INTRODUCTION

Anemia has been defined by the World Health Organization (WHO) as a hemoglobin
(Hgb) concentration <13.0 g/dL for adult males and postmenopausal women and a Hgb
<12.0 g/dL for premenopausal women [1]. Based upon these criteria, nearly 90 percent
of patients with a glomerular filtration rate (GFR) <25 to 30 mL/min have anemia, many
with Hgb levels <10 g/dL [2].
Ever since the approval of recombinant human erythropoietin (epoetin alfa, EPO) by the
US Food and Drug Administration (FDA), this and other erythropoiesis-stimulating
agents (ESAs) have become the standard of care for the treatment of the anemia that
occurs in most patients with advanced chronic kidney disease (CKD) and end-stage
renal disease (ESRD). As a result, mean Hgb and hematocrit (Hct) levels in patients
with CKD, particularly those on dialysis, rose steadily through 2005 [3,4]. By 2006, 90
percent of patients maintained on chronic dialysis in the United States received ESAs,
with a mean Hgb level among dialysis patients of 12.0 g/dL [4,5]; two-thirds of all
patients had Hgb levels between 11 and 13 g/dL [4].
Anemia has also been implicated as a contributing factor in many of the symptoms
associated with reduced kidney function. These include fatigue, depression, reduced
exercise tolerance, dyspnea, and cardiovascular consequences, such as left ventricular
hypertrophy (LVH) and left ventricular systolic dysfunction [6]. It is also associated with
an increased risk of morbidity and mortality, principally due to cardiac disease and
stroke [7-10], and with an increased risk of hospitalization, hospital length of stay, and
mortality in patients with predialysis CKD [11-14]. Associations, however, do not prove
causality; thus, these associations may reflect underlying comorbid conditions and
severity of illness that contribute to both the severity of anemia, reduced
responsiveness to ESAs, and poorer outcomes.
A review of the data relating to target Hgb or Hct levels for patients with anemia due to
renal disease treated with ESAs is presented here. Issues relating to EPO, darbepoetin,

and iron administration are presented separately. (See "Erythropoietin for the anemia of
chronic

kidney

disease

among

predialysis

and

peritoneal

dialysis

patients" and "Erythropoietin for the anemia of chronic kidney disease in hemodialysis
patients" and "Darbepoetin alfa for the management of anemia in chronic kidney
disease" and "Iron balance in non-dialysis, peritoneal dialysis, and home hemodialysis
patients" and "Use of iron preparations in hemodialysis patients".)
INDICATIONS FOR TREATMENT

An overview of treatment options for anemia among dialysis and non-dialysis chronic
kidney disease (CKD) patients, including the relative indications for treatment with
erythropoiesis-stimulating agents (ESAs) versus transfusion is presented elsewhere.
(See "Erythropoietin for the anemia of chronic kidney disease in hemodialysis patients",
section on 'Indications' and "Erythropoietin for the anemia of chronic kidney disease
among predialysis and peritoneal dialysis patients", section on 'Whom to treat and
target hemoglobin level'.)
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1.

World Health Organization. Nutritional Anaemias: Report of a WHO Scientific Group.

Geneva, Switzerland: World Health Organization, 1968.

2.

Kazmi WH, Kausz AT, Khan S, et al. Anemia: an early complication of chronic renal
insufficiency. Am J Kidney Dis 2001; 38:803.

3.

Obrador GT, Roberts T, St Peter WL, et al. Trends in anemia at initiation of dialysis in the
United States. Kidney Int 2001; 60:1875.

4.

Hariharan S, Yang H. Introduction. Am J Kidney Dis. 2006; 47:S1.

5.

Centers for Medicare and Medicaid Services, Kinney R. 2005 Annual Report: ESRD
Clinical Performance Measures Project. Am J Kidney Dis 2006; 48:S1.

6.

Levin A, Thompson CR, Ethier J, et al. Left ventricular mass index increase in early renal
disease: impact of decline in hemoglobin. Am J Kidney Dis 1999; 34:125.

7.

Jurkovitz CT, Abramson JL, Vaccarino LV, et al. Association of high serum creatinine and
anemia increases the risk of coronary events: results from the prospective communitybased atherosclerosis risk in communities (ARIC) study. J Am Soc Nephrol 2003; 14:2919.

8.

