Iron Availability, Inflammation, and ESA Responsiveness in Maintenance Hemodialysis: A Patient-Month Longitudinal Analysis

Iron Availability, Inflammation, and ESA Responsiveness in Maintenance Hemodialysis: A Patient-Month Longitudinal Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Iron Availability, Inflammation, and ESA Responsiveness in Maintenance Hemodialysis: A Patient-Month Longitudinal Analysis Yukinobu Ikegishi This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9073383/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Anemia management in patients receiving maintenance hemodialysis relies on erythropoiesis-stimulating agents (ESAs) and intravenous (IV) iron supplementation. However, the relationship between iron administration, iron indices, and ESA responsiveness remains complex in routine clinical practice. In particular, whether regular low-dose IV iron supplementation consistently improves ESA responsiveness has not been well characterized using high-resolution longitudinal data. Methods We conducted a single-center retrospective longitudinal observational study in maintenance hemodialysis patients with at least 12 months of available monthly data. Patient-month–level observations included hemoglobin, ESA dose, IV iron dose, transferrin saturation (TSAT), ferritin, albumin, C-reactive protein (CRP), and clinical stress indicators. ESA responsiveness was assessed using the erythropoiesis resistance index (ERI). To examine temporal relationships, prior-month IV iron exposure was evaluated in relation to contemporaneous ERI. Linear mixed-effects models with patient-level random intercepts were used to account for repeated measurements. Results A total of 57 maintenance hemodialysis patients contributed 684 patient-month observations. Median hemoglobin was 11.1 g/dL (IQR 10.2–11.9), and median ERI was 14.0 (IQR 8.45–19.34). At comparable monthly IV iron doses, TSAT and ferritin showed substantial variability across patient-months. In mixed-effects analyses, prior-month IV iron dose was not significantly associated with ERI in the primary model. In contrast, lower TSAT and lower serum albumin were independently associated with higher ERI, indicating reduced ESA responsiveness. Conclusions In maintenance hemodialysis patients managed with regular low-dose IV iron supplementation, iron exposure did not uniformly translate into improved ESA responsiveness. Substantial variability in iron indices and ERI suggests heterogeneous iron utilization, potentially reflecting functional iron deficiency. These findings support a longitudinal, response-guided approach to anemia management that integrates iron indices with ESA responsiveness rather than relying on iron dosing alone. Functional iron unavailability Hemodialysis Anemia Iron dysregulation ESA hyporesponsiveness Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Anemia is a common and clinically important complication in patients receiving maintenance hemodialysis. Erythropoiesis-stimulating agents (ESAs) and intravenous (IV) iron supplementation are central components of anemia management; however, ESA hyporesponsiveness remains frequent and is associated with increased morbidity, mortality, and healthcare costs ( 1 , 11 ). While iron deficiency is a major contributor to ESA hyporesponsiveness, the relationship between iron administration, iron indices, and erythropoietic response is often complex in routine clinical practice ( 2 , 3 ). In Japan, IV iron is typically administered as low-dose, regular supplementation, often on a weekly basis, with careful monitoring of ferritin levels to avoid iron overload ( 4 , 5 ). This practice differs from bolus or high-dose maintenance strategies commonly used in Western countries. Despite this relatively standardized approach, clinicians frequently encounter patients in whom anemia control remains suboptimal even with ongoing iron supplementation. Traditional iron indices, such as transferrin saturation (TSAT) and serum ferritin, do not always reliably reflect iron availability for erythropoiesis, particularly in the presence of inflammation or altered iron utilization ( 3 , 8 , 9 ). Previous large registry studies in Japan have demonstrated cross-sectional associations between iron indices and hemoglobin or ESA dose ( 4 , 5 ). However, these analyses are limited by low temporal resolution and lack detailed information on actual iron dosing patterns. In contrast, monthly longitudinal data capturing iron exposure, iron indices, and ESA responsiveness may better reflect real-world anemia management and uncover heterogeneity in treatment response that is obscured in cross-sectional analyses ( 10 ). Therefore, we conducted a single-center longitudinal observational study to examine the monthly relationship between IV iron exposure, iron indices, and ESA responsiveness in maintenance hemodialysis patients managed under low-dose intravenous iron supplementation practices. By integrating patient-month–level data over a 12-month period, we aimed to clarify whether iron exposure uniformly translates into improved ESA responsiveness and to identify patterns suggestive of impaired iron utilization in routine hemodialysis care ( 2 , 8 , 12 ). Methods Study design and population This was a single-center, retrospective longitudinal observational study conducted in maintenance hemodialysis patients. Adult patients undergoing maintenance hemodialysis at our center were eligible for inclusion if they had at least 12 consecutive months of available monthly data on hemoglobin, ESA dose, IV iron administration, and iron indices. Patients with incomplete longitudinal data or receiving dialysis modalities other than maintenance hemodialysis were excluded. The study was conducted in accordance with the Declaration of Helsinki. The study protocol was approved by the institutional ethics committee, and written informed consent was obtained from all participants. Data collection and variables Clinical and laboratory data were collected retrospectively from electronic medical records and dialysis charts. Data were organized in a longitudinal format, with each row representing one patient-month. The following variables were recorded monthly: Hemoglobin concentration (g/dL) ESA dose, expressed as the total weekly dose: ESA therapy consisted of erythropoiesis-stimulating agents used in routine clinical practice (epoetin alfa or darbepoetin alfa), and doses were converted to equivalent units when necessary. Intravenous iron dose, aggregated as the total monthly dose (mg); months without iron administration were recorded as 0 mg Transferrin saturation (TSAT, %) Serum ferritin (ng/mL) Serum albumin (g/dL) C-reactive protein (CRP, mg/dL) Physical stress indicators, including hospitalization, infection, or other clinically significant stressors during the month (coded as present or absent) Definition of ESA responsiveness ESA responsiveness was assessed using the erythropoiesis resistance index (ERI), defined as the weekly ESA dose divided by the product of hemoglobin concentration and body weight (ESA dose / [Hb × body weight]). Higher ERI values indicate reduced responsiveness to ESA therapy, consistent with commonly used definitions in dialysis studies. ERI was evaluated as a time-varying outcome at the patient-month level. Iron status categorization Iron status was categorized based on TSAT and serum ferritin values at each patient-month. Patient-months were classified into four categories: 1.TSAT < 20% and ferritin < 100 ng/mL, 2.TSAT < 20% and ferritin ≥ 100 ng/mL, 3.TSAT ≥ 20% and ferritin < 100 ng/mL, and 4.TSAT ≥ 20% and ferritin ≥ 100 ng/mL. These categories were used to explore heterogeneity in ESA responsiveness across different iron states. Statistical analysis Descriptive statistics were