STATE-OF-THE-ART PAPER
Anemia: The Point of Convergence or Divergence for Kidney Disease and Heart Failure?
Amir Kazory, MD and
Edward A. Ross, MD*
Division of Nephrology, Hypertension, and Transplantation, University of Florida, Gainesville, Florida
Manuscript received September 16, 2008;
accepted October 22, 2008.
* Reprint requests and correspondence: Dr. Edward A. Ross, Division of Nephrology, Hypertension, and Transplantation, University of Florida, Box 100224, 1600 SW Archer Road, Gainesville, Florida 32610-0224 (Email: rossea{at}medicine.ufl.edu).
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Abstract
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Cardiorenal anemia syndrome refers to the simultaneous presence of anemia, heart failure (HF), and chronic kidney disease (CKD) that forms a pathologic triangle with an adverse impact on morbidity and mortality. The reciprocal relationships among these 3 components have been the subject of a number of trials with inconsistent and sometimes paradoxic results. In this paper, the pathophysiologic concepts underlying interactions among these 3 conditions are discussed. Then, the similarities and dissimilarities of the relationships between anemia and either HF or CKD are considered; explanations are provided for differences in the results of the currently available studies. Erythropoietin-stimulating agent protocols are usually based on the results of studies designed for the CKD population, and upper hemoglobin target levels are chosen to avoid cardiovascular complications. It is not yet clear whether those renal guidelines are optimal for patients with HF, especially because those patients may have reversible components of kidney dysfunction, both HF and renal parameters improving with anemia correction. We review these issues and suggest a pragmatic approach to the care of patients with HF until such time that controlled trials establish definitive anemia treatment goals that are dynamic and disease specific, rather than those that adopt a more simplistic hemoglobin-specific approach.
Key Words: kidney disease • heart failure • anemia • erythropoietin • ESAs
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Abbreviations and Acronyms
| | CHF = congestive heart failure | | CKD = chronic kidney disease | | EF = ejection fraction | | EPO = erythropoietin | | ESA = erythropoiesis-stimulating agent | | ESRD = end-stage renal disease | | GFR = glomerular filtration rate | | HF = heart failure | | LV = left ventricular | | NYHA = New York Heart Association |
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Chronic kidney disease (CKD) and heart failure (HF) share a number of causes (e.g., hypertension), features (e.g., malnutrition), and risk factors (e.g., older age). It is not then surprising to see these 2 pathologic situations coexist in a large number of patients. CKD is highly prevalent in patients with HF, with a substantial number of them even progressing to end-stage renal disease (ESRD) (1). In a meta-analysis of 16 studies, Smith et al. (2) found that 63% of the 80,098 patients with HF concomitantly had some degree of impaired renal function, and 29% presented with severe CKD. This is of great clinical relevance because it is well known that renal dysfunction in patients with HF is associated with an increased risk of adverse outcomes (1,2). In a study by Hillege et al. (3) on 1,906 patients with HF, impaired renal function was found to be an even stronger predictor of mortality than ejection fraction (EF) or New York Heart Association (NYHA) functional class. The reciprocal relationship also holds true and has been the subject of much interest: cardiovascular disease is a very common comorbidity in patients with CKD or ESRD and is the leading cause of mortality in this patient population. Indeed, HF is the key component of cardiovascular morbidity and mortality across the entire spectrum of CKD with a 2-year cumulative probability of 39.5% (4). In a study of the Medicare population, Foley et al. (5) found that 39.9% of patients with CKD had HF on initial presentation, and another 30.7% developed it over the next year. Not only is HF the most common type of cardiovascular disease seen in patients new to ESRD, but according to the U.S. Renal Data System 2007 annual data report, approximately two-thirds of incident dialysis patients develop HF within 3 years (4).
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Anemia in HF
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The prevalence of anemia in the HF population has been subject to very wide variations based on its definition and the study population. Currently, there is no specific hemoglobin concentration that has universally been accepted as a clinically relevant definition for anemia in HF. Some studies have applied the World Health Organization classification in their analyses (6,7), whereas others have chosen a hemoglobin level of <12 or 12.5 g/dl (8,9). Overall, the majority of studies indicate that the prevalence of anemia in the HF population is >20%; many have reported it as high as 50% (10). In the OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure) registry that contained information on 48,612 patients hospitalized for HF, 51.2% of the cohort had hemoglobin levels of <12.1 g/dl and 25% were moderately to severely anemic (hemoglobin levels of 5 to 10.7 g/dl) (11). In addition, the prevalence of anemia increases significantly with disease severity. Although it can be very high in selected patients with advanced HF, fewer patients with mild to moderate or new-onset HF are anemic.
Most studies have found that anemia is associated with an increased risk of adverse outcomes in the HF population (10). In the OPTIMIZE-HF registry, a lower hemoglobin level was independently associated with higher all-cause and cardiovascular mortality and morbidity in hospitalized patients with HF (11). Similarly, Tang et al. (12) recently reported that even in the ambulatory setting, the presence of persistent anemia conferred poor survival in these patients. In this study, for each 1-g/dl decrease in the hemoglobin level, there was a 20% increase in the multivariate adjusted risk of death. Many investigations, however, are difficult to compare because of diverse ranges of hemoglobin values and possible confounding effects of other aspects of cardiac disease (e.g., degree of left ventricular [LV] systolic dysfunction).
