The Impact of Intravenous Iron on Renal Injury and Function Markers in Patients With Chronic Kidney Disease and Iron Deficiency Without Anemia

Xenophon Kassianides, Adil Mohammad Hazara, Iain C. Macdougall, Philip A. Kalra and Sunil Bhandari Academic Renal Research Department, Hull University Teaching Hospitals NHS Trust and Hull York Medical School, Hull, UK; Department of Renal Medicine, King’s College Hospital, London, UK; and Department of Renal Medicine, Salford Royal NHS Foundation Trust and University of Manchester, Manchester, UK


INTRODUCTION
I ntravenous (i.v.) iron is often used in the management of iron deficiency anemia in patients with nondialysis-dependent chronic kidney disease (CKD). Guidelines advocate a "high dose, low frequency approach," which is more easily achievable in modern practice owing to new i.v. iron therapies. 1 Concerns however persist regarding hypersensitivity and oxidative stress. 1 These arise owing to earlier experience with older i.v. iron compounds (e.g., iron sucrose) suggesting possible nephrotoxicity owing to increased proteinuria, a phenomenon credited both directly and indirectly to oxidative damage. 2 Newer (third generation) i.v. iron preparations (ferric carboxymaltose, ferric derisomaltose [FDI], ferumoxytol) have a more compact structure and exhibit different modes of iron release compared with their predecessors. 3 This limits their pro-oxidant effect and potentially any resulting nephrotoxicity. As there is increasing real-world evidence on the utility and costeffectiveness of high-dose treatment with thirdgeneration i.v. iron preparations in populations with non-dialysis-dependent CKD, S1 it is important to explore whether any negative renal impact exists after their administration.
As part of the multicenter, double-blind, pilot, randomized, controlled "Iron & Heart" trial, markers of renal function (cystatin C and creatinine) and injury (proteinuria-glomerular damage, neutrophil-associated lipocalin [NGAL]-tubular damage) were measured. The study was primarily designed to evaluate the impact of i.v. iron (FDI) at a high dose (1000 mg) in patients with non-dialysisdependent CKD and iron deficiency but not anemia on 6minute walk test, as an objective measure of functional status. 4 This was performed to establish whether similar positive effects as those exhibited in patients with heart failure exist in this population. Here, we report on the renal-associated secondary objectives evaluating the renal effect of high-dose FDI in this patient group (Supplementary Methods).

RESULTS
A total of 54 patients were recruited and randomized to receive FDI (n ¼ 26) or placebo (n ¼ 28). Baseline characteristics of the study participants are presented in Table 1. The 2 groups were well-matched with no significant differences in the majority of characteristics. Although baseline serum creatinine was significantly lower in the FDI group (158 vs. 201 mmol/L, P ¼ 0.03), estimated glomerular filtration rate (eGFR) calculated using both creatinine and cystatin C were not significantly different between the 2 groups.
After the FDI infusion, no significant changes were detected in the serum levels of creatinine and cystatin C nor the eGFR (Supplementary Figures S1 and S2). At baseline, the eGFR of participants in the FDI group was greater than those receiving placebo; this overall advantage was not altered throughout the study. There were no significant changes in the serum levels of NGAL in either of the treatment arms throughout the follow-up period. In the FDI group, NGAL levels at baseline, 1 month, and 3 months were 323.5, 313.9, and 356.1 ng/ml, respectively (baseline-1 month: P ¼ 0.39; baseline-3 months: P ¼ 0.29) and 365.2, 370.7, and 390.6 ng/ml, respectively, in the placebo group (baseline-1 month: P ¼ 0.73; baseline-3 months: P ¼ 0.71) ( Figure 1).

DISCUSSION
In this study, kidney injury and function markers remained unchanged after administration of high-dose FDI at 1 and 3 months. FDI use was not associated with increases in serum levels of NGAL, a sensitive marker of acute renal tubular damage, or increases in proteinuria throughout follow-up. These findings suggest that FDI did not lead to any short term tubular or glomerular injury.
A proteinuric effect of i.v. iron has been previously displayed in patients receiving iron sucrose (100 mg) when compared with oral iron, within 15 minutes of administration. 2 Despite a return to baseline within 24 hours, that study concluded that certain i.v. iron compounds could be associated with nephrotoxicity. In this study, with FDI, there was no increase in proteinuria level at any follow-up point compared with placebo. In addition, there was no statistically significant change in NGAL with FDI treatment, similar to the IRON-TURTLE trial using a dose of 1000 mg of ferric

