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Hemoglobin Variability Predicts Mortality in Dialysis Patients

Posted: Friday, November 23, 2007

Hemoglobin variability over time in dialysis patients proved a strong predictor of death from any cause, according to a new study. 
Harold I. Feldman, M.D., of the University of Pennsylvania, and colleagues, reported in the December issue of the Journal of the American Society of Nephrology, that for each 1 g/dL increase in hemoglobin variability (Hb-Var), the risk of death increased 33% after adjustment for multiple covariates,

Preliminary evidence has suggested that the effects of hemoglobin on clinical outcomes may not be captured by the absolute level of hemoglobin alone or measures of hemoglobin change over time.  Measuring hemoglobin variability provides a novel way of marking the relationship between anemia and outcomes in end-stage renal disease.

The researchers conducted a retrospective analysis of 34,963 dialysis patients from the national Fresenius Medical Care database to focus on hemoglobin variability (Hb-Var) independent of absolute values and trends over time. Patients were enrolled during two six-month periods in 1996.

The primary survival analysis considered 19,150 patients with no missing hemoglobin or covariate values. Hemoglobin concentration over time was modeled with linear regression for each patient, and the model was then used to define the patient's absolute level of hemoglobin, temporal trend in hemoglobin, and hemoglobin variability (residual standard deviation).
Similar to other studies, the authors observed a 19% reduction in rate of death for each 1 g/dL increase in the level of hemoglobin.

In addition, however, survival analyses indicated that each 1 g/dL increase in the residual standard deviation was associated with a mortality hazard ratio of 1.33 (95% CI: 1.22 to 1.45) even after adjusting for multiple covariates. These included age, duration of ESRD, average hemoglobin level, serum albumin, aspartate aminotransferase, calcium, intact parathyroid hormone level, iron level, and erythropoietin dose.

The relationship between hemoglobin variability and mortality, measured by the residual standard deviation of hemoglobin, remained significant even after adjusting for absolute hemoglobin levels and trends over time, the researchers said.
The consistency of these results across various modeling strategies supports the hypothesis that hemoglobin variability represents an important physiologic stress, the researchers said.

Repeated episodes of relative ischemia and tissue hypoxia in ESRD may cause organ dysfunction or injury. The myocardium may be particularly vulnerable to hemoglobin variability, as it compensates for periods of reduced oxygen delivery with increased output and myocardial cell growth. The results may be repeated activation and resetting of cardiac growth signals, and the development of pathologic changes such as left ventricular dilation or hypertrophy, the researchers said.

The autonomic nervous system may also be vulnerable to hemoglobin variability, they said, as autonomic dysfunction has been observed in other conditions that predispose patients to fluctuating hemoglobin levels, such as sickle cell anemia.
Alterations in cardiac and autonomic nervous system function are particularly relevant in ESRD, as cardiovascular morbidity and mortality are very common in these patients.

If hemoglobin variability is shown to have a causal association with mortality in future clinical trials, it could become a novel target for reducing morbidity and prolonging survival of dialysis patients, the researchers said.

Practice Pearl: Explain to interested patients that this retrospective study suggests that for patients on dialysis whose hemoglobin levels are carefully monitored, fluctuation in these levels was independently associated with mortality. 

Source: Diabetes In Control: Yang W, "Hemoglobin variability and mortality in ESRD" J Am Soc Nephrol 2007; 18: 3164-3170.

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