Roxadustat-Associated Recurrent Infections in a CKD Patient: A Case Report 

Roxadustat-Associated Recurrent Infections in a CKD Patient: A Case Report | 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 Roxadustat-Associated Recurrent Infections in a CKD Patient: A Case Report Mehmet Murat¹, Gizem Dursun², Gamze Kalın Ünüvar³, Tuğba Yılmaz⁴, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6759775/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 Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) approved for the treatment of anemia in patients with chronic kidney disease (CKD). Although randomized clinical trials have reported infections as adverse events, real-world data on infection risk remain limited. Case presentation: We report the case of an 81-year-old female patient with CKD who developed recurrent urinary tract infections and pneumonia following roxadustat therapy. The patient experienced multiple hospitalizations and had laboratory findings consistent with infection during treatment. Despite extensive evaluations, no microbial growth was detected, and sterile pyuria persisted. A Naranjo score of 6 indicated a probable adverse drug reaction. After discontinuation of roxadustat and completion of antibiotic therapy, both clinical symptoms and laboratory markers improved. Conclusion This case highlights the importance of increased clinical awareness regarding the potential immunomodulatory effects of roxadustat, particularly in elderly or immunocompromised CKD patients. Further post-marketing surveillance and real-world studies are needed to better assess its safety profile. Roxadustat Chronic kidney disease (CKD) Recurrent infections Adverse drug reaction Anemia treatment Case report Introduction Anemia is a frequent and clinically significant complication of chronic kidney disease (CKD), with its prevalence increasing in parallel with the progression of renal dysfunction (1). Traditionally, erythropoiesis-stimulating agents (ESAs) have been the cornerstone of anemia management in CKD; however, hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) have emerged as a novel therapeutic class offering an alternative approach (2). Roxadustat, one such HIF-PHI, has demonstrated efficacy in increasing hemoglobin levels in patients with CKD, both on and off dialysis (4). Nevertheless, concerns regarding its safety profile remain, particularly in relation to infection risk. In the present case, recurrent urinary tract infections and pneumonia developed following the initiation of roxadustat therapy. Case presentation An 81-year-old woman with a medical history of hypertension, familial Mediterranean fever (FMF), congestive heart failure, and chronic kidney disease (CKD) presented with progressive shortness of breath and bilateral leg swelling that had persisted for approximately one year and worsened over the preceding three months. She also reported generalized weakness, chills, productive cough, dyspnea, and dysuria. On physical examination, bilateral pretibial edema (+++/+++++) was noted, along with basal rales on lung auscultation. Chest radiography revealed pulmonary infiltration and blunting of the costophrenic angles. Initial laboratory investigations demonstrated leukocytosis with a white blood cell (WBC) count of 14.94×10³/µL, hemoglobin of 8.9 g/dL, platelet count of 271×10³/µL, neutrophils at 13.65×10³/µL, serum creatinine at 1.15 mg/dL, elevated C-reactive protein (CRP) at 87.9 mg/L, and procalcitonin level of 5.26 ng/mL. Complete urinalysis showed WBCs: 4/high power field (HPF), bacteria: 2/HPF, and leukocyte esterase: 25 Leu/µL. Based on clinical and laboratory findings, she was diagnosed with cardiorenal syndrome, pneumonia, and urinary tract infection (UTI), and was hospitalized for further management. The patient reported experiencing recurrent episodes of dysuria despite adherence to hygiene precautions and had been hospitalized three times in the preceding three months due to urinary tract infections. During each admission, she received ceftriaxone for seven days and completed her last course of antibiotic therapy approximately 15 days prior to the current hospitalization. To evaluate persistent sterile pyuria and rule out genitourinary tuberculosis, genitourinary ultrasonography, acid-resistant bacilli (ARB) testing, polymerase chain reaction (PCR), and mycobacterial culture of the urine were performed, all of which returned negative results. The patient's medication history revealed that she had been initiated on roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), four months prior to presentation for anemia associated with CKD. Laboratory parameters before roxadustat initiation revealed WBCs: 3/HPF, RBCs: 0/HPF, bacteria: 2/HPF, and leukocyte esterase: 25 Leu/µL with a negative nitrite test. However, subsequent urinalysis performed during active complaints showed a marked increase in inflammatory markers: WBCs >204.55/HPF, RBCs: 35/HPF, leukocytes: 500 Leu/µL, and a positive nitrite result, suggesting a significant urinary tract inflammatory response (Table 1). Given the timing of symptom onset and laboratory abnormalities relative to roxadustat initiation, the possibility of a drug-induced predisposition