Infection-related glomerulonephritis presenting as acute kidney injury and nephrotic syndrome caused by human adenovirus III successfully treated with cyclosporine and methylprednisolone pulse therapy

Infection-related glomerulonephritis presenting as acute kidney injury and nephrotic syndrome caused by human adenovirus III successfully treated with cyclosporine and methylprednisolone pulse therapy | 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 Research Article Infection-related glomerulonephritis presenting as acute kidney injury and nephrotic syndrome caused by human adenovirus III successfully treated with cyclosporine and methylprednisolone pulse therapy Koichi Kamei, Tomoya Kaneda, Kentaro Nishi, Masao Ogura, Kentaro Ogata, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6236033/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 Infection-related glomerulonephritis (IRGN) caused by adenovirus is a rare condition, and there are no reports of kidney biopsy. Herein, we report a 2-year-old boy with IRGN caused by human adenovirus Ⅲ who required dialysis due to acute kidney injury and subsequently presented with persistent nephrotic syndrome. Kidney biopsy showed diffuse endocapillary proliferation with 30% cellular crescents. Histological staining showed positivity for nephritis-associated plasmin receptor (NAPlr) and plasmin activity in the glomeruli. The patient received cyclosporine and methylprednisolone pulse therapy once a month and 1 mg/kg of oral prednisolone every other day. Thereafter, he achieved complete remission. According to our case, NAPlr staining could be positive in IRGN caused by viral infections. The combination of cyclosporine and methylprednisolone pulse therapy might be effective for the severe type of IRGN. Adenovirus Cyclosporin Infection-related glomerulonephritis Methylprednisolone pulse therapy Nephritis-associated plasmin receptor Figures Figure 1 Introduction Post-streptococcal acute glomerulonephritis (PSAGN) is the most common type of infection-related glomerulonephritis (IRGN). Adenovirus commonly causes tubulointerstitial nephritis and hemorrhagic cystitis. However, previous reports about IRGN caused by adenovirus are limited [ 1 ]. Moreover, there are no reports on the histological evaluation of adenovirus-induced IRGN, and the detailed pathogenesis of IRGN is still unknown. Herein, we report a boy with IRGN caused by human adenovirus Ⅲ who required dialysis due to acute kidney injury and who subsequently presented with persistent nephrotic syndrome. Case presentation The patient was a 2-year-old boy. He had been healthy without a remarkable medical history. Further, he did not present with a family history of kidney disease. Nine days before admission, the patient developed fever and bulbar conjunctival congestion. He was diagnosed with adenovirus infection using the antigen test by a physician at a nearby hospital. Five days before admission, he developed vomiting, diarrhea, and abdominal pain. On the day of admission, he had decreased kidney function based on the examination performed at a nearby institution. Therefore, he was transferred to our center. He weighed 13.45 kg, with an increase of 0.85 kg, and his blood pressure was 135/79 mmHg, which indicated hypertension. There were no significant chest or abdominal findings. However, mild eyelid and lower-leg edema was observed. The blood test results indicating anemia, prominent kidney dysfunction, and hypocomplementemia were as follows: hemoglobin, 9.9 g/dL; total protein, 5.2 g/dL; albumin, 1.7 g/dL; blood urea nitrogen, 174.9 mg/dL; creatinine, 2.27 mg/dL; uric acid, 14.8 mg/dL; sodium, 130 mEq/L; potassium, 6.7 mEq/L; calcium, 7.8 mg/dL; phosphorus, 8.4 mg/dL; C-reactive protein, 6.37 mg/dL; cystatin C, 3.18 mg/L; C3, 30 mg/dL; C4, 2 mg/dL; and CH50, < 12.0 U/mL. The patient tested negative for antinuclear antibodies, anti-ds-DNA-IgG, anti-RNP antibodies, antineutrophil cytoplasmic antibodies, and anti-glomerular basement membrane antibodies. The urine tests revealed the following results: protein, 4+; occult blood, 3+; red blood cell count, 50–99/HPF; white blood cell count, 50–99/HPF; and protein-to-creatinine ratio, 9.30 g/gCr. Kidney biopsy revealed that almost all glomeruli had endocapillary proliferation with 30% cellular