Anaemia of CKD

By the end of this chapter you should be able to:

• Explain the multifactorial mechanism of CKD anaemia, centred on relative erythropoietin deficiency.
• Describe how hepcidin and inflammation produce functional iron deficiency.
• Work up anaemia in CKD rather than attributing it to the kidney by default.
• Interpret transferrin saturation and ferritin to distinguish functional from absolute iron deficiency.
• Replete iron appropriately, choosing intravenous iron where it is preferred.
• Set a moderate haemoglobin target with ESAs and explain why normalisation causes harm.
• Investigate ESA hyporesponsiveness before escalating the dose.
• Describe the HIF-stabiliser class and the role of transfusion.

• CKD anaemia is multifactorial, but its core is a relative deficiency of erythropoietin as the kidney's EPO-producing cells are lost to fibrosis.
• Iron deficiency — absolute and functional — is the other major driver, and the two are usually treated together.
• Hepcidin, raised by inflammation and reduced renal clearance, blocks intestinal iron absorption and traps iron in stores, producing functional iron deficiency.
• Because hepcidin and inflammation distort the markers, a high ferritin does not exclude iron deficiency — a low transferrin saturation with a normal or high ferritin is functional iron deficiency.
• Anaemia in a CKD patient should be worked up, not assumed to be the kidney — exclude blood loss, B12 and folate deficiency, and haemolysis.
• Iron is repleted first, often before or alongside an ESA; intravenous iron is preferred in haemodialysis and is reliable where absorption is blocked.
• Erythropoiesis-stimulating agents correct the EPO deficiency, but the haemoglobin target is moderate, not normal.
• Trials that normalised haemoglobin with ESAs increased cardiovascular events, stroke, and thrombosis without improving quality of life.
• Target a haemoglobin of roughly 10 to 11.5 g/dL, avoid exceeding about 13, and use the lowest ESA dose that avoids transfusion and symptoms.
• ESA hyporesponsiveness — most often iron deficiency or inflammation — must be investigated before escalating the dose, since high doses themselves cause harm.
• HIF stabilisers (prolyl-hydroxylase inhibitors) are oral agents that stabilise hypoxia-inducible factor, raising endogenous erythropoietin and improving iron availability.
• They are non-inferior to ESAs for haemoglobin, with oral convenience, though cardiovascular safety varies by agent and thromboembolism is a caution.
• Transfusion is minimised — it risks sensitisation before transplantation, iron overload, and volume load — and reserved for symptomatic or acute anaemia.
• Throughout, treat the treatable: iron, B12 and folate, infection and inflammation, and hyperparathyroidism.

Anaemia is the complication patients feel. As the kidney fails it makes less of the hormone that drives red-cell production and, through inflammation and hepcidin, hides the iron the marrow needs. The treatment story is one of correcting a deficiency — of erythropoietin, of iron — while heeding the hard-won lesson that more is not better: the trials that tried to normalise haemoglobin did harm. The newer HIF stabilisers add an oral option built on the body's own oxygen-sensing pathway.

The mechanism: EPO, iron, and hepcidin

CKD anaemia is multifactorial, but one mechanism is central: the peritubular interstitial cells that produce erythropoietin are progressively lost to the fibrosis of Chapter 2, so the kidney makes too little EPO for the degree of anaemia — a relative, not absolute, deficiency. On top of this sits iron deficiency, which comes in two forms. Absolute iron deficiency reflects true depletion from blood loss or poor intake and absorption. Functional iron deficiency is more characteristic of CKD: there is iron in the body, but it cannot be mobilised to the marrow, and the gatekeeper is hepcidin. Hepcidin, the master iron-regulatory hormone, is raised in CKD both by the chronic inflammation of the disease and by reduced renal clearance; it degrades ferroportin, blocking iron absorption from the gut and trapping iron inside macrophages and stores. The result is a marrow starved of iron despite adequate or even high body stores — functional iron deficiency. Inflammation compounds everything, suppressing erythropoiesis and shortening red-cell survival, and uraemia shortens the red-cell lifespan further.

Reading the iron studies

Because hepcidin and inflammation distort the iron markers, interpreting them is a diagnostic skill in its own right. The two numbers are the transferrin saturation, which reflects iron available for erythropoiesis, and ferritin, which reflects stored iron — but ferritin is also an acute-phase reactant, rising with inflammation independent of true stores. So the trap is a high ferritin read as 'iron-replete' when the patient is functionally iron-deficient. The pattern that matters: a low transferrin saturation with a low ferritin is absolute iron deficiency, while a low transferrin saturation with a normal or high ferritin is functional iron deficiency — iron present but locked away by hepcidin. Recognising functional iron deficiency is what licenses giving iron to a patient whose ferritin looks reassuring, and it is one of the commonest misreadings in CKD anaemia.