to infection was considered. A causality assessment using the Naranjo Adverse Drug Reaction Probability Scale yielded a score of 6, consistent with a "probable" adverse drug reaction (Table 2). Following discontinuation of roxadustat and completion of antibiotic therapy, the patient exhibited clinical improvement and normalization of inflammatory markers. She was discharged in stable condition with appropriate follow-up recommendations . Written informed consent could not be obtained from the patient despite reasonable efforts. The case has been fully anonymized and contains no identifiable personal information. Table 1: Summary of laboratory and urinalysis findings across three consecutive hospitalizations 1st hospitalization 1 st day Discharge day 2st hospitalization 1 st day Discharge day 3st hospitalization 1 st day Discharge day Hg 7,9 g/dL 9,7 g/dL 9,2 g/dL 9,5 g/dL 8,9 g/dL not available CRP 47,89 mg/L 7,53 mg/L 64,84 mg/L 30,1mg/L 87,91 mg/L not available Proc 0,2 ng/mL 0,19ng/mL 7,28 ng/mL 0,67ng/mL 5,26 ng/mL not available Creatinine 1,12 mg/dL 1,66 mg/dL 1,34 mg/dL 1,05 mg/dL 1,15 mg/dL not available Complete urinalysis WBC:8 HPF Leu:25Leu/μl WBC:0 HPF Leu:negLeu/μl WBC:10 HPF Leu:25 Leu/μl WBC:- Leu:- WBC:4 HPF Leu:25 Leu/μl not available Note: The table presents changes in clinical and biochemical parameters over time, including infection markers, renal function, and urinalysis results. All data are original and specific to this patient. Table 2: Naranjo Algorithm Scoring System for the Assessment of Adverse Drug Reactions Scoring: ≥9 definite, 5-8: probable, 1-4: possible, ≤0: doubtful Yes No Don't Know Score 1. Are there previous conclusive reports on this reaction? +1 0 0 +1 2. Did the adverse reaction appear after the suspected drug was administered? +2 -1 0 +2 3. Did the adverse reaction improve when the drug was discontinued or a specific antagonists was administered? +1 0 0 0/? 4. Did the adverse reaction reappear when the drug was readministered? +2 -1 0 0 5. Are there alternative causes that could on their own have caused the reaction? -1 +2 0 +2 6. Did the reaction reappear when a placebo was given? -1 +1 0 0 7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic? +1 0 0 0 8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased? +1 0 0 0 9. Did the patient have a similar reaction to the same or similar drug in any previous exposure? +1 0 0 0 10. Was the adverse event confirmed by any objective evidence? +1 0 0 +1 TOTAL SCORE 6 SCORE POSSİBLE Discussion To our knowledge, this is among the first case reports to highlight a possible association between roxadustat use and recurrent infections, including urinary tract infections and pneumonia, in a real-world clinical setting. Although phase 3 trials have demonstrated a higher incidence of urinary tract infections (12.8% vs. 8.0%) and pneumonia (11.9% vs. 9.4%) in patients receiving roxadustat compared to placebo [ 5 , 12 ], the mechanisms underlying these observations remain incompletely understood. In our case, the temporal relationship between drug initiation and infection onset, the resolution of symptoms following drug discontinuation, and a Naranjo score of 6—classified as “probable”—provide a structured rationale for suspecting roxadustat as a contributing factor [ 8 , 9 , 10 ]. The immunomodulatory effects of roxadustat, mediated through hypoxia-inducible factors (HIF-1α and HIF-2α), are thought to influence T-cell differentiation, shifting immune responses from proinflammatory (Th1, Th17) to anti-inflammatory (Th2, Treg) phenotypes [ 6 , 7 ]. While this mechanism may have potential therapeutic benefits in autoimmune or inflammatory diseases, it could simultaneously impair host defense against bacterial pathogens, particularly in elderly and immunocompromised individuals with chronic kidney disease (CKD) [ 3 , 11 ]. This dual nature raises concerns about the broader clinical implications of HIF prolyl hydroxylase inhibitors. Given the increasing adoption of roxadustat in the management of CKD-related anemia, clinicians should remain vigilant for emerging adverse effects, especially in high-risk populations. Our findings suggest a need for more robust pharmacovigilance systems and prospective observational studies to assess the safety and immune-related consequences of roxadustat use in clinical practice. Conclusion Although clinical trials have not consistently demonstrated significant off-target adverse effects of roxadustat, our case highlights the need for heightened clinical vigilance. In patients who are elderly, immunocompromised, or at risk for recurrent infections—particularly those who are transplant candidates—roxadustat may contribute to increased infection susceptibility. Clinicians should carefully evaluate new-onset or persistent infections in the context of roxadustat therapy and consider drug-related immunomodulation as a potential factor. Ongoing pharmacovigilance and further observational studies are essential to fully characterize the safety profile of this agent in real-world populations. Abbreviations CKD: Chronic Kidney Disease, UTI: Urinary Tract Infection, ADR: Adverse Drug Reaction CRP: C-Reactive Protein , Proc: Procalcitonin , HPF: High Power Field; PCR: Polymerase Chain Reaction Declarations Ethics approval and consent to participate Not applicable. Consent for publication Written informed consent was obtained from the patient for the publication of anonymized personal and clinical information included in this case report. The consent covers both clinical data and any potentially identifying elements. Competing interests The authors declare that they have no competing interests. Funding No specific funding was received for this work. Author Contribution M.M. conceived the study, collected patient data, and wrote the main manuscript text. G.D., G.K.