# Anemia: Targets, ESAs, and Hyporesponsiveness

*Part of the Maintenance Hemodialysis mastery module. This page covers hemoglobin targets, erythropoiesis-stimulating agents (ESAs), and hyporesponsiveness. Iron, HIF-PH inhibitors, and transfusion are on the companion page, [Anemia: iron, HIF-PH inhibitors, and transfusion](https://urinenephrology.org/mastery/maintenance-hd/iron-hif-transfusion-hd.html).*

## Bottom Line

The hemoglobin lesson is the most expensive lesson in nephrology. It took two decades of trials to learn that a normal number is not a healthy patient.

- **KDIGO rewrote the anemia guideline in January 2026** — its first full update since 2012, summarized for internists in *Annals* in September 2026 ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1),[2](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-2),[3](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-3)). For dialysis it keeps ESA initiation at a hemoglobin (Hb) of **9.0–10.0 g/dL or below** (2D), makes the ceiling a recommendation — **target below 11.5 g/dL** (1D) — and prefers an **ESA over a HIF-PH inhibitor** as first-line therapy (2D) ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1)).
- **The US label is stricter than the guideline.** Epoetin labeling says to reduce or interrupt the dose when Hb **approaches or exceeds 11 g/dL** in dialysis patients ^([4](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-4)). A unit protocol has to pick one number and say so.
- **The hemodialysis target trials are the Normal Hematocrit Trial and Parfrey 2005** ^([5](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-5),[6](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-6)). CHOIR, CREATE, and TREAT — the trials most often quoted — enrolled non-dialysis CKD ^([7](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-7),[8](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-8),[9](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-9)). The direction of harm is the same; the population is not.
- **ESA hyporesponsiveness is a prognosis, not a dosing problem.** Poor responders die more, whichever drug they receive ^([10](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-10),[11](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-11),[12](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-12)). Find the cause — iron, inflammation, access infection, underdialysis, hyperparathyroidism, blood loss — and avoid escalating beyond double the stable dose ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1)).
- **KDIGO 2026 allows a 3–4-month HIF-PHI trial** for persistent hyporesponsiveness when there is a reason to raise Hb (practice points 3.7.2–3.7.4). The caveat: the truly hyporesponsive and inflamed patients were excluded from the HIF-PHI trials ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1),[13](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-13)).

## What Changed: KDIGO 2012 to KDIGO 2026

The 2026 guideline supersedes the 2012 document. For hemodialysis, the changes that matter most are below; the 2012 column also reflects the KDOQI US commentary on that guideline ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1),[13](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-13),[14](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-14),[15](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-15)).

| Domain | KDIGO 2012 | KDIGO 2026 |
|----|----|----|
| ESA initiation, dialysis | Start when Hb 9.0–10.0 g/dL (2B) | Hb ≤9.0–10.0 g/dL (Rec 3.2.1, **2D**) |
| ESA ceiling | Generally not above 11.5 (2C); never intentionally above 13 (1A) | **Target below 11.5 g/dL** (Rec 3.3.1, **1D**) |
| Hb monitoring, HD maintenance | At least monthly (not graded) | At least every 3 months (PP 3.4.3.3) — a looser floor |
| First-line agent | ESA (HIF-PHIs did not exist) | **ESA rather than HIF-PHI** (Rec 3.1.1, 2D) |
| Hyporesponsiveness | Initial and acquired definitions | Same definitions; a 3–4-month HIF-PHI trial may be considered (PP 3.7.2–3.7.4) |
| Iron initiation, HD | Trial of IV iron if TSAT ≤30% and ferritin ≤500 ng/mL (2C) | Initiate if ferritin ≤500 ng/mL and TSAT ≤30% (Rec 2.1, 2D) |
| Iron ceiling | Avoid if ferritin consistently \>500 (not graded) | Reasonable to withhold routine iron if **ferritin \>700 ng/mL or TSAT ≥40%** (PP 2.2) |
| Iron-deficiency terms | “Absolute” and “functional” | “Systemic iron deficiency” and “iron-restricted erythropoiesis” |

Rec = graded recommendation; PP = practice point (ungraded). In KDIGO notation, 1 is a recommendation and 2 a suggestion; the letter grades the certainty of evidence, from A (high) to D (very low). Both headline hemoglobin numbers on this page rest on D-grade evidence.

## 1. Why Hemodialysis Patients Are Anemic

Five mechanisms stack. Only one of them is erythropoietin.

**Relative erythropoietin deficiency.** The anemia of CKD is typically normocytic and normochromic and is driven primarily by a relative reduction in renal erythropoietin (EPO) synthesis, reflecting both lost kidney mass and a disrupted renal oxygen-sensing mechanism ^([13](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-13)). “Relative” is the key word: the EPO level is inappropriately low for the degree of anemia, not necessarily low in absolute terms.

**Hepcidin and inflammation.** Inflammation drives hepatic hepcidin, which downregulates the iron exporter ferroportin on enterocytes and macrophages. Dietary iron is not absorbed and stored iron is not released ^([13](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-13),[16](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-16)). The result is **iron-restricted erythropoiesis**: a normal or high ferritin with a low transferrin saturation (TSAT) ^([13](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-13),[17](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-17)). This is why oral iron works poorly in hemodialysis, why ferritin misleads, and why every infection, catheter, and failed graft shows up in the ESA dose.

