Chronic kidney disease and reduced renal COX2 expression in xanthinuria: a case-control study

Chronic kidney disease and reduced renal COX2 expression in xanthinuria: a case-control study | 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 Chronic kidney disease and reduced renal COX2 expression in xanthinuria: a case-control study Marie-Hélène Normand, François Gougeon, Naeem Bhojani, Mélanie Dieudé, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8652828/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Background Xanthinuria is a rare inherited metabolic disorder caused by xanthine dehydrogenase (XDH) deficiency, leading to excessive urinary xanthine excretion. It is associated with kidney stones and, in exceptional cases, renal failure. To date, no kidney biopsy findings have been reported in cases of xanthinuria. We present the first documented biopsy from such a patient, revealing a reduction in cyclooxygenase-2 (COX2) expression. Case presentation A 38-year-old man of Afghan origin presented with flank pain and a staghorn calculus in the right kidney. Laboratory tests revealed impaired renal function with serum creatinine at 192 µmol/L. Percutaneous nephrolithotomy was performed to remove the stone, and infrared analysis confirmed its 100% xanthine composition. Genetic sequencing identified two pathogenic variants in the XDH gene, confirming type I xanthinuria. Despite stone removal, renal function progressively declined during the following months, with serum creatinine reaching 238 µmol/L and significant albuminuria. Imaging revealed no residual stones or atrophy of the right kidney, while the left kidney remained free of lithiasis. A biopsy of the left kidney demonstrated advanced chronic kidney disease with fibrosis, without crystal deposits or stones. As the etiology of nephropathy remained unclear, we assessed COX2 expression, an enzyme involved in prostaglandin synthesis, in the left kidney tissue. Compared with healthy controls and biopsies from other advanced chronic kidney disease cases, the xanthinuria biopsy showed considerably reduced tubular COX2 expression. The patient ultimately developed end-stage renal failure at age 41 and underwent successful kidney transplantation, achieving excellent graft function 32 months post-transplant. Conclusions This case provides the first histopathological evidence of chronic kidney disease in xanthinuria without crystal deposition and identifies reduced tubular COX2 expression as a potential pathogenic mechanism. These findings support hypotheses from animal models suggesting that xanthine dehydrogenase deficiency may impair prostaglandin synthesis, contributing to kidney fibrosis and possibly abnormal nephrogenesis. Further investigation of similar cases could improve our understanding of rare metabolic disorders and inform strategies to preserve kidney function. xanthinuria xanthine dehydrogenase chronic kidney disease cyclooxygenase-2 case report Figures Figure 1 Background Xanthinuria (OMIM #278300) is a rare metabolic disease characterized by the excretion of large amounts of xanthine in the urine. Two forms of the disease sharing an identical clinical presentation have been identified. Type I is linked to a genetic deficiency in xanthine dehydrogenase (XDH) ( 1 ), whereas type II is caused by a mutation in the molybdenum cofactor sulfurase (MOCOS) gene ( 2 ). Xanthinuria is associated with the occurrence of kidney stones, although some patients may remain asymptomatic. Renal failure is a rarely reported complication, particularly in cases of urinary obstruction caused by stones ( 3 ). Crystal precipitation in the renal parenchyma might also cause tubulointerstitial injury, as described in adenine phosphoribosyltransferase (APRT) deficiency, another rare disease of purine metabolism ( 4 ). However, the links between XDH and chronic kidney disease (CKD) remain poorly characterized, as does the existence of specific mechanisms, if any, that could lead to renal damage. Piret et al reported on a mouse model of recessive renal failure linked to XDH nonsense mutations ( 5 ). In this study, XDH deficiency was associated with the development of kidney fibrosis without stone or crystalline deposits. A striking finding was a decrease in tubular cyclooxygenase-2 (COX2) expression, an enzyme responsible for prostaglandin synthesis from arachidonic acid. In another model of