Proteinuria induced by parenteral iron in chronic kidney disease--a comparative randomized controlled trial

Abstract

Background 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.

Figures

Figure 1.

A schematic showing study procedures.

Figure 2.

Trial flow. Seventy-five patients were randomized into the trial. One patient randomized to ferric gluconate (FG) and two patients randomized to iron sucrose (IS) were withdrawn before receiving their first dose of the study drug. Two patients who received drug did not complete the study. One IS patient experienced a fatal myocardial infarction (after a motor vehicle accident) after visit 1. One FG patient withdrew from the study after visit 2 because of the length of the study visits. Therefore, 70 patients completed the study.

Figure 3.

(A) Single-dose exposure to iron. Log urine protein-to-creatinine ratio at each of the collection periods is shown stratified by ACEI use. Urine samples were collected preinfusion (0) and at 15, 30, 60, 120, and 180 minutes postinfusion (labeled 1 through 5). (B) Data for log albumin-to-creatinine ratios. Results were very similar to that seen for urine protein-to-creatinine ratios. See text for details.

Figure 4.

Multiple dose exposure response to iron. Change in postdose urine protein-to-creatinine ratio at each of the five visits after the baseline visit is shown stratified by ACEI use (see text for how these were calculated). The proteinuric response to IV iron was dependent on the type of iron and ACEI use. In the ACEI naïve group, ferric gluconate tended to cause less proteinuria with repeated iron administration; iron sucrose did not mitigate or aggravate proteinuria. Among patients on ACEIs, in contrast to ferric gluconate, which produced transient proteinuria (no more than 10% greater than basal level of proteinuria), iron sucrose produced a proteinuric response that was on average 78% more compared with ferric gluconate. This greater proteinuric response with iron sucrose was consistent and persistent.

Figure 5.

Multiple dose exposure response to iron. Change in postdose urine albumin-to-creatinine ratio at each of the five visits after the baseline visit is shown stratified by ACEI or ARB use. The albuminuric response to IV iron was dependent on the type of iron and ACEI/ARB use. In the non-ACEI/ARB stratum, ferric gluconate tended to cause less albuminuria with repeated iron administration; iron sucrose did not mitigate or aggravate albuminuria. Among patients on ACEIs/ARBs, in contrast to ferric gluconate, which produced transient albuminuria (no more than 10% greater than basal level of proteinuria), iron sucrose produced a proteinuric response that was on average 135% more compared with ferric gluconate. This greater proteinuric response with iron sucrose was consistent and persistent.