Abramson JL, Jurkovitz CT, Vaccarino V, et al. Chronic kidney disease, anemia, and
incident stroke in a middle-aged, community-based population: the ARIC Study. Kidney Int
2003; 64:610.

9.

Sarnak MJ, Tighiouart H, Manjunath G, et al. Anemia as a risk factor for cardiovascular
disease in The Atherosclerosis Risk in Communities (ARIC) study. J Am Coll Cardiol 2002;
40:27.

10.

McClellan WM, Flanders WD, Langston RD, et al. Anemia and renal insufficiency are
independent risk factors for death among patients with congestive heart failure admitted to
community hospitals: a population-based study. J Am Soc Nephrol 2002; 13:1928.

11.

Ma JZ, Ebben J, Xia H, Collins AJ. Hematocrit level and associated mortality in
hemodialysis patients. J Am Soc Nephrol 1999; 10:610.

12.

Xia H, Ebben J, Ma JZ, Collins AJ. Hematocrit levels and hospitalization risks in
hemodialysis patients. J Am Soc Nephrol 1999; 10:1309.

13.

Collins AJ, Li S, St Peter W, et al. Death, hospitalization, and economic associations

among incident hemodialysis patients with hematocrit values of 36 to 39%. J Am Soc
Nephrol 2001; 12:2465.

14.

Collins AJ, Ma JZ, Ebben J. Impact of hematocrit on morbidity and mortality. Semin
Nephrol 2000; 20:345.

15.

http://www.fda.gov/Drugs/DrugSafety/ucm259639.htm (Accessed on July 28, 2011).

16.

Strippoli GF, Craig JC, Manno C, Schena FP. Hemoglobin targets for the anemia of
chronic kidney disease: a meta-analysis of randomized, controlled trials. J Am Soc Nephrol
2004; 15:3154.

17.

Volkova N, Arab L. Evidence-based systematic literature review of

hemoglobin/hematocrit and all-cause mortality in dialysis patients. Am J Kidney Dis 2006;
47:24.

18.

Parfrey PS. Target hemoglobin level for EPO therapy in CKD. Am J Kidney Dis 2006;
47:171.

19.

Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low
hematocrit values in patients with cardiac disease who are receiving hemodialysis and
epoetin. N Engl J Med 1998; 339:584.

20.

Phrommintikul A, Haas SJ, Elsik M, Krum H. Mortality and target haemoglobin

concentrations in anaemic patients with chronic kidney disease treated with erythropoietin:
a meta-analysis. Lancet 2007; 369:381.

21.

Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes
and chronic kidney disease. N Engl J Med 2009; 361:2019.

22.

NKF-DOQI clinical practice guidelines for the treatment of anemia of chronic renal
failure. National Kidney Foundation-Dialysis Outcomes Quality Initiative. Am J Kidney Dis
1997; 30:S192.

23.

IV. NKF-K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease:
update 2000. Am J Kidney Dis 2001; 37:S182.

24.

NKF-K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease. Am J

Kidney Dis 2006; 47(Suppl 4):S1.

25.

KDOQI. KDOQI Clinical Practice Guideline and Clinical Practice Recommendations for
anemia in chronic kidney disease: 2007 update of hemoglobin target. Am J Kidney Dis
2007; 50:471.

26.

KDIGO clinical practice guidelines for anemia in chronic kidney disease. Kidney Int
Suppl 2012; 2:288.

27.

Berns JS, Elzein H, Lynn RI, et al. Hemoglobin variability in epoetin-treated hemodialysis
patients. Kidney Int 2003; 64:1514.

28.

Lacson E Jr, Ofsthun N, Lazarus JM. Effect of variability in anemia management on

hemoglobin outcomes in ESRD. Am J Kidney Dis 2003; 41:111.

29.

Fishbane S, Berns JS. Hemoglobin cycling in hemodialysis patients treated with

recombinant human erythropoietin. Kidney Int 2005; 68:1337.

30.

Li S, Collins AJ. Association of hematocrit value with cardiovascular morbidity and

mortality in incident hemodialysis patients. Kidney Int 2004; 65:626.

31.

Ofsthun N, Labrecque J, Lacson E, et al. The effects of higher hemoglobin levels on

mortality and hospitalization in hemodialysis patients. Kidney Int 2003; 63:1908.

32.

