Atypical HUS is caused by acquired or hereditary abnormalities of factors that dampen activation of complement by the alternative pathway. Their absence leads to excessive activation of complement, with ensuing microvascular injury and microvascular thrombosis. The C5-9 membrane attack complex appears to have a central role, as a therapeutic antibody that inhibits this complex turns off platelet consumption and improves renal function. Interestingly, abnormalities of the alternative pathway of complement activation also may lead to C3 glomerulonephritis and dense deposit disease, as discussed earlier.
TTP is caused by acquired or inherited deficiencies in ADAMTS13 (a disintegrin and metalloprotease with thrombospondin-like motifs), a plasma protease that cleaves von Willebrand factor (vWF) multimers into smaller sizes. Acquired defects in ADAMTS13 are caused by inhibitory autoantibodies directed against ADAMTS13, while inherited deficiencies stem from mutations in the ADAMTS13 gene. Deficiencies of ADAMTS13 result in the formation of abnormally large vWF multimers that activate platelets spontaneously, leading to platelet aggregation and thrombosis in multiple organs, including the kidney.
MORPHOLOGYThemorphologiclesionsareverysimilarinallformsofTMAregardlessoftheetiology.Thrombiareseeninglomerularcapillariesandalsothearteriolesandsometimesthelargerarteriesinmoreseverecases.Additionalglomerularchangesresultingfromendothelialinjuryincludewideningofthesubendothelialspace,duplicationorsplittingofGBMs,andlysisofmesangialcells.Corticalnecrosisalsomayoccurinseverecases.IfTMApersists,scarringofglomerulimaydevelop.Exceptforvaryingamountsoffibrinogenintheglomeruliandarterioles,immunofluorescencestudiesaretypicallynegative.
The clinical course varies according to the etiology and the severity of the morphologic changes. More severe vascular changes are typically associated with a less favorable outcome.
Shiga toxin–associated HUS is characterized by the sudden onset, usually after a gastrointestinal or flulike prodromal episode, of bleeding manifestations (especially hematemesis and melena), severe oliguria, hematuria, microangiopathic hemolytic anemia, and (in some individuals) prominent neurologic changes. This disease is one of the main causes of acute kidney injury in children. If the acute kidney injury is managed properly with dialysis, most patients recover in a matter of weeks. The long-term prognosis (over 15–25 years), however, is not uniformly favorable, as about 25% of affected children eventually develop renal insufficiency.
The onset of atypical HUS is usually sudden, without prodromal diarrhea. The outcome is significantly poorer than in Shiga toxin–mediated HUS. The case-fatality ratio is approximately 20%, and only 60% to 70% of patients recover renal function. Plasma exchange can be used to temporarily restore missing factors (in those with inherited disease) or remove pathogenic antibodies. Since most complement factors are produced in the liver, liver transplantation can be curative. More recently, antibody inhibitors of the membrane attack complex have been shown to be effective in reducing thrombosis and improving renal function, and are now considered to be the first-line therapy in “complement-mediated” forms of HUS.
The typical onset of TTP is also sudden, with a dominant involvement of the central nervous system, and the kidneys are less commonly involved than in Shiga toxin and atypical HUS. Without therapy, TTP typically follows a rapidly fatal course, with survival rates of approximately 10%. With the advent of plasma exchange therapy that replaces ADAMTS 13, the prognosis has improved dramatically. In those patients who survive, residual renal abnormalities are rare.