Intravenous iron in chronic kidney disease without anaemia but iron deficiency: A scoping review

Abstract

Iron deficiency (ID) is a prevalent complication of chronic kidney disease (CKD), often managed reactively when associated with anaemia. This scoping review evaluates the evidence supporting intravenous (IV) iron therapy in non-anaemic individuals with CKD and ID, focusing on safety, efficacy, and emerging therapeutic implications. Current diagnostic markers, including serum ferritin, transferrin saturation, and reticulocyte haemoglobin content, are reviewed alongside their limitations in the context of inflammation and variability. The pathophysiology of ID in CKD is explored, highlighting the roles of hepcidin, hypoxia-inducible factor pathways, and uraemic toxins. Comparative studies reveal that IV iron offers a more rapid correction of iron stores, improved compliance, and fewer gastrointestinal side effects compared to oral iron. Evidence from trials such as “iron and heart” and “iron and muscle” suggests potential benefits of IV iron on functional capacity and fatigue, though findings were statistically non-significant. Insights from heart failure trials support the safety and efficacy of IV iron in improving quality of life and reducing hospitalizations, with newer formulations like ferric derisomaltose demonstrating favourable safety profiles. This review underscores the need for standardized screening protocols for ID in CKD, even in the absence of anaemia, to facilitate earlier intervention. Future research should prioritise robust outcome measures, larger sample sizes, and person-specific treatment strategies to optimise dosing and administration frequency. Tailored approaches to IV iron therapy have the potential to significantly improve functional outcomes, quality of life, and long-term health in people with CKD.

Key Words: Iron; Chronic kidney disease; Cardiovascular; Disease; Glomerular filtration rate

Core Tip: Intravenous iron therapy can effectively address iron deficiency in individuals with chronic kidney disease who are non-dialysis-dependent and not anaemic, particularly when oral iron is insufficient. This review highlights the pathophysiology of iron deficiency in chronic kidney disease, the advantages of newer intravenous iron formulations, and the potential benefit of treatment in managing symptoms like restless legs syndrome. However, evidence on improvements in physical function remain uncertain, and more research is needed to refine treatment protocols.

INTRODUCTION

It is estimated that chronic kidney disease (CKD) affects about 4.2 % of people in England[1]. Iron deficiency (ID) is a recognized complication of CKD, frequently presenting with symptoms such as lethargy, dyspnoea and headache, whilst restless legs syndrome (RLS) is a less frequent yet important, recognized symptom[2]. In 2015, the National Institute for Health and Care Excellence (NICE) updated its guidelines regarding ID in CKD and recommended the use of percentage of hypochromic red blood cells (HRC) (> 6%) as the first-line diagnostic test, if processed within 6 hours, given its high sensitivity and specificity of 82% and 95%, respectively[3,4]. Alternatively, reticulocyte haemoglobin content (CHr) (< 29 pg) or reticulocyte haemoglobin equivalent can be used. If these tests are unavailable, transferrin saturation (TSAT) (< 20 %) and serum ferritin (SF) (< 100 μg/L) can be used in combination to assess iron status. Although SF is a reliable measure of ID, a normal to high levels of SF do not exclude ID especially in the presence of inflammation, which induces the activation of ferritin[5]. Similarly, TSAT is calculated using serum iron and total iron binding capacity, with the former fluctuating depending on nutritional intake and circadian rhythm[6,7]. Multiple studies have investigated the effect of fasting to overcome this variation but have failed to prove its benefit[7-9].

The current thresholds for the different diagnostic tests were set based on available evidence and health economic analysis[3]. There are no clear guidelines regarding monitoring frequency of iron status in ID without anaemia. In clinical practice, ID is corrected when anaemia develops, which in the context of CKD is a haemoglobin (Hb) < 110 g/L and estimated glomerular filtration rate (eGFR) < 60 mL/minute/1.73 m². There is no international consensus on a safe upper limit of SF; however, NICE recommends that SF should not exceed 800 μg/L in people with non-dialysis dependent CKD (ND-CKD) who are being treated with iron[3-5]. Multiple factors, including the severity of ID, venous access, and previous response to therapy, determine the choice between oral preparations and parenteral iron[10].

