Hemoglobinuria-associated acute kidney injury in hemolytic uremic syndrome without renal thrombotic microangiopathy

Hemoglobinuria-associated acute kidney injury in hemolytic uremic syndrome without renal thrombotic microangiopathy | 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 Hemoglobinuria-associated acute kidney injury in hemolytic uremic syndrome without renal thrombotic microangiopathy Nicoletta Mancianti, Sergio Antonio Tripodi, Jingjing LI, Andrea Guarnieri, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8155876/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 19 Mar, 2026 Read the published version in BMC Nephrology → Version 1 posted 16 You are reading this latest preprint version Abstract Background Hemolytic uremic syndrome (HUS) is defined by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury (AKI), classically attributed to renal thrombotic microangiopathy (TMA). Case presentation: A 64-year-old woman with hypertension treated with an ACE inhibitor presented with asthenia, nausea, dark urine, and oliguria. Laboratory tests showed AKI (serum creatinine 4.5 mg/dL), thrombocytopenia (46 × 10⁹/L), and hemolysis (LDH > 1,800 U/L, schistocytes, low haptoglobin). Procalcitonin was markedly elevated; complement and ADAMTS13 were normal. A positive direct Coombs test suggested pneumococcal-associated or secondary HUS, but extensive microbiological studies were negative. Suspected STEC-HUS was managed with plasma exchange (subsequently discontinued), supportive therapy, and hemodialysis from day 3. Hematologic abnormalities resolved, but renal function worsened, with serum creatinine peaking at 10 mg/dL on day 6. Kidney biopsy on day 7 revealed acute tubular injury with hemoglobin pigment casts and no evidence of TMA. Dialysis was withdrawn, and renal recovery followed. Conclusions This case highlights that AKI in HUS is not invariably due to TMA; hemoglobinuria-induced tubular injury can be the dominant lesion. When hematologic recovery contrasts with persistent renal dysfunction, pigment nephropathy should be suspected and biopsy considered when feasible. To our knowledge, this is the first reported case of HUS with full clinical triad but biopsy-proven tubular injury without renal TMA. Figures Figure 1 Introduction Hemolytic uremic syndrome (HUS) is defined by the triad of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and acute kidney injury (AKI), and is classically associated with renal thrombotic microangiopathy (TMA), considered its hallmark histologic lesion ( 1 ). TMA is characterized clinically by MAHA, thrombocytopenia, and ischemic organ injury. Although multiple organs may be involved, the kidney is predominantly affected. Among TMA syndromes, the most frequent are Shiga toxin–producing Escherichia coli HUS (STEC-HUS) and thrombotic thrombocytopenic purpura (TTP), followed by atypical HUS (aHUS) and secondary forms ( 2 – 4 ). aHUS is largely driven by genetic or acquired complement abnormalities, most commonly involving complement factor H, but also C3, factor B, factor I, or CD46. Mutations in non-complement proteins, such as diacylglycerol kinase ε, plasminogen, factor XII, or thrombomodulin, have also been described ( 7 – 14 ). Secondary HUS develops in association with infections, autoimmune disease, malignancy, transplantation, pregnancy-related disorders (e.g., pre-eclampsia/HELLP), or cytotoxic drugs, with dysregulated complement activation implicated in some cases ( 15 ). Kidney biopsy remains the gold standard for diagnosing renal TMA and excluding other causes of kidney injury. However, in typical HUS biopsy is rarely performed in the acute phase because of thrombocytopenia, and most histologic data derive from autopsy studies or exceptional cases ( 5 , 6 ). Consequently, biopsy-proven descriptions of renal lesions in HUS are exceedingly limited, and AKI is often presumed to reflect TMA without direct confirmation. Importantly, hemoglobinuria itself can cause acute tubular injury in a variety of contexts beyond HUS, such as paroxysmal nocturnal hemoglobinuria, transfusion reactions, autoimmune hemolytic anemia, or myoglobinuria. Notably, in these conditions, hemoglobin cast nephropathy produces AKI through heme-mediated tubular toxicity, oxidative stress, and cast obstruction ( 16 – 18 ). We report the case of a patient fulfilling the full clinical triad of HUS, in whom renal biopsy revealed hemoglobinuria-associated tubular injury without evidence of TMA. To our knowledge, this represents the first biopsy-proven case described in the literature. Case presentation A 64-year-old woman with hypertension treated with an ACE inhibitor, presented with 2 daysof asthenia, nausea, vomiting, and dark urine, followed by 24 hours of oliguria. Admission findings: Blood pressure 