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).
CONCLUSION: 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.