Blog entry by mohammad katout
Enormous advances continue to be made to enhance our understanding of the challenging “thrombotic microangiopathies TMA”
It is becoming clear, recently, that distinct disease mechanisms underlie the group of diseases formerly designated as TTP/HUS. Advances in molecular pathology led to the recognition of three different diseases: typical HUS caused by Shiga toxin-producing Escherichia coli (STEC-HUS); atypicalHUS (aHUS), associated with genetic or acquired disorders of regulatory components of the complement system; and TTP that results from a deficiency of ADAMTS13, a plasma metalloprotease that cleaves von Willebrand factor.
Interestingly close to 20,000 articles in TMA have been published since 1945, with striking increase after the completion of human genome sequencing in 2001 as more disease-causing mutations had been identified.
The increasingly better clinical characterization and definition of the role of complement in HUS has pushed our understanding forward in an unprecedented way. Defining complement dysregulation as central to disease pathogenesis has paved the way to targeted therapeutics and improved patient clinical outcome.
Complement-mediated TMA (the preferred term) is not just a disease of children, as evidenced by the largest reported cohorts by Noris and colleagues 2010; Fremeaux-Bacchi and associates, 2013. The child-to-adult ratio is nearly comparable with respect to age-at-presentation, ranging from <1 year of age to 85 years. Interestingly the male-to-female ratio is similar in younger patients, whereas there is a female preponderance in adults (Fremeaux-Bacchi et al., 2013). Triggering events are documented in 39–70% of individuals and include most often diarrhea, respiratory illness and pregnancy.
Chantal Loirat and her colleagues recently published “An international consensus approach to the management of atypical hemolytic uremic syndrome in children” in Pediatric Nephrology Journal providing a consensus clinical practice recommendations generated by HUS International (expert group of clinicians and basic scientists with a focused interest in HUS).
They provided evidence-based answers where available (already scarce), while relying mostly on the published anecdotal literature. The consensus raises many questions as it answers: for instance when to withdraw treatment in countries where therapy is already available? On the other hand, one of the major concerns is the geographical disparity in treatment availability due to the high cost of the drug in limited resources nations worldwide. It also emphasizes the need to carefully design future studied and use data from international registries to better understand this challenging disease.
1. Noris, M., Caprioli, J., Bresin, E., Mossali, C., Pianetti, G., Gamba, S., Daina, E., Fenili, C., Castelletti, F., Sorosina, A., Piras, R., Donadelli, R., Maranta, R., van der Meer, I., Conway, E.M., Zipfel, P.F., Goodship, T.H., Remuzzi, G., 2010. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin. J. Am. Soc. Nephrol. 5, 1844–1859
2. Fremeaux-Bacchi, V., Fakhouri, F., Garnier, A., Bienaime, F., Dragon-Durey, M.A., Ngo, S., Moulin, B., Servais, A., Provot, F., Rostaing, L., Burtey, S., Niaudet, P., Deschenes, G., Lebranchu, Y., Zuber, J., Loirat, C., 2013. Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults. Clin. J. Am. Soc. Nephrol. 8, 554–562
3. Loirat C, Fakhouri F, Ariceta G, Besbas N, Bitzan M, Bjerre A, Coppo R, Emma F, Johnson S, Karpman D, Landau D, Langman CB, Lapeyraque AL, Licht C, Nester C, Pecoraro C, Riedl M, van de Kar NC, Van de Walle J, Vivarelli M, Frémeaux-Bacchi V; HUS International.An international consensus approach to the management of atypical hemolytic uremic syndrome in children. Pediatr Nephrol.2016;31(1):15-39