Treatment of anemia in patients on dialysis

INTRODUCTION — Anemia is extremely common among patients on hemodialysis and underlies some of the symptoms associated with reduced kidney function, including fatigue, depression, reduced exercise tolerance, and dyspnea. Anemia is also associated with increased morbidity and mortality related to cardiovascular disease and an increased risk of hospitalization and hospital length of stay [1-4].

Screening for and treating anemia is a routine part of the care of patients on hemodialysis. This topic provides an approach to screening and treating anemia among such patients. The treatment of iron deficiency among patients on dialysis is discussed elsewhere. (See "Treatment of iron deficiency in patients on dialysis".)

The screening and treatment of anemia in patients with nondialysis chronic kidney disease (CKD) and in patients on peritoneal dialysis are discussed elsewhere. (See "Treatment of anemia in nondialysis chronic kidney disease".)

DEFINITION — Most nephrologists use the World Health Organization (WHO) criteria to define anemia. Anemia is defined by WHO as a hemoglobin (Hb) concentration <13 g/dL for adult males and postmenopausal females and an Hb concentration <12 g/dL for premenopausal females [5]. (See "Diagnostic approach to anemia in adults", section on 'Caveats for normal ranges'.)

However, the WHO definition of anemia does not define goals of treatment among patients on hemodialysis. Even when typically treated, patients on hemodialysis will still have anemia as defined above. This is because, among patients on hemodialysis, the treatment of anemia typically involves erythropoiesis-stimulating agents (ESAs) to avoid severe anemia and reduce the need for blood transfusions but not to normalize Hb levels. Multiple studies have shown that, among patients with CKD (including those on hemodialysis), using ESAs to correct Hb to normal increases the risk of adverse outcomes. (See 'Treatment' below.)

In discussions below, we use specific Hb targets to define indications for and goals of treatment.

SURVEILLANCE

Initial surveillance — Upon initiation of maintenance dialysis, all patients should be evaluated for anemia with a complete blood count (CBC), particularly if they have not been serially monitored or treated for anemia prior to initiation of dialysis and do not have a recent CBC at the time dialysis is initiated. The vast majority of patients on dialysis will have anemia due to some combination of iron deficiency and other chronic kidney disease (CKD)-specific factors, rather than some other identifiable cause (eg, folate or vitamin B12 deficiency).

Patients who are found to be anemic (hemoglobin [Hb] <12 to 13 g/dL as defined above) should be evaluated for its cause. The initial evaluation of anemia is generally the same for patients with CKD as in the general population (algorithm 1). The evaluation should include red blood cell indices, reticulocyte count, serum iron, total iron-binding capacity (TIBC), percent transferrin saturation (TSAT; plasma iron divided by TIBC x 100), serum ferritin, serum folate and vitamin B12 levels, and testing for occult blood in stool. (See "Diagnostic approach to anemia in adults".)

Continued monitoring — The vast majority of patients who receive dialysis in the United States undergo monitoring of Hb weekly or monthly, and of TSAT and ferritin monthly or quarterly, based upon protocols used by individual dialysis units.

We check Hb monthly unless there is a clinical indication for more frequent testing (such as recent blood loss or major surgical procedures). TSAT and ferritin should be checked at least every three months unless there is a clinical indication for more frequent testing (eg, assessing response to intravenous [IV] iron, recent blood loss). (See 'Indications for treatment' below and 'Erythropoiesis-stimulating agents (ESAs)' below.)

PREVENTION OF ANEMIA WITH MAINTENANCE IRON — We administer maintenance intravenous (IV) iron to most patients on dialysis with the exception of:

●Patients with active bacterial or fungal infection.

●Patients who have a transferrin saturation (TSAT) of >40 percent or a serum ferritin of >700 ng/mL; however, some clinicians would continue to use IV iron unless the ferritin was >1300 ng/mL.

The dosing of maintenance iron is discussed at length elsewhere. (See "Treatment of iron deficiency in patients on dialysis", section on 'Maintenance dose iron'.)

The yearly estimated iron loss in patients on hemodialysis is typically 1 to 2 g (approximately 100 to 200 mg monthly) and can be as high as 4 to 5 g in some patients [6]. A maintenance dose of iron (oral or IV) is usually needed to replenish such losses, especially among patients treated with erythropoiesis-stimulating agents (ESAs) or hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF PHIs). (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Blood loss' and "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Redistribution after erythropoietin/erythropoiesis-stimulating agents' and "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Absolute versus functional deficiency'.)

