Liposomal Amphotericin B-Induced Distal Renal Tubular Acidosis in a Patient with T-ALL and Febrile Neutropenia: A Diagnostic Challenge

Liposomal Amphotericin B-Induced Distal Renal Tubular Acidosis in a Patient with T-ALL and Febrile Neutropenia: A Diagnostic Challenge | 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 Liposomal Amphotericin B-Induced Distal Renal Tubular Acidosis in a Patient with T-ALL and Febrile Neutropenia: A Diagnostic Challenge Yunus Can Özalp, Hüseyin Yavuz Şahin, Bahadır Ceylan, Aydın Ünal, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6533569/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 We report a rare case of distal renal tubular acidosis (dRTA) induced by liposomal amphotericin B (Ambisome) in a 29-year-old female with relapsed T-cell acute lymphoblastic leukemia (T-ALL), admitted for febrile neutropenia and opportunistic infections. Despite clinical stability under multiple broad-spectrum antimicrobials, serial arterial blood gases revealed persistent non-anion gap hyperchloremic metabolic acidosis, hypokalemia, and preserved renal function. The acidosis developed shortly after Ambisome initiation and resolved following its discontinuation, suggesting a causal relationship. This case emphasizes the importance of considering tubular toxicity even with liposomal amphotericin B and maintaining vigilance for dRTA in immunocompromised patients. Amphotericin B Liposomal Formulation Distal Renal Tubular Acidosis T-ALL Drug-Induced Nephrotoxicity Introduction Amphotericin B is a polyene antifungal agent widely used in the treatment of systemic fungal infections. The liposomal formulation (Ambisome) was developed to reduce nephrotoxicity associated with the conventional compound. Although considered safer, Ambisome has occasionally been implicated in causing renal tubular dysfunction, including distal renal tubular acidosis (dRTA), a condition characterized by impaired hydrogen ion secretion in the distal nephron. We present a diagnostically challenging case of dRTA in an immunocompromised patient treated with liposomal amphotericin B, aiming to highlight the importance of recognizing rare toxicities even with modern drug formulations. Case Presentation A 29-year-old female with a known history of T-cell acute lymphoblastic leukemia (T-ALL), previously treated with CALGB and Hyper-CVAD protocols, was admitted with febrile neutropenia. On admission, her antimicrobial regimen included cefoperazone-sulbactam, later escalated to a combination of ceftazidime-avibactam (Zavicefta), foscarnet, tigecycline, amikacin, and liposomal amphotericin B (Ambisome), targeting multidrug-resistant Pseudomonas spp. and possible fungal co-infection. Despite clinical stability, laboratory monitoring revealed progressive non-anion gap metabolic acidosis with serum bicarbonate levels decreasing to 14 mmol/L, serum chloride elevation (112 mmol/L), and persistent hypokalemia (3.1 mmol/L), while serum creatinine remained within normal limits. Arterial blood gases confirmed hyperchloremic acidosis. The metabolic disturbance emerged within 48 hours of Ambisome initiation and resolved completely after discontinuation of the drug. Differential Diagnosis Sepsis-associated lactic acidosis and uremic acidosis were excluded due to stable hemodynamics, normal lactate levels, and preserved renal function. Proximal (type 2) RTA was ruled out by the absence of glycosuria, aminoaciduria, and bicarbonaturia. Type 4 RTA was unlikely due to normokalemia. Autoimmune causes (e.g., Sjögren’s syndrome) were not supported clinically or serologically. Management and Outcome Management and Outcome Ambisome was discontinued based on the temporal relationship with the metabolic acidosis. Potassium and bicarbonate replacement were administered intravenously, with rapid correction of acidosis and electrolyte abnormalities within 48 hours. The patient remained clinically stable and completed the rest of her antimicrobial treatment without further renal complications. Discussion This case illustrates an uncommon but clinically significant adverse effect of liposomal amphotericin B. dRTA results from a defect in hydrogen ion secretion in the alpha-intercalated cells of the distal nephron, leading to metabolic acidosis and hypokalemia despite preserved glomerular filtration. While conventional amphotericin B has well-established nephrotoxicity, the liposomal form is considered less harmful due to altered pharmacokinetics and reduced tubular exposure. However, accumulating evidence, including rare case reports and animal models, suggests that liposomal amphotericin B can still cause renal tubular damage, especially in vulnerable patients such as those with hematologic malignancies receiving multiple nephrotoxic agents. Early identification and drug discontinuation are essential to prevent complications. Conclusion Clinicians should maintain a high index of suspicion for dRTA in patients receiving liposomal amphotericin B who develop metabolic acidosis and hypokalemia with normal renal function. Prompt recognition and drug withdrawal are key to recovery and avoiding unnecessary investigations or treatment delays. Abbreviations dRTA Distal Renal Tubular Acidosis T-ALL T-cell Acute Lymphoblastic Leukemia NGMA Non-Gap Metabolic Acidosis Ambisome Liposomal Amphotericin B Declarations Ethics approval and consent to participate Not applicable. This is a