{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T02:13:18Z","timestamp":1783476798659,"version":"3.55.0"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2021,3,24]],"date-time":"2021-03-24T00:00:00Z","timestamp":1616544000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2021,3,24]],"date-time":"2021-03-24T00:00:00Z","timestamp":1616544000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Nephrol"],"published-print":{"date-parts":[[2021,12]]},"DOI":"10.1007\/s40620-021-01015-z","type":"journal-article","created":{"date-parts":[[2021,3,24]],"date-time":"2021-03-24T11:02:21Z","timestamp":1616583741000},"page":"1915-1924","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["HMGB-1 and TGF\u03b2-1 highlight immuno-inflammatory and fibrotic processes before proteinuria onset in pediatric patients with Alport syndrome"],"prefix":"10.1093","volume":"34","author":[{"given":"R.","family":"Chimenz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V.","family":"Chirico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Basile","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Carcione","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G.","family":"Conti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Monardo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Lacquaniti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,3,24]]},"reference":[{"key":"1015_CR1","first-page":"19","volume":"33","author":"V Bruni","year":"2019","unstructured":"Bruni V, Petrisano M, Tarsitano F, Falvo F, Parisi F, Cucinotta U et al (2019) \u201cFocus on pediatric nephrology\u201d Alport\u2019s syndrome. J Biol Regul Homeost Agents 33:19\u201324","journal-title":"J Biol Regul Homeost Agents"},{"key":"1015_CR2","first-page":"1","volume":"33","author":"R Chimenz","year":"2019","unstructured":"Chimenz R (2019) Introduction to the special issue: \u201cFocus on pediatric nephrology.\u201d J Biol Regul Homeost Agents 33:1","journal-title":"J Biol Regul Homeost Agents"},{"key":"1015_CR3","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1038\/jhg.2017.28","volume":"62","author":"K Nozu","year":"2017","unstructured":"Nozu K, Minamikawa S, Yamada S, Oka M, Yanagita M, Morisada N et al (2017) Characterization of contiguous gene deletions in COL4A6 and COL4A5 in Alport syndrome-diffuse leiomyomatosis. J Hum Genet 62:733\u2013735","journal-title":"J Hum Genet"},{"key":"1015_CR4","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1038\/ng857","volume":"30","author":"I Meloni","year":"2002","unstructured":"Meloni I, Muscettola M, Raynaud M, Longo I, Bruttini M, Moizard MP et al (2002) FACL4, encoding fatty acid-CoA ligase 4, is mutated in nonspecific X-linked mental retardation. Nat Genet 30:436\u2013440","journal-title":"Nat Genet"},{"key":"1015_CR5","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1007\/s00467-003-1366-z","volume":"19","author":"W Proesmans","year":"2004","unstructured":"Proesmans W, Van Dyck M (2004) Enalapril in children with Alport syndrome. Pediatr Nephrol 19:271\u2013275","journal-title":"Pediatr Nephrol"},{"key":"1015_CR6","doi-asserted-by":"publisher","first-page":"2521","DOI":"10.1093\/ndt\/gfq797","volume":"26","author":"NJ Webb","year":"2011","unstructured":"Webb NJ, Lam C, Shahinfar S (2011) Efficacy and safety of losartan in children with Alport syndrome\u2014results from a subgroup analysis of prospective, randomized, placebo- or amlodipine-controlled trial. Nephrol Dial Transplant 26:2521\u20132526","journal-title":"Nephrol Dial Transplant"},{"key":"1015_CR7","doi-asserted-by":"publisher","first-page":"1837","DOI":"10.1007\/s00467-013-2490-z","volume":"28","author":"M Giani","year":"2013","unstructured":"Giani M, Mastrangelo A, Villa R, Turolo S, Marra G, Tirelli AS et al (2013) Alport syndrome: the