Proteinuria Induced by Parenteral Iron in Chronic Kidney Disease—A Comparative Randomized Controlled Trial

Abstract

SummaryBackground and objectives Among patients with chronic kidney disease (CKD), differences in proteinuria are seen between intravenous iron preparations after a single dose exposure. This study examined differences in proteinuria between two intravenous iron preparations after multiple doses.Design, setting, participants, & measurements Patients with iron-deficiency anemia and CKD, stratified by angiotensin converting enzyme inhibitor (ACEI)/angiotensin receptor-blocker (ARB) use, were randomized to iron sucrose or ferric gluconate. Each patient at 12 centers received 100 mg of study drug weekly for 5 weeks. Urine protein/urine creatinine ratio was measured before each dose and frequently thereafter for 3 hours.Results Postbaseline data were available from 33 patients receiving iron sucrose and 29 patients receiving ferric gluconate. Although neither preparation of intravenous iron increased the predose level of proteinuria, the proteinuric response to intravenous iron was dependent on the type of iron and ACEI/ARB use. Without ACEIs/ARBs, ferric gluconate tended to cause less proteinuria with repeated iron administration; iron sucrose did not mitigate or aggravate proteinuria. Among patients receiving ACEIs/ARBs, in contrast to ferric gluconate, which produced only mild transient proteinuria, iron sucrose produced a consistent and persistent proteinuric response that was on average 78% greater.Conclusions Although multiple doses of either intravenous iron did not increase basal levels of proteinuria, postdose proteinuria was greater with iron sucrose than with ferric gluconate. These data suggest that nephrotoxicity of iron may depend on type of intravenous iron and on ACEI/ARB use. The long-term effects on kidney function need to be further evaluated.

Iron supplementation associates with low mortality in pre-dialyzed advanced chronic kidney disease patients receiving erythropoiesis-stimulating agents: a nationwide database analysis

“…Zager et al [30,31] demonstrated that parenteral iron not only induced intracellular iron accumulation, marked lipid peroxidation and cell injury in isolated mouse and human tubular epithelial cells but also showed nephrotoxicity after IV iron injection in vivo. Three small studies on patients with CKD demonstrated that short-term IV iron administration caused transient proteinuria and urinary excretion of tubular enzymes [32][33][34]. Because of the lack of data about baseline serum creatinine and proteinuria, our study results are not sufficient to demonstrate that the patients treated with iron really have a higher risk to reach dialysis.…”

Renal function in patients with non-dialysis chronic kidney disease receiving intravenous ferric carboxymaltose: an analysis of the randomized FIND-CKD trial

“…Similar analyses have been performed in repeated dose studies. In a multicenter, randomized trial, 62 patients with ND-CKD and iron deficiency anemia received a weekly dose of either iron sucrose or ferric gluconate (100 mg) for 5 weeks [19]. Basal levels of proteinuria were similar, but increased post-dosing, with a greater increase with iron sucrose than ferric gluconate [19].…”

“…In a multicenter, randomized trial, 62 patients with ND-CKD and iron deficiency anemia received a weekly dose of either iron sucrose or ferric gluconate (100 mg) for 5 weeks [19]. Basal levels of proteinuria were similar, but increased post-dosing, with a greater increase with iron sucrose than ferric gluconate [19]. This was consistent with results from an earlier single-dose study from the same group which showed that a single dose of iron sucrose (100 mg) provoked a significantly higher urinary protein to creatinine ratio than ferric gluconate [20].…”

“…Clinical evidence relating to a possible effect of IV iron therapy on renal function is limited. Single-dose and short-term (5-week) studies from one center have indicated that iron sucrose may induce renal injury mediated by oxidative stress and inflammation [19–23]. However, the recently published REVOKE study, which randomized patients with ND-CKD to IV iron sucrose or oral iron, showed neither a difference in renal function decline (based on GFR measured by iothalamate clearance) nor in proteinuria during follow-up lasting up to 2 years [24].…”

Efficacy and Tolerability of Accelerated-Dose Low-Molecular-Weight Iron Dextran (Cosmofer) in Patients with Chronic Kidney Disease

“…Several animal models have demonstrated the potential detrimental effects of free iron on glomerular function [23], as well as clinical studies by Agarwal et al [24,25]. More recent clinical data on the neutral effects of IV iron on renal function are encouraging [26].…”