Abstract
E. coli associated Hemolytic Uremic Syndrome (epidemic hemolytic uremic syndrome, eHUS) caused by Shiga toxin-producing bacteria is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury that cause acute renal failure in up to 65% of affected patients. We hypothesized that the mannose-binding lectin (MBL) pathway of complement activation plays an important role in human eHUS, as we previously demonstrated that injection of Shiga Toxin-2 (Stx-2) led to fibrin deposition in mouse glomeruli that was blocked by co-injection of the anti-MBL-2 antibody 3F8. However, the markers of platelet thrombosis in affected mouse glomeruli were not delineated. To investigate the effect of 3F8 on markers of platelet thrombosis, we used kidney sections from our mouse model (MBL-2+/+ Mbl-A/C-/-; MBL2 KI mouse). Mice in the control group received PBS, while mice in a second group received Stx-2, and those in a third group received 3F8 and Stx-2. Using double immunofluorescence (IF) followed by digital