Exercise in Patients on Dialysis: A Multicenter, Randomized Clinical Trial.

Previous studies have suggested the benefits of physical exercise for patients on dialysis. We conducted the Exercise Introduction to Enhance Performance in Dialysis trial, a 6-month randomized, multicenter trial to test whether a simple, personalized walking exercise program at home, managed by dialysis staff, improves functional status in adult patients on dialysis. The main study outcomes included change in physical performance at 6 months, assessed by the 6-minute walking test and the five times sit-to-stand test, and in quality of life, assessed by the Kidney Disease Quality of Life Short Form (KDQOL-SF) questionnaire. We randomized 296 patients to normal physical activity (control; n=145) or walking exercise (n=151); 227 patients (exercise n=104; control n=123) repeated the 6-month evaluations. The distance covered during the 6-minute walking test improved in the exercise group (mean distance±SD: baseline, 328±96 m; 6 months, 367±113 m) but not in the control group (baseline, 321±107 m; 6 months, 324±116 m; P<0.001 between groups). Similarly, the five times sit-to-stand test time improved in the exercise group (mean time±SD: baseline, 20.5±6.0 seconds; 6 months, 18.2±5.7 seconds) but not in the control group (baseline, 20.9±5.8 seconds; 6 months, 20.2±6.4 seconds; P=0.001 between groups). The cognitive function score (P=0.04) and quality of social interaction score (P=0.01) in the kidney disease component of the KDQOL-SF improved significantly in the exercise arm compared with the control arm. Hence, a simple, personalized, home-based, low-intensity exercise program managed by dialysis staff may improve physical performance and quality of life in patients on dialysis.

Fitness for entering a simple exercise program and mortality: a study corollary to the exercise introduction to enhance performance in dialysis (EXCITE) trial.

BACKGROUND/AIMS: In this corollary analysis of the EXCITE study, we looked at possible differences in baseline risk factors and mortality between subjects excluded from the trial because non-eligible (n=216) or because eligible but refusing to participate (n=116). METHODS: Baseline characteristics and mortality data were recorded. Survival and independent predictors of mortality were assessed by Kaplan-Meier and Cox regression analyses. RESULTS: The incidence rate of mortality was higher in non-eligible vs. eligible non-randomized patients (21.0 vs. 10.9 deaths/100 persons-year; P<0.001). The crude excess risk of death in non-eligible patients (HR 1.96; 95% CI 1.36 to 2.77; P<0.001) was reduced after adjustment for risk factors which differed in the two cohorts including age, blood pressure, phosphate, CRP, smoking, diabetes, triglycerides, cardiovascular comorbidities and history of neoplasia (HR 1.60; 95% CI 1.10 to 2.35; P=0.017) and almost nullified after including in the same model also information on deambulation impairment (HR 1.16; 95% CI 0.75 to 1.80; P=0.513). CONCLUSIONS: Deambulation ability mostly explains the difference in survival rate in non-eligible and eligible non-randomized patients in the EXCITE trial. Extending data analyses and outcome reporting also to subjects not taking part in a trial may be helpful to assess the representability of the study population.

Physical performance and clinical outcomes in dialysis patients: a secondary analysis of the EXCITE trial.

BACKGROUND/AIMS: Scarce physical activity predicts shorter survival in dialysis patients. However, the relationship between physical (motor) fitness and clinical outcomes has never been tested in these patients. METHODS: We tested the predictive power of an established metric of motor fitness, the Six-Minute Walking Test (6MWT), for death, cardiovascular events and hospitalization in 296 dialysis patients who took part in the trial EXCITE (ClinicalTrials.gov Identifier: NCT01255969). RESULTS: During follow up 69 patients died, 90 had fatal and non-fatal cardiovascular events, 159 were hospitalized and 182 patients had the composite outcome. In multivariate Cox models - including the study allocation arm and classical and non-classical risk factors - an increase of 20 walked metres during the 6MWT was associated to a 6% reduction of the risk for the composite end-point (P=0.001) and a similar relationship existed between the 6MWT, mortality (P<0.001) and hospitalizations (P=0.03). A similar trend was observed for cardiovascular events but this relationship did not reach statistical significance (P=0.09). CONCLUSIONS: Poor physical performance predicts a high risk of mortality, cardiovascular events and hospitalizations in dialysis patients. Future studies, including phase-2 EXCITE, will assess whether improving motor fitness may translate into better clinical outcomes in this high risk population.

