Utility of Tissue Biopsy in Amoxicillin-Clavulanate induced Concomitant Hepatic Failure and Renal Failure: A Case Report

Utility of Tissue Biopsy in Amoxicillin-Clavulanate induced Concomitant Hepatic Failure and Renal Failure: 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 Utility of Tissue Biopsy in Amoxicillin-Clavulanate induced Concomitant Hepatic Failure and Renal Failure: A Case Report John A. Das, Saima Azad, Meghan E. Kapp, Wendy Liu, Vinh Nguyen This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4901006/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 Mar, 2025 Read the published version in SN Comprehensive Clinical Medicine → Version 1 posted 4 You are reading this latest preprint version Abstract Several reports indicate that amoxicillin-clavulanate can cause both liver injury as well as acute kidney injury. However, the majority of the existing literature has described liver-related injury, with fewer reports noting kidney injury. In this report, we describe a case of concomitant drug induced liver injury (DILI) and acute interstitial nephritis (AIN) as a result of amoxicillin-clavulanate exposure. A 62-year-old African American male presented with one week of generalized weakness, painless jaundice, nausea, vomiting, and diarrhea. Prior to admission, the patient had completed a 10-day course of amoxicillin-clavulanate for bacterial sinusitis. Upon admission, laboratory data revealed transaminitis and elevated creatinine levels suggestive of liver injury and renal failure. Through tissue biopsy of both organs, the diagnosis of amoxicillin-clavulanate induced acute liver injury and acute tubulointerstitial nephritis with bile cast nephropathy was made. This case highlights the critical role of tissue biopsy in reaching a unifying diagnosis for this rare adverse effect of amoxicillin-clavulanate. drug-induced renal failure amoxicillin-clavulanate tissue biopsy Figures Figure 1 Figure 2 Figure 3 Introduction Antibiotics have been identified as a cause for drug-induced liver injury, and less frequently, acute renal failure. However, simultaneous injury to both organs is rare [ 1 – 2 ]. In amoxicillin-clavulanate associated hepatic injury, it is suspected that organ damage occurs from drug-protein adducts causing an immunologic response [ 2 – 3 ]. The injury is thought to be related to the clavulanic acid component of the antibiotic rather than amoxicillin, and manifests as a mixed hepatocellular–cholestatic injury [ 4 – 5 ]. In several cases of drug-induced hepatic injury, the presentation is delayed, occurring four weeks after amoxicillin-clavulanate has been discontinued [ 6 ]. The severity of injury is variable, taking upwards of 4–24 weeks to see improvement after drug discontinuation; however, fulminant acute liver failure can occur and transplantation may be required [ 4 ]. Drug-induced acute kidney injury manifests itself in the form of acute interstitial nephritis, and crystal nephropathy may be present in patients exposed to amoxicillin-clavulanate. A review of existing literature did not evidence the existence of concomitant liver injury and renal failure, making this a rare case, if not the first ever of its kind. In this case, drug-induced dual organ failure secondary to Amoxicillin-Clavulanate usage was diagnosed through tissue biopsy, which revealed bland cholestasis of the liver and of the kidney. Case A 62-year-old African American male with known hypertension, gout, and alcohol use disorder presented to the emergency department with worsening weakness, weight loss, dyspnea, nausea, vomiting, and diarrhea. Two weeks prior to presentation, he was diagnosed with sinusitis and was started on amoxicillin-clavulanate (875 mg-125 mg) twice daily for a ten-day course. On initial examination, the patient appeared jaundiced with significant scleral icterus. His abdominal examination was notable for mild distension without organomegaly. Laboratory evaluation revealed a sodium of 127 mmol/L, potassium of 7.6 mmol/L, blood urea nitrogen of 98, creatinine of 6.6 mg/dL (baseline creatinine of 1.4 mg/dL), total bilirubin of 20.5, alkaline phosphatase of 397, aspartate transaminase of 138, alanine transaminase of 88, and International Normalized Ratio of 11.4 with pro-time of 127.9. A complete blood count was notable for 9.5% eosinophils with a total level of 