{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T03:51:43Z","timestamp":1785210703463,"version":"3.55.0"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2020,12,24]],"date-time":"2020-12-24T00:00:00Z","timestamp":1608768000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP 19K17742"],"award-info":[{"award-number":["JP 19K17742"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,12,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The inability of enzyme replacement therapy (ERT) to prevent progression of Fabry nephropathy (FN) in the presence of &amp;gt;1\u2009g\/day proteinuria underscores the necessity of identifying effective biomarkers for early diagnosis of FN preceding proteinuria. Here we attempted to identify biomarkers for early detection of FN.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Fifty-one Fabry disease (FD) patients were enrolled. Urinary mulberry bodies (uMBs) were immunostained for globotriaosylceramide (Gb3) and renal cell markers to determine their origin. The association between semiquantitative uMB excretion and the histological severity of podocyte vacuolation was investigated in seven patients using the vacuolated podocyte:glomerular average area ratio. The association between the semiquantitative estimate of uMB excretion and duration of ERT was analyzed. A longitudinal study was conducted to assess the effect of ERT on uMB excretion.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Thirty-two patients (63%) had uMBs, while only 31% showed proteinuria. The uMBs were positive for Gb3, lysosomal-associated membrane protein 1 and podocalyxin, suggesting they were derived from lysosomes with Gb3 accumulation in podocytes. We observed more severe podocyte vacuolation with increased uMB excretion (P\u2009=\u20090.03 for trend); however, the same was not observed with increased proteinuria. The percentage of patients with substantial uMB excretion increased with shorter ERT duration (P\u2009=\u20090.018). Eighteen-month-long ERT reduced uMB excretion (P\u2009=\u20090.03) without affecting proteinuria.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>uMB excretion, implying ongoing podocyte injury, preceded proteinuria in most patients. Semiquantitative uMB estimates can serve as novel biomarkers for early FN diagnosis and for monitoring the efficacy of FD-specific therapies.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/ndt\/gfaa298","type":"journal-article","created":{"date-parts":[[2020,10,29]],"date-time":"2020-10-29T12:10:01Z","timestamp":1603973401000},"page":"53-62","source":"Crossref","is-referenced-by-count":12,"title":["Urinary mulberry bodies as a potential biomarker for early diagnosis and efficacy assessment of enzyme replacement therapy in Fabry nephropathy"],"prefix":"10.1093","volume":"37","author":[{"given":"Hiroaki","family":"Yonishi","sequence":"first","affiliation":[{"name":"Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoko","family":"Namba-Hamano","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Hamano","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Hotta","sequence":"additional","affiliation":[{"name":"Laboratory for Clinical Investigation, Osaka University Hospital, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinsuke","family":"Sakai","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Minami","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wataru","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Laboratory for Clinical Investigation, Osaka University Hospital, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ikuhiro","family":"Maeda","sequence":"additional","affiliation":[{"name":"Laboratory for Clinical Investigation, Osaka University Hospital, Osaka, Japan"},{"name":"Department of Medical Technology, Osaka University Hospital, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoh","family":"Hidaka","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Osaka University Graduate School of Medicine, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshitsugu","family":"Takabatake","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norio","family":"Sakai","sequence":"additional","affiliation":[{"name":"Division of Health Sciences, Child Healthcare and Genetic Science Laboratory, Osaka University Graduate School of Medicine, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshitaka","family":"Isaka","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,12,24]]},"reference":[{"key":"2021123116175777000_gfaa298-B1","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1136\/hrt.68.9.323","article-title":"Fabry\u2019s disease with complete atrioventricular block: histological evidence of involvement of the conduction system","volume":"68","author":"Ikari","year":"1992","journal-title":"Br Heart J"},{"key":"2021123116175777000_gfaa298-B2","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1016\/j.amjcard.2005.05.033","article-title":"Prevalence