{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T14:08:19Z","timestamp":1791209299728,"version":"4.1.0"},"reference-count":58,"publisher":"Archives of Pathology and Laboratory Medicine","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Context.\u2014Alport syndrome and thin glomerular basement membrane nephropathy (TBMN) are genetically heterogenous conditions characterized by structural abnormalities in the glomerular basement membrane and an initial presentation that usually involves hematuria. Approximately 40% of patients with TBMN are heterozygous carriers for autosomal recessive Alport syndrome, with mutations at the genetic locus encoding type IV collagen \u03b13 [\u03b13(IV)] and \u03b14 chains. However, although the clinical course of TBMN is usually benign, Alport syndrome, particularly the X-linked form with mutations in the locus encoding the \u03b15 chain of type IV collagen [\u03b15(IV)], typically results in end-stage renal disease. Electron microscopy is essential to diagnosis of TBMN and Alport syndrome on renal biopsy, although electron microscopy alone is of limited value in distinguishing between TBMN, the heterozygous carrier state of X-linked Alport syndrome, autosomal recessive Alport syndrome, and even early stages of X-linked Alport syndrome.<\/jats:p>\n                  <jats:p>Objectives.\u2014To review diagnostic pathologic features of each of the above conditions, emphasizing the need for immunohistology for \u03b13(IV) and \u03b15(IV) in addition to electron microscopy to resolve this differential diagnosis on a renal biopsy. The diagnostic value of immunofluorescence studies for \u03b15(IV) on a skin biopsy in family members of patients with Alport syndrome also is reviewed.<\/jats:p>\n                  <jats:p>Data Sources.\u2014Original and comprehensive review articles on the diagnosis of Alport syndrome and TBMN from the past 35 years, primarily the past 2 decades, and experience in our own renal pathology laboratory.<\/jats:p>\n                  <jats:p>Conclusions.\u2014Although Alport syndrome variants and TBMN do not show characteristic light microscopic findings and can be difficult to differentiate from each other even by electron microscopy, using a combination of electron microscopy and immunohistology for \u03b13(IV) and \u03b15(IV) enables pathologists to definitively diagnose these disorders on renal biopsy in most cases.<\/jats:p>","DOI":"10.5858\/133.2.224","type":"journal-article","created":{"date-parts":[[2021,2,12]],"date-time":"2021-02-12T09:21:54Z","timestamp":1613121714000},"page":"224-232","source":"Crossref","is-referenced-by-count":93,"title":["Alport Syndrome and Thin Glomerular Basement Membrane Nephropathy: A Practical Approach to Diagnosis"],"prefix":"10.5858","volume":"133","author":[{"given":"Mark","family":"Haas","sequence":"first","affiliation":[{"name":"From the Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Md"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"3906","reference":[{"key":"2021021102114801300_i1543-2165-133-2-224-b1","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/0002-9343(81)90571-4","article-title":"Alport's syndrome: a report of 58 cases and a review of the literature.","volume":"70","author":"Gubler","year":"1981","journal-title":"Am J Med"},{"key":"2021021102114801300_i1543-2165-133-2-224-b2","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1038\/ki.1985.63","article-title":"Genetic heterogeneity of Alport syndrome.","volume":"27","author":"Feingold","year":"1985","journal-title":"Kidney Int"},{"key":"2021021102114801300_i1543-2165-133-2-224-b3","first-page":"940","article-title":"Genetic heterogeneity among kindreds with Alport syndrome.","volume":"38","author":"Hasstedt","year":"1986","journal-title":"Am J Human Genet"},{"key":"2021021102114801300_i1543-2165-133-2-224-b4","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1038\/ki.1996.459","article-title":"Alport syndrome.","volume":"50","author":"Kashtan","year":"1996","journal-title":"Kidney Int"},{"key":"2021021102114801300_i1543-2165-133-2-224-b5","first-page":"73","article-title":"Alport syndrome: clinical update.","volume":"6","author":"Wester","year":"1995","journal-title":"J Am Acad Audiol"},{"key":"2021021102114801300_i1543-2165-133-2-224-b6","first-page":"1527","article-title":"Alport's syndrome: