The patient described here was found to have a mutation in the
CD46 gene encoding membrane cofactor protein (c.1058C>T, p.Ala353Val). This mutation has been described previously in aHUS and is known to be functionally significant [
7]. Of the three aHUS patients described by Fang et al. [
7], one developed ESRF. Because MCP is a transmembrane molecule, its role is limited to the surface of endothelial cells, and a
CD46 mutation does not lead to systemic complement dysregulation. The clinical implication of a
CD46 mutation was analysed in two large series of patients with aHUS [
2,
3]. The conclusions drawn from both studies were that
CD46 mutations are associated with a less severe course: no patients in the series reached ESRF during the first episode [
2], and 86% of patients remained long-term dialysis-free [
3]. Also, kidney transplantation was generally successful [
2,
3]. No beneficial effect of plasma therapy on the prevention of ESRF could be demonstrated in either series. In the French series [
2], favorable outcome occurred in eight (89%) of nine episodes that were treated with plasma therapy and 15 (88%) of 17 untreated episodes; in the Italian series [
3], complete or partial remission (defined by healing of hematological symptoms but persistence of renal sequelae) was achieved in 91% of plasma-treated episodes but also in 100% of the non-treated episodes. However, the authors could not exclude that in those patients who did not recover spontaneously, plasma therapy failed because it was not adequately administered. We have previously shown that the success of plasma therapy in aHUS due to a
CFH mutation depends on the strategy used. Only intensive PE at presentation followed by prophylactic treatment was efficient in our earlier study [
6]. Based on this result, we used a similar approach in the management of this patient with a
CD46 mutation. In contrast to many previously reported MCP-associated aHUS patients who have a relapsing course with complete recovery after each relapse, our patient had a single episode, which was unusually severe (prolonged dialysis, severe hypertension) but which resolved completely and was subsequently followed by a progressive deterioration in renal function without any clinical evidence of a significant acute microangiopathy episode (no thrombopenia, no acute hemolytic anemia). The presence of several at risk polymorphisms of
CD46 and
CFH may have enhanced the pathogenic role of the CD46 mutation on the glomerular endothelium. During the initial presentation, there was a temporal relationship between plasma therapy and an improvement in the clinical condition. However, this improvement was slow, and it is questionable whether this was a result of the treatment or a spontaneous evolution. The delay before the initiation of PE may have eventually played a role in this slow recovery. Subsequently, regular prophylactic PE was unable to prevent the development of ESRF despite intensification in the frequency of PE from weekly to daily. It is probable that ongoing low-grade chronic thrombotic microangiopathy, as evidenced by continuously slightly increased plasma LDH plasma levels and a low haptoglobin until the time of nephrectomy, had a significant role in the progression to ESRF. The response to PE in this patient is, therefore, in keeping with the suggestion from the authors of the two previous studies [
2,
3], that plasma therapy is unlikely to be of therapeutic benefit in
CD46 mutation-associated aHUS, at least when given preventively. However, because the results of mutation screening of complement genes are not available for weeks or months after presentation, all patients who present with aHUS should be treated with PE. When the results of the mutation screening eventually become known, these can guide both the PE strategy to prevent relapses and the approach to transplantation if and when patients reach ESRF—but clear-cut recommendation concerning the treatment of relapses cannot be given here.