INTRODUCTION — Anemia is extremely common among hemodialysis patients 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 hemodialysis patients. This topic provides an approach to screening and treating anemia among such patients. The treatment of iron deficiency among dialysis patients is discussed elsewhere. (See "Treatment of iron deficiency in dialysis patients".)
The screening and treatment of anemia in nondialysis chronic kidney disease (CKD) patients and in peritoneal dialysis patients 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 hemodialysis patients. Even when typically treated, hemodialysis patients will still have anemia as defined above. This is because, among hemodialysis patients, 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 chronic kidney disease (CKD) patients (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 dialysis patients 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 CKD patients as in the general population (algorithm 1). The evaluation should include red blood cell (RBC) 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 IV iron, recent blood loss). (See 'Indications for treatment' below and 'Erythropoiesis-stimulating agents for anemic iron replete patients' below.)
PREVENTION OF ANEMIA WITH MAINTENANCE IRON — We administer maintenance intravenous (IV) iron to most dialysis patients 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 dialysis patients", section on 'Maintenance dose iron'.)
The yearly estimated iron loss in hemodialysis patients 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). (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 hemodialysis patients [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, 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, dialysis patients 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 treat to achieve a specific clinical goal (eg, to minimize hospitalization for transfusions, optimize management of heart failure) rather than aiming for a specific hemoglobin 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 dialysis patients 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 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 dialysis patients", section on 'Loading dose iron' and "Treatment of iron deficiency in dialysis patients", 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 dialysis patients 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), but iron should be given first with repeat assessment of Hb prior to starting the ESA. If Hb remains less than 10 g/dL after iron stores are replete, then most patients are started on an ESA. (See 'Hb <10 g/dL and TSAT >30 percent' 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 maintenance hemodialysis patients", 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 dialysis patients", section on 'Loading dose iron'.)
Hb <10 g/dL and TSAT >30 percent — Such patients are usually started on an ESA, taking into consideration specific patient characteristics, such as functional and cognitive status, life expectancy, and other factors. Patients who have a history of stroke or malignancy or an active malignancy are important exceptions for treatment with ESAs; in such patients, a decision to use an ESA must be individualized after weighing risks and benefits of treatment with the patient. (See 'Contraindications' below and 'Likelihood of clinical benefit' above.)
The dosing and titration of ESA is discussed below. (See 'Initial dosing' below and 'Dose titration' below.)
Among patients who are being treated with an ESA, IV iron should be administered while continuing ESA treatment (unless goal Hb has been reached or exceeded, in which case the ESA is reduced or stopped). Iron stores become depleted in such patients as a result of an ESA-induced increase in erythropoiesis. The correction of iron deficiency may, therefore, allow for a reduction in the ESA dose [15-24]. The dosing of IV iron for such patients is presented elsewhere. (See "Treatment of iron deficiency in dialysis patients", 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 and have Hb <10 g/dL and ferritin >500 ng/mL, we increase the ESA dose without giving IV iron, provided that the patient is not on a very high erythropoietin dose already (generally defined as 20,000 to 30,000 units per week). If the increased ESA dose does not raise the Hb level sufficiently, we often prescribe supplemental iron (with or without a further increase in erythropoietin 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 dialysis patients".)
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. 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, 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 maintenance hemodialysis patients", section on 'Monitoring and intervention'.)
TREATMENT
Iron for anemic patients with iron deficiency — The details regarding dosing regimens using various iron formulations and adverse effects of iron therapy are discussed elsewhere. (See "Treatment of iron deficiency in dialysis patients".)
Erythropoiesis-stimulating agents for anemic iron replete patients — ESAs are effective in treating anemia. Among hemodialysis patients with severe anemia, ESAs reduce the need for transfusion [26,27] and improve quality-of-life symptoms, exercise tolerance, and left ventricular hypertrophy, which has been associated with higher mortality [28-33].
Contraindications — We avoid the use of ESAs among dialysis patients who have a malignancy, particularly those in whom cure is anticipated, or who have had a stroke, since such patients may be at a higher risk for adverse effects from ESAs [34]. The treatment of such patients should be individualized after careful consideration and discussion of the possible risks and benefits of ESA therapy. (See 'Adverse effects of erythropoiesis-stimulating agents' below.)
The optimal target Hb for ESA dosing is not known. Recommendations for target levels are discussed below. (See 'Target levels' below.)
