Atherosclerosis 233 (2014) 123e129
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Chronic kidney disease on hemodialysis is associated with decreased serum PCSK9 levels H. Abujrad a, J. Mayne b, M. Ruzicka c, f, M. Cousins a, A. Raymond a, J. Cheesman c, M. Taljaard d, e, A. Sorisky a, f, K. Burns c, f, T.C. Ooi a, f, * a
Division of Endocrinology and Metabolism, Department of Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada Division of Nephrology, Department of Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada d Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada e Ottawa Hospital Research Institute, Clinical Epidemiology Program, Ottawa, Ontario, Canada f Ottawa Hospital Research Institute, Chronic Disease Program, Ottawa, Ontario, Canada b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 23 August 2013 Received in revised form 3 December 2013 Accepted 9 December 2013 Available online 8 January 2014
Objectives: Serum low density lipoprotein-cholesterol (LDL-C) correlates positively with serum PCSK9 in the general population, consistent with PCSK9 being a determinant of LDL-C levels. Patients with chronic kidney disease (CKD) on hemodialysis (HD) have lower total cholesterol (TC) and LDL-C compared to the general population. Serum PCSK9 and its relationship with serum lipids have not been reported in CKD patients on HD (CKD-HD). Methods: We measured serum PCSK9 by ELISA and lipid levels in 66 CKD-HD patients and compared them to 178 non-CKD subjects. Since statins increase serum PCSK9 levels, CKD-HD patients were separated into those not on statin therapy (HD-NS, n ¼ 32) and those taking statins (HD-S, n ¼ 34). No control subjects were on statin therapy. Results: Serum PCSK9, TC, LDL-C and HDL-C levels were significantly lower in the CKD-HD group (n ¼ 66) compared to the control group. HD-NS patients showed lower PCSK9, TC and LDL-C levels than control subjects and PCSK9 levels correlated with TC and LDL-C levels (r ¼ 0.35, p ¼ 0.050; r ¼ 0.423, p ¼ 0.0158 respectively) as well as TG levels (r ¼ 0.413, p ¼ 0.0188). In HD-S patients, PCSK9 levels were not significantly different from the non-CKD group. There was no correlation between PCSK9 levels and TC and LDL-C levels in the HD-S group. Conclusion: Our data are the first quantitative analysis of serum PCSK9 levels in CKD-HD patients. We show that serum PCSK9 in HD-NS patients is decreased and it retains a positive correlation with LDL-C, suggesting that PCSK9 may remain a significant determinant of LDL-C in CKD-HD subjects. We also show that statin therapy disrupts the correlation between LDL-C and PCSK9 in CKD-HD patients. These data suggest that the regulation of LDL-C by PCSK9 remains intact in CKD-HD patients. PCSK9 may also play a role in the metabolism of triglyceride-rich lipoproteins in CKD-HD patients. Ó 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Chronic kidney disease Hemodialysis PCSK9 LDL-C Statin
1. Introduction Patients with stage 5 chronic kidney disease (CKD) on hemodialysis (HD) therapy have low normal to low serum levels of total cholesterol (TC) and low density lipoprotein-cholesterol (LDLC) compared to the general population [1]). CKD-HD patients are affected by several conditions including anorexia, malnutrition,
* Corresponding author. The Ottawa Hospital e Riverside Campus, 1967 Riverside Drive, Room 4-09, Ottawa, Ontario K1H 7W9, Canada. Tel.: þ1 613 738 8400x81950; fax: þ1 613 738 8396. E-mail address: [email protected] (T.C. Ooi). 0021-9150/$ e see front matter Ó 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.atherosclerosis.2013.12.030
