Medicine – Anaemia of Chronic Kidney Disease

Anaemia of chronic kidney disease (CKD) is a common complication of progressive renal impairment. The older term “anaemia of chronic renal failure (CRF)” is now more commonly replaced by anaemia of CKD.

The anaemia develops mainly because diseased kidneys produce insufficient erythropoietin (EPO), although iron deficiency, inflammation, shortened red-cell survival and other factors may also contribute.

1. Relationship to Renal Function

The original note states:

“GFR <35 mL/min.”

Anaemia does become increasingly common as GFR declines, but there is no single GFR threshold at which renal anaemia begins.

It becomes particularly important in:

Moderate-to-advanced CKD, especially CKD stages 4 and 5.

Patients with diabetes may sometimes develop anaemia at a relatively earlier stage of CKD.

2. Normal Erythropoietin Production

Erythropoietin (EPO) is a glycoprotein hormone produced predominantly by specialised interstitial cells in the:

Kidneys.

Its major function is to stimulate:

Red blood cell production in the bone marrow.

3. Normal Response to Hypoxia

When tissue oxygen delivery falls, healthy kidneys detect the reduced oxygen availability and increase:

EPO production.

EPO then acts on erythroid precursor cells in the bone marrow, increasing:

Erythropoiesis.

This raises the circulating red-cell mass and improves oxygen delivery.

4. EPO Deficiency in CKD

In CKD, progressive tubulointerstitial damage reduces the kidney’s ability to produce an appropriate amount of:

Erythropoietin.

Consequently, the bone marrow receives inadequate stimulation for red-cell production.

This is the major mechanism responsible for:

Anaemia of CKD.

5. EPO Is Relatively Deficient

The problem is best described as:

Relative erythropoietin deficiency.

The patient may still have measurable EPO in the blood, but the concentration is inappropriately low for the degree of anaemia.

6. Type of Anaemia

Classically, anaemia of CKD is:

Normocytic

and

Normochromic.

Therefore:

Low haemoglobin + normal MCV + advanced CKD → consider renal anaemia.

However, another abnormality such as iron deficiency can alter this pattern.

7. Additional Causes of Anaemia in CKD

EPO deficiency is central, but CKD-associated anaemia is often:

Multifactorial.

Other contributing factors include:

Iron deficiency.

Chronic inflammation.

Reduced availability of stored iron.

Shortened red-cell survival.

Blood loss.

Nutritional deficiencies.

Dialysis-related blood loss in selected patients.

8. Iron Deficiency

Iron deficiency is particularly important because adequate iron is required for:

Haemoglobin synthesis

and for an effective response to:

Erythropoiesis-stimulating therapy.

Iron deficiency may be:

Absolute

or

Functional.

9. Absolute Iron Deficiency

In absolute iron deficiency, the body’s actual iron stores are depleted.

Possible causes in CKD include:

Chronic blood loss.

Gastrointestinal bleeding.

Repeated blood sampling.

Dialysis-associated losses.

Reduced dietary intake or absorption.

10. Functional Iron Deficiency

In functional iron deficiency, iron stores may be present but iron cannot be mobilised effectively for:

Erythropoiesis.

This occurs particularly in chronic inflammatory states.

An important mediator is:

Hepcidin.

11. Hepcidin

Hepcidin is a major regulator of iron metabolism.

It reduces:

Intestinal iron absorption

and

Release of stored iron from macrophages.

Hepcidin levels can be elevated in CKD because of:

Inflammation

and

Reduced renal clearance.

12. Effect of Increased Hepcidin

Increased hepcidin means iron may remain trapped in storage sites rather than being made available to the bone marrow.

Therefore, a CKD patient may have:

Adequate or elevated ferritin

but still have insufficient iron available for erythropoiesis.

This is why ferritin alone is not sufficient to assess iron status.

13. Shortened Red-Cell Survival

Uraemia can reduce the normal lifespan of circulating:

Red blood cells.

This contributes further to anaemia.

Therefore, CKD anaemia reflects both:

Reduced red-cell production

and

Reduced red-cell survival.

14. Clinical Features

Symptoms depend on the severity and rate of development of the anaemia.

Possible features include:

Fatigue.

Weakness.

Reduced exercise tolerance.

Breathlessness on exertion.

Palpitations.

Dizziness.

Reduced concentration.

15. Cardiovascular Consequences

Severe or prolonged anaemia increases cardiac workload.

It may contribute to:

Tachycardia.

Left ventricular hypertrophy.

Worsening heart failure.

Reduced exercise capacity.