summarized as medians with interquartile ranges (IQRs) for continuous variables and as counts with percentages for categorical variables. Associations between monthly IV iron dose and iron indices (TSAT and ferritin) were explored at the patient-month level using scatter plots. To assess the temporal relationship between iron exposure and ESA responsiveness, IV iron dose administered in the prior month was evaluated in relation to contemporaneous ERI (lagged analysis). ERI distributions were compared across iron status categories to identify patterns consistent with heterogeneous iron utilization. All analyses were conducted using patient-month–level data, accounting for repeated observations within individuals. Statistical analyses were performed using standard statistical software, and figures were generated to visually illustrate key associations. Given the exploratory nature of the study, emphasis was placed on consistency and clinical interpretability of observed patterns rather than formal hypothesis testing. Mixed-effects models were additionally applied to account for within-patient repeated measures in exploratory analyses. We fitted linear mixed-effects models with patient-specific random intercepts. The primary exposure was prior-month IV iron dose (lagged by 1 month). In the primary model, we adjusted for markers of inflammation/nutrition and clinical stressors. In a secondary model, we additionally adjusted for iron indices (TSAT and ferritin) to explore whether the association was explained by iron status. Statistical analyses were performed using R version 4.5.2. Results Cohort and monthly measurements. We analyzed 57 maintenance hemodialysis patients contributing 684 patient-month observations. In the patient-month dataset, the median monthly IV iron dose was 40 mg/month (IQR 0–160), whereas the baseline value was 0 (IQR 0–40). Median hemoglobin was 11.1 g/dL (IQR 10.2–11.9). Median ERI was 14.0 ESA dose (IU/kg/week) / Hb (IQR 8.45–19.34), median weekly ESA dose was 9,000 IU/week (IQR 4,500–12,000), and median monthly intravenous iron dose was 40 mg/month (IQR 0–160). Median TSAT was 18% (IQR 13–24) and median ferritin was 64 ng/mL (IQR 35.5–100). Median albumin was 3.4 g/dL (IQR 3.1–3.7) and median CRP was 0.08 mg/dL (IQR 0.025–0.31). Association between IV iron exposure and iron indices. At comparable monthly IV iron doses, TSAT and ferritin varied widely across patient-months (Fig. 1 A–B), indicating heterogeneous iron responsiveness under low-dose, regular supplementation. Prior-month IV iron exposure and ESA responsiveness. Prior-month IV iron exposure showed heterogeneous association with contemporaneous ERI (Fig. 2 ), suggesting that monthly iron administration does not uniformly translate into improved ESA responsiveness. Iron status categories. Among patient-months with available TSAT and ferritin (n = 675), the most frequent category was TSAT < 20% with ferritin < 100 ng/mL (50.2%), followed by TSAT ≥ 20% with ferritin < 100 ng/mL (24.3%), TSAT ≥ 20% with ferritin ≥ 100 ng/mL (17.3%), and TSAT < 20% with ferritin ≥ 100 ng/mL (8.1%) (Fig. 3 ). Mixed-effects models. In linear mixed-effects models with patient-specific random intercepts, 617 observations were included after excluding patient-months with missing covariates. Prior-month IV iron dose was not significantly associated with log(ERI + 1) in the primary model adjusted for albumin, logCRP, and physical stress (β = 0.000104 per mg; p = 0.400). Physical stress was associated with higher log(ERI + 1) (β = 0.135; p = 0.019). In the secondary model additionally adjusting for iron indices, lower TSAT and lower albumin were independently associated with higher log(ERI + 1) (TSAT: β=−0.0108 per 1%; p < 0.001; albumin: β=−0.118; p = 0.0078), whereas ferritin was not (p = 0.623). Prior-month IV iron dose showed a small positive association with log(ERI + 1) in the secondary model. (β = 0.000257 per mg; p = 0.050) (Table 2 ). Table 1 Baseline characteristics of the study population (n = 57) Variable Value Age, years 75 (64–82) Male sex, n (%) 32 (56%) Dialysis vintage, months 74 (37–123) Hemoglobin, g/dL 10.9 (10.0–11.5) ESA dose, IU/week 9000 (4500–12000) Erythropoiesis resistance index (ERI) (ESA dose (IU/kg/week) / Hb) 14.4 (8.3–19.0) IV iron dose, mg/month 0 (0–40) TSAT, % 18 (11–23) Ferritin, ng/mL 58 (31–105) Albumin, g/dL 3.4 (3.1–3.7) CRP, mg/dL 0.10 (0.03–0.44) Dry weight, kg 50.9 (44.5–61.5) Physical stress, n (%) 1 (1.8%) Table 2 Mixed-effects models evaluating factors associated with ESA responsiveness (log[ERI + 1]) Variable Model 1 β (95% CI) p value Model 2 β (95% CI) p value Prior-month IV iron dose (mg) 0.00010 (− 0.00014 to 0.00035) 0.40 0.00026 (0.00000 to 0.00052) 0.050 TSAT (%) — — −0.01077 (− 0.01364 to − 0.00791) < 0.001 Log ferritin — — −0.00856 (− 0.04269 to 0.02558) 0.62 Log CRP 0.00138 (− 0.01575 to 0.01851) 0.88 0.00229 (− 0.01415 to 0.01874) 0.79 Albumin (g/dL) −0.06500 (− 0.15521 to 0.02522) 0.16 −0.11752 (− 0.20410 to − 0.03094) 0.008 Physical stress (present) 0.13504 (0.02176 to 0.24832) 0.019 0.10789 (− 0.00062 to 0.21640) 0.051 Additional exploratory analyses further evaluated determinants of ESA responsiveness. ERI showed a modest but significant inverse correlation with TSAT (Supplementary Fig. 1). In addition, patient-months with elevated CRP levels exhibited significantly higher ERI compared with those with lower CRP levels (Supplementary Fig. 2). When TSAT and CRP were examined jointly, ERI was highest among patient-months characterized by both low TSAT and elevated CRP, suggesting a combined influence of impaired iron availability and inflammation on ESA responsiveness (Supplementary Fig. 3). Discussion Main findings In this longitudinal observational study of maintenance hemodialysis patients managed under the low-dose, regular intravenous iron supplementation commonly practiced in Japan, we observed substantial heterogeneity in the relationship between iron exposure and ESA responsiveness. At comparable monthly IV iron doses, both TSAT and ferritin varied widely across patient-month observations, indicating heterogeneous iron responsiveness ( 2 , 3 ). Moreover, prior-month iron administration showed a heterogeneous association with contemporaneous ERI, suggesting that iron availability alone does not fully explain ESA hyporesponsiveness in routine hemodialysis care ( 1 , 6 , 7 ). Comparison with previous studies Our findings extend prior registry-based observations from Japan by providing a higher temporal resolution assessment of iron exposure and iron indices. While large registry studies have described cross-sectional associations between TSAT, ferritin, and anemia-related outcomes ( 4 , 5 ), these analyses often lack detailed information on actual iron dosing patterns and temporal relationships with ESA responsiveness. By leveraging patient-month–level longitudinal data, the present study captures dynamic variability in iron exposure and erythropoietic response that may be obscured in conventional cross-sectional analyses. These results suggest that, even within a relatively standardized dosing culture, a subset of patients exhibit persistent ESA hyporesponsiveness despite ongoing iron administration ( 10 , 11 ). Interpretation and mechanisms A clinically relevant observation was the discordance between TSAT and ferritin in a subset of patient-months. Low TSAT despite relatively higher ferritin is consistent with impaired iron utilization rather than absolute iron deficiency ( 8 , 9 ). In such settings, escalating IV iron may not yield proportional hematologic benefit and could increase iron burden without improving erythropoiesis ( 2 , 3 ). Although inflammation likely contributes to this phenotype, ferritin is influenced by multiple biological factors and may