**Blood loss on dialysis.** Every treatment costs blood — sampling, dialyzer and circuit residual, clotting, and post-needle bleeding. Sargent’s measured-loss studies, done with 1990s-era circuits, projected **2,516 to 5,126 mL of blood lost per year** on conventional thrice-weekly hemodialysis ^([18](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-18)). As derived arithmetic (not from the source): at Hb 11 g/dL a milliliter of blood carries roughly 0.38 mg of iron, so those losses equal roughly **0.9 to 1.9 g of iron per year**. That is why nearly every hemodialysis patient on an ESA needs ongoing IV iron.

**Shortened red-cell survival.** In a small chromium-51 study of 22 patients, red-cell half-life was **14.5 days** in thrice-weekly hemodialysis patients versus **23.5 days** in healthy controls — unchanged from measurements made half a century earlier and not improved by nocturnal or short-daily hemodialysis ^([19](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-19)).

**Contributors that can be fixed.** Underdialysis blunts the EPO response: raising the urea reduction ratio (URR) from 60.7% to 72% for six weeks raised hematocrit from 28.4% to 32.3% in an uncontrolled comparison ^([20](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-20)). Severe secondary hyperparathyroidism with marrow fibrosis tripled the EPO dose needed (174 versus 56 U/kg three times weekly) ^([21](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-21)). KDIGO 2026 lists the rest: nonadherence, hypothyroidism, infection or inflammation, dialysis-related and gastrointestinal blood loss, malnutrition, iron or B12/folate deficiency, marrow disorders including pure red-cell aplasia (PRCA), hemolysis, and malignancy ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1)).

## 2. Evaluation and Monitoring

### Definition and the initial panel

KDIGO 2026 keeps the WHO definition of anemia — **Hb below 13 g/dL in men and below 12 g/dL in women** — and replaces the old initial panel with a **CBC, reticulocyte count, ferritin, and TSAT** (PP 1.2.1) ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1)). B12 and folate are no longer routine at diagnosis; they move to an expanded panel ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1)). The European Renal Best Practice (ERBP) commentary pushes back: test them in macrocytosis, cognitive impairment, malnutrition, diabetes, advanced age, and frailty — which describes much of a dialysis unit ^([13](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-13)).

Hemoglobin beats hematocrit in dialysis because hematocrit swings more with plasma volume ^([13](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-13)). Draw it pre-dialysis, on a consistent day of the week, so that the monthly number reflects biology rather than ultrafiltration.

### How often

| What | KDIGO 2026 (hemodialysis) | FDA ESA or HIF-PHI label |
|----|----|----|
| Hb, stable on ESA | At least every 3 months (PP 3.4.3.3) | At least monthly ^([4](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-4)) |
| Hb after ESA start or dose change | Every 2–4 weeks (PP 3.4.3.2) | At least weekly until stable ^([4](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-4)) |
| Ferritin and TSAT | Every 1–3 months (PP 2.5); sooner after ESA or HIF-PHI start or increase, blood loss, hospitalization, or a large rise in ferritin or TSAT | Before and during treatment ^([4](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-4)) |
| Hb on a HIF-PHI | 2–4 weeks after start or change, then every 4 weeks (PP 3.6.1) | Vadadustat: at start or adjustment, then monthly ^([22](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-22)) |

Source for the KDIGO column: ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1)). KDIGO 2026’s “every 3 months” is a minimum, and it is looser than KDIGO 2012, which asked for Hb at least monthly during maintenance ESA therapy in dialysis ^([14](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-14)). Nothing in the 2026 guideline argues against monthly testing, and the label asks for it.

### Ferritin and TSAT: what they can and cannot tell you

- **Ferritin is an acute-phase reactant.** A ferritin above 800 ng/mL with a TSAT below 20% has become a common pattern in dialysis, and it usually means inflammation-locked iron rather than overload ^([17](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-17)).
- **TSAT reflects iron available to the marrow right now.** It is sensitive to timing: it jumps after an IV iron dose, and most observational studies never report when TSAT was drawn relative to iron ^([13](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-13)). Draw iron studies at the scheduled draw, before that session’s iron dose, and record the date of the last IV iron.
- **A high ferritin does not mean no response to iron.** DRIVE (RCT) randomized 134 anemic hemodialysis patients with **ferritin 500–1,200 ng/mL and TSAT ≤25%** on high-dose epoetin to ferric gluconate 125 mg for eight sessions or no iron. Hb rose **1.6 versus 1.1 g/dL** at six weeks (P=0.028), and the benefit was the same above and below a ferritin of 800 ^([23](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-23)). Six weeks is short, and DRIVE says nothing about long-term safety at those ferritins.

Clinical Pearl — read the pair, not the number

Low TSAT plus low ferritin (below 200 ng/mL in hemodialysis) is **systemic iron deficiency**: give iron and look for blood loss. Low TSAT plus high ferritin is **iron-restricted erythropoiesis**: look for the inflammation — catheter, wound, old graft, occult infection — before assuming overload ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1),[13](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-13)). A ferritin below **45 ng/mL**, or microcytosis with an MCV below 80 fL, should prompt evaluation for gastrointestinal, urologic, or gynecologic blood loss (PP 1.2.3) ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1)).