This is particularly important because CKD patients already have a high cardiovascular risk.

16. Investigation

Anaemia in a patient with CKD should not automatically be assumed to result from:

EPO deficiency.

Other causes should be excluded.

Initial assessment commonly includes:

Full blood count.

MCV.

Reticulocyte count where appropriate.

Ferritin.

Transferrin saturation – TSAT.

17. Additional Investigations

Depending on the clinical situation, additional tests may include:

Vitamin B12.

Folate.

Markers of inflammation.

Tests for haemolysis.

Investigation for gastrointestinal or other blood loss.

The purpose is to identify reversible causes before attributing the anaemia entirely to CKD.

18. Ferritin

Serum ferritin provides information about:

Body iron stores.

A low ferritin strongly supports:

Absolute iron deficiency.

However, ferritin is also an:

Acute-phase reactant.

19. Limitation of Ferritin

Because ferritin increases during inflammation, a patient with CKD may have:

Normal or elevated ferritin

despite having insufficient iron available for erythropoiesis.

Therefore ferritin should usually be interpreted together with:

Transferrin saturation – TSAT.

20. Transferrin Saturation

TSAT estimates how much circulating transferrin is carrying iron that can be delivered to tissues.

A low TSAT suggests:

Reduced iron availability.

Therefore:

Ferritin → iron stores.

TSAT → circulating iron availability.

Both are useful in CKD.

21. Management Principles

Treatment aims to:

Correct iron deficiency.

Improve haemoglobin and symptoms.

Use erythropoiesis-stimulating therapy when appropriate.

Avoid unnecessary blood transfusion.

Treat other reversible causes of anaemia.

22. Iron Replacement

Iron deficiency should be corrected before or alongside erythropoiesis-stimulating therapy.

Iron can be administered:

Orally

or

Intravenously.

The best route depends on:

CKD stage.

Dialysis status.

Severity of iron deficiency.

Response to previous oral iron.

Tolerance.

23. Intravenous Iron

The original note states:

“If ferritin <100, give intravenous iron.”

This is too simplified for modern practice.

Decisions about iron therapy are generally based on:

Ferritin + TSAT + haemoglobin + dialysis status + clinical context.

A single ferritin threshold should not be used in isolation.

24. Iron in Haemodialysis

Patients receiving:

Haemodialysis

frequently require intravenous iron because of ongoing iron losses and the difficulty of maintaining sufficient available iron.

Therefore:

IV iron is commonly used in haemodialysis patients.

25. Oral Iron

In patients with CKD who are not receiving haemodialysis, treatment may begin with:

Oral iron

in suitable circumstances.

If oral treatment is:

Ineffective, poorly tolerated, or inadequate,

intravenous iron may be considered.

26. Erythropoiesis-Stimulating Agents

The original notes refer to:

Subcutaneous EPO injections.

The broader modern term is:

Erythropoiesis-stimulating agents – ESAs.

These drugs stimulate the bone marrow to increase:

Red blood cell production.

27. Examples of ESAs

Examples include:

Epoetin alfa.

Epoetin beta.

Darbepoetin alfa.

Different preparations have different durations of action and dosing schedules.

28. Administration of ESAs

ESAs may be administered:

Subcutaneously

or

Intravenously

depending on the agent and clinical setting.

Therefore, ESA therapy is not restricted to:

Subcutaneous injection alone.

29. When ESA Therapy Is Considered

ESA therapy is generally considered when a CKD patient has persistent clinically important anaemia after:

Iron deficiency and other reversible causes have been assessed and treated.

The decision depends on:

Haemoglobin concentration.

Symptoms.

Rate of haemoglobin decline.

Need to avoid transfusion.

Cardiovascular and thrombotic risks.

30. Why Iron Must Be Adequate

ESAs stimulate the bone marrow to make new red cells.

This substantially increases the marrow’s requirement for:

Iron.

If iron availability is inadequate, the patient may show a poor response to ESA treatment.

Therefore:

ESA + inadequate iron → poor erythropoietic response.

31. ESA Treatment Is Not Designed to Normalise Haemoglobin Completely

An important modern principle is that ESA therapy should not routinely attempt to restore haemoglobin to the normal range of a healthy person.

Excessive correction has been associated with increased risk of adverse cardiovascular and thrombotic events.

Therefore, treatment targets are:

Individualised

rather than simply aiming for a completely normal haemoglobin.

32. Adverse Effects of ESA Therapy

Important complications include:

Hypertension.

Thrombotic events.

Vascular-access thrombosis.

Excessive haemoglobin elevation may increase:

Cardiovascular risk.