700 eosinophils. Urinalysis revealed a specific gravity of 1020 with 6–10 red blood cells on high-power field. Hepatitis serologies were unremarkable, and cytoplasmic (c-ANCA) and atypical perinuclear (p-ANCA) titers were 1:20 and 1:80, respectively. Complement (C3, C4) levels, antinuclear (ANA), and anti-glomerular basement antibodies antibodies were within normal limits. A computerized tomography scan of the abdomen was initially performed, which revealed gallbladder wall thickening. This study was followed by right upper quadrant ultrasonography to allow further visualization of the biliary tree, which showed a minimally distended gallbladder with cholelithiasis and focally dilated intrahepatic ducts in the left lobe of the liver. Given concern for renal failure with a possible need for renal replacement therapy, the patient was admitted to the medical intensive care unit for closer monitoring. To reverse his coagulopathy, he was given fresh frozen plasma and vitamin K, resulting in an improvement of his INR to 1.1 In addition, he was started on high-dose methylprednisolone for empiric treatment of suspected autoimmune hepatitis. However, given the lack of a definitive diagnosis with an alternative differential diagnosis of drug-induced liver injury, a decision was made to pursue biopsies of the kidney and liver. A percutaneous core kidney biopsy revealed diffuse acute tubular injury with bile cast nephropathy (Fig. 1 ), focal acute tubulointerstitial nephritis, moderate arteriolar hyalinosis and mild arteriosclerosis (Fig. 2 ). There are hepatocyte reactive changes with significant nuclear anisocytosis and acidophil bodies indicating apoptotic hepatocytes (see Fig. 3 ). Collectively, the biopsy findings were suggestive of amoxicillin-induced renal and hepatic injury. In light of this, the patient was continued on high-dose IV steroids (which he received for a total of five days) that were transitioned to an eighteen-day oral prednisone taper. His creatinine gradually normalized to baseline without the need for renal replacement therapy. The patient’s LFTs remained mildly elevated on the day of discharge. Discussion Antibiotics are necessary in many medical conditions, though acute kidney injury is an adverse effect that may occur from their use [ 9 ]. Similarly, amoxicillin-clavulanate is widely used in the primary care setting and has the rare side effect of drug-induced liver injury [ 10 – 12 ]. A study published in 2022 analyzing the patient charts of a large electronic health record system showed that among 1,445,171 first-time exposures to amoxicillin-clavulanate, 6476 had acute liver injuries and 2240 of those were unexplained. Those who were elderly, of the male gender and ethnically Native American or Alaskan Native, had a higher incidence of unexplained acute liver injuries [ 7 – 8 ]. According to the US Drug Induced Liver Injury Network, amoxicillin-clavulanate has been identified as the most common cause of non-acetaminophen idiosyncratic drug-induced liver injury. A study performed in 2019 concluded that it is beneficial for clinicians to monitor hepatic enzyme levels, as well as bilirubin levels, in order to recognize liver-related side effects from amoxicillin-clavulanate [ 13 ]. Although patients on amoxicillin-clavulanate usually are on this drug for a short period of time, in the event that transaminitis is detected, the antibiotic should be discontinued [ 14 ]. It should also be noted that acute kidney injury in form of acute interstitial nephritis and crystal nephropathy can also be observed among patients who have been exposed to amoxicillin-clavulanate. In regard to renal injury, two mechanisms have been well described: acute interstitial nephritis and crystal nephropathy [ 9 ]. What is clear is that there is an immuno-allergic mechanism to the injury to both organs with respect to amoxicillin-clavulanate, but interestingly, in liver injury this seems to be precipitated by the clavulanate component of the antibiotic [ 4 ]. In our patient’s case, a dual tissue biopsy of liver and kidney was critical to determine the pathophysiology behind the aberrant lab values and organ failures. The presence of bile casts evidences the patient’s underlying liver injury, which was commensurate with his transaminitis, high bilirubin and elevated alkaline phosphatase. Acute