malabsorption, and inflammation [2,3]) that may alter serum TC and LDL-C levels, but the exact mechanisms responsible for the lower LDL-C are not clear. Proprotein convertase subtilisin/kexin 9 (PCSK9) is a 72-kD glycoprotein that is highly expressed [4]) and secreted by the liver [5]), and has been recently shown to be a determining factor for LDL metabolism [4,6e8]). PCSK9 binds to the epidermal growth factor (EGF)-like repeat A of the LDL receptor (LDLR) and decreases recycling of LDLR from endosomes to the cell surface [9]), which results in an increase in the channeling of LDLR to lysosomes where it undergoes degradation [10]). Pharmacologic inhibition of PCSK9 with fully human monoclonal antibodies lowers LDL-C levels in
124
H. Abujrad et al. / Atherosclerosis 233 (2014) 123e129
humans both as monotherapy [11e13]) and as add-on to statin therapy [14e17]). Serum LDL-C levels positively correlate with serum PCSK9 levels in the general population [18e20]), consistent with PCSK9 being a determinant of serum LDL-C levels. Serum PCSK9 levels have not been reported in patients with CKD-HD and their relationship to serum lipid levels in these patients has not been examined. Accordingly, if the positive correlation between LDL-C and PCSK9 levels is maintained in CKD-HD, we predict that PCSK9 levels will be lower in the CKD-HD cohort compared to the general population. To explore whether CKD modifies the previously established association between PCSK9 and LDL-C, we measured serum PCSK9 and lipid levels in CKD-HD patients, with and without statin therapy, and compared them to non-CKD subjects. We also examined whether the correlation between PCSK9 and LDL-C is maintained in patients with CKD-HD. 2. Materials and methods 2.1. Patient cohorts CKD-HD patients were originally recruited for a larger observational cohort study which is on-going. Blood samples from the observational study were used for PCSK9 and lipid measurements. This additional work was approved by the Ottawa Hospital Research Ethics Board. Serum samples from 66 CKD stage 5 patients with duration of HD < 2 years were included in the study. Each patient had 1e4 samples taken at 6-month intervals. Each sample was collected in a non-fasting state immediately before an HD session. Samples were grouped according to time from the onset of HD into
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Chronic kidney disease on hemodialysis is associated with decreased serum PCSK9 levels H. Abujrad a, J. Mayne b, M. Ruzicka c, f, M. Cousins a, A. Raymond a, J. Cheesman c, M. Taljaard d, e, A. Sorisky a, f, K. Burns c, f, T.C. Ooi a, f, * a
Division of Endocrinology and Metabolism, Department of Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada Division of Nephrology, Department of Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada d Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada e Ottawa Hospital Research Institute, Clinical Epidemiology Program, Ottawa, Ontario, Canada f Ottawa Hospital Research Institute, Chronic Disease Program, Ottawa, Ontario, Canada b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 23 August 2013 Received in revised form 3 December 2013 Accepted 9 December 2013 Available online 8 January 2014
Objectives: Serum low density lipoprotein-cholesterol (LDL-C) correlates positively with serum PCSK9 in the general population, consistent with PCSK9 being a determinant of LDL-C levels. Patients with chronic kidney disease (CKD) on hemodialysis (HD) have lower total cholesterol (TC) and LDL-C compared to the general population. Serum PCSK9 and its relationship with serum lipids have not been reported in CKD patients on HD (CKD-HD). Methods: We measured serum PCSK9 by ELISA and lipid levels in 66 CKD-HD patients and compared them to 178 non-CKD subjects. Since statins increase serum PCSK9 levels, CKD-HD patients were separated into those not on statin therapy (HD-NS, n ¼ 32) and those taking statins (HD-S, n ¼ 34). No control subjects were on statin therapy. Results: Serum PCSK9, TC, LDL-C and HDL-C levels were significantly lower in the CKD-HD group (n ¼ 66) compared to the control group. HD-NS patients showed lower PCSK9, TC and LDL-C levels than control subjects and PCSK9 levels correlated with TC and LDL-C levels (r ¼ 0.35, p ¼ 0.050; r ¼ 