INTRODUCTION — Anemia is common among patients with chronic kidney disease (CKD). In addition to causing disabling symptoms, severe anemia may affect cardiovascular function in nondialysis CKD and dialysis patients. Among nondialysis CKD patients, severe anemia may be associated with more rapid progression of CKD, including to end-stage kidney disease (ESKD).

This topic reviews the effects of anemia on cardiovascular dysfunction, particularly left ventricular hypertrophy (LVH) and heart failure (HF), and on the progression of kidney dysfunction in CKD patients.

Other signs and symptoms of anemia (which are the same in CKD patients as among individuals without kidney disease) are discussed elsewhere. (See "Diagnostic approach to anemia in adults", section on 'Correlation with symptoms'.)

The treatment of anemia among CKD patients is discussed elsewhere. (See "Treatment of anemia in nondialysis chronic kidney disease" and "Treatment of anemia in dialysis patients".)

CARDIOVASCULAR — Cardiovascular disease is a major cause of morbidity and mortality in patients with CKD, including those undergoing maintenance dialysis [1]. Even patients with mild CKD have a greater burden of prevalent cardiovascular disease compared with similar age controls [2]. (See "Chronic kidney disease and coronary heart disease" and "Overview of screening and diagnosis of heart disease in patients on dialysis".)

Severe anemia is an important, independent risk factor for the development and progression of left ventricular hypertrophy (LVH) and heart failure (HF) and of adverse cardiovascular outcomes, including mortality [3-5].

We discuss here the contribution of anemia to LVH, HF, and mortality in end-stage kidney disease (ESKD) patients, as well as effects of treatment with erythropoiesis-stimulating agents (ESAs) on LVH and HF. Understanding the role of anemia and its treatment is important in understanding the pathophysiology underlying LVH and HF in dialysis patients. However, this information is not used to determine indications or goals of treatment with ESAs. Randomized trials that have examined clinical outcomes among patients treated with ESAs and are used to determine indications and goals of treatment are discussed elsewhere. (See "Treatment of anemia in nondialysis chronic kidney disease", section on 'Erythropoiesis-stimulating agents' and "Treatment of anemia in dialysis patients", section on 'Erythropoiesis-stimulating agents for anemic iron replete patients'.)

Left ventricular hypertrophy — LVH is a major risk factor for cardiovascular morbidity and mortality in ESKD patients [6,7]. Among patients with ESKD or near ESKD, the reported prevalence of LVH is nearly 75 to 80 percent, with a higher prevalence among those of greatest dialysis vintage [8,9].

Role of anemia — Anemia has been identified as a risk factor for the development of LVH in dialysis and nondialysis CKD patients [3-5,10,11]. In an observational study including 432 hemodialysis and peritoneal dialysis patients, anemia was independently associated with an increase in left ventricular mass index [11]. In an analysis of data from the Atherosclerosis Risk in Communities Study (ARIC), among nondialysis CKD patients, anemia was predictive of left ventricular diameter after adjusting for kidney function and blood pressure [5].

Pathophysiology — Potential mechanisms that may explain the relationship between anemia and the development of LVH among CKD patients include [12-16]:

●Effects of reduced oxygen delivery to the myocardium, perhaps leading to increased myocyte necrosis and apoptosis

●Anemia-related increased cardiac output and reduced systemic vascular resistance

●Increased oxidative stress

●Activation of the sympathetic nervous system

A decrease in circulating endogenous erythropoietin caused by kidney disease may contribute to LVH among CKD patients. Erythropoietin receptors are present in cardiac tissue [17], and erythropoietin may have direct effects on myocardial function [16].

Effect of anemia treatment on LVH — The treatment of severe anemia with ESAs is associated with improvement of left ventricular hypertrophy (LVH). The best data are from a 2009 meta-analysis of 15 studies including 1731 patients [18]. Among patients with baseline severe anemia (defined as hemoglobin [Hb] levels <10 g/dL with mean baseline Hb levels as low as 5.9 g/dL in individual studies), ESA treatment to increase Hb levels to ≤12 g/dL was associated with significant reductions in left ventricular mass index (-32.7 g/m², 95% CI -49.4 to -16.1). The treatment of moderate anemia (ie, Hb ≥10 g/dL) to either Hb levels >12 g/dL or ≤12 g/dL was not associated with significant changes in the left ventricular mass index.

Whether the regression of LVH in CKD patients who are treated for severe anemia is associated with improved cardiac outcomes has not been well studied. Any such analysis may be confounded by other factors that affect outcomes, such as ESA-induced increases in blood pressure and LVH geometry [19].