This scoping review will discuss the evidence behind recommending intravenous (IV) iron to people with CKD not on dialysis, with proven ID but no anaemia, with a Hb within range (110-150 g/L).

PATHOPHYSIOLOGY OF ID IN CKD

ID can be defined as absolute or functional; in absolute ID, the iron stores are severely reduced in the bone marrow, liver and spleen, thus limiting the production of red blood cells. In functional ID, there are adequate iron stores in the bone marrow but insufficient utilisation by erythroid progenitor cells, leading to a supply/demand mismatch[11-13].

The hypoxia-inducible factor (HIF) pathway regulates several genes in response to oxygen-deprivation. In healthy kidneys, HIFs are responsible for regulating the production of erythropoietin and transferrin receptors[13]. HIF-1α levels have been shown to increase with CKD stage 3-4 compared with stage 1-2, thus resulting in more erythropoiesis which could lead to functional ID[14,15].

Hepcidin, a hormone produced by hepatocytes, induces the degradation of ferroportin, an exporter that controls the release of iron into plasma and extracellular fluid[16]. Thus, increased hepcidin levels due to poor kidney excretion in the proximal tubules, impairs iron release from duodenal enterocytes, splenic macrophages and Kupffer cells[17]. Moreover, interleukin-6 has been shown to upregulate hepcidin in response to inflammation, with recent studies also suggesting a unique role of activin B.

The European uraemic toxin work group identified 146 uraemic toxins and categorized them based on molecular characteristics[18]. Most notably, indoxyl sulfate, is difficult to filter through conventional dialysis methods and further studies have confirmed that it inhibits the activation of HIF genes, shortens erythrocyte survival and induces hepcidin production[19-22]. Furthermore, uraemia is known to impair the glycoprotein IIb/IIIa complex, causing poor platelet adhesion[23]. It is estimated that people with ND-CKD lose approximately 1.2 L of gastrointestinal blood per year, whilst those on dialysis lose 2.3 L per year; this corresponds to 0.4 and 0.7 g of iron, respectively[24].

TREATMENT MODALITIES

ID can be addressed using oral formulations or IV preparations. The bioavailability of iron is estimated to be between 14%-18% for mixed diets and 5%-12% for vegetarian diets in people with no iron stores (SF < 15 μg/L)[25]. Ferric iron, must be reduced to ferrous, to allow for absorption through duodenal enterocytes[26]. Traditional oral formulations consist of ferrous salts with sulfate, fumarate and gluconate, while novel formulations include ferric citrate, ferric maltol, liposomal iron and sucrosomial iron[27]. The use of oral preparations is challenged by the undesirable side effects such as nausea, constipation, diarrhoea and dyspepsia, thus limiting efficacy and compliance[28]. Although newer compounds may have a better side effect profile than traditional formulations, the evidence is yet to emerge[29]. Given that traditional ferrous salts are least expensive, widely available and have established efficacies, they remain the mainstay of oral iron repletion[30].

Specifically, ferric citrate was proven to reduce hyperphosphataemia in people with dialysis dependent CKD (DD-CKD), and to correct ID anaemia (IDA) in people with ND-CKD, with long-term data yet to be published[31,32]. Additionally, it was superior to ferrous sulfate in improving TSAT and SF in people with CKD stage 3b-5 and IDA[33]. Another new formulation, heme iron polypeptide, was proven to have similar efficacy at maintaining Hb as IV iron sucrose but was poor at improving SF[34]. A randomized trial compared oral liposomal iron to IV ferrous gluconate in people with IDA and ND-CKD stage 3-5; SF and TSAT showed a significant progressive increase from baseline with IV iron but remained stable with oral iron. Hb levels were similar at 3 months but fell rapidly to baseline in the oral iron group following discontinuation[35]. Liposomal iron demonstrated a more favourable side effect profile, with gastrointestinal issues affecting 12% of people; compliance to this treatment was notably high at 96%. In contrast, the IV iron group experienced a range of adverse effects: 18% reported gastrointestinal problems, 12% had reactions at the infusion site, 18% suffered from headaches, and 12% developed hypotension. The AEGIS-CKD randomized trial investigated the effects of ferric maltol on people with CKD stage 3-4 and IDA; at 16 weeks, ferric maltol significantly improved Hb, TSAT and SF, and the Hb was maintained at 52 weeks[36].

