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The Oncologist, Vol. 14, No. suppl_1, 22-33, September 2009; doi:10.1634/theoncologist.2009-S1-22
© 2009 AlphaMed Press

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Iron Metabolism, Iron Deficiency, Thrombocytosis, and the Cardiorenal Anemia Syndrome

Anatole Besaraba,b, Walter Hermann Hörlc, Donald Silverbergd

aWayne State University, Detroit, Michigan, USA; bHenry Ford Hospital, Detroit, Michigan, USA; cDivision of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria; dDepartment of Nephrology, Tel Aviv Medical Center, Tel Aviv, Israel

Key Words. Iron metabolism • Erythropoiesis-stimulating agents • Iron deficiency • Cardiorenal anemia syndrome • Thrombocytosis • Coagulopathy

Correspondence: Anatole Besarab, M.D., Henry Ford Hospital, Division of Nephrology and Hypertension, Department of Internal Medicine, 2799 West Grand Blvd., CFP-511, Detroit, Michigan 48301, USA. Telephone: 248-916-2713; Fax: 248-916-2554; e-mail: abesara1{at}hfhs.org

Received February 25, 2009; accepted for publication May 18, 2009.

Disclosures: Anatole Besarab: Honoraria: Amgen, AMAG Pharma, Watson Pharma, Hoffmann-La Roche; Research funding/contracted research: AMAG Pharma; Walter Hermann Hörl: None; Donald Silverberg: Consultant/advisory role: Amgen.

The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer reviewers.


   ABSTRACT
Top
 Abstract
Introduction
 Optimizing Hb
 Iron, Thrombocytosis, and...
 Cardiorenal Anemia Syndrome
 Summary
 Author Contributions
 References
 
In treating moderate to severe anemia of chronic kidney disease (CKD), oral iron is effective only in a minority of nondialysis patients. Intravenous iron is more effective and can raise levels of hemoglobin even without the use of erythropoiesis-stimulating agents (ESAs). Unfortunately, the current assays of iron status that are presently widely available are not especially helpful in predicting response. In patients on dialysis, i.v. iron is effective over a wide range of serum ferritin from <100 ng/ml to 800 ng/ml. None of the three available randomized controlled trials comparing oral with i.v. iron showed evidence of nephrotoxicity caused by i.v. iron.

Iron deficiency is a risk factor for thrombocytosis and should, wherever possible, be avoided. Optimal coadministration of iron may reduce the risk for ESA-driven cardiovascular events. Increased total body iron stores (imperfectly reflected by serum ferritin levels in CKD) do not appear to be related to such events or hospitalization in CKD; it is unclear what other risk factors and mechanisms need to be considered.

In the appreciable proportion of patients with both renal and cardiac dysfunction, management is further complicated by a vicious circle (which can be characterized as cardiorenal anemia syndrome) in which CKD, heart failure, and anemia exacerbate each other. In such patients, correction of anemia appears to improve cardiac function and quality of life without a greater risk for adverse events.


   INTRODUCTION
Top
 Abstract
 Introduction
Optimizing Hb
 Iron, Thrombocytosis, and...
 Cardiorenal Anemia Syndrome
 Summary
 Author Contributions
 References
 
Iron is an essential element for living cells, and a lack of iron is associated with growth arrest and anemia. Links between iron accumulation and the formation of toxic free radicals and progressive tissue damage have been suggested, and an excess of iron (as well as deficiency) may lead to a higher risk for cardiovascular events. These issues merit careful consideration, as do studies of the relative efficacy and safety of i.v. and oral iron supplementation, and any predictive relationship between baseline values of hemoglobin (Hb) and iron handling and response to supplementation. This paper reviews targeted Hb levels in nephrology patients, the optimal management of iron, the use of iron during treatment with erythropoiesis-stimulating agents (ESAs), thrombocytosis and the link to vascular impact, and the interlocking relationship among congestive heart failure (CHF), renal dysfunction, and anemia, and suggests that management of the latter may improve cardiac and renal function and quality of life.


   OPTIMIZING HB
Top
 Abstract
 Introduction
 Optimizing Hb
Iron, Thrombocytosis, and...
 Cardiorenal Anemia Syndrome
 Summary
 Author Contributions
 References
 
Hb Levels: Uncertainties Caused by Optimum Level and Variability
In the otherwise healthy but stable anemic individual, Hb levels vary around the mean with a standard deviation (SD) <0.6 g/dl, but there is no temporal trend over weeks to months [1]. In hemodialysis patients with chronic kidney disease (CKD), the variation in Hb is far broader, and an SD of 1.2 g/dl is typical (Fig. 1). Hence, however successful we are in achieving a given mean value for Hb in our patients, many individual Hb observations will fall outside any recommended range of values over the course of time. Only 8%–18% of dialysis patients maintain a stable Hb concentration throughout a 6- to 12-month period [2, 3]. The reason for paying attention to such Hb variability is the associated morbidity and mortality in hemodialysis patients [3–5]. A full understanding of this phenomenon and its significance remain unclear, but it may relate to the unphysiologic way in which ESAs and iron are used to manage anemia. In CKD patients not on dialysis, the variability in Hb is greater in those receiving than in those not receiving ESAs. In nondialysis CKD patients, parenteral iron is also infrequently used.