135/75 mmHg; creatinine 4.5 mg/dL; platelets 46 × 10^9/L; hemoglobin 12 g/dL; LDH > 1,800 U/L; low haptoglobin; indirect hyperbilirubinemia; schistocytes on peripheral smear; procalcitonin > 100 ng/mL. Complement levels were normal; ADAMTS13 activity 34% (report received the day after the plasmapheresis session). Given suspected TTP/HUS, one plasma exchange was performed, antibiotics were withheld due to suspected STEC-HUS, and intravenous fluids were administered. ACE inhibitor was suspended. Evolution: Over 72 hours, gastrointestinal symptoms and inflammatory markers normalized without antibiotics; microbiological work-up, including stool Shiga toxin testing, was negative. Hemolysis and thrombocytopenia improved, but AKI worsened, requiring dialysis from day 3. A positive direct Coombs test initially raised suspicion for pneumococcal-associated HUS (pnHUS) or other pathogen-related forms (e.g., Legionella, CMV). However, all targeted investigations, including the FilmArray stool panel, were negative. Table 1 summarizes the laboratory trends and key clinical events during hospitalization. Table 1 Laboratory parameters and key clinical events during hospitalization Day Creatinine (mg/dL) Hemoglobin (g/dL) Platelets (×10^9/L) LDH (U/L) Procalcitonin (ng/mL) Key events 1 4.5 11.8 46 > 1800 > 100 Hospital admission 2 6.6 11.7 44 1045 45 Plasma exchange 3 8.1 10.3 52 340 28 Start dialysis 4 8.8 10.0 72 320 6.8 – 5 9.0 9.7 94 280 3.5 – 6 9.9 9.8 136 331 2 Dialysis stopped (Recovery of urine output) 7 10.0 9.9 137 290 3 Renal biopsy 14 1.2 10.0 254 210 0 Renal recovery Renal biopsy summary: The specimen showed preserved glomeruli without microthrombi and only mild vascular changes. The predominant alterations were tubular—ectasia, vacuolization, focal necrosis, and abundant brown granular casts consistent with hemoglobin deposition. Minimal interstitial inflammation and focal tubular atrophy were present. Immunofluorescence and Congo red staining were negative. Overall, the findings supported acute tubular injury of ischemic/toxic origin, most likely due to hemoglobinuria, without evidence of thrombotic microangiopathy (TMA). ( Fig. 1 ). Plasma exchange was discontinued. With supportive care, kidney function improved; dialysis was withdrawn within 1 week, and complete renal recovery was achieved. Discussion Our patient fulfilled the clinical triad of HUS (MAHA, thrombocytopenia, and AKI). In such settings, renal injury is typically attributed to TMA, the canonical histopathologic lesion of HUS ( 1 , 2 ). However, kidney biopsy is rarely performed during the acute phase due to thrombocytopenia and bleeding risk, and most histologic data derive from autopsies or a handful of biopsies ( 5 , 6 ). As a result, the presumption that AKI in HUS invariably reflects TMA is largely indirect. In this case, once platelet counts normalized, biopsy revealed acute tubular injury with hemoglobin casts, without evidence of TMA. This finding challenges the conventional paradigm and suggests that hemoglobinuria-associated tubular injury may represent an alternative mechanism of AKI in HUS. Pigment nephropathy is well recognized in other hemolytic or myopathic disorders—including paroxysmal nocturnal hemoglobinuria, autoimmune hemolytic anemia, transfusion reactions, and rhabdomyolysis—where it produces acute tubular necrosis via heme-mediated oxidative injury, cast obstruction, and synergistic ischemic stress ( 16 – 18 ). The positive direct Coombs test raised suspicion for pneumococcal-associated or other secondary HUS forms, but targeted microbiological investigations were negative, supporting the interpretation that hemoglobinuria itself was the primary driver of AKI the primary driver of AKI, particularly in the presence of additional hemodynamic stressors (e.g., ACE inhibitor use, systemic inflammation). To our knowledge, this is the first report of a patient with full clinical features of HUS and biopsy-proven tubular injury without renal TMA. Only very few reports of HUS without TMA on biopsy exist, and these date back decades ( 19 ), underscoring the rarity of such cases. Clinically, this distinction is important. In patients with HUS who exhibit rapid hematologic and infectious resolution but persistent AKI, pigment nephropathy should be considered. When bleeding risk is acceptable, kidney biopsy provides crucial diagnostic clarity, avoiding unnecessary plasma exchange and guiding supportive management. Conclusion This case highlights that in HUS, AKI may arise from hemoglobinuria-induced tubular injury rather than TMA. Renal biopsy, when feasible, can provide essential diagnostic insights and reshape management. Declarations Funding This work received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Ethical statement: not applicable. Consent