interstitial nephritis, which was evidenced by multifocal eosinophil-rich interstitial infiltrates, is supportive and in line with the immuno-allergic response that occurs in amoxicillin-clavulanate drug-induced liver injury. Our use of steroids to treat both acute interstitial nephritis, along with drug-induced liver injury, followed the recommendation of prior studies that suggested that the use of steroids has clinical benefit, in addition to the withdrawal of the offending agent [ 15 ]. This case study demonstrates a rare occurrence in which a patient developed concomitant drug-induced liver injury and renal failure. It reminds the medical community that though antibiotics, such as amoxicillin-clavulanate, are widely used in the treatment of infection, they are not without consequences. Thus, careful antibiotic stewardship is paramount. As our findings in this case report are novel in medical literature, clinicians can be made aware of the possibility of amoxicillin-clavulanate adversely impacting multiple organ systems. Additionally, tissue biopsy has great utility in diagnosing amoxicillin-clavulanate induced concomitant hepatic failure and renal failure. In our case, the pathological results revealed findings consistent with the immuno-allergic response that occurs in amoxicillin-clavulanate drug induced liver injury. As this relays the etiology behind the multiorgan failure, tissue biopsy is an essential component in guiding the treatment of patients afflicted with concomitant hepatic failure and renal failure caused by amoxicillin-clavulanate. Declarations Informed consent was obtained from the patient, who also consented to the publishing of this case report. The corresponding author is Dr. John A. Das and correspondence can be made to [email protected] Declarations The participant has consented to the submission of the case report to the journal. Author Contribution JAD, SA, MEK, WL, and VN report no disclosures. The authors declare that they have no conflicts of interest related to the research, authorship, or publication of this article. No funding was received to assist with the preparation of this manuscript.All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by JAD, SA, and VN. The first draft of the manuscript was written by JD and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.Informed consent was obtained from the patient, who also consented to the publishing of this case report. References Labriola L, Jadoul M, Daudons M, Pirson Y, Lambert M. Massive amoxycillin crystalluria causing anuric acute renal failure. Clin Nephrol. 2003;59(6):455–457. doi: 10.5414/cnp59455 Gu S, Rajendiran G, Forest K, et al. Drug-induced liver injury with commonly used antibiotics in the all of us research Program. Clin Pharmacol Ther. 2023;114(2):404–412. doi: 10.1002/cpt.2930 Appiah J, Prasad A, Shah V, et al. Amoxicillin-clavulanate induced liver injury in a young female. Cureus. 2023;15(1). doi: 10.7759/cureus.33445 Fontana RJ, Shakil AO, Greenson JK, Boyd I, Lee WM. Acute liver failure due to amoxicillin and amoxicillin/clavulanate. Dig Dis Sci. 2005;50(10):1785–1790. doi: 10.1007/s10620-005-2938-5 DeLemos AS, Ghabril M, Rockey DC, et al. Amoxicillin-clavulanate-induced liver injury. Dig Dis Sci. 2016;61(8):2406–2416. doi: 10.1007/s10620-016-4121-6 Nicoletti P, Dellinger A, Li YJ, et al. Identification of reduced ERAP2 expression and a novel HLA allele as components of a risk score for susceptibility to liver injury due to amoxicillin-clavulanate. Gastroenterology. 2023;164(3):454–466. doi: 10.1053/j.gastro.2022.11.036 Suzuki A, Tillmann H, Williams J, et al. Assessment of the frequency, phenotypes, and outcomes of acute liver injury associated with amoxicillin/clavulanate in 1.4 million patients in the veterans health administration. Drug Saf. 2023;46(2):129–143. doi: 10.1007/s40264-022-01255-3 Ferreira I, Gouveia C, Vasques C Sr, Faria C, Pedroso A. Drug-induced liver injury caused by amoxicillin/clavulanate. Cureus . 2020;12(12):e12234. 2020. doi: 10.7759/cureus.12234 Clifford KM, Selby AR, Reveles KR, et al. The risk and clinical implications of antibiotic-associated acute kidney injury: a review of the clinical data for agents with signals from the food and drug administration's adverse event reporting system (FAERS) database. Antibiotics (Basel) . 2022;11(10):1367. 