Figure 1
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  		Figure 1. In hemodialysis patients with chronic kidney disease, variation around the mean hemoglobin (Hb) is >> normal.

Abbreviation: SD, standard deviation.

 
The current Kidney Disease Outcomes Quality Initiative (KDOQI) goal is for CKD patients to have an Hb level in the 11–12 g/dl range, with an SD of 1.1–1.4 g/dl [6]. The SD in the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial was 0.9 g/dl [7]. If 85% of hemodialysis patients were to have an Hb level >11g/dl, as was achieved in 2005 in the U.S., 63% would have a level in excess of 12 g/dl, and, in any given month, 32% would have values >13 g/dl. Yet the U.S. Food and Drug Administration has recommended a lower upper limit of 12 g/dl. Despite this warning, current practice in the U.S. permits the achievement of a rolling Hb average of up to 13 g/dl over a 3-month period because the Centers for Medicare and Medicaid Services (CMS), the major payer of health care to dialysis patients, reimburses epoetin alfa up to an upper limit of 400,000 IU per month (or 2,000 µg darbepoetin/month).

The upper Hb limit for CKD patients has been set by the meta-analyses of randomized controlled trials (RCTs) on Hb targets, treated with erythropoietin (EPO), suggesting that Hb targets >13 g/dl, versus <12 g/dl, are associated with a higher mortality risk [8]. Indeed, the three largest RCTs—the CHOIR trial (n = 1,433) [9], the Normal Hematocrit Cardiac Trial (NHCT) (n = 1,232), [10] and the Early Anemia Treatment with Epoetin Beta (CREATE) trial (n = 600) [11]—all had trends toward a greater mortality risk. The pooled result showed an all-cause mortality risk of nearly 20% in the higher Hb target groups. The consistency of a direction of greater mortality must be taken seriously. Yet a post hoc analysis of the NHCT, the largest randomized Hb target trial conducted among hemodialysis patients to date, determined that the achieved Hb level was not associated with a higher risk for death [12]. Similarly, Szczech et al. [7] recently showed, in a post hoc analysis of the CHOIR trial, that study patients who achieved their target had better outcomes than those who did not. Among subjects who achieved their target, no greater risk was associated with the higher Hb goal.

In reality, we cannot be certain of the optimum Hb value for CKD/end-stage renal disease patients. To date, no RCTs have compared the outcome when Hb levels are 11–11.9 g/dl with the outcome when they are in the higher range of 12–12.9 g/dl, and it is unlikely that such a trial will be conducted. However, data are available from observational studies of large databases such as those of the U.S. Renal Data System, Fresenius Medical Care, and the national database of a large dialysis organization (DaVita) [13–15]. Analyses of these suggest that the survival time is longer and the hospitalization rate is lower with increasing Hb level [16, 17]. After adjustments for demographic and laboratory information, the time-averaged Hb level of 12–12.9 g/dl was associated with approximately half the mortality rate, compared with an Hb level of 10–10.4 g/dl [18]. No adverse effects of Hb up to a value of 13 g/dl were noted in that study, and they were manifest only after the Hb level exceeded 13.5 g/dl. The dose of ESAs decreased as higher levels of Hb were achieved, which suggests that appropriate titration is being attempted. However, within narrow ranges of Hb, there is a dose-dependent association with mortality [19].

It is important to realize that the health of the patient, the target Hb level, the achieved Hb level, and the ESA dose are all interrelated. It is not possible, from the current literature, to determine the relative importance of a higher Hb level itself as the primary cause of the greater risk for death when targeting higher Hb levels. It should be remembered that there are no RCTs assessing the effects of treating hyporesponsive patients (a group that post hoc analyses suggest are at the highest risk for adverse events) to a lower rather than a higher Hb target (i.e., <11 g/dl rather than 11–13 g/dl). One must be keenly aware of serious confounding from the interrelationship of anemia and ESA resistance with illness in CKD patients. Patients with comorbidities such as malnutrition and inflammation are relatively resistant to ESAs, and invariably require greater cumulative ESA doses to attain target Hb levels. In practice, clinicians can compromise on the dose being used and accept a lower Hb level (either voluntarily or when proscribed by a third-party payer such as CMS) for a given patient; this is not possible within the confines of an RCT, in which the dose is escalated per protocol in hyporesponsive individuals. It is simplistic to attribute the risk simply to the "target" Hb alone for the adverse outcomes achieved in RCTs. Rather, the clinician must realize that a very complex relationship exists between cardiovascular events/mortality and the achieved Hb level and the rate of change in Hb prior to events. In general, a U-shaped curve exists, with a nadir for each Hb stratum for no change in Hb, with risk increasing as the prevailing Hb decreases from 13 g/dl to 10 g/dl [20]. Of course, the ESA dose increases inversely with the prevalent Hb level and, possibly, even more so as the Hb level falls abruptly.

