Impact of Antiglycemic & Immunosuppressive Therapies on NETosis in Diabetes & Kidney Disease (NETs - Neutrophil Traps)

NCT06821919 | Recruiting DMC

• 1 other identifier: 0108-22-NHR
• Study Type: observational
• Target: 70
• Locations: 1 country
• Sites: 1

Brief Summary

This study aims to investigate whether new glucose-lowering medications, such as SGLT2 inhibitors (e.g., Forxiga/Jardiance) and GLP-1 receptor agonists (e.g., Ozempic), can reduce NETosis in diabetic patients, thereby mitigating secondary complications such as cardiovascular disease and kidney damage. By targeting dysregulated NET formation, the study seeks to establish a link between reduced NETosis and improved clinical outcomes in diabetes. Additionally, the study will evaluate the effects of immunosuppressive therapies on NETosis in patients with immune-mediated kidney diseases, such as ANCA-associated vasculitis. By correlating NETosis activity with disease progression and treatment response, this research will assess whether reducing NETosis contributes to better management of inflammation and secondary morbidity in these conditions. Through these evaluations, the study aims to identify potential therapeutic strategies to improve outcomes in both diabetic and chronic kidney disease populations.

Conditions

Diabetes Mellitus; Kidney Disease

Keywords

NETosis; Diabetes mellitus; kidney disease; glomerulonephritis

Outcome Measures

Primary Outcomes (4)

• NETosis marker- citrullinated histone H3 (citH3)

  * NETosis markers: NET formation will be assessed in sera blood samples across all groups. * Focus on Naïve Patients: Emphasis will be placed on evaluating the initial effects of antiglycemic medications in diabetic patients and the impact of immunosuppressive therapy in CKD patients with immune-mediated diseases. * Samples will be collected at identical intervals and compared among diabetic andCKD, groups to assess differences in NETosis levels over time (controls- only baseline NETosis markers) and in response to treatment. All serum samples will be diluted 1:2 and citrullinated histone H3 (citH3) will be quantified using the Citrullinated Histone H3 ELISA Kit: O.D. (501620; Cayman Chemical, Ann Arbor, USA).

  Before treatment, 1,2 , 3, 6 and 12 months after starting anti-diabetic drugs or immunosuppression

• NETosis marker- Myeloperoxidase

  Samples will be collected at identical intervals and compared among diabetic andCKD, groups to assess differences in NETosis levels over time (controls- only baseline NETosis markers) and in response to treatment. All serum samples will be diluted 1:2 . MPO measurement will be conducted using Myeloperoxidase ELISA Kit , ng/ml (501410; Cayman Chemical).

  Before treatment, 1,2,3,6 and12 moths after treatment.

• NETosis marker- Neutrophil elastase (NE)

  Samples will be collected at identical intervals and compared among diabetic andCKD, groups to assess differences in NETosis levels over time (controls- only baseline NETosis markers) and in response to treatment. All serum samples will be diluted 1:2 , and NE measurement will be conducted using Human Neutrophil Elastase ELISA Kit, ng/ml (ab204730; Abcam

  Before treatment, 1,2 , 3, 6 and 12 months after starting anti-diabetic drugs or immunosuppression

• NETosis marker: Peptidylarginine deiminase 4-PAD4

  Samples will be collected at identical intervals and compared among diabetic andCKD, groups to assess differences in NETosis levels over time (controls- only baseline NETosis markers) and in response to treatment. All serum samples will be diluted 1:2 and PAD4 measurement will be conducted using (PADI4 ELISA Kit, ng/ml (ELH-PADI4, RayBiotech) according to the manufacturer's instructions

  Before treatment, 1,2 , 3, 6 and 12 months after starting anti-diabetic drugs or immunosuppression

Secondary Outcomes (4)

• Kidney function

  Before treatment, 1,2 , 3, 6 and 12 months, and each year (during 5 years) after starting anti-diabetic drugs or immunosuppression therapy.

