Anaemia in chronic kidney disease

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Healthy kidneys increase erythropoietin when tissue oxygen falls. Diseased peritubular interstitial cells provide an inadequate response for the degree of anaemia, leaving erythroid production low. Uraemic inflammation increases hepcidin, which traps iron in macrophages and reduces intestinal absorption. Dialysis sampling and circuit losses, gastrointestinal bleeding, reduced red-cell lifespan, nutritional deficiency and hyperparathyroidism add to the burden. The result often becomes apparent as filtration declines but severity is not predicted perfectly by eGFR.

Assessment separates renal physiology from treatable co-pathology. Review trend, MCV, reticulocyte response and film. Ferritin estimates storage but is an acute-phase reactant; transferrin saturation reflects circulating iron availability but varies. NICE and UK Kidney Association recommendations use both, interpreted with dialysis status and inflammation. Macrocytosis, pancytopenia, reticulocytosis, haemolysis or a sudden decline is not explained by erythropoietin deficiency and needs its own pathway. In older adults, gastrointestinal blood loss and malignancy must not be missed.

Treatment starts with cause correction and shared goals. Iron route depends on CKD stage, dialysis, severity, tolerance and likelihood of absorption. ESA choice and interval follow renal protocols; response is reviewed over weeks and doses are reduced or withheld when haemoglobin rises too rapidly or exceeds the agreed range. Transfusion can be life saving for severe symptomatic anaemia or acute loss but is not maintenance treatment, especially before transplantation. Oral HIF-PH inhibitors offer another option for eligible adults but do not remove the need to correct iron, assess thrombosis and review non-response.

Key points

CKD anaemia is usually normocytic and hypoproliferative, driven by inadequate erythropoietin response, inflammation, iron restriction and shortened red-cell survival.
Do not attribute anaemia to kidney disease solely from a reduced eGFR; blood loss, iron deficiency, B12 or folate deficiency, haemolysis and marrow disease still require assessment.
Check full blood count, reticulocytes, ferritin and transferrin saturation, with CRP and clinical context because ferritin rises during inflammation and may mask unavailable iron.
Absolute iron deficiency means depleted stores, while functional deficiency means iron is present but hepcidin-mediated sequestration limits delivery to erythroblasts.
Oral iron may suit non-dialysis CKD when tolerated and likely to work; intravenous iron is often required in haemodialysis or after inadequate oral response.
Erythropoiesis-stimulating agents are considered after correctable causes and iron status are addressed, particularly in dialysis or symptomatic anaemia where transfusion avoidance matters.
ESA treatment aims for an individual stable haemoglobin range rather than normalising population values; high targets and rapid rises increase vascular risk.
Blood pressure must be controlled before and during ESA therapy, and dose changes use the rate of haemoglobin response rather than reflexively chasing a single result.
Hypoxia-inducible-factor prolyl-hydroxylase inhibitors are oral alternatives for selected adults under current NICE recommendations, with class-specific thrombotic and tumour cautions.
A poor ESA response should prompt review of iron availability, inflammation, infection, blood loss, dialysis adequacy, hyperparathyroidism, medicines and marrow disorders before escalating dose.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Erythropoietin insufficiency

Tubulointerstitial damage prevents an appropriate erythropoietin rise for the prevailing oxygen deficit, reducing erythroid progenitor survival and marrow red-cell output as CKD advances.

Iron-restricted erythropoiesis

Blood loss, poor intake and dialysis deplete iron, while inflammation-driven hepcidin blocks absorption and macrophage release even when measurable stores remain.

Additional uraemic factors

Shortened erythrocyte survival, repeated phlebotomy, dialysis-circuit loss, hyperparathyroidism, inflammation and some medicines can compound the hypoproliferative renal mechanism.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Blunted oxygen signalling
Damaged renal interstitial cells fail to translate hypoxia into sufficient erythropoietin, so marrow production remains inappropriately low for the haemoglobin concentration.
2
Hepcidin iron blockade
Reduced renal clearance and inflammatory stimulation raise hepcidin, causing ferroportin internalisation and limiting movement of stored and absorbed iron into plasma.
3
Reduced red-cell longevity
Uraemic toxins, mechanical dialysis stress and inflammation shorten circulating erythrocyte survival, increasing production demand that the erythropoietin-deficient marrow cannot meet.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Hypoproliferative pattern

A usually normocytic anaemia with low or inappropriately normal reticulocytes develops as kidney impairment and inflammatory iron restriction progress.