xanthine oxidoreductase deficiency, XOR-/- mice also presented decreased COX2 expression and renal dysplasia with severe fibrosis, ( 6 ) similar to observations made in COX2 deficient animals ( 7 ) ( 8 ). Taken together, these data suggest that XDH deficiency may decrease COX2 expression and promote renal dysplasia and fibrosis. However, whether these animal observations apply to human pathology remains unknown. To the best of our knowledge, there are no reports in the literature of kidney biopsies from patients with xanthinuria. Case presentation We report here the case of a 38-year-old man of Afghan origin who presented with a staghorn stone in his right kidney. His left kidney was pelvic but free of lithiasis. Renal function was impaired, with a serum creatinine level of 192 µmol/l (eGFR 37 ml/min/1.73m 2 ). The patient underwent percutaneous nephrolithotomy, and infrared analysis showed that the stone was 100% xanthine. Next-generation sequencing of the MOCOS and XDH genes was later performed by Prevention Genetics (Marshfield, Wisconsin, USA) and revealed two mutations in the XDH gene (c.140dup et c.2729C > T), further confirming the diagnosis of xanthinuria. Uricemia was undetectable, as expected in this context. Over the following months after the urological procedure, kidney function continued to worsen, accompanied by high-grade albuminuria. Imaging showed the absence of residual stones and atrophy of the right kidney, sequelae of the obstruction. Fourteen months after the percutaneous nephrolithotomy, the serum creatinine level was 238 µmol/l (eGFR 28 ml/min/1.73m 2 ), and urinary protein-to-creatinine ratio was 0.347 g/mmol. A biopsy of the left kidney was performed and revealed advanced kidney disease with diffuse glomerulosclerosis and tubulointerstitial fibrosis (Fig. 1 A). The immunofluorescence study was negative, and, noteworthily, no crystals were observed in the renal parenchyma. The cause of this nephropathy remained unclear in the absence of renal obstruction, stones or atrophy of the left kidney. Inspired by data stemming from murine models of xanthinuria, we studied the renal expression of COX2 in the biopsy from our patient with xanthinuria compared with renal biopsies from healthy controls and CKD patients (Additional file 1). The latter had CKD at an advanced stage related to diabetic nephropathy, nonspecific focal segmental glomerulosclerosis (FSGS) and interstitial fibrosis tubular atrophy (IFTA) or glomerulosclerosis without a clearly identified cause other than hypertensive nephropathy. As in our index case of xanthinuria, CKD biopsies showed extensive fibrosis, affecting approximately 50% of the renal parenchyma (Fig. 1 A-C). Across all groups, COX2 expression was primarily observed in proximal tubules, whereas COX2 expression in distal tubules was very weak (Additional file 2). Strikingly, COX2 tubular expression was stunted in the xanthinuria biopsy compared to normal and CKD biopsies (Fig. 1 D, E). These observations corroborate previous findings by Piret et al in a murine model of recessive renal failure associated with XDH nonsense mutations. Unfortunately, our patient with xanthinuria reached end-stage renal failure at 41-year-old. Afterwards, the patient underwent renal transplantation with an excellent outcome and normal graft function 32 months post-transplantation, with a serum creatinine level of 93 µmol/l (eGFR 32 ml/min/1.73m 2 ). Discussion and Conclusions Here, we document the first renal biopsy for a patient diagnosed with xanthinuria. Kidney biopsy showed advanced glomerulosclerosis and fibrosis. In the absence of urinary obstruction and crystal deposits in the parenchyma, the cause of this nephropathy continued to be uncertain. Additionally, it remained unclear why our patient developed such severe disease when xanthinuria is not systematically associated with renal failure. A powerful insight resulting from this first investigation of a xanthinuria biopsy is a reduction in renal tubular COX2 expression compared with other advanced CKD cases and healthy controls. These results corroborate previous animal studies linking XDH deficiency, reduced tubular COX2 expression, and the development of kidney fibrosis. Notably, COX2 was shown to play an important role in prenatal kidney development ( 8 ) and in postnatal nephron generation ( 9 ). Thus, XDH deficiency and reduced COX2 expression may play