Scleroderma Renal Crisis as a Genetic Complementopathy

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Abstract Systemic sclerosis (SSc), also called scleroderma, is a rare disease characterized by fibrosis of connective tissues. Some patients with SSc develop a complication called scleroderma renal crisis (SRC), which is characterized by sudden onset of new high blood pressure and evidence of kidney damage. Though patients can be treated with ACE inhibitors, there is still a high morbidity. Many individuals require kidney transplant or dialysis. The pathology of SRC is strikingly similar to a different set of sudden onset kidney diseases called thrombomicroangiopathies, or TMAs. TMAs often have an identified genetic cause, primarily by excessive activation of the complement cascade. Complement activity is an enzymatic cascade that is used to fight infections and dispose of cellular/tissue debris. In individuals with TMAs the complement system activates inappropriately and damages the kidney. Because of the similarity to these two conditions, we propose that SRC may actually be caused in some people by complement activation due to the presence of rare genetic variants. We will identify rare variants associated with altered complement function in both Caucasians (Aim 1) and African-Americans (Aim 2) that have scleroderma and either did or did not develop SRC. By comparing only individuals with scleroderma to each other, we will increase our chances of finding genetic risk variants for SRC only. In Aim 3, we will perform immunohistochemistory on SRC kidney biopsies to identify complement deposition. Ultimately, if our hypothesis proves correct, it will open the door for the development of novel clinical tests to identify individuals with scleroderma at risk of renal crisis, and we would also be able to try new therapeutics that block excessive activation of complement.