ABSTRACT
Background
Iron deficiency is common in patients receiving haemodialysis and contributes to adverse outcomes. Conventional iron biomarkers, including ferritin and transferrin saturation (TSAT), have limitations and may be less accessible in some settings. Reticulocyte haemoglobin equivalent (RET‐He) is a lower‐cost, potentially more accessible marker for detection of iron deficiency. This study evaluated whether RET‐He‐guided intravenous iron supplementation is non‐inferior to TSAT‐guided supplementation in haemodialysis patients.
Methods
In this randomized non‐inferiority trial, 160 haemodialysis patients were randomized to a TSAT‐guided group (n = 79) or RET‐He‐guided group (n = 81). Intravenous iron was administered in both groups according to prespecified protocols. The primary outcome was the erythropoietin resistance index (ERI) at 3 and 6 months. RET‐He guidance was considered non‐inferior if the upper bound of the 95% confidence interval (CI) for the between‐group mean difference was ≤ 160 units/week/g/dL. Secondary outcomes included all‐cause mortality, hospitalization, cardiovascular events, blood transfusion, and infection.
Results
Baseline characteristics were comparable between groups. RET‐He‐guided supplementation was non‐inferior to TSAT‐guided supplementation for ERI at 3 months (mean difference, −35.92; 95% CI, −155.60 to 90.29; p = 0.001 for non‐inferiority) and 6 months (mean difference, −39.68; 95% CI, −187.01 to 107.64; p = 0.004 for non‐inferiority). The RET‐He group received significantly lower cumulative intravenous iron doses. Secondary outcomes did not differ significantly, although the trial was not powered for these clinical outcomes.
Conclusion
RET‐He‐guided intravenous iron supplementation was non‐inferior to TSAT‐guided supplementation for reducing ERI over 6 months. Use of RET‐He may offer a lower‐cost and more accessible strategy for anaemia management in haemodialysis patients, particularly in resource‐limited settings.
Keywords: erythropoietin resistance index (ERI), iron supplement, reticulocyte haemoglobin equivalent (RET‐he)
Summary at Glance
RET‐He‐guided intravenous iron supplementation is noninferior to TSAT‐guided supplementation in reducing the erythropoietin resistance index (ERI), while requiring significantly lower cumulative iron doses.
These findings highlight RET‐He as a lower‐cost, more accessible, and clinically relevant strategy for anaemia management in patients receiving chronic haemodialysis, particularly in resource‐limited settings and regions where TSAT testing may be less readily available.
1. Background and Rationale
Iron deficiency in patients with end stage kidney disease (ESKD) is associated with adverse clinical outcomes, particularly cardiovascular outcomes such as heart failure and increasing all‐cause mortality. Being used as the current standard diagnostic tests, conventional iron biomarkers such as ferritin and transferrin saturation (TSAT) [1], are influenced by acute‐phase responses including inflammation and infection, have limited accessibility in out‐hospital dialysis centers, involve long turnaround times, and can be costly in certain countries. Reticulocyte haemoglobin equivalent (RET‐He) is a novel parameter that assesses functional iron status by measuring the haemoglobin content in reticulocytes. This parameter can detect iron deficiency at an early stage, serves as an early marker of response to iron therapy [2] and is unaffected by acute‐phase responses. RET‐He has been validated in various populations, including patients with ESKD and is cheaper than the conventional iron biomarkers [3, 4]. However, no trial has used RET‐He to guide intravenous iron supplementation.
Results from the PIVOTAL (Proactive IV Iron Therapy in Haemodialysis Patients) trial [5], indicate that proactive monthly administration of 400 mg intravenous iron in patients with serum ferritin < 700 mg/L and TSAT < 40% reduces erythropoietin stimulating agents (ESAs) use and lowers the composite risk of all‐cause death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization from heart failure compared with a reactive low‐dose intravenous iron initiated at ferritin < 200 mg/L or TSAT < 20%. However, the potential benefits of more liberal intravenous iron use in HD patients must be balanced against potential risks. Excessive intravenous iron administration in HD may exacerbate oxidative stress, inflammation, and endothelial dysfunction and could increase the risk of bacterial infections and cardiovascular events [6, 7, 8].
The current Clinical Practice Guidelines (CPG) for Anaemia in CKD patients in Thailand, 2021 [9] recommend that IV iron supplements are preferred over oral iron supplements in haemodialysis patients with anaemia and absolute iron deficiency (TSAT < 20% and ferritin < 200 ng/mL) or functional iron deficiency (TSAT < 20% and ferritin > 200 ng/mL) and iron supplement should be stopped when TSAT > 40% or ferritin > 800 ng/mL to prevent hemochromatosis (iron overload).