detrimental roles in nephrogenesis. Under this hypothesis, the nephropathy observed in our patient could reflect the progression of renal dysplasia. While our observations are intriguing and hypotheses generating, the meticulous analysis of additional cases of patients with xanthinuria and CKD would be critical to unravel the physiopathology involved in these unusual presentations. We hope that our work will encourage other nephrologists who encounter such exceptional observations to study them in depth. This, along with further studies in animal models, may lead to advances in our understanding of the mechanisms involved in rare diseases and to the acquisition of a better understanding of key determinants of kidney homeostasis. Abbreviations Xanthine dehydrogenase (XDH), molybdenum cofactor sulfurase (MOCOS), adenine phosphoribosyltransferase (APRT), chronic kidney disease (CKD), cyclooxygenase-2 (COX2), estimated glomerular filtration rate (eGFR), focal segmental glomerulosclerosis (FSGS), interstitial fibrosis tubular atrophy (IFTA). Declarations Ethics approval and consent to participate : The study design was approved by the research ethics committee of the CRCHUM (21.020) and all patients provided informed written consent. Clinical trial number: not applicable. Consent for publication : Patient gave written informed consent for their personal and clinical details to be published in this study. Availability of data and materials : The datasets generated and analyzed during this study are included within this article and its additional files. Competing interests : The authors declare that they have no financial competing interests. Funding : The authors received financial support from the renal department of the Centre hospitalier de l'Université de Montréal (CHUM) for this work. Unrelated to this study, GB received honorary consulting fees from Novartis and Otsuka, GB participated in the advisory board of Otsuka on ADPKD and MD is the Director of Research Operations Medical Affairs and Innovation for Héma-Québec . Authors' contributions : GB and MD were responsible for the research idea and study design. MHN performed the histological examination of renal biopsies and was a major contributor in writing the manuscript. FG and NB corroborated MHN’s histological analysis. MD and GB were major contributors in writing the manuscript and provided supervision and mentorship. All authors substantially participated in the study design, drafted the manuscript, made revisions and approved the final manuscript. Acknowledgements : The authors would like to acknowledge the contribution of Véronique Barrès and Liliane Meunier from the molecular pathology core facility of the CHUM Research Center (CRCHUM). References Ichida K, Amaya Y, Kamatani N, et al. Identification of two mutations in human xanthine dehydrogenase gene responsible for classical type I xanthinuria. J Clin Invest . 1997;99:2391-7. Ichida K, Matsumura T, Sakuma R, et al. Mutation of human molybdenum cofactor sulfurase gene is responsible for classical xanthinuria type II. Biochem Biophys Res Commun . 2001;282:1194-200. Bradbury MG, Henderson M, Brocklebank JT, et al. Acute renal failure due to xanthine stones. Pediatr Nephrol . 1995;9:476-7. Bollee G, Harambat J, Bensman A, et al. Adenine phosphoribosyltransferase deficiency. Clin J Am Soc Nephrol . 2012;7:1521-7. Piret SE, Esapa CT, Gorvin CM, et al. A mouse model of early-onset renal failure due to a xanthine dehydrogenase nonsense mutation. PLoS ONE . 2012;7:e45217. Ohtsubo T, Rovira, II, Starost MF, et al. Xanthine oxidoreductase is an endogenous regulator of cyclooxygenase-2. Circ Res . 2004;95:1118-24. Norwood VF, Morham SG, Smithies O. Postnatal development and progression of renal dysplasia in cyclooxygenase-2 null mice. Kidney Int . 2000;58:2291-300. Dinchuk JE, Car BD, Focht RJ, et al. Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II. Nature . 1995;378:406-9. Frolich S, Slattery P, Thomas D, et al. Angiotensin II-AT1-receptor signaling is necessary for cyclooxygenase-2-dependent postnatal nephron generation. Kidney Int . 