not reliably reflect bioavailable iron in hemodialysis patients ( 3 , 8 ). These findings are particularly relevant in the context of Japanese dialysis practice, where intravenous iron is typically administered as low-dose maintenance therapy with careful monitoring to avoid iron overload. Even under this relatively conservative dosing strategy, our results demonstrate substantial heterogeneity in iron indices and ESA responsiveness, suggesting that iron utilization differs across patients. The discordance between TSAT and ferritin observed in some patient-months is also compatible with functional iron deficiency mediated by inflammation-induced hepcidin elevation, which restricts iron mobilization from storage sites and limits iron availability for erythropoiesis ( 8 , 9 ). Importantly, our findings suggest that iron availability rather than iron dose may play a more important role than iron dose in determining ESA responsiveness in routine hemodialysis practice. An additional consideration is the potential influence of treatment indication bias when interpreting the relationship between IV iron dose and iron indices. In routine clinical practice, intravenous iron is typically administered in response to declining TSAT or worsening anemia. Consequently, patient-months with lower TSAT are more likely to receive higher iron doses, which may produce an apparent inverse association between iron dose and TSAT in observational analyses. This pattern likely reflects reactive treatment decisions rather than a biological effect of iron administration. The present findings therefore highlight the importance of distinguishing iron exposure from iron availability when evaluating ESA responsiveness in longitudinal dialysis datasets. Clinical implications This study also highlights the potential value of ERI as a dynamic marker of treatment response in longitudinal analyses. Monthly ERI trajectories may capture clinically meaningful heterogeneity in ESA responsiveness that is not evident from single-timepoint measurements ( 6 , 7 , 10 ). From a practical perspective, evaluating whether ERI improves following iron exposure—rather than assuming benefit based on dosing alone—may help guide more individualized anemia management ( 1 , 12 ). Integrating TSAT with longitudinal ERI monitoring may therefore help identify patients in whom additional iron administration is unlikely to improve anemia control and prompt evaluation of alternative contributors to ESA hyporesponsiveness. Limitations Several limitations should be acknowledged. First, this was a single-center retrospective study with a modest number of patients; however, the longitudinal design yielded a substantial number of patient-month observations, enabling repeated within-patient assessment across time ( 10 ). Second, residual confounding is possible because unmeasured factors—such as occult blood loss, access-related inflammation, iron formulation differences, or other biological modifiers—may influence iron indices and ESA responsiveness ( 1 , 3 , 8 ). Third, mechanistic biomarkers of iron metabolism, such as hepcidin, were not available and could provide further insight into pathways of impaired iron utilization ( 8 , 9 ). Finally, the observational nature of the study precludes causal inference regarding iron dosing strategies ( 12 ). Conclusions In Japanese maintenance hemodialysis patients managed with regular low-dose IV iron supplementation, iron exposure was not uniformly associated with improved ESA responsiveness. TSAT and ferritin showed substantial variability at comparable iron doses, and ERI remained persistently elevated in a subset of patient-month observations despite iron administration, consistent with heterogeneous iron responsiveness and possible impaired iron utilization. These findings support a longitudinal, response-informed approach to anemia management that integrates iron indices with ESA responsiveness rather than relying solely on iron dosing. Data Sharing Statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Due to ethical restrictions and institutional regulations, individual-level patient data cannot be publicly shared. De-identified aggregate data, analytic code for risk score calculation, and detailed methodological information are available to qualified researchers for the purpose of reproducing the results reported in this article. Reporting Checklist Statement (STROBE) This study was conducted and reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. The completed STROBE checklist is provided as Supplementary Material. Declarations Data Sharing Statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Due to ethical restrictions and institutional regulations, individual-level patient data cannot be publicly shared. De-identified aggregate data, analytic code for risk score calculation, and detailed methodological information are available to qualified researchers for the purpose of reproducing the results reported in this article. Reporting Checklist Statement (STROBE) This study was conducted and reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. The completed STROBE checklist is provided as Supplementary Material. Funding The authors received no financial support for the research, authorship, or publication of this article. Conflicts of Interest The authors declare that they have no conflicts of interest related to this work. Ethics Approval This retrospective study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Fuefuki Central Hospital (Approval No. Fuefuki Rin 25-10; January 10, 2026). Written informed consent was obtained from all participants prior to inclusion in the study. Patient data were anonymized before analysis. Author Contribution Y.I. conceived and designed the study, collected and analyzed the data, and wrote the manuscript. Data Availability The data that support the findings of this study are available from the corresponding author upon reasonable request. Due to ethical restrictions and institutional regulations, individual-level patient data cannot be publicly shared. De-identified aggregate data, analytic code for risk score calculation, and detailed methodological information are available to qualified researchers for the purpose of reproducing the results reported in this article. References Macdougall IC, Bircher AJ, Eckardt KU, et al. ESA resistance in chronic kidney disease: mechanisms and management. Nat Rev Nephrol. 2012;8:479–492. Locatelli F, Bárány P, Covic A, et al. Erythropoiesis-stimulating agents and iron therapy in chronic kidney disease. Nephrol Dial Transplant. 2013;28:803–814. Coyne DW. Iron indices: what do they really mean? Kidney Int Suppl. 2006;69:S4–S8. Yamamoto H, Nishi S, Tomo T, et al. Practice patterns of anemia management in Japanese hemodialysis patients. Clin Exp Nephrol. 2018;22:109–117. Akizawa T, Okumura H, Alexandre AF, et al. Current status of anemia management in Japanese dialysis patients. Ther Apher Dial. 2015;19(Suppl 1):8–16. Kaysen GA, Müller HG, Ding J, et al. Erythropoietin resistance in end-stage renal disease: role of inflammation and iron. Kidney Int. 2001;59:2241–2249. Panichi V, Rosati A, Bigazzi R, et al. Erythropoietin resistance index and mortality in dialysis patients. Nephrol Dial Transplant. 2008;23:2339–2346. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352:1011–1023. Wish JB. Assessing iron status: beyond serum ferritin and transferrin saturation. Clin J Am Soc Nephrol . 2006;1(Suppl 1):S4–S8. Kalantar-Zadeh K, Hoffken B, Wunsch H, et al. Epidemiology of anemia in dialysis patients. Am J Kidney Dis. 2009;54:106–116. Bradbury BD, Danese MD, Gleeson M, et al. Erythropoietin hyporesponsiveness and mortality in dialysis patients. Am J Kidney Dis. 2009;54:727–735. Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney Int Suppl. 