INTRODUCTION — Erythropoiesis-stimulating agents (ESAs) are commonly used to treat anemia associated with chronic kidney disease (CKD). ESA resistance, or hyporesponsiveness, is a term used to describe patients who do not achieve the desired hemoglobin (Hb) concentration despite higher than usual doses of ESAs or who require increasingly higher ESA doses to maintain an Hb concentration [1].
ESA resistance is generally relative rather than complete, and, as such, ESA hyporesponsiveness is a more accurate description. This topic reviews ESA hyporesponsiveness in CKD patients. Recommendations for dosing and administration of ESAs in CKD and dialysis patients are discussed elsewhere. (See "Treatment of anemia in nondialysis chronic kidney disease" and "Treatment of anemia in patients on dialysis".)
DEFINITION AND CRITERIA — As noted above, ESA hyporesponsiveness is a term used to describe patients who do not achieve the desired hemoglobin (Hb) concentration despite higher than usual doses of ESAs or who require increasingly higher ESA doses to maintain a target Hb concentration [1].
Criteria for ESA hyporesponsiveness are not well defined. We use the Kidney Disease Outcomes Quality Initiative (KDOQI) criteria of inability to achieve or maintain a desired Hb concentration using a maximum dose of 450 units/kg per week intravenous erythropoietin or 300 units/kg per week subcutaneous erythropoietin [2]. Criteria for other ESAs, such as darbepoetin and methoxy polyethylene glycol-epoetin beta, have not been defined, since precise dose conversions are not known. Package inserts suggest that 45,000 units/week of epoetin corresponds roughly to 100 mcg/week of darbepoetin.
Other criteria have been suggested by European Best Practice Guidelines and Kidney Disease: Improving Global Outcomes (KDIGO) [3,4]:
●Failure to attain or maintain desired Hb concentration with 300 units/kg per week of erythropoietin (approximately 20,000 units/week) and 1.5 mcg/kg per week of darbepoetin alfa (approximately 100 mcg/week) [4].
●Having no increase in Hb concentration after the first month of appropriate weight-based dosing and/or requiring two increases in ESA doses up to 50 percent beyond the dose at which the patient had originally been stable [3].
A practical definition of an ESA-resistant patient is one who requires a dose that is greater than that given to 90 percent of patients in a given facility.
EPIDEMIOLOGY — One contemporary, retrospective study identified ESA hyporesponsiveness, defined as two consecutive hemoglobin (Hb) levels <10 g/dL while receiving epoetin >7700 units per dose, in 12.5 percent of hemodialysis patients [5].
ESA hyporesponsiveness among patients on peritoneal dialysis has not been well studied but is likely much less common than among hemodialysis patients as peritoneal dialysis patients generally tend to have higher Hb levels and require lower ESA doses [6,7].
CAUSES — Iron deficiency and infection and/or inflammation are the two most common causes of ESA hyporesponsiveness. These and other causes are discussed below.
Iron deficiency — Iron deficiency is a common cause of ESA hyporesponsiveness. Iron deficiency may be absolute (which is often due to external blood losses) or functional (related to ESA administration or anemia of chronic disease). All patients with ESA hyporesponsiveness should be assessed for absolute and functional iron deficiency. (See "Diagnosis of iron deficiency in chronic kidney disease", section on 'Definitions'.)
Infection or inflammation — Chronic inflammation is common among hemodialysis patients and an important cause of ESA hyporesponsiveness [8-12]. Dialysis catheters are a common cause of chronic inflammation. Other causes include skin or wound infections; failed kidney transplant; and occult infection of an old, nonfunctioning arteriovenous graft [10-13]. The role of hepatitis C as a cause of ESA hyporesponsiveness has not been studied. (See "Inflammation in patients with kidney function impairment" and "Anemia of chronic disease/anemia of inflammation" and "Kidney transplantation in adults: Management of the patient with a failed kidney transplant".)
Inadequate dialysis — Inadequate dialysis may cause ESA hyporesponsiveness [14,15]. In an old study of 20 stable hemodialysis patients who were modestly under-dialyzed (mean urea reduction ratio [URR] 60.7 percent), increasing the dialysis dose was associated with an increase in hematocrit despite a constant dose of ESA [14]. Differences in the dialysis membrane may have affected the ESA response since the increase in urea clearance was achieved by changing to a larger dialyzer with a different membrane. However, the dialyzer membrane has not been shown to affect the ESA response in other studies [16-18].
An increase in the dialysis dose is unlikely to increase ESA response in patients who are already being adequately dialyzed (ie, single-pool Kt/V ≥1.0 to 1.2) [14,19,20]. (See "Prescribing and assessing adequate hemodialysis", section on 'Target Kt/V'.)
