Anemia of Chronic Kidney Disease

Background

• Anemia of chronic kidney disease (CKD) is a hypoproliferative, normocytic, and normochromic anemia associated with high mortality, morbidity and reduced health-related quality of life.
• Chronic kidney disease (CKD) results in decreased renal erythropoietin synthesis (mostly produced by the peritubular interstitial cells of the kidneys), leading to apoptosis of erythroid progenitor cells, which in turn leads to reduced reticulocyte and red blood cell production and worsening anemia. In addition, there may be a shortened half-life of erythrocytes.
• Patients with CKD may also have absolute or functional iron deficiency, and anemia may also result from concomitant acute and chronic inflammatory conditions.
• Prevalence of anemia increases with severity of CKD with prevalence of > 50% in patients with CKD stage 4 or 5.

Evaluation

• Perform complete blood count which includes blood cell counts and evaluation of red cell indices to assess degree of anemia (Strong recommendation).
  • Anemia in adults is defined by World Health Organization as a hemoglobin (Hb) of < 11 g/dL (110 g/L) in pregnant women, < 12 g/dL (120 g/L) in nonpregnant women, and < 13 g/dL (130 g/L) in men.
  • Anemia is typically normocytic unless other conditions such as, iron deficiency, inherited hemoglobinopathies, or other nutrient deficiencies are also present.
  • Reticulocyte count is low due to impaired bone marrow response to anemia.
• Investigate cause of anemia (regardless of severity of CKD or renal replacement therapy requirement) when Hb level is < 11 g/dL (110 g/L) or < 10.5 g/dL (105 g/L) if the patient is < 2 years old or symptoms of anemia develop.
  • Assessment of iron stores and iron availability for erythropoiesis:
    • Perform iron studies, which should include serum ferritin measurement to assess iron stores and ≥ 1 of (Strong recommendation):
      • transferrin saturation (TSAT)
      • percentage of hypochromic red blood cells (%HRC)
      • reticulocyte Hb count (CHr) or equivalent (reticulocyte Hb equivalent [Ret-He])
    • In select cases, bone marrow exam is recommended, especially when there is a suspicion that high serum ferritin value (> 1,200 mcg/L) may not accurately represent iron storage pool (Strong recommendation).
  • Measure glomerular filtration rate (GFR) to assess kidney function. Consider CKD as a cause of anemia in patients with GFR of < 60 mL/minute/1.73 m² (< 45 mL/minute/1.73 m² in patients with diabetes) if no other causes have been identified (such as blood loss or nutritional deficiency) (Weak recommendation).
  • Investigate for other causes of anemia especially if there are ≥ 1 of:
    • severity of the anemia that is disproportionate to kidney function deficit
    • acute drop in hemoglobin over day to weeks
    • evidence of iron deficiency:
      • If iron deficiency is present in patients with CKD and anemia, careful clinical assessment should be performed prior to initiation of therapy.
      • In patients with no obvious source of blood loss, iron deficiency obligates looking for occult forms of blood loss.
    • evidence of hemolysis
    • evidence of bone marrow disorder as manifest by leukopenia and/or thrombocytopenia
• Routine measurement of erythropoietin level is not recommended (Strong recommendation).

