Treatment of renal anaemia
Current Challenges in the Management of CKD-Related Anaemia
Hb Cycling and Time Out of Target Range
International guidelines recommend raising Hb levels >11 g/dL for correction of CKD-related anaemia, but these levels are not maintained in most patients. According to the US Renal Data System 2006 Annual Data Report, approximately half of dialysis patients treated with current ESAs have Hb levels outside the target range at any given time.1 Hb levels are in a constant state of flux in most patients, and can fall rapidly. Institutional practices designed to compensate for changes in Hb can frequently result in overshooting or dropping below target levels.
More than 90% of haemodialysis patients experience Hb cycling. This was the finding of a retrospective analysis of 281 haemodialysis patients treated with epoetin. The study, which was conducted to quantify the phenomenon of recurrent cyclic fluctuations of Hb levels during ESA therapy,3 analysed cycling (cycles of amplitude >1.5 g/dL and >8 weeks’ duration) and excursions (half of one full cycle). (At the time of the analysis, the NKF/KDOQI recommended a target Hb range of 11.0–12.0 g/dL.) On average, the patients had approximately three excursions (half of one cycle) a year, with mean Hb levels reaching 12.8 g/dL at the peak of the excursions and 10.3 g/dL at the nadir. The causes of Hb cycling appeared to be multifactorial: changes in epoetin dose were associated with initiation of 84% of Hb up-excursions (on average, patients in this study experienced six dose changes annually); other factors included iron supplementation practices and hospitalisation. The authors suggest that extending the dosing interval with ESAs with a short half-life may also contribute to the problem of Hb cycling.3
Hb cycling is observed in >90% of patients receiving epoetin and generally occurs between three and four times per year.
In another retrospective study, only 5% of epoetin-treated patients with a mean Hb value within the target range at the start of the analysis stayed within that range for 6 consecutive months (Figure 4). This study, published in 2005, analysed data from CKD patients on dialysis in the Fresenius Medical Care-North America database.2 (As in the study described above, the NKF/KDOQI recommended target Hb range was 11.0–12.0 g/dL.)
Figure 4. Percentages of patients remaining within the guideline Hb target
Adapted from Collins et al 2005.17
Similarly, in an analysis of US patients published in 2006, only 6.5% of patients with stage 5 CKD maintained stable Hb levels over 6 months within the target range of 11–12.5 g/dL called for by the Centers for Medicare & Medicaid Services.4,5 The lowest hospitalisation and mortality rates in the follow-up period occurred in the patients who remained stable in the target range.5
Several factors contribute to the difficulty of maintaining Hb levels within target range: the narrow range and changing patient disease states (e.g. infections, hospitalisations), which may contribute to epoetin resistance by increasing overall inflammation.6
Fluctuating Hb levels are evidence that the anaemia is not being effectively managed. Hb cycling, which does not occur during normal homeostasis, may be associated with increased morbidity and mortality.4,5,7–9 High-amplitude Hb swings have been associated with increased risk of hospitalisation,4,5 and recently reported analyses show that greater Hb variability is associated with an increase in mortality of between 33% and 45% among haemodialysis patients.8,9 Changes in Hb levels may also encourage more frequent dose changes as clinicians attempt to maintain Hb within guideline target levels, possibly exacerbating Hb cycling, leading to reduced oxygen delivery to patients’ target organs and placing greater demands on nephrologists and other healthcare professionals.3
References:
1. U.S. Renal Data System, USRDS 2006 Annual Data Report: Atlas of End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2006.
2. Collins AJ, Brenner RM, Ofman JJ, Chi EM, Stuccio-White N, Krishnan M, Solid C, Ofsthun NJ, Lazarus JM. Epoetin alfa use in patients with ESRD: an analysis of recent US prescribing patterns and hemoglobin outcomes. Am J Kidney Dis. 2005;46:481–488.
3. Fishbane S, Berns JS. Hemoglobin cycling in hemodialysis patients treated with recombinant human erythropoietin. Kidney Int. 2005;68:1337–1343.
4. Ebben JP, Gilbertson DT, Foley RN, Collins AJ. Hemoglobin level variability: associations with comorbidity, intercurrent events, and hospitalizations. Clin J Am Soc Nephrol. 2006;1:1205–1210.
5. Gilbertson D, Ebben J, Collins A. The effect of hemoglobin variability on hospitalization and mortality. Nephrol Dial Transplant. 2006;21(Suppl 4):iv169 (abstract SP458).
6. Gilbertson DT, Weinhandl E, Ebben J, Collins AJ. An investigation of the temporal relationship between hemoglobin levels and EPO doses. J Am Soc Nephrol. 2005;16:875A (abstract PUB430).
7. Gilbertson DT, Ebben JP, Bradbury B, Dunning SC, Collins AJ. The effect of hemoglobin (Hb) variability and trends on mortality. J Am Soc Nephrol. 2006;17:582A (abstract SA-PO032).
8. Feldman HI, Israni RK, Yang W, Fishbane F, Joffe M. Hemoglobin variability (HgbVar) and mortality among hemodialysis patients. J Am Soc Nephrol. 2006;17:583A (abstract SA-PO034).
9. Feldman HI, Joffe, M, Yang W, Israni R, Fishbane S. Causal analysis of hemoglobin variability and mortality among hemodialysis patients. J Am Soc Nephrol. 2006;17:583A (abstract SA-PO035)