Etiology Pathogenesis

The lesion of thrombotic microangiopathy may be seen in malignant hypertension, systemic lupus erythematosus, especially when antiphospholipid antibodies are present, pregnancy, scleroderma, and secondary to toxins and in HIV patients (8,13-16). Drugs, especially cyclosporine and mitomycin, may also cause HUS (14). Bone marrow transplant patients may develop HUS months after transplantation. In addition, genetic predisposition for thrombotic microangiopathy has been described. Familial forms of HUS and TTP occur, and are likely underrecognized (7,17,18). Familial HUS may be due to mutations in factor H, a regulator of complement, or rarely membrane cofactor protein (MCP), a cell-bound complement regulator

(19). Familial TTP is due to constitutional deficiency of a von Willebrand factor-cleaving protease, whereas a nonfamilial form of TTP seems to be caused by an acquired inhibitor of this protease. This protease is now called ADAMTS13 (a member of the "a disintegrin and metalloprotease with ihrombospondin type 1 repeats" family of zinc metalloproteases) (7).

Common underlying infectious agents leading to hemolytic uremic syndrome have been identified. The typical diarrhea-associated (D+) form of HUS is most often associated with the shiga-like toxin or verotoxin (4,9,12). With atypical HUS (D-) no diarrheal prodrome is seen, and shiga-like toxin is not identified. Most of these infections are due to the Escherichia coli serotype O157 : H7. Verotoxin was associated with ~90% of cases of HUS in children in North America and Europe. Undercooked hamburger meat is most closely associated with such outbreaks in North America, pointing to cattle as an important reservoir for the implicated E. coli serotype O157 : H7. In addition, this E. coli strain can be transmitted from person to person, and outbreaks associated with swallowing contaminated lake water or ingestion of contaminated fruit or vegetables or cider have occurred.

The mature verotoxin has alpha and beta subunits. The beta subunits interacts with the target cell, most often the endothelial cell, binding to the glycolipid Gb3 protein. The alpha unit is cleaved and taken up by endocy-tosis, inactivating 60S ribosomes, thereby causing cell death. The Gb3 receptor for verotoxin is highly expressed in human kidney, perhaps underlying the susceptibility of the kidney to this toxin (19). However, Gb3 levels were not different in normal children vs. adults, so the excess risk of children for D + HUS cannot be simply explained by overexpression of Gb3

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