Several well-designed trials have demonstrated that patients require a lower ESA dose and maintain a higher Hb when maintenance iron therapy is given [7-11]. The efficacy and safety of maintenance iron was evaluated in a trial of 2141 patients on hemodialysis [7]. At the beginning of the trial, all patients were receiving ESA therapy and had a serum ferritin of <400 ng/mL and TSAT <30 percent. Patients were randomly assigned to receive high-dose IV iron sucrose administered proactively (400 mg monthly, unless the serum ferritin level was >700 ng/mL or TSAT was ≥40 percent) or low-dose iron sucrose administered reactively (400 mg given if serum ferritin was <200 ng/mL or TSAT was <20 percent). The median monthly dose of IV iron was 264 mg in the proactive group and 145 mg in the reactive group. At a median follow-up of 2.1 years, there was no difference between the groups in the composite of nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for heart failure, or death. However, patients in the proactive treatment group required lower ESA doses (median monthly dose 29,757 versus 38,805 units) and were less likely to receive blood transfusions compared with those in the reactive group. Rates of adverse events, including infection, were comparable between the two groups [7,12].

INDICATIONS FOR TREATMENT — In the absence of treatment, patients on dialysis can develop severe anemia (typically with hemoglobin [Hb] 6 to 8 g/dL). Such severe anemia is associated with increased morbidity and mortality, cardiovascular events, and increased risk of hospitalization and prolonged length of hospital stay [1-4]. Anemia is also associated with fatigue, depression, reduced exercise tolerance, and dyspnea. Thus, treatment of anemia is likely to be beneficial for many patients on dialysis.

We treat anemia among patients who have a likelihood of clinical benefit from treatment of their anemia and who meet laboratory-based criteria for treatment.

Likelihood of clinical benefit — For most patients receiving dialysis, the goal of treatment of anemia is to mitigate symptoms from anemia and reduce the likelihood of needing a blood transfusion. Whether treating anemia also improves patient-important endpoints (eg, mortality, morbidity, cardiovascular events, and hospitalizations) is uncertain. Most patients on dialysis who have anemia will experience an improvement in symptoms and well-being with treatment, and this beneficial effect is likely to be more pronounced among patients who are treated for severe anemia (eg, Hb <8 g/dL).

However, patients who have certain comorbidities (eg, bedbound, limited functional capacity, dementia, etc) are unlikely to derive the same benefit from increasing the Hb as someone who is more active and symptomatic from anemia. We may avoid treating anemia in patients with such comorbidities, or we may treat to achieve a specific clinical goal (eg, to minimize hospitalization for transfusions, optimize management of heart failure) rather than aiming for a specific Hb target.

Laboratory-based indications for treatment — The laboratory-based indications for treatment take into account the severity of anemia and the presence or absence of iron deficiency. These indications are based upon the principle that most patients on dialysis should have an Hb level of at least 10 g/dL; although, as noted above, lower levels may be appropriate in some patients (eg, bedbound patients) (algorithm 1). (See 'Likelihood of clinical benefit' above.)

The management approach of anemia outlined below is primarily based upon our clinical experience and not on high-quality data.

Hb <10 g/dL and TSAT ≤30 percent — Such patients should be treated with a loading dose of intravenous (IV) iron with repeated courses, as needed, until the transferrin saturation (TSAT) is >30 percent. Our preferred regimens for the loading dose of iron and the adverse effects of IV iron are discussed elsewhere. (See "Treatment of iron deficiency in patients on dialysis", section on 'Loading dose iron' and "Treatment of iron deficiency in patients on dialysis", section on 'Adverse effects'.)

IV iron is sometimes withheld among patients with an Hb <10 g/dL and TSAT ≤30 percent if the ferritin is elevated. The upper limit of ferritin beyond which a loading dose of IV iron is avoided varies widely among clinicians, ranging generally between 500 and 1300 ng/mL. However, some patients with elevated ferritin levels may benefit from IV iron [13].

In addition, IV iron should be avoided in those with signs or symptoms of an active infection; such patients should undergo appropriate evaluation and treatment prior to treatment with iron.

Among anemic patients on dialysis with a TSAT ≤30 percent, those with a TSAT of <20 percent and ferritin of <200 ng/mL are likely to be iron deficient by bone marrow biopsy (the gold standard test for iron deficiency) [14]. Conversely, patients with a TSAT of 20 to 30 percent and ferritin of 200 to 500 ng/mL are unlikely to be iron deficient by bone marrow biopsy but may still respond to IV iron administration with an increase in Hb. The administration of iron replenishes iron stores and increases iron available for erythropoiesis, leading to an increase in Hb levels [15-25].

Patients initiated on IV iron may also benefit from an erythropoiesis-stimulating agent (ESA) or a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF PHI), but iron should be given first with repeat assessment of Hb prior to starting the ESA or HIF PHI. If Hb remains less than 10 g/dL after iron stores are replete, then most patients are started on an ESA although a HIF PHI may be considered in select patients. (See 'Hb <10 g/dL and TSAT >30 percent' below and 'Choice of therapy in iron replete patients' below.)