The effects of administered ESAs on myocardial function may be independent of effects on anemia [16,20]. Erythropoietin may have direct effects on myocardial function [16,17]. ESA administration reduced cellular damage and myocyte apoptosis and lowered infarct size and subsequent left ventricular dilatation and functional decline in some animal and in vitro models of ischemic reperfusion [17,21-24]. In another animal model of acute myocardial infarction, erythropoietin led to a small reduction in infarct size but also led to myocardial dilatation [25].

Additionally, a systematic review and meta-analysis concluded that short-term administration of ESAs (ie, immediately before or within three days after percutaneous coronary intervention) did not improve cardiac function, infarct size, or mortality in patients with myocardial infarction [26].

Heart failure

Role of anemia in patients with heart failure — Severe anemia and CKD are independent risk factors for the development of HF [3-5,27].

Prior to the availability of ESAs, one study of 432 dialysis patients (mean baseline Hb level of 8.8 g/dL) found that each 1 g/dL lower Hb was associated with an higher odds of left ventricular dilatation (odds ratio [OR] 1.46), de novo HF (OR 1.28), and recurrent HF (OR 1.20) [11].

Effect of treatment of anemia on heart failure — Uncontrolled studies, none very recent, have described improvement in the clinical manifestations of HF after prolonged treatment of anemia in CKD patients [28-31]. As an example, in one study of 126 CKD patients with HF, an increase in the mean Hb level from 10.3 to 13.1 g/dL (with intravenous iron and ESAs) over a mean period of 12 months was associated with a rise in the mean left ventricular ejection fraction (33 to 40 percent), falls in the mean New York Heart Association (NYHA) class (3.8 to 2.7), and number of hospitalizations (3.7/patient to 0.2/patient) [29]. An index of fatigue and shortness of breath also fell significantly. Similar results were noted in another uncontrolled study that included 179 CKD patients with severe HF studied over a mean of nearly 12 months [30].

A systematic review of nine randomized trials of ESAs in HF, not all specifically in patients with CKD, concluded that anemia treatment improved exercise duration and capacity, ejection fraction, NYHA class, quality-of-life indicators, and HF-related hospitalizations [32]. Another meta-analysis of randomized, controlled trials found that ESA treatment improved dyspnea and NYHA class; there was no significant improvement in mortality or hospitalization, but there was increased risk of thromboembolic events [33]. Consistent with this are results of a large, randomized, double-blind trial of over 2000 patients with systolic HF and anemia to receive either darbepoetin alfa to achieve a target Hb of 13 g/dL or placebo. The was no difference in the primary outcome, which was a composite of death from any cause or hospitalization for worsening HF, but there was an increase in thromboembolic events and a nonsignificant increase in strokes [34]. An absence of clinical benefit among HF patients was also reported in the smaller Study of Anemia in Heart Failure (STAMINA-HeFT) trial comparing darbepoetin and placebo [35]. A 2017 update of cardiology society guidelines recommended against use of ESAs in patients with HF and anemia [36]. Increased morbidity and/or mortality has been associated with attaining normal or near-normal Hb levels with ESAs. (See "Treatment of anemia in nondialysis chronic kidney disease", section on 'Target hemoglobin value'.)

Coronary heart disease — Exercise-mediated cardiac ischemia is also ameliorated with partial correction of severe anemia.

Mortality — Anemia is an important, independent risk for mortality [3-5]. In one study of 432 dialysis patients with a mean baseline Hb level of 8.8 g/dL, after adjusting for age, diabetes, ischemic heart disease, blood pressure, and serum albumin, each 1 g/dL lower Hb was associated with increased mortality (OR 1.14) [11].

The combination of anemia and LVH may be associated with an even higher risk of adverse cardiovascular outcomes [37]. Among 2423 CKD patients in four population-based studies, the presence of anemia and LVH was correlated with the risk of the primary composite outcome of myocardial infarction, stroke, and death [37]. LVH was associated with an increased risk for composite and cardiac outcomes (hazard ratio [HR] 1.67, 95% CI 1.34-2.07 and HR 1.62, 95% CI 1.18-2.24, respectively), while anemia was associated with increased risk for only the composite outcome (HR 1.51, 95% CI 1.27-1.81). The combination was associated with a higher increased risk for both study outcomes compared with individuals with neither risk factor (HR 4.15, 95% CI 2.62-6.56 and HR 3.92, 95% CI 2.05-7.48).

