Complement and the atypical hemolytic uremic syndrome in children

Abstract

Over the past decade, atypical hemolytic uremic syndrome (aHUS) has been demonstrated to be a disorder of the regulation of the complement alternative pathway. Among approximately 200 children with the disease, reported in the literature, 50% had mutations of the complement regulatory proteins factor H, membrane cofactor protein (MCP) or factor I. Mutations in factor B and C3 have also been reported recently. In addition, 10% of children have factor H dysfunction due to anti-factor H antibodies. Early age at onset appears as characteristic of factor H and factor I mutated patients, while MCP-associated HUS is not observed before age 1 year. Low C3 level may occur in patients with factor H and factor I mutation, while C3 level is generally normal in MCP-mutated patients. Normal plasma factor H and factor I levels do not preclude the presence of a mutation in these genes. The worst prognosis is for factor H-mutated patients, as 60% die or reach end-stage renal disease (ESRD) within the first year after onset of the disease. Patients with mutations in MCP have a relapsing course, but no patient has ever reached ESRD in the first year of the disease. Half of the patients with factor I mutations have a rapid evolution to ESRD, but half recover. Early intensive plasmatherapy appears to have a beneficial effect, except in MCP-mutated patients. There is a high risk of graft loss for HUS recurrence or thrombosis in all groups except the MCP-mutated group. Recent success of liver-kidney transplantation combined with plasmatherapy opens this option for patients with mutations of factors synthesized in the liver. New therapies such as factor H concentrate or complement inhibitors offer hope for the future.

Fig. 1

Complement activation and control. aHUS is a disease resulting from inefficient protection of the surfaces of the host’s endothelial cells in the setting of complement activation. (1) Activation of complement and covalent attachment of complement C3 to the microbial surfaces. C3b binds CFB, inducing formation of the alternative C3 convertase (C3bBb) and amplification of the C3 cleavage. (2) Protection of self cell surfaces. Regulation of the cleavage of C3 is critical. Under normal conditions the formation of C3 convertase is tightly controlled by CFH, MCP, and CFI. (3) In the case of aHUS, activation is uncontrolled and C3 convertase is formed, resulting in formation of inflammatory mediators. CFH does not attach to surfaces through its heparin/anionic-binding sites, and, thus, CFB binds C3b. Degradation of C3b to iC3b is defective in the absence of CFI and its cofactors (CFH and MCP) (from [24], with permission of the authors and Wiley–Blackwell Publishing)

Fig. 2

CFH mutations in the French (upper line) and Italian (lower line) pediatric cohorts. Mutations in blue indicate low plasma CFH level; mutations in black indicate normal plasma CFH level. Ho homozygous

Fig. 3

C3 plasma concentration in 101 children with aHUS (Italian and French pediatric cohorts), according to genetic subgroup. Triangles homozygous mutation; horizontal line represents 2SDs of normal

Fig. 4

MCP mutations in the Italian (left) and French (right) pediatric cohorts. Ho homozygous

Fig. 5

CFI mutations in the French (upper line) and Italian (lower line) pediatric cohorts

Fig. 6

Intrafamilial phenotype variability in a family with heterozygous CFH mutation (W 1183 R, SCR 20). Ages are given in years. Affected individuals are indicated by filled symbols, deceased individuals by a diagonal line. Carriers of CFH mutation are indicated by asterisks. m months