617 zinc intake and may be associated with a micro cytic anemia and leukopenia, and is correct able with supplementation [71] Anemia with concurrent lymphopenia or thrombocytopenia should prompt an ev[.]
32 Management of Anemia in Children Receiving Chronic Dialysis zinc intake and may be associated with a microcytic anemia and leukopenia, and is correctable with supplementation [71] Anemia with concurrent lymphopenia or thrombocytopenia should prompt an evaluation for malignancy, autoimmune disease, or drug toxicity Uremia itself contributes to anemia in children on dialysis Accumulated uremic toxins and associated oxidative stress can induce changes in erythrocyte cell membranes and cytoskeletons which promote hemolysis and a shortened cell life span, with red cell survival time decreased by as much as 50% compared to healthy subjects [72] Thus, inadequate dialysis may contribute to the risk for anemia In adults on chronic hemodialysis, more hours of dialysis per week have been associated with higher hemoglobin levels and a lower required ESA dose [73, 74] Erythropoietin Levels EPO deficiency is a diagnosis of exclusion In the setting of normal renal function, plasma EPO levels increase exponentially with decreasing hemoglobin, and values may rise from the normal range of approximately 15 units/liter to as high as 10,000 units/liter [9] Thus, measuring plasma levels of EPO in children with kidney disease is not useful to clarify the contribution of relative EPO deficiency to anemia, because even if EPO levels are detectable above the normal range, they may still be inappropriately low for the degree of anemia present Laboratory Assessment of Iron Status In clinical practice, the most commonly utilized biomarkers of stored iron remain serum ferritin and transferrin saturation (TSAT) KDIGO recommends iron supplementation in children on dialysis to maintain TSAT >20% and ferritin >100 ng/mL and recommends IV iron supplementation in children on hemodialysis [28] Both ferritin and TSAT have limited sensitivity and specificity to predict bone marrow iron stores and erythropoietic response to iron supplementation 617 Distinguishing hepcidin-mediated impaired iron trafficking from absolute iron deficiency anemia presents a clinical challenge, as both disorders are characterized by a microcytic anemia with low reticulocyte counts, decreased serum iron concentration, and low transferrin saturation However, serum ferritin levels can be helpful in distinguishing the disorders; absolute iron deficiency is associated with a low ferritin concentration, while impaired trafficking is characterized by normal or elevated serum ferritin, reflecting iron sequestration in the reticuloendothelial system In contrast, in patients with functional iron deficiency on ESA therapy, the rate of enteral iron absorption or release from reticuloendothelial cells is inadequate to meet the demands for erythropoiesis; these patients often have low TSAT values with normal or high levels of ferritin, suggesting that patients may benefit from treatment with intravenous iron [75, 76] The limitations of serum ferritin as a marker of accessible stored iron are, however, well established, including higher ferritin levels being associated with lower hemoglobin levels and ferritin serving as an acute phase reactant [33, 77] Although ferritin is measured in serum, its function is as an intracellular iron-storage protein Although we assume in clinical practice that the serum concentrations reflect some steady-state “leakage” of intracellular ferritin, the process by which ferritin enters the circulation is not well understood [76] TSAT has recognized limitations as well, including diurnal fluctuations and reduction in the setting of malnutrition and chronic disease [78] There is thus a need for diagnostic tests which more accurately predict the need for or response to iron therapy A study in pediatric dialysis patients found that the reticulocyte hemoglobin content (Ret-He), which is not an acute phase reactant and reflects iron availability for incorporation into reticulocytes over the previous 2–4 days, performed better than either ferritin or TSAT to distinguish between iron deficiency and suboptimal ESA dosing [78] Thus, Ret-He may be an attractive alternative indicator of iron status in clinical practice, although it remains limited currently as it is only measured by flow cytometry [78] Percentage of hypochro- M A Atkinson and B A Warady 618 mic red blood cells (% HRC) is another laboratory marker of iron status that can assess iron availability for incorporation into red cells % HRC >6% suggests poor hemoglobin production due to iron deficiency and may be helpful in distinguishing patients with elevated ferritin levels who may benefit from additional, potentially intravenous iron supplementation [79] %HRC also requires flow cytometry for measurement, which may limit its availability in clinical laboratories which measure hemoglobin by electrical impedance and not have access to the equipment