In this study, we prospectively conducted a multicenter cluster randomized controlled non‐inferiority trial to compare the efficacy of RET‐He‐guided versus TSAT‐guided intravenous iron supplement in HD patients. The primary outcome was the erythropoietin resistance index (ERI) at 3‐month, 6‐month follow up. Secondary outcomes included all‐cause mortality, hospitalization, cardiovascular events, blood transfusion, and infection.
2. Materials and Methods
2.1. Study Designs
This multicenter, cluster‐randomized non‐inferiority trial was prospectively carried out over 6 months. Each haemodialysis center (cluster) was randomized to either the RET‐He–guided (intervention) or TSAT‐guided (control) intravenous iron supplementation protocol (Figure 1A,B). This sampling technique was useful when a large population that's geographically dispersed, making it impractical or costly to sample every individual in the population. The trial was registered at ClinicalTrials.gov (NCT06906835) and conducted in accordance with the Declaration of Helsinki and the International Council for Harmonization's Good Clinical Practice guidelines. Written informed consent was obtained from all participants. The study was approved by the Institutional Review Board, Faculty of Medicine, Chulalongkorn University (IRB no. 0202/67).
FIGURE 1.
(A) Protocol for TSAT guided group. (B) Protocol for RET‐He guided group. *Due to the lack of a standard iron supplementation dose in RET‐He guided, we assumed an equivalent dose range of RET‐He from Almashjary et al. [2] with TSAT and ferritin levels. Abbreviations: IV—intravenous, RET‐HE—reticulocyte haemoglobin content, TSAT—transferrin saturation,.
2.2. Participants
The study was conducted in patients with ESKD on chronic haemodialysis with anaemia requiring erythropoietin therapy recruiting from haemodialysis centers (cluster sites). Eligible participants were adults aged 18–80 years undergoing chronic haemodialysis for at least 6 months, had been on erythropoietin therapy for at least 6 months, and had haemoglobin (Hb) levels < 13.0 g/dL in males and < 12.0 g/dL in females. Exclusion criteria comprised serum ferritin > 800 ng/mL or transferrin saturation (TSAT) > 40%, active infection or malignancy, a history of hematologic diseases (including thalassaemia major, hemolysis, myelofibrosis, or myelodysplastic syndrome), use of marrow‐suppressive or immunosuppressive medications, active heart failure, recent myocardial infarction or stroke (within the past 6 months), and history of gastrointestinal or external bleeding or blood transfusion (within the past 6 months). Written informed consent was provided by all participants prior to enrollment.
2.3. Randomization
This study employed a cluster randomization design, in which participants within the same haemodialysis center received the same treatment protocol. The randomization sequence was pre‐defined and concealed prior to center recruitment.
2.4. Study Intervention
Participants were allocated into two groups to receive intravenous iron supplementation according to pre‐specified protocols. In the TSAT‐guided group (Figure 1A), iron dosing frequency was determined based on TSAT and serum ferritin levels. In the RET‐He–guided group (Figure 1B), dosing frequency was determined based on reticulocyte haemoglobin equivalent (RET‐He), with serum ferritin used as a safety threshold to avoid iron overload. Due to the absence of a standard RET‐He–guided dosing regimen, dosing frequency in the RET‐He group was adapted from the equivalent TSAT/ferritin thresholds described by Almashjary et al. [2]. All types of erythropoiesis‐stimulating agents were converted to epoetin beta–equivalent doses based on the study by Vega A et al. [10].
2.5. Statistical Analysis
The primary outcome, ERI, was log‐transformed to address non‐normality and analysed using a linear mixed model (LMM), adjusting for relevant covariates. Non‐inferiority was established if the upper bound of the 95% confidence interval from the LMM did not exceed the non‐inferiority margin of 160 unit/week/g/dL. A one‐sided Z test was used to confirm non‐inferiority, with a p‐value of less than 0.025 indicating statistical significance.
Secondary outcomes were evaluated for superiority using appropriate models, with non‐normally distributed data log‐transformed prior to analysis. The correlation between continuous outcomes was assessed using LMMs, adjusting for relevant covariates. Pre‐specified subgroup analyses were conducted based on haemodialysis frequency; sensitivity analyses were performed according to baseline iron status and thalassaemia status, cost comparison between protocol per evaluation and annually per patient.
