Anemia in Chronic Kidney Disease

9 Anemia in Chronic Kidney Disease Jeffrey S. Berns, MD, Tiffany C. Wong, MD, and Solomon Dawson, MD OUTLINE Pathogenesis, 136 Clinical Consequences of Anemia and Effects of Correction, 137 Health-Related Quality of Life (HRQoL), 137 Cognitive Function, 137 Cardiovascular Disease and Mortality, 138 Therapies for Chronic Kidney Disease–Related Anemia, 138 Erythropoiesis-Stimulating Agents, 138

Iron, 140 Other Therapies, 142 Target Hemoglobin Levels for Erythropoiesis-Stimulating Agent–Treated Patients, 142 Data From Clinical Trials, 142 US Regulatory and Fiscal Policy, 143 Clinical Practice Guidelines for ErythropoiesisStimulating Agents and Iron Therapy, 143 Erythropoiesis-Stimulating Agent Hyporesponsiveness, 143

Anemia, a reduction in blood hemoglobin (Hgb) concentration or hematocrit (Hct), is common among patients with chronic kidney disease (CKD), stemming primarily from a reduction in endogenous erythropoietin production by the diseased kidneys. There is an incremental and monotonic increase in the prevalence of anemia with reduced glomerular filtration rate (GFR).1 Using the World Health Organization (WHO) definition of anemia as a Hgb concentration less than 13.0 g/dL for adult males and postmenopausal women, and an Hgb less than 12.0 g/dL for premenopausal women,2 as many as 90% of patients with CKD and a GFR less than 30 mL/ min have anemia, and many have Hgb levels less than 10 g/ dL.3 The prevalence of anemia in any population sample with CKD varies depending on the level of GFR and definition of anemia. In general population studies, the prevalence of anemia defined as an Hgb level less than 11.0 g/dL was approximately 1.3%, 5.2%, and 44.1% among patients with estimated GFRs of 60 to 89, 30 to 59, and 15 to 29 mL/min/1.73 m2, respectively.4 The low Hgb concentration in individuals with anemia reduces the oxygen carrying capacity of blood and in turn reduces tissue oxygenation delivery, which may adversely affect health and quality of life and predispose individuals to excess morbidity and mortality. There has been a proliferation of research and clinical practice guidelines seeking to define the effects of anemia and its treatments in patients with CKD, including those on dialysis, and to identify therapeutic goals that maximize health outcomes. Limitations of treatments for CKD-associated anemia and the potential risks of such therapies have also been more clearly delineated. In this chapter, we discuss the pathogenesis of anemia in CKD, the clinical consequences of anemia, current therapies, and recommended therapeutic goals for patients with CKD. 

PATHOGENESIS

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Anemia in CKD is characterized by a normochromic normocytic appearance of circulating red blood cells without the expected increase in bone marrow erythroid progenitor cells and circulating reticulocytes expected with an observed low Hgb concentration. The anemia associated with CKD derives principally from inadequate production of the hormone erythropoietin by the kidneys, with reduced red cell life span and other factors contributing.5 Identification and purification of erythropoietin and cloning of the erythropoietin gene led to the production of a recombinant erythropoietin hormone6,7; therapeutic administration of this agent confirmed the primacy of erythropoietin in the pathogenesis of the anemia from CKD.8,9 Impairment of the erythropoietic response to endogenous or exogenous erythropoietin due to the “uremic milieu” may also contribute to the anemia of CKD, with various polyamines, parathyroid hormone, and inflammatory cytokines being other potential inhibitors of erythropoiesis.10 Interestingly, recent evidence has demonstrated the capacity to pharmacologically stimulate erythropoietin synthesis by the kidneys even in individuals with very advanced kidney disease and anemia.11 Erythropoietin is a circulating glycoprotein of 165 amino acids with three N-linked and one O-linked carbohydrate chains. Before birth, the hormone is produced in the liver, whereas postnatally it is synthesized primarily by peritubular interstitial cells in the kidneys.12 Erythropoietin is normally present in the circulation in low concentrations (0.01 to 0.03 U/mL) under basal conditions, but the concentration increases 100-fold to 1000-fold in response to hypoxia and anemia,13 in a process regulated by hypoxia-inducible factor-1 (HIF-1). HIF-1 is a transcription factor that binds to a hypoxia response element in the erythropoietin gene and other hypoxia-responsive genes, increasing their transcription; expression of the HIF-1α subunit of the HIF-1 complex

CHAPTER 9  Anemia in Chronic Kidney Disease increases rapidly in response to hypoxia, whereas in the presence of oxygen, HIF-1α rapidly undergoes proteosomal degradation after ubiquitination by the von Hippel–Lindau protein complex.14,15 Erythropoietin receptors are present on erythroid precursors, with the greatest expression on colony forming unit-erythroid cells; stimulation by erythropoietin induces their proliferation and maturation into mature erythrocytes. Erythropoietin receptors are not found on mature red blood cells. The erythropoietin receptor is a preformed dimer. Binding of erythropoietin to the receptor changes its conformation, leading to activation of the intracellular mediator kinase Janus kinase-2 (JAK-2) via transphosphorylation, subsequent phosphorylation of other intracellular tyrosine kinases, and stimulation of a complex signal transduction cascade that eventuates in erythrocyte production.16,17 Erythropoietin deficiency and the anemia of CKD may be preceded or exacerbated by states of absolute or functional iron deficiency; these will be discussed in detail later in this chapter. In addition, patients with CKD may have anemia on the basis of other conditions, such as vitamin B12 or folate deficiency, bleeding, hemolysis, infection/inflammation, bone marrow infiltration, inherited hemoglobinopathies, and medications. Among patients on chronic hemodialysis (HD), other factors include blood loss during the dialysis treatment, subclinical infection, or inflammation related to HD catheters or thrombosed synthetic bridge grafts, severe secondary hyperparathyroidism, and grossly inadequate dialytic solute clearance. 