2012;2:279–335. Additional Declarations No competing interests reported. Supplementary Files SupplementaryFigure1.tif SupplementaryFigure2.tif SupplementaryFigure.tif Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9073383","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":606663807,"identity":"39c6f2de-4ae9-4820-860a-5d050e024a37","order_by":0,"name":"Yukinobu Ikegishi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9UlEQVRIiWNgGAWjYDACZjYgYcCQwMbewMAMEzQgTgvPAWK1MLCByQQGiQSEFrzA4Dhb4sMvBXV5fJJvDD8XVNgw8Lc3MBQX4NNymO2wsYzB4WI26Rxj6Rln0hgkzhxgMJ6BVwt7m7SEwYHENukcA2netsMMBkAXGvPg19L+W8KgLrFN8ozxbyK1sB1j/GDAnNgmwWNGnC2Sh9mSpYEaE9t40sqsec6k8UicOdiA1y98548Zfvzxpy5xfvvhzbd5Kmzk+NubjxnjCzGFA8DYhDiDAxyBQDZjmzEeHQzyDUAlP8BM9gcwQebH+LSMglEwCkbBiAMAXbJGJ/pgVTwAAAAASUVORK5CYII=","orcid":"","institution":"Fuefuki Central Hospital","correspondingAuthor":true,"prefix":"","firstName":"Yukinobu","middleName":"","lastName":"Ikegishi","suffix":""}],"badges":[],"createdAt":"2026-03-09 13:10:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9073383/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9073383/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104993814,"identity":"bb862cbe-b1da-42ad-814d-296775dc0c8b","added_by":"auto","created_at":"2026-03-19 15:57:08","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":525363,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure 1A. Monthly IV iron dose and TSAT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eScatter plot showing the relationship between monthly intravenous (IV) iron dose and transferrin saturation (TSAT) at the patient-month level (n = 684).\u003c/p\u003e\n\u003cp\u003eEach dot represents one patient-month observation. Numbers above each IV iron category indicate the number of observations. TSAT values varied widely at comparable IV iron doses, indicating substantial heterogeneity in iron availability despite similar iron exposure.\u003c/p\u003e\n\u003cp\u003eSpearman correlation coefficient: r = −0.23, p \u0026lt; 0.001.\u003c/p\u003e","description":"","filename":"Figure1A.png","url":"https://assets-eu.researchsquare.com/files/rs-9073383/v1/fe7c09a971b62e444f74ecbf.png"},{"id":104993752,"identity":"7641c0bc-0b0d-4359-8eba-26b2f0b96487","added_by":"auto","created_at":"2026-03-19 15:56:58","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":397364,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure 1B. Monthly IV iron dose and ferritin\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eScatter plot illustrating the association between monthly IV iron dose and serum ferritin levels at the patient-month level (n = 684).\u003c/p\u003e\n\u003cp\u003eFerritin values showed marked variability across iron dosing levels, including elevated ferritin in patient-months without IV iron administration. This finding suggests that ferritin levels may be influenced by factors other than iron dose, such as inflammation or altered iron metabolism.\u003c/p\u003e\n\u003cp\u003eSpearman correlation coefficient: r = 0.06, p = 0.144.\u003c/p\u003e","description":"","filename":"Figure1B.png","url":"https://assets-eu.researchsquare.com/files/rs-9073383/v1/cc6556ed6dc74ac6915c77bc.png"},{"id":104993647,"identity":"2623ea90-ed18-4144-9630-da31f4fab328","added_by":"auto","created_at":"2026-03-19 15:56:38","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":355385,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePrior-month IV iron exposure and ESA responsiveness\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eScatter plot showing the relationship between IV iron dose administered in the prior month (lag 1) and erythropoiesis resistance index (ERI) at the patient-month level (n = 684).\u003c/p\u003e\n\u003cp\u003eDespite similar levels of prior-month iron exposure, ERI demonstrated wide dispersion, indicating that IV iron administration did not uniformly translate into improved ESA responsiveness.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-9073383/v1/bfa55ba976af10b44b18ffbb.png"},{"id":104993639,"identity":"a87b8a18-aae0-4867-be14-b5ce0c7cd010","added_by":"auto","created_at":"2026-03-19 15:56:34","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":218900,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eERI stratified by TSAT and ferritin categories\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDistribution of erythropoiesis resistance index (ERI) according to combined TSAT and ferritin categories at the patient-month level (n = 684).\u003c/p\u003e\n\u003cp\u003eIron status categories were defined as:\u003c/p\u003e\n\u003cp\u003eTSAT \u0026lt;20% and ferritin \u0026lt;100 ng/mL\u003c/p\u003e\n\u003cp\u003eTSAT \u0026lt;20% and ferritin ≥100 ng/mL\u003c/p\u003e\n\u003cp\u003eTSAT ≥20% and ferritin \u0026lt;100 ng/mL\u003c/p\u003e\n\u003cp\u003eTSAT ≥20% and ferritin ≥100 ng/mL\u003c/p\u003e\n\u003cp\u003ePatient-months characterized by low TSAT despite preserved ferritin (TSAT \u0026lt;20% and ferritin ≥100 ng/mL), a pattern consistent with functional iron unavailability, tended to show higher ERI values compared with other categories.\u003c/p\u003e\n\u003cp\u003eKruskal–Wallis test: p \u0026lt; 0.001.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-9073383/v1/84a37b8183a537bdfe212499.png"},{"id":104993872,"identity":"2e406583-d335-4678-b2b1-e54cc77a3e0c","added_by":"auto","created_at":"2026-03-19 15:57:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2287260,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9073383/v1/d63afd2e-b5c3-41ab-b1b4-7aa46f21d2a7.pdf"},{"id":104993764,"identity":"bd406a7f-f7ca-4f14-8e35-46cbc0320100","added_by":"auto","created_at":"2026-03-19 15:56:59","extension":"tif","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":225050,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigure1.tif","url":"https://assets-eu.researchsquare.com/files/rs-9073383/v1/2dd35c07059c75edbeaa40b3.tif"},{"id":104993689,"identity":"22ce5fb9-1baa-4b93-96e4-a2408ea39430","added_by":"auto","created_at":"2026-03-19 15:56:51","extension":"tif","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":90420,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigure2.tif","url":"https://assets-eu.researchsquare.com/files/rs-9073383/v1/55853653f320875a7412b11e.tif"},{"id":104993673,"identity":"3390cfcc-e59b-407e-b190-df73fe947fd4","added_by":"auto","created_at":"2026-03-19 15:56:43","extension":"tif","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":104356,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigure.tif","url":"https://assets-eu.researchsquare.com/files/rs-9073383/v1/81264078c6434a0204a3cbee.tif"}],"financialInterests":"No competing interests reported.","formattedTitle":"Iron Availability, Inflammation, and ESA Responsiveness in Maintenance Hemodialysis: A Patient-Month Longitudinal Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAnemia is a common and clinically important complication in patients receiving maintenance hemodialysis. Erythropoiesis-stimulating agents (ESAs) and intravenous (IV) iron supplementation are central components of anemia management; however, ESA hyporesponsiveness remains frequent and is associated with increased morbidity, mortality, and healthcare costs (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). While iron deficiency is a major contributor to ESA hyporesponsiveness, the relationship between iron administration, iron indices, and erythropoietic response is often complex in routine clinical practice (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn Japan, IV iron is typically administered as low-dose, regular supplementation, often on a weekly basis, with careful monitoring of ferritin levels to avoid iron overload (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). This