for publication Written informed consent for publication of the clinical details and any accompanying images was obtained from the patient Data availability All data generated or analysed during this study are included in this published article Author Contribution Author ContributionsN.M. conceived the case report, managed the patient, collected clinical data, and drafted the manuscript.S.A.T. performed and interpreted the histopathological analyses and critically revised the manuscript.L.J. contributed to the histopathological review and figure preparation.A.G. contributed to clinical management, diagnostic work-up, and manuscript editing.G.G. provided senior clinical supervision and approved the final version of the manuscript. References George JN, Nester CM. Syndromes of thrombotic microangiopathy. N Engl J Med. 2014;371(7):654–66. Mele C, Remuzzi G, Noris M. Hemolytic uremic syndrome. Semin Immunopathol. 2014;36(4):399–420. Laszik ZG, Kambham N, Silva FG. Thrombotic Microangiopathies. In: Jennette JC, Olson JL, Silva FD, D’Agati VD, editors. Heptinstall’s Pathology of the Kidney. 7th ed. Philadelphia: Wolters Kluwer; 2015. pp. 739–814. Shrivastava M, Shah N. Pregnancy Associated Thrombotic Microangiopathy. People’s J Sci Res. 2016;9:76–86. Remuzzi G, Ruggenenti P. The hemolytic uremic syndrome. Kidney Int. 1995;48:2–19. Karpman D, Hakansson A, Perez MT, et al. Apoptosis of renal cortical cells in the hemolytic-uremic syndrome. Kidney Int. 1998;54(2):553–63. Caprioli J, Noris M, Brioschi S, et al. Genetics of HUS: the impact of complement factor H mutations. J Am Soc Nephrol. 2006;17(3):840–7. Fremeaux-Bacchi V, Fakhouri F, Garnier A, et al. Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults. Clin J Am Soc Nephrol. 2013;8(4):554–62. Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:1676–87. Lemaire M, Fremeaux-Bacchi V, Schaefer F, et al. Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nat Genet. 2013;45(5):531–6. Bu F, Maga T, Meyer NC, et al. Comprehensive genetic analysis of complement and coagulation genes in atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2014;25(1):55–64. Dragon-Durey MA, Loirat C, Cloarec S, et al. Anti–factor H autoantibodies associated with atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2005;16(2):555–63. Delvaeye M, Noris M, De Vriese A, et al. Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:345–57. Noris M, Remuzzi G. Atypical hemolytic uremic syndrome: from bench to bedside. Clin J Am Soc Nephrol. 2010;5(10):1844–59. Kavanagh D, Goodship TH, Richards A. Atypical hemolytic uremic syndrome. Semin Nephrol. 2013;33(6):508–30. Dvanajscak Z, Walker PD, Cossey LN, Messias NC, Boils CL, Larsen CP. Hemolysis-associated hemoglobin cast nephropathy: clinicopathologic characterization of 27 cases. Pathol Res Pract. 2019;215(10):152575. Mahmud S, Muciño-Bermejo J, Hidalgo J, et al. Hemoglobin cast nephropathy: clinical features and outcomes. Kidney Int Rep. 2020;5(9):1476–80. Patel PS, Singh S, Goel P, et al. Pigment-induced acute kidney injury: a case series and review. Cureus. 2024;16(4):e58472. Pourrat O, Deray G, Isnard H, et al. Adult hemolytic uremic syndrome: six cases without renal TMA on biopsy. Nephrol Dial Transpl. 1994;9(10):1420–3. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 19 Mar, 2026 Read the published version in BMC Nephrology → Version 1 posted Editorial decision: Revision requested 28 Jan, 2026 Reviews received at journal 27 Jan, 2026 Reviewers agreed at journal 27 Jan, 2026 Reviews received at journal 08 Jan, 2026 Reviews received at journal 04 Jan, 2026 Reviews received at journal 30 Dec, 2025 Reviewers agreed at journal 22 Dec, 2025 Reviewers agreed at journal 21 Dec, 2025 Reviewers agreed at journal 21 Dec, 2025 Reviewers agreed at journal 20 Dec, 2025 Reviewers agreed at journal 20 Dec, 2025 Reviewers invited by journal 11 Dec, 2025 Editor assigned by journal 11 Dec, 2025 Editor invited by journal 01 Dec, 2025 Submission checks completed at journal 28 Nov, 2025 First submitted to journal 28 Nov, 2025 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. 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15:02:29","extension":"html","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":49094,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8155876/v1/ed148296f87c5ba532c2ee42.html"},{"id":98328139,"identity":"8e351a5e-d51d-49a6-baf4-b8e3c60d8366","added_by":"auto","created_at":"2025-12-16 15:02:29","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":163123,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA \u003c/strong\u003eRenal cortex (hematoxylin and eosin, low magnification): preserved glomeruli with dilatation of proximal tubules with granular brown cast compatible with hemoglobin is observed in the tubular lumen. \u003cstrong\u003eB\u003c/strong\u003e Proximal tubules (hematoxylin and eosin, high magnification): tubular epithelial cell swelling and vacuolation with luminal sloughing leading to the formation of an epithelial cast.