case report and review of ocular manifestations.","volume":"9","author":"Chance","year":"1977","journal-title":"Ann Ophthalmol"},{"key":"2021021102114801300_i1543-2165-133-2-224-b7","first-page":"518","article-title":"Lenticonus anterior and Alport's syndrome.","volume":"56","author":"Nielsen","year":"1978","journal-title":"Arch Ophthalmol"},{"key":"2021021102114801300_i1543-2165-133-2-224-b8","doi-asserted-by":"crossref","first-page":"2543","DOI":"10.1056\/NEJMra022296","article-title":"Alport's syndrome, Goodpasture's syndrome, and type IV collagen.","volume":"348","author":"Hudson","year":"2003","journal-title":"N Engl J Med"},{"key":"2021021102114801300_i1543-2165-133-2-224-b9","doi-asserted-by":"crossref","first-page":"1736","DOI":"10.1681\/ASN.V991736","article-title":"Alport syndrome and thin glomerular basement membrane disease.","volume":"9","author":"Kashtan","year":"1998","journal-title":"J Am Soc Nephrol"},{"key":"2021021102114801300_i1543-2165-133-2-224-b10","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/S0046-8177(98)90123-X","article-title":"X-Linked Alport syndrome in females.","volume":"29","author":"Meleg-Smith","year":"1998","journal-title":"Hum Pathol"},{"key":"2021021102114801300_i1543-2165-133-2-224-b11","article-title":"Alport's syndrome, thin basement membrane nephropathy, nail-patella syndrome, and type III collagen glomerulopathy.","author":"Gubler"},{"key":"2021021102114801300_i1543-2165-133-2-224-b12","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1093\/hmg\/3.8.1269","article-title":"Mutations in the type IV collagen \u03b13 (COL4A3) gene in autosomal recessive Alport syndrome.","volume":"3","author":"Lemmink","year":"1994","journal-title":"Hum Mol Genet"},{"key":"2021021102114801300_i1543-2165-133-2-224-b13","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1038\/ng0994-77","article-title":"Identification of mutations in the \u03b13(IV) and \u03b14(IV) collagen genes in autosomal recessive Alport syndrome.","volume":"8","author":"Mochizuki","year":"1994","journal-title":"Nat Genet"},{"key":"2021021102114801300_i1543-2165-133-2-224-b14","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1681\/ASN.V12197","article-title":"Structure of the human type IV collagen gene COL4A3 and mutations in autosomal Alport syndrome.","volume":"12","author":"Heidet","year":"2001","journal-title":"J Am Soc Nephrol"},{"key":"2021021102114801300_i1543-2165-133-2-224-b15","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1093\/ndt\/12.8.1595","article-title":"Autosomal dominant Alport syndrome linked to the type IV collagen \u03b13 and \u03b14 genes (COL4A3 and COL4A4).","volume":"12","author":"Jefferson","year":"1997","journal-title":"Nephrol Dial Transplant"},{"key":"2021021102114801300_i1543-2165-133-2-224-b16","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.1093\/ndt\/16.10.2008","article-title":"Identification of a new mutation in the \u03b14(IV) collagen gene in a family with autosomal dominant Alport syndrome and hypercholesterolemia.","volume":"16","author":"Ciccarese","year":"2001","journal-title":"Nephrol Dial Transplant"},{"key":"2021021102114801300_i1543-2165-133-2-224-b17","doi-asserted-by":"crossref","first-page":"1870","DOI":"10.1111\/j.1523-1755.2000.00358.x","article-title":"Autosomal dominant Alport syndrome caused by a COL4A3 splice site mutation.","volume":"58","author":"van der Loop","year":"2000","journal-title":"Kidney Int"},{"key":"2021021102114801300_i1543-2165-133-2-224-b18","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1053\/ajkd.2001.29217","article-title":"A comparison of the clinical, histopathologic, and ultrastructural phenotypes in carriers of X-linked and autosomal recessive Alport's syndrome.","volume":"38","author":"Dagher","year":"2001","journal-title":"Am J Kidney Dis"},{"key":"2021021102114801300_i1543-2165-133-2-224-b19","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1053\/hupa.2002.125374","article-title":"Histopathology, ultrastructure, and clinical phenotypes in thin glomerular basement membrane disease variants.","volume":"33","author":"Liapis","year":"2002","journal-title":"Hum Pathol"},{"key":"2021021102114801300_i1543-2165-133-2-224-b20","doi-asserted-by":"crossref","first-page":"1596","DOI":"10.1038\/ki.1997.219","article-title":"Thin GBM nephropathy: premature glomerular