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Editorials |

Anemia Management in Chronic Kidney Disease: Bursting the Hemoglobin Bubble FREE

Daniel E. Weiner, MD, MS; and Dana C. Miskulin, MD, MS
[+] Article and Author Information

From Tufts Medical Center, Boston, MA 02111.


Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-0890.

Requests for Single Reprints: Daniel E. Weiner, MD, MS, Tufts Medical Center, 800 Washington Street, Box 391, Boston, MA 02111; e-mail, dweiner@tuftsmedicalcenter.org.

Current Author Addresses: Drs. Weiner and Miskulin: Tufts Medical Center, 800 Washington Street, Box 391, Boston, MA 02111.


Ann Intern Med. 2010;153(1):53-55. doi:10.7326/0003-4819-153-1-201007060-00250
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Until the approval of recombinant erythropoietin therapy in 1989, many patients receiving dialysis were severely anemic and needed transfusions to maintain a hemoglobin level greater than 70 g/L (13). Recombinant erythropoietin was greeted as a panacea for anemia in chronic kidney disease (CKD) and was approved for use with considerable fanfare, relatively little clinical trial data, and few reservations. Early reports (46) described sustained increases in hemoglobin levels accompanied by improvements in exercise tolerance, quality of life, and cognitive functioning, with relatively few adverse events. These benefits were seen with only modest increases in target hemoglobin level, often to 90 to 100 g/L.

Current strategies for anemia management in CKD crudely attempt to mimic precise feedback mechanisms. Endogenous release of erythropoietin in response to anemia prevents apoptosis of early bone-marrow erythrocyte progenitors and permits proliferation, maturation, and increased output of erythrocytes, whereas erythropoietin suppression and subsequent increased apoptosis in erythroid progenitors occur in settings of higher erythrocyte mass (7). Because endogenous erythropoietin levels are often higher in persons with CKD than in control participants, most anemia in CKD must be multifactorial, with either concurrent bone marrow resistance to erythropoietin (often due to iron deficiency and inflammation) or increased erythrocyte destruction or loss contributing to anemia. For persons without substantial erythropoietin resistance, smaller epoetin doses will increase erythrocyte production and prolong erythrocyte life, whereas for persons with erythropoietin resistance, supraphysiologic doses of epoetin may be required to approach hemoglobin targets. Erythropoietin has effects beyond erythrocytosis, including hemoglobin-independent hypertension (8) and angiogenesis (9), which are probably promoted by exogenous nonphysiologic administration.

The question that naturally followed the early trials of erythropoiesis-stimulating agents (ESAs) was whether further increases in hemoglobin levels would improve tissue oxygenation, thereby reducing the high rates of adverse events in patients with CKD. This prompted the Normal Hematocrit Trial (10), in which 1233 patients receiving hemodialysis with high cardiovascular risk were randomly assigned to a target of a normal hematocrit (42%) versus a lower hematocrit (30%). The hemoglobin-normalization group received very high epoetin doses (mean, 450 U/kg per week). Mortality and myocardial infarction were more common in the group with the higher hematocrit target (P = 0.06), and the study was stopped early because of futility). Despite this result, ESA use and hemoglobin values both progressively increased over the subsequent decade in U.S. patients receiving dialysis (3). Although this bubble was remarkable, it probably reflected results from large observational studies showing better outcomes with higher hemoglobin levels (11); post hoc analyses of clinical trials suggesting that not achieving the target hemoglobin level, rather than the target level itself, was associated with greater mortality (10, 12); and financial incentives promoting greater ESA use (13).