### Reticulocyte hemoglobin (CHr or Ret-He)

Reticulocyte hemoglobin measures iron delivered to red cells made in the last few days. In 164 hemodialysis patients, a CHr **below 26 pg** predicted a reticulocyte response to IV iron with **sensitivity 100% and specificity 80%**, outperforming ferritin and TSAT — in a 32-patient challenge subset (diagnostic cohort) ^([24](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-24)). KDIGO 2026 did not adopt CHr; ERBP notes that other guidelines do ^([13](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-13)). Where the laboratory reports it, reticulocyte hemoglobin is a reasonable tiebreaker when ferritin and TSAT disagree. Several cutoffs circulate, and none is guideline-endorsed in 2026.

### When to look further

If iron indices do not explain the anemia, KDIGO’s expanded panel (PP 1.2.2) is a peripheral smear, haptoglobin, LDH, CRP, B12, folate, liver tests, serum protein electrophoresis with immunofixation and free light chains, urine Bence-Jones protein, TSH, PTH, and fecal occult blood ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1)). Add reticulocytes to separate a hypoproliferative marrow from hemolysis or bleeding ^([13](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-13)).

## 3. Hemoglobin Targets and ESA Safety

### The trials

| Trial | Population and design | Target arms | Primary result | Absolute effect and notes |
|----|----|----|----|----|
| **Normal Hematocrit Trial** (Besarab 1998) ^([5](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-5)) | **Hemodialysis**, n=1,233, with CHF or ischemic heart disease; RCT | Hematocrit 42% vs 30% (epoetin) | Death or first MI: 202 vs 164 events; RR 1.3 (95% CI 0.9–1.9); halted early | 32.7% vs 26.7% — **ARI 6.0%, NNH 17** over approximately 29 months. The report filed with the FDA showed **RR 1.28 (1.06–1.56)** ^([25](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-25)) |
| **Parfrey 2005** ^([6](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-6)) | **Incident hemodialysis**, n=596, no symptomatic heart disease; double-blind RCT | Hb 13.5–14.5 vs 9.5–11.5 | No difference in LV volume index (7.6% vs 8.3% change) | Surrogate endpoint. Higher arm: more headache and cerebrovascular events; vitality modestly better |
| **CHOIR** (Singh 2006) ^([7](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-7)) | Non-dialysis CKD, n=1,432; open-label RCT | Hb 13.5 vs 11.3 (epoetin alfa) | Death, MI, CHF hospitalization, or stroke: **HR 1.34 (1.03–1.74)** | 17.5% vs 13.5% — **ARI 4.0%, NNH 26** over a median 16 months; no quality-of-life gain |
| **CREATE** (Drüeke 2006) ^([8](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-8)) | CKD G3–4, n=603; RCT | Hb 13–15 vs 10.5–11.5 (SC epoetin beta) | First CV event: **HR 0.78 (0.53–1.14)**, P=0.20 | More patients reached dialysis in the high arm (127 vs 111, P=0.03); general health and physical function better |
| **TREAT** (Pfeffer 2009) ^([9](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-9)) | Type 2 diabetes with non-dialysis CKD, n=4,038; placebo-controlled RCT | Darbepoetin to Hb approximately 13 vs placebo (rescue below 9) | Death or CV event **HR 1.05 (0.94–1.17)** | Stroke 5.0% vs 2.6%, **HR 1.92 (1.38–2.68); ARI 2.4%, NNH 42**. Transfusion 14.8% vs 24.5%: **ARR 9.7%, NNT 11**. Amgen-funded ^([10](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-10)) |

**Meta-analyses of RCTs.** Across nine target trials (n=5,143), higher targets increased all-cause mortality (**RR 1.17, 1.01–1.35**) and access thrombosis (**RR 1.34, 1.16–1.54**) ^([26](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-26)). Across 27 trials (n=10,452), higher targets increased stroke (**RR 1.51**), hypertension (**RR 1.67**), and access thrombosis (**RR 1.33**); mortality was not significantly higher (**RR 1.09, 0.99–1.20**) ^([27](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-27)). The 2023 Cochrane network meta-analysis (117 trials, 25,237 participants) found that ESAs prevent transfusion versus placebo with low-to-moderate certainty and have uncertain effects on death ^([28](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-28)).

### Reading these trials critically

- **Population.** Three of the five famous trials enrolled non-dialysis CKD. The hemodialysis evidence is the Normal Hematocrit Trial (a harm signal in patients with heart disease) and Parfrey (no structural benefit, more cerebrovascular events). The direction agrees; the applicability is borrowed.
- **The published Normal Hematocrit Trial understated the harm.** Coyne compared the 1996 FDA-filed report with the 1998 *NEJM* paper: randomization to the higher target increased the primary endpoint and death with conventional 95% confidence intervals that excluded 1, and the reported physical-function benefit was a secondary association with achieved Hb, not a randomized effect ^([25](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-25)). The normal-hematocrit arm also received more IV iron dextran and had lower dialysis adequacy ^([5](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-5)).
- **Target or dose?** In CHOIR, the harm tracked a high epoetin dose and failure to reach target, not the achieved Hb itself ^([29](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-29)). In TREAT, the lowest-quartile initial responders received higher doses and had more cardiovascular events (**aHR 1.31**) and deaths (**aHR 1.41**) ^([10](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-10)). In the Normal Hematocrit Trial’s high arm, the least responsive quartile had 34% one-year mortality versus 14% in the most responsive ^([11](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-11)). These are secondary analyses, confounded by the sickness that causes hyporesponse, but they are why “don’t escalate into resistance” became doctrine.
- **Surrogate endpoints cut both ways.** Hb is a surrogate. The trials that moved it furthest moved outcomes the wrong way.

