The use of erythropoietic-stimulating agents (ESAs) in patients with chronic kidney disease (CKD) remains controversial. In fact, recent findings by the Food and Drug Administration (FDA) have suggested that hemoglobin (Hb) targets over 12 g/dL in patients with CKD offer no benefit and may actually increase morbidity and mortality. However, many nephrologists feel that the quality of life (QOL) of patients with CKD is improved with ESA treatment, but few controlled studies demonstrate an improvement in health-related QOL measures. Therefore, a recent study examined the relationship between health-related QOL and anemia severity in a cohort of CKD patients. The CKD Renalsoft Informatics Observational Study (CRIOS) is a prospective study designed to collect data on clinical care practices for renal replacement therapy and health-related QOL assessments.

In the study, 1,186 CKD patients completed the Kidney Disease Quality of Life Short Form Questionnaire (KDQOL-SF), a reliable survey widely used in the assessment of patients with kidney disease. Patients were bracketed into their respective stages of CKD, and Hb levels were grouped into four categories (<11 g/dL, 11 to <12 g/dL, 12 to <13 g/dL, and ≥13 g/dL). In all Hb categories and stages of CKD, significant improvements in QOL domains were observed with increasing Hb levels when only Hb levels were accounted for in the analysis. Also, after adjusting for age, race, gender, stage of CKD, history of iron and ESA use, and the presence or absence of diabetes, a significant association remained in all four physical components of the KDQOL-SF. Furthermore, no significant interactions were found between Hb levels and the use of ESAs, indicating that the association between QOL and Hb levels was independent of ESA use.

The results of this study offer some new understanding to the current controversy over ESA use in CKD patients. While some studies show adverse effects from increasing Hb levels, this study shows significant improvements in QOL in CKD patients. This observation has important implications for the treatment of CKD patients, since currently approved FDA claims do not reflect the QOL improvements observed in this study. However, given the small scale of the study, the findings may not be generalizable to the broader population of CKD patients, and therefore, further prospective trials are needed to analyze the QOL domain changes that occur with ESA use.

Finkelstein FO, Story K, Firanek C, Mendelssohn D, Barre P, Takano T, Soroka S, Mujais S. Health-Related Quality of Life and Hemoglobin Levels in Chronic Kidney Disease Patients. Clin J Am Soc Nephrol. 2008 Nov 5.

NAAC Expert Commentary:
There has been much debate and discussion over the last two years about the QOL impact of ESA use in CKD patients. Much of this discussion was sparked by the CHOIR study,¹ which found no QOL benefit from higher Hb levels, and the simultaneously published CREATE study, which did find a QOL benefit.² While other prospective studies have also suggested a QOL benefit with higher Hb levels,³ the sustainability of QOL improvement with ESA treatment has not been proven. Although this study by Finkelstein et al further supports the concept that higher Hb levels are associated with better QOL in CKD patients, the study leaves other important questions unanswered. These findings are similar to those of Lefebvre et al,⁴ who also reported higher QOL scores across the Hb spectrum and showed dramatically better QOL scores as Hb levels increased from about 9 to 11 g/dL. However, the “dose-response” relationship was considerably less pronounced for most QOL components above 9-11 g/dL.

Several points must be kept in mind when considering this study. For example, the study did not assess changes in QOL scores associated with increasing the Hb level in individual patients; rather, Hb level and QOL scores were examined at single time points. Consequently, we cannot conclude that raising Hb levels causes an increase in QOL. Additionally, since many patients were not on ESA therapy, we should not draw conclusions about any relationship between ESA use and QOL. One problem with all of our studies of anemia management is the lumping together of all CKD patients; it seems likely that this may obscure important differences that might be observed, otherwise. The QOL improvement with higher Hb levels may be very different in a younger, more active individual who works full time in a demanding job, as compared with an older, more sedentary individual with other major comorbidities that could be more critical determinants of QOL.

For now, this study supports prior conclusions and clinical judgment that (1) an Hb level of 11-13 g/dL, with or without ESA treatment, is associated with better QOL and greater physical function, compared to lower Hb levels, and that (2) even higher Hb levels are associated with continued, but perhaps, less improvement in QOL. Nevertheless, this improvement may by offset by an increase in morbidity or mortality.^1,5 Furthermore, a secondary analysis of the CHOIR study suggests that factors other than higher Hb levels may have been important determinants of the outcomes observed in that study.⁶

Still unanswered is whether better QOL is due to higher Hb levels or whether better QOL and higher Hb levels are simply co-occurring in healthier patients. What is currently needed are prospective studies looking more closely at (1) QOL parameters within the Hb range of 10-13 g/dL, (2) the sustainability of changes in QOL, and (3) a closer examination of QOL in different subsets of CKD patients.

References

1. Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, Reddan D; CHOIR Investigators. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006 Nov 16;355(20):2085-98. Link.
2. Drüeke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, Burger HU, Scherhag A; CREATE Investigators. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006 Nov 16;355(20):2071-84. Link.
3. Canadian Erythropoietin Study Group. Association between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving haemodialysis. BMJ. 1990 Mar 3;300(6724):573-8. Link.
4. Lefebvre P, Vekeman F, Sarokhan B, Enny C, Provenzano R, Cremieux PY. Relationship between hemoglobin level and quality of life in anemic patients with chronic kidney disease receiving epoetin alfa. Curr Med Res Opin. 2006 Oct;22(10):1929-37. Link.
5. 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. N Engl J Med. 1998 Aug 27;339(9):584-90. Link.
6. Szczech LA, Barnhart HX, Inrig JK, Reddan DN, Sapp S, Califf RM, Patel UD, Singh AK. Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes. Kidney Int. 2008 Sep;74(6):791-8. Link.

Last Updated: December 03, 2008