effects of spironolactone on proteinuria and urinary TGF-\u03b21. Pediatr Nephrol 28:1837\u20131842","journal-title":"Pediatr Nephrol"},{"key":"1015_CR8","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1159\/000381480","volume":"130","author":"E Daina","year":"2015","unstructured":"Daina E, Cravedi P, Alpa M, Roccatello D, Gamba S, Perna A et al (2015) A multidrug, antiproteinuric approach to Alport syndrome: a ten-year cohort study. Nephron 130:13\u201320","journal-title":"Nephron"},{"key":"1015_CR9","doi-asserted-by":"publisher","first-page":"2277","DOI":"10.1093\/ndt\/gfu254","volume":"29","author":"A Mallett","year":"2014","unstructured":"Mallett A, Tang W, Clayton PA, Stevenson S, McDonald SP, Hawley CM et al (2014) End-stage kidney disease due to Alport syndrome: outcomes in 296 consecutive Australia and New Zealand Dialysis and Transplant Registry cases. Nephrol Dial Transplant 29:2277\u20132286","journal-title":"Nephrol Dial Transplant"},{"key":"1015_CR10","first-page":"e741","volume":"29","author":"S Shang","year":"2019","unstructured":"Shang S, Peng F, Wang T, Wu X, Li P, Li Q et al (2019) Genotype\u2013phenotype correlation and prognostic impact in Chinese patients with Alport syndrome. Mol Genet Genom Med. 29:e741","journal-title":"Mol Genet Genom Med."},{"key":"1015_CR11","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1053\/j.ajkd.2009.04.029","volume":"54","author":"AS Levey","year":"2009","unstructured":"Levey AS, Cattran D, Friedman A, Miller WG, Sedor J, Tuttle K et al (2009) Proteinuria as a surrogate outcome in CKD: report of a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration. Am J Kidney Dis 54:205\u2013226","journal-title":"Am J Kidney Dis"},{"key":"1015_CR12","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1053\/j.ackd.2010.09.002","volume":"17","author":"P Devarajan","year":"2010","unstructured":"Devarajan P (2010) The use of targeted biomarkers for chronic kidney disease. Adv Chronic Kidney Dis 17:469\u2013479","journal-title":"Adv Chronic Kidney Dis"},{"key":"1015_CR13","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1007\/s00467-013-2494-8","volume":"29","author":"HW Schnaper","year":"2014","unstructured":"Schnaper HW (2014) Remnant nephron physiology and the progression of chronic kidney disease. Pediatr Nephrol 29:193\u2013202","journal-title":"Pediatr Nephrol"},{"key":"1015_CR14","doi-asserted-by":"publisher","first-page":"1662","DOI":"10.1046\/j.1523-1755.1999.00744.x","volume":"56","author":"R Sayers","year":"1999","unstructured":"Sayers R, Kalluri R, Rogers KD, Shiel CF, Meehan DT, Cosgrove D (1999) Role for transforming growth factor-beta1 in Alport renal disease progression. Kidney Int 56:1662\u20131673","journal-title":"Kidney Int"},{"key":"1015_CR15","doi-asserted-by":"publisher","first-page":"2145","DOI":"10.1093\/ndt\/17.12.2145","volume":"17","author":"DS Goumenos","year":"2002","unstructured":"Goumenos DS, Tsakas S, El Nahas AM, Alexandri S, Oldroyd S, Kalliakmani P et al (2002) Transforming growth factor-\u03b21 in the kidney and urine of patients with glomerular disease and proteinuria. Nephrol Dial Transplant 17:2145\u20132152","journal-title":"Nephrol Dial Transplant"},{"key":"1015_CR16","doi-asserted-by":"publisher","first-page":"5429","DOI":"10.4049\/jimmunol.178.9.5429","volume":"178","author":"JMM den Haan","year":"2007","unstructured":"den Haan JMM, Kraal G, Bevan MJ (2007) Cutting edge: lipopolysaccharide induces IL-10-producing regulatory CD4+ T cells that suppress the CD8+ T cell response. J Immunol 178:5429\u20135433","journal-title":"J Immunol"},{"key":"1015_CR17","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.1007\/s00431-014-2327-1","volume":"173","author":"V Chirico","year":"2014","unstructured":"Chirico V, Lacquaniti A, Salpietro V, Munaf\u00f2 