Apparent reversibility does not exclude myelodysplastic syndrome: a diagnostic pitfall with copper deficiency in a hemodialysis patient

Apparent reversibility does not exclude myelodysplastic syndrome: a diagnostic pitfall with copper deficiency in a hemodialysis patient | 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 Case Report Apparent reversibility does not exclude myelodysplastic syndrome: a diagnostic pitfall with copper deficiency in a hemodialysis patient Yukinobu Ikegishi This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8821005/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 in patients undergoing long-term hemodialysis is multifactorial and frequently refractory to standard therapy. In elderly patients, myelodysplastic syndrome (MDS) must be considered; however, several reversible conditions—most notably copper deficiency—can closely mimic MDS both clinically and morphologically, posing a significant diagnostic challenge. Case Presentation: An 89-year-old Japanese man receiving maintenance hemodialysis for end-stage renal disease developed progressive, erythropoiesis-stimulating agent–resistant anemia and became transfusion-dependent. Bone marrow examination revealed dysplastic changes compatible with low-risk MDS. Because copper deficiency is a well-recognized cause of MDS-like anemia in dialysis patients, detailed evaluation was performed; however, serial measurements showed normal serum copper and ceruloplasmin levels, with no evidence of zinc excess. Cytogenetic analysis demonstrated clonal chromosomal abnormalities, supporting the diagnosis of MDS. During the clinical course, hemoglobin levels improved transiently following resolution of systemic inflammation and optimization of volume status, despite no escalation of disease-specific therapy, creating the appearance of a reversible disorder. Conclusion: This case highlights a critical diagnostic pitfall in hemodialysis patients: apparent reversibility of anemia does not necessarily exclude underlying MDS. Although copper deficiency should be carefully evaluated in patients with MDS-like features, clonal cytogenetic abnormalities and persistent cytopenia remain key determinants of diagnosis. Comprehensive assessment and longitudinal observation are essential to avoid misdiagnosis of MDS in this complex population. Hemodialysis Myelodysplastic syndrome Copper deficiency Refractory anemia Figures Figure 1 Figure 2 Introduction Anemia is a common and clinically significant complication in patients with end-stage renal disease (ESRD), arising from multifactorial mechanisms including impaired erythropoietin production, disordered iron metabolism, chronic inflammation, and comorbid conditions such as infection or malnutrition [ 1 – 3 ]. Although erythropoiesis-stimulating agents (ESAs) and intravenous iron supplementation constitute the cornerstone of anemia management in this population, a subset of patients exhibits refractory or progressive anemia, necessitating careful evaluation for alternative or coexisting etiologies [ 1 , 4 ]. Among these, myelodysplastic syndrome (MDS) represents an important diagnostic consideration, particularly in elderly patients. MDS is a clonal hematopoietic stem cell disorder characterized by ineffective hematopoiesis, morphologic dysplasia, and variable degrees of cytopenia, often leading to transfusion dependence [ 5 , 6 ]. However, in patients with ESRD, the diagnosis of MDS is often challenging because several reversible conditions—most notably chronic inflammation, nutritional deficiencies, and trace element abnormalities—can produce bone marrow findings that closely resemble MDS [ 7 , 8 ]. Copper deficiency is a well-recognized but underdiagnosed cause of refractory anemia in patients undergoing long-term hemodialysis. Importantly, copper deficiency may present with MDS-like bone marrow morphology, including multilineage dysplasia, and can demonstrate a reversible clinical course following appropriate supplementation particularly in dialysis patients [ 7 , 8 ]. This overlap poses a significant diagnostic pitfall, as transient hematologic improvement does not necessarily exclude an underlying clonal marrow disorder. Luspatercept, an erythroid maturation agent targeting late-stage erythropoiesis through modulation of the transforming growth factor-β (TGF-β) superfamily signaling pathway, has been approved for the treatment of transfusion-dependent anemia in patients with lower-risk MDS, particularly those with ring sideroblasts or SF3B1 mutations [ 9 , 10 ]. Nevertheless, its efficacy in patients with significant comorbidities, such as ESRD or active inflammatory states, remains incompletely characterized. Here, we report a diagnostically challenging case of transfusion-dependent anemia in an elderly hemodialysis patient in whom MDS and copper deficiency were initially difficult to distinguish. Despite a clinical course that appeared partially reversible following resolution of inflammation and volume overload, persistent anemia and the presence of clonal cytogenetic abnormalities ultimately supported the diagnosis of low-risk MDS. This case underscores the importance of comprehensive differential diagnosis in ESRD-associated anemia and highlights that apparent reversibility does not preclude underlying MDS in this population. Case Presentation An 89-year-old Japanese man with ESRD secondary to hypertensive nephrosclerosis had been receiving maintenance hemodialysis (HD) three times per week for four-hour sessions over a three-year period. At the initiation of HD, anemia was managed with darbepoetin alfa (60 µg/week) and intravenous iron (ferric hydroxide sucrose complex, Fesin®), maintaining hemoglobin (Hb) levels between 9 and 10 g/dL. At month 24 of HD (Year 2), the patient’s anemia worsened, with Hb levels dropping below 8 g/dL, prompting an increase in darbepoetin alfa to 80 µg/week. Laboratory evaluation indicated absolute iron deficiency (ferritin ~ 30 ng/mL, TSAT < 10%). Intravenous iron was increased to three times weekly, but Hb levels remained low, and the patient became transfusion-dependent, receiving periodic transfusions of two units of packed red blood cells. At month 28, bone marrow aspiration revealed normocellular marrow with 0.6% myeloblasts and 10–50% dysplasia in the megakaryocytic lineage. Cytogenetic analysis demonstrated chromosomal abnormalities consistent with low-risk myelodysplastic syndrome (MDS), in the absence of ring sideroblasts. Serum levels of copper, zinc, and ceruloplasmin were within normal limits. Upper gastrointestinal endoscopy revealed no significant abnormalities (Table 1 ). Table 1 Reference Range At Time of Anemia Progression (Month 28) At Time of Pneumonia Admission (Month 33) WBC (/µL) 6,600–8,100 4,600 7,000 Hemoglobin (g/dL) 13.7–16.8 8.2 7.6 Hematocrit (%) 40.7–50.1 27.5 26.2 Platelet (×10³/µL) 158–348 196 90 CRP (mg/dL) 0.00–0.14 0.2 7.2 Ferritin (ng/mL) 21–274 60 59 TSAT (%) > 20 6 9 Reticulocyte (%) 0.1–2.6 1.0 2.1 Albumin (g/dL) 4.1–5.1 3.1 2.9 Zinc (µg/dL) 80–130 54 66 Copper (µg/dL) 66–130 97 132 Ceruloplasmin (mg/dL) 21–37 25 35 hANP (pg/mL) 0–43 129 292 Folate (ng/mL) 3.6–12.9 - 4.1 Vitamin B12 (pg/mL) 