Diabetes is the leading cause of chronic kidney disease (CKD) and is associated with excessive cardiovascular morbidity and mortality (1,2). Anemia is common among those with diabetes and CKD and greatly contributes to patient outcomes (3,4). Observational studies indicate that low Hb levels in such patients may increase risk for progression of kidney disease and cardiovascular morbidity and mortality (5). Controlled clinical trials of anemia treatment with erythropoietin stimulating agents (ESAs) demonstrated improved quality of life (QOL) but have not demonstrated improved outcomes (6 –10). In some trials, ESA treatment for high Hb levels is associated with worse outcomes such as increased thrombosis risk (6,11). Consequently, the U.S. Food and Drug Administration (FDA) and the National Kidney Foundation (NKF) have modified their recommendations regarding anemia treatment for CKD patients (12). The objectives of this review are to 1) update clinicians on the prevalence, causes, and clinical consequences of anemia; 2) discuss the benefits and risks of treatment; and 3) provide insight into anemia management based on clinical trial evidence in patients with diabetes and kidney disease who are not on dialysis. DEFINITION AND PREVALENCE OF ANEMIA IN CKD The NKF defines anemia in CKD as an Hb level 50% of these patients have severe anemia (hematocrit 1 g/dl within a 4-week period, the dose should be held, as more rapid increases may be associated with increased risk for adverse events such as hypertension. Functional iron deficiency should be suspected in any patient not responding to ESA treatment, and patient compliance with iron therapy should be investigated. Routine measurement of iron stores including serum iron, iron binding capacity, and ferritin should be monitored monthly for 3 months then quarterly once Hb target is achieved (56,60). Adverse side effects of therapy In clinical trials, up to 25% of patients experience an increase in blood pressure or develop overt hypertension (blood pressure >140/90 mmHg) (8,27,47,61 –63). Thus, ESA should not be used to treat anemia in patients with uncontrolled blood pressure. Moreover, increases in blood pressure should be looked for in any anemic CKD patient treated with an ESA, and dose adjustments in ESA, iron, or antihypertension medications should be undertaken as needed. Common side effects include local pain or tissue reaction to subcutaneous injection and development of flu-like symptoms within hours or days of administration of an ESA. A rare but serious form of pure red cell aplasia can occur during ESA treatment, including in those treated with epoetin and darbepoetin (64,65). The anemia is sudden in onset and can occur as early as 2 months after initiation of treatment. As noted above, ESA may increase risk for death and cardiovascular events and thrombotic events. The risk is reported in those with Hb levels >12 g/dl in some clinical trials. Therefore, it is prudent to modify the dose of ESA to reduce the likelihood of excursions of Hb exceeding 13 g/dl as recommended by the NKF (51). Adverse effects of iron use are described above and include gastrointestinal side effects with oral preparations and anaphylactic reactions with intravenous preparations. AREAS OF UNCERTAINTY Analysis of available evidence from clinical trials clearly indicates that there is enough uncertainty regarding the risk-to-benefit ratio of treatment of anemic CKD patients with ESA to warrant additional major randomized clinical trials (66). TREAT is an ongoing study that will provide additional new information on whether treatment per se can improve cardiovascular outcomes in patients with type 2 diabetes, anemia, and CKD (50). Because nearly 50% of new cases of ESRO in the U.S. are attributed to diabetes, further studies are needed to help guide management of anemia. Areas of uncertainty that remain include establishment of the optimal individual Hb level—the level at which patient QOL is maximized and morbidity and mortality risks are minimized. The optimal dose of a given ESA, the frequency of dosing, and the indication and target Hb range remain controversial. For example, should ESA dosing begin at an Hb level of 10, 11, or 12 g/dl? Another area of uncertainty concerns the diagnosis and management of erythropoietin hyporesponsiveness, for which there is no widely accepted, standardized definition. This confounds the analysis of clinical trials in which higher doses of ESA and higher Hb occur in those randomized to higher Hb targets. Additional studies are needed to understand the nature and extent of hyporesponsiveness to erythropoietin in patients with CKD—an area of high priority for future research. However, it is not established whether the benefits of improved QOL measures outweigh the risks of cardiovascular morbidity and the economic costs related to treatment to achieve a higher Hb level. Another area of uncertainty related to hyporesponsiveness is the role of iron use in treating anemia. New research that provides a better understanding of the role of inflammation in iron metabolism, utilization, and the response to ESA treatment is another important research priority. SUMMARY Anemia is common and contributes to both poor QOL and increased risk for adverse outcomes including death. Treatment of anemia improves QOL; however, thus far, evidence is lacking for a benefit of anemia treatment on progression of kidney disease and cardiovascular outcomes. The NKF recommends that physicians consider treating anemia in patients with diabetes and kidney disease when Hb is <11 g/dl in patients. Further, they recommend a Hb target of 11–12 g/dl, not to exceed 13 g/dl, when using an ESA as part of the therapeutic regimen for managing anemia. Currently available ESA combined with iron supplementation can be used safely and effectively to achieve this goal. However, available clinical trial evidence leaves sufficient uncertainty regarding the optimal Hb target and ESA dose for a given individual. For this reason, the NKF recommends individualizing treatment of anemia with ESA. Additional randomized clinical trials are needed to more precisely define these parameters for an individual patient. Future studies are also needed to elaborate the mechanisms of anemia in patients with diabetes and CKD including the role of iron metabolism, inflammation, and resistance.