C, Calabr\u00f2 MP, Buemi M et al (2014) High-mobility group box 1 (HMGB1) in childhood: from bench to bedside. Eur J Pediatr 173:1123\u20131136","journal-title":"Eur J Pediatr"},{"key":"1015_CR18","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1530\/EJE-13-0037","volume":"168","author":"T Arrigo","year":"2013","unstructured":"Arrigo T, Chirico V, Salpietro V, Munaf\u00f2 C, Ferra\u00f9 V, Gitto E et al (2013) High-mobility group protein B1: a new biomarker of metabolic syndrome in obese children. Eur J Endocrinol 168:631\u2013638","journal-title":"Eur J Endocrinol"},{"key":"1015_CR19","doi-asserted-by":"publisher","first-page":"1370","DOI":"10.1080\/0886022X.2016.1216711","volume":"38","author":"R Chimenz","year":"2016","unstructured":"Chimenz R, Lacquaniti A, Colavita L, Chirico V, Fede C, Buemi M et al (2016) High mobility group box 1 and tumor growth factor \u03b2: useful biomarkers in pediatric patients receiving peritoneal dialysis. Ren Fail 38:1370\u20131376","journal-title":"Ren Fail"},{"key":"1015_CR20","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1111\/j.1600-065X.2007.00574.x","volume":"220","author":"ME Bianchi","year":"2007","unstructured":"Bianchi ME, Manfredi AA (2007) High-mobility group box 1 (HMGB1) protein at the crossroads between innate and adaptive immunity. Immunol Rev 220:35\u201346","journal-title":"Immunol Rev"},{"key":"1015_CR21","doi-asserted-by":"publisher","first-page":"1878","DOI":"10.1681\/ASN.2009101048","volume":"21","author":"H Wu","year":"2010","unstructured":"Wu H, Ma J, Wang P (2010) HMGB1 contributes to kidney ischemia reperfusion injury. J Am Soc Nephrol 21:1878\u20131890","journal-title":"J Am Soc Nephrol"},{"key":"1015_CR22","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1097\/MNH.0b013e3283294b98","volume":"18","author":"ER Rademacher","year":"2009","unstructured":"Rademacher ER, Sinaiko AR (2009) Albuminuria in children. Curr Opin Nephrol Hypertens 18:246\u2013251","journal-title":"Curr Opin Nephrol Hypertens"},{"key":"1015_CR23","doi-asserted-by":"publisher","first-page":"1012","DOI":"10.1177\/0961203316631629","volume":"25","author":"KM Abulaban","year":"2016","unstructured":"Abulaban KM, Song H, Zhang X et al (2016) Predicting decline of kidney function in lupus nephritis using urine biomarkers. Lupus 25:1012\u20131018","journal-title":"Lupus"},{"key":"1015_CR24","doi-asserted-by":"publisher","first-page":"R36","DOI":"10.1186\/ar3747","volume":"14","author":"A Zickert","year":"2012","unstructured":"Zickert A, Palmblad K, Sundelin B, Chavan S, Tracey KJ, Bruchfeld A et al (2012) Renal expression and serum levels of high mobility group box 1 protein in lupus nephritis. Arthritis Res Ther 14:R36","journal-title":"Arthritis Res Ther"},{"key":"1015_CR25","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1111\/cei.12422","volume":"178","author":"AW de Souza","year":"2014","unstructured":"de Souza AW, Abdulahad WH, Sosicka P, Bijzet J, Limburg PC, Stegeman CA et al (2014) Are urinary levels of high mobility group box 1 markers of active nephritis in anti-neutrophil cytoplasmic antibody-associated vasculitis? Clin Exp Immunol 178:270\u2013278","journal-title":"Clin Exp Immunol"},{"key":"1015_CR26","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1159\/000109396","volume":"28","author":"RP Woroniecki","year":"2008","unstructured":"Woroniecki RP, Shatat IF, Supe K, Du Z, Kaskel FJ (2008) Urinary cytokines and steroid responsiveness in idiopathic nephrotic syndrome of childhood. Am J Nephrol 28:83\u201390","journal-title":"Am J Nephrol"},{"key":"1015_CR27","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1111\/j.1440-1797.2011.01459.x","volume":"16","author":"J Zieg","year":"2011","unstructured":"Zieg J, Blahova K, Seeman T, Bronsky J, Dvorakova H, Pechova