after at least 3 months of supplementation. An assay measuring both 25(OH)D(2) and 25(OH)D(3) is recommended. Dark-skinned or veiled individuals not exposed much to the sun, elderly and institutionalized individuals may be supplemented (800 IU/day) without baseline testing.

Oxidative stress mediates a reduced expression of the activating receptor NKG2D in NK cells from end-stage renal disease patients.

To characterize the immune defect of patients with end-stage renal disease (ESRD), we performed NK cell subset analysis in 66 patients with ESRD treated by hemodialysis (n = 59) or peritoneal dialysis (n = 7). Compared with healthy blood donors, patients undergoing chronic dialysis showed a profound decrease in NKG2D(+) cells within both the CD8(+) T cell (58% vs 67%, p = 0.03) and NK cell (39% vs 56%, p = 0.002) populations. CD56(dim) cells, which comprise the majority of NK cells in the periphery, were more affected in this regard than were CD56(bright) cells. Uremic serum could decrease NKG2D expression on NK cells from healthy donors. Among factors that could contribute to the decrease in NKG2D expression in ESRD patients, reactive oxygen species (ROS) play a major role. We found that catalase could reverse the effects of uremic serum on NKG2D expression (p < 0.001) and that ROS down-regulated NKG2D at the mRNA level and at the NK cell surface. Additionally, ESRD patients had both increased membrane-bound MHC class I-related chain A (MICA) on monocytes (p = 0.04) and increased soluble MICA (203 pg/ml vs 110 pg/ml; p < 0.001). Both ROS and uremic serum could significantly increase in vitro the expression of the NKG2D ligand MICA on the renal epithelial cell line HK-2. Taken together, these studies suggest for the first time that both low NKG2D expression and up-regulation of its ligand MICA are related to ROS production and may be involved in the immune deficiency of ESRD patients.

Insufficient therapeutic management of hypertensive patients with renal failure in France.

BACKGROUND: Hypertension is both the cause and consequence of chronic renal failure (CRF). The prevalence of CRF, which itself is a cardiovascular risk factor, is not well known in France. AIMS: To estimate the prevalence of renal dysfunction among hypertensive patients who were seen by general practitioners (GP); to assess the drug management of hypertension in these patients according to their renal status. METHODS: A transversal observational study among patients of both genders aged 18 or more, with arterial blood pressure greater than 130/80 mmHg (i.e., over CRF-recommended blood pressure) or under antihypertensive drugs who were recruited in France by GP. RESULTS: Among the 2315 included patients, 1908 could be analyzed for their renal function. Of these, 70.5% had an estimated glomerular filtration rate (GFR) of 89 ml/min per 1.73 m(2) or lower. One third of these patients (31.4%) were suffering from renal failure (GFR

Assessment and significance of arterial stiffness in patients with chronic kidney disease.

PURPOSE OF REVIEW: To review the most recent publications concerning the pathophysiology and clinical impact of arterial stiffening in patients with chronic kidney disease and those with end-stage renal disease. RECENT FINDINGS: The results of recent studies confirmed that arterial stiffening is independently associated with decreased glomerular filtration rate and increased decline in parallel kidney function, and is predictive of kidney disease progression and the patient's cardiovascular outcome. Arterial stiffening is of multifactorial origin, including arterial calcifications, systemic inflammation, malnutrition, vitamin deficiencies, endothelial dysfunction, and bone activity. SUMMARY: Arterial stiffness and intensity of wave reflections are considered the principal determinants of systolic blood and pulse pressures, and their measurements are increasingly used to assess cardiovascular risk. Aortic stiffness has independent predictive value for all-cause and cardiovascular mortality in general populations and in patients with end-stage renal disease. Arterial stiffening in patients with chronic kidney disease and those with end-stage renal disease is of multifactorial origin with extensive arterial calcifications representing a major covariate. Carotid-femoral pulse wave velocity is a direct measure of aortic stiffness and is the 'gold standard' for its evaluation in clinical and epidemiological studies.

Association of bone activity, calcium load, aortic stiffness, and calcifications in ESRD.

An inverse relationship between arterial calcifications and bone activity has been documented in patients with ESRD. Calcium overload is associated with arterial calcification, which is associated with arterial stiffening. Whether bone activity interacts with calcium load, aortic stiffness, or arterial calcification is unknown. This study assessed the impact of bone activity on the relationships between the dosage of calcium-containing phosphate binders and aortic stiffness (measured by pulse wave velocity) or abdominal aorta calcification score. Aortic stiffness and calcification were both positively associated with calcium load and negatively associated with bone activity. A significant interaction was found between dosage of calcium-containing phosphate binders and bone activity such that calcium load had a significantly greater influence on aortic calcifications and stiffening in the presence of adynamic bone disease. Independent of any other factor, including dosage of calcium-containing phosphate binders, adynamic bone was associated with greater aortic stiffening, suggesting cross-talk between the bone and arterial walls.

Arterial structure and function in end-stage renal disease.

