Vitamin C Effects on Erythropoiesis

The management of anemia utilizes much of the resources dedicated to patients on dialysis; hemoglobin, ferritin, transferrin saturation, erythropoietin therapy and the intravenous administration of iron complexes (IV-iron) are reviewed extensively for each patient, with dose adjustments monthly or even at more frequent intervals. Improved vitamin C status may lead to improved anemia management in these patients. The biochemistry of vitamin C and iron are intimately related; at the level of the gastrointestinal tract, vitamin C helps maintain iron as Fe2+, which is more soluble than Fe3+ at the alkaline pH of the small intestine, and is more readily absorbed across the intestinal mucosa [12, 13]. However, the iron requirements of dialysis patients are greater than most persons with normal renal function, and several investigations [14, 15] have reported that oral iron supple ments have limited ability to meet the iron needs of these patients. The consensus among dialysis clinicians is therefore that IV-iron is obligatory in these patients, although further study may document the beneficial effects of dietary vitamin C on utilization of oral iron.

Vitamin C can affect mobilization of iron from Kupffer cells and other sites in the reticuloendothelial system (RES). When storage iron accumulates beyond the requirement of the body for iron, it may be converted from ferritin to hemosiderin, a form of iron with limited bio-availability, which can accumulate in the bone marrow of dialysis patients [16]. Studies in guinea pigs have shown that vitamin C aids the conversion of hemosiderin iron to ferritin iron [17], which can be exported from the storage cell and carried on transferrin to sites of red blood cell synthesis in the bone marrow. In Bantu siderosis [18], administration of dietary vitamin C supplements led to a significant increase in serum iron, indicating that vitamin C was helping to mobilize stored iron in these patients. During the initial phase of vitamin C therapy in siderotic subjects, there was an accelerated release of urinary oxalic acid [19], consistent with conversion of vitamin C to dehydroascorbate by interaction with stored ferric ion, followed by catabolism of dehydroascorbate to oxalate. Dialysis patients may also accumulate excess iron stores in the gastrointestinal mucosa [ 20], which could lead to rapid breakdown of vitamin C provided by the diet, and limit the impact of supplemental vitamin C on plasma vitamin C levels.

IV-iron may only be partially utilized for Hb synthesis in dialysis patients. A dose of 1 g iron could theoretically produce 300 g Hb, which should increase Hb to 15 g/dl, from a baseline value of 10 g/dl. But the usual outcome of a standard 1-gram course of IV-iron administered to hemodialysis patients is to increase Hb to only 11 g/dl [14, 21], which indicates that 20% of the iron was available for Hb production. In a 1-year study of chronic kidney disease patients (stage 3 renal failure), a 2.4-gram IV-iron regimen led to 10-20% of the predicted increment of Hb in the bloodstream [22], the remainder may have gone into long-term storage in the reticuloendothelial system, and accumulation of large deposits of hepatic iron has been documented in hemodialysis patients after prolonged IV-iron therapy [23].

The interactions of vitamin C with intravenous iron complexes provide in vitro evidence for potentially positive actions of vitamin C supplements in hemodialysis patients. These iron complexes contain relatively little 'free' iron, about 1-5% [24], and there is probably limited immediate release of iron to the bloodstream after injec tion. The iron complexes are generally taken into the ly-sosomal apparatus within a few hours [25, 26] [ and the iron is released following decomposition of the complex within the storage cell [27]. However, at mildly acidic pH (ca. 4-5), which is the pH of the lysosomal vacuole [28] [ vitamin C can release large amounts of the iron content from the complexes, and as much as 60% of the iron can be solubilized in several hours [Handelman, in preparation] . Improved vitamin C status could assist in utilizing IV-iron after its uptake into the lysosome.

These actions of vitamin C have been exploited in several longitudinal studies that used intravenous vitamin C to improve erythropoiesis and decrease erythropoietin (EPO) requirements in patients with low Hb levels [2931] [ These investigators selected patients who required high-EPO doses and who had elevated ferritin levels, indicative of a state of EPO resistance. Intravenous vitamin C (1,000-3,000 mg/week) was able in many of these patients to reduce EPO requirements and increase blood Hb levels, although negative results have also been reported [32] [ Similar effects of high plasma vitamin C were observed in a cross-sectional study of plasma vitamin C and EPO requirements [33].

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