We evaluated biomarkers related to kidney fibrosis for the outcome of patients with IgA nephropathy (IgAN). Clinical parameters (estimated glomerular filtration rate, hypertension, proteinuria) and histological findings were assessed in 134 patients with IgAN at the time of diagnosis and followed up prospectively (mean follow-up time, 56.5 months). We measured biomarkers of collagen and laminin turnover in serum and urine collected at the time of kidney biopsy using a novel enzyme-linked immunosorbent assay. Linear discriminant analysis and logistic regression models were used to predict the patient's kidney outcome. Five serum and urine biomarkers of laminin and collagen turnover (sLG1M, sPRO-C3, sPRO-C6, uPRO-C6/Cr, uC3M/Cr) could significantly differentiae IgAN patients with a worse prognosis. Clinical parameters (glomerular filtration rate (GFR), proteinuria) distinguished patients at risk of IgAN progression with a specificity of 87.3% and a sensitivity of 45.2% (area under the curve-AUC 0.751). The addition of the biomarkers significantly increased the prognostic ability with a specificity of 85.1% and a sensitivity of 73.3% (AUC 0.905). We have identified three serum (sLG1M, sPRO-C3, sPRO-C6) and two urinary markers (uPRO-C6/Cr, u-C3M /Cr) that significantly improve the prognostic ability of markers of kidney function to identify an IgAN patient's risk of progressing to ESKD.

Consultant of Chemometrics 140 00 Prague Czech Republic

Department of Clinical and Transplant Pathology Institute of Clinical and Experimental Medicine 140 21 Prague Czech Republic

Department of Nephrology 1st Faculty of Medicine and General University Hospital Charles University 128 08 Prague Czech Republic

Institute of Medical Biochemistry and Laboratory Diagnostics 1st Faculty of Medicine and General University Hospital Charles University 128 08 Prague Czech Republic

Nordic Bioscience 2730 Herlev Denmark

Zobrazit více v PubMed

Boor P., Ostendorf T., Floege J. Renal fibrosis: Novel insights into mechanisms and therapeutic targets. Nat. Rev. Nephrol. 2010;6:643–656. doi: 10.1038/nrneph.2010.120. PubMed DOI

Gross M.L., Ritz E. Hypertrophy and fibrosis in the cardiomyopathy of uremia—Beyond coronary heart disease. Semin. Dial. 2008;21:308–318. doi: 10.1111/j.1525-139X.2008.00454.x. PubMed DOI

Papasotiriou M., Genovese F., Klinkhammer B.M., Kunter U., Nielsen S.H., Karsdal M.A., Floege J., Boor P. Serum and urine markers of collagen degradation reflect renal fibrosis in experimental kidney diseases. Nephrol. Dial. Transpl. 2015;30:1112–1121. doi: 10.1093/ndt/gfv063. PubMed DOI

Genovese F., Boor P., Papasotiriou M., Leeming D.J., Karsdal M.A., Floege J. Turnover of type III collagen reflects disease severity and is associated with progression and microinflammation in patients with IgA nephropathy. Nephrol. Dial. Transpl. 2016;31:472–479. doi: 10.1093/ndt/gfv301. PubMed DOI

Barbour S.J., Reich H.N. Risk stratification of patients with IgA nephropathy. Am. J. Kidney Dis. 2012;59:865–873. doi: 10.1053/j.ajkd.2012.02.326. PubMed DOI

Soylemezoglu O., Wild G., Dalley A.J., MacNeil S., Milford-Ward A., Brown C.B., Nahas A. Urinary and serum type III collagen: Markers of renal fibrosis. Nephrol. Dial. Transpl. 1997;12:1883–1889. doi: 10.1093/ndt/12.9.1883. PubMed DOI

Morita M., Uchigata Y., Hanai K., Ogawa Y., Iwamoto Y. Association of urinary type IV collagen with GFR decline in young patients with type 1 diabetes. Am. J. Kidney Dis. 2011;58:915–920. doi: 10.1053/j.ajkd.2011.04.019. PubMed DOI

Okonogi H., Nishimura M., Utsunomiya Y., Hamaguchi K., Tsuchida H., Miura Y., Suzuki S., Kawamura T., Hosoya T., Yamada K. Urinary type IV collagen excretion reflects renal morphological alterations and type IV collagen expression in patients with type 2 diabetes mellitus. Clin. Nephrol. 2001;55:357–364. PubMed

