Modeling a biofluid-derived extracellular vesicle surface signature to differentiate pediatric idiopathic nephrotic syndrome clinical subgroups.
Extracellular vesicles
Idiopathic nephrotic syndrome
Protein biomarkers
Steroid resistance
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
28 10 2024
28 10 2024
Historique:
received:
17
04
2024
accepted:
16
10
2024
medline:
29
10
2024
pubmed:
29
10
2024
entrez:
29
10
2024
Statut:
epublish
Résumé
Idiopathic Nephrotic Syndrome (INS) is a common childhood glomerular disease requiring intense immunosuppressive drug treatments. Prediction of treatment response and the occurrence of relapses remains challenging. Biofluid-derived extracellular vesicles (EVs) may serve as novel liquid biopsies for INS classification and monitoring. Our cohort was composed of 105 INS children at different clinical time points (onset, relapse, and persistent proteinuria, remission, respectively), and 19 healthy controls. The expression of 37 surface EV surface markers was evaluated by flow cytometry in serum (n = 83) and urine (n = 74) from INS children (mean age = 10.1, 58% males) at different time points. Urine EVs (n = 7) and serum EVs (n = 11) from age-matched healthy children (mean age = 7.8, 94% males) were also analyzed. Tetraspanin expression in urine EVs was enhanced during active disease phase in respect to the remission group and positively correlates with proteinuria levels. Unsupervised clustering analysis identified an INS signature of 8 markers related to immunity and angiogenesis/adhesion processes. The CD41b, CD29, and CD105 showed the best diagnostic scores separating the INS active phase from the healthy condition. Interestingly, combining urinary and serum EV markers from the same patient improved the precision of clinical staging separation. Three urinary biomarkers (CD19, CD44, and CD8) were able to classify INS based on steroid sensitivity. Biofluid EVs offer a non-invasive tool for INS clinical subclassification and "personalized" interventions.
Identifiants
pubmed: 39468184
doi: 10.1038/s41598-024-76727-w
pii: 10.1038/s41598-024-76727-w
doi:
Substances chimiques
Biomarkers
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
25765Subventions
Organisme : Ministero dell'Istruzione, dell'Università e della Ricerca
ID : 2022B9WC3F
Organisme : IMPACTsim S.p.A funding support
ID : Grant P-0038
Informations de copyright
© 2024. The Author(s).
Références
Eddy, A. A. & Symons, J. M. Nephrotic syndrome in childhood. Lancet. 362, 629–639 (2003).
doi: 10.1016/S0140-6736(03)14184-0
pubmed: 12944064
Kitsou, K., Askiti, V., Mitsioni, A. & Spoulou, V. The immunopathogenesis of idiopathic nephrotic syndrome: a narrative review of the literature. Eur. J. Pediatr. 181, 1395–1404 (2022).
doi: 10.1007/s00431-021-04357-9
pubmed: 35098401
Noone, D. G., Iijima, K. & Parekh, R. Idiopathic nephrotic syndrome in children. Lancet. 392, 61–74 (2018).
doi: 10.1016/S0140-6736(18)30536-1
pubmed: 29910038
Tullus, K., Webb, H. & Bagga, A. Management of steroid-resistant nephrotic syndrome in children and adolescents. Lancet Child. Adolesc. Health. 2, 880–890. https://doi.org/10.1016/S2352-4642(18)30283-9 (2018).
doi: 10.1016/S2352-4642(18)30283-9
pubmed: 30342869
Hahn, D., Hodson, E. M., Willis, N. S. & Craig, J. C. Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database Syst Rev (2015). (2015).
Trautmann, A. et al. Long-term outcome of steroid-resistant nephrotic syndrome in children. J. Am. Soc. Nephrol. 28, 3055–3065 (2017).
doi: 10.1681/ASN.2016101121
pubmed: 28566477
pmcid: 5619960
Shah, R., Patel, T. & Freedman, J. E. Circulating Extracellular vesicles in Human Disease. N. Engl. J. Med. 379, 958–966 (2018).
doi: 10.1056/NEJMra1704286
pubmed: 30184457
El Andaloussi, S., Mäger, I., Breakefield, X. O. & Wood, M. J. A. Extracellular vesicles: biology and emerging therapeutic opportunities. Nat. Rev. Drug Discovery 12, 347–357 (2013). (2013).