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8155876/v1/513ba0709ef55256ef955fda.jpg"},{"id":105223445,"identity":"1da7ce4a-3f25-4a40-9484-7c5b616815de","added_by":"auto","created_at":"2026-03-23 16:06:49","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":577039,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8155876/v1/6067b087-b482-4fc2-b784-3bc29acd9b62.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Hemoglobinuria-associated acute kidney injury in hemolytic uremic syndrome without renal thrombotic microangiopathy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHemolytic uremic syndrome (HUS) is defined by the triad of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and acute kidney injury (AKI), and is classically associated with renal thrombotic microangiopathy (TMA), considered its hallmark histologic lesion (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTMA is characterized clinically by MAHA, thrombocytopenia, and ischemic organ injury. Although multiple organs may be involved, the kidney is predominantly affected. Among TMA syndromes, the most frequent are Shiga toxin\u0026ndash;producing \u003cem\u003eEscherichia coli\u003c/em\u003e HUS (STEC-HUS) and thrombotic thrombocytopenic purpura (TTP), followed by atypical HUS (aHUS) and secondary forms (\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eaHUS is largely driven by genetic or acquired complement abnormalities, most commonly involving complement factor H, but also C3, factor B, factor I, or CD46. Mutations in non-complement proteins, such as diacylglycerol kinase ε, plasminogen, factor XII, or thrombomodulin, have also been described (\u003cspan additionalcitationids=\"CR8 CR9 CR10 CR11 CR12 CR13\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Secondary HUS develops in association with infections, autoimmune disease, malignancy, transplantation, pregnancy-related disorders (e.g., pre-eclampsia/HELLP), or cytotoxic drugs, with dysregulated complement activation implicated in some cases (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eKidney biopsy remains the gold standard for diagnosing renal TMA and excluding other causes of kidney injury. However, in typical HUS biopsy is rarely performed in the acute phase because of thrombocytopenia, and most histologic data derive from autopsy studies or exceptional cases (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Consequently, biopsy-proven descriptions of renal lesions in HUS are exceedingly limited, and AKI is often presumed to reflect TMA without direct confirmation.\u003c/p\u003e \u003cp\u003eImportantly, hemoglobinuria itself can cause acute tubular injury in a variety of contexts beyond HUS, such as paroxysmal nocturnal hemoglobinuria, transfusion reactions, autoimmune hemolytic anemia, or myoglobinuria. Notably, in these conditions, hemoglobin cast nephropathy produces AKI through heme-mediated tubular toxicity, oxidative stress, and cast obstruction (\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWe report the case of a patient fulfilling the full clinical triad of HUS, in whom renal biopsy revealed hemoglobinuria-associated tubular injury without evidence of TMA. To our knowledge, this represents the first biopsy-proven case described in the literature.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eA 64-year-old woman with hypertension treated with an ACE inhibitor, presented with 2 daysof asthenia, nausea, vomiting, and dark urine, followed by 24 hours of oliguria.\u003c/p\u003e \u003cp\u003eAdmission findings: Blood pressure 135/75 mmHg; creatinine 4.5 mg/dL; platelets 46 \u0026times; 10^9/L; hemoglobin 12 g/dL; LDH\u0026thinsp;\u0026gt;\u0026thinsp;1,800 U/L; low haptoglobin; indirect hyperbilirubinemia; schistocytes on peripheral smear; procalcitonin\u0026thinsp;\u0026gt;\u0026thinsp;100 ng/mL. Complement levels were normal; ADAMTS13 activity 34% (report received the day after the plasmapheresis session).\u003c/p\u003e \u003cp\u003eGiven suspected TTP/HUS, one plasma exchange was performed, antibiotics were withheld due to suspected STEC-HUS, and intravenous fluids were administered. ACE inhibitor was suspended.\u003c/p\u003e \u003cp\u003eEvolution: Over 72 hours, gastrointestinal symptoms and inflammatory markers normalized without antibiotics; microbiological work-up, including stool Shiga toxin testing, was negative. Hemolysis and thrombocytopenia improved, but AKI worsened, requiring dialysis from day 3. A positive direct Coombs test initially raised suspicion for pneumococcal-associated HUS (pnHUS) or other pathogen-related forms (e.g., Legionella, CMV). However, all targeted investigations, including the FilmArray stool panel, were negative.