233–914 - 297 AST / ALT (U/L) 13–30 / 10–42 12 / 8 28 / 16 γ-GTP (U/L) 13–64 33 36 Fibrinogen (mg/dL) 150–400 - 24.8 PT (%) / aPTT (sec) 70–130 / 24–34 - 71 / 24.8 Fecal occult blood Negative (-) (-) At Time of Anemia Progression (Month 28) Upper gastrointestinal endoscopy: No significant abnormalities detected. Bone marrow aspiration findings: Bone marrow blasts accounted for 0.6%, within the normal range. Megakaryocytic dysplasia is present in 10–50% of cells. Cytogenetic testing revealed chromosomal abnormalities. (Loss of the Y chromosome was observed in 4 out of 20 cells.) At Time of Pneumonia Admission (Month 33) Chest CT: Bilateral pleural effusion and lower lobe-predominant infiltrates. ECG: No ischemic changes observed. Echocardiography: EF 60%; no wall motion abnormalities or valvular disease. To reduce transfusion requirements, luspatercept (75 mg subcutaneously every three weeks) was initiated at month 30. A total of four doses were administered. During this period, the patient developed exertional dyspnea. Serum human atrial natriuretic peptide (hANP) rose to 200 pg/mL, suggestive of volume overload, possibly related to anemia and subclinical heart failure. Electrocardiography and transthoracic echocardiography ruled out ischemia and structural heart disease. The patient’s estimated dry weight was gradually reduced during dialysis, which improved volume status and symptoms. On month 33, the patient was hospitalized for fever and worsening dyspnea. CRP was elevated 8.0 mg/dL, and chest CT revealed bilateral pleural effusions and pulmonary infiltrates, consistent with pneumonia. Treatment included broad-spectrum antibiotics and further adjustment of dry weight. This led to resolution of infection, normalization of CRP, and radiographic improvement. Following recovery, Hb levels increased spontaneously to > 9 g/dL, despite no changes in erythropoiesis-stimulating agent or iron therapy (Fig. 2 ). Transfusion support was discontinued, and the patient remained transfusion-independent for the following seven months without recurrence of severe anemia. Discussion This case illustrates a diagnostic challenge posed by refractory anemia in elderly patients undergoing long-term hemodialysis, particularly when bone marrow findings overlap between potentially reversible nutritional disorders and clonal hematologic diseases. In patients with end-stage renal disease (ESRD), anemia is rarely attributable to a single mechanism; instead, impaired erythropoietin production, chronic inflammation, iron dysregulation, volume overload, infection, and nutritional deficiencies often coexist and interact [ 1 – 4 ]. As a result, distinguishing primary bone marrow disorders such as myelodysplastic syndrome (MDS) from secondary, potentially reversible causes of anemia remains clinically challenging. Copper deficiency is a well-recognized mimicker of MDS in this population. Patients receiving maintenance hemodialysis are at increased risk of trace element imbalance due to reduced dietary intake, impaired gastrointestinal absorption, and interactions with other micronutrients, particularly zinc. Copper deficiency is known to cause refractory anemia and neutropenia and may produce bone marrow findings that closely resemble MDS, including dysplasia affecting multiple hematopoietic lineages [ 7 , 8 ]. Several reports have documented cases initially diagnosed as MDS that were later attributed to copper deficiency–related cytopenia, with hematologic improvement following copper supplementation [ 7 , 8 ]. These observations underscore copper deficiency as an important diagnostic consideration, particularly when anemia demonstrates apparent reversibility. The present case shared several clinical features commonly reported in copper deficiency–associated anemia. The patient developed progressive, erythropoiesis-stimulating agent–resistant anemia with transfusion dependence, and bone marrow examination revealed dysplastic changes. Moreover, hemoglobin levels increased following resolution of systemic inflammation and correction of volume overload, despite no escalation of disease-specific therapy, creating the appearance of a partially reversible disorder. These findings appropriately warranted consideration of copper deficiency in the differential diagnosis. However, several findings supported the diagnosis of MDS rather than copper deficiency. Serum copper and ceruloplasmin levels were within the normal range, and there was no evidence of zinc excess or malabsorptive gastrointestinal disease [ 7 , 8 ]. In addition, cytogenetic analysis demonstrated clonal chromosomal abnormalities consistent with low-risk MDS according to the World Health Organization classification, a feature not expected in isolated nutritional deficiency–related cytopenia [ 5 , 6 ]. Although hemoglobin levels improved temporarily, anemia did not fully resolve and remained chronic, arguing against a purely reversible nutritional etiology. Taken together, these findings support low-risk MDS as the most plausible diagnosis despite the atypical and partially reversible clinical course. The transient improvement in anemia observed in this case warrants careful interpretation. Transient suppressive factors, including infection, inflammation, and volume overload, are common in dialysis patients and are well recognized to inhibit erythropoiesis through multiple mechanisms [ 1 – 4 ]. Inflammatory cytokines such as interleukin-6 can induce hepatic hepcidin production, leading to functional iron deficiency and impaired iron availability despite adequate iron stores [ 3 , 4 ]. In addition, inflammatory mediators may directly suppress hematopoietic progenitor cell proliferation [ 6 ]. Resolution of these modifiable factors may therefore result in temporary hematologic improvement, even in patients with underlying clonal marrow disorders. Copper deficiency can transiently improve cytopenia, but does not exclude the presence of underlying myelodysplastic syndrome, particularly when clonal cytogenetic abnormalities are identified. Several limitations merit consideration. This report describes a single case, and the relative contribution of inflammation control and delayed pharmacologic effects of luspatercept to hemoglobin improvement cannot be fully distinguished [ 9 , 10 ]. Nevertheless, this case highlights an important diagnostic pitfall: in patients undergoing hemodialysis, MDS and copper deficiency may present with overlapping clinical and morphologic features, and apparent reversibility alone should not be used to dismiss the possibility of clonal hematopoiesis. Mini-review: Copper Deficiency as a Mimicker of Myelodysplastic Syndrome in Hemodialysis Patients Copper deficiency is an underrecognized but clinically important cause of cytopenia in patients undergoing maintenance hemodialysis. Copper plays a critical role in hematopoiesis through its involvement in iron mobilization, mitochondrial function, and oxidative metabolism, primarily mediated by copper-dependent enzymes such as ceruloplasmin, cytochrome c oxidase, and superoxide dismutase [ 7 , 8 ]. Deficiency of copper impairs iron transport from macrophages to developing erythroid