Finally, in most RCTs we simply do not know whether or not iron was being used appropriately as a tool in efforts to reduce the variability in Hb and to minimize the dose of ESA. As an aid in the process of balancing the use of iron and ESAs, several principles can be borne in mind. First, the dose of the ESA should be kept as low as possible. Iron deficiency invariably results in a higher dose of ESA to achieve the same Hb. Secondly, it is important that trends in Hb be carefully analyzed. A falling Hb level in a patient previously sensitive to an ESA suggests interference in erythropoiesis. When the Hb level is likely to exceed 12.5 g/dl, this should be anticipated, and appropriate adjustment should be made to the ESA dose several weeks in advance. However, ESA dose modification should not be in response to isolated Hb values, but rather to the trend. In dialysis patients, these can be obtained twice a month, and any value differing by >1 g/dl from the previous mean value needs to be confirmed before changing the ESA dose. It is quite common to see a rapid increase in Hb following a parenteral course of i.v. iron to correct functional iron deficiency in both nondialysis and dialysis CKD patients.

The Role and Handling of Iron and Measurement of Iron Status
Although EPO and iron are both vital to erythropoiesis, they are involved at different stages of the process of differentiation and maturation from pluripotent stem cell to erythrocyte (Fig. 2) [21–23]. EPO is crucial over an approximately 10- to 13-day period when burst-forming unit–erythroid (BFU-E) cells are transforming into colony-forming units–erythroid (CFU-E) that differentiate into proerythroblasts, because, in its absence, apoptosis within the CFU-E and BFU-E stages occurs [21–23]. During this longer stage of erythropoiesis, very little iron is incorporated into Hb within the cell. In contrast, iron incorporation into Hb synthesis is evident during the second, later, shorter (3–4 days) stage as erythroblasts develop into reticulocytes. At this time, a lack of iron can impair full hemoglobinization of the RBCs, leading to both true and, when less severe, functional iron deficiency.


Figure 2
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  		Figure 2. Erythropoietin (EPO) and iron are both important in erythropoiesis [21–23].

 
In the healthy adult, only 1–2 mg iron per day is absorbed from the intestinal tract, yet the total body stores are much larger. Muscle myoglobin contains about 300 mg of elemental iron, and 600 mg resides in storage within reticuloendothelial macrophages. The great majority of body iron, 1,800–2,000 mg, is incorporated as Hb in circulating erythrocytes (Fig. 3) [24]. Movement among the compartments (muscle, intestine, to and from macrophages, to developing RBCs in marrow) under normal circumstances can only occur through the plasma iron transporting protein transferrin. Each day, around 20–25 mg iron must be delivered to the bone marrow for synthesis of Hb in new RBCs whereas 20–25 mg iron is returned to macrophages through removal of old RBCs by phagocytosis. Yet the total amount of iron bound to transferrin at any moment is only 3 mg. Thus, during normal erythropoiesis, transferrin-bound iron must turn over six to seven times per day.


Figure 3
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  		Figure 3. The balance of iron in the healthy adult: Distribution of iron in adults [24].

 
The key role of transferrin, both in the absorption of iron and in its delivery to tissues, poses a problem for patients with CKD, especially those on dialysis. Because transferrin is a negative acute-phase reactant, its concentration is low in such patients. In the cytokine milieu in CKD, iron-binding capacity is likely to average about 220 µg/dl, versus the normal value of 330 µg/dl, reducing the iron content from 3 mg to 2 mg. From the outset, therefore, the amount of available iron bound to transferrin in the patient is low, and the need to produce 24 ml daily of packed RBCs requires that the iron pool be turned over at least 12 times. Transfer of iron from the gut to plasma and its subsequent movement are regulated by hepcidin. This peptide, an endogenous antimicrobial peptide secreted by the liver, binds, internalizes, and degrades ferroportin—the only means by which iron can be exported from cells, whether they are enterocytes, macrophages of the reticuloendothelial system, or hepatocytes [25]. An assay for hepcidin would therefore be a useful aid in iron diagnostics. In its absence, we depend on three principal diagnostic tests: serum ferritin, transferrin saturation (TSAT), and reticulocyte Hb content (CHr) (Fig. 4A). Although all are easy to use, and none is more than moderately expensive, they differ appreciably in accuracy and variability. The accuracy of serum ferritin is poor as a measure of iron availability in CKD patients, and there is considerable variation among and within the four available assays (Fig. 4B). TSAT (which measures iron bound to transferrin) is moderately accurate, but again highly variable, in part because of diurnal variation. CHr measures Hb entering reticulocytes during terminal differentiation and hence reflects the effectiveness of erythropoiesis. It is highly accurate and, of the three tests, has the lowest coefficient of variability [26]. However, it is the least widely available assay.


Figure 4
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  		Figure 4. Tests to evaluate iron status. (A): Iron diagnostics tests. (B): Attributes of the three iron diagnostic tests.