\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e summarizes the laboratory trends and key clinical events during hospitalization.\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\u003eLaboratory parameters and key clinical events during hospitalization\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDay\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCreatinine (mg/dL)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHemoglobin (g/dL)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePlatelets (\u0026times;10^9/L)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLDH (U/L)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eProcalcitonin (ng/mL)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eKey events\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;1800\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eHospital admission\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1045\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePlasma exchange\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e340\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eStart dialysis\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e320\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e280\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e136\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e331\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eDialysis stopped (Recovery of urine output)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e137\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e290\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eRenal biopsy\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e254\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e210\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eRenal recovery\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\u003eRenal biopsy summary: The specimen showed preserved glomeruli without microthrombi and only mild vascular changes. The predominant alterations were tubular\u0026mdash;ectasia, vacuolization, focal necrosis, and abundant brown granular casts consistent with hemoglobin deposition. Minimal interstitial inflammation and focal tubular atrophy were present. Immunofluorescence and Congo red staining were negative. Overall, the findings supported acute tubular injury of ischemic/toxic origin, most likely due to hemoglobinuria, without evidence of thrombotic microangiopathy (TMA). \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e).\u003c/b\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003ePlasma exchange was discontinued. With supportive care, kidney function improved; dialysis was withdrawn within 1 week, and complete renal recovery was achieved.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur patient fulfilled the clinical triad of HUS (MAHA, thrombocytopenia, and AKI). In such settings, renal injury is typically attributed to TMA, the canonical histopathologic lesion of HUS (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). However, kidney biopsy is rarely performed during the acute phase due to thrombocytopenia and bleeding risk, and most histologic data derive from autopsies or a handful of biopsies (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). As a result, the presumption that AKI in HUS invariably reflects TMA is largely indirect.\u003c/p\u003e \u003cp\u003eIn this case, once platelet counts normalized, biopsy revealed acute tubular injury with hemoglobin casts, without evidence of TMA. This finding challenges the conventional paradigm and suggests that hemoglobinuria-associated tubular injury may represent an alternative mechanism of AKI in HUS. Pigment nephropathy is well recognized in other hemolytic or myopathic disorders\u0026mdash;including paroxysmal nocturnal hemoglobinuria, autoimmune hemolytic anemia, transfusion reactions, and rhabdomyolysis\u0026mdash;where it produces acute tubular necrosis via heme-mediated oxidative injury, cast obstruction, and synergistic ischemic stress (\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe positive direct Coombs test raised suspicion for pneumococcal-associated or other secondary HUS forms, but targeted microbiological investigations were negative, supporting the interpretation that hemoglobinuria itself was the primary driver of AKI the primary driver of AKI, particularly in the presence of additional hemodynamic stressors (e.g., ACE inhibitor use, systemic inflammation).