M et al (2011) Urinary transforming growth factor-beta1 in children with obstructive uropathy. Nephrology 16:595\u2013598","journal-title":"Nephrology"},{"key":"1015_CR28","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1038\/ki.2012.383","volume":"83","author":"MG Wong","year":"2013","unstructured":"Wong MG, Perkovic V, Woodward M, Chalmers J, Li Q, Hillis GS et al (2013) Circulating bone morphogenetic protein-7 and transforming growth factor-beta1 are better predictors of renal end points in patients with type 2 diabetes mellitus. Kidney Int 83:278\u2013284","journal-title":"Kidney Int"},{"key":"1015_CR29","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1046\/j.1523-1755.2003.00779.x","volume":"63","author":"O Gross","year":"2003","unstructured":"Gross O, Beirowski B, Koepke ML, Kuck J, Reiner M, Addicks K et al (2003) Preemptive ramipril therapy delays renal failure and reduces renal fibrosis in COL4A3-knockout mice with Alport syndrome. Kidney Int 63:438\u2013446","journal-title":"Kidney Int"},{"key":"1015_CR30","doi-asserted-by":"crossref","unstructured":"Gross O, Perin L, Deltas C (2014) Alport syndrome from bench to bedside: the potential of current treatment beyond RAAS blockade and the horizon of future therapies. Nephrol Dial Transplant 29:iv124\u2013iv130","DOI":"10.1093\/ndt\/gfu028"},{"key":"1015_CR31","first-page":"238","volume":"19","author":"W Chen","year":"2019","unstructured":"Chen W, Tang D, Dai Y, Diao H (2019) Establishment of microRNA, transcript and protein regulatory networks in Alport syndrome induced pluripotent stem cells. Mol Med Rep 19:238\u2013250","journal-title":"Mol Med Rep"},{"key":"1015_CR32","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1038\/s41581-019-0234-4","volume":"16","author":"SCW Tang","year":"2020","unstructured":"Tang SCW, Yiu WH (2020) Innate immunity in diabetic kidney disease. Nat Rev Nephrol 16:206\u2013222","journal-title":"Nat Rev Nephrol"},{"key":"1015_CR33","doi-asserted-by":"publisher","first-page":"F143","DOI":"10.1152\/ajprenal.00398.2012","volume":"305","author":"H Mudaliar","year":"2013","unstructured":"Mudaliar H, Pollock C, Komala MG, Chadban S, Wu HL, Panchapakesan U et al (2013) The role of Toll-like receptor proteins (TLR) 2 and 4 in mediating inflammation in proximal tubules. Am J Physiol Ren Physiol 305:F143\u2013F154","journal-title":"Am J Physiol Ren Physiol"},{"key":"1015_CR34","doi-asserted-by":"publisher","first-page":"F69","DOI":"10.1152\/ajprenal.00484.2014","volume":"308","author":"S Tian","year":"2015","unstructured":"Tian S, Zhang L, Tang J, Guo X, Dong K, Chen SY (2015) HMGB1 exacerbates renal tubulointerstitial fibrosis through facilitating M1 macrophage phenotype at the early stage of obstructive injury. Am J Physiol Ren Physiol 308:F69\u2013F75","journal-title":"Am J Physiol Ren Physiol"},{"key":"1015_CR35","doi-asserted-by":"publisher","first-page":"368.e1","DOI":"10.1016\/j.cmi.2014.11.004","volume":"21","author":"V Chirico","year":"2015","unstructured":"Chirico V, Lacquaniti A, Leonardi S, Grasso L, Rotolo N, Romano C et al (2015) Acute pulmonary exacerbation and lung function decline in patients with cystic fibrosis: high-mobility group box 1 (HMGB1) between inflammation and infection. Clin Microbiol Infect 21:368.e1\u20139","journal-title":"Clin Microbiol Infect"},{"key":"1015_CR36","doi-asserted-by":"publisher","first-page":"F873","DOI":"10.1152\/ajprenal.00092.2012","volume":"303","author":"MM Rabadi","year":"2012","unstructured":"Rabadi MM, Ghaly T, Goligorksy MS, Ratliff BB (2012) HMGB1 in renal ischemic injury. Am J Physiol Renal Physiol 303:F873\u2013F885","journal-title":"Am J Physiol Renal Physiol"},{"key":"1015_CR37","doi-asserted-by":"publisher","first-page":"R184","DOI":"10.1186\/ar4015","volume":"14","author":"DA