Anemia is a frequent complication in chronic kidney disease (CKD) patients1,2 while iron deficiency (ID) is a common cause of anemia in CKD and is highly prevalent in this population, independent of the CKD stage.3 Current clinical guidelines on anemia in CKD recommend iron therapy only when ID and anemia coexist4–6 but there are no indications for correction of ID in CKD, independently of the presence of anemia.

Iron is involved in vital cellular and body functions, including oxygen transport and storage (hemoglobin and myoglobin), energy production, DNA synthesis and repair, immune function, among others.7 In fact, clinical symptoms in patients with CKD, often attributed to anemia, may also be due to ID. Prior studies have shown that ID in CKD is associated with an increased risk of morbidity and mortality and a worse quality of life (QoL), regardless of the presence of anemia.8–10 In patients with heart failure (HF) with reduced ejection fraction and ID, intravenous (IV) iron supplementation improved functional status, QoL, and reduced the risk of HF hospitalization in patients with and without anemia.11–14

Two randomized controlled trials of IV iron vs placebo in ID non-anemic non-dialysis CKD (ND-CKD) patients have recently been published.15,16 Both trials failed to demonstrate the superiority of ID correction with IV iron in improving the functional capacity or the QoL. However, patients were relatively younger than current non-dialysis CKD patients and had a relatively good baseline physical status.

We hypothesized that treating ID with IV iron in an unselected mildly anemic ND-CKD population would result in short-term improvements in functional capacity and other patient-reported outcomes (PROMs), independent of hemoglobin levels. The 6-minute walk test (6-MWT) is a reliable tool for assessing functional capacity, as it predicts peak oxygen uptake in hemodialysis patients.17 To test this, we evaluated the early effects of IV ferric carboxymaltose (FCM) on functional capacity and other PROMs in ND-CKD patients with mild anemia and ID

Of the 45 patients who received IV FCM, 4 did not complete the follow-up (one due to a COVID-19 infection, one due to a chronic obstructive pulmonary disease exacerbation, one due to a hip fracture, and one due to a change of residence). The demographic and clinical baseline characteristics of the 41 patients included are shown in Table 1. The mean dose of IV FCM administered was 616.2±163.8mg.

Co primary endpoint

After the infusion of IV FCM, there was an improvement in the distance covered in the 6MWT both at week 1 and at week 4. (Raw data is presented in Table 1 of supplementary material). Inferential analysis confirmed the improvement of the distance walked in 6min after IV FCM administration at the two time points as shown in Fig. 2. LSM [95% confidence interval] for baseline distance completed was 297.27 [269.83–324.71]m. At week 1 and week 4 there was an increase in the meters walked reaching 318.3 [290.71–345.98] and 321.7 [293.92–349.56] respectively (p=0.006 week 1 vs baseline and p=0.002 week 4 vs baseline).

Fig. 2.

Changes in 6MWT. α, changes between basal and week 1. δ, changes between baseline and week 4. Inferential analysis of adjusted data.

Secondary end-points: changes in PGA, EQ-5D and Piper fatigue scale

For the secondary end points raw data are presented in Table 1 supplementary material. In the inferential analysis we did not find significant improvements in these tests at week 1, but there were significant improvements of the scores at week 4 of all questionnaires (PGA, EQ-5D, and Piper fatigue scale). (Fig. 3). LSM [95% confidence interval] for PGA were: baseline: 66.4 [61.72–71.02] points, week 1: 71.8 [66.98–76.53] points, and for week 4: 73.8 [68.88–78.66] points (p=0.1 for baseline vs week 1 and p=0.018 for baseline vs week 4). For EQ-5D the LSM values were, baseline: 0.75 [0.70–0.79] points, week 1: 0.78 [0.73–0.83] points and week 4: 0.8 [0.75–0.85] points (p=0.2 for baseline vs week 1 and p=0.04 for baseline vs week 4). Finally there were significant decreases of the Piper fatigue scale at week 4. The LSM values were baseline: 4.5 [4.02–4.90], week 1: 3.9 [3.51–4.42] and week 4: 3.6 [3.19–4.13] (p=0.12 for baseline vs week 1 and p<0.008 for baseline vs week 4).

Fig. 3.

Changes in (a) EQ-5D questionnaire, (b) PGA questionnaire, (c) Piper fatigue scale changes between basal and week 1. δ Changes between basal and week 4.

The main finding of the present study is the early and significant improvement in functional capacity, as measured by the 6-MWT, in patients with ND-CKD, mild anemia and ID after treatment with IV FCM, even in the absence of significant changes in hemoglobin levels. The improvement was seen early (1 week) and was maintained at 4 weeks. This finding suggest the deleterious effect of ID on the physical performance, independent of serum hemoglobin, in ND-CKD patients.21 The changes in the 6-MWT observed in our study were not only statistically, but also are clinically significant, according to previous studies.22,23 Furthermore, there was a significant improvement in the PGA, as well as in QoL and fatigue scores at 4 weeks, suggesting a deleterious role of ID, independent of anemia, in some PROMs in this population. These benefits can be attributed to the correction of ID due to its early effect (1 week) and since hemoglobin did not increase significantly from baseline. In fact, in a previous study in patients with CKD, the correction of anemia with ESA did not improve the 6MWT.24

ID is common in CKD.3,25 However, the deleterious effect of ID beyond anemia and whether it should be treated or not in CKD is a subject of increasing interest.8 Several studies have shown that ID in this population is associated with worse clinical outcomes9,10,26 as well as a poorer QoL,10 thus suggesting that ID should be considered for treatment independent of the presence of anemia in CKD patients, but confirming evidence from interventional studies is scarce.