Vascular endothelial growth factor, left ventricular dysfunction and mortality in hemodialysis patients.

OBJECTIVES: Vascular endothelial growth factor induces nitric oxide-dependent angiogenic effects and participates in the inflammatory response. This cytokine is over-expressed in the myocardium in experimental models of pressure overload and renal mass ablation, and vascular endothelial growth factor is increased in end-stage renal disease. We investigated the relationship between vascular endothelial growth factor, left ventricular function (by midwall fractional shortening) and mortality in a prospective cohort study in 228 hemodialysis patients. RESULTS: Serum vascular endothelial growth factor concentration was associated directly with interleukin-6 and tumor necrosis factor-alpha (P < 0.01) and inversely with albumin (P = 0.007) but was independent of the endogenous inhibitor of nitric oxide synthesis, asymmetric dimethylarginine. Vascular endothelial growth factor was inversely related with midwall fractional shortening (P = 0.002) and predicted mortality (P = 0.02). In multivariate analyses testing the involvement of this angiogenic cytokine in left ventricular dysfunction and death, these links remained substantially unmodified after adjustment for Framingham risk factors, risk factors peculiar to end-stage renal disease (Hb, Ca, P) and previous cardiovascular complications. However, these links became weaker and not significant when biomarkers of inflammation and asymmetric dimethylarginine were sequentially introduced into the multivariate models. In crude and adjusted analyses, left ventricular function was lowest in patients who displayed both high vascular endothelial growth factor and high asymmetric dimethylarginine, intermediate in patients with either high vascular endothelial growth factor or high asymmetric dimethylarginine and highest in those with low asymmetric dimethylarginine and low vascular endothelial growth factor (P = 0.001). CONCLUSION: Vascular endothelial growth factor is associated with left ventricular systolic dysfunction and mortality in hemodialysis patients. Vascular endothelial growth factor appears to be in the pathway whereby inflammation and nitric oxide inhibition lead to cardiomyopathy and death in hemodialysis patients.

Low triiodothyronine and cardiomyopathy in patients with end-stage renal disease.

OBJECTIVES AND METHODS: Low free plasma triiodothyronine (fT3) is associated with inflammation and cardiovascular damage in patients with end-stage renal disease (ESRD). We investigated the relationship between fT3, left ventricular systolic function and left ventricular mass in a group of 234 dialysis patients, and modelled the association between fT3 and cardiomyopathy in statistical analyses including both direct (interleukin-6 and C-reactive protein) and inverse (serum albumin) acute phase inflammation markers. RESULTS: Plasma fT3 concentration in dialysis patients was significantly (P < 0.001) reduced in comparison with healthy participants and clinically euthyroid patients with normal renal function. Left ventricular systolic function was depressed (P

Left ventricular systolic function monitoring in asymptomatic dialysis patients: a prospective cohort study.

Although it is well established that compromised systolic function predicts cardiovascular (CV) complications in symptomatic and asymptomatic patients with ESRD, it still is unknown whether repeated echocardiographic measurements of systolic function in asymptomatic patients with ESRD is useful for monitoring the evolution of cardiomyopathy in these patients. The prognostic value for CV events of changes in systolic function, as measured by midwall fractional shortening (mwFS) in a cohort of 191 dialysis patients, was tested. Echocardiography was performed twice, 17 +/- 2 mo apart. Changes in mwFS (ch-mwFS) that occurred between the second and the first echocardiographic studies then were used to predict CV events during the ensuing 27 +/- 13 mo. After the second echocardiographic study, 85 patients had incident CV events. In a Kaplan-Meier analysis, there was a graded increase in the risk for fatal and nonfatal CV events across ch-mwFS quartiles (P = 0.005). On multivariate Cox regression analysis, ch-mwFS maintained an independent association with CV outcomes. In this analysis, the risk for CV events was 51% lower in patients who manifested an increase in mwFS (hazard ratio 0.49; 95% confidence interval 0.27 to 0.88; P = 0.02) than in those who had a decrease in mwFS. Changes in mwFS have an independent prognostic value for CV events, and periodic echocardiographic studies of systolic function are useful for monitoring asymptomatic dialysis patients.

