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A4176 - Cholesterylester Transfer Protein (CETP) Gain-of-Function (GOF) Genotype R468Q and Development of Sepsis-Associated Acute Kidney Injury (AKI)
Author Block: K. Roveran Genga, M. Trinder, H. Kong, A. K. Leung, T. Shimada, K. R. Walley, J. A. Russell, L. Brunham, J. H. Boyd; Centre for Heart and Lung Innovation - St. Paul's Hospital - University of British Columbia, Vancouver, BC, Canada.
Rationale: Previously, we demonstrated that high density cholesterol (HDL-c) levels drop acutely in sepsis and the magnitude of this drop was one of the strongest predictors of development of sepsis-associated AKI. CETP single nucleotide polymorphism (SNP) GOF R468Q (rs1800777) has been associated with lower HDL-c levels in the healthy population. It is not clear whether the presence of this variant results in greater risk of development of sepsis-associated AKI.
Methods: Cohort #1: 202 patients enrolled in the emergency department following activation of the institutional sepsis protocol at St. Paul’s Hospital, Vancouver, Canada from 2011 to 2015. The enrolled patients were classified in 2 groups: those who developed clinically significant sepsis-associated AKI (AKI KDIGO stages 2 and 3, and those who did not develop it (AKI KDIGO stages 0 and 1). Lipids were measured at admission and patients were genotyped for CETP variant rs1800777. Pre-sepsis lipid levels were retrieved from patients’ health records. We evaluated the associations between CETP GOF genotype and the development of clinically significant sepsis-associated AKI using logistic regression models with adjustments for age, gender, APACHE II score and ethnicity (Caucasian vs. non-Caucasian). We also compared the pre-sepsis and sepsis admission HDL-c levels according to the presence of this SNP. Cohort #2: 532 patients enrolled into the Vasopressin in Septic Shock Trial (VASST) were genotyped for CETP variant rs1800777 and its association with sepsis associated AKI was analyzed. No lipid data was available in VASST.
Results: Cohort #1: The frequency of one copy of CETP rs1800777 was 5% (n=10). Patients who carried this SNP had slightly lower pre-sepsis HDL-c levels compared to non-carriers (40.86 mg/dL vs. 46.26 mg/dL, p=0.589). However, significantly lower HDL-c levels at sepsis admission were observed among the carriers (21.50 mg/dL vs. 35.28 mg/dL, p=0.003), and went on to develop a more pronounced drop in the HDL-c levels during sepsis compared to baseline pre-sepsis levels (47% reduction vs 24% reduction, p=0.069). In the overall cohort 60 patients (29.7%) developed AKI stages 2 and 3. The presence of CETP rs1800777 was strongly associated with an increased risk of clinically significant sepsis-associated AKI (adjusted OR: 4.83, 95% CI: 1.02 - 22.81; p=0.04). Cohort #2: We confirmed that the presence of CETP rs1800777 was strongly associated with an increased risk of clinically significant sepsis-associated AKI (adjusted OR: 2.33, p=0.02).
Conclusion: CETP GOF genotype was independently associated with increased risk of development of sepsis-associated AKI in two independent cohorts.