For descriptive statistics, continuous variables were summarized as mean ± standard deviation for normally distributed data or as median with interquartile range (IQR) for non‐normally distributed data, and categorical variables as counts and percentages. All analyses were performed according to the per‐protocol population using STATA SE Version 18.0.
Based on individual patient data from a multicenter randomized controlled trial in Thailand by Susantitaphong et al. [7], which reported a baseline ERI of 788 ± 124 unit/week/g/dL and a 20% (160 unit/week/g/dL) reduction with IV iron, the non‐inferiority margin was set at 160 unit/week/g/dL. Using an intra‐cluster correlation coefficient of 0.18, the required sample size for a cluster randomized design with a continuous outcome was calculated in STATA SE 18.0. With 20 participants per cluster, 80 participants per group, and an allowance for 25% dropout, the study was powered at 80% with a one‐sided α of 0.025.
3. Results
3.1. Baseline Characteristics
A total of 641 participants were assessed for eligibility. After screening, 217 participants met initial inclusion criteria and underwent laboratory evaluation (Figure 2). After exclusion, 160 participants were randomized with 79 participants to the TSAT‐guided group and 81 to the RET‐He‐guided group (Figure 2). Baseline characteristics (Table 1) including age, sex, co‐morbidity, haemodialysis frequency, haemoglobin concentration, iron status parameters (serum iron, ferritin, serum total iron binding capacity (TIBC), TSAT, reticulocyte haemoglobin equivalent (RET‐He)), and ESA doses (units/week) as well as ESA types were well balanced between groups at randomization. The baseline ERI was 864.54 ± 366.28 units/week/g/dL in the TSAT‐guided group and 843.60 ± 384.09 units/week/g/dL in the RET‐He‐guided group, indicating a similar degree of erythropoietin resistance at the start of the study. Notably, the prevalence of thalassaemia trait was higher in the RET‐He‐guided group (30.9%) compared with the TSAT‐guided group (16.5%).
FIGURE 2.
Consort flow diagram.
TABLE 1.
Baseline Characteristics.
| TSAT‐guided group (N = 79) | RET‐He‐guided group (N = 81) | |
|---|---|---|
| Age (Years) | 54.87 ± 11.61 | 60.88 ± 13.25 |
| Sex (%Men) | 53 (67.1%) | 39 (48.1%) |
| Underlying disease: Case (%) | ||
| Diabetes mellitus | 29 (36.7%) | 49 (60.5%) |
| Hypertension | 74 (93.7%) | 77 (95.1%) |
| Chronic glomerulonephritis | 9 (11.4%) | 5 (6.1%) |
| HD frequency (times/week): Case (%) | ||
| 2 | 18 (22.8%) | 27 (33.3%) |
| ≥ 3 | 61 (77.2%) | 54 (66.7%) |
| Hemoglobin typing: case (%) | ||
| Normal | 66 (83.5%) | 56 (69.1%) |
| Thalassemia trait | 13 (16.5%) | 25 (30.9%) |
| Iron status | ||
| Absolute iron deficiency a | 11 (13.9%) | 6 (7.4%) |
| Functional iron deficiency b | 68 (86.1%) | 75 (92.6%) |
| Erythropoietin stimulating agents (ESA) | ||
| Epoetin alfa | 77 (97.5%) | 71 (87.7%) |
| Epoetin beta | 0 (0%) | 6 (7.4%) |
| Darbepoetin alfa | 2 (2.5%) | 4 (4.9%) |
| Hemoglobin (g/dL) | 10.07 ± 1.35 | 10.02 ± 1.30 |
| Serum iron (mcg/dL) | 49.10 ± 14.93 | 52.11 ± 15.18 |
| Serum total iron binding capacity (TIBC) (mcg/dL) | 201.02 ± 43.29 | 193.81 ± 36.82 |
| Serum ferritin (ng/mL) | 352.23 ± 230.44 | 346.11 ± 198.63 |
| Transferrin saturation (%) | 24.60 ± 7.54 | 27.38 ± 7.70 |
| Reticulocyte count hemoglobin equivalent (pg/cell) | 30.25 ± 3.64 | 29.94 ± 3.72 |
| Erythropoietin stimulating agents (ESA) (equivalent dose to epoetin alfa) unit/week | 8,456 ± 3,218 | 8,335 ± 3,403 |
| Erythropoietin resistance index (ERI) (Unit/week/g/dL) | 864.54 ± 366.28 | 843.60 ± 384.09 |
TSAT < 20% and ferritin < 200 ng/mL.
