Highlights of Kidney Disease: Improving Global Outcomes Clinical Practice Guidelines for Anemia in Chronic Kidney Disease

The World Health Organization defines anemia in adults and children older than 15 years as a hemoglobin concentration (Hb) <13.0 g/dL in male individuals and <12.0 g/dL in female individuals. In children aged 1.5 to 5 years anemia is defined as Hb <11 g/dL, in those 5 to 12 years as <11.5 g/dL, and in those 12 to 15 years as <12 g/dL (1).

The Hb falls as GFR falls, but the relationship is nonlinear. In hemodialysis patients, Hb often falls below 8 g/dL if anemia is untreated, whereas in nondialysis patients with chronic kidney disease (CKD) patients, higher Hb levels are usual unless the patients are close to initiating dialysis or have another contributing cause.

The initial investigation of anemia should include a complete blood count, absolute reticulocyte count, serum ferritin and transferrin saturation to diagnose iron deficiency, and serum B12 and folate levels to diagnose rare but treatable vitamin deficiencies. A high index of suspicion for gastrointestinal blood loss in the presence of iron deficiency is advisable.

The three major interventions to treat anemia in patients with CKD include iron, erythropoiesis-stimulating agents (ESAs), and blood transfusions. An individualized approach to anemia therapy was stressed by the KDIGO Work Group, in which the potential benefits of the therapy (avoidance of blood transfusions and improvement of anemia-related symptoms) were balanced against the risk of harm caused by the intervention, rather than a group approach targeting particular ranges of Hb.

Iron

Determination of serum ferritin is the most common test for evaluation of iron storage, and transferrin saturation for the availability of iron to support erythropoiesis. These markers of iron deficiency in CKD have limited sensitivity and specificity to diagnose diminished bone marrow iron stores and to predict the erythropoietic response to iron supplementation (2). No iron intervention trials have been sufficiently powered or long enough in duration to enable assessment of long-term safety, and no studies have addressed the clinical benefit, cost effectiveness, and risk-to-benefit comparison of using different transferrin saturation and ferritin levels as a trigger for iron supplementation.

The KDIGO Work Group sought to make recommendations of iron supplementation that would balance diagnostic sensitivity and specificity of iron status tests with assumptions regarding safety, with the understanding that intravenous iron would be necessary in dialysis patients or in CKD nondialysis patients whose Hb had not increased after a 1- to 3-month trial of oral iron therapy. Consequently, it was suggested that for adult CKD patients with anemia not receiving iron or ESA therapy, or those receiving ESA therapy who were not receiving iron supplementation, a trial of intravenous iron was reasonable if 1) an increase of Hb without starting ESA treatment was desired or a decrease in ESA dose was desired, and 2) transferrin saturation was ≤30 percent and ferritin was ≤500 µg/mL. This advice was predicated on the understanding that the potential increase in Hb would achieve clinical goals, such as transfusion avoidance or improvement in anemia-related symptoms, and the Hb response and clinical response to iron supplementation would determine subsequent use of intravenous iron. In other words, the objective of iron supplementation was not to achieve particular iron status test targets but rather to provide a clinical benefit to the patient.

The previous Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines for iron use in children were not changed because there were no new data since 2005 (3). Consequently, it was recommended that all children with CKD and anemia not receiving iron or ESA therapy be given oral iron (or intravenous iron in hemodialysis patients) when transferrin saturation was ≤20 percent and ferritin was ≤100 µg/mL. In children receiving ESA therapy but not iron supplementation, oral iron (or intravenous iron in hemodialysis patients) was recommended to maintain transferrin saturation >20 percent and ferritin >100 µg/mL.

Erythropoiesis-stimulating agents

Objective evidence to support the treatment of Hb <9 g/dL with ESAs is quite strong because transfusion benefits are substantial and the quality-of-life improvements are clinically important (4). However, the safety of ESAs in treating severe anemia (arbitrarily defined as baseline Hb <10 g/dL) has not been evaluated in large placebo-controlled trials.