Patients who have an elevated ferritin (>500 ng/mL) with a low TSAT may also benefit from an evaluation for occult sources of inflammation (eg, osteomyelitis) because high ferritin levels can act as an acute phase reactant. Such patients should also be evaluated for malnutrition because low TSAT is a negative acute phase reactant and can suggest a malnourished state. (See "Protein intake in patients on maintenance hemodialysis", section on 'Monitoring and intervention'.)

Patients who do not respond to the loading dose of iron with an increase in Hb and iron indices should be evaluated for potential sources of bleeding, particularly gastrointestinal blood loss. Additionally, a loading dose of iron may need to be repeated. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Blood loss' and "Treatment of iron deficiency in patients on dialysis", section on 'Loading dose iron'.)

Hb <10 g/dL and TSAT >30 percent — Such patients are usually started on an ESA although a HIF PHI may be considered in select patients (see 'Choice of therapy in iron replete patients' below). The decision to start ESA/HIF PHI therapy should account for specific patient characteristics, such as functional and cognitive status, life expectancy, and other factors. Patients who have a history of stroke or malignancy or who have an active malignancy are important exceptions for treatment with ESAs/HIF PHIs; in such patients, a decision to use an ESA or HIF PHI must be individualized after weighing risks and benefits of treatment with the patient. (See 'Likelihood of clinical benefit' above and 'Contraindications' below.)

The dosing and titration of ESAs and HIF PHIs are discussed below. (See 'Initial dosing and titration of ESAs' below and 'Dosing of HIF PHIs' below.)

Among patients who are being treated with an ESA or HIF PHI, IV iron should be administered while continuing treatment (unless goal Hb has been reached or exceeded, in which case the ESA or HIF PHI is reduced or stopped). Iron stores become depleted in such patients as a result of an ESA/HIF PHI–induced increase in erythropoiesis. The correction of iron deficiency may, therefore, allow for a reduction in the ESA or HIF PHI dose [15-24]. The dosing of IV iron for such patients is presented elsewhere. (See "Treatment of iron deficiency in patients on dialysis", section on 'Maintenance dose iron'.)

However, we do not routinely administer IV iron to patients who have a TSAT >30 percent and a ferritin >500 ng/mL, since no studies have proven a benefit of iron among such patients. However, each patient should be individually assessed, and some clinicians continue IV iron administration in patients with ferritin levels >500 ng/mL.

For patients who are being treated with an ESA or HIF PHI and have Hb <10 g/dL and ferritin >500 ng/mL, we increase the ESA or HIF PHI dose without giving IV iron, provided that the patient is not on a very high ESA/HIF PHI dose already (see 'Initial dosing and titration of ESAs' below and 'Dosing of HIF PHIs' below). If the increased ESA/HIF PHI dose does not raise the Hb level sufficiently, we often prescribe supplemental iron (with or without a further increase in ESA/HIF PHI dose). There is some evidence that IV iron, in association with an increase in ESA dose, can increase Hb levels at least over the short term among patients with high ferritin values. In the Dialysis Patients' Response to IV Iron with Elevated Ferritin (DRIVE) study, among 134 patients with Hb levels <11 g/dL, ferritin levels ≥500 ng/mL, and TSAT levels ≤25 percent, those assigned to IV iron had a larger increase in Hb in response to ESA at six weeks of follow-up [13]. However, the difference in Hb response at six weeks is of unclear clinical significance, and long-term, meaningful clinical outcomes were not assessed. The long-term clinical benefit and safety of providing additional supplemental iron in the setting of anemia with persistently elevated ferritin levels remain to be determined.

Hb ≥10 g/dL and TSAT ≤20 percent and ferritin ≤200 ng/mL — Such patients are likely iron deficient. However, the treatment of the iron deficiency with a loading dose of iron among such patients is controversial. We treat such patients, especially those receiving hemodialysis, with a loading dose of IV iron until the TSAT is 20 to 30 percent because blood loss with hemodialysis will eventually lead to anemia with Hb <10 g/dL.

Individual agents, maintenance, and loading doses for iron therapy are discussed elsewhere. (See "Treatment of iron deficiency in patients on dialysis".)

Hb ≥10 g/dL and TSAT >20 percent and ferritin >200 ng/mL — Such patients are not treated with a loading dose of iron or an ESA/HIF PHI. However, they can be treated with a maintenance dose of iron until the TSAT is >40 percent or the ferritin is >700 ng/mL. (See 'Prevention of anemia with maintenance iron' above.)

Hb ≥10 g/dL with discrepant TSAT and ferritin — The management of patients who have an Hb≥10 g/dL and either a TSAT ≤20 percent and ferritin >200 ng/mL or a TSAT >20 percent and ferritin ≤200 ng/mL is controversial. Some of our contributors do not treat such patients with either iron or an ESA/HIF PHI, while others treat such patients with iron.