CLINICAL CONSEQUENCES OF ANEMIA AND EFFECTS OF CORRECTION Health-Related Quality of Life (HRQoL) The symptoms of anemia are nonspecific and can overlap with those of advanced kidney failure and uremia. They include fatigue, shortness of breath and dyspnea on exertion, impaired exercise tolerance, difficulty concentrating, headaches, lightheadedness, impaired sexual function, and diminished sense of well-being. Before the availability of recombinant human erythropoietin and other similar agents, many patients on dialysis had Hgb levels in the range of 5 to 7 g/dL.8,18 Once it became possible to improve Hgb levels with recombinant human erythropoietin in both dialysis patients and patients with CKD not on dialysis, it became clear that various measures of health-related quality of life (HRQoL) improved in association with partial correction from very severe to more moderate degrees of anemia.19-22 There has been a renewed interest in this area, particularly as the potential benefits and risks of using erythropoiesis-stimulating agents (ESAs; a general term that will be used in this chapter to refer to the recombinant human erythropoietin, darbepoetin, and other similar or related pharmacological preparations) to raise Hgb levels from moderate to more normal Hgb levels have been examined. With this intervention, improvement in various HRQoL parameters, such as physical function, energy, and fatigue, school performance in

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children, and vitality, as well as reduction in hospitalization rates have been documented in some randomized controlled trials and observational cohort studies, whereas other studies have found minimal or no benefit.23-31 A recent metaanalysis of 17 randomized controlled trials concluded that use of ESAs to raise Hgb levels did not significantly improve overall HRQoL in patients with CKD, including those on dialysis.32 Heterogeneity among the patient populations studied and the short duration of most studies is a limitation of assessments of HRQoL in this population, and the long-term persistence of HRQoL benefit occurring in response to anemia in CKD patients remains unknown. Depending on the instrument used for assessment and the population studied, some HRQoL domains, such as fatigue and vitality, may show more improvement than others such as social and emotional functioning, mental health, and pain. In addition, some domains not measured by some of the more commonly used instruments such as sleep, cognitive functioning, and sexual functioning may improve with ESA treatment.33 In the absence of definitive evidence in this regard, the US Food and Drug Administration (FDA) revised ESA product labeling to remove claims that ESAs improve patients’ quality of life, symptoms of anemia, fatigue, or general well-being. Nonetheless, it is still recommended that ESA therapy be individualized, particularly in younger patients, a group that has not been well studied, and in those with fewer comorbidities.34-37 

Cognitive Function Decreased oxygen delivery to the central nervous system is expected to result in impairment in cognitive function, an effect that should be amenable through anemia correction. A number of randomized trials have demonstrated a favorable effect of anemia treatment on cognitive function in dialysis patients. In this population, full38 and partial39 anemia correction have been demonstrated to improve performance on neuropsychiatric testing and electrophysiological markers of cognitive function. Additional evidence suggests that complete normalization of Hgb is superior to partial correction in this regard,40 an effect that must be weighed against potential detrimental effects on survival (discussed in the next section). Partial anemia correction has also been associated with improvement in intelligence quotient, concentration, memory, and speed of information processing,41 as well as improvements in sleep quality and wakefulness.42 To date, little work has been done to examine the cognitive effects of anemia correction among patients with earlier stages of CKD who are not on dialysis. One study demonstrated that anemia correction results in improvement in electrophysiological markers of cognitive function,43 but none have examined clinical outcomes such as neuropsychiatric testing. Given the lesser severity of anemia in the milder stages of CKD, it is unclear whether extrapolation of data from dialysis patients is warranted. In fact, in a recent prospective observational study, anemia (using the WHO definition) was not associated with either baseline cognitive impairment or change in cognitive function over time.44 Thus for CKD patients who are not on dialysis, provision of anemia therapy with the intent of improving cognitive function is probably not warranted at this time. 