crescents (Fig. 1 ). Further, interstitial edema, dilation of the tubular lumen, and flattening of the tubular epithelium were observed. Deposits of IgG (3+), IgA (2+), IgM (3+), C3 (3+), C4d (+), and C1q (2+) were observed along the peripheral capillary walls on immunofluorescence. Electron microscopy showed humps under the epithelial cells and small amount of deposits under the endothelium and in the mesangial area. Nephritis-associated plasmin receptor (NAPlr) staining had positive results in 10 of 13 glomeruli, and plasmin activity was positive in 9 of 10 glomeruli. Regarding the cause of nephritis, the throat culture had negative results, and streptococcus was not detected. The anti-streptolysin-O antibody was mildly high at 422 (normal: <239) IU/mL. The parvovirus B19-IgM level was 0.91 (normal: <0.81). Using the particle agglutination method, the mycoplasma antibody level was 40 (< 40) times. Based on the complement fixation test, the antibody against adenovirus count was significantly high at 16 (< 4) times. According to the neutralization test, the type III antibody was significantly high at 16 (< 4) times. The patient also tested positive for antifactor B antibody, which indicated IRGN. After admission, the patient received continuous hemodialysis for 5 days for acute kidney injury. After two courses of methylprednisolone pulse therapy (MPT) (30 mg/kg of methylprednisolone for 3 days in one course) and 2 mg/kg of oral prednisolone, the patient’s kidney function immediately recovered. However, nephrotic syndrome (1.5–2.0 g/dL of serum albumin and 10–50 g/g of urine protein creatinine ratio) persisted for > 1 month. The serum C3 and C4 levels normalized on day 24. Candesartan was started on day 43 and cyclosporine (CsA) on day 47. MPT was continued once a month, and 1 mg/kg of prednisolone was continued every other day. The patient’s proteinuria gradually decreased, and he achieved complete remission on day 107. Fourteen months after the onset, the patient achieved complete remission with normal urinalysis and kidney function. Discussion Herein, we report a 2-year-old boy with IRGN caused by human adenovirus Ⅲ. The patient met the five diagnostic criteria for IRGN that was proposed by Nasr SH [ 2 ]. He also tested positive for the antifactor B antibody, which is related to IRGN [ 3 ]. To the best of our knowledge, this is the first case report which showed antifactor B antibody positivity in IRGN caused by viral infection and adenovirus IRGN in which pathological evaluation was performed via kidney biopsy. As the patient’s anti-streptolysin-O antibody level was slightly elevated, the streptococcal infection could not be ruled out. However, the throat culture result was negative. Further, the low serum C4 level and C1q deposition in the glomeruli indicated the dominant activation of the classical pathways. These findings are not typical in patients with PSAGN in whom dominant activation of the alternative pathways is common. NAPlr is the same substance as streptococcal gyceraldehyde-3-phosphate dehydrogenase (GAPDH). NAPlr, which is deposited in the glomeruli, binds to plasmin, maintains its activity, and causes inflammation in the basement membrane and mesangium by its proteolytic activity and by the activation and accumulation of macrophages and neutrophils [ 4 ]. Previously, NAPlr was believed to be specific to PSAGN. Nonetheless, in recent years, pneumococcal, staphylococci, and mycoplasma GAPDH has also been found to cross-react with anti-NAPlr (streptococcal GAPDH) antibody. NAPlr staining shows positivity for these IRGNs in the glomeruli. A recent study has reported an adult case of NAPlr-positive IRGN caused by parvovirus B19 [ 5 ]. Our case report first presented IRGN caused by adenovirus in which glomerular positive staining for NAPlr was confirmed histologically. Thus, NAPlr positivity could be observed in not only bacterial IRGN but also viral IRGN. Because IRGN usually resolves spontaneously, immunosuppressive therapy is not indicated. However, cases of severe kidney dysfunction or prolonged nephrotic syndrome or cases of crescentic glomerulonephritis usually require highly intense immunosuppressive treatment. The effect of immunosuppressive treatment for IRGN is not fully established. The combination of CsA and MPT was