33. ESA Resistance

If haemoglobin fails to improve adequately despite ESA therapy, consider:

Iron deficiency.

Inflammation or infection.

Ongoing blood loss.

Inadequate dialysis.

Hyperparathyroidism.

Nutritional deficiency.

Haematological disease.

The ESA dose should not simply be increased indefinitely without identifying the reason for poor response.

34. Blood Transfusion

Red-cell transfusion may be necessary in selected patients with:

Severe symptomatic anaemia.

Acute major blood loss.

Haemodynamic instability.

However, repeated transfusions are generally avoided when possible in potential kidney-transplant candidates.

35. Why Transfusions Are Avoided in Transplant Candidates

Blood transfusions can expose the patient to foreign:

HLA antigens.

This may cause:

HLA sensitisation.

Sensitisation can make it more difficult to find a compatible kidney donor and may increase transplant immunological risk.

Therefore:

Avoid unnecessary transfusion in potential renal-transplant candidates.

36. Anaemia of CKD – Pathophysiology Note Form

CKD → renal interstitial damage.

Renal damage → inadequate EPO production.

Low EPO stimulation → reduced bone-marrow erythropoiesis.

CKD → inflammation + increased hepcidin.

Increased hepcidin → reduced intestinal iron absorption + reduced release of stored iron.

Reduced iron availability → impaired haemoglobin synthesis.

Uraemia → shortened RBC survival.

Final result → predominantly normocytic normochromic anaemia.

37. Anaemia of CKD – Investigation Note Form

Full blood count:

Low haemoglobin.

Usually normocytic and normochromic.

Ferritin:

Assesses iron stores.

Low level strongly suggests absolute iron deficiency.

Can be falsely elevated by inflammation.

TSAT:

Assesses available circulating iron.

Should be interpreted with ferritin.

Other tests when indicated:

Vitamin B12.

Folate.

Reticulocytes.

Inflammatory markers.

Haemolysis screen.

Assessment for blood loss.

38. Anaemia of CKD – Treatment Note Form

Step 1:

Confirm anaemia and assess alternative causes.

Step 2:

Assess iron status using:

Ferritin.

TSAT.

Step 3:

Correct iron deficiency.

Oral iron may be appropriate in some non-dialysis patients.

IV iron is commonly used in haemodialysis and when oral therapy is inadequate.

Step 4:

Consider an ESA for persistent significant CKD-related anaemia.

Examples:

Epoetin.

Darbepoetin.

Step 5:

Monitor:

Haemoglobin.

Blood pressure.

Iron status.

Response to therapy.

Step 6:

Avoid unnecessary blood transfusion, particularly in potential transplant recipients.

39. Important Corrections to the Original Notes

The statement:

“GFR <35 mL/min”

should not be treated as an absolute diagnostic threshold.

A better principle is:

ANAEMIA BECOMES MORE COMMON AND MORE SEVERE AS CKD PROGRESSES, PARTICULARLY IN ADVANCED CKD.

The statement:

“Caused by lack of EPO”

is fundamentally correct but incomplete.

CKD anaemia is usually multifactorial:

RELATIVE EPO DEFICIENCY + IRON RESTRICTION + INFLAMMATION + SHORTENED RBC SURVIVAL ± BLOOD LOSS.

The statement:

“Subcutaneous EPO injections”

is better modernised to:

ERYTHROPOIESIS-STIMULATING AGENTS – ESAs, GIVEN SUBCUTANEOUSLY OR INTRAVENOUSLY DEPENDING ON THE CLINICAL SETTING.

The statement:

“Ferritin <100 → IV iron”

is too rigid.

Iron treatment should be guided by:

FERRITIN + TSAT + HAEMOGLOBIN + DIALYSIS STATUS + CLINICAL CONTEXT.

Key Clinical Pattern

Think:

ADVANCED CKD + NORMOCYTIC NORMOCHROMIC ANAEMIA → RELATIVE EPO DEFICIENCY.

The central mechanism is:

↓ RENAL FUNCTION → ↓ APPROPRIATE EPO PRODUCTION → ↓ BONE-MARROW RBC PRODUCTION → ANAEMIA.

But remember the important additional pathway:

CKD/INFLAMMATION → ↑ HEPCIDIN → ↓ AVAILABLE IRON → WORSENING ANAEMIA.

Management can be remembered as:

CHECK IRON → REPLACE IRON WHEN INDICATED → ESA WHEN APPROPRIATE → MONITOR Hb AND BP → AVOID UNNECESSARY TRANSFUSION.