Post-diarrheal uremic syndrome (HUS) is the most common cause of acute renal failure in infants and young children, and is a substantial cause of chronic kidney damage and failure. The diarrhea is caused by enterohemorrhagic E. coli (e.g., E. coli 0157:H7) that produces potent cytotoxins known as Shiga-like toxins (SLTs) or Verotoxins (VTs). There is strong circumstantial evidence that SLT and Lipopolysaccharide (LPS) gain access to the circulation from the gut, damage renal endothelial cells and activate a complex pathogenic cascade that results in oliguric renal failure. Our limited understanding of the pathogenic cascade, however, has hampered efforts to develop effective intervention strategies. A non-human primate model (baboon) will be used to test the hypothesis that acute renal failure in SLT/LPS induced HUS results from increased prothrombotic, vasoconstrictive, and lipid peroxidation activity coupled to decreased antithrombotic, vasodilatory, and antioxidant activity, and that correcting this imbalance favorably influences the natural history of the syndrome. More specifically, purified SLT-I and LPS will be infused into baboons, after which the magnitude and sequence of the appearance of markers of endothelial and renal tubular cell injury, lipid peroxidation, white blood cell, platelet and coagulation cascade activation, and substance that modulate thrombosis and vascular tone will be determined. The importance of LPS in the pathogenic cascade will be measured by determining if LPS causes up-regulation of renal GB3 toxin receptors, and if so, if up-regulation is associated with cytokine production. Once the pathogenic cascade has been characterized, the up-regulated prothrombotic, vasoconstrictive, and lipid peroxidation systems will be selectively and collectively blocked, and the down-regulated antithrombotic, vasodilatory and antioxidant systems will be stimulated. This will provide information concerning the relative importance of each in the pathogenesis of the syndrome, and will identify intervention strategies that can be used to interrupt the pathogenic cascade and thereby prevent full expression of the syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052083-05
Application #
6177830
Study Section
Special Emphasis Panel (SRC (01))
Program Officer
Moxey-Mims, Marva M
Project Start
1996-09-30
Project End
2004-08-31
Budget Start
2000-09-01
Budget End
2004-08-31
Support Year
5
Fiscal Year
2000
Total Cost
$209,871
Indirect Cost
Name
University of Utah
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Siegler, Richard L; Pysher, Theodore J; Tesh, Vernon L et al. (2005) Reduced nitric oxide bioavailability in a baboon model of Shiga toxin mediated hemolytic uremic syndrome (HUS). Ren Fail 27:635-41
Clayton, Frederic; Pysher, Theodore J; Lou, Randall et al. (2005) Lipopolysaccharide upregulates renal shiga toxin receptors in a primate model of hemolytic uremic syndrome. Am J Nephrol 25:536-40
Siegler, Richard L; Obrig, Tom G; Pysher, Theodore J et al. (2003) Response to Shiga toxin 1 and 2 in a baboon model of hemolytic uremic syndrome. Pediatr Nephrol 18:92-6
Siegler, Richard L; Pysher, Theodore J; Tesh, Vernon L et al. (2002) Renal prostacyclin biosynthesis in a baboon model of Shiga toxin mediated hemolytic uremic syndrome. Nephron 92:363-8
Andreoli, Sharon P; Trachtman, Howard; Acheson, David W K et al. (2002) Hemolytic uremic syndrome: epidemiology, pathophysiology, and therapy. Pediatr Nephrol 17:293-8
Siegler, Richard L; Pysher, Theodore J; Tesh, Vernon L et al. (2002) Prophylactic heparinization is ineffective in a primate model of hemolytic uremic syndrome. Pediatr Nephrol 17:1053-8
Pysher, Theodore J; Siegler, Richard L; Tesh, Vernon L et al. (2002) von Willebrand Factor expression in a Shiga toxin-mediated primate model of hemolytic uremic syndrome. Pediatr Dev Pathol 5:472-9
Siegler, R L; Pysher, T J; Lou, R et al. (2001) Response to Shiga toxin-1, with and without lipopolysaccharide, in a primate model of hemolytic uremic syndrome. Am J Nephrol 21:420-5
Siegler, R L; Pysher, T J; Tesh, V L et al. (2001) Response to single and divided doses of Shiga toxin-1 in a primate model of hemolytic uremic syndrome. J Am Soc Nephrol 12:1458-67
Taylor Jr, F B; Tesh, V L; DeBault, L et al. (1999) Characterization of the baboon responses to Shiga-like toxin: descriptive study of a new primate model of toxic responses to Stx-1. Am J Pathol 154:1285-99