Cardiovascular Complications In Dialysis Patients Research Articles

Risk of Major Cardiovascular Disease after Exposure to Contrast Media: A Nationwide Population-Based Cohort Study on Dialysis Patients.

Contrast associated kidney injury is caused by side effects of iodinated contrast media (ICM), including inflammation. Chronic inflammation among dialysis patient contributes to atherosclerosis, which leads to simultaneous conditions of the kidney, brain, and vasculature. Data to investigate the pathologic effects of ICM on cardiovascular complications in dialysis patients are lacking. Dialysis patients who had been exposed to ICM from computed tomography (ICM-CT) were allocated as the ICM-CT cohort (N = 3751), whereas dialysis patients without ICM exposure were randomly allocated as the non-ICM cohort (N = 17,196). Furthermore, 540 pairs were selected for analyses through propensity score-matching in terms of age, sex, comorbidities, dialysis vintage, and index date. During a median follow-up of 10.3 years, ICM-CT cohort had significantly higher risks in the following, compared with non-ICM cohort: all-cause mortality (adjusted hazard ratio [aHR], 1.36; 95% confidence interval [CI], 1.26-1.47), cardiovascular events (aHR,1.67; 95% CI, 1.39-2.01), acute coronary syndrome (adjusted HR: 2.92; 95% CI, 1.72-4.94), sudden cardiac arrest (aHR, 1.69; 95% CI, 0.90-3.18), heart failure (aHR, 1.71; 95% CI,1.28-2.27), and stroke (aHR, 1.84; 95% CI,1.45-2.35). The proinflammatory ICM is significantly associated with an increased risk of major cardiovascular events in patients on dialysis.

PS-C03-5: REAL-WORLD DATA OF BLOOD PRESSURE IN DIALYSIS PATIENTS WITH AND WITHOUT DIABETES IN JAPAN USING THE WEB-BASED DATABASE

Objective: Diabetic nephropathy was the most common primary disease among patients undergoing dialysis, and the number is growing each year. Despite advancements in dialysis technique, cardiovascular complications and mortality in dialysis patients with diabetes remain higher than in those without diabetes. Furthermore, hypertension is commonly known to contribute to the development of cardiovascular complications in dialysis patients, and we aimed to compare the systolic blood pressure (SBP) in dialysis patients with and without diabetes using the Web-based Analysis of Dialysis Data Archives (WADDA) system database. Design and Methods: From 2014 to 2020, we enrolled dialysis patients who had their predialysis SBP measured using the WADDA system 2.1. We classified SBP and evaluated its trends over time by gender, age, and presence of diabetes using the Japanese Society of Hypertension guidelines 2019 (JSH2019). Furthermore, we looked at the relationship between SBP and cardiovascular death in patients with and without diabetes. Results: Dialysis patients with diabetes (n = 168,227) had a mean age of 69.2 (11.7) years versus 69.4 (13.3) years, a mean predialysis history of 5.5 (5.3) years versus 9.4 (9.3 years), and a mean dialysis SBP of 156.6 (25.0) mmHg versus 147.9 (23.6) mmHg, respectively. Dialysis patients with diabetes had higher rates of cardiovascular complications than those without diabetes. From 2014 to 2020, the percentage and absolute values of hypertension were higher in dialysis patients with diabetes than across all age groups and in both men and women. Patients with cerebrovascular death had a higher rate of hypertension, but there was no difference in the rate of grade I and II hypertension between the two groups. Conclusion: We summarized the recent trends in SBP of Japanese dialysis patients with and without diabetes using the WADDA system. Dialysis patients with diabetes had higher SBP than those without diabetes in all age groups and in both men and women. As a result, optimal blood pressure management for dialysis patients with and without diabetes is important for the prevention of cerebrovascular death.

