Effect of dialysis dose and membrane flux on hemoglobin cycling in hemodialysis patients

Many studies found that hemoglobin (Hb) fluctuation was closely related to the prognosis of the maintenance hemodialysis patients. We investigated the association of factors relating dialysis dose and dialyzer membrane with Hb levels. We undertook a randomized clinical trial in 140 patients undergoing thrice‐weekly dialysis and assigned patients randomly to a standard or high dose of dialysis; Hb level was measured every month for 12 months. In the standard‐dose group, the mean (±SD) urea reduction ratio was 65.1% ± 7.3%, the single‐pool Kt/V was 1.26 ± 0.11, and the equilibrated Kt/V was 1.05 ± 0.09; in the high‐dose group, the values were 73.5% ± 8.7%, 1.68 ± 0.15, and 1.47 ± 0.11, respectively. The standard deviation (SD) and residual SD (liner regression of Hb) values of Hb were significantly higher in the standard‐dose group and low‐flux group. The percentage achievement of target Hb in the high‐dose dialysis group and high‐flux dialyzer group was significantly higher than the standard‐dose group and low‐flux group, respectively. Patients undergoing hemodialysis thrice weekly appear to have benefit from a higher dialysis dose than that recommended by current KDQQI (Kidney Disease Qutcome Quality Initiative) guidelines or from the use of a high‐flux membrane, which is in favor of maintaining stable Hb levels.     

Mortality risk in hemodialysis patients according to anemia control and erythropoietin dosing

There is no consensus about the toxicity of erythropoiesis‐stimulating agents among hemodialysis patients. We aimed to calculate the risk of death according to anemia control and erythropoietin (EPO) dosing among end‐stage renal disease patients undergoing hemodialysis. We retrospectively studied 156 end‐stage renal disease patients on hemodialysis from a single renal unit during 12 months. Participants were classified according to anemia control into four groups: excellent (A), good (B), moderate (C) and bad (D) control. They were also classified according to EPO dosing into two groups: usual and high EPO dosing. The Cox proportional hazards regression model, adjusted for the difference in age, sex, time on dialysis, comorbidity, albumin, and Kt/V index, was performed to calculate the risk of death according to anemia control and EPO dosing profiles. Multivariate analysis by backward stepwise logistic regression was used to calculate the risk of death according to the variables that differed in the comparison between survivors and nonsurvivors. The hazard ratio of death was not significant according to anemia control profile C/D vs. A/B, but hazard ratio was 2.967 (95% confidence interval [CI] = 1.132–7.777; P = 0.027) for high EPO dosing profile patients. The multivariate analysis showed comorbidity (odds ratio [OR] = 8.958; 95% CI = 2.843–26.223; P < 0.001], high EPO dosing profile (OR = 5.172; 95% CI = 1.663–16,081; P = 0.005), age (OR = 1.056; 95% CI = 1.020–1.094; P = 0.002), and mean hemoglobin (OR = 0.435; 95% CI = 0.267–0.709; P = 0.001) to be predictive of death. Even though we cannot conclude that mortality risk is due to EPO toxicity, hemodialysis patients using high EPO dosing must be seen as at risk.     

Statin use is associated with lower inflammation and erythropoietin responsiveness index in hemodialysis patients

