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Anemia Management With Chronic Kidney Disease Comorbidity

Summary
Basic Information
Treatment
Special Considerations
Follow-Up

Jul.02.2021

Anemia Management With Chronic Kidney Disease Comorbidity

Summary

Key Points

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 desired²
- 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

Basic Information

Terminology

Anemia is hemoglobin level less than 12 g/dL in adult females and less than 13 g/dL in adult males^1,2
Chronic kidney disease is abnormality in kidney structure or function present for longer than 3 months that affects health³
- Estimated GFR less than 60 mL/minute/1.73m² indicates decreased function³
The most severe chronic kidney disease (requiring hemodialysis or kidney transplant) is kidney failure with replacement therapy⁴
- End-stage renal disease is commonly used as a synonym

Pathophysiology

Chronic kidney disease can cause anemia and exacerbate underlying anemia through multiple mechanisms²

Chronic kidney disease causes hypoproliferative anemia, which correlates with chronic kidney disease severity⁵
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) (Table 1)

Table 1. Summary of findings suggesting anemia due to chronic kidney disease.

Clinical course	Chronic development of anemia Absence of findings suggesting that other causes of anemia are dominant (see Table 2)
CBC	Normocytic (MCV 80-100 fL) anemia WBC and platelet counts within reference ranges Severity of anemia proportional to severity of CKD
Iron studies	Ferritin and TSAT may be within reference ranges, consistent with functional iron deficiency, or may suggest absolute iron deficiency (see Table 3)

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 dysfunction⁶
- 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 treatment⁶
Other common contributing causes of anemia in patients with chronic kidney disease are alcohol use, nutritional deficiencies, medication effects, and genetic disorders (Table 2)

Table 2. Selected history and physical examination elements to determine severity, acuity, and cause of anemia in chronic kidney disease.
History	Considerations
Alcohol use	Alcohol can directly reduce RBC production, contribute to gastrointestinal blood loss and hypersplenism, and contribute to nutritional deficiencies
Nutritional intake	Limited diets can contribute to folate and vitamin B₁₂ deficiency
Family history, geographic background, and ethnic origin	Family history of anemia may point to specific causes Certain hemoglobinopathies and G6PD deficiency are more common in persons with Middle Eastern or African ancestry
Prescription medications	Methotrexate, hydroxyurea, and others interfere with RBC production Drug-induced immune hemolysis, methemoglobinemia (with or without hemolysis), and oxidative hemolysis are other mechanisms
Symptoms	Time course is important for acuity and differential diagnosis Chest pain or dizziness may suggest severe anemia and need for urgent hospitalization and transfusion Subjective fever, weight loss, night sweats, malaise, and related symptoms suggest infectious, inflammatory, or oncologic causes
Blood loss	Gastrointestinal blood loss and heavy menses are common contributors
Physical examination
Cardiovascular	Forceful heartbeat, vigorous peripheral pulsations, or systolic crescendo-decrescendo murmur may suggest more severe or acute anemia
Integument	Pallor of mucous membranes, nail beds, and palmar creases may suggest more severe anemia Petechiae suggest concomitant thrombocytopenia or platelet dysfunction
Spleen and lymph nodes	Splenomegaly may suggest hemolysis, infection, malignancy, or congestion resulting in hypersplenism Lymphadenopathy suggests infection or hematologic malignancy

Treatment

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 transfusion⁷

Determine factors driving anemia⁸

Routine evaluation includes CBC with differential, absolute reticulocyte count, and serum levels of ferritin, transferrin saturation, iron, B₁₂, and folate (Table 3)²

Table 3. Routine laboratory evaluation of anemia in chronic kidney disease.
Test	Considerations
CBC	In anemia due to CKD, hemoglobin is usually low, and WBC and platelet counts are within reference range Pancytopenia or bicytopenia necessitates peripheral blood smear examination and usually hematologist consultation
MCV	Anemia 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 level	Affected by iron stores (decreases with reduced iron stores) and inflammation (increases with inflammation) CKD is generally an inflammatory state, complicating interpretation Serum ferritin of 100 ng/mL or less may indicate absolute iron deficiency in chronic kidney disease⁵
TSAT level	20% or less may indicate an absolute iron deficiency in CKD (insufficient bone marrow iron stores)⁵ 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 level	Less than 200 pg/mL is consistent with deficiency; additional testing can determine cause 200-300 pg/mL is indeterminate; methylmalonic acid and homocysteine testing warranted
Serum folate level	Less than 2 ng/mL is consistent with folate deficiency 2-4 ng/mL is indeterminate; methylmalonic acid and homocysteine testing warranted

