Current issues in IV iron therapy
Optimization of Anemia Management in NDD-CKD Without Erythropoietin Therapy
Iron deficiency commonly complicates anemia in NDD-CKD patients. As many as 25% to 40% of males and 35% to 85% of females with anemia and NDD-CKD show evidence of iron deficiency.1 IV iron therapy can provide effective anemia management, even in the absence of an erythropoietin, in a substantial fraction of these patients. A randomized, controlled, multicenter trial examined response to iron therapy in patients with NDD-CKD Stage 3-5, anemia and moderately low iron indices (TSAT < 25%, ferritin < 300 ng/mL). Among 47 patients who did not receive erythropoietin therapy, 18 (38%) achieved a Hb increase of ≥1.0 g/dL and 28 (60%) achieved a KDOQI-recommended Hb level of ≥11 g/dL after administration of 1000 mg of IV iron sucrose in divided doses.1 Thus, IV iron sucrose alone can be effective in the management of CKD-associated anemia in non-dialysis patients, even in the absence of erythropoietin therapy.
ESA and Hb Levels in Pre-dialysis Patients With Cardiovascular Risk
CKD is recognized as an independent cardiovascular disease (CVD) risk state, particularly in the elderly.2 Cardiovascular complications manifested in the pre-dialysis period- including increased prevalence of sudden death, congestive heart failure (CHF), myocardial ischemia, and cardiac arrhythmias-may be prevented or reduced by the correction of anemia in pre-dialysis patients. Evidence from both uncontrolled and controlled studies suggests that early correction of anemia with ESA and IV iron in patients at risk improves cardiac function as well as renal function, dramatically reducing the need for hospitalization.3
However, the optimal level of Hb correction has not been defined. Recent clinical data have demonstrated that targeting a higher Hb (13 g/dL) in the management of anemia, while potentially making patients feel better, is associated with an increased risk for CHF and actually mortality, thus signaling a potential safety concern with targeting higher Hb.4
The actual cause of these risks is not completely understood. Is the increased risk caused by the rate of rise of Hb, the absolute level of Hb, or the dosing of ESA as has been suggested in prior observational analyses?5
Until more is understood, prudent dosing of IV iron at the recommended rates for Hb maintenance should be followed. The improvement of anemia in CKD, even in pre-dialysis patients, may help avoid cardiovascular complications. Cooperation between nephrologists and cardiologists cannot be underestimated.
Free Iron and Labile Iron
While no IV iron agent contains free iron, all IV iron agents have biologically active or labile iron. A study by Van Wyck et al examined the relationship between labile iron and several IV iron agents in vitro.6 The results indicated approximately 2%-6% of total iron in IV iron agents is available for in vitro transferrin-iron donation, a measure of bioactive labile iron activity. Additionally the labile iron fractions varied according to the sequence ferric gluconate > iron sucrose > iron dextran [INFed®] > iron dextran [Dexferrum®].
This labile iron has been associated with oxidative stress and infections through in vitro and in vivo studies. Although iron is a known and potent cause of oxidative stress, experimental7 and clinical evidence that IV iron causes CAD or contributes to atherogenesis or heart disease in renal failure is lacking. Additionally, despite evidence that IV iron agents may enhance bacterial growth in vitro, prospective multicenter clinical trials8 and large scale retrospective studies in chronic kidney disease patients have found no discernable relationship between the incidence of infection and either IV iron dosing or levels of iron status tests.