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overview I am a Professor of Paediatrics at the University of Toronto and Staff Physician in the Division of Nephrology, The Hospital for Sick Children (SickKids). In addition, I am Senior Associate Scientist in the Cell Biology Program of the SickKids Research Institute. I am also cross appointed as Associate Member to the Institute of Medical Science (IMS) and Laboratory Medicine and Pathobiology (LMP) of the University of Toronto. My research focuses on complement-mediated renal diseases such as atypical hemolytic-uremic syndrome (aHUS) and membranoproliferative glomerulonephritis (MPGN) / C3 glomerulopathy (C3G). My research has translational character and includes both clinical and basic research: I have established an international registry with biorepository (www.kidcom.ca). In addition, I have also established a basic research program focusing on the pathogenesis of complement-mediated thrombotic microangiopathy (TMA). In particular, I am investigating the consequences of complement activation on endothelial cells, platelets and neutrophils, and the interaction of these cells in TMA pathogenesis. The results of my research can change our understanding of the pathophysiology of aHUS and may ultimately allow for the development of new treatment strategies not only for aHUS but also other complement-mediated diseases. I am the chair of HUS International (HUSi), and chair of the International aHUS Registry. I serve on the editorial board of Kidney International, Nephrology Dialysis and Transplantation and Pediatric Nephrology, and have published numerous peer-reviewed articles and book chapters related to my research focus. Innovations Advancing diagnosis and treatment of aHUS and related conditions We reported the successful use of eculizumab in aHUS, DEAP HUS, refractory MPGN, antibody-medicated kidney transplant rejection, and post HSCT TMA in children. Modelling vascular endothelium and TMA and aHUS pathology We established blood outgrowth endothelial cells (BOECs) from normal donors and aHUS patients as an approach to study vascular endothelium, in particular the response to complement activation. By using the BioFlux microfluidic system we established a model system to study interactions of endothelium, platelets, neutrophils and complement. A major contribution relates to the investigating of complement and von Willebrand Factor (VWF) identifying VWF as new complement regulator on ECs. Investigating platelet-complement interactions Platelets interact with the AP regulator Factor H (CFH), which is also synthesized by megakaryocytes and can be taken up by platelets in vivo and in vitro. We demonstrated that platelet CFH is functional, bioavailabel and released from stimulated platelets. Investigating neutrophil-endothelium-complement interactions We recently observed that several complement proteins are present in neutrophils and that CRP/properdin mediates complement deposition on NETs and that NETs trap bacteria while complement kills them. We also studied the interaction of neutrophils with complement-challenged endothelial cells, neutrophils and platelets, observing that complement dysregulation stimulates neutrophil adhesion to endothelial cells with subsequent platelet aggregation. Establishing a registry and biorepository for patients with complement-mediated diseases We took a leadership role in establishing an international registry with biorepository that maintains for patients with complement-mediated diseases such as aHUS and C3G (www.kidcom.ca).

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  • Nephrology