Фибрилляция предсердий у диализных пациентов (опыт одного центра)

The aim of the research is to determine frequency of atrial fi brillation; factors that lead to the formation of atrial fi brillation and the development of cardiovascular complications in dialysis patients. Material and methods. Analysis of current clinical practice in one out-patient hemodialysis center. Results. The incidence of atrial fi brillation in dialysis patients is 10.5 %. Most patients (72.4 %) had a paroxysmal form of atrial fi brillation. Th ere is clinical and laboratory characteristics of patients with atrial fi brillation. Atrial fi brillation occurred in 58.6 % of dialysis patients in average in 45 [15.4; 70.5] months after the beginning of regular hemodialysis, the rest got it in pre-dialysis period. Th e main factor associated with the development of atrial fi brillation on dialysis is the duration of dialysis therapy. Dialysis patients with atrial fi brillation are characterized by more pronounced systemic infl ammation and a higher incidence of hyperparathyroidism compared with patients without atrial fi brillation. Cardiovascular complications developed in 41.4 % dialysis patients with atrial fibrillation. Anuria is a factor associated with the development of myocardial infarction and stroke. Conclusion. Atrial fibrillation is found in every tenth dialysis patient. An increase in atrial fi brillation was noted along with an increase in hemodialysis duration. To optimize dialysis treatment of patients with atrial fibrillation further research is needed

The Impact of Dialysis Modality on Left Ventricular Function in Patient with End Stage Kidney Disease

Introduction: Cardiovascular disease is frequent in end-stage kidney disease patients, and is a major cause of morbidity and mortality. This study was carried out to assess the comparative cardiac effects of hemodialysis and continuous ambulatory peritoneal dialysis on left ventricular function.Methods: A prospective observational study was carried out in patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis at least for 6 months. The duration of the study was from June 2019 to May 2020. CAPD consists of 3 to 4 exchanges/day and haemodialysis 2-3 times/week for 4 hours. Baseline characteristics age, gender, dialysis duration, hypertension, diabetes and hyperlipidaemia were collected. The same cardiologist performed all echocardiography at the end of hemodialysis session in hemodialysis patients and after the drain of dialysate in peritoneal dialysis patients.Results: Sixty patients (40 hemodialyses, 20 peritoneal dialyses) were enrolled. The mean age of the patient was 53.71±13.00 years (range 25-76). There was a slightly higher number of male in the hemodialysis group (p= 0.065). Systolic and diastolic blood pressure were significantly higher in hemodialysis groups (p<0.001). Regarding left ventricular parameters, hemodialysis patients had a higher prevalence of left ventricular diastolic dysfunction, left ventricular hypertrophy, left ventricular mass compared to peritoneal dialysis patients. Pericardial effusion and thickening were present higher in hemodialysis patients and was statistically significant (p<0.05).Conclusion: The modality of dialysis influence left ventricular function. Left ventricle dysfunction is prevalent among hemodialysis patients compared to peritoneal dialysis. Echocardiographic follow up is essential as this could improve the management of cardiovascular complications in dialysis patients.

Study of Serum Magnesium level and Atherosclerotic Changes in Patient on Maintenance Hemodialysis

Background: Cardiovascular complications in dialysis patients focused on atherosclerosis. Serum magnesium has a role in cardiovascular complications in dialysis patients. Objectives: This study aimed to study the correlation between serum magnesium level and atherosclerotic changes in patients on maintenance hemodialysis. Patients and methods: This prospective study included 60 patients with end-stage renal disease patients on maintenance HD, divided into Group I: (20 patients) with normal serum magnesium level (1.7 -2.8 mg/dl), Group II (20 patients) with low serum magnesium level ( 2.8mg/dl.). Serum magnesium and lipid profile and intima-media thickness (IMT) of both common carotid arteries were measured. Results: Our results showed a significant negative association between level of serum Mg and IMT complex of both common carotid (P = 0.045) and ischemic heart disease in the studied patients (P = 0.012). The binary logistic regression for the predictors for IHD and CCA-IMT, we found that serum magnesium not an independent factor for atherosclerosis but we found that age and DM (P ˂ 0.001) followed by cholesterol and triglycerides (P ˂ 0.05) are the most independent factors for CCA-IMT. Also, age (with OR: 95% confidence Interval) (0.145:1.26-1.06) (P ˂ 0.001) and triglycerides (1.02:1.05-1.002), (P ˂ 0.05) are the independent factors for IHD. Conclusion: Our study revealed a significant inverse correlation between level of serum Mg and CCA-IMT and IHD in the studied HD patients. Thus, we suggest that regular screening of HD patients for serum Mg and CIMT with special consideration to diabetic and old patients is recommended to stratify their CV risk.