Multiple etiologies have been proposed for anemia in the setting of HF (Table 1). These include occult gastrointestinal bleeding owing to concomitant use of aspirin, hemodilution, inhibition of either erythropoietin (EPO) synthesis (i.e., possibly secondary to use of angiotensin-converting inhibitors or angiotensin receptor blockers), and nutritional iron deficiencies caused by anorexia (13–15). However, the cause that may provide the most insight into the pathophysiology is unresponsiveness to EPO. Indeed, compared with patients with ESRD who are functionally anephric and have absolute EPO deficiency, patients with congestive heart failure (CHF) typically have elevated plasma EPO levels (16,17). The loss of EPO sensitivity is thought to be due to chronic inflammation, as evidenced by increases in a multitude of inflammatory cytokines. Further complicating analysis of the literature is the finding that erythropoiesis-stimulating agent (ESA)-induced improvement in anemia can be associated with improvements in CHF and reduction in cytokine levels (18). The syndrome of inflammation, EPO resistance, and anemia could hypothetically identify patients with high-risk CHF and confound therapeutic trials: 1) patients would need to be randomized based on markers of inflammation; 2) analyses would have to account for the ESA dose needed to achieve a target hemoglobin level; and 3) there might be very large doses of ESA (and iron) necessary in protocols with high hemoglobin level end points. The latter concern is at the crux of many controversies in this field. Do adverse outcomes in therapeutic trials occur because of targets of high (i.e., normal or near-normal) hemoglobin levels or are the complications due to the increased doses of ESA (and iron) needed to achieve that degree of erythropoiesis in the setting of systemic inflammation? This issue has profound implications in terms of ESA usage for a variety of medical illnesses, as already manifested by recent hemoglobin-oriented Food and Drug Administration-mandated changes in ESA labeling. The question of drug toxicity (rather than the hemoglobin level per se) does have a basis in the literature. ESAs are known to have adverse effects, including those owing to inhibition of the nitric oxide pathway, worsening hypertension, and blood viscosity. It is also noteworthy that higher doses of EPO have been shown to diminish nitric oxide production and release in certain circumstances (e.g., high blood pressure and uremic environments), leading to adverse vascular effects (19). Iron therapy (which, alone, is reported to alleviate anemia and improve cardiac function in some studies of patients with CHF [20–23]) increases oxidative stress. Unfortunately, to date no large prospective study has been specifically designed to investigate this topic. Randomizing patients to receive either blood transfusions or ESA/iron could be a strategy to clarify the role of ESA (and iron) as independent risks; however, there have been no large trials so far in this regard. As described later, resolving the central question of whether adverse events are due to the hemoglobin level or drug effect could explain why many observational (i.e., epidemiologic) investigations have demonstrated better outcomes with higher hemoglobin values, even though at those same levels some therapeutic trials showed worsened end points. Unfortunately, it is not known whether the results of this and other large, multicenter, randomized, controlled trials of ESAs in CKD populations can be applied to patients with CHF. In this regard, discussed in the following section are attributes of patients with anemia and HF that are either similar to or different from those with renal disease (points of "convergence" or "divergence," respectively).
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Anemia in CKD
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Although it is a relatively recent focus in the cardiology literature, anemia has been a long-recognized, common, and well-studied complication of CKD. Anemia occurs early in the course of the disease and worsens as kidney function declines. In a multicenter survey on 5,222 patients with CKD, McClellan et al. (24) showed that anemia (hemoglobin level  12 g/dl) was present in 47.7% of the study population. The prevalence of anemia was strongly associated with declining glomerular filtration rate (GFR); the percentage of patients with hemoglobin levels 12 g/dl increased from 26.7% to 75.5% when GFR decreased from  60 to <15 ml/min/1.73 m2.
Although decreased EPO production is largely responsible for development of anemia in patients with advanced CKD, several other etiologies have also been considered (Table 2). Decreased red blood cell life span owing to the presence of uremic toxins, chronic blood loss secondary to platelet dysfunction, nutritional (e.g., folate) deficiencies, iron deficiency (functional or absolute), and elevated inflammatory cytokine levels that suppress the bone marrow are among these factors (25) (Fig. 1).
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Figure 1 Proposed Pathophysiology Underlying Anemia and Its Correction in Patients With Both CHF and Renal Dysfunction (The Cardiorenal Syndrome)
CHF = congestive heart failure; ESA = erythropoiesis-stimulating agent; + and – = positive and negative effects, respectively.
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Anemia is recognized as an independent risk factor for progression of renal disease in patients with CKD (26), and tissue hypoxia is one of the proposed mechanisms. Furthermore, in a study of 6,541 patients with CKD, anemia was found to be an independent predictive factor for reaching ESRD and needing replacement therapy (27). Anemia has also been considered a risk multiplier in the presence of cardiovascular disease, the common comorbidity of CKD. In a retrospective study on 88,657 patients with elevated serum creatinine levels, Walker et al. (28) found that patients with anemia had an increased risk for progression of CKD to dialysis as well as a higher (2 to 5 times) risk for myocardial infarction. Interestingly, the risk for hospitalization with HF declined regularly with increasing hemoglobin levels.
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Anemia: The Point of Convergence
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In 2004, the National Heart, Lung, and Blood Institute convened a working group of investigators to examine the available data concerning interactions between the cardiovascular system and kidneys and to develop recommendations for future studies (29). The definition of the cardiorenal syndrome as a "state in which therapy to relieve congestive HF symptoms is limited by further worsening kidney function" arose from the work carried out by that group (30). Since then, the definition of the cardiorenal syndrome has been expanded to stress the bidirectional nature of the relationship between the kidney and the heart: a "pathophysiological disorder in which acute or chronic dysfunction of one organ may induce acute or chronic dysfunction in the other" (30). The biologic mediators for this clinical interaction are thought to be hyperactivity of the sympathetic nervous system, the renin-angiotensin-aldosterone system, imbalance of nitric oxide and reactive oxygen species, and the chronic inflammatory state (19). These mediators, also called "cardiorenal connectors," display mutual interactions and induce positive feedback loops at many points (31). The clinically relevant concept of the cardiorenal syndrome is that renal and cardiac dysfunction mutually amplify progressive failure of both systems; CKD can cause or worsen HF, and HF also can cause or worsen CKD.