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

Treat the underlying cause
- Mainstay of treatment for anemia due to chronic kidney disease is iron optimization and use of erythropoietin stimulating agents
- Other reversible causes of anemia, such as nutritional deficiencies (eg, vitamin B₁₂, folate), toxins, or drugs, should be addressed and managed appropriately
Iron optimization
- Iron parameter thresholds in chronic kidney disease (an inflammatory state) differ from those in the general population⁹
  - Serum iron parameters (serum transferrin saturation and ferritin) imperfectly reflect iron stores in chronic kidney disease
  - In chronic kidney disease, much of the iron may be sequestered (and not available for erythropoiesis) even with sufficient total body iron
  - Goals of iron repletion for patients with chronic kidney disease:
    - Serum transferrin saturation level greater than 20%
    - Ferritin level greater than 200 ng/dL
- Serum transferrin saturation level of 20% or less and serum ferritin level of 100 ng/mL or less (serum ferritin level 200 ng/mL or less for persons on hemodialysis) may indicate absolute iron deficiency (insufficient bone marrow iron stores)⁵
- Serum transferrin saturation level of 20% to 30% with ferritin level within reference range or elevated may indicate functional iron deficiency (iron stores are sufficient but may be sequestered and not available for erythropoiesis)¹⁰
- Iron supplements increase hemoglobin in absolute and functional iron deficiency¹¹
- Most adult patients will need 500 to 1000 mg of iron to replete iron stores and correct absolute iron deficiency¹²
- IV iron is more effective than oral iron in chronic kidney disease¹¹
  - Enteral iron absorption is impaired in chronic kidney disease owing to upregulated hepcidin
  - No clear guidelines exist for IV iron dosing in functional iron deficiency
- Oral iron may be effective for maintaining stores or for those with milder chronic kidney disease (eg, estimated GFR above 30 mL/minute/1.73 m²)¹³
- Oral iron formulations are available in:
  - Generic OTC form: ferrous sulfate (65 mg per tablet) and ferrous gluconate (27-48 mg per tablet)
  - Prescription form¹⁴
    - Ferric citrate is a prescription oral iron replacement that is effective for anemia in nondialysis chronic kidney disease¹⁵
- IV iron is often needed for severe deficiency or for those with more severe chronic kidney disease (eg, estimated GFR below 30 mL/minute/1.73 m²) in whom enteral iron absorption is impaired and iron stores are sequestered¹⁶
- IV iron could cause oxidative stress and contribute to infections, but this is uncertain¹⁷
  - Although some clinicians prefer to avoid IV iron in patients with active infections,² it would be acceptable to proceed with IV iron in individual cases if the infection is being actively treated
- Anaphylaxis is a rare but serious adverse effect of IV iron¹⁸
  - Exact risk is unclear
    - Claims data showed risks up to 68 per 100,000 persons exposed¹⁹
    - Trial meta-analysis showed no anaphylactic events in greater than 10,000 administrations²⁰
  - Perform slow initial infusion with close observation for reactions²
    - Nonallergic, non–life-threatening reactions ("Fishbane reactions") with transient flushing and back and chest pain are estimated to occur in 1% of infusions²¹
      - Hold infusion until reaction resolves, then restart at slower rate with close monitoring²²
  - Risks appear similar among currently available IV iron formulations²⁰
    - High-molecular-weight iron dextran had higher anaphylaxis risk and is no longer available²³
Erythropoiesis stimulating agents
- Use in tandem with iron repletion or after iron repletion if adequate iron stores have been attained but target hemoglobin of 10-11g/dL has not been reached ²
  - A commonly used threshold for iron repletion is serum transferrin saturation level greater than 20% and ferritin level greater than 200 ng/mL⁵
- Approved agents in the United States are recombinant human erythropoietin and analogs (epoetin alfa, darbepoetin alfa, and methoxy polyethylene glycol-epoetin beta)
- Adverse effects include worsening hypertension²⁴
  - Mortality and cardiovascular events occurred with higher target hemoglobin levels in randomized trials²⁴
    - Adverse effects may be due to higher dose or higher achieved hemoglobin level
    - Mortality, or combined mortality/cardiovascular risk, increased by 5% to 34% with higher hemoglobin targets (13-14 g/dL versus 9-11 g/dL) in chronic kidney disease²⁵
    - Stroke risk increased by 92% with hemoglobin target 13 g/dL (versus 9 g/dL or greater) in nondialysis patients with chronic kidney disease and diabetes²⁶
  - Erythropoietin stimulating agents
    - In trials of patients with hemodialysis, have been associated with a systolic and diastolic increases of around 10 mm Hg
    - In trials of patients both on and off hemodialysis, increases hypertension-related adverse events²⁷
    - 2012 KDIGO guidelines recommend avoidance of therapy with erythropoietin stimulating agents for patients with active malignancy owing to increased risk of mortality²
- Minimum dose of erythropoietin stimulating agents needed to achieve hemoglobin 10 g/dL or greater is recommended for most patients²
  - Target hemoglobin increase of 1 to 2 g/dL per month to achieve this goal
  - Using erythropoietin stimulating agents to achieve hemoglobin greater than 11.5 g/dL is not recommended
  - Dosage usually rounded to closest dosage form available
- Individualized higher hemoglobin targets may be appropriate in some circumstances²
- Some people may have quality of life improvements with hemoglobin level greater than 11.5 g/dL and will accept the higher risks

