Effect of different intravenous iron preparations on lymphocyte intracellular reactive oxygen species generation and subpopulation survival

Abstract

Background: Infections in hemodialysis (HD) patients lead to high morbidity and mortality rates and are associated with early cardiovascular mortality, possibly related to chronic inflammation. Intravenous (IV) iron is widely administered to HD patients and has been associated with increased oxidative stress and dysfunctional cellular immunity. The purpose of this study was to examine the effect of three commercially available IV iron preparations on intracellular reactive oxygen species generation and lymphocyte subpopulation survival. Methods: Peripheral blood mononuclear cells (PBMC) were isolated from healthy donor buffy coat. PBMC were cultured and incubated with 100 μg/mL of sodium ferric gluconate (SFG), iron sucrose (IS) or iron dextran (ID) for 24 hours. Cells were then probed for reactive oxygen species (ROS) with dichlorofluorescein-diacetate. In separate studies, isolated PBMCs were incubated with the 25, 50 or 100 μg/mL iron concentrations for 72 hours and then stained with fluorescein conjugated monoclonal antibodies for lymphocyte subpopulation identification. Untreated PBMCs at 24 hours and 72 hours served as controls for each experiment. Results: All three IV iron preparations induced time dependent increases in intracellular ROS with SFG and IS having a greater maximal effect than ID. The CD4+ lymphocytes were most affected by IV iron exposure, with statistically significant reduction in survival after incubation with all three doses (10, 25 and 100 μg/mL) of SFG, IS and ID. Conclusion: These data indicate IV iron products induce differential deleterious effects on CD4+ and CD16+ human lymphocytes cell populations that may be mediated by intracellular reactive oxygen species generation. Further studies are warranted to determine the potential clinical relevance of these findings.

Considerations and Challenges in Defining Optimal Iron Utilization in Hemodialysis

“…[61][62][63] Not surprisingly, IVI formulations have been shown to induce oxidative stress, inflammation and cellular toxicity, pro-oxidant cell signaling, tissue inflammation, cellular iron deposition, and cytotoxicity in cell culture models, animal models, and acutely in human participants [63][64][65][66][67] with more labile compounds inducing more toxicity than those with larger carbohydrate shells. 68,69 IVI has also been associated with immune dysfunction, augmentation of bacterial growth, and increased Gram-positive bacteria growth in vitro. 67,[69][70][71] Taken collectively, these studies underscore the need for comprehensive clinical and translational investigations to evaluate the effect of differences in formulation, pharmacokinetic, and pharmacodynamic characteristics and to determine whether repeated induction of oxidative stress from IVI has long-term sequelae.…”

“…68,69 IVI has also been associated with immune dysfunction, augmentation of bacterial growth, and increased Gram-positive bacteria growth in vitro. 67,[69][70][71] Taken collectively, these studies underscore the need for comprehensive clinical and translational investigations to evaluate the effect of differences in formulation, pharmacokinetic, and pharmacodynamic characteristics and to determine whether repeated induction of oxidative stress from IVI has long-term sequelae.…”

Safety Issues in Iron Treatment in CKD

“…55 High doses of IV iron products also have been shown to impair PMN's phagocytic and bactericidal capacities. [56][57][58][59] Finally, iron preparations decrease whereas ESAs, which reduce iron stores, enhance the response to hepatitis B vaccination, 60 and iron overload increases the risk and severity of infections 61,62 by facilitating microbial growth and virulence.…”

Iron Localization and Infectious Disease in Chronic Kidney Disease Patients

“…In terms of peripheral blood leukocytes, therapeutic concentrations of iron in media diminished CD4+ lymphocyte survival through the intracellular oxidative stress caused by iron, which leads to apoptosis [17] . Deicher et al [18] demonstrated that high-dose parenteral iron impaired the intracellular killing of S. aureus by PMNLs.…”