Patients who have an elevated ferritin (>500 ng/mL) with a low TSAT may also benefit from an evaluation for occult sources of inflammation (eg, osteomyelitis) because high ferritin levels can act as an acute phase reactant. Such patients should also be evaluated for malnutrition because low TSAT is a negative acute phase reactant and can suggest a malnourished state. (See "Protein intake in patients on maintenance hemodialysis", section on 'Monitoring and intervention'.)

TREATMENT

Iron for anemic patients with iron deficiency — The first step in the management of anemia in a patient on dialysis is to treat absolute or functional iron deficiency, if present. In many patients, treatment with intravenous (IV) iron may increase Hb levels sufficiently such that an erythropoiesis-stimulating agent (ESA) or HIF PHI is not needed. Laboratory-based indications for iron therapy are presented above (see 'Laboratory-based indications for treatment' above).

Absolute and functional iron deficiency in patients with chronic kidney disease (including patients on dialysis), various iron formulations and dosing regimens, and adverse effects of iron therapy are discussed in detail elsewhere. (See "Diagnosis of iron deficiency in chronic kidney disease" and "Treatment of iron deficiency in patients on dialysis".)

Choice of therapy in iron replete patients — For patients on dialysis who are iron replete and have an indication for the treatment of anemia (see 'Indications for treatment' above), we suggest ESAs rather than HIF PHIs as first-line therapy. Although studies show comparable efficacy of ESAs and HIF PHIs, we prefer ESAs because of greater clinical experience with these agents and the relative lack of long-term safety data for HIF PHIs. However, HIF PHI therapy, which is administered orally, is an alternative option for patients who have any of the following features:

●Documented ESA allergy or history of ESA-associated pure red cell aplasia.

●Preference for an oral agent (HIF PHI) rather than subcutaneous ESA administration. This is predominantly an issue for patients on peritoneal dialysis and home hemodialysis since patients treated with in-center hemodialysis can receive an ESA intravenously during dialysis.

●ESA hyporesponsiveness. For patients with ESA hyporesponsiveness, the priority is to diagnose and treat the cause (see "Hyporesponse to erythropoiesis-stimulating agents (ESAs) in chronic kidney disease"). However, for a patient with an unknown or untreatable cause of ESA hyporesponsiveness, a trial of HIF PHI therapy is reasonable. Because the role of HIF PHIs in this setting is uncertain, we would not continue HIF PHI treatment in patients with ESA hyporesponsiveness unless the Hb concentration significantly improves within two to three months of converting from ESA to HIF PHI therapy. (See 'Dosing of HIF PHIs' below.)

For patients on dialysis, ESAs and HIF PHIs generally have similar rates of efficacy and major adverse effects (cardiovascular and otherwise) [26-30]. The safety and efficacy of the HIF PHI daprodustat (the only HIF PHI approved for use in the United States) were evaluated in a trial of 2964 patients on dialysis (mean hemoglobin [Hb] 10.4 g/L) who were randomly assigned to daprodustat (dose range 4 to 24 mg daily, depending on previous ESA dose) or an injectable ESA (epoetin alfa for those on hemodialysis and darbepoetin alfa for those on peritoneal dialysis); patients were followed for a median of 2.5 years [26]. The mean change in Hb concentration was 0.28 g/dL with daprodustat therapy and 0.10 g/dL with ESA therapy. Rates of major adverse cardiovascular events (a composite of death, nonfatal myocardial infarction (MI), and nonfatal stroke) were also similar between the treatment groups (25.2 versus 26.7 percent for daprodustat and epoetin alfa, respectively), as were rates of other adverse events. Trials evaluating the safety and efficacy of the HIF PHIs vadadustat and roxadustat among patients on dialysis have reported findings similar to those found in trials of daprodustat [28-30].

Data supporting the efficacy of HIF PHI therapy in patients with ESA hyporesponsiveness are sparse [31,32]. Chronic inflammation is a common cause of ESA hyporesponsiveness in patients on dialysis; some trials showed greater efficacy of HIF PHI compared with ESA therapy in patients with high levels of C-reactive protein and high ESA doses at baseline [33], but other trials have not [26-28].

Contraindications — Because HIF PHIs increase endogenous erythropoietin levels, they have similar adverse effects to ESAs. We avoid the use of ESAs and HIF PHIs among patients on dialysis who have a (potentially curable) malignancy, uncontrolled hypertension, or a history of stroke, since such patients may be at a higher risk for adverse effects [34]. The treatment of such patients with an ESA or a HIF PHI should be individualized after careful consideration and discussion of the possible risks and benefits of therapy. (See 'Adverse effects of ESAs' below and 'Adverse effects of HIF PHIs' below.)