Ü., and T.Y. contributed to clinical data interpretation and manuscript editing. İ.K. provided nephrology consultation, literature review support, and critical manuscript revisions. All authors reviewed and approved the final version of the manuscript. Availability of data and materials All data generated or analysed during this study are included in this published article. References Li QY, Xiong QW, Yao X, Liu F, Tang X, Fu H, Tong T, Mao J, Peng WX. Roxadustat: Do we know all the answers? Biomolecules Biomed. 2023;23(3):354–63. Del Balzo U, Signore PE, Walkinshaw G, Seeley TW, Brenner MC, Wang Q, Guo G, Arend MP, Flippin LA, Chow FA, Gervasi DC, Kjaergaard CH, Langsetmo I, Guenzler V, Liu DY, Klaus SJ, Lin A, Neff TB. Nonclinical characterization of the hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat, a novel treatment of anemia of chronic kidney disease. J Pharmacol Exp Ther. 2020;374(2):342–53. Zhu X, Jiang L, Wei X, Long M, Du Y. Roxadustat: Not just for anemia. Front Pharmacol. 2022;13:971795. Chen N, Hao C, Liu BC, Lin H, Wang C, Xing C, Liang X, Jiang G, Liu Z, Li X, Zuo L, Luo L, Wang J, Zhao MH, Liu Z, Cai GY, Hao L, Leong R, Wang C, Liu C, Yu KP. Roxadustat treatment for anemia in patients undergoing long-term dialysis. N Engl J Med. 2019;381(11):1011–22. Akizawa T, Iwasaki M, Yamaguchi Y, Majikawa Y, Reusch M. Phase 3, randomized, double-blind, active-comparator (darbepoetin alfa) study of oral roxadustat in CKD patients with anemia on hemodialysis in Japan. J Am Soc Nephrol. 2020;31(7):1628–39. Tao JH, Barbi J, Pan F. Hypoxia-inducible factors in T lymphocyte differentiation and function. A review in the theme: Cellular responses to hypoxia. Am J Physiol – Cell Physiol. 2015;309(9):C580–9. Eleftheriadis T, Pissas G, Mavropoulos A, Nikolaou E, Filippidis G, Liakopoulos V, Stefanidis I. In mixed lymphocyte reaction, the hypoxia-inducible factor prolyl-hydroxylase inhibitor roxadustat suppresses cellular and humoral alloimmunity. Arch Immunol Ther Exp. 2020;68(6):31. LiverTox. (2019). Adverse Drug Reaction Probability Scale (Naranjo) in drug-induced liver injury. National Institute of Diabetes and Digestive and Kidney Diseases. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, Janecek E, Domecq C, Greenblatt DJ. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30(2):239–45. Naranjo CA, Busto U, Sellers EM. Difficulties in assessing adverse drug reactions in clinical trials. Prog Neuro-psychopharmacol Biol Psychiatry. 1982;6(4–6):651–7. Eleftheriadis T, Pissas G, Liakopoulos V, Stefanidis I. On the increased event rate of urinary tract infection and pneumonia in CKD patients treated with roxadustat for anemia. J Am Soc Nephrol. 2021;32(6):1537. Fishbane S, El-Shahawy MA, Pecoits-Filho R, Van BP, Houser MT, Frison L, Little DJ, Guzman NJ, Pergola PE. Roxadustat for treating anemia in patients with CKD not on dialysis: Results from a randomized phase 3 study. J Am Soc Nephrol. 2021;32(3):737–55. Additional Declarations No competing interests reported. Supplementary Files CAREchecklistEnglish2013.pdf 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-6759775","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":485225295,"identity":"102bc960-dd4d-46d1-8eae-e31152c64497","order_by":0,"name":"Mehmet Murat¹","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABD0lEQVRIiWNgGAWjYFACHjiL8QGCy0ZISwKIwcxsgKKFhwgtbBIIUTxadNt7j274+GNb4vb288cqPu6xkzE43v6A4UPZYQZ76QNYtZidOZd2c0bC7cQ5Z5LZbs54lsxjcOaMAeOMc4cZePgSsGu5kWN2mweoZQZDMtttngMHeAxu5DAw87YBteBwmdn9N2a3/4C08D9mK/4D0nL/+QPmv/i03OAxu80A0iKRzMbMALaFwYCZEZ+WMzlmN3vSbhvPkHhsLNlzIJlH8kyOwcGec+k8PGdwaDl+xuzGD5vbsjP4Ex9++HHAzp7v+PGHD36UWcux92DXggkUDjAwABGemMQA8g3Eqx0Fo2AUjIKRAQAmGGOTMBVs9QAAAABJRU5ErkJggg==","orcid":"","institution":"Erciyes University","correspondingAuthor":true,"prefix":"","firstName":"Mehmet","middleName":"","lastName":"Murat¹","suffix":""},{"id":485225296,"identity":"b293ab82-dc91-4927-b6eb-5371eb6a62ae","order_by":1,"name":"Gizem Dursun²","email":"","orcid":"","institution":"Erciyes University","correspondingAuthor":false,"prefix":"","firstName":"Gizem","middleName":"","lastName":"Dursun²","suffix":""},{"id":485225299,"identity":"e54f8871-dfdd-485c-934b-1cac1bdb4bc3","order_by":2,"name":"Gamze Kalın Ünüvar³","email":"","orcid":"","institution":"Erciyes University","correspondingAuthor":false,"prefix":"","firstName":"Gamze","middleName":"Kalın","lastName":"Ünüvar³","suffix":""},{"id":485225302,"identity":"bb8e8f5a-b86d-4e49-9007-c0168b2e692e","order_by":3,"name":"Tuğba Yılmaz⁴","email":"","orcid":"","institution":"Erciyes