Anemia

Anemia of CKD and Inflammation

Interpret ferritin and transferrin saturation in inflammatory states, distinguish absolute iron deficiency from iron-restricted erythropoiesis, evaluate anemia in chronic kidney disease, and use iron, erythropoiesis-stimulating agents, HIF-PH inhibitors, and transfusion appropriately.

Audience: internal medicine residents Last reviewed: July 2026

Bedside approach

Answer these questions first

Is the anemia explained by CKD severity? Review the hemoglobin trend, eGFR, dialysis status, reticulocyte response, and competing causes.
Is absolute iron deficiency present? Low ferritin strongly supports depleted iron stores, but thresholds depend on the population and clinical context.
Is iron restricted by inflammation? Low serum iron and TSAT with normal or elevated ferritin and low-normal transferrin may suggest functional iron restriction.
Could both processes coexist? CKD, inflammation, gastrointestinal bleeding, phlebotomy, and dialysis-related losses commonly overlap.
Are reversible causes corrected? Address iron deficiency, B12 or folate deficiency, bleeding, hemolysis, infection, inflammation, and medication effects.
What is the treatment goal? Reduce symptoms and transfusion exposure while avoiding excessive hemoglobin rise and treatment-related cardiovascular or thrombotic harm.

Urgent escalation

  • Hemodynamic instability or active major bleeding
  • Severe symptomatic anemia or ischemic symptoms
  • Rapid unexplained hemoglobin decline
  • Hemolysis with thrombocytopenia or organ injury
  • Severe hypertension during erythropoietic therapy
  • Suspected thromboembolism, stroke, or vascular-access thrombosis
  • Pancytopenia, circulating blasts, or suspected marrow failure

1. Initial evaluation

  1. Confirm the anemia and review prior hemoglobin, MCV, RDW, transfusions, bleeding events, procedures, and fluid administration.
  2. Obtain an absolute reticulocyte count and review the peripheral smear.
  3. Check ferritin, serum iron, TIBC or transferrin, and transferrin saturation.
  4. Review kidney function, dialysis status, inflammation, infection, malignancy, autoimmune disease, and recent hospitalization.
  5. Assess for B12 or folate deficiency, hemolysis, thyroid disease, blood loss, medication toxicity, and marrow disease when indicated.
  6. Treat reversible causes before escalating erythropoietic therapy.

Common initial tests

  • CBC with differential and prior-count review
  • Absolute reticulocyte count
  • Peripheral smear
  • Ferritin
  • Serum iron
  • TIBC or transferrin
  • Transferrin saturation
  • Creatinine and estimated GFR

Cause-directed tests

  • Vitamin B12 and folate
  • LDH, bilirubin, haptoglobin, and DAT
  • CRP or ESR when clinically useful
  • TSH
  • SPEP, immunofixation, and free light chains
  • Occult bleeding evaluation
  • Bone-marrow evaluation when indicated

2. Why inflammation causes anemia

Inflammatory signaling increases hepatic hepcidin production. Hepcidin binds ferroportin, reducing iron export from macrophages and enterocytes. This lowers circulating iron availability even when storage iron is present. [2]

Inflammation may also reduce erythropoietin production or marrow responsiveness, shorten red-cell survival, and suppress erythropoiesis.

Ferritin reflects both iron storage and inflammation. The more inflamed the patient, the less useful ferritin becomes as a stand-alone test.

3. Interpret the iron pattern

Feature Absolute iron deficiency Functional iron restriction Mixed deficiency and inflammation
Ferritin Usually reduced Often normal or elevated May be low, normal, or elevated depending on inflammatory intensity
Serum iron Reduced Reduced Reduced
TIBC or transferrin Often increased Often reduced or normal Variable
TSAT Reduced Reduced Reduced
Iron stores Depleted Present but poorly available Reduced stores plus impaired mobilization
Typical settings Blood loss, reduced intake, malabsorption, pregnancy, or frequent donation Infection, autoimmune disease, cancer, CKD, or critical illness CKD with blood loss, inflammatory bowel disease, cancer, or chronic infection
No single ferritin or TSAT threshold applies to every clinical population. Use the current disease-specific guideline, laboratory method, dialysis status, symptoms, and treatment history.

Interactive tool

Iron-pattern interpreter

This tool identifies broad laboratory patterns. It does not determine whether iron treatment is indicated.

Enter the iron studies

Interpretation

Enter the available laboratory values.

