Proprotein Convertase Subtilisin/Kexin Type 9 in Kidney Disease

David Schmit; Danilo Fliser; Thimoteus Speer

Disclosures

Nephrol Dial Transplant. 2019;34(7):1266-1271. 

In This Article

Abstract and Introduction

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.

Introduction

Chronic kidney disease (CKD) is associated with a substantially increased risk for atherosclerotic cardiovascular diseases (CVDs).[1,2] Beside the presence of CKD-related cardiovascular (CV) risk factors (e.g. oxidative stress, inflammation, anaemia), the prevalence of traditional CV risk factors such as arterial hypertension, diabetes mellitus and dyslipidaemia in CKD patients is high.[2,3] For several years the pathophysiological role of low-density lipoprotein (LDL) in the development of atherosclerotic CVD has been extensively studied in the general population as well as in CKD patients.[4–7] In 1971, it was documented in the Framingham study that higher serum cholesterol levels are associated with an increased risk for CV events.[8] In a plethora of subsequent experimental studies, a detailed role for LDL in the initiation and progression of atherosclerotic vascular lesions was established.[5] LDL activates endothelial cells in the inner layer of the vascular wall, inducing endothelial dysfunction (Figure 1). Such activated endothelial cells express cell adhesion molecules, such as vascular cell adhesion molecule 1, on their surface, which mediate adhesion of circulating leucocytes (e.g. monocytes) and their transmigration into the subendothelial layer. There these cells are again stimulated by LDL, which induces their differentiation into tissue macrophages. These macrophages acquire LDL and finally become foam cells. This represents a crucial initial step in the pathogenesis of atherosclerosis. Notably, it has been documented that LDL accumulating in the vascular wall is prone to be post-translationally modified, e.g. by oxidation or carbamylation, which is particularly relevant to patients with CKD.[9–13] Such modified LDL represents a strong promoter of atherosclerotic CVD.

Figure 1.

Role of LDL in the development of atherosclerotic lesions. (A) normal vascular wall. (B) endothelial dysfunction. (C) initiation of atherosclerotic lesion formation. (D) atherosclerotic plaque formation. EC, endothelial cells; SMC, smooth muscle cells; CAM, cell adhesion molecules.

A growing body of evidence suggests that lowering LDL cholesterol (LDL-C) reduces CV events in patients with prevalent CVD (i.e. secondary prevention) and patients at high risk for CVD (i.e. primary prevention). Until now, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been extensively studied and are currently the most widely used LDL-lowering agents. It has been shown that lowering LDL-C by 1 mmol/L (i.e. 38.7 mg/dL) reduces the relative risk of coronary events by 22% in an almost linear manner.[14,15] This has been further supported by genetic association studies in which, genetically, lifelong lowered LDL caused by single nucleotide polymorphisms (SNPs) in LDL-regulating genes is associated with reduced CV risk.[16,17] Since statins have been used in clinical practice for many years, analyses on their long-term use are now available. In the West of Scotland Coronary Prevention Study, 20 years after randomization to either pravastatin or placebo, the CV event rate in participants of the pravastatin treatment arm was still significantly reduced as compared with the placebo group, without any serious safety concerns.[18] Patients with CKD are considered at high or very high CV risk and therefore recent guidelines recommend lipid-lowering therapy in all CKD patients not on dialysis with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2.[19] In dialysis patients, the evidence for lipid-lowering therapy is weaker.[20,21] Therefore the Kidney Disease: Improving global Outcomes (KDIGO) guidelines suggest continuing statin treatment initiated before renal replacement therapy and in dialysis patients with manifest CVD, but not newly initiating lipid-lowering therapy as a primary prevention approach.[22] While the KDIGO guidelines do not recommend a specific LDL-C target to be achieved,[22] the guidelines of the European Society of Cardiology recommend an LDL-C target of <70 mg/dL (<1.82 mmol/L) for CKD patients with an eGFR <30 mL/min/1.73 m2 and <100 mg/dL (<2.6 mmol/L) for those with an eGFR of 30–59 mL/min/1.73 m2.

Reduced kidney function may represent a risk factor for statin-related adverse outcomes such as myopathy. It has been shown that the relative risk of myopathy in patients treated with high-dose simvastatin (i.e. 80 mg daily) was 2.5 [95% confidence interval (CI) 1.6–3.9] times higher in subjects with an eGFR <60 mL/min/1.73 m2 as compared with those with an eGFR ≥60 mL/min/1.73 m2.[23] Moreover, treatment with higher doses of statins such as atorvastatin has not yet been evaluated to be safe in patients with advanced CKD. In 28 randomized intervention trials with statin therapy comprising 183 419 subjects, <3% of the participants had an eGFR <30 mL/min/1.73 m2.[20] In patients with lower eGFR, the reduction of major CV events was smaller under statin treatment and, in addition, in patients on dialysis, lower reductions of LDL-C have been achieved.[20] Therefore a combination of statins with other lipid-lowering agents might represent a reasonable approach in CKD patients to adequately lower LDL-C. For this purpose, novel LDL-lowering agents such as inhibitors of the proprotein convertase subtilisin/kexin type 9 (PCSK9) serine protease could be of particular interest for the treatment of hypercholesterolaemia in CKD patients.

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