Towards Clinical Translation of Urinary Vitronectin for Non-invasive Detection and Monitoring of Renal Fibrosis in Kidney Transplant Patients

Overview

Journal J Transl Med

Publisher Biomed Central

Specialties Biomedical Engineering
General Medicine

Date 2024 Nov 16

PMID 39548536

Authors

Marta Clos-Sansalvador

Omar Taco

Paula Rodriguez-Martinez

Sergio G Garcia

Miriam Font-Moron

Jordi Bover

Anna Vila-Santandreu

Marcella Franquesa

Javier Juega

Francesc E Borras

Affiliations

Soon will be listed here.

Abstract

Background: Interstitial fibrosis and tubular atrophy (IFTA) is a critical factor in the prognosis of kidney health. Currently, IFTA quantitation in kidney biopsy samples is crucial for diagnosis and assessing disease severity, but the available non-invasive biomarkers are not satisfactory. Proteomic studies identified urinary vitronectin (VTN) as a potential biomarker for kidney fibrosis. As mass spectrometry techniques are not practical for use in clinical settings, we tested whether evaluation of urinary VTN levels through enzyme-linked immunosorbent assay (ELISA) can help monitor fibrotic changes in kidney transplant recipients and prove the clinical viability of the assay.

Methods: A total of 58 kidney transplant (KTx) patients who underwent renal biopsy were included in the study. Patients were categorized into two groups referred as no fibrosis (0%) or with fibrosis (≥ 5%) based on their histological findings. In a subsequent/follow-up analysis, the time elapsed from transplantation was also considered. The urinary levels of VTN were measured using ELISA.

Results: VTN (p = 0.0180) and VTN normalized by urinary creatinine levels (p = 0.0037), were significantly increased in patients with fibrotic grafts. When focusing on patients with long-term grafts (> 3 years from transplantation, n = 36), VTN exhibited superior potential in identifying fibrotic grafts compared to albuminuria (VTN p = 0.0040 vs. albuminuria p = 0.0132). Importantly, in this group, while albuminuria correctly identified 71% of fibrotic patients, the combination of VTN plus albuminuria correctly classified 89% of fibrotic grafts detected by renal biopsy.

Conclusions: VTN has emerged as a valid indicator of renal fibrosis. Of interest, urinary levels of VTN in combination with conventional clinical parameters (such as albuminuria) significantly improved the non-invasive detection of renal fibrosis in kidney transplant patients.

References

Bulow R, Boor P . Extracellular Matrix in Kidney Fibrosis: More Than Just a Scaffold. J Histochem Cytochem. 2019; 67(9):643-661. PMC: 6713975. DOI: 10.1369/0022155419849388. View

Betjes M, Roelen D, van Agteren M, Kal-van Gestel J . Causes of Kidney Graft Failure in a Cohort of Recipients With a Very Long-Time Follow-Up After Transplantation. Front Med (Lausanne). 2022; 9:842419. PMC: 9207199. DOI: 10.3389/fmed.2022.842419. View

Agborbesong E, Bissler J, Li X . Liquid Biopsy at the Frontier of Kidney Diseases: Application of Exosomes in Diagnostics and Therapeutics. Genes (Basel). 2023; 14(7). PMC: 10379367. DOI: 10.3390/genes14071367. View

Bhavsar N, Kottgen A, Coresh J, Astor B . Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) as predictors of incident CKD stage 3: the Atherosclerosis Risk in Communities (ARIC) Study. Am J Kidney Dis. 2012; 60(2):233-40. PMC: 3399971. DOI: 10.1053/j.ajkd.2012.02.336. View

Ciregia F, Deroyer C, Cobraiville G, Plener Z, Malaise O, Gillet P . Modulation of αβ integrin in osteoarthritis-related synovitis and the interaction with VTN competing for TGF-β1 activation. Exp Mol Med. 2021; 53(2):210-222. PMC: 8080589. DOI: 10.1038/s12276-021-00558-2. View