2017;91:818-29. Additional Declarations No competing interests reported. Supplementary Files Additionalfile1.docx Additional Material Additional file 1: .doc, Material and Methods, Detailed description of the participants, study design and immunohistochemistry protocol used in this study. Additionalfile2COX2tubules.xlsx Additional file 2: .xls, Tubular COX2 expression, Histological analysis of renal COX2 expression in distal and proximal tubules in biopsies of xanthinuria patient compared to healty controls and CKD patients. CAREchecklistEnglish2013.pdf Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 26 Feb, 2026 Reviews received at journal 26 Feb, 2026 Reviewers agreed at journal 25 Feb, 2026 Reviews received at journal 18 Feb, 2026 Reviewers agreed at journal 14 Feb, 2026 Reviewers invited by journal 12 Feb, 2026 Editor assigned by journal 12 Feb, 2026 Editor invited by journal 30 Jan, 2026 Submission checks completed at journal 30 Jan, 2026 First submitted to journal 30 Jan, 2026 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-8652828","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":591362528,"identity":"b5dc1cd8-8e8b-41e4-b519-375994ae123f","order_by":0,"name":"Marie-Hélène Normand","email":"","orcid":"","institution":"Centre Hospitalier de l’Université de Montréal","correspondingAuthor":false,"prefix":"","firstName":"Marie-Hélène","middleName":"","lastName":"Normand","suffix":""},{"id":591362529,"identity":"5e22e011-ab29-43ef-a91b-635e1fcbce42","order_by":1,"name":"François Gougeon","email":"","orcid":"","institution":"Centre Hospitalier de l’Université de Montréal","correspondingAuthor":false,"prefix":"","firstName":"François","middleName":"","lastName":"Gougeon","suffix":""},{"id":591362530,"identity":"cbf203ff-937d-4a3a-8132-83ae66f04636","order_by":2,"name":"Naeem Bhojani","email":"","orcid":"","institution":"Centre Hospitalier de l’Université de Montréal","correspondingAuthor":false,"prefix":"","firstName":"Naeem","middleName":"","lastName":"Bhojani","suffix":""},{"id":591362531,"identity":"91ba1d24-c322-47e4-b108-0fc8a82516cd","order_by":3,"name":"Mélanie Dieudé","email":"data:image/png;base64,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","orcid":"","institution":"University of Montreal","correspondingAuthor":true,"prefix":"","firstName":"Mélanie","middleName":"","lastName":"Dieudé","suffix":""},{"id":591362532,"identity":"da50f99c-70e3-40d6-9594-a47fb7fdf6d0","order_by":4,"name":"Guillaume Bollée","email":"","orcid":"","institution":"Centre Hospitalier de l’Université de Montréal","correspondingAuthor":false,"prefix":"","firstName":"Guillaume","middleName":"","lastName":"Bollée","suffix":""}],"badges":[],"createdAt":"2026-01-20 20:34:39","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8652828/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8652828/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102964286,"identity":"cad55177-0f16-42dd-9f7e-9848e7c5c734","added_by":"auto","created_at":"2026-02-19 04:22:00","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":8960325,"visible":true,"origin":"","legend":"\u003cp\u003eHistopathologic evaluation of a xanthinuria patient with extensive renal fibrosis and reduced COX2 tubular expression.\u003c/p\u003e\n\u003cp\u003eMasson’s trichrome staining (A-C) and anti-COX2 immunohistochemistry staining (D-E) of kidney biopsies from a type I xanthinuria patient (n=1) compared to normal (n=4), FSGS/IFTA (n=4), glomerulosclerosis (n=4) and diabetic nephropathy biopsies (n=4). (A) Representative images of Masson’s trichrome-stained kidney biopsies (10X magnification). The xanthinuria and CKD biopsies present important renal glomerulosclerosis (B) and tubulointerstitial fibrosis (C) compared with healthy controls. (D) Representative images of kidney biopsy sections stained with anti-COX2 (10X magnification). Anti-COX2 immunohistochemical staining of the xanthinuria patient’s biopsy showed reduced COX2 tubular expression in contrast to normal and CKD biopsies (E). Data is presented as mean ± SEM. High power field (HPF). P values were calculated using unpaired Student’s t-tests (*P \u0026lt; 0.05, **P \u0026lt; 0.01, and ***P \u0026lt; 0.001).\u003c/p\u003e","description":"","filename":"Figure1COX2.png","url":"https://assets-eu.researchsquare.com/files/rs-8652828/v1/5d4e1d2333c61371ff7a042c.png"},{"id":102965698,"identity":"56775794-da92-4ddf-a19e-0812bc1e5676","added_by":"auto","created_at":"2026-02-19 04:32:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":8358188,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8652828/v1/00a9c77c-3a5e-4ab4-b145-7f0714a2927a.pdf"},{"id":102964276,"identity":"c21c9ebe-d441-44e1-812d-61b994c26e9a","added_by":"auto","created_at":"2026-02-19 04:21:59","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":19496,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAdditional Material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional file 1\u003c/strong\u003e: .doc, Material and Methods, Detailed description of the participants, study design and immunohistochemistry protocol used in this study.