Additional contraindications unique to HIF PHIs include severe hepatic impairment (ie, Child-Pugh Class C) and the concomitant administration of strong CYP2C8 inhibitors, such as gemfibrozil. Circulating levels of daprodustat are markedly higher in such patients due to hepatic metabolism of the drug. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis", section on 'Child-Pugh classification' and 'Adverse effects of HIF PHIs' below.)

Target Hb levels — The optimal target Hb for patients treated with an ESA or an HIF PHI is not known. In most patients on dialysis who are treated with ESAs or HIF PHIs, we maintain Hb levels between 10 and 11.5 g/dL. We do not target an Hb concentration >13 g/dL.

However, different Hb targets are reasonable in some patients. As examples, patients who are unlikely to benefit from being less anemic do not need to achieve an Hb >10 g/dL. Similarly, patients who desire an Hb >11.5 g/dL For further relief from symptoms of anemia and who are prepared to accept the risks associated with higher Hb targets achieved with ESAs or HIF PHIs do not need to remain below 11.5 g/dL, as long as their Hb does not exceed 13 g/dL. (See 'Adverse effects of ESAs' below and 'Adverse effects of HIF PHIs' below.)

In clinical practice, it is difficult to maintain individual patient Hb values within a narrow range [35-38]. While we try to maintain Hb levels between 10 to 11.5 g/dL in most patients, Hb levels >11.5 g/dL and <10 g/dL will occur transiently in many patients due to a variety of factors and should prompt a gradual dose adjustment in the ESA or HIF PHI being used. Such transient elevations of Hb to >11.5 g/dL are not likely to be associated with important clinical consequences although some (but not all) studies have reported an association between greater degrees of Hb variability and adverse clinical outcomes [39].

Our target Hb range reflects the results of clinical studies and recognizes that anemia treatment should be individualized. The US Food and Drug Administration (FDA) boxed warning on ESAs and HIF PHIs states that Hb targets >11 g/dL are not recommended [40]. While this recommendation is appropriate for most patients, our upper target Hb limit of 11.5 g/dL acknowledges that some patients may have better anemia symptom control and quality of life (eg, improved exercise capacity) with Hb >11 g/dL and is based on Hb concentrations generally not exceeding 11.5 g/dL in the control group of major randomized controlled trials. Our practice is consistent with the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 guidelines [34].

Among all patients with chronic kidney disease (CKD) (ie, dialysis and nondialysis), multiple studies have shown that Hb targets >13 g/dL are associated with adverse outcomes [41-48]. The best data among patients on hemodialysis come from the Normal Hematocrit Trial (NHT), in which 1233 patients on hemodialysis with cardiac disease, defined as having a diagnosis of heart failure or ischemic heart disease, and baseline Hb values of 9 to 11 g/dL on an ESA were randomly assigned to achieve and maintain an Hb of either 14 or 10 g/dL [41]. The study was terminated after 29 months due to safety concerns raised by an independent data monitoring committee. The group targeted to Hb 14 g/dL (ie, normal Hb) had a higher risk of the combined endpoint of death or nonfatal MI (relative risk [RR] 1.3, 95% CI 0.9-1.9). After 29 months, there were 183 deaths and 19 nonfatal Mis in the 14 g/dL group versus 150 and 14, respectively, in the 10 g/dL group. The one- and two-year mortality rates were 7 percent higher in the 14 g/dL group than in the 10 g/dL group. In addition, the risk of thrombosis of grafts and fistulae in the 14 g/dL group was higher than in the 10 g/dL group. No differences were initially reported between the groups for all-cause hospitalization or other endpoints such as nonfatal MI or stroke [41]. However, according to the subsequent trial report submitted to the US FDA, the higher Hb group had a higher rate of hospitalization although the difference was not statistically significant (RR 1.14, 95% CI 0.99-1.30) [49].

In addition to these data, which were limited to patients on hemodialysis, a number of meta-analyses and systematic reviews have been performed, mostly including patients with nondialysis CKD [42,43,45,47,48]. Although limited by heterogeneity, most suggest that targeting higher Hb levels with ESAs does not lower mortality and can increase cardiovascular risk and the risk of malignancy. (See "Treatment of anemia in nondialysis chronic kidney disease", section on 'Adverse effects'.)

Compared with lower Hb levels, higher Hb levels achieved with the use of ESAs may not offer an improvement in health-related quality of life (HRQOL). This was best demonstrated in a meta-analysis of 17 trials (with approximately 2500 patients on dialysis), in which a higher Hb threshold did not result in a clinically meaningful improvement in scores achieved on two validated survey-based instruments for assessment of HRQOL [50]. However, the confidence in the findings of this meta-analysis was limited by the high risk of bias and heterogeneity among the included studies.

