Current Drug Therapy

Anemia of chronic kidney disease: When normalcy becomes undesirable

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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.


  • 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.



The last several years have seen increased debate over the appropriate hemoglobin target range when using erythropoiesis-stimulating agents (ESAs) to treat the anemia of chronic kidney disease and kidney failure. But several recent studies have raised alarms, and in November 2006 the US Food and Drug Administration (FDA) issued a new warning regarding the use of ESAs in renal disease.

For a perspective on the use of erythropoiesis-stimulating agents in cancer patients, see the related editorial .

This article will discuss the history of ESAs and the current guidelines for their use. ESAs are also indicated to treat anemia in patients undergoing cancer chemotherapy or surgery, but those uses will not be discussed in this article.


The first ESA, Epogen, was approved by the FDA in 1989 to treat anemia associated with kidney disease.

Since then, ESAs have made a revolutionary change in the care of patients with kidney failure by allowing them to avoid blood transfusions, which were the norm, and by improving the quality of life, although the evidence for the latter is less compelling. 1 The benefits of avoiding the use of blood products include a lower risk of reactions, lower cost, and avoiding sensitization of the human lymphocyte antigen (HLA) system in kidney transplant candidates.

To date, however, no randomized, placebo-controlled clinical trial with adequate power to detect a reduction in adverse clinical outcomes (hospitalizations, nonfatal cardiovascular events, or deaths) has assessed the effect of raising hemoglobin levels with ESAs in patients with chronic kidney disease or end-stage renal disease. Nevertheless, several small studies have shown ESAs to have favorable effects on surrogate end points, and an impressive amount of observational data have shown higher survival rates with higher hemoglobin levels. 2–6


During ESA treatment, the FDA first approved a target hemoglobin range of 10 to 11 g/dL, and subsequently changed it to 10 to 12 g/dL in 1994. The National Kidney Foundation, in its 1997 practice guidelines, endorsed a target range of 11 to 12 g/dL.

US Renal Data System. USRDS 2006 annual data report: Atlas of chronic kidney disease and end-stage renal disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2006.

Figure 1. Top, mean monthly hemoglobin concentration and mean erythropoietin dose per week in prevalent hemodialysis patients. Bottom, patient distribution by monthly hemoglobin concentration (g/dL) in hemodialysis patients.

Throughout the 1990s and the early 2000s, nephrologists mounted a wholehearted drive for higher hemoglobin levels, taking patients with chronic kidney disease and end-stage renal disease to an impressive sustained increase in their average hemoglobin levels year after year ( Figure 1 ).7

The US Normal Hematocrit Study (1998) struck a sour note. In this study, 1,233 dialysis patients with cardiovascular disease were randomized to either a low hematocrit target (33%) or a normal hematocrit target (42%). The trial was stopped early when the investigators recognized that more patients in the normal-hematocrit group had died, that the difference was nearing statistical significance, and that continuing the study was unlikely to reveal a benefit in the normal-hematocrit group. Also of note, the incidence of vascular access thrombosis was higher in the normal-hematocrit group. 8

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