Distinct Histopathologic Changes Elicited in Baboon Kidneys after Challenge with Shiga Toxin Type 1 or 2 from Enterohemorrhagic E. coli.
Joel M Henderson, Shinichiro Kurosawa, Deborah J Stearns-Kurosawa. Boston University Medical Center, MA
Background: Shiga toxin-producing E. coli (STEC) are an important cause of regional outbreaks of acute hemorrhagic enteritis and hemolytic uremic syndrome. Long-term renal impairment is often a consequence of STEC infection. STEC may produce either or both of two virulent toxins, Stx1 and Stx2, which share similar structure and cell receptors. Despite similarities, STEC producing primarily Stx2 is more often associated with kidney injury in patients, and the mechanism is not known. We investigated effects of each Shiga-like toxin on kidneys in a baboon model.
Design: Anesthetized juvenile baboons (Papio) were challenged with an i.v. toxin dose (Stx1:10, 50, 100 ng/kg; Stx2: 10, 50 ng/kg), and followed until euthanasia was performed up to seven days post challenge. Necropsy kidney tissue was processed for standard renal histopathologic examination.
Results: Kidneys from Stx2-challenged animals showed the most severe changes. High dose Stx2 (n=6; 50 ng/kg, euthanasia <128hrs) elicited severe changes including interstitial hemorrhage (most prominent in the medulla), prominent tubulointerstitial injury and polymorphonuclear inflammation, and striking apoptotic changes in glomerular mesangial cells. Glomerular capillary wall changes (thickening, double contours) were overall mild and focal with high-dose Stx2. In contrast, higher dose Stx1 (n=10; 50, 100ng/kg; euthanasia <74hrs) resulted in more substantial glomerular capillary wall changes (moderate thickening and double contouring) along with moderate tubular injury. Mesangial apoptotic changes were not seen in Stx1-challenged animals. Low dose Stx2 (n=4; 10ng/kg) and low dose Stx1 (n=3; 10ng/kg) showed minor or no significant changes, respectively.
Conclusions: Overall kidney injury was more severe after Stx2 challenge, although euthanasia was required earlier in Stx1 animals, possibly obscuring further Stx1-mediated damage with time. The pattern of glomerular injury with Stx1 challenge featured prominent “HUS-like" capillary wall changes, whereas that with Stx2 challenge was predominantly characterized by mesangial cell apoptotic changes. Thus, Stx1 and Stx2 had distinct effects on the glomerulus, with endothelial injury predominating with Stx1 and mesangial injury predominating with Stx2. The novel finding of Stx2-induced mesangial cell injury raises new avenues of investigation into mechanisms of renal damage after STEC infection.
Category: Kidney (does not include tumors)
Wednesday, March 2, 2011 1:00 PM
Poster Session VI # 250, Wednesday Afternoon