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. 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.

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 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. 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. 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. 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.

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, full and partial 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, 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, as well as improvements in sleep quality and wakefulness.

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, 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. 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.

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, and its prevalence is strongly associated with the degree of anemia. In this population, LVH is a potent marker for cardiovascular morbidity and mortality, 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. 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. 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. 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. 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.

Among patients with CKD who are not on dialysis, observational studies suggested that higher Hgb levels were associated with improved survival, and that anemia therapy was associated with improved longevity among patients going on to require dialysis. Observational studies examining the association between higher Hgb levels and mortality among patients on hemodialysis have yielded mixed findings, with some demonstrating a benefit, and others not. 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. 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.

Erythropoiesis-Stimulating Agents

Since the first descriptions of the use of recombinant human erythropoietin in hemodialysis patients in the late 1980s, 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.

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 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. 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.

“Biosimilar” erythropoietic agents (also termed follow-on biologicals ) 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. 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.

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. 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. 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.

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) ; fortunately, with product reformulation, PRCA related to its use appears to have largely disappeared. Isolated instances of antibody-mediated PRCA related to other ESAs have been rarely reported.

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 ). 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. 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. Darbepoetin and methoxy polyethylene glycol epoetin beta, with their longer biological half-lives, can often be effectively administered once or twice monthly.

Besides induction of iron deficiency, the primary adverse effects of ESAs are exacerbation of hypertension and hemodialysis access thrombosis. 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. 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. Others have also found that requiring or receiving higher ESA doses was independently associated with higher mortality. 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, 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. An increased stroke risk with ESAs was also seen in an older study among dialysis patients and a more recent study among US veterans with CKD but not others. Nonetheless, caution is advised about ESA use in patients with a history of stroke or malignancy.

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, these tests are of rather low sensitivity and specificity. 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. 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.

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. Complexities of iron handling in the body and the impact of inflammation on the hepcidin–ferroportin axis have become increasingly elucidated. 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, evidence nonetheless suggests that a course of iron repletion in such patients may raise Hgb levels and lower ESA requirements. 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.

A full evaluation of a patient’s anemia, including complete blood count, reticulocyte count, tests for iron stores, and vitamin B ₁₂ and folate levels should be assessed when Hgb levels fall below normal, 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 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. 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. 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. 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. 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. Ferric carboxymaltose has been associated with development of hypophosphatemia caused by renal phosphate wasting in patients with CKD not on dialysis but otherwise appears to be generally well tolerated.

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. 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.

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 patients ; this preparation was not effective in patients on peritoneal dialysis but may be of benefit in patients with CKD who are not on dialysis.

In hemodialysis patients, IV iron is the preferred route for iron supplementation. 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, 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.

The use of IV iron has increased among HD patients, in particular. 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. However, others have concluded that there is not a significant risk of infection or mortality with IV iron administration in HD patients, although one recent study suggested the possibility of infection-related mortality, but not all-cause or cardiovascular mortality, with high cumulative doses. Two recent prospective trials of IV iron supplementation in patients with CKD provided discordant results, with one indicating an increased risk of infection, whereas another found no evidence of this concern. 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.

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. 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. 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, androgens, pentoxifylline, and statins. Due to limitations previously mentioned, most notably absence of convincing evidence that these agents improve patient outcomes, their use is generally not recommended.

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.

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. 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. 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. The primary endpoints were the composite of death or 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. 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.

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.

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.

Clinical Practice Guidelines for Erythropoiesis-Stimulating 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. 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.

Major recommendations of the most recent anemia guideline regarding Hgb target levels and iron tests from the KDIGO are summarized here. 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. 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. 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. 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. This recommendation stems in part from a report from the TREAT study in patients with CKD who were not on dialysis and may not be relevant or applicable to a dialysis-treated population.

The most common cause of ESA hyporesponsiveness is iron deficiency. 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. 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. 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 grafts. Hospitalized patients have lesser degrees of ESA responsiveness than their nonhospitalized counterparts. 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 B ₁₂ 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. 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. As noted previously, PRCA should also be considered in assessing patients with ESA hyporesponsiveness, particularly if they were previously responsive.