title: Proprotein convertase subtilisin-kexin type 9 is elevated in proteinuric subjects: relationship with lipoprotein response to antiproteinuric treatment.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Thirty-nine kidney patients (e-GFR 61 ± 29 mL/min/1.73 m(2), 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).
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, The Netherlands. a.kwakernaak@umcg.nl
authors.forename: Arjan J
authors.initials: AJ
authors.lastname: Kwakernaak
authors.forename: Gilles
authors.initials: G
authors.lastname: Lambert
authors.forename: Maartje C J
authors.initials: MC
authors.lastname: Slagman
authors.forename: Femke
authors.initials: F
authors.lastname: Waanders
authors.forename: Gozewijn D
authors.initials: GD
authors.lastname: Laverman
authors.forename: Francine
authors.initials: F
authors.lastname: Petrides
authors.forename: Bert D
authors.initials: BD
authors.lastname: Dikkeschei
authors.forename: Gerjan
authors.initials: G
authors.lastname: Navis
authors.forename: Robin P F
authors.initials: RP
authors.lastname: Dullaart
mesh_terms: D000328:Adult; D004039:Diet, Sodium-Restricted; D005260:Female; D006801:Humans; D008074:Lipoproteins / Q000097:blood / Q000187:drug effects*; D017706:Lisinopril / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000097:blood*; D011507:Proteinuria / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D012697:Serine Endopeptidases / Q000097:blood*; D013777:Tetrazoles / Q000627:therapeutic use*; D014633:Valine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000068756:Valsartan
chemical_list: D008074:Lipoproteins; D013777:Tetrazoles; D000068756:Valsartan; D017706:Lisinopril; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D014633:Valine