A novel biomarker of laminin turnover is associated with disease progression and mortality in chronic kidney disease

PLoS One. 2018 Oct 1;13(10):e0204239. doi: 10.1371/journal.pone.0204239. eCollection 2018.

Abstract

Background: Patients with chronic kidney disease (CKD) have increased risk of development of end-stage renal disease (ESRD) and early mortality. Fibrosis is the central pathogenic process in CKD and is caused by dysregulated extracellular matrix (ECM) remodeling. The laminin γ1 chain (LAMC1) is a core structural protein present in the basement membrane of several organs, including the kidneys. We hypothesized that dysregulation of LAMC1 remodeling could be associated with a higher risk of adverse clinical outcomes in patients with CKD.

Methods: A novel immunoassay targeting LG1M, a specific MMP-9-generated neo-epitope fragment of LAMC1, was developed and used to measure the levels of the fragment in urine and serum from 492 patients from the Renal Impairment in Secondary Care (RIISC) study, a prospective cohort of patients with high-risk CKD. Patients were monitored for a median follow-up time of 3.5 years. Associations between serum and urine LG1M levels and progression of CKD at 12 months were assessed by a multivariable logistic regression model. The association with ESRD or mortality was assessed by Kaplan-Meier survival curves and Cox proportional hazards regression.

Results: Forty-six (11%) of the 416 patients who reached 12-month follow-up had progression of CKD; during the study follow-up, 125 patients (25.4%) developed ESRD and 71 patients (14.4%) died. Serum and urine levels of LG1M correlated with baseline eGFR (r = -0.43, p<0.0001 and r = -0.17, p = 0.0002, respectively). Serum levels of LG1M were higher in patients with one-year progression of CKD compared to those who did not progress (p<0.01). Baseline serum levels of LG1M were associated with development of ESRD (HR 3.2, 95% CI 1.99-5.2 for patients in the highest LG1M tertile compared to patient in the lowest tertile). Baseline urinary levels of LG1M (uLG1M) were significantly associated with mortality (HR 5.0, 95% CI 2.8-8.9, p<0.0001 for patients in the highest LG1M tertile compared to patients in the lowest tertile). Urine LG1M was retained in the model for prediction of mortality (HR per standard deviation of uLG1M: 1.01, 95% CI 1.00-1.02, p = 0.001).

Conclusions: LG1M, a marker of basement membrane remodeling, is increased in serum and urine of patients with CKD and levels are associated with one-year disease progression, development of ESRD, and mortality.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Biomarkers / blood*
  • Biomarkers / urine*
  • Cohort Studies
  • Disease Progression
  • Epitopes / blood*
  • Epitopes / urine*
  • Extracellular Matrix / metabolism
  • Female
  • Humans
  • Kidney Failure, Chronic / epidemiology
  • Laminin / immunology*
  • Logistic Models
  • Male
  • Matrix Metalloproteinase 9 / metabolism
  • Middle Aged
  • Proportional Hazards Models
  • Prospective Studies
  • Renal Insufficiency, Chronic / metabolism
  • Renal Insufficiency, Chronic / mortality*

Substances

  • Biomarkers
  • Epitopes
  • Laminin
  • laminin gamma 1
  • MMP9 protein, human
  • Matrix Metalloproteinase 9

Grants and funding

This work was supported by the Danish Research Fund (Den Danske Forskningsfond) to SHN. The Binding Site Ltd (Birmingham, UK) is acknowledged for the funding of the research fellowship of AF. The funder Nordic Bioscience provided support in the form of salaries for authors SHN, DGKR, MK and FGE, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The funder Binding Site Ltd. provided support in the form of salaries for author AF, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.