ApoM and Major Adverse Cardiovascular Events in Chronic Kidney Disease: A Prospective Cohort Study

Abstract

Background: Cardiovascular disease is the leading cause of mortality in patients with chronic kidney disease (CKD). APOM plays a critical role in reverse cholesterol transport by facilitating the formation of pre-β-HDL (high-density lipoprotein) and enabling the binding of S1P (sphingosine-1-phosphate) to HDL, a complex involved in several antiatherogenic processes. In this study, we sought to investigate the potential association between plasma APOM levels and the risk of adverse cardiovascular outcomes in individuals with CKD.

Methods: Plasma APOM levels were quantified using a sandwich ELISA-based assay. Plasma S1P levels were measured by high-performance liquid chromatography. The primary end point was a composite of major adverse cardiovascular events (MACE) and all-cause mortality.

Results: In this secondary analysis of the CARE FOR HOMe study (Cardiovascular and Renal Outcome in CKD 2-4 Patients-The Fourth Homburg Evaluation), 463 nondialysis patients with CKD stages G2 to G4 were included. Plasma APOM levels exhibited a significant inverse association with the risk of MACE (standardized hazard ratio, 0.60 [95% CI, 0.49-0.75]; P<0.001) and all-cause mortality (standardized hazard ratio, 0.63 [95% CI, 0.48-0.83]; P<0.001). This inverse association with MACE remained robust after adjusting for established cardiovascular and renal risk factors. These findings were further corroborated in an independent cohort of 822 patients with CKD from the Copenhagen CKD study. Plasma S1P levels showed an inverse association with MACE in univariable analyses; however, this relationship lost statistical significance after multivariable adjustments.

Conclusions: Our findings demonstrate a significant association between low plasma APOM levels and an increased risk of MACE in patients with CKD. These results suggest that APOM may play a role in cardiovascular protection in this vulnerable population.

Keywords: apolipoproteins M; cholesterol; humans; renal insufficiency, chronic; risk factors.

Figure 1.

Plasma levels of APOM are reduced in patients with advanced estimated glomerular filtration rate categories in the CARE FOR HOMe study (Cardiovascular and Renal Outcome in CKD 2–4 Patients–The Fourth Homburg Evaluation). Plasma levels of APOM in patients stratified by severity stages of chronic kidney disease (A). APOM/high-density lipoprotein cholesterol (HDL-C) ratio to correct for differences in HDL-C levels (B). Association of plasma APOM with prevalent cardiovascular disease (CVD; C), prevalent diabetes (D), and lipid-lowering medication (E). Data are presented as boxplots, displaying the median, interquartile range, and minimum and maximum values. Differences between groups were analyzed by the Kruskal-Wallis test followed by post hoc Dunn multiple comparison test.

Figure 2.

Correlation of plasma APOM levels with clinical characteristics in patients with chronic kidney disease (CKD) of the CARE FOR HOMe study (Cardiovascular and Renal Outcome in CKD 2–4 Patients–The Fourth Homburg Evaluation). Each cell of the heatmap represents a pairwise Spearman correlation between the 2 parameters indicated in the respective row and column. Significant correlations (P<0.05) are indicated with the corresponding Spearman correlation coefficient. Nonsignificant correlations can still be inferred from the color but are not explicitly indicated. BMI indicates body mass index; BP, blood pressure; CRP, c-reactive protein; eGFR, estimated glomerular filtration rate; GOT, glutamic oxaloacetic transaminase; HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol; IMT, intima-media thickness; LDL-C, low-density lipoprotein cholesterol; and proBNP, pro-B-type natriuretic peptide.

Figure 3.

Risk of adverse outcomes among patients with chronic kidney disease (CKD) of the CARE FOR HOMe study (Cardiovascular and Renal Outcome in CKD 2–4 Patients–The Fourth Homburg Evaluation) and tertiles of APOM plasma levels. Kaplan-Meier plots with subsequent log-rank tests for risk of major atherosclerotic cardiovascular events (MACE*; A) and all-cause mortality (B) are shown. The number of patients at each time point is presented below the graph. *Composite of MACE, including death of any cause.

Figure 4.

Hazard ratios (HRs) per 1 SD increase and 95% CIs from Cox regression analyses. Plasma APOM levels were standardized and used as continuous variables, and risk with major atherosclerotic cardiovascular events (MACE)* and all-cause mortality was assessed. The adjusted model includes age, sex, and estimated glomerular filtration rate. *Composite of MACE, including all-cause mortality.

Figure 5.

APOM, but not high-density lipoprotein cholesterol (HDL-C), is inversely associated with the risk of major adverse cardiovascular events (MACE) in the CARE FOR HOMe study (Cardiovascular and Renal Outcome in CKD 2–4 Patients–The Fourth Homburg Evaluation). Hazard ratios per 1 SD increase and 95% CIs. HR indicates hazard ratio. *Univariable analyses. **Analyses adjusted for either APOM or HDL-C.