precursors, leading to ineffective erythropoiesis and anemia that is frequently resistant to erythropoiesis-stimulating agents (ESAs) [ 7 , 8 ]. Copper deficiency–associated cytopenia Clinically, copper deficiency most commonly manifests as anemia and neutropenia, while thrombocytopenia is less frequent. In dialysis patients, multiple factors predispose to copper deficiency, including inadequate dietary intake, chronic inflammation, impaired gastrointestinal absorption, and competitive inhibition by excess zinc. Even in the absence of overt zinc supplementation, subtle zinc–copper imbalance may develop due to altered trace element handling in chronic kidney disease. Several reports have demonstrated that copper deficiency–associated anemia in dialysis patients is often severe, progressive, and transfusion-dependent, closely resembling low-risk myelodysplastic syndrome (MDS). Importantly, hematologic abnormalities frequently improve following copper supplementation, reinforcing the concept that copper deficiency represents a potentially reversible cause of MDS-like cytopenia. Bone marrow findings mimicking myelodysplastic syndrome A key diagnostic challenge lies in the bone marrow morphology associated with copper deficiency. Characteristic findings include multilineage dysplasia, vacuolization of erythroid and myeloid precursors, nuclear irregularities, and increased iron deposition within erythroblasts [ 7 , 8 ]. These changes may closely fulfill morphologic criteria for MDS, particularly low-risk subtypes without excess blasts. Unlike true clonal MDS, however, copper deficiency–associated dysplasia is non-clonal and reversible. Several studies have documented normalization of bone marrow morphology following copper repletion, emphasizing the importance of recognizing this entity to avoid misdiagnosis and inappropriate long-term management. Nevertheless, morphology alone is insufficient to reliably distinguish copper deficiency from MDS, particularly in elderly patients or those with multiple comorbidities. Reported cases of copper deficiency misdiagnosed as MDS Multiple case reports and small case series have described patients initially diagnosed with MDS who were later found to have copper deficiency [ 7 , 8 ]. In these cases, patients often presented with ESA-resistant anemia, neutropenia, and dysplastic marrow findings. Copper supplementation resulted in hematologic recovery and resolution of dysplasia, leading to revision of the initial diagnosis. Dialysis patients appear to be disproportionately represented among such reports, highlighting the vulnerability of this population to trace element imbalance. These observations have led to widespread recommendations that copper deficiency should be routinely excluded in patients with suspected MDS, particularly when cytopenia is accompanied by potentially reversible clinical features. Diagnostic pitfalls in dialysis patients Despite these insights, the diagnostic distinction between copper deficiency and MDS remains challenging in real-world practice. Serum copper and ceruloplasmin levels may be within the normal range, particularly in the setting of inflammation, as ceruloplasmin is an acute-phase reactant [ 3 , 4 , 7 ]. Thus, normal biochemical indices do not necessarily exclude functional copper deficiency or impaired intracellular copper utilization. Furthermore, dialysis patients frequently experience transient suppressive factors, including infection, inflammation, volume overload, and malnutrition, all of which may independently exacerbate anemia and suppress erythropoiesis. Resolution of these factors can lead to spontaneous improvement in hemoglobin levels, creating the misleading impression of a reversible disorder. This phenomenon complicates diagnostic interpretation, especially when improvement occurs without disease-specific therapy. Clinical implications: reversibility does not exclude MDS The present case highlights an important but less emphasized clinical principle: apparent reversibility of cytopenia does not exclude underlying MDS. While improvement following copper supplementation strongly argues against clonal disease, improvement associated with resolution of inflammation or optimization of dialysis conditions may occur even in patients with bona fide MDS. In such cases, transient hematologic recovery reflects modulation of secondary suppressive factors rather than remission of the underlying clonal disorder [ 5 , 6 ]. Cytogenetic analysis remains a cornerstone for distinguishing MDS from nutritional mimickers. The presence of clonal chromosomal abnormalities provides strong evidence for MDS and is not expected in isolated copper deficiency. Persistent cytopenia, even after correction of reversible factors, further supports a clonal etiology. Summary Copper deficiency represents a critical diagnostic mimicker of MDS in patients undergoing hemodialysis and should be systematically evaluated in cases of unexplained or ESA-resistant anemia. However, clinicians should be aware that transient hematologic improvement does not necessarily indicate a reversible nutritional disorder. Comprehensive assessment incorporating trace element evaluation, cytogenetics, and longitudinal observation is essential to avoid both underdiagnosis and overdiagnosis of MDS in this complex population. Conclusion This case underscores that, in hemodialysis patients, copper deficiency and myelodysplastic syndrome (MDS) may present with strikingly similar clinical and morphologic features. Apparent reversibility of anemia following resolution of systemic inflammation or correction of volume overload does not necessarily exclude underlying MDS. Comprehensive evaluation, including trace element assessment and cytogenetic analysis, is essential for accurate diagnosis. Declarations Funding Not applicable. Conflicts of interest / Competing interests The authors declare no conflicts of interest. Ethics approval Not applicable. This case report did not require institutional ethics approval according to local institutional policies. Consent to participate Written informed consent to participate in this case study was obtained from the patient. Written Consent for publication Written informed consent for publication of clinical details and accompanying images was obtained from the patient. Availability of data and material Not applicable. Code availability Not applicable. Acknowledgment: The authors would like to thank the dialysis unit staff at Fuefuki Central Hospital for their support and contributions to this submission. References Babitt JL, Lin HY. Mechanisms of anemia in CKD. J Am Soc Nephrol. 2012;23(10):1631–1634. https://doi.org/10.1681/ASN.2011111078 Kalantar-Zadeh K, Hoffken B, Wunsch H, et al. Diagnosis of iron deficiency anemia in renal disease. Am J Kidney Dis. 1995;26(6):927–936. https://doi.org/10.1016/0272-6386(95)90627-2 Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352(10):1011–1023. https://doi.org/10.1056/NEJMra041809 Gluba-Brzózka A, Franczyk B, Olszewski R, et al. The influence of inflammation on anemia in CKD patients. Int J Mol Sci. 2020;21(3):725. https://doi.org/10.3390/ijms21030725 Santini V, Consagra A. How to use luspatercept and erythropoiesis-stimulating agents in low‐risk myelodysplastic syndrome. Br J Haematol. 