2022. doi: 10.3390/antibiotics11101367 Vilà-Nadal G, Lleonart Bellfill R, Martí Garrido J, Baliellas Comellas C, Corominas Sánchez M. Recurrent drug-induced liver injury with cetirizine and amoxicillin-clavulanate potassium. J Investig Allergol Clin Immunol. 2019;29(4):321–322. doi: 10.18176/jiaci.0397 Robles M, Toscano E, Cotta J, Lucena MI, Andrade RJ. Antibiotic-induced liver toxicity: mechanisms, clinical features and causality assessment. Curr Drug Saf. 2010;5(3):212–222. doi: 10.2174/157488610791698307 Andrade RJ, Tulkens PM. Hepatic safety of antibiotics used in primary care. J Antimicrob Chemother. 2011;66(7):1431–1446. doi: 10.1093/jac/dkr159 Pellegrino AM, Annicchiarico Petruzzelli L, Riccio E, Pisani A. Idiosyncratic hepatic toxicity in autosomal dominant polycystic kidney disease (ADPKD) patient in combined treatment with tolvaptan and amoxicillin/clavulanic acid: a case report. BMC Nephrol . 2019;20(1):426. 2019. doi: 10.1186/s12882-019-1612-7 Moreno L, Sánchez-Delgado J, Vergara M, Casas M, Miquel M, Dalmau B. Recurrent drug-induced liver injury (DILI) with ciprofloxacin and amoxicillin/clavulanic. Rev Esp Enferm Dig. 2015;107(12):767–768. doi: 10.17235/reed.2015.3810/2015 Sanchez-Alamo B, Cases-Corona C, Fernandez-Juarez G. Facing the Challenge of Drug-Induced Acute Interstitial Nephritis. Nephron. 2023;147(2):78–90. doi: 10.1159/000525561 . Epub 2022 Jul 13. PMID: 35830831. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 04 Mar, 2025 Read the published version in SN Comprehensive Clinical Medicine → Version 1 posted Editorial decision: Revision requested 16 Aug, 2024 Editor assigned by journal 16 Aug, 2024 Submission checks completed at journal 15 Aug, 2024 First submitted to journal 12 Aug, 2024 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-4901006","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":341035908,"identity":"7d147387-b9e5-4ef3-9ebd-e8cad99cb4d8","order_by":0,"name":"John A. 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However, simultaneous injury to both organs is rare [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e–\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In amoxicillin-clavulanate associated hepatic injury, it is suspected that organ damage occurs from drug-protein adducts causing an immunologic response [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e–\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The injury is thought to be related to the clavulanic acid component of the antibiotic rather than amoxicillin, and manifests as a mixed hepatocellular–cholestatic injury [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e–\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In several cases of drug-induced hepatic injury, the presentation is delayed, occurring four weeks after amoxicillin-clavulanate has been discontinued [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The severity of injury is variable, taking upwards of 4–24 weeks to see improvement after drug discontinuation; however, fulminant acute liver failure can occur and transplantation may be required [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Drug-induced acute kidney injury manifests itself in the form of acute interstitial nephritis, and crystal nephropathy may be present in patients exposed to amoxicillin-clavulanate. A review of existing literature did not evidence the existence of concomitant liver injury and renal failure, making this a rare case, if not the first ever of its kind. In this case, drug-induced dual organ failure secondary to Amoxicillin-Clavulanate usage was diagnosed through tissue biopsy, which revealed bland cholestasis of the liver and of the kidney.\u003c/p\u003e "},{"header":"Case","content":"\u003cp\u003eA 62-year-old African American male with known hypertension, gout, and alcohol use disorder presented to the emergency department with worsening weakness, weight loss, dyspnea, nausea, vomiting, and diarrhea. Two weeks prior to presentation, he was diagnosed with sinusitis and was started on amoxicillin-clavulanate (875 mg-125 mg) twice daily for a ten-day course. On initial examination, the patient appeared jaundiced with significant scleral icterus. His abdominal examination was notable for mild distension without organomegaly. Laboratory evaluation revealed a sodium of 127 mmol/L, potassium of 7.6 