Levey A, Stevens L, Schmid C, Zhang Y, Castro 3rd A, Feldman H . A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009; 150(9):604-12. PMC: 2763564. DOI: 10.7326/0003-4819-150-9-200905050-00006. View

Duarte-Rojo A, Altamirano J, Feld J . Noninvasive markers of fibrosis: key concepts for improving accuracy in daily clinical practice. Ann Hepatol. 2012; 11(4):426-39. View

Lee H, Jung N, Lee D, Lee H, Yang J, Kim Y . Discovery of Biomarkers Related to Interstitial Fibrosis and Tubular Atrophy among Kidney Transplant Recipients by mRNA-Sequencing. J Pers Med. 2023; 13(8). PMC: 10455123. DOI: 10.3390/jpm13081242. View

. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021; 100(4S):S1-S276. DOI: 10.1016/j.kint.2021.05.021. View

10.

Argiles A, Siwy J, Duranton F, Gayrard N, Dakna M, Lundin U . CKD273, a new proteomics classifier assessing CKD and its prognosis. PLoS One. 2013; 8(5):e62837. PMC: 3653906. DOI: 10.1371/journal.pone.0062837. View

11.

De Rosa S, Greco M, Rauseo M, Annetta M . The Good, the Bad, and the Serum Creatinine: Exploring the Effect of Muscle Mass and Nutrition. Blood Purif. 2023; 52(9-10):775-785. PMC: 10623400. DOI: 10.1159/000533173. View

12.

Reeve J, Einecke G, Mengel M, Sis B, Kayser N, Kaplan B . Diagnosing rejection in renal transplants: a comparison of molecular- and histopathology-based approaches. Am J Transplant. 2009; 9(8):1802-10. DOI: 10.1111/j.1600-6143.2009.02694.x. View

13.

Chulia-Peris L, Carreres-Rey C, Gabasa M, Alcaraz J, Carretero J, Pereda J . Matrix Metalloproteinases and Their Inhibitors in Pulmonary Fibrosis: EMMPRIN/CD147 Comes into Play. Int J Mol Sci. 2022; 23(13). PMC: 9267107. DOI: 10.3390/ijms23136894. View

14.

Erdbrugger U, Blijdorp C, Bijnsdorp I, Borras F, Burger D, Bussolati B . Urinary extracellular vesicles: A position paper by the Urine Task Force of the International Society for Extracellular Vesicles. J Extracell Vesicles. 2021; 10(7):e12093. PMC: 8138533. DOI: 10.1002/jev2.12093. View

15.

Pontillo C, Mischak H . Urinary peptide-based classifier CKD273: towards clinical application in chronic kidney disease. Clin Kidney J. 2017; 10(2):192-201. PMC: 5499684. DOI: 10.1093/ckj/sfx002. View

16.

Honkanen E, Teppo A, Tornroth T, Groop P, Gronhagen-Riska C . Urinary transforming growth factor-beta 1 in membranous glomerulonephritis. Nephrol Dial Transplant. 1998; 12(12):2562-8. DOI: 10.1093/ndt/12.12.2562. View

17.

Koukoulis G, Shen J, Virtanen I, Gould V . Vitronectin in the cirrhotic liver: an immunomarker of mature fibrosis. Hum Pathol. 2002; 32(12):1356-62. DOI: 10.1053/hupa.2001.29675. View

18.

Varma V, Kajdacsy-Balla A, Akkina S, Setty S, Walsh M . Predicting Fibrosis Progression in Renal Transplant Recipients Using Laser-Based Infrared Spectroscopic Imaging. Sci Rep. 2018; 8(1):686. PMC: 5766495. DOI: 10.1038/s41598-017-19006-1. View

19.

Rayego-Mateos S, Valdivielso J . New therapeutic targets in chronic kidney disease progression and renal fibrosis. Expert Opin Ther Targets. 2020; 24(7):655-670. DOI: 10.1080/14728222.2020.1762173. View

20.

Fuster-Martinez I, Calatayud S . The current landscape of antifibrotic therapy across different organs: A systematic approach. Pharmacol Res. 2024; 205:107245. DOI: 10.1016/j.phrs.2024.107245. View