and clinical significance of cardiac arrhythmia in Anderson-Fabry disease","volume":"96","author":"Shah","year":"2005","journal-title":"Am J Cardiol"},{"key":"2021123116175777000_gfaa298-B3","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.amjcard.2006.07.088","article-title":"Significance of asymmetric basal posterior wall thinning in patients with cardiac Fabry\u2019s disease","volume":"99","author":"Kawano","year":"2007","journal-title":"Am J Cardiol"},{"key":"2021123116175777000_gfaa298-B4","doi-asserted-by":"crossref","first-page":"S139","DOI":"10.1097\/01.ASN.0000016683.73778.78","article-title":"Natural history and treatment of renal involvement in Fabry disease","volume":"13(Suppl 2","author":"Branton","year":"2002","journal-title":"J Am Soc Nephrol"},{"key":"2021123116175777000_gfaa298-B5","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/ana.410400105","article-title":"Cerebrovascular complications of Fabry\u2019s disease","volume":"40","author":"Mitsias","year":"1996","journal-title":"Ann Neurol"},{"key":"2021123116175777000_gfaa298-B6","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1056\/NEJM200107053450102","article-title":"Safety and efficacy of recombinant human alpha-galactosidase A replacement therapy in Fabry\u2019s disease","volume":"345","author":"Eng","year":"2001","journal-title":"N Engl J Med"},{"key":"2021123116175777000_gfaa298-B7","doi-asserted-by":"crossref","first-page":"2743","DOI":"10.1001\/jama.285.21.2743","article-title":"Enzyme replacement therapy in Fabry disease: a randomized controlled trial","volume":"285","author":"Schiffmann","year":"2001","journal-title":"JAMA"},{"key":"2021123116175777000_gfaa298-B8","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1056\/NEJMoa1510198","article-title":"Treatment of Fabry\u2019s disease with the pharmacologic chaperone migalastat","volume":"375","author":"Germain","year":"2016","journal-title":"N Engl J Med"},{"key":"2021123116175777000_gfaa298-B9","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1590\/S1415-47572012000600009","article-title":"Enzyme replacement therapy for Fabry disease: a systematic review and meta-analysis","volume":"35","author":"Alegra","year":"2012","journal-title":"Genet Mol Biol"},{"key":"2021123116175777000_gfaa298-B10","doi-asserted-by":"crossref","first-page":"e598","DOI":"10.1371\/journal.pone.0000598","article-title":"Treatment of Fabry disease: outcome of a comparative trial with agalsidase alfa or beta at a dose of 0.2 mg\/kg","volume":"2","author":"Vedder","year":"2007","journal-title":"PLoS One"},{"key":"2021123116175777000_gfaa298-B11","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/j.ymgme.2018.02.014","article-title":"Fabry disease revisited: management and treatment recommendations for adult patients","volume":"123","author":"Ortiz","year":"2018","journal-title":"Mol Genet Metab"},{"key":"2021123116175777000_gfaa298-B12","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.ymgme.2018.06.004","article-title":"European expert consensus statement on therapeutic goals in Fabry disease","volume":"124","author":"Wanner","year":"2018","journal-title":"Mol Genet Metab"},{"key":"2021123116175777000_gfaa298-B13","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s13023-015-0253-6","article-title":"Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: the European Fabry Working Group consensus document","volume":"10","author":"Biegstraaten","year":"2015","journal-title":"Orphanet J Rare Dis"},{"key":"2021123116175777000_gfaa298-B14","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1136\/jmedgenet-2014-102797","article-title":"Ten-year outcome of enzyme replacement therapy with agalsidase beta in patients with Fabry disease","volume":"52","author":"Germain","year":"2015","journal-title":"J Med Genet"},{"key":"2021123116175777000_gfaa298-B15","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1161\/CIRCULATIONAHA.108.794529","article-title":"Long-term effects of enzyme replacement therapy on Fabry cardiomyopathy: evidence for a better outcome with early treatment","volume":"119","author":"Weidemann","year":"2009","journal-title":"Circulation"},{"key":"2021123116175777000_gfaa298-B16","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1681\/ASN.2008080870","article-title":"Agalsidase alfa and kidney dysfunction in Fabry disease","volume":"20","author":"West","year":"2009","journal-title":"J Am Soc Nephrol"},{"key":"2021123116175777000_gfaa298-B17","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1681\/ASN.2006080816","article-title":"Sustained, long-term renal stabilization after 54 months of agalsidase beta therapy in patients with Fabry disease","volume":"18","author":"Germain","year":"2007","journal-title":"J Am Soc