Thrombotic microangiopathy and intravenous immunoglobulin therapy

Abstract

Sirs, I read with interest the article in this journal titled “Intravenous gamma globulin for thrombotic microangiopathy of unknown etiology” by Ito et al. [1], particularly the diagnosis of this patient and the effectiveness of intravenous immunoglobulin (IVIG). The reported patient exhibited hypertension, acute and chronic renal failure, normal ADAM metallopeptidase with thrombospondin type 1 motif 13 (ADAMTS13) activity, and an absence of inhibitory autoantibodies to ADAMTS13, which are clinical findings more common in atypical hemolytic uremic syndrome (HUS) than in thrombotic thrombocytopenic purpura (TTP) [2]. Complement dysregulation plays an important role in the pathogenesis of atypical HUS [2, 3]. Thirty to 50% of patients with atypical HUS exhibit gene mutations for regulators of complement activation, including complement factor H (CFH), membrane cofactor protein (MCP), or factor I (IF) [2–4]. In addition, some patients with atypical HUS without mutations in CFH, MCP, or IF may exhibit CFH autoantibodies [5]. Uncontrolled complement activation due to gene mutations or acquired antibodies to these complement regulatory proteins leads to glomerular and vascular endothelial injury and results in atypical HUS [2]. Although Ito et al. stated in the abstract that CFH deficiency was excluded in their patient, they did not provide detailed data regarding the complement system of this patient. Thus, it is possible that this patient might exhibit gene mutations for CFH, MCP, or IF or have antibodies to these complement regulatory proteins. Although IVIG has been used for TTP, the effectiveness of IVIG for TTP is still controversial [6, 7], and no report has demonstrated the efficacy of IVIG for atypical HUS [1]. Ito et al. reported an improved clinical condition and laboratory data following IVIG whereas plasma exchange (PE) was ineffective [1]. The beneficial effect of PE in atypical HUS is believed to be due to elevation of the levels of complement regulatory proteins by supplementation of deficient regulators or removal of antibodies to these regulators [4]. Therefore, PE is ineffective in patients with atypical HUS when it cannot increase the levels of complement regulatory proteins in these patients. On the other hand, IVIG has many immunoregulatory effects, including attenuation of complement activation [8]. IVIG acts as a scavenger for activated complement components such as C3b [8, 9] and may attenuate activation of alternative complement pathway regardless of CFH, MCP, or IF levels. Thus, IVIG may be effective for some patients with atypical HUS with complement dysregulation who are unresponsiveness to PE.