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

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

doi:10.1016/j.ekir.2023.01.031

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

Kidney Int Rep. 2023 Feb 4;8(4):884-897. doi: 10.1016/j.ekir.2023.01.031. eCollection 2023 Apr.

Authors

Yelena Drexler^{1

2}, Judith Molina^{1

2}, Tali Elfassy^{1

2}, Ruixuan Ma³, Christina Christoffersen^{4

5}, Makoto Kurano⁶, Yutaka Yatomi⁶, Laura H Mariani⁷, Gabriel Contreras^{1

2}, Sandra Merscher^{1

2}, Alessia Fornoni^{1

2}

Affiliations

¹ Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA.
² Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, USA.
³ Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, Florida, USA.
⁴ Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁵ Department of Clinical Biochemistry, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark.
⁶ Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan.
⁷ Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.

Abstract

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.

Keywords: apolipoprotein M; biomarkers; glomerular disease; nephrotic syndrome; outcome prediction.

Abstract

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