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Cardiovascular Disease and Mortality As Hgb concentration falls, there is a commensurate reduction in blood-oxygen carrying capacity. To maintain constant tissue oxygen delivery, cardiac output is increased via augmentation of heart rate and stroke volume in conjunction with peripheral vasodilatation. As part of the compensatory process, left ventricular geometry is altered, with increases in left ventricular end-diastolic volume and wall thickness. Thus left ventricular hypertrophy (LVH) is common among patients with CKD,45 and its prevalence is strongly associated with the degree of anemia.46 In this population, LVH is a potent marker for cardiovascular morbidity and mortality,47 with observational data demonstrating a clear association between greater degrees of anemia and increased risk of myocardial infarction, stroke, cardiovascular events, and all-cause mortality among patients with CKD.48 These observations led some to hypothesize that anemia correction would result in both an improvement in left ventricular geometry with reduction in LVH (e.g., decreased hypertrophy) and better cardiovascular outcomes. Studies have demonstrated a beneficial effect of partial correction of severe anemia on cardiac structural markers among patients with CKD not on dialysis.49-51 Anemia therapy has been shown to induce regression of LVH and echocardiographic evidence of favorable left ventricular remodeling. Evidence suggests that complete correction of anemia to normal Hgb levels does not provide benefit beyond partial correction in this regard.24,52,53 Similarly, studies generally have failed to demonstrate a beneficial effect of normalization or near-normalization of anemia therapy on clinical cardiovascular outcomes among HD patients and patients with CKD not on dialysis.24,53-55 In the only large randomized placebo-controlled trial of ESA therapy (darbepoetin) in diabetic patients with CKD not on dialysis, treatment did not reduce death or occurrence of adverse cardiovascular events, but was associated with an increased stroke risk.29,56,57 Among patients with CKD who are not on dialysis, observational studies suggested that higher Hgb levels were associated with improved survival,48,58 and that anemia therapy was associated with improved longevity among patients going on to require dialysis.59,60 Observational studies examining the association

between higher Hgb levels and mortality among patients on hemodialysis have yielded mixed findings, with some demonstrating a benefit,61-65 and others not.26,66,67 However, Hgb levels are likely to reflect underlying health status, suggesting that these findings may be confounded. Several large randomized trials, including the placebo-controlled study noted previously, have not demonstrated a mortality benefit of ESA treatment aimed at restoring normal or near-normal Hgb levels.24,54,55,57,68 Recent systematic reviews and updated clinical practice guidelines have cautioned against the normalization of Hgb levels with ESA treatment in dialysis and nondialysis CKD patients.35,69-71 

THERAPIES FOR CHRONIC KIDNEY DISEASE– RELATED ANEMIA Erythropoiesis-Stimulating Agents Since the first descriptions of the use of recombinant human erythropoietin in hemodialysis patients in the late 1980s,8,18 ESAs have been the mainstay of anemia therapy for anemia in adults and children with CKD including those not on dialysis, on HD and peritoneal dialysis, and after renal transplantation. Many studies have demonstrated the efficacy of ESAs in raising blood Hgb concentration. Erythropoietin alpha was the first ESA approved for use and was demonstrated to be superior to placebo in this regard among patients with CKD.8,18,72,73 Currently available ESAs are a class of recombinant preparations of human erythropoietin or its structural analogs, although other types of agents are undergoing clinical trials. In the United States, this includes epoetin alpha, darbepoetin alfa, and methoxy polyethylene glycol-epoetin beta (Table 9.1). A variety of other similar agents are available in other countries. Recombinant human erythropoietin (epoetin) has an identical amino acid backbone as the native hormone and has biochemical and immunological properties that are virtually indistinguishable from human erythropoietin. Darbepoetin alfa is a hyperglycosylated structural analog of recombinant human erythropoietin with a five amino acid substitution and five N-linked carbohydrate chains, two more

TABLE 9.1  Erythropoiesis Stimulating Agents Approved for Use in the United States Preparation

Approved Starting Dosagea

Commentsb

Epoetin alpha

50–100 U/kg 3 times per wk

Darbepoetin alpha

0.45 mcg/kg IV or SC weekly or 0.75 mcg/kg every 2 weeks

Methoxy polyethylene glycol-epoetin beta

0.6 mcg/kg every 2 weeks

IV recommended in HD patients Weekly or every 2 wk SC dosing typically used in patients with CKD not on dialysis US dosage forms: 2000; 3000; 4000; 10,000; 20,000; 40,000 U/mL IV recommended in HD patients Weekly to monthly dosing typically used US dosage forms: 10, 25, 40, 60, 100, 150, 200, 300, 500 mcg/0.4–1.0 mL IV or SC administration Every 2 wk to monthly dosing typically used US dosage forms: 30, 50, 75, 100, 200 mcg/0.3 mL

aAll

require subsequent dose titration depending on goal Hgb level. facilities typically use specific dosing protocols. In many patients with CKD not on dialysis and on home dialysis, unit-based dosing rather than weight-based dosing will be used. CKD, Chronic kidney disease; HD, hemodialysis; Hgb, hemoglobin; IV, intravenous; SC, subcutaneous. bDialysis