Anemia, a common feature of both CKD and HF, seems to be another piece of this puzzle. It can cause or worsen CKD and HF and be the consequence of either of these 2 conditions as well. This has prompted some authors to expand this concept with special emphasis on the role of anemia in a vicious cycle; the term "cardiorenal anemia syndrome" has recently emerged and is increasingly used to describe this association (32). It implies that there is a cause-and-effect relationship between any 2 of these pathologic conditions and that anemia can lead to the development of CKD and HF through the aforementioned pathophysiologic pathways. For example, in a study on more than 1 million Medicare elderly patients, Herzog et al. (33) found that CKD, HF, and anemia are additive in increasing mortality and the risk of developing ESRD.
Anemia, CKD, and HF thus form a pathologic triangle, mutually amplifying their impacts on morbidity and mortality. These relationships highlight the pathophysiologic basis whereby anemia may not merely be a "marker" of more severe disease in CKD or HF but rather a "mediator" for development of the diseases. As described later, this concept is of paramount importance in establishing the targets of anemia correction. Some patients with anemia have concurrent but unrelated parenchymal cardiac and renal diseases; for these patients, it would be reasonable to use the well-established national guidelines for correction of anemia in the CKD population. Other individuals, however, may have cardiac disease that plays a primary role in worsening renal dysfunction. It is the latter subset of patients that is most intriguing because of the theoretical possibility that amelioration of anemia would lead, in turn, to improvement in HF and then better renal function. Indeed, the results of a number of studies are consistent with this hypothesis (34,35). In a study on 179 patients with moderate to severe HF and mild to moderate CKD, Silverberg et al. (35) reported that correction of anemia through administration of EPO and iron was followed by improvement in the LV systolic function as well as blocking the progression of CKD. Other investigations have shown similar demonstrations of either stabilization or improvement in renal function after the correction of anemia; however, most have studied small numbers of patients and used different hemoglobin goals (36–38). We believe that it is critically important to be able to identify the group of patients that will have a hemodynamic-mediated improvement in renal function. They might theoretically fare better with cardiac disease-specific hemoglobin targets, which could be quite different than guidelines for those individuals with primary renal disease.
Relative EPO deficiency and resistance to EPO are also 2 major pathologic phenomena that link the anemia of CKD with that of HF. Although endogenous EPO levels are higher in patients with CKD compared with those in healthy individuals, they are inappropriately low for the degree of anemia (relative EPO deficiency) (39,40). Anemia persists in patients with CKD despite the average EPO levels being approximately 5 times higher than those in healthy individuals (EPO resistance) (41). As previously noted, similar to the CKD population, serum EPO levels have been found to be high in patients with HF (16) but disproportionately low for the degree of anemia (17). Conversely, it has recently been hypothesized that high EPO levels could be beneficial by dampening the cardiorenal connectors (19,42) through extrahematopoietic effects in addition to the traditional benefits from anemia correction.
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Anemia: The Point of Divergence
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As mentioned earlier, in addition to the cause-and-effect relationship, the term cardiorenal anemia syndrome implies that common pathophysiologic pathways drive the interplay of the 3 components of the syndrome. One might anticipate that modifications (i.e., improvement or deterioration) of a single component of this triad would result in changes in a similar direction in the other two. For instance, as HF worsens, the GFR would decline and anemia would worsen, with a consequent increase in mortality. However, there can be unanticipated interactions between these disease states, such as the impact of anemia correction in patients with CKD or HF. It seems that, for reasons not yet well known and dependent on the degree of anemia correction, there may be different, or even opposite, effects on the clinical outcomes of patients with CKD compared with those of patients with HF. For example, anemia has been recognized as an independent risk factor for progression of kidney disease (27) and has been shown to portend a poor prognosis in patients with CKD (43); however, complete normalization of the hemoglobin levels has not been associated with improvement in outcomes in this population. Indeed, recent studies have consistently found that correction of anemia in patients with CKD actually increases the risk of adverse outcomes, although it might improve cardiac function and structure (44). The CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) study evaluated the effects of achieving relatively high hemoglobin levels (13.5 g/dl) compared with lower hemoglobin levels (11.3 g/dl) on cardiovascular outcomes in a CKD population. This study was prematurely halted because of a surprisingly higher rate of adverse events in the high hemoglobin group (45). A similar randomized, controlled trial (CREATE [Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta] study) evaluated the impact of complete compared with partial correction of hemoglobin levels in a CKD population (46). Complete correction of anemia again failed to demonstrate any improvement in cardiovascular events. Another study of patients with cardiac disease (HF or ischemic heart disease) on hemodialysis was previously halted after 29 months because of a surprisingly increased rate of adverse outcomes in the group with a normal hematocrit therapeutic goal (47). Thus, the guidelines for the management of anemia in patients with CKD have recently been updated to reflect the practical consequences of the aforementioned clinical trials (48). Notably, however, all of these trials were open label, not all actually achieved the targeted hemoglobin levels, and there was a concern over potentially confounding adverse effects of intravenous iron dosing needed for erythropoiesis. The currently ongoing TREAT (Trial to Reduce Cardiovascular Events With Aranesp Therapy) is a large, randomized, placebo-controlled, double-blind study that aims to evaluate the effect of increasing hemoglobin levels (to 13 g/dl) on cardiovascular end points in patients with anemia and CKD (and diabetes) (49). These conflicting findings (in observational vs. therapeutic trials) again highlight our lack of understanding of the pathophysiology of erythropoiesis in inflammatory conditions, adverse effects from the hemoglobin level, or the doses of pharmaceuticals used to reach that goal. Importantly, a recent secondary analysis of the CHOIR study suggested that the high cardiovascular event rates were limited to those patients receiving large ESA doses and having suboptimal hemoglobin responses. Individuals who achieved higher hemoglobin levels with relatively low pharmaceutical doses did not have the vascular complications (50).