Abbreviations: CHr, reticulocyte hemoglobin content; Fe, iron; Hb, hemoglobin; MCV, mean corpuscular volume; sFt, serum ferritin; sTfR, soluble transferrin receptor; TSAT, transferrin saturation.

 
Efficacy and Safety of i.v. and Oral Iron in CKD Patients Not Dependent on Dialysis
Iron deficiency is common among CKD patients with anemia. According to data from the National Health and Nutrition Examination Survey 3 study, 35%–40% of CKD grade 3–4 patients (men and women) meet the KDOQI criteria for iron deficiency, that is, they have a TSAT <20% and a ferritin level <100 ng/ml [27]. This proportion rises as patients approach the need for dialysis.

Gotloib et al. [28] prospectively studied the effect of giving 3 months of i.v. iron to 47 nondialyzed CKD patients, only one of whom had evidence of iron availability as shown by deposits in bone marrow, despite a ferritin level >200 ng/ml in the majority. Clearly, serum ferritin is a poor predictor of iron status in CKD patients [28]. By 1 month after the third treatment of i.v. iron, the Hb level had risen from 10.16 g/dl to 11.96 g/dl, the serum iron level had risen from 46.8 µg/dl to 64.3 µg/dl, and the TSAT had risen from 13% to 22%. Serum ferritin (which is a poor indicator of iron status in this population, as in those on dialysis) showed little change, rising from 224 ng/ml to 275 ng/ml. As would be expected following correction of iron deficiency, the transferrin level fell from 235 mg/dl to 204 mg/dl.

In patients with severe anemia who are receiving an ESA, i.v. iron is more effective than oral iron in raising the Hb level. This was well demonstrated by the RCT of Aggarwal et al. [29], who studied iron dextran in patients with an initial Hb level of 5.8–6.3 g/dl. In contrast to such severe anemia, two other trials (both involving iron sucrose), in which patients had higher initial Hb levels of 9.7–9.8 g/dl or 9.9 g/dl, also found a statistical difference between i.v. and oral iron preparations [30, 31]. In the first study, clinical success following weekly 200-mg i.v. iron push over 5 minutes for a total of five doses was evaluated from the perspective of the percentage of patients with combined endpoints of rises in Hb and ferritin; Hb, ferritin, and TSAT; and Hb and TSAT. These CKD patients had increases in both Hb and ferritin following i.v. iron therapy, whereas those treated with oral iron had smaller increases in Hb but without increases in iron stores. Iron sucrose was found to be an effective and safe anemia treatment in this population [30].

Van Wyck et al. [32] conducted another RCT of i.v. iron sucrose (given as 1 g in divided i.v. doses over 14 days) versus 325 mg oral iron given three times daily for 56 days. Patients were not on dialysis, had an estimated glomerular filtration rate (eGFR) <60 ml/minute per 1.73 m2, an initial Hb level ≤11 g/dl, a TSAT ≤25%, and a ferritin level ≤300 ng/ml or lower [32]. Many patients were not on ESAs. In those who were, the dose was maintained unchanged.

Levels of Hb rose significantly faster and further in patients on i.v. iron. After 56 days, 60% of the patients receiving i.v. iron had an Hb level ≥11 g/dl. The comparable figure for patients on the oral formulation was 43%. Almost twice as many i.v. iron patients (44% versus 28%) achieved at least the targeted 1-g/dl increase in Hb. The superiority of i.v. over oral iron was particularly clear in patients receiving ESAs, those with more severe anemia (baseline Hb ≤10 g/dl), and those with a low GFR (≤45 ml/minute). However, with the possible exception of CHr, assays of baseline iron status were of no value in predicting the likelihood of response to i.v. iron.

To some extent, outpatient administration of i.v. iron is limited by the complexity of the procedure (need for multiple doses or long infusion times) and therefore avoided by many medical practitioners. To solve this issue, a new iron formulation that can be given in amounts of 510 mg over <1 minute has been developed [33]. Efficacy was measured early, at day 35, because >1 g of iron could be administered i.v. within 5 ± 3 days. Among patients who were not receiving ESAs, the Hb level increased 0.62 g/dl ± 1.02 g/dl with ferumoxytol and 0.13 g/dl ± 0.93 g/dl with oral iron. Among patients who were receiving ESAs, the Hb level increased 1.16 g/dl ± 1.49 g/dl with ferumoxytol and 0.19 ± 1.14 g/dl with oral iron. More patients in the ferumoxytol group had an Hb increase ≥1.1 g/dl.

Importantly, i.v. iron at the doses used in some of these studies had no adverse effect on renal function. In fact, the evidence was for less GFR decline: The GFR fell by a mean of 1.45 ml/minute per 1.73 m2 in the i.v. iron group, compared with 4.40 ml/minute per 1.73 m2 among patients taking oral iron (p = .01) [32]. The studies of Aggarwal et al. [29] and Stoves et al. [31] also showed no difference in the rate of decline in the GFR between the oral and i.v. iron groups. Changes in the rate of decline in the GFR were not examined in the study by Charytan et al. [30], or in the studies with ferumoxytol.