Study of Serum Magnesium level and Atherosclerotic Changes in Patient on Maintenance Hemodialysis

Background: Cardiovascular complications in dialysis patients focused on atherosclerosis. Serum magnesium has a role in cardiovascular complications in dialysis patients. Objectives: This study aimed to study the correlation between serum magnesium level and atherosclerotic changes in patients on maintenance hemodialysis. Patients and methods: This prospective study included 60 patients with end-stage renal disease patients on maintenance HD, divided into Group I: (20 patients) with normal serum magnesium level (1.7 -2.8 mg/dl), Group II (20 patients) with low serum magnesium level ( 2.8mg/dl.). Serum magnesium and lipid profile and intima-media thickness (IMT) of both common carotid arteries were measured. Results: Our results showed a significant negative association between level of serum Mg and IMT complex of both common carotid (P = 0.045) and ischemic heart disease in the studied patients (P = 0.012). The binary logistic regression for the predictors for IHD and CCA-IMT, we found that serum magnesium not an independent factor for atherosclerosis but we found that age and DM (P ˂ 0.001) followed by cholesterol and triglycerides (P ˂ 0.05) are the most independent factors for CCA-IMT. Also, age (with OR: 95% confidence Interval) (0.145:1.26-1.06) (P ˂ 0.001) and triglycerides (1.02:1.05-1.002), (P ˂ 0.05) are the independent factors for IHD. Conclusion: Our study revealed a significant inverse correlation between level of serum Mg and CCA-IMT and IHD in the studied HD patients. Thus, we suggest that regular screening of HD patients for serum Mg and CIMT with special consideration to diabetic and old patients is recommended to stratify their CV risk.

Cardiovascular complications in hemodialysis patients: current approaches to prolong and improve quality of patients’ life

Cardiovascular complications are a leading cause of morbidity and mortality in dialysis patients. Cardiovascular mortality is more than 40% of the total mortality in this cohort of patients. Recently, there has been an increase in publications on the role of uremic toxins, including “middle molecules”, in the development and progression of cardiovascular complications in dialysis patients.
 Conventional low-flux (LF) hemodialysis well removes small molecular weight uremic toxins not bound with protein. Evidence for the role of "middle molecules" in the development of many complications, including cardiovascular complications, has contributed to the emergence and development of such dialysis therapy methods as high-flux (HF) hemodialysis, hemofiltration (HF) and hemodiafiltration (HDF).
 Further evolution of membrane technology has led to the development of protein-leaking membranes or super-flux or high cutoff (HCO) membranes. These membranes are capable of removing molecules in excess of the molecular weight of albumin. The use of these membranes is limited because of the risk of hypoalbuminemia.
 Today, the closest approximation to the natural glomerular membrane is the so-called Middle Cut-Off (MCO) membrane. The use of MSO membranes is implemented in a new method of dialysis therapy - expanded hemodialysis (HDx). The method is defined as a treatment where diffusion and convection are conveniently combined inside a hollow-fibre dialyser equipped with an MCO membrane. A standard hemodialysis machine is used for the HDx. Increased removal of large medium molecules in HDx may lead to an improvement of clinical outcomes, including a decrease of the cardiovascular events incidence, an all-cause and cardiovascular mortality reduction in dialysis patients.

Cardiovascular complications in chronic dialysis patients.

