{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:46:58Z","timestamp":1787028418552,"version":"build-2736575974"},"reference-count":38,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2019,9,22]],"date-time":"2019-09-22T00:00:00Z","timestamp":1569110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","award":["18H02588"],"award-info":[{"award-number":["18H02588"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","award":["18K06786"],"award-info":[{"award-number":["18K06786"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Kidney transplantation is the treatment of choice for patients with advanced chronic kidney disease (CKD) and end stage renal disease (ESRD). However, acute rejection (AR) is a common complication in kidney transplantation and is associated with reduced graft survival. Current diagnosis of AR relies mainly on clinical monitoring including serum creatinine, proteinuria, and confirmation by histopathologic assessment in the biopsy specimen of graft kidney. Although an early protocol biopsy is indispensable for depicting the severity of pathologic lesions in subclinical acute rejection (subAR), it is not acceptable in some cases and cannot be performed because of its invasive nature. Therefore, we examined the detection of noninvasive biomarkers that are closely related to the pathology of subAR in protocol biopsies three months after kidney transplantation. In this study, the urinary level of microtubule-associated protein 1 light chain 3 (LC3), monocyte chemotactic protein-1 (MCP-1), liver-type fatty acid-binding protein (L-FABP), neutrophil gelatinase-associated lipocalin (NGAL), and human epididymis secretory protein 4 (HE4) were measured three months after kidney transplantation. Urine samples of 80 patients undergoing kidney transplantation between August 2014 to September 2016, were prospectively collected after three months. SubAR was observed in 11 patients (13.8%) in protocol biopsy. The urinary levels of LC3, MCP-1, NGAL, and HE4 were significantly higher in patients with subAR than in those without, while those of L-FABP did not differ between the two groups. Multivariate regression models, receiver-operating characteristics (ROC), and areas under ROC curves (AUC) were used to identify predicted values of subAR. Urinary HE4 levels were able to better identify subAR (AUC = 0.808) than the other four urinary biomarkers. In conclusion, urinary HE4 is increased in kidney transplant recipients of subAR three months after kidney transplantation, suggesting that HE4 has the potential to be used as a novel clinical biomarker for predicting subAR.<\/jats:p>","DOI":"10.3390\/ijms20194699","type":"journal-article","created":{"date-parts":[[2019,9,23]],"date-time":"2019-09-23T03:26:32Z","timestamp":1569209192000},"page":"4699","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Urinary Human Epididymis Secretory Protein 4 as a Useful Biomarker for Subclinical Acute Rejection Three Months after Kidney Transplantation"],"prefix":"10.3390","volume":"20","author":[{"given":"Soichiro","family":"Tajima","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rao","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Shigematsu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"},{"name":"Department of Clinical Pharmacology and Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Noguchi","sequence":"additional","affiliation":[{"name":"Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keizo","family":"Kaku","sequence":"additional","affiliation":[{"name":"Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Tsuchimoto","sequence":"additional","affiliation":[{"name":"Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiro","family":"Okabe","sequence":"additional","affiliation":[{"name":"Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3589-5989","authenticated-orcid":false,"given":"Satohiro","family":"Masuda","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"},{"name":"Department of Clinical Pharmacology and Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"},{"name":"Department of Pharmacy, International University of Health and Welfare Narita Hospital, Minami-Aoyama, Minato-ku, Tokyo 107-0062, Japan"},{"name":"Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, International University of Health and Welfare Narita Hospital, Minami-Aoyama, Minato-ku, Tokyo 107-0062, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,9,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2006","DOI":"10.1111\/j.1600-6143.2006.01436.x","article-title":"The significance of subclinical rejection and the value of protocol biopsies","volume":"6","author":"Nankivell","year":"2006","journal-title":"Am. J. Transplant."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1097\/01.tp.0000225783.86950.c2","article-title":"Treatment of subclinical rejection diagnosed by protocol biopsy of kidney transplants","volume":"82","author":"Kee","year":"2006","journal-title":"Transplantation"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1111\/j.1600-6143.2009.02966.x","article-title":"Impact of subclinical inflammation on the development of interstitial fibrosis and tubular atrophy in kidney transplant recipients","volume":"10","author":"Heilman","year":"2010","journal-title":"Am. J. Transplant."