In marked contrast to these negative or neutral studies in CKD populations, a number of studies of patients with HF have reported that correction of anemia to normal or near-normal levels is associated with beneficial impact on cardiovascular outcomes. Silverberg et al. (32) were the first to evaluate the role of anemia correction in the HF population. In a randomized, open label study on 32 patients with HF, they found that an increase in hemoglobin level was followed by improvement in NYHA functional class and LVEF. Palazzuoli et al. (51) in a randomized, double blind, placebo-controlled study of 40 patients with moderate to severe HF found that correction of anemia was associated with improvement in NYHA functional class, B-type natriuretic peptide levels, and even renal function. The apparent discrepancy between the findings of studies on aggressive anemia correction in patients with CKD as compared with those in patients with HF has continued over time. In a more recent randomized, controlled trial of 40 patients with LVEF of 35%, Toblli et al. (20) reported that correction of anemia (via administration of intravenous iron) was followed by improvement in NYHA functional class, LVEF, and renal function. It is important to put these positive anemia-correction HF investigations in the perspective of a number of more recent negative findings. Specifically, it should be emphasized that the results of multicenter trials have not always supported those of smaller single-center studies (52). Ponikowski et al. (53) in a multicenter, randomized, double-blind, placebo-controlled trial of 41 patients with anemia and HF failed to show any improvement in NYHA functional class after correction of anemia. Similarly, in another multicenter, randomized, placebo-controlled study, correction of hemoglobin level did not change the NYHA functional class or LVEF (54). Finally, the results of the largest multicenter, double-blind, placebo-controlled trial (STAMINA-HeFT [Study of Anemia in Heart Failure–Heart Failure Trial]) were recently published (55). It included 319 patients with HF (EF 40%) with anemia (hemoglobin level of 9 to 12 g/dl). Of the patients treated with darbepoetin alfa, 85% achieved 2 consecutive hemoglobin levels of 14 g/dl during the study. Correction of anemia in these patients did not significantly improve exercise duration, NYHA functional class, or even health-related quality of life. Despite these trials with negative findings and a paucity of data concerning mortality, it has generally been viewed that the preponderance of evidence supports a beneficial impact of anemia correction on HF symptoms, LVEF, and quality of life. Not surprisingly, however, there is no generally accepted consensus for the details of treatment guidelines, protocols, or hemoglobin target levels in patients with HF.
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Anemia Correction: Different Outcomes for CKD Versus HF?
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The apparent disparate impact of anemia correction for CKD versus HF in some trials emphasizes our limited understanding of the bidirectional relationships in the triad of the cardiorenal anemia syndrome. In other words, the fact that these conditions coexist in a large number of patients, that they can cause and worsen each other, and that they have an additive effect on increasing mortality does not necessarily mean that the pathophysiologic basis of their linkage would be the same. For example, although severe anemia seems to be a "mediator" for worse outcomes in both patients with HF and patients with renal failure, milder degrees could be a partial "defense mechanism" in patients with parenchymal CKD. Indeed, in experimental models of CKD, chronic moderate anemia reduced glomerular injury, whereas raising hemoglobin values by use of EPO resulted in accelerated glomerulosclerosis (56,57). If this hypothesis is true, it is conceivable that overly aggressive correction of anemia in patients with CKD can result in abrogation of such a defense mechanism with a subsequent increase in the rate of adverse outcomes. This concept would thereby support the use of a narrow therapeutic hemoglobin window in renal disease-specific erythropoietic guidelines.
Another possible explanation for this apparent divergence would be the fact that in most of these studies, the intervention was limited to the administration of ESAs either in the form of EPO (50) or the longer-acting analog (darbepoetin alfa) (21,58). Anemia correction is not necessarily synonymous to administration of ESAs. Indeed, a few studies have chosen to use other interventions (e.g., intravenous iron alone or a combination of iron and ESAs) to correct anemia in the HF population (19–22). Similarly, continuous EPO receptor activator, with a unique pharmacologic profile including a longer elimination half-life and slower clearance rate, has recently been developed for correction of anemia in patients with CKD (59) and has been used in patients with and without ESRD (60,61). Therefore, upon reviewing these studies, it needs to be kept in mind that the results (positive or negative) might be due to other drug-related effects, rather than the impact of anemia correction per se. This concept is further reinforced by recent findings on the physiologic effects of EPO that go far beyond erythropoiesis (e.g., reduction in apoptosis and stimulation of endothelial progenitor cell proliferation) (19,42,62). One can then postulate that besides their role in erythropoiesis and correction of anemia, ESAs could exert extrahematopoietic effects that are different in the heart and the kidney, explaining the discrepancies in the findings of the aforementioned clinical studies.
