Parenteral Iron Sucrose-Induced Renal Preconditioning: Differential Ferritin Heavy and Light Chain Expression in Plasma, Urine and Internal Organs.

Abstract

Experimental data suggest that iron sucrose (FeS) injection, used either alone or in combination with other pro-oxidants, can induce renal preconditioning , in part, by up-regulating cytoprotective ferritin levels. However, the rapidity, degree, composition (heavy vs. light chain), and renal ferritin changes following FeS administration in humans remain to be defined. To address these issues, healthy human volunteers (HVs; n,9) and stage 3-4 CKD patients (n,9) were injected once with FeS (120, 240, or 360 mg). Plasma ferritin was measured from 0-8 days post-injection as an overall index of ferritin generation. Urinary ferritin served as a biomarker of renal ferritin production. FeS induced rapid (<2hrs), dose-dependent, plasma ferritin increases in all subjects, peaking at ~3-5x baseline within 24-48 hrs. Significant urinary ferritin increases (~3x), without significant / dose-dependent changes in albuminuria, NGAL, or NAG excretion, were observed. Western blotting with ferritin heavy chain (Fhc)- and light chain (Flc)-specific antibodies demonstrated that FeS raised plasma Flc, but not Fhc, levels. Conversely, FeS increased both Fhc and Flc in urine. To assess sites of FeS-induced ferritin generation, organs from FeS-treated mice were probed for Fhc, Flc, and their mRNAs. FeS predominantly raised hepatic Flc. Conversely, marked Fhc and Flc elevations developed in kidney and spleen. No cardio-pulmonary ferritin increases occurred. Ferritin mRNAs remained unchanged throughout, implying post-transcriptional ferritin production. We conclude that FeS induces rapid, dramatic, and differential Fhc and Flc up-regulation in organs. Renal Fhc and Flc increases, in the absence of nephrotoxicity, suggest potential FeS utility as a clinical renal preconditioning agent.