1. What causes anemia in patients with kidney disease?

The anemia of chronic kidney disease (CKD) is primarily caused by deficiency of erythropoietin (EPO). The kidneys are the major source of EPO, and as kidney function declines, production of EPO declines proportionately. Several other factors decrease red blood cell (RBC) life span from the normal 120 days to approximately 70–80 days in patients with CKD. These include:

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  RBC trauma due to microvascular disease from diabetes or hypertension

  
  
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  Blood loss from hemodialysis (HD)

  
  
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  Increased incidence of gastrointestinal bleeding from peptic ulcer disease and angiodysplasia of the bowel

  
  
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  Increased oxidative stress

2. What are the adverse effects of anemia?

Anemia leads to decreased oxygen-carrying capacity of the blood and decreased delivery of oxygen to tissues. This results in fatigue (both with exercise and at rest), decreased cognitive function, loss of libido, and decreased sense of well-being. The increased workload on the heart may lead to left ventricular hypertrophy. Observational studies of dialysis patients in the 1990s demonstrated decreased hospitalizations and mortality among patients with higher hemoglobin (Hb) levels, but these may have been confounded by comorbidities that decreased Hb levels and also led to poorer outcomes. Randomized controlled trials (RCTs) of erythropoiesis-stimulating agents (ESAs) to raise Hb levels have not led to improved outcomes or consistently improved quality-of-life (QOF; Table 19.1 and question 17).

3. How does one evaluate anemia in a patient with CKD?

EPO deficiency is a diagnosis of exclusion, and checking EPO levels in patients with CKD is generally not indicated. The routine evaluation of such patients should include:

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  Measurement of RBC indices

  
  
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  Reticulocyte count

  
  
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  Transferrin saturation (TSAT)

  
  
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  Serum ferritin

  
  
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  Stool for occult blood testing

If these tests reveal no alternative cause of anemia, it can be presumed that the anemia is primarily due to EPO deficiency.

4. How does one interpret TSAT?

TSAT is calculated by dividing the serum iron level by the total iron-binding capacity. The total iron-binding capacity reflects circulating transferrin, the major iron-binding protein in plasma. TSAT correlates with the amount of iron available for erythropoiesis, because only circulating iron is available to the bone marrow for incorporation into RBC. Patients with TSAT <20% have decreased iron delivery to the erythroid marrow, but supplemental iron can only correct this if the iron is effectively released from storage sites to the transferrin carrier protein.

5. How does one interpret the serum ferritin?

The serum ferritin level correlates with storage iron, located primarily in the reticuloendothelial system. Interpretation of serum ferritin levels is confounded by ferritin being an acute-phase reactant and rising with acute or chronic inflammation. In patients with CKD, serum ferritin level <100 ng/mL correlates with a deficiency in storage iron; such patients almost invariably respond to supplemental iron therapy.

6. What is functional iron deficiency?

Functional iron deficiency is a bone marrow iron supply-demand mismatch in a patient with normal or elevated iron stores. It can occur in the setting of inflammation when elevated hepcidin levels impair the release of storage iron to circulating transferrin. It can also occur in patients treated with pharmacologic doses of ESAs when the bone marrow is stimulated to produce RBCs faster than the transferrin carrier protein can deliver adequate iron substrate. In such patients, TSAT tends to be low or low-normal, whereas serum ferritin level may be normal or even high. The operative definition of functional iron deficiency is based on a response to intravenous (IV) iron supplementation characterized by either an increase in Hb or a decrease in ESA requirements to achieve the same Hb.

7. What is the role of IV iron?

Studies have demonstrated that functional iron deficiency is common in patients with end-stage kidney disease (ESKD) who are treated with ESAs and that IV iron supplementation decreases ESA requirements by 20% to 25%. In CKD patients with iron deficiency anemia not receiving ESAs, 1 gm IV iron generally raises the Hb 1 gm/dL. For iron-deficient, non-hemodialysis patients who fail oral iron therapy, IV iron can be given in larger doses over fewer treatments for patient convenience and vein sparing. In HD patients, IV iron is generally administered in smaller, more frequent doses through the dialysis circuit.

8. What are the adverse effects of IV iron?

IV iron may be associated with acute reactions such as nausea/vomiting and hypotension, which are likely related to free iron in the preparation. IV iron may be associated with allergic or anaphylactic reactions to the carbohydrate that binds the iron. There have been concerns regarding the long-term effects of IV iron administration, including iron accumulation in tissues, oxidative damage to endothelial cells, and increased susceptibility to infection. Retrospective studies in HD patients have shown an association with adverse clinical outcomes and monthly IV iron doses over 400 mg, but it is impossible to exclude confounding by indication. In a prospective study comparing IV and oral iron in patients with nondialysis patients with iron deficiency anemia, patients receiving IV iron had a 2.51 higher incidence of cardiovascular events and a 2.12 increased risk of hospitalization due to infection over a 2-year follow-up period. This supports the Kidney Disease Improving Global Outcomes recommendation that in patients with nondialysis CKD and iron deficiency anemia, a 1- to 3-month trial of oral iron therapy be considered prior to initiating IV iron therapy.