Complement System, Diabetes, Diabetic Kidney Disease
Conditions
Keywords
diabetes, diabetic kidney disease, complement system, C3, CD59, MAC, MBL, C3a, C3b, C5a, new antidiabetic drugs
Brief summary
Diabetes is a chronic condition marked by long-term elevated blood glucose levels. There are more types of diabetes; the majority of patients have type 1 or type 2 diabetes. Over long period of time, high blood sugar damages blood vessels and organs. One of the most common complications is diabetic kidney disease, which can slowly lead to kidney failure. People with this condition also have a much higher risk of heart and blood vessel diseases. Newer research shows that the immune system, especially the complement system (a group of proteins that help defend the body), may also play a role in worsening kidney disease in diabetes. High blood sugar can activate these proteins, and they have been found in kidney tissue of patients with diabetic kidney disease. The goal of this study is to find out how much the complement system contributes to kidney damage in diabetes, whether it affects different groups of patients differently, and whether it is linked to blood vessel health or the stage of kidney disease. The study will also assess if improved diabetes control is linked to reduced complement system activity.
Detailed description
Diabetes is a chronic disease characterized by long-term elevated blood glucose levels. Several types of diabetes are known, with most affected individuals having type 1 or type 2 diabetes. Long-term elevation of blood glucose affects various organs in the body, a condition referred to as chronic complications of diabetes. Since elevated blood glucose damages both small and large blood vessels, complications are classified as microvascular (damage to small vessels) and macrovascular (damage to large vessels). Diabetic kidney disease is the main microvascular complication in both type 1 and type 2 diabetes and is also the leading cause of kidney failure. Changes in the kidneys develop over many years. Gradual deterioration of kidney function is monitored using laboratory parameters. Along with declining kidney function, blood pressure also increases, and cardiovascular diseases begin to develop- the risk of these rises exponentially with worsening kidney function. Cardiovascular diseases represent the leading cause of mortality among people with diabetes. Traditionally, diabetic kidney disease was considered as non-inflammatory condition. Its development was attributed to impaired glucose metabolism and elevated blood pressure. Consequently, achieving optimal blood glucose and blood pressure values has been regarded as key to preventing chronic complications. However, diabetes itself represents an additional risk factor for cardiovascular disease compared with individuals without diabetes. Thus, individuals with diabetic kidney disease are even more prone to cardiovascular events. In these patients it is especially important to follow treatment guidelines and to treat elevated blood glucose and blood pressure as intensively as possible. For individuals with diabetic kidney disease, medications from the group of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are prescribed for the treatment of high blood pressure. Both medication groups also have a protective effect on the kidneys and slow the decline of kidney function. Angiotensin is a substance in the body responsible for raising blood pressure-when its action is inhibited, blood pressure decreases. The investigators now know that inflammation and the immune system also play a role in the development of chronic diabetic complications. The complement system (a group of proteins in the blood involved in immune responses) is becoming recognized for its importance. Current studies do not suggest that the complement system plays a key role in the onset of the disease; however, its role in the progression of diabetic kidney disease and possibly in the occurrence of different forms of the disease has become evident. Hyperglycaemia increases the activity of certain complement proteins and activates specific pathways, while the hyperglycaemic environment also impairs the regulation of some proteins. Kidney biopsies of individuals with diabetic kidney disease have shown the presence of complement proteins in kidney tissue, and gene expression analyses have identified activation of complement-related genes. The purpose of this study is to determine whether and to what extent activation of the complement system contributes to diabetic kidney disease and to define potential differences among different groups of individuals with diabetes. Additionally, the investigators aim to determine whether there is a connection between complement system activation and arterial function, as well as between complement system activation and the stage of kidney disease. The investigators will also investigate whether diabetes control influences complement system activation and whether previous kidney biopsy findings correspond with laboratory results.
Interventions
None listed
Sponsors
University Medical Centre Ljubljana
Study design
Observational model
COHORT
Time perspective
CROSS_SECTIONAL
Eligibility
Sex/Gender
ALL
Age
40 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* body mass index below 30 kg/m² * unknown macrovascular complications * treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers at the highest tolerated dose
Exclusion criteria
* a body mass index above 30 kg/m² * macrovascular complications
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Level of complement system activation | An additional visit to the diabetes outpatient clinic is planned within one year, where this will be determined. | The investigators will determine components of the complement system in blood and urine samples. * Blood parameters: * S compl. component C3: 0.6-1.3 g/L, ↓ consumpt.; ↑ inflam., * S compl. component C4: 0.1-0.3 g/L,↓ classical/lectin \| ↑ inflam., * S fact. B: 166-399 mg/L, ↓ AP (alter. path.) consumpt. \| ↑ AP act., * S fact. H: 380.6-674.9 mg/L, ↓ regul. \| ↑ compensation, * S fact. I: 21.2-42.1 mg/L, ↓ regul. \| ↑ compensation, * S soluble C5b-9 lytic complex (sC5b-9): 127-303 ng/mL, ↑ terminal compl., * S fact. B fragment Bb: 0.49-1.42 µg/mL, ↑ AP act., * S fact. H antibodies (anti-FH): \< 10 U/mL, ↑ AP dysreg., * S C1q antibodies (anti-C1q): \< 10 U/mL, ↑ classical pathway, * S C3a: man.ref., ↑ compl. act., * S C3c: man. ref., ↑ C3 breakdown, * S C5a: man. ref., ↑ strong act. * Urine parameter : * Urinary soluble C5b-9 lytic complex (sC5b-9): \< 30 ng/mL, ↑ renal compl. act. Expressed in different mass units (mg,g,µg,ng) or activity units (U) per volume units of blood serum (mL,L). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| IMT thickness | An additional visit to the diabetes outpatient clinic is planned within one year, where the examination will be performed. | The investigators will measure the intima-media thickness (IMT) with ultrasound. Result will be expressed in millimetres. A thickness greater than 1.0 mm is considered pathological. |
| Carotid-femoral pulse wave velocity (PWV) | An additional visit to the diabetes outpatient clinic is planned within one year, where the examination will be performed. | The investigators will evaluate arterial stiffness and central hemodynamics non-invasively using applanation tonometry and pulse wave analysis. Results will be expressed in metres per second (m/s). Higher PWV values indicate increased arterial stiffness and reduced arterial elasticity. Augmentation Index (AIx), or AIx@75, represents the contribution of the reflected pulse wave to central systolic pressure and reflects arterial compliance and wave reflection. Higher AIx values indicate increased arterial stiffness and enhanced wave reflection. Because AIx is influenced by heart rate, it is commonly adjusted to a standardized heart rate of 75 beats per minute (AIx@75). |
| Endothelial Function | An additional visit to the diabetes outpatient clinic is planned within one year, where the examination will be performed. | The investigators will use peripheral arterial tonometry . The measurement is performed using a finger-mounted pneumatic probe, which detects pulsatile volume changes in the fingertip. The device's software analyses the change in pulse amplitude before and after occlusion, calculating the Reactive Hyperemia Index (RHI), which serves as a quantitative marker of endothelial function and has no unit. Lower RHI values indicate endothelial dysfunction and impaired nitric oxide-mediated vasodilation.Higher RHI values reflect preserved endothelial function. Augmentation Index (AIx), derived from EndoPAT, reflects arterial stiffness and wave reflection in peripheral arteries. Higher AIx values indicate increased arterial stiffness and adverse vascular properties. Lower AIx values suggest better arterial compliance. |
Countries
Slovenia
Contacts
PRINCIPAL_INVESTIGATORMiodrag Janić
Outcome results
None listed