Kidney function is associated with an altered protein composition of high-density lipoprotein

Abstract

Patients with chronic kidney disease (CKD) exhibit a myriad of metabolic derangements including dyslipidemia characterized by low plasma concentrations of high-density lipoprotein (HDL)-associated cholesterol. However, the effects of kidney disease on HDL composition have not been comprehensively determined. Here we used a targeted mass spectrometric approach to quantify 38 proteins contained in the HDL particles within a CKD cohort of 509 participants with a broad range of estimated glomerular filtration rates (eGFR) (CKD stages I-V, and a mean eGFR of 45.5 mL/min/1.73m2). After adjusting for multiple testing, demographics, comorbidities, medications, and other characteristics, eGFR was significantly associated with differences in four HDL proteins. Compared to participants with an eGFR of 60 mL/min/1.73m2 or more, those with an eGFR under 15 mL/min/1.73m2 exhibited 1.89-fold higher retinol binding protein 4 (95% confidence interval 1.34-2.67), 1.52-fold higher apolipoprotein C-III (1.25-1.84),0.70-fold lower apolipoprotein L1 (0.55-0.92), and 0.64-fold lower vitronectin (0.48- 0.85). Although the HDL apolipoprotein L1 was slightly lower among African-American than among Caucasian individuals, the relationship to eGFR did not differ by race. After adjustment, no HDL-associated proteins associated with albuminuria. Thus, modest changes in the HDL proteome provide preliminary evidence for an association between HDL proteins and declining kidney function, but this needs to be replicated. Future analyses will determine if HDL proteomics is indeed a clinical predictor of declining kidney function or cardiovascular outcomes.

Alteration of HDL Protein Composition with Hemodialysis Initiation

“…Because the same amount of HDL protein was used for each sample, changes in relative protein concentrations represent changes in the amount of protein per 10 mg total HDL protein. We quantified 38 proteins that are abundant in the HDL proteome and have been previously assayed using the same protocol (13,(15)(16)(17).…”

“…However, these findings do not distinguish the potential effects of longstanding kidney failure from those of the hemodialysis procedure itself, which stimulates proinflammatory and prothrombotic pathways. A recent study of HDL composition among patients not on dialysis across a wide range of kidney function showed associations of lower eGFR with higher HDL-associated concentrations of retinol binding protein 4 (RBP4) and APOC3 and lower HDL-associated concentrations of APOL1 and vitronectin (13).…”

ESRD‐induced dyslipidemia—Should management of lipid disorders differ in dialysis patients?

“…End stage renal disease is associated with a significant reduction in serum concentrations of apoAI and HDL particle . This is accompanied by reduced HDL cholesterol content and altered lipid and protein composition including enrichment with TGs and proinflammatory proteins including serum amyloid A . In addition, in patients with ESRD compared to normal controls, there is a significant decrease in HDL antioxidant, anti‐inflammatory, and antithrombotic properties .…”

“…29,30 This is accompanied by reduced HDL cholesterol content and altered lipid and protein composition including enrichment with TGs and proinflammatory proteins including serum amyloid A. 19,31,32 In addition, in patients with ESRD compared to normal controls, there is a significant decrease in HDL antioxidant, anti-inflammatory, and antithrombotic properties. [33][34][35][36] Furthermore, HDL-associated vasoprotective effects including nitric oxide mediated vasodilatation are diminished in CKD and there is a significant disruption in HDL-mediated reverse cholesterol transport (RCT).…”

Proteomic and metabolomic approaches in the search for biomarkers in chronic kidney disease

“…Changes in eGFR were significantly associated with the levels of four proteins contained in the high density lipoprotein (HDL) particles of a cohort of 509 CKD patients. Patients with kidney failure exhibited higher levels of retinol-binding protein 4, apolipoprotein C-III, versus lower apolipoprotein L1 and vitronectin [34]. In a small sample of seven CKD stage 5 patients, albumin, apolipoprotein A-II and complement factor C8 γ-and β-chains were shown differentially depleted compared to seven matched healthy controls [35].…”