Prospective study of neuropeptide y as an adverse cardiovascular risk factor in end-stage renal disease.

Chronic renal insufficiency is a situation characterized by high plasma concentration of neuropeptide Y (NPY). Because this neuropeptide interferes with cardiovascular (CV) function, it is possible that it is involved in the high CV-related morbidity and mortality of these patients. To test this hypothesis, a follow-up study was performed (average duration, 34 mo; range 0.2 to 52.0 mo) in a cohort of 277 patients with end-stage renal disease receiving chronic dialysis. Univariate analysis revealed that plasma NPY was directly related to plasma norepinephrine (r = 0.37, P < 0.001) and epinephrine (r = 0.17, P = 0.005), exceeding the upper limit of the normal range in the majority of patients with end-stage renal disease (170 of 277, 61%). One hundred thirteen patients had one or more fatal and nonfatal CV events; 112 patients died, 66 of them (59%) of CV causes. Plasma NPY failed to predict all-cause mortality but was an independent predictor of adverse CV outcomes (hazard ratio [10 pmol/L increase in plasma NPY], 1.32; 95% confidence interval, 1.09 to 1.60; P = 0.004) in a Cox proportional-hazard model that included a series of traditional and nontraditional CV risk factors. Plasma NPY maintained its predictive power for CV events in statistical model including plasma norepinephrine. Plasma NPY predicts incident CV complications in end-stage renal disease. Controlled trials are needed to establish whether interference with the sympathetic system, NPY, or both may reduce the high CV morbidity and mortality of dialysis patients.

Neuropeptide Y, left ventricular mass and function in patients with end stage renal disease.

OBJECTIVE: Neuropeptide Y (NPY) is released during sympathetic stimulation and mediates the central effects of the adipostatic hormone leptin. The plasma concentration of NPY and leptin is increased in patients with end stage renal disease (ESRD), but it is unknown whether these substances are related to biochemical markers of sympathetic activity and to alterations in left ventricular (LV) mass and function in these patients. DESIGN: We investigated the relationship between NPY, norepinephrine (NE), leptin and echocardiographic measurements in a cross-sectional study in 198 patients with ESRD. RESULTS: NPY was directly related to plasma NE and heart rate but it was largely independent of arterial pressure and of retention of metabolic waste products. NPY was significantly higher in patients with LV hypertrophy and in those with LV systolic dysfunction than in those without these alterations. Of note, NPY emerged as an independent correlate of LV mass index and of LV ejection fraction (LVEF) (both P

Troponin is related to left ventricular mass and predicts all-cause and cardiovascular mortality in hemodialysis patients.

Cardiac troponin T (cTnT) predicts death and cardiovascular outcomes in clinically stable patients with end-stage renal disease. Because this protein is synthesized exclusively in myocardial cells, its predictive power for these outcomes may be because it reflects, besides cardiac ischemia, left ventricular (LV) mass, which is a strong predictor of cardiovascular death in this population per se. We tested the relationship between cTnT level and LV mass and the predictive power of this cardiac protein for all-cause and cardiovascular mortality in a cohort of hemodialysis patients (n = 199) without acute coronary syndrome and heart failure followed up for an average of 35 months (range, 0.8 to 52 months). cTnT was measured by means of a third-generation electrochemiluminescence immunoassay. cTnT level was related directly to interventricular septum (r = 0.36; P < 0.001) and posterior wall thickness (r = 0.40; P < 0.001), as well as LV mass (r = 0.45; P < 0.001). On multivariate analysis, after age, LV mass was the strongest independent predictor of cTnT level (beta = 0.28; P < 0.001). Serum cTnT level was significantly related to all-cause and cardiovascular mortality on univariate analysis (P < 0.001). On multivariate Cox regression analysis, the adjusted risk for all-cause death was 2.39 times (95% confidence interval [CI], 1.13 to 5.06; P = 0.02) greater in patients in the third cTnT tertile than the first tertile, and a similar pattern emerged for cardiovascular mortality (hazard ratio, 2.35; 95% CI, 1.01 to 5.49; P = 0.048). In hemodialysis patients, plasma cTnT level is independently related to LV mass and predicts all-cause and cardiovascular mortality. These data support the hypothesis that this marker can be usefully applied for risk stratification in clinically stable dialysis patients.

