Chapter 445 Anemia of Chronic Disease and Renal Disease
445.1 Anemia of Chronic Disease
The anemia of chronic disease (ACD), also referred to as “anemia of inflammation,” is found in conditions where there is chronic immune activation. This anemia thus complicates a number of systemic diseases associated with infection (e.g., HIV, bronchiectasis, osteomyelitis) or autoimmunity (e.g., rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease) as well as some hematologic and solid malignancies. Despite diverse underlying causes, the erythroid abnormalities are similar, although incompletely understood. Erythrocytes have a mildly decreased life span, felt to be, at least in part, secondary to erythrophagocytosis by activated macrophages. However, it is the relative failure of the bone marrow to respond adequately to the increased destruction that perpetuates the anemia. Erythropoietin (EPO) levels are modestly increased but are often inadequate. More importantly, inflammation induces a blunted response and relative resistance to EPO.
Another contributing factor is decreased iron availability. Inflammation causes iron retention by the reticuloendothelial system, creating limited availability for erythropoiesis. The serum iron is low, although tissue macrophages have abundant iron. Iron availability is further compromised by decreased intestinal absorption. One hypothesis has been that the underlying medical conditions cause the release of inflammatory cytokines, interleukin-1 (IL-1), tumor necrosis factor (TNF), and interleukin-6 (IL-6), which lead to the production of interferon-β (IFN-β) and interferon-γ (IFN-γ). This hypothesis is supported by the observation that IFN-β and IFN-γ cause a disorder in experimental animals similar to the anemia of chronic disease. IL-6 induces the production of hepcidin, an iron-regulating protein. Hepcidin, which is made in the liver, blocks the release of iron from macrophages and also decreases intestinal iron absorption. Its increased production and the associated decrease in iron availability lead to an impairment of heme synthesis and ultimately to decreased proliferation of erythroid precursors.
Although the important symptoms and signs associated with anemia of chronic disease are those of the underlying disease, the mild to moderate anemia can affect the patient’s quality of life.
Hemoglobin concentrations are generally 6-9 g/dL. The anemia is usually normochromic and normocytic, although some patients have modest hypochromia and microcytosis. Absolute reticulocyte counts are normal or low, and leukocytosis is common. The serum iron level is low, without the increase in total iron-binding capacity (serum transferrin) that occurs in iron deficiency. This pattern of low serum iron and low to normal iron-binding protein (serum transferrin) is a regular and valuable diagnostic feature. The serum ferritin level may be elevated. The bone marrow has normal cellularity; the RBC precursors are low to adequate, marrow hemosiderin may be increased, and granulocytic hyperplasia may be present. A common clinical challenge is to identify concomitant iron deficiency in patients with an inflammatory disease (Chapters 441 and 449). A trial of iron therapy might help resolve the issue, although there may be no response when inflammation persists, caused by the underlying disease.
Anemia of chronic disease does not respond to iron unless there is concomitant deficiency. Transfusions raise the hemoglobin concentration temporarily but are rarely indicated. If the underlying systemic disease can be controlled, the anemia will resolve. Recombinant human EPO can increase the hemoglobin level and improve activity and the sense of well-being. In this instance, treatment with iron is usually necessary for an optimal EPO effect.
Andrews NC. Anemia of inflammation: the cytokine-hepcidin link. J Clin Invest. 2004;113:1251-1253.
Cazzola M, Ponchio L, de Benedetti F, et al. Defective iron supply for erythropoiesis and adequate endogenous erythropoietin production in the anemia associated with systemic-onset juvenile chronic arthritis. Blood. 1996;87:4824-4830.
Ganz T. Molecular pathogenesis of anemia of chronic disease. Pediatr Blood Cancer. 2006;46:554-557.
Means RT. Hepcidin and anaemia. Blood Rev. 2004;18:219-225.
Weiss G. Iron metabolism in the anemia of chronic disease. Biochim Biophys Acta. 2009;1790:682-693.
Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352:1011-1023.
445.2 Anemia of Renal Disease
Anemia is common in children with chronic renal disease. The anemia is usually normocytic, and the absolute reticulocyte count is normal or low. Although the anemia seen in chronic renal disease shares some features with the anemia of chronic disease, its major cause is decreased EPO production by diseased kidneys. The second important cause of the anemia is absolute and/or functional iron deficiency due to chronic blood loss (from blood sampling, surgeries, and dialysis) as well as disturbances in the iron metabolic pathway. In adults, lower glomerular filtration rate (GFR) has been associated with lower hemoglobin concentration, and hemoglobin has been reported to decline below a GFR threshold of 40-60 mL/min/1.73 m2. In children with chronic kidney disease hemoglobin levels decline as the GFR decreases below 43 mL/min/1.73 m2.
There are limited data regarding hemoglobin target levels in children with chronic kidney disease, and the FDA hemoglobin level of 10-12 g/dL recommended for adults has been suggested for children as well.
Recombinant human EPO is used to treat anemia in children with renal failure. Dosing varies with age and dialysis modality. Darbepoetin (a synthetic form of EPO with fewer N-linked oligosaccharide chains) appears to be equally effective and has the benefit of less-frequent dosing as a consequence of a longer half-life. Iron therapy is also needed, because EPO treatment demands additional iron for hemoglobin synthesis. Iron supplementation can reduce the EPO dose needed to maintain the target hemoglobin.
Production of neutralizing antibodies to EPO is an uncommon but serious complication that will result in a refractory red cell aplasia. Treatment of this complication with an agonist peptide to the EPO receptor can correct this antibody-induced pure red cell aplasia.
Fadrowski JF, Pierce CB, Cole SR, et al. Hemoglobin decline in children with chronic kidney disease: baseline results from the chronic kidney disease in children prospective cohort study. Clin J Am Soc Nephrol. 2008;3:457-462.
Keithi-Reddy SR, Singh AK. Hemoglobin target in chronic kidney disease: a pediatric perspective. Pediatr Nephrol. 2009;24:431-434.
Koshy SM, Geary DF. Anemia in children with chronic kidney disease. Pediatr Nephrol. 2008;23:209-219.
Macdougall IC, Rossert J, Casadevall N, et al. Peptide-based erythropoietin-receptor agonist for pure red-cell aplasia. N Engl J Med. 2009;361:1848-1855.