Mitomycin- and calcineurin-associated HUS, endothelial dysfunction and endothelial repair: a new paradigm for the puzzle?

Abstract

Thrombotic microangiopathies (TMA) are multisystem disorders characterized by the formation of platelet-rich, fibrin-poor thrombi within the microvasculature. While there have been major advances into the cause of certain types of TMAs that have led to rational treatment choices [1], TMA secondary to chemotherapeutic and calcineurin inhibitors remains a black box both in terms of pathogenesis and treatment. Here we report a case of mitomycin-associated haemolytic uremic syndrome (HUS) resistant to conventional treatment but which responded to chronic end-stage renal disease management consisting of haemodialysis and erythropoietin treatment. We hypothesized that haemodialysis and erythropoietin may play a role in ‘healing’ the endothelial injury. To support our hypothesis, we measured the markers of endothelial cell injury (circulating endothelial cells) and a marker of endothelial repair (CD34þ endothelial progenitor cell migratory activity) in a second case of TMA secondary to calcineurin therapy. We demonstrate that, in drug-induced HUS, there is increased endothelial injury and a defective repair mechanism and that correcting uraemia, with renal replacement therapy, and treatment with specific medications aimed at enhancing endothelial repair may be able to alter the course of the disease. These findings not only suggest a mechanism for drug-induced TMA, but also suggest a rational line of therapy for a disease that heretofore was treated with supportive care. Methods