Nephrol"},{"key":"2021123116175777000_gfaa298-B18","doi-asserted-by":"crossref","first-page":"77","DOI":"10.7326\/0003-4819-146-2-200701160-00148","article-title":"Agalsidase-beta therapy for advanced Fabry disease: a randomized trial","volume":"146","author":"Banikazemi","year":"2007","journal-title":"Ann Intern Med"},{"key":"2021123116175777000_gfaa298-B19","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1159\/000369309","article-title":"Foot process effacement is an early marker of nephropathy in young classic Fabry patients without albuminuria","volume":"129","author":"Tondel","year":"2015","journal-title":"Nephron"},{"key":"2021123116175777000_gfaa298-B20","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1001\/jama.1977.03270380065023","article-title":"Urinary ultrastructural findings in Fabry disease","volume":"237","author":"Katz","year":"1977","journal-title":"JAMA"},{"key":"2021123116175777000_gfaa298-B21","doi-asserted-by":"crossref","first-page":"123","DOI":"10.3109\/01913128309141831","article-title":"Myelin bodies in urine sediment in hemizygotes with Anderson-Fabry disease","volume":"5","author":"Wenk","year":"1983","journal-title":"Ultrastruct Pathol"},{"key":"2021123116175777000_gfaa298-B22","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1111\/j.1346-8138.1985.tb01540.x","article-title":"Concentric lamellar spheres in urine from a female carrier of and patients with Fabry\u2019s disease\u2013with special reference to polarization and electron microscopic comparison with nephrotic syndrome","volume":"12","author":"Nagao","year":"1985","journal-title":"J Dermatol"},{"key":"2021123116175777000_gfaa298-B23","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1053\/j.ajkd.2007.11.039","article-title":"Urinalysis: core curriculum 2008","volume":"51","author":"Fogazzi","year":"2008","journal-title":"Am J Kidney Dis"},{"key":"2021123116175777000_gfaa298-B24","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/s13730-012-0038-x","article-title":"Fabry\u2019s disease discovered with chance urinary mulberry cells: a case report","volume":"2","author":"Nakamichi","year":"2013","journal-title":"CEN Case Rep"},{"key":"2021123116175777000_gfaa298-B25","doi-asserted-by":"crossref","first-page":"2903","DOI":"10.2169\/internalmedicine.55.7084","article-title":"Fabry disease diagnosed based on the detection of urinary mulberry bodies","volume":"55","author":"Honda","year":"2016","journal-title":"Intern Med"},{"key":"2021123116175777000_gfaa298-B26","doi-asserted-by":"crossref","first-page":"e004538","DOI":"10.1161\/CIRCHEARTFAILURE.117.004538","article-title":"Detection of urinary mulberry bodies leads to diagnosis of Fabry cardiomyopathy: a simple clue in the urine sediment","volume":"10","author":"Yano","year":"2017","journal-title":"Circ Heart Fail"},{"key":"2021123116175777000_gfaa298-B27","doi-asserted-by":"crossref","first-page":"3385","DOI":"10.2169\/internalmedicine.1177-18","article-title":"A cardiac variant of Fabry disease diagnosed with chance urinary mulberry cells","volume":"57","author":"Onishi","year":"2018","journal-title":"Intern Med"},{"key":"2021123116175777000_gfaa298-B28","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1006\/abbi.1994.1144","article-title":"Generation of one set murine monoclonal antibodies specific for globo-series glycolipids: evidence for differential distribution of the glycolipids in rat small intestine","volume":"310","author":"Kotani","year":"1994","journal-title":"Arch Biochem Biophys"},{"key":"2021123116175777000_gfaa298-B29","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/s10038-006-0369-6","article-title":"Corrective effect on Fabry mice of yeast recombinant human alpha-galactosidase with N-linked sugar chains suitable for lysosomal delivery","volume":"51","author":"Sakuraba","year":"2006","journal-title":"J Hum Genet"},{"key":"2021123116175777000_gfaa298-B30","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1515\/jtim-2015-0003","article-title":"Podocyturia: what is in a name?","volume":"3","author":"Trimarchi","year":"2015","journal-title":"J Transl Int Med"},{"key":"2021123116175777000_gfaa298-B31","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1007\/s40620-016-0271-z","article-title":"Podocyturia is significantly elevated in untreated vs. treated Fabry adult patients","volume":"29","author":"Trimarchi","year":"2016","journal-title":"J Nephrol"},{"key":"2021123116175777000_gfaa298-B32","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1038\/sj.ki.5002222","article-title":"The spectrum of podocytopathies: a unifying view of glomerular diseases","volume":"71","author":"Wiggins","year":"2007","journal-title":"Kidney Int"},{"key":"2021123116175777000_gfaa298-B33","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.7326\/0003-4819-63-6-1059","article-title":"Fabry\u2019s disease (angiokeratoma corporis diffusum): case report on a rare