PCSK9 and ENaC in nephrotic syndrome in man

Marked hypercholesterolemia is common in patients with nephrotic syndrome (NS),
but the exact underlying pathophysiology is
unknown. A common accepted theory is that proteinuria causes a low serum
oncotic pressure which leads to reactive hepatic
protein synthesis including lipoproteins. More recent studies showed that
proprotein convertase subtilisin/kexin type 9 (PCSK9) in
plasma is elevated in patients with NS, and that PCSK9 decreased low-density
lipoprotein (LDL) receptor mediated LDL cholesterol
clearance from the circulation, possibly being the most important mechanism
causing hypercholesterolemia. Generally thought to be
mainly liver-derived, a recent study in mice with NS demonstrated that PCSK9 is
principally upregulated in the cortical collecting
duct, and suggested that this kidney-derived PCSK9 is responsible for the
hypercholesterolemia. This study also showed that
PCSK9 is a chaperone of the epithelial sodium channel (ENaC), and that blocking
ENaC causes further upregulation of PCSK9. If
these mechanisms occur in men as well, PCSK9 inhibitors form a rational therapy
for nephrotic syndrome induced
hypercholesterolemia.

The aim of this pilot study is to further unravel the pathophysiologic
mechanism of NS-induced hypercholesterolemia which will
further guide the treatment of patients with NS.
Given the recent insights on PCSK9-ENaC inhibition, our hypothesis is that
PCSK9-inhibition will lower plasma cholesterol in NS,
whereas ENaC-inhibition will increase it.

An intervention study in which 10 patients with NS and hypercholesterolemia
will receive one 150 mg gift of the PCSK9-inhibitor
alirocumab. Five of these 10 patients will receive 20 mg of the ENaC-blocker
amiloride on the five days before alirocumab
injection.

Five patients will receive 20 mg amiloride orally on two consecutive days and
receive 150 mg alirocumab as a subcutaneous
injection on the third day, and five patients will only receive 150 mg
evolocumab as a subcutaneous injection.

In the amiloride/alirocumab group, four blood samples and three urine samples
will be taken. In the alirocumab only group, three
blood samples and three urine samples will be taken. The risks of the study are
minor. Amiloride, regularly prescribed for patients in
NS, is on the market for over 50 years and is on the WHO List of Essential
Medicines. There is a small risk of inducing hyperkalemia
or hypotension. However, laboratory values and blood pressure will be closely
monitored and patients with pre-existing
hyperkalemia or hypotension will be excluded from participation in the study.
Alirocumab is approved for use in patients
with hypercholesterolemia. Nasopharyngeal complaints and injection site
reactions have been reported in some cases. No known
interactions have been described between amiloride and alirocumab.