Identification of Glomerular and Plasma Apolipoprotein M as Novel Biomarkers in Glomerular Disease

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Yelena Drexler
  • Judith Molina
  • Tali Elfassy
  • Ruixuan Ma
  • Christoffersen, Christina
  • Makoto Kurano
  • Yutaka Yatomi
  • Laura H. Mariani
  • Gabriel Contreras
  • Sandra Merscher
  • Alessia Fornoni

Introduction: Dysregulation of sphingolipid and cholesterol metabolism contributes to the pathogenesis of glomerular diseases (GDs). Apolipoprotein M (ApoM) promotes cholesterol efflux and modulates the bioactive sphingolipid sphingosine-1-phosphate (S1P). Glomerular ApoM expression is decreased in patients with focal segmental glomerulosclerosis (FSGS). We hypothesized that glomerular ApoM deficiency occurs in GD and that ApoM expression and plasma ApoM correlate with outcomes. Methods: Patients with GD from the Nephrotic Syndrome Study Network (NEPTUNE) were studied. We compared glomerular mRNA expression of ApoM (gApoM), sphingosine kinase 1 (SPHK1), and S1P receptors 1 to 5 (S1PR1–5) in patients (n = 84) and controls (n = 6). We used correlation analyses to determine associations between gApoM, baseline plasma ApoM (pApoM), and urine ApoM (uApoM/Cr). We used linear regression to determine whether gApoM, pApoM, and uApoM/Cr were associated with baseline estimated glomerular filtration rate (eGFR) and proteinuria. Using Cox models, we determined whether gApoM, pApoM, and uApoM/Cr were associated with complete remission (CR) and the composite of end-stage kidney disease (ESKD) or ≥40% eGFR decline. Results: gApoM was reduced (P < 0.01) and SPHK1 and S1PR1 to 5 expression was increased (P < 0.05) in patients versus controls, consistent with ApoM/S1P pathway modulation. gApoM positively correlated with pApoM in the overall cohort (r = 0.34, P < 0.01) and in the FSGS (r = 0.48, P < 0.05) and minimal change disease (MCD) (r = 0.75, P < 0.05) subgroups. Every unit decrease in gApoM and pApoM (log2) was associated with a 9.77 ml/min per 1.73 m2 (95% confidence interval [CI]: 3.96−15.57) and 13.26 ml/min per 1.73 m2 (95% CI: 3.57−22.96) lower baseline eGFR, respectively (P < 0.01). From Cox models adjusted for age, sex, or race, pApoM was a significant predictor of CR (hazard ratio [HR]: 1.85; 95% CI: 1.06–3.23). Conclusions: pApoM is a potential noninvasive biomarker of gApoM deficiency and strongly associates with clinical outcomes in GD.

TidsskriftKidney International Reports
StatusAccepteret/In press - 2023

Bibliografisk note

Funding Information:
YD is supported by Grant Number UL1TR002736 , Miami Clinical and Translational Science Institute , from the National Center for Advancing Translational Sciences and the National Institute on Minority Health and Health Disparities . The Nephrotic Syndrome Study Network (NEPTUNE) is part of the Rare Diseases Clinical Research Network (RDCRN), which is funded by the National Institutes of Health and led by the National Center for Advancing Translational Sciences (NCATS) through its Division of Rare Diseases Research Innovation. NEPTUNE is funded under grant number U54DK083912 as a collaboration between NCATS and the National Institute of Diabetes and Digestive and Kidney Diseases. Additional funding and/or programmatic support is provided by the University of Michigan, NephCure Kidney International, and the Halpin Foundation. RDCRN consortia are supported by the RDCRN Data Management and Coordinating Center, funded by NCATS and the National Institute of Neurological Disorders and Stroke under U2CTR002818.

Publisher Copyright:
© 2023 International Society of Nephrology

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