Patients with end-stage renal disease are prone to inflammation and inflammation is related to erythropoietin-stimulating agent hyporesponsiveness and mortality in this population. Statins have been demonstrated to reduce cardiovascular mortality in selected populations of end-stage renal disease patients. These drugs have pleiotrophic effects such as anti-inflammation. In this retrospective analysis, we determined whether the use of statins improves inflammation and inflammation-related anemia in a cohort of hemodialysis patients. Data were analyzed from Fresenius Medical Care Dialysis Clinics in Turkey between 2005 and 2007. Seventy prevalent hemodialysis patients who were on statins at the start of the study and have been on statins during follow-up (statin users) and 1293 patients who were not on statin at the start of the study and had never been prescribed any lipid-modifying drugs during follow-up (statin nonusers) were included in the study. High-sensitive C-reactive protein levels were significantly decreased in statin users (1.50±1.49 vs. 1.33±1.11 mg/L, P=0.05) compared with nonusers (1.93±3.22 vs. 2.05±2.77 mg/L). Hemoglobin levels and the rate of erythropoietin-stimulating agent users were similar. However, the prescribed erythropoietin-stimulating agent dose (31.6±27.5 vs. 47.3±45.2 U/kg/week, P<0.05) and the erythropoietin response index (2.90±2.73 vs. 4.51±4.48 U/kg/week/Hb, P=0.001) were lower in statin users compared with statin nonusers. On stepwise multiple regression analysis, gender, high-sensitive C-reactive protein, duration of hemodialysis, serum ferritin, and statin use were independent determinants of the erythropoietin responsiveness index. Our results suggest that statin treatment leads to lower inflammation and improves hematopoiesis in hemodialysis patients.     

Effect of ethnicity on erythropoietin therapy response for hemodialysis patients: A retrospective study

Anemia is a common feature in chronic kidney disease patients due to deficiency of erythropoietin (EPO). Diseased kidneys are unable to produce EPO, which enhances red blood cell production from the bone marrow. Recombinant human EPO in hemodialysis patients was introduced with perfect outcomes as a hormonal substitutive treatment. Some ethnic minority groups have high prevalence of anemia associated with chronic kidney diseases. The aim of this study is to evaluate the differences between African Caribbeans and Caucasians’ EPO therapy response with regard to hemoglobin (Hb), some factors affecting it and some comorbid conditions. A retrospective study for 6 months of 100 patients on hemodialysis was conducted on two ethnic minorities groups; 46 patients were African Caribbean and 54 patients were Caucasian, who received EPO therapy at once or three times weekly dose at the Hanbury Dialysis Unit of Royal London Hospital. There were three types of EPO therapy used: Aranesp, Mircera and Neorecormon. Forty‐six patients were African Caribbean and 54 patients were Caucasian. There were 63.4% of patients treated by Aranesp while 13% were given Mircera; 22.8% of the sample used Neorecorman. It was shown that the chosen comorbid conditions had higher percentage in the African Caribbeans than in Caucasians. Diabetic and/or hypertensive patients are almost double the patient numbers. In addition, sickle cell anemia is only present in African Caribbeans. There were 43.5% of African Caribbeans and 81.1% of Caucasians who met the standards of Hb level. There was no significant difference between African Caribbeans and Caucasians regarding parathyroid hormone, c‐reactive protein, B12, mean corpuscular volume, ferritin, and folate. In this study, there was a significant difference in the Hb levels between African Caribbean and Caucasian groups. Sixty percent of African Caribbeans had mean Hb less than normal levels. However, they received lower EPO dose than Caucasians. As a result, this may affect the whole treatment and therapy which may lead to anemic complications.     

Exceeding hemoglobin target levels in US hemodialysis patients receiving epoetin, 1999 to 2002

Despite emerging concerns that exceeding anemia targets with erythropoiesis stimulating agents may be risky for hemodialysis patients, the magnitude of and risk factors for the problem have received little attention, particularly regarding year-to-year comparisons. We studied monthly hemoglobin and epoetin levels in 41,101 patients aged at least 65 years who initiated hemodialysis between 1999 and 2002, with upper targets defined by hemoglobin levels of 120 and 130 g/L, respectively. While baseline hemoglobin values and epoetin doses rose from year to year, their rates of change during follow-up declined (p<0.0001). Similar patterns were seen after reaching hemoglobin levels of 110 g/L; comparing 1999 to 2002, the proportions reaching 120 and 130 g/L in the ensuing 9 months increased from 90% to 96% (p<0.0001) and from 56% to 69%, respectively (p<0.0001). Multivariate analysis showed that, while more recent years of dialysis inception and initial epoetin dose were associated with all 3 outcomes, higher baseline hemoglobin levels were associated with reaching levels of 110 and 120 g/L, but not 130 g/L. Exceeding hemoglobin level targets has become widespread in the United States and is associated with changes in epoetin dosing practices.     