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1111\/j.1600-6143.2005.00811.x","article-title":"Kidney allograft fibrosis and atrophy early after living donor transplantation","volume":"5","author":"Cosio","year":"2005","journal-title":"Am. J. Transplant."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1097\/01.TP.0000128613.74683.D9","article-title":"Delta analysis of posttransplantation tubulointerstitial damage","volume":"78","author":"Nankivell","year":"2004","journal-title":"Transplantation"},{"key":"ref_6","first-page":"494","article-title":"Effect of subclinical rejection on renal allograft histology and function at 6 months","volume":"28","author":"Rush","year":"1996","journal-title":"Transplant. Proc."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1097\/01.ASN.0000056189.02819.32","article-title":"The impact of repeated subclinical acute rejection on the progression of chronic allograft nephropathy","volume":"14","author":"Shishido","year":"2003","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1097\/00007890-199502270-00012","article-title":"Sequential protocol biopsies in renal transplant patients. Clinico-pathological correlations using the Banff schema","volume":"59","author":"Rush","year":"1995","journal-title":"Transplantation"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1016\/j.kint.2015.11.021","article-title":"Autophagy in acute kidney injury","volume":"89","author":"Kaushal","year":"2016","journal-title":"Kidney Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1418","DOI":"10.3109\/0886022X.2013.828309","article-title":"Efficacy of antisense monocyte chemoattractant protein-1 (MCP-1) in a rat model of mesangial proliferative glomerulonephritis","volume":"35","author":"Liu","year":"2013","journal-title":"Ren. Fail."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1016\/j.bcp.2012.12.019","article-title":"Urinary chemokine (C-C motif) ligand 2 (monocyte chemotactic protein-1) as a tubular injury marker for early detection of cisplatin-induced nephrotoxicity","volume":"85","author":"Nishihara","year":"2013","journal-title":"Biochem. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1042\/bj2880285","article-title":"Molecular identification of the liver- and the heart-type fatty acid-binding proteins in human and rat kidney. Use of the reverse transcriptase polymerase chain reaction","volume":"288","author":"Maatman","year":"1992","journal-title":"Biochem. J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"F114","DOI":"10.1152\/ajprenal.00469.2014","article-title":"Human liver-type fatty acid-binding protein protects against tubulointerstitial injury in aldosterone-induced renal injury","volume":"308","author":"Ichikawa","year":"2015","journal-title":"Am. J. Physiol. Renal. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1007\/s00467-009-1397-1","article-title":"Neutrophil gelatinase-associated lipocalin (NGAL): A new marker of cyclosporine nephrotoxicity?","volume":"25","author":"Wasilewska","year":"2010","journal-title":"Pediatr. Nephrol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1016\/S0140-6736(05)74811-X","article-title":"Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery","volume":"365","author":"Mishra","year":"2005","journal-title":"Lancet"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1038\/nature07208","article-title":"Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance","volume":"455","author":"Nedjic","year":"2008","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Tsuchimoto, A., Shinke, H., Uesugi, M., Kikuchi, M., Hashimoto, E., Sato, T., Ogura, Y., Hata, K., Fujimoto, Y., and Kaido, T. (2014). Urinary Neutrophil Gelatinase-Associated Lipocalin: A Useful Biomarker for Tacrolimus-Induced Acute Kidney Injury in Liver Transplant Patients. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0110527"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1042\/bj20020869","article-title":"A locus on human chromosome 20 contains several genes expressing protease inhibitor domains with homology to whey acidic protein","volume":"368","author":"Clauss","year":"2002","journal-title":"Biochem. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/nm.2989","article-title":"Identification of human epididymis protein-4 as a fibroblast-derived mediator of fibrosis","volume":"19","author":"LeBleu","year":"2013","journal-title":"Nat. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"67748","DOI":"10.18632\/oncotarget.11682","article-title":"Elevated serum concentrations of HE4 as a novel biomarker of disease severity and renal fibrosis in kidney disease","volume":"7","author":"Wan","year":"2016","journal-title":"Oncotarget"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1093\/labmed\/lmx036","article-title":"Human Epididymis Protein 4 as a Potential Biomarker of Chronic Kidney Disease in Female Patients With Normal Ovarian Function","volume":"48","author":"Yuan","year":"2017","journal-title":"Lab. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1258\/acb.2011.011258","article-title":"Elevated human epididymis protein 4 concentrations in chronic kidney disease","volume":"49","author":"Nagy","year":"2012","journal-title":"Ann. Clin. Biochem."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Nakagawa, S., Nishihara, K., Miyata, H., Shinke, H., Tomita, E., Kajiwara, M., Matsubara, T., Iehara, N., Igarashi, Y., and Yamada, H. (2015). Molecular Markers of Tubulointerstitial Fibrosis and Tubular Cell Damage in Patients with Chronic Kidney Disease. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0136994"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1016\/j.it.2008.07.001","article-title":"Novel innate immune functions of the whey acidic protein family","volume":"29","author":"Bingle","year":"2008","journal-title":"Trends. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Wang, L., Sun, Y., Cai, X., and Fu, G. (2018). The diagnostic value of human epididymis protein 4 as a novel biomarker in patients with renal dysfunction. Int. Urol. Nephrol.","DOI":"10.1007\/s11255-018-1930-x"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1111\/tri.12266","article-title":"The use of NGAL and IP-10 in the prediction of early acute rejection in highly sensitized patients following HLA-incompatible renal transplantation","volume":"27","author":"Field","year":"2014","journal-title":"Transpl. Int."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1007\/s11255-012-0321-y","article-title":"Neutrophil gelatinase-associated lipocalin is a sensitive biomarker for the early diagnosis of acute rejection after living-donor kidney transplantation","volume":"45","author":"Kohei","year":"2013","journal-title":"Int. Urol. Nephrol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1097\/TP.0b013e31824fd892","article-title":"Urinary neutrophil gelatinase-associated lipocalin accurately detects acute allograft rejection among other causes of acute kidney injury in renal allograft recipients","volume":"93","author":"Heyne","year":"2012","journal-title":"Transplantation"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1159\/000374071","article-title":"Autophagy protects renal tubular cells against ischemia \/ reperfusion injury in a time-dependent manner","volume":"36","author":"Guan","year":"2015","journal-title":"Cell Physiol. Biochem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"861","DOI":"10.4161\/auto.24111","article-title":"Endosome-mediated autophagy: An unconventional MIIC-driven autophagic pathway operational in dendritic cells","volume":"9","author":"Kondylis","year":"2013","journal-title":"Autophagy"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1126\/science.1136880","article-title":"Autophagy-dependent viral recognition by plasmacytoid dendritic cells","volume":"315","author":"Lee","year":"2007","journal-title":"Science"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"266","DOI":"10.4161\/auto.3908","article-title":"Maintaining T lymphocyte homeostasis: Another duty of autophagy","volume":"3","author":"Pua","year":"2007","journal-title":"Autophagy"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e111","DOI":"10.1038\/cddis.2010.89","article-title":"Ischemic preconditioning induces autophagy and limits necrosis in human recipients of fatty liver grafts, decreasing the incidence of rejection episodes","volume":"2","author":"Sebagh","year":"2011","journal-title":"Cell Death Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1038\/ki.2009.422","article-title":"Urinary liver-type fatty acid-binding protein predicts adverse outcomes in acute kidney injury","volume":"77","author":"Ferguson","year":"2010","journal-title":"Kidney Int."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/sj.ki.5002721","article-title":"Liver fatty acid-binding protein as a biomarker of acute kidney injury after cardiac surgery","volume":"73","author":"Portilla","year":"2008","journal-title":"Kidney Int."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.cca.2018.05.006","article-title":"Serum human epididymis secretory protein 4 as a potential biomarker of renal fibrosis in kidney transplantation recipients","volume":"483","author":"Luo","year":"2018","journal-title":"Clin. Chim. Acta"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1681\/ASN.V8121930","article-title":"Evaluation of pathologic criteria for acute renal allograft rejection: Reproducibility, sensitivity, and clinical correlation","volume":"8","author":"Colvin","year":"1997","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1053\/j.ajkd.2008.12.034","article-title":"Revised equations for estimated GFR from serum creatinine in Japan","volume":"53","author":"Matsuo","year":"2009","journal-title":"Am. J. Kidney Dis."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/19\/4699\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:22:59Z","timestamp":1760188979000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/19\/4699"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,22]]},"references-count":38,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2019,10]]}},"alternative-id":["ijms20194699"],"URL":"https:\/\/doi.org\/10.3390\/ijms20194699","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,22]]}}}