Work it up, don't assume

It is tempting, in a CKD patient, to attribute any anaemia to the kidney and reach for an ESA. That is a mistake. CKD anaemia is a diagnosis that coexists with, and can mask, other causes, so the anaemia is worked up: a full blood count with indices (CKD anaemia is typically normocytic and normochromic, so a microcytosis points to iron deficiency or thalassaemia and a macrocytosis to B12 or folate deficiency), reticulocytes, iron studies, B12 and folate, and a search for blood loss or haemolysis where indicated. Missing a treatable cause — a colonic cancer behind the iron deficiency, a B12 deficiency — because the anaemia was assumed to be 'just the CKD' is a serious and avoidable error. Attribute to CKD only after the other causes are addressed.

Iron first

Iron repletion comes first, often before or alongside an ESA, because correcting iron deficiency raises haemoglobin in its own right and reduces the ESA dose needed. The route matters. In haemodialysis, intravenous iron is preferred: it is reliable, it bypasses the hepcidin-blocked gut, and proactive higher-dose intravenous iron has been shown safe and to reduce ESA requirements and cardiovascular events. In non-dialysis CKD and peritoneal dialysis, oral iron may suffice, though absorption is often poor when hepcidin is high, so intravenous iron is used when the oral route fails. A reasonable threshold to offer an iron trial is a transferrin saturation at or below 30% with a ferritin at or below 500, aiming to replete enough to support erythropoiesis without driving iron overload.

ESAs and the haemoglobin target — the central lesson

Erythropoiesis-stimulating agents — epoetin and darbepoetin — replace the missing EPO and were, for a time, used to normalise haemoglobin on the assumption that more was better. The trials demolished that assumption. Studies that targeted a normal or near-normal haemoglobin with ESAs found increased cardiovascular events, an excess of stroke, more thrombosis including vascular-access thrombosis, and no improvement in quality of life or survival — harm without benefit. The resulting principle is one of the most important in the chapter: do not normalise haemoglobin. Target a moderate haemoglobin of roughly 10 to 11.5 g/dL, do not deliberately exceed about 13, and use the lowest ESA dose that avoids transfusion and relieves symptoms, individualising for the patient. The goal of ESA therapy is to avoid the harms of severe anaemia and transfusion, not to restore a normal blood count.

When the ESA isn't working

A patient whose haemoglobin will not rise despite an ESA is hyporesponsive, and the wrong response is to keep escalating the dose, because high ESA doses are themselves associated with harm. The right response is to find the cause. By far the commonest is iron deficiency, absolute or functional, so iron status is rechecked first. After that come inflammation and occult infection, secondary hyperparathyroidism with its marrow fibrosis, B12 and folate deficiency, ongoing blood loss, malnutrition, and — rarely — pure red-cell aplasia from anti-erythropoietin antibodies or an underlying malignancy. Each is addressed on its own terms. Escalating the ESA without finding the reason exposes the patient to the dose-related harms while leaving the real problem untreated, so hyporesponsiveness is an instruction to investigate, not to push harder.

HIF stabilisers and transfusion

The newest option works through the body's own oxygen sensor. In hypoxia, hypoxia-inducible factor is stabilised and drives erythropoietin production and improved iron availability, including a fall in hepcidin; in normoxia, prolyl-hydroxylase enzymes degrade it. The HIF prolyl-hydroxylase inhibitors — the HIF stabilisers — inhibit that degradation, stabilising HIF to raise endogenous-pattern erythropoietin and mobilise iron, all from an oral tablet. In trials they are non-inferior to ESAs for haemoglobin, with the convenience of oral dosing, though their cardiovascular safety varies by agent and class cautions include thromboembolism and a theoretical concern in active malignancy given HIF's role in angiogenesis. They are an emerging addition rather than a wholesale replacement. Transfusion, finally, is kept to a minimum: it carries the risks of sensitisation that can compromise future transplantation, of iron overload, and of volume loading, so it is reserved for symptomatic or acute anaemia rather than used to chase a number.