0.423, p ¼ 0.0158 respectively) as well as TG levels (r ¼ 0.413, p ¼ 0.0188). In HD-S patients, PCSK9 levels were not significantly different from the non-CKD group. There was no correlation between PCSK9 levels and TC and LDL-C levels in the HD-S group. Conclusion: Our data are the first quantitative analysis of serum PCSK9 levels in CKD-HD patients. We show that serum PCSK9 in HD-NS patients is decreased and it retains a positive correlation with LDL-C, suggesting that PCSK9 may remain a significant determinant of LDL-C in CKD-HD subjects. We also show that statin therapy disrupts the correlation between LDL-C and PCSK9 in CKD-HD patients. These data suggest that the regulation of LDL-C by PCSK9 remains intact in CKD-HD patients. PCSK9 may also play a role in the metabolism of triglyceride-rich lipoproteins in CKD-HD patients. Ó 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Chronic kidney disease Hemodialysis PCSK9 LDL-C Statin
1. Introduction Patients with stage 5 chronic kidney disease (CKD) on hemodialysis (HD) therapy have low normal to low serum levels of total cholesterol (TC) and low density lipoprotein-cholesterol (LDLC) compared to the general population [1]). CKD-HD patients are affected by several conditions including anorexia, malnutrition,
* Corresponding author. The Ottawa Hospital e Riverside Campus, 1967 Riverside Drive, Room 4-09, Ottawa, Ontario K1H 7W9, Canada. Tel.: þ1 613 738 8400x81950; fax: þ1 613 738 8396. E-mail address: [email protected] (T.C. Ooi). 0021-9150/$ e see front matter Ó 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.atherosclerosis.2013.12.030
malabsorption, and inflammation [2,3]) that may alter serum TC and LDL-C levels, but the exact mechanisms responsible for the lower LDL-C are not clear. Proprotein convertase subtilisin/kexin 9 (PCSK9) is a 72-kD glycoprotein that is highly expressed [4]) and secreted by the liver [5]), and has been recently shown to be a determining factor for LDL metabolism [4,6e8]). PCSK9 binds to the epidermal growth factor (EGF)-like repeat A of the LDL receptor (LDLR) and decreases recycling of LDLR from endosomes to the cell surface [9]), which results in an increase in the channeling of LDLR to lysosomes where it undergoes degradation [10]). Pharmacologic inhibition of PCSK9 with fully human monoclonal antibodies lowers LDL-C levels in
124
H. Abujrad et al. / Atherosclerosis 233 (2014) 123e129
humans both as monotherapy [11e13]) and as add-on to statin therapy [14e17]). Serum LDL-C levels positively correlate with serum PCSK9 levels in the general population [18e20]), consistent with PCSK9 being a determinant of serum LDL-C levels. Serum PCSK9 levels have not been reported in patients with CKD-HD and their relationship to serum lipid levels in these patients has not been examined. Accordingly, if the positive correlation between LDL-C and PCSK9 levels is maintained in CKD-HD, we predict that PCSK9 levels will be lower in the CKD-HD cohort compared to the general population. To explore whether CKD modifies the previously established association between PCSK9 and LDL-C, we measured serum PCSK9 and lipid levels in CKD-HD patients, with and without statin therapy, and compared them to non-CKD subjects. We also examined whether the correlation between PCSK9 and LDL-C is maintained in patients with CKD-HD. 2. Materials and methods 2.1. Patient cohorts CKD-HD patients were originally recruited for a larger observational cohort study which is on-going. Blood samples from the observational study were used for PCSK9 and lipid measurements. This additional work was approved by the Ottawa Hospital Research Ethics Board. Serum samples from 66 CKD stage 5 patients with duration of HD < 2 years were included in the study. Each patient had 1e4 samples taken at 6-month intervals. Each sample was collected in a non-fasting state immediately before an HD session. Samples were grouped according to time from the onset of HD into