In another study of 415 CKD patients, the combination of anemia and LVH also increased the risk of a cardiovascular event (defined as cardiovascular death, hospitalization for unstable angina or HF, nonfatal myocardial infarction, ventricular arrhythmia, or transient ischemic attack/stroke) (HR 4.3, 95% CI 1.4-13) [38]. As noted above, however, treatment of anemia to normal or near-normal Hb levels with ESAs does not reduce morbidity or mortality among patients with CKD, including dialysis patients. (See 'Effect of anemia treatment on LVH' above.)

PROGRESSION OF CHRONIC KIDNEY DISEASE — Anemia may be a risk factor for progression of CKD, including to end-stage kidney disease (ESKD) [39,40]. As an example, one four-year study of over 1500 patients with diabetic nephropathy found that, compared with patients with the highest baseline hemoglobin (Hb) levels (>13.8 g/dL), patients with lower Hb levels had a nearly twofold increase in the adjusted risk of developing ESKD [41]. In another study of 415 CKD patients, the combination of anemia and left ventricular hypertrophy (LVH) was also associated with faster renal decline compared with patients with no anemia and no LVH (estimated glomerular filtration rate [eGFR] slope -2.66±0.23 versus -0.59±0.23 mL/min/1.73 m² per year) and compared with patients with LVH but no anemia (eGFR slope -1.05±0.26 mL/min/1.73 m² per year) [38]. Several other studies have similarly supported the relationship between anemia and more rapid CKD progression in various populations [42-44].

The mechanism for a faster decline in kidney function with more severe anemia is not known with certainty but might involve low-grade kidney ischemia or effects of underlying inflammation causing both anemia and CKD progression. From animal models of ischemic and nephrotoxic kidney injury, various mechanisms by which erythropoietin might have renoprotective effects have been proposed. These include reduced apoptosis, increased tubular regeneration, decreased caspase activity, and decreased interstitial fibrosis [45-48].

There is conflicting evidence concerning the effect of correction of anemia on the rate of progression of renal failure [49-54]. In the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT), 4038 patients with type 2 diabetes and CKD (eGFR between 20 to 60 mL/min/1.73 m²) were randomly assigned to receive darbepoetin alfa to achieve a target Hb level of 13 g/dL or to placebo, with darbepoetin administered if the Hb level was <9 g/dL [55]. The mean achieved Hb level was 12.5 g/dL and 10.6 g/dL in the darbepoetin and placebo groups, respectively. At a median follow-up of 29 months, there was no difference between groups in the risk of ESKD (16.8 versus 16.3 percent in placebo, hazard ratio [HR] 1.02, 95% CI 0.87-1.18). (See "Treatment of anemia in dialysis patients".)

A secondary analysis of the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial [53], however, found a greater risk of a CKD progression composite endpoint (doubling of the creatinine, initiation of kidney replacement therapy [KRT], or death) and a greater rate of KRT initiation in the higher Hb target group [56]. Authors of one meta-analysis noted that larger trials of anemia treatment in patients with CKD suggested a trend for increased risk of CKD progression with higher Hb targets; in the overall pooled analysis, however, no difference was detected between higher versus lower targets [57]. A meta-analysis that included 19 studies and 993 participants concluded that, for most measures of CKD progression, erythropoiesis-stimulating agent (ESA) treatment was not different than placebo or no treatment [58].

Another study found no benefit of two years of low-dose ESA treatment on CKD progression in patients with diabetes mellitus or a kidney transplant [59]A meta-analysis examining studies of ESA effects on kidney transplant outcomes and progression of CKD concluded that there was not a significant protective effect of ESA treatment on CKD progression [60].

SUMMARY AND RECOMMENDATIONS

●Among dialysis patients, severe anemia is a risk factor for the development and progression of left ventricular hypertrophy (LVH), heart failure (HF), and mortality. (See 'Role of anemia' above and 'Role of anemia in patients with heart failure' above.)

●The treatment of severe anemia with erythropoiesis-stimulating agents (ESAs) is associated with improvement of LVH and clinical manifestations of HF. However, increased morbidity and/or mortality have been associated with attaining normal or near-normal hemoglobin (Hb) levels with ESAs. (See 'Effect of anemia treatment on LVH' above and 'Effect of treatment of anemia on heart failure' above and 'Mortality' above.)

●Among nondialysis chronic kidney disease (CKD) patients, anemia may be a risk factor for progression of kidney dysfunction to end-stage kidney disease (ESKD). The treatment of moderate anemia with ESAs has not been convincingly demonstrated to decrease progression to ESKD. (See 'Progression of chronic kidney disease' above.)