Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + ANEMIA OF CHRONIC RENAL DISEASE Download Section PDF Listen +++ +++ Etiology and Pathogenesis ++ Reduced renal production of erythropoietin (EPO) and inflammation and hepcidin-induced iron restriction are the most significant factors in the development of anemia in renal insufficiency. A modest reduction in red cell life span occurs in uremia, probably as a result of metabolic impairment of red cells. Iron deficiency occurs from blood loss in dialysis tubing, laboratory testing, or external bleeding, sometimes as a result of uremia-induced platelet dysfunction. Furthermore, increased hepcidin blocks iron absorption in the gut and iron release from macrophage stores (in part ameliorated by therapy with EPO or other erythropoiesis-stimulating agents [ESAs]). The plasma volume varies widely in renal failure, with consequent variations in the hemoglobin concentration. +++ Clinical and Laboratory Features ++ The anemia is normocytic and normochromic with a reduced blood concentration of reticulocytes relative to the degree of anemia. Gastrointestinal and gynecologic bleeding occurs in one third to one half of all patients with chronic renal failure. Acanthocytes or schistocytes may be seen on the blood film. Total and differential leukocyte count and platelet count are usually normal. Platelet function is abnormal, in relationship to the degree of uremia. Cellularity and blood cell maturation sequences in the marrow are normal. Despite the anemia, there is no compensatory erythroid hyperplasia. +++ Therapy, Course, and Prognosis ++ Replacement therapy with EPO or other ESA corrects the anemia in nearly all patients. Amelioration of the anemia improves the quality of life for uremic patients. EPO and iron are usually given intravenously in dialysis patients. A target hemoglobin level of 10 to 11 g/dL is recommended. Adequate iron and folate supply should be maintained to achieve an optimal response with ESA therapy. If transferrin iron saturation is less than 30% and ferritin is less than 300 ng/mL, intravenous iron therapy usually increases hemoglobin levels or decreases ESA doses required, whether or not patients are on hemodialysis. Long-acting ESA preparations (eg, darbepoetin) given subcutaneously may be more convenient and, perhaps, safer for patients not undergoing dialysis because plasma ESA levels are lower but more sustained. Complications of EPO therapy include hypertension, seizures, increased cardiovascular morbidity and mortality and thrombosis of shunts; hemoglobin levels of greater than 11 g/dL should be avoided. Blood pressure should be carefully monitored throughout the treatment. A small number of patients do not respond to EPO or require higher doses, most often because of iron deficiency, infection, or inflammation. Common causes of EPO hyporesponsiveness are listed in Table 5–1. Chronic hemodialysis may improve the platelet dysfunction. ++Table Graphic Jump LocationTABLE 5–1Common Causes of Erythropoietin HyporesponsivenessView Table||Download (.pdf) TABLE 5–1 Common Causes of Erythropoietin Hyporesponsiveness Infection, inflammation Cancer, administration of chemotherapy or radiotherapy Hyperparathyroidism Iron deficiency Folate deficiency Sickle cell anemia Thalassemia Other hemolytic anemia Myelodysplastic syndrome + ANEMIA OF INFLAMMATION Download Section PDF Listen +++ +++ Definition ++ Anemia of inflammation (AI) is associated with (1) infection or (2) inflammatory or neoplastic disease. AI is also referred to as anemia of chronic disease. In nonhospitalized patients, 1 to 2 months of sustained disease is required for anemia to develop. During critical illness, anemia similar to AI can develop much more rapidly, accelerated by frequent diagnostic phlebotomy, other occult blood loss, or suppression of erythropoiesis by high concentrations of circulating inflammatory cytokines and shortening of erythrocyte survival. The hemoglobin level is usually between 7 and 11 g/dL, and in the higher range (10–11 g/dL), it may be asymptomatic. The characteristic laboratory features of AI are listed in Table 5–2. ++Table Graphic Jump LocationTABLE 5–2LABORATORY STUDIES OF IRON METABOLISM IN IRON-DEFICIENCY ANEMIA (IDA) AND ANEMIA OF INFLAMMATION (AI)View Table||Download (.pdf) TABLE 5–2 LABORATORY