In terms of oxidative stress, another area of initial uncertainty given the colloidal nature of the material administered, acute i.v. iron administration appears safe: any oxidant effects seen in vivo are transient, long-term clinical trials have shown no adverse effect on renal function, and observational data suggest that this extends even to repeated doses. However, the cumulative iron burden may be of concern. Ferritin levels will increase, and high ferritin can lead to high tissue iron and a pro-oxidant milieu. No long-term safety studies of i.v. iron have been carried out in patients with ferritin levels >500 ng/ml, and evidence of efficacy in this group was limited or nonexistent until the Dialysis Patients Response to IV Iron with Elevated Ferritin (DRIVE) study was performed in three stages [34–36]. The results of that study and epidemiologic observations indicate that the greater prevalence of multiple comorbidities among anemic patients with CKD has made the use of serum ferritin and transferrin saturation more challenging in diagnosing iron deficiency [37]. Because the inflammatory state inhibits the mobilization of iron from reticuloendothelial stores, many patients have a serum ferritin level >800 ng/ml, suggesting iron overload, and transferrin saturation <20%, suggesting iron deficiency. This is where the measurement of hepcidin, a hepatic polypeptide, may provide aid in the pathophysiology of iron mobilization.

Management of iron is an integral part of anemia management in our CKD clinic. We use a Computerized Anemia Management Program that assigns patients to no additional iron, Nephron FA twice daily (a multivitamin supplement with iron), or INFeD® 1 g (an iron dextran injection; Watson Pharmaceuticals, Inc., Corona, CA) based on an initial classification according to ferritin (>500 ng/ml versus <500 ng/ml), followed by a further classification according to TSAT and Hb. Using this program, data on 586 patients suggest that 79% can achieve an Hb level in the target range of 10.5–12.5 mg/dl (Fig. 5). Although infusional iron regimens may not be appropriate in many office settings, the possible approval of novel formulations, such as ferumoxytol, may usefully enhance/extend treatment options in the U.S. and Europe.


Figure 5
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  		Figure 5. The Detroit Computerized Anemia Management Program protocol statistics.

Abbreviation: Hb, hemoglobin.

 

   IRON, THROMBOCYTOSIS, AND CARDIOVASCULAR EVENTS
Top
 Abstract
 Introduction
 Optimizing Hb
 Iron, Thrombocytosis, and...
Cardiorenal Anemia Syndrome
 Summary
 Author Contributions
 References
 
Both a lack of iron and iron excess are associated with a greater risk for thromboembolic events (TEs). Iron deficiency may lead to reactive thrombocytosis [38]. This is usually mild, although severe iron deficiency has been documented as causing marked thombocytosis (>1 million platelets/µl) complicated by central retinal vein occlusion [39]. Cases of cerebral venous sinus thrombosis associated with iron deficiency and a normal platelet count have also been reported [40]. Among six children with iron deficiency and ischemic stroke or venous thrombosis, four had concomitant thrombocytosis [41].

According to a recent review from the University of Giessen, severe anemia along with thrombophilia and hypercholesterolemia are independent risk factors for cerebral venous thrombosis [42].

Iron Deficiency or Overload and Thrombosis: Potential Mechanisms
Franchini et al. [43] describe a range of mechanisms as potential explanations for the link between iron deficiency and thrombosis. In non-CKD patients, there is a correlation between thrombosis and an elevated EPO level [43], and the more severe the iron deficiency the higher the level of endogenous EPO. In this setting, iron repletion rapidly reduces the EPO level.

Secondly, there is a degree of homology in the amino acid sequence between thrombopoietin and EPO [44]. Treatment with EPO can cause functional iron deficiency [34, 45], and this can lead to thrombocytosis [45, 46], which could predispose to a greater risk for cardiovascular events [46].

Thirdly, iron deficiency anemia, particularly in the setting of underlying atherosclerotic disease, may cause platelet aggregation as a result of increased oxidative stress. It has also been suggested that a hypercoagulable state could be induced by the reduced deformability of microcytic RBCs. Finally, anemic hypoxia secondary to iron deficiency could lead to greater metabolic stress.

These hypothesized mechanisms may account for the association between iron deficiency anemia and reversible focal deficits and stroke. Elsewhere in this volume, Spivak et al. [47] discuss additional factors of potential relevance, such as the stimulation by EPO of proinflammatory cytokines and reduction in plasma volume.

In relation to the association between iron overload and thrombosis, evidence is indirect. According to the "iron hypothesis" developed some years ago by Sullivan [48], chronic iron depletion protects against ischemic heart disease and may be responsible for the lower risk for cardiovascular events in menstruating women (although the role of estrogen is a compelling alternative explanation). There are as many trials providing evidence against Sullivan's hypothesis as there are trials supporting it. One study demonstrated accelerated thrombus formation in iron overloaded animals [49]. In this model, control animals, with a serum iron of 161 µg/dl, had all succumbed to carotid artery thrombosis by 120 minutes. Of the iron-loaded animals, with a serum iron level of 226 µg/dl, all died within 40 minutes. However, although this was claimed to be a model of mild iron overload, the accumulation of iron in the spleen and liver suggest otherwise.

