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Abstract: TH-PO429

A Novel Non-Invasive Biomarker Targeting LG3 From Perlecan Can Identify Lupus Nephritis (LN) Patients and Differentiate LN Subclasses

Session Information

Category: Glomerular Diseases

  • 1301 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Laursen, Clara Fia Gøricke, Nordic Bioscience, Herlev, Herlev , Denmark
  • Møller, Alexandra L., Nordic Bioscience, Herlev, Herlev , Denmark
  • Sparding, Nadja, Nordic Bioscience, Herlev, Herlev , Denmark
  • Genovese, Federica, Nordic Bioscience, Herlev, Herlev , Denmark
  • Karsdal, Morten Asser, Nordic Bioscience, Herlev, Herlev , Denmark
  • Hruskova, Zdenka, Univerzita Karlova, Praha, Czechia
  • Tesar, Vladimir, Univerzita Karlova, Praha, Czechia
Background

Perlecan is an extracellular matrix (ECM) protein important for kidney development and function. Unbalanced turnover of ECM proteins is a hallmark of chronic and fibrotic diseases. Cleavage fragments of perlecan could thus provide important knowledge in kidney disease pathologies. LG3 is a fragment liberated from endorepellin, a signalling molecule from perlecan with antiangiogenic and autophagic properties where LG3 harbours most of the activity. LG3 has been demonstrated to be associated with e.g end-stage renal disease (ESRD), chronic allograft nephropathy and lupus nephritis (LN). In LN, LG3 autoantibodies have been suggested to contribute to the characteristic microvascular damage occuring. Until now it has not been possible to distinguish LG3 from endorepellin or intact perlecan by ELISA.

Methods

We developed a technically robust and accurate competitive enzyme-linked immunosorbent assay biomarker, with a monoclonal antibody specifically targeting the N-terminal site of LG3 generated by BMP-1 cleavage. The LG3 assay was validated in healthy donor serum, plasma heparin, EDTA and urine samples. Moreover, the biological relevance of LG3 was evaluated in serum (n=48) and urine (n=52) from patients with LN, as well as serum (n=65) and urine (n= 48) from age and gender-matched healthy controls for comparison. All urine values were corrected for urinary creatinine.

Results

Levels of LG3 were significantly elevated in patients with LN in both serum (P<0.0001) and urine (P=0.0008), compared to healthy controls. Moreover, urine LG3 levels were able to significantly distinguish patients diagnosed with class IV or class IV+V LN, with class IV being the most common subclass as well as having the worst prognosis, from the other subclasses (P=0.0023). Class IV LN can further be divided into diffuse segmental (S) or global (G) LN, with significantly increased levels of urine LG3 levels in class IV-G LN (P=0.0430), associated with a higher risk of ESRD compared to class IV-S.

Conclusion

These results suggest a possible association of LG3 with LN pathogenesis and demonstrates the diagnostic potential of the biomarker. To evaluate the prognostic, predictive and pharmacodynamic potential of the novel biomarker more studies need to be conducted.