administered for refractory nephrotic syndrome in IRGN, and it successfully achieved complete remission. We believe that the combination of CsA and MPT might be an effective treatment option for the severe type of IRGN. In conclusion, we report a boy with a severe type of IRGN caused by human adenovirus Ⅲ. Immunofluorescence staining showed NAPlr positivity in the glomeruli. The combination of CsA and MPT was effective for prolonged nephrotic syndrome in IRGN, and the patient successfully achieved complete remission. In the future, large-scale studies should be performed to evaluate the role of NAPlr as a biomarker of virus-induced IRGN and the appropriate strategy for immunosuppressive treatment against severe IRGN. Summary – What is new? Adenovirus could cause IRGN with positive glomerular staining for NAPlr and plasmin activity. The combination of CsA and MPT might be effective for the severe type of IRGN. Declarations Competing Interests: Koichi Kamei received research funding from the Public Foundation of Vaccination Research Center and the Taiju Life Social Welfare Foundation; donations from Chugai Pharmaceutical, Teijin Pharma, Kyowa Kirin, Taiho Pharmaceutical, Shionogi, Daiichi Sankyo, and Mitsubishi Tanabe Pharma; and lecture fees from Terumo. These fundings have no relationship with this work. Consent for publication: Informed consent was obtained from the parents. Author contributions: Koichi Kamei, who is the first author, prepared the manuscript. Tomoya Kaneda, Kentaro Nishi and Masao Ogura were involved in the management of the patient. Kentaro Ogata identified the kidney pathology. Takashi Oda performed the immunofluorescence staining for NAPlr and in situ zymography for plasmin activity and evaluated the serum antifactor B antibody. All authors contributed to the work and revised the manuscript. Acknowledgments: We thank Enago for editing the draft of this manuscript. We also thank Dr. Toshihiro Sawai (Shiga University) for analyzing the complement pathways and editing the manuscript and Takako Yoshioka for identifying the kidney pathology. References Garty BZ, Amir A, Scheuerman O, Hoffer V, Marcus N (2009) Post-infectious glomerulonephritis associated with adenovirus infection. Isr Med Assoc J 11:758–759. Nasr SH, Radhakrishnan J, D'Agati VD (2013) Bacterial infection-related glomerulonephritis in adults. Kidney Int 83:792–803. https://doi.org/10.1038/ki.2012.407. Chauvet S, Berthaud R, Devriese M, Mignotet M, Vieira Martins P, Robe-Rybkine T, Miteva MA, Gyulkhandanyan A, Ryckewaert A, Louillet F, Merieau E, Mestrallet G, Rousset-Rouvière C, Thervet E, Hogan J, Ulinski T, Villoutreix BO, Roumenina L, Boyer O, Frémeaux-Bacchi VJ (2020) Anti-factor B antibodies and acute postinfectious GN in children. J Am Soc Nephrol 31:829–840. https://doi.org/10.1681/ASN.2019080851. Oda T, Yamakami K, Omasu F, Suzuki S, Miura S, Sugisaki T, Yoshizawa N (2005) Glomerular plasmin-like activity in relation to nephritis-associated plasmin receptor in acute poststreptococcal glomerulonephritis. J Am Soc Nephrol 16:247–254. https://doi.org/10.1681/ASN.2004040341. Takahashi H, Wada Y, Yamazaki T, Takeuchi K, Abe T, Naito S, Aoyama T, Sano T, Moriya R, Oda T, Takeuchi Y (2024) Parvovirus B19-related membranoproliferative glomerulonephritis presenting with positive glomerular staining for nephritis-associated plasmin receptor: a case report and review of the literature. CEN Case Rep. Dec 15. Online ahead of print. https://doi.org/10.1007/s13730-024-00956-1. 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-6236033","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":430093934,"identity":"ea5216a0-c979-4044-aaee-1a69248031f0","order_by":0,"name":"Koichi Kamei","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2ElEQVRIiWNgGAWjYBACCRCRwJAgB6TYGHjAYgeI02JMohagpsQGhBYCQLL9dOKDBwxp6dvZDz978IahVo6B8Sx+a6R5cjcbJDDk5O7sSTM3nMNwHOjCcwl4tcgx5G6TSPxXkbvhBg+bNA/DMaALzxjg18L/dvuPBIaKdAOitUhL5G4DhlhOAlRLDWEtkjPebpZIYEgz3HAmzUxyjsEBYzZCfpE4n7vx4w+GZHmD44efSbypqJPjlyAQYmjA4DADm8QZUnQwMNQxMPD3kKZlFIyCUTAKhj0AACAeQ6wBOp/+AAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-3528-6961","institution":"Division of Nephrology and Rheumatology, National Center for Child Health and