Management

• Iron therapy:
  • The goal of iron therapy is to treat iron deficiency and prevent iron deficiency in patients on erythropoietin-stimulating agents (ESAs), and to minimize dose of ESA or avoid use altogether.
  • In adults, replete with iron to achieve ≥ 1 of:
    • increase in Hb concentration without starting ESA treatment in a patient not on iron or erythropoietin-stimulating agent (ESA) therapy and TSAT is ≤ 30% and ferritin is ≤ 500 mcg/L (Weak recommendation)
    • increase in Hb concentration or decrease in ESA dose in patient on ESA therapy and TSAT is ≤ 30% and serum ferritin is ≤ 500 mcg/L (Weak recommendation)
    • %HRC < 6% / CHr > 29 pg / serum ferritin > 100 mcg/L and TSAT > 20% (Strong recommendation)
  • In children, replete iron if ≥ of 1:
    • TSAT is ≤ 20% and serum ferritin is ≤ 100 mcg/L, if not receiving iron or ESA therapy (Strong recommendation)
    • to maintain TSAT > 20% and serum ferritin > 100 mcg/L, if receiving ESA therapy but not already on iron supplementation (Strong recommendation).
  • Choice of oral or IV depends on severity of iron deficiency, previous response and side effects, availability of venous access, need to initiate ESA therapy, and if the patient is on hemodialysis (most patients on hemodialysis will require IV iron).
  • Iron therapy is not suggested if serum ferritin is > 800-1,200 mcg/L.
• Erythropoiesis-stimulating agent (ESA):
  • ESA treatment aims to partially correct anemia rather than completely correct anemia to reduce risk of cardiovascular events and other adverse events.
  • All correctable causes of anemia (including iron deficiency and inflammation) should be addressed before initiation of ESA treatment.
  • Initiation of ESA therapy:
    • Adults:
      • In patients not on dialysis, consider initiating ESA if Hb level is < 10 g/dL (100 g/L) (Weak recommendation).
      • In patients on hemodialysis or peritoneal dialysis, consider ESA therapy to prevent Hb level from dropping to < 9 g/dL (90 g/L) by initiating ESA therapy at Hb 9-10 g/dL (90-100 g/L) (Weak recommendation).
    • In pediatric patients, consider making decision regarding Hb level at which ESA therapy is to be initiated on a case-by-case basis (Weak recommendation).
    • Suggested initial dosing for commonly used ESAs:
      • Epoetin alfa (first generation short-duration of action ESA):
        • Starting dose for adults with CKD is 50-100 units/kg once a week when administered subcutaneously in patients not on hemodialysis or 3 times weekly when administered IV for patients on hemodialysis.
        • Starting dose for pediatric patients (age ≥ 1 month) with CKD is 50 units/kg IV or subcutaneously 3 times weekly.
      • Darbepoetin alfa (second generation longer-duration of action ESA):
        • Starting dose for adults on hemodialysis is
        • 0.45 mcg/kg IV per week for patients on or subcutaneously every 2-4 weeks.
        • Starting dose for adults with CKD not on hemodialysis is 0.45 mcg/kg subcutaneously every 4 weeks.
        • Starting dose for pediatric patients on hemodialysis is 0.45 mcg/kg IV or subcutaneously once weekly or if not on dialysis, 0.75 mcg/kg IV or subcutaneously every 2 weeks.
      • see Prescribing information for additional information, including dosing of other ESAs
  • Route of administration:
    • In patients not on dialysis or on peritoneal dialysis, use subcutaneous route.
    • In patients on hemodialysis, consider IV or subcutaneous ESA administration but IV route may be more convenient (Weak recommendation). However, it is now standard practice to administer ESA subcutaneously even in dialysis units.
  • Target Hb:
    • In adults, consider Hb target of 10-12 g/dL (100-120 g/L) (Weak recommendation).
    • In pediatric patients, recommended target Hb varies by guideline organization, but ranges from 9.5 g/dL to 12 g/dL (95-120 g/L), depending on the age.
  • Monitoring:
    • During initial stages of ESA therapy, Hb level should be measured at least monthly.
    • During maintenance stage of ESA therapy, Hb level should be measured:
      • at least every 3 months for patients with nondialysis-dependent CKD
      • at least monthly for patients on dialysis
  • Dose adjustment:
    • In adults, adolescents (age 14-17 years, and children aged ≥ 2 years, consider dose adjustment when Hb level is < 10.5-11.5 g/dL (105-115 g/L) (Weak recommendation).
    • In children aged < 2 years, ESA dose should be adjusted before Hb level reaches outside of target to help maintain Hb concentration within the target range.
    • Suggested dose adjustment strategy for most ESAs (see Prescribing information for additional guidance):
      • Increase in dose should not occur more frequently than once every 4 weeks but dose reduction may occur more frequently. Frequent dose adjustments should be avoided.
      • In patients with rapid rise in Hb (for example, > 1 g/dL [10 g/L] in any 2-week span), consider reducing dose by 25% or more as needed.
      • In Patients with inadequate response (Hb increase < 1 g/dL [10 g/L] after 4 weeks), consider increasing dose by 25%.
• Blood transfusion:
  • Avoid red blood cell transfusion as much as possible, especially if renal transplantation is an option, to minimize risk of alloimmunization (Strong recommendation).
  • Consider transfusion only in urgent situations such as requiring rapid correction of anemia to stabilize patient (for example, in case of acute hemorrhage or prior to surgery) (Weak recommendation).