Initial dosing — In the United States, most patients on hemodialysis are treated with epoetin alfa or pegylated epoetin beta. 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 Food and Drug Administration (FDA). The Kidney Disease Outcomes Quality Initiative (KDOQI) and Kidney Disease: Improving Global Outcomes (KDIGO) anemia guidelines do not specify a starting dose but state that the dose should be individualized [34,35]. 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 hemoglobin <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 [36-39].
Dose titration — We titrate the dose upwards as necessary to achieve the target Hb level (see 'Target levels' below). The dose of ESA required to reach the target Hb varies widely among dialysis patients [40-43]. 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 erythropoiesis-stimulating agents' below and "Hyporesponse to erythropoiesis-stimulating agents (ESAs) in chronic kidney disease".)
The typical Hb rise with a new ESA dose is generally in the range of 1 to 2 g/dL per month. The dose of ESA should be modified in patients whose Hb rises above this rate. As an example, among patients with an Hb rise greater than 2.5 to 3 g/dL per month, ESA should be either be held or the dose reduced by at least 50 percent. 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 13 g/dL [44]. (See 'Continued monitoring' above.)
Route of administration — Subcutaneous ESA administration is used in patients receiving peritoneal dialysis. Either intravenous (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 [40,45]. This was best shown in a trial in which 208 hemodialysis patients were randomly assigned to either subcutaneous or IV epoetin [40]. 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 hemodialysis patients 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 myocardial infarction [MI], or stroke) were more common in IV epoetin-treated patients, perhaps due to the higher epoetin dose [45].
However, IV administration is often favored by hemodialysis patients 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 hemodialysis patients received ESAs intravenously [46], and a similar practice of preferential IV administration in hemodialysis patients has been reported in other countries [47].
Target levels — The optimal target Hb level for patients on dialysis is not well defined. In most patients on dialysis who are treated with ESAs, 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 a Hb >10 g/dL. Similarly, patients who desire a 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 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 erythropoiesis-stimulating agents' below.)
In clinical practice, it is difficult to maintain individual patient Hb values within a narrow range [48-51]. While we try to maintain Hb levels between 10 to 11.5 g/dL in most patients, Hb levels >11.5 g/dL will occur transiently in many patients due to a variety of factors and should prompt a gradual dose reduction in the ESA 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 [52].
Our target Hb range reflects the results of clinical studies and recognizes that anemia treatment should be individualized. The US FDA boxed warning on ESAs states that Hb targets >11 g/dL are not recommended [53]. 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 KDIGO 2012 guidelines [34].
Among all chronic kidney disease (CKD) patients (ie, dialysis and nondialysis), multiple studies have shown that Hb targets >13 g/dL are associated with adverse outcomes [26,54-60]. The best data among hemodialysis patients come from the Normal Hematocrit Trial (NHT), in which 1233 hemodialysis patients 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 [26]. 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 [26]. 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) [61].
In addition to these data, which were limited to hemodialysis patients, a number of meta-analyses and systematic reviews have been performed, mostly including nondialysis CKD patients [54,55,57,59,60]. 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 dialysis patients), 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 [62]. However, the confidence in the findings of this meta-analysis was limited by the high risk of bias and heterogeneity among the included studies.
Adverse effects of erythropoiesis-stimulating agents — Some adverse effects have only been described when ESAs are used to attain a normal Hb. As noted above, these include increased mortality, cardiovascular events, and malignancy (see 'Target levels' above). There is also an increased risk of hemodialysis access thrombosis when ESAs are used to maintain normal or near-normal Hb [26,63,64]. 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 [63].
Hypertension may be observed with ESAs [26,54,58,64-66]. The risk of hypertension appears to be independent of the target Hb [26,67,68]. (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 [69], although we believe that this is uncommon today. Although the reported incidence ranges from 2 to 17 percent [54,69,70], 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, included studies were of both predialysis and dialysis CKD patients, which may have resulted in an underestimate of incidence among dialysis patients [54].
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".)
It is not possible to predict in advance who will develop seizures with an ESA. Prodromal symptoms including persistent headache or visual disturbances that develop in the early weeks after institution of an ESA suggest the possibility that seizures will occur. The presence of other ESA-related reactions or side effects (such as exacerbated hypertension or a rapid rise in Hb) may suggest the possibility of seizures.
