The Role of Proprotein-convertase-subtilisin/Kexin-type 9 in Kidney Damage in Nephrotic Syndrom

Hyperlipidemias Clinical Trial

— PCSK9  

Official title:

The Role of Proprotein-convertase-subtilisin/Kexin-type 9 in Kidney Damage in Nephrotic Syndrom

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06373913
• Other study ID #: MASP2NSRZL
• Status: Recruiting
• Start date: June 1, 2023
• Est. completion date: July 30, 2028

Study information

• Verified date: February 2024
• Source: Kolding Sygehus
• Contact: Rikke Z Langkilde, MD, phd
• Phone: 004576362554
• Email: rikke.zachar.langkilde[@]rsyd.dk
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Nephrotic syndrome (NS) is characterized by gross proteinuria (>3.5 g/day), hypoalbuminaemia, edema and often hyperlipidemia. Hyperlipidemia is correlated with increased morbidity and mortality.

The study aim is to investigate the role of the protein convertase subtilisin/kexin type 9 (PCSK9) in hyperlipidemia of NS, which has been suggested to play an important role. This is done by testing the following hypotheses:

1. PCSK9 is increased in patients with NS and hyperlipidemia compared to kidney-healthy controls

2. The level of PCSK9 in plasma correlates to the degree of proteinuria.

3. PCSK9 i increased in the kidney tissue of patients with NS

The study will compare plasma levels of PCSK9 in correlation with degree of protein in the urine between test persons with NS and kidney healthy controls. Furthermore the investigators will study the the degree of PCSK9 in the kidney in biopsies obtained from test persons with nephrotic syndrome and test persons without proteinuria.

Description:

Hyperlipidemia in kidney disease is associated with a substantially increase of risk in development of atherosclerotic cardiovascular disease (CVD) (European Atherosclerosis Society 2011). Furthermore animal studies have suggested that hyperlipidemia escalates progression of glomerular injury.

Nephrotic syndrome (NS) - the feature of many primary and secondary glomerulopathies - is characterized by gross proteinuria (>3.5 g/day), hypoalbuminaemia, edema and often hyperlipidemia. The protein Convertase subtilisin/kexin 9 (PCSK9) is over expressed in NS and has been suggested to play an important role in developing of hyperlipidemia. PCSK9 increases the LDL receptor degradation by preventing it from recycling to the cell membrane, resulting in increased plasma LDL cholesterol.

PCSK9 is produced primarily in the liver, but to a lesser extent in the brain, intestine and kidney. A recent study found that the expression of renal PCSK9 is increased in mice with experimental NS compared to controls. The investigators want to further explore this.

The overall aim is to decrease morbidity and mortality associated with NS and hyperlipidemia, by testing the following hypotheses:

1. PCSK9 is increased in patients with NS and hyperlipidemia compared to kidney-healthy controls

2. The level of PCSK9 in plasma correlates to the degree of proteinuria.

3. PCSK9 i increased in the kidney tissue of patients with NS

The study want to compare plasma levels of PCSK9 in correlation with degree of protein in the urine between test persons with NS and kidney healthy controls. Furthermore the investigators will study the the degree of PCSK9 in the kidney in biopsies obtained from test persons with nephrotic syndrome and test persons without proteinuria in a subgroup of the test persons assigned to kidney biopsy regardless of the project.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 75
• Est. completion date: July 30, 2028
• Est. primary completion date: July 30, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 18 years old

• Patients admitted to the Medical Department and/or the Medical Emergency Department, Kolding Sygehus.

Exclusion Criteria:

• Refusal to give informed consent

• Treatment with PCSK9 inhibitors

• Any acute or chronic condition that would limit the ability of the patient to participate in the study

• Control group: proteinuria

Related Conditions & MeSH terms

• Hyperlipidemias
• Nephrosis
• Nephrotic Syndrome

Locations

Country	Name	City	State
Denmark	Kolding Sygehus, Lillebælt Hospital	Kolding

Sponsors (3)

Lead Sponsor	Collaborator
Kolding Sygehus	Odense University Hospital, Vejle Hospital

Country where clinical trial is conducted

Denmark, 

References & Publications (3)

Haas ME, Levenson AE, Sun X, Liao WH, Rutkowski JM, de Ferranti SD, Schumacher VA, Scherer PE, Salant DJ, Biddinger SB. The Role of Proprotein Convertase Subtilisin/Kexin Type 9 in Nephrotic Syndrome-Associated Hypercholesterolemia. Circulation. 2016 Jul 5;134(1):61-72. doi: 10.1161/CIRCULATIONAHA.115.020912. — View Citation

Liu S, Vaziri ND. Role of PCSK9 and IDOL in the pathogenesis of acquired LDL receptor deficiency and hypercholesterolemia in nephrotic syndrome. Nephrol Dial Transplant. 2014 Mar;29(3):538-43. doi: 10.1093/ndt/gft439. Epub 2013 Oct 28. — View Citation

Molina-Jijon E, Gambut S, Mace C, Avila-Casado C, Clement LC. Secretion of the epithelial sodium channel chaperone PCSK9 from the cortical collecting duct links sodium retention with hypercholesterolemia in nephrotic syndrome. Kidney Int. 2020 Dec;98(6):1449-1460. doi: 10.1016/j.kint.2020.06.045. Epub 2020 Aug 1. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Plasma PCSK9 correlated to the degree of protein in the urine	PCSK9 in plasma measured by ELISA, correlated to protein in 24hour urine	Measured at inclusion and for the nephrotic group after remission, if this is accomplished within a year
Primary	Degree of PCSK9 in kidney tissue	Immunohistochemistry; degree of staining a in test persons, who are subjected to kidney biopsy.	Measured at inclusion in test person group, if this is performed within in the study period (before august 2028).
Secondary	Localization of PCSK9 in kidney tissue	Immunohistochemistry; localization of staining a in test persons, who are subjected to kidney biopsy.	Measured at inclusion in test person group, if this is performed within in the study period (before august 2028).