Orally administrated Juzen-taiho-to/TJ-48 ameliorates erythropoietin (rHuEPO)-resistant anemia in patients on hemodialysis

Maintenance of the red blood cell volume is a fundamental aspect of ensuring oxygen supply to the tissue. Recombinant human erythropoietin (rHuEPO) was approved for marketing in Japan in 1990 for the treatment of anemia in patients on dialysis. Recombinant human erythropoietin caused a significant increase in hemoglobin (Hb) levels in patients on dialysis. However, not all have a good response to rHuEPO therapy; the causes of rHuEPO failure include iron deficiency, infection, uremia, and interaction of some drugs. Juzen-taiho-to (TJ-48), a mixture of extracts from 10 medicinal herbs, has been used traditionally to treat patients with anemia, anorexia, or fatigue. To clarify the effect of TJ-48 on erythropoietin-resistant anemia, we studied the effect of TJ-48 in patients on hemodialysis with erythropoietin-resistant anemia. We divided 42 end-stage renal disease patients on hemodialysis with erythropoietin-resistant anemia (Hb<10.0 g/dL with rHuEPO 9000 U/wk or 15 U/kg/wk treatment) into 2 groups as follows: a TJ-48-treated group (TJ-48 group, 7.5 g/d, n=22) and a TJ-48 nontreated (control group, n=20). At the beginning of this study, there was no significant difference between the groups in age, sex, serum creatinine, blood urea nitrogen, serum iron, and ferritin. After 12 weeks of treatment, the Hb level had significantly increased from 8.4 +/- 1.1 to 9.5 +/- 1.3 g/dL (P=0.0272) in the TJ-48 group. C-reactive protein (CRP) had significantly decreased from 1.4 +/- 1.7 to 0.6 +/- 0.8 mg/dL (P=0.0438). There was a significant negative correlation between Hb and CRP in the TJ-48 group (r(2)=0.121, P=0.0066). In contrast, in the control group, Hb and CRP showed no significant changes throughout this study. Nor was there a significant correlation between Hb and CRP in the control group. In conclusion, TJ-48 was effective in improving erythropoietin-resistant anemia in end-stage renal disease patients. This effect was, at least in part, due to the anti-inflammatory effect of TJ-48 in patients on hemodialysis.     

Effect of protein-energy malnutrition on erythropoietin requirement in maintenance hemodialysis patients

Possible interactions between inflammatory and nutritional markers and their impact on recombinant human erythropoietin (rHuEPO) hyporesponsiveness are not well understood. We investigated the role of nutritional status in rHuEPO requirement in maintenance hemodialysis (MHD) patients without evidence of inflammation. This cross-sectional study included 88 MHD patients. The associations between required rHuEPO dose and malnutrition-inflammation score (MIS) and several laboratory values known to be related to nutrition and/or inflammation were analyzed. Anthropometric measures including body mass index, triceps skinfold thickness, and midarm circumferences were also measured. Twenty-three patients with serum C-reactive protein levels >10 mg/L were excluded from the analysis. The remaining 65 patients (male/female, 41/24; age 49.1+/-11.4 years; dialysis duration 99.7+/-63.0 months) were studied. These patients had moderate malnutrition and the average MIS was 7.4 (range 3-17). The average weekly dose of administered rHuEPO was 69.1+/-63.1 U/kg. Malnutrition-inflammation score had a positive correlation with the serum concentration of tumor necrosis factor-alpha, whereas it had a negative correlation with anthropometric measures, total iron-binding capacity, prealbumin, phosphorus, creatinine, and triglyceride. According to Pearson's correlation analysis, significant relationships of increased MIS with increased required rHuEPO dose and rHuEPO responsiveness index (EPO divided by hematocrit) were observed (p=0.008, r=-0.326; p=0.017, r=-0.306, respectively). Recombinant human erythropoietin dose requirement is correlated with MIS and adverse nutritional status in MHD patients without evidence of inflammation. Further research should focus on reversing the undergoing microinflammation for a better outcome in dialysis patients.     