Myette, R. L. & Burger, D. Relapse in steroid-sensitive nephrotic syndrome: are extracellular vesicles the missing link? Am. J. Physiol. Ren. Physiol. 321, F656–F658 (2021).
doi: 10.1152/ajprenal.00349.2021
Uddin, J. et al. Extracellular vesicles: the future of therapeutics and drug delivery systems. Prod. Hosting Elsevier Behalf KeAi. https://doi.org/10.1016/j.ipha.2024.02.004 (2024).
doi: 10.1016/j.ipha.2024.02.004
Welsh, J. A. et al. Minimal information for studies of extracellular vesicles (MISEV2023): from basic to advanced approaches. J. Extracell. Vesicles. 13, e12404 (2024).
doi: 10.1002/jev2.12404
pubmed: 38326288
pmcid: 10850029
Ståhl, A., lie, Johansson, K., Mossberg, M., Kahn, R. & Karpman, D. Exosomes and microvesicles in normal physiology, pathophysiology, and renal diseases. Pediatr. Nephrol. 34, 11 (2019).
doi: 10.1007/s00467-017-3816-z
pubmed: 29181712
Erdbrügger, U. et al. Urinary extracellular vesicles: a position paper by the Urine Task Force of the International Society for Extracellular Vesicles. J. Extracell. Vesicles. 10, e12093 (2021).
doi: 10.1002/jev2.12093
pubmed: 34035881
pmcid: 8138533
Takizawa, K. et al. Urinary extracellular vesicles signature for diagnosis of kidney disease. iScience 25(11):105416 (2022).
Hogan, M. C. et al. Identification of biomarkers for PKD1 using urinary exosomes. J. Am. Soc. Nephrol. 26, 1661–1670 (2015).
doi: 10.1681/ASN.2014040354
pubmed: 25475747
Morikawa, Y. et al. Elevated levels of urinary extracellular vesicle fibroblast-specific protein 1 in patients with active crescentic glomerulonephritis. Nephron. 141, 177–187 (2019).
doi: 10.1159/000495217
pubmed: 30540988
Corbetta, S. et al. Urinary exosomes in the diagnosis of Gitelman and Bartter syndromes. Nephrol. Dialysis Transplantation. 30, 621–630 (2015).
doi: 10.1093/ndt/gfu362
Zhang, J. et al. Excretion of urine extracellular vesicles bearing markers of activated immune cells and calcium/phosphorus physiology differ between calcium kidney stone formers and non-stone formers. BMC Nephrol. 22, 1–10 (2021).
doi: 10.1186/s12882-021-02417-8
Grange, C., Dalmasso, A., Cortez, J. J., Spokeviciute, B. & Bussolati, B. Exploring the role of urinary extracellular vesicles in kidney physiology, aging, and disease progression. Am. J. Physiol. Cell. Physiol. 325, C1439 (2023).
doi: 10.1152/ajpcell.00349.2023
pubmed: 37842748
pmcid: 10861146
Siddall, E. C. & Radhakrishnan, J. The pathophysiology of edema formation in the nephrotic syndrome. Kidney Int. 82, 635–642 (2012).
doi: 10.1038/ki.2012.180
pubmed: 22718186
Barreiro, K. et al. Comparison of urinary extracellular vesicle isolation methods for transcriptomic biomarker research in diabetic kidney disease. J. Extracell. Vesicles. 10, e12038 (2020).
doi: 10.1002/jev2.12038
pubmed: 33437407
Grange C, et al. Urinary Extracellular Vesicles Carrying Klotho Improve the Recovery of Renal Function in an Acute Tubular Injury Model. Mol Ther. 28, 490—502 (2020) [published correction appears in Mol Ther. 2024 Sep 17:S1525-0016(24)00604-X].