In 2006, CREATE (Cardiovascular Risk Reduction in Early Anemia Treatment with Epoetin) and CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) finally burst the high-hemoglobin bubble. These 2 large randomized trials (1415) that enrolled patients with stage 3 to 4 CKD found either no benefit or potential harm associated with targeting normal hemoglobin levels versus levels of 105 to 115 g/L. Concurrently, trials in patients with cancer were consistently finding increased mortality associated with ESA use (albeit at far higher doses than those used in CKD) (16). Of note, the largest ESA study to date (17) continued, despite calls that it should be stopped. Randomly assigning 4038 participants with stage 3 to 4 CKD, TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) compared hemoglobin normalization using darbepoetin with placebo, although salvage ESA could be given for hemoglobin levels less than 90 g/L. Published in late 2009, TREAT (18) revealed no difference between randomization groups in the primary outcome, although an increased risk for stroke was associated with targeting normalization.

The publication of TREAT prompted the updated systematic review and meta-analysis by Palmer and colleagues in this issue (19). This well-executed meta-analysis mostly confirms earlier findings, showing that higher hemoglobin targets are associated with fewer transfusions but increase hypertension, access thrombosis, and stroke. Of note, the meta-analysis revealed a trend toward increased risk for all-cause mortality and serious cardiovascular events with targeting hemoglobin levels greater than 130 g/L as compared with control participants with hemoglobin levels between 100 and 115 g/L.

Given the emphasis of recent clinical trials on targeting high hemoglobin levels, critical knowledge gaps remain, most notably the absence of information on lower hemoglobin targets (<125 g/L). The largest randomized, placebo-controlled outcome study to explore this range was the 1990 Canadian Erythropoietin Study Group (CESG) trial (5), which included 118 patients and lasted only 6 months. The placebo group in the CESG trial had a mean hemoglobin concentration of 74 g/L (SD, 12), compared with 2 treatment groups that achieved mean hemoglobin levels of 102 g/L (SD, 10) and 117 g/L (SD, 17), respectively, by using 50% to 60% less epoetin than the normalization group in the Normal Hematocrit Trial. In the CESG trial, substantial benefits to quality of life and physical performance were associated with the 2 higher hemoglobin targets, although outcome measures did not differ between the 2 treatment groups. Subsequent larger clinical trials have not shown clinically meaningful sustained improvements in quality of life, although hemoglobin levels for the control groups in these studies were similar to those in the treatment groups of the CESG trial (10, 1415, 18). A second knowledge gap is the lack of data to facilitate individualization of therapies. Higher-functioning persons are probably more aware of the symptoms of anemia than more sedentary persons, thereby deriving greater benefit from higher hemoglobin targets (20). In this context, it is ironic that the major clinical trials focused on participants with prevalent cardiovascular disease or diabetes. A third gap, pertaining to the use of iron and other anemia-management agents, is the lack of data on concurrent administration of multiple anemia therapies.

We cannot disentangle the effects of higher hemoglobin targets from the higher cumulative ESA (and iron) administration required to achieve those targets, which leaves us uncertain about whether higher hemoglobin levels are the wrong goal or whether we lack the proper means to safely get there. What we definitively know is limited: Targeting hemoglobin levels greater than 130 g/L with epoetin or darbepoetin is probably more harmful than beneficial for most persons. Critical questions remain:

Is there a lower hemoglobin limit above which most patients derive a benefit with epoetin therapy, and what is that level?

Is there a subset of persons who feel better with higher hemoglobin levels for whom higher levels should be targeted?

Would risk be reduced if other agents, including iron, were increasingly used instead of high-dose erythropoietin or darbepoetin?

Is low-dose ESA therapy safe?

How should we treat persons with ESA resistance?

Before abandoning epoetin and darbepoetin and returning to the era of severe anemia and frequent transfusions, additional adequately powered clinical trials are needed to specifically address each of these questions and thereby balance the potential harms associated with ESAs against benefits that were noted in the earliest placebo studies. Until then, the bursting of the hemoglobin bubble is another cautionary reminder that observational data may be misleading and that medicine is the art of treating the individual patient, which requires extrapolation of available knowledge to individuals' clinical circumstances while recognizing deficits in existing knowledge, maximizing limited resources, and involving patients in their own care decisions.