Abdulahad","year":"2012","unstructured":"Abdulahad DA, Westra J, Bijzet J, Dolff S, van Dijk MC, Limburg PC et al (2012) Urine levels of HMGB1 in systemic lupus erythematosus patients with and without renal manifestations. Arthritis Res Ther 14:R184","journal-title":"Arthritis Res Ther"},{"key":"1015_CR38","doi-asserted-by":"publisher","first-page":"4230","DOI":"10.1242\/jcs.03492","volume":"120","author":"T Hayashida","year":"2007","unstructured":"Hayashida T, Wu MH, Pierce A, Poncelet AC, Varga J, Schnaper HW (2007) MAP-kinase activity necessary for TGFbeta1-stimulated mesangial cell type I collagen expression requires adhesion dependent phosphorylation of FAK tyrosine 397. J Cell Sci 120:4230\u20134240","journal-title":"J Cell Sci"},{"key":"1015_CR39","doi-asserted-by":"publisher","first-page":"C1335","DOI":"10.1152\/ajpcell.00279.2003","volume":"286","author":"R Ortega-Velazquez","year":"2004","unstructured":"Ortega-Velazquez R, Gonzalez-Rubio M, Ruiz-Torres MP, Diez-Marques ML, Iglesias MC, Rodriguez-Puyol M et al (2004) Collagen I upregulates extracellular matrix gene expression and secretion of TGF-beta 1 by cultured human mesangial cells. Am J Physiol Cell Physiol 286:C1335\u2013C1343","journal-title":"Am J Physiol Cell Physiol"},{"key":"1015_CR40","doi-asserted-by":"publisher","first-page":"110","DOI":"10.2353\/ajpath.2007.060158","volume":"170","author":"K Hahm","year":"2007","unstructured":"Hahm K, Lukashev ME, Luo Y, Yang WJ, Dolinski BM, Weinreb PH et al (2007) Alphav beta6 integrin regulates renal fibrosis and inflammation in Alport mouse. Am J Pathol 170:110\u2013125","journal-title":"Am J Pathol"},{"key":"1015_CR41","doi-asserted-by":"publisher","first-page":"109","DOI":"10.2119\/2007-00107.Bruchfeld","volume":"14","author":"A Bruchfeld","year":"2008","unstructured":"Bruchfeld A, Qureshi AR, Lindholm B, Barany P, Yang L, Stenvinkel P, Tracey KJ (2008) High mobility group box protein-1 correlates with renal function in chronic kidney disease (CKD). Mol Med 14:109\u2013115","journal-title":"Mol Med"}],"container-title":["Journal of Nephrology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s40620-021-01015-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s40620-021-01015-z\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s40620-021-01015-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T15:55:17Z","timestamp":1777564517000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/joneph\/article\/34\/6\/1915\/8325873"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,24]]},"references-count":41,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["1015"],"URL":"https:\/\/doi.org\/10.1007\/s40620-021-01015-z","relation":{},"ISSN":["1121-8428","1724-6059"],"issn-type":[{"value":"1121-8428","type":"print"},{"value":"1724-6059","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,24]]},"assertion":[{"value":"16 September 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 March 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 March 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declaration"}},{"value":"The authors have no financial relationships relevant to this article to disclose.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Financial disclosure"}},{"value":"The study was approved by the Local Ethics Committee for Medical Research and carried out in accordance with the Helsinki Declaration.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Both parents of each patient provided informed consent permitting data sampling and analysis at the time of initiation of the study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Both parents of each patient provided consent fort the publication of data at the time of initiation of the study.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}]}}