Ferritin may be increased by inflammation, infection, liver disease, malignancy, recent IV iron, and transfusion. Recent iron treatment may also alter the pattern.

4. Anemia in chronic kidney disease

CKD-associated anemia is generally hypoproliferative and often normocytic. Reduced erythropoietin production and impaired marrow responsiveness contribute, while iron deficiency and inflammatory restriction frequently coexist. [1]

Do not assume CKD is the only cause

  • Review the rate and timing of hemoglobin decline.
  • Assess absolute and functional iron deficiency.
  • Look for gastrointestinal, menstrual, procedural, or dialysis-related blood loss.
  • Evaluate B12 and folate when appropriate.
  • Exclude hemolysis when laboratory or smear findings suggest it.
  • Review infection, inflammation, malignancy, and medications.
  • Consider marrow disease when other cytopenias or abnormal cells are present.
A sudden hemoglobin decline is not typical of uncomplicated erythropoietin deficiency. Search for bleeding, hemolysis, acute illness, dilution, phlebotomy, or marrow suppression.

5. Iron treatment

Iron treatment decisions in CKD depend on dialysis status, ferritin, TSAT, symptoms, hemoglobin, current ESA or HIF-PHI use, prior response, transfusion risk, and the likelihood of benefit or harm. [1]

Oral iron may be reasonable when

  • The deficiency is mild or moderate.
  • The patient is not receiving hemodialysis.
  • There is no urgent need for iron repletion.
  • Absorption is expected to be adequate.
  • The patient can tolerate and adhere to treatment.

IV iron may be favored when

  • The patient receives hemodialysis.
  • Oral iron is ineffective or poorly tolerated.
  • Malabsorption is likely.
  • Inflammatory restriction limits oral response.
  • More rapid repletion is clinically important.
  • Ongoing blood loss increases iron requirements.

Before giving additional iron

  • Review cumulative iron exposure and recent IV doses.
  • Review ferritin and TSAT trends rather than one isolated value.
  • Assess active infection and the urgency of treatment.
  • Confirm that continued blood loss is being addressed.
  • Consider iron overload when ferritin and TSAT are persistently high.
Avoid reflexively giving repeated iron solely because the serum iron is low. In inflammatory states, serum iron may remain low despite substantial storage iron.

6. Erythropoiesis-stimulating agents

ESA treatment should be individualized after correctable causes have been addressed. The decision incorporates symptoms, hemoglobin trend, transfusion risk, dialysis status, cardiovascular risk, thrombosis risk, blood pressure, cancer history, and patient preferences. [1]

Before starting or increasing an ESA

  • Confirm adequate iron availability.
  • Assess adherence and recent dose history.
  • Check for bleeding or hemolysis.
  • Evaluate inflammation or infection.
  • Review blood pressure control.
  • Consider B12, folate, thyroid, and marrow disorders.
  • Review malignancy and thrombotic history.

Major cautions

  • Hypertension
  • Stroke and thromboembolic risk
  • Vascular-access thrombosis
  • Excessively rapid hemoglobin increase
  • Use in patients with active or prior malignancy
  • ESA hyporesponsiveness requiring escalating doses
The aim is generally to use the lowest effective treatment intensity that reduces clinically important anemia and transfusion exposure. Do not pursue normalization of hemoglobin as a routine goal.

7. HIF-prolyl-hydroxylase inhibitors

HIF-prolyl-hydroxylase inhibitors stimulate endogenous erythropoietic pathways and influence iron metabolism. Availability and indications vary by country.

In the United States, daprodustat is approved for anemia due to CKD in adults who have received dialysis for at least four months. It is not approved for CKD-associated anemia in adults who are not receiving dialysis. [4]

Before use

  • Confirm that the patient meets the locally approved indication.
  • Review thrombotic and cardiovascular risk.
  • Review malignancy history and other contraindications or warnings.
  • Assess iron status and correct reversible causes.
  • Review drug interactions and liver-related precautions.
  • Follow current prescribing information and nephrology guidance.
Do not treat HIF-PHI drugs as interchangeable with ESAs or assume that approval is the same across countries. Verify the current local label.

