The cardiovascular system compensates for low blood oxygenation by delivering a greater volume of blood to the tissues. The necessary adaptive changes – chronic vasodilation, volume and pressure overload, increased heart rate, and increased cardiac output – ultimately result in left ventricular hypertrophy (LVH) 2713, whose prevalence is estimated at 39% in Stage 2 CKD, 50% in Stage 3 CKD 67, and 60%-74% in Stage 4 7. In a Canadian prospective study of patients with creatinine clearance = 25 mL/min to 75 mL/min7, each 0.5 g/dL Hb decrease conferred a 32% increased likelihood of developing LVH [odds ratio = 1.32, 95% confidence interval (CI) 1.10 to 1.69, P = 0.004]. Decreasing Hb was an independent risk factor for left ventricular growth when the analysis controlled for residual kidney function 7.

Chronic LVH and mechanical heart stress resulting from anemia contribute to development of congestive heart failure (CHF) 46. Anemia has been described as a "mortality multiplier" in patients with comorbid CKD and CHF 53. In the ANCHOR study 48 of 59,772 adults with CHF, 42.6% had anemia at baseline (Hb <12 g/dL for women, <13 g/dL for men). In this cohort, anemia showed a graded, independent relationship to mortality in CHF patients, the risk of death rising from 16% for 12.0–12.9 g/dL to 248% for <9.0 g/d, which compared to a reference group with Hb 13.0 g/dL to 13.9 g/dL represents adjusted hazard ratios of 1.16 and 3.48, respectively. Hb levels in relation to risk showed a J-shaped curve in this population, not all of whom had CKD; Hb levels either below 13.0 g/dL or above 17.0 g/dL were associated with increased risk of hospitalization and mortality 48.

Anemia of CKD contributes to coronary ischemia by reducing oxygen delivery. In the Atherosclerosis Risk in Communities (ARIC) study 50, anemia independently predicted coronary heart disease in CKD patients. Participants with anemia and elevated serum creatinine (≥1.2 mg/dL in women or ≥1.5 mg/dL in men) had increased risk for coronary heart disease over 10.5 years of follow-up (relative risk = 2.74, 95% CI 1.42 to 5.28) 50. Elevated creatinine without anemia did not significantly increase coronary risk (relative risk 1.20, 95% CI 0.86 to 1.67) 50.

Untreated anemia of CKD is also associated with increased risk of progression to renal replacement. In a retrospective US Veterans' Affairs cohort, each 1.0 g/dL increase in time-averaged Hb conferred a 26% reduction in risk for renal replacement (hazard ratio = 0.74, 95% CI 0.65 to 0.84) 51. Among diabetic nephropathy patients in the Reduction of Endpoint in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study 52, Hb <11.3 g/dL roughly doubled the risk of renal replacement onset (hazard ratio = 1.99, 95% CI 1.34 to 2.95, 3.4 years mean follow-up), and every 1 g/dL Hb decrease increased renal replacement risk by 11% 52.

Data from both the CHOIR 60 and CREATE 61 studies have generated concern that Hb targets >13 g/dL are associated with increased incidence of cardiovascular complications and serious adverse events. In CHOIR, 125 endpoint events (composite of death, myocardial infarction, hospitalized CHF without dialysis, or stroke) occurred in the high-Hb group versus 97 events in the low-Hb group (HR, 1.34; 95% CI, 1.03 to 1.74; P = 0.03). CHOIR's surprising results echo those of an earlier prospective trial 63 in dialysis patients that was terminated early because of a trend toward higher rates of death and first non-fatal myocardial infarction with Hct targets of 42% versus 30%. Nevertheless, the lowest mortality rates in the latter study occurred in those patients with the highest Hct (32–42%).

In CHOIR 60, the lower Hb target (11.3 g/dL) was associated with a significantly higher incidence of myocardial infarction reported as an adverse event than the higher Hb target (13.5 g/dL) (10 patients [1.5%] vs 19 patients [3%], P = 0.05).

In CREATE 61, the high-Hb group reported a greater incidence of hypertensive episodes (89 patients [30%] vs 59 patients [20%]; P < 0.005) and headaches (31 patients [10%] vs 16 patients [5%]; P = 0.03) in comparison with the low-Hb group. These findings, together with earlier reports of hypertension in ESA-treated CKD patients 5864656667 emphasize the need to monitor blood pressure carefully during erythropoietic treatment. Current labeling of approved agents warns against beginning anemia treatment in the presence of uncontrolled hypertension 6869.

The currently ongoing Trial to Reduce Cardiovascular Events with Aranesp (TREAT) 70 is a double-blind study comparing darbepoetin alfa treatment (Hb target, 13 g/dL) versus placebo in patients with type 2 diabetes and CKD to assess effects on cardiovascular morbidity due to acute myocardial ischemia. Placebo recipients are eligible for a rescue darbepoetin administration only if their Hb falls below 9 g/dL. TREAT has currently enrolled 3500 of 4000 planned patients 71 – more than CREATE and CHOIR combined. Patients will be followed until the required number of endpoint events for analysis have accrued (i.e., TREAT is an event-driven study). Its Data Safety Monitoring Board recently evaluated interim results in view of CREATE, CHOIR, and the March 2007 Food and Drug Administration (FDA) advisory 7273 and allowed TREAT to continue 71.

