Proprotein convertase subtilisin–kexin type 9 is elevated in proteinuric subjects: Relationship with lipoprotein response to antiproteinuric treatment

• Published in: Atherosclerosis Vol. 226; no. 2; pp. 459 - 465
• Main Authors: Kwakernaak, Arjan J., Lambert, Gilles, Slagman, Maartje C.J., Waanders, Femke, Laverman, Gozewijn D., Petrides, Francine, Dikkeschei, Bert D., Navis, Gerjan, Dullaart, Robin P.F.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ireland Ltd 01.02.2013; Elsevier
• Subjects: Adult; analogs & derivatives; Antiproteinuric treatment; atherosclerosis; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; blood; Blood and lymphatic vessels; body mass index; Cardiology. Vascular system; Cardiovascular; Chronic kidney disease; correlation; Diet, Sodium-Restricted; drug effects; drug therapy; enzymology; Female; General and cellular metabolism. Vitamins; high density lipoprotein cholesterol; Humans; kidneys; LDL cholesterol; Lipoproteins; Lipoproteins - blood; Lipoproteins - drug effects; Lisinopril; Lisinopril - therapeutic use; low density lipoprotein cholesterol; low sodium diet; Male; Medical sciences; metabolism; Middle Aged; nephrosis; Non-HDL cholesterol; patients; Pharmacology. Drug treatments; Proprotein Convertase 9; Proprotein convertase subtilisin–kexin type 9; Proprotein Convertases; Proprotein Convertases - blood; Proteinuria; Proteinuria - blood; Proteinuria - drug therapy; Proteinuria - enzymology; Serine Endopeptidases; Serine Endopeptidases - blood; sodium; Tetrazoles; Tetrazoles - therapeutic use; therapeutic use; Valine; Valine - analogs & derivatives; Valine - therapeutic use; Valsartan; Proprotein convertase subtilisin–kexin type 9; Chronic kidney disease; Non-HDL cholesterol; LDL cholesterol; Antiproteinuric treatment; Proteinuria; Kidney disease; Human; Urinary system disease; Proprotein convertase subtilisin-kexin type 9; Cholesterol LDL; Cardiovascular disease; Lipoprotein; Vascular disease; Treatment; Cholesterol HDL; Renal failure; Atherosclerosis
• ISSN: 0021-9150; 1879-1484; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2012.11.009

LDL-receptor deficiency may provide a mechanism which contributes to atherogenic lipoprotein abnormalities in experimental nephrosis and in humans with glomerular proteinuria. The proprotein convertase subtilisin–kexin type 9 (PCSK9) pathway plays a key role in lipoprotein metabolism by promoting LDL-receptor degradation. We tested whether plasma PCSK9 is elevated in proteinuric states, and determined relationships of PCSK9 with lipoprotein responses to proteinuria reduction. Thirty-nine kidney patients (e-GFR 61 ± 29 mL/min/1.73 m2, proteinuria 1.9 [0.9–3.3] g/day; 19 on statin treatment) were studied during 2 randomized double-blind 6-week periods on either lisinopril (40 mg/day) and a regular sodium diet (194 ± 49 mmol Na+/day; baseline treatment) or lisinopril plus valsartan (320 mg/day) and a low sodium diet (102 ± 52 mmol Na+/day; maximal treatment), and compared to age- and sex-matched controls. Maximal treatment decreased proteinuria to 0.5 [0.3–1.1] g/day (P < 0.001). Plasma PCSK9 was increased at baseline in proteinuric subjects (213 [161–314] vs. 143 [113–190] ug/L in controls, P ≤ 0.001), irrespective of statin use, e-GFR and BMI. PCSK9 correlated with proteinuria at baseline (R = 0.399, P = 0.018) and at maximal antiproteinuric treatment (R = 0.525, P = 0.001), but did not decrease during proteinuria reduction (P = 0.84). Individual changes in total cholesterol (R = 0.365, P = 0.024), non-HDL cholesterol (R = 0.333, P = 0.041), and LDL cholesterol (R = 0.346, P = 0.033) were correlated positively with individual PCSK9 responses. PCSK9 at baseline independently predicted the total/HDL cholesterol ratio response to treatment (P = 0.04). Plasma PCSK9 was elevated in proteinuria, predicted lipoprotein responses to proteinuria reduction but remained unchanged after proteinuria reduction. Inhibition of the PCSK9 pathway may provide a novel treatment strategy in proteinuric subjects. ► Plasma PCSK9 is elevated in subjects with glomerular proteinuria. ► PCSK9 is associated with apoB-lipoproteins in glomerular proteinuria. ► Changes in PCSK9 are associated with lipoprotein responses to proteinuria reduction. ► PCSK9 at baseline predicts the total/HDL cholesterol ratio response to antiproteinuric treatment.