\u003c/p\u003e \u003cp\u003eTo our knowledge, this is the first report of a patient with full clinical features of HUS and biopsy-proven tubular injury without renal TMA. Only very few reports of HUS without TMA on biopsy exist, and these date back decades (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e), underscoring the rarity of such cases.\u003c/p\u003e \u003cp\u003eClinically, this distinction is important. In patients with HUS who exhibit rapid hematologic and infectious resolution but persistent AKI, pigment nephropathy should be considered. When bleeding risk is acceptable, kidney biopsy provides crucial diagnostic clarity, avoiding unnecessary plasma exchange and guiding supportive management.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis case highlights that in HUS, AKI may arise from hemoglobinuria-induced tubular injury rather than TMA. Renal biopsy, when feasible, can provide essential diagnostic insights and reshape management.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical statement:\u003c/strong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003enot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent for publication of the clinical details and any accompanying images was obtained from the patient\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analysed during this study are included in this published article\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAuthor ContributionsN.M. conceived the case report, managed the patient, collected clinical data, and drafted the manuscript.S.A.T. performed and interpreted the histopathological analyses and critically revised the manuscript.L.J. contributed to the histopathological review and figure preparation.A.G. contributed to clinical management, diagnostic work-up, and manuscript editing.G.G. provided senior clinical supervision and approved the final version of the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGeorge JN, Nester CM. Syndromes of thrombotic microangiopathy. N Engl J Med. 2014;371(7):654\u0026ndash;66.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMele C, Remuzzi G, Noris M. Hemolytic uremic syndrome. Semin Immunopathol. 2014;36(4):399\u0026ndash;420.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLaszik ZG, Kambham N, Silva FG. Thrombotic Microangiopathies. In: Jennette JC, Olson JL, Silva FD, D\u0026rsquo;Agati VD, editors. Heptinstall\u0026rsquo;s Pathology of the Kidney. 7th ed. Philadelphia: Wolters Kluwer; 2015. pp. 739\u0026ndash;814.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShrivastava M, Shah N. Pregnancy Associated Thrombotic Microangiopathy. People\u0026rsquo;s J Sci Res. 2016;9:76\u0026ndash;86.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRemuzzi G, Ruggenenti P. The hemolytic uremic syndrome. Kidney Int. 1995;48:2\u0026ndash;19.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKarpman D, Hakansson A, Perez MT, et al. Apoptosis of renal cortical cells in the hemolytic-uremic syndrome. Kidney Int. 1998;54(2):553\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCaprioli J, Noris M, Brioschi S, et al. Genetics of HUS: the impact of complement factor H mutations. J Am Soc Nephrol. 2006;17(3):840\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFremeaux-Bacchi V, Fakhouri F, Garnier A, et al. Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults. Clin J Am Soc Nephrol. 2013;8(4):554\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNoris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:1676\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLemaire M, Fremeaux-Bacchi V, Schaefer F, et al. Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nat Genet. 2013;45(5):531\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBu F, Maga T, Meyer NC, et al. Comprehensive genetic analysis of complement and coagulation genes in atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2014;25(1):55\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDragon-Durey MA, Loirat C, Cloarec S, et al. Anti\u0026ndash;factor H autoantibodies associated with atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2005;16(2):555\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDelvaeye M, Noris M, De Vriese A, et al. Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:345\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNoris M, Remuzzi G. Atypical hemolytic uremic syndrome: from bench to bedside. Clin J Am Soc Nephrol. 2010;5(10):1844\u0026ndash;59.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKavanagh D, Goodship TH, Richards A. Atypical hemolytic uremic syndrome. Semin Nephrol. 2013;33(6):508\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDvanajscak Z, Walker PD, Cossey LN, Messias NC, Boils CL, Larsen CP. Hemolysis-associated hemoglobin cast nephropathy: clinicopathologic characterization of 27 cases. Pathol Res Pract. 2019;215(10):152575.