Development","correspondingAuthor":true,"prefix":"","firstName":"Koichi","middleName":"","lastName":"Kamei","suffix":""},{"id":430093935,"identity":"63174762-7917-40d7-bb40-8cebac2c19df","order_by":1,"name":"Tomoya Kaneda","email":"","orcid":"","institution":"Division of Nephrology and Rheumatology, National Center for Child Health and Development","correspondingAuthor":false,"prefix":"","firstName":"Tomoya","middleName":"","lastName":"Kaneda","suffix":""},{"id":430093936,"identity":"71e4ecf0-f4f6-4a7e-911c-319836fd7fbf","order_by":2,"name":"Kentaro Nishi","email":"","orcid":"","institution":"Division of Nephrology and Rheumatology, National Center for Child Health and Development","correspondingAuthor":false,"prefix":"","firstName":"Kentaro","middleName":"","lastName":"Nishi","suffix":""},{"id":430093937,"identity":"0a010ed9-1ed8-4af0-8fcf-4afbb16001b8","order_by":3,"name":"Masao Ogura","email":"","orcid":"","institution":"Division of Nephrology and Rheumatology, National Center for Child Health and Development","correspondingAuthor":false,"prefix":"","firstName":"Masao","middleName":"","lastName":"Ogura","suffix":""},{"id":430093938,"identity":"a3924353-7a07-4449-9cd5-f26922ab9bf1","order_by":4,"name":"Kentaro Ogata","email":"","orcid":"","institution":"Department of Pathology, National Center for Child Health and Development","correspondingAuthor":false,"prefix":"","firstName":"Kentaro","middleName":"","lastName":"Ogata","suffix":""},{"id":430093939,"identity":"8a3ba73e-e3df-4633-b6a8-132dfb09f68c","order_by":5,"name":"Takashi Oda","email":"","orcid":"","institution":"Department of Nephrology and Blood Purification, Kidney Disease Center, Tokyo Medical University Hachioji Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Takashi","middleName":"","lastName":"Oda","suffix":""}],"badges":[],"createdAt":"2025-03-16 06:32:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6236033/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6236033/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":79320334,"identity":"f4539117-e56a-4ab2-914c-e60f0cdfd616","added_by":"auto","created_at":"2025-03-27 04:23:02","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1937622,"visible":true,"origin":"","legend":"\u003cp\u003eKidney biopsy findings\u003c/p\u003e\n\u003cp\u003ea. Glomeruli presenting with endocapillary proliferation and cellular crescents on light microscopy (periodic acid-Schiff staining, ×400).\u003c/p\u003e\n\u003cp\u003eb-d. Granular deposits along peripheral capillary walls on immunofluorescence staining (b, IgG 3+; c, C3 3+; d, C1q 2+).\u003c/p\u003e\n\u003cp\u003ee, Humps under epithelial cells (＊) and deposits in mesangial area (←) on electron microscopy.\u003c/p\u003e\n\u003cp\u003ef. Subepithelial deposits (＊) and subendothelial deposits (←) beneath the newly formed glomerular basement membrane (◀).\u003c/p\u003e\n\u003cp\u003eg. Immunofluorescence staining revealed nephritis-associated plasmin receptor (NAPlr) positivity in glomeruli.\u003c/p\u003e\n\u003cp\u003eh. In situ zymography revealed plasmin activity positivity in glomeruli.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6236033/v1/b97dc0a55cc5d56c36bf16d0.png"},{"id":81037534,"identity":"4b988bfe-a8a5-4504-8a75-b97783065e4e","added_by":"auto","created_at":"2025-04-21 12:38:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2108029,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6236033/v1/bc11f511-8b06-4147-9ef9-4555f8610c44.pdf"}],"financialInterests":"","formattedTitle":"Infection-related glomerulonephritis presenting as acute kidney injury and nephrotic syndrome caused by human adenovirus III successfully treated with cyclosporine and methylprednisolone pulse therapy","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePost-streptococcal acute glomerulonephritis (PSAGN) is the most common type of infection-related glomerulonephritis (IRGN). Adenovirus commonly causes tubulointerstitial nephritis and hemorrhagic cystitis. However, previous reports about IRGN caused by adenovirus are limited [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Moreover, there are no reports on the histological evaluation of adenovirus-induced IRGN, and the detailed pathogenesis of IRGN is still unknown. Herein, we report a boy with IRGN caused by human adenovirus Ⅲ who required dialysis due to acute kidney injury and who subsequently presented with persistent nephrotic syndrome.