### The FDA position

The ESA boxed warning (epoetin alfa label, revised April 2024) states that ESAs increase the risk of death, myocardial infarction, stroke, venous thromboembolism, **thrombosis of vascular access**, and tumor progression; that targeting **Hb above 11 g/dL** increased serious cardiovascular risk; that **no trial has identified a hemoglobin target, ESA dose, or dosing strategy that does not increase these risks**; and that the lowest dose sufficient to reduce transfusion should be used ^([4](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-4)). For adults on dialysis the label says: initiate when Hb is below 10 g/dL; **reduce or interrupt when Hb approaches or exceeds 11 g/dL** ^([4](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-4)).

### The guideline position

- **Start:** Hb **9.0–10.0 g/dL or below** in dialysis (Rec 3.2.1, 2D) ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1)).
- **Ceiling:** **target below 11.5 g/dL** (Rec 3.3.1, 1D) — now a “we recommend” ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1)). The 2012 “never intentionally above 13 (1A)” statement no longer appears as a separate recommendation.
- **Individualize** within that range for symptoms, transfusion risk, and cardiovascular or cancer risk (PP 3.1.1, 3.3.1) ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1)).
- **ERBP dissents at the floor.** It would not let Hb routinely fall below 10 g/dL and endorses a 10–12 g/dL maintenance band ^([13](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-13)). The KDOQI commentary on the 2012 guideline made a related point: there was little evidence that 11–11.5 is unsafe, and a lower bound of 9 may increase transfusion ^([15](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-15)).

Label (11) versus guideline (11.5)

The US label and KDIGO 2026 disagree by half a gram. They are compatible if a protocol **targets 10–11 g/dL and reduces or holds at 11 g/dL or above**, which satisfies both. A protocol that targets up to 11.5 is guideline-concordant but outside the label’s dosing instructions ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1),[4](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-4)). Which number a unit uses is a medical-director decision, and the protocol should state it.

### What happened when the US lowered its targets

After the 2011 bundled payment and FDA label change, the share of US hemodialysis patients with **Hb above 11 g/dL fell from 68% (2006) to 28% (2016)**, and the share below 9 g/dL rose from 5% to 9%. Adjusted MACE (**aHR 0.95**), stroke (**0.83**), and mortality (**0.87**) were lower after the policy change; MI was slightly higher (**1.04**) ^([30](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-30)). Transfusions rose, but modestly — approximately a 7% relative increase in the monthly probability of transfusion ^([31](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-31)). These are observational, interrupted-time-series data layered on secular improvements in dialysis care. They are consistent with the trials. They do not prove them.

## 4. Erythropoiesis-Stimulating Agents

### The agents

| Agent | Half-life class | HD starting dose | HD adjustment | Evidence notes |
|----|----|----|----|----|
| Epoetin alfa (Epogen, Procrit); epoetin alfa-epbx (Retacrit) | Short | 50–100 U/kg three times weekly | +25 U/kg/dose if Hb rise is below 1.0 g/dL after 4 weeks; −10 to 25 U/kg/dose if the rise exceeds 2 g/dL in 4 weeks | Biosimilar equivalent to the originator IV in hemodialysis (RCT; Hb difference −0.12 g/dL; no PRCA) ^([32](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-32)) |
| Darbepoetin alfa (Aranesp) | Intermediate | 0.45 µg/kg weekly or 0.75 µg/kg every 2 weeks | ±25% by the same Hb rules | Long-acting agents have similar potency IV and SC ^([13](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-13)) |
| Methoxy PEG-epoetin beta (Mircera) | Long | 0.6 µg/kg every 2 weeks | ±30–50 µg/dose by the same Hb rules | MAXIMA (RCT): IV every 2 or 4 weeks non-inferior to epoetin for Hb (n=673) ^([33](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-33)). Cardiovascular safety non-inferior to short-acting ESAs (RCT): MACE **HR 1.03 (0.93–1.15)**, n=2,818 ^([34](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-34)) |

Starting doses and adjustments are from KDIGO 2026 Table 7 ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1)). No ESA has shown an outcome advantage over another; the Cochrane network meta-analysis found comparative effects uncertain ^([28](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-28)).

### Route: IV or subcutaneous

In a VA trial (RCT) of 208 hemodialysis patients, subcutaneous epoetin maintained hematocrit with a **32% lower dose** than IV ^([35](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-35)). That saving applies to short-acting epoetin, not to darbepoetin or methoxy PEG-epoetin beta ^([13](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-13)). KDIGO 2026 leaves the route to patient preference, local practice, and cost (PP 3.4.2.1) ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1)); the epoetin label recommends IV for hemodialysis ^([4](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-4)). The historical cautionary tale is anti-EPO antibody pure red-cell aplasia, linked mainly to subcutaneous exposure — 13 patients with neutralizing antibodies in Casadevall’s original series ^([13](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-13),[36](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-36)). Giving the ESA IV into the circuit, as US units do, is reasonable.

