Blood pressure variability as an adverse prognostic risk factor in end-stage renal disease.

BACKGROUND: Prospective and case-control studies show that blood-pressure variability is an independent risk factor for severe organ damage and cardiovascular events in hypertensives. We prospectively studied the association between systolic blood pressure variability and cardiovascular mortality and mortality from all causes in end-stage renal disease patients. METHODS AND RESULTS: The subjects were 144 patients (86 men, 58 women; mean age+/-SD, 52+/-13 years) who underwent dialysis in the same dialysis centre and were examined for blood-pressure variability. The study period was 38 months beginning in January 1995, during which six cardiovascular and seven noncardiovascular fatalities occurred. Coefficient of variation in systolic blood pressure in 1994, as an indicator of systolic blood pressure variability, ranged from 7.8 to 14.6%. Cumulative incidence of death from all causes was related to coefficient of variation in systolic blood pressure. The difference between the maximum and minimum systolic blood pressure (deltaSBP) in 1994 ranged from 44 to 146 mmHg (mean+/-SD, 78+/-13 mmHg) and correlated significantly with coefficient of variation in systolic blood pressure (r = 0.65, P<0.0001). Cox regression analysis was used to identify the independent predictors for mortality. The hazard ratio for death from all causes increased 1.63 times per 1% increase in coefficient of variation in systolic blood pressure (hazard ratio; 95% confidence interval: 1.63; 1.05-2.53) and 1.03 times per 1 mmHg increase in deltaSBP (1.08; 1.03-1.14). CONCLUSION: These results suggest that systolic blood pressure variability may be a significant prognostic factor in end-stage renal disease.     

Novel cardiovascular risk factors in end-stage renal disease

Traditional risk factors only in part explain the risk differential between the general population and the population of patients with chronic nephropathies. Uncontrolled hyperphosphatemia and high calcium phosphate product constitute risk factors for cardiovascular calcifications, cardiac ischemia, and adverse cardiovascular outcomes, yet inflammation may be an even more important trigger of vascular calcification than these metabolic derangements. Homocysteine predicts cardiovascular events in ESRD, but evidence that this sulfur amino acid is directly implicated in the high cardiovascular mortality of uremic patients is still lacking. It seems unlikely that Chlamydia pneumoniae is a major risk factor in dialysis patients because the association between anti-Chlamydia antibodies and incident cardiovascular events seems to depend largely on the confounding effect of some traditional risk factors. Oxidative stress and raised plasma concentration of asymmetric dimethylarginine (ADMA) are pervasive in ESRD, and high ADMA in these patients may be at least in part the expression of the high rate of generation of oxidants. ADMA per se seems responsible for a 52% increase in the risk of death and for a 34% increase in the risk of cardiovascular events in dialysis patients.     

Secondary hyperparathyroidism and its therapy as a cardiovascular risk factor among end-stage renal disease patients

Secondary hyperparathyroidism (HPTH) was initially viewed as a disorder of the skeletal system; however, recent population-based data have associated markers of HPTH with an increased cardiovascular mortality among patients with end-stage renal disease (ESRD). This has stimulated much interest in further evaluating secondary HPTH as a cardiovascular disease risk factor, as well as the putative role of its therapy. This article explores the current state of scientific evidence concerning the pathophysiology of cardiovascular disease among the ESRD population and potential risk factors for its development, including markers of HPTH, and its therapies.     

The challenge of cardiovascular risk factors in end-stage renal disease

Due to the impressive cardiovascular (CV) morbidity and mortality in uremic patients, assessment of CV risk factors in the dialysis population is a crucial challenge in nephrology. Cardiovascular risk factors in dialysis patients may have a different significance in ESRD patients compared to the general population. The Framingham risk equation seems not to be valid in chronic uremia. Furthermore, new powerful outcome predictors have emerged in recent years: pulse pressure, dipping status, pulse wave velocity, augmentation index. The concept of "U"-shaped association between blood pressure (as well as cholesterolemia) and mortality are extensively discussed. The authors are focusing on the value of office and ambulatory blood pressure measurements in the uremic population. An extensive evaluation of blood pressure and vascular compliance in dialysis patients is proposed. Efficient dialysis, ACE-inhibitors and beta-blockers, statins, antiplatelet treatment and adequate control of calcium-phosphorus metabolism should be the mainstay of therapy in the ESRD patients with several CV risk factors.     