Several large randomized control trials of ESA therapy in moderate anemia, where baseline Hb was >10 g/dL, have been reported (59). The intervention in these trials was complete correction of anemia with ESAs, compared with partial correction with ESAs in four trials and with placebo in one trial. In the largest trial—the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT)—correction of anemia did not diminish cardiovascular or renal events, and there was a substantially increased risk of stroke (9). The harm-to-benefit tradeoff was one stroke for five transfusions prevented by the high Hb target. Compared with placebo, darbepoetin conferred a consistent but small improvement in fatigue and overall quality of life for a duration of 97 weeks (10). Analysis of these trials led to the guidance outlined in Table 1.

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ESA hyporesponsiveness

Relative resistance to the effects of ESAs is a common problem, and hyporesponsiveness is one of the strongest predictors of cardiovascular and mortality risk (11). This may be the result of a comorbidity that prevented an increase in Hb and caused the adverse outcomes, and hyporesponsiveness was just a marker for this comorbidity. However, the possibility that high ESA doses used in hyporesponsive patients are toxic in themselves cannot be excluded. The definition of initial hyporesponsiveness was derived from the secondary analysis of TREAT (11). Patients were classified by the Work Group as hyporesponsive if they had no increase in Hb from baseline after the first month of treatment with appropriate weight-based dosing, which was conventional in 2011. In such patients, avoidance of repeated ESA dose escalation beyond double the initial weight-based dose was suggested. Acquired ESA hyporesponsiveness may also occur, classified by the Work Group as requiring two increases in ESA doses up to 50 percent beyond the dose at which they had been stable, in an effort to maintain a stable Hb. In such patients, avoidance of repeated ESA dose escalation beyond double the dose at which they had been stable was suggested. The Work Group suggestions for initial and acquired hyporesponsiveness imply that maximal ESA doses should be no greater than four times the initial weight-based appropriate doses.

Red blood cell transfusions

In iron-replete CKD patients with anemia, the choice between ESA and red blood cell transfusion should be individualized, taking into account the balance between benefits and harms for each treatment. Acute reactions to blood transfusions and mistransfusions occur surprisingly frequently; transmission of infection, although now rare, is a major concern; and sensitization to human leukocyte antigen is a concern for patients eligible for organ transplantation. The more important guidelines for transfusion use are presented in Table 2.

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Notes

[1] Patrick S. Parfrey, MB, BCh, MD Cork, MRCP, FRCPC, is affiliated with Memorial University Medical School, St. John’s, Newfoundland, Canada. John J. V. McMurray, MD, FRCP (Edin), FESC, FACC, is affiliated with the BHF Glasgow Cardiovascular Research Centre, Glasgow, United Kingdom.

References

1. Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney Int 2012; 2(Suppl):279–335.

2. Stancu S, et al. Can the response to iron therapy be predicted in anemic nondialysis patients with chronic kidney disease? Clin J Am Soc Nephrol 2010; 5:409–416.

3. National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis 2006; 47:S1–S146.

4. Canadian Erythropoietin Study Group. Association between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving haemodialysis. BMJ 1990; 300:573–578.

5. Besarab A, 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; 339:584–590.

6. Parfrey PS, et al. Double-blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease. J Am Soc Nephrol 2005; 16:2180–2189.

7. Drueke TB, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006; 355:2071–2084.

8. Singh AK, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006; 355:2085–2098.

9. Pfeffer MA, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 2009; 361:2019–2032.

10. Lewis EF, et al. Darbepoetin alfa impact on health status in diabetes patients with kidney disease; a randomized trial. Clin J Am Soc Nephrol 2011; 6:845–855.

11. Solomon SD, et al. Erythropoietic response and outcomes in kidney disease and type 2 diabetes. N Engl J Med 2010; 363:1146–1155.


April 2013 (Vol. 5, Number 4)