The nephrology and cardiology literature showing that anemia correction yielded disparate outcomes in the CKD and HF populations might also be in part due to differences in study design. The large-scale trials in patients with CKD were specifically structured to assess either a composite of several cardiovascular events (45,46) or the length of time to death or first nonfatal myocardial infarction as their primary end points (47). The mean duration of observation for the primary end point in patients in the CREATE study was almost 3 years; the median follow-up period was 16 months for patients in the CHOIR study and 14 months for those in the normal hematocrit study (45–47). The investigations were specifically powered to detect the differences in adverse outcomes during these follow-up periods. This approach needs to be cautiously compared with those from studies on anemia correction in patients with HF, which have generally included smaller number of patients with shorter durations of follow-up. Furthermore, the primary end points in these cardiology trials have mostly been improvement in exercise tolerance, NYHA functional class, LVEF, and health-related quality of life (efficacy rather than safety) (51,58). The fact that they did not detect any increase in adverse outcomes (unlike the CKD investigations) might thus partially be due to their being underpowered and having short follow-up periods. The need to more rigorously evaluate the safety of anemia correction in the HF population has been well recognized, and a large-scale, double-blind, randomized phase 3 morbidity and mortality trial (RED-HF [Reduction of Events with Darbepoetin Alfa in Heart Failure]) is currently ongoing to specifically determine anemia correction's impact on the morbidity and mortality of these patients (63).
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The Target Hemoglobin Level for Patients With Both CKD and HF
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Concerning the treatment of anemia in patients who present with cardiorenal anemia syndrome, the main unresolved issue is determining the safest hemoglobin level to target with pharmacologic therapy (64). Although there is no clear-cut answer to this question yet, there are some clues. Regarding the cardiac constituent of the syndrome, we simply do not know definitively what the impact of anemia correction or normalization would be on the mortality and morbidity of the HF population. As noted earlier, even in terms of its effect on exercise tolerance, symptoms, and quality of life, the current data are controversial. Therefore, it seems reasonable to look at the renal component of the syndrome for which there are large-scale, randomized trials specifically designed to answer this question (45–47). Because HF and CKD coexist in a large number of patients, even if these studies were designed and intended for the CKD population, they have invariably included significant number of patients with coexisting HF; it was present in 32% of patients in the CREATE study and 23% of those in the CHOIR study. Although no subgroup analysis is currently available for these studies to assess whether patients presenting with concurrent CKD and HF followed the general pattern found in the study population as a whole, in the absence of any conflicting data, there would be no reason to assume that this subgroup of patients responded differently. As noted earlier, until such time when we can identify individuals who have reversible hemodynamic renal dysfunction (and who theoretically benefit from HF rather than renal hemoglobin guidelines), it seems reasonable to suggest that correction of anemia in patients with cardiorenal anemia syndrome be based on guidelines for patients with only CKD (48). The problem with this pragmatic approach of using the relatively modest "renal" hemoglobin targets (i.e., 10 to 12 g/dl) is that based on some cardiology trials, there are substantial numbers of patients who might benefit from more aggressive anemia correction. In the analysis of Young et al. (11), fully a quartile of patients were in the 12- to 13.5-g/dl group. Silverberg et al. (36) included a subgroup with 12 to 13.5 g/dl, Mancini et al. (65) described patients who reached a 14.3-g/dl hemoglobin level, Comin-Colet et al. (37) reported dosing to 13.7 g/dl, and Felker et al. (66) described those with hemoglobin values of 13.9%. Importantly, Golden et al. (67) described the better outcomes with hematocrits >42% (well above CKD guidelines) compared with values <35%. Similarly, there were reported benefits from hemoglobin levels of 14 to 14.9 g/dl, rather than <10.9 g/dl (68), as well as the lowest mortality for patients with values in the 14.5- to 15.4-g/dl range (69). Therefore, this hemoglobin target gap between the 12 g/dl of national CKD guidelines and approximately 14 g/dl from a few HF studies presents a therapeutic conundrum. The "hematogap" affects such a large group of patients with HF that it warrants in-depth investigation. Our opinion is that because the adverse cardiovascular outcomes from the high-hematocrit CKD trials were both unanticipated and severe (i.e., halting some trials), those targets should only be used for HF in the setting of rigorous research protocols with ongoing safety monitoring. Besides, trials need to be powered to account for a subset of patients who may have such hemodynamic improvement in their renal dysfunction (i.e., transitioning from CKD stage 3 back to 2) that they would fall under a different (perhaps higher) hemoglobin target protocol. We summarize in Figure 2
our proposed iterative strategy for anemia correction that encompasses the concept of how enhanced kidney function in turn alters the hemoglobin target; specific goals would depend on whether the individual was being treated in clinical practice or using a research protocol. Notably, it is anticipated that the baseline GFR for patients enrolled in the RED-HF trial will be approximately 53 ml/min/1.73m2 (63). This trial therefore will hopefully provide clinicians with valuable information on the impact of anemia correction in patients who present with both CKD and HF and might set new target hemoglobin levels for these patients.
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Figure 2 Proposed Iterative Strategy for Anemia Correction in Patients With CKD and HF
*Using ferritin levels as a criteria for iron depletion is controversial as they can be confounded by inflammatory conditions. CHF = congestive heart failure; CKD = chronic kidney disease; ESA = erythropoiesis-stimulating agent; ESRD = end-stage renal disease; Fe sat = iron saturation; GFR = glomerular filtration rate; HF = heart failure; Hgb = hemoglobin concentration.