Plasma norepinephrine predicts survival and incident cardiovascular events in patients with end-stage renal disease.

BACKGROUND: Sympathetic tone is consistently raised in patients with end-stage renal disease (ESRD). We therefore tested the hypothesis that sympathetic activation is associated with mortality and cardiovascular events in a cohort of 228 patients undergoing chronic hemodialysis who did not have congestive heart failure at baseline and who had left ventricular ejection fraction >35%. METHODS AND RESULTS: The plasma concentration of norepinephrine (NE) was used as a measure of sympathetic activity. Plasma NE exceeded the upper limit of the normal range (cutoff 3.54 nmol/L) in 102 dialysis patients (45%). In a multivariate Cox regression model that included all univariate predictors of death as well as the use of sympathicoplegic agents and beta-blockers, plasma NE proved to be an independent predictor of this outcome (hazard ratio [1-nmol/L increase in plasma NE]: 1.07, 95% CI 1.01 to 1.14, P=0.03). Similarly, plasma NE emerged as an independent predictor of fatal and nonfatal cardiovascular events (hazard ratio [1-nmol/L increase in plasma NE] 1.08, 95% CI 1.02 to 1.15, P=0.01) in a model that included previous cardiovascular events, pulse pressure, age, diabetes, smoking, and use of sympathicoplegic agents and beta-blockers. The adjusted relative risk for cardiovascular complications in patients with plasma NE >75th percentile was 1.92 (95% CI 1.20 to 3.07) times higher than in those below this threshold (P=0.006). CONCLUSIONS: Sympathetic nerve overactivity is associated with mortality and cardiovascular outcomes in ESRD. Controlled trials with antiadrenergic drugs are needed to determine whether interference with the sympathetic system could reduce the high cardiovascular morbidity and mortality in dialysis patients.

Adiponectin, metabolic risk factors, and cardiovascular events among patients with end-stage renal disease.

Adiponectin (ADPN), which is a secretory protein of adipose tissue, attenuates endothelial inflammatory responses in vitro. Among human subjects, plasma ADPN concentrations are reduced among patients with atherosclerotic complications but are substantially increased among patients with advanced renal failure. The clinical and biochemical correlates of plasma ADPN levels were investigated and the predictive power of ADPN levels with respect to survival rates and cardiovascular events was prospectively tested in a cohort of 227 hemodialysis patients, who were monitored for 31 +/- 13 mo. Plasma ADPN levels were 2.5 times higher (P < 0.0001) among dialysis patients (15.0 +/- 7.7 microg/ml) than among healthy subjects (6.3 +/- 2.0 microg/ml), were independent of age, and were higher (P = 0.03) among women (15.2 +/- 7.9 microg/ml) than among men (14.0 +/- 7.4 microg/ml). For both genders, plasma ADPN levels were inversely related to body mass index values, plasma leptin levels, insulin levels, serum triglyceride levels, and homeostatic model assessment index values. Furthermore, plasma ADPN levels were directly related to HDL cholesterol levels and inversely related to von Willebrand factor levels. Plasma ADPN levels were lower (P < 0.05) among patients who experienced new cardiovascular events (13.7 +/- 7.3 microg/ml) than among event-free patients (15.8 +/- 7.8 microg/ml). There was a 3% risk reduction for each 1 microg/ml increase in plasma ADPN levels, and the relative risk of adverse cardiovascular events was 1.56 times (95% confidence interval, 1.12 to 1.99 times) higher among patients in the first ADPN tertile, compared with those in the third tertile. Plasma ADPN levels are an inverse predictor of cardiovascular outcomes among patients with end-stage renal disease. Furthermore, ADPN is related to several metabolic risk factors in a manner consistent with the hypothesis that this protein acts as a protective factor for the cardiovascular system.