Does Iron-Deficient Erythropoiesis Play a Role in the Thrombosis Seen with ESAs?
It was recently argued that treatment with exogenous ESAs can induce functional iron deficiency, and hence increased platelet production, and that this phenomenon underlies the higher than expected rates of TEs seen in certain recent trials [34, 45]. The corollary of this hypothesis is that coadministration of iron and the ESA (or even pretreatment with iron) should diminish ESA-driven thrombocytosis.

The DRIVE study focused on dialysis patients with a very high need for EPO (>20,000 units/week), an Hb level <11 g/dl, a TSAT <25%, and a serum ferritin level >500 ng/ml [34]. Baseline serum ferritin levels exceeded those given in many of the guidelines. Control patients who were not given i.v. iron showed a decrease in serum ferritin with treatment whereas ferritin increased significantly in those receiving i.v. iron. The latter group showed a significantly greater likelihood of achieving the Hb target (46.9% versus 29.2%), leading the authors to conclude that i.v. iron supplementation may be helpful in these patients.

In the DRIVE II study that followed, platelet counts were not reported. However, an editorial comment noted subsequently that iron supplementation in this high ferritin population was associated with a mean decrease of 29,000 platelets/µl. The relevance of such a reduction in avoiding thromboembolic complications in our patients is not yet clear. Among patients given ferric gluconate, transferrin saturation rose from baseline to the end of week 6 and then fell back toward the starting value over the next 12 weeks [35]. Among control patients, levels had fallen below baseline at the end of week 6 and remained low.

In long-term hemodialysis patients, TSAT shows a steady and consistent decline as blood platelet counts rise over the range 100,000–400,000/µl [15]. This observation is of an association only, but is compatible with a causative relationship between iron deficiency and elevated platelet count.

In this same group (of >40,000 patients), the hazard ratio (HR) for all-cause mortality (at all Hb levels) was higher in the 15% of patients with relative thrombocytosis (a platelet count >300,000/µl) than in those with lower values [15]. Again, in the same group of patients, the HR for 3-year, all-cause mortality rose with increasing number of recombinant human EPO (rHuEPO) units administered per week (averaged over each calendar quarter). The HR was around 0.8 when 1–5,000 units rHuEPO were administered, around 1 with 10–15,000 units administered, and >1.4 when ≥25,000 units are given. The odds ratios for iron depletion and for relative thrombocytosis both increased significantly with the amount of rHuEPO administered. The likely explanation for the link with thrombocytosis is the homology between EPO and thrombopoietin [44]. Fifty percent of patients with a low TSAT (<20%) and a normal or high ferritin level have evidence of ongoing inflammatory processes, which may be a contributory factor in the higher risk for thrombosis.

The precise criteria for iron overload and deficiency in the CKD population remain unclear, and the conventional definition of a normal ferritin level as >500 ng/ml was brought into question by this study [15]. The upper serum ferritin limit of 500 ng/ml is opinion based. More than 50% of the dialysis patient population in the U.S. have a ferritin level >500 ng/ml. Significantly higher mortality occurs only at a serum ferritin level >1,200 ng/ml [46].

The multivariate-adjusted association between quarterly serum ferritin and all-cause mortality over 2 years in >58,000 maintenance hemodialysis patients showed a new KDOQI range >200 ng/ml, compared with the old KDOQI range of up to 800 ng/ml [46].


   CARDIORENAL ANEMIA SYNDROME
Top
 Abstract
 Introduction
 Optimizing Hb
 Iron, Thrombocytosis, and...
 Cardiorenal Anemia Syndrome
Summary
 Author Contributions
 References
 
Anemia is frequent in patients with CHF. In a major meta-analysis of 34 studies, the prevalence of anemia was 37.2% [50]. In the same analysis, the HR for mortality associated with anemia was 1.46 (p < .001). Prospective data from the Mayo Clinic show that patients with anemia have a higher mortality rate than those with normal Hb levels throughout the first 3 years following a diagnosis of heart failure [51]. Taking into account the effect of other relevant risk factors, the 2-year mortality rate is ~20% in patients with an Hb level of 14–15.9 g/dl, but double that in patients with an Hb level <10 g/dl. The risk for hospitalization among patients with an Hb level <9 g/dl is double that of CHF patients with an Hb level in the range of 13–13.9 g/dl [52]. Among patients in the Studies of Left Ventricular Dysfunction, a randomized placebo controlled study of angiotensin-converting enzyme (ACE) inhibitors in asymptomatic and symptomatic systolic heart failure, progressive reductions in hematocrit and in the GFR had additive and independent effects on the relative risk (RR) for mortality [52]. Among these CHF patients, Hb level was an independent predictor (along with older age, female sex, nonwhite ethnicity, worsening ejection fraction, and New York Heart Association [NYHA] class) of rapid progression of CKD [54, 55]. Interestingly, although severity of heart failure and severity of anemia independently predicted worsening renal function, the presence of diabetes and hypertension and the use of diuretics or ACE inhibitors did not [54, 55]. Such findings pose the important question: Why is anemia so damaging to the cardiovascular and renal system?