disease","volume":"63","author":"Dempsey","year":"1965","journal-title":"Ann Intern Med"},{"key":"2021123116175777000_gfaa298-B34","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1001\/archderm.1965.01600090014003","article-title":"Angiokeratoma corporis diffusum (Fabry\u2019s disease)","volume":"91","author":"Vongemmingen","year":"1965","journal-title":"Arch Dermatol"},{"key":"2021123116175777000_gfaa298-B35","doi-asserted-by":"crossref","first-page":"3195","DOI":"10.1093\/ndt\/gfr084","article-title":"Targeted urine microscopy in Anderson-Fabry disease: a cheap, sensitive and specific diagnostic technique","volume":"26","author":"Selvarajah","year":"2011","journal-title":"Nephrol Dial Transplant"},{"key":"2021123116175777000_gfaa298-B36","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1053\/ajkd.2001.26826","article-title":"Clinical features and genotype of adenine phosphoribosyltransferase deficiency in iceland","volume":"38","author":"Edvardsson","year":"2001","journal-title":"Am J Kidney Dis"},{"key":"2021123116175777000_gfaa298-B37","doi-asserted-by":"crossref","first-page":"3359","DOI":"10.1093\/ndt\/gfm479","article-title":"A urine finding in obese patients","volume":"22","author":"Verdesca","year":"2007","journal-title":"Nephrol Dial Transplant"},{"key":"2021123116175777000_gfaa298-B38","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.ymgme.2017.07.002","article-title":"Genotype, phenotype and disease severity reflected by serum lysoGb3 levels in patients with Fabry disease","volume":"123","author":"Nowak","year":"2018","journal-title":"Mol Genet Metab"},{"key":"2021123116175777000_gfaa298-B39","doi-asserted-by":"crossref","first-page":"2812","DOI":"10.1073\/pnas.0712309105","article-title":"Elevated globotriaosylsphingosine is a hallmark of Fabry disease","volume":"105","author":"Aerts","year":"2008","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021123116175777000_gfaa298-B40","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.bbadis.2010.09.007","article-title":"Reduction of elevated plasma globotriaosylsphingosine in patients with classic Fabry disease following enzyme replacement therapy","volume":"1812","author":"van Breemen","year":"2011","journal-title":"Biochim Biophys Acta"},{"key":"2021123116175777000_gfaa298-B41","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1681\/ASN.2012030316","article-title":"Agalsidase benefits renal histology in young patients with Fabry disease","volume":"24","author":"T\u00f8ndel","year":"2013","journal-title":"J Am Soc Nephrol"},{"key":"2021123116175777000_gfaa298-B42","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1136\/jmedgenet-2015-103471","article-title":"Antiproteinuric therapy and Fabry nephropathy: factors associated with preserved kidney function during agalsidase-beta therapy","volume":"52","author":"Warnock","year":"2015","journal-title":"J Med Genet"},{"key":"2021123116175777000_gfaa298-B43","doi-asserted-by":"crossref","first-page":"1933","DOI":"10.1046\/j.1523-1755.2002.00675.x","article-title":"Globotriaosylceramide accumulation in the Fabry kidney is cleared from multiple cell types after enzyme replacement therapy","volume":"62","author":"Thurberg","year":"2002","journal-title":"Kidney Int"},{"key":"2021123116175777000_gfaa298-B44","doi-asserted-by":"crossref","first-page":"2168","DOI":"10.1093\/ndt\/gfp528","article-title":"Scoring system for renal pathology in Fabry disease: report of the International Study Group of Fabry Nephropathy (ISGFN)","volume":"25","author":"Fogo","year":"2010","journal-title":"Nephrol Dial Transplant"},{"key":"2021123116175777000_gfaa298-B45","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1136\/jmedgenet-2017-104826","article-title":"Reduction of podocyte globotriaosylceramide content in adult male patients with Fabry disease with amenable GLA mutations following 6 months of migalastat treatment","volume":"54","author":"Mauer","year":"2017","journal-title":"J Med Genet"}],"container-title":["Nephrology Dialysis Transplantation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ndt\/article-pdf\/37\/1\/53\/41998888\/gfaa298.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ndt\/article-pdf\/37\/1\/53\/41998888\/gfaa298.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,31]],"date-time":"2021-12-31T16:18:55Z","timestamp":1640967535000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ndt\/article\/37\/1\/53\/6046594"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,24]]},"references-count":45,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12,24]]},"published-print":{"date-parts":[[2021,12,31]]}},"URL":"https:\/\/doi.org\/10.1093\/ndt\/gfaa298","relation":{},"ISSN":["0931-0509","1460-2385"],"issn-type":[{"value":"0931-0509","type":"print"},{"value":"1460-2385","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,1]]},"published":{"date-parts":[[2020,12,24]]}}}