This review article focuses on the most significant cardiovascular complications in dialysis patients [sudden cardiac death (SCD), acute coronary syndromes, heart failure, and atrial fibrillation]. Current and ongoing research aims to quantify the rate and pattern of significant arrhythmia in dialysis patients and to determine the predominant mechanism of SCD. Preliminary findings from these studies suggest a high rate of atrial fibrillation and that bradycardia and asystole may be more frequent than ventricular arrhythmia as a cause of sudden death. A recently published matched cohort study in dialysis patients who received a defibrillator for primary prevention showed that there was no significant difference in mortality rates between defibrillator-treated patients and propensity-matched controls. Two randomized controlled trials are currently recruiting participants and will hopefully answer the question of whether implantable or wearable cardioverter defibrillators can prevent SCD. An observational study using United States Renal Data System data demonstrated how difficult it is to keep hemodialysis patients on warfarin, as more than two-thirds discontinued the drug during the first year. The ISCHEMIA-CKD trial may provide answers about the optimal strategy for the treatment of atherosclerotic coronary disease in patients with advanced chronic kidney disease. The article reviews the diagnosis of acute coronary syndromes in dialysis patients, current literature on myocardial revascularization, and data on fatal and nonfatal cardiac arrhythmia. The new classification of heart failure in end-stage renal disease is reviewed. Finally, available cohort studies on warfarin for stroke prevention in dialysis patients with atrial fibrillation are reviewed.

Comparison of the Effects of Dialysis Methods (Haemodialysis vs Peritoneal Dialysis) on Diastolic Left Ventricular Function Dialysis Methods and Diastolic Function.

Introduction:In patients undergoing chronic dialysis, several factors appear to influence the occurrence of cardiac abnormalities. The aim of our study was to evaluate the effects of two different methods of renal replacement therapy (chronic haemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD)) on left ventricular (LV) diastolic function.Patients and Methods:We enrolled 63 patients: 21 patients on CAPD, and 42 age- and gender-matched patients on HD; 35 patients were men (55.6%). Median of age was 46.4 (35-57) years. The median duration of renal replacement therapy was 3(2-5) years.Results:The two groups (HD vs PD) were similar concerning body mass index, dialysis duration and cardiovascular risk factors. The comparison of echocardiographic parameters showed statistically significant differences between two groups, regarding the presence of calcification, cardiac effusion, severely abnormal left ventricular hypertrophy(LVH) and the ratio of mitral velocity to early diastolic velocity of the mitral annulus (E/e’) >13 (p= 0.001, p= 0.003, p= 0.02, p= 0.004, respectively). In multivariate analysis, an E/e’>13 was higher in PD group ( OR= 5.8, CI [1.3-25.5], p=0.002).Conclusion:The method of dialysis seems to influence LV diastolic function. We observed a higher prevalence of diastolic LV dysfunction in the PD group. Echocardiographic follow up is essential as this could improve the management of cardiovascular complications in dialysis patients.

Low Dentin Matrix Protein 1 Is Associated With Incident Cardiovascular Events in Peritoneal Dialysis Patients.

Recent reports demonstrated that dentin matrix protein 1 (DMP1) acts as an inhibitor of vascular calcification and might be a potential biomarker for chronic kidney disease-mineral and bone disorder; however, no clinical investigations regarding DMP1 have been performed in dialysis patients. We investigated the prognostic value of DMP1 on cardiovascular outcomes in prevalent peritoneal dialysis patients. We recruited 223 prevalent peritoneal dialysis patients and divided them into high and low DMP1 groups according to log-transformed plasma DMP1 levels. Lateral lumbar spine radiographs were used for measurement of vascular calcification. Major cardiovascular events were compared between the two groups. A Cox proportional hazards analysis determined DMP1 was independently associated with cardiovascular outcomes. In vitro mouse osteocytes were cultured in media containing indoxyl sulfate (IS), and the expressions of DMP1 were examined. The mean age was 52.1 ± 11.8 years, and 116 (52.0%) patients were male. The median value of log DMP1 was 0.91 (0.32-2.81 ng/mL). The multiple logistic regression analysis indicated that DMP1 levels were independently associated with the presence of vascular calcification after adjustment for multiple confounding factors (odds ratio = 0.719; 95% confidence interval [CI] 0.522-0.989; p = 0.043). During a mean follow-up duration of 34.6 months, incident cardiovascular events were observed in 41 (18.4%) patients. A Kaplan-Meier plot showed that the low DMP1 group had a significantly higher rate of incident cardiovascular events compared with the high DMP1 group (log-rank test, p = 0.026). In addition, multiple Cox analysis showed that low DMP1 was significantly associated with incident cardiovascular events (log 1 increase: hazard ratio = 0.855; 95% CI 0.743-0.984; p = 0.029) after adjustment for multiple confounding factors. In IS-stimulated osteocytes, mRNA and protein expression levels of DMP1 were significantly decreased compared with control osteocytes. We showed that low DMP1 levels were significantly associated with presence of vascular calcification and were independently associated with the incident cardiovascular events in prevalent peritoneal dialysis patients. DMP1 might be a potential factor contributing to cardiovascular complications in dialysis patients. © 2016 American Society for Bone and Mineral Research.