Pisoni RL, Bragg-Gresham JL, Young EW, et al. Anemia management and outcomes
from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J
Kidney Dis 2004; 44:94.

33.

Li S, Foley RN, Collins AJ. Anemia, hospitalization, and mortality in patients receiving
peritoneal dialysis in the United States. Kidney Int 2004; 65:1864.

34.

Robinson BM, Joffe MM, Berns JS, et al. Anemia and mortality in hemodialysis patients:
accounting for morbidity and treatment variables updated over time. Kidney Int 2005;
68:2323.

35.

Messana JM, Chuang CC, Turenne M, et al. Association of quarterly average achieved
hematocrit with mortality in dialysis patients: a time-dependent comorbidity-adjusted model.
Am J Kidney Dis 2009; 53:503.

36.

Wolfe RA, Hulbert-Shearon TE, Ashby VB, et al. Improvements in dialysis patient
mortality are associated with improvements in urea reduction ratio and hematocrit, 1999 to
2002. Am J Kidney Dis 2005; 45:127.

37.

Regidor DL, Kopple JD, Kovesdy CP, et al. Associations between changes in
hemoglobin and administered erythropoiesis-stimulating agent and survival in hemodialysis
patients. J Am Soc Nephrol 2006; 17:1181.

38.

Locatelli F, Pisoni RL, Combe C, et al. Anaemia in haemodialysis patients of five

European countries: association with morbidity and mortality in the Dialysis Outcomes and
Practice Patterns Study (DOPPS). Nephrol Dial Transplant 2004; 19:121.

39.

Lu WX, Jones-Burton C, Zhan M, et al. Survival benefit of recombinant human

erythropoietin administration prior to onset of end-stage renal disease: variations across
surrogates for quality of care and time. Nephron Clin Pract 2005; 101:c79.

40.

Gilbertson DT, Ebben JP, Foley RN, et al. Hemoglobin level variability: associations with
mortality. Clin J Am Soc Nephrol 2008; 3:133.

41.

Palmer SC, Navaneethan SD, Craig JC, et al. Meta-analysis: erythropoiesis-stimulating

agents in patients with chronic kidney disease. Ann Intern Med 2010; 153:23.

42.

Clement FM, Klarenbach S, Tonelli M, et al. The impact of selecting a high hemoglobin
target level on health-related quality of life for patients with chronic kidney disease: a
systematic review and meta-analysis. Arch Intern Med 2009; 169:1104.

43.

Coyne DW. The health-related quality of life was not improved by targeting higher
hemoglobin in the Normal Hematocrit Trial. Kidney Int 2012; 82:235.

44.

Dreke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with
chronic kidney disease and anemia. N Engl J Med 2006; 355:2071.

45.

Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic
kidney disease. N Engl J Med 2006; 355:2085.

46.

www.clinicaltrials.gov (Accessed on April 27, 2007).

47.

Parfrey PS, Foley RN, Wittreich BH, et al. Double-blind comparison of full and partial
anemia correction in incident hemodialysis patients without symptomatic heart disease. J
Am Soc Nephrol 2005; 16:2180.

48.

Ritz E, Laville M, Bilous RW, et al. Target level for hemoglobin correction in patients with
diabetes and CKD: primary results of the Anemia Correction in Diabetes (ACORD) Study.
Am J Kidney Dis 2007; 49:194.

49.

Moreno F, Sanz-Guajardo D, Lpez-Gmez JM, et al. Increasing the hematocrit has a

beneficial effect on quality of life and is safe in selected hemodialysis patients. Spanish
Cooperative Renal Patients Quality of Life Study Group of the Spanish Society of
Nephrology. J Am Soc Nephrol 2000; 11:335.

50.

McMahon LP, Mason K, Skinner SL, et al. Effects of haemoglobin normalization on

quality of life and cardiovascular parameters in end-stage renal failure. Nephrol Dial
Transplant 2000; 15:1425.

51.

Double-blind, placebo-controlled study of the therapeutic use of recombinant human

erythropoietin for anemia associated with chronic renal failure in predialysis patients. The
US Recombinant Human Erythropoietin Predialysis Study Group. Am J Kidney Dis 1991;
18:50.

52.

Pickett JL, Theberge DC, Brown WS, et al. Normalizing hematocrit in dialysis patients
improves brain function. Am J Kidney Dis 1999; 33:1122.

53.