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In summary, investigations have thus far yielded important insights into the pathophysiology of the cardiorenal anemia syndrome and have been the basis for ESA protocols currently in use; however, those trials have raised a number of unanswered questions, many of which unfortunately revolve around the possible benefit or harm from high hemoglobin targets in patients with HF with parenchymal as opposed to hemodynamically reversible renal dysfunction. We have stressed the need to monitor patients for changes in their renal function to properly categorize them and thereby determine the appropriate disease-specific therapeutic hemoglobin goal. Ongoing large trials will hopefully resolve these questions, and until such time we believe a conservative approach to ESA protocols is warranted outside of the setting of rigorously monitored protocols.
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References
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1. McClellan WM, Lagston RD, Presley R. Medicare patients with cardiovascular disease have a high prevalence of chronic kidney disease and a high rate of progression to end-stage renal disease J Am Soc Nephrol 2004;15:1912-1919.[Abstract/Free Full Text]2. Smith GL, Lichtman JH, Bracken MB, et al. Renal impairment and outcomes in heart failure J Am Coll Cardiol 2006;47:1987-1996.[Abstract/Free Full Text] 3. Hillege HL, Girbes ARJ, de Kam PJ, et al. Renal function, neurohormonal activation, and survival; in patients with chronic heart failure Circulation 2000;102:203-210.[Abstract/Free Full Text] 4. Collins AJ, Foley R, Herzog C, et al. Excerpts from the United States Renal Data 2007 annual data report Am J Kidney Dis 2008;51(Suppl 1):S1-S320.[Web of Science][Medline] 5. Foley RN, Murray AM, Li S, et al. Chronic kidney disease and the risk for cardiovascular disease, renal replacement, and death in the United States Medicare population, 1998 to 1999 J Am Soc Nephrol 2005;16:489-495.[Abstract/Free Full Text] 6. Horwich TB, Fonarow GC, Hamilton MA, et al. Anemia is associated with worse symptoms, greater impairment in functional capacity and a significant increase in mortality in patients with advanced heart failure J Am Coll Cardiol 2002;39:1780-1786.[Abstract/Free Full Text] 7. Sarnak MJ, Tighiouart H, Manjunath G, et al. Anemia as a risk factor for cardiovascular disease in the Atherosclerosis Risk In Communities (ARIC) study J Am Coll Cardiol 2002;40:27-33.[Abstract/Free Full Text] 8. Szachniewicz J, Petruk-Kowalczyk J, Majda J, et al. Anaemia is an independent predictor of poor outcome in patients with chronic heart failure Int J Cardiol 2003;90:303-308.[CrossRef][Web of Science][Medline] 9. Arant CB, Wessel TR, Olson MB, et al. Hemoglobin level is an independent predictor for adverse cardiovascular outcomes in women undergoing evaluation for chest pain: results from the National Heart, Lung, and Blood Institute Women's Ischemia Syndrome Evaluation Study J Am Coll Cardiol 2004;43:2009-2014.[Abstract/Free Full Text] 10. Tang YD, Katz SD. The prevalence of anemia in chronic heart failure and its impact on the clinical outcomes Heart Fail Rev 2008;13:387-392.[CrossRef][Web of Science][Medline] 11. Young JB, Abraham WT, Albert NM, et al. Relation of low hemoglobin and anemia to morbidity and mortality in patients hospitalized with heart failure (insight from the OPTIMIZE-HF registry) Am J Cardiol 2008;101:223-230.[CrossRef][Web of Science][Medline] 12. Tang WH, Tong W, Jain A, et al. Evaluation and long-term prognosis of new-onset, transient, and persistent anemia in ambulatory patients with chronic heart failure J Am Coll Cardiol 2008;51:569-576.[Abstract/Free Full Text] 13. Mitchell J. Emerging role of anemia in heart failure Am J Cardiol 2007;99(Suppl):15D-20D.[Web of Science][Medline] 14. Anand IS. Heart failure and anemia: mechanisms and pathophysiology Heart Fail Rev 2008;13:379-386.[CrossRef][Web of Science][Medline] 15. Palazzuoli A, Gallotta M, Iovine F, et al. Anaemia in heart failure: a common interaction with renal insufficiency called the cardiorenal-anaemia syndrome Int J Clin Pract 2008;62:281-286.[Web of Science][Medline] 16. George J, Patal S, Wexler D, et al. Circulating erythropoietin levels and prognosis in patients with congestive heart failure: comparison with neurohormonal and inflammatory markers Arch Int Med 2005;165:1304-1309.[Abstract/Free Full Text] 17. van der Meer P, Voors AA, Lipsic E, et al. Prognostic value of plasma erythropoietin on mortality in patients with chronic heart failure J Am Coll Cardiol 2004;44:63-67.[Abstract/Free Full Text] 18. Kourea K, Parissis JT, Farmakis D, et al. Effects of darbopoetin-alpha on plasma pro-inflammatory cytokines, anti-inflammatory cytokine interleukin-10 and soluble Fas/Fas ligand systemin anemic patients with chronic heart failure Atherosclerosis 2008;199:215-221.[CrossRef][Web of Science][Medline] 19. Jie KE, Verhaar MC, Cramer MJM, et al. Erythropoietin and the cardiorenal syndrome: cellular mechanisms on the cardiorenal connectors Am J Physiol Renal Physiol 2006;291:F932-F944.