The improvement in functional capacity with IV iron supplementation in our study agrees with previous results in ID patients with heart failure and reduced ejection fraction,12–14 as well with the improved aerobic capacity with iron therapy in ID athletes without anemia,27 suggesting a potential benefit on skeletal muscle energetics.28 Two randomized trials have been published which, similarly to our study, tried to demonstrate the benefit of IV iron therapy vs placebo on functional capacity in ND-CKD non-anemic ID patients. Both trials were placebo-controlled. However, both trials failed to show a benefit vs placebo in functional capacity. Bhandari et al. randomized 54 patients with a mean age of 59.6±11.7 years and a mean eGFR of 31.1ml/min/1.73m2 to receive 1000mg of ferric derisomaltose. The mean distance walked by the treatment group did not improve after treatment with IV iron at 1 and 3 months. The same authors acknowledge the limitations of the study, including an imbalance in baseline characteristics with a younger treatment group.15 Similarly, Greenwood et al. randomized 75 patients with ND-CKD mean age 57 years and mean eGFR was 35ml/min/1.73m2 to receive 1000mg of FCM or placebo. In this well conducted trial, there were no significant differences at 4 and 12 weeks, despite observing a numerical increase of 44 meters in the distance walked in the 6MWT in the group that received FCM vs 20m in the placebo group, this increase did not reach statistical significance.16 Both studies acknowledge that their patients had a good functional capacity at baseline.

The population included in both trials is certainly younger and in better physical condition than our population, as evidenced by the distance they covered at baseline in the 6MWT, which is significantly greater than in our group of older patients. In our opinion, our population more accurately represents the actual ND-CKD population with a mean age of 74.9±9.5 years, and a poorer physical condition, as demonstrated by the baseline distance walked in the 6MWT, which was around 100 meters less than the two mentioned studies.

We also aimed to analyze the impact of correcting ID on several PROMs. Utilizing tools for PROMs assessment is crucial for evaluating both the disease burden and the effectiveness of therapeutic interventions.

In the CKDopps study there was an association between ID and a poorer QoL, especially in the physical domain.11 In our study, we found an improvement in QoL at 4 weeks after adjustment, in contrast with the study of Bhandari et al.,15 but in agreement with the study of Agarwal et al.29

We also found significant improvements in the PGA and Pipper fatigue scale in our patients at 4 weeks after adjustment, suggesting the beneficial effect of ID correction on fatigue and well being, in contrast with the study of Greenwood et al.16

IV FCM was safe in our study, since no AE were reported and among patients that did not complete the study, reasons for discontinuation were not related to the study drug. There was a mild transient decrease in serum phosphorus levels at one week with partial recovery at four weeks, but no single patient experienced severe or clinical hypophosphatemia, as previously reported.30 The mean administered dose of IV FCM in our study (616mg) was calculated using the Ganzoni formula and is consistent with dosing strategies used in previous heart failure11 and nephrology trials, including the study by Greenwood et al. in ND-CKD patients, where a single FCM 1g dose was well tolerated and associated with functional improvements.16 Future studies should assess the benefits of simplified fixed-dose regimens (e.g., FCM 500mg single dose).

We acknowledge that the main limitation of this study is the absence of a placebo group. We opted for a single-arm study without a placebo group due to limited resources, and considering that the results in functional capacity (an objective measure) would be valid with this design. Furthermore, the present work is a pilot study. Our aim is, based on the current data, to conduct a randomized placebo-controlled study with a larger sample size in a ND-CKD population with these characteristics, since unlike previous trials, we observed significant benefits of the intervention in this older population with mild anemia and poorer physical status.

To our knowledge, this is the first study to suggest the short-term benefit of IV FCM administration in improving physical function and other PROMs in elderly patients with CKD, ID, and mild anemia, despite no changes in serum in serum Hb levels, suggesting that the benefit was independent of anemia correction. Given the limitations of our study—small sample size, short time of follow-up, and absence of a control group—these findings should be considered as hypothesis-generating. Therefore adequately powered, randomized controlled trials with longer follow-up and the assessment of clinically relevant outcomes are needed to confirm these results.

This work has received an unrestricted grant from Vifor Pharma.

MJP declares that have received speaker fees from Astellas, CSL Vifor and GSK.

AC declares that have received consultancy fees from AstraZeneca, Astellas, Boehringer Ingelheim, CSL Vifor, GSK, Lilly, Novonordisk and Otsuka and speaker fees from CSL Vifor, Astellas, Amgen, Bayer, Boehringer Ingelheim, Lilly, GSK, Novonordisk and Sanofi Mexico outside the submitted work.

JN has received consultancy and speaker fees and lectures from Astra Zeneca, Alleviant, Amgen, Bayer, Boehringer Ingelheim, CSL VIFOR, Daiichi Sankyo, GSK, Lilly, Pfizer, Novartis, Novonordisk, and Rovi.

JLG has been received consultancy fees from Astellas, GSK, CSL VIFOR, and speaker fees from AstraZeneca, Boehringer Ingelheim, Esteve, Bayer, Lilly, Astellas and Novonordisk.

JC, EGC, BG, MM, RDE, MGR, IT and CP declare no competing interest.

Data are available on reasonable request.