Nondrug and Supportive Care

Mitigate ongoing blood loss⁸
- 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 rejection²⁸

Drug Therapy

Table 4. Drug Therapy: Anemia management with chronic kidney disease comorbidity.
Medication	Therapeutic use	Dosage	Safety concerns	Notable adverse reactions	Special considerations
Iron agents
Ferric carboxymaltose	CKD patients with anemia if an increase in Hgb concentration without starting ESA treatment or a decrease in ESA dose is desired and TSAT and ferritin are below targets^D1,D2 May be used as alternative to oral therapy or after failure of oral therapy in CKD ND patients^D1,D2 IV iron is more effective than oral iron for improvement in Hgb and quality of life for CKD 3a-5D^D1,D3-D5 Routine supplementation is not recommended if TSAT > 30% and serum ferritin > 500 ng/mL^D1,D2	≥ 50 kg: 750 mg IV every 7 days for 2 doses or 15 mg/kg/dose (Max: 1000 mg/dose) IV once < 50 kg: 15 mg/kg/dose IV every 7 days for 2 doses Max dose: 750 mg/dose for 2-dose treatment course or 1000 mg/dose for single-dose treatment course May repeat treatment course if iron deficiency recurs^D6	Avoid use in patients with active systemic infections^D1	Flushing Hypertension Hypophosphatemia Nausea Serious hypersensitivity reactions^D6	Assess Hgb and iron parameters (serum ferritin and TSAT) during therapy^D1 Monitor serum phosphate concentrations in patients at risk for low serum phosphate who require a repeat course of treatment^D6 Monitor for hypersensitivity reactions during and after administration for at least 30 minutes and until clinically stable^D6 Lab assays may overestimate serum iron and transferrin bound iron by also measuring the iron in ferric carboxymaltose in the 24 hours after administration^D6
Ferric citrate	Alternative to IV iron for 1-3 month trial in CKD ND patients with anemia if an increase in Hgb concentration without starting ESA treatment or a decrease in ESA dose is desired and TSAT and ferritin are below targets^*D1,D2 If goals are not met with a 1-3 month course of oral iron, consider IV iron therapy^D1 Routine supplementation is not recommended if TSAT > 30% and serum ferritin > 500 ng/mL^{D1, D2}	Initial dose: 1 tablet PO 3 times daily; each tablet contains 210 mg elemental iron Adjust dose as needed to achieve and maintain target hemoglobin Max dose: 12 tablets/day PO^D7	Contraindicated in patients with iron overload syndromes (e.g., hemochromatosis)^D7	Abdominal pain Constipation Cough Diarrhea Hyperkalemia Iron overload Nausea Stool discoloration Vomiting^D7	Assess iron parameters (serum ferritin and TSAT) during therapy^D1
Ferrous sulfate	Alternative to IV iron for 1-3 month trial in CKD ND patients with anemia if an increase in Hgb concentration without starting ESA treatment or a decrease in ESA dose is desired and TSAT and ferritin are below targets^*D1,D2 If goals are not met with a 1-3 month course of oral iron, consider IV iron therapy^D1 Routine supplementation is not recommended if TSAT > 30% and serum ferritin > 500 ng/mL^D1,D2	325 mg PO 3 times daily^D1,D8,D9	Drug interactions: separate administration of certain other oral medications due to decreased absorption^D9	Abdominal pain Constipation Diarrhea Esophageal ulceration Esophagitis Heartburn Iron overload Nausea^D10-D12	Assess iron parameters (serum ferritin and TSAT) during therapy^D1 Variable intestinal absorption and GI adverse effects limit efficacy^D1