2025;201:1–10. https://doi.org/10.1111/bjh.20126 Parisi S, Finelli C, Fazio A, et al. Erythropoiesis regulation in myelodysplastic syndromes and β-thalassemia: molecular insights and clinical implications. Int J Mol Sci. 2021;22(2):827. https://doi.org/10.3390/ijms22020827 Ikegishi Y, Abe R, Maehata A, Takiyama Y.Diagnostic pitfalls of ESA-resistant anemia due to functional copper deficiency in a dialysis patient: a myelodysplastic syndrome mimic.CEN Case Rep. 2026;15:37. Published January 27, 2026. Ikegishi Y, Abe R, Maehata A, Takiyama Y.Acute-onset copper deficiency following surgery in a dialysis patient: diagnostic challenges and risk factor interaction.Intern Med. 2025 Sep 4. doi: 10.2169/internalmedicine.5960-25 . Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. N Engl J Med. 2020;382(2):140–151. https://doi.org/10.1056/NEJMoa1908892 Komrokji RS, Aguirre LE, Al Ali NH, et al. Activity of luspatercept and ESAs combination for treatment of anemia in lower-risk myelodysplastic syndromes. Blood Adv. 2023;7(14):3677–3685. https://doi.org/10.1182/bloodadvances.2022009753 Additional Declarations No competing interests reported. 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. 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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-8821005","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":592148463,"identity":"2495406f-d1d5-48b3-a340-a884758398aa","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":"2026-02-08 10:55:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8821005/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8821005/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102993026,"identity":"e9a392e2-a4fb-435a-a341-d1a119c1f64f","added_by":"auto","created_at":"2026-02-19 11:45:10","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":39879,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOverall clinical course since initiation of dialysis.\u003c/strong\u003e\u003cbr\u003e\n \u003cstrong\u003eTop panel:\u003c/strong\u003eTrends in hemoglobin (red line), platelet count (green line), and white blood cell count (gray line) are shown. Multiple transfusions of 2 units of packed red blood cells (red arrows) were administered due to worsening anemia. A shaded purple area indicates a period of inflammation associated with pneumonia, during which a transient drop in platelet count was observed. Luspatercept (purple arrows) was introduced during this period.\u003cbr\u003e\n \u003cstrong\u003eMiddle panel:\u003c/strong\u003eSerum ferritin levels (red bars) and transferrin saturation (TSAT; blue dots) throughout the course.\u003cbr\u003e\n \u003cstrong\u003eBottom panel:\u003c/strong\u003eChanges in C-reactive protein (CRP; orange line) and human atrial natriuretic peptide (hANP; blue line) are shown. Elevation of CRP and hANP was observed in parallel with the onset of pneumonia-related inflammation.\u003c/p\u003e","description":"","filename":"OnlineFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8821005/v1/cd9d37802d8de0c207aabf6d.png"},{"id":103050637,"identity":"86ca9816-4285-48a1-b4f0-589999aeac31","added_by":"auto","created_at":"2026-02-20 07:52:43","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":33482,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eClinical course after 24 months since initiation of dialysis.\u003c/strong\u003e\u003cbr\u003e\n \u003cstrong\u003e(A)\u003c/strong\u003eHemoglobin levels (red line), serum ferritin (gray bars), and transferrin saturation (TSAT, blue dots) are shown. A significant correlation was observed between hemoglobin and TSAT values. The orange-shaded area indicates the period of pneumonia-associated inflammation, during which anemia progression and thrombocytopenia were observed.\u003cbr\u003e\n \u003cstrong\u003e(B)\u003c/strong\u003eTreatment course, including the administration of darbepoetin alfa (80 μg/week), Fesin (iron formulation) once or three times weekly, and luspatercept (purple arrows). Intravenous ceftriaxone (1 g/day) was administered during pneumonia.\u003cbr\u003e\n \u003cstrong\u003e(C)\u003c/strong\u003eC-reactive protein (CRP, red line) and human atrial natriuretic peptide (hANP, blue line) levels. CRP elevation was followed by hospitalization due to pneumonia (orange area).\u003cbr\u003e\n \u003cstrong\u003e(D)\u003c/strong\u003e Serum levels of copper (Cu, orange bars), ceruloplasmin (green line), and zinc (Zn, blue line). While zinc levels decreased during the course, copper and ceruloplasmin levels remained stable without noticeable decline\u003c/p\u003e","description":"","filename":"OnlineFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8821005/v1/78280710c5320a1cf7e4fa1b.png"},{"id":108961210,"identity":"5d29c3d8-0440-42cb-85a2-6df5b0461ff8","added_by":"auto","created_at":"2026-05-11 08:45:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":318860,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8821005/v1/cd3ec26e-1146-4118-a70d-aec031cd2f3c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Apparent reversibility does not exclude myelodysplastic syndrome: a diagnostic pitfall with copper deficiency in a hemodialysis patient","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAnemia is a common and clinically significant complication in patients with end-stage renal disease (ESRD), arising from multifactorial mechanisms including impaired erythropoietin production, disordered iron metabolism, chronic inflammation, and comorbid conditions such as infection or malnutrition [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Although erythropoiesis-stimulating agents (ESAs) and intravenous iron supplementation constitute the cornerstone of anemia management in this population, a subset of patients exhibits refractory or progressive anemia, necessitating careful evaluation for alternative or coexisting etiologies [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAmong these, myelodysplastic syndrome (MDS) represents an important diagnostic consideration, particularly in elderly patients. MDS is a clonal hematopoietic stem cell disorder characterized by ineffective hematopoiesis, morphologic dysplasia, and variable degrees of cytopenia, often leading to transfusion dependence [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, in patients with ESRD, the diagnosis of MDS is often challenging because several reversible conditions\u0026mdash;most notably chronic inflammation, nutritional deficiencies, and trace element abnormalities\u0026mdash;can produce bone marrow findings that closely resemble MDS [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCopper deficiency is a well-recognized but underdiagnosed cause of refractory anemia in patients undergoing long-term hemodialysis. Importantly, copper deficiency may present with MDS-like bone marrow morphology, including multilineage dysplasia, and can demonstrate a reversible clinical course following appropriate supplementation particularly in dialysis patients [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. This overlap poses a significant diagnostic pitfall, as transient hematologic improvement does not necessarily exclude an underlying clonal marrow disorder.