Clinical trial NCT06373913: The Role of Proprotein-convertase-subtilisin/Kexin-type 9 in Kidney Damage in Nephrotic Syndrom
Official title: The Role of Proprotein-convertase-subtilisin/Kexin-type 9 in Kidney Damage in Nephrotic Syndrom
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Hyperlipidemias
Nephrotic Syndrome
Lead sponsor: Kolding Sygehus
Sponsor class: OTHER
Collaborators: name: Odense University Hospital
name: Vejle Hospital
First posted: 2024-04-18
Enrollment: 75
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: CROSS_SECTIONAL
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.

Brief 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Plasma PCSK9 correlated to the degree of protein in the urine
timeFrame: Measured at inclusion and for the nephrotic group after remission, if this is accomplished within a year
measure: Degree of PCSK9 in kidney tissue
timeFrame: Measured at inclusion in test person group, if this is performed within in the study period (before august 2028).
Secondary outcomes:
measure: Localization of PCSK9 in kidney tissue
timeFrame: Measured at inclusion in test person group, if this is performed within in the study period (before august 2028).
Other outcomes:
Locations:
city: Kolding
country: Denmark
facility: Kolding Sygehus, Lillebælt Hospital
Study officials:
References:
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.
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.
citation: 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.