The Role of Proprotein-convertase-subtilisin/Kexin-type 9 in Kidney Damage in Nephrotic Syndrom (PCSK9)

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.

Study Overview

• Status: Recruiting
• Conditions: Hyperlipidemias; Nephrotic Syndrome

Detailed 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.

• Study Type: Observational
• Enrollment (Estimated): 75

Contacts and Locations

• Study Contact: Name: Rikke Z Langkilde, MD, phd; Phone Number: 004576362554; Email: rikke.zachar.langkilde@rsyd.dk
• Study Contact Backup: Name: Anne D Thuesen, md, phd; Phone Number: 004576360555; Email: Anne.Daugaard.Thuesen2@rsyd.dk

Study Locations

• Denmark
  • Kolding, Denmark, 6000
    • Recruiting
    • Kolding Sygehus, Lillebælt Hospital
    • Contact: Anne D Thuesen, md, phd; Phone Number: 004576360555; Email: Anne.Daugaard.Thuesen2@rsyd.dk
    • Contact: Rikke Z Langkilde, md, phd; Phone Number: 004576362554

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patient with >3.5 g/day of proteinuria will be included in the nephrotic syndrome group. Control test subjects will be excluded if proteinuria occur.

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Nephrotic syndrome; Patients with nephrotic syndrome (n=32). Blood samples and 24 hour urine samples will be obtained an all participants. Kidney biopsy will be used from 11 test persons, whos been subjected to kidney biopsy unrelated to the research project. 3
Kidney healthy controls; Patient with normal kidney function and no proteinuria (n=32). Blood samples and 24 hour urine samples will be obtained an all participants.
Kidney biopsy control; Patients without proteinuria who is subjected to kidney biopsy regardless of the research project.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).

Collaborators and Investigators

• Sponsor: Kolding Sygehus
• Collaborators: Odense University Hospital; Vejle Hospital

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2023
• Primary Completion (Estimated): July 30, 2027
• Study Completion (Estimated): July 30, 2028

Study Registration Dates

• First Submitted: October 10, 2023
• First Submitted That Met QC Criteria: April 15, 2024
• First Posted (Actual): April 18, 2024

Study Record Updates

• Last Update Posted (Estimated): September 9, 2025
• Last Update Submitted That Met QC Criteria: September 2, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Metabolic Diseases; Dyslipidemias; Lipid Metabolism Disorders; Nephrosis; Nutritional and Metabolic Diseases; Hyperlipidemias; Nephrotic Syndrome
• Other Study ID Numbers: MASP2NSRZL

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No