Anemia management with chronic kidney disease comorbidity

Anemia management with chronic kidney disease comorbidity 

  • Anemia is hemoglobin level less than 12 g/dL in adult females and less than 13 g/dL in adult males
  • Chronic kidney disease is abnormality in kidney structure or function present for longer than 3 months that affects health
    • Estimated GFR less than 60 mL/minute/1.73m2 indicates decreased function
  • The most severe chronic kidney disease (requiring hemodialysis or kidney transplant) is kidney failure with replacement therapy
    • End-stage renal disease is commonly used as a synonym


  • Chronic kidney disease can cause anemia and exacerbate underlying anemia through multiple mechanisms
    • Chronic kidney disease causes hypoproliferative anemia, which correlates with chronic kidney disease severity
    • Hypoproliferative anemia occurs through 3 primary mechanisms:
      • Low erythropoietin
      • Disordered iron uptake and use
      • Inflammation
    • Hypoproliferative state can lead to exacerbation of anemia from other causes (eg, iron deficiency, blood loss, nutritional deficiencies) by reducing the body’s ability to compensate
    • Onset of anemia due to chronic kidney disease is often indolent and follows the course of chronic kidney disease
    • Anemia from chronic kidney disease is often normocytic (mean corpuscular volume 80-100 fL) 

Summary of findings suggesting anemia due to chronic kidney disease.

Clinical courseChronic development of anemiaAbsence of findings suggesting that other causes of anemia are dominant
CBCNormocytic (MCV 80-100 fL) anemiaWBC and platelet counts within reference rangesSeverity of anemia proportional to severity of CKD
Iron studiesFerritin and TSAT may be within reference ranges, consistent with functional iron deficiency, or may suggest absolute iron deficiency

Caption: CKD, chronic kidney disease; MCV, mean corpuscular volume; TSAT, serum transferrin saturation.

  • Occult bleeding is another common source of anemia among patients with chronic kidney disease
    • Chronic kidney disease predisposes patients to gastrointestinal blood loss, through development of arteriovenous malformations and platelet dysfunction
    • Although chronic kidney disease itself can potentiate iron deficiency through disordered uptake (leading to a functional deficit), evaluation for occult blood loss may be needed if iron deficiency is identified
    • Hemodialysis causes a small amount of blood loss with each treatment
  • Other common contributing causes of anemia in patients with chronic kidney disease are alcohol use, nutritional deficiencies, medication effects, and genetic disorders

Selected history and physical examination elements to determine severity, acuity, and cause of anemia in chronic kidney disease.

Alcohol useAlcohol can directly reduce RBC production, contribute to gastrointestinal blood loss and hypersplenism, and contribute to nutritional deficiencies
Nutritional intakeLimited diets can contribute to folate and vitamin B12 deficiency
Family history, geographic background, and ethnic originFamily history of anemia may point to specific causesCertain hemoglobinopathies and G6PD deficiency are more common in persons with Middle Eastern or African ancestry
Prescription medicationsMethotrexate, hydroxyurea, and others interfere with RBC productionDrug-induced immune hemolysis, methemoglobinemia (with or without hemolysis), and oxidative hemolysis are other mechanisms
SymptomsTime course is important for acuity and differential diagnosisChest pain or dizziness may suggest severe anemia and need for urgent hospitalization and transfusionSubjective fever, weight loss, night sweats, malaise, and related symptoms suggest infectious, inflammatory, or oncologic causes
Blood lossGastrointestinal blood loss and heavy menses are common contributors
Physical examination
CardiovascularForceful heartbeat, vigorous peripheral pulsations, or systolic crescendo-decrescendo murmur may suggest more severe or acute anemia
IntegumentPallor of mucous membranes, nail beds, and palmar creases may suggest more severe anemiaPetechiae suggest concomitant thrombocytopenia or platelet dysfunction
Spleen and lymph nodesSplenomegaly may suggest hemolysis, infection, malignancy, or congestion resulting in hypersplenismLymphadenopathy suggests infection or hematologic malignancy

Caption: G6PD, glucose-6-phosphate dehydrogenase.


Approach to Treatment

  • Includes assessment of anemia severity, diagnosis and mitigation of reversible causes, and use of iron supplements and erythropoietin stimulating agents
    • Determine severity and acuity of anemia
      • Life-threatening anemia, as indicated by abnormal vital signs (tachycardia and hypotension), signs of end organ dysfunction, or laboratory findings of an acute change or critically low hemoglobin or hematocrit should prompt rapid stabilization and transfer to an acute care setting for immediate blood transfusion
    • Determine factors driving anemia
      • Routine evaluation includes CBC with differential, absolute reticulocyte count, and serum levels of ferritin, transferrin saturation, iron, B12, and folate

Routine laboratory evaluation of anemia in chronic kidney disease.