\u003c/p\u003e","description":"","filename":"Additionalfile1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8652828/v1/17d747115466c8e65c28fdae.docx"},{"id":102892564,"identity":"b50c1435-03c9-4204-8ce0-d62637630393","added_by":"auto","created_at":"2026-02-18 05:26:00","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":25686,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAdditional file 2\u003c/strong\u003e: .xls, Tubular COX2 expression, Histological analysis of renal COX2 expression in distal and proximal tubules in biopsies of xanthinuria patient compared to healty controls and CKD patients.\u003c/p\u003e","description":"","filename":"Additionalfile2COX2tubules.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8652828/v1/3e1f7dba92c2d45c9c1705f3.xlsx"},{"id":102892565,"identity":"c45335d6-4ac7-4c3b-839f-dcbb0ceb2cd2","added_by":"auto","created_at":"2026-02-18 05:26:00","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":1296646,"visible":true,"origin":"","legend":"","description":"","filename":"CAREchecklistEnglish2013.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8652828/v1/3ea5e9c2e34aa4fd336b7603.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Chronic kidney disease and reduced renal COX2 expression in xanthinuria: a case-control study","fulltext":[{"header":"Background","content":"\u003cp\u003eXanthinuria (OMIM #278300) is a rare metabolic disease characterized by the excretion of large amounts of xanthine in the urine. Two forms of the disease sharing an identical clinical presentation have been identified. Type I is linked to a genetic deficiency in xanthine dehydrogenase (XDH) (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e), whereas type II is caused by a mutation in the molybdenum cofactor sulfurase (MOCOS) gene (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eXanthinuria is associated with the occurrence of kidney stones, although some patients may remain asymptomatic. Renal failure is a rarely reported complication, particularly in cases of urinary obstruction caused by stones (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Crystal precipitation in the renal parenchyma might also cause tubulointerstitial injury, as described in adenine phosphoribosyltransferase (APRT) deficiency, another rare disease of purine metabolism (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). However, the links between XDH and chronic kidney disease (CKD) remain poorly characterized, as does the existence of specific mechanisms, if any, that could lead to renal damage.\u003c/p\u003e \u003cp\u003ePiret et al reported on a mouse model of recessive renal failure linked to XDH nonsense mutations (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). In this study, XDH deficiency was associated with the development of kidney fibrosis without stone or crystalline deposits. A striking finding was a decrease in tubular cyclooxygenase-2 (COX2) expression, an enzyme responsible for prostaglandin synthesis from arachidonic acid. In another model of xanthine oxidoreductase deficiency, XOR-/- mice also presented decreased COX2 expression and renal dysplasia with severe fibrosis, (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) similar to observations made in COX2 deficient animals (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Taken together, these data suggest that XDH deficiency may decrease COX2 expression and promote renal dysplasia and fibrosis. However, whether these animal observations apply to human pathology remains unknown. To the best of our knowledge, there are no reports in the literature of kidney biopsies from patients with xanthinuria.