practice differs from bolus or high-dose maintenance strategies commonly used in Western countries. Despite this relatively standardized approach, clinicians frequently encounter patients in whom anemia control remains suboptimal even with ongoing iron supplementation. Traditional iron indices, such as transferrin saturation (TSAT) and serum ferritin, do not always reliably reflect iron availability for erythropoiesis, particularly in the presence of inflammation or altered iron utilization (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePrevious large registry studies in Japan have demonstrated cross-sectional associations between iron indices and hemoglobin or ESA dose (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). However, these analyses are limited by low temporal resolution and lack detailed information on actual iron dosing patterns. In contrast, monthly longitudinal data capturing iron exposure, iron indices, and ESA responsiveness may better reflect real-world anemia management and uncover heterogeneity in treatment response that is obscured in cross-sectional analyses (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTherefore, we conducted a single-center longitudinal observational study to examine the monthly relationship between IV iron exposure, iron indices, and ESA responsiveness in maintenance hemodialysis patients managed under low-dose intravenous iron supplementation practices. By integrating patient-month\u0026ndash;level data over a 12-month period, we aimed to clarify whether iron exposure uniformly translates into improved ESA responsiveness and to identify patterns suggestive of impaired iron utilization in routine hemodialysis care (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and population\u003c/h2\u003e \u003cp\u003eThis was a single-center, retrospective longitudinal observational study conducted in maintenance hemodialysis patients. Adult patients undergoing maintenance hemodialysis at our center were eligible for inclusion if they had at least 12 consecutive months of available monthly data on hemoglobin, ESA dose, IV iron administration, and iron indices. Patients with incomplete longitudinal data or receiving dialysis modalities other than maintenance hemodialysis were excluded.\u003c/p\u003e \u003cp\u003e The study was conducted in accordance with the Declaration of Helsinki. The study protocol was approved by the institutional ethics committee, and written informed consent was obtained from all participants.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData collection and variables\u003c/h3\u003e\n\u003cp\u003eClinical and laboratory data were collected retrospectively from electronic medical records and dialysis charts. Data were organized in a longitudinal format, with each row representing one patient-month. The following variables were recorded monthly:\u003c/p\u003e \u003cp\u003eHemoglobin concentration (g/dL)\u003c/p\u003e \u003cp\u003eESA dose, expressed as the total weekly dose: ESA therapy consisted of erythropoiesis-stimulating agents used in routine clinical practice (epoetin alfa or darbepoetin alfa), and doses were converted to equivalent units when necessary.\u003c/p\u003e \u003cp\u003eIntravenous iron dose, aggregated as the total monthly dose (mg); months without iron administration were recorded as 0 mg\u003c/p\u003e \u003cp\u003eTransferrin saturation (TSAT, %)\u003c/p\u003e \u003cp\u003eSerum ferritin (ng/mL)\u003c/p\u003e \u003cp\u003eSerum albumin (g/dL)\u003c/p\u003e \u003cp\u003eC-reactive protein (CRP, mg/dL)\u003c/p\u003e \u003cp\u003ePhysical stress indicators, including hospitalization, infection, or other clinically significant stressors during the month (coded as present or absent)\u003c/p\u003e\n\u003ch3\u003eDefinition of ESA responsiveness\u003c/h3\u003e\n\u003cp\u003eESA responsiveness was assessed using the erythropoiesis resistance index (ERI), defined as the weekly ESA dose divided by the product of hemoglobin concentration and body weight (ESA dose / [Hb \u0026times; body weight]). Higher ERI values indicate reduced responsiveness to ESA therapy, consistent with commonly used definitions in dialysis studies. ERI was evaluated as a time-varying outcome at the patient-month level.\u003c/p\u003e\n\u003ch3\u003eIron status categorization\u003c/h3\u003e\n\u003cp\u003eIron status was categorized based on TSAT and serum ferritin values at each patient-month. Patient-months were classified into four categories:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e1.TSAT\u0026thinsp;\u0026lt;\u0026thinsp;20% and ferritin\u0026thinsp;\u0026lt;\u0026thinsp;100 ng/mL,\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e2.TSAT\u0026thinsp;\u0026lt;\u0026thinsp;20% and ferritin\u0026thinsp;\u0026ge;\u0026thinsp;100 ng/mL,\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e3.TSAT\u0026thinsp;\u0026ge;\u0026thinsp;20% and ferritin\u0026thinsp;\u0026lt;\u0026thinsp;100 ng/mL, and\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e4.TSAT\u0026thinsp;\u0026ge;\u0026thinsp;20% and ferritin\u0026thinsp;\u0026ge;\u0026thinsp;100 ng/mL.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eThese categories were used to explore heterogeneity in ESA responsiveness across different iron states.\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eDescriptive statistics were summarized as medians with interquartile ranges (IQRs) for continuous variables and as counts with percentages for categorical variables. Associations between monthly IV iron dose and iron indices (TSAT and ferritin) were explored at the patient-month level using scatter plots.\u003c/p\u003e \u003cp\u003eTo assess the temporal relationship between iron exposure and ESA responsiveness, IV iron dose administered in the prior month was evaluated in relation to contemporaneous ERI (lagged analysis). ERI distributions were compared across iron status categories to identify patterns consistent with heterogeneous iron utilization.\u003c/p\u003e \u003cp\u003eAll analyses were conducted using patient-month\u0026ndash;level data, accounting for repeated observations within individuals. Statistical analyses were performed using standard statistical software, and figures were generated to visually illustrate key associations. Given the exploratory nature of the study, emphasis was placed on consistency and clinical interpretability of observed patterns rather than formal hypothesis testing.\u003c/p\u003e \u003cp\u003eMixed-effects models were additionally applied to account for within-patient repeated measures in exploratory analyses. We fitted linear mixed-effects models with patient-specific random intercepts. The primary exposure was prior-month IV iron dose (lagged by 1 month). In the primary model, we adjusted for markers of inflammation/nutrition and clinical stressors. In a secondary model, we additionally adjusted for iron indices (TSAT and ferritin) to explore whether the association was explained by iron status.\u003c/p\u003e \u003cp\u003eStatistical analyses were performed using R version 4.5.2.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e \u003cb\u003eCohort and monthly measurements.\u003c/b\u003e \u003c/p\u003e \u003cp\u003eWe analyzed 57 maintenance hemodialysis patients contributing 684 patient-month observations. In the patient-month dataset, the median monthly IV iron dose was 40 mg/month (IQR 0\u0026ndash;160), whereas the baseline value was 0 (IQR 0\u0026ndash;40). Median hemoglobin was 11.1 g/dL (IQR 10.2\u0026ndash;11.9). Median ERI was 14.0 ESA dose (IU/kg/week) / Hb (IQR 8.45\u0026ndash;19.34), median weekly ESA dose was 9,000 IU/week (IQR 4,500\u0026ndash;12,000), and median monthly intravenous iron dose was 40 mg/month (IQR 0\u0026ndash;160). Median TSAT was 18% (IQR 13\u0026ndash;24) and median ferritin was 64 ng/mL (IQR 35.5\u0026ndash;100). Median albumin was 3.4 g/dL (IQR 3.1\u0026ndash;3.7) and median CRP was 0.08 mg/dL (IQR 0.025\u0026ndash;0.31).