Traditional and emerging cardiovascular risk factors in end-stage renal disease

Patients with end-stage renal disease face a particularly high risk of cardiovascular disease and total mortality. Part of their increased risk is due to a higher prevalence of established risk factors, such as arterial hypertension, diabetes, smoking, and anemia. Hypertension and diabetes have a very high prevalence in dialysis patients and play a major role in their high mortality and morbidity. Hyperparathyroidism, hyperhomocysteinemia and disordered lipid metabolism represent factors that are peculiarly altered by the uremic state. Inflammatory processes, high sympathetic activity, and the accumulation of an endogenous inhibitor of NO synthase (ADMA), have recently emerged as cardiovascular risk factors of paramount importance. Sleep apnea has been linked with nocturnal hypertension and could be implicated in the high prevalence of concentric hypertrophy of the left ventricle in these patients. Hypertension control, as well as appropriate treatment of anemia and cessation of smoking, constitutes a fundamental area of intervention in dialysis patients. It appears possible that, in the near future, control of chronic inflammatory processes of high sympathetic activity and endothelial dysfunction will further help to curb the exceedingly high cardiovascular mortality of patients on chronic dialysis treatment.     

Traditional and non-traditional risk factors as contributors to atherosclerotic cardiovascular disease in end-stage renal disease

Cardiovascular disease (CVD) remains the main cause of morbidity and mortality in patients with end-stage renal disease (ESRD). Although traditional risk factors, such as diabetes mellitus, hypertension, dyslipidemia and advanced age, are prevalent in ESRD patients they may not be sufficient by themselves to account for the high prevalence of CVD in patients with this condition. Thus, the search for other, non-traditional, risk factors that may be involved in the pathogenesis of uremic CVD has been an area of intense study. Data suggest that the accelerated atherosclerotic process of ESRD may involve several interrelated processes, such as oxidative stress, endothelial dysfunction and vascular calcification, in a milieu of constant low-grade inflammation. The cause(s) of inflammation in ESRD are multifactorial and, while it may reflect underlying CVD, an acute-phase reaction may also be a direct cause of vascular injury via several pathogenetic mechanisms. Available data suggest that pro-inflammatory cytokines play a central role in the genesis of both malnutrition and CVD in ESRD. Thus, it could be speculated that suppression of the vicious cycle of malnutrition, inflammation and atherosclerosis (MIA syndrome) would improve survival in dialysis patients. Recent evidence has demonstrated strong associations between inflammation and both increased oxidative stress and endothelial dysfunction in ESRD patients. As there is not yet any recognized, or even proposed, treatment for ESRD patients with chronic inflammation it would be of obvious interest to study the long-term effect of various anti-inflammatory treatment strategies on the nutritional and cardiovascular status as well as outcome of these patients.     

Insulin resistance as an independent predictor of cardiovascular mortality in patients with end-stage renal disease

Insulin resistance is closely associated with atherosclerosis and cardiovascular mortality in the general population. Patients with end-stage renal disease (ESRD) are known to have insulin resistance, advanced atherosclerosis, and a high cardiovascular mortality rate. We evaluated whether insulin resistance is a predictor of cardiovascular death in a cohort of ESRD. A prospective observational cohort study was performed in 183 nondiabetic patients with ESRD treated with maintenance hemodialysis. Insulin resistance was evaluated by the homeostasis model assessment method (HOMA-IR) using fasting glucose and insulin levels at baseline, and the cohort was followed for a mean period of 67 mo. Forty-nine deaths were recorded, including 22 cardiovascular deaths. Cumulative incidence of cardiovascular death by Kaplan-Meier estimation was significantly different between subjects in the top tertile of HOMA-IR (1.40 to 4.59) and those in the lower tertiles of HOMA-IR (0.28 to 1.39), and the hazard ratio (HR) was 2.60 (95% confidence interval [CI], 1.12 to 6.01; P = 0.026) in the univariate Cox proportional hazards model. In multivariate Cox models, the positive association between HOMA-IR and cardiovascular mortality remained significant (HR, 4.60; 95% CI, 1.83 to 11.55; P = 0.001) and independent of age, C-reactive protein, and presence of preexisting vascular complications. Further analyses showed that the effect of HOMA-IR on cardiovascular mortality was independent of body mass index, hypertension, and dyslipidemia. In contrast, HOMA-IR did not show such a significant association with noncardiovascular mortality. These results indicate that insulin resistance is an independent predictor of cardiovascular mortality in ESRD.     