Ferumoxytol	CKD patients with anemia if an increase in Hgb concentration without starting ESA treatment or a decrease in ESA dose is desired and TSAT and ferritin are below targets^D1,D2 May be used as alternative to oral therapy or after failure of oral therapy in CKD ND patients^D1,D2 IV iron is more effective than oral iron for improvement in Hgb and quality of life for CKD 3a-5D^D1,D3-D5 Routine supplementation is not recommended if TSAT > 30% and serum ferritin > 500 ng/mL^D1,D2	510 mg IV once, followed by a repeat dose in 3-8 days^D13 Single doses of 1020 mg IV have also been used^D14 Usual dose: 1020 mg/treatment course^D13 May repeat treatment course if iron deficiency recurs^D13	BOXED WARNING: risk for serious hypersensitivity/anaphylaxis reactions^D13 Contraindicated in patients with a history of allergic reaction to any IV iron product^D13 Avoid use in patients with active systemic infections^D1 Use with caution in patients with multiple drug allergies or asthma due to increased risk for anaphylaxis^D13,D15	Arthralgia Headache Hypotension Iron overload Serious hypersensitivity reactions^D13,D14	Evaluate hematologic response (Hgb, ferritin, iron and TSAT) at least 1 month after the second dose^D13 Monitor for hypersensitivity reactions during and after administration for at least 30 minutes and until clinically stable^D13 If administered during HD, give at least 60 minutes into session and once blood pressure is stable^D13 Interferes with MRI for up to 3 months after last dose^D13
Iron dextran	CKD patients with anemia if an increase in Hgb concentration without starting ESA treatment or a decrease in ESA dose is desired and TSAT and ferritin are below targets^D1,D2 May be used as alternative to oral therapy or after failure of oral therapy in CKD ND patients^D1,D2 IV iron is more effective than oral iron for improvement in Hgb and quality of life for CKD 3a-5D^D1,D3-D5 Routine supplementation is not recommended if TSAT > 30% and serum ferritin > 500 ng/mL^D1,D2	100 mg IV once daily until target dose achieved; administer 25 mg test dose before remainder of first therapeutic dose^D15 Single doses of 1000 mg IV have also been used^D16,D18 Usual dose: 500-1000 mg/treatment course^D17	BOXED WARNING: risk for serious hypersensitivity/anaphylaxis reactions^D15 Avoid use in patients with active systemic infections^D1 Use with caution in patients with multiple drug allergies or asthma due to increased risk for anaphylaxis^D15 Use with caution in patients with severe hepatic impairment^D15 Potential for acute exacerbation of joint pain/swelling in patients with rheumatoid arthritis^D15	Iron overload Serious hypersensitivity reactions^D15	Assess Hgb and iron parameters (serum ferritin and TSAT) during therapy^D1 Monitor for hypersensitivity reactions during and after test dose administration for at least 1 hour and during all subsequent administrations^D15 Serum iron determinations may not be clinically useful for 3 weeks after administration^D15 May cause falsely elevated serum bilirubin and falsely decreased serum calcium concentrations^D15
Iron sucrose	CKD patients with anemia if an increase in Hgb concentration without starting ESA treatment or a decrease in ESA dose is desired and TSAT and ferritin are below targets^D1,D2 May be used as alternative to oral therapy or after failure of oral therapy in CKD ND patients^D1,D2 IV iron is more effective than oral iron for improvement in Hgb and quality of life for CKD 3a-5D^D1,D3-D5 Routine supplementation is not recommended if TSAT > 30% and serum ferritin > 500 ng/mL ^D1,D2	Initial dose, CKD ND: 200 mg IV for 5 doses over 14 days; limited data with 500 mg IV every 14 days for 2 doses Initial dose, HD-dependent CKD: 100 mg IV per consecutive HD session Initial dose, PD-dependent CKD: 300 mg IV every 14 days for 2 doses, followed by 400 mg IV once another 14 days later Usual dose: 1000 mg/treatment course May repeat course if iron deficiency recurs^D19	Avoid use in patients with active systemic infections^D1	Hypotension Iron overload Serious hypersensitivity reactions^D19	Assess Hgb and iron parameters (serum ferritin and TSAT) during therapy^D1 Monitor for hypersensitivity reactions during and for at least 30 minutes after administration and until clinically stable^D19