retrospective single-patient case report. Consent for publication Written informed consent was obtained from the patient for publication of anonymized clinical details and any accompanying images. Availability of data and materials All data generated or analyzed during this study are included in this published article. Competing Interests The authors declare that they have no competing interests. Funding The authors received no financial support for the research, authorship, or publication of this article. Authors' contributions Y.C.O. conceived the study, collected data, and drafted the manuscript. H.Y.S. contributed to patient care and clinical interpretation. B.C. provided infectious disease expertise. A.U. contributed nephrology evaluation and literature support. S.M. guided the hematologic context and manuscript review. All authors reviewed and approved the final manuscript. Acknowledgements We thank the intensive care and infectious disease teams at Istanbul Medipol University for their multidisciplinary support. 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6533569","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":463757179,"identity":"c222a831-2d2c-4f50-a2d4-0883559eb357","order_by":0,"name":"Yunus Can Özalp","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA80lEQVRIiWNgGAWjYJADxgMMFUCKmbmBeD0HGM6AtDCSooWxDWwbfi0GN3KPSf6oscvj5z/84HDhvNpo/naglh8V2/BoyUuT5jmWXCzZcMzg8Mxtx3NnHGZsYOw5cxuPlhwzacYG5sQNBxsMDvNuO5bbANTCzNiGX4vkz4b6xA2H2T8c5p1zLHc+MVokeBsOJ244xgO0paEmdwMhLZJn3hhb8xw7njizh6fg8IxjB3I3ArUcxOcXvuM5hjd/1FQn9vMf3/i4oKYud975wwcf/KjArUXhABKHmYHhMJhxAJtSGJBvQNVSh0/xKBgFo2AUjFAAAEG9YSfZ+eAAAAAAAElFTkSuQmCC","orcid":"","institution":"Istanbul Medipol University","correspondingAuthor":true,"prefix":"","firstName":"Yunus","middleName":"Can","lastName":"Özalp","suffix":""},{"id":463757181,"identity":"bf5ee140-052a-4927-bfc9-1e7e4e1a3d14","order_by":1,"name":"Hüseyin Yavuz Şahin","email":"","orcid":"","institution":"Istanbul Medipol University","correspondingAuthor":false,"prefix":"","firstName":"Hüseyin","middleName":"Yavuz","lastName":"Şahin","suffix":""},{"id":463757183,"identity":"c2add1c6-17c0-47d3-bd0e-f5e8b1eb365d","order_by":2,"name":"Bahadır Ceylan","email":"","orcid":"","institution":"Istanbul Medipol University","correspondingAuthor":false,"prefix":"","firstName":"Bahadır","middleName":"","lastName":"Ceylan","suffix":""},{"id":463757186,"identity":"8cb92d72-4d65-4c6e-8ca0-8fb454a0bdf2","order_by":3,"name":"Aydın Ünal","email":"","orcid":"","institution":"Istanbul Medipol University","correspondingAuthor":false,"prefix":"","firstName":"Aydın","middleName":"","lastName":"Ünal","suffix":""},{"id":463757188,"identity":"49751530-5733-42d9-a5a3-2f26deaebeee","order_by":4,"name":"Senem Maral","email":"","orcid":"","institution":"Istanbul Medipol University","correspondingAuthor":false,"prefix":"","firstName":"Senem","middleName":"","lastName":"Maral","suffix":""}],"badges":[],"createdAt":"2025-04-26 08:08:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6533569/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6533569/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":86193802,"identity":"026aa950-001d-4f6b-9ba4-05c8bf4e0e1d","added_by":"auto","created_at":"2025-07-07 20:31:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":330999,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6533569/v1/0e36ea76-8eef-4679-8fc3-fb1c5b035b8a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Liposomal Amphotericin B-Induced Distal Renal Tubular Acidosis in a Patient with T-ALL and Febrile Neutropenia: A Diagnostic Challenge","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAmphotericin B is a polyene antifungal agent widely used in the treatment of systemic fungal infections. The liposomal formulation (Ambisome) was developed to reduce nephrotoxicity associated with the conventional compound. Although considered safer, Ambisome has occasionally been implicated in causing renal tubular dysfunction, including distal renal tubular acidosis (dRTA), a condition characterized by impaired hydrogen ion secretion in the distal nephron.\u003c/p\u003e \u003cp\u003eWe present a diagnostically challenging case of dRTA in an immunocompromised patient treated with liposomal amphotericin B, aiming to highlight the importance of recognizing rare toxicities even with modern drug formulations.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 29-year-old female with a known history of T-cell acute lymphoblastic leukemia (T-ALL), previously treated with CALGB and Hyper-CVAD protocols, was admitted with febrile neutropenia. On admission, her antimicrobial regimen included cefoperazone-sulbactam, later escalated to a combination of ceftazidime-avibactam (Zavicefta), foscarnet, tigecycline, amikacin, and liposomal amphotericin B (Ambisome), targeting multidrug-resistant Pseudomonas spp. and possible fungal co-infection.\u003c/p\u003e \u003cp\u003eDespite clinical stability, laboratory monitoring revealed progressive non-anion gap metabolic acidosis with serum bicarbonate levels decreasing to 14 mmol/L, serum chloride elevation (112 mmol/L), and persistent hypokalemia (3.1 mmol/L), while serum creatinine remained within normal limits. Arterial blood gases confirmed hyperchloremic acidosis. The metabolic disturbance emerged within 48 hours of Ambisome initiation and resolved completely after discontinuation of the drug.