Iron deficiency anemia is very prevalent in end stage renal disease (ESRD) patients. Patients with ESRD require phosphate binders for hyperphosphatemia and erythropoiesis-stimulating agents (ESAs) and intravenous (IV) iron for anemia. In patients with ESRD, iron deficiency occurs more frequently, because of increased external losses of iron, decreased availability of the body's storage of iron, and perhaps a deficit in intestinal iron absorption.
ESRD patients tend to lose about 3 grams of iron every year from chronic bleeding, frequent phlebotomy and blood trapping in the dialysis apparatus. Total body iron stores of about 20-25 mg are mostly maintained by recycling from senescent red blood cell (RBC) count by macrophages of the reticulo-endothelial system. In addition, to true iron deficiency, many ESRD patients have functional iron deficiency, characterized by impaired iron release from body stores that is unable to meet the demand for erythropoiesis (also called reticuloendothelial cell iron blockade). These patients have low serum transferrin saturation (TSAT, a measure of circulating iron) and normal or high serum ferritin (a marker of body iron stores). Dietary iron absorption under usual circumstances accounts for only 1-2 mg/day and is almost equal to daily iron losses from intestinal and skin cell shedding.
For treatment of anemia caused by chronic renal disease, the United States Food and Drug Administration (FDA) has approved the use of ESA therapy. There are two ESAs licensed for the treatment of anemia of CKD in the Unites States: epoetin alfa and darbopoetin alfa. Both are glycoproteins that are manufactured using recombinant DNA technology. They stimulate erythropoiesis through the same mechanism of action as endogenous erythropoietin. The starting dose of epoetin is 50 units/kg (3000-4000 units/dose) once or twice a week, and darbepoetin is started at 0.45 mcg/kg and can be administered every 2-4 weeks. To avoid impaired erythropoiesis caused by true iron deficiency or functional iron deficiency, iron stores should be fully replenished before and during ESA therapy. ESA therapy is considered safe. However, major adverse effects should be acknowledged, including an increased risk of death, thromboembolic complications, stroke, heart attack, aplastic anemia, tumor progression, and others. To minimize risks of these adverse events, careful monitoring of hemoglobin levels, along with adjustment of ESA dosing, to maintain the lowest hemoglobin level clinically needed is recommended.
Given that ESRD is a pro-inflammatory condition, substantial elevation in serum ferritin is very common in ESRD patients. The role of iron replacement therapy in ESRD patients with high serum ferritin but low transferrin saturation is not clear at all. In fact, most anemia management protocols recommend stopping iron replacement when ferritin levels are greater than 1,200 ng/ml, even if the TSAT is below 20%. The United States Renal Data System (USRDS) reports for that 55% of prevalent ESRD patients (2012-2014) have a ferritin \>800 ng/ml and 22% had ferritin\>1200 ng/ml. In one of our local dialysis centers, close to 45% of patients seem to have a ferritin greater than 1,200 ng/ml and about 20% have a combination of low TSAT and high ferritin.
Ferric citrate (Auryxia) is a novel, iron-based phosphate binder that increases iron stores and decreases IV iron and ESA usage while maintaining hemoglobin levels, and may decrease the cost of ESRD care. By binding phosphate in the GI tract and decreasing absorption, ferric citrate lowers the phosphate concentration in the serum. In addition to effects on serum phosphorus levels, Auryxia has been shown to increase serum iron parameters, including ferritin, iron and TSAT. In dialysis patients treated with Auryxia in a 52-week study in which IV iron could also be administered, mean (SD) ferritin levels rose from 593 (293) ng/mL to 895 (482) ng/mL, mean (SD) TSAT levels rose from 31% (11) to 39% (17) and mean (SD) iron levels rose from 73 (29) mcg/dL to 88 (42) mcg/dL. In contrast, in patients treated with active control, these parameters remained relatively constant.