Sodium ferric gluconate complex	CKD patients with anemia if an increase in Hgb concentration without starting ESA treatment or a decrease in ESA dose is desired and TSAT and ferritin are below targets^D1,D2 May be used as alternative to oral therapy or after failure of oral therapy in CKD ND patients^D1,D2 IV iron is more effective than oral iron for improvement in Hgb and quality of life for CKD 3a-5D^D1,D3-D5 Routine supplementation is not recommended if TSAT > 30% and serum ferritin > 500 ng/mL^D1,D2	Initial dose: 125 mg IV per HD session^D20 Single doses of 250 mg IV per HD session have also been used^D21 Usual dose: 1000 mg/treatment course^D20	Avoid use in patients with active systemic infections^D1	Hypotension Iron overload Serious hypersensitivity reactions^D20	Assess Hgb and iron parameters (serum ferritin and TSAT) during therapy^D1 Monitor for hypersensitivity reactions during and for at least 30 minutes after administration and until clinically stable^D20
Erythropoiesis-stimulating agents^†
Darbepoetin alfa	CKD patients with anemia^D22 Initiate in CKD ND patients at high risk for transfusion and related risks when Hgb ≤ 10 g/dL^‡D1,D2 Initiate in CKD 5D patients when Hgb 9-10 g/dL^D1,D2 Ensure adequate iron stores before initiation and during therapy^{D1,D2,D17,D22} Correct or exclude other causes of anemia before initiating therapy^D1,D22	Initial dose, CKD ND: 0.45 mcg/kg IV/subcutaneously every 4 weeks^D22 Initial dose, HD-dependent CKD: 0.45 mcg/kg IV/subcutaneously once weekly or 0.75 mcg/kg IV/subcutaneously every 2 weeks^D22 Dose titration: Titrate dose by 25% every 4 weeks to target Hgb. For Hgb rise > 1 g/dL in any 2 weeks, decrease dose by 25% or more. Reduce or interrupt dose if Hgb > 10 g/dL for CKD ND and if Hgb approaches or > 11 g/dL for HD-dependent CKD. Use lowest dose that maintains Hgb ≥ 10 g/dL and reduces RBC transfusions.^D1,D22 If inadequate response over 12-week escalation, increasing dose further is unlikely to improve response and may increase risks; discontinue if responsiveness does not improve^§D1,D22	BOXED WARNING: increased risk of death, MI, stroke, VTE, vascular access thrombosis, and tumor progression or recurrence^D22 Contraindicated in patients with uncontrolled hypertension or those who develop PRCA after treatment with any ESA^D22 Use with caution in patients with a history of cardiovascular disease, stroke, seizures, or malignancy^D1,D22	Dyspnea Fluid overload Hypertension Peripheral edema PRCA Procedural hypotension Seizures Serious skin reactions Thromboembolism^D22	Monitor iron status (TSAT and ferritin) at least every 3 months and more frequently when initiating or increasing ESA dose, when there is blood loss, after an IV iron course, and in other circumstances where iron stores may be depleted^{D1,D2,D17,D22} Monitor Hgb at least weekly when initiating therapy and with dose adjustments; once stable, monitor every 3 months for CKD ND patients and at least monthly for CKD 5D patients^D1,D22 Subcutaneous route is preferred for CKD ND or CKD 5PD, and IV route is preferred for CKD 5D^D1,D22