CHAPTER 9  Anemia in Chronic Kidney Disease than erythropoietin, which increases the potential maximum number of sialic acid residues from 14 to 22, increases its in vivo potency, and extends its serum half-life approximately twofold to threefold.74 Methoxy polyethylene glycol-epoetin beta is a chemically synthesized substituted analog of erythropoietin with receptor-binding kinetics that are different from other ESAs and a very low plasma clearance. The biological half-life is approximately 6 times greater than darbepoetin and 20 times greater than epoetin alpha.75-77 “Biosimilar” erythropoietic agents (also termed follow-on biologicals)78 have been approved for use in the European Union and elsewhere but are not yet approved in the United States. These agents are similar to already approved biological medicines such as recombinant human erythropoietin. Due to inherent heterogeneity of biological agents, including biosimilar ESAs, different regulations are required compared with other generic medications. As such, specific regulatory approval pathways have been established in the United States, Europe, and elsewhere that allow for approval of these products as being similar but not necessarily identical to the original product.79 Although it is difficult to directly compare two versions of a biopharmaceutical agent and prove equivalent efficacy and safety, studies to date suggest that most of these agents are generally equivalent to ESAs previously in use, although further analysis is needed to confirm that the side-effect profile is also similar.80-82 Currently available ESAs can be given in patients with CKD not on dialysis and in patients who are on dialysis by either intravenous (IV) or subcutaneous (SC) administration. Although the clinical efficacy of darbepoetin and methoxy polyethylene glycol-epoetin beta appear to be similar regardless of whether they are administered IV or SC, studies have found that the shorter-acting epoetin is more effective by approximately 50% when administered subcutaneously.83 Each of these may be administered by IV or SC injection. SC administration is generally preferred for those patients with CKD who are not on dialysis or who are on home hemodialysis or peritoneal dialysis, whereas the approved prescribing information for those treated by maintenance HD in the United States recommends IV administration of epoetin and darbepoetin with either IV or SC administration of methoxy polyethylene glycol-epoetin beta. Unlike currently available ESAs, which require parenteral (IV or SC) administration, a new class of orally available agents is undergoing testing in clinical trials and may be available in the near future. Hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors stimulate endogenous synthesis of erythropoietin and also enhance iron utilization.84-88 If approved, these agents have the potential to markedly change anemia management in patients with CKD, including those on dialysis, due to their oral administration, avoidance of high peak levels of ESAs, and beneficial effects on iron utilization and balance.89 SC administration of one particular formulation of erythropoietin alpha has been associated with an unusually high risk of developing neutralizing antierythropoietin antibody-mediated pure red cell aplasia (PRCA)90; fortunately,

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with product reformulation, PRCA related to its use appears to have largely disappeared.91 Isolated instances of antibody-mediated PRCA related to other ESAs have been rarely reported.91,92 Recommendations vary regarding the initial ESA dosing regimen and the specific Hgb level at which initiation of ESA therapy should be considered. Depending on individual circumstances, an Hgb level <10 g/dL is often considered an appropriate level in many patients to start an ESA, provided that iron deficiency and other causes of anemia have been excluded or treated (Table 9.2).71 Once started, usage should be tailored to individual clinical circumstances, patient comorbidities, pretreatment Hgb levels, and quality-of-life expectations. In addition, after initiation of ESA therapy, care should be taken to titrate dosing to maintain Hgb levels in the desired range (generally in the range of 10 to 11.5 g/dL), avoid targeting and maintaining Hgb levels greater than 13 g/dL (discussed in the next section), and to ensure adequate provision of iron necessary for adequate erythropoiesis.35,71,93 The short-acting epoetin is typically administered three times weekly to maintenance HD patients and once every 1 to 2 weeks in patients with CKD who are not on dialysis.94,95 Darbepoetin and methoxy polyethylene glycol epoetin beta, with their longer biological half-lives, can often be effectively administered once or twice monthly.96-99 Besides induction of iron deficiency, the primary adverse effects of ESAs are exacerbation of hypertension and hemodialysis access thrombosis.100 As discussed elsewhere in this chapter, in several large prospective, randomized controlled trials, however, hemodialysis patients and patients with CKD not on dialysis targeted to achieve normal or near-normal Hgb levels tended to have poorer outcomes, leading to an ongoing discussion of whether the high ESA doses (needed to achieve higher Hgb levels) are directly toxic in some way.24,53-55 A secondary analysis of one of the recent large trials in patients with CKD suggested that high ESA doses appeared to independently explain the poorer outcome in patients assigned to the higher Hgb target group.101 Others have also found that requiring or receiving higher ESA doses was independently associated with higher mortality.63 This has led some to speculate that particularly high doses of ESAs may have adverse effects on survival not mediated by changes in Hgb concentration,101-103 although the mechanism for this effect, if real, remains obscure. Nonetheless, this has led to increasing caution about the use of very high ESA doses. Two other concerns with ESA therapy relate to use in patients with a history of stroke or malignancy. The TREAT study found an increased risk of stroke among patients with CKD receiving darbepoetin, particularly in those with a prior stroke, and also noted an increased risk of cancer-related death in those with a history of cancer.30 An increased stroke risk with ESAs was also seen in an older study among dialysis patients104 and a more recent study among US veterans with CKD105 but not others.106,107 Nonetheless, caution is advised about ESA use in patients with a history of stroke or malignancy.35,71 

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TABLE 9.2  Kidney Disease: Improving Global Outcomes Guidelines for Anemia Management