CBCIn anemia due to CKD, hemoglobin is usually low, and WBC and platelet counts are within reference rangePancytopenia or bicytopenia necessitates peripheral blood smear examination and usually hematologist consultation
MCVAnemia due to chronic kidney disease is usually normocytic (MCV 80-100 fL)Microcytosis or macrocytosis point to another cause or contributor (eg, nutrient deficiencies, hemoglobinopathies)
Serum ferritin levelAffected by iron stores (decreases with reduced iron stores) and inflammation (increases with inflammation)CKD is generally an inflammatory state, complicating interpretationSerum ferritin of 100 ng/mL or less may indicate absolute iron deficiency in chronic kidney disease
TSAT level20% or less may indicate an absolute iron deficiency in CKD (insufficient bone marrow iron stores) 20%-30%, with normal or elevated ferritin level, suggests functional iron deficiency in CKD (iron stores are sufficient but may be sequestered and not available for erythropoiesis)
Serum vitamin B12 levelLess than 200 pg/mL is consistent with deficiency; additional testing can determine cause200-300 pg/mL is indeterminate; methylmalonic acid and homocysteine testing warranted
Serum folate levelLess than 2 ng/mL is consistent with folate deficiency2-4 ng/mL is indeterminate; methylmalonic acid and homocysteine testing warranted

Caption: CKD, chronic kidney disease; MCV, mean corpusular volume; TSAT, serum transferrin saturation.

    • Additional evaluation guided by history, physical examination, and laboratory studies should evaluate for other causes of anemia

Nondrug and Supportive Care

  • Mitigate ongoing blood loss
    • Consider evaluation for occult gastrointestinal blood loss
    • In patients on hemodialysis, minimize treatment-associated blood loss
      • If there is frequent posttreatment bleeding from hemodialysis fistula or graft, refer to interventional radiologist or nephrologist for stenosis evaluation and treatment
      • If there is frequent hemodialysis filter clotting resulting in circuit blood loss, ensure adequate blood pump speed and hemodialysis anticoagulation regimen
  • Avoid blood transfusions if possible, especially in patients who have received or may receive kidney transplant because transfusion may increase risk for rejection

Drug Therapy

Persistent or Recurrent Disease

  • Persistent or recurrent anemia can be a sign of ongoing blood loss, iron deficiency, nutrient deficiency, and/or systemic inflammation
  • Inadequate response to erythropoietin stimulating agents (or increasing erythropoietin stimulating agent requirement) despite adequate iron, folate, and B12 stores is called erythropoietin stimulating agent hyporesponsiveness
    • Investigate for infections (including occult infections) or other causes of inflammation
    • Check intact parathyroid hormone levels because severe secondary hyperparathyroidism can contribute
    • Evaluate for malignancy, bone marrow disorders, and sickle cell disease, with hematologist consultation

Admission Criteria

  • Symptomatic anemia needing urgent blood transfusion
    • Warrants emergency department evaluation and treatment
    • Inpatient admission may be needed for evaluation and treatment for ongoing blood loss or hemolysis

Special Considerations

Older Adults

  • Anemia prevalence increases in older persons with chronic kidney disease
  • Prevalence and severity of anemia increase as GFR decreases below 60 mL/minute because of impaired synthesis of erythropoietin; contributing factors include iron deficiency, chronic inflammation, and malnutrition
  • Anemia in older adults is associated with increased risk for cardiovascular and cerebrovascular disease, hospitalization, functional decline, reduced quality of life, and mortality
  • Although opinions vary about optimal target hemoglobin level in the setting of erythropoietin therapy, older adults with chronic kidney disease should be treated with similar target hemoglobin levels as other patients

Limited Life Expectancy

  • No specific guideline recommendations for management of anemia in patients with chronic kidney disease with limited life expectancy
  • Individualized decision-making could include higher hemoglobin targets aimed at improving quality of life, with the trade-off of increased risk for cardiovascular events or mortality

Active Bleeding

  • Patients with kidney dysfunction may suffer prolonged bleeding episodes because chronic kidney disease impairs platelet function and erythropoiesis response
  • Among patients with active, severe bleeding, hemodialysis or desmopressin (0.3-0.4 mcg/kg once, IV or subcutaneous) may improve platelet function and hemostasis
    • However, this should not delay efforts to stabilize patient and control source of bleeding


  • Management is like that of adults but with adjusted drug dosages
  • Adverse effects of erythropoiesis stimulating agents in children are unclear because studies are limited


  • Physiologic hemodilution due to increased plasma volume occurs during pregnancy, which may exacerbate underlying anemia in patients with chronic kidney disease
  • Iron deficiency may be even more prevalent because iron deficiency in pregnancy is common even in the absence of chronic kidney disease
  • Use of iron and erythropoietin stimulating agents is similar to use in other patients with chronic kidney disease
    • Risk/benefit balance for use of iron and erythropoietin stimulating agents in pregnancy is unclear