mmol/L, blood urea nitrogen of 98, creatinine of 6.6 mg/dL (baseline creatinine of 1.4 mg/dL), total bilirubin of 20.5, alkaline phosphatase of 397, aspartate transaminase of 138, alanine transaminase of 88, and International Normalized Ratio of 11.4 with pro-time of 127.9. A complete blood count was notable for 9.5% eosinophils with a total level of 700 eosinophils. Urinalysis revealed a specific gravity of 1020 with 6–10 red blood cells on high-power field. Hepatitis serologies were unremarkable, and cytoplasmic (c-ANCA) and atypical perinuclear (p-ANCA) titers were 1:20 and 1:80, respectively. Complement (C3, C4) levels, antinuclear (ANA), and anti-glomerular basement antibodies antibodies were within normal limits. A computerized tomography scan of the abdomen was initially performed, which revealed gallbladder wall thickening. This study was followed by right upper quadrant ultrasonography to allow further visualization of the biliary tree, which showed a minimally distended gallbladder with cholelithiasis and focally dilated intrahepatic ducts in the left lobe of the liver.\u003c/p\u003e\u003cp\u003eGiven concern for renal failure with a possible need for renal replacement therapy, the patient was admitted to the medical intensive care unit for closer monitoring. To reverse his coagulopathy, he was given fresh frozen plasma and vitamin K, resulting in an improvement of his INR to 1.1 In addition, he was started on high-dose methylprednisolone for empiric treatment of suspected autoimmune hepatitis. However, given the lack of a definitive diagnosis with an alternative differential diagnosis of drug-induced liver injury, a decision was made to pursue biopsies of the kidney and liver. A percutaneous core kidney biopsy revealed diffuse acute tubular injury with bile cast nephropathy (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), focal acute tubulointerstitial nephritis, moderate arteriolar hyalinosis and mild arteriosclerosis (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). There are hepatocyte reactive changes with significant nuclear anisocytosis and acidophil bodies indicating apoptotic hepatocytes (see Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Collectively, the biopsy findings were suggestive of amoxicillin-induced renal and hepatic injury. In light of this, the patient was continued on high-dose IV steroids (which he received for a total of five days) that were transitioned to an eighteen-day oral prednisone taper. His creatinine gradually normalized to baseline without the need for renal replacement therapy. The patient’s LFTs remained mildly elevated on the day of discharge.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAntibiotics are necessary in many medical conditions, though acute kidney injury is an adverse effect that may occur from their use [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Similarly, amoxicillin-clavulanate is widely used in the primary care setting and has the rare side effect of drug-induced liver injury [\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. A study published in 2022 analyzing the patient charts of a large electronic health record system showed that among 1,445,171 first-time exposures to amoxicillin-clavulanate, 6476 had acute liver injuries and 2240 of those were unexplained. Those who were elderly, of the male gender and ethnically Native American or Alaskan Native, had a higher incidence of unexplained acute liver injuries [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. According to the US Drug Induced Liver Injury Network, amoxicillin-clavulanate has been identified as the most common cause of non-acetaminophen idiosyncratic drug-induced liver injury. A study performed in 2019 concluded that it is beneficial for clinicians to monitor hepatic enzyme levels, as well as bilirubin levels, in order to recognize liver-related side effects from amoxicillin-clavulanate [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Although patients on amoxicillin-clavulanate usually are on this drug for a short period of time, in the event that transaminitis is detected, the antibiotic should be discontinued [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. It should also be noted that acute kidney injury in form of acute interstitial nephritis and crystal nephropathy can also be observed among