\u003c/p\u003e \u003cp\u003e \u003cb\u003eAssociation between IV iron exposure and iron indices.\u003c/b\u003e \u003c/p\u003e \u003cp\u003eAt comparable monthly IV iron doses, TSAT and ferritin varied widely across patient-months (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003eA\u0026ndash;B), indicating heterogeneous iron responsiveness under low-dose, regular supplementation.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003ePrior-month IV iron exposure and ESA responsiveness.\u003c/p\u003e \u003cp\u003ePrior-month IV iron exposure showed heterogeneous association with contemporaneous ERI (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003e), suggesting that monthly iron administration does not uniformly translate into improved ESA responsiveness.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eIron status categories.\u003c/b\u003e \u003c/p\u003e \u003cp\u003eAmong patient-months with available TSAT and ferritin (n\u0026thinsp;=\u0026thinsp;675), the most frequent category was TSAT\u0026thinsp;\u0026lt;\u0026thinsp;20% with ferritin\u0026thinsp;\u0026lt;\u0026thinsp;100 ng/mL (50.2%), followed by TSAT\u0026thinsp;\u0026ge;\u0026thinsp;20% with ferritin\u0026thinsp;\u0026lt;\u0026thinsp;100 ng/mL (24.3%), TSAT\u0026thinsp;\u0026ge;\u0026thinsp;20% with ferritin\u0026thinsp;\u0026ge;\u0026thinsp;100 ng/mL (17.3%), and TSAT\u0026thinsp;\u0026lt;\u0026thinsp;20% with ferritin\u0026thinsp;\u0026ge;\u0026thinsp;100 ng/mL (8.1%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eMixed-effects models.\u003c/b\u003e \u003c/p\u003e \u003cp\u003eIn linear mixed-effects models with patient-specific random intercepts, 617 observations were included after excluding patient-months with missing covariates. Prior-month IV iron dose was not significantly associated with log(ERI\u0026thinsp;+\u0026thinsp;1) in the primary model adjusted for albumin, logCRP, and physical stress (β\u0026thinsp;=\u0026thinsp;0.000104 per mg; p\u0026thinsp;=\u0026thinsp;0.400). Physical stress was associated with higher log(ERI\u0026thinsp;+\u0026thinsp;1) (β\u0026thinsp;=\u0026thinsp;0.135; p\u0026thinsp;=\u0026thinsp;0.019). In the secondary model additionally adjusting for iron indices, lower TSAT and lower albumin were independently associated with higher log(ERI\u0026thinsp;+\u0026thinsp;1) (TSAT: β=\u0026minus;0.0108 per 1%; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; albumin: β=\u0026minus;0.118; p\u0026thinsp;=\u0026thinsp;0.0078), whereas ferritin was not (p\u0026thinsp;=\u0026thinsp;0.623). Prior-month IV iron dose showed a small positive association with log(ERI\u0026thinsp;+\u0026thinsp;1) in the secondary model. (β\u0026thinsp;=\u0026thinsp;0.000257 per mg; p\u0026thinsp;=\u0026thinsp;0.050) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of the study population (n\u0026thinsp;=\u0026thinsp;57)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eValue\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e75 (64\u0026ndash;82)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale sex, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (56%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDialysis vintage, months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e74 (37\u0026ndash;123)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemoglobin, g/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.9 (10.0\u0026ndash;11.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eESA dose, IU/week\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9000 (4500\u0026ndash;12000)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eErythropoiesis resistance index (ERI)\u003c/p\u003e \u003cp\u003e(ESA dose (IU/kg/week) / Hb)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.4 (8.3\u0026ndash;19.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIV iron dose, mg/month\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0\u0026ndash;40)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTSAT, %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (11\u0026ndash;23)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFerritin, ng/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58 (31\u0026ndash;105)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlbumin, g/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.4 (3.1\u0026ndash;3.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRP, mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.10 (0.03\u0026ndash;0.44)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDry weight, kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50.9 (44.5\u0026ndash;61.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhysical stress, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMixed-effects models evaluating factors associated with ESA responsiveness (log[ERI\u0026thinsp;+\u0026thinsp;1])\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eModel 1 β\u003c/p\u003e \u003cp\u003e(95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eModel 2 β\u003c/p\u003e \u003cp\u003e(95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior-month IV iron dose (mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.00010\u003c/p\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.00014 to 0.00035)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.00026\u003c/p\u003e \u003cp\u003e(0.00000 to 0.00052)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.050\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTSAT (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026minus;0.01077\u003c/p\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.01364 to \u0026minus;\u0026thinsp;0.00791)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLog ferritin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026minus;0.00856\u003c/p\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.04269 to 0.02558)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.62\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLog CRP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.00138\u003c/p\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.01575 to 0.01851)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.00229\u003c/p\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.01415 to 0.01874)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.79\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlbumin (g/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026minus;0.06500\u003c/p\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.15521 to 0.02522)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026minus;0.11752\u003c/p\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.20410 to \u0026minus;\u0026thinsp;0.03094)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhysical stress (present)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.13504\u003c/p\u003e \u003cp\u003e(0.02176 to 0.24832)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.10789\u003c/p\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.00062 to 0.21640)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.051\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAdditional exploratory analyses further evaluated determinants of ESA responsiveness. ERI showed a modest but significant inverse correlation with TSAT (Supplementary Fig.\u0026nbsp;1). In addition, patient-months with elevated CRP levels exhibited significantly higher ERI compared with those with lower CRP levels (Supplementary Fig.\u0026nbsp;2). When TSAT and CRP were examined jointly, ERI was highest among patient-months characterized by both low TSAT and elevated CRP, suggesting a combined influence of impaired iron availability and inflammation on ESA responsiveness (Supplementary Fig.