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

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

Yelena Drexler  1   2 , Judith Molina  1   2 , Tali Elfassy  1   2 , Ruixuan Ma  3 , Christina Christoffersen  4   5 , Makoto Kurano  6 , Yutaka Yatomi  6 , Laura H Mariani  7 , Gabriel Contreras  1   2 , Sandra Merscher  1   2 , Alessia Fornoni  1   2
Affiliations

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

Yelena Drexler et al. Kidney Int Rep. .

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.

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Figures

Figure 1
Figure 1
Glomerular ApoM expression and ApoM/S1P pathway modulation in GD. (a) gApoM expression in GD patients vs controls, P <0.001. (b) gApoM expression in subgroups vs controls, ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001, ∗∗∗∗P < 0.0001; ns, nonsignificant. (c) Glomerular SPHK1 expression in GD patients vs controls, P < 0.05. (d) Glomerular SPHK2 expression in GD patients vs controls. (e-h) Glomerular expression of S1PR1-5 in GD patients vs controls, P < 0.05 for all comparisons except S1PR5 vs controls. ApoM, apolipoprotein M; FSGS, focal segmental glomerulosclerosis; GD, glomerular disease; MCD, minimal change disease; MN, membranous nephropathy; S1P, sphingosine-1-phosphate; SPHK1, sphingosine kinase 1; SPHK2, sphingosine kinase 2; S1PR1-5, S1P receptors 1 to 5.
Figure 1
Figure 1
Glomerular ApoM expression and ApoM/S1P pathway modulation in GD. (a) gApoM expression in GD patients vs controls, P <0.001. (b) gApoM expression in subgroups vs controls, ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001, ∗∗∗∗P < 0.0001; ns, nonsignificant. (c) Glomerular SPHK1 expression in GD patients vs controls, P < 0.05. (d) Glomerular SPHK2 expression in GD patients vs controls. (e-h) Glomerular expression of S1PR1-5 in GD patients vs controls, P < 0.05 for all comparisons except S1PR5 vs controls. ApoM, apolipoprotein M; FSGS, focal segmental glomerulosclerosis; GD, glomerular disease; MCD, minimal change disease; MN, membranous nephropathy; S1P, sphingosine-1-phosphate; SPHK1, sphingosine kinase 1; SPHK2, sphingosine kinase 2; S1PR1-5, S1P receptors 1 to 5.
Figure 2
Figure 2
Correlations between gApoM, pApoM, and uApoM/Cr in GD and among subgroups. (a) Correlation between gApoM expression and pApoM in the GD cohort. (b) Correlation between gApoM expression and pApoM in the FSGS subgroup. (c) Correlation between gApoM expression and pApoM in the MCD subgroup. (d) Correlation between gApoM expression and uApoM/Cr in the GD cohort. FSGS, focal segmental glomerulosclerosis; GD, glomerular disease; MCD, minimal change disease.
Figure 3
Figure 3
Associations between gApoM and pApoM with baseline eGFR. (a) Linear regression showing the association between gApoM expression and baseline eGFR in the GD cohort. (b) Linear regression showing the association between pApoM and baseline eGFR in the GD cohort. ApoM, apolipoprotein M; eGFR, estimated glomerular filtration rate.
Figure 4
Figure 4
Associations between gApoM, pApoM, and uApoM with baseline UPCR. (a) Association between pApoM and baseline UPCR. (b) Association between pApoM and UPCR, stratified by baseline eGFR >60 mL/min/1.73 m2. (c) Association between pApoM and UPCR, stratified by baseline eGFR <60 mL/min/1.73 m2. (d) Association between pApoM and UPCR, stratified by baseline UPCR >3 g/g (UPCR log2 >1.585). (e) Association between pApoM and UPCR, stratified by baseline UPCR <3 g/g (UPCR log2 >1.585). (f) Association between pApoM and UPCR, stratified by plasma S1P above the median. (g) Association between pApoM and UPCR, stratified by plasma S1P below the median. (h) Association between uApoM/Cr and baseline UPCR in the GD cohort. eGFR, estimated glomerular filtration rate; pS1P, plasma sphingosine-1-phosphate; UPCR, urine protein-to-creatinine ratio.
Figure 4
Figure 4
Associations between gApoM, pApoM, and uApoM with baseline UPCR. (a) Association between pApoM and baseline UPCR. (b) Association between pApoM and UPCR, stratified by baseline eGFR >60 mL/min/1.73 m2. (c) Association between pApoM and UPCR, stratified by baseline eGFR <60 mL/min/1.73 m2. (d) Association between pApoM and UPCR, stratified by baseline UPCR >3 g/g (UPCR log2 >1.585). (e) Association between pApoM and UPCR, stratified by baseline UPCR <3 g/g (UPCR log2 >1.585). (f) Association between pApoM and UPCR, stratified by plasma S1P above the median. (g) Association between pApoM and UPCR, stratified by plasma S1P below the median. (h) Association between uApoM/Cr and baseline UPCR in the GD cohort. eGFR, estimated glomerular filtration rate; pS1P, plasma sphingosine-1-phosphate; UPCR, urine protein-to-creatinine ratio.
Figure 5
Figure 5
Associations between pApoM and complete remission. CI, confidence interval; eGFR, estimated glomerular filtration rate; HR, hazard ratio; UPCR, urine protein-to-creatinine ratio.
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