\u003c/p\u003e \u003cp\u003eLuspatercept, an erythroid maturation agent targeting late-stage erythropoiesis through modulation of the transforming growth factor-β (TGF-β) superfamily signaling pathway, has been approved for the treatment of transfusion-dependent anemia in patients with lower-risk MDS, particularly those with ring sideroblasts or SF3B1 mutations [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Nevertheless, its efficacy in patients with significant comorbidities, such as ESRD or active inflammatory states, remains incompletely characterized.\u003c/p\u003e \u003cp\u003eHere, we report a diagnostically challenging case of transfusion-dependent anemia in an elderly hemodialysis patient in whom MDS and copper deficiency were initially difficult to distinguish. Despite a clinical course that appeared partially reversible following resolution of inflammation and volume overload, persistent anemia and the presence of clonal cytogenetic abnormalities ultimately supported the diagnosis of low-risk MDS. This case underscores the importance of comprehensive differential diagnosis in ESRD-associated anemia and highlights that apparent reversibility does not preclude underlying MDS in this population.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eAn 89-year-old Japanese man with ESRD secondary to hypertensive nephrosclerosis had been receiving maintenance hemodialysis (HD) three times per week for four-hour sessions over a three-year period. At the initiation of HD, anemia was managed with darbepoetin alfa (60 \u0026micro;g/week) and intravenous iron (ferric hydroxide sucrose complex, Fesin\u0026reg;), maintaining hemoglobin (Hb) levels between 9 and 10 g/dL.\u003c/p\u003e \u003cp\u003eAt month 24 of HD (Year 2), the patient\u0026rsquo;s anemia worsened, with Hb levels dropping below 8 g/dL, prompting an increase in darbepoetin alfa to 80 \u0026micro;g/week. Laboratory evaluation indicated absolute iron deficiency (ferritin\u0026thinsp;~\u0026thinsp;30 ng/mL, TSAT\u0026thinsp;\u0026lt;\u0026thinsp;10%). Intravenous iron was increased to three times weekly, but Hb levels remained low, and the patient became transfusion-dependent, receiving periodic transfusions of two units of packed red blood cells.\u003c/p\u003e \u003cp\u003eAt month 28, bone marrow aspiration revealed normocellular marrow with 0.6% myeloblasts and 10\u0026ndash;50% dysplasia in the megakaryocytic lineage. Cytogenetic analysis demonstrated chromosomal abnormalities consistent with low-risk myelodysplastic syndrome (MDS), in the absence of ring sideroblasts. Serum levels of copper, zinc, and ceruloplasmin were within normal limits. Upper gastrointestinal endoscopy revealed no significant abnormalities (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\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\u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference Range\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt Time of Anemia Progression (Month 28)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAt Time of Pneumonia Admission (Month 33)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWBC (/\u0026micro;L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6,600\u0026ndash;8,100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4,600\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7,000\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\u003e13.7\u0026ndash;16.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHematocrit (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40.7\u0026ndash;50.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelet (\u0026times;10\u0026sup3;/\u0026micro;L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e158\u0026ndash;348\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e196\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e90\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\u003e0.00\u0026ndash;0.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.2\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\u003e21\u0026ndash;274\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e59\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\u0026gt;\u0026thinsp;20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReticulocyte (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.1\u0026ndash;2.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.1\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\u003e4.1\u0026ndash;5.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZinc (\u0026micro;g/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80\u0026ndash;130\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCopper (\u0026micro;g/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e66\u0026ndash;130\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e132\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCeruloplasmin (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21\u0026ndash;37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ehANP (pg/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u0026ndash;43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e129\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e292\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFolate (ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.6\u0026ndash;12.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVitamin B12 (pg/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e233\u0026ndash;914\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e297\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAST / ALT (U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13\u0026ndash;30 / 10\u0026ndash;42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 / 8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28 / 16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eγ-GTP (U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13\u0026ndash;64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFibrinogen (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e150\u0026ndash;400\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePT (%) / aPTT (sec)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e70\u0026ndash;130 / 24\u0026ndash;34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e71 / 24.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFecal occult blood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(-)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(-)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cb\u003eAt Time of Anemia Progression (Month 28)\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eUpper gastrointestinal endoscopy: No significant abnormalities detected.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eBone marrow aspiration findings: Bone marrow blasts accounted for 0.6%, within the normal range. Megakaryocytic dysplasia is present in 10\u0026ndash;50% of cells. Cytogenetic testing revealed chromosomal abnormalities. (Loss of the Y chromosome was observed in 4 out of 20 cells.)