On the other hand, IV iron preparations greatly differ in pharmacokinetics, dosage, adverse reactions and molecular structure. Initially, iron dextran was the first preparation used but later found to be associated with a significant incidence of anaphylactic reactions, thus limiting its clinical benefits. As a result, some countries, including the United States, require a test dose of iron dextran prior to the full dose, but United Kingdom practice focuses on careful administration and monitoring. Other formulations such as iron sucrose, gluconate and ferumoxytol appear to have a lower incidence of anaphylaxis[37]. Newer preparations such as ferric carboxy maltose (FCM) and ferric derisomaltose (FDI) are more stable than earlier generations of IV iron, prompting slower degradation of the iron complex[38]. This results in lower levels of labile iron which is responsible for oxidative stress and accelerated atherosclerosis[39,40]. Moreover, FDI has a longer half-life than FCM (20.3 hours for FDI vs 6.82 hours for FCM) along with lower levels of non-transferrin-bound iron, a measure of labile iron[41,42]. The FERWON-NEPHRO trial compared the safety and efficacy of IV FDI to IV iron sucrose in people with ND-CKD and IDA; at 4 weeks, Hb was significantly greater in the FDI arm but was not different to the iron sucrose group at 8 weeks[43]. Also, the increase from baseline in SF and TSAT was significantly higher with FDI in the first 2 weeks but was non-inferior to iron sucrose at 4 and 8 weeks. The occurrence of severe hypersensitivity reactions was comparable between the two groups, however, the FDI group had significantly lower composite cardiovascular adverse events; this was not a primary outcome measure.

Furthermore, iron administration carries a potential infection risk by promoting the growth of bacteria[44,45]. In addition, several studies have detailed a link between iron and neutrophil dysfunction[46,47]. The FIND-CKD and REVOKE trials aimed to elucidate long-term safety of IV iron but came to different conclusions[48,49]. The validity of these findings is uncertain and should be approached with caution due to the reporting of adverse events, including exclusion criteria, censoring of data and relatively small sample size[50]. Robust results from the PIVOTAL, DRIVE I and II trials provided the evidence behind the liberal approach to IV iron in people who have DD-CKD[51-53]. Also, the PIVOTAL trial showed no significant difference in the rate of hospitalization for infection between the proactive high-dose IV iron group (given unless SF > 700 μg/L or TSAT ≥ 40%) and the reactive low-dose IV iron group (only given when SF < 200 μg/L or TSAT < 20%). Nevertheless, the use of IV iron, as opposed to oral iron, allows for a more rapid correction of iron levels and helps mitigate concerns regarding compliance and iron absorption.

The results of a meta-analysis, conducted in 2016, reinforced current kidney disease: Improving global outcomes (KDIGO) 2012 guidance on the use of IV iron, as opposed to oral, in people undergoing long-term dialysis[54,55]. Regarding ND-CKD stage 3-5, significantly more people reached an elevation in Hb of at least 10 g/L with IV iron, regardless of preparation. Likewise, TSAT and SF were significantly higher with IV iron. The safety analysis showed that there is no increase in immediate adverse events with IV iron, later supported by another meta-analysis[56]. A Cochrane review of 39 studies, published in 2019, provided evidence that people who received IV iron have increased Hb, SF and TSAT[57]. Although the number of people who experienced allergic reactions or hypotension was higher with IV iron, the number of people who had gastrointestinal side effects was lower. Furthermore, they concluded that it was uncertain whether IV iron reduces cardiovascular mortality. One out of five studies reported a 4.8% improvement in quality of life (QoL) with IV iron in people who have IDA and ND-CKD stage 3-5, as assessed by the SF-12 physical composite score[58] (Table 1).

Table 1 Summary of advantages and disadvantages of oral vs intravenous iron repletion.

