Anemia and Its Treatment in Patients With End-Stage Kidney Disease

Erythropoietin Deficiency

The erythropoietic system functions to ensure an adequate supply of erythrocytes and hemoglobin to support the delivery of oxygen to the body’s organs and tissues. When anemia or hypoxia develops, cells recognize oxygen deprivation, and a large group of genes is activated that protect cells from damage due to hypoxia. The process is mediated by stabilization of hypoxia-inducible factors (HIF). In the kidneys, activation of the HIF system plays a particularly important role by regulating the activity of renal erythropoietin-producing (REP) cells.

As the kidneys fail, erythropoietin deficiency develops. The deficiency is relative in that serum levels of erythropoietin are actually higher in CKD than among normal controls but lower than what the levels should be for the degree of anemia ( Fig. 37.1 ). In ESKD, levels become frankly deficient, and most patients will require ESA therapy on a chronic basis.

Iron Deficiency and Inflammation

Most hemodialysis patients become iron deficient, which contributes to the development of anemia. Iron deficiency in these patients is multifactorial in origin. The most apparent cause is that blood (and iron) is lost during every hemodialysis treatment. There is blood retained in the dialysis filter and lines and occasional bleeding that occurs during and after the treatment. This has been estimated to result in 3–10 mg of iron lost per treatment. In addition, frequent blood draws for laboratory testing and blood loss during surgical or interventional procedures adds to negative iron balance. Another source of blood loss is gastrointestinal bleeding, which is more common among dialysis patients and results in episodic worsening of iron deficiency.

In the early years of the ESA era, from 1989–1995, absolute iron deficiency (deficient bone marrow iron stores) was common. For example, in 1993, 54% of U.S. hemodialysis patients had transferrin saturation (TSAT) < 20% and 56% had serum ferritin < 200 ng/mL; 96% of patients had serum ferritin < 800 ng/mL. In contrast, in 2020, as a result of widespread intravenous (IV) iron treatment, 750 ng/mL is approximately the mean U.S. serum ferritin in hemodialysis patients. This indicates that absolute iron deficiency is probably much less common than it had been previously. But, there is still evidence of reduced iron availability, even when adequate iron storage is present. For example, treatment with IV iron may result in increased hemoglobin and reduced ESA dose requirements despite serum ferritin > 500 ng/mL. Clinically apparent iron deficiency in the presence of adequate iron storage is often termed functional iron deficiency .

One reason for functional iron deficiency is that during ESA treatment, even normal iron stores may not supply adequate iron for pharmacologically accelerated erythropoiesis. For example, most humans may have 2000–3000 mg of iron in their bodies. However, only approximately 1/1000 of this, about 2–3 mg, circulates in the bloodstream. During ESA treatment, this may not be enough iron to allow for production of iron-replete erythrocytes.

A second reason for functional iron deficiency relates to the liver-derived protein hepcidin, which serves as the body’s primary regulator of iron homeostasis. During iron overload, hepcidin blocks intestinal iron absorption and release of iron from the body’s storage tissues. In iron-deficient states, hepcidin production is reduced, and iron absorption and release from storage tissues are enhanced. In this way, hepcidin acts to maintain iron homeostasis.

Hepcidin has a secondary function beyond its iron homeostasis function. That is, its production is also increased potently in states of inflammation, independent of iron status. Although the stimulus for hepcidin production is different, the effect is the same, reduced iron availability. In patients with infections causing inflammation, this is an adaptive response that may limit iron available to microorganisms. In dialysis patients, inflammation is often present even without infection. The etiology is unclear, perhaps due to atherosclerosis, infection, uremic toxins, or other factors yet to be identified. As a result of the inflammation, many dialysis patients have reduced iron availability due to hepcidin induction. This form of functional iron deficiency may be maladaptive in that it makes anemia more difficult to treat with no clear positive effect on the patient. Because iron is blocked in storage tissues, serum ferritin may appear normal or high, while measures of circulating iron like TSAT may be normal to low.

Reduced Erythrocyte Survival

Red cell half-life is reduced among patients with advanced kidney disease. The exact magnitude of reduction has been difficult to characterize. While the normal red cell life is approximately 120 days, estimates in dialysis patients have been as low as 40–80 days. The mechanisms behind the reduced erythrocyte lifespan in ESKD patients have not been fully elucidated. Uremic toxins, low-grade hemolysis due to shearing by dialysis needles, and other factors have all been implicated. Shortened erythrocyte half-life (for example, due to hemolysis) can be compensated for in nonuremic individuals through accelerated erythrocyte production. In patients on dialysis, erythropoietin deficiency limits this ability.

Infection

Infection contributes to anemia in ESKD patients. Increases in serum hepcidin and reduced availability of iron for erythropoiesis (as described above) play important roles. In addition, infection by itself may interfere with red cell production. Certain infections can also cause hemolysis, leading to red cell loss. Hemoglobin concentrations often decrease in chronic infections but may decline in acute infections as well. One interesting source of occult infection seen in dialysis patients occurs in previously used but currently nonfunctioning arteriovenous grafts. These infections are hard to detect but may be an important cause of ESA hyporesponsiveness.

Hyperparathyroidism

Hyperparathyroidism contributes to the anemia of CKD, at least in part due to fibrosis of the bone marrow. The best proof of this relationship may be that after parathyroidectomy, anemia tends to improve whether hyperparathyroidism was primary or secondary to other factors. The decision on whether parathyroidectomy is necessary should not be based on anemia but rather on more traditional mineral and bone parameters. Medical treatment of hyperparathyroidism does appear to have a beneficial effect on anemia. Goicoechea et al. treated 28 patients with hyperparathyroidism with IV-activated vitamin D therapy. The result of treatment was an improvement in hemoglobin concentration and reduction in ESA dose requirements.