When erythropoietic agents were first introduced, animal data suggesting a potential adverse effect on renal disease progression was a focus of concern. Subsequent research linked this effect with increases in blood pressure associated with rapidly rising Hb levels, an effect that was prevented by appropriate control of Hb and blood pressure. A recent review suggests that treating anemia of CKD does not hasten progression to renal replacement 74; indeed, some studies point to possible renoprotection (Table 2). In a retrospective study of US veterans 55, the rate of decline in kidney function (least-squares slope of the reciprocal of serum creatinine) was almost halved after the onset of epoetin use as compared with the pre-treatment rate. In a 2004 randomized study 58 comparing epoetin treatment targeted to Hb >13 g/dL with deferred treatment beginning at <9 g/dL, roughly half as many patients required renal replacement in the early group (10 of 45 patients) as in the late group (18 of 43 patients).

In CREATE 61, although the rates of eGFR change did not differ between groups, a significantly higher rate of progression to dialysis occurred in patients assigned to a high-Hb level (13 to 15 g/dL) than a low-Hb level (10.5 to 11.5 g/dL). In CHOIR 60, in contrast, proportions of patients requiring renal replacement did not differ between groups with Hb targets of 11.3 or 13.5 g/dL.

There is a paucity of information on the effect of anemia treatment on measured GFR. Effects of anemia treatment on renal function were assessed by disparate methods among the studies cited in Table 2 and those in the Cochrane systematic review 67. Discordances among renal results in CREATE, CHOIR, and previous studies point to the need for a further randomized trial of anemia therapy in which change in the rate of decline in measured GFR is a primary endpoint.

In patients on dialysis, untreated anemia can result in objective cognitive deficits 75, and treatment of anemia is associated with improved cognitive and social functioning 76. Thus, cognitive and quality-of-life effects have also been assessed in patients at earlier stages of CKD receiving anemia treatment. A meta-analysis in this population associates erythropoietin use with improved physical function, energy, sense of well-being, and ability to work 67. In CREATE, mean quality-of-life scores were higher in the normalized Hb group (13.0 g/dL to 15.0 g/dL) than the low-Hb group (10.5 g/dL to 11.5 g/dL) during the first year and became similar between groups thereafter 61. In CHOIR, quality of life did not differ between Hb target groups. Thus, improvement in quality of life with erythropoietic treatment may be intuitive but is not yet proven.

Screening for anemia and other comorbidities is essential for patients diagnosed with Stage 3 CKD 16. The course of CKD is often gradual (years to decades), and decline in Hb, like decline in eGFR, may be evident only with periodic evaluation. Annual determination of renal function and Hb levels may suffice for slowly progressing or early CKD 16. Patients with moderate-to-severe CKD may require more frequent Hb monitoring since the likelihood of anemia is greater in this population; more frequent monitoring (at least monthly) is also required during treatment with stimulants of erythropoiesis. Patients with an eGFR below 30 mL/min/1.73 m² are considered appropriate for referral to a nephrologist, and many PCPs and nephrologists prefer a higher eGFR referral trigger as Stage 3 approaches. It is prudent to screen for anemia in CKD patients during and after acute episodes of uncontrolled comorbid disease (eg, poor glycemic control).

All patients with independent risk factors for CKD-related anemia warrant close hematologic evaluation during follow-up clinic visits. In addition, diabetic patients are twice as likely to develop anemia as their nondiabetic counterparts at the same level of renal function 3770, and the prevalence of anemia in patients with cardiovascular disease is also significant 4243. Patients should also be checked for malnutrition and vitamin deficiency syndromes.

A Hb level below 12.0 g/dL in women or 13.5 g/dL in men warrants clinical work-up for anemia (Table 3). In general, CKD-related anemia is normochromic and normocytic with bone marrow of normal cellularity. With impaired production and/or activity of erythropoietin, the anemia is usually hypoproliferative, as determined by the absolute reticulocyte count.

While the propriety of treating anemia of CKD is well established to within a Hb target range of 11–12 g/dL, full normalization of Hb in these patients remains controversial, and benefits remain unproven. New guidelines published by the Kidney Disease Outcomes Quality Initiative (KDOQI) in August 2007 recommend a Hb target range of 11–12 g/dL for patients with CKD 29. The CHOIR 60 and CREATE 61 studies indicate evidence of risk and no evidence of benefit from treating to Hb levels >13.0 g/dL as compared with ≤12 g/dL. A 2007 FDA advisory 7273 recommends maintaining Hb within the range of 10–12 g/dL. Evidence reviewed in the KDOQI guidelines 1629 suggests that treating to maintain Hb at or above 11 g/dL provides quality of life benefits without increased adverse events. Routine monitoring (preferably monthly) of blood pressure, renal function, Hb, and iron studies is required to obtain the most effective regimen of erythropoietic therapy 6869. The current FDA advisory 7273 recommends more frequent Hb monitoring (twice weekly) during initial correction of anemia and after ESA dose changes.

It is essential to control hypertension before and during stimulated erythropoiesis 7273. Determination of serum ferritin and transferrin saturation is advised before initiation of erythropoietic therapy and every 1–3 months during therapy (Table 3) 16. Patients with stable Hb in the target range who are receiving a stable dose of an erythropoietic agent should have their Hb checked monthly 16. In iron-deficient patients, oral supplementation with inorganic iron salts may be sufficient, but more often parenteral iron is required in the form of iron gluconate or iron sucrose, which have supplanted iron dextran because of superior safety profiles. Physiologic levels of folate, vitamin B₁₂, and pyridoxine can be maintained with oral supplementation.