observational studies have shown a strong detrimental relationship among anemia , chronic kidney disease ( ckd ) , and mortality ; it is therefore logical to consider whether correcting anemia can improve patient outcomes . however , the failure of randomized trials to find a benefit of higher hemoglobin concentrations suggests that the anemiaoutcome association may be confounded by unknown factors . a low hemoglobin concentration may result from reduced red blood cell volume ( true anemia ) and/or from an increased extracellular water ( ecw ) volume ( hemodilution ) ( figure 1 ) . our recent study has shown that ecw volume overload is a common issue in nondialysisdependent ckd ( ndckd ) patients . however , the prevalence of hemodilution in ckd is unclear , and its clinical impact has not been elucidated . a low hemoglobin concentration may result from reduced red blood cell volume ( true anemia ) and/or from an increased extracellular water volume ( hemodilution ) . ckd indicates chronic kidney disease ; epo , erythropoietin ; gfr , glomerular filtration rate ; raas , renin angiotensin  aldosterone system ; rbc , red blood cell . in a secondary analysis of the trial to reduce cardiovascular events with aranesp therapy ( treat ) , patients with a poor response to darbepoetin alfa had an increased risk of cardiovascular outcomes . however , it is difficult to ascertain whether this increased risk was due to the preexisting characteristics of the patients , an increased dose of erythropoiesisstimulating agents ( esas ) , or both . we recently found that volume overload is strongly associated with both traditional and nontraditional risk factors for ckd progression and cardiovascular disease ( cvd ) in ndckd patients . because esa treatment further increases the blood volume , the benefits of anemia correction by esa may have been masked by the negative effects of increased fluid retention . therefore , testing for an interaction between fluid status , hemoglobin concentrations , and outcomes in ckd patients seems warranted . in the present study , we hypothesized that fluid status would be closely associated with hemoglobin concentrations and outcomes in patients with ckd . to test this hypothesis , we evaluated the influence of fluid retention on hemoglobin concentrations and the cardiovascular and renal outcomes in a prospective cohort of 326 patients with stage 3 to 5 ndckd , using a novel bioimpedance spectroscopy device to measure the fluid status . the study design and patients were previously described . briefly , 338 clinically stable stage 3 to 5 ndckd patients were recruited from the outpatient clinics between september 1 , 2011 and december 31 , 2012 . all patients received the integrated multidisciplinary ckd care program in taiwan , focusing on dietary salt and protein restriction , nephrotoxin avoidance , and strict blood pressure and glycemic control . for each patient , a thorough medical history was taken and the medical chart was reviewed at the time of study enrollment . the definition of cvd included coronary artery disease , as documented by coronary angiography or a history of myocardial infarction , class iii to iv congestive heart failure , or cerebrovascular accident . the study protocol complies with the declaration of helsinki and was approved by the institutional review board of taipei tzu chi hospital . fluid status was assessed by using the body composition monitor ( bcm , fresenius medical care , bad homburg , germany ) , a novel bioimpedance spectroscopy device , and was represented by the level of overhydration ( oh ) . the bcm measures the electrical responses at 50 different frequencies between 5 and 1000 khz . oh is derived from the impedance data based on a 3compartment model developed by chamney et al the 3 compartments are lean tissue mass , adipose tissue mass , and oh . oh is the difference between the amount of ecw in tissue that is detected by the bcm and the amount of water present in tissue predicted using physiological models under normal ( euvolemic ) conditions . therefore , the oh value obtained from the bcm can be compared directly with that of the normal population . volume overload was defined as a relative oh value ( oh normalized to ecw or oh / ecw ) 7% , corresponding to the value of the 90th percentile for the reference cohort . the bcm device has been validated in a study involving 350 healthy people with the same ethnic background in taiwan . we performed a repeat body composition measurement 6 months after enrollment and found no significant changes in the oh levels over time ( paired t test , p=0.563 ) . anemia was defined in accordance with