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 truedecreaseinredbloodcellmass.6 Inarandomized,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.18 Currently, there is no supporting information on an established hemoglobin concentration below which the risk of maternal mortality increases.19 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 ND-CKD 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 CKD-associated 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% asthe thresholdofvolume overload, wefound a prevalence of hemodilution of 63% in the anemic ND-CKD 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 ND-CKD 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 interleukin-6 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.
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