Absolute iron loss

Low ferritin and transferrin saturation support depleted stores, often from gastrointestinal, menstrual, circuit or phlebotomy loss.

Functional iron restriction

Low transferrin saturation with preserved or raised ferritin during inflammation suggests iron is stored but unavailable to erythropoiesis.

Non-renal warningRed flag

Rapid decline, bleeding, fragments, leucopenia, thrombocytopenia or marked macrocytosis requires urgent investigation beyond CKD.

ESA hyporesponse

Little haemoglobin improvement despite supervised treatment raises iron restriction, inflammation, infection, inadequate dialysis, blood loss or marrow pathology.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Full count, reticulocytes and filmFirst step
Why
Confirm phenotype and detect competing marrow or haemolytic disease.
Interpretation and limitations
Normocytic underproduction is typical; abnormal white cells, platelets, fragments, macro-ovalocytes or reticulocytosis redirect the work-up.
02
Ferritin and transferrin saturation
Why
Assess storage and circulating iron availability together.
Interpretation and limitations
Interpret against CRP, recent iron and dialysis; ferritin can be high despite restricted erythropoiesis and neither measure should stand alone.
03
Vitamin B12 and folate
Why
Exclude correctable haematinic deficiency before stimulating marrow.
Interpretation and limitations
Borderline results need clinical and laboratory correlation; treatment response does not remove the need to identify malabsorption or dietary cause.
04
Renal profile and CKD trend
Why
Relate anaemia to kidney stage and treatment safety.
Interpretation and limitations
Falling filtration supports renal contribution but does not prove exclusivity; potassium and dialysis status influence treatment selection.
05
CRP and infection assessment
Why
Identify inflammation causing functional restriction and ESA resistance.
Interpretation and limitations
Raised CRP is non-specific; investigate access infection, inflammatory disease and other sources from symptoms and examination.
06
Haemolysis and blood-loss tests
Why
Investigate an atypical or rapid fall.
Interpretation and limitations
Use bilirubin, LDH, haptoglobin, antiglobulin testing and site-directed bleeding assessment; faecal testing follows current cancer and GI pathways.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Occult blood loss

Gastrointestinal bleeding, heavy menstruation, dialysis-circuit loss and repeated sampling can cause true iron deficiency and a faster haemoglobin decline than renal physiology alone.

Nutritional deficiency

Iron, vitamin B12 or folate deficiency changes indices and treatment; macrocytosis or neurological features should not be dismissed because uraemia coexists.

Haemolysis

Dialysis equipment problems, mechanical valves, immune disease and microangiopathy can produce reticulocytosis, LDH elevation, low haptoglobin and fragments rather than simple underproduction.

Marrow disease

Myelodysplasia, plasma-cell disease, cancer infiltration or aplasia should be considered when other cell lines, film morphology, calcium, protein studies or symptoms are abnormal.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Diagnostic gateDo not anchor on eGFRFirst stepHaemoglobin falls below the reference range in a person with CKD.

1Review tempo, symptoms, bleeding, medicines and dialysis losses and obtain count, reticulocytes, film, iron indices, B12 and folate.
2Investigate gastrointestinal or gynaecological loss, inflammation, haemolysis and marrow disease when indices, trajectory or other cell lines are not typical.
3Attribute a renal component only after integrating kidney stage and competing causes, then agree symptom, transfusion-avoidance and transplant goals with nephrology.

02Iron correctionRestore available ironAbsolute or functional iron deficiency limits erythropoiesis.

1Select oral or intravenous iron using dialysis status, severity, tolerance, prior response and current renal guideline thresholds.
2For intravenous treatment calculate protocol dose, screen active infection and reaction risk, administer in an equipped setting and avoid exceeding iron-status ceilings.
3Recheck haemoglobin, ferritin and transferrin saturation after an appropriate interval and investigate continuing loss when iron need recurs rapidly.

03Erythropoiesis supportUse the lowest effective stimulationAnaemia remains symptomatic or transfusion-prone after correctable causes and iron availability are addressed.