\u0026nbsp;3).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eMain findings\u003c/h2\u003e \u003cp\u003eIn this longitudinal observational study of maintenance hemodialysis patients managed under the low-dose, regular intravenous iron supplementation commonly practiced in Japan, we observed substantial heterogeneity in the relationship between iron exposure and ESA responsiveness. At comparable monthly IV iron doses, both TSAT and ferritin varied widely across patient-month observations, indicating heterogeneous iron responsiveness (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Moreover, prior-month iron administration showed a heterogeneous association with contemporaneous ERI, suggesting that iron availability alone does not fully explain ESA hyporesponsiveness in routine hemodialysis care (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eComparison with previous studies\u003c/h2\u003e \u003cp\u003eOur findings extend prior registry-based observations from Japan by providing a higher temporal resolution assessment of iron exposure and iron indices. While large registry studies have described cross-sectional associations between TSAT, ferritin, and anemia-related outcomes (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e), these analyses often lack detailed information on actual iron dosing patterns and temporal relationships with ESA responsiveness. By leveraging patient-month\u0026ndash;level longitudinal data, the present study captures dynamic variability in iron exposure and erythropoietic response that may be obscured in conventional cross-sectional analyses. These results suggest that, even within a relatively standardized dosing culture, a subset of patients exhibit persistent ESA hyporesponsiveness despite ongoing iron administration (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eInterpretation and mechanisms\u003c/h2\u003e \u003cp\u003eA clinically relevant observation was the discordance between TSAT and ferritin in a subset of patient-months. Low TSAT despite relatively higher ferritin is consistent with impaired iron utilization rather than absolute iron deficiency (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). In such settings, escalating IV iron may not yield proportional hematologic benefit and could increase iron burden without improving erythropoiesis (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Although inflammation likely contributes to this phenotype, ferritin is influenced by multiple biological factors and may not reliably reflect bioavailable iron in hemodialysis patients (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThese findings are particularly relevant in the context of Japanese dialysis practice, where intravenous iron is typically administered as low-dose maintenance therapy with careful monitoring to avoid iron overload. Even under this relatively conservative dosing strategy, our results demonstrate substantial heterogeneity in iron indices and ESA responsiveness, suggesting that iron utilization differs across patients. The discordance between TSAT and ferritin observed in some patient-months is also compatible with functional iron deficiency mediated by inflammation-induced hepcidin elevation, which restricts iron mobilization from storage sites and limits iron availability for erythropoiesis (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eImportantly, our findings suggest that iron availability rather than iron dose may play a more important role than iron dose in determining ESA responsiveness in routine hemodialysis practice.\u003c/p\u003e \u003cp\u003eAn additional consideration is the potential influence of treatment indication bias when interpreting the relationship between IV iron dose and iron indices. In routine clinical practice, intravenous iron is typically administered in response to declining TSAT or worsening anemia. Consequently, patient-months with lower TSAT are more likely to receive higher iron doses, which may produce an apparent inverse association between iron dose and TSAT in observational analyses. This pattern likely reflects reactive treatment decisions rather than a biological effect of iron administration. The present findings therefore highlight the importance of distinguishing iron exposure from iron availability when evaluating ESA responsiveness in longitudinal dialysis datasets.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eClinical implications\u003c/h2\u003e \u003cp\u003eThis study also highlights the potential value of ERI as a dynamic marker of treatment response in longitudinal analyses. Monthly ERI trajectories may capture clinically meaningful heterogeneity in ESA responsiveness that is not evident from single-timepoint measurements (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). From a practical perspective, evaluating whether ERI improves following iron exposure\u0026mdash;rather than assuming benefit based on dosing alone\u0026mdash;may help guide more individualized anemia management (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Integrating TSAT with longitudinal ERI monitoring may therefore help identify patients in whom additional iron administration is unlikely to improve anemia control and prompt evaluation of alternative contributors to ESA hyporesponsiveness.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eSeveral limitations should be acknowledged. First, this was a single-center retrospective study with a modest number of patients; however, the longitudinal design yielded a substantial number of patient-month observations, enabling repeated within-patient assessment across time (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Second, residual confounding is possible because unmeasured factors\u0026mdash;such as occult blood loss, access-related inflammation, iron formulation differences, or other biological modifiers\u0026mdash;may influence iron indices and ESA responsiveness (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Third, mechanistic biomarkers of iron metabolism, such as hepcidin, were not available and could provide further insight into pathways of impaired iron utilization (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Finally, the observational nature of the study precludes causal inference regarding iron dosing strategies (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn Japanese maintenance hemodialysis patients managed with regular low-dose IV iron supplementation, iron exposure was not uniformly associated with improved ESA responsiveness. TSAT and ferritin showed substantial variability at comparable iron doses, and ERI remained persistently elevated in a subset of patient-month observations despite iron administration, consistent with heterogeneous iron responsiveness and possible impaired iron utilization. These findings support a longitudinal, response-informed approach to anemia management that integrates iron indices with ESA responsiveness rather than relying solely on iron dosing.\u003c/p\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eData Sharing Statement\u003c/h2\u003e \u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request. Due to ethical restrictions and institutional regulations, individual-level patient data cannot be publicly shared. De-identified aggregate data, analytic code for risk score calculation, and detailed methodological information are available to qualified researchers for the purpose of reproducing the results reported in this article.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eReporting Checklist Statement (STROBE)\u003c/h2\u003e \u003cp\u003e This study was conducted and reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. The completed STROBE checklist is provided as Supplementary Material.