Clinical Research Directory

Immune System in Diabetic Kidney Disease

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.

Meningococcal Vaccination in Patients on Complement Inhibitors

Myasthenia gravis is an autoimmune neurological disorder caused by autoantibodies directed predominantly against components of the postsynaptic membrane of the neuromuscular junction. Anti-aquaporin-4 antibody-associated neuromyelitis optica (AQP4-IgG) is an autoimmune inflammatory disease of the central nervous system (CNS) characterized by three main clinical manifestations: transverse myelitis, optic neuritis, and postrema area syndrome. Over the past five years, the FDA and EMA have approved complement inhibitor drugs for the treatment of generalized myasthenia gravis with anti-AChR antibody positivity and for neuromyelitis optica spectrum disorders with anti-AQP4 antibody positivity. Eculizumab is a humanized monoclonal antibody that binds to the C5 fragment of the human complement specifically and with high affinity, inhibiting its cleavage in C5a and C5b and preventing the formation of the membrane attachment C5b-9 complex (MAC) of the terminal portion of the complement cascade. This monoclonal antibody maintains the early components of complement activation (C3b), which are essential for the opsonization of microorganisms and the clearance of immune complexes. Ravulizumab is a monoclonal antibody derived from eculizumab, through the substitution of four specific amino acids, which binds specifically to complement protein C5. These substitutions increase the dissociation of the monoclonal antibody from the C5 fragment within the endosome and promote the recycling of the neonatal Fc receptor-mediated unbound antibody, extending its half-life and duration of action up to an interval of 8 weeks. Zilucoplan is a synthetic macrocyclic peptide composed of 15 amino acids that specifically binds the complement protein C5, inhibiting its cleavage into C5a and C5b by C5 convertase, which results in an underregulation of MAC assembly and cytolytic activity. In addition, this drug binds the C5b fraction of C5, creating a steric encumbrance for the binding of C5b to C6 and preventing subsequent assembly of the MAC if any C5b is formed. Due to their mechanism of action, eculizumab, ravulizumab and zilucoplan result in an increased susceptibility of the patient to systemic infections by encapsulated bacteria (S. pneumoniae, H. influenzae, N. meningitidis). To reduce the risk of infection, all patients should be vaccinated against serogroups A, B, C, W, Y at least 2 weeks prior to treatment; patients who start treatment before 2 weeks after administration of meningococcal vaccines should be given appropriate antibiotic prophylaxis for up to 2 weeks after vaccination. Currently, there is no global agreement on the vaccination schedule to be followed after the first dose. According to Italian guidelines, a booster dose is recommended for the monovalent vaccine only at least 1 month after the first administration and a period of antibiotic prophylaxis beyond the first two weeks after the first doses is not indicated. The primary objective of the study is to evaluate the antibody titles after tetravalent meningococcal vaccination (serogroups A, C, W, Y) in patients candidate to complement inhibitors therapy.