STUDIES OF IRON METABOLISM IN IRON-DEFICIENCY ANEMIA (IDA) AND ANEMIA OF INFLAMMATION (AI) IDA (n = 48) AI (n = 58) Combination (n = 17) Hemoglobin, g/L 93 ± 16 (96) 102 ± 12 (103) 88 ± 20 (90) MCV, fL 75 ± 9 (75) 90 ± 7 (91) 78 ± 9 (79) Iron, μmol/L (n = 10–40) 8 ± 11 (4) 10 ± 6 (9) 6 ± 3 (6) Transferrin, g/L (n = 2.1–3.4 m, 2.0–3.1 f) 3.3 ± 0.4 (3.3) 1.9 ± 0.5 (1.8) 2.6 ± 0.6 (2.4) Transferrin saturation, % 12 ± 17 (5.7) 23 ± 13 (21) 12 ± 7 (8) Ferritin, μg/L (n = 15–306 m, 5–103 f) 21 ± 55 (11) 342 ± 385 (195) 87 ± 167 (23) TfR, mg/L (n = 0.85–3.05) 6.2 ± 3.5 (5.0) 1.8 ± 0.6 (1.8) 5.1 ± 2.0 (4.7) TfR/log ferritin 6.8 ± 6.5 (5.4) 0.8 ± 0.3 (0.8) 3.8 ± 1.9 (3.2) f, female; m, male; n, normal; TfR, transferrin receptor. Diagnosis was defined by marrow iron stain and appropriate coexisting disease. Patients with a combination of no stainable marrow iron and either coexisting disease or elevated CRP were classified as “COMBINATION.” Normal ranges for this laboratory for males (m) and females (f) are indicated. Measurements are presented as mean ± SD (median). Reproduced with permission from Punnonen K, Irjala K, Rajamäki A: Serum transferrin receptor and its ratio to serum ferritin in the diagnosis of iron deficiency, Blood 1997 Feb 1;89(3):1052-1057. +++ Pathogenesis ++ Inflammation leads to interleukin (IL)-6 production, which induces hepatocyte hepcidin production, which in turn blocks intestinal iron absorption and iron release from macrophages and hepatocytes. Hepcidin binds to ferroportin, the primary cell surface iron exporter, and causes its degradation. Impaired intestinal iron uptake and impaired release of iron from macrophages lead to a low level of serum iron and consequent low saturation of transferrin. Enhanced activity of macrophages increases rate of erythrocyte destruction. Production of EPO is decreased in response to anemia, and the ability of erythroid precursors to respond to EPO is impaired. Both of these are also related to inflammatory cytokine production (IL-1, tumor necrosis factor, interferons). +++ Clinical and Laboratory Features ++ Symptoms of anemia, if mild, are usually overshadowed by symptoms of the primary disease. Common conditions leading to AI are shown in Table 5–3. There is a low reticulocyte index for the degree of anemia. Diagnosis, especially differentiation from iron-deficiency anemia (IDA), depends on laboratory findings (see Table 5–2). — Initially there is normochromic, normocytic anemia; hypochromic, microcytic features develop as anemia progresses. — Low serum iron level and somewhat decreased serum transferrin concentration occur, with decreased percent transferrin saturation. — Level of serum ferritin, an acute phase protein, is elevated. — Marrow contains increased storage iron, but the percentage of normal sideroblasts is decreased. ++Table Graphic Jump LocationTABLE 5–3Common Conditions Associated with Anemia of InflammationView Table||Download (.pdf) TABLE 5–3 Common Conditions Associated with Anemia of Inflammation Category Diseases Associated with Anemia of Inflammation Infection AIDS/HIV, tuberculosis, malaria (contributory), osteomyelitis, chronic abscesses, sepsis Inflammation Rheumatoid arthritis, other rheumatologic disorders, inflammatory bowel diseases, systemic inflammatory response syndrome Malignancy Carcinomas, myeloma, lymphomas Cytokine dysregulation Anemia of aging Source: Williams Hematology, 9th ed, Chap. 37, Table 37–1. +++ Differential Diagnosis ++ Drug-induced marrow suppression or drug-induced hemolysis Iron-deficiency anemia characterized by low serum iron, increased transferrin, decreased transferrin saturation, absent storage iron, and markedly decreased serum ferritin Anemia of chronic renal failure Myelophthisic anemia caused by carcinoma or lymphoma replacing marrow hematopoietic tissue +++ Therapy ++ No treatment may be necessary, other than for the underlying disease. Packed red cell transfusions may be given, if the anemia is symptomatic. Although rarely indicated, EPO therapy may be effective especially when given in combination with intravenous iron, as in anemia of chronic renal disease. — Hypertension and a risk of thrombotic complications occur with use of EPO preparations. ++ For more detailed discussion, see Tomas Ganz:Chap. 37 in Williams Hematology, 9th ed.