How is anemia associated with Chronic Kidney Disease (CKD) managed?

Anemia in Chronic Kidney Disease: Pathophysiology and Management

Manage CKD-associated anemia by first correcting iron deficiency (targeting ferritin >100 μg/L and TSAT >20%), then initiating ESA therapy only when hemoglobin falls below 10 g/dL, with a target hemoglobin of 11 g/dL (acceptable range 10-12 g/dL), never exceeding 11.5 g/dL to avoid cardiovascular complications. 1, 2

Pathophysiology of CKD-Associated Anemia

The anemia of CKD is multifactorial, with several distinct mechanisms contributing to its development:

Primary Mechanism

• Insufficient erythropoietin (EPO) production by diseased kidneys is the primary cause of anemia in CKD patients 3
• Reduced EPO production leads to inadequate stimulation of red blood cell maturation in bone marrow 3

Contributing Factors

• Iron deficiency (both absolute and functional) where iron demand kinetically exceeds iron supply 3, 4
• Functional iron deficiency occurs due to inflammation-mediated hepcidin elevation, which sequesters iron in the reticuloendothelial system despite adequate total body iron stores 3
• Shortened RBC survival and poor bone marrow responsiveness 3
• Direct bone marrow suppression from uremic toxins 3
• Blood loss from repeated laboratory testing, dialyzer retention, and gastrointestinal bleeding 3
• Secondary hyperparathyroidism, chronic inflammation, aluminum toxicity, and nutritional deficiencies 3

Diagnostic Approach

Initial Assessment

• Hemoglobin measurement is preferred over hematocrit due to better reproducibility across laboratories 1
• Anemia in CKD is defined as hemoglobin <12 g/dL in females and <13.5 g/dL in males 1
• All CKD patients should be screened for anemia during initial evaluation 4

Iron Status Evaluation

The diagnostic criteria for iron deficiency differ in CKD compared to the general population:

Absolute Iron Deficiency: 3, 4

• TSAT <20% AND
• Ferritin <100 mg/L in non-dialysis CKD patients
• Ferritin <200 mg/L in hemodialysis patients

Functional Iron Deficiency: 3, 4

• TSAT <20% AND
• Ferritin >100 mg/L in non-dialysis patients
• Ferritin >200 mg/L in hemodialysis patients

Important Caveat

Current diagnostic parameters (ferritin and TSAT) have significant limitations and are not reliable for estimating body iron stores or predicting response to therapy, particularly in chronic inflammatory states 3, 1. Newer parameters like reticulocyte hemoglobin content and percentage of hypochromic RBCs may provide more accurate functional assessment 3.

Management Algorithm

Step 1: Iron Repletion (ALWAYS FIRST)

Iron supplementation must precede ESA therapy to ensure adequate iron stores for effective erythropoiesis 1, 2

Target Iron Parameters: 2

• Serum ferritin >100 μg/L
• TSAT >20%

Route Selection:

For hemodialysis patients: 1

• Proactive monthly intravenous iron 400 mg is recommended when ferritin <700 mg/L and TSAT <40%
• This approach decreases ESA requirements and improves cardiovascular outcomes and mortality 1

For non-dialysis CKD patients: 4

• Either intravenous or oral iron supplementation is acceptable
• Oral iron may have poor gastrointestinal tolerance and adherence issues 3

Step 2: ESA Therapy Initiation

Initiation Criteria (ALL must be met): 2

• Hemoglobin <10 g/dL (9-10 g/dL in dialysis patients)
• Iron stores corrected (ferritin >100 μg/L, TSAT >20%)
• Other reversible causes of anemia treated
• Do NOT initiate if hemoglobin ≥10 g/dL 2

Additional Considerations Before Starting ESA: 2

• Rate of hemoglobin decline
• Previous response to iron therapy
• Risk of transfusion requirement
• Presence of anemia-attributable symptoms

Step 3: Hemoglobin Targets

Target hemoglobin: 11 g/dL (acceptable range 10-12 g/dL) 1, 2

Critical Upper Limits: 2

• Never maintain hemoglobin >11.5 g/dL
• Never intentionally target hemoglobin >13 g/dL
• Exceeding these targets increases cardiovascular events, stroke, hypertension, and mortality risk 2

Step 4: Monitoring

Hemoglobin monitoring: 2

• At least monthly after ESA initiation
• Adjust dose based on hemoglobin levels, rate of change, and clinical circumstances

Iron parameters: 2

• Regular evaluation of ferritin and TSAT
• Maintain ferritin and TSAT above threshold values

Available Therapeutic Agents

Erythropoiesis-Stimulating Agents (ESAs)

FDA-approved ESAs for CKD anemia: 5, 6

• Epoetin alfa (Procrit, Retacrit)
• Indicated to decrease need for RBC transfusion in CKD patients on dialysis and not on dialysis
• Not shown to improve quality of life, fatigue, or patient well-being 5, 6

Novel Therapies: HIF-Prolyl Hydroxylase Inhibitors (HIF-PHIs)

Potential advantages: 3

• Oral dosing more convenient
• May improve iron utilization, particularly oral iron
• May be more effective in chronic inflammatory states

Potential concerns requiring caution: 3

• Risk of tumor growth enhancement
• Risk of worsening retinopathy in diabetic patients
• Risk of cyst growth in autosomal dominant polycystic kidney disease
• Less extensive clinical experience compared to ESAs

Contraindications and High-Risk Situations

Use ESAs with extreme caution in: 2

• Active malignancy
• History of stroke
• Chronic cardiovascular disease

Avoid excessive ESA dosing: 2

• High ESA doses driven by hyporesponsiveness should be avoided
• Associated with increased hospitalizations, cardiovascular events, and mortality 7

Common Pitfalls to Avoid

1. Starting ESAs before correcting iron deficiency - This leads to ESA hyporesponsiveness and wastes resources 1, 2

2. Over-correction of anemia - Targeting hemoglobin >13 g/dL or maintaining >11.5 g/dL increases cardiovascular risk and mortality 2

3. Relying solely on ferritin and TSAT - These parameters have significant limitations in inflammatory states; consider newer markers when available 3, 1

4. Ignoring infection risk with iron therapy - Be aware that iron administration may increase infection risk in susceptible patients 1

5. Failing to address underlying causes - Always optimize treatment of the underlying kidney disease and address reversible causes of anemia before escalating therapy 1