Heparin use during dialysis sessions induces an increase in the antiangiogenic factor soluble Flt1

Soluble Flt1 (sFlt1) is a potent inhibitor of vascular endothelial growth factor, secreted mainly by the placenta, endothelial cells and monocytes. Increased sFlt1 serum levels correlate with endothelial dysfunction and cardiovascular complications in dialysis patients. However, the impact of dialysis by itself on sFlt1 serum levels remains unknown. We assessed sFlt1 kinetics during dialysis and the impact of different dialysis techniques [high-flux haemodialysis (HD), haemodiafiltration (HDF)] and heparinization procedures on sFlt1 serum levels in 48 patients on regular dialysis. sFlt1 serum levels increased as early as 1 min after the start of dialysis and peaked at 15 min before returning to baseline at 4 h [mean peak level 2551 pg/mL, versus 102 before dialysis (P < 0.0001)]. sFlt1 kinetics were similar with two different dialysis membranes. In contrast, when unfractionated heparin (UH) and low-molecular-weight heparin (LMWH) were omitted during dialysis (HD or pre-dilution HDF), no significant increase in sFlt1 levels occurred. Conversely, delayed administration of LMWH (after 30 min of a heparin-free HD) induced a sharp increase in sFlt1. Similarly, when UH and LMWH were omitted and citrate-based dialysate or a heparin-coated membrane was used, sFlt1 levels remained unchanged. When heparinization procedures were the same, no difference in sFlt1 levels was noted between HD and HDF. In vitro, UH and LMWH failed to induce sFlt1 release by monocytes from controls or HD patients. These findings suggest that priming of monocytes on the extracorporeal circuit is required for heparin-induced sFlt1 release or that endothelial cells contribute to this increase. Our results indicate that heparin-based HD induces a major sFlt1 release, which may exacerbate the anti-angiogenic state and thus endothelial dysfunction, commonly found in dialysis patients.

Peritoneal Dialysis as Compared with Hemodialysis Is Associated with Higher Overhydration but Non-Inferior Blood Pressure Control and Heart Function

Background/Aims: Fluid overload is an important factor causing cardiovascular complications in dialysis patients. We compared fluid status, blood pressure (BP) and heart function between peritoneal dialysis (PD) patients and hemodialysis (HD) patients. Methods: We recruited 94 PD and 75 HD patients in our hospital. Fluid status was assessed by bioimpedance spectroscopy. Home BP was recorded. Use of antihypertensives was retrieved by chart review. In each group, 39 patients received echocardiographic examinations. Results: PD patients’ fluid status was similar to that of predialysis HD patients. PD patients had lower systolic BP. E/E′ and left ventricular mass index (LVMI) showed no significant intergroup difference. In multiple linear regression analyses, overhydration (OH)/extracellular water ratio >0.15 was associated with higher systolic BP, E/E′ and LVMI. Conclusions: While PD was associated with higher OH but non-inferior BP control and heart function, OH was indeed related to poor BP control, diastolic dysfunction and left ventricular hypertrophy.