TSAT < 20% and ferritin > 200 ng/mL.
3.2. Primary Outcome
At 3 and 6 months (Table 2), the ERI values were 804.76 ± 345.43 and 755.45 ± 353.26 units/week/g/dL in the TSAT‐guided group, and 821.64 ± 322.92 and 757.05 ± 401.28 units/week/g/dL in the RET‐He‐guided group, respectively. Non‐inferiority analysis using a prespecified margin of ≤ 160 units/week/g/dL demonstrated that the RET‐He‐guided group exhibited non‐inferior efficacy to the TSAT‐guided group in reducing ERI at both the 3 and 6 months, with mean differences of −32.65 (95% CI: −155.60 to 90.29, p for non‐inferiority = 0.001) and −39.68 (95% CI: −187.01 to 107.64, p for non‐inferiority = 0.004), respectively. After adjusting for thalassaemia trait status at 6 months, the results remained consistent, confirming the non‐inferiority mean difference: –77.25 (95% CI: −311.59 to 157.08, p for non‐inferiority = 0.023) (Figure 3).
TABLE 2.
The erythropoietin resistance index (ERI) during the 6‐month follow‐up period.
| ERI (Unit/week/g/dL) | TSAT‐guided group | RET‐He‐guided group | Mean differences (95% CI) |
|---|---|---|---|
| 3rd month | 804.76 ± 345.43 | 821.64 ± 322.92 | −32.65 (−155.60 to 90.29) |
| 6th month | 755.45 ± 353.26 | 757.05 ± 401.28 | −39.68 (−187.01 to 107.64) |
The prespecified non‐inferiority margin for the upper bound of the 95% CI was set at ≤ 160 units/week/g/dL.
FIGURE 3.
Non‐inferiority results.
Other outcomes at the 3 and 6 months demonstrated no significant differences between the two groups in haemoglobin concentration, serum iron, TIBC, TSAT, and serum ferritin. Mean average ESA doses were also comparable in the 3 and 6 months (Table 3). Importantly, the RET‐He‐guided group received significantly lower cumulative IV iron dose at both the 3 months, 495 ± 243 versus 592 ± 279 mg/3 months (p = 0.01) and the 6 months, 413 ± 248 versus 501 ± 302 mg/3 months (p = 0.03).
TABLE 3.
Laboratory parameters: Hb, iron study, RET‐He, ESA dose, IV iron dose during the 6‐month follow‐up period.
| Time | TSAT‐guided group | RET‐He‐guided group | p | |
|---|---|---|---|---|
| Hb (mg/dL) | 3rd month | 10.45 ± 1.34 | 10.24 ± 1.23 | 0.16 |
| 6th month | 10.27 ± 1.38 | 10.11 ± 1.41 | 0.25 | |
| Serum iron (mcg/dL) | 3rd month | 57.35 ± 22.87 | 53.64 ± 16.32 | 0.13 |
| 6th month | 56.53 ± 16.71 | 60.49 ± 24.86 | 0.86 | |
| TIBC (mcg/dL) | 3rd month | 199.46 ± 32.18 | 187.13 ± 36.12 | 0.98 |
| 6th month | 201.58 ± 30.27 | 198.71 ± 35.04 | 0.70 | |
| Ferritin (ng/mL) | 3rd month | 416.12 ± 234.51 | 504.23 ± 457.76 | 0.92 |
| 6th month | 410.15 ± 223.23 | 469.69 ± 394.53 | 0.86 | |
| TSAT (%) | 3rd month | 28.52 ± 9.53 | 29.51 ± 9.51 | 0.73 |
| 6th month | 28.17 ± 7.95 | 31.11 ± 13.34 | 0.94 | |
| RET‐He (pg/cell) | 3rd month | 31.16 ± 3.33 | 30.68 ± 3.34 | 0.20 |
| 6th month | 31.52 ± 2.95 | 30.68 ± 3.28 | 0.06 | |
| ESA dose (unit/week) | 3rd month | 8157 ± 3077 | 8309 ± 3212 | 0.62 |
| 6th month | 7542 ± 3280 | 7392 ± 3582 | 0.40 | |
| Iron dose (mg/3 months) | 3rd month | 592 ± 279 | 495 ± 243 | 0.01 |
| 6th month | 501 ± 302 | 413 ± 248 | 0.03 |
3.3. DSubgroup Analysis: Haemodialysis Frequency 2 Times/Week Group vs. 3 Times/Week Group
Subgroup analysis by haemodialysis frequency 2 times/week group showed that the values of ERI at the 3 and 6 months were 869.17 ± 364.05 and 797.68 ± 372.42 units/week/g/dL in the TSAT‐guided group and 802.57 ± 318.38 and 741.78 ± 370.33 units/week/g/dL in the RET‐He‐guided group (N = 26) (p for non‐inferiority = 0.19 and 0.23, respectively).
