623 inflammatory stimuli that induce its production, including IL 6 [111] Fully human anti hepcidin antibodies have been successfully developed and applied in animal models [112] ESA Hyporesponsivenes[.]
32 Management of Anemia in Children Receiving Chronic Dialysis inflammatory stimuli that induce its production, including IL-6 [111] Fully human anti-hepcidin antibodies have been successfully developed and applied in animal models [112] ESA Hyporesponsiveness: Definition and Risk Factors There will be patients who, despite iron supplementation combined with escalating ESA dosing, fail to increase hemoglobin levels above 10 g/ dL. KDIGO defines initial ESA hyporesponsiveness as no increase in hemoglobin concentration from baseline after the first month of appropriate weight-based dosing and acquired ESA hyporesponsiveness as a requirement for two increases in ESA doses up to 50% beyond the dose which they had previously required to maintain a stable hemoglobin concentration [28] An alternative definition is a persistent hemoglobin deficit after 3 months of high-dose ESA treatment (rHuEPO in excess of 400 units/kg weekly or darbepoetin alfa in excess of 1 μg/kg weekly) [67, 113] In the IPPN registry, ESA resistance and escalated ESA dosing have been associated with inflammation, fluid retention, and hyperparathyroidism [33] The observational association between higher ESA doses and mortality in pediatric patients may, in turn, reflect the impact of chronic inflammatory processes which negatively impact patient survival, rather than a direct ESA effect on the risk for death While ESA hyporesponsiveness may be chronic, it can also be seen in the context of shorter-term clinical events such as infections or surgical procedures which may negatively impact the response to ESA therapy Thus, the potential risks and benefits of escalation in ESA dose vs administration of intravenous iron vs red blood cell transfusion in this setting must be assessed for individual patients [28] Attention should also be paid to determining whether affected patients may be suffering from vitamin or mineral deficiencies resulting from malnutrition Other potential causes of ESA hyporesponsiveness include the following: 623 one Disease Secondary B to Hyperparathyroidism Severe hyperparathyroidism can contribute to anemia and ESA hyporesponsiveness due to decreased bone marrow production of red blood cells due to myelofibrosis [96, 114, 115] Medications There are a variety of medications that can contribute to anemia in dialysis patients including, but not limited to, ACE inhibitors and anti- metabolites causing bone marrow suppression A review of the medication list for potential medications contributing to anemia should be undertaken for any dialysis patient with ESA-resistant anemia Aluminum Toxicity Although aluminum-based compounds are used far less frequently in the management of hyperphosphatemia than in the past, awareness of aluminum toxicity is important Chronic use of aluminum-based antacids and phosphate binders remains the most common cause of aluminum toxicity in patients with ESKD. In animal studies, aluminum has been shown to induce partial resistance to EPO and to increase heme oxygenase activity, which subsequently increases destruction of the heme protein [116, 117] Hypervolemia Patients with less residual urine output and who are clinically judged to be fluid-overloaded demonstrate lower hemoglobin levels, suggesting that some portion of treatment-resistant anemia may in fact be due to the chronic dilution of the red cell mass in an expanded extracellular volume [33] This should be addressed with more effective ultrafiltration M A Atkinson and B A Warady 624 Anti-rHuEPO Antibodies Iron Therapy ESA-induced pure red cell aplasia (PRCA) is an increasingly rare hematologic disorder that was first described in the late 1990s PRCA is characterized by a severe and progressive normocytic anemia, reticulocytopenia, and the almost complete absence of erythroid precursors in the bone marrow, with affected patients becoming transfusion dependent [118] ESA-induced PRCA is secondary to the development of neutralizing antibodies which block the interaction between an ESA (including epoetin alfa or beta, darbepoetin alfa, or endogenous EPO) and its receptor [118] Most initial cases of ESA-induced PRCA were seen in countries where epoetin alfa formulated with a polysorbate 80 stabilizer was administered to CKD patients subcutaneously; regulatory advisories have subsequently discouraged this practice [119] KDIGO recommends iron supplementation in children on dialysis to maintain TSAT >20% and ferritin >100 ng/mL and recommends intravenous iron supplementation in children on hemodialysis [28] Red Blood Cell Transfusion Despite best efforts in anemia management, and often in the setting of ESA hyporesponsiveness, patients sometimes require packed red blood cell transfusion The decision to transfuse should not be based on an arbitrary hemoglobin level, but rather guided by symptoms and after weighing the specific risks and benefits for the individual patient Red blood cell transfusions are associated with an increased risk for the development of human leukocyte antigen (HLA) antibodies In adults, leukoreduction of blood products is an ineffective means to decrease HLA sensitization, and red cell transfusions lead to clinically significant increases in HLA antibody strength and breadth [120, 121] These antibodies serve as a barrier to future transplantation and may adversely affect graft outcomes [120, 121] More studies are needed to define the risks associated with red cell transfusion in children with regard to HLA sensitization and graft outcomes Oral Iron Supplementation Most children on dialysis will require iron supplementation as part of their anemia treatment plan in order to maintain hemoglobin levels and replete iron stores Children on hemodialysis in particular may have chronic blood loss via the dialysis circuit which exacerbates iron deficiency Enteral iron supplementation is relatively inexpensive, highly available, and generally safe and efficacious in children with chronic kidney disease, although GI side effects of nausea or constipation are sometimes reported Although true intolerance is relatively rare, it may be a contributing factor to the poor adherence that may arise to prescribed oral supplementation In addition, co-administration of iron with phosphate binders or antacids can limit absorption due to changes in gastric pH [64] The usual dosing range for oral iron supplementation is 3–6 mg/kg/day of elemental iron, either daily or divided into two daily doses The most commonly available oral iron preparations come in ferrous (Fe2+) or ferric (Fe3+) forms, including ferrous sulfate and ferric iron polymaltose complexes [16] Ferrous sulfate has better bioavailability (10–15%) than ferric iron and is available in prolonged release forms [16] Some ferric polymaltose complex formulations are available with added vitamins C, B12, and folic acid to enhance iron absorption and replete other vitamins associated with red blood cell production However, there is no evidence that ferric iron formulations are superior to ferrous preparations for oral supplementation in children on dialysis 32 Management of Anemia in Children Receiving Chronic Dialysis Intravenous Iron Supplementation Children on dialysis often benefit from iron preparations administered intravenously due to the poor enteral absorption or poor tolerance associated with oral administration There are an increasing number of available iron preparations for clinicians opting for intravenous therapy (Table 32.4) Early IV iron compounds were formulated as inorganic iron oxyhydroxide complexes, which could result in the release of labile iron directly into the plasma leading to the formation of highly reactive free radicals associated with severe toxicity, including hypotension Newer preparations surround the iron oxyhydroxide core with carbohydrate shells of different sizes and polysaccharide branch characteristics [123] The shell characteristics determine how long the iron remains circulating, with larger molecular weight formulations such as iron dextran resulting in longer plasma residence, while products with smaller shells are more labile and likely to release iron directly into the plasma before it can be metabolized in the reticuloendothelial system [124–126] Intravenous iron therapy can be delivered as a loading phase, using consecutive doses 625 to replete iron stores, or as smaller maintenance doses given weekly IV iron has been shown to be effective in repleting iron stores in children In 2005, Gillespie and Wolf published a meta-analysis that combined clinical data on IV iron use in children on HD [127] They evaluated nine studies including eight cohort studies and one prospective trial with historical controls, and they showed increased hemoglobin, ferritin, and transferrin saturation levels and reduced use of ESAs with IV iron use In 2004, Warady et al performed an RCT to examine the preferential route of iron administration for children The authors prospectively randomized 35 iron-replete children