Cardiovascular disease is a major cause of morbidity and mortality in patients with end-stage renal disease (ESRD). Macrovascular disease develops rapidly in ESRD patients and is responsible for the high incidence of left ventricular hypertrophy, ischemic heart disease, cerebrovascular accidents, and peripheral artery diseases. Occlusive lesions due to atheromatous plaques frequently cause these complications; however, atherosclerosis represents only one form of structural response to metabolic and hemodynamic alterations interfering with the "natural" process of aging. The spectrum of arterial alterations in ESRD is broader, including large artery remodeling, changes in viscoelastic properties, and stiffening of arterial walls. Nonatheromatous remodeling principally changes the dampening function of arteries, characterized by stiffening of arterial walls and with deleterious effects on the left ventricle and coronary perfusion. The origin of arterial stiffening in ESRD patients is multifactorial, with extensive arterial calcifications as an important covariate.

In vivo shear stress determines circulating levels of endothelial microparticles in end-stage renal disease.

Shear stress is a major determinant of endothelial apoptosis, but its role in the in vivo release of shed membrane microparticles by endothelial cells remains unknown. Thus, we sought to evaluate the possible relationship between circulating endothelial microparticle levels and laminar shear stress in end-stage renal disease patients with high cardiovascular risk, whose levels of endothelial microparticles are elevated. In 34 hemodialyzed patients, we analyzed the relationships between brachial artery and aortic shear stress and circulating microparticles levels. Only endothelial microparticles were inversely correlated with laminar shear stress values (P<0.0001) or its components shear rate and whole blood viscosity, independent of age or arterial blood pressure. Changes in hematocrit resulting from hemodialysis-induced hemoconcentration or erythropoietin anemia improvement induced a significant increase in whole blood viscosity and shear stress and were associated with a significant decrease in endothelial microparticles with a significant and inverse correlation with changes in hematocrit/hemoglobin or laminar shear stress. These results demonstrate that, in end-stage renal disease patients, laminar shear stress is an important determinant of plasma levels of endothelial microparticles. Anemia as an important determinant of whole blood viscosity and shear stress, contributes to endothelial apoptosis, and could play an indirect role in the pathogenesis of accelerated arteriosclerosis in this high-risk population.

Mineral metabolism and arterial functions in end-stage renal disease: potential role of 25-hydroxyvitamin D deficiency.

In ESRD, arterial function is abnormal, characterized by decreased capacitive function (arterial stiffening) and reduced conduit function, shown by diminished flow-mediated dilation (FMD). The pathophysiology of these abnormalities is not clear, and this cross-sectional study analyzed possible relationships among arterial alterations and cardiovascular risk factors, including mineral metabolism parameters, such as serum parathormone, and vitamin D "nutritional" and "hormonal" status by measuring serum 25-hydroxyvitamin D [25(OH)D(3)] and 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] levels. Aortic stiffness (pulse wave velocity), brachial artery (BA) distensibility (echotracking; n = 42), BA FMD (hand-warming; n = 37), and arterial calcification scores (echography and plain x-rays) were measured in 52 stable and uncomplicated patients who were on hemodialysis. 25(OH)D(3) and 1,25(OH)(2)D(3) serum levels were low and weakly correlated (r = 0.365, P < 0.05). After adjustment for BP and age, multivariate analyses indicated that 25(OH)D(3) and 1,25(OH)(2)D(3) were negatively correlated with aortic pulse wave velocity (P < 0.001) and positively correlated with BA distensibility (P < 0.01) and FMD (P < 0.001). Arterial calcification scores were not independently associated with 25(OH)D(3) and 1,25(OH)(2)D(3) serum concentrations. These results suggest that nutritional vitamin D deficiency and low 1,25(OH)(2)D(3) could be associated with arteriosclerosis and endothelial dysfunction in patients who have ESRD and are on hemodialysis.

Local shear stress and brachial artery functions in end-stage renal disease.

Physiologic laminar shear stress (SS) is crucial for normal vascular structure and function. As a result of anemia-related lower whole-blood viscosity (WBV), SS could be reduced in patients with ESRD and might be associated with arterial functional alterations. In 44 patients with ESRD and 25 control subjects, brachial artery (BA) compliance and BA diameter changes (flow-mediated dilation [FMD[) were evaluated in response to local shear rate and SS changes during hand warming-induced hyperemia. Patients with ESRD and control subjects had similar BA blood flow, but SS was lower in patients with ESRD (P < 0.001), with lower shear rate (P < 0.01) and lower WBV (P < 0.0001). In control subjects, SS was positively (and physiologically) correlated with arterial diameter (P < 0.001). In contrast, in patients with ESRD, larger arterial diameter was associated with low SS (P < 0.05) and increased arterial wall elastic modulus (P < 0.001). Anemia-associated low WBV aggravates low shear rate, further contributing to SS reduction. These abnormalities were associated with decreased vasodilating response to endothelial mechanical stimulation. Compared with control subjects, BA compliance and FMD increases in response to hand warming-induced increased SS were lower in ESRD patients (P < 0.01), whereas their BA diameter response to glyceryl trinitrate did not differ. The long-term WBV and SS increases after anemia correction improved FMD (P < 0.01) and BA compliance (P < 0.05) and heightened arterial wall sensitivity to mechanical stimulation. Maintenance low SS as a result of anemia could play an indirect role in arterial dysfunction in patients with ESRD.

