MAC-Inhibition in Heymann Nephritis

Wider research context / theoretical framework Membranous nephropathy (MN) is an autoimmune disease which damages the renal corpuscles or glomeruli, the filtration unit of the kidney, by auto-antibody mediated injury and is the most common cause of significant urinary protein loss and, ultimately, irreversible loss of renal function in approximately one-third of cases. Recent findings highlighted the role of complement-mediated injury to the glomerular epithelial cells through the assembly of the membrane attack complex (MAC). Hypotheses/research questions /objectives New therapy options offer a targeted blockade of the complement system, which will be investigated in vivo in this study. We hope that the inhibition of complement activation will reverse or at least stop renal damage and restore renal function. This is a critical new approach since only 70% of the patients with idiopathic MN will respond to immunosuppressive agents, and there is a need for rapid anti-inflammatory action in those who will respond before antibodies decrease. A biotechnologically developed antibody called eculizumab has been established as a potent complement inhibitor for almost ten years and used in various kidney diseases such as paroxysmal nocturnal hemoglobinuria or atypical hemolytic uremic syndrome. Early analysis of its application in MN patients indicated that eculizumab was used at too low doses in those highly nephrotic patients. Hence pre-clinical data was critically needed. Approach/methods In a first series of experiments, timely and quantitatively changing doses of rat-specific anti-C5 antibody have been applied in a long-known and systematically investigated animal model of the same disease called Heymann nephritis (HN). We will use an equivalent to eculizumab, especially inhibiting rat C5. It will enable us to test in vivo the pharmacokinetics and the effects of the C5-inhibition in HN at serum and urinary levels, as well as at histology level employing highly precise multiplex fluorescent immunohistochemistry with high-throughput confocal microscopy and targeted mass spectrometry. We will also investigate MAC in urinary exosomes as a biomarker of disease activity and therapy, which could be translated into human MN. We aim to deliver new therapeutic possibilities for this often severe and disabling disorder and new biomarkers of activity to guide therapy. Level of originality / innovation The novelties of this project lie in revisiting the efficacy and pharmacokinetics of antibody-mediated C5-inhibition in HN and by extension MN. Interest for this antibody goes beyond MN to other organ-specific autoimmune diseases where it will potentially serve as add-on therapy to conventional immunosuppression. Primary researchers involved Erwin-Schrödinger-Auslandsstipendien PR_Abstract_en - Dr. Nicolas Kozakowski Nicolas Kozakowski will be the researcher in charge of all experimental steps of the project and will stay under the scientific direction of Prof. Pierre Ronco and Dr. Hanna Debiec, both renowned scientists in the field of membranous nephropathy.