Causes and consequences of inflammation on anemia management in hemodialysis patients

Inflammation is common among hemodialysis patients, and evidence is accumulating to suggest that inflammation is a major contributor to morbidity and mortality. Several factors have been suggested as potential causes of inflammation, including infections and the atherosclerosis process, as well as etiologies directly related to kidney disease such as reduced renal function and dialysis. Among several inflammatory biomarkers investigated, serum C-reactive protein (CRP) is the most widely used. In hemodialysis patients, raised CRP levels have been shown to be predictive of cardiovascular events, hospitalization, and all-cause and cardiovascular mortality. Elevated CRP levels may correlate with comorbidities and intercurrent events, all of which may impact the response to erythropoiesis-stimulating agents (ESAs) and lead to higher ESA doses. Most dialysis facilities do not routinely measure CRP, despite recommendations by the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative. Regular measurement of CRP levels may help providers to understand change in ESA dosing and identify patients at risk for cardiovascular events. This review explores the inter-relationships between inflammation, CRP levels, and anemia management in patients receiving hemodialysis.     

Effect of recombinant human erythropoietin on insulin resistance in hemodialysis patients

Insulin resistance is a characteristic feature of uremia. Insulin resistance and concomitant hyperinsulinemia are present irrespective of the type of renal disease. Treatment with recombinant human erythropoietin (rHuEPO) was said to be associated with improvement in insulin sensitivity in uremic patients. The aim of this study was to compare insulin resistance in adult uremic hemodialysis (HD) patients including diabetic patients treated with or without rHuEPO. A total of 59 HD patients were studied, patients were divided into 2 groups of subjects: 30 HD patients on regular rHuEPO treatment (group A), and 29 HD patients not receiving rHuEPO (group B) diabetic patients were not excluded. Full medical history and clinical examination, hematological parameters, lipid profile, serum albumin, parathyroid horomone, Kt/V, fasting glucose, and insulin levels were measured in all subjects. Homeostasis Model Assessment of Insulin Resistance (HOMA‐IR) was used to compare insulin resistance. The results of this study showed that the mean insulin level of HD patients treated with rHuEPO (group A) (17.5 ± 10.6 μU/mL) was significantly lower than patients without rHuEPO (group B) (28.8 ± 7.7 μU/mL), (P<0.001). Homeostasis Model Assessment of Insulin Resistance levels in group A were significantly lower than in group B (3.8 ± 2.97, 7.98 ± 4.9, respectively, P<0.001). Insulin resistance reflected by HOMA‐IR levels among diabetic patients in group A was significantly lower than among diabetic patients in group B (3.9 ± 3.2, 9.4 ± 7.2, respectively, P<0.001). Also, HOMA‐IR levels among nondiabetic patients in group A were significantly lower than among nondiabetic patients in group B (3.7 ± 2.85, 6.9 ± 1.43, respectively, P<0.01). We found a statistically significant negative correlation between duration of erythropoietin treatment, fasting blood glucose, insulin levels, and insulin resistance (r=?0.62, ?0.71, and ?0.57, P<0.001). Patients treated with rHuEPO showed less insulin resistance compared with patients not treated with rHuEPO in diabetic and nondiabetic patients and, duration of erythropoietin treatment is negatively correlated with insulin levels and insulin resistance in HD patients.     

