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

NCT ID: NCT06821919

Last Updated: 2025-02-12

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 70 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2024-05-13
• Study Completion Date: 2031-12-30

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.

Detailed Description

Neutrophil extracellular traps (NETs) are an essential component of the innate immune system, designed to trap and neutralize invading pathogens. NETosis, the process by which neutrophils release decondensed chromatin (DNA and histones) decorated with antimicrobial proteins such as myeloperoxidase (MPO) and neutrophil elastase (NE), is a critical mechanism in host defense. This process is induced by stimuli such as PMA, antibodies, cytokines, chemokines, and sterile triggers, including high glucose, cholesterol, and hypoxia. This stimulation activates the Raf-MEK-ERK pathway and NADPH oxidase-dependent production of reactive oxygen species.1,2 An increase in cytosolic calcium cations activates NADPH oxidases and acts as a cofactor for peptidylarginine deiminase 4 (PAD4). PAD4 catalyzes citrullinated histone H3 (Cit-H3) inducing chromatin decondensation, resulting in a cell extrusion of mixture of DNA and bactericidal proteins, including MPO and NE, which all serves as a specific markers of NETosis.1,2 While beneficial in infection settings, excessive or dysregulated NET formation can cause significant tissue damage and organ dysfunction. NETs have been implicated in the pathogenesis of various acute and chronic inflammatory diseases, including myocardial infarction, atherosclerosis, autoimmune diseases, diabetes, and chronic kidney disease (CKD). Elevated NETosis markers, including cell-free DNA (cfDNA) and Cit-H3, are commonly observed in these conditions, underscoring their role in disease progression.3 Given the dual nature of NETosis, understanding how different factors influence this process is critical for developing targeted therapies. This study focuses on two key aspects: evaluating the effects of antiglycemic medications on NETosis and investigating NETosis across different stages of immune-mediated kidney disease before and after immunosuppressive therapy.

(The hemodialysis part of this trial is not included in the current protocol)

Part 1: Evaluating the Effects of Antiglycemic Medications on NETosis Dysregulated NETosis in diabetic and CKD patients contributes to systemic inflammation and organ damage. Studies have shown elevated levels of NETosis markers, such as cfDNA and Cit-H3, in these populations. While metformin has demonstrated the ability to reduce NET formation in diabetic patients, the effects of newer glucose-lowering agents, including SGLT2 inhibitors and GLP-1 receptor agonists, remain unexplored.4 Both SGLT2 inhibitors and GLP-1 receptor agonists have demonstrated robust cardiovascular and renal protective effects.5 This study aims to evaluate their impact on basal and stimulated NETosis in diabetic and CKD patients with various etiologies. By analyzing NETosis markers before and after treatment, this research will provide insights into whether these agents can modulate NETosis, thereby offering additional anti-inflammatory benefits and reducing disease-associated complications.

Part 2: Evaluating NETosis at Different Stages of Immune-Mediated Kidney Disease and After Immunosuppressive Therapy Immune-mediated kidney diseases, such as ANCA-associated vasculitis, involve heightened NETosis that contributes to kidney injury and systemic inflammation.2 Chronic kidney disease resulting from these conditions often exhibits elevated NET formation, exacerbating disease progression. This study seeks to investigate the dynamics of NETosis at various stages of CKD caused by immune-mediated diseases.

In addition, the effects of immunosuppressive therapy on NETosis will be assessed. Immunosuppressive medications, a cornerstone in the treatment of diseases like ANCA-associated vasculitis, can influence neutrophil activity. By monitoring NETosis markers, including cfDNA, Cit-H3, MPO, and NE, before and after initiating immunosuppressive therapy, the study aims to identify patterns of response and the potential therapeutic modulation of NETosis.

Conclusion This comprehensive investigation into the effects of antiglycemic medications and immunosuppressive therapy on NETosis will provide critical insights into the interplay between treatment, inflammation, and disease progression in diabetic and CKD patients. These findings may help pave the way for targeted interventions aimed at modulating NETosis and improving outcomes in high-risk populations.

Conditions

Diabetes Mellitus; Kidney Disease

Study Design

• Observational Model Type: CASE_ONLY
• Study Time Perspective: PROSPECTIVE

Study Groups

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.

No interventions assigned to this group

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.

No interventions assigned to this group

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.

No interventions assigned to this group

Eligibility Criteria

Inclusion Criteria

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.

Exclusion Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Western Galilee Hospital-Nahariya

OTHER_GOV

Sponsor Role: lead

Responsible Party

Etty Kruzel-Davila

Director of the Nephrology Department

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Galilee Medical Center

Nahariya, , Israel

Site Status: RECRUITING

Countries

Israel

Central Contacts

Etty Kruzel-Davila, MD

Role: CONTACT

ETTYK@gmc.gov.il

972-4-9107619

Olga Vdovich, MD

Role: CONTACT

olgav@gmc.gov.il

Facility Contacts

Etty Kruzel-Davila, MD

Role: primary

ETTYK@gmc.gov.il

972-4-9107619

Study Documents

Document Type: Study Protocol

View Document

Other Identifiers

0108-22-NHR

Identifier Type: -

Identifier Source: org_study_id