Available therapies

Erythropoiesis-stimulating agents (ESAs) — We use ESAs as first-line agents for the treatment of anemia in iron replete patients who are on dialysis (see 'Choice of therapy in iron replete patients' above). Among patients on hemodialysis with severe anemia, ESAs reduce the need for transfusion [41,51] and improve quality-of-life symptoms, exercise tolerance, and left ventricular hypertrophy, which has been associated with higher mortality [52-57].

Initial dosing and titration of ESAs — In the United States, most patients on hemodialysis are treated with epoetin alfa or pegylated epoetin beta.

●Initial dosing – The starting dose of these and other ESAs among patients receiving hemodialysis are as follows:

•Epoetin alfa – 50 to 100 units/kg administered three times per week

•Methoxy polyethylene glycol-epoetin (pegylated epoetin beta) – 0.6 mcg/kg administered every two weeks

•Epoetin alfa-epbx – 50 to 100 units/kg administered three times per week

•Darbepoetin – 0.45 mcg/kg every week or 0.75 mcg/kg every two weeks

An optimal initial ESA dosing regimen has not been established. The starting doses of ESAs presented above are based upon recommendations of the US FDA. The Kidney Disease Outcomes Quality Initiative (KDOQI) and KDIGO anemia guidelines do not specify a starting dose but state that the dose should be individualized [34,58]. Some experts reserve initial ESA doses at the higher end of recommended ranges for patients with more severe anemia (eg, epoetin alfa 100 units/kg three times per week in patients with Hb <8 g/dL). In practice, the initial dose of ESA will vary according to dialysis facility protocol.

The risk of cardiovascular events and all-cause mortality among the various formulations of ESAs, including the ones dosed less frequently, appears to be comparable [59-62].

●Dose titration – We titrate the dose upwards as necessary to achieve the target Hb level (see 'Target Hb levels' above). The dose of ESA required to reach the target Hb varies widely among patients on dialysis [63-66]. Generally, the dose is adjusted monthly in response to the Hb.

Repeated dose escalations should be avoided among patients whose Hb does not improve with ESAs, given concern that high ESA doses may be associated with adverse outcomes independent of the Hb level. Instead, clinicians should investigate the cause of ESA hyporesponsiveness. The dose maximum of ESA varies among experts and ranges between an epoetin alfa dose of 20,000 units per week to 20,000 per dialysis treatment. (See 'Adverse effects of ESAs' below and "Hyporesponse to erythropoiesis-stimulating agents (ESAs) in chronic kidney disease".)

The ESA should be held or dose-reduced in patients with an Hb rise greater than 2 g/dL per month. Reducing the ESA dose is consistent with the KDIGO anemia guidelines [34]. Holding the dose, rather than reducing the dose, is likely appropriate in patients whose Hb exceeds 12 g/dL on two successive measurements obtained one week apart. (See 'Continued monitoring' above.)

Route of administration — Subcutaneous ESA administration is used in patients receiving peritoneal dialysis. Either IV or subcutaneous ESA administration may be used in patients receiving hemodialysis.

Several studies have shown that the subcutaneous dose of ESA required to achieve a target Hb is approximately 30 percent less than that required with IV administration [63,67]. This was best shown in a trial in which 208 patients on hemodialysis were randomly assigned to either subcutaneous or IV epoetin [63]. At 26 weeks, the average subcutaneous epoetin to achieve target Hb levels was lower than the IV dose (95 versus 140 units/kg per week). This is an important consideration since higher ESA doses (independent of Hb) may be associated with worse cardiovascular outcomes. A retrospective study of over 62,000 patients on hemodialysis confirmed that equivalent Hb levels were obtained with 25 percent less epoetin administered subcutaneously compared with IV administration and also found that death and/or hospitalization for cardiovascular complications (heart failure, acute MI, or stroke) were more common in IV epoetin–treated patients, perhaps due to the higher epoetin dose [67].

However, IV administration is often favored by patients on hemodialysis because subcutaneous administration is associated with significantly greater discomfort and IV access is available during the hemodialysis treatment. In the United States, over 95 percent of patients on hemodialysis received ESAs intravenously [68], and a similar practice of preferential IV administration in patients on hemodialysis has been reported in other countries [69].

Adverse effects of ESAs — The risk of serious ESA side effects increases when ESAs are used to attain a normal Hb. As noted above, these include increased mortality, cardiovascular events, and malignancy (see 'Target Hb levels' above). There is also an increased risk of hemodialysis access thrombosis when ESAs are used to maintain normal or near-normal Hb [41,70,71]. In the NHT trial, access thrombosis occurred in 39 percent in the 14 g/dL group compared with 29 percent in the 10 g/dL group [70].