The Cardiovascular Effects of Anemia
Comparing nonanemic CHF patients with people who are anemic (because of iron deficiency or blood loss) but not in heart failure shows an intriguing pattern of similarities and differences [56, 57]. Relative to relevant controls, nonanemic CHF patients show substantially greater systemic vascular resistance, because these patients by definition have reduced cardiac output. In "pure" anemia, in contrast, systemic vascular resistance is lower [56]. Plasma volume is increased in both settings, but more so in patients with pure anemia. Renal blood flow falls markedly in otherwise normal anemic patients, as it does in nonanemic CHF patients. Anemia without heart failure is associated with a rise in norepinephrine, renin, aldosterone, atrial natriuretic peptide (ANP), and vasopressin, as is CHF without anemia. Correction of anemia by blood transfusion returns all these parameters to normal [56]. Hence, anemia per se is associated with many of the same pathophysiological changes that are seen in heart failure [56, 57]. It is therefore not surprising that it has an independently damaging effect.

It appears that anemia can exacerbate heart failure through a vicious circle in which tissue hypoxia and release of nitric oxide cause peripheral vasodilation, leading to decreased blood pressure, which causes increased sympathetic activation, renal vasoconstriction, reduced renal function, and activation of the renin–angiotensin aldosterone system and vasopressin (Fig. 6A) [56, 58, 59]. This in turn leads to fluid retention, left ventricular hypertrophy and dilatation, worsening heart failure, release of B-type natriuretic peptide (BNP) arising from stress on the myocardium, and, to complete the vicious circle, further anemia [56, 58, 59]. The cardiorenal anemia syndrome is shown diagrammatically in Figure 6B.


Figure 6
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  		Figure 6. Pathophysiology of the cardiorenal anemia syndrome. (A): Schematic diagram showing how anemia causes fluid retention and heart failure [56, 58, 59]. (B): Anemia and progression of cardiovascular disease: the cardiorenal anemia syndrome.

Abbreviation: ADH, antidiuretic hormone; BNP, brain natriuretic peptide; CHF, congestive heart failure; GFR, glomerular filtration rate; LVH, left ventricular hypertrophy; NO, nitric oxide.

 
At the Mayo Clinic, the mean Hb level in hospitalized CHF patients fell from 12.3 g/dl in 1987 to 11.7 g/dl in 2002 [60]. The increased prevalence of anemia in CHF over this period could be a result of a variety of factors, such as greater age (mean, 74 years in the 2002 sample versus 72 years for patients admitted to the hospital in the 1987 sample), a higher prevalence of diabetes (39% versus 31%), and poorer renal function as reflected in a lower mean GFR (55 versus 73 ml/minute per 1.73 m2) and higher creatinine level (1.72 versus 1.46 mg/dl).

The anemia of CHF is likely a result of several factors, including: decreased EPO production in the kidney because of renal failure, increased release of cytokines such as interleukin-6 and tumor necrosis factor-{alpha}, which also cause decreased EPO production in the kidneys, as well as increased EPO resistance in the bone marrow, decreased iron absorption from the gut, and decreased release of iron from the reticuloendothelial system [61–64]. There are potentially also adverse effects of treatment of CHF on the hematopoietic system. ACE inhibitors may increase the risk of developing anemia because angiotensin stimulates the production of RBCs. Its blockade results not only in a reduction in that stimulus but also the release of the inhibitor of RBC proliferation N-acetyl-seryl-aspartyl-proline. Angiotensin receptor blockers also contribute to anemia by reducing access of angiotensin II, a growth factor for early erythroid progenitor cells. Other factors may also cause anemia, including hemodilution, diabetes (which decreases EPO production and increases EPO resistance), blood loss from the stomach and colon caused by aspirin or warfarin, and atrophic gastritis leading to reduced absorption of iron and vitamin B12 [61–64].

The Effect of Treating Anemia on CHF
Ten controlled studies have investigated the effect of using ESAs to treat anemia in CHF patients [65]. These studies succeeded in raising the mean Hb level to 12–13 g/dl, with no adverse effects and some benefits. The use of ESAs with oral or i.v. iron (in controlled and uncontrolled studies) has been associated with significant improvements in exercise capacity, oxygen use, left ventricular ejection fraction (LVEF), left ventricular hypertrophy and dilation, NYHA class, BNP, renal function, fatigue, caloric intake, and overall quality of life [65]. Sleep apnea is common in CHF patients, and a reduction in the number of these events, along with increased levels of oxygen saturation during sleep, has also been seen with anemia correction with rHuEPO and i.v. iron [66].