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eThe patient was a 2-year-old boy. He had been healthy without a remarkable medical history. Further, he did not present with a family history of kidney disease. Nine days before admission, the patient developed fever and bulbar conjunctival congestion. He was diagnosed with adenovirus infection using the antigen test by a physician at a nearby hospital. Five days before admission, he developed vomiting, diarrhea, and abdominal pain. On the day of admission, he had decreased kidney function based on the examination performed at a nearby institution. Therefore, he was transferred to our center. He weighed 13.45 kg, with an increase of 0.85 kg, and his blood pressure was 135/79 mmHg, which indicated hypertension. There were no significant chest or abdominal findings. However, mild eyelid and lower-leg edema was observed. The blood test results indicating anemia, prominent kidney dysfunction, and hypocomplementemia were as follows: hemoglobin, 9.9 g/dL; total protein, 5.2 g/dL; albumin, 1.7 g/dL; blood urea nitrogen, 174.9 mg/dL; creatinine, 2.27 mg/dL; uric acid, 14.8 mg/dL; sodium, 130 mEq/L; potassium, 6.7 mEq/L; calcium, 7.8 mg/dL; phosphorus, 8.4 mg/dL; C-reactive protein, 6.37 mg/dL; cystatin C, 3.18 mg/L; C3, 30 mg/dL; C4, 2 mg/dL; and CH50, \u0026lt;\u0026thinsp;12.0 U/mL. The patient tested negative for antinuclear antibodies, anti-ds-DNA-IgG, anti-RNP antibodies, antineutrophil cytoplasmic antibodies, and anti-glomerular basement membrane antibodies. The urine tests revealed the following results: protein, 4+; occult blood, 3+; red blood cell count, 50\u0026ndash;99/HPF; white blood cell count, 50\u0026ndash;99/HPF; and protein-to-creatinine ratio, 9.30 g/gCr.\u003c/p\u003e \u003cp\u003eKidney biopsy revealed that almost all glomeruli had endocapillary proliferation with 30% cellular crescents (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Further, interstitial edema, dilation of the tubular lumen, and flattening of the tubular epithelium were observed. Deposits of IgG (3+), IgA (2+), IgM (3+), C3 (3+), C4d (+), and C1q (2+) were observed along the peripheral capillary walls on immunofluorescence. Electron microscopy showed humps under the epithelial cells and small amount of deposits under the endothelium and in the mesangial area. Nephritis-associated plasmin receptor (NAPlr) staining had positive results in 10 of 13 glomeruli, and plasmin activity was positive in 9 of 10 glomeruli.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eRegarding the cause of nephritis, the throat culture had negative results, and streptococcus was not detected. The anti-streptolysin-O antibody was mildly high at 422 (normal: \u0026lt;239) IU/mL. The parvovirus B19-IgM level was 0.91 (normal: \u0026lt;0.81). Using the particle agglutination method, the mycoplasma antibody level was 40 (\u0026lt;\u0026thinsp;40) times. Based on the complement fixation test, the antibody against adenovirus count was significantly high at 16 (\u0026lt;\u0026thinsp;4) times. According to the neutralization test, the type III antibody was significantly high at 16 (\u0026lt;\u0026thinsp;4) times. The patient also tested positive for antifactor B antibody, which indicated IRGN.\u003c/p\u003e \u003cp\u003eAfter admission, the patient received continuous hemodialysis for 5 days for acute kidney injury. After two courses of methylprednisolone pulse therapy (MPT) (30 mg/kg of methylprednisolone for 3 days in one course) and 2 mg/kg of oral prednisolone, the patient\u0026rsquo;s kidney function immediately recovered. However, nephrotic syndrome (1.5\u0026ndash;2.0 g/dL of serum albumin and 10\u0026ndash;50 g/g of urine protein creatinine ratio) persisted for \u0026gt;\u0026thinsp;1 month. The serum C3 and C4 levels normalized on day 24. Candesartan was started on day 43 and cyclosporine (CsA) on day 47. MPT was continued once a month, and 1 mg/kg of prednisolone was continued every other day. The patient\u0026rsquo;s proteinuria gradually decreased, and he achieved complete remission on day 107. Fourteen months after the onset, the patient achieved complete remission with normal urinalysis and kidney function.