Hypertension may be observed with ESAs [41,42,46,71-73]. The risk of hypertension appears to be independent of the target Hb [41,74,75]. (See "Hypertension associated with erythropoiesis-stimulating agents (ESAs) in patients with chronic kidney disease".)

A rapid rise in blood pressure may cause hypertensive encephalopathy accompanied by seizures [76] although we believe that this is uncommon today. Although the reported incidence ranges from 2 to 17 percent [42,76,77], most studies that have reported on seizure incidence are from the early 1990s, when ESA doses and Hb targets were higher than are typically used today. A 2004 meta-analysis showed no increase in the incidence of seizures among patients treated with an ESA compared with those not treated with an ESA; however, the meta-analysis included patients with nondialysis CKD and patients on dialysis, which may have resulted in an underestimate of incidence among patients on dialysis [42].

There is little evidence of increased incidence of seizures in normotensive patients treated with an ESA. (See "Hypertension associated with erythropoiesis-stimulating agents (ESAs) in patients with chronic kidney disease".)

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF PHIs) — We use HIF PHIs to treat anemia in selected iron replete patients on dialysis (see 'Choice of therapy in iron replete patients' above). Unlike ESAs that replace endogenous erythropoietin, HIF PHIs stimulate transcription of the erythropoietin gene in the kidneys and liver, leading to increased levels of endogenous erythropoietin. HIF PHIs also may increase the amount of iron available for erythropoiesis by increasing intestinal iron absorption and/or decreasing iron sequestration. However, studies have not consistently demonstrated meaningful reductions in IV iron use among patients on dialysis treated with HIF PHIs rather than ESAs.

Dosing of HIF PHIs — Daprodustat is the only HIF PHI approved for use in the United States, and this approval is limited to patients on dialysis. Regulatory agencies in Europe, Asia, and South America have approved a variety of HIF PHIs, including daprodustat, vadadustat and roxadustat.

●Initial dosing – An optimal initial HIF PHI dosing regimen has not been established. In practice, the initial dose of HIF PHI will vary according to dialysis facility protocol. The starting doses of daprodustat presented below are based upon recommendations of the US FDA.

•Conversion from ESA therapy – The starting dose of daprodustat for patients switching from an ESA generally ranges from 4 to 12 mg daily, depending on the dose of ESA [78].

Although most studies of daprodustat have examined once daily dosing, less frequent daprodustat dosing (ie, three times a week) may be an option. In a 52-week trial in which 407 patients on hemodialysis were randomly assigned to daprodustat (dose range 2 to 48 mg) three times weekly at dialysis or to epoetin alfa continuation, the mean change in Hb concentration and rates of adverse events were similar between the treatment groups [27].

•Dosing in patients not taking an ESA – For patients not already receiving an ESA, the starting dose of daprodustat depends on the Hb concentration and generally ranges from 1 to 4 mg daily [78].

•Dosing in liver disease and drug interactions – Because daprodustat is metabolized by the liver, the recommended starting dose varies according to hepatic function and the concomitant use of other medications that affect the liver:

-Reduced hepatic clearance – Patients who have moderate hepatic impairment (ie, Child-Pugh Class B) or who take intermediate CYP2C8 (P450 2C8) inhibitors (eg, clopidogrel) should take one half the starting dose of daprodustat (unless starting at the lowest possible dose of 1 mg). Circulating levels of daprodustat are higher in such patients due to reduced hepatic clearance of the drug. No dose adjustment is required for mild hepatic impairment (ie, Child-Pugh Class A). Daprodustat should be avoided in patients who have severe hepatic impairment or who take strong CYP2C8 inhibitors. (See 'Contraindications' above and "Cirrhosis in adults: Overview of complications, general management, and prognosis", section on 'Child-Pugh classification'.)

-Increased hepatic clearance – Patients taking CYP2C8 inducers (eg, rifampin) may have increased hepatic clearance of daprodustat; the Hb and dose of daprodustat should be monitored closely when starting or stopping a CYP2C8 inducer.

●Dose titration – As with ESA therapy, the dose of daprodustat is titrated as necessary to achieve the target Hb level (see 'Target Hb levels' above). Generally, the dose is adjusted monthly in response to the Hb concentration.

Repeated dose escalations should be avoided among patients whose Hb does not improve with HIF PHIs, given concern that high doses may be associated with adverse outcomes independent of the Hb level. Instead, clinicians should investigate the cause of inadequate response, in the same way as for patients with ESA hyporesponsiveness. (See 'Adverse effects of HIF PHIs' below and "Hyporesponse to erythropoiesis-stimulating agents (ESAs) in chronic kidney disease".)