Epoetin alfa	CKD patients with anemia^D23 Initiate in CKD ND patients at high risk for transfusion and related risks when Hgb ≤ 10 g/dL^‡D1,D2 Initiate in CKD 5D patients when Hgb 9-10 g/dL^D1,D2 Ensure adequate iron stores before initiation and during therapy^{D1,D2,D17,D23} Correct or exclude other causes of anemia prior to initiating therapy^D1,D23	Initial dose: 50-100 units/kg IV/subcutaneously 3 times weekly^D23 Dose titration: Titrate dose by 25% every 4 weeks to target Hgb. For Hgb rise > 1 g/dL in any 2 weeks, decrease dose by 25% or more. Reduce or interrupt dose if Hgb > 10 g/dL for CKD ND and if Hgb approaches or > 11 g/dL for HD-dependent CKD. Use lowest dose that maintains Hgb ≥ 10 g/dL and reduces RBC transfusions.^D1,D23 If inadequate response over 12-week escalation, increasing dose further is unlikely to improve response and may increase risks; discontinue if responsiveness does not improve^§D1,D23	BOXED WARNING: increased risk of death, MI, stroke, VTE, vascular access thrombosis, and tumor progression or recurrence^D23 Contraindicated in patients with uncontrolled hypertension or those who develop PRCA after treatment with any ESA^D23 Use with caution in patients with a history of cardiovascular disease, stroke, seizures, or malignancy^D1,D23	Arthralgia Hypertension PRCA Seizures Serious skin reactions Thromboembolism^D23	Monitor iron status (TSAT and ferritin) at least every 3 months and more frequently when initiating or increasing ESA dose, when there is blood loss, after an IV iron course, and in other circumstances where iron stores may be depleted^{D1,D2,D17,D23} Monitor Hgb at least weekly when initiating therapy and with dose adjustments; once stable, monitor every 3 months for CKD ND patients and at least monthly for CKD 5D patients^D1,D23 Subcutaneous route is preferred for CKD ND or CKD 5PD, and IV route is preferred for CKD 5D^D1,D23
Methoxy polyethylene glycol-epoetin beta	CKD patients with anemia^D24 Initiate in CKD ND patients at high risk for transfusion and related risks when Hgb ≤ 10 g/dL^‡D1,D2 Initiate in CKD 5D patients when Hgb 9-10 g/dL^D1 Ensure adequate iron stores before initiation and during therapy^{D1,D2,D17,D24} Correct or exclude other causes of anemia prior to initiating therapy^D1,D24	Initial dose: 0.6 mcg/kg IV/subcutaneously every 2 weeks^D24 Dose titration: Titrate dose by 25% every 4 weeks to target Hgb. For Hgb rise > 1 g/dL in any 2 weeks, decrease dose by 25% or more. Reduce or interrupt dose if Hgb > 10 g/dL for CKD ND and if Hgb approaches or > 11 g/dL for HD-dependent CKD. Use lowest dose that maintains Hgb ≥ 10 g/dL and reduces RBC transfusions. May use twice the every-2-week dose once monthly.^D1,D24 If inadequate response over 12-week escalation, increasing dose further is unlikely to improve response and may increase risks; discontinue if responsiveness does not improve^§D1,D24	BOXED WARNING: increased risk of death, MI, stroke, VTE, vascular access thrombosis, and tumor progression or recurrence^D24 Contraindicated in patients with uncontrolled hypertension and those who develop PRCA after treatment with any ESA^D24 Use with caution in patients with a history of cardiovascular disease, stroke, seizure, or malignancy^D1,D24	Diarrhea Hypertension Nasopharyngitis PRCA Seizures Serious skin reactions Thromboembolism^D24	Monitor iron status (TSAT and ferritin) at least every 3 months and more frequently when initiating or increasing ESA dose, when there is blood loss, after an IV iron course, and in other circumstances where iron stores may be depleted^{D1,D2,D17,D24} Monitor Hgb at least weekly when initiating therapy and with dose adjustments; once stable, monitor every 3 months for CKD ND patients and at least monthly for CKD 5D patients^D1,D24 Subcutaneous route is preferred for CKD ND or CKD 5PD, and IV route is preferred for CKD 5D^D1,D24