In 3 times/week group, the values of ERI at the 3 and 6 months were 784.09 ± 340.24 and 741.93 ± 349.74 units/week/g/dL in the TSAT‐guided group and 831.36 ± 327.92 and 765.35 ± 420.88 units/week/g/dL in the RET‐He‐guided group (p for non‐inferiority = 0.005 and 0.01, respectively).
3.4. Sensitivity Analysis: Thalassaemia Trait Group
Subgroup analysis by Thalassaemia trait group illustrated that the values of ERI at the 3 and 6 months were 766.46 ± 390.77 and 692.24 ± 378.99 units/week/g/dL in the TSAT‐guided group and 908.19 ± 404.94 and 807.18 ± 483.80 units/week/g/dL in the RET‐He‐guided group (p for non‐inferiority = 0.45 and 0.39, respectively).
3.5. Sensitivity Analysis: Absolute Iron Deficiency Status
Subgroup analysis by absolute iron deficiency status showed comparable ERI values in the 3 and 6 months, 598.38 ± 356.50 and 511.21 ± 386.58 units/week/g/dL in the TSAT‐guided group and 720.48 ± 334.57 and 296.50 ± 290.85 units/week/g/dL in the RET‐He‐guided group (p for non‐inferiority = 0.25 and 0.61, respectively).
3.6. Secondary Outcomes
Secondary outcomes assessed during the 6‐month follow‐up period included iron overload, blood transfusions, infections, hospitalizations, cardiovascular events, and all‐cause mortality. The incidences of these adverse events were comparable between the TSAT‐guided and RET‐He‐guided groups, indicating a similar safety profile for both iron supplementation protocols (Table 4).
TABLE 4.
Adverse events (secondary outcomes).
| TSAT‐guided group (N = 79) | RET‐He‐guided group (N = 81) | |
|---|---|---|
| Death | 6 (7.6%) | 7 (8.6%) |
| Hospitalization | 6 (7.6%) | 7 (8.6%) |
| Cardiovascular events | 3 (3.8%) | 2 (2.5%) |
| Infection | 4 (5.1%) | 4 (4.9%) |
| Blood transfusions | 3 (3.8%) | 5 (6.2%) |
| Iron overload (stop IV Iron) | 11 (13.9%) | 12 (14.8%) |
Iron overload: Ferritin ≥ 800 ng/mL, TSAT ≥ 40%, RET‐He > 36 pg/cell.
3.7. Laboratory Cost Comparison
RET‐He guided protocol reduced laboratory costs compared to the conventional TSAT‐guided protocol (USD 10.61 vs. 14.85 per evaluation), savings USD 4.24 per evaluation and USD 16.97 annually per patient, based on the four evaluations 4 times per year (every three months) recommended by the Nephrology Society of Thailand (Table 5).
TABLE 5.
Direct laboratory cost comparison and annual savings per patient.
| Monitoring protocol | Component assays and unit costs a | Total cost per evaluation (USD) b | Annual cost per patient (USD) b , c |
|---|---|---|---|
| RET‐He guided protocol | RET‐He: USD 1.21—Serum Ferritin: USD 9.39 | 10.61 | 42.42 |
| TSAT guided protocol | Serum Iron: USD 3.03—TIBC: USD 2.42—Serum Ferritin: USD 9.39 | 14.85 | 59.39 |
| Net Savings with RET‐He | Cost reduction per patient | 4.24 | 16.97 |
Unit costs are based on the official medical reimbursement fee schedule of the Comptroller General's Department (CGD) of Thailand.
USD values are converted at an exchange rate of 1 USD = 33.00 THB.
Annual costs are based on a monitoring frequency of four (every 3‐month) evaluation cycles per year.
4. Discussion
Previous studies have demonstrated that RET‐He is a reliable predictor for detecting and diagnosing iron deficiency anaemia in the general population and chronic haemodialysis patients [2, 3]. However, evidence on RET‐He‐guided iron supplementation protocols remains limited. In this study, the RET‐He‐guided protocol was non‐inferior to the TSAT‐guided protocol for ERI over 6 months and required significantly lower cumulative intravenous iron doses. These findings suggest that RET‐He‐guided supplementation may reduce iron exposure while maintaining an acceptable ESA resistance profile.