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eHerein, we report a 2-year-old boy with IRGN caused by human adenovirus Ⅲ. The patient met the five diagnostic criteria for IRGN that was proposed by Nasr SH [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. He also tested positive for the antifactor B antibody, which is related to IRGN [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. To the best of our knowledge, this is the first case report which showed antifactor B antibody positivity in IRGN caused by viral infection and adenovirus IRGN in which pathological evaluation was performed via kidney biopsy. As the patient\u0026rsquo;s anti-streptolysin-O antibody level was slightly elevated, the streptococcal infection could not be ruled out. However, the throat culture result was negative. Further, the low serum C4 level and C1q deposition in the glomeruli indicated the dominant activation of the classical pathways. These findings are not typical in patients with PSAGN in whom dominant activation of the alternative pathways is common.\u003c/p\u003e \u003cp\u003eNAPlr is the same substance as streptococcal gyceraldehyde-3-phosphate dehydrogenase (GAPDH). NAPlr, which is deposited in the glomeruli, binds to plasmin, maintains its activity, and causes inflammation in the basement membrane and mesangium by its proteolytic activity and by the activation and accumulation of macrophages and neutrophils [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Previously, NAPlr was believed to be specific to PSAGN. Nonetheless, in recent years, pneumococcal, staphylococci, and mycoplasma GAPDH has also been found to cross-react with anti-NAPlr (streptococcal GAPDH) antibody. NAPlr staining shows positivity for these IRGNs in the glomeruli. A recent study has reported an adult case of NAPlr-positive IRGN caused by parvovirus B19 [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Our case report first presented IRGN caused by adenovirus in which glomerular positive staining for NAPlr was confirmed histologically. Thus, NAPlr positivity could be observed in not only bacterial IRGN but also viral IRGN.\u003c/p\u003e \u003cp\u003eBecause IRGN usually resolves spontaneously, immunosuppressive therapy is not indicated. However, cases of severe kidney dysfunction or prolonged nephrotic syndrome or cases of crescentic glomerulonephritis usually require highly intense immunosuppressive treatment. The effect of immunosuppressive treatment for IRGN is not fully established. The combination of CsA and MPT was administered for refractory nephrotic syndrome in IRGN, and it successfully achieved complete remission. We believe that the combination of CsA and MPT might be an effective treatment option for the severe type of IRGN.\u003c/p\u003e \u003cp\u003eIn conclusion, we report a boy with a severe type of IRGN caused by human adenovirus Ⅲ. Immunofluorescence staining showed NAPlr positivity in the glomeruli. The combination of CsA and MPT was effective for prolonged nephrotic syndrome in IRGN, and the patient successfully achieved complete remission. In the future, large-scale studies should be performed to evaluate the role of NAPlr as a biomarker of virus-induced IRGN and the appropriate strategy for immunosuppressive treatment against severe IRGN.\u003c/p\u003e"},{"header":"Summary – What is new?","content":"\u003cp\u003eAdenovirus could cause IRGN with positive glomerular staining for NAPlr and plasmin activity. The combination of CsA and MPT might be effective for the severe type of IRGN.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eCompeting Interests:\u003c/h2\u003e\n\u003cp\u003eKoichi Kamei received research funding from the Public Foundation of Vaccination Research Center and the Taiju Life Social Welfare Foundation; donations from Chugai Pharmaceutical, Teijin Pharma, Kyowa Kirin, Taiho Pharmaceutical, Shionogi, Daiichi Sankyo, and Mitsubishi Tanabe Pharma; and lecture fees from Terumo. These fundings have no relationship with this work.\u003c/p\u003e\n\u003ch2\u003eConsent for publication:\u003c/h2\u003e\n\u003cp\u003eInformed consent was obtained from the parents.