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eWe report here the case of a 38-year-old man of Afghan origin who presented with a staghorn stone in his right kidney. His left kidney was pelvic but free of lithiasis. Renal function was impaired, with a serum creatinine level of 192 µmol/l (eGFR 37 ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e). The patient underwent percutaneous nephrolithotomy, and infrared analysis showed that the stone was 100% xanthine. Next-generation sequencing of the \u003cem\u003eMOCOS\u003c/em\u003e and \u003cem\u003eXDH\u003c/em\u003e genes was later performed by Prevention Genetics (Marshfield, Wisconsin, USA) and revealed two mutations in the \u003cem\u003eXDH\u003c/em\u003e gene (c.140dup et c.2729C \u0026gt; T), further confirming the diagnosis of xanthinuria. Uricemia was undetectable, as expected in this context. Over the following months after the urological procedure, kidney function continued to worsen, accompanied by high-grade albuminuria. Imaging showed the absence of residual stones and atrophy of the right kidney, sequelae of the obstruction. Fourteen months after the percutaneous nephrolithotomy, the serum creatinine level was 238 µmol/l (eGFR 28 ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e), and urinary protein-to-creatinine ratio was 0.347 g/mmol. A biopsy of the left kidney was performed and revealed advanced kidney disease with diffuse glomerulosclerosis and tubulointerstitial fibrosis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). The immunofluorescence study was negative, and, noteworthily, no crystals were observed in the renal parenchyma.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe cause of this nephropathy remained unclear in the absence of renal obstruction, stones or atrophy of the left kidney. Inspired by data stemming from murine models of xanthinuria, we studied the renal expression of COX2 in the biopsy from our patient with xanthinuria compared with renal biopsies from healthy controls and CKD patients (Additional file 1). The latter had CKD at an advanced stage related to diabetic nephropathy, nonspecific focal segmental glomerulosclerosis (FSGS) and interstitial fibrosis tubular atrophy (IFTA) or glomerulosclerosis without a clearly identified cause other than hypertensive nephropathy. As in our index case of xanthinuria, CKD biopsies showed extensive fibrosis, affecting approximately 50% of the renal parenchyma (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA-C). Across all groups, COX2 expression was primarily observed in proximal tubules, whereas COX2 expression in distal tubules was very weak (Additional file 2). Strikingly, COX2 tubular expression was stunted in the xanthinuria biopsy compared to normal and CKD biopsies (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eD, E). These observations corroborate previous findings by Piret et al in a murine model of recessive renal failure associated with XDH nonsense mutations. Unfortunately, our patient with xanthinuria reached end-stage renal failure at 41-year-old. Afterwards, the patient underwent renal transplantation with an excellent outcome and normal graft function 32 months post-transplantation, with a serum creatinine level of 93 µmol/l (eGFR 32 ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e).\u003c/p\u003e "},{"header":"Discussion and Conclusions","content":"\u003cp\u003eHere, we document the first renal biopsy for a patient diagnosed with xanthinuria. Kidney biopsy showed advanced glomerulosclerosis and fibrosis. In the absence of urinary obstruction and crystal deposits in the parenchyma, the cause of this nephropathy continued to be uncertain. Additionally, it remained unclear why our patient developed such severe disease when xanthinuria is not systematically associated with renal failure. A powerful insight resulting from this first investigation of a xanthinuria biopsy is a reduction in renal tubular COX2 expression compared with other advanced CKD cases and healthy controls. These results corroborate previous animal studies linking XDH deficiency, reduced tubular COX2 expression, and the development of kidney fibrosis. Notably, COX2 was shown to play an important role in prenatal kidney development (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) and in postnatal nephron generation (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Thus, XDH deficiency and reduced COX2 expression may play detrimental roles in nephrogenesis. Under this hypothesis, the nephropathy observed in our patient could reflect the progression of renal dysplasia.