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Identification of Glomerular and Plasma Apolipoprotein M as Novel Biomarkers in Glomerular Disease
Yelena Drexler1,2, Judith Molina1,2, Tali Elfassy1,2
1Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA.
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.
Insights
Plasma apolipoprotein M (pApoM) is a potential noninvasive biomarker for glomerular apolipoprotein M (gApoM) deficiency in glomerular diseases (GDs). Lower pApoM levels correlate with reduced kidney function and predict treatment outcomes.
Area of Science:
- Nephrology
- Metabolic pathways
- Biomarker discovery
Background:
- Sphingolipid and cholesterol metabolism dysregulation contributes to glomerular diseases (GDs).
- Apolipoprotein M (ApoM) influences cholesterol efflux and sphingosine-1-phosphate (S1P) levels.
- Reduced glomerular ApoM (gApoM) is observed in focal segmental glomerulosclerosis (FSGS).
Purpose of the Study:
- To investigate glomerular ApoM deficiency in GD.
- To determine the correlation between ApoM expression and clinical outcomes in GD patients.
Main Methods:
- Studied 84 GD patients and 6 controls from the Nephrotic Syndrome Study Network (NEPTUNE).
- Compared glomerular mRNA expression of ApoM (gApoM), SPHK1, and S1PR1-5.
- Analyzed correlations between gApoM, plasma ApoM (pApoM), urine ApoM (uApoM/Cr), and clinical outcomes (eGFR, proteinuria, remission, ESKD).
Main Results:
- gApoM was reduced, while SPHK1 and S1PR1-5 expression was increased in patients versus controls.
- gApoM positively correlated with pApoM across the cohort and in FSGS/MCD subgroups.
- Decreased gApoM and pApoM were associated with lower baseline eGFR.
- pApoM predicted complete remission (CR) in Cox models.
Conclusions:
- Plasma ApoM (pApoM) serves as a potential noninvasive biomarker for glomerular ApoM (gApoM) deficiency in GD.
- pApoM levels are strongly associated with clinical outcomes in patients with glomerular diseases.
