Netrin-1: a potential universal biomarker for acute kidney injury
2008; American Physical Society; Volume: 294; Issue: 4 Linguagem: Inglês
10.1152/ajprenal.00085.2008
ISSN1931-857X
Autores Tópico(s)Connective Tissue Growth Factor Research
ResumoEDITORIAL FOCUSNetrin-1: a potential universal biomarker for acute kidney injuryAlexei G. BasnakianAlexei G. BasnakianPublished Online:01 Apr 2008https://doi.org/10.1152/ajprenal.00085.2008This is the final version - click for previous versionMoreFiguresReferencesRelatedInformationPDF (52 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat acute kidney injury (AKI) is commonly associated with high mortality and morbidity rates, which strongly depend on the time of the diagnosis to allow therapeutic interventions. Recent studies clearly indicate that routine assessments of kidney function based on serum creatinine and blood urea nitrogen measurements and a fall in urine output are outdated because they fail to identify early stages of renal dysfunction and structural injury (5).The kidney has a remarkable capacity to withstand insults for an extended period of time. The sensitivities of individual renal cells to injury vary depending on their type, position in the nephron, local vascularization, and the nature of injury. The resulting kidney injury is a product of the interplay between cell dysfunction, cell death, proliferation, inflammation, and recovery. This sequence of events potentially provides time to diagnose and determine the cause of kidney failure in the event that sensitive and specific tests for early kidney injury are available.In their study, Ramesh and colleagues (8) demonstrated that netrin-1 can be used as an early biomarker of AKI. Netrin-1 is a 50- to 75-kDa laminin-like protein that has been previously recognized as a chemotropic and cell survival factor in nervous system development with possible roles in neovascularization, cell adhesion, and tumorigenesis (3). None of the above indicated that netrin-1 could be used as a biomarker of kidney injury.According to Ramesh and colleagues (8), netrin-1 is excreted in the urine as early as 1 h after injury and reaches a dramatic 30- to 40-fold increase by 3 h and a peak by 6 h after the insult. Netrin-1 excretion preceded by many hours any increase in blood urea nitrogen and serum creatinine. The presented data demonstrated that netrin-1 satisfies the requirements, which are usually applied to the AKI biomarkers. Such biomarkers are expected to appear very early after the injury and to be sensitive and specific to the kidney. To allow prompt diagnostics, AKI biomarkers optimally should be detected using quick and noninvasive procedures.The authors tested four types of mouse kidney injury models, including ischemia-reperfusion and three toxic impacts: cisplatin, endotoxin, and folic acid. All of these were shown to induce netrin-1 excretion. This observation clearly makes netrin-1 a biomarker, which is universal for hypoxic and toxic renal injury. The universality of netrin-1 excretion suggests it may be potentially applicable to various types of AKI, including cases with unknown causes of AKI.The magnitude and the significance of rapid netrin-1 excretion induced by kidney insults make it outstanding among all known renal injury markers, including previously described neutrophil gelatinase-associated lipocalin (4), IL-18 (7), kidney injury molecule-1 (1), N-acetyl-glucosaminidase (9), cysteine-rich protein 61 (6), hepatocyte growth factor (10), meprin Aβ (2), and exosomal fetuin-A (11). Importantly, the mode by which netrin-1 reacts to AKI differs from all of the previously known markers. Urinary levels of netrin-1 return back to normal level during reperfusion, suggesting that it also can be used as a prognostic marker for renal recovery, which would significantly increase its clinical value.Ramesh and coauthors (8) also examined the importance of netrin-1 as a marker for acute renal failure of various etiologies in humans. While it was undetectable in urine of healthy volunteers, the overwhelming majority of patients had dramatically increased urinary netrin-1.Since netrin-1 already looks like an unusual marker, this finding not only adds to the list of potential markers but strengthens the