Where the evidence is firm, and where it is moving

The firm centre is the haemoglobin-target lesson: multiple large trials agree that normalising haemoglobin with ESAs harms, and the moderate target is grade-A practice. The benefit of iron repletion and the proactive intravenous-iron strategy in haemodialysis are well supported. What is still moving is the HIF-stabiliser story — non-inferiority for haemoglobin is established, but the long-term cardiovascular and safety profile differs between agents and is still being defined — and the precise optimal iron and haemoglobin targets remain matters of judgement at the edges. The honest position is to treat the anti-normalisation lesson as settled, to replete iron and use the lowest effective ESA dose, to investigate hyporesponsiveness rather than out-dose it, and to adopt HIF stabilisers thoughtfully as their comparative evidence matures.

Table 7.1 — Causes of anaemia in CKD

Table 7.2 — Interpreting iron studies

Table 7.3 — Iron therapy

Table 7.4 — ESAs and the haemoglobin target

Table 7.5 — Causes of ESA hyporesponsiveness

Table 7.6 — HIF stabilisers and transfusion

Visualise & Map

Each chain runs from physiology to a named bedside action; read the arrows as “leads to.”

EPO deficiency. Fibrosis → loss of peritubular EPO-producing cells → relative erythropoietin deficiency → reduced erythropoiesis → anaemia → ACTION: replace EPO with an ESA (or HIF stabiliser) to a moderate target.

The hepcidin block. Inflammation + reduced renal clearance → high hepcidin → ferroportin degraded → gut absorption blocked + iron trapped in stores → functional iron deficiency (low TSAT, high ferritin) → ACTION: give iron (intravenously where absorption is blocked), reading TSAT not just ferritin.

Inflammation. Chronic inflammation → ↑ hepcidin + suppressed erythropoiesis + shortened RBC survival → anaemia and ESA hyporesponsiveness → ACTION: seek and treat infection/inflammation rather than escalating the ESA.

The HIF pathway. Prolyl-hydroxylase normally degrades HIF → inhibiting it stabilises HIF → ↑ endogenous EPO + ↓ hepcidin/↑ iron availability → ACTION: use an oral HIF stabiliser as an alternative to an ESA, mindful of agent-specific safety.

The target harm. Normalising haemoglobin with ESAs → high Hb + ESA effects → thrombosis, stroke, CV events, no QoL gain → ACTION: target a moderate haemoglobin (~10–11.5) at the lowest effective dose.

Clinical Reasoning

One triad per mechanism the narrative exposed: the physiology, why it matters, and the bedside move.

Safety & Evidence

Panel A — Red flags

Panel B — Never do

Pitfall 1 — Assuming it's the CKD

Pitfall 2 — Trusting ferritin alone

Pitfall 3 — Chasing a normal haemoglobin

Pitfall 4 — Out-dosing hyporesponsiveness

Pitfall 5 — Liberal transfusion

Graded statements (by evidence type)

Patient Decisions

Natural-frequency estimates for orientation, from the anaemia trials; they vary with baseline risk. They convey the size of the anaemia decisions, expressed per 100 comparable patients.

Apply & Test

Paste-ready notes. Tick the boxes that apply and delete the rest; make the work-up, the iron interpretation, and the moderate target explicit.

Template 1 — Anaemia work-up and iron/ESA plan

• Hb ___ ; indices: ☐ normocytic ☐ microcytic (iron/thalassaemia) ☐ macrocytic (B12/folate); reticulocytes ___ .
• Iron studies: TSAT ___ , ferritin ___ → ☐ absolute ☐ functional iron deficiency ☐ replete.
• Other causes screened: ☐ B12/folate ☐ blood loss/GI ☐ haemolysis ☐ infection/inflammation ☐ PTH.
• Iron: ☐ IV (HD / oral failed) ☐ oral; trial if TSAT ≤ 30% and ferritin ≤ 500.
• ESA / HIF stabiliser started: target Hb 10–11.5; lowest effective dose; ☐ will not normalise/exceed ~13.
• Transfusion: ☐ not indicated ☐ symptomatic/acute only (sensitisation/overload noted).

Template 2 — ESA hyporesponsiveness evaluation

• Hb not responding despite ESA dose ___ ; escalation withheld pending work-up: ☐ yes.
• Iron rechecked (commonest cause): TSAT ___ , ferritin ___ → ☐ repleted.
• Inflammation/infection sought: ☐ yes; CRP ___ .
• PTH ___ (hyperparathyroidism); B12/folate ___ ; blood-loss search: ☐ done.
• Pure red-cell aplasia / malignancy considered if picture fits: ☐ yes.
• Cause identified and treated rather than dose escalated: ☐ yes — cause ___ .