? A diverse group of rare disorders characterized by thrombotic microangiopathy (TMA), a distinctive histopathologic entity characterized by primary endothelial injury, represents an important cause of morbidity and mortality in pediatric patients. There are two major clinical phenotypes associated with TMA - hemolytic uremic syndrome and thrombotic thrombocytopenic purpura. These orphan diseases can be triggered by infectious agents, drugs, underlying medical conditions, organ transplantation, or genetic abnormalities in various circulating or membrane bound proteins. Unfortunately, there is controversy about the appropriate pathophysiological categorization and diagnostic criteria for these entities. Moreover, because these illnesses are rare, there is a paucity of data about their disease mechanism, incidence, natural history, and optimal treatment. Finally, the low incidence of these diseases has hampered efforts to develop novel therapies and to evaluate efficacy in well designed randomized controlled clinical trials. In this fully independent R21 application, we propose to form a consortium of clinical sites and dedicated laboratories with the long-term objective of studying all forms of TMA that occur in pediatric patients.
The specific aims of this collaborative effort will be to: (1) establish an international network of participating centers; (2) establish a registry and web-based database and create a biorepository for patients with TMA; (3) describe the epidemiology and clinical features of all forms of TMA and perform a longitudinal observational study of patients with severe disease; and (4) clarify the underlying genetic causes in a subgroup of TMA, atypical HUS. The significance of an International Network and Registry for TMA is two-fold: (1) it will enhance understanding of these rare diseases and provide an opportunity to test potential therapies in a timely manner; and (2) by increasing knowledge about the endothelial injury and the regulation of the coagulation and complement cascades in TMA, this project is likely to have much broader relevance to a number of diseases characterized by endothelial dysfunction, disordered thrombosis, and complement activation. These include essential hypertension, diabetes, hyperlipidemia, myocardial infarction, and chronic kidney disease. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DK071221-02
Application #
7230000
Study Section
Special Emphasis Panel (ZDK1-GRB-7 (O3))
Program Officer
Eggers, Paul Wayne
Project Start
2006-04-01
Project End
2010-03-31
Budget Start
2007-04-01
Budget End
2010-03-31
Support Year
2
Fiscal Year
2007
Total Cost
$211,320
Indirect Cost
Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
110565913
City
Manhasset
State
NY
Country
United States
Zip Code
11030
Trachtman, Howard (2013) Drugs and trials: lessons from Plato. Clin Ther 35:688-91
Trachtman, Howard (2013) HUS and TTP in Children. Pediatr Clin North Am 60:1513-26
Delvaeye, Mieke; Noris, Marina; De Vriese, Astrid et al. (2009) Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med 361:345-57
Martinez-Barricarte, Ruben; Pianetti, Gaia; Gautard, Ruxandra et al. (2008) The complement factor H R1210C mutation is associated with atypical hemolytic uremic syndrome. J Am Soc Nephrol 19:639-46
Noris, M; Remuzzi, G (2008) Translational mini-review series on complement factor H: therapies of renal diseases associated with complement factor H abnormalities: atypical haemolytic uraemic syndrome and membranoproliferative glomerulonephritis. Clin Exp Immunol 151:199-209
Castelletti, Federica; Donadelli, Roberta; Banterla, Federica et al. (2008) Mutations in FN1 cause glomerulopathy with fibronectin deposits. Proc Natl Acad Sci U S A 105:2538-43
Caprioli, Jessica; Remuzzi, Giuseppe (2008) A mouse model of non-Shiga toxin-associated haemolytic uraemic syndrome. Nephrol Dial Transplant 23:462-5
Kavanagh, David; Richards, Anna; Noris, Marina et al. (2008) Characterization of mutations in complement factor I (CFI) associated with hemolytic uremic syndrome. Mol Immunol 45:95-105
Caprioli, Jessica; Remuzzi, Giuseppe (2007) Complement hyperactivation may cause atypical haemolytic uraemic syndrome--gain-of-function mutations in factor B. Nephrol Dial Transplant 22:2452-4