Effect of Hemodialysis on Plasma Myeloperoxidase Activity in End Stage Renal Disease Patients.

End stage renal disease (ESRD) patients on hemodialysis (HD) have an increased oxidative stress, with a high risk of atherosclerosis and other co-morbid conditions. Recent studies have suggested that myeloperoxidase (MPO)-mediated oxidative stress may play a role in the pathogenesis of cardiovascular complications in dialysis patients. Furthermore, dialysis treatment 'per se' can aggravate oxidative stress. Hence this study was designed to determine whether HD leads to an alteration in the plasma levels of MPO and malondialdehyde (MDA), a marker of oxidative stress in ESRD patients on maintenance HD. To study the effect of HD, plasma MPO and MDA were determined before and after HD in forty ESRD patients (24 men and 16 women, age between 8 and 71years, median being 40.5years) on maintenance HD. Plasma MPO and MDA were assayed by spectrophotometric methods. Haematological and other biochemical parameters were obtained from patients' case records. Plasma MPO and MDA levels were significantly higher after HD when compared with pre-dialysis levels (p<0.05). There was no correlation between MPO and MDA (r=0.184, p=0.10) and other biochemical parameters (p>0.05). However, there was a significant correlation between MPO and MDA with haemodialysis vintage (p<0.05). In univariate regression analysis duration of HD (β=1.470, p=0.045, β=0.388, p=0.013), was independently associated with MPO and MDA. Although HD is indispensable for survival of patients with ESRD, it is fraught with undesirable side-effects, such as an increase in the plasma MPO and MDA levels. The elevated levels of MPO contribute to the increased oxidative stress as free radicals are produced by the reaction catalyzed by it.

Clinical Characteristics and Cardiovascular Outcomes of Hemodialysis Patients with Atrial Fibrillation: A Prospective Follow-Up Study

Background/Aims: Among the cardiovascular complications in dialysis patients, atrial fibrillation (AF) is the most common arrhythmia. The purpose of this study was to clarify the characteristics and mortality of hemodialysis patients with AF, which are not completely elucidated. Methods: The prevalence of AF in patients undergoing hemodialysis in our institutions was assessed. Patients with AF (AF group) and without AF (control group) were included in this study. Patients in the control group were matched for several important clinical risk factors. For further analysis, AF patients were divided into two groups on the basis of the type of AF (chronic AF (CAF) and paroxysmal AF (PAF) groups). These patients were evaluated for their clinical characteristics, laboratory data and echocardiographic parameters and prospectively followed up for 48 months. Results: Among 328 study patients, 30 had AF (9.1%). Left atrial diameter (LAD) and the left ventricular mass index were significantly greater in the AF group than in the control group. Furthermore, cardiovascular and all-cause mortality and cumulative incidence of cardiovascular events were significantly higher in the AF group than in the control group, and tended to be higher in the CAF group. Conclusions: Our findings demonstrated that the prevalence of AF as 9.1% in hemodialysis patients, and that AF, especially CAF, were associated with high mortality.

Impairments of the biological properties of serum albumin in patients on haemodialysis