RESEARCH LETTER
carboxymaltose in patients with heart failure and CKD and correlating with in vivo and in vitro evidence relevant to third-generation i.v. iron compounds. 5,6 Indeed, such evidence has indicated that thirdgeneration i.v. iron compounds seem to be "bioneutral" in terms of renal injury and oxidative stress when compared with earlier preparations. S2 In this study, no detriment in terms of creatinine or cystatin C (and their derived eGFR) was observed with FDI compared with placebo. This is in agreement with previous studies with non-dialysis CKD participants. 5,7,8 The REVOKE trial (n ¼ 136, non-dialysisdependent CKD with iron deficiency anemia) compared i.v. iron sucrose with oral iron in terms of measured glomerular filtration rate using iothalamate clearance in a 2-year period. 7 Measured glomerular filtration rate declined similarly irrespective of treatment modality and after additional demographic, medication, and comorbidity adjustments. 7 During the FIND-CKD trial, 626 non-dialysis-dependent CKD patients were  randomized to oral iron or i.v. ferric carboxymaltose and similarly demonstrated no difference in eGFR between the 2 treatment modalities in a 12-month period. 8 In patients with CKD and reduced ejection fraction, administration of high dose ferric carboxymaltose also did not produce any impact on cystatin C or other markers of renal function. 5 It is noteworthy that an analysis of the FAIR-HF trial evaluating the impact of ferric carboxymaltose in patients with established systolic heart failure concluded that correction of iron deficiency with i.v. ferric carboxymaltose led to a statistically significant improvement in eGFR when compared with placebo. 9 The neutral results of this study on renal injury may be caused by a combination of factors potentially associated with the iron preparation used. Intriguingly, alleviation of iron deficiency may be renoprotective with recent evidence suggesting correction of iron deficiency in murine uremic models promotes an overall antioxidant effect, whereas the notion of renal preconditioning through activation of the NRFT2 pathway is also explored. S3,S4 Several limitations are present in this study, and the results therefore need to be treated with caution. The study did not focus on an ultra-acute effect of i.v. iron as that previously displayed in literature. This study focused on short-to medium-term renal damage after i.v. iron administration, and it is therefore not possible to draw any conclusions on a potential cumulative effect of repeated iron administrations. In addition, as these are secondary outcomes, the study is underpowered to detect true statistical significance.
In conclusion, the results from the Iron and Heart trial with FDI treatment add further to the safety evidence surrounding the use of i.v. iron in patients with non-dialysis-dependent CKD, especially in terms of renal injury and function. Further markers of nephrotoxicity can be incorporated in such research (e.g., urinary NGAL, beta-2-microglobulin) to investigate further possible renal injury. These results are reassuring with regard to the safety of conducting further large-scale trials in the treatment of iron-deficient patients with CKD but not anemia to identify any impact on quality of life and functional status, similar to that already found in patients with heart failure. DISCLOSURE SB, ICM, and PAK have received honoraria for lectures, attended expert opinion committees and advisory boards, and received educational funds to attend international nephrology meetings from Pharmacosmos A/S and Vifor Pharma. XK and AMH declared no competing interests.

ACKNOWLEDGMENTS
This study received a favorable opinion from the Northern Regional Ethics Service (NRES) Committee Yorkshire & The Humber-Leeds East, United Kingdom (approval reference number 10/H1306/40) and has been registered with the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT number: 2014-004133-16). The authors thank all participants in the study for their kind cooperation throughout and the teams facilitating iron delivery and maintenance of the database in London (King's College Hospital), Hull (Hull Royal Infirmary), and Manchester (Salford Royal Infirmary) (including Vikki Jubb, Archie Lamplugh, and Ahmed Ziedan). The Iron & Heart study received funding from the Kidney Research UK by an unrestricted grant from Pharmacosmos A/S to support all aspects of the study. The funders had no role in the study design, data collection and analysis, and preparation of the manuscript for publication.

AUTHOR CONTRIBUTIONS
XK was involved in the collection, maintenance, analysis and interpretation of data and drafting the article. AMH was involved in the analysis and interpretation of data and critical revision of the article. SB (chief investigator) participated in all aspects of the study, obtained funding for the study, and critically revised the manuscript. ICM and PAK contributed to the design of the study and critically reviewed the drafts of the manuscript. All authors have provided intellectual content of critical importance to the work described and have read and approved the final version to be published. The order of authorship has been a joint decision of the co-authors based on substantial contribution to conception and design, execution, analysis, and interpretation of data.

SUPPLEMENTARY MATERIAL
Supplementary File (PDF) Supplementary Methods. Supplementary References. Figure S1. Changes in serum creatinine and cystatin C in the FDI and placebo groups. Figure S2. Changes in eGFR in the FDI and placebo groups.