\u003c/p\u003e\u003cp\u003eWhile our observations are intriguing and hypotheses generating, the meticulous analysis of additional cases of patients with xanthinuria and CKD would be critical to unravel the physiopathology involved in these unusual presentations. We hope that our work will encourage other nephrologists who encounter such exceptional observations to study them in depth. This, along with further studies in animal models, may lead to advances in our understanding of the mechanisms involved in rare diseases and to the acquisition of a better understanding of key determinants of kidney homeostasis.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eXanthine dehydrogenase (XDH), molybdenum cofactor sulfurase (MOCOS), adenine phosphoribosyltransferase (APRT), chronic kidney disease (CKD), cyclooxygenase-2 (COX2), estimated glomerular filtration rate (eGFR), focal segmental glomerulosclerosis (FSGS), interstitial fibrosis tubular atrophy (IFTA).\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e: The study design was approved by the research ethics committee of the CRCHUM (21.020) and all patients provided informed written consent. Clinical trial number: not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e: Patient gave written informed consent for their personal and clinical details to be published in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e: The datasets generated and analyzed during this study are included within this article and its additional files.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e: The authors declare that they have no financial competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: The authors received financial support from the renal department of the Centre hospitalier de l'Université de Montréal (CHUM) for this work. Unrelated to this study, GB received honorary consulting fees from Novartis and Otsuka, GB participated in the advisory board of Otsuka on ADPKD and MD is the Director of Research Operations Medical Affairs and Innovation for Héma-Québec\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e: GB and MD were responsible for the research idea and study design. MHN performed the histological examination of renal biopsies and was a major contributor in writing the manuscript. FG and NB corroborated MHN’s histological analysis. MD and GB were major contributors in writing the manuscript and provided supervision and mentorship. All authors substantially participated in the study design, drafted the manuscript, made revisions and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e: The authors would like to acknowledge the contribution of Véronique Barrès and Liliane Meunier from the molecular pathology core facility of the CHUM Research Center (CRCHUM).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eIchida K, Amaya Y, Kamatani N, et al. Identification of two mutations in human xanthine dehydrogenase gene responsible for classical type I xanthinuria. \u003cem\u003eJ Clin Invest\u003c/em\u003e. 1997;99:2391-7.\u003c/li\u003e\n\u003cli\u003eIchida K, Matsumura T, Sakuma R, et al. Mutation of human molybdenum cofactor sulfurase gene is responsible for classical xanthinuria type II. \u003cem\u003eBiochem Biophys Res Commun\u003c/em\u003e. 2001;282:1194-200.\u003c/li\u003e\n\u003cli\u003eBradbury MG, Henderson M, Brocklebank JT, et al. Acute renal failure due to xanthine stones. \u003cem\u003ePediatr Nephrol\u003c/em\u003e. 1995;9:476-7.\u003c/li\u003e\n\u003cli\u003eBollee G, Harambat J, Bensman A, et al. Adenine phosphoribosyltransferase deficiency. \u003cem\u003eClin J Am Soc Nephrol\u003c/em\u003e. 2012;7:1521-7.\u003c/li\u003e\n\u003cli\u003ePiret SE, Esapa CT, Gorvin CM, et al. A mouse model of early-onset renal failure due to a xanthine dehydrogenase nonsense mutation. \u003cem\u003ePLoS ONE\u003c/em\u003e. 2012;7:e45217.\u003c/li\u003e\n\u003cli\u003eOhtsubo T, Rovira, II, Starost MF, et al. Xanthine oxidoreductase is an endogenous regulator of cyclooxygenase-2. \u003cem\u003eCirc Res\u003c/em\u003e. 2004;95:1118-24.\u003c/li\u003e\n\u003cli\u003eNorwood VF, Morham SG, Smithies O. Postnatal development and progression of renal dysplasia in cyclooxygenase-2 null mice. \u003cem\u003eKidney Int\u003c/em\u003e. 2000;58:2291-300.\u003c/li\u003e\n\u003cli\u003eDinchuk JE, Car BD, Focht RJ, et al. Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II. \u003cem\u003eNature\u003c/em\u003e. 1995;378:406-9.