C1q deficiency is an inheritable immune disorder attributed to biallelic pathogenic mutations in C1q genes (C1QA, C1QB, or C1QC). Patients with C1q deficiency demonstrate increased susceptibility to severe infections and systemic autoimmune conditions, particularly systemic lupus erythematosus (SLE) and lupus-like disease. Thrombotic microangiopathy (TMA) is a histopathologic finding of vascular endothelial injury often associated with hemolytic anemia, thrombocytopenia, and acute kidney injury. Patients with SLE are at risk for developing TMA due to excessive complement activation in the setting of autoantibody immune complexes. However, TMA has not been reported in a patient with C1q deficiency with SLE.
We report an 11-year-old child with known C1q deficiency and associated SLE who presented with hypertensive crisis, acute kidney injury, hemolytic anemia, and thrombocytopenia. A kidney biopsy demonstrated lupus nephritis. Additionally, glioblastoma (GBM) remodeling and an arteriolar fibrin thrombus were observed, consistent with TMA. Immunofluorescent staining for C4d, a marker of complement activation via the classical or lectin pathways, was negative. An abnormally elevated soluble C5b-9 complex was observed in plasma, suggestive of terminal complement activation. Genetic variants or autoantibodies that might cause a disorder of complement dysregulation, other than the known C1q deficiency, were excluded.
Treatment consisted of immunosuppression with steroids, mycophenolate mofetil, and tofacitinib for SLE and lupus nephritis, and aggressive blood pressure control, including continuous renal replacement therapy. For her TMA, she was started on eculizumab and anticoagulation with bivalirudin and ultimately required 12 rounds of therapeutic plasma exchange before indices of microangiopathic cell damage improved. The patient was discharged in stable condition on intermittent hemodialysis and is now undergoing evaluation for hematopoietic stem cell and renal transplantation.
Excessive complement activation contributes to TMA pathogenesis in patients with SLE and lupus nephritis. This case highlights that TMA can occur in the absence of classical complement activation and provides insight into the mechanisms that underlie TMA and lupus nephritis. In this patient, activation of the alternative complement pathway in the setting of systemic autoimmunity may have potentiated TMA. We provide a framework for therapeutic options that may include terminal complement inhibition, anticoagulation, and plasma exchange, in addition to SLE-directed therapies.