End-stage renal disease (ESRD) is associated with enhanced oxidative stress and may contribute to substantial cardiovascular complications in dialysis patients. Recent studies suggested that human serum albumin (HSA), the major plasma protein, may possess a direct vasculoprotective antioxidant effect. In this study, we investigated if such protective effect is impaired in uremic milieu. Thirty-one ESRD patients on maintenance haemodialysis and 22 age-matched healthy controls were recruited. Serum albumin was purified and changes in biological properties of HSA were analysed by several biochemistry techniques, spectrophotometric measurements, ligand-binding assays and western blot analysis. We found that both dityrosine (0.25 +/- 0.1 vs 0.15 +/- 0.07, P < 0.001), and carbonyl (10.5 +/- 1.88 nmol/mg vs 5.29 +/- 1.21 nmol/mg, P < 0.001) contents were increased in the uremic HSA. Decreased thiol activity of plasma was also noted and may be related to dimerization of HSA. In addition, uremic HSA had shown impaired ligand-binding capability such as haemin (0.37 x 10(7)/M vs 2.18 x 10(7)/M, P < 0.001), bilirubin (0.08 x 10(6)/M vs 0.15 x 10(6)/M, P < 0.05) and cis-parinaric acid (3.8 x 10(7)/M vs 2.9 x 10(7)/M, P < 0.05). Furthermore, using two different systems namely copper mediated oxidation of human low density lipoproteins and the free radicals mediated haemolysis test, we have demonstrated that the observed changes of uremic HSA can affect its antioxidant properties. In conclusion, the present study demonstrated that the quality and integrity of HSA molecule in dialysis patients were subtly altered and impaired its biological properties. Oxidative alterations of this major plasma protein might adversely affect its vasculoprotective effects in dialysis patients.

Oxidative stress in uremia.

Oxidative stress has been described as 'a disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. In uremic patients, an increase in oxidative stress may occur because of the loss of residual renal function, and may be exacerbated by dialysis. This review will focus on the emerging biochemical evidence of an increase in oxidative stress in uremic patients, the relationship with renal replacement therapy, and the potential linkages to acute-phase inflammation, malnutrition, and adverse cardiovascular outcomes in uremic patients. Many studies from multiple research laboratories around the world have recently utilized in-vivo biomarkers to describe increased oxidative stress in uremic patients. An emerging literature suggests that there are links between an increase in oxidative stress, endothelial dysfunction, an increase in acute-phase inflammation, and an accelerated risk of cardiovascular complications in dialysis patients. Additional uremia-associated metabolic abnormalities, including hyperhomocysteinemia, intravenous iron exposure, and biocompatibility changes related to dialysis, may contribute to an increase in oxidative stress. Finally, two well-conducted pilot clinical randomized trials have suggested that antioxidant therapy may have efficacy in reducing cardiovascular events in uremic patients. The implications of the findings of a generalized increase in oxidative stress associated with uremia have led to the suggestion that antioxidative therapy may be efficacious in reducing cardiovascular complications. Pilot studies have suggested potential efficacy for this approach. However, further large-scale randomized clinical trials will be required to establish a compelling, evidence-based approach to the use of antioxidants in patients with uremia.

Evolving concepts of pathogenesis of cardiovascular disease in chronic uremia: Role of hyperparathyroidism, calcium-phosphate metabolism, and their therapy

W hemodialysis was introduced for the treatment of end-stage renal disease (ESRD), nephrologists were faced with the development of several new complications. Bone alterations and secondary hyperparathyroidism were between those complications and gave rise to major interest in experimental and clinical research. Although disturbances of calcium and phosphate metabolism were considered principally as factors controlling secretion of parathyroid hormone, PTH was considered as a major uremic toxin associated with bone disease and many nonskeletal disorders including cardiovascular complications. In in vitro studies, PTH was shown to have chronotropic and inotropic effects on isolated cardiomyocytes. These changes were associated with increased intracellular calcium content; disturbed lipoprotein metabolism; and altered mitochondrial energy production, storage, and utilization. These experimental studies were certainly interesting, but the clinical relevance was uncertain. Indeed, in ESRD patients, the secondary hyperparathyroidism was not associated with uniform cardiovascular abnormalities, the cardiovascular effects of parathyroidectomy or nonsurgical control of PTH levels were minimal or absent, and skeletal complications were rarely the cause of death. The role of PTH and associated calciumphosphate disorders on pathogenesis of cardiovascular disorders were recently reanalyzed. Several reports in the literature have suggested that hyperphosphatemia, in association with hyperparathyroidism or hypoparathyroidism and vitamin D3 or calcium overload, was an independent predictor of death and the possible culprit associated with cardiovascular complications in dialysis patients. Cardiovascular disease is the major cause of mortality and morbidity in patients suffering from ESRD. Atherosclerosis and aortic stiffening are the major vascular compliactions observed. Atheromatous plaques of ESRD patients are more frequently and more intensively calcified than those of nonuremic subjects, and several recent studies have shown the presence of extensive and almost generalized vascular calcifications in patients undergoing hemodialysis. Moreover, the extent of calcifications as such is an independent factor to cardiovascular mortality. These calcifications concern not only plaques (intimal calcifications) but also diffuse medial calcifications. Although the arterial calcifications are associated with nonspecific classical factors such as age, diabetes, or smoking habits, there is a growing body of evidence that alterations of phosphate and calcium metabolism play a predominant role. For many years, calcifications were considered to be caused by passive mineral precipitation associated with elevated calcium x phosphate product. Recent studies have shown that this process may be active involving mechanisms normally found in bone. Phosphate seems to be of primary importance in the initiation of cardiovascular calcification through the change of the vascular smooth muscle phenotype and induction of the expression by vascular smooth muscle cells of osteocalcin abd Cbfa-1, which are markers of osteoblastic differention. The pathogenic role of PTH as such is less clear than previously suspected, and extensive calcifications are frequently observed in patients with low bone activity and adynamic bone disease. Of note, in the general population, the cardiovascular calcifications are inversely correlated with bone density in osteoporotic