patients who have been exposed to amoxicillin-clavulanate. In regard to renal injury, two mechanisms have been well described: acute interstitial nephritis and crystal nephropathy [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. What is clear is that there is an immuno-allergic mechanism to the injury to both organs with respect to amoxicillin-clavulanate, but interestingly, in liver injury this seems to be precipitated by the clavulanate component of the antibiotic [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In our patient\u0026rsquo;s case, a dual tissue biopsy of liver and kidney was critical to determine the pathophysiology behind the aberrant lab values and organ failures. The presence of bile casts evidences the patient\u0026rsquo;s underlying liver injury, which was commensurate with his transaminitis, high bilirubin and elevated alkaline phosphatase. Acute interstitial nephritis, which was evidenced by multifocal eosinophil-rich interstitial infiltrates, is supportive and in line with the immuno-allergic response that occurs in amoxicillin-clavulanate drug-induced liver injury. Our use of steroids to treat both acute interstitial nephritis, along with drug-induced liver injury, followed the recommendation of prior studies that suggested that the use of steroids has clinical benefit, in addition to the withdrawal of the offending agent [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis case study demonstrates a rare occurrence in which a patient developed concomitant drug-induced liver injury and renal failure. It reminds the medical community that though antibiotics, such as amoxicillin-clavulanate, are widely used in the treatment of infection, they are not without consequences. Thus, careful antibiotic stewardship is paramount. As our findings in this case report are novel in medical literature, clinicians can be made aware of the possibility of amoxicillin-clavulanate adversely impacting multiple organ systems. Additionally, tissue biopsy has great utility in diagnosing amoxicillin-clavulanate induced concomitant hepatic failure and renal failure. In our case, the pathological results revealed findings consistent with the immuno-allergic response that occurs in amoxicillin-clavulanate drug induced liver injury. As this relays the etiology behind the multiorgan failure, tissue biopsy is an essential component in guiding the treatment of patients afflicted with concomitant hepatic failure and renal failure caused by amoxicillin-clavulanate.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eInformed consent was obtained from the patient, who also consented to the publishing of this case report.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe corresponding author is Dr. John A. Das and correspondence can be made to [email protected]\u0026nbsp;\u003c/p\u003e\u003ch2\u003eDeclarations\u003c/h2\u003e \u003cp\u003e The participant has consented to the submission of the case report to the journal.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eJAD, SA, MEK, WL, and VN report no disclosures. The authors declare that they have no conflicts of interest related to the research, authorship, or publication of this article. No funding was received to assist with the preparation of this manuscript.All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by JAD, SA, and VN. The first draft of the manuscript was written by JD and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.Informed consent was obtained from the patient, who also consented to the publishing of this case report.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLabriola L, Jadoul M, Daudons M, Pirson Y, Lambert M. Massive amoxycillin crystalluria causing anuric acute renal failure. Clin Nephrol. 2003;59(6):455\u0026ndash;457. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.5414/cnp59455\u003c/span\u003e\u003cspan address=\"10.5414/cnp59455\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGu S, Rajendiran G, Forest K, et al. Drug-induced liver injury with commonly used antibiotics in the all of us research Program. Clin Pharmacol Ther. 2023;114(2):404\u0026ndash;412. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/cpt.2930\u003c/span\u003e\u003cspan address=\"10.1002/cpt.2930\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAppiah J, Prasad A, Shah V, et al. Amoxicillin-clavulanate induced liver injury in a young female. Cureus. 