RET‐He provides an earlier and more dynamic assessment of functional iron availability, as it is unaffected by inflammation or infection, which can alter TSAT and ferritin levels. Unlike these markers, RET‐He directly reflects iron availability for erythropoiesis at an early stage, potentially enabling more timely intervention. As an automated parameter measured alongside the reticulocyte count on standard complete blood count analysers, RET‐He may also improve accessibility, shorten turnaround time, and reduce the logistical and financial burden associated with external laboratory testing.
Iron supplementation is more complex in patients with hemoglobinopathy such as thalassaemia due to the high risk of iron overload. This issue has not been addressed in previous international anaemia guidelines. Given the high prevalence of thalassaemia trait in certain areas including Southeast Asia and its impact on hematologic parameters, this finding is clinically relevant. Thalassaemia trait may affect iron metabolism, ESA responsiveness, and the interpretation of iron biomarkers, including RET‐He [11]. Prior studies also demonstrated the applicability of RET‐He‐guided iron therapy in populations with varied baseline hemoglobinopathies [2, 3], however, these studies did not further explore in chronic haemodialysis patients with hemoglobinopathies.
Interestingly, our findings have important clinical implications. In our study, the proportion of patients with thalassaemia traits was higher in the RET‐He‐guided group than in the TSAT‐guided group. After adjustment for thalassaemia trait status, the RET‐He‐guided group still maintained non‐inferior efficacy in reducing ERI compared to the TSAT‐guided group. These findings support the use of RET‐He as a functional iron marker even in a population with a high prevalence of hemoglobinopathy. These results could support the use of RET‐He in chronic haemodialysis with hemoglobinopathies, especially in Asian countries which have a high prevalence of hemoglobinopathies.
Regarding safety, there were no significant differences between groups in the rates of adverse events including iron overload, blood transfusions, hospitalization, cardiovascular events, and all‐cause mortality over a 6‐month period. These findings are supported by the results of the PIVOTAL trial [5] and meta‐analyses [11], demonstrating the importance of balancing iron supplementation against risks such as infection and cardiovascular events.
4.1. Strengths and Limitations
The strengths of our study include this is the first research using RET‐He‐guided intravenous iron supplementation in haemodialysis patients. Second, the multicenter design with cluster randomization enhances the generalizability of the study results across a broader population. Third, the use of standardized treatment protocols ensured consistency in intervention delivery across all study sites.
However, there are certain limitations. First, the RET‐He‐guided intravenous iron supplementation protocol still requires ferritin measurement to monitor iron overload. Second, although sensitivity analyses were performed to adjust the imbalance in thalassaemia trait prevalence between the groups, this variable might introduce confounding influence. Third, the RET‐He cut‐off values used in this study were based on previous literature due to the absence of standardized guidelines, highlighting the need for further research to validate optimal thresholds.
4.2. Implications for Practice and Future Research
The results of our study support the use of the RET‐He‐guided IV iron supplementation protocol as non‐inferior to the TSAT‐guided protocol for guiding intravenous iron therapy in haemodialysis patients. Incorporating RET‐He‐guided IV iron supplementation protocol into routine anaemia management protocols could help reduce both laboratory and intravenous iron costs.
Future research should focus on validating RET‐He thresholds in diverse populations, evaluating cost‐effectiveness in national health systems, and exploring long‐term outcomes including cardiovascular morbidity and mortality.
5. Conclusion
Our cluster randomized controlled trial demonstrated that the RET‐He‐guided intravenous iron supplementation protocol is non‐inferior to the standard TSAT‐guided protocol in reducing the ERI among haemodialysis patients. Combined with a comparable safety profile between both groups, with no significant differences in adverse events, these findings support RET‐He as a reliable, lower‐cost, highly accessible, and logistically efficient alternative for guiding iron therapy in the management of anaemia in haemodialysis patients.
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgements
This investigator‐initiated trial was supported by a grant from Sysmex, which had no involvement in the trial design, oversight, data collection, data analysis, interpretation of the findings, or manuscript preparation. We sincerely thank Professor Stephen J. Kerr, PhD, for his advice on the sample size calculation, and Associate Professor Phandee Watanaboonyongcharoen, MD, MSc, for her advice and coordination related to laboratory medicine. We also thank all patients for their participation, as well as the dialysis nursing staff at the participating dialysis centers and the clinical trial coordinators for their invaluable support and dedication throughout the study.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
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Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.