Guidelines Issued for Treatment of Anemia in Patients With Chronic Kidney Disease

Laurie Barclay
December 17, 2007 — Recommendations to treat anemia in patients with chronic kidney disease (CKD) in the primary care setting are reviewed in the December issue of the Southern Medical Journal. The report focuses on the association of anemia in CKD with diabetes, cardiovascular disease, and poor disease outcome, and provides practical guidelines for early recognition and management of this common but modifiable risk factor, including use of available agents to treat the anemia.
"Anemia is a common comorbidity associated with chronic kidney disease (CKD); it starts early in the course of the disease and worsens as renal function declines," writes Jan N. Basile, MD, from the Ralph H. Johnson Veterans Administration Medical Center and the Medical University of South Carolina in Charleston, South Carolina. "Anemia associated with declining kidney function is predominantly due to inadequate renal production of the hormone erythropoietin in response to low hemoglobin (Hb) levels, but regardless of the etiology, anemia in CKD results in fatigue, reduced exercise capacity, impaired cognitive and immune function, and reduced quality of life. Moreover, anemia of CKD significantly contributes to disease burden by causing or exacerbating existing comorbidities."
Anemia can be viewed as a risk multiplier in CKD, because patients with anemia vs those without anemia and with similar comorbidities have a significantly increased risk for death. Diabetes and hypertension are the 2 leading causes of CKD, and these conditions are typically first recognized and managed by the primary care clinician.
Thanks to the growing epidemic of diabetes and hypertension, the global prevalence of CKD is dramatically and rapidly increasing. Therefore, it is essential that the primary care clinician recognize CKD and the underlying risk factors, with adequate management of risk factors to delay progression to end-stage renal disease (ESRD) and to improve patient outcomes.
As kidney function worsens, erythropoietin production decreases, resulting in the frequent comorbidity of anemia with CKD. Another cause of anemia in CKD is iron deficiency, and potential contributing factors may include decreased red blood cell lifespan, chronic blood loss, secondary hyperparathyroidism, inflammation, nutritional (folate) deficiency, and buildup of uremic toxins and other inhibitors of erythropoiesis.
Anemia in CKD exacerbates the comorbidities of diabetes and hypertension, contributing to poor disease outcome and higher mortality, even in patients with only mild renal impairment. Poor cardiovascular outcomes occur frequently in patients with CKD, mandating continued research concerning the relationship between anemia correction in CKD and cardiovascular morbidity.
Fortunately, anemia is easy to diagnose and is usually highly responsive to therapy. The primary care clinician can easily perform an anemia evaluation and begin treatment, following management plans established in the National Kidney Foundation Kidney Disease Outcome Quality Initiative guidelines.
All patients with CKD, regardless of stage or cause, should be screened for anemia, which should be diagnosed and evaluated when Hb level is less than 12.0 g/dL in adult women and less than 13.5 g/dL in adult men. Assessment for anemia should include a complete blood count including Hb, mean corpuscular Hb (MCH), mean corpuscular volume (MCV), mean corpuscular Hb concentration (MCHC), white blood cell count and differential and platelet count, absolute reticulocyte count, serum ferritin level, and serum transferrin saturation (TSAT) level. Absolute iron deficiency is defined as a TSAT level of less than 20% and a serum ferritin level of less than 100 ng/mL; this must be corrected before starting therapy with erythropoiesis-stimulating agents (ESAs). Other possible causes of anemia should also be addressed before starting treatment with ESAs.
Oral administration for iron therapy is most convenient (at least 200 mg of elemental iron for most adult patients with CKD), but absorption is poor, sometimes requiring multiple smaller doses scheduled around mealtimes. Adverse effects may include nausea and vomiting. Some patients with CKD may require intravenous (IV) administration as iron dextran or iron sucrose. Rarely, patients may experience serious, life-threatening acute reactions to IV administration of iron.
According to current US guidelines, target Hb level in patients with CKD is 11 g/dL or more. Caution is warranted when Hb levels are intentionally maintained at more than 13 g/dL.
For patients with renal disease who undergo dialysis, ESAs are a cornerstone of treatment of anemia. However, evidence from recent studies suggests that earlier treatment of anemia in CKD may postpone the onset of ESRD and improve survival. Before initiation of dialysis, anemia of CKD is underrecognized and undertreated, although this is when normalization of anemia could have the most benefit on disease outcome. Timely treatment of anemia of CKD may improve disease outcomes, benefit quality of life, and potentially slow the progression of renal decline.
"Because of the enormous strain CKD places on the healthcare system, the burden of managing patients with, or at risk for CKD often falls upon the primary care physician," the study author writes. "An important part of the care of a CKD patient is the recognition and proper management of comorbidities to slow the progression of renal decline, and positively affect disease outcome."
Now that there are several classes of ESAs, treatment of anemia in CKD can be individualized based on specific patient needs. ESAs are available for subcutaneous administration, and there are extended dosing schedules that are more convenient for patients, thereby improving compliance.
Recombinant human erythropoietin (rHuEPO), first introduced in 1989, is effective and safe for decreasing morbidity and hospitalization costs while increasing patient quality of life. Epoetin alfa, or recombinant endogenous human erythropoietin, was first indicated for treatment of anemia in patients with CKD and renal failure. Darbepoetin alfa, an rHuEPO with 8 more sialic acid residues than epoetin alfa, has a lower binding affinity for the erythropoietin receptor than epoetin alfa but a 3-fold longer serum half-life and greater biologic activity. Two additional ESAs in development are continuous erythropoietin receptor activator and Hematide.
The recommended starting dose for epoetin alfa is 50 to 100 U/kg 3 times a week, but Hb can be increased and adequately maintained by dosing weekly or even every 2 to 4 weeks. For darbepoetin alfa, the recommended starting dose is 0.45 µg/kg once weekly, but target Hb may be achieved in some patients with 1 dose every 2 weeks.
ESA therapy may increase blood pressure, and it is therefore contraindicated in patients with uncontrolled hypertension. Rarely, patients treated with ESAs may develop antierythropoietin antibodies causing pure red cell aplasia. Antierythropoietin antibodies may make the anemia refractory to ESA therapy.
"Evidence suggests that ESA therapy can decrease the morbidity and mortality associated with CKD, slow the progression of renal disease, improve some aspects of CV function, reduce overall medical costs, and improve patient quality of life," the study author concludes. "This situation presents a critical opportunity for the primary care practitioner to recognize and manage anemia to both reduce renal risk factors and slow functional renal decline in the patient with CKD. Future studies will determine the optimal Hb level for outcome improvement in these individuals."
Dr. Basile had disclosed various financial relationships with the National Heart, Lung, and Blood Institute, Boehringer Ingelheim, Novartis, AstraZeneca, Merck, Abbott, Forest, GSK, Pfizer, and Sankyo.
South Med J. 2007;100:1200-1207.