(2012)71

Use of iron agents

Iron monitoring Cautions regarding IV iron Initiating use of ESAs

ESA maintenance therapy Cautions regarding ESA use

Balance the potential benefits of avoiding or minimizing blood transfusions, ESA therapy, and anemia-related symptoms against the risk of harm in individual patients Suggest a trial of IV iron (or in CKD ND patients alternatively a 1–3 mo trial of oral iron therapy) if an increase in Hgb concentration, avoidance of an ESA or an ESA dose reduction is desired, if TSAT is <30% and ferritin is <500 ng/mL Evaluate iron status (TSAT and ferritin) at least every 3 mo during ESA therapy; more frequently when initiating or increasing ESA dose, with blood loss, after a course of iron Monitor for 60 min after infusion with iron dextran (recommended) and other irons (suggested) Avoid administering IV iron to patients with active systemic infections Suggest ESA therapy not be initiated for CKD ND patients with Hgb ≥10 g/dL Individualize decision to initiate ESA therapy in CKD ND patients with Hgb <10 g/dL Suggest ESA therapy be used in CKD 5D patients to avoid having Hgb <9.0 g/dL by initiating ESA when Hgb is 9.0–10.9 g/dL Suggest ESAs not be used to maintain Hgb >11.5 g/dL Individualize therapy as some patients may have improvement quality of life with Hgb <11.5 g/dL and be willing to accept the risks Use ESA therapy with great caution, if at all, in CKD patients with active malignancy, history of stroke, or history of malignancy Recommend that ESAs not be used to intentionally increase Hgb >13.0 g/dL In patients with ESA hyporesponsiveness, suggest avoiding repeated dose escalations beyond doubling the initial weight-based dose

CKD, Chronic kidney disease; CKD ND, CKD not on dialysis; CKD 5D, patients on dialysis; ESA, erythropoiesis-stimulating agent; Hgb, hemoglobin; IV, intravenous; TSAT, transferrin saturation.

Iron Adequate iron stores are essential for erythropoiesis, whether in response to endogenous erythropoietin or ESA therapy. Because erythropoiesis itself consumes iron, assessment of the adequacy of available iron before and during ESA administration is a routine part of anemia management in patients with CKD, including those on dialysis. Inadequacy of iron can take one of two forms: absolute iron deficiency and functional iron deficiency. Absolute iron deficiency is defined by a lack of bone marrow iron and is common among hemodialysis patients, in particular, due to loss of iron via the dialytic circuit, access surgery, and frequent phlebotomy, but is also common among CKD patients who are not on dialysis. Although the diagnosis of absolute iron deficiency in this population has been suggested by transferrin saturation (TSAT) <20% or serum ferritin level <100 ng/mL for patients with CKD not on dialysis or on peritoneal dialysis and <200 ng/mL for hemodialysis patients,108 these tests are of rather low sensitivity and specificity.109-112 In fact, little or no bone marrow iron may be present in patients with CKD despite serum ferritin and TSAT levels that would not have predicted such severe iron deficiency.112,113 As such, simply supplementing iron and observing whether there is an increase in Hgb and/or a reduction in required ESA dose for a goal Hgb level is often undertaken in practice. Other markers of iron status and availability are also used, primarily outside the United States, which may have better operational characteristics compared with serum ferritin and TSAT.110,111,114 Functional iron deficiency is defined by normal bone marrow reticuloendothelial iron stores, but inability to mobilize iron for erythropoiesis, usually stemming from systemic

inflammation and/or malnutrition.115,116 Complexities of iron handling in the body and the impact of inflammation on the hepcidin–ferroportin axis have become increasingly elucidated.117 The presence of functional iron deficiency is suggested when serum ferritin levels are >200 ng/dL with TSAT levels <30%. Although total body iron stores are not reduced in this setting, and some experts and clinical practice guidelines recommend against administration of additional IV iron to most patients with serum ferritin levels greater than 500 to 800 ng/mL,71 evidence nonetheless suggests that a course of iron repletion in such patients may raise Hgb levels118 and lower ESA requirements.119 A recent metaanalysis of 34 studies of supplemental iron in hemodialysis patients with functional iron deficiency found that IV iron significantly increased Hgb levels, serum ferritin, and TSAT without increased risk of adverse events, although increases in some markers of oxidative stress of uncertain clinical relevance were noted.120 A full evaluation of a patient’s anemia, including complete blood count, reticulocyte count, tests for iron stores, and vitamin B12 and folate levels should be assessed when Hgb levels fall below normal,121 and certainly before the initiation of ESA therapy. Patients with absolute iron deficiency should receive iron supplementation, either as oral or intravenous iron, and have their Hgb levels remeasured when iron stores have normalized before initiation of ESA therapy. This is particularly important because intravenous iron supplementation alone will significantly increase Hgb levels in patients with iron deficiency, with many patients achieving Hgb levels of 10 to 12 g/dL without ESA treatment. Adequacy of iron stores should be reassessed 1 to 2 months after initiation of

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TABLE 9.3  Parenteral Iron Preparations Iron Preparation Low MW iron dextran

Dosage (single dose)a (as elemental iron) 100 to >1000 mg

Iron sucrose Ferric gluconate Ferumoxytol

200–300 mg 125 mg/250 mg 510 mg/1020 mg

Ferric carboxymaltose 750 mg to 20 mg/kg body weight Iron isomaltoside (not available 500 mg to 20 mg/kg body weight in United States) Ferric pyrophosphate citrate Provides 5–7 mg per dialysis (via dialysate) treatment

Test Dose Requirement? Special Precautions Yes (25 mg); FDA black box warning regarding risk of anaphylaxis Nob Nob Nob; FDA black box warning regarding risk of hypersensitivity/ anaphylaxis reactions Only limited experience with >510 mg dosing; should not administer faster than 510 mg/15 min Nob Nob Nob

aIncludes

off-label use with higher single dose than approved. infusion for all intravenous products initially with observation for infusion reactions is recommended. FDA, US Food and Drug Administration; MW, molecular weight. bSlow