Kawase T., Shimizu A., Adachi E., Tojimbara T., Nakajima I., Fuchinoue S., Sawada T. Collagen IV is upregulated in chronic transplant nephropathy. Transpl. Proc. 2001;33:1207–1208. doi: 10.1016/S0041-1345(00)02388-5. PubMed DOI

Abrahamson D.R., St John P.L. Laminin distribution in developing glomerular basement membranes. Kidney Int. 1993;43:73–78. doi: 10.1038/ki.1993.13. PubMed DOI

Catania J.M., Chen G., Parrish A.R. Role of matrix metalloproteinases in renal pathophysiologies. Am. J. Physiol. Ren. Physiol. 2007;292:F905–F911. doi: 10.1152/ajprenal.00421.2006. PubMed DOI

Genovese F., Manresa A., Leeming D.J., Karsdal M.A., Boor P. The extracellular matrix in the kidney: A source of novel non-invasive biomarkers of kidney fibrosis? Fibrogenesis Tissue Repair. 2014;7:4. doi: 10.1186/1755-1536-7-4. PubMed DOI PMC

Karsdal M. Biochemistry of Collagens, Laminins and Elastin. Elsevier; Amsterdam, The Netherlands: 2016.

Nielsen S.H., Rasmussen DG K., Brix S., Fenton A., Jesky M., Ferro C.H.J., Karsdal M., Genovese F., Cockwell P. A novel biomarker of laminin turnover is associated with disease progression and mortality in chronic kidney disease. PLoS ONE. 2018;13:e0204239. doi: 10.1371/journal.pone.0204239. PubMed DOI PMC

Nielsen M.J., Veidal S.S., Karsdal M.A., Ørsnes-Leeming D.J., Vainer B., Gardner S.D., Hamatake R., Goodman Z.D., Schuppan D., Patel K. Plasma Pro-C3 (N-terminal type III collagen propeptide) predicts fibrosis progression in patients with chronic hepatitis. Liver Int. 2015;35:429–437. doi: 10.1111/liv.12700. PubMed DOI

Genovese F., Kring D., Rasmussen G., Karsdal M.A., Jesky M.A., Ferro Ch Fenton A., Cockwell P. Imbalanced turnover of collagen type III is associated with disease progression and mortality in high-risk chronic kidney disease patients. Clin. Kidney J. 2021;14:593–601. doi: 10.1093/ckj/sfz174. PubMed DOI PMC

Zwirner J., Burg M., Schulze M., Brunkhorst R., Götze O., Koch K.M., Floege J. Activated complement C3: A potentially novel predictor of progressive IgA nephropathy. Kidney Int. 1997;51:1257–1264. doi: 10.1038/ki.1997.171. PubMed DOI

Janssen U.L., Bahlmann F., Köhl J., Zwirner J., Haubitz M., Floege J. Activation of the acute phase response and complement C3 in patients with IgA nephropathy. Am. J. Kidney Dis. 2000;35:21–28. doi: 10.1016/S0272-6386(00)70296-4. PubMed DOI

Stribos E.G.D., Nielsen S.H., Brix S., Karsdal M.A., Seelen M.A., van Goor H., Bakker S.J.L., Olinga P., Mutsaers H.A.M., Genovese F. Non-invasive quantification of collagen turnover in renal transplant recipients. PLoS ONE. 2017;12:e0175898. doi: 10.1371/journal.pone.0175898. PubMed DOI PMC

Nielsen M.J., Nedergaard A.F., Sun S., Veidal S.S., Larsen L., Zheng Q., Suetta C., Henriksen K., Christiansen K., Karsdal M.A., et al. The neo-epitope specific PRO-C3 ELISA measures true formation of type III collagen associated with liver and muscle parameters. Am. J. Trans. Res. 2013;19:303–315. PubMed PMC

Sun S., Henriksen K., Karsdal M.A., Byrjalsen I., Rittweger J., Armrecht G., Belavy D.L., Felsenberg D., Nedergaard A.F. Collagen Type III and VI Turnover in Response to Long-Term Immobilization. PLoS ONE. 2015;10:e0144525. doi: 10.1371/journal.pone.0144525. PubMed DOI PMC

Unique Biomarkers of Collagen Type III Remodeling Reflect Different Information Regarding Pathological Kidney Tissue Alterations in Patients with IgA Nephropathy