Targeting Normal Hemoglobin Levels to Reduce Transfusions in Hemodialysis Patients
Anemia is highly prevalent among ESRD patients, as a result of diminished erythropoietin production. Erythropoietin stimulating agents (ESAs) have been used successfully to address inadequate renal erythropoietin production in patients with chronic kidney disease (CKD). However, the safety of normal target levels for hemoglobin (Hb) production remains unclear. In addition, the effects of different Hb targets on blood transfusion requirements have not been well characterized. It is important to understand this relationship for clinical decision-making, as well as because of potential transfusion-related infection deleterious immunomodulatory effects in patients whom renal transplantation is a consideration. Therefore, Foley et al conducted a study to test the hypothesis that normal Hb targets can reduce transfusion rates compared with conventional targets.
The study population was comprised of 596 incident hemodialysis patients without symptomatic cardiac disease. This was a randomized, controlled trial comparing normal Hb targets to partial correction of anemia, when treating with epoetin alfa. Patients were randomly assigned to Hb target levels of either 9.5-11.5 g/dL (low target) or 13.5-14.5 g/dL (high target). Patients and physicians were masked to treatment assignment, but doctors had access to ongoing Hb values. The study took place in 95 treatment centers in 10 countries between February 2000 and June 2001.
Adverse events occurred within 4 weeks before the first transfusion and were diverse and similar across both study groups. There were 20 deaths in low target subjects and 13 deaths in high target subjects (not significantly different). Blood cell transfusions differed significantly according to the study group, with 9.1% (high target) and 19.3% (low target) receiving blood transfusions. Hemoglobin levels measured immediately preceding transfusions were similar in both groups. Other multivariate associations of transfusion included baseline Hb level, epoetin dose, transferrin saturation, sex, dialysis duration, body mass index, European or Canadian study site, dialysis vascular access, and serum albumin level.
The authors concluded that based on the data, targeting normal Hb levels can lower blood transfusion requirements in incident hemodialysis patients without symptomatic cardiac disease, in which the mortality rates are low.
Foley RN, Curtis BM, Parfrey PS. Hemoglobin targets and blood transfusions in hemodialysis patients without symptomatic cardiac disease receiving erythropoietin therapy. Clin J Am Soc Nephrol. 2008 Nov;3(6):1669-75.
NAAC Expert Commentary
Anemia management is a near universal clinical issue of importance for patients with CKD and receiving hemodialysis (HD). The availability of safe and effective ESAs and intravenous iron preparations has made it possible to manipulate the Hb level and treat the complication of anemia very effectively, precluding the need for repeated blood transfusions in most patients. What remains somewhat controversial is the optimal target Hb level for ESA-treated patients, primarily for reasons of safety – a controversy that has prompted slightly different treatment recommendations from the U.S. Food and Drug Administration (FDA) and the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (KDOQI).1,2
In this study, Foley et al evaluated the impact of a “high” and “low” target Hb level on cardiac morphology in adult patients on HD without cardiac disease, while also investigating the on-study transfusion history of these patients. The study revealed that the (1) proportion of patients transfused per year and (2) per patient transfusion rate were significantly lower in those patients targeted to the higher Hb level, with no substantial difference in the incidence of adverse events. These findings are important as they provide observational data supporting a possible strategy to decrease the risk of transfusion related complications.
The study had a number of limitations, though, which included: (1) treating physicians having knowledge of the Hb levels (2) the lack of information on the indications for transfusion, and (3) the inability to generalize the study results to those patients with cardiac disease. However, further data on this subject is clearly warranted in our quest to individualize therapy in this era of healthcare reform in the most cost effective manner possible.
References
- U.S. Food and Drug Administration. Communication About an Ongoing Safety Review Erythropoiesis-Stimulating Agents (ESAs) Epoetin alfa (marketed as Procrit, Epogen) Darbepoetin alfa (marketed as Aranesp). Link. Accessed: March 2008.
- National Kidney Foundation. KDOQI Clinical Practice Guideline and Clinical Practice Recommendations for anemia in chronic kidney disease: 2007 update of hemoglobin target. Am J Kidney Dis. 2007 Sep;50(3):471-530. Link.