2023;15(1). doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.7759/cureus.33445\u003c/span\u003e\u003cspan address=\"10.7759/cureus.33445\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFontana RJ, Shakil AO, Greenson JK, Boyd I, Lee WM. Acute liver failure due to amoxicillin and amoxicillin/clavulanate. Dig Dis Sci. 2005;50(10):1785\u0026ndash;1790. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s10620-005-2938-5\u003c/span\u003e\u003cspan address=\"10.1007/s10620-005-2938-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDeLemos AS, Ghabril M, Rockey DC, et al. Amoxicillin-clavulanate-induced liver injury. Dig Dis Sci. 2016;61(8):2406\u0026ndash;2416. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s10620-016-4121-6\u003c/span\u003e\u003cspan address=\"10.1007/s10620-016-4121-6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNicoletti P, Dellinger A, Li YJ, et al. Identification of reduced ERAP2 expression and a novel HLA allele as components of a risk score for susceptibility to liver injury due to amoxicillin-clavulanate. Gastroenterology. 2023;164(3):454\u0026ndash;466. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1053/j.gastro.2022.11.036\u003c/span\u003e\u003cspan address=\"10.1053/j.gastro.2022.11.036\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSuzuki A, Tillmann H, Williams J, et al. Assessment of the frequency, phenotypes, and outcomes of acute liver injury associated with amoxicillin/clavulanate in 1.4 million patients in the veterans health administration. Drug Saf. 2023;46(2):129\u0026ndash;143. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s40264-022-01255-3\u003c/span\u003e\u003cspan address=\"10.1007/s40264-022-01255-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFerreira I, Gouveia C, Vasques C Sr, Faria C, Pedroso A. Drug-induced liver injury caused by amoxicillin/clavulanate. \u003cem\u003eCureus\u003c/em\u003e. 2020;12(12):e12234. 2020. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.7759/cureus.12234\u003c/span\u003e\u003cspan address=\"10.7759/cureus.12234\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eClifford KM, Selby AR, Reveles KR, et al. The risk and clinical implications of antibiotic-associated acute kidney injury: a review of the clinical data for agents with signals from the food and drug administration's adverse event reporting system (FAERS) database. \u003cem\u003eAntibiotics (Basel)\u003c/em\u003e. 2022;11(10):1367. 2022. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/antibiotics11101367\u003c/span\u003e\u003cspan address=\"10.3390/antibiotics11101367\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVil\u0026agrave;-Nadal G, Lleonart Bellfill R, Mart\u0026iacute; Garrido J, Baliellas Comellas C, Corominas S\u0026aacute;nchez M. Recurrent drug-induced liver injury with cetirizine and amoxicillin-clavulanate potassium. J Investig Allergol Clin Immunol. 2019;29(4):321\u0026ndash;322. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.18176/jiaci.0397\u003c/span\u003e\u003cspan address=\"10.18176/jiaci.0397\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRobles M, Toscano E, Cotta J, Lucena MI, Andrade RJ. Antibiotic-induced liver toxicity: mechanisms, clinical features and causality assessment. Curr Drug Saf. 2010;5(3):212\u0026ndash;222. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2174/157488610791698307\u003c/span\u003e\u003cspan address=\"10.2174/157488610791698307\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAndrade RJ, Tulkens PM. Hepatic safety of antibiotics used in primary care. J Antimicrob Chemother. 2011;66(7):1431\u0026ndash;1446. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/jac/dkr159\u003c/span\u003e\u003cspan address=\"10.1093/jac/dkr159\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePellegrino AM, Annicchiarico Petruzzelli L, Riccio E, Pisani A. Idiosyncratic hepatic toxicity in autosomal dominant polycystic kidney disease (ADPKD) patient in combined treatment with tolvaptan and amoxicillin/clavulanic acid: a case report. \u003cem\u003eBMC Nephrol\u003c/em\u003e. 2019;20(1):426. 2019. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12882-019-1612-7\u003c/span\u003e\u003cspan address=\"10.1186/s12882-019-1612-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoreno L, S\u0026aacute;nchez-Delgado J, Vergara M, Casas M, Miquel M, Dalmau B. Recurrent drug-induced liver injury (DILI) with ciprofloxacin and amoxicillin/clavulanic. Rev Esp Enferm Dig. 2015;107(12):767\u0026ndash;768. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.17235/reed.2015.3810/2015\u003c/span\u003e\u003cspan address=\"10.17235/reed.2015.3810/2015\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSanchez-Alamo B, Cases-Corona C, Fernandez-Juarez G. Facing the Challenge of Drug-Induced Acute Interstitial Nephritis. Nephron. 2023;147(2):78\u0026ndash;90. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1159/000525561\u003c/span\u003e\u003cspan address=\"10.1159/000525561\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Epub 2022 Jul 13. PMID: 35830831.\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":"sn-comprehensive-clinical-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sncm","sideBox":"Learn more about [SN Comprehensive Clinical Medicine](https://www.springer.com/journal/42399)","snPcode":"42399","submissionUrl":"https://submission.nature.com/new-submission/42399/3","title":"SN Comprehensive Clinical Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"drug-induced, renal failure, amoxicillin-clavulanate, tissue biopsy","lastPublishedDoi":"10.21203/rs.3.rs-4901006/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4901006/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eSeveral reports indicate that amoxicillin-clavulanate can cause both liver injury as well as acute kidney injury. However, the majority of the existing literature has described liver-related injury, with fewer reports noting kidney injury. In this report, we describe a case of concomitant drug induced liver injury (DILI) and acute interstitial nephritis (AIN) as a result of amoxicillin-clavulanate exposure. A 62-year-old African American male presented with one week of generalized weakness, painless jaundice, nausea, vomiting, and diarrhea. Prior to admission, the patient had completed a 10-day course of amoxicillin-clavulanate for bacterial sinusitis. Upon admission, laboratory data revealed transaminitis and elevated creatinine levels suggestive of liver injury and renal failure. Through tissue biopsy of both organs, the diagnosis of amoxicillin-clavulanate induced acute liver injury and acute tubulointerstitial nephritis with bile cast nephropathy was made. This case highlights the critical role of tissue biopsy in reaching a unifying diagnosis for this rare adverse effect of amoxicillin-clavulanate.\u003c/p\u003e","manuscriptTitle":"Utility of Tissue Biopsy in Amoxicillin-Clavulanate induced Concomitant Hepatic Failure and Renal Failure: A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-14 10:20:29","doi":"10.21203/rs.3.rs-4901006/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-08-16T09:18:18+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-08-16T06:07:08+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-08-16T03:52:11+00:00","index":"","fulltext":""},{"type":"submitted","content":"SN Comprehensive Clinical Medicine","date":"2024-08-12T13:47:14+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"sn-comprehensive-clinical-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sncm","sideBox":"Learn more about [SN Comprehensive Clinical Medicine](https://www.springer.com/journal/42399)","snPcode":"42399","submissionUrl":"https://submission.nature.com/new-submission/42399/3","title":"SN Comprehensive Clinical Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"0c44b1d1-4ca7-44dc-9773-adc57c9840c2","owner":[],"postedDate":"October 14th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-03-10T17:10:11+00:00","versionOfRecord":{"articleIdentity":"rs-4901006","link":"https://doi.org/10.1007/s42399-025-01814-6","journal":{"identity":"sn-comprehensive-clinical-medicine","isVorOnly":false,"title":"SN Comprehensive Clinical Medicine"},"publishedOn":"2025-03-04 15:56:56","publishedOnDateReadable":"March 4th, 2025"},"versionCreatedAt":"2024-10-14 10:20:29","video":"","vorDoi":"10.1007/s42399-025-01814-6","vorDoiUrl":"https://doi.org/10.1007/s42399-025-01814-6","workflowStages":[]},"version":"v1","identity":"rs-4901006","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4901006","identity":"rs-4901006","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}