concept that a panel of markers may be the best solution to predict, diagnose, and monitor the loss of kidney function. It would be interesting to test whether netrin-1 is a predictive biomarker for delayed graft function following kidney transplantation, hypotension due to hemodialysis or cardiovascular surgery, and various nephrotoxicant- or sepsis-induced renal injuries. In addition, urinary netrin-1 may be potentially useful for identifying the type of injured cells and determining the nephron segment affected by the injury.It is very likely that netrin-1 is mechanistically linked to renal injury since its release is so rapid. However, the exact mechanisms will need to be a subject for further studies. Ramesh et al. (8) showed that renal injury caused an elevation of netrin-1 in tubular epithelial cells; however, netrin-1 mRNA was not induced. Thus the increased urinary excretion of netrin-1 seems to be caused by an induction of protein synthesis and the release of presynthesized protein. The authors suggested that netrin-1 facilitates cell proliferation and regeneration in response to injury and thus may be a marker of renal recovery. Therefore, it is also very likely that netrin-1 has the potential of being used as a therapeutic target to facilitate kidney recovery after injury.AUTHOR NOTESAddress for reprint requests and other correspondence: A. G. Basnakian, Div. of Nephrology, Dept. of Internal Medicine, Univ. of Arkansas for Medical Sciences, Little Rock, AR 72205 (e-mail: basnakianalexeig@uams.edu) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationREFERENCES1 Han WK, Bailly V, Abichandani R, Thadhani R, Bonventre JV. Kidney injury molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney Int 62: 237–244, 2002.Crossref | PubMed | ISI | Google Scholar2 Herzog C, Seth R, Shah SV, Kaushal GP. Role of meprin A in renal tubular epithelial cell injury. Kidney Int 71: 1009–1018, 2007.Crossref | PubMed | ISI | Google Scholar3 Mehlen P, Furne C. Netrin-1: when a neuronal guidance cue turns out to be a regulator of tumorigenesis. Cell Mol Life Sci 62: 2599–2616, 2005.Crossref | PubMed | ISI | Google Scholar4 Mishra J, Ma Q, Prada A, Mitsnefes M, Zahedi K, Yang J, Barasch J, Devarajan P. 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Kidney Int 70: 1847–1857, 2006.Crossref | PubMed | ISI | Google Scholar Cited ByDiagnostic Efficacy of Serum and Urinary Netrin-1 in the Early Detection of Diabetic Nephropathy5 January 2023 | Journal of Investigative Medicine, Vol. 69, No. 6Locus and gene-based GWAS meta-analysis identifies new diabetic nephropathy genes16 November 2017 | Immunogenetics, Vol. 70, No. 6Proteomics and Metabolomics for AKI DiagnosisSeminars in Nephrology, Vol. 38, No. 1Evaluation of Netrin‐1 Levels and Albuminuria in Patients With Diabetes13 April 2016 | Journal of Clinical Laboratory Analysis, Vol. 30, No. 6BIOMARKERS OF DRUG NEPHROTOXICITY30 September 2015 | Russian Journal of Biotherapy, Vol. 14, No. 3Urinary netrin-1 and KIM-1 as early biomarkers for septic acute kidney injury26 August 2014 | Renal Failure, Vol. 36, No. 10Enabling Innovative Translational Research in Acute Kidney Injury7 December 2011 | Clinical and Translational Science, Vol. 5, No. 1Sepsis and Acute Kidney InjuryJournal of the American Society of Nephrology, Vol. 22, No. 6Emergence of biomarkers in nephropharmacologyBiomarkers in Medicine, Vol. 4, No. 6 More from this issue > Volume 294Issue 4April 2008Pages F729-F730 Copyright & PermissionsCopyright © 2008 the American Physiological Societyhttps://doi.org/10.1152/ajprenal.00085.2008PubMed18305096History Published online 1 April 2008 Published in print 1 April 2008 Metrics Downloaded 296 times See more details Referenced in 1 patents 19 readers on Mendeley 1 readers on CiteULike 11 CITATIONS 11 Total citations 1 Recent citation 1.72 Field Citation Ratio 0.24 Relative Citation Ratio publications12supporting0mentioning11contrasting0Smart Citations120110Citing PublicationsSupportingMentioningContrastingView CitationsSee how this article has been cited at scite.aiscite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made. See more details Referenced in 1 patents 19 readers on Mendeley 1 readers on CiteULike
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