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High-Density Lipoprotein Lipidomics and Mortality in CKD
Benjamin Lidgard1, Andrew N Hoofnagle1, Leila R Zelnick1
1University of Washington, Seattle, WA.
Insights
Dysfunctional high-density lipoprotein (HDL) in chronic kidney disease (CKD) is linked to mortality. Specific HDL lipids like ceramides and phosphatidylcholines increase mortality risk, suggesting they are novel cardiovascular risk factors in CKD.
Area of Science:
- Nephrology
- Cardiovascular Research
- Lipidomics
Background:
- Patients with chronic kidney disease (CKD) exhibit dysfunctional high-density lipoprotein (HDL) particles lacking cardioprotective effects.
- Altered lipid composition of HDL may underlie these functional deficits and contribute to cardiovascular risk in CKD.
Purpose of the Study:
- To investigate the association between specific HDL lipids (ceramides, sphingomyelins, phosphatidylcholines) and all-cause mortality in patients with CKD.
- To identify potential novel cardiovascular risk factors within HDL particles in the context of CKD.
Main Methods:
- Utilized data from a longitudinal prospective cohort of adult patients with CKD (excluding dialysis/transplant).
- Isolated HDL particles via density gradient ultracentrifugation and quantified lipid abundance using liquid chromatography tandem mass spectrometry (LC-MS/MS).
- Employed Cox regression models adjusted for multiple confounders and controlled for false discovery rates (FDR).
Main Results:
- Over a median follow-up of 6.12 years, 168 deaths occurred.
- Increased relative abundance of HDL ceramides, long-chain fatty acid sphingomyelins, and saturated/monounsaturated phosphatidylcholines were significantly associated with higher all-cause mortality risk (FDR < 5%).
- Sphingomyelins with very long fatty acids showed a trend towards lower mortality risk.
Conclusions:
- Specific HDL lipid classes, including ceramides and certain phosphatidylcholines, are associated with increased all-cause mortality risk in CKD patients.
- These findings suggest that the altered lipid composition of HDL particles may represent a novel cardiovascular risk factor in CKD.
- Further research is needed to explore the precise mechanisms and clinical implications of these HDL lipid alterations.
Rationale & Objective:
Patients with chronic kidney disease (CKD) have dysfunctional high-density lipoprotein (HDL) particles that lack cardioprotective properties; altered lipid composition may be associated with these changes. To investigate HDL lipids as potential cardiovascular risk factors in CKD, we tested the associations of HDL ceramides, sphingomyelins, and phosphatidylcholines with mortality.
Study Design:
We leveraged data from a longitudinal prospective cohort of participants with CKD.
Setting & Participants:
We included participants aged greater than 21 years with CKD, excluding those on maintenance dialysis or with prior kidney transplant.
Exposure:
HDL particles were isolated using density gradient ultracentrifugation. We quantified the relative abundance of HDL ceramides, sphingomyelins, and phosphatidylcholines via liquid chromatography tandem mass spectrometry (LC-MS/MS).
Outcomes:
Our primary outcome was all-cause mortality.
Analytical Approach:
We tested associations using Cox regressions adjusted for demographics, comorbid conditions, laboratory values, medication use, and highly correlated lipids with opposed effects, controlling for multiple comparisons with false discovery rates (FDR).
Results:
There were 168 deaths over a median follow-up of 6.12 years (interquartile range, 3.71-9.32). After adjustment, relative abundance of HDL ceramides (HR, 1.22 per standard deviation; 95% CI, 1.06-1.39), sphingomyelins with long fatty acids (HR, 1.44; 95% CI, 1.05-1.98), and saturated and monounsaturated phosphatidylcholines (HR, 1.22; 95% CI, 1.06-1.41) were significantly associated with increased risk of all-cause mortality (FDR < 5%).
Limitations:
We were unable to test associations with cardiovascular disease given limited power. HDL lipidomics may not reflect plasma lipidomics. LC-MS/MS is unable to differentiate between glucosylceramides and galactosylceramides. The cohort was comprised of research volunteers in the Seattle area with CKD.
Conclusions:
Greater relative HDL abundance of 3 classes of lipids was associated with higher risk of all-cause mortality in CKD; sphingomyelins with very long fatty acids were associated with a lower risk. Altered lipid composition of HDL particles may be a novel cardiovascular risk factor in CKD.
Plain-Language Summary:
Patients with chronic kidney disease have abnormal high-density lipoprotein (HDL) particles that lack the beneficial properties associated with these particles in patients with normal kidney function. To investigate if small lipid molecules found on the surface of HDL might be associated with these changes, we tested the associations of lipid molecules found on HDL with death among patients with chronic kidney disease. We found that several lipid molecules found on the surface of HDL were associated with increased risk of death among these patients. These findings suggest that lipid molecules may be risk factors for death among patients with chronic kidney disease.
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