Evaluating Recurring Iron Deficiency and Anemia in Patients with IBD
Anemia occurs in approximately one-third of patients with inflammatory bowel disease (IBD). The most frequent cause of this common complication is iron deficiency (ID). Causes of ID are not limited to continuous or recurrent blood loss through ulcerations of the bowel mucosa, but also include decreased iron intake or limited absorption of iron. In chronic inflammatory disease or IBD, increased cytokine levels suppress erythropoiesis directly or through inhibition of erythropoietin (EPO) production. The resulting condition is referred to as anemia of chronic disease, which is also present in IBD and occurs with ID. Anemia-specific symptoms are associated with a decreased quality of life, reduced ability to work, and in severe cases, hospitalization or increased length of stay. IBD management includes intravenous and oral iron preparations and the addition of erythropoiesis-stimulating agents (ESAs) can normalize hemoglobin levels in patients who do not respond to intravenous iron alone. It is important to understand the frequency and timing of recurring anemia and ID after successful treatment with iron sucrose and the effect of ESA administration.
A retrospective analysis was conducted by Kulnigg et al on records of patients who had participated in one of three prospective clinical trials that had evaluated the use of iron sucrose (with and without erythropoietin) for the treatment of anemia in IBD. The risk for recurrence of anemia was also evaluated.
Eighty-eight patients were evaluated: patients received a mean iron dose of 2,500 mg and 33 patients had also received ESA treatment. Anemia recurred in a median of 10 months, while ID recurred within 19 months. Among patients with a post-treatment ferritin level <100 μg/L, ID recurred faster (but not anemia), as compared to patients with a post-treatment ferritin level 100-400 μg/L. Maintenance treatment with high target goals for ferritin may be able to delay recurrence of ID. However, recurrence of anemia cannot be delayed by this treatment.
Kulnigg S, Teischinger L, Dejaco C, Waldhör T, Gasche C. Rapid recurrence of IBD-associated anemia and iron deficiency after intravenous iron sucrose and erythropoietin treatment. Am J Gastroenterol. 2009 Jun;104(6):1460-67.
NAAC Expert Commentary
This study by Kulnigg et al attempted to gather data on short and long term outcomes of anemia treatment in patients with IBD. This involved providing intravenous iron sucrose with and without ESAs to anemic patients with Crohn’s disease and ulcerative colitis. The two most common forms of anemia in these patients are iron deficiency anemia (due to excess blood loss from the GI tract, poor absorption, and/or poor intake) and anemia of chronic disease (due to suppression of the bone marrow by pro-inflammatory agents).
The data was obtained from three separate IBD trials in the pre-infliximab era with no information regarding extent, severity, or duration of the inflammatory disease or details of concomitant medical or surgical treatment. All of these factors can greatly impact the duration and severity of anemia and more importantly the response to treatment observed in these patients. Iron/ESA dosage and timing of therapy was at the discretion of the individual physicians with no set schedule. The most useful conclusion gleaned from the data was that aiming for a post treatment ferritin level of 400 mcg/L resulted in prevention of iron deficiency within 1-5 years of treatment.
Physicians who plan to care for patients with IBD need to realize that close follow up of hemoglobin and iron levels, as well as prompt treatment with iron with or without ESA therapy can help to provide a better quality of life for these patients. The addition of infliximab and other “biologic agents” that can attenuate inflammation and bleeding and heal inflamed mucosa may also result in a lower incidence of chronic blood loss and ID in these patients, thereby reducing the need for iron replacement therapy. In the meantime, since active inflammation can falsely raise ambient ferritin levels in IBD patients, aiming for a post treatment ferritin level of 400mcg/L appears to be a reasonable and safe standard.
Antibiotics can cause anemia by a variety of mechanisms, including global suppression of bone marrow function, red cell hemolysis, and suppression of red cell production directly or indirectly by impairing erythropoietin production. Of course, infection can cause anemia through the same mechanisms and it may be difficult to differentiate between antibiotics or infection as the cause.