University","correspondingAuthor":false,"prefix":"","firstName":"Tuğba","middleName":"","lastName":"Yılmaz⁴","suffix":""},{"id":485225304,"identity":"fa9bf33f-d9d8-4403-a376-11ed2179e9c4","order_by":4,"name":"İsmail Koçyiğit⁵","email":"","orcid":"","institution":"Erciyes University","correspondingAuthor":false,"prefix":"","firstName":"İsmail","middleName":"","lastName":"Koçyiğit⁵","suffix":""}],"badges":[],"createdAt":"2025-05-27 13:08:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6759775/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6759775/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90333801,"identity":"6e300b79-5322-4362-ba0c-b5097e6d9502","added_by":"auto","created_at":"2025-09-01 13:47:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":461239,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6759775/v1/4cbac328-38ba-429d-b86f-b993dc6f5355.pdf"},{"id":86840975,"identity":"ff12ed33-6fa0-47b7-b2ec-99469ecddb4e","added_by":"auto","created_at":"2025-07-16 08:00:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":732987,"visible":true,"origin":"","legend":"","description":"","filename":"CAREchecklistEnglish2013.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6759775/v1/b9f0f167c10007c1d7ff5fa3.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Roxadustat-Associated Recurrent Infections in a CKD Patient: A Case Report ","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAnemia is a frequent and clinically significant complication of chronic kidney disease (CKD), with its prevalence increasing in parallel with the progression of renal dysfunction (1). Traditionally, erythropoiesis-stimulating agents (ESAs) have been the cornerstone of anemia management in CKD; however, hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) have emerged as a novel therapeutic class offering an alternative approach (2). Roxadustat, one such HIF-PHI, has demonstrated efficacy in increasing hemoglobin levels in patients with CKD, both on and off dialysis (4). Nevertheless, concerns regarding its safety profile remain, particularly in relation to infection risk. In the present case, recurrent urinary tract infections and pneumonia developed following the initiation of roxadustat therapy.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eAn 81-year-old woman with a medical history of hypertension, familial Mediterranean fever (FMF), congestive heart failure, and chronic kidney disease (CKD) presented with progressive shortness of breath and bilateral leg swelling that had persisted for approximately one year and worsened over the preceding three months. She also reported generalized weakness, chills, productive cough, dyspnea, and dysuria. On physical examination, bilateral pretibial edema (+++/+++++) was noted, along with basal rales on lung auscultation. Chest radiography revealed pulmonary infiltration and blunting of the costophrenic angles.\u003c/p\u003e\n\u003cp\u003eInitial laboratory investigations demonstrated leukocytosis with a white blood cell (WBC) count of 14.94\u0026times;10\u0026sup3;/\u0026micro;L, hemoglobin of 8.9 g/dL, platelet count of 271\u0026times;10\u0026sup3;/\u0026micro;L, neutrophils at 13.65\u0026times;10\u0026sup3;/\u0026micro;L, serum creatinine at 1.15 mg/dL, elevated C-reactive protein (CRP) at 87.9 mg/L, and procalcitonin level of 5.26 ng/mL. Complete urinalysis showed WBCs: 4/high power field (HPF), bacteria: 2/HPF, and leukocyte esterase: 25 Leu/\u0026micro;L. Based on clinical and laboratory findings, she was diagnosed with cardiorenal syndrome, pneumonia, and urinary tract infection (UTI), and was hospitalized for further management.\u003c/p\u003e\n\u003cp\u003eThe patient reported experiencing recurrent episodes of dysuria despite adherence to hygiene precautions and had been hospitalized three times in the preceding three months due to urinary tract infections. During each admission, she received ceftriaxone for seven days and completed her last course of antibiotic therapy approximately 15 days prior to the current hospitalization.\u003c/p\u003e\n\u003cp\u003eTo evaluate persistent sterile pyuria and rule out genitourinary tuberculosis, genitourinary ultrasonography, acid-resistant bacilli (ARB) testing, polymerase chain reaction (PCR), and mycobacterial culture of the urine were performed, all of which returned negative results.\u003c/p\u003e\n\u003cp\u003eThe patient\u0026apos;s medication history revealed that she had been initiated on roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), four months prior to presentation for anemia associated with CKD. Laboratory parameters before roxadustat initiation revealed WBCs: 3/HPF, RBCs: 0/HPF, bacteria: 2/HPF, and leukocyte esterase: 25 Leu/\u0026micro;L with a negative nitrite test. However, subsequent urinalysis performed during active complaints showed a marked increase in inflammatory markers: WBCs \u0026gt;204.55/HPF, RBCs: 35/HPF, leukocytes: 500 Leu/\u0026micro;L, and a positive nitrite result, suggesting a significant urinary tract inflammatory response (Table 1).\u003c/p\u003e\n\u003cp\u003eGiven the timing of symptom onset and laboratory abnormalities relative to roxadustat initiation, the possibility of a drug-induced predisposition to infection was considered. A causality assessment using the Naranjo Adverse Drug Reaction Probability Scale yielded a score of 6, consistent with a \u0026quot;probable\u0026quot; adverse drug reaction (Table 2).