Non-traditional cardiovascular disease risk factors in end-stage renal disease: oxidate stress and hyperhomocysteinemia

Studies in experimental animals have shown that oxidative stress and hyperhomocyst(e)inemia culminate in abnormal vascular and endothelial regulation, functional nitric oxide deficiency, vascular hypertrophy, and atherosclerosis. Oxidative stress is accompanied by increased advanced glycation endproducts and oxidized low density lipoproteins. Studies of patients with end-stage renal disease provide extensive indirect, evidence of increased oxidative stress and more than ninety percent are hyperhomocyt(e)inemic. Presently, only uncontrolled or observational studies are available to assess the effects of anti-oxidant therapy for oxidative stress or folate therapy for hyperhomocyst(e)inemia in these patients. Promising developments include the reports of beneficial effects of a vitamin E coated dialyzer, and the reduction in homocyst(e)ine levels in patients with end-stage renal disease given an intravenous folate metabolite. However, there is presently no therapy available to reverse fully oxidative stress or hyperhomocyst(e)inemia. Therefore, the causative role of these nontraditional risk factors of cardiovascular disease remains untested.     

Endothelin and cardiovascular remodelling in end-stage renal disease

Background. Plasma endothelin (ET) is elevated in end-stage renal disease (ESRD), but the origin and consequences of this increase remain unclear. In the present study we analysed the relationships between plasma ET levels and cardiovascular alterations in ESRD. Methods and results. Common carotid artery (CCA) intima-media thickness (IMT) and diameter, atherosclerotic plaque occurrence, and left ventricular (LV) geometry and function were determined by ultrasound imaging in 76 haemodialysis patients and in 57 age-, sex-, and blood pressure-matched controls. Arterial stiffness was evaluated via carotid-femoral pulse wave velocity (CF-PWV), forearm post-ischaemic vasodilation was measured by venous plethysmography, and plasma ET levels were determined using a specific immunoenzymoassay. Compared with controls, ESRD patients had elevated plasma ET levels (1.6±1.4 vs 4.6±3.8 pg/ml; P<0.001), increased LV mass (P<0.001), increased CCA-IMT (P<0.001), a higher prevalence of atherosclerotic plaques (P<0.001) and increased CF-PWV (P<0.01). Plasma ET levels correlation positively with LV outflow velocity integral (r=0.57; P<0.0001), stroke index (P<0.01), and baseline forearm blood flow (P<0.001) which were all significantly higher in ESRD patients than in controls (P<0.01). After adjustment for age, blood pressure, haemoglobin levels, gender and body dimensions, plasma ET levels were significantly correlated to LV mass (r=0.46; P<0.001), CCA-IMT and CCA intima -media cross-sectional area (r=0.41; P<0.001), and CF-PWV (p<0.05). Post-ischaemic forearm vasodilation was decreased in ESRD (85±31 vs 119±28%; P<0.001) and there was a negative correlation between post-ischaemic flow recovery and ET levels (r=-0.49; P<0.001). In ESRD patients, plasma ET levels were positively and independently correlated with the prevalence of CCA atherosclerotic plaque (P<0.01). Conclusions. These results indicate that the increased plasma ET levels in ESRD patients are associated with left ventricular hypertrophy and arterial intima-media thickening, suggesting that increased ET concentrations in ESRD patients may be of pathophysiological significance in the process of cardiovascular remodelling.     

Kidney disease as an independent risk factor for cardiovascular events.

Although the high risk for cardiovascular events in patients with end-stage renal disease (ESRD) is well known, recent data provide compelling evidence that even mild to moderate kidney disease is an important and independent risk factor for cardiac events. This increased risk does not seem to be explained by traditional risk factors as defined by the Framingham cohort. The examination of nontraditional risk factors has resulted in the identification of, among others, oxidant stress, hyperhomocystinemia, carbamylation, nitric oxide synthase inhibitors, and abnormal lipoproteins as potential pathways to explain the accelerated atherosclerosis in patients with kidney disease. Well-designed clinical trials should lead to the clarification of the relative importance of these factors in the pathogenesis of atherosclerotic disease.     