the world health organization as hemoglobin concentrations < 13.0 g / dl in men and < 12.0 g / dl in women . the primary outcome , morbidity and mortality from cardiovascular causes , was a composite of myocardial infarction , hospitalization for congestive heart failure or unstable angina , or death from cardiovascular causes . the secondary outcome , the renal outcome , was the first occurrence of a decline in the estimated glomerular filtration rate ( egfr ) 50% or endstage renal disease needing chronic dialysis . changes in the egfr were confirmed at least 4 weeks after treatment of potentially reversible factors . the timing of initiation of chronic dialysis was determined in accordance with the regulations of the national health insurance administration of taiwan , which suggest beginning dialysis at an egfr level < 5 ml / min per 1.73 m. for the primary cardiovascular outcome , patients were censored at the time of their last outpatient visit , noncardiovascular death , or end of followup period , whereas for the secondary renal outcome , patients were censored at the time of their last outpatient visit , death , or end of followup period . all variables were expressed as frequencies and percentages for categorical data and as the meanssds or medians and interquartile ranges for continuous data with or without a normal distribution , respectively . the baseline characteristics were compared using a  test for categorical variables and student t test or mann  whitney u test for continuous variables . age , sex , and clinically relevant variables with a p value 0.10 in the univariate analysis were fitted . ckd patients were stratified by the presence or absence of anemia and volume overload into 3 groups : no anemia , true anemia ( relative oh < 7% ) , or anemia with excess oh ( relative oh 7% ) . cox proportional hazards modeling was used to estimate hazard ratios ( hrs ) and 95% cis with unadjusted and multivariate adjusted models for the cardiovascular and renal outcomes separately . the proportional hazard assumption , the constant hr over time , was evaluated by comparing estimated log  log survival curves for all timeindependent covariates . all assessed log  log survival plots graphically showed 2 parallel lines , indicating no violation of the assumption . analyses were performed using spss ( statistical package for the social sciences ) version 20.0 software ( spss inc , chicago , il ) . the study design and patients were previously described . briefly , 338 clinically stable stage 3 to 5 ndckd patients were recruited from the outpatient clinics between september 1 , 2011 and december 31 , 2012 . all patients received the integrated multidisciplinary ckd care program in taiwan , focusing on dietary salt and protein restriction , nephrotoxin avoidance , and strict blood pressure and glycemic control . for each patient , a thorough medical history was taken and the medical chart was reviewed at the time of study enrollment . the definition of cvd included coronary artery disease , as documented by coronary angiography or a history of myocardial infarction , class iii to iv congestive heart failure , or cerebrovascular accident . the study protocol complies with the declaration of helsinki and was approved by the institutional review board of taipei tzu chi hospital . fluid status was assessed by using the body composition monitor ( bcm , fresenius medical care , bad homburg , germany ) , a novel bioimpedance spectroscopy device , and was represented by the level of overhydration ( oh ) . the bcm measures the electrical responses at 50 different frequencies between 5 and 1000 khz . oh is derived from the impedance data based on a 3compartment model developed by chamney et al the 3 compartments are lean tissue mass , adipose tissue mass , and oh . oh is the difference between the amount of ecw in tissue that is detected by the bcm and the amount of water present in tissue predicted using physiological models under normal ( euvolemic ) conditions . therefore , the oh value obtained from the bcm can be compared directly with that of the normal population . volume overload was defined as a relative oh value ( oh normalized to ecw or oh / ecw ) 7% , corresponding to the value of the 90th percentile for the reference cohort . the bcm device has been validated in a study involving 350 healthy people with the same ethnic background in taiwan . we performed a repeat body composition measurement 6 months after enrollment and found no significant changes in the oh levels over time ( paired t test , p=0.563 ) . anemia was defined in accordance with the world health organization as hemoglobin concentrations < 13.0 g / dl in men and < 12.0 g / dl in women . the primary outcome , morbidity and mortality from cardiovascular causes , was a composite of myocardial infarction , hospitalization for congestive heart failure or unstable angina , or death from cardiovascular causes . the secondary outcome , the renal outcome , was the first occurrence of a decline in the estimated glomerular filtration rate ( egfr ) 50% or endstage renal disease needing chronic dialysis . changes in the egfr were confirmed at least 4 weeks after treatment of potentially reversible factors . the timing of initiation of chronic dialysis was determined in accordance with the regulations of the national health insurance administration of taiwan , which suggest beginning dialysis at an egfr level < 5 ml / min per 1.73 m. for the primary cardiovascular outcome , patients were censored at the time of their last outpatient visit , noncardiovascular death , or end of followup period , whereas for the secondary renal outcome , patients were censored at the time of their last outpatient visit , death , or end of followup period . all variables were expressed as frequencies and percentages for categorical data and as the meanssds or medians and interquartile ranges for continuous data with or without a normal distribution , respectively . the baseline characteristics were compared using a  test for categorical variables and student t test or mann  whitney u test for continuous variables . age , sex , and clinically relevant variables with a p value 0.10 in the univariate analysis were fitted . ckd patients were stratified by the presence or absence of anemia and volume overload into 3 groups : no anemia , true anemia ( relative oh < 7% ) , or anemia with excess oh ( relative oh 7% ) . cox proportional hazards modeling was used to estimate hazard ratios ( hrs ) and 95% cis with unadjusted and multivariate adjusted models for the cardiovascular and renal outcomes separately . the proportional hazard assumption , the constant hr over time , was evaluated by comparing estimated log  log survival curves for all timeindependent covariates . all assessed log log survival plots graphically showed 2 parallel lines , indicating no violation of the assumption . a 2tailed pvalue < 0.05 was considered statistically significant . analyses were performed using spss ( statistical package for the social sciences ) version 20.0 software ( spss inc , chicago , il ) . out of a total of 338 stage 3 to 5 ndckd patients , 12 patients were excluded from the analysis due to starting chronic dialysis within the first month after enrollment ( n=4 ) or were lost to followup after the initial visit ( n=8 ) . patients with anemia were further divided based on the presence of volume overload ( anemia with excess oh ) or not ( true anemia ) . the patients in the 2 groups were similar with regard to age , sex , smoking history , egfr , and ferritin levels , but diabetes and cvd were more prevalent in the volume overload group . additionally , patients with anemia with excess oh were found to have significantly lower serum albumin , as well as higher systolic blood pressure , urine proteintocreatinine ratio , nterminal probrain natriuretic peptide , and interleukin6 at baseline , compared with patients with true anemia . baseline characteristics of the study cohort according to the presence or absence of anemia and volume overload bp indicates blood pressure ; cvd , cardiovascular disease ; egfr , estimated glomerular filtration rate ; il6 , interleukin6 ; ntprobnp , nterminal probrain natriuretic peptide ; oh , overhydration ; raas , renin  angiotensin correlations between hemoglobin and other variables in all patients ( n=326 ) are shown in table 2 . fluid status , as defined by oh , was negatively correlated with hemoglobin concentrations at baseline ( r=0.438 , p<0.001 ) ( figure 2 ) . in multivariate regression analysis , oh remained an independent predictor of hemoglobin concentrations , second only to egfr . ckd indicates chronic kidney disease ; cvd , cardiovascular disease ; egfr , estimated glomerular filtration rate ; il6 , interleukin6 ; ntprobnp , nterminal probrain natriuretic peptide ; oh , overhydration ; raas , renin coefficient  refers to how many sds a dependent variable will change , per sd increase in the predictor variable . the higher the coefficient  value , the greater the impact of a predictor variable on hemoglobin concentrations . ntprobnp is highly correlated with overhydration and thus not included in the multivariate models to avoid collinearity . fluid status , as defined by relative overhydration ( oh ) , was negatively correlated with