Evaluation of neopterin levels in patients undergoing hemodialysis

Neopterin is a diagnostic or a prognostic biomarker for several pathologies including renal diseases. However, the association between neopterin status and causative main reasons such as diabetes and hypertension for renal disease remains unclear. The aim of the study was to evaluate neopterin levels in diabetes and hypertension patients treated with/without hemodialysis. According to primary renal disorders, the patients undergoing hemodialysis were classified into 4 groups as diabetic nephropathy, hypertensive nephropathy, reflux nephropathy or interstitial nephritis, and others. The controls consisted of healthy subjects, hypertensive subjects, and diabetic individuals without any renal disorder. In the study, both urinary and serum neopterin levels were measured using high performance liquid chromatography and enzyme‐linked immunosorbant assay in patients undergoing regular hemodialysis therapy (n=71). The effects of the duration of hemodialysis and treatment of erythropoietin and/or iron on neopterin levels were also evaluated. Neopterin levels were found to be higher in hemodialysis patients than in the healthy controls (P<0.05). A significant difference in neopterin levels was also found between diabetic control patients and diabetic nephropathy patients (P<0.05). A similar significant difference was detected in neopterin levels between hypertensive patients with/without nephropathy (P<0.05). Neopterin may be an early critical marker for progression of nephropathy in diabetic and hypertensive patients in early stages.     

Perihospitalization patterns of hemoglobin levels and erythropoiesis‐stimulating agent doses in US hemodialysis patients, 1998–2009

Anemia management in hemodialysis patients is of primary importance for clinicians and dialysis providers. Through a retrospective claims analysis, we studied prevalent US hemodialysis patients 1998–2009, and examined patterns of hemoglobin levels and erythropoiesis‐stimulating agent (ESA, epoetin [EPO], and darbepoetin [DPO] ) doses surrounding hospitalization events. Medicare outpatient claims were used to determine monthly ESA doses and associated hemoglobin levels. ESA dose trajectories were defined with repeated measures models incorporating an autoregressive covariance matrix that compared subsequent measurements with the index month of hospitalization, with variance component covariance matrices chosen for pair‐wise comparisons. Regarding prehospitalization hemoglobin levels, a biphasic pattern occurred in both the EPO (1998–2009, n = 161,242) and DPO (2004–2009, n = 4391) populations; levels rose from 1998 to 2004, fell thereafter in the EPO population, and fell after 2006 or 2007 in the DPO population. In the EPO population, the proportions of patients with hemoglobin less than 10 g/dL were 30.1% in 1998, 14.5% in 2004, and 28.3% in 2009; corresponding values for the DPO population were 21.0% in 2004 and 31.6% in 2009. While some degree of year‐to‐year variability occurred, EPO dose trends were less pronounced, with an apparent peak in 2004 followed by a modest decline; trends were similar for DPO. Trends in EPO dose trajectories did not completely parallel those for hemoglobin level; while EPO doses increased yearly up to 2004, doses stabilized, but did not materially decrease after 2004. No definite annual trends for DPO dose trajectories were apparent.     

Correlates affecting survival in chronic hemodialysis patients: The combined impact of albumin and high hemoglobin levels on improving outcomes,local and national results

While national mortality rates for end‐stage renal disease (ESRD) patients remain high, for the past 4 years, lower than expected local mortality rates have been consistently seen in our facilities. Because of these progressive improvements in mortality rates, a study of 687 hemodialysis patients over a 4‐year period, 2003 through 2006, was undertaken to analyze which factors may be contributing to the enhanced survival rates. We also examined the partially overlapping United States Renal Data System clinical performance measures national data sets of hemodialysis patients for 2001 to 2004. Proportional hazards and logistic regression models were used to determine significant predictors of short‐term survival. Variables tested included hemoglobin (Hb), albumin, calcium, phosphorus, infections, hospitalizations, URR, Kt/V, erythropoietic stimulating agents (epoetin‐α) use, and comorbid conditions. The local and national models identified albumin, Hgb, and hospitalization as statistically significant predictors of survival. Local models also found years of dialysis as a significant predictor. Locally, there was a 69‐fold increase from 16.1 deaths/1000 patient years for albumin ≥4.0 with Hgb≥14.0 to 1115.9 deaths/1000 patient‐years for albumin <3.5 with Hgb<11.0. The increase nationally is a 4‐fold increase from 96 deaths/1000 patient‐years for albumin ≥4.0 with Hgb≥14.0 to 406 deaths/1000 patient‐years for albumin <3.5 with Hgb<11.0. There was no evidence that higher erythropoietic stimulating agents dose levels were associated with higher mortality rates, independent of the other significant factors. In conclusion, the findings indicate that individually higher Hgb and albumin levels are associated with increased survival, and when higher Hgb levels are in association with high albumin levels, the survival rates and hospitalizations are synergistically improved.     

