Proprotein convertase subtilisin/kexin type 9 in kidney disease

Abstract

Chronic kidney disease (CKD) is associated with a substantially increased risk for the development of atherosclerotic cardiovascular (CV) disease. Accordingly, CV mortality is increased even in the earliest stages of CKD. In the general population and in CKD patients, high plasma levels of low-density lipoprotein cholesterol (LDL-C) are crucially involved in the initiation and progression of atherosclerotic vascular lesions. Lowering LDL-C by use of statins and/or ezetimibe represents the gold standard of lipid-lowering therapy, with a great body of evidence from several large clinical trials. Statin therapy reduces CV events in patients with normal and impaired kidney function alike, while the evidence for patients on maintenance haemodialysis is weaker. The inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) serine protease represents a novel lipid-lowering tool. Currently the monoclonal antibodies evolocumab and alirocumab are the approved PCSK9 inhibitors. Despite maximum-tolerated statin therapy, they efficiently further reduce LDL-C plasma levels without any major adverse effects. Moreover, in large clinical outcome trials, both antibodies have been proven to lower CV events. Notably, the LDL-lowering capacity was independent of baseline kidney function and also efficient in patients with moderate CKD. However, patients with severely impaired kidney function, that is, the population at the highest CV risk, have been excluded from those trials. The relevance of the LDL-independent effects of PCSK9 inhibitors, such as lowering lipoprotein(a) or ameliorating dyslipidaemia in patients with nephrotic syndrome, has to be determined. Therefore further specific studies assessing the effects and outcomes of PCSK9-inhibiting treatment in CKD patients are warranted.

Keywords: PCSK9 inhibition; cardiovascular disease; chronic kidney disease; low-density lipoproteins.