A pooled analysis of 473 patients included in the Study of Anemia in Heart Failure—Heart Failure Trial [67] and another controlled trial of darbepoetin [68] showed a significantly lower risk for the combined endpoint of all-cause mortality or first heart failure-related hospitalization (HR, 0.67; confidence interval, 0.44–1.03; p = .06) in patients treated with the ESA rather than placebo [67, 68]. In a recent meta-analysis of seven of these randomized trials of erythropoietic agents in CHF patients, including 363 treated patients and 287 controls, there was a significantly lower risk for CHF hospitalization (RR, 0.59; p = .006) [69]. No differences occurred in mortality or in the incidence of hypertension, venous thrombosis, pulmonary embolus, cerebrovascular disorder, myocardial infarction, or other cardiovascular events [69].

The data monitoring committee scrutinizing early results from the ongoing Reduction of Events with Darbepoetin alfa in Heart Failure study, a double-blind, multicentered, placebo-controlled trial of darbepoetin in anemic CHF patients, which now includes >1,000 patients treated for 6–18 months and has an Hb target of 13 g/dl, also found no evidence of a higher frequency of adverse events in the treated group [70].

In total, almost 4,000 patients have been entered into the current double-blind, placebo-controlled Trial to Reduce Cardiovascular Events with Aranesp® (Amgen, Thousand Oaks, CA) Therapy study of darbepoetin in nondialyzed diabetic patients with renal insufficiency and an initial Hb level of 9–11 g/dl [71]. The target Hb level in that trial is 13 g/dl. The data safety monitoring board has not recommended any change in the conduct of the study, suggesting there is no excess in adverse events so far in the treated group.

In addition to increasing Hb, it is thought that EPO can have other potentially beneficial effects in CHF patients. These include reduced apoptosis of myocytes, reduced cardiac fibrosis, and reduced secretion of inflammatory mediators, a positive antioxidant effect, and neovascularization. The latter effect was demonstrated in a rat model of myocardial infarction [72].

Three recent studies of i.v. iron alone in anemic CHF patients, two uncontrolled studies [73, 74], and one double-blind placebo-controlled study [74], have shown improved Hb, LVEF, NYHA class, left ventricular hypertrophy, and dilation, reduced heart rate and pulmonary artery pressure, and superior quality of life, exercise capacity, renal function, BNP, C-reactive protein, and hospitalization rate. The higher the dose of i.v. iron given, the greater the Hb response. These studies suggest that iron deficiency may play a key role in the anemia of CHF. Large controlled studies on this subject are currently in progress.


   SUMMARY
Top
 Abstract
 Introduction
 Optimizing Hb
 Iron, Thrombocytosis, and...
 Cardiorenal Anemia Syndrome
 Summary
Author Contributions
 References
 
Iron deficiency is common during ESA treatment of anemia in a wide number of circumstances. Observational studies, post hoc analyses of RCTs, and clinical experience have pointed to an excess in thrombotic vascular events in such ESA-treated patients. Although ESAs may have direct procoagulant effects when administered in supraphysiologic amounts, recent analyses have pointed to iron deficiency and changes in platelet number and reactivity as possible contributors to this excess risk. There is no level A evidence (RCT) that avoidance of iron deficiency under all conditions of treating anemia with ESAs will reduce vascular events. An RCT to examine the question directly cannot be done on ethical grounds. Which of several possible mechanisms is operating to increase the observed risk associated with iron deficiency cannot be discerned from the observational/analytical data available, but iron-induced changes in platelet number or reactivity should be cause for concern. We believe that changes in platelet reactivity are more likely to be the culprit, but also more difficult to prove than changes in platelet number. Good clinical practice dictates that iron deficiency, functional or absolute, should be avoided.


   AUTHOR CONTRIBUTIONS
Top
 Abstract
 Introduction
 Optimizing Hb
 Iron, Thrombocytosis, and...
 Cardiorenal Anemia Syndrome
 Summary
 Author Contributions
References
 
Conception/design: Anatole Besarab, Walter Hermann Hörl, Donald Silverberg

Manuscript writing: Anatole Besarab, Walter Hermann Hörl, Donald Silverberg

Final approval of manuscript: Anatole Besarab

The authors take full responsibility for the content of this article and thank Rob Stepney, medical writer, and Julia O'Regan, Bingham Mayne and Smith, Edinburgh, supported by an educational grant from Ortho Biotech, a division of Janssen-Cilag Europe, for their assistance in preparing a first draft of the manuscript based on an oral presentation at a meeting held on November 20, 2008 in Sitges, Spain, organized by a Scientific Committee of Matti Aapro, Mario Dicato, Pere Gascón, Francesco Locatelli, Jerry Spivak, and Jay Wish.


   REFERENCES
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 Abstract
 Introduction
 Optimizing Hb
 Iron, Thrombocytosis, and...
 Cardiorenal Anemia Syndrome
 Summary
 Author Contributions
 References
 

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