Daniel E. Weiner, MD, MS

Dana C. Miskulin, MD, MS

Tufts Medical Center

Boston, MA 02111

References

Eschbach JW, Abdulhadi MH, Browne JK, Delano BG, Downing MR, Egrie JC, et al..  Recombinant human erythropoietin in anemic patients with end-stage renal disease. Results of a phase III multicenter clinical trial. Ann Intern Med. 1989; 111:992-1000. PubMed
 
Goodnough LT, Strasburg D, Riddell J 4th, Verbrugge D, Wish J.  Has recombinant human erythropoietin therapy minimized red-cell transfusions in hemodialysis patients? Clin Nephrol. 1994; 41:303-7. PubMed
 
Ibrahim HN, Ishani A, Foley RN, Guo H, Liu J, Collins AJ.  Temporal trends in red blood transfusion among US dialysis patients, 1992-2005. Am J Kidney Dis. 2008; 52:1115-21. PubMed
CrossRef
 
Nissenson AR, Korbet S, Faber M, Burkart J, Gentile D, Hamburger R, et al..  Multicenter trial of erythropoietin in patients on peritoneal dialysis. J Am Soc Nephrol. 1995; 5:1517-29. PubMed
 
Canadian Erythropoietin Study Group.  Association between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving haemodialysis. BMJ. 1990; 300:573-8. PubMed
 
Revicki DA, Brown RE, Feeny DH, Henry D, Teehan BP, Rudnick MR, et al..  Health-related quality of life associated with recombinant human erythropoietin therapy for predialysis chronic renal disease patients. Am J Kidney Dis. 1995; 25:548-54. PubMed
 
Rice L, Alfrey CP.  The negative regulation of red cell mass by neocytolysis: physiologic and pathophysiologic manifestations. Cell Physiol Biochem. 2005; 15:245-50. PubMed
 
Vaziri ND, Zhou XJ, Naqvi F, Smith J, Oveisi F, Wang ZQ, et al..  Role of nitric oxide resistance in erythropoietin-induced hypertension in rats with chronic renal failure. Am J Physiol. 1996; 271:113-22. PubMed
 
Arcasoy MO.  The non-haematopoietic biological effects of erythropoietin. Br J Haematol. 2008; 141:14-31. PubMed
 
Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, 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; 339:584-90. PubMed
 
Vlagopoulos PT, Tighiouart H, Weiner DE, Griffith J, Pettitt D, Salem DN, et al..  Anemia as a risk factor for cardiovascular disease and all-cause mortality in diabetes: the impact of chronic kidney disease. J Am Soc Nephrol. 2005; 16:3403-10. PubMed
 
Szczech LA, Barnhart HX, Inrig JK, Reddan DN, Sapp S, Califf RM, et al..  Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes. Kidney Int. 2008; 74:791-8. PubMed
 
Thamer M, Zhang Y, Kaufman J, Cotter D, Dong F, Hernán MA.  Dialysis facility ownership and epoetin dosing in patients receiving hemodialysis. JAMA. 2007; 297:1667-74. PubMed
 
Drüeke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, et al., CREATE Investigators.  Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006; 355:2071-84. PubMed
 
Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, et al., CHOIR Investigators.  Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006; 355:2085-98. PubMed
 
Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J, et al..  Erythropoietin or Darbepoetin for patients with cancer—meta-analysis based on individual patient data. Cochrane Database Syst Rev. 2009; CD007303. PubMed
 
Pfeffer MA.  Critical missing data on erythropoiesis-stimulating agents in CKD: first beat placebo [Editorial]. Am J Kidney Dis. 2008; 51:366-9. PubMed
 
Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, et al., TREAT Investigators.  A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009; 361:2019-32. PubMed
 
Palmer SC, Navaneethan SD, Craig JC, Johnson DW, Tonelli M, Garg AX, et al..  Meta-analysis: erythropoiesis-stimulating agents in patients with chronic kidney disease. Ann Intern Med. 2010; 153:23-33.
 