### Dose-adjustment rules: convergent across label and guideline

- **Do not increase more often than every 4 weeks.** Decreases may be more frequent ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1),[4](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-4)).
- **Rapid rise:** Hb up **more than 1 g/dL in any 2-week period** → reduce by **25% or more** (label) ^([4](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-4)). KDIGO: a rise of more than 1.0 g/dL in 2–4 weeks after initiation → reduce by 25–50% (PP 3.4.1.2) ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1)).
- **Slow rise:** Hb up less than 1 g/dL after 4 weeks → increase by 25% ^([4](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-4)).
- **Falling Hb:** “to avoid a rapid decline in Hb, consider reducing the ESA dose rather than holding ESA therapy, as long as the Hb does not exceed 11.5 g/dL” (PP 3.4.3.2) ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1)).
- **Twelve weeks without response:** further escalation is unlikely to help and may increase risk; evaluate other causes ^([4](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-4)).

Clinical Pearl — hemoglobin cycling is mostly iatrogenic

In an observational study of 281 hemodialysis patients, **more than 90% cycled**, averaging 3.1 excursions a year with a mean amplitude of 2.5 g/dL. The most common trigger of an upswing was an ESA dose increase (84%); of a downswing, a dose reduction (62%) or hold (15%) ^([37](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-37)). Hold-and-restart protocols manufacture the roller coaster. Small, early reductions flatten it.

### ESA hyporesponsiveness

**Definition.** KDIGO 2026 keeps its 2012 relative definitions (Table 10) ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1)):

- **Initial:** no Hb increase after the first month on appropriate weight-based dosing.
- **Acquired:** two dose increases of up to 50% beyond a previously stable dose are needed to hold Hb steady.
- **Stop point:** avoid repeated escalation beyond **double** the initial or previously stable dose.

Absolute-dose definitions also circulate — for example, KDOQI’s more than 450 IU/kg/week of IV epoetin or more than 300 IU/kg/week subcutaneously ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1),[13](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-13)). Prevalence depends almost entirely on which definition is used ^([13](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-13)).

**Prognosis.** In a secondary analysis of ASCEND-D (observational within a trial), baseline hyporesponsiveness — 12–20% of patients by three definitions — predicted MACE with an **aHR of 1.32–1.36**, with no interaction by randomized drug ^([12](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-12)). The patient is the risk; the drug is not the rescue.

**Causes and first moves.**

| Cause | Clue | First move |
|----|----|----|
| Iron deficiency, systemic or restricted | TSAT below 20%, low CHr | IV iron course; recheck ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1),[23](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-23)) |
| Inflammation or infection | High ferritin with low TSAT, rising CRP; catheter, wound, failed or old non-functioning AV graft | Find and treat the source ^([13](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-13),[16](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-16)) |
| Blood loss | Ferritin below 45, MCV below 80, positive stool guaiac, access bleeding | GI, urologic, or gynecologic evaluation ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1)) |
| Underdialysis | Low spKt/V or URR, access recirculation | Fix the access and the prescription ^([20](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-20)) |
| Severe hyperparathyroidism | High PTH, marrow fibrosis | Treat the hyperparathyroidism ^([21](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-21)) |
| B12 or folate deficiency | Macrocytosis, cognitive change | Replace ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1),[13](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-13)) |
| Hemolysis | LDH up, haptoglobin down, abnormal smear | Smear; check water and dialysate ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1)) |
| Marrow disease (MDS, myeloma, PRCA) | Low reticulocytes, other cytopenias, M-protein | Hematology ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1),[36](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-36)) |
| Hypothyroidism | TSH | Replace ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1)) |
| Drugs | ACE inhibitors or ARBs, proton pump inhibitors | Review; rarely worth stopping ^([13](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-13)) |
| Nonadherence with home subcutaneous dosing | Missed doses | Supervised dosing ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1)) |

**A stepwise workup.** The sequence below condenses the causes above into an order of operations ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1),[13](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-13)):

1.  **Iron first.** TSAT below 20% or a low CHr → IV iron. A ferritin below 45 or MCV below 80 → blood-loss evaluation.
2.  **Then inflammation.** A rising CRP or a plausible source → treat the catheter, wound, failed graft, or occult infection.
3.  **Then the rest of the list.** Check Kt/V, PTH, B12 and folate, TSH, LDH and haptoglobin, the smear, and protein electrophoresis with free light chains.
4.  **Cause found** → treat it and reassess in 4–8 weeks.
5.  **No cause, no symptoms, low transfusion risk** → accept a lower Hb and do not escalate beyond twice the stable dose.
6.  **No cause, but symptomatic or at transfusion risk** → a 3–4-month HIF-PHI trial or transfusion; stop the HIF-PHI if there is no response.
7.  **Sudden severe anemia with reticulocytes near zero** → suspect PRCA: stop the ESA and involve hematology.

Practice points 3.7.2–3.7.4 allow the **3–4-month HIF-PHI trial** for persistent hyporesponsiveness when there is a reason to raise Hb, at the lowest effective dose, discontinued if it fails ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1)). ERBP supports the trial but notes that the truly hyporesponsive and inflamed patients were excluded from the HIF-PHI trials ^([13](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-13)) — so the trial is a reasonable experiment, not an evidence-based rescue. For suspected ESA-related PRCA: stop the ESA, transfuse as needed, involve hematology, and consider a HIF-PHI (PP 3.7.6) ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1)). US availability and the HIF-PHI trial evidence are covered in [the companion page](https://urinenephrology.org/mastery/maintenance-hd/iron-hif-transfusion-hd.html#hif-phi).