Changes in the dialysis modality also may affect ESA responsiveness [6,7]. The effect of short daily and long nocturnal hemodialysis on anemia and ESA response is discussed separately. (See "Outcomes associated with nocturnal hemodialysis", section on 'Anemia'.)
Use of ultrapure dialysate has been associated with improved hemoglobin (Hb) concentrations and reduced ESA requirements [21-23]. This association is believed to be related to reduced inflammation. Ultrapure dialysate is dialysate that is of much higher microbiologic purity than is required by some international and national standards. (See "Ultrapure dialysis fluid", section on 'Potential clinical benefits of ultrapure dialysis fluid'.)
Other — Other conditions associated with ESA hyporesponsiveness include severe hyperparathyroidism with osteitis fibrosis cystica, malignancy, bone marrow disorders such as myelodysplastic syndrome and multiple myeloma, and hemoglobinopathies, such as sickle cell disease. B12 and folate deficiencies have also been reported in ESA hyporesponsive patients [24].
Pure red cell aplasia, a condition of complete ESA hyporesponsiveness, has been associated with the subcutaneous administration of a particular brand of ESA, which is no longer available. (See "Pure red cell aplasia (PRCA) due to anti-erythropoiesis-stimulating agent antibodies".)
Some reports suggest that the administration of angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor antagonists may cause relative ESA hyporesponsiveness, but this does not seem to be clinically important or common [25-27]. This effect may have genetic determinants [28]. Possible mechanisms of ESA hyporesponsiveness in this setting are discussed elsewhere. (See "Kidney transplantation in adults: Posttransplant erythrocytosis".)
OUR APPROACH TO ESA HYPORESPONSIVENESS — It is important to carefully evaluate erythropoiesis-stimulating agent (ESA)-resistant patients. ESA hyporesponsiveness is associated with increased mortality, and many causes of ESA hyporesponsiveness can be addressed. Our approach is as follows:
●We exclude both absolute and functional iron deficiency and treat with iron, if present. Even in the absence of documented absolute iron deficiency, some patients will have an increase in hemoglobin concentration with additional iron supplementation given intravenously. (See "Treatment of iron deficiency in dialysis patients" and "Treatment of iron deficiency in nondialysis chronic kidney disease (CKD) patients".)
●We make sure patients are adequately dialyzed. Among patients who are not achieving the minimum Kt/V, we modify the dialysis prescription to increase the amount of delivered dialysis. (See "Prescribing and assessing adequate hemodialysis" and "Prescribing peritoneal dialysis".)
●We perform a careful physical exam to exclude occult infection, with particular attention to thrombosed arteriovenous grafts. (See "Physical examination of the arteriovenous graft", section on 'Detection of specific problems'.)
Observational studies suggest that removal of old grafts is associated with improved ESA responsiveness [11]. Among those with a hemodialysis catheter, placement of arteriovenous access and removal of the catheter may also improve ESA responsiveness.
●Among patients with severe hyperparathyroidism, we attempt to restore optimal parathyroid hormone (PTH) concentrations with pharmacologic therapy or parathyroidectomy. Treatment of hyperparathyroidism improves ESA response [29-31]. (See "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease".)
In patients with ESA hyporesponsiveness, the ESA can be stopped or continued at a low dose that helps to minimize transfusion requirements with use of transfusions as needed to manage anemia-related symptoms [32]. Results of a single, phase IIa, exploratory study indicated that the hypoxia-inducible factor prolyl hydroxylase inhibitor daprodustat increased hemoglobin (Hb) in two of seven hemodialysis patients who remained on treatment for 16 weeks [33]. Additional studies will be needed to assess the role of this newer class of ESAs in dialysis patients hyporesponsive to epoetins [34].
OUTCOMES
Mortality — ESA hyporesponsiveness is associated with increased mortality [35-37]. In one observational study of hemodialysis patients in the United States, patients who had hemoglobin (Hb) <9.5 g/dL and received larger ESA dose changes over an 11-month period had a higher mortality risk (hazard ratio [HR] 1.32) [35]. In another study that used data from the Normal Hematocrit Cardiac Trial, a higher erythropoietin-responsiveness measure (defined as the ratio of the weekly hematocrit change per ESA dose increase) was associated with lower mortality (with an adjusted HR of 0.41 for highest versus lowest quartiles) [36].