ESA therapy and periodically thereafter, as treatment will often deplete iron stores. By virtue of repeated blood loss nearly all hemodialysis patients will require maintenance therapy to maintain adequate iron stores.122 Patients demonstrating continued (or new) iron insufficiency with an Hgb level less than desired and levels of TSAT <30% and ferritin <500 ng/mL (see Table 9.2) should receive another course of iron repletion. Consideration should be given in such patients to maintenance iron therapy to avoid ongoing iron insufficiency.123-125 Once Hgb has reached a steady state and a stable ESA dose has been reached, measurement of iron stores can be made every 3 months. Supplemental iron can be given orally, intravenously, or via dialysate (hemodialysis). Most oral iron preparations are inexpensive, available without a prescription, and of relatively similar efficacy. Use of oral iron avoids bypassing the normal gastrointestinal (GI) tract regulation of iron balance but use of one of the most commonly used oral iron preparations, ferrous sulfate, in particular is limited by GI side effects. Metaanalyses and systematic reviews have consistently shown superiority of IV compared with oral iron for treatment of anemia in patients with CKD, on dialysis and not.126-128 Intravenous preparations including iron dextran, iron sucrose, ferric gluconate in sucrose complex, ferumoxytol, and ferric carboxymaltose are available in the United States (Table 9.3). A high-molecular-weight formulation of iron dextran is no longer readily available and is not recommended for use due to a higher risk of serious allergic/anaphylactic reactions compared with a low-molecular-weight formulation and other parenteral iron products.129-131 Iron isomaltoside is available in some countries outside the United States. The choice among intravenous agents is often governed by formulary considerations in dialysis units, hospitals, and clinics; there is little evidence to suggest superior efficacy of any one agent over another. Iron sucrose is the most commonly used preparation among HD patients in the United States. Iron dextran requires a test dose before initial

administration to assess for allergic reactions although some recommend cautious administration with the initial dose of other IV irons as well. Ferumoxytol and ferric carboxymaltose can be given in higher doses per administration than the others, reducing the number of needed infusions. Iron dextran and ferumoxytol have “black box” warnings in the United States regarding risk of severe hypersensitivity reactions and anaphylaxis; other side effects with these products seem to be similar to other iron preparations.132-134 Ferric carboxymaltose has been associated with development of hypophosphatemia caused by renal phosphate wasting in patients with CKD not on dialysis135-137 but otherwise appears to be generally well tolerated.138 Ferric pyrophosphate citrate is available in the United States for delivery of iron via dialysate during hemodialysis by adding it to the liquid bicarbonate concentrate and appears to be helpful in maintaining iron stores and reducing need for supplemental IV iron.139-141 Oral ferric citrate is approved for use as a phosphate binder but has also been shown to be a potential source of supplemental iron in both dialysis patients and patients with CKD not on dialysis, increasing Hgb levels and iron stores while reducing the need for IV iron.139,142-145 Oral iron repletion should be accomplished using a total daily dose of 200 mg of elemental iron. This is often given in divided doses to minimize GI side effects such as constipation. Individual iron preparations vary in their content of elemental iron; none has been shown to be clearly superior in terms of efficacy or tolerability. One small study suggested that an oral heme iron preparation may be effective and well-tolerated in HD patients146; this preparation was not effective in patients on peritoneal dialysis147 but may be of benefit in patients with CKD who are not on dialysis.148 In hemodialysis patients, IV iron is the preferred route for iron supplementation.35,71 For patients with CKD who are not on dialysis and peritoneal dialysis patients who do not respond to or tolerate a 1 to 3 month course of oral iron, intravenous iron repletion should be administered. Typically,

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iron repletion for iron deficiency is accomplished via administration of approximately 1000 mg of iron with subsequent assessment of iron stores, Hgb level, and ESA responsiveness. The Kidney Disease: Improving Global Outcomes (KDIGO) recommendations suggest limiting iron replacement to patients with TSAT <30% and serum ferritin <500 ng/mL (see Table 9.2). There continues to be a debate about the need to limit additional iron in patients with high serum ferritin levels, particularly when TSAT levels are not elevated.35,118,149-152 The use of IV iron has increased among HD patients, in particular.153,154 This has come with concern about the long-term safety of large cumulative doses of parenteral iron. Iron sequestration is one means by which the body protects itself against invading pathogens. Thus some have speculated that administration of intravenous iron may promote infection as well as increase cardiovascular disease and mortality. Some early observational studies indicated an association between increased rates of bacterial infection and colonization and intravenous iron administration in hemodialysis patients.155,156 However, others have concluded that there is not a significant risk of infection or mortality with IV iron administration in HD patients,157-160 although one recent study suggested the possibility of infection-related mortality, but not all-cause or cardiovascular mortality, with high cumulative doses.161 Two recent prospective trials of IV iron supplementation in patients with CKD provided discordant results, with one indicating an increased risk of infection,162 whereas another found no evidence of this concern.138 Nonetheless, many clinicians avoid supplemental iron administration in the presence of an active infection due to the theoretical risk and likelihood of poor response to supplemental iron in this setting.35 