We generally do not escalate the dose of daprodustat to higher than 12 mg daily. Although the maximum recommended dose of daprodustat according to the package insert is 24 mg per day, we do not believe the safety of such high doses has been established. In most major trials, the median dose of daprodustat has ranged between 2 and 6 mg daily, with few patients receiving doses greater than 12 mg per day [26,79,80].

The HIF PHI should be held or dose-reduced in patients with an Hb rise greater than 2 g/dL per month. Holding the dose, rather than reducing the dose, is likely appropriate in patients whose Hb exceeds 12 g/dL on two successive measurements obtained one week apart.

Adverse effects of HIF PHIs — In randomized trials comparing ESAs and HIF PHIs in patients on dialysis, ESAs and HIF PHIs demonstrate similar side effect profiles [26-30]. (See 'Adverse effects of ESAs' above and 'Contraindications' above.)

The quantitative and qualitative similarity of side effects associated with ESAs and HIF PHIs in patients on dialysis may be expected since HIF PHIs exert their effect, at least in part, by increasing endogenous erythropoietin levels. However, HIF pathways regulate or interact with many biologic processes and have numerous nonerythropoietic effects. Thus, there remains a theoretical concern that long-term use of HIF PHIs may impose additional risks compared with ESAs in regard to a variety of adverse events, including cancer, thrombosis, cardiovascular disease, and progression of diabetic retinopathy [81]. The approval of daprodustat in the United States was accompanied by a regulatory directive to conduct long-term, prospective observational studies comparing the safety of daprodustat with ESAs.

TRANSFUSION — Red blood cell transfusions will immediately raise hemoglobin (Hb) levels. However, they may be associated with significant complications that include transfusion-transmitted infection (rare), immunologic sensitization, iron overload syndromes, volume overload, and/or transfusion reactions. Transfusions are rarely administered in patients on chronic dialysis but are indicated for treatment of severe or symptomatic chronic anemia unresponsive to erythropoiesis-stimulating agent (ESA) and iron therapy. (See "Hyporesponse to erythropoiesis-stimulating agents (ESAs) in chronic kidney disease".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anemia in chronic kidney disease".)

SUMMARY AND RECOMMENDATIONS

●Goals of therapy – The goal of anemia treatment for patients on dialysis is to mitigate symptoms and reduce the likelihood of needing a blood transfusion. Most patients on dialysis who have anemia will experience an improvement in symptoms and well-being with treatment, and this benefit is likely to be most pronounced among patients who are treated for severe anemia (eg, hemoglobin [Hb] <8 g/dL). (See 'Introduction' above and 'Likelihood of clinical benefit' above.)

●Surveillance – We routinely monitor all patients on dialysis for anemia and iron deficiency. Most patients who receive dialysis in the United States undergo monitoring of Hb weekly or monthly, and of transferrin saturation (TSAT) and ferritin monthly or quarterly, based upon protocols used by individual dialysis units. (See 'Surveillance' above.)

●Indications for treatment – The treatment of anemia includes intravenous (IV) iron and/or treatment with either an erythropoiesis-stimulating agent (ESA) or a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF PHI). The selection of therapy depends on the presence of absolute or functional iron deficiency and on the severity of anemia. (See 'Indications for treatment' above.)

●Approach to treatment

•Iron – The first step in the management of anemia in a patient on dialysis is to treat absolute or functional iron deficiency, if present. In many patients, treatment with IV iron may increase Hb levels sufficiently such that an ESA or HIF PHI is not needed. (See 'Iron for anemic patients with iron deficiency' above.)

•Choice of therapy in iron replete patients – For patients on dialysis who are iron replete and have an indication for the treatment of anemia, we suggest ESAs rather than HIF PHIs as first-line therapy (Grade 2B). HIF PHI therapy is an alternative option for selected patients. Details about dosing and administration of these agents are discussed above. (See 'Choice of therapy in iron replete patients' above and 'Erythropoiesis-stimulating agents (ESAs)' above and 'Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF PHIs)' above.)

•Target Hb levels – The optimal Hb for patients treated with an ESA or a HIF PHI is unknown, and the target Hb should be individualized. For most patients on dialysis who are treated with ESAs or HIF PHIs, we suggest targeting Hb levels in the range of 10 to 11.5 g/dL, rather than higher or lower levels (Grade 2C). In such patients with Hb levels >11.5 g/dL, the dose of the ESA or HIF PHI should be reduced to maintain Hb levels in the suggested range. (See 'Target Hb levels' above.)

•Adverse effects – The risks of ESA therapy include major adverse cardiovascular events, malignancy, dialysis access thrombosis, and hypertension. Because HIF PHIs increase endogenous erythropoietin levels, they have similar adverse effects to ESAs. Given the serious and varied side effect profile of these agents, the lowest dose necessary to achieve a desired Hb level should be used. (See 'Adverse effects of ESAs' above and 'Adverse effects of HIF PHIs' above.)