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cb\u003eAt Time of Pneumonia Admission (Month 33)\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eChest CT: Bilateral pleural effusion and lower lobe-predominant infiltrates.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eECG: No ischemic changes observed.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eEchocardiography: EF 60%; no wall motion abnormalities or valvular disease.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTo reduce transfusion requirements, luspatercept (75 mg subcutaneously every three weeks) was initiated at month 30. A total of four doses were administered.\u003c/p\u003e \u003cp\u003eDuring this period, the patient developed exertional dyspnea. Serum human atrial natriuretic peptide (hANP) rose to 200 pg/mL, suggestive of volume overload, possibly related to anemia and subclinical heart failure. Electrocardiography and transthoracic echocardiography ruled out ischemia and structural heart disease. The patient\u0026rsquo;s estimated dry weight was gradually reduced during dialysis, which improved volume status and symptoms.\u003c/p\u003e \u003cp\u003eOn month 33, the patient was hospitalized for fever and worsening dyspnea. CRP was elevated 8.0 mg/dL, and chest CT revealed bilateral pleural effusions and pulmonary infiltrates, consistent with pneumonia. Treatment included broad-spectrum antibiotics and further adjustment of dry weight. This led to resolution of infection, normalization of CRP, and radiographic improvement.\u003c/p\u003e \u003cp\u003eFollowing recovery, Hb levels increased spontaneously to \u0026gt;\u0026thinsp;9 g/dL, despite no changes in erythropoiesis-stimulating agent or iron therapy (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Transfusion support was discontinued, and the patient remained transfusion-independent for the following seven months without recurrence of severe anemia.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis case illustrates a diagnostic challenge posed by refractory anemia in elderly patients undergoing long-term hemodialysis, particularly when bone marrow findings overlap between potentially reversible nutritional disorders and clonal hematologic diseases. In patients with end-stage renal disease (ESRD), anemia is rarely attributable to a single mechanism; instead, impaired erythropoietin production, chronic inflammation, iron dysregulation, volume overload, infection, and nutritional deficiencies often coexist and interact [\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. As a result, distinguishing primary bone marrow disorders such as myelodysplastic syndrome (MDS) from secondary, potentially reversible causes of anemia remains clinically challenging.\u003c/p\u003e \u003cp\u003eCopper deficiency is a well-recognized mimicker of MDS in this population. Patients receiving maintenance hemodialysis are at increased risk of trace element imbalance due to reduced dietary intake, impaired gastrointestinal absorption, and interactions with other micronutrients, particularly zinc. Copper deficiency is known to cause refractory anemia and neutropenia and may produce bone marrow findings that closely resemble MDS, including dysplasia affecting multiple hematopoietic lineages [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Several reports have documented cases initially diagnosed as MDS that were later attributed to copper deficiency\u0026ndash;related cytopenia, with hematologic improvement following copper supplementation [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. These observations underscore copper deficiency as an important diagnostic consideration, particularly when anemia demonstrates apparent reversibility.\u003c/p\u003e \u003cp\u003eThe present case shared several clinical features commonly reported in copper deficiency\u0026ndash;associated anemia. The patient developed progressive, erythropoiesis-stimulating agent\u0026ndash;resistant anemia with transfusion dependence, and bone marrow examination revealed dysplastic changes. Moreover, hemoglobin levels increased following resolution of systemic inflammation and correction of volume overload, despite no escalation of disease-specific therapy, creating the appearance of a partially reversible disorder. These findings appropriately warranted consideration of copper deficiency in the differential diagnosis.\u003c/p\u003e \u003cp\u003eHowever, several findings supported the diagnosis of MDS rather than copper deficiency. Serum copper and ceruloplasmin levels were within the normal range, and there was no evidence of zinc excess or malabsorptive gastrointestinal disease [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In addition, cytogenetic analysis demonstrated clonal chromosomal abnormalities consistent with low-risk MDS according to the World Health Organization classification, a feature not expected in isolated nutritional deficiency\u0026ndash;related cytopenia [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Although hemoglobin levels improved temporarily, anemia did not fully resolve and remained chronic, arguing against a purely reversible nutritional etiology. Taken together, these findings support low-risk MDS as the most plausible diagnosis despite the atypical and partially reversible clinical course.\u003c/p\u003e \u003cp\u003eThe transient improvement in anemia observed in this case warrants careful interpretation. Transient suppressive factors, including infection, inflammation, and volume overload, are common in dialysis patients and are well recognized to inhibit erythropoiesis through multiple mechanisms [\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Inflammatory cytokines such as interleukin-6 can induce hepatic hepcidin production, leading to functional iron deficiency and impaired iron availability despite adequate iron stores [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In addition, inflammatory mediators may directly suppress hematopoietic progenitor cell proliferation [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Resolution of these modifiable factors may therefore result in temporary hematologic improvement, even in patients with underlying clonal marrow disorders. Copper deficiency can transiently improve cytopenia, but does not exclude the presence of underlying myelodysplastic syndrome, particularly when clonal cytogenetic abnormalities are identified.\u003c/p\u003e \u003cp\u003eSeveral limitations merit consideration. This report describes a single case, and the relative contribution of inflammation control and delayed pharmacologic effects of luspatercept to hemoglobin improvement cannot be fully distinguished [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Nevertheless, this case highlights an important diagnostic pitfall: in patients undergoing hemodialysis, MDS and copper deficiency may present with overlapping clinical and morphologic features, and apparent reversibility alone should not be used to dismiss the possibility of clonal hematopoiesis.