### ESA adverse effects that matter at the chair

- **Hypertension.** About 25% of dialysis patients needed new or increased antihypertensives after epoetin initiation; uncontrolled hypertension is a contraindication, and the label says to reduce or withhold the ESA if blood pressure becomes difficult to control ^([4](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-4)). The pressor effect is partly independent of the rise in red-cell mass ^([38](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-38)).
- **Access thrombosis.** Higher targets raise access thrombosis by approximately a third ^([26](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-26),[27](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-27)), and the label lists thrombosis of vascular access in the boxed warning ^([4](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-4)).
- **Stroke.** TREAT: HR 1.92 ^([9](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-9)).
- **Seizures,** especially in the first months of therapy — monitor for premonitory symptoms ^([4](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-4)).
- **Cancer.** The boxed warning covers tumor progression; KDIGO asks for shared decision-making about ESA use in active or prior cancer, especially when treatment aims at cure (PP 3.4.3.5) ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1),[4](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-4)).
- **Circuit clotting.** Patients on an ESA may need more heparin during hemodialysis ^([4](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-4)).

## Evidence Gaps

1.  **No modern hemodialysis trial of Hb targets within the 9.5–11.5 range.** The 11.5 ceiling is a 1D recommendation built on older, mostly non-dialysis trials ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1)).
2.  **Target versus dose.** Is the harm from a high Hb, from high ESA exposure, or from the illness that causes hyporesponse? Only secondary analyses speak to it ^([10](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-10),[11](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-11),[29](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-29)).
3.  **Treating hyporesponsiveness.** No RCT shows that any intervention in hyporesponders improves outcomes; anti-inflammatory approaches such as IL-6 blockade remain investigational ^([13](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-13)).
4.  **Sex differences.** Women on dialysis need higher ESA doses; whether the same targets apply is unknown ^([13](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-13)).
5.  **Patient-reported outcomes.** The fatigue and quality-of-life benefits of ESAs remain modest or uncertain ^([7](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-7),[9](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-9)).

## At the Chair

For the dialysis nurse

The nurse runs the anemia protocol; the nephrologist owns the exceptions. The evidence on this page translates into a few chair-side habits: check the most recent Hb against the protocol band before each ESA dose; check blood pressure first, because uncontrolled hypertension is a contraindication ^([4](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-4)); report a rise of more than 1 g/dL in 2 weeks, since the label calls for a dose cut of 25% or more ^([4](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-4)); and report any hospitalization for stroke, MI, venous thromboembolism, or access thrombosis, because an ESA should then be reviewed by the physician ^([1](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html#ref-1)).

Hold and report rules are on [Nursing card N10 — Anemia protocol: ESA and iron hold/report rules](https://urinenephrology.org/mastery/maintenance-hd/nursing/N10-Anemia-Protocol-Nursing.html).