	Oral iron	Intravenous iron
Advantages	(1) Practicality; (2) Sparing of vascular access; and (3) Less costs	(1) Improved compliance; and (2) Less gastrointestinal side effects
Disadvantages	(1) May be less tolerable due to side effects; and (2) Slower at achieving target levels	(1) Needle phobia; (2) Travel time to hospital; (3) Time off work; (4) Anaphylaxis; and (5) Skin reactions

COST ANALYSIS OF IRON SUPPLEMENTATION

A United Kingdom study compared the costs of FDI and FCM in treating IDA[59]. It concluded that the mean number of infusions per person was 1.38 with FDI vs 1.92 with FCM, corresponding to Great British Pound (GBP) 579 vs GBP 910, respectively, in those who achieved a minimum increase of 20 g/L of Hb. This suggests that FDI may achieve the target with fewer infusions and lower costs based on the figures used in the cost analysis. An Italian study analysed the costs of oral sucrosomial iron compared with IV iron gluconate for treating IDA in ND-CKD, showing that the average cost per person per cycle was European Dollar (Euro) 1302.30 for IV iron, whilst oral iron cost Euro 111.05 on average[60]. Higher doses of FCM and FDI can be administered in a single IV infusion but were scarcely available in Italy at the time of the study, thus were not considered comparators. These alternatives would have potentially decreased the costs associated with IV iron in this study. Participants in these studies likely require more frequent infusions due to their anaemic status, hence these results could represent the maximum cost in treating non-anaemic ID.

MONITORING OF ID IN CKD

KDIGO has not specified the monitoring frequency of iron status in CKD without anaemia. However, those who receive erythropoiesis-stimulating agents (ESA) therapy should have their iron status checked every 3 months, including when initiating or changing dose of treatment.

Fortunately, KDIGO does specify the frequency of testing for anaemia. People with CKD without anaemia should have their Hb checked annually (CKD stage 3), biannually (ND-CKD stage 3-4) or every 3 months (DD-CKD). Should anaemia be diagnosed, Hb should then be monitored every 3 months (ND-CKD stage 3-5 or on peritoneal dialysis) or every month if receiving haemodialysis.

INTERNATIONAL GUIDELINES AND RECOMMENDATIONS

There is no international consensus on the optimal management of ID in people with CKD, in fact, most guidelines do not address the issue of treating ID without anaemia in people with CKD. The 2012 KDIGO guidelines recommend a trial of iron repletion if an increase in Hb or decrease in ESA dose is desired, given if TSAT ≤ 30% and SF ≤ 500 μg/L[55,61]. For DD-CKD, this would be achieved with IV iron, in contrast to ND-CKD where oral iron is preferred. The choice of IV iron in ND-CKD depends on the individual’s severity of ID, venous access, compliance and cost. KDIGO recommends that SF should not exceed 500 μg/L.

In 2013, the European renal best practice anaemia working group issued a position paper to help clinicians in the interpretation of KDIGO guidance[62]. They suggested iron repletion (either IV or orally as tolerated) if there is an absolute ID (TSAT < 20% and SF < 100 μg/L). If an increase in Hb is desired for people not on ESA, initiation of iron therapy must be on the basis that TSAT < 25% and SF < 200 μg/L in ND-CKD, or TSAT < 25% and SF < 300 μg/L in DD-CKD, provided that parameters remain below the ceiling of TSAT of 30% and SF of 500 μg/L.

Similarly, the national kidney foundation-kidney disease outcomes quality initiative provided a commentary on the KDIGO guidelines[63]. They believe that a recommendation of an upper SF limit is arbitrary and emerging trials, such as DRIVE, merit consideration. The NICE (2015) and UKKA (2017) guidelines are similar to that of KDIGO but increased the ceiling of SF to 800 μg/L in light of recent evidence[3,64].

CURRENT GUIDELINES AND EMERGING RESEARCH

The 2017 UKKA guidelines have not addressed treating ID in non-anaemic people with CKD, despite emerging trials. The iron and heart trial, a double-blinded randomized trial, investigated the effects of 1000 mg of IV FDI on exercise capacity compared to a placebo infusion in non-anaemic people with ID and CKD stage 3b-5[65]. The six-minute walk test (6MWT) at baseline, 1 month and 3 months post-therapy was used to evaluate functional capacity, showing no statistical difference between the FDI and placebo groups at 1 month (P = 0.736) and 3 months (P = 0.741), despite a numerical increase. The trial revealed a significant increase in SF and TSAT at 1 month and 3 months (P < 0.001) in the IV iron arm, but no significant change in Hb levels, though there was an upwards trend in the FDI group.