Pulse pressure is an independent risk factor of cardiovascular disease in renal transplant patients

Elevated pulse pressure in the general population has been shown to be associated with cardiovascular disease, which is the main cause of death in renal transplant patients. We investigated the effects that a wide pulse pressure has on cardiovascular disease after renal transplantation in a cohort of 532 transplant patients with functioning grafts for more than one year. Patients were classified into two groups depending on whether the one-year pulse pressure was less than or greater than 65 mm Hg. We analyzed patient survival, posttransplant cardiovascular disease and principle causes of death. Five- and ten-year patient survival were lower among the group with higher pulse pressures. The main cause of death was vascular disease in both groups. The presence of posttransplant cardiovascular disease was higher among the group with higher pulse pressures (RR=1.73). In addition, the incidence of an elevated pulse pressure was directly associated with recipient age and posttransplant diabetes mellitus. In conclusion, pulse pressure represents an independent risk factor for increased cardiovascular morbidity and mortality in renal transplant patients.     

Proteinuria and decreased body mass index as a significant risk factor in developing end-stage renal disease

Background  Body mass index (BMI) is a significant predictor of developing end-stage renal disease (ESRD). The relation between a change in BMI (ΔBMI) and the incidence of ESRD has not been examined in any large epidemiologic studies. Methods  We determined the ΔBMI in subjects who participated in the Okinawa General Health Maintenance Association (OGHMA) screenings in 1983 and again in 1993. Screenees were free of ESRD at the 1993 screening and were then monitored until the end of 2000 to determine whether they developed ESRD. Participants were identified using ID numbers, birthdates, and other identifiers. Details of every ESRD patient treated in Okinawa are maintained in an independent community-based dialysis registry. Multivariate logistic analyses were performed to determine the significance of a ΔBMI on the incidence of ESRD using SAS. The ethics committee of the OGHMA approved the study protocol. Only coded data were used for this study. Results  Among the 92,364 subjects aged 30–89 years screened in 1983, 29,011 (31.4%) returned for the 1993 screening. The median ΔBMI was 2.1%, and the subjects were divided into two groups: ΔBMI < 2.1% (G1) and ΔBMI ≥ 2.1% (G2). The cumulative incidence of ESRD was 0.31% in G1 (ESRD in 44) and 0.14% in G2 (ESRD in 21). The odds ratio (95% confidence interval) of developing ESRD based on a ΔBMI was 2.268 (1.284–4.000, P < 0.01) after adjusting for age, sex, systolic blood pressure, BMI in 1983, and proteinuria. Conclusion  The findings of the present study suggest that a ΔBMI is an independent risk factor for the incidence of ESRD, especially for those with proteinuria. The reasons for the BMI change were not recorded in this study. Unintentional weight loss, however, might warrant evaluation for the presence or progression of chronic kidney disease.     

Familiality of cardiovascular mortality in end-stage renal disease patients

A very high rate of cardiovascular (CV) death is well recognized in individuals with end-stage renal disease (ESRD). Besides many other factors, this excess risk may also be related to familiality. We tested this hypothesis by estimating the risk of CV death among both ESRD patients and their relatives. In this case-control study, we used the Utah Population Database (UPDB), which includes genealogy records, state-wide death certificates as well as other data sets. These have been linked to the University of Utah Health Sciences Enterprise Data Warehouse which provides multiple diagnosis data sources. Patients with ESRD either on dialysis or who received a kidney transplant were identified in the clinical databases at the University of Utah Dialysis Program and Kidney Transplant Program or from Utah death certificates. CV deaths were identified by the reporting on the death certificates. The relative risks for CV death, adjusted for several potential confounders in the ESRD patients (n = 516) and in their first-degree (n = 2,418) and second-degree (n = 7,720) relatives were estimated in relation to the general population. Using information from death certificates, ESRD patients were found to have disproportionately increased risk for CV mortality (relative risk or RR = 2.4; 95% CI 2.11-2.72), compared to the general population. First-degree relatives of ESRD patients were also found to have an increased CV mortality risk (RR = 1.10; 95% CI 1.01-1.20). When the specific categories of CVD were analyzed, the first-degree relatives also had higher risks for death from acute myocardial infarction (RR = 1.20; 95% CI 1.03-1.40) or heart failure (RR = 1.32; 95% CI 1.12-1.56). An increased risk for CV mortality was, however, not observed in second-degree relatives of ESRD patients, except for the subcategory of hypertensive heart disease (RR = 1.24, 95% CI 1.01-1.49). In conclusion, this study suggests that, in addition to many putative risk factors, the increased risk of CV death in ESRD patients may have a familial contribution.