doi: 10.1016/j.ymthe.2019.11.013
pubmed: 31818691
Burrello, J. et al. Identification of a serum and urine extracellular vesicle signature predicting renal outcome after kidney transplant. Nephrol. Dialysis Transplantation. 38, 764–777 (2023).
doi: 10.1093/ndt/gfac259
Ayuko Hoshino, A. et al. Extracellular vesicle and particle biomarkers define multiple human cancers. Cell. 182, 1044–1061. https://doi.org/10.1016/j.cell.2020.07.009 (2020).
doi: 10.1016/j.cell.2020.07.009
pubmed: 32795414
pmcid: 7522766
Mashad, G. M., El, Ibrahim, S. A. E. H. & Abdelnaby, S. A. A. Immunoglobulin G and M levels in childhood nephrotic syndrome: two centers Egyptian study. Electron. Physician. 9, 3728 (2017).
doi: 10.19082/3728
pubmed: 28465799
pmcid: 5410898
Ding, H., Li, L. X., Harris, P. C., Yang, J. & Li, X. Extracellular vesicles and exosomes generated from cystic renal epithelial cells promote cyst growth in autosomal dominant polycystic kidney disease. Nature Communications 2021 12:1 12, 1–18 (2021).
Noren Hooten, N., Byappanahalli, A. M., Vannoy, M., Omoniyi, V. & Evans, M. K. Influences of age, race, and sex on extracellular vesicle characteristics. Theranostics. 12, 4459–4476 (2022).
doi: 10.7150/thno.72676
pubmed: 35673574
pmcid: 9169362
Lipska-Ziętkiewicz, B. S. Genetic Steroid-Resistant Nephrotic Syndrome Overview. GeneReviews® (2021).
Santorelli, L. et al. Diagnostics urinary extracellular vesicle protein profiles discriminate different clinical subgroups of children with idiopathic nephrotic syndrome. https://doi.org/10.3390/diagnostics11030456 (2021).
Cereda, C. W. et al. Extracellular vesicle surface markers as a Diagnostic Tool in transient ischemic attacks. https://doi.org/10.1161/STROKEAHA.120.033170 (2021).
Castellani, C. et al. Circulating extracellular vesicles as non-invasive biomarker of rejection in heart transplant. J. Heart Lung Trans.. 39, 1136–1148 (2020).
doi: 10.1016/j.healun.2020.06.011
Blijdorp, C. J. et al. Comparing approaches to normalize, quantify, and characterize urinary extracellular vesicles. J. Am. Soc. Nephrol. 32, 1210–1226 (2021).
doi: 10.1681/ASN.2020081142
pubmed: 33782168
pmcid: 8259679
Adedeji, A. O. et al. Investigating the value of urine volume, Creatinine, and cystatin C for urinary biomarkers normalization for Drug Development studies. Int. J. Toxicol. 38, 12–22 (2019).
doi: 10.1177/1091581818819791
pubmed: 30673360
Gunasekaran, P. M., Luther, J. M. & Byrd, J. B. For what factors should we normalize urinary extracellular mRNA biomarkers? Biomol. Detect. Quantif 17: 100090 (2019).
Eneman, B., Levtchenko, E., van den Heuvel, B., Van Geet, C. & Freson, K. Platelet abnormalities in nephrotic syndrome. Pediatr. Nephrol. 31, 1267–1279 (2016).
doi: 10.1007/s00467-015-3173-8
pubmed: 26267676
Martins, S. R. et al. Cell-derived microparticles and Von Willebrand factor in Brazilian renal transplant recipients. Nephrology. 24, 1304–1312 (2019).
doi: 10.1111/nep.13657
pubmed: 31482669
Bauer, C. et al. Minimal change disease is Associated with endothelial glycocalyx degradation and endothelial activation. Kidney Int. Rep. 7, 797–809 (2022).
