Short summary

Nephrotic syndrome (NS) is characterized by gross proteinuria (>3.5 g/day), hypoalbumineamia, edema and hyperlipidemia. Hyperlipidemia is associated with a substantially increased risk for the development of atherosclerotic cardiovascular disease. The protein convertase subtilisin/kexin type 9 (PCSK9) is overexpressed in NS and has been suggested to play an important role in hypercholesterolemia. We aim to investigate PCSK9 levels in kidney and serum in patients with NS compared to controls.

Rationale

Nephrotic syndrome (NS) - the feature of many primary and secondary glomerulopathies - is characterized by gross proteinuria (>3.5 g/day), hypoalbumineamia, edema and hyperlipidemia. Concerning the hyperlipidemia patients present with elevated plasma cholesterol, triglyceride and low-density lipoprotein (LDL). Increased hyperlipidemia is associated with a substantially increased risk for the development of atherosclerotic cardiovascular disease (CVD) (ESC/EAS 2011), animal studies have suggested that hyperlipidemia escalates progression of glomerular injury and NS predispose the patient to cardiovascular events.

The protein convertase subtilisin/kexin type 9 (PCSK9) is overexpressed in NS and has been suggested to play an important role in hypercholesterolemia. PCSK9 accelerates LDL receptor (LDL-R) degradation in a non-proteolytical manner, by preventing it from recycling, thereby causing serum LDL cholesterol to increase, promoting atherosclerosis and heart disease. The protease is primarily produced in the liver, but also in small amounts in brain, intestines and kidney. A recent study found PCSK9 expression of the kidney increased in mice with experimental NS, compared to controls.

PCSK9 secretion occurs in a highly regulated manner and circulates in both mature and inactive form. Studies in mice have shown that PCSK9 levels inversely relates to LDLR protein abundance. One study found PCSK9 levels were higher in moderate proteinuric patient than in healthy subjects and that PCSK9 correlated directly with proteinuria and LDL(7). Another study compared PCSK9 and LDL levels in a group of nephrotic patients at presentation (proteinuria 5.2 g/g creatinine) and at remission (proteinuria 0.14 g/g creatinine), showing where a decrease of both LDL and PCSK9 was detected, however the correlation with degree of proteinuria was not reported.

An injectable monoclonal antibody targeting PCSK9, preventing it from interacting with LDL-R, are available and currently being used in patients with familial hypercholesterolemia, who are intolerant to statins. As the serum lipid profile in NS generates a high risk of cardiovascular events, aggressive therapy seem to be indicated, thus if PCSK9 plays a crucial role, the patient group may benefit from treatment with PCSK9 antibody.

In the study we aim to explore the hypothesis that increased PCSK9 is detected in kidney and serum in patients with nephrotic syndrome compared to healthy control subjects and the levels of PCSK9 correlates with the degree of proteinuria.

Description of the cohort

The participants will be included at Lillebælt Hospital (Kolding) from the Emergency Department, the Department of Internal medicine and the out patient clinic of Kidney disease. The study is a case-control study with participant with nephrotic syndrom and kidney healthy controls. Based on power calculations 32 test persons will be included in each group. Furthermore 11 from the nephrotic group, who gets biopsy due to working out diagnosis, will be included in testing of PCSK9 in the tissue. These will be compared to 11 patient getting kidney biopsy without nephrotic syndrome.

Data and biological material

Blod samples, urine, kidney biopsies, data from patient journal

Collaborating researchers and departments

Odense University Hospital, Department of Pathology

• MD, phd Kirsten Madsen