McMahon LP, McKenna MJ, Sangkabutra T, et al. Physical performance and associated
electrolyte changes after haemoglobin normalization: a comparative study in haemodialysis
patients. Nephrol Dial Transplant 1999; 14:1182.

54.

Foley RN, Curtis BM, Parfrey PS. Erythropoietin therapy, hemoglobin targets, and quality
of life in healthy hemodialysis patients: a randomized trial. Clin J Am Soc Nephrol 2009;
4:726.

55.

Gandra SR, Finkelstein FO, Bennett AV, et al. Impact of erythropoiesis-stimulating

agents on energy and physical function in nondialysis CKD patients with anemia: a
systematic review. Am J Kidney Dis 2010; 55:519.

56.

Johansen KL, Finkelstein FO, Revicki DA, et al. Systematic review and meta-analysis of
exercise tolerance and physical functioning in dialysis patients treated with erythropoiesisstimulating agents. Am J Kidney Dis 2010; 55:535.

57.

Lewis EF, Pfeffer MA, Feng A, et al. Darbepoetin alfa impact on health status in diabetes
patients with kidney disease: a randomized trial. Clin J Am Soc Nephrol 2011; 6:845.

58.

Churchill DN, Muirhead N, Goldstein M, et al. Probability of thrombosis of vascular

access among hemodialysis patients treated with recombinant human erythropoietin. J Am
Soc Nephrol 1994; 4:1809.

59.

Furuland H, Linde T, Ahlmn J, et al. A randomized controlled trial of haemoglobin

normalization with epoetin alfa in pre-dialysis and dialysis patients. Nephrol Dial Transplant
2003; 18:353.

60.

Vaziri ND. Mechanism of erythropoietin-induced hypertension. Am J Kidney Dis 1999;

33:821.

61.

Berns JS, Rudnick MR, Cohen RM, et al. Effects of normal hematocrit on ambulatory
blood pressure in epoetin-treated hemodialysis patients with cardiac disease. Kidney Int
1999; 56:253.

62.

Inrig JK, Barnhart HX, Reddan D, et al. Effect of hemoglobin target on progression of
kidney disease: a secondary analysis of the CHOIR (Correction of Hemoglobin and
Outcomes in Renal Insufficiency) trial. Am J Kidney Dis 2012; 60:390.

63.

Tonelli M, Winkelmayer WC, Jindal KK, et al. The cost-effectiveness of maintaining

higher hemoglobin targets with erythropoietin in hemodialysis patients. Kidney Int 2003;
64:295.

64.

Roberts TL, Foley RN, Weinhandl ED, et al. Anaemia and mortality in haemodialysis
patients: interaction of propensity score for predicted anaemia and actual haemoglobin
levels. Nephrol Dial Transplant 2006; 21:1652.

65.

Kilpatrick RD, Critchlow CW, Fishbane S, et al. Greater epoetin alfa responsiveness is
associated with improved survival in hemodialysis patients. Clin J Am Soc Nephrol 2008;
3:1077.

66.

Bradbury BD, Wang O, Critchlow CW, et al. Exploring relative mortality and epoetin alfa
dose among hemodialysis patients. Am J Kidney Dis 2008; 51:62.

67.

Fishbane S, Besarab A. Mechanism of increased mortality risk with erythropoietin

treatment to higher hemoglobin targets. Clin J Am Soc Nephrol 2007; 2:1274.

68.

Szczech LA, Barnhart HX, Inrig JK, et al. Secondary analysis of the CHOIR trial epoetinalpha dose and achieved hemoglobin outcomes. Kidney Int 2008; 74:791.

69.

Singh AK. Resolved: Targeting a higher hemoglobin is associated with greater risk in
patients with CKD anemia: pro. J Am Soc Nephrol 2009; 20:1436.

70.

Solomon SD, Uno H, Lewis EF, et al. Erythropoietic response and outcomes in kidney
disease and type 2 diabetes. N Engl J Med 2010; 363:1146.

71.

Rosner MH, Bolton WK. The mortality risk associated with higher hemoglobin: is the
therapy to blame? Kidney Int 2008; 74:695.

72.

Zhang Y, Thamer M, Cotter D, et al. Estimated effect of epoetin dosage on survival

among elderly hemodialysis patients in the United States. Clin J Am Soc Nephrol 2009;
4:638.