\u003c/p\u003e\n\u003cp\u003eFollowing discontinuation of roxadustat and completion of antibiotic therapy, the patient exhibited clinical improvement and normalization of inflammatory markers. She was discharged in stable condition with appropriate follow-up recommendations\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent could not be obtained from the patient despite reasonable efforts. The case has been fully anonymized and contains no identifiable personal information.\u003c/p\u003e\n\u003cp\u003eTable 1: \u0026nbsp;Summary of laboratory and urinalysis findings across three consecutive hospitalizations\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"740\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 12.027%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0811%;\"\u003e\n \u003cp\u003e1st hospitalization \u0026nbsp;1 st day\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.8108%;\"\u003e\n \u003cp\u003eDischarge day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0811%;\"\u003e\n \u003cp\u003e2st hospitalization \u0026nbsp;1 st day\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.4324%;\"\u003e\n \u003cp\u003eDischarge day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0811%;\"\u003e\n \u003cp\u003e3st hospitalization \u0026nbsp;1 st day\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4865%;\"\u003e\n \u003cp\u003eDischarge day\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 12.027%;\"\u003e\n \u003cp\u003eHg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0811%;\"\u003e\n \u003cp\u003e7,9 g/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.8108%;\"\u003e\n \u003cp\u003e9,7 g/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0811%;\"\u003e\n \u003cp\u003e9,2 g/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.4324%;\"\u003e\n \u003cp\u003e9,5 g/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0811%;\"\u003e\n \u003cp\u003e8,9 g/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4865%;\"\u003e\n \u003cp\u003enot available\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 12.027%;\"\u003e\n \u003cp\u003eCRP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0811%;\"\u003e\n \u003cp\u003e47,89 mg/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.8108%;\"\u003e\n \u003cp\u003e7,53 mg/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0811%;\"\u003e\n \u003cp\u003e64,84 mg/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.4324%;\"\u003e\n \u003cp\u003e30,1mg/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0811%;\"\u003e\n \u003cp\u003e87,91 mg/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4865%;\"\u003e\n \u003cp\u003enot available\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 12.027%;\"\u003e\n \u003cp\u003eProc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0811%;\"\u003e\n \u003cp\u003e0,2\u0026nbsp;ng/mL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.8108%;\"\u003e\n \u003cp\u003e0,19ng/mL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0811%;\"\u003e\n \u003cp\u003e7,28 ng/mL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.4324%;\"\u003e\n \u003cp\u003e0,67ng/mL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0811%;\"\u003e\n \u003cp\u003e5,26 ng/mL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4865%;\"\u003e\n \u003cp\u003enot available\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 12.027%;\"\u003e\n \u003cp\u003eCreatinine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0811%;\"\u003e\n \u003cp\u003e1,12 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.8108%;\"\u003e\n \u003cp\u003e1,66 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0811%;\"\u003e\n \u003cp\u003e1,34 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.4324%;\"\u003e\n \u003cp\u003e1,05 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0811%;\"\u003e\n \u003cp\u003e1,15 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4865%;\"\u003e\n \u003cp\u003enot available\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 12.027%;\"\u003e\n \u003cp\u003eComplete urinalysis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0811%;\"\u003e\n \u003cp\u003eWBC:8 HPF\u003c/p\u003e\n \u003cp\u003eLeu:25Leu/\u0026mu;l\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.8108%;\"\u003e\n \u003cp\u003eWBC:0 HPF\u003c/p\u003e\n \u003cp\u003eLeu:negLeu/\u0026mu;l\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0811%;\"\u003e\n \u003cp\u003eWBC:10 HPF\u003c/p\u003e\n \u003cp\u003eLeu:25 Leu/\u0026mu;l\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.4324%;\"\u003e\n \u003cp\u003eWBC:-\u003c/p\u003e\n \u003cp\u003eLeu:-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0811%;\"\u003e\n \u003cp\u003eWBC:4 HPF\u003c/p\u003e\n \u003cp\u003eLeu:25 Leu/\u0026mu;l\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.4865%;\"\u003e\n \u003cp\u003enot available\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eNote: The table presents changes in clinical and biochemical parameters over time, including infection markers, renal function, and urinalysis results. All data are original and specific to this patient. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2:\u0026nbsp;\u003c/strong\u003eNaranjo Algorithm Scoring System for the Assessment of Adverse Drug Reactions\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eScoring: \u0026ge;9 \u0026nbsp;definite, 5-8: probable, 1-4: possible, \u0026le;0: doubtful\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"699\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56.6334%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8417%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eYes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8417%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.13124%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDon\u0026apos;t Know\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.5521%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eScore\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 56.6334%;\"\u003e\n \u003cp\u003e1. Are there previous conclusive reports on this reaction?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8417%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e+1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8417%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.13124%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.5521%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e+1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56.6334%;\"\u003e\n \u003cp\u003e2.\u0026nbsp;Did the adverse reaction appear after the suspected drug was administered?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8417%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e+2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8417%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.13124%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.5521%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e+2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56.6334%;\"\u003e\n \u003cp\u003e\u0026nbsp;3. Did the adverse reaction improve when the drug was discontinued or a specific antagonists was administered?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8417%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e+1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8417%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.13124%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.5521%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0/?\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 56.6334%;\"\u003e\n \u003cp\u003e4. Did the adverse reaction reappear when the drug was readministered?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8417%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e+2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8417%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.13124%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.5521%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56.6334%;\"\u003e\n \u003cp\u003e5. Are there alternative causes that could on their own have caused the reaction?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8417%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8417%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e+2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.13124%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.5521%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e+2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 56.6334%;\"\u003e\n \u003cp\u003e6. Did the reaction reappear when a placebo was given?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8417%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8417%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e+1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.13124%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.5521%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 56.6334%;\"\u003e\n \u003cp\u003e7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8417%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e+1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8417%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.13124%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.5521%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 56.6334%;\"\u003e\n \u003cp\u003e8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8417%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e+1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8417%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.13124%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.5521%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56.6334%;\"\u003e\n \u003cp\u003e9. Did the patient have a similar reaction to the same or similar drug in any previous exposure?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8417%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e+1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8417%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.13124%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.5521%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56.6334%;\"\u003e\n \u003cp\u003e10. Was the adverse event confirmed by any objective evidence?