A second randomized trial, the iron and muscle trial, investigated the effects of a one-off 1000 mg IV FCM infusion on the 6MWT, in people with CKD stage 3-4 with ID but without anaemia[66]. The results showed a non-significant increase from baseline in the 6MWT at 4 weeks (P = 0.261) and 12 weeks (P = 0.338) in the intervention group when compared to placebo. Interestingly, the mean 6MWT in the FCM group dropped by 4 meters at 4 weeks from baseline but increased by 44 meters at 12 weeks; that is 24 meters more than in the placebo group. Additionally, there was a modest but non-significant improvement in physical function as assessed by the sit-to-stand 60 tests, improving by 2 reps at 12 weeks from baseline in the intervention arm (P = 0.990). Conversely, the difference in SF and TSAT levels were statistically significant at 4 and 12 weeks from baseline (P < 0.001), while the difference in Hb was only significant at 12 weeks (P = 0.009).

The absence of statistically significant findings in the primary endpoint may be attributed to the limited sample sizes (54 participants in the iron and heart trial and 75 in the iron and muscle trial) and the relatively short follow-up periods in both studies. Additionally, the participants appeared to be in relatively good health, as reflected by the comparatively high baseline 6MWT distances (401 meters in iron and heart and 427 meters in iron and muscle), potentially limiting the scope for measurable improvement. This contrasts with heart failure (HF) trials, such as CONFIRM-HF, where the baseline 6MWT was significantly lower (e.g., 295 meters), providing a greater opportunity for improvement[67].

QUALITY ASSESSMENT OF INCLUDED TRIALS

The quality of the iron and heart and iron and muscle trials was assessed using the Cochrane risk of bias tool, a widely accepted framework for evaluating potential bias in randomized controlled trials[68]. This tool examines five domains to determine the overall risk of bias. The first domain, bias arising from the randomization process, evaluates whether the allocation sequence was adequately generated and concealed to ensure participants had an equal chance of assignment and to prevent manipulation. The second domain, bias due to deviations from intended interventions, assesses adherence to the intended interventions, accounting for factors like co-interventions or deviations, such as participants crossing over to other treatments. The third domain, bias due to missing outcome data, investigates how missing data were handled, including reasons for dropouts and whether analyses included all participants as originally randomized. The fourth domain, bias in measurement of the outcome, focuses on whether outcomes were measured in a blinded manner using validated measures to avoid inconsistencies. Finally, the fifth domain, bias in the selection of the reported result, examines whether the reported outcomes were pre-specified in the trial protocol and free from selective reporting.

For both trials, the overall risk of bias was judged to be low across all domains. This robust assessment process enhances confidence in the trials, suggesting that, while their results were statistically non-significant, they were well-conducted and should be considered in the development of future guidelines.

COMPARATIVE STUDIES AND IMPLICATIONS FOR CLINICAL PRACTICE

The ExplorIRON-CKD study recruited 26 participants to compare the effects of FDI and FCM on people with ND-CKD stage 3a-5[69,70]. Although the study included both anaemic and non-anaemic participants, the median baseline Hb was 100.3 g/L, below the lower limit of normal in CKD[71]. They reported a statistically significant (P < 0.001) improvement in functional status following IV iron, regardless of the compound, using the 1-minute sit-to-stand test as a reliable measure of functional status in CKD[72]. Furthermore, there was a significant improvement (P = 0.048) in fatigue with the FDI group at 3 months from baseline, assessed using a visual analogue scale. Significance was also achieved within the whole cohort in 3 out of 8 items (P < 0.05) of the short-form 36 (SF-36), whilst 7 out of 8 showed numerical increases. When assessed simultaneously, these domains provided the best monitoring for fatigue resolution[73]. The PHOSPHARE-IBD study highlighted the risk of hypophosphataemia with FCM, explaining the non-significant increase in fatigue resolution in the FCM group[74]. The constellation of effects relating to FCM can be described as the “6H syndrome” which include high fibroblast growth factor, hypophosphataemia, hyperphosphaturia, hypovitaminosis D, hypocalcaemia, and secondary hyperparathyroidism[75]. Additionally, the FDI arm consisted of younger participants with a lower prevalence of HF, which are potential confounders.