doi: 10.1016/j.ekir.2021.11.037
pubmed: 35497798
Royal, V. et al. Ultrastructural characterization of proteinuric patients predicts clinical outcomes. J. Am. Soc. Nephrol. 31, 841–854 (2020).
doi: 10.1681/ASN.2019080825
pubmed: 32086276
pmcid: 7191920
Cara-Fuentes, G. et al. β1-Integrin blockade prevents podocyte injury in experimental models of minimal change disease. Nefrología (2022). https://doi.org/10.1016/J.NEFRO.2022.11.004
Nagatani, K., Sakashita, E., Endo, H. & Minota, S. A novel multi-biomarker combination predicting relapse from long-term remission after discontinuation of biological drugs in rheumatoid arthritis. Sci. Rep. 11, 20771 (2021).
doi: 10.1038/s41598-021-00357-9
pubmed: 34675298
pmcid: 8531387
Melo, S. A. et al. Glypican1 identifies cancer exosomes and facilitates early detection of cancer HHS Public Access. Nature. 523, 177–182 (2015).
doi: 10.1038/nature14581
pubmed: 26106858
pmcid: 4825698
Shi, R. et al. Exosomal levels of miRNA-21 from cerebrospinal fluids associated with poor prognosis and tumor recurrence of glioma patients. Oncotarget 6(29): 26971–81 (2015).
Burrello, J. et al. Characterization of circulating Extracellular Vesicle Surface antigens in patients with primary Aldosteronism. Hypertension. 78, 726–737 (2021).
doi: 10.1161/HYPERTENSIONAHA.121.17136
pubmed: 34304584
Zhou, H. et al. Urinary exosomal Wilms’ tumor-1 as a potential biomarker for podocyte injury. Am. J. Physiol. Ren. Physiol. 305, F553 (2013).
doi: 10.1152/ajprenal.00056.2013
Chen, T. et al. Increased urinary exosomal microRNAs in children with idiopathic nephrotic syndrome. EBioMedicine. 39, 552–561 (2019).
doi: 10.1016/j.ebiom.2018.11.018
pubmed: 30467011
Trevillian, P., Paul, H., Millar, E., Hibberd, A. & Agrez, M. V. αvβ6 integrin expression in diseased and transplanted kidneys. Kidney Int. 66, 1423–1433 (2004).
doi: 10.1111/j.1523-1755.2004.00904.x
pubmed: 15458435
Myette, R. L. et al. Urinary podocyte-derived large extracellular vesicles are increased in paediatric idiopathic nephrotic syndrome. Nephrol. Dialysis Trans. 38, 2089–2091 (2023).
doi: 10.1093/ndt/gfad086
Lee, H. K. et al. Urinary exosomal WT1 in childhood nephrotic syndrome. Pediatr. Nephrol. 27, 317–320 (2012).
doi: 10.1007/s00467-011-2035-2
pubmed: 22076591
Fan, Y. et al. Expression of endothelial cell Injury marker Cd146 correlates with Disease Severity and predicts the renal outcomes in patients with Diabetic Nephropathy. Cell. Physiol. Biochem. 48, 63–74 (2018).
doi: 10.1159/000491663
pubmed: 30001528
Deng, Y. et al. Peripheral blood lymphocyte subsets in children with nephrotic syndrome: a retrospective analysis. BMC Nephrol. 24, 7 (2023).
doi: 10.1186/s12882-022-03015-y
pubmed: 36627573
pmcid: 9830737
Lama, G. et al. T-Lymphocyte populations and cytokines in Childhood Nephrotic Syndrome. doi: (2002). https://doi.org/10.1053/ajkd.2002.32769
Roca, N. et al. CD44-negative parietal–epithelial cell staining in minimal change disease: association with clinical features, response to corticosteroids and kidney outcome. Clin. Kidney J. 15, 545 (2022).
doi: 10.1093/ckj/sfab215
pubmed: 35211308