Enhanced expression of hemoglobin scavenger receptor and heme oxygenase‐1 is associated with aortic valve stenosis in patients undergoing hemodialysis

A high prevalence and a rapid progression of aortic valve stenosis (AS) in patients undergoing hemodialysis (HD) has been reported. In these circumstances, intraleaflet hemorrhage of aortic valve may be related to the development of AS in HD patients. We immunohistochemically examined the relationship among intraleaflet hemorrhage, neovascularization, hemoglobin scavenger receptor (CD163), and heme oxygenase‐1 (HO‐1) using surgically resected aortic valve specimens from AS patients undergoing HD. The study population consisted of 26 HD patients and 25 non‐HD patients with severe AS who had undergone aortic valve replacement. Frozen aortic valve samples surgically obtained from AS patients were stained immunohistochemically with antibodies against smooth muscle cells, macrophages, glycophorin‐A (a protein specific to erythrocyte membranes), CD31, CD163, and HO‐1. Morphometric analysis demonstrated that the CD163‐positive macrophage score, the number of CD31‐positive microvessels, and the percentage of glycophorin‐A and HO‐1‐positive area were significantly higher in HD patients than in non‐HD patients (CD163‐positive macrophage score, P < 0.0001; CD31‐positive microvessels, P < 0.0001; glycophorin‐A, P < 0.0001; HO‐1, P < 0.0001). Double immunostaining for CD163 or HO‐1 and macrophages revealed that the majority of CD163‐ or HO‐1‐positive cells were macrophages. Furthermore, CD163‐positive macrophage score was positively correlated with glycophorin‐A, HO‐1‐positive area, and the number of CD31‐positive microvessels (glycophorin‐A, R = 0.66, P < 0.0001; HO‐1, R = 0.50, P < 0.0005; microvessels, R = 0.38, P < 0.01). These findings suggest a positive association among intraleaflet hemorrhage, neovascularization, and enhanced expression of CD163 and HO‐1 as a response to intraleaflet hemorrhage in stenotic aortic valves in AS patients undergoing HD.     

Integration of clinical and imaging data to predict death in hemodialysis patients

In a prior publication, we demonstrated that a model integrating clinical and simple imaging data predicted the presence and severity of coronary artery calcification in prevalent hemodialysis patients. Herein we report the ability of the same model to predict all‐cause death. We assessed all‐cause mortality in 141 consecutive maintenance hemodialysis patients from two dialysis centers followed for a median of 79 months from enrollment. Patients were risk stratified according to a simple cardiovascular calcification index (CCI) that included patient's age, dialysis vintage, calcification of the cardiac valves, and abdominal aorta. The mean patients’ age was 55 ± 14 years. Abdominal aorta calcification was present in 57% of the patients, and 44% and 38% had aortic and mitral valve calcification, respectively. During follow‐up, 75 deaths (93 deaths per 1000 person‐years) were recorded. The CCI was linearly associated with risk of death, such that the unadjusted hazard risk (HR) increased by 12% for each point increase in CCI (P < 0.001). Further adjustments for age, sex, study center, diabetes mellitus, history of cardiovascular disease, hypertension, congestive heart failure, left ventricular hypertrophy, systolic, and diastolic blood pressure did not substantially change the strength of this association (HR 1.10; 95%CI: 1.00–1.21; P = 0.03). The CCI is a simple clinical model that can be used to risk stratify maintenance hemodialysis patients.     