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eDifferential Diagnosis\u003c/h2\u003e \u003cp\u003eSepsis-associated lactic acidosis and uremic acidosis were excluded due to stable hemodynamics, normal lactate levels, and preserved renal function. Proximal (type 2) RTA was ruled out by the absence of glycosuria, aminoaciduria, and bicarbonaturia. Type 4 RTA was unlikely due to normokalemia. Autoimmune causes (e.g., Sj\u0026ouml;gren\u0026rsquo;s syndrome) were not supported clinically or serologically.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eManagement and Outcome\u003c/h3\u003e\n\u003cdiv class=\"Heading\"\u003eManagement and Outcome\u003c/div\u003e \u003cp\u003eAmbisome was discontinued based on the temporal relationship with the metabolic acidosis. Potassium and bicarbonate replacement were administered intravenously, with rapid correction of acidosis and electrolyte abnormalities within 48 hours. The patient remained clinically stable and completed the rest of her antimicrobial treatment without further renal complications.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis case illustrates an uncommon but clinically significant adverse effect of liposomal amphotericin B. dRTA results from a defect in hydrogen ion secretion in the alpha-intercalated cells of the distal nephron, leading to metabolic acidosis and hypokalemia despite preserved glomerular filtration. While conventional amphotericin B has well-established nephrotoxicity, the liposomal form is considered less harmful due to altered pharmacokinetics and reduced tubular exposure.\u003c/p\u003e \u003cp\u003eHowever, accumulating evidence, including rare case reports and animal models, suggests that liposomal amphotericin B can still cause renal tubular damage, especially in vulnerable patients such as those with hematologic malignancies receiving multiple nephrotoxic agents. Early identification and drug discontinuation are essential to prevent complications.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eClinicians should maintain a high index of suspicion for dRTA in patients receiving liposomal amphotericin B who develop metabolic acidosis and hypokalemia with normal renal function. Prompt recognition and drug withdrawal are key to recovery and avoiding unnecessary investigations or treatment delays.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003edRTA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDistal Renal Tubular Acidosis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eT-ALL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eT-cell Acute Lymphoblastic Leukemia\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNGMA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNon-Gap Metabolic Acidosis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAmbisome\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLiposomal Amphotericin B\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003ch3\u003eEthics approval and consent to participate\u003c/h3\u003e\n\u003cp\u003eNot applicable. This is a retrospective single-patient case report.\u003c/p\u003e\n\u003ch3\u003eConsent for publication\u003c/h3\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for publication of anonymized clinical details and any accompanying images.\u003c/p\u003e\n\u003ch3\u003eAvailability of data and materials\u003c/h3\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article.\u003c/p\u003e\n\u003ch3\u003eCompeting Interests\u003c/h3\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003ch3\u003eFunding\u003c/h3\u003e\n\u003cp\u003eThe authors received no financial support for the research, authorship, or publication of this article.\u003c/p\u003e\n\u003ch3\u003eAuthors' contributions\u003c/h3\u003e\n\u003cp\u003eY.C.O. conceived the study, collected data, and drafted the manuscript.\u003cbr\u003e\u0026nbsp;H.Y.S. contributed to patient care and clinical interpretation.\u003cbr\u003e\u0026nbsp;B.C. provided infectious disease expertise.\u003cbr\u003e\u0026nbsp;A.U. contributed nephrology evaluation and literature support.\u003cbr\u003e\u0026nbsp;S.M. guided the hematologic context and manuscript review.\u003cbr\u003e\u0026nbsp;All authors reviewed and approved the final manuscript.\u003c/p\u003e\n\u003ch3\u003eAcknowledgements\u003c/h3\u003e\n\u003cp\u003eWe thank the intensive care and infectious disease teams at Istanbul Medipol University for their multidisciplinary support.\u003c/p\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":"Amphotericin B, Liposomal Formulation, Distal Renal Tubular Acidosis, T-ALL, Drug-Induced Nephrotoxicity","lastPublishedDoi":"10.21203/rs.3.rs-6533569/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6533569/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eWe report a rare case of distal renal tubular acidosis (dRTA) induced by liposomal amphotericin B (Ambisome) in a 29-year-old female with relapsed T-cell acute lymphoblastic leukemia (T-ALL), admitted for febrile neutropenia and opportunistic infections. Despite clinical stability under multiple broad-spectrum antimicrobials, serial arterial blood gases revealed persistent non-anion gap hyperchloremic metabolic acidosis, hypokalemia, and preserved renal function. The acidosis developed shortly after Ambisome initiation and resolved following its discontinuation, suggesting a causal relationship. 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