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData Sharing Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request. Due to ethical restrictions and institutional regulations, individual-level patient data cannot be publicly shared. De-identified aggregate data, analytic code for risk score calculation, and detailed methodological information are available to qualified researchers for the purpose of reproducing the results reported in this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eReporting Checklist Statement (STROBE)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted and reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. The completed STROBE checklist is provided as Supplementary Material.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors received no financial support for the research, authorship, or publication of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflicts of interest related to this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Fuefuki Central Hospital (Approval No. Fuefuki Rin 25-10; January 10, 2026). Written informed consent was obtained from all participants prior to inclusion in the study. Patient data were anonymized before analysis.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eY.I. conceived and designed the study, collected and analyzed the data, and wrote the manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request. Due to ethical restrictions and institutional regulations, individual-level patient data cannot be publicly shared. De-identified aggregate data, analytic code for risk score calculation, and detailed methodological information are available to qualified researchers for the purpose of reproducing the results reported in this article.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMacdougall IC, Bircher AJ, Eckardt KU, et al. ESA resistance in chronic kidney disease: mechanisms and management. \u003cem\u003eNat Rev Nephrol.\u003c/em\u003e 2012;8:479\u0026ndash;492.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLocatelli F, B\u0026aacute;r\u0026aacute;ny P, Covic A, et al. Erythropoiesis-stimulating agents and iron therapy in chronic kidney disease. \u003cem\u003eNephrol Dial Transplant.\u003c/em\u003e 2013;28:803\u0026ndash;814.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCoyne DW. Iron indices: what do they really mean? \u003cem\u003eKidney Int Suppl.\u003c/em\u003e 2006;69:S4\u0026ndash;S8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYamamoto H, Nishi S, Tomo T, et al. Practice patterns of anemia management in Japanese hemodialysis patients. \u003cem\u003eClin Exp Nephrol.\u003c/em\u003e 2018;22:109\u0026ndash;117.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAkizawa T, Okumura H, Alexandre AF, et al. Current status of anemia management in Japanese dialysis patients. \u003cem\u003eTher Apher Dial.\u003c/em\u003e 2015;19(Suppl 1):8\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKaysen GA, M\u0026uuml;ller HG, Ding J, et al. Erythropoietin resistance in end-stage renal disease: role of inflammation and iron. \u003cem\u003eKidney Int.\u003c/em\u003e 2001;59:2241\u0026ndash;2249.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePanichi V, Rosati A, Bigazzi R, et al. Erythropoietin resistance index and mortality in dialysis patients. \u003cem\u003eNephrol Dial Transplant.\u003c/em\u003e 2008;23:2339\u0026ndash;2346.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWeiss G, Goodnough LT. Anemia of chronic disease. \u003cem\u003eN Engl J Med.\u003c/em\u003e 2005;352:1011\u0026ndash;1023.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWish JB. Assessing iron status: beyond serum ferritin and transferrin saturation. \u003cem\u003eClin J Am Soc Nephrol\u003c/em\u003e. 2006;1(Suppl 1):S4\u0026ndash;S8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKalantar-Zadeh K, Hoffken B, Wunsch H, et al. Epidemiology of anemia in dialysis patients. \u003cem\u003eAm J Kidney Dis.\u003c/em\u003e 2009;54:106\u0026ndash;116.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBradbury BD, Danese MD, Gleeson M, et al. Erythropoietin hyporesponsiveness and mortality in dialysis patients. \u003cem\u003eAm J Kidney Dis.\u003c/em\u003e 2009;54:727\u0026ndash;735.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. \u003cem\u003eKidney Int Suppl.\u003c/em\u003e 2012;2:279\u0026ndash;335.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Functional iron unavailability, Hemodialysis, Anemia, Iron dysregulation, ESA hyporesponsiveness","lastPublishedDoi":"10.21203/rs.3.rs-9073383/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9073383/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eAnemia management in patients receiving maintenance hemodialysis relies on erythropoiesis-stimulating agents (ESAs) and intravenous (IV) iron supplementation. However, the relationship between iron administration, iron indices, and ESA responsiveness remains complex in routine clinical practice. In particular, whether regular low-dose IV iron supplementation consistently improves ESA responsiveness has not been well characterized using high-resolution longitudinal data.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe conducted a single-center retrospective longitudinal observational study in maintenance hemodialysis patients with at least 12 months of available monthly data. Patient-month\u0026ndash;level observations included hemoglobin, ESA dose, IV iron dose, transferrin saturation (TSAT), ferritin, albumin, C-reactive protein (CRP), and clinical stress indicators. ESA responsiveness was assessed using the erythropoiesis resistance index (ERI). To examine temporal relationships, prior-month IV iron exposure was evaluated in relation to contemporaneous ERI. Linear mixed-effects models with patient-level random intercepts were used to account for repeated measurements.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 57 maintenance hemodialysis patients contributed 684 patient-month observations. Median hemoglobin was 11.1 g/dL (IQR 10.2\u0026ndash;11.9), and median ERI was 14.0 (IQR 8.45\u0026ndash;19.34). At comparable monthly IV iron doses, TSAT and ferritin showed substantial variability across patient-months. In mixed-effects analyses, prior-month IV iron dose was not significantly associated with ERI in the primary model. In contrast, lower TSAT and lower serum albumin were independently associated with higher ERI, indicating reduced ESA responsiveness.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eIn maintenance hemodialysis patients managed with regular low-dose IV iron supplementation, iron exposure did not uniformly translate into improved ESA responsiveness. Substantial variability in iron indices and ERI suggests heterogeneous iron utilization, potentially reflecting functional iron deficiency. These findings support a longitudinal, response-guided approach to anemia management that integrates iron indices with ESA responsiveness rather than relying on iron dosing alone.\u003c/p\u003e","manuscriptTitle":"Iron Availability, Inflammation, and ESA Responsiveness in Maintenance Hemodialysis: A Patient-Month Longitudinal Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-19 15:55:30","doi":"10.21203/rs.3.rs-9073383/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3e90e860-11cb-47b7-9337-9c4056b91a73","owner":[],"postedDate":"March 19th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-10T01:24:29+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-19 15:55:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9073383","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9073383","identity":"rs-9073383","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}