## References

1.  Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. KDIGO 2026 Clinical Practice Guideline for the Management of Anemia in Chronic Kidney Disease (CKD). *Kidney Int*. 2026;109(1S):S1-S99. [PMID: 41485812](https://pubmed.ncbi.nlm.nih.gov/41485812/)
2.  Babitt JL, Berns JS, Bozkurt B, et al. Executive Summary of the KDIGO 2026 Clinical Practice Guideline for the Management of Anemia in Chronic Kidney Disease (CKD). *Kidney Int*. 2026;109(1):44-56. [PMID: 41485807](https://pubmed.ncbi.nlm.nih.gov/41485807/)
3.  Hedayati SS, Babitt JL, Berns JS, et al. Evaluation and Management of Anemia in Chronic Kidney Disease: Synopsis of the Kidney Disease: Improving Global Outcomes 2026 Clinical Practice Guideline. *Ann Intern Med*. 2026 Sep 15 (online ahead of print). [PMID: 42735412](https://pubmed.ncbi.nlm.nih.gov/42735412/)
4.  Amgen Inc. EPOGEN (epoetin alfa) injection, prescribing information. Revised April 2024 (FDA Reference ID 5373326). [Official source](https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/103234s5378lbl.pdf)
5.  Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. *N Engl J Med*. 1998;339(9):584-590. [PMID: 9718377](https://pubmed.ncbi.nlm.nih.gov/9718377/)
6.  Parfrey PS, Foley RN, Wittreich BH, et al. Double-blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease. *J Am Soc Nephrol*. 2005;16(7):2180-2189. [PMID: 15901766](https://pubmed.ncbi.nlm.nih.gov/15901766/)
7.  Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease (CHOIR). *N Engl J Med*. 2006;355(20):2085-2098. [PMID: 17108343](https://pubmed.ncbi.nlm.nih.gov/17108343/)
8.  Drüeke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia (CREATE). *N Engl J Med*. 2006;355(20):2071-2084. [PMID: 17108342](https://pubmed.ncbi.nlm.nih.gov/17108342/)
9.  Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease (TREAT). *N Engl J Med*. 2009;361(21):2019-2032. [PMID: 19880844](https://pubmed.ncbi.nlm.nih.gov/19880844/)
10. Solomon SD, Uno H, Lewis EF, et al. Erythropoietic response and outcomes in kidney disease and type 2 diabetes. *N Engl J Med*. 2010;363(12):1146-1155. [PMID: 20843249](https://pubmed.ncbi.nlm.nih.gov/20843249/)
11. Kilpatrick RD, Critchlow CW, Fishbane S, et al. Greater epoetin alfa responsiveness is associated with improved survival in hemodialysis patients. *Clin J Am Soc Nephrol*. 2008;3(4):1077-1083. [PMID: 18417744](https://pubmed.ncbi.nlm.nih.gov/18417744/)
12. McCausland FR, et al. Association of different definitions of erythropoiesis-stimulating agent hyporesponsiveness with major adverse cardiovascular events: insights from ASCEND-D. *Kidney360*. 2025;6(9):1541-1548. [PMID: 40333020](https://pubmed.ncbi.nlm.nih.gov/40333020/)
13. Del Vecchio L, Cases A, Eisenga MF, et al. KDIGO 2026 Clinical Practice Guideline for Anemia in Chronic Kidney Disease (CKD): a commentary from the European Renal Best Practice (ERBP). *Nephrol Dial Transplant*. 2026;41(8):1554-1572. [PMID: 41604211](https://pubmed.ncbi.nlm.nih.gov/41604211/)
14. KDIGO Anemia Work Group. KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. *Kidney Int Suppl*. 2012;2:279–335. Historical guideline, superseded by KDIGO 2026. [Official current and historical guideline resources](https://kdigo.org/guidelines/anemia-in-ckd/).
15. Kliger AS, Foley RN, Goldfarb DS, et al. KDOQI US commentary on the 2012 KDIGO Clinical Practice Guideline for Anemia in CKD. *Am J Kidney Dis*. 2013;62(5):849-859. [PMID: 23891356](https://pubmed.ncbi.nlm.nih.gov/23891356/)
16. Babitt JL, Lin HY. Molecular mechanisms of hepcidin regulation: implications for the anemia of CKD. *Am J Kidney Dis*. 2010;55(4):726-741. [PMID: 20189278](https://pubmed.ncbi.nlm.nih.gov/20189278/)
17. Wish JB. Assessing iron status: beyond serum ferritin and transferrin saturation. *Clin J Am Soc Nephrol*. 2006;1(Suppl 1):S4-S8. [PMID: 17699374](https://pubmed.ncbi.nlm.nih.gov/17699374/)
18. Sargent JA, Acchiardo SR. Iron requirements in hemodialysis. *Blood Purif*. 2004;22(1):112-123. [PMID: 14732819](https://pubmed.ncbi.nlm.nih.gov/14732819/)
19. Ly J, Marticorena R, Donnelly S. Red blood cell survival in chronic renal failure. *Am J Kidney Dis*. 2004;44(4):715-719. [PMID: 15384023](https://pubmed.ncbi.nlm.nih.gov/15384023/)
20. Ifudu O, Feldman J, Friedman EA. The intensity of hemodialysis and the response to erythropoietin in patients with end-stage renal disease. *N Engl J Med*. 1996;334(7):420-425. [PMID: 8552143](https://pubmed.ncbi.nlm.nih.gov/8552143/)
21. Rao DS, Shih MS, Mohini R. Effect of serum parathyroid hormone and bone marrow fibrosis on the response to erythropoietin in uremia. *N Engl J Med*. 1993;328(3):171-175. [PMID: 8417383](https://pubmed.ncbi.nlm.nih.gov/8417383/)
22. Akebia Therapeutics. VAFSEO (vadadustat) tablets, prescribing information with boxed warning, revised March 2024 (FDA Reference ID 5354686). [Official source](https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/215192s000lbl.pdf)
23. Coyne DW, Kapoian T, Suki W, et al. Ferric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: results of the Dialysis Patients' Response to IV Iron with Elevated Ferritin (DRIVE) Study. *J Am Soc Nephrol*. 2007;18(3):975-984. [PMID: 17267740](https://pubmed.ncbi.nlm.nih.gov/17267740/)
24. Fishbane S, Galgano C, Langley RC Jr, et al. Reticulocyte hemoglobin content in the evaluation of iron status of hemodialysis patients. *Kidney Int*. 1997;52(1):217-222. [PMID: 9211366](https://pubmed.ncbi.nlm.nih.gov/9211366/)
25. Coyne DW. The health-related quality of life was not improved by targeting higher hemoglobin in the Normal Hematocrit Trial. *Kidney Int*. 2012;82(2):235-241. [PMID: 22437411](https://pubmed.ncbi.nlm.nih.gov/22437411/)
26. Phrommintikul A, Haas SJ, Elsik M, Krum H. Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: a meta-analysis. *Lancet*. 2007;369(9559):381-388. [PMID: 17276778](https://pubmed.ncbi.nlm.nih.gov/17276778/)
27. Palmer SC, Navaneethan SD, Craig JC, et al. Meta-analysis: erythropoiesis-stimulating agents in patients with chronic kidney disease. *Ann Intern Med*. 2010;153(1):23-33. [PMID: 20439566](https://pubmed.ncbi.nlm.nih.gov/20439566/)
28. Chung EY, Palmer SC, Saglimbene VM, et al. Erythropoiesis-stimulating agents for anaemia in adults with chronic kidney disease: a network meta-analysis. *Cochrane Database Syst Rev*. 2023;2:CD010590. [PMID: 36791280](https://pubmed.ncbi.nlm.nih.gov/36791280/)
29. Szczech LA, Barnhart HX, Inrig JK, et al. Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes. *Kidney Int*. 2008;74(6):791-798. [PMID: 18596733](https://pubmed.ncbi.nlm.nih.gov/18596733/)
30. Park H, Desai R, Liu X, et al. Medicare bundled payment policy on anemia care, major adverse cardiovascular events, and mortality among adults undergoing hemodialysis. *Clin J Am Soc Nephrol*. 2022;17(6):851-860. [PMID: 35589388](https://pubmed.ncbi.nlm.nih.gov/35589388/)
31. Hirth RA, Turenne MN, Wilk AS, et al. Blood transfusion practices in dialysis patients in a dynamic regulatory environment. *Am J Kidney Dis*. 2014;64(4):616-621. [PMID: 24560166](https://pubmed.ncbi.nlm.nih.gov/24560166/)
32. Fishbane S, Singh B, Kumbhat S, et al. Intravenous epoetin alfa-epbx versus epoetin alfa for treatment of anemia in end-stage kidney disease. *Clin J Am Soc Nephrol*. 2018;13(8):1204-1214. [PMID: 29921734](https://pubmed.ncbi.nlm.nih.gov/29921734/)
33. Levin NW, Fishbane S, Cañedo FV, et al. Intravenous methoxy polyethylene glycol-epoetin beta for haemoglobin control in patients with chronic kidney disease who are on dialysis: a randomised non-inferiority trial (MAXIMA). *Lancet*. 2007;370(9596):1415-1421. [PMID: 17950856](https://pubmed.ncbi.nlm.nih.gov/17950856/)
34. Locatelli F, Hannedouche T, Fishbane S, et al. Cardiovascular safety and all-cause mortality of methoxy polyethylene glycol-epoetin beta and other erythropoiesis-stimulating agents in anemia of CKD: a randomized noninferiority trial. *Clin J Am Soc Nephrol*. 2019;14(12):1701-1710. [PMID: 31420350](https://pubmed.ncbi.nlm.nih.gov/31420350/)
35. Kaufman JS, Reda DJ, Fye CL, et al. Subcutaneous compared with intravenous epoetin in patients receiving hemodialysis. *N Engl J Med*. 1998;339(9):578-583. [PMID: 9718376](https://pubmed.ncbi.nlm.nih.gov/9718376/)
36. Casadevall N, Nataf J, Viron B, et al. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. *N Engl J Med*. 2002;346(7):469-475. [PMID: 11844847](https://pubmed.ncbi.nlm.nih.gov/11844847/)
37. Fishbane S, Berns JS. Hemoglobin cycling in hemodialysis patients treated with recombinant human erythropoietin. *Kidney Int*. 2005;68(3):1337-1343. [PMID: 16105069](https://pubmed.ncbi.nlm.nih.gov/16105069/)
38. Krapf R, Hulter HN. Arterial hypertension induced by erythropoietin and erythropoiesis-stimulating agents (ESA). *Clin J Am Soc Nephrol*. 2009;4(2):470-480. [PMID: 19218474](https://pubmed.ncbi.nlm.nih.gov/19218474/)

