Treatment of Anemia in Elderly Patients with CKD

Recombinant human erythropoietin (epoetin) therapy revolutionized the treatment of anemia in patients on dialysis with CKD not receiving dialysis (44, 45). More recently, a longer-acting darbepoetin alfa erythro-poiesis stimulating agent (ESA) has become available (46-49), and soon, newer form with varying mechanisms of action will likely become available for clinical use (46, 50). The risks and benefits of epoetin and darbepoetin therapy in the general population of patients with CKD have been well recognized and will not be addressed here further. Unfortunately, the specific risks and benefits, as well costs, of such treatment in the elderly have not been well characterized.

Among normal (i.e., no CKD) elderly subjects, responsiveness to exogenous epoetin does not appear to be impaired compared to younger subjects

(32, 51). Limited data suggest that epoetin responsiveness in older dialysis patients is similar to younger patients (52, 53). Despite similar monthly epoetin doses, the mean monthly Hgb level among dialysis patients 75 years and older tend to be lower than younger patients, suggesting that this population group are not substantially hyporesponsive to epoetin therapy (10).

Among elderly hemodialysis patients, the impact of epoetin therapy on QOL has been mixed. While one small study questioned the benefit (54), a larger, controlled trial found that the improvements in QOL scores after 6 month of epoetin treatment were of similar magnitude in hemodialysis patients 60 years of age and older compared to those less than 60 years, although absolute QOL scores were lower both before and after treatment in the older subjects (55).

Given the limited data available, elderly patients with CKD, whether on dialysis or not, should probably be evaluated and treated for their anemia as generally recommended for patients with CKD regardless of age (5). The most recent clinical practice guidelines and recommendations for the National Kidney Foundation KDOQI for Anemia in CKD recommend that Hgb testing be carried out at least annually in all patients with CKD, regardless of stage or cause, and that a diagnosis of anemia should be made and evaluation should be undertaken when the Hgb level is less than 13.5 g/dL in adult males and 12.0 g/dL in adult females. This evaluation should include a complete blood count (CBC), red blood cell indices (mean corpuscular hemoglobin [MCH], mean corpuscular volume [MCV], mean corpuscular hemoglobin concentration [MCHC]), white blood cell count, and differential and platelet count, absolute reticulocyte count, serum ferritin to assess iron stores, and serum TSAT or content of Hb in reticulo-cytes (CHr) to assess adequacy of iron for erythropoiesis.

Among patients treated with ESA therapy and/or iron, the recommended lower limit of Hgb in patients with CKD is 11.0 g/dL. In the opinion of the KDOQI Anemia Work Group, there was insufficient evidence to recommend routinely maintaining Hgb levels at 13.0 g/dL or greater in ESA-treated patients. Since adequate iron stores are essential for optimal erythropoiesis, with or without ESA therapy, the Anemia Work Group recommended that sufficient iron should be administered to generally maintain the serum ferritin concentration greater than 200 ng/mL in hemodialysis patients and greater than 100 ng/mL in CKD patients not on dialysis and those on peritoneal dialysis, with a TSAT greater than 20% in all patients. In addition, in the opinion of the Work Group, there was insufficient evidence to recommend routine administration of IV iron if serum ferritin level is greater than 500 ng/mL. When ferritin level is greater than 500 ng/mL, decisions regarding IV iron administration need to consider ESA responsiveness, Hgb levels over time, the TSAT level, and the patient's clinical status.

Recent studies have reinforced the recommendation to maintain Hgb levels below 13 g/dL, and have raised concern that even this level of anemia correction may be excessive in patients with CKD. A randomized, controlled trial in hemodialysis patients, which compared a target hematocrit level of 30% versus 42%, was stopped early when it became apparent that there was no benefit in patients assigned to the higher hematocrit target (56). The risk of the primary composite outcome of first nonfatal myocardial infarction or death was 30% higher in the normal hematocrit group than the low hemat-ocrit group, although this was not statistically significantly different when the study was stopped. The incidence of thrombosis of vascular access sites was higher in the normal hematocrit group than in the low hematocrit. There were no differences in the rates of occurrence for all-cause hospitalization for all causes, nonfatal myocardial infarction, angina pectoris requiring hospi-talization, congestive heart failure requiring hospitalization, coronary-artery bypass grafting, or percutaneous transluminal coronary angioplasty.

More recently, a large randomized, controlled trial in patients with CKD not on dialysis was also terminated early, with a significantly higher rate of composite events (death, MI, hospitalization for congestive heart failure without renal replacement therapy, and stroke) among subjects randomized to a target Hgb level of 13.0-13.5 g/dL compared to those randomized to a target Hgb level of 10.5-11.0 g/dL (a later protocol amendment changed the targets to 13.5 g/dL and 11.3 g/dL, respectively) (57). For unclear reasons, a mean Hgb level of only 12.6 g/dL was achieved in the higher target group. The risk for the single outcome events of death and CHF hospital-ization approached being statistically significantly greater (p = 0.07) in the higher Hgb group. Other studies have also shown either no benefit or a significant trend towards increased risk for some outcomes when Hgb levels are normalized with ESA therapy in CKD patients (58-60). Thus, until further analysis and information becomes available, most ESA-treated patients with CKD should have their Hgb levels maintained above 11.0 g/dL but below 13.0 g/dL, and perhaps even lower. A recent FDA alert, issued after two recently published CKD studies (57, 58), advised adherence to prescribing information for currently available ESAs recommending that the target hemoglobin be maintained in the range of 10-12 g/dL (http://www.fda.gov/cder/drug/InfoSheets/HCP/RHE_HCP.htm).

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