\u003c/p\u003e\n\u003ch3\u003eMini-review: Copper Deficiency as a Mimicker of Myelodysplastic Syndrome in Hemodialysis Patients\u003c/h3\u003e\n\u003cp\u003eCopper deficiency is an underrecognized but clinically important cause of cytopenia in patients undergoing maintenance hemodialysis. Copper plays a critical role in hematopoiesis through its involvement in iron mobilization, mitochondrial function, and oxidative metabolism, primarily mediated by copper-dependent enzymes such as ceruloplasmin, cytochrome c oxidase, and superoxide dismutase [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Deficiency of copper impairs iron transport from macrophages to developing erythroid precursors, leading to ineffective erythropoiesis and anemia that is frequently resistant to erythropoiesis-stimulating agents (ESAs) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eCopper deficiency–associated cytopenia\u003c/h3\u003e\n\u003cp\u003eClinically, copper deficiency most commonly manifests as anemia and neutropenia, while thrombocytopenia is less frequent. In dialysis patients, multiple factors predispose to copper deficiency, including inadequate dietary intake, chronic inflammation, impaired gastrointestinal absorption, and competitive inhibition by excess zinc. Even in the absence of overt zinc supplementation, subtle zinc\u0026ndash;copper imbalance may develop due to altered trace element handling in chronic kidney disease.\u003c/p\u003e \u003cp\u003eSeveral reports have demonstrated that copper deficiency\u0026ndash;associated anemia in dialysis patients is often severe, progressive, and transfusion-dependent, closely resembling low-risk myelodysplastic syndrome (MDS). Importantly, hematologic abnormalities frequently improve following copper supplementation, reinforcing the concept that copper deficiency represents a potentially reversible cause of MDS-like cytopenia.\u003c/p\u003e\n\u003ch3\u003eBone marrow findings mimicking myelodysplastic syndrome\u003c/h3\u003e\n\u003cp\u003eA key diagnostic challenge lies in the bone marrow morphology associated with copper deficiency. Characteristic findings include multilineage dysplasia, vacuolization of erythroid and myeloid precursors, nuclear irregularities, and increased iron deposition within erythroblasts [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. These changes may closely fulfill morphologic criteria for MDS, particularly low-risk subtypes without excess blasts.\u003c/p\u003e \u003cp\u003eUnlike true clonal MDS, however, copper deficiency\u0026ndash;associated dysplasia is non-clonal and reversible. Several studies have documented normalization of bone marrow morphology following copper repletion, emphasizing the importance of recognizing this entity to avoid misdiagnosis and inappropriate long-term management. Nevertheless, morphology alone is insufficient to reliably distinguish copper deficiency from MDS, particularly in elderly patients or those with multiple comorbidities.\u003c/p\u003e\n\u003ch3\u003eReported cases of copper deficiency misdiagnosed as MDS\u003c/h3\u003e\n\u003cp\u003eMultiple case reports and small case series have described patients initially diagnosed with MDS who were later found to have copper deficiency [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In these cases, patients often presented with ESA-resistant anemia, neutropenia, and dysplastic marrow findings. Copper supplementation resulted in hematologic recovery and resolution of dysplasia, leading to revision of the initial diagnosis.\u003c/p\u003e \u003cp\u003eDialysis patients appear to be disproportionately represented among such reports, highlighting the vulnerability of this population to trace element imbalance. These observations have led to widespread recommendations that copper deficiency should be routinely excluded in patients with suspected MDS, particularly when cytopenia is accompanied by potentially reversible clinical features.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eDiagnostic pitfalls in dialysis patients\u003c/h2\u003e \u003cp\u003eDespite these insights, the diagnostic distinction between copper deficiency and MDS remains challenging in real-world practice. Serum copper and ceruloplasmin levels may be within the normal range, particularly in the setting of inflammation, as ceruloplasmin is an acute-phase reactant [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Thus, normal biochemical indices do not necessarily exclude functional copper deficiency or impaired intracellular copper utilization.\u003c/p\u003e \u003cp\u003eFurthermore, dialysis patients frequently experience transient suppressive factors, including infection, inflammation, volume overload, and malnutrition, all of which may independently exacerbate anemia and suppress erythropoiesis. Resolution of these factors can lead to spontaneous improvement in hemoglobin levels, creating the misleading impression of a reversible disorder. This phenomenon complicates diagnostic interpretation, especially when improvement occurs without disease-specific therapy.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eClinical implications: reversibility does not exclude MDS\u003c/h3\u003e\n\u003cp\u003eThe present case highlights an important but less emphasized clinical principle: apparent reversibility of cytopenia does not exclude underlying MDS. While improvement following copper supplementation strongly argues against clonal disease, improvement associated with resolution of inflammation or optimization of dialysis conditions may occur even in patients with bona fide MDS. In such cases, transient hematologic recovery reflects modulation of secondary suppressive factors rather than remission of the underlying clonal disorder [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCytogenetic analysis remains a cornerstone for distinguishing MDS from nutritional mimickers. The presence of clonal chromosomal abnormalities provides strong evidence for MDS and is not expected in isolated copper deficiency. Persistent cytopenia, even after correction of reversible factors, further supports a clonal etiology.\u003c/p\u003e\n\u003ch3\u003eSummary\u003c/h3\u003e\n\u003cp\u003eCopper deficiency represents a critical diagnostic mimicker of MDS in patients undergoing hemodialysis and should be systematically evaluated in cases of unexplained or ESA-resistant anemia. However, clinicians should be aware that transient hematologic improvement does not necessarily indicate a reversible nutritional disorder. Comprehensive assessment incorporating trace element evaluation, cytogenetics, and longitudinal observation is essential to avoid both underdiagnosis and overdiagnosis of MDS in this complex population.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis case underscores that, in hemodialysis patients, copper deficiency and myelodysplastic syndrome (MDS) may present with strikingly similar clinical and morphologic features. Apparent reversibility of anemia following resolution of systemic inflammation or correction of volume overload does not necessarily exclude underlying MDS. Comprehensive evaluation, including trace element assessment and cytogenetic analysis, is essential for accurate diagnosis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest / Competing interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. This case report did not require institutional ethics approval according to local institutional policies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent to participate in this case study was obtained from the patient.