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Anemia of chronic kidney disease: When normalcy becomes undesirable

Cleveland Clinic Journal of Medicine. 2008 May;75(5):353-356
May 1, 2008|Cleveland Clinic Journal of Medicine
Sevag G. Demirjian, MD;Saul Nurko, MD
Author and Disclosure Information

Sevag G. Demirjian, MD
Section of Extracorporeal Therapy, Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic

Saul Nurko, MD
Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic

Address: Sevag G. Demirjian, MD, Department of Nephrology and Hypertension, A51, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail demirjs@ccf.org

ABSTRACTIn patients with chronic kidney disease and renal failure, hemoglobin levels have been rising in parallel with more intensive use of erythropoiesis-stimulating agents (ESAs). However, several recent studies indicate that raising hemoglobin to normal levels with ESAs can be too much of a good thing. Compared with partial correction, normalization of hemoglobin did not improve outcome, and it may have led to more frequent adverse events. The US Food and Drug Administration (FDA) now recommends a hemoglobin goal in the range of 10 to 12 g/dL.

 

KEY POINTS

  • ESAs reduce the need for blood transfusions and possibly improve quality of life.
  • It is unclear if higher hemoglobin levels per se actually caused the adverse events in these trials. Event rates were highest in patients who responded poorly to ESAs.
  • We concur with the FDA’s recommendation that the hemoglobin level be raised to no higher than 12 g/dL with ESAs in patients with chronic kidney disease or renal failure.
  • Transient excursions of the hemoglobin level above 12 g/dL should not be a cause for panic. Rather, the next ESA dose should be reduced.

AN FDA ALERT

On November 16, 2006, the FDA issued an alert and required that ESA product labeling include a new boxed warning with the following information12:

  • Use the lowest dose of an ESA (Procrit, Epogen, or Aranesp) that will gradually raise the hemoglobin concentration to the lowest level sufficient to avoid the need for blood transfusion.
  • ESAs should not be given to treat symptoms of anemia or poor quality of life.
  • Maintain the hemoglobin level in the target range of 10 to 12 g/dL.
  • Decrease the dose if the hemoglobin level increases by more than 1 g/dL in any 2-week period.

ANOTHER LOOK AT THE DATA

In post hoc analyses, data from the US Normal Hematocrit and CHOIR studies were analyzed on an “as-treated” basis instead of on an intention-to-treat basis as originally reported.13,14 Although the original studies found no survival advantage (and perhaps harm) with higher hemoglobin targets (ie, by intention-to-treat analysis), when the investigators looked at the actual hemoglobin levels achieved, they found that event rates were higher with low hemoglobin levels.

Such discordant findings highlight the importance of randomized experimental designs to avoid bias due to confounding factors (measured and unmeasured) linked to both hemoglobin level and outcome. To reconcile the above findings, we offer the following observations:

  • In each treatment group, event rates were higher among those who responded poorly to ESAs (hyporesponders). This finding undermines the intuitive assumption that higher achieved hemoglobin levels were causing volume-related events (congestive heart failure or pulmonary edema) and thrombotic events. Of note, rapid changes in hemoglobin levels in either direction further increased the frequency of events among hyporesponders (which might be associated with the more aggressive algorithm needed in the higher target group).
  • Within each treatment group, the difference in event rates is unlikely to be explained by the variation in hemoglobin within its narrow range. Rather, it was mostly due to a higher burden of disease among the hyporesponders. This problem—called targeting bias—is peculiar to therapies that are adjusted according to a target level, eg, of serum hemoglobin.15 Therefore, any association of mortality with achieved hemoglobin within the individual target hemoglobin group is more likely due to other factors such as patient comorbidities.
  • Patients assigned to the higher hemoglobin targets received more than just higher doses of ESAs: they also got more of other interventions such as intravenous iron supplementation. Therefore, the results of the trials reflect not only the target level achieved but also the independent effects of the study drug, the co-interventions, and the treatment algorithm.

TAKE-HOME POINTS

Partial correction of the anemia associated with kidney disease reduces transfusion requirements, but normalizing the hemoglobin level does not confer survival benefit and may be harmful. In accordance with the FDA recommendations and the available evidence, we agree that the goal for treating anemia associated with kidney disease should be partial correction: the upper boundary of hemoglobin should be 12 g/dL. However, transient trespasses beyond the upper boundary in day-to-day clinical practice should not trigger a panic response in the health care provider (as seen with hyperkalemia, for instance). Rather, they should result in appropriate and timely treatment adjustments.

Further efforts should explore the merits of treatment algorithms that minimize rapid changes in hemoglobin levels, as well as dose limitation of ESAs and co-interventions among hyporesponders.

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