Investigational agents — Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF PHIs) are a novel class of oral ESAs that may be a potential future option for treatment of anemia in patients on dialysis. Unlike other 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. The following HIF PHIs have been evaluated in clinical trials:
●Daprodustat – The safety and efficacy of the HIF PHI daprodustat were evaluated in a trial of 2964 patients on dialysis (mean hemoglobin 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 [71]. The mean change in hemoglobin 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, 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. The efficacy of less frequent dosing of daprodustat was examined in a subsequent 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; the mean change in hemoglobin concentration and rates of adverse events were similar between the treatment groups [72].
●Vadadustat – The safety and efficacy of vadadustat among prevalent patients on dialysis were examined in a trial of 3554 patients who were randomly assigned to receive the HIF PHI, vadadustat, or darbepoetin alfa [73]. Vadadustat (at a dose of 150 to 600 mg) and darbepoetin were titrated to target an Hb of 10 to 11 g/dL among patients in the United States and 10 to 12 g/dL among patients in other countries. All trial participants were also offered treatment with iron to maintain a transferrin saturation (TSAT) >20 percent and serum ferritin >100 ng/mL.
Between weeks 40 and 52 after randomization, prevalent dialysis patients assigned to vadadustat were less likely to maintain target Hb (44 versus 51 percent), although rates of red cell transfusion were similar (2.0 versus 1.9 percent of prevalent dialysis patients). Findings from a corresponding trial of 369 incident patients on dialysis with the same study design reached similar conclusions [73].
Combining patients from both trials, rates of mortality (13.0 versus 12.9 percent), nonfatal stroke (1.3 versus 1.9 percent), hospitalization for heart failure (3.9 versus 4.0 percent), and nonfatal MI (3.9 versus 4.5 percent) were similar. Other adverse events (eg, hypertension, diarrhea, pneumonia) were lower in the vadadustat group, both among prevalent (55 versus 58 percent) and incident (50 versus 57 percent) dialysis patients.
●Roxadustat – Smaller trials evaluating the safety and efficacy of the HIF PHI roxadustat among patients on dialysis have reported findings similar to those found in trials of daprodustat and vadadustat [74,75].
Since HIF pathways regulate or interact with many biologic processes, there is concern about nonerythropoietic adverse effects, such as increased risk of cancer, thrombosis, cardiovascular disease, progression of diabetic retinopathy, and CKD, among others, which will require long-term follow-up of treated patients [76]. None of these agents are yet approved for use in the United States.
TRANSFUSION — Red blood cell transfusions will immediately raise hemoglobin 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 chronic dialysis patients but are indicated for treatment of severe or symptomatic chronic anemia unresponsive to erythropoiesis-stimulating agent 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
●Anemia contributes to many of the symptoms associated with reduced kidney function. The partial correction of anemia provides benefit. (See 'Introduction' above and 'Indications for treatment' above.)
●We routinely monitor all dialysis patients for anemia and iron deficiency. Our approach is generally consistent with the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. (See 'Surveillance' above.)
●The treatment of anemia includes erythropoiesis-stimulating agents (ESAs) and/or intravenous (IV) iron. The selection of the individual therapy depends on the severity of anemia and on the presence of iron deficiency. (See 'Indications for treatment' above.)
●The treatment of anemia among dialysis patients should be individualized.
•The optimal target Hb level for patients on dialysis is not well defined. We suggest targeting hemoglobin (Hb) levels in the range of 10 to 11.5 g/dL, rather than higher levels, in most hemodialysis patients who are treated with ESAs (Grade 2C). In such patients with Hb levels >11.5 g/dL, appropriate measures should be instituted, such as decreasing the dose of the ESA or increasing the dosing interval, to maintain Hb levels in the range of 10 to 11.5 g/dL. (See 'Erythropoiesis-stimulating agents for anemic iron replete patients' above.)
•We recommend NOT administering ESAs to achieve Hb levels >13 g/dL (Grade 1B). Hb targets >13 g/dL are associated with adverse outcomes. (See 'Target levels' above and 'Adverse effects of erythropoiesis-stimulating agents' above.)
●Given limited information indicating a possible association between ESA dose, mortality, and other adverse outcomes, the lowest dose necessary to achieve a desired Hb level should be used, and excessively high doses in patients with ESA hyporesponsiveness should be avoided. (See 'Target levels' above and 'Adverse effects of erythropoiesis-stimulating agents' above.)