or software required for testing [80] oal Hemoglobin Levels in Children G on Dialysis There have been a series of clinical practice guidelines for the management of anemia in dialysis patients published over the last 10–15 years, which have included recommendations for target hemoglobin levels In 2007, the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI), in response to data from adult trials in which the use of ESAs to target higher hemoglobin levels was associated with adverse outcomes, published a revised recommendation advising that in patients receiving an ESA, the hemoglobin target should generally be in the range of 11–12 g/dL and should not exceed 13 g/dL [81] Subsequently, the KDIGO guidelines were created from systematic literature searches and supplemental evidence from October 2010 to March 2012 They did not recommend a hemoglobin threshold for initiation of ESAs in pediatric patients, but recommended that providers consider all potential benefits and harms prior to starting ESA therapy For pediatric patients on ESAs, the target hemoglobin recommended was 11–12 g/dl [28] The National Institute for Health and Care Excellence (NICE) in the United Kingdom last updated its guidelines in 2015 For patients who are on ESAs, the recommended hemoglobin target was 10 to 12 g/dL in children >2 years old and adults and 9.5–11.5 g/dL in children younger than 2 years old [82] In terms of initiation of ESA treatment, a common threshold in clinical practice is a hemoglobin 13 g/dL also demonstrated an increased risk for stroke [102] Consequently, in 2011 the US FDA changed the ESA product labeling to recommend the lowest possible ESA dose to prevent red blood cell transfusions and that the dose should be reduced or interrupted for hemoglobin >11 g/dL [103] However, this label change did not distinguish between pediatric and adult CKD patients Although no such randomized controlled trials have been conducted in pediatric patients, observational data has demonstrated that higher ESA doses are associated with an increased risk for mortality in children on chronic dialysis [33, 38, 104] No clinical trials in adults have identified whether the higher hemoglobin level or the higher ESA dose specifically contributes to the increased risk for adverse outcomes, but a pro- M A Atkinson and B A Warady spective study in adults on dialysis found that those with naturally occurring higher hemoglobin levels >12 g/dL were not at increased risk for mortality [105, 106] In a similar study conducted in ESA-treated children on dialysis, Rheault et al demonstrated that hemoglobin level >12 g/dL was not associated with an increased risk for either mortality or hospitalization [40] The specific mechanisms for the adverse cardiovascular outcomes observed with ESA use have yet to be defined, but may include trophic effects on vascular endothelial or smooth muscle cells [107] Greater blood viscosity at higher hemoglobin concentrations may also contribute by increasing vascular endothelial wall stress [1] While exposure to supraphysiologic EPO concentrations may have detrimental off-target effects, the disparate burden and duration of cardiovascular disease and other comorbidities including diabetes in adults compared to children may result in the risk for such ESA-associated outcomes being substantially lower in children on dialysis However, given the lack of evidence, similar levels of caution are applied to ESA use in children Other reported side effects of ESAs include hypertension, which seems to be independent of achieved hemoglobin level, and increased risk for vascular access thrombosis [108] Novel Erythropoiesis-Stimulating Agents Novel ESA-independent CKD-related anemia therapies are in varying stages of development Small-molecule hypoxia-inducible factor (HIF) stabilizers/prolyl hydroxylase domain inhibitors modulate HIF-controlled gene products and are capable of inducing endogenous erythropoietin production even in the setting of decreased renal oxygen consumption, likely by increasing hepatic erythropoietin production [12] They have been shown to increase hemoglobin and decrease hepcidin in adult trials, but trials have not yet been conducted in children [109–111] Inhibitors of HIF can be administered orally in highly bioavailable preparations Investigational strategies for direct hepcidin modulation include monoclonal antibodies aimed directly at hepcidin or at the ... components to those of the licensed products emerged and were approved in the United States and Europe; this process will likely continue, 32 Management of Anemia in Children Receiving Chronic Dialysis... periods of time and thus may cause higher- than-intended hemoglobin levels in clinical practice This can be avoided by using lower starting doses and making less frequent dose adjustments than... every or 4 weeks) to be non-inferior to weekly dosing regimens in maintaining hemoglobin [100, 101] This could be an attractive option for allowing less-frequent ESA dosing in regions where darbepoetin