hemoglobin concentrations ( r=0.438 , p<0.001 ) . we stratified the entire study cohort into 3 groups ( no anemia , true anemia , or anemia with excess oh ) and examined their relationship with the cardiovascular and renal outcomes in timetoevent analyses . during a median followup of 2.2 years , there were 3 cardiovascular endpoint events ( 2.9% ) in the noanemia group , 5 ( 6.1% ) in the trueanemia group , and 37 ( 26.6% ) in the anemia with excess oh group ( table 3 ) . for renal endpoint events , there were 9 ( 8.6% ) in the noanemia group , 17 ( 20.7% ) in the trueanemia group , and 70 ( 50.4% ) in the anemia with excess oh group . by multivariate regression analysis , there was no difference in cardiovascular and renal risks between patients with true anemia and those with no anemia . patients with anemia with excess oh had a significantly increased risk of the cardiovascular and renal outcomes relative to those with no anemia . moreover , the hr was also statistically different for patients with anemia with excess oh ( reference group ) from those with true anemia ( adjusted hr for cardiovascular outcome , 0.31 ; 95% ci , 0.12 to 0.82 ; p=0.018 , and adjusted hr for renal outcome , 0.42 ; 95% ci , 0.23 to 0.74 ; p=0.003 , respectively ) . the predictive power of hemoglobin for cardiovascular and renal risks attenuated after adjustment for oh ( table 4 ) . hazard ratios of different anemia groups in relation to the cardiovascular and renal outcomes multivariate adjusted model : age , cardiovascular disease , diabetes mellitus , systolic blood pressure , estimated glomerular filtration rate , and a urine proteintocreatinine ratio cut at 0.5 . hazard ratios ( hr ) of hemoglobin concentrations in relation to the cardiovascular and renal outcomes multivariate adjusted model : age , cardiovascular disease , diabetes mellitus , systolic blood pressure , estimated glomerular filtration rate , and a urine proteintocreatinine ratio cut at 0.5 . out of a total of 338 stage 3 to 5 ndckd patients , 12 patients were excluded from the analysis due to starting chronic dialysis within the first month after enrollment ( n=4 ) or were lost to followup after the initial visit ( n=8 ) . patients with anemia were further divided based on the presence of volume overload ( anemia with excess oh ) or not ( true anemia ) . the patients in the 2 groups were similar with regard to age , sex , smoking history , egfr , and ferritin levels , but diabetes and cvd were more prevalent in the volume overload group . additionally , patients with anemia with excess oh were found to have significantly lower serum albumin , as well as higher systolic blood pressure , urine proteintocreatinine ratio , nterminal probrain natriuretic peptide , and interleukin6 at baseline , compared with patients with true anemia . baseline characteristics of the study cohort according to the presence or absence of anemia and volume overload bp indicates blood pressure ; cvd , cardiovascular disease ; egfr , estimated glomerular filtration rate ; il6 , interleukin6 ; ntprobnp , nterminal probrain natriuretic peptide ; oh , overhydration ; raas , renin  angiotensin correlations between hemoglobin and other variables in all patients ( n=326 ) are shown in table 2 . fluid status , as defined by oh , was negatively correlated with hemoglobin concentrations at baseline ( r=0.438 , p<0.001 ) ( figure 2 ) . in multivariate regression analysis ckd indicates chronic kidney disease ; cvd , cardiovascular disease ; egfr , estimated glomerular filtration rate ; il6 , interleukin6 ; ntprobnp , nterminal probrain natriuretic peptide ; oh , overhydration ; raas , renin coefficient  refers to how many sds a dependent variable will change , per sd increase in the predictor variable . the higher the coefficient  value , the greater the impact of a predictor variable on hemoglobin concentrations . ntprobnp is highly correlated with overhydration and thus not included in the multivariate models to avoid collinearity . fluid status , as defined by relative overhydration ( oh ) , was negatively correlated with hemoglobin concentrations ( r=0.438 , p<0.001 ) . we stratified the entire study cohort into 3 groups ( no anemia , true anemia , or anemia with excess oh ) and examined their relationship with the cardiovascular and renal outcomes in timetoevent analyses . during a median followup of 2.2 years , there were 3 cardiovascular endpoint events ( 2.9% ) in the noanemia group , 5 ( 6.1% ) in the trueanemia group , and 37 ( 26.6% ) in the anemia with excess oh group ( table 3 ) . for renal endpoint events , there were 9 ( 8.6% ) in the noanemia group , 17 ( 20.7% ) in the trueanemia