RLS AND IRON SUPPLEMENTATION

People with CKD have a two to three times higher prevalence of RLS than the general population[76]. The exact pathophysiology of RLS remains unclear, but some studies have proposed that a reduction in iron in the brain disrupts the dopaminergic system, producing RLS symptoms[77]. Although dopamine agonists were formerly used as first-line therapy for RLS, their tendency to cause paradoxical worsening of symptoms, known as augmentation, has limited their use in clinical practice[78]. The international RLS study group recommends iron supplementation for people with RLS when SF < 75 μg/L or TSAT < 45%[79]. One meta-analysis showed that people with augmented RLS had significantly lower SF levels compared to people with non-augmented RLS, despite there being no significant difference in Hb between the two arms[80]. This indicates that ID, regardless of anaemia, is an independent risk factor for augmented RLS, hence treating ID is crucial in RLS management.

Limited studies have investigated the effectiveness of IV iron on CKD-associated RLS. Interestingly, two studies found a significant improvement in international RLS severity scale (IRLS) scores after 2 weeks in people receiving IV iron dextran or iron sucrose[81,82]. One systematic review concluded that IV iron was not superior to pramipexole, a dopamine agonist, in the treatment of RLS which suggests that IV iron improves symptoms and QoL of people with RLS[83]. A randomized trial comparing FCM to placebo in non-anaemic people with RLS and ID found that FCM led to a significant improvement in IRLS scores by week 12[84].

IRON SUPPLEMENTATION IN HF

IV FCM is recommended for symptomatic HF to improve symptoms and QoL, following the publication of two randomized trials, CONFIRM-HF and FAIR-HF[67,85]. For the CONFIRM-HF trial, the mean Hb was 124 g/L and mean eGFR was 65 mL/minute/1.73 m²[67]. FAIR-HF included both anaemic and non-anaemic people; mean Hb 120 g/L and mean eGFR 64 mL/minute/1.73 m²[86]. The IRONMAN trial further explored the effects of IV iron on cardiovascular mortality and hospitalization as their primary end point; mean Hb 121 g/L, median age 73 years, 92% were white, 74% were male and the median follow-up was 2.7 years[87]. It concluded that the FDI arm had a lower rate of cardiovascular death or hospital admission per 100 person-years. However, the difference was not statistically significant in the initial analysis but became significant after sensitivity analysis adjusting for corona virus disease 2019 (COVID-19). The Minnesota living with HF questionnaire (MLHFQ) score was significantly lower in the FDI group at 4 months but the 6MWT and EuroQoL five dimensions questionnaire QoL questionnaire were not significantly different. The IRONMAN study excluded people with an eGFR < 15 mL/minute/1.73 m² and the median eGFR was 51 mL/minute/1.73 m². The COVID-19 adjusted sensitivity analysis of the IRONMAN trial reinforced the findings of the AFFIRM-AHF trial which showed that IV FCM significantly reduced HF hospitalizations or cardiovascular death, with limited impact on QoL measures[88].

HEART-FID, the largest up-to-date randomized trial of IV iron in HF and ID, showed no statistical difference between FCM and placebo in improving HF hospitalization, cardiovascular mortality, or 6MWT (P = 0.019)[89]. It included 3065 people who have HF with a reduced ejection fraction; mean age 69 years, 34% were female, 86% were white, mean Hb was 125 g/L. The pre-specified significance level was set at 0.01 which is more robust than the conventional 0.05 target for clinical trials, otherwise this trial would have achieved significance. Nonetheless, the trial confirmed the safety of FCM in people with HF. On the other hand, the result of a recent meta-analysis, which included the results of CONFIRM-HF, AFFIRM-AHF and HEART-FID trials, provided strong evidence favouring the clinical benefits of FCM in reducing cardiovascular death and hospitalization[90].

Toblli et al[91] explored the effects of a weekly 200 mg IV iron sucrose complex (ISC) infusion on anaemic people with chronic HF and CKD, but not on dialysis. The follow-up period was 5 weeks, and all people had ID (SF < 100 μg/L and/or TSAT ≤ 20%). The results showed a significant improvement in New York Heart Association functional class, MLHFQ and 6MWT for those who received ISC. Despite the small sample size of 40, this study provides similar findings to IRONMAN and AFFIRM-AHF trials[87,88].