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMahmud S, Muci\u0026ntilde;o-Bermejo J, Hidalgo J, et al. Hemoglobin cast nephropathy: clinical features and outcomes. Kidney Int Rep. 2020;5(9):1476\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePatel PS, Singh S, Goel P, et al. Pigment-induced acute kidney injury: a case series and review. Cureus. 2024;16(4):e58472.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePourrat O, Deray G, Isnard H, et al. Adult hemolytic uremic syndrome: six cases without renal TMA on biopsy. Nephrol Dial Transpl. 1994;9(10):1420\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8155876/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8155876/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eHemolytic uremic syndrome (HUS) is defined by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury (AKI), classically attributed to renal thrombotic microangiopathy (TMA).\u003c/p\u003e\u003ch2\u003eCase presentation:\u003c/h2\u003e \u003cp\u003eA 64-year-old woman with hypertension treated with an ACE inhibitor presented with asthenia, nausea, dark urine, and oliguria. Laboratory tests showed AKI (serum creatinine 4.5 mg/dL), thrombocytopenia (46 \u0026times; 10⁹/L), and hemolysis (LDH\u0026thinsp;\u0026gt;\u0026thinsp;1,800 U/L, schistocytes, low haptoglobin). Procalcitonin was markedly elevated; complement and ADAMTS13 were normal. A positive direct Coombs test suggested pneumococcal-associated or secondary HUS, but extensive microbiological studies were negative. Suspected STEC-HUS was managed with plasma exchange (subsequently discontinued), supportive therapy, and hemodialysis from day 3. Hematologic abnormalities resolved, but renal function worsened, with serum creatinine peaking at 10 mg/dL on day 6. Kidney biopsy on day 7 revealed acute tubular injury with hemoglobin pigment casts and no evidence of TMA. Dialysis was withdrawn, and renal recovery followed.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThis case highlights that AKI in HUS is not invariably due to TMA; hemoglobinuria-induced tubular injury can be the dominant lesion. When hematologic recovery contrasts with persistent renal dysfunction, pigment nephropathy should be suspected and biopsy considered when feasible. To our knowledge, this is the first reported case of HUS with full clinical triad but biopsy-proven tubular injury without renal TMA.\u003c/p\u003e","manuscriptTitle":"Hemoglobinuria-associated acute kidney injury in hemolytic uremic syndrome without renal thrombotic microangiopathy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-16 15:02:25","doi":"10.21203/rs.3.rs-8155876/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-01-28T06:17:17+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-27T16:32:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"30669248338173988874000533386927251520","date":"2026-01-27T12:06:32+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-08T18:19:05+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-04T18:16:35+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-30T18:29:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"284447545277632276499378141654634029077","date":"2025-12-22T20:18:54+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"311378515783910703310072745928010089309","date":"2025-12-22T04:19:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"90124031668398904779168015692701485641","date":"2025-12-22T04:05:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"190567167369520360300015801485799839221","date":"2025-12-20T16:16:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"230745971791356058819195172668895176822","date":"2025-12-20T07:40:27+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-11T08:24:08+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-11T08:09:27+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-12-01T06:25:07+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-28T17:45:17+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Nephrology","date":"2025-11-28T17:37:44+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c9c7c82d-ddbe-40fc-a291-4d06eca5eb7b","owner":[],"postedDate":"December 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-23T16:03:24+00:00","versionOfRecord":{"articleIdentity":"rs-8155876","link":"https://doi.org/10.1186/s12882-026-04887-0","journal":{"identity":"bmc-nephrology","isVorOnly":false,"title":"BMC Nephrology"},"publishedOn":"2026-03-19 15:59:35","publishedOnDateReadable":"March 19th, 2026"},"versionCreatedAt":"2025-12-16 15:02:25","video":"","vorDoi":"10.1186/s12882-026-04887-0","vorDoiUrl":"https://doi.org/10.1186/s12882-026-04887-0","workflowStages":[]},"version":"v1","identity":"rs-8155876","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8155876","identity":"rs-8155876","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}