8. Inadequate response to iron or erythropoietic therapy

Problem Clinical clues Next steps
Ongoing blood loss Falling hemoglobin, recurrent iron deficiency, gastrointestinal symptoms, menstrual loss, procedures, or dialysis-circuit loss Identify and control the source rather than repeatedly replacing iron alone.
Inflammation or infection Elevated inflammatory markers, acute illness, low TSAT, and poor marrow response Treat the underlying condition and reassess treatment need.
Inadequate iron delivery Poor adherence, oral intolerance, malabsorption, continued loss, or insufficient cumulative dose Confirm administration history and consider a different route.
Hemolysis Increased LDH or bilirubin, reduced haptoglobin, abnormal smear, hemoglobinuria, or increased reticulocytes Complete a directed hemolysis evaluation.
Nutritional deficiency B12, folate, copper, or broader nutritional-risk factors Confirm and replace the deficient nutrient.
Marrow disease Additional cytopenias, dysplasia, blasts, monoclonal protein, or progressive unexplained anemia Hematology evaluation and marrow testing when appropriate.
ESA-related pure red-cell aplasia Severe anemia, profound reticulocytopenia, and abrupt loss of prior response Stop and urgently evaluate through nephrology and hematology.
Escalating an ESA dose without identifying the cause of hyporesponsiveness can increase harm while leaving the actual problem untreated.

9. Red-cell transfusion

Transfusion decisions should reflect symptoms, hemodynamic status, active bleeding, ischemia, hemoglobin trajectory, comorbid disease, transplant candidacy, and the expected response to other treatment.

Potential benefits

  • Rapid increase in oxygen-carrying capacity
  • Immediate treatment during major bleeding or severe symptoms
  • Temporary support while the underlying cause is corrected

Potential harms

  • Transfusion-associated circulatory overload
  • Alloimmunization
  • Transfusion reactions
  • Iron accumulation with repeated transfusion
  • Potential sensitization relevant to future transplantation
Kidney-transplant candidates may have particular reasons to minimize avoidable transfusion because alloimmunization can complicate future donor matching. Do not withhold urgently necessary transfusion.

10. When to involve specialists

Nephrology

  • Advanced CKD or dialysis
  • ESA or HIF-PHI initiation
  • Complex IV iron decisions
  • Persistent treatment hyporesponsiveness
  • Transplant-candidacy considerations
  • Difficult blood-pressure or volume management

Hematology

  • Unexplained or progressive anemia
  • Additional cytopenias
  • Abnormal smear, blasts, or dysplasia
  • Hemolysis
  • Monoclonal protein or suspected marrow disease
  • Profound reticulocytopenia or suspected pure red-cell aplasia

11. Resident summary

  1. CKD-associated anemia is usually hypoproliferative, but CKD does not exclude another cause.
  2. Low ferritin supports absolute iron deficiency, but normal or elevated ferritin does not exclude deficiency during inflammation.
  3. Low TSAT with normal or elevated ferritin may reflect functional iron restriction.
  4. Absolute deficiency and inflammatory restriction frequently coexist.
  5. Treat reversible causes before escalating ESA or HIF-PHI therapy.
  6. Use erythropoietic therapy to reduce clinically important anemia and transfusion exposure—not to normalize hemoglobin routinely.
  7. Investigate poor response rather than repeatedly increasing the dose.
  8. Consider transfusion symptoms, bleeding, ischemia, transplant candidacy, and treatment alternatives.

12. Knowledge check

Question 1

A patient with active inflammatory disease has low serum iron, low TSAT, low-normal TIBC, and elevated ferritin. Which mechanism is most likely contributing?

Question 2

Which statement about ferritin is most accurate in an inflamed patient?

Question 3

A patient with CKD has a sudden hemoglobin decline. What is the best next approach?

Question 4

Which patient meets the United States indication described for daprodustat?

References

  1. Kidney Disease: Improving Global Outcomes. KDIGO 2026 Clinical Practice Guideline for Anemia in Chronic Kidney Disease. KDIGO guideline
  2. Weiss G, Ganz T, Goodnough LT. Anemia of inflammation. Blood. 2019;133:40–50. Open article
  3. Fertrin KY. Diagnosis and management of iron deficiency in chronic inflammatory conditions. ASH Education Program. 2020. Open article
  4. United States Food and Drug Administration. JESDUVROQ (daprodustat) prescribing information and approval information. FDA label
  5. Carson JL, et al. Red blood cell transfusion: 2023 AABB international guidelines. JAMA. 2023. AABB summary

Educational disclaimer

This guide is intended for clinician education and does not replace current prescribing information, local laboratory interpretation, nephrology or hematology consultation, dialysis protocols, transfusion-service guidance, or individualized clinical judgment. Severe symptomatic anemia, active bleeding, suspected hemolysis, and treatment-related cardiovascular or thrombotic complications require urgent local escalation.