Jessica Caprioli1, Li Peng, Giuseppe Remuzzi. 1. Mario Negri Institute for Pharmacological Research, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Bergamo, Italy. caprioli@marionegri.it
Abstract
PURPOSE OF REVIEW: Recent studies have provided a better understanding of the molecular mechanisms responsible for hemolytic uremic syndromes. In this review, we summarize biochemical and genetic data that may lead to new clinical approaches. RECENT FINDINGS: The structures and modes of action of Shiga toxins have been deciphered. Patients with non-Shiga-like toxin hemolytic uremic syndrome have been found to carry mutations in three genes that encode for regulators of the complement system (factor H, membrane cofactor protein, and factor I). SUMMARY: Shiga-like toxin-1 and Shiga-like toxin-2 regulate genes that encode for chemokines, cytokines, cell adhesion molecules, and transcription factors involved in immune response and apoptosis. Mutations in factor H, membrane cofactor protein and factor I have recently been identified. Reduced expression of compliment regulators might prevent restriction of complement deposition on glomerular endothelial cells, leading to microvascular cell damage and tissue injury. Shiga-like toxin hemolytic uremic syndrome in children has a favorable prognosis in 90% of cases; kidney transplantation shows a good graft survival rate (80%) in children who progress to end stage renal disease. As for non-Shiga-like toxin hemolytic uremic syndrome, treatment with plasma infusion or exchange has been used with controversial effects. Kidney transplantation is not recommended in those patients with mutations in factor H and factor I; however, a kidney transplant corrects membrane cofactor protein dysfunction. These findings vividly underscore the clinical heterogeneity of outcomes depending upon the nature of the underlying cause of the disease.
PURPOSE OF REVIEW: Recent studies have provided a better understanding of the molecular mechanisms responsible for hemolytic uremic syndromes. In this review, we summarize biochemical and genetic data that may lead to new clinical approaches. RECENT FINDINGS: The structures and modes of action of Shiga toxins have been deciphered. Patients with non-Shiga-like toxin hemolytic uremic syndrome have been found to carry mutations in three genes that encode for regulators of the complement system (factor H, membrane cofactor protein, and factor I). SUMMARY: Shiga-like toxin-1 and Shiga-like toxin-2 regulate genes that encode for chemokines, cytokines, cell adhesion molecules, and transcription factors involved in immune response and apoptosis. Mutations in factor H, membrane cofactor protein and factor I have recently been identified. Reduced expression of compliment regulators might prevent restriction of complement deposition on glomerular endothelial cells, leading to microvascular cell damage and tissue injury. Shiga-like toxin hemolytic uremic syndrome in children has a favorable prognosis in 90% of cases; kidney transplantation shows a good graft survival rate (80%) in children who progress to end stage renal disease. As for non-Shiga-like toxin hemolytic uremic syndrome, treatment with plasma infusion or exchange has been used with controversial effects. Kidney transplantation is not recommended in those patients with mutations in factor H and factor I; however, a kidney transplant corrects membrane cofactor protein dysfunction. These findings vividly underscore the clinical heterogeneity of outcomes depending upon the nature of the underlying cause of the disease.
Authors: Harin Rhee; Sang Heon Song; Yong Jae Lee; Hyun Ju Choi; Jin Hee Ahn; Eun Young Seong; Soo Bong Lee; Ihm Soo Kwak Journal: Clin Exp Nephrol Date: 2011-08-10 Impact factor: 2.801
Authors: Emily M Mallick; Megan E McBee; Vijay K Vanguri; Angela R Melton-Celsa; Katherine Schlieper; Brad J Karalius; Alison D O'Brien; Joan R Butterton; John M Leong; David B Schauer Journal: J Clin Invest Date: 2012-10-08 Impact factor: 14.808