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8417%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e+1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8417%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.13124%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.5521%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e+1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56.6334%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTOTAL SCORE\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8417%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8417%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.13124%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.5521%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e6 SCORE POSSİBLE\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo our knowledge, this is among the first case reports to highlight a possible association between roxadustat use and recurrent infections, including urinary tract infections and pneumonia, in a real-world clinical setting. Although phase 3 trials have demonstrated a higher incidence of urinary tract infections (12.8% vs. 8.0%) and pneumonia (11.9% vs. 9.4%) in patients receiving roxadustat compared to placebo [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], the mechanisms underlying these observations remain incompletely understood. In our case, the temporal relationship between drug initiation and infection onset, the resolution of symptoms following drug discontinuation, and a Naranjo score of 6\u0026mdash;classified as \u0026ldquo;probable\u0026rdquo;\u0026mdash;provide a structured rationale for suspecting roxadustat as a contributing factor [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe immunomodulatory effects of roxadustat, mediated through hypoxia-inducible factors (HIF-1α and HIF-2α), are thought to influence T-cell differentiation, shifting immune responses from proinflammatory (Th1, Th17) to anti-inflammatory (Th2, Treg) phenotypes [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. While this mechanism may have potential therapeutic benefits in autoimmune or inflammatory diseases, it could simultaneously impair host defense against bacterial pathogens, particularly in elderly and immunocompromised individuals with chronic kidney disease (CKD) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. This dual nature raises concerns about the broader clinical implications of HIF prolyl hydroxylase inhibitors.\u003c/p\u003e\u003cp\u003eGiven the increasing adoption of roxadustat in the management of CKD-related anemia, clinicians should remain vigilant for emerging adverse effects, especially in high-risk populations. Our findings suggest a need for more robust pharmacovigilance systems and prospective observational studies to assess the safety and immune-related consequences of roxadustat use in clinical practice.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eAlthough clinical trials have not consistently demonstrated significant off-target adverse effects of roxadustat, our case highlights the need for heightened clinical vigilance. In patients who are elderly, immunocompromised, or at risk for recurrent infections\u0026mdash;particularly those who are transplant candidates\u0026mdash;roxadustat may contribute to increased infection susceptibility. Clinicians should carefully evaluate new-onset or persistent infections in the context of roxadustat therapy and consider drug-related immunomodulation as a potential factor. Ongoing pharmacovigilance and further observational studies are essential to fully characterize the safety profile of this agent in real-world populations.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCKD: Chronic Kidney Disease, UTI: Urinary Tract Infection, ADR: Adverse Drug Reaction CRP: C-Reactive Protein , Proc: Procalcitonin , HPF: High Power Field; \u0026nbsp;PCR: Polymerase Chain Reaction\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for the publication of anonymized personal and clinical information included in this case report. The consent covers both clinical data and any potentially identifying elements.\u003c/p\u003e\n\u003ch2\u003eCompeting interests\u003c/h2\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eNo specific funding was received for this work.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eM.M. conceived the study, collected patient data, and wrote the main manuscript text. G.D., G.K.\u0026Uuml;., and T.Y. contributed to clinical data interpretation and manuscript editing. İ.K. provided nephrology consultation, literature review support, and critical manuscript revisions. All authors reviewed and approved the final version of the manuscript.\u003c/p\u003e\n\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e\n\u003cp\u003eAll data generated or analysed during this study are included in this published article.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLi QY, Xiong QW, Yao X, Liu F, Tang X, Fu H, Tong T, Mao J, Peng WX. Roxadustat: Do we know all the answers? Biomolecules Biomed. 