1Discuss an ESA or eligible HIF-PH inhibitor with renal specialists, considering dialysis, transplant candidacy, cancer, thrombosis, blood pressure and patient preference.
2Start the protocol regimen and adjust gradually to rate of rise and an individual target range, never attempting routine normalisation of haemoglobin.
3EscalationIf response is inadequate, reassess adherence, iron, inflammation, access infection, dialysis, hyperparathyroidism, blood loss and marrow disease before large dose escalation.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

Replenishes stores and supplies erythropoiesis when oral absorption or inflammatory availability is inadequate.

Intravenous iron

The renal service calculates product-specific elemental iron and gives divided or total-dose infusions within licensed limits, haemodialysis timing and current ferritin and transferrin-saturation thresholds.

Observe for hypersensitivity and extravasation, avoid indiscriminate dosing during active systemic infection and monitor cumulative iron rather than treating ferritin in isolation.

Replaces deficient erythropoietic signalling to reduce symptoms and transfusion exposure after iron and other causes are addressed.

Epoetin alfa

Use a renal-protocol subcutaneous or intravenous starting dose and interval, then titrate no more often than recommended according to haemoglobin trajectory, dialysis and individual response.

Control hypertension and monitor rapid haemoglobin rise, stroke, vascular-access thrombosis and pure red-cell aplasia; avoid targeting a normal population haemoglobin.

Stabilises hypoxia-inducible factors and stimulates endogenous erythropoietin and iron mobilisation as an alternative CKD anaemia strategy.

Roxadustat

For eligible adults, specialists select the oral dose three times weekly from prior ESA exposure and weight, then adjust using the licensed haemoglobin-response algorithm.

Review thrombosis, hypertension, seizure, malignancy, liver function, interactions and pregnancy; iron availability and alternative anaemia causes still require correction.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Cardiorespiratory strain

Reduced oxygen carriage worsens exertional limitation, angina and heart failure, while overly rapid correction can increase blood pressure and vascular events.

Transfusion sensitisation

Donor red-cell exposure can produce HLA or red-cell antibodies, complicating future kidney transplantation and subsequent compatible transfusion support.

ESA-related vascular harm

Excessive haemoglobin targets, rapid rises and uncontrolled hypertension increase stroke, access thrombosis and other cardiovascular risk during erythropoiesis stimulation.

Iron toxicity

Unnecessary cumulative intravenous or oral iron can increase tissue burden and infusion reactions, while withholding needed iron perpetuates ESA resistance and symptoms.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Measure haemoglobin at protocol intervals after starting or changing ESA or HIF-PH therapy and act on both absolute value and rate of rise.
Check blood pressure at each relevant contact and withhold or adjust stimulation through renal guidance if hypertension becomes uncontrolled.
Repeat ferritin and transferrin saturation during iron and ESA treatment, accounting for inflammation, dialysis losses and recent infusions.
Track symptoms, exercise tolerance, heart failure, angina and transfusion exposure rather than treating a laboratory target without patient benefit.
Investigate new hyporesponse with CRP, dialysis adequacy, access review, bleeding assessment, haematinics, parathyroid status and marrow clues.
Maintain a transfusion and antibody record and revisit transplant candidacy before elective red-cell exposure whenever clinical urgency permits.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Ferritin is contextual

Inflammation raises ferritin while hepcidin withholds iron, so apparent storage does not always mean erythroblasts can access it.

Normalisation is harmful

Pushing haemoglobin toward healthy-population values with high ESA exposure increases vascular harm without corresponding clinical benefit.

CKD is not an exclusion

Kidney disease can coexist with cancer, gastrointestinal bleeding, haemolysis or myelodysplasia, especially when the pattern changes abruptly.

Transfusion has future effects

A unit given today can generate antibodies that complicate later kidney transplantation, so urgency and long-term goals both matter.

11Common pitfallsFrequent interpretation and management errors.

01
Calling every anaemia at low eGFR renal.
02
Using ferritin alone to judge iron availability.
03
Starting ESA before correcting iron or bleeding.
04
Chasing a normal haemoglobin with escalating doses.
05
Ignoring transplant sensitisation during elective transfusion.