group , and 70 ( 50.4% ) in the anemia with excess oh group . by multivariate regression analysis , there was no difference in cardiovascular and renal risks between patients with true anemia and those with no anemia . patients with anemia with excess oh had a significantly increased risk of the cardiovascular and renal outcomes relative to those with no anemia . moreover , the hr was also statistically different for patients with anemia with excess oh ( reference group ) from those with true anemia ( adjusted hr for cardiovascular outcome , 0.31 ; 95% ci , 0.12 to 0.82 ; p=0.018 , and adjusted hr for renal outcome , 0.42 ; 95% ci , 0.23 to 0.74 ; p=0.003 , respectively ) . we also performed multivariate cox analyses with hemoglobin as a continuous variable . the predictive power of hemoglobin for cardiovascular and renal risks attenuated after adjustment for oh ( table 4 ) . hazard ratios of different anemia groups in relation to the cardiovascular and renal outcomes multivariate adjusted model : age , cardiovascular disease , diabetes mellitus , systolic blood pressure , estimated glomerular filtration rate , and a urine proteintocreatinine ratio cut at 0.5 . hazard ratios ( hr ) of hemoglobin concentrations in relation to the cardiovascular and renal outcomes multivariate adjusted model : age , cardiovascular disease , diabetes mellitus , systolic blood pressure , estimated glomerular filtration rate , and a urine proteintocreatinine ratio cut at 0.5 . our data show that fluid status , defined as the oh level , is one of the major determinants of low hemoglobin concentrations in patients with stage 3 to 5 ckd . anemia in these patients was not only independently related to their impaired renal function , but also to an increased fluid status . furthermore , anemia with excess oh was associated with more traditional and nontraditional cardiovascular risk factors and a higher risk of cardiovascular morbidity and mortality and ckd progression as compared with true anemia . anemia is common among patients with ckd and is known to impair their prognosis . in our study population of ckd stage 3 to 5 , the prevalence of anemia was 68% , which is compatible with previously published data showing that 50% to 60% of patients with stage 4 ckd are anemic , and the prevalence of anemia increases to 75% to 92% in patients reaching stage 5 ckd although treatment with esas markedly improved patientperceived quality of life and reduced the need for blood transfusions , the results from the correction of hemoglobin and outcomes in renal insufficiency ( choir ) , cardiovascular risk reduction by early anemia treatment with epoetin  ( create ) , and treat trials all demonstrated an increased risk of ckd progression or cardiovascular events such as stroke , thrombosis , or death at nearly normal hemoglobin concentrations and higher esa doses in patients with ndckd . however , the many confounding factors that accompany ckd may have prevented clinicians from discerning the specific role anemia plays in the poor outcomes . patients with ckd have similarities to those with heart failure in that both populations frequently retain fluid and have excessively high cardiovascular mortality . previous data in patients with advanced heart failure have shown that approximately half of the patients with anemia have hemodilution rather than a true decrease in red blood cell mass . in a randomized , doubleblind trial , swedberg et al evaluated the effects of darbepoetin alfa on clinical outcomes in patients with systolic heart failure and anemia . although darbepoetin alfa treatment led to an early and sustained increase in the hemoglobin concentration , the use of darbepoetin alfa did not reduce the risk of the primary outcome of death or hospitalization for worsening heart failure compared with placebo . moreover , more patients had thromboembolic events in the treatment group than in the placebo group , an observation similar to the findings of the treat study . therefore , the hemoglobin concentration may simply be a surrogate marker for poor prognosis , which indicates esa resistance caused by inflammation , impaired iron utilization , or fluid retention in patients with ckd or congestive heart failure , rather than a therapeutic target . hemodilution was first described in pregnant women and is believed to be an adaptive mechanism . during pregnancy , the maternal plasma volume expands 45% on average to meet the greater needs of the placental circulation . therefore , hemoglobin concentrations are diluted and the threshold for a diagnosis of anemia , which is defined as hemoglobin < 12.0 g / dl in nonpregnant women , is