One observational study emphasised that ID, irrespective of anaemia, had a pronounced impact on prognostic markers in people with HF[92]. Those who were iron-deficient performed significantly worse in cardiopulmonary exercise testing than those who were iron-replete (P = 0.02). Furthermore, there was a 4-fold increase in the risk of mortality in people with IDA than iron-replete people with or without anaemia.

Another observational study involving 1198 people with HF showed that 32% had ID without anaemia at baseline[93]. Exercise capacity was significantly limited in those with ID than people who had anaemia not caused by ID (P < 0.001). These results support the proactive approach of correcting ID in the absence of anaemia to improve QoL outcomes and possibly reduce hospitalization in people with HF.

The 2021 European society of cardiology guidelines gave a class I recommendation (is recommended/indicated) to screen all people with HF for ID (diagnosed when SF < 100 μg/L, or SF 100-299 μg/L and TSAT < 20%)[94]. Also, they give a class II-a recommendation (should be considered) for the use of IV iron supplementation with FCM for people with HF and ID to improve QoL, exercise capacity and hospitalization (Table 2).

Table 2 Summary of discussed chronic kidney disease and heart failure trials.

Trial	n	Intervention	Primary outcome	Secondary outcome
Iron and heart	54	IV FDI vs placebo in people with CKD stage 3b-5 with ID but not anaemic	Non-significant increase in 6MWT at 1 month (P = 0.736) and 3 months (P = 0.741)	At 1-month, significant change in SF and TSAT (P < 0.001)
Iron and muscle	75	IV FCM vs placebo in people with CKD stage 3-4 with ID but not anaemic	Non-significant increase in 6MWT at 4 weeks (P = 0.261)	At 12 weeks, significant change in SF (P < 0.001), TSAT (P = 0.019) and Hb (P = 0.009)
ExplorIRON-CKD	26	IV FDI vs IV FCM in ND-CKD people with ID with/without anaemia	Significant change in iFGF-23 at 1-2 days favouring FCM (P < 0.001)	Significant improvement in functional status regardless of compound used (P < 0.001)
CONFIRM-HF	304	IV FCM vs placebo in people with chronic HF and ID	Significant change in 6MWT at 24 weeks from baseline (P = 0.002)	Significant improvement in NYHA from weeks 24 (P = 0.004) and onwards (P < 0.001)
FAIR-HF	459	IV FCM vs placebo in people with chronic HF and ID	Significant improvement in patient global assessment and NYHA class at 24 weeks (P < 0.001)	Significant improvement in 6MWT from weeks 4 onwards (P < 0.001)
IRONMAN	1137	Long term effects of IV FDI on cardiovascular events in people with HF	Significant reduction in hospital admissions for HF and cardiovascular death (P = 0.047) after adjusting for COVID-19	Non-significant change in 6MWT at 4 months (P = 0.90) and 20 months (P = 0.068)
AFFIRM-AHF	1132	IV FCM vs placebo in people following an episode of acute HF	Significant reduction in HF hospitalizations and deaths up to 52 weeks (P = 0.024) after adjusting for COVID-19	Significant reduction in cardiovascular hospitalizations and deaths up to 52 weeks (P = 0.024) after adjusting for COVID-19
HEART-FID	3065	IV FCM vs placebo in people with HF and ID following recent HF hospitalization	Non-significant improvement in hospitalization, mortality and 6MWT (P = 0.019)	Non-significant reduction in cardiovascular hospitalizations and death (hazard ratio = 0.93)

NYHA: New York Heart Association; IV: Intravenous; FDI: Ferric derisomaltose; CKD: Chronic kidney disease; ID: Iron deficiency; 6MWT: Six-minute-walk test; SF: Serum ferritin; TSAT: Transferrin saturation; FCM: Ferric carboxy maltose; Hb: Haemoglobin; ND-CKD: Non-dialysis dependent chronic kidney disease; FGF: Fibroblast growth factor; HF: Heart failure; COVID-19: Corona virus disease 2019.

