Project 2 - Longitudinal study of complement-mediated TMA

PROJECT SUMMARY – PROJECT 2 The overall goal of this project is to develop the first multicenter, prospective, longitudinal natural history study of complement-mediated TMA (CM-TMA also called atypical hemolytic uremic syndrome) to comprehensively investigate short- and long-term outcomes including renal, cardiovascular, neurologic, and patient reported outcomes. In CM-TMA, excessive complement activation triggers inflammation, platelet activation and direct endothelial injury causing microvascular thrombosis. CM-TMA is considered a genetic disease – up to 50% of patients harbor rare germline variants in complement genes; however, complement mutations are neither necessary nor sufficient to cause disease. The penetrance of these variants in only ≈ 20% and complement amplifying conditions (pregnancy, infection, autoimmunity, and malignancy) often trigger CM-TMA. We have developed a cell-based assay that measures complement-mediated cell injury induced by patient serum and can distinguish CM-TMA from other TMAs. We recently established an improved and commercially scalable version of the assay called the bioluminescent modified Ham assay. Using this ‘biosensor’ with pathway specific inhibitors, we showed that complement activation in CM-HUS is predominantly driven by autoreactive IgM that activates the classical pathway, with mutations in the alternative pathway predisposing to additional complement dysregulation. This is a paradigm shift since CM-CMA was considered a disorder of primary alternative complement pathway dysregulation for over 50 years. Terminal complement inhibitors have drastically reduced risk of end-stage renal disease and death from acute TMA. However, little is known about long-term renal and extra-renal outcomes such as rates of progressive renal disease, cardiovascular disease and hypertension that have never been systematically and prospectively evaluated. With the large USTMA consortium with 22 high-volume clinical sites, and our novel, scalable and commercially feasible bioluminescent modified Ham assay, this proposal will answer the most pressing questions in CM-TMA today: (1) what are the long-term renal, cardiovascular, and neurologic outcomes of CM-TMA? (2) does functional complement activation during TMA remission (measured by the bio-mHam) or the presence of complement mutations increase the risk of these adverse long-term sequelae, and (3) develop a repository to facilitate using the bio-mHam to functionally interrogate the role of complement in secondary TMA, and the significance variants of uncertain significance, both which are areas of uncertainty. In aim 1 of this project, we will develop a longitudinal registry of adults and children with CM-TMA to evaluate the long-term clinical outcomes, complications and comorbidities, including performing serial brain MRI to detect subclinical ischemic injury in a subset of participants. In aim 2, we will evaluate whether persistent complement activation during CM-TMA clinical remission is associated with relapse risk, decline in renal function, and cardiovascular disease.