Hemochromatosis gene mutations and treatment of anemia in patients on hemodialysis

Hemochromatosis causes iron overload by enhanced intestinal absorption. This study examined erythropoietin and intravenous (IV) iron requirements in hemodialysis (HD) patients with HFE mutations. Patients on HD for >90 days with no cause of anemia except chronic kidney disease were tested for HFE mutations (H63D and C282Y). Intravenous iron and erythropoietin doses were adjusted to achieve recommended targets. Monthly hemoglobin (Hb), ferritin, mean corpuscular volume, mean cell hemoglobin, erythropoietin, and IV iron doses for 3 consecutive months were averaged. Of 172 patients, 71 (41.3%) had ≥1 HFE mutation: 24 (14%) C282Y heterozygotes, 40 (23.3%) H63D heterozygotes, 5 compound heterozygotes, and 2 homozygotes. Comparing patients with ≥1 HFE mutation to those without mutations showed no significant difference in Hb or serum ferritin. There was a trend toward lower median weekly erythropoietin dose in patients with ≥1 HFE mutation (94.0 vs. 135.4 U/kg body weight; P=0.13). There was no difference in median weekly IV iron dose (1.0 vs. 0.9 mg/kg body weight; P=0.56). Comparing the 30 patients with a C282Y mutation to patients without HFE mutations produced similar results. Comparing the 47 patients with an H63D mutation, with those without HFE mutations, no discernable trend was observed. In this study, patients with HFE gene mutations on HD for established renal failure do not require less iron supplementation to achieve recommended Hb targets. We observed a trend toward lower erythropoietin requirement in patients possessing C282Y mutations. Larger studies may clarify the role of HFE mutations, regulators of iron metabolism and erythropoiesis in chronic kidney disease.     

Impact of intradialytic exercise on arterial compliance and B-type natriuretic peptide levels in hemodialysis patients

Cardiovascular (CV) disease is the most common cause of mortality in end-stage kidney disease (ESKD), and arterial stiffness, measured by pulse wave velocity (PWV), is an independent predictor of all-cause and CV mortality. B-type natriuretic peptide (BNP) levels are high in patients with CV disease and ESKD, and increases in BNP may also be a marker of CV risk. Regular exercise has many benefits on quality of life and physical strength and may also improve CV risk, but few studies have addressed the impact of exercise on CV risk in ESKD. We performed a prospective cross-over trial in 19 hemodialysis (HD) patients to assess the impact of regular exercise on surrogate markers of CV risk-arterial compliance and BNP levels. Exercise involved the use of a bicycle ergometer for minimum 30 min at each HD session for 3 months, with a 1-month washout period. Group A (n=9) exercised for the first 3 months only, while group B (n=10) performed no intradialytic exercise initially and exercised for 3 months at cross-over (month 4). Pulse wave velocity was performed using a SphygmoCor device, with concurrent measurements of BNP and other serum markers, at the commencement of the study, at 3 months, and on completion. The mean PWV (A: 10.4+/-3.1 m/s, B: 9.8+/-3.8 at baseline) showed a trend toward improvement with exercise (A: 8.7+/-2.7, p=0.07), and no significant change without (B: 10.5+/-3.6, p=0.31). After cross-over, there was an increase in PWV in group A with cessation of exercise (9.75+/-2.4, p=0.01 vs. 3 months) and an improvement in group B with exercise (9.33+/-2.3, p=0.11 vs. 3 months). When comparing PWV after 3 months of exercise vs. 3 months of no exercise (paired t test), there was a significant difference in favor of exercise (9.04+/-0.59 vs. 10.16+/-0.74, p=0.008). The mean BNP levels following 3 months of exercise were also lower than those after 3 months of no exercise (504.4+/-101.2 vs. 809.4+/-196.1[N<100], p=0.047). There was an overall improvement in PWV, and to a lesser extent BNP levels, with 3 months of intradialytic exercise compared with no exercise, suggesting that regular exercise in ESKD may be associated with improvements in arterial compliance and a reduction in CV risk.