• Urine protein/ creatinine ratio

  Before treatment, 1,2 , 3, 6 and 12 months, and each year (during 5 years) after starting anti-diabetic drugs or immunosuppression therapy

• Major adverse cardiovascular events (MACE)

  1,2 , 3, 6 and 12 months, and each year (during 5 years) after starting anti-diabetic drugs or immunosuppression therapy

• All cause mortality

  1,2 , 3, 6 and 12 months, and each year (during 5 years) after starting anti-diabetic drugs or immunosuppression therapy

Study Arms (3)

Diabetes mellitus patients

2\. Diabetic Patients (DM Therapy Study) * Sample Size: 20 diabetic patients. * Group 1: 10 patients treated with Forxiga/Jardiance (SGLT2 inhibitors). * Group 2: 10 patients treated with Ozempic (GLP-1 agonist). * Patient Criteria: o Patients naïve to SGLT2 inhibitors and GLP-1 receptor agonists to ensure the observed effects are attributable to the initiation of these therapies. * Sample Collection: * Serum samples (6 ml in serum separator tubes). * Two tubes (12 ml total) will be collected per participant at each time point: Before starting treatment and at 1, 2, 3, 6, and 12 months after initiating medication. * Inclusion Criteria: * Diabetic patients aged 18 years or older (men and women). * Patients who have not previously received SGLT2 inhibitors or GLP-1 receptor agonists. * Exclusion Criteria: * Patients with conditions affecting NETosis, including autoimmunity, hematologic or oncologic diseases, or positive for HIV or Hepatitis B/C.

Chronic kidney disease (CKD) patients

Chronic Kidney Disease (CKD) Patients (Evaluation of Immunosuppressive Therapy) * Sample Size: 50 CKD patients with various etiologies. * Focus: o This part of the study will specifically evaluate immune-mediated kidney disease, such as ANCA-associated vasculitis, and the effects of immunosuppressive therapy on NETosis. * Objective: * Assess NETosis markers (e.g., cfDNA, Cit-H3, MPO, NE) before initiating immunosuppressive treatment and at 1, 2, 3, 6, and 12 months of therapy. * Correlate NETosis dynamics with clinical variables, including disease activity, renal function, and inflammatory markers. * Sample Collection: o Serum samples (6 ml in serum separator tubes). o Two tubes (12 ml total) will be collected per participant at each time point: Before starting treatment and at 1, 2, 3, 6, and 12 months after initiating medication. * Exclusion Criteria: * Patients with acute infections, hematologic or oncologic diseases, or positive for HIV or Hepatitis B/C.

10 healthy participants will be recruited to the control group (for both studies).

Control Group * Sample Size: 10 healthy participants. * Objective: o Serve as controls for both the diabetic and CKD studies. * Sample Collection: * Two tubes (12 ml total) will be collected per participant * Eligibility: * Healthy individuals without underlying medical conditions.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

DM therapy study: - Diabetic patients aged 18 years or older (men and women). * Patients who have not previously received SGLT2 inhibitors or GLP-1 receptor agonists. • Exclusion Criteria: * Patients with conditions affecting NETosis, including autoimmunity, hematologic or oncologic diseases, or positive for HIV or Hepatitis B/C. Chronic kidney disease (CKD) patients :This study will include 50 CKD patients with various etiologies, with a focus on those with immune-mediated kidney diseases, such as ANCA-associated vasculitis. The primary aim is to evaluate the effects of immunosuppressive therapy on NETosis. All patients will be naïve to prior immunosuppressive therapy to ensure the observed effects are directly attributable to the initiation of treatment. • Exclusion Criteria: o Patients with acute infections, hematologic or oncologic diseases, or positive for HIV or Hepatitis B/C

You may qualify if:

• DM therapy study: - Diabetic patients aged 18 years or older (men and women).
• Patients who have not previously received SGLT2 inhibitors or GLP-1 receptor agonists.
• Chronic kidney disease (CKD) patients :50 CKD patients with various etiologies.
• Focus:
• This part of the study will specifically evaluate immune-mediated kidney disease, such as ANCA-associated vasculitis, and the effects of immunosuppressive therapy on NETosis.

You may not qualify if:

• Patients with acute infections, hematologic or oncologic diseases, or positive for HIV or Hepatitis B/C

Sponsors & Collaborators

• Western Galilee Hospital-Nahariya: lead

Study Sites (1)

Galilee Medical Center

Nahariya, 2210001, Israel

RECRUITING

Biospecimen

Retention: SAMPLES WITHOUT DNA

Serum samples to examine NETosis markers

MeSH Terms

Conditions

Diabetes Mellitus; Kidney Diseases; Glomerulonephritis

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Nephritis

Central Study Contacts

Etty Kruzel-Davila, MD

CONTACT

972-4-9107619; ETTYK@gmc.gov.il

Olga Vdovich, MD

CONTACT

olgav@gmc.gov.il

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of the Nephrology Department

Study Record Dates

• First Submitted: January 26, 2025
• First Posted: February 12, 2025
• Study Start: May 13, 2024
• Primary Completion (Estimated): December 30, 2030
• Study Completion (Estimated): December 30, 2031
• Last Updated: February 12, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE

Locations

IL (1)