The effect of ESA hyporesponsiveness on mortality among peritoneal dialysis patients has not been well studied. One study from Korea suggested that ESA hyporesponsiveness was associated with higher mortality among hemodialysis patients but not peritoneal dialysis patients [38]. However, other studies that have compared hemodialysis and peritoneal dialysis have not found such an association [39,40].
The increased mortality associated with ESA hyporesponsiveness is likely due to the underlying cause of ESA hyporesponsiveness. However, some studies have suggested that the increased mortality is related to the higher ESA doses that are used in these patients [37,41-47]. As an example, in an unadjusted analysis of the Correction of Hemoglobin in the Outcomes in Renal Insufficiency (CHOIR) trial, an increased risk of the primary composite endpoint (death, myocardial infarction, heart failure, or stroke) at four months was associated with both an inability to achieve target levels and higher doses of epoetin (>20,000 units per week) [46]. However, adjusted analysis found that only high-dose epoetin therapy resulted in an independent increased risk of the primary composite endpoint (HR 1.57, 95% CI 1.04-2.36). This increased risk was observed in both high- and low-target Hb groups, particularly among those unable to reach target Hb levels.
While most studies have focused on hyporesponsiveness during ongoing chronic ESA treatment, the relationship between initial Hb response to darbepoetin was assessed in the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) study [37]. Patients who did not respond to the initial two doses of darbepoetin had higher rates of a composite cardiovascular endpoint and death compared with those with a better initial treatment response.
In addition, a meta-regression analysis of 31 trials (12,956 patients) found that all-cause mortality was associated with higher first three-month and total-study-period mean ESA dose independent of Hb level [48,49]. There was a similar trend for cardiovascular mortality that was not statistically significant. Higher total-study-period mean ESA dose also was associated with an increased rate of hypertension, stroke, and thrombotic events, including dialysis vascular access-related thrombotic events.
However the association between higher ESA doses and mortality has not been shown in all studies. In one observational study of older hemodialysis patients, doses of epoetin that exceeded 30,000 units per week were not associated with harm or benefit [50].
Progression of chronic kidney disease (CKD) — ESA hyporesponsiveness may be associated with more rapid progression to end-stage kidney disease (ESKD) [51]. This was suggested by a study of 194 consecutive CKD patients who started ESAs between 2002 and 2006 [52]. Patients were classified as poor, intermediate, and good responders based upon their response to the first administered ESA dose. Responsiveness was calculated according to the formula: (Hb1-Hb0)/time/ESA dose where Hb1 and Hb0 correspond to Hb values at the first visit after ESA administration and at baseline, respectively; time refers to the period between visits; and ESA dose is the first weekly dose prescribed. ESA responsiveness was expressed as g/dL/month, standardized to 10 mcg/week. During a median follow-up of three years, poor responsiveness was associated with a higher risk of ESKD (HR 2.49, 95% CI 1.28-4.84). The mechanism underlying this possible association is not known.
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
●Definition and criteria – Erythropoiesis-stimulating agents (ESAs) are commonly used to treat anemia associated with chronic kidney disease (CKD). Patients who do not achieve the desired hemoglobin (Hb) concentration despite higher than usual ESA doses or who require increasingly higher ESA doses to maintain an Hb concentration are considered ESA resistant. Criteria for ESA hyporesponsiveness are not well defined. (See 'Introduction' above and 'Definition and criteria' above.)
●Causes – Causes of ESA hyporesponsiveness include absolute and functional iron deficiency, infection or inflammation, inadequate dialysis, severe hyperparathyroidism (with osteitis fibrosa cystica), and malignancy or hematologic disorders. (See 'Causes' above.)
●Approach to ESA hyporesponsiveness – It is important to carefully evaluate ESA-resistant patients for potential causes. Our approach is as follows (see 'Our approach to ESA hyporesponsiveness' above):
•We exclude both absolute and functional iron deficiency and treat with iron, if present.
•We make sure patients are adequately dialyzed. Among patients who are not achieving the minimum Kt/V, we modify the dialysis prescription to increase the amount of delivered dialysis.
•We perform a careful physical exam to exclude occult infection, with particular attention to thrombosed arteriovenous grafts.
•Among patients with severe hyperparathyroidism, we attempt to restore optimal parathyroid hormone (PTH) concentrations with pharmacologic therapy or parathyroidectomy.
●Outcomes – ESA hyporesponsiveness has been associated with increased mortality among both patients on hemodialysis and those on peritoneal dialysis, as well as patients with CKD who are not on dialysis. This is likely due to the underlying cause of ESA hyporesponsiveness, although higher ESA doses used in these patients may also contribute to higher risk of adverse events including death. (See 'Outcomes' above.)