Other Therapies Whereas ESAs and iron repletion are the primary therapeutic modalities for anemia management in CKD, other agents have been investigated for potential roles in augmenting the effect of ESA treatment, although none are of proven efficacy or clinical value and none have been shown to enhance patient outcomes.35,71,163-165 Vitamin C (ascorbic acid), administered intravenously at each hemodialysis session, has been shown in several small short-term studies to improve ESA responsiveness, particularly in hemodialysis patients with high serum ferritin levels and functional iron deficiency.166-170 This effect is thought to be through antioxidant effects, mobilization of iron stores for erythropoiesis, and enhancement of iron utilization. Long-term safety has not been proven and the affect on important clinical outcomes is unknown. Other adjuvants to ESA therapy that have been used in the past or proposed for clinical use include L-carnitine,171,172 androgens,173–175 pentoxifylline,176-178 and statins.179,180 Due to limitations previously mentioned, most notably absence of convincing evidence that these agents improve patient outcomes, their use is generally not recommended. 

TARGET HEMOGLOBIN LEVELS FOR ERYTHROPOIESIS-STIMULATING AGENT–TREATED PATIENTS Ideally, the Hgb level achieved in each ESA-treated patient with CKD would be individually tailored depending on such factors as functional capacity and limitations, other comorbidities such as coronary artery disease and heart failure, and life expectancy. Historically, target Hgb levels have generally instead been influenced more by regulation by the FDA and healthcare payers, quality assurance programs in dialysis units, and clinical practice guideline recommendations. Whereas many observational cohort studies in the past indicated an association between Hgb levels greater than 12 to 13 g/dL in both dialysis patients and patients with CKD not on dialysis, more recent evidence, including that from prospective randomized trials, indicates that there is little benefit, and even potential risk to targeting or maintaining Hgb levels of 13 g/dL or higher in many CKD patients.24,30,53-55,69,100

Data From Clinical Trials There are now at least four large prospective randomized controlled trials evaluating target Hgb levels in patients with CKD. The “Normal Hematocrit Trial,” in hemodialysis patients with cardiac disease, was terminated early when it was determined that the group targeted to normal values had a higher mortality that was approaching, but had not yet attained, statistical significance. Mortality rates were 7% higher in the normal Hct group than in the low Hct group.54,68 The CHOIR trial (Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease) randomly assigned CKD patients with anemia to achieve a target Hgb of either 13.5 or 11.3 g/day, with the primary study endpoint being a composite of death, myocardial infarction, stroke, and hospitalization for heart failure without renal replacement therapy.55 The study was stopped early when it was determined that is was unlikely to show any benefit of the higher Hgb level and there was a significantly higher number of events in the higher Hgb group. There was no improvement in quality of life with higher Hgb levels. In the CREATE trial (Cardiovascular Risk Reduction in Early Anemia Treatment with Epoetin Beta), patients with CKD and anemia were randomly assigned to a normal (13 to 15 g/dL) or subnormal (10.5 to 11.5 g/dL) Hgb level.24 The primary endpoint was a composite of eight cardiovascular events, including sudden death, myocardial infarction, acute heart failure, stroke, transient ischemic attack, hospitalization for angina pectoris or arrhythmia, or complications of peripheral vascular disease. At 3 years, there was a similar risk of experiencing the primary endpoint in both groups, although there was a nonsignificant trend toward more events in the higher Hgb group. In the TREAT trial (Trial to Reduce Cardiovascular Events with Aranesp Therapy), patients with CKD and diabetes were randomly assigned to receive darbepoetin alfa to achieve an Hgb level of approximately 13 g/dL or placebo, with darbepoetin given only as “rescue” therapy if the Hgb was <9.0 g/ dL.30 The primary endpoints were the composite of death or

CHAPTER 9  Anemia in Chronic Kidney Disease a cardiovascular event and death or end-stage renal disease (ESRD). At 48 months, there was not a significant difference between groups for either composite endpoint but there was a significant increase in the risk of fatal and nonfatal stroke in the darbepoetin group.56 Of note is that this is the only large placebo-controlled trial assessing outcomes associated with ESA use in patients with CKD. A systematic review of 27 studies including over 10,000 subjects found that using ESAs to target a higher Hgb level of 12 to 15 g/dL compared with a lower Hgb level of 9.5 to 11.5 g/dL was associated with an increased risk of stroke, hypertension, and vascular access thrombosis but did not find a higher risk for mortality, serious cardiovascular events, or progression of CKD to ESRD.181 

US Regulatory and Fiscal Policy The use of ESAs in dialysis patients in the United States has been governed by various regulatory policies since recombinant human erythropoietin was approved by the FDA in 1989, including policies governing reimbursement for ESAs to dialysis and other healthcare providers. The target Hct range for EPO therapy approved by the FDA when the drug was initially introduced was 30% to 33%. The ESA label in the United States now warns of a greater risk of death, serious adverse cardiovascular events, and stroke when ESAs are used to target Hgb levels >11 g/dL and recommends initiation of treatment with an ESA only when the Hgb is <10 g/dL. The package insert also notes that no Hgb level, ESA dose, or ESA dosing strategies have been identified that reduce these risks and recommends use of the lowest possible ESA dose sufficient to reduce the need for red blood cell transfusions. A specific Hgb target or minimum Hgb level is not recommended.93,182 In 2011 the Centers for Medicare & Medicaid Services (CMS) in the United States introduced a new prospective payment system for dialysis treatment reimbursements that included the costs of certain medications, including ESAs (often referred to as bundling), creating a disincentive for high ESA dose use. This was followed by a decline in ESA use and Hgb levels, an increase in intravenous iron use, rising serum ferritin levels, and a small increase in blood transfusion rates, without an increase in mortality or other major cardiovascular events.153,183,184 