obsolescence is associated with hypertension and late onset renal failure.","volume":"51","author":"Nieuwhof","year":"1997","journal-title":"Kidney Int"},{"key":"2021021102114801300_i1543-2165-133-2-224-b21","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1172\/JCI118893","article-title":"Benign familial hematuria due to mutation of the type IV collagen \u03b14 gene.","volume":"98","author":"Lemmink","year":"1996","journal-title":"J Clin Invest"},{"key":"2021021102114801300_i1543-2165-133-2-224-b22","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1046\/j.1523-1755.2001.060002480.x","article-title":"COL4A4 mutation in thin glomerular basement membrane disease previously described in Alport syndrome.","volume":"60","author":"Buzza","year":"2001","journal-title":"Kidney Int"},{"key":"2021021102114801300_i1543-2165-133-2-224-b23","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1046\/j.1523-1755.2003.00234.x","article-title":"Thin basement membrane nephropathy.","volume":"64","author":"Savage","year":"2003","journal-title":"Kidney Int"},{"key":"2021021102114801300_i1543-2165-133-2-224-b24","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1159\/000013499","article-title":"Evidence for genetic heterogeneity in benign familial hematuria.","volume":"19","author":"Piccini","year":"1999","journal-title":"Am J Nephrol"},{"key":"2021021102114801300_i1543-2165-133-2-224-b25","doi-asserted-by":"crossref","first-page":"3004","DOI":"10.1681\/ASN.2007040444","article-title":"COLA3\/COLA4 mutations producing focal segmental glomerulosclerosis and renal failure in thin basement membrane nephropathy.","volume":"18","author":"Voskarides","year":"2007","journal-title":"J Am Soc Nephrol"},{"key":"2021021102114801300_i1543-2165-133-2-224-b26","doi-asserted-by":"crossref","first-page":"699","DOI":"10.5858\/2006-130-699-TGBMNI","article-title":"Thin glomerular basement membrane nephropathy: incidence in 3471 consecutive renal biopsies examined by electron microscopy.","volume":"130","author":"Haas","year":"2006","journal-title":"Arch Pathol Lab Med"},{"key":"2021021102114801300_i1543-2165-133-2-224-b27","first-page":"43","article-title":"Measurement of glomerular basement membrane thickness and its application to the diagnosis of thin-membrane nephropathy.","volume":"116","author":"Dische","year":"1992","journal-title":"Arch Pathol Lab Med"},{"key":"2021021102114801300_i1543-2165-133-2-224-b28","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1038\/ki.1982.82","article-title":"Development of glomerular lesions in experimental long-term diabetes in the rat.","volume":"21","author":"Hirose","year":"1982","journal-title":"Kidney Int"},{"key":"2021021102114801300_i1543-2165-133-2-224-b29","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1056\/NEJM198901053200103","article-title":"Thin-basement-membrane nephropathy in adults with persistent hematuria.","volume":"320","author":"Tiebosch","year":"1989","journal-title":"N Engl J Med"},{"key":"2021021102114801300_i1543-2165-133-2-224-b30","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1093\/oxfordjournals.ndt.a092104","article-title":"Glomerular basement membrane thinning in adults: clinicopathological correlations of a new diagnostic approach.","volume":"7","author":"McLay","year":"1992","journal-title":"Nephrol Dial Transplant"},{"key":"2021021102114801300_i1543-2165-133-2-224-b31","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1093\/ndt\/11.7.1256","article-title":"Glomerular basement membrane thickness\u2014a comparison of two methods of measurement in patients with unexplained hematuria.","volume":"11","author":"Das","year":"1996","journal-title":"Nephrol Dial Transplant"},{"key":"2021021102114801300_i1543-2165-133-2-224-b32","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1136\/jcp.40.3.318","article-title":"Thin basement membrane syndrome in adults.","volume":"40","author":"Abe","year":"1987","journal-title":"J Clin Pathol"},{"key":"2021021102114801300_i1543-2165-133-2-224-b33","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.semnephrol.2005.01.006","article-title":"Pathology of thin basement membrane nephropathy.","volume":"25","author":"Foster","year":"2005","journal-title":"Semin Nephrol"},{"key":"2021021102114801300_i1543-2165-133-2-224-b34","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1093\/oxfordjournals.ndt.a027334","article-title":"New