\u003c/p\u003e\n\u003ch2\u003eAuthor contributions:\u003c/h2\u003e\n\u003cp\u003eKoichi Kamei, who is the first author, prepared the manuscript. Tomoya Kaneda, Kentaro Nishi and Masao Ogura were involved in the management of the patient. Kentaro Ogata identified the kidney pathology. Takashi Oda performed the immunofluorescence staining for NAPlr and in situ zymography for plasmin activity and evaluated the serum antifactor B antibody. All authors contributed to the work and revised the manuscript.\u003c/p\u003e\n\u003ch2\u003eAcknowledgments:\u003c/h2\u003e\n\u003cp\u003eWe thank Enago for editing the draft of this manuscript. We also thank Dr. Toshihiro Sawai (Shiga University) for analyzing the complement pathways and editing the manuscript and Takako Yoshioka for identifying the kidney pathology.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGarty BZ, Amir A, Scheuerman O, Hoffer V, Marcus N (2009) Post-infectious glomerulonephritis associated with adenovirus infection. Isr Med Assoc J 11:758\u0026ndash;759.\u003c/li\u003e\n\u003cli\u003eNasr SH, Radhakrishnan J, D\u0026apos;Agati VD (2013) Bacterial infection-related glomerulonephritis in adults. Kidney Int 83:792\u0026ndash;803. https://doi.org/10.1038/ki.2012.407. \u003c/li\u003e\n\u003cli\u003eChauvet S, Berthaud R, Devriese M, Mignotet M, Vieira Martins P, Robe-Rybkine T, Miteva MA, Gyulkhandanyan A, Ryckewaert A, Louillet F, Merieau E, Mestrallet G, Rousset-Rouvi\u0026egrave;re C, Thervet E, Hogan J, Ulinski T, Villoutreix BO, Roumenina L, Boyer O, Fr\u0026eacute;meaux-Bacchi VJ (2020) Anti-factor B antibodies and acute postinfectious GN in children. J Am Soc Nephrol 31:829\u0026ndash;840. https://doi.org/10.1681/ASN.2019080851.\u003c/li\u003e\n\u003cli\u003eOda T, Yamakami K, Omasu F, Suzuki S, Miura S, Sugisaki T, Yoshizawa N (2005) Glomerular plasmin-like activity in relation to nephritis-associated plasmin receptor in acute poststreptococcal glomerulonephritis. J Am Soc Nephrol 16:247\u0026ndash;254. https://doi.org/10.1681/ASN.2004040341. \u003c/li\u003e\n\u003cli\u003eTakahashi H, Wada Y, Yamazaki T, Takeuchi K, Abe T, Naito S, Aoyama T, Sano T, Moriya R, Oda T, Takeuchi Y (2024) Parvovirus B19-related membranoproliferative glomerulonephritis presenting with positive glomerular staining for nephritis-associated plasmin receptor: a case report and review of the literature. CEN Case Rep. Dec 15. Online ahead of print. https://doi.org/10.1007/s13730-024-00956-1. \u003c/li\u003e\n\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":"Adenovirus, Cyclosporin, Infection-related glomerulonephritis, Methylprednisolone pulse therapy, Nephritis-associated plasmin receptor","lastPublishedDoi":"10.21203/rs.3.rs-6236033/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6236033/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eInfection-related glomerulonephritis (IRGN) caused by adenovirus is a rare condition, and there are no reports of kidney biopsy. Herein, we report a 2-year-old boy with IRGN caused by human adenovirus Ⅲ who required dialysis due to acute kidney injury and subsequently presented with persistent nephrotic syndrome. Kidney biopsy showed diffuse endocapillary proliferation with 30% cellular crescents. Histological staining showed positivity for nephritis-associated plasmin receptor (NAPlr) and plasmin activity in the glomeruli. The patient received cyclosporine and methylprednisolone pulse therapy once a month and 1 mg/kg of oral prednisolone every other day. Thereafter, he achieved complete remission. According to our case, NAPlr staining could be positive in IRGN caused by viral infections. The combination of cyclosporine and methylprednisolone pulse therapy might be effective for the severe type of IRGN.\u003c/p\u003e","manuscriptTitle":"Infection-related glomerulonephritis presenting as acute kidney injury and nephrotic syndrome caused by human adenovirus III successfully treated with cyclosporine and methylprednisolone pulse therapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-27 04:22:57","doi":"10.21203/rs.3.rs-6236033/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":"b9976d15-2afb-4f42-a9dd-ae75e9de48dc","owner":[],"postedDate":"March 27th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-04-21T12:38:46+00:00","versionOfRecord":[],"versionCreatedAt":"2025-03-27 04:22:57","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6236033","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6236033","identity":"rs-6236033","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}