### Also in the Maintenance Hemodialysis module

Part of the Maintenance Hemodialysis mastery module. [Module index](https://urinenephrology.org/mastery/maintenance-hd/index.html).

- **M17b:** [Anemia: iron, HIF-PH inhibitors, and transfusion](https://urinenephrology.org/mastery/maintenance-hd/iron-hif-transfusion-hd.html)
- **M18:** [Examining and cannulating the AVF/AVG](https://urinenephrology.org/mastery/maintenance-hd/avf-avg-exam-cannulation.html)
- **M19:** [Catheter care, lock solutions, and bloodstream infection](https://urinenephrology.org/mastery/maintenance-hd/catheter-care-crbsi.html)
- **Module:** [Treating hypertension on dialysis](https://urinenephrology.org/mastery/maintenance-hd/treating-hypertension-dialysis.html)
- **Module:** [CKD-MBD monitoring on HD](https://urinenephrology.org/mastery/maintenance-hd/ckd-mbd-monitoring-hd.html)
- **Module:** [Adequacy, nutrition, depression/cognition — and what quality metrics miss](https://urinenephrology.org/mastery/maintenance-hd/adequacy-nutrition-cognition-quality-metrics.html)
- **Clinical Mastery:** [Vascular access selection in older patients starting hemodialysis (ACCESS HD)](https://urinenephrology.org/mastery/dialysis-advanced/vascular-access-older-patients.html)
- **Clinical Mastery:** [Enterococcal endocarditis in hemodialysis patients](https://urinenephrology.org/mastery/dialysis-advanced/enterococcal-endocarditis-hemodialysis.html)
- **Complete white paper:** [Screening and health maintenance in maintenance hemodialysis](https://urinenephrology.org/mastery/dialysis-advanced/screening-tests-hemodialysis.html#anemia-monitoring) — §8.1 anemia monitoring, updated to KDIGO 2026


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[Website version](https://urinenephrology.org/mastery/maintenance-hd/anemia-targets-esa-hyporesponsiveness.html) · Markdown synchronized October 3, 2026.