SPECIAL POPULATIONS AND CONSIDERATIONS

Given that CKD is relatively uncommon in the paediatric population, there are limited studies regarding the prevalence of ID or anaemia in this population. One study estimated the prevalence of severe CKD, defined as eGFR < 30 mL/minute/1.73 m², to be 81.2 per million children under 16 years old in the United Kingdom[95]. NICE follows KDIGO guidelines in the diagnosis of anaemia of CKD in children; Hb < 11.0 g/dL (aged 0.5-5 years), < 11.5 (aged 5-12 years), < 12.0 (aged 12-15 years)[3,55]. The threshold for treating ID is TSAT ≤ 20% and SF ≤ 100 μg/L, which is identical to that of the adult population. The evidence for monitoring of ID does not differ to the adult population. The treatment for children is mainly with oral iron except for DD-CKD which is mainly IV iron. In the United Kingdom, the number of licensed iron preparations for children is limited, posing a challenge in the effective management of ID in the paediatric population with CKD.

For the elderly population, the presence of comorbidities and inflammation complicates the diagnosis of absolute ID given that SF may be chronically elevated. Polypharmacy can affect iron absorption or interact with iron repletion strategies. Ultimately, balancing the risks and benefits of treatment in this population must be careful whilst also considering the overall health status and QoL.

In high-income countries, roughly 3% of pregnant women suffer from CKD[96]. During pregnancy, iron is an essential nutrient for the development of the foetus and IDA is associated with an increased risk of preterm birth[97]. The UKKA published guidelines on pregnancy and renal disease (2019) using the same thresholds as those established for non-pregnant individuals[98,99]; SF < 100 μg/L, TSAT < 20%, HRC > 6%, CHr < 25 pg. Evidently, the cut-off for CHr at 25 pg (sensitivity 76% and specificity 81%) differs from the UKKA 2017 guidelines which set the cut off at 29 pg (sensitivity 57% and specificity 93%); they do not provide a rationale for this change[100,101]. Admittedly, the specificity and sensitivity of these markers in pregnancy is not known. On the other hand, the British Society for Haematology advises the use of SF < 30 μg/L as the only marker for diagnosing ID in pregnancy; this threshold was not in the context of CKD[102]. The choice between oral iron repletion vs parenteral iron in pregnant people is similar to those who are not pregnant, although there are safety issues regarding the use of IV iron in the first trimester[95].

The European anaemia of CKD alliance raised concerns regarding some QoL tools used in clinical practice such as the SF-36 and the 12-item short form survey[103]. Instead, they suggest the implementation of the new, validated, anaemia-specific questionnaire containing 23 items, CKD and anaemia questionnaire[104]; this was later updated in 2022 to contain 21 items. This change should help doctors assess the burden of disease routinely in a shorter amount of time.

CONCLUSION

Emerging studies on IV iron in non-anaemic individuals with CKD have provided valuable insights into its potential clinical applications. While the iron and heart and iron and muscle trials did not demonstrate statistically significant results, they reported numerical improvements in functional capacity, fatigue and physical function, suggesting a need for further research to explore these promising trends. Evidence from HF trials, which included participants with CKD, has highlighted the benefits of iron repletion in addressing ID without anaemia, further supporting its therapeutic potential in this population. Additionally, the ExplorIRON-CKD study suggested that FDI may be preferable to FCM in CKD populations due to its potentially lower impact on markers of bone turnover. Future studies should not only aim for larger sample sizes and robust endpoints such as the 6MWT to improve reproducibility, but also investigate earlier identification and treatment of ID. Screening strategies for ID in non-anaemic individuals should be standardized to ensure timely intervention, as earlier use of IV iron may yield greater benefits. To translate these findings into clinical practice, more specific recommendations are warranted. Clinicians would benefit from clear guidance on selecting IV iron preparations, considering factors such as safety, efficacy, person-specific characteristics, and the emerging evidence favouring FDI for its potential bone-protective properties. Establishing standardized protocols for when to initiate IV iron therapy is equally important. This could include routine screening of people with CKD for ID, even in the absence of anaemia, with clearly defined thresholds for SF and TSAT levels to guide intervention. Furthermore, practical advice on optimizing dosing strategies, such as whether to use fixed doses or weight-based approaches, and determining the ideal frequency of administration, would support more consistent and effective use of IV iron. Future research should aim to refine these dosing regimens while considering person-specific factors such as disease severity and treatment goals. These efforts, combined with a focus on earlier intervention and robust outcome measures, will ensure that IV iron therapy is maximized to improve QoL, functional capacity, and long-term outcomes for individuals with CKD.