Two Cases of Autoimmune and Genetic Triggers of Thrombotic Microangiopathy Involving Complement Mutations in Systemic Sclerosis

Introduction: Thrombotic microangiopathy (TMA) is a life-threatening condition. While both autoimmune diseases, such as systemic sclerosis (SSc), and atypical hemolytic-uremic syndrome (aHUS) with mutations in the complement pathway, are known etiologies of TMA, their combined role has not been well characterized. We present 2 cases of acute kidney injury (AKI) illustrating a "two-hit" hypothesis: autoimmune activation and underlying complement gene mutations, leading to TMA. Case Description: Case 1: A 72-year-old woman presented with anasarca and arthralgias. Skin induration was noted on exam. Her blood pressure (BP) was 184/83 mmHg. Labs showed hemoglobin 7.9 g/dL, platelets 81000/µL, high LDH, and low haptoglobin. Serum creatinine (sCr) was 1.5 mg/dL, and UPCR was 1.5 g/g. ANA and RNA polymerase III antibodies were positive. Genetic testing showed a heterozygous missense mutation in exon 11 of the CFI gene and multiple CFH polymorphisms. Kidney biopsy confirmed TMA. She was treated with eculizumab, which was discontinued due to gram-negative bacteremia and lack of clinical improvement. Case 2: A 67-year-old woman with known SSc presented with encephalopathy and dyspnea. Her BP was 254/114 mmHg. Skin hardening was noted on exam. Labs revealed a sCr rising from 2.7 to 6.8 mg/dL, requiring dialysis by day 12. UPCR was 0.96 g/g. Hematologic parameters were stable; RNA polymerase III antibody was negative. Genetic testing revealed heterozygous missense variants in CFHR5 (exon 20) and ADAMTS13. Kidney biopsy showed glomeruli with chronic microangiopathy without thrombi. She was treated with captopril but remained dialysis-dependent. Eculizumab was not administered due to family concerns regarding infection risk. Discussion: These cases illustrate the convergence of autoimmune endothelial injury and complement dysregulation in the pathogenesis of TMA. SSc may trigger vascular injury and scleroderma renal crisis, while complement gene mutations (e.g., CFI, CFHR5) impair regulation of the alternative pathway, promoting complement-mediated TMA. Our report supports the “two-hit” hypothesis in TMA and highlights the importance of adding genetics to the autoimmune work-up in patients with SSc. Complement inhibition may be a valuable therapeutic option in selected cases.