Nocturnal Hypoxemia Predicts Incident Cardiovascular Complications in Dialysis Patients

Nocturnal hypoxemia secondary to sleep apnea has long been implicated as a cardiovascular risk factor in renal failure, but to date there is no study that links nocturnal hypoxemia to cardiovascular outcomes in end-stage renal disease. Fifty uremic patients on regular dialysis treatment without primary sleep apnea, pulmonary diseases, or other illnesses that may cause sleep apnea underwent pulse oximetry studies during night and were followed up for 32 mo. Average nocturnal SaO(2), minimal SaO(2), and the number of episodes of hypoxemia were similar in patients who died during the follow-up and in patients who survived, and none of these parameters predicted all-cause mortality. Average nocturnal SaO(2) was significantly lower (P = 0.006) in patients who had cardiovascular events during the follow-up (94.7 +/- 2.9%) than in event-free patients (97.1 +/- 1.3%). In a Cox model, average nocturnal SaO(2) was the second factor in rank explaining these outcomes. In this model a 1% decrease in average nocturnal SaO(2) was associated with a 33% increase in the incident risk of fatal and nonfatal cardiovascular events. Furthermore the risk of cardiovascular events was 5.05 times higher in patients with average nocturnal SaO(2) <95% (95% CI 1.61 to 15.86) than in those above this threshold (P = 0.005). This study adds weight to the hypothesis that nocturnal hypoxemia in dialysis patients represents an important cardiovascular risk factor.

Iron overload and cardiovascular complications in dialysis patients.

Patients with end-stage renal disease (ESRD) are at a markedly increased risk for cardiovascular complications compared with the general population. In addition to traditional cardiovascular risk factors such as diabetes mellitus, hypertension, hyperlipidaemia or cigarette smoking, a number of population-specific factors are implicated, such as anaemia, hyperhomocysteinaemia, hyperphosphataemia and vascular calcification, as well as inflammation and oxidative stress. Iron overload has been suggested to increase the cardiovascular risk in the general population. Iron supplementation is a widespread clinical practice in ESRD, especially in patients on maintenance haemodialysis (HD). Iron may therefore contribute to cardiovascular complications through effects on low-density lipoprotein oxidation and endothelial dysfunction. Although the effects of iron stores and iron therapy on cardiovascular risk are not well defined in HD patients, the 'iron hypothesis' deserves attention: serum ferritin is a marker of morbidity and mortality in HD patients, and the administration of high amounts of intravenous iron increases the risks of hospitalization and death. In contrast to intravenous iron therapy, intestinal iron absorption is regulated by body iron stores and is suppressed in the presence of infection and iron overload. Prospective studies are needed to clarify the influence of iron stores and iron therapy on overall and cardiovascular morbidity and mortality in ESRD patients.