2023;23(3):354\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDel Balzo U, Signore PE, Walkinshaw G, Seeley TW, Brenner MC, Wang Q, Guo G, Arend MP, Flippin LA, Chow FA, Gervasi DC, Kjaergaard CH, Langsetmo I, Guenzler V, Liu DY, Klaus SJ, Lin A, Neff TB. Nonclinical characterization of the hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat, a novel treatment of anemia of chronic kidney disease. J Pharmacol Exp Ther. 2020;374(2):342\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhu X, Jiang L, Wei X, Long M, Du Y. Roxadustat: Not just for anemia. Front Pharmacol. 2022;13:971795.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChen N, Hao C, Liu BC, Lin H, Wang C, Xing C, Liang X, Jiang G, Liu Z, Li X, Zuo L, Luo L, Wang J, Zhao MH, Liu Z, Cai GY, Hao L, Leong R, Wang C, Liu C, Yu KP. Roxadustat treatment for anemia in patients undergoing long-term dialysis. N Engl J Med. 2019;381(11):1011\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAkizawa T, Iwasaki M, Yamaguchi Y, Majikawa Y, Reusch M. Phase 3, randomized, double-blind, active-comparator (darbepoetin alfa) study of oral roxadustat in CKD patients with anemia on hemodialysis in Japan. J Am Soc Nephrol. 2020;31(7):1628\u0026ndash;39.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTao JH, Barbi J, Pan F. Hypoxia-inducible factors in T lymphocyte differentiation and function. A review in the theme: Cellular responses to hypoxia. Am J Physiol \u0026ndash; Cell Physiol. 2015;309(9):C580\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEleftheriadis T, Pissas G, Mavropoulos A, Nikolaou E, Filippidis G, Liakopoulos V, Stefanidis I. In mixed lymphocyte reaction, the hypoxia-inducible factor prolyl-hydroxylase inhibitor roxadustat suppresses cellular and humoral alloimmunity. Arch Immunol Ther Exp. 2020;68(6):31.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLiverTox. (2019). Adverse Drug Reaction Probability Scale (Naranjo) in drug-induced liver injury. \u003cem\u003eNational Institute of Diabetes and Digestive and Kidney Diseases.\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNaranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, Janecek E, Domecq C, Greenblatt DJ. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30(2):239\u0026ndash;45.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNaranjo CA, Busto U, Sellers EM. Difficulties in assessing adverse drug reactions in clinical trials. Prog Neuro-psychopharmacol Biol Psychiatry. 1982;6(4\u0026ndash;6):651\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEleftheriadis T, Pissas G, Liakopoulos V, Stefanidis I. On the increased event rate of urinary tract infection and pneumonia in CKD patients treated with roxadustat for anemia. J Am Soc Nephrol. 2021;32(6):1537.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFishbane S, El-Shahawy MA, Pecoits-Filho R, Van BP, Houser MT, Frison L, Little DJ, Guzman NJ, Pergola PE. Roxadustat for treating anemia in patients with CKD not on dialysis: Results from a randomized phase 3 study. J Am Soc Nephrol. 2021;32(3):737\u0026ndash;55.\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":"Roxadustat, Chronic kidney disease (CKD), Recurrent infections, Adverse drug reaction, Anemia treatment, Case report","lastPublishedDoi":"10.21203/rs.3.rs-6759775/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6759775/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eRoxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) approved for the treatment of anemia in patients with chronic kidney disease (CKD). Although randomized clinical trials have reported infections as adverse events, real-world data on infection risk remain limited.\u003c/p\u003e\u003ch2\u003eCase presentation:\u003c/h2\u003e\u003cp\u003eWe report the case of an 81-year-old female patient with CKD who developed recurrent urinary tract infections and pneumonia following roxadustat therapy. The patient experienced multiple hospitalizations and had laboratory findings consistent with infection during treatment. Despite extensive evaluations, no microbial growth was detected, and sterile pyuria persisted. A Naranjo score of 6 indicated a probable adverse drug reaction. After discontinuation of roxadustat and completion of antibiotic therapy, both clinical symptoms and laboratory markers improved.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThis case highlights the importance of increased clinical awareness regarding the potential immunomodulatory effects of roxadustat, particularly in elderly or immunocompromised CKD patients. Further post-marketing surveillance and real-world studies are needed to better assess its safety profile.\u003c/p\u003e","manuscriptTitle":"Roxadustat-Associated Recurrent Infections in a CKD Patient: A Case Report ","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-16 08:00:18","doi":"10.21203/rs.3.rs-6759775/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":"304d9176-de05-44d4-88d4-d24ec747e4c7","owner":[],"postedDate":"July 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-09-01T13:39:01+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-16 08:00:18","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6759775","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6759775","identity":"rs-6759775","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}