Kidney Transplant

  • Anemia often resolves with restoration of kidney function
  • Anemia with intact kidney function should lead to comprehensive evaluation including consideration of viral infections because of immunosuppression
  • Immunosuppressants themselves may contribute to anemia and input of a transplant specialist is important
    • Antimetabolites (mycophenolate mofetil, mycophenolate sodium, azathioprine) and sirolimus can cause bone marrow suppression and anemia
  • With declining transplant function, anemia of chronic kidney disease commonly recurs and is managed as in other patients with chronic kidney disease


  • As an inflammatory state, alters iron serum parameters, making interpretation difficult
    • Reassess iron stores once infection resolves
  • Although some clinicians prefer to avoid IV iron in patients with active infections, in some cases it is acceptable to proceed with IV iron if infection is being actively treated
  • Reduces erythropoietin stimulating agent responsiveness
    • If increase in hemoglobin level is necessary, higher doses or blood transfusion may be required (both strategies have risk)



  • For patients with anemia who are not being treated with an erythropoietin stimulating agents, hemoglobin concentration should be measured:
    • Every 3 months in patients with chronic kidney disease who are not on hemodialysis
    • At least monthly in patients on hemodialysis
  • For patients receiving an erythropoietin stimulating agent, check CBC at least monthly during initiation phase and every 3 months during maintenance phase
    • Check iron status (serum transferrin saturation and ferritin levels) at least every 3 months
    • Test iron status more frequently when starting or increasing erythropoietin stimulating agent dose, when adjusting iron therapy, and after blood loss


  • Anemia in chronic kidney disease is associated with increased mortality and cardiovascular disease, reduced health-related quality of life and cognitive function, and increased need for blood transfusions
    • Results from 4 pooled longitudinal cohort studies showed:
      • Anemia was independently associated with increased mortality among patients with chronic kidney disease compared with those without anemia
      • Risk of myocardial infarction, stroke, or death was 51% higher among patients with anemia compared with those without
    • in an observational study, health-related quality of life was significantly lower among patients with chronic kidney disease with lower hemoglobin levels
    • In a large chronic kidney disease cohort study, each decrease in hemoglobin of 1 g/dL was associated with 9% increased odds of cognitive impairment, independently of other factors
  • Trials of anemia treatment in chronic kidney disease have demonstrated reductions in some (not all) complications
    • Risks of mortality and cardiovascular events have not been reduced with treatment
    • Health-related quality of life was not shown to improve with anemia treatment, in a meta-analysis
    • Cognitive function has been shown to improve with anemia treatment in hemodialysis patients
    • Among patients with severe anemia, achieving target hemoglobin levels is associated with improvement in left ventricular hypertrophy
    • Multiple Cochrane reviews have demonstrated that erythropoietin stimulating agent treatment reduces need for transfusion


  • Chronic kidney disease is a progressive disease and as kidney function declines more intensive anemia treatment is usually needed
    • Correction of anemia has not been shown to reduce chronic kidney disease progression


  • Referral to nephrologist for diagnosis, evaluation, and treatment of anemia of chronic kidney disease is important
  • Refer to gastroenterologist for evaluation of suspected gastrointestinal blood loss
  • Refer to hematologist for anemia out of proportion to degree of chronic kidney disease or when cause of anemia is uncertain


  • Chronic kidney disease causes hypoproliferative anemia, which correlates with chronic kidney disease severity and may exacerbate anemia from other causes (eg, blood loss, nutritional deficiencies, toxins/drugs)
  • Clinicians should evaluate for causes and contributors to anemia besides chronic kidney disease, especially if severity of anemia is disproportionate to severity of chronic kidney disease
  • Treatment of anemia reduces need for blood transfusions and may improve some clinical outcomes
    • Target hemoglobin of 10 to 11.5 is appropriate for most patients
  • Iron status monitoring and iron repletion are essential
    • Serum transferrin saturation greater than 20% and ferritin greater than 200 ng/mL are commonly used thresholds in chronic kidney disease
  • IV iron is more effective than oral iron
  • Once iron is replete, erythropoietin stimulating agent use may be appropriate if further hemoglobin increase is desired
    • Evaluate serum transferrin saturation and ferritin every 3 months (or more frequently) during therapy with erythropoietin stimulating agents
    • Test serum transferrin saturation more frequently when starting or increasing erythropoietin stimulating agents
    • Hemoglobin/CBC should be measured at least every 3 weeks in patients being treated with erythropoietin stimulating agents
    • When starting or adjusting erythropoietin stimulating agents, measure hemoglobin at least monthly
    • When on maintenance erythropoietin stimulating agent, measure hemoglobin at least every 3 months in patients not on hemodialysis, and at least monthly in patients on hemodialysis

Alarm Signs and Symptoms

  • As with anemia in other populations, signs or symptoms that suggest symptomatic or severe anemia should prompt urgent evaluation and management in an emergency care setting; they include:
    • Acutely worsening or severe fatigue
    • Dizziness
    • Chest pain
    • Shortness of breath
    • Pallor
    • Ongoing blood loss


Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. WHO. 2011. Accessed June 3, 2021.


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