\u003c/li\u003e\n\u003cli\u003eFrolich S, Slattery P, Thomas D, et al. Angiotensin II-AT1-receptor signaling is necessary for cyclooxygenase-2-dependent postnatal nephron generation. \u003cem\u003eKidney Int\u003c/em\u003e. 2017;91:818-29.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"xanthinuria, xanthine dehydrogenase, chronic kidney disease, cyclooxygenase-2, case report","lastPublishedDoi":"10.21203/rs.3.rs-8652828/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8652828/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eXanthinuria is a rare inherited metabolic disorder caused by xanthine dehydrogenase (XDH) deficiency, leading to excessive urinary xanthine excretion. It is associated with kidney stones and, in exceptional cases, renal failure. To date, no kidney biopsy findings have been reported in cases of xanthinuria. We present the first documented biopsy from such a patient, revealing a reduction in cyclooxygenase-2 (COX2) expression.\u003c/p\u003e\u003ch2\u003eCase presentation\u003c/h2\u003e \u003cp\u003eA 38-year-old man of Afghan origin presented with flank pain and a staghorn calculus in the right kidney. Laboratory tests revealed impaired renal function with serum creatinine at 192 \u0026micro;mol/L. Percutaneous nephrolithotomy was performed to remove the stone, and infrared analysis confirmed its 100% xanthine composition. Genetic sequencing identified two pathogenic variants in the \u003cem\u003eXDH\u003c/em\u003e gene, confirming type I xanthinuria. Despite stone removal, renal function progressively declined during the following months, with serum creatinine reaching 238 \u0026micro;mol/L and significant albuminuria. Imaging revealed no residual stones or atrophy of the right kidney, while the left kidney remained free of lithiasis. A biopsy of the left kidney demonstrated advanced chronic kidney disease with fibrosis, without crystal deposits or stones. As the etiology of nephropathy remained unclear, we assessed COX2 expression, an enzyme involved in prostaglandin synthesis, in the left kidney tissue. Compared with healthy controls and biopsies from other advanced chronic kidney disease cases, the xanthinuria biopsy showed considerably reduced tubular COX2 expression. The patient ultimately developed end-stage renal failure at age 41 and underwent successful kidney transplantation, achieving excellent graft function 32 months post-transplant.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThis case provides the first histopathological evidence of chronic kidney disease in xanthinuria without crystal deposition and identifies reduced tubular COX2 expression as a potential pathogenic mechanism. These findings support hypotheses from animal models suggesting that xanthine dehydrogenase deficiency may impair prostaglandin synthesis, contributing to kidney fibrosis and possibly abnormal nephrogenesis. Further investigation of similar cases could improve our understanding of rare metabolic disorders and inform strategies to preserve kidney function.\u003c/p\u003e","manuscriptTitle":"Chronic kidney disease and reduced renal COX2 expression in xanthinuria: a case-control study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-18 05:25:55","doi":"10.21203/rs.3.rs-8652828/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-02-27T04:35:21+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-27T04:07:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"171114378995994264926698197248564339471","date":"2026-02-25T11:22:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-18T13:20:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"126165786743750957672410891237080710046","date":"2026-02-14T13:16:56+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-12T06:12:34+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-12T06:10:09+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-01-31T04:23:54+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-30T18:18:42+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Nephrology","date":"2026-01-30T18:14:43+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1bd50c3a-42b3-4556-bd03-57f4be92f801","owner":[],"postedDate":"February 18th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-15T12:08:20+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-18 05:25:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8652828","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8652828","identity":"rs-8652828","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}