Prisant A.  TREAT versus treatment: a patient's view of a scientific interpretation. Am J Kidney Dis. 2010; 55:A31-2. PubMed
 

Figures

Tables

References

Eschbach JW, Abdulhadi MH, Browne JK, Delano BG, Downing MR, Egrie JC, et al..  Recombinant human erythropoietin in anemic patients with end-stage renal disease. Results of a phase III multicenter clinical trial. Ann Intern Med. 1989; 111:992-1000. PubMed
 
Goodnough LT, Strasburg D, Riddell J 4th, Verbrugge D, Wish J.  Has recombinant human erythropoietin therapy minimized red-cell transfusions in hemodialysis patients? Clin Nephrol. 1994; 41:303-7. PubMed
 
Ibrahim HN, Ishani A, Foley RN, Guo H, Liu J, Collins AJ.  Temporal trends in red blood transfusion among US dialysis patients, 1992-2005. Am J Kidney Dis. 2008; 52:1115-21. PubMed
CrossRef
 
Nissenson AR, Korbet S, Faber M, Burkart J, Gentile D, Hamburger R, et al..  Multicenter trial of erythropoietin in patients on peritoneal dialysis. J Am Soc Nephrol. 1995; 5:1517-29. PubMed
 
Canadian Erythropoietin Study Group.  Association between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving haemodialysis. BMJ. 1990; 300:573-8. PubMed
 
Revicki DA, Brown RE, Feeny DH, Henry D, Teehan BP, Rudnick MR, et al..  Health-related quality of life associated with recombinant human erythropoietin therapy for predialysis chronic renal disease patients. Am J Kidney Dis. 1995; 25:548-54. PubMed
 
Rice L, Alfrey CP.  The negative regulation of red cell mass by neocytolysis: physiologic and pathophysiologic manifestations. Cell Physiol Biochem. 2005; 15:245-50. PubMed
 
Vaziri ND, Zhou XJ, Naqvi F, Smith J, Oveisi F, Wang ZQ, et al..  Role of nitric oxide resistance in erythropoietin-induced hypertension in rats with chronic renal failure. Am J Physiol. 1996; 271:113-22. PubMed
 
Arcasoy MO.  The non-haematopoietic biological effects of erythropoietin. Br J Haematol. 2008; 141:14-31. PubMed
 
Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, 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; 339:584-90. PubMed
 
Vlagopoulos PT, Tighiouart H, Weiner DE, Griffith J, Pettitt D, Salem DN, et al..  Anemia as a risk factor for cardiovascular disease and all-cause mortality in diabetes: the impact of chronic kidney disease. J Am Soc Nephrol. 2005; 16:3403-10. PubMed
 
Szczech LA, Barnhart HX, Inrig JK, Reddan DN, Sapp S, Califf RM, et al..  Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes. Kidney Int. 2008; 74:791-8. PubMed
 
Thamer M, Zhang Y, Kaufman J, Cotter D, Dong F, Hernán MA.  Dialysis facility ownership and epoetin dosing in patients receiving hemodialysis. JAMA. 2007; 297:1667-74. PubMed
 
Drüeke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, et al., CREATE Investigators.  Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006; 355:2071-84. PubMed
 
Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, et al., CHOIR Investigators.  Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006; 355:2085-98. PubMed
 
Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J, et al..  Erythropoietin or Darbepoetin for patients with cancer—meta-analysis based on individual patient data. Cochrane Database Syst Rev. 2009; CD007303. PubMed
 
Pfeffer MA.  Critical missing data on erythropoiesis-stimulating agents in CKD: first beat placebo [Editorial]. Am J Kidney Dis. 2008; 51:366-9. PubMed
 
Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, et al., TREAT Investigators.  A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009; 361:2019-32. PubMed
 
Palmer SC, Navaneethan SD, Craig JC, Johnson DW, Tonelli M, Garg AX, et al..  Meta-analysis: erythropoiesis-stimulating agents in patients with chronic kidney disease. Ann Intern Med. 2010; 153:23-33.
 
Prisant A.  TREAT versus treatment: a patient's view of a scientific interpretation. Am J Kidney Dis. 2010; 55:A31-2. PubMed
 

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