[Abstract/Free Full Text] 20. Toblli JE, Lombrana A, Duarte P, et al. Intravenous iron reduces NT-pro-brain natriuretic peptide in anemic patients with chronic heart failure and renal insufficiency J Am Coll Cardiol 2007;50:1657-1665.[Abstract/Free Full Text] 21. Okonko DO, Grzeslo A, Witkowski T, et al. Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency J Am Coll Cardiol 2008;51:103-112.[Abstract/Free Full Text] 22. Bolger AP, Bartlett FR, Penston HS, et al. Intravenous iron alone for the treatment of anemia in patients with chronic heart failure J Am Coll Cardiol 2006;48:1225-1227.[Abstract/Free Full Text] 23. Usmanov RI, Zueva EB, Silverberg DS, Shaked M. Intravenous iron without erythropoietin for the treatment of iron deficiency anemia in patients with moderate to severe heart failure and chronic kidney insufficiency J Nephrol 2008;21:236-242.[Web of Science][Medline] 24. McClellan W, Aronoff SL, Bolton WK, et al. The prevalence of anemia in patients with chronic kidney disease Curr Med Res Opin 2004;20:1501-1510.[CrossRef][Web of Science][Medline] 25. Basile JN. Clinical considerations and practical recommendations for the primary care practitioner in the management of anemia of chronic kidney disease South Med J 2007;100:1200-1207.[Web of Science][Medline] 26. Bahlmann KH, Kielstein JT, Haller H, Fliser D. Erythropoietin and progression of CKD Kidney Int Suppl 2007;107:S21-S25.[Medline] 27. Johnson ES, Thorp ML, Yang X, et al. Predicting renal replacement therapy and mortality in CKD Am J Kidney Dis 2007;50:559-565.[CrossRef][Web of Science][Medline] 28. Walker AM, Schneider G, Yeaw J, et al. Anemia as predictor of cardiovascular events in patients with elevated serum creatinine J Am Soc Nephrol 2006;17:2293-2298.[Abstract/Free Full Text] 29. NHLBI Working Group Cardio-Renal Connections in Heart Failure and Cardiovascular DiseaseAugust 20, 2004 http://www.nhlbi.nih.gov/meetings/workshops/cardiorenal-hf-hd.htm 2006Accessed March 10, 2008. 30. Ronco C, House AA, Haapio M. Cardiorenal syndrome: refining the definition of a complex symbiosis gone wrong Intensive Care Med 2008;34:957-962.[CrossRef][Web of Science][Medline] 31. Bongartz LG, Cramer MJ, Doevendans PA, et al. The severe cardiorenal syndrome: "Guyton revisited." Eur Heart J 2005;26:11-17.[Abstract/Free Full Text] 32. Silverberg DS, Wexler D, Sheps D, et al. The effect of correction of mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron: a randomized controlled study J Am Coll Cardiol 2001;37:1775-1780.[Abstract/Free Full Text] 33. Herzog CA, Muster HA, Li S, Collins AJ. Impact of congestive heart failure, chronic kidney disease, and anemia on survival in the Medicare population J Card Fail 2004;10:467-472.[CrossRef][Web of Science][Medline] 34. Silverberg DS, Wexler D, Blum M, et al. Aggressive therapy of congestive heart failure and associated chronic renal failure with medications and correction of anemia stops or slows down the progression of both diseases Perit Dial Int 2001;21(Suppl 3):S236-S240.[Abstract/Free Full Text] 35. Silverberg DS, Wexler D, Blum M, et al. The effect of correction of anemia in diabetic and non-diabetics with severe resistant congestive heart failure and chronic renal failure by subcutaneous erythropoietin and intravenous iron Nephrol Dial Transplant 2003;18:141-146.[Abstract/Free Full Text] 36. Silverberg DS, Wexler D, Blum M, et al. The use of subcutaneous erythropoietin and intravenous iron for the treatment of the anemia of severe, resistant congestive heart failure improves cardiac and renal function, functional cardiac class, and markedly reduces hospitalizations J Am Coll Cardiol 2000;35:1737-1744.[Abstract/Free Full Text] 37. Comin-Colet J, Bruguera J, Garcia C, et al. Effect on hospitalization and functional status of correction of mild anemia with subcutaneous erythropoietin and intravenous iron in patients with severe advanced chronic heart failure and mild renal dysfunction. Heart Failure Meeting of the European Society of Cardiology; June 11–16, 2005; Lisbon, Portugal. 38. Delgado RM, Radovancevic R, van Rossem CC, Bracey A, Radovancevic R. Effect of administration of recombinant human erythropoietin in heart failure patients(abstr) Eur Heart J 2004;25(Suppl 1):386A.[CrossRef] 39. Caro J, Brown S, Miller O, et al. Erythropoietin levels in uremic nephric and anephric patients J Lab Clin Med 1979;93:449-458.[Web of Science][Medline] 40. Fehr T, Ammann P, Garzoni D, et al. Interpretation of erythropoietin levels in patients with various degrees of renal insufficiency and anemia Kidney Int 2004;66:1206-1211.[CrossRef][Web of Science][Medline] 41. Mason-Garcia M, Beckman BS, Brookins JW, et al. Development of a new radioimmunoassay for erythropoietin using recombinant erythropoietin Kidney Int 1990;38:969-975.[Web of Science][Medline] 42. van der Putten K, Braam B, Jie KE, Gaillard CA. Mechanisms of disease: erythropoietin resistance in patients with both heart and kidney failure Nat Clin Pract Nephrol 2008;4:47-57.[CrossRef][Web of Science][Medline] 43. Levy WC. Anemia in heart failure J Am Coll Cardiol 2008;51:577-578.