Cardiovascular disease in the dialysis population: prognostic significance of arterial disorders.

PURPOSE OF REVIEW: Cardiovascular disease is a major factor in the high mortality of patients with end-stage renal disease, and this population is particularly appropriate to analyse the impact of cardiovascular risk markers on outcome. RECENT FINDINGS: Cardiovascular risk markers in end-stage renal disease include age, left ventricular mass, carotid intima-media thickness, blood pressure and aortic stiffness (pulse wave velocity). Aortic pulse wave velocity has been shown to be an independent predictor of cardiovascular mortality in patients with end-stage renal disease and the general population. Aortic pulse wave velocity has the highest sensitivity and specificity as a predictor of cardiovascular death in end-stage renal disease patients. Pulse wave velocity is an integrated index of vascular function and structure, and is a major determinant of systolic hypertension, thereby increasing left ventricular afterload, left ventricular hypertrophy and left ventricular oxygen consumption. Decreased diastolic blood pressure, another consequence of arterial stiffening, is associated with decreased coronary perfusion contributing to ischaemic heart disease and evolution of adaptive into maladaptive left ventricular hypertrophy. SUMMARY: Aortic stiffness measurements could serve as an important tool in identifying end-stage renal disease patients at higher risk of cardiovascular disease. The ability to identify these patients would lead to better risk stratification and earlier and more cost-effective preventive therapy.

Arteriosclerosis, vascular calcifications and cardiovascular disease in uremia.

PURPOSE OF REVIEW: Arterial calcification in chronic kidney disease (CKD) is associated with increased cardiovascular risk. The mechanisms responsible for arterial calcification include alterations of mineral metabolism and expression of mineral-regulating proteins. RECENT FINDINGS: Arterial calcification is similar to bone formation, involving differentiation of vascular smooth muscle cells (VSMCs) into phenotypically distinct osteoblast-like cells. Elevated phosphate and/or calcium trigger a concentration-dependent increase of calcium precipitates in VSMC in vitro. The calcification is initiated by VSMC release of membrane-bound matrix vesicles and formation of apoptotic bodies. The presence of serum prevents these changes, indicating the presence of calcification inhibitors. Arterial calcification occurs in two sites: the tunica intima and tunica media. Intimal calcification is a marker of atherosclerotic disease and is associated with arterial stenotic lesions. Medial calcification influences outcome by promoting arterial stiffening whose principal consequences are left-ventricular hypertrophy and altered coronary perfusion. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in CKD patients. Age, duration of dialysis, smoking and diabetes are risk factors for the development of arterial calcification in end-stage renal disease. Oversuppression of parathyroid hormone and low bone turnover potentiate the development of arterial calcification. SUMMARY: Arterial disease in CKD patients is characterized by extensive calcification. Evidence has accumulated pointing to the active and regulated nature of the calcification process. Elevated phosphate and calcium may stimulate sodium-dependent phosphate cotransport involving osteoblast-like changes in cellular gene expression. Arterial calcification is responsible for stiffening of the arteries with increased left-ventricular afterload and abnormal coronary perfusion as the principal clinical consequences.

Circulating endothelial microparticles are associated with vascular dysfunction in patients with end-stage renal failure.

Endothelial dysfunction and arterial stiffness are major determinants of cardiovascular risk in patients with end-stage renal failure (ESRF). Microparticles are membrane fragments shed from damaged or activated cells. Because microparticles can affect endothelial cells, this study investigated the relationship between circulating microparticles and arterial dysfunction in patients with ESRF and identified the cellular origin of microparticles associated with these alterations. Flow cytometry analysis of platelet-free plasma from 44 patients with ESRF indicated that circulating levels of Annexin V+ microparticles were increased compared with 32 healthy subjects, as were levels of microparticles derived from endothelial cells (three-fold), platelets (16.5-fold), and erythrocytes (1.6-fold). However, when arterial function was evaluated noninvasively in patients with ESRF, only endothelial microparticle levels correlated highly with loss of flow-mediated dilation (r = -0.543; P = 0.004), increased aortic pulse wave velocity (r = 0.642, P < 0.0001), and increased common carotid artery augmentation index (r = 0.463, P = 0.0017), whereas platelet-derived, erythrocyte-derived, and Annexin V+ microparticle levels did not. In vitro, microparticles from patients with ESRF impaired endothelium-dependent relaxations and cyclic guanosine monophosphate generation, whereas microparticles from healthy subjects did not. Moreover, in vitro endothelial dysfunction correlated with endothelial-derived (r = 0.891; P = 0.003) but not platelet-derived microparticle concentrations. In fact, endothelial microparticles alone decreased endothelial nitric oxide release by 59 +/- 7% (P = 0.025). This study suggests that circulating microparticles of endothelial origin are tightly associated with endothelial dysfunction and arterial dysfunction in ESRF.