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWritten Consent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent for publication of clinical details and accompanying images was obtained from the patient.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCode availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgment:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank the dialysis unit staff at Fuefuki Central Hospital for their support and contributions to this submission.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBabitt JL, Lin HY. Mechanisms of anemia in CKD. J Am Soc Nephrol. 2012;23(10):1631\u0026ndash;1634. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1681/ASN.2011111078\u003c/span\u003e\u003cspan address=\"10.1681/ASN.2011111078\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKalantar-Zadeh K, Hoffken B, Wunsch H, et al. Diagnosis of iron deficiency anemia in renal disease. Am J Kidney Dis. 1995;26(6):927\u0026ndash;936. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/0272-6386(95)90627-2\u003c/span\u003e\u003cspan address=\"10.1016/0272-6386(95)90627-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWeiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352(10):1011\u0026ndash;1023. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1056/NEJMra041809\u003c/span\u003e\u003cspan address=\"10.1056/NEJMra041809\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGluba-Brz\u0026oacute;zka A, Franczyk B, Olszewski R, et al. The influence of inflammation on anemia in CKD patients. Int J Mol Sci. 2020;21(3):725. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/ijms21030725\u003c/span\u003e\u003cspan address=\"10.3390/ijms21030725\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSantini V, Consagra A. How to use luspatercept and erythropoiesis-stimulating agents in low‐risk myelodysplastic syndrome. Br J Haematol. 2025;201:1\u0026ndash;10. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/bjh.20126\u003c/span\u003e\u003cspan address=\"10.1111/bjh.20126\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eParisi S, Finelli C, Fazio A, et al. Erythropoiesis regulation in myelodysplastic syndromes and β-thalassemia: molecular insights and clinical implications. Int J Mol Sci. 2021;22(2):827. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/ijms22020827\u003c/span\u003e\u003cspan address=\"10.3390/ijms22020827\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIkegishi Y, Abe R, Maehata A, Takiyama Y.Diagnostic pitfalls of ESA-resistant anemia due to functional copper deficiency in a dialysis patient: a myelodysplastic syndrome mimic.CEN Case Rep. 2026;15:37. Published January 27, 2026.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIkegishi Y, Abe R, Maehata A, Takiyama Y.Acute-onset copper deficiency following surgery in a dialysis patient: diagnostic challenges and risk factor interaction.Intern Med. 2025 Sep 4. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2169/internalmedicine.5960-25\u003c/span\u003e\u003cspan address=\"10.2169/internalmedicine.5960-25\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. N Engl J Med. 2020;382(2):140\u0026ndash;151. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1056/NEJMoa1908892\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa1908892\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKomrokji RS, Aguirre LE, Al Ali NH, et al. Activity of luspatercept and ESAs combination for treatment of anemia in lower-risk myelodysplastic syndromes. Blood Adv. 2023;7(14):3677\u0026ndash;3685. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1182/bloodadvances.2022009753\u003c/span\u003e\u003cspan address=\"10.1182/bloodadvances.2022009753\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\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":"Hemodialysis, Myelodysplastic syndrome, Copper deficiency, Refractory anemia","lastPublishedDoi":"10.21203/rs.3.rs-8821005/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8821005/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e \u003cp\u003eAnemia in patients undergoing long-term hemodialysis is multifactorial and frequently refractory to standard therapy. In elderly patients, myelodysplastic syndrome (MDS) must be considered; however, several reversible conditions\u0026mdash;most notably copper deficiency\u0026mdash;can closely mimic MDS both clinically and morphologically, posing a significant diagnostic challenge.\u003c/p\u003e\u003ch2\u003eCase Presentation:\u003c/h2\u003e \u003cp\u003eAn 89-year-old Japanese man receiving maintenance hemodialysis for end-stage renal disease developed progressive, erythropoiesis-stimulating agent\u0026ndash;resistant anemia and became transfusion-dependent. Bone marrow examination revealed dysplastic changes compatible with low-risk MDS. Because copper deficiency is a well-recognized cause of MDS-like anemia in dialysis patients, detailed evaluation was performed; however, serial measurements showed normal serum copper and ceruloplasmin levels, with no evidence of zinc excess. Cytogenetic analysis demonstrated clonal chromosomal abnormalities, supporting the diagnosis of MDS. During the clinical course, hemoglobin levels improved transiently following resolution of systemic inflammation and optimization of volume status, despite no escalation of disease-specific therapy, creating the appearance of a reversible disorder.\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e \u003cp\u003eThis case highlights a critical diagnostic pitfall in hemodialysis patients: apparent reversibility of anemia does not necessarily exclude underlying MDS. Although copper deficiency should be carefully evaluated in patients with MDS-like features, clonal cytogenetic abnormalities and persistent cytopenia remain key determinants of diagnosis. Comprehensive assessment and longitudinal observation are essential to avoid misdiagnosis of MDS in this complex population.\u003c/p\u003e","manuscriptTitle":"Apparent reversibility does not exclude myelodysplastic syndrome: a diagnostic pitfall with copper deficiency in a hemodialysis patient","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-19 11:45:05","doi":"10.21203/rs.3.rs-8821005/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":"February 19th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Rejected","date":"2026-05-11T08:34:09+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-11T04:34:22+00:00","index":33,"fulltext":""},{"type":"reviewerAgreed","content":"50011709728692767167307178024926763015","date":"2026-05-10T22:59:48+00:00","index":32,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-05-11T08:44:38+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-19 11:45:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8821005","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8821005","identity":"rs-8821005","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}