Complement-mediated thrombotic microangiopathy associated with lupus nephritis

Abstract

Complement-mediated thrombotic microangiopathy (CM-TMA) is a clinical disorder driven by the generation of excess complement. It is characterized by thrombocytopenia and microangiopathic hemolytic anemia (MAHA)withmicrovascular thrombosis resulting in systemic organ damage (TMA). One form of CM-TMA, atypical hemolytic uremic syndrome (aHUS), is characterized by pathologic complement activation due to the loss of the natural regulators of the complement system, which results in systemic endothelial and organ damage. Lupus erythematosus is amultisystemimmune complex disorder associated with activation of complement, as well as renal failure termed lupus nephritis (LN). A subset of these patients also develop TMA, with progressive lifethreatening thrombocytopenia, MAHA, and progressive renal failure similar to aHUS. This subset of patients is poorly responsive to corticosteroids, cyclophosphamide, immunomodulation, and plasma exchange. In this article, we report 11 cases of LN associated with TMA progressing through these therapies, 10 of which were successfully treated with complement inhibition. Complement-regulatory protein mutations, including complement factor H (CFH), factor I, factor B, membrane cofactor/(CD46) and thrombomodulin, and CFH-related 1-3, were identified in 6 of 10 patients tested. One patient had a loss of a renal allograft. Three patients had concurrent antiphospholipid syndrome. Two of the 3 patients had normal D-dimers at this presentation.We believe that this subset of lupus patients, with clinical and pathologic manifestations of aHUS, define a separate entity that we believe should be termed CM-TMA associated with LN.