PCSK9 and Cardiovascular Disease in Individuals with Moderately Decreased Kidney Function

Abstract

Background and objectives: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of lipid homeostasis. Studies investigating the association between PCSK9 and cardiovascular disease in large cohorts of patients with CKD are limited.

Design, setting, participants, & measurements: The association of PCSK9 concentrations with prevalent and incident cardiovascular disease was investigated in 5138 White participants of the German Chronic Kidney Disease study with a median follow-up of 6.5 years. Inclusion criteria were eGFR of 30-60 or >60 ml/min per 1.73 m² in the presence of overt proteinuria (urine albumin-creatinine ratio >300 mg/g or equivalent). Prevalent cardiovascular disease was defined as a history of nonfatal myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, carotid arteries interventions, and stroke. Incident major adverse cardiovascular disease events included death from cardiovascular causes, acute nonfatal myocardial infarction, and nonfatal stroke.

Results: Median PCSK9 concentration in the cohort was 285 ng/ml (interquartile range, 231-346 ng/ml). There was no association between PCSK9 concentrations and baseline eGFR and albuminuria. With each 100-ng/ml increment of PCSK9, the odds for prevalent cardiovascular disease (n=1284) were 1.22-fold (95% confidence interval, 1.12 to 1.34; P<0.001) higher in a model with extended adjustment for major confounders. This association was stronger in nonstatin than statin users (P value for interaction =0.009). During follow-up, 474 individuals experienced a major adverse cardiovascular disease event, and participants in PCSK9 quartiles 2-4 had a 32%-47% higher risk compared with those in quartile 1 (P<0.05). Subgroup analysis revealed that this association was restricted to those participants who already had cardiovascular disease at baseline (all hazard ratios >1.75; P=0.01). In addition, PCSK9 showed a valuable gain in classification accuracy for both prevalent cardiovascular disease (net reclassification index =0.27; 95% confidence interval, 0.20 to 0.33) and incident major adverse cardiovascular disease events during follow-up (net reclassification index =0.10; 95% confidence interval, 0.01 to 0.21) when added to an extended adjustment model.

Conclusions: Our findings reveal no relation of PCSK9 with baseline eGFR and albuminuria but a significant association between higher PCSK9 concentrations and risk of cardiovascular disease independent of traditional risk factors, including LDL cholesterol levels.Clinical Trial registry name and registration number: German Chronic Kidney Disease Study (GCKD), DRKS 00003971.

Keywords: PCSK9; cardiovascular disease; chronic kidney disease; prospective.

Graphical abstract

Figure 1.

Distribution of serum proprotein convertase subtilisin/kexin type 9 (PCSK9) concentrations in the German Chronic Kidney Disease (GCKD) study. The bar plot represents the PCSK9 serum concentrations, comparing participants under statin treatment (n=2440) with the nonstatin-treated individuals (n=2698) in the GCKD study population. Individuals treated with statins have significantly higher levels of PCSK9 than untreated individuals.