Iron-Deficiency Anemia in Non-Dialysis-Dependent CKD: An Overview of Clinical Trials

Iron-Deficiency Anemia in Non-Dialysis-Dependent CKD: An Overview of Clinical Trials


The optimum iron therapy regimen in patients with non-dialysis-dependent chronic  kidney disease (NDD-CKD) is poorly established.1 Ferinject® assessment was an  open-label, multicenter, randomized trial in patients with iron deficiency anemia (IDA) and NDD-CKD (FIND-CKD).1 A total of 626 patients with NDD-CKD, anemia, and iron  deficiency (ID) who were not taking erythropoiesis-stimulating agents (ESAs) participated.1 Intravenous (IV) ferric carboxymaltose (FCM), aiming at a higher  (400–600 g/L) or lower (100–200 g/L) ferritin level, or oral iron treatment were given to  patients in a 1:1:2 randomization.1 The primary end point was time to initiation of  other therapies including an ESA, other iron medication, or a blood transfusion, or hemoglobin (Hb) trigger of two consecutive values 10 g/dL during weeks 8–52.1 In the  high-ferritin FCM, low-ferritin FCM, and oral iron groups, the primary end point  occurred in 36 patients (23.5%), 49 patients (32.2%), and 98 patients (31.8%), respectively.1 

When compared to oral iron, high-ferritin FCM increased Hb more, and a higher percentage of patients experienced an increase in Hb of more than 1 g/dL.1 All groups  experienced equal rates of adverse events including severe adverse events.1 In contrast to oral iron, IV FCM aiming for a ferritin of 400–600 g/L quickly reached and  maintained Hb levels, delaying or reducing the need for alternative therapy for  anemia, such as ESAs.1 No renal damage was noted within the trial’s constraints, and  there was no change in cardiovascular or infectious events.1


Parenteral iron supplementation is commonly necessary for IDA in NDD-CKD,  although current treatments frequently call for several administrations.2 In patients with IDA and NDD-CKD, the effectiveness and cardiovascular safety of FCM, a  non-dextran parenteral iron enabling large single-dose infusions, was compared to  iron sucrose.2 A total of 2584 participants were randomly assigned to receive either  two doses of FCM 750 mg given over the course of one week or iron sucrose 200 mg  given as up to five infusions over the course of 14 days.2 The mean change in highest  Hb from baseline to day 56 served as the primary efficacy endpoint.2 All-cause  mortality, nonfatal myocardial infarction, nonfatal stroke, unstable angina, congestive  heart failure, arrhythmias, and hyper- and hypotensive events were all primary  composite safety endpoints.2 

In the FCM group, the mean Hb increase was 1.13 g/dL, whereas in the iron sucrose  group, it was 0.92 g/dL.2 With the exception of Stage 2 CKD, similar results were seen  across all subgroups.2 The number of participants who experienced a Hb increase of 1.0 g/dL between day 56 and baseline was higher in the FCM group (48.6 versus  41.0%).2 Regarding the primary composite safety endpoint, encompassing the major  adverse cardiac events of mortality, myocardial infarction, or stroke, there was no  meaningful difference between FCM and iron sucrose recipients.2 The FCM group  showed a statistically significant difference in the frequency of protocol-de ned,  mostly temporary hypertensive episodes.2 This study demonstrates that in patients  with NDD-CKD and IDA, two 750-mg FCM infusions are a safe and effective alternative  to multiple lower-dose iron sucrose infusions.2 


In patients with both dialysis-dependent (DD) and NDD-CKD, hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) effectively raised Hb levels, according to phase 2 and phase 3 clinical investigations.3 Nevertheless, clinical trials have not consistently  shown that HIF-PHIs have an impact on iron control.3 To assess the effects of six HIF-PHIs on iron regulation in patients with NDD-CKD, a systematic review and  meta-analysis of randomized controlled trials was conducted.3 From commencement  through April 20, 2020, electronic databases were searched for relevant studies.3 The  inverse-variance method was used to analyze changes from baseline in the levels of  iron, ferritin, hepcidin, TSAT, and TIBC.3 

The included studies’ meta-analysis revealed that in patients with NDD-CKD, HIF-PHIs decreased TSAT, ferritin, and hepcidin, raised TIBC and did not influence blood iron despite increased erythropoiesis.3 According to this study’s comprehensive evaluation, HIF-PHIs promote patients with NDD-CKD to utilize iron.3 This is significant because HIF-PHIs are linked to elevated transferrin levels and TIBC, which lower TSAT.3 Thus, the  decrease in TSAT following HIF-PHIs should not be construed as ID.3 


Even though ID affects patients with CKD frequently and negatively impacts their quality of life and disease course, current recommendations do not support treating ID without anemia in this patient population.4 There are questions about how IV iron can affect oxidative stress, inflammation, and endothelial function.4 The effects of a single dose of IV iron versus a placebo on indicators of oxidative stress, inflammation,  and endothelial function in non-anemic iron deficient patients with CKD (serum  ferritin 100 g/L and/or TSAT 20%) were investigated.4 A total of 54 participants were randomized to receive ferric derisomaltose (FDM) or a placebo.4

When compared to placebo, FDM was linked with a non-significant cant drop in mean F2-isoprostane and no effect on thiobarbituric acid reactive chemicals.4 Inflammatory indicators showed no effect.4 At the 1-month and 3-month follow-ups, the IV iron group showed a slight but statistically significant increase in E-selectin.4 These findings imply prolonged oxidative stress or inflammation are not brought on by the administration of FDM to iron-deficient patients with CKD who are not on dialysis.4 To assess the advantages of IV iron administration in this patient population, larger studies are necessary.4