Efficacy and Safety of PCSK9 Inhibitors in Hypercholesterolemia Associated With Refractory Nephrotic Syndrome

Abstract

Introduction: Treatment of hypercholesterolemia in refractory nephrotic syndrome remains a therapeutic challenge. There is not enough evidence supporting the efficacy of statins, and these drugs can be associated with an increased incidence of adverse effects. Herein we summarize our clinical experience with 12 patients suffering from refractory nephrotic syndrome with associated vascular disease and uncontrolled hypercholesterolemia despite treatment with statins who were treated with proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors.

Methods: Twelve adult patients with primary nephrotic syndrome refractory to multiple lines of immunosuppressive treatment who suffered from clinical atheromatous vascular disease were treated with PCSK9 inhibitors according to the prescription guidelines for secondary prevention of cardiovascular events. Eight patients with refractory nephrotic syndrome without vascular disease treated with atorvastatin comprised the control group.

Results: Four weeks after treatment with PCSK9 inhibitors, a statistically significant decrease in total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels was observed without significant changes in serum albumin levels or proteinuria. The mean LDL-C decrease was 36.8% ± 4.9% mmol/L at 4 weeks and remained unchanged throughout the follow-up period. In the control group, there were no significant changes in the levels of total cholesterol or LDL-C during the follow-up period. At the diagnosis of nephrotic syndrome, plasma PCSK9 levels were 334 ± 40 ng/mL and correlated significantly with serum LDL-C levels (r = 0.49, P = 0.023). Six months after starting treatment with PCSK9 inhibitors, plasma PCSK9 levels were significantly reduced to values of 190 ± 36 ng/mL (P = 0.001) with a mean relative reduction of 42.3% ± 12.6%. No local adverse effects were seen at the injection site and no significant changes were seen in the levels of transaminase, creatine phosphokinase, or aldolase.

Conclusion: PCSK9 inhibitors may be an effective and safe alternative for the treatment of hypercholesterolemia associated with refractory nephrotic syndrome.

Keywords: PSCK9 inhibitors; dyslipidemia; hypercholesterolemia; nephrotic syndrome.

Graphical abstract

Figure 1

(a) Evolution of serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), albumin, and proteinuria along follow-up in patients treated with proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors. Results are shown as error bars representing the means and 95% confidence intervals. (I) Before the diagnosis of nephrotic syndrome. (II) Between the diagnosis of nephrotic syndrome and the start of treatment with PCSK9 inhibitors. (III) Along the follow-up period after starting treatment with PCSK9 inhibitors. (b) Evolution of serum levels of TC, LDL- C, albumin, and proteinuria along follow-up in control group. Results are shown as error bars representing the means and 95% confidence intervals. TC and LDL-C measured in millimoles per liter, serum albumin measured in grams per deciliter, and proteinuria measured in grams per day. The values correspond to the monthly controls carried out after the diagnosis of nephrotic syndrome and at the last available follow-up. Normal value ranges for each parameter are shown by the red lines. 0, At the start of treatment with PCSK-9 inhibitors, 1–6 monthly values after starting treatment with PCSK9 inhibitors; bas, before the diagnosis of nephrotic syndrome; dx, at diagnosis of nephrotic syndrome, pre1 and pre2 during follow-up after the diagnosis of nephrotic syndrome and before starting treatment with PCSK9 inhibitors; dx NS, time of diagnosis of nephrotic syndrome; LFU, last follow-up.

Figure 1

(a) Evolution of serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), albumin, and proteinuria along follow-up in patients treated with proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors. Results are shown as error bars representing the means and 95% confidence intervals. (I) Before the diagnosis of nephrotic syndrome. (II) Between the diagnosis of nephrotic syndrome and the start of treatment with PCSK9 inhibitors. (III) Along the follow-up period after starting treatment with PCSK9 inhibitors. (b) Evolution of serum levels of TC, LDL- C, albumin, and proteinuria along follow-up in control group. Results are shown as error bars representing the means and 95% confidence intervals. TC and LDL-C measured in millimoles per liter, serum albumin measured in grams per deciliter, and proteinuria measured in grams per day. The values correspond to the monthly controls carried out after the diagnosis of nephrotic syndrome and at the last available follow-up. Normal value ranges for each parameter are shown by the red lines. 0, At the start of treatment with PCSK-9 inhibitors, 1–6 monthly values after starting treatment with PCSK9 inhibitors; bas, before the diagnosis of nephrotic syndrome; dx, at diagnosis of nephrotic syndrome, pre1 and pre2 during follow-up after the diagnosis of nephrotic syndrome and before starting treatment with PCSK9 inhibitors; dx NS, time of diagnosis of nephrotic syndrome; LFU, last follow-up.

Figure 2

Individual evolution of the levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), albumin, and proteinuria along follow-up. 0, At the start of treatment with proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors, 1–6 monthly values after starting treatment with PCSK9 inhibitors; basal, before the diagnosis of nephrotic syndrome; dx, at diagnosis of nephrotic syndrome, pre1 and pre2 during follow-up after the diagnosis of nephrotic syndrome and before starting treatment with PCSK9 inhibitors; LFU: last follow-up.

Figure 3

Serum proprotein convertase subtilisin kexin 9 (PCSK9) levels before and after treatment with PCSK9 inhibitors. PCSK9 pre, Plasma levels of PCSK9 at the time of diagnosis of nephrotic syndrome and before starting treatment with PCSK9 inhibitors; PCSK9 post, plasma levels of PCSK9 6 months after starting treatment with PCSK9 inhibitors and atorvastatin withdrawal.