subgroup of primary IgA nephritis with thin glomerular basement membrane (GBM): syndrome or association.","volume":"11","author":"Berthoux","year":"1996","journal-title":"Nephrol Dial Transplant"},{"key":"2021021102114801300_i1543-2165-133-2-224-b35","doi-asserted-by":"crossref","first-page":"17","DOI":"10.3109\/01913128809048473","article-title":"Ultrastructural changes of glomerular basement membrane in IgA nephritis: relationship to hematuria.","volume":"12","author":"Taguchi","year":"1988","journal-title":"Ultrastruct Pathol"},{"key":"2021021102114801300_i1543-2165-133-2-224-b36","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/S0272-6386(12)70217-2","article-title":"An overview of renal pathology in insulin-dependent diabetes mellitus in relationship to altered glomerular hemodynamics.","volume":"20","author":"Fioretto","year":"1992","journal-title":"Am J Kidney Dis"},{"key":"2021021102114801300_i1543-2165-133-2-224-b37","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1007\/BF00862588","article-title":"Glomerular basement membrane thickness in children: a morphometric study.","volume":"2","author":"Morita","year":"1988","journal-title":"Pediatr Nephrol"},{"key":"2021021102114801300_i1543-2165-133-2-224-b38","doi-asserted-by":"crossref","first-page":"527","DOI":"10.3109\/15513818709161416","article-title":"Glomerular basement membrane and lamina densa in infants and children: an ultrastructural evaluation.","volume":"7","author":"Vogler","year":"1987","journal-title":"Pediatr Pathol"},{"key":"2021021102114801300_i1543-2165-133-2-224-b39","first-page":"794","article-title":"Benign familial hematuria.","volume":"112","author":"Yoshikawa","year":"1988","journal-title":"Arch Pathol Lab Med"},{"key":"2021021102114801300_i1543-2165-133-2-224-b40","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1159\/000418643","article-title":"Significance of thin glomerular basement membranes in hematuric children.","volume":"80","author":"Gubler","year":"1990","journal-title":"Contrib Nephrol"},{"key":"2021021102114801300_i1543-2165-133-2-224-b41","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1038\/ki.1994.296","article-title":"Association of thin glomerular basement membrane with other glomerulopathies.","volume":"46","author":"Cosio","year":"1994","journal-title":"Kidney Int"},{"key":"2021021102114801300_i1543-2165-133-2-224-b42","doi-asserted-by":"crossref","first-page":"E15","DOI":"10.1016\/S0272-6386(00)70033-3","article-title":"Thin basement membrane disease with heavy proteinuria or nephrotic syndrome at presentation.","volume":"35","author":"Nogueira","year":"2000","journal-title":"Am J Kidney Dis"},{"key":"2021021102114801300_i1543-2165-133-2-224-b43","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1111\/j.1523-1755.2004.00835.x","article-title":"Signs and symptoms of thin basement membrane nephropathy: a prospective regional study on primary glomerular disease\u2014the Limburg Renal Registry.","volume":"66","author":"van Paassen","year":"2004","journal-title":"Kidney Int"},{"key":"2021021102114801300_i1543-2165-133-2-224-b44","doi-asserted-by":"crossref","first-page":"324","DOI":"10.3109\/00313028409068545","article-title":"Peripheral glomerular capillary wall lesions in IgA nephropathy and their implications.","volume":"16","author":"Ng","year":"1984","journal-title":"Pathology"},{"key":"2021021102114801300_i1543-2165-133-2-224-b45","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1002\/path.1711500206","article-title":"Lysis of the glomerular basement membrane in children with IgA nephropathy and Henoch-Shonlein nephritis.","volume":"150","author":"Yoshikawa","year":"1986","journal-title":"J Pathol"},{"key":"2021021102114801300_i1543-2165-133-2-224-b46","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/0002-9343(81)90571-4","article-title":"Alport's syndrome: a report of 58 cases and a review of the literature.","volume":"70","author":"Gubler","year":"1981","journal-title":"Am J Med"},{"key":"2021021102114801300_i1543-2165-133-2-224-b47","first-page":"506","article-title":"Renal pathology in hereditary nephritis with nerve deafness.","volume":"82","author":"Krickstein","year":"1966","journal-title":"Arch Pathol"},{"key":"2021021102114801300_i1543-2165-133-2-224-b48","first-page":"172","article-title":"Familial