Clinical Practice Guidelines for ErythropoiesisStimulating Agents and Iron Therapy

Several national and international organizations and societies have developed clinical practice guidelines and recommendations for anemia management in patients with CKD including specific target Hgb and iron levels; these are generally similar, although differences in some of the specifics, such as upper and lower Hgb level limits, do exist.35,71,110,185,186 All have concluded that partial correction of anemia to an Hgb level of approximately 10 to 11 g/dL is reasonable in many patients with ESRD and CKD who are not on dialysis but that higher Hgb targets should generally be avoided.

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Major recommendations of the most recent anemia guideline regarding Hgb target levels and iron tests from the KDIGO are summarized here.35,71 These international guidelines, last updated in 2012, recommend that ESA therapy not be initiated in patients with CKD who are not on dialysis if the Hgb is ≥10.0 g/dL and if <10.0 g/dL that ESA therapy be individualized based on the rate at which the Hgb is falling, response to iron replacement, estimated transfusion risk, symptoms, and potential risks of ESA treatment. For patients on dialysis, it is recommended that ESA therapy be used to avoid having the Hgb concentration fall to <9.0 g/dL by initiating treatment when the Hgb is in the 9.0 to 10.0 g/ dL range, although it was noted that some individual patients might benefit from starting an ESA even with a Hgb >10.0 g/ dL. These guidelines recommend that ESAs not be used to maintain Hgb concentrations >11.5 g/dL in most patients, noting that a somewhat higher level may be appropriate in some patients (who understand and are willing to accept the risks). Others have suggested that a target Hgb <11.0 g/dL is more appropriate given the available evidence and FDA statement.35 A strong recommendation was also made to avoid intentionally increasing the Hgb to >13.0 g/dL with ESAs. 

Erythropoiesis-Stimulating Agent Hyporesponsiveness

Not all patients have a brisk or fully desired therapeutic response to standard ESA doses and are thus considered to have ESA hyporesponsiveness or resistance. Hyporesponsiveness to ESA therapy is clearly associated with poorer outcomes than is responsiveness to lower ESA doses.187-191 Although there is no widely accepted and scientifically validated definition, a reasonable definition of ESA hyporesponsiveness is a weekly epoetin requirement of more than 450 U/kg IV or 300 U/kg SC in a hemodialysis patient.115,192 ESA hyporesponsiveness has been even less well defined in patients with CKD not on dialysis and those on peritoneal dialysis. Another approach to defining hyporesponsiveness, from the KDIGO guidelines, is the lack of an increase in Hgb after the first month of appropriate weight-based dosing and/or a need for two increases in ESA dose up to 50% beyond the dose as which the patient was previously stable.71 This recommendation stems in part from a report from the TREAT study in patients with CKD who were not on dialysis188 and may not be relevant or applicable to a dialysis-treated population.35 The most common cause of ESA hyporesponsiveness is iron deficiency.115 Provided that adequate monitoring and repletion of iron stores is undertaken, this cause should be apparent and treatable with oral or intravenous iron administration. Among iron-replete patients, inflammation and infection are important causes of ESA hyporesponsiveness.193 The proposed mechanism is thought to be disruption of erythropoiesis in the bone marrow by proinflammatory cytokines such as interleukin-1, tumor necrosis factor-α, and interferon-γ.193,194 In cases where systemic inflammation is suspected as a cause of ESA hyporesponsiveness but no source is identified, consideration should be given to the possibility of occult infection of thrombosed arteriovenous access

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SECTION II  Complications and Management of Chronic Kidney Disease

grafts.195 Hospitalized patients have lesser degrees of ESA responsiveness than their nonhospitalized counterparts.196 Likely, this relates to the higher prevalence of inflammation, infection, and malnutrition—and frequent phlebotomy—in this population. Other potential causes or contributors to ESA hyporesponsiveness include inadequate dialytic clearance, secondary hyperparathyroidism, aluminum overload, and deficiency in vitamin B12 and folic acid. Administration of angiotensin-converting enzyme inhibitors (ACE) inhibitors and angiotensin receptor blockers (ARBs) has also been suggested to inhibit the response to ESAs. The underlying mechanisms may relate to reduction in erythroid burst forming units in the bone marrow due to decreased angiotensin II synthesis or decreased degradation of an inhibitor of erythropoiesis by ACE inhibitors or ARBs by direct inhibition of

the erythropoietic stimulating effect of angiotensin II.197,198 Although the clinical impact of this effect is small in most patients, adjustment of the renin angiotensin system inhibition can be considered as an approach that may improve Hgb levels or responsiveness to ESA. Severe secondary hyperparathyroidism may also be associated with impaired erythropoiesis, presumably due to disruption of the bone marrow architecture although toxic effects of parathyroid hormone on erythropoietin synthesis, erythropoiesis, and red blood cell survival have also been postulated.199,200 As noted previously, PRCA should also be considered in assessing patients with ESA hyporesponsiveness, particularly if they were previously responsive. A full list of references is available at www.expertconsult.com.

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