[Free Full Text] 44. Pappas KD, Gouva CD, Katopodis KP, et al. Correction of anemia with erythropoietin in chronic kidney disease (stage 3 and 4): effects on cardiac performance Cardiovasc Drug Ther 2008;22:37-44.[CrossRef][Web of Science][Medline] 45. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease N Engl J Med 2006;355:2085-2098.[CrossRef][Medline] 46. Drüeke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia N Engl J Med 2006;355:2071-2084.[CrossRef][Medline] 47. Besarab A, Bolton K, Browne JK, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin N Engl J Med 1998;339:584-590.[CrossRef][Web of Science][Medline] 48. National Kidney Foundation KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease Am J Kidney Dis 2006;47(Suppl 3):S11-S145.[CrossRef][Medline] 49. Mix TC, Brenner RM, Cooper ME, et al. Rationale—Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT): evolving the management of cardiovascular risk in patients with chronic kidney disease Am Heart J 2005;149:408-413.[CrossRef][Web of Science][Medline] 50. Szczech LA, Barnhart HX, Inrig JK, et al. Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes Kidney Int 2008;74:791-798.[CrossRef][Web of Science][Medline] 51. Palazzuoli A, Silverberg D, Iovine F, et al. Erythropoietin improves anemia exercise tolerance and renal function and reduces B-type natriuretic peptide and hospitalization in patients with heart failure and anemia Am Heart J 2006;152:1096.e9-1096.e15. 52. Murphy NF, McDonald K. Treatment of anaemia in chronic heart failure—optimal approach still unclear Eur Heart J 2007;28:2185-2187.[Free Full Text] 53. Ponikowski P, Anker SD, Szachniewicz J, et al. Effect of darbopoetin alfa on exercise tolerance in anemic patients with symptomatic chronic heart failure J Am Coll Cardiol 2007;49:753-762.[Abstract/Free Full Text] 54. van Veldhuisen DJ, Dickstein K, Cohen-Solal A, et al. Randomized, double-blind, placebo-controlled study to evaluate the effect of two dosing regimens of darbopoetin alfa in patients with heart failure and anaemia Eur Heart J 2007;28:2208-2216.[Abstract/Free Full Text] 55. Ghali JK, Anand IS, Abraham WT, et al. Randomized double-blind trial of darbopoetin alfa in patients with symptomatic heart failure and anemia Circulation 2008;117:526-535.[Abstract/Free Full Text] 56. Brimble KS, McFarlane A, Winegard N, et al. Effect of chronic kidney disease on red blood cell rheology Clin Hemorheol Microcirc 2006;34:411-420.[Medline] 57. Remuzzi G, Ingelfinger JR. Correction of anemia—payoffs and problems N Engl J Med 2006;355:2144-2146.[CrossRef][Web of Science][Medline] 58. Belonje AMS, de Boor RA, Voors AA. Recombinant human Epo treatment: beneficial in chronic kidney disease, chronic heart failure, or both? Cardiovasc Drugs Ther 2008;22:1-2.[CrossRef][Web of Science][Medline] 59. Locatelli F, Reigner BCERA. : pharmacodynamics, pharmacokinetics, and efficacy in patients with chronic kidney disease Expert Opin Investig Drugs 2007;16:1649-1661.[CrossRef][Web of Science][Medline] 60. Provenzano R, Besarab A, Macdougall IC, et al. The continuous erythropoietin activator (C.E.R.A.) corrects anemia at extended administration intervals in patients with chronic kidney disease not on dialysis: results of a phase II study Clin Nephrol 2007;67:306-317.[Web of Science][Medline] 61. Macdougall IC, Walker R, Provenzano R, et al. C.E.R.A. corrects anemia in patients with chronic kidney disease not on dialysis: results from a randomized clinical trial Clin J Am Soc Nephrol 2008;3:337-347.[Abstract/Free Full Text] 62. Guglin ME, Koul D. Cardiovascular effects of erythropoietin: anemia and beyond Cardiol Rev 2006;14:200-204.[CrossRef][Medline] 63. van Veldhuisen DJ, McMurray JJV. Are erythropoietin stimulating proteins safe and efficacious in heart failure?. Why we need an adequately powered randomized outcome trial. Eur J Heart Fail 2007;9:110-112.[Free Full Text] 64. Kazory A, Ross EA. Contemporary trends in the pharmacologic and extracorporeal management of heart failure: a nephrologic perspective Circulation 2008;117:975-983.[Abstract/Free Full Text] 65. Mancini DM, Katz SD, Lang C, et al. Effect of erythropoietin on exercise capacity in patients with moderate to severe chronic heart failure Circulation 2003;107:294-299.[Abstract/Free Full Text] 66. Felker GM, Gattis WA, Leimberger JD, et al. Usefulness of anemia as a predictor of death and rehospitalization in patients with decompensated heart failure Am J Cardiol 2003;92:625-628.[CrossRef][Web of Science][Medline] 67. Golden JS, Fallick CC, Josephson SR, et al. Baseline hematocrit predicts clinical outcomes in heart failure Circulation 2002;106(Suppl 2):3358A. 68. Reinecke H, Trey T, Wellmann J, et al. Hemoglobin-related mortality in patients undergoing percutaneous coronary interventions Eur Heart J 2003;24:2142-2150.[Abstract/Free Full Text] 69. Sharma R, Francis DP, Pitt B, et al. Haemoglobin predicts survival in patients with chronic heart failure: a substudy of the ELITE II trial Eur Heart J 2004;25:1021-1028.[Abstract/Free Full Text]
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Abstract
Anemia in HF