Peripheral Gangrene in Children With Atypical Hemolytic Uremic Syndrome

Abstract

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy with severe clinical manifestation, frequent recurrence, and poor long-term prognosis. It is usually caused by abnormalities in complement regulation. We report 2 cases of children affected by a catastrophic extrarenal complication. A 4-year-old Indian girl developed gangrene of the finger tips 2 days after initial presentation of aHUS. Factor H autoantibodies were identified. Renal function continued to decline despite daily plasma exchanges, and she was started on peritoneal dialysis 5 days after admission. The distal tips of the left hand remained gangrenous with a line of demarcation. Three weeks later, she did not return for follow-up and died at home because of dialysis-related complications. An Arabic girl developed end-stage renal disease due to aHUS in the fourth month after birth. A de novo activating C3 mutation was found. At age 9 months, she suddenly developed ischemic changes in fingers of both hands and several toes. The lesions progressed, and several finger tips became gangrenous despite intense plasma exchange therapy. The decision was made to administer complement blocking therapy with the C5 antibody eculizumab. All nonnecrotic digits rapidly regained perfusion. The 3 already gangrenous fingers healed with loss of the end phalanges. During maintenance, eculizumab aHUS activity subsided completely and some late recovery of renal function was observed. aHUS may present by thrombotic macroangiopathy of small peripheral arteries. Eculizumab appears effective in preserving tissue viability if administered before gangrene occurs and should be considered as first-line rescue therapy in such cases.

Mapping interactions between complement C3 and regulators using mutations in atypical hemolytic uremic syndrome

“…Sporadic aHUS was found in 97 patients, and 33 patients were identified in 14 different pedigrees. 15,16,[21][22][23][24][25][26][27][28][29][30][31][32][33] Table 1). Fifteen of the 42 mutations were recurrent (identified in $2 unrelated aHUS patients from the same or different cohorts; Figure 1; supplemental Table 2).…”

“…The data reported here and available in the literature indicate that 48 C3 variants have been identified in 130 aHUS patients. 15,16,[21][22][23][24][25][26][27][28][29][30][31][32] Two additional rare single nucleotide polymorphisms, K133Q and R713W, have been seen in aHUS patients, but their frequency does not differ from that of the normal population. 23 The R139W mutation was identified in 42% (14 of 33 cases) and 78% (11 of 14 cases) of aHUS patients with C3 mutations in France 16 and The Netherlands, 26 respectively.…”

“…Therefore, the low C3 level at disease onset may be a predictor of early ESRD. Of the available information for eculizumab-treated patients, 60 there were 4 published cases with a C3 mutation (R570Q, 61 R570W, 28 P1640L, 21 and an unspecified C3 mutation 30 ) and 12 known cases from this series. In all but 1 case, the treatment was successful: 10 after transplantation and 1 in whom aHUS activity subsided completely with a late recovery of renal function of the native kidney, and, in 3 cases, remission was achieved but the renal function did not recover.…”

An international consensus approach to the management of atypical hemolytic uremic syndrome in children

“…Further studies are required to establish the benefit of complement blockade treatment in STEC-HUS adults [1,3]. Table 3 juxtaposes clinical features described in three subgroups of aHUS with pediatric onset: HUS with/without complement mutation, with anti-CFH antibody or DGKE mutation [3,9,[50][51][52][53][54][55][56][57][58][59]. Most patients with HUS due to a complement mutation carry a heterozygous mutation.…”

“…However, eculizumab was impressively effective in two children with lifethreatening aHUS and acute distal ischemia (digital gangrene) [55] and skin necrosis with intestinal perforation [121], and two adults with ulcerative skin lesions [122]. That eculizumab may be efficacious to rescue central nervous system involvement is suggested by nine case reports, including four in children [87,90,110,[123][124][125][126][127].…”