Persistent or Recurrent Disease

Persistent or recurrent anemia can be a sign of ongoing blood loss, iron deficiency, nutrient deficiency, and/or systemic inflammation²⁹
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 inflammation³¹
- Check intact parathyroid hormone levels because severe secondary hyperparathyroidism can contribute³⁰
- Evaluate for malignancy, bone marrow disorders, and sickle cell disease, with hematologist consultation³²

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 disease³³
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 malnutrition³⁴
Anemia in older adults is associated with increased risk for cardiovascular and cerebrovascular disease, hospitalization, functional decline, reduced quality of life, and mortality³⁴
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 patients³⁴

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 mortality³⁵

Active Bleeding

Patients with kidney dysfunction may suffer prolonged bleeding episodes because chronic kidney disease impairs platelet function and erythropoiesis response³⁶
Among patients with active, severe bleeding, hemodialysis or desmopressin (0.3-0.4 mcg/kg once, IV or subcutaneous) may improve platelet function and hemostasis³⁷
- However, this should not delay efforts to stabilize patient and control source of bleeding

Children

Management is like that of adults but with adjusted drug dosages³⁸
Adverse effects of erythropoiesis stimulating agents in children are unclear because studies are limited³⁹

Pregnancy

Physiologic hemodilution due to increased plasma volume occurs during pregnancy, which may exacerbate underlying anemia in patients with chronic kidney disease⁴⁰
Iron deficiency may be even more prevalent because iron deficiency in pregnancy is common even in the absence of chronic kidney disease⁴¹
Use of iron and erythropoietin stimulating agents is similar to use in other patients with chronic kidney disease⁴⁰
- Risk/benefit balance for use of iron and erythropoietin stimulating agents in pregnancy is unclear⁴⁰

Kidney Transplant

Anemia often resolves with restoration of kidney function⁴²
Anemia with intact kidney function should lead to comprehensive evaluation including consideration of viral infections because of immunosuppression⁴³
Immunosuppressants themselves may contribute to anemia and input of a transplant specialist is important⁴⁴
- Antimetabolites (mycophenolate mofetil, mycophenolate sodium, azathioprine) and sirolimus can cause bone marrow suppression and anemia⁴⁴
With declining transplant function, anemia of chronic kidney disease commonly recurs and is managed as in other patients with chronic kidney disease⁴²

Infection

As an inflammatory state, alters iron serum parameters, making interpretation difficult^2,17
- Reassess iron stores once infection resolves
Although some clinicians prefer to avoid IV iron in patients with active infections,² in some cases it is acceptable to proceed with IV iron if infection is being actively treated
Reduces erythropoietin stimulating agent responsiveness⁴⁵
- If increase in hemoglobin level is necessary, higher doses or blood transfusion may be required (both strategies have risk)

Follow-Up

Monitoring

For patients with anemia who are not being treated with an erythropoietin stimulating agents, hemoglobin concentration should be measured²:
- 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 phase²
- 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

Complications

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 transfusions¹⁰
- 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 anemia⁴⁶
  - Risk of myocardial infarction, stroke, or death was 51% higher among patients with anemia compared with those without⁴⁶
- in an observational study, health-related quality of life was significantly lower among patients with chronic kidney disease with lower hemoglobin levels⁴⁷
- 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 factors⁴⁸
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 treatment²⁴
- Health-related quality of life was not shown to improve with anemia treatment, in a meta-analysis⁴⁹
- Cognitive function has been shown to improve with anemia treatment in hemodialysis patients⁵⁰
- Among patients with severe anemia, achieving target hemoglobin levels is associated with improvement in left ventricular hypertrophy⁵¹
- Multiple Cochrane reviews have demonstrated that erythropoietin stimulating agent treatment reduces need for transfusion^{26, 52, 53}

Prognosis

Chronic kidney disease is a progressive disease and as kidney function declines more intensive anemia treatment is usually needed¹⁰
- Correction of anemia has not been shown to reduce chronic kidney disease progression⁵⁴

Referral

Referral to nephrologist for diagnosis, evaluation, and treatment of anemia of chronic kidney disease is important²
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

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