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RPA Guidance on Use of ESAs in CKD

Creation/Revision Date: March 08, 2010

Background

In January 2010, an RPA workgroup was convened to offer guidance to RPA membership on the use of erythropoiesis-stimulating agents (ESAs) in chronic kidney disease (CKD) in the wake of studies outlining concerns regarding the safety and utility of ESA use for CKD and ESRD. It also assessed the issue of target Hb for CKD patients in light of recent trials, especially the TREAT trial, and assessed whether the results of that and other CKD trials can be extrapolated to ESRD patients. 

ESA-treatment studies in nondialysis CKD have resulted in a solid body of evidence that is helpful for guiding patient care. However, like all studies of heterogeneous populations, the conclusions drawn do not necessary reflect the advantages and disadvantages of ESA use to any particular individual. Practitioners should rely on guidelines as a general basis for treatment, but care decisions should be individualized for the characteristics of the specific patient. As such, RPA offers the following recommendations for approaching the patient with CKD/ESRD and anemia:

Recommendations

  1. ESA treatment in nondialysis CKD patients to a target Hb>13 gm/dl has been found to increase cardiovascular and other risks, without   consistent signs of benefit.


  2. ESA treatment in nondialysis CKD to target Hgb 10-13 gm/dl has not been adequately tested. Since this limits the ability of clinicians to balance risk against benefit, RPA feels that no clear treatment recommendations can be made in this range. Practitioners should consider their patient's clinical characteristics, and include the patient in consideration of potential benefits and risks of ESA treatment in this range.  We do note a just-published systematic literature review of prospective studies examining energy and physical function in CKD patients with anemia in this range, showing that treatment of anemia with ESAs improves both of these measures. 


  3. ESA use for nondialysis CKD patients with Hb<10 gm/dl reduces the need for transfusions and may improve patient reported outcomes. Particularly for patients who are candidates for kidney transplantation, avoidance of blood transfusions may reduce presensitization and improve the likelihood of finding a good donor-recipient match. 


  4.  While there are no good, modern era studies of CKD patients with profound anemia, older, less rigorous studies show impairment in physical functioning and quality of life when ESRD patients have profound anemia. Since it is unlikely that rigorous studies of CKD/ESRD patients with profound anemia will be performed, we suggest that nephrologists consider treatment for patients with symptomatic anemia with these steps:


    a.  Evaluate patients with anemia to exclude and treat causes of anemia other than CKD.

    b.  Always measure iron status during anemia evaluation and replete iron when deficiency is diagnosed. ESAs should not be administered until the effect of iron repletion is assessed after 6-8 weeks. 

    c. Consider the risks and benefits of blood transfusions and ESAs and treat anemia to achieve adequate Hb levels.

    d. Monitor carefully all patients treated for anemia, particularly to avoid high doses of ESAs to achieve a target  Hb.  


  5. The CKD population has differences from the patients who have reached ESRD and are treated with hemodialysis. Hemodialysis patients often have more co-morbidities and are sicker than nondialysis CKD patients. Hemodialysis is associated with its own unique clinical     problems. The hemodialysis procedure itself causes chronic blood loss and may reduce the quality of life. Therefore, the benefits of ESAs are likely to be valued more in this population. Moreover, studies of ESA treatment in hemodialysis have been more consistent in indicating improved quality of life. Thus, RPA believes that hemodialysis represents a different clinical setting than nondialysis CKD, and that the current target hemoglobin range of 10.0 to 12.0 gm/dl represents a prudent range for these patients. Especially large doses of ESA should be avoided because of possible increased risk

         

Footnote

A recent study (JAMA 303:857) of mortality risk for hemodialysis patients with anemia using the USRDS data base gives us evidence that both the degree of anemia and the dose of ESA impact mortality. At low Hct (<30%) mortality was high compared with higher Hct, and dialysis centers using higher doses of ESA had lower mortality rates than centers using lower ESA doses. For patients with high Hct (>36%), mortality was the lowest, but higher doses of ESAs were associated with higher mortality rates. While this was not a prospective, randomized controlled trial, its method examining prescribing patterns in individual dialysis facilities, showing association between anemia management practice and mortality risk, is of interest. 

Reference List

  1. Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, Schwab SJ, Goodkin DA: The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. New Engl J Med 1998;339:584-590.
  2. Collins AJ, Li S, St.Peter WL, Ebben J, Roberts T, Ma JZ, Manning W: Death, Hospitalization, and Economic Associations among Incident Hemodialysis Patients with Hematocrit Values of 36 to 39%. Journal of the American Society of Nephrology 2001;12:2465-2473.
  3. Drueke TB, Locatelli F, Clyne N, Eckhardt K, MacDougall IC, Tsakiris D, Burger H, Scherhag A: Normalization of Hemoglobin Level in Patients with Chronic Kidney Disease and Anemia. The New England Journal of Medicine 2006;355:2071-2084.
  4. Fishbane S: Erythropoiesis – stimulating agent treatment with full anemia correction: a new perspective. Kidney International 2009;75:358-365.
  5. Pfeffer MA, Burdmann EA, Chen C, Cooper ME, de Zeeuw D, Eckhardt K, Feyzi JM, Ivanovich P, Kewalramani R, Levey A, Lewis EF, McGill JB, McMurray JJV, Parfrey P, Parving H-H, Remuzzi G, Singh AK, Solomon SD, Toto R: A Trial of Darbepoetin Alfa in Type 2 Diabetes and Chronic Kidney Disease. The New England Journal of Medicine 2009;361:2019-2032.
  6. Rosner MH, Bolton WK: The mortality risk associated with higher hemoglobin: is therapy to blame? Kidney International 2008;74:695-697.
  7. Szczech L, Barnhart HX, Inrig JK, Reddan DN, Sapp S, Califf RM, Patel UO, Singh AK: Secondary analysis of the CHOIR trial epoetin – a dose and achieved hemoglobin outcomes. Kidney International 2008;74:791-798
  8. Singh AK: Does TREAT give the boot to ESAs in the Treatment of CKD Anemia? Journal of American Society of Nephrology 2009;DOI:1681/ASN.2009111127.
  9. Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Woldson M, Reddan D: Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease. The New England Journal of Medicine 2006;355:2085-2098.
  10. Unger EF, Thompson AM, Blank MJ, Temple R: Erythropoiesis – Stimulating Agents - Time for Reevaluation. The New England Journal of Medicine 2010;362/3:198-192.
  11. Singh AJ, Himmelfarb J, Szczech L: Resolved: Target higher hemoglobin is associated with greater risk in patients with CKD, Pro and Con. J Am Soc Nephrol. 2009 Jul;20(7):1441-3.
  12. Brookhart MA, Schneeweiss S, Avorn J, Bradbury BD, Liu J, Winkelmayer WC: Comparative mortality risk of anemia management practices in incident hemodialysis patients. J Amer Med Assn 2010; 303:857-864.
  13. Shravanthi R, Finkelstein FO, Bennett AV, Lewis EF, Brazg T, Martin ML: Impact of erythropoiesis-stimulating agents on energy and physical function in nondialysis CKD patients with anemia: A systematic review. Amer J Kidney Dis 2010; 55:519-534.
  14. Johansen KL, Finkelstein FO, Revicki DA, Gitlin M, Evans C, Mayne TJ: Systematic review and meta-analysis of exercise tolerance and physical functioning in dialysis patients treated with erythropoiesis-stimulating agents. Amer J Kidney Dis 2010; 55:535-548. 

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