hematuria: clinico-pathological correlations.","volume":"17","author":"Yoshikawa","year":"1982","journal-title":"Clin Nephrol"},{"key":"2021021102114801300_i1543-2165-133-2-224-b49","first-page":"473","article-title":"Characteristic ultrastructural lesion of the glomerular basement membrane in progressive hereditary nephritis (Alport's syndrome).","volume":"27","author":"Hinglais","year":"1972","journal-title":"Lab Invest"},{"key":"2021021102114801300_i1543-2165-133-2-224-b50","first-page":"203","article-title":"Hereditary nephropathy (Alport syndrome): correlation of clinical data with glomerular basement membrane alterations.","volume":"13","author":"Rumpelt","year":"1980","journal-title":"Clin Nephrol"},{"key":"2021021102114801300_i1543-2165-133-2-224-b51","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1681\/ASN.V961023","article-title":"Ultrastructural and immunohistochemical findings in Alport's syndrome: a study of 108 patients from 97 Italian families with particular emphasis on COL4A5 gene mutation correlations.","volume":"9","author":"Mazzucco","year":"1998","journal-title":"J Am Soc Nephrol"},{"key":"2021021102114801300_i1543-2165-133-2-224-b52","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1097\/00000478-199904000-00008","article-title":"Diffuse glomerular basement membrane lamellation in renal allografts from pediatric donors to adult recipients.","volume":"23","author":"Nadasdy","year":"1999","journal-title":"Am J Surg Pathol"},{"key":"2021021102114801300_i1543-2165-133-2-224-b53","first-page":"516","article-title":"The nonspecificity of the ultrastructural alterations in hereditary nephritis with additional observations on benign familial hematuria.","volume":"31","author":"Hill","year":"1974","journal-title":"Lab Invest"},{"key":"2021021102114801300_i1543-2165-133-2-224-b54","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1038\/ki.1994.413","article-title":"Immunohistochemical study of alpha 1-5 chains of type IV collagen in hereditary nephritis.","volume":"46","author":"Nakanishi","year":"1994","journal-title":"Kidney Int"},{"key":"2021021102114801300_i1543-2165-133-2-224-b55","first-page":"986","article-title":"Type IV collagen \u03b15 chain: normal distribution and abnormalities in X-linked Alport syndrome revealed by monoclonal antibody.","volume":"144","author":"Yoshioka","year":"1994","journal-title":"Am J Pathol"},{"key":"2021021102114801300_i1543-2165-133-2-224-b56","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1046\/j.1523-1755.1999.00357.x","article-title":"Identification of COL4A5 defects in Alport's syndrome by immunohistochemistry of skin.","volume":"55","author":"van der Loop","year":"1999","journal-title":"Kidney Int"},{"key":"2021021102114801300_i1543-2165-133-2-224-b57","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1038\/sj.ki.5002365","article-title":"Collagen \u03b15 and \u03b12(IV) chain coexpression: analysis of skin biopsies of Alport patients.","volume":"72","author":"Patey-Mariaud de Serre","year":"2007","journal-title":"Kidney Int"},{"key":"2021021102114801300_i1543-2165-133-2-224-b58","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1038\/ki.1995.163","article-title":"Autosomal recessive Alport syndrome: immunohistochemical study of type IV collagen chain distribution.","volume":"47","author":"Gubler","year":"1995","journal-title":"Kidney Int"}],"container-title":["Archives of Pathology &amp; Laboratory Medicine"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/meridian.allenpress.com\/aplm\/article-pdf\/133\/2\/224\/2767063\/1543-2165-133_2_224.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/meridian.allenpress.com\/aplm\/article-pdf\/133\/2\/224\/2767063\/1543-2165-133_2_224.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T19:34:23Z","timestamp":1764790463000},"score":1,"resource":{"primary":{"URL":"https:\/\/aplm.kglmeridian.com\/view\/journals\/arpa\/133\/2\/article-p224.xml"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,2,1]]},"references-count":58,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2009,2,1]]}},"URL":"https:\/\/doi.org\/10.5858\/133.2.224","relation":{},"ISSN":["1543-2165","0003-9985"],"issn-type":[{"value":"1543-2165","type":"electronic"},{"value":"0003-9985","type":"print"}],"subject":[],"published":{"date-parts":[[2009,2,1]]}}}