modified to < 11.0 g / dl . currently , there is no supporting information on an established hemoglobin concentration below which the risk of maternal mortality increases . we hypothesize that anemia in ckd is , at least in part , also an adaptive response to the underlying state of fluid retention , cardiac dysfunction , and arteriosclerosis . moderate anemia results in reduced blood viscosity and blood volume , which decreases left ventricular afterload and may improve microvascular perfusion in ckd patients . from this viewpoint , it seems reasonable that the recently published kidney disease improving global outcomes ( kdigo ) guideline further reduced the hemoglobin threshold for the initiation of esa therapy to < 10.0 g / dl in ndckd patients . therefore , before esa therapy to override the anemia of ckd is considered , the potential benefits of reducing blood transfusions and anemiarelated symptoms must be weighed carefully against the potential risks of harm . otherwise , the sustained dosedependent rise in hemoglobin and blood volume would predispose ckd patients to a further increase in vascular resistance and blood pressure , which may aggravate cardiovascular damage and ckd progression . the optimal treatment of ckdassociated anemia must target the underlying mechanisms . in ckd patients , a progressive decline in gfr , activation of the renin angiotensin  aldosterone system , and superimposed cardiovascular comorbidities contribute to salt and water retention . using relative oh 7% as the threshold of volume overload , we found a prevalence of hemodilution of 63% in the anemic ndckd population . volume overload , as assessed by bioimpedance spectroscopy devices , has been recognized as an important contributor to the poor cardiovascular or renal outcomes in hemodialysis and ndckd patients . in addition to the deleterious effects of high blood pressure , circumferential stretch from fluid retention activates endothelial cells , resulting in an increase in proinflammatory cytokines . in the present study , anemic patients with excess oh had significantly higher levels of interleukin6 compared with those with true anemia . accumulating evidence has shown that inflammation contributes to both the development of cvd and the progression of ckd . the interaction among hemodilution , cvd , and ckd progression is complex . in our study , patients with hemodilution had a higher proportion of comorbid conditions including diabetes mellitus and cvd , which might confound the association between hemodilution and clinical outcomes . after adjustment for potential confounders , hemodilution remained an independent predictor of the adverse outcomes . our findings have important clinical implications , suggesting that a concomitant meticulous correction of volume overload can be considered to be incorporated into the treatment for ckd anemia . however , our observational study was not able to establish causality , and we caution against translating the results of our study into therapeutic practice . future therapeutic trials of ckd anemia should attempt to characterize the patients ' fluid status . first , as is the case for any observational study , there remain unknown and unmeasured confounding factors . second , oh as detected by the bcm comprises an increase of ecw volume in both intra and extravascular spaces . while it is the increase in the intravascular compartment , also known as the plasma volume , that results in hemodilution , the bcm is unable to distinguish between the 2 compartments . however , previous studies have indicated that in situations of volume overload , excess water was retained within both intra and extravascular components , increasing in approximately the same proportion . in our study , we excluded patients with frank nephrotic syndrome or chronic inflammatory diseases , which are often associated with vascular leak and disproportionate distribution of the retained fluid . as a result , a relative oh of 15.6% ( table 1 ) would amount to an increase in plasma volume of 0.5 l , which might explain the difference in hemoglobin between the true anemia group and the anemia with excess oh group . third , we did not measure red blood cell mass , the  gold standard  for differentiating between true anemia and hemodilution , because red blood cell mass is essentially decreased in ckd patients due to depressed red blood cell production . accordingly , true anemia may coexist with hemodilution in ckd patients . identification of ckd patients with hemodilution is clinically important because it is very likely that the treatment strategy for anemia should be different in these patients . finally , the overall cvd event rate was low , as reflected by a relatively wide ci in the cardiovascular end point . actually , ckd patients in taiwan , in contrast to those in western countries , are more likely to develop endstage renal disease than to suffer a cvd event . the limited number of cvd events limits the ability to adjust for other potentially important covariates of interest . first , as is the case for any observational study , there remain unknown and unmeasured confounding factors . second , oh as detected by the bcm comprises an increase of ecw volume in both intra and extravascular spaces . while it is the increase in the intravascular compartment , also known as the plasma volume , that results in hemodilution , the bcm is unable to distinguish between the 2 compartments . however , previous studies have indicated that in situations of volume overload , excess water was retained within both intra and extravascular components , increasing in approximately the same proportion . in our study , we excluded patients with frank nephrotic syndrome or chronic inflammatory diseases , which are often associated with vascular leak and disproportionate distribution of the retained fluid . as a result , a relative oh of 15.6% ( table 1 ) would amount to an increase in plasma volume of 0.5 l , which might explain the difference in hemoglobin between the true anemia group and the anemia with excess oh group . third , we did not measure red blood cell mass , the  gold standard  for differentiating between true anemia and hemodilution , because red blood cell mass is essentially decreased in ckd patients due to depressed red blood cell production . accordingly , true anemia may coexist with hemodilution in ckd patients . identification of ckd patients with hemodilution is clinically important because it is very likely that the treatment strategy for anemia should be different in these patients . finally , the overall cvd event rate was low , as reflected by a relatively wide ci in the cardiovascular end point . actually , ckd patients in taiwan , in contrast to those in western countries , are more likely to develop endstage renal disease than to suffer a cvd event . the limited number of cvd events limits the ability to adjust for other potentially important covariates of interest . fluid retention appears to be an important factor for the development of low hemoglobin concentrations in patients with ckd . patients with anemia with excess oh tend to have worse outcomes than patients with true anemia , suggesting that volume overload may serve as an important mechanism contributing to the adverse outcomes in anemic ckd patients . hence , further research is warranted to clarify whether , instead of increasing erythropoiesis , the correction of volume overload should be the main target to achieve better outcomes in ckdassociated anemia .
backgroundobservational studies have demonstrated an association between anemia and adverse outcomes in patients with chronic kidney disease ( ckd ) . however , randomized trials failed to identify a benefit of higher hemoglobin concentrations , suggesting that the anemiaoutcome association may be confounded by unknown factors.methods and resultswe evaluated the influence of fluid status on hemoglobin concentrations and the cardiovascular and renal outcomes in a prospective cohort of 326 patients with stage 3 to 5 ckd . 
 fluid status , as defined by overhydration ( oh ) level measured with bioimpedance , was negatively correlated with hemoglobin concentrations at baseline ( r=0.438 , p<0.001 ) . in multivariate regression analysis 
 , oh remained an independent predictor of hemoglobin , second only to estimated glomerular filtration rate . 
 patients were stratified into 3 groups : no anemia ( n=105 ) , true anemia ( n=82 ) , and anemia with excess oh ( n=139 ) ( relative oh level 7% , the 90th percentile for the healthy population ) . during a median followup of 2.2 years , there was no difference in cardiovascular and renal risks between patients with true anemia and those with no anemia in the adjusted cox proportional hazards models . 
 however , patients with anemia with excess oh had a significantly increased risk of cardiovascular morbidity and mortality and ckd progression relative to those with true anemia and those with no anemia , respectively.conclusionsfluid retention is associated with the severity of anemia and adverse cardiovascular and renal outcomes in patients with ckd . 
 further research is warranted to clarify whether the correction of fluid retention , instead of increasing erythropoiesis , would improve outcomes of ckdassociated anemia .