[Acute renal failure and thrombotic microangiopathy (TM)]

Thrombotic microangiopathy (TM) is a disorder characterized by fibrin formation and platelet aggregation in the small arteries and capillaries. Two main clinical settings are reported in association with this disorder: hemolitic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). Both conditions share common findings such as microangiopathic anemia and thrombocytopenia. HUS is more frequent in children and is mainly characterized by renal symptoms, whereas PTT is dominated by neurologic abnormalities. However, in many patients, the clinical distinction between HUS and PTT is not clear; therefore, some authors consider the two syndromes as manifestations of the same entity. In children, the most common cause of HUS is an enteric infection caused by cytotoxin-producing bacteria (mainly Escherichia coli with serotype O157:H7). This toxin--the Shiga toxin--can bind to glomerular endothelial cells and stimulate the production of cytokines and the secretion of von Willebrand factor (vWf). TM may be caused by drugs such as cyclosporin, tacrolimus, mytomicin C, ticlopidine, quinine, and oral contraceptives. It may be associated with disorders of pregnancy (severe pre-eclampsia and postpartum HUS) or with systemic disorders such as systemic lupus erythematosus (SLE), antiphospholipid syndrome, systemic sclerosis, and human immunodeficiency virus (HIV) infection. Abnormalities of the gene of complement factor H have been found in familial HUS and in some sporadic cases of HUS not associated with diarrhea. Factor H abnormalities induce an uncontrolled complement activation that can activate the coagulation cascade. In familial PTT, genetic abnormalities of the cleaving metalloproteinase of fWf ADAMTS 13 have been identified. In other patients with TTP, antibodies inhibiting this enzyme have been found. As a consequence of plasma ADAMTS 13 deficiency, unusually large vWf multimers are produced. This abnormality, in the presence of an increased shear stress, stimulates platelet adhesion and aggregation.

Knowledge of the type of causative abnormality is relevant to a therapeutic approach. Children with diarrheal HUS usually do not benefit from plasma infusion or exchange, whereas in patients with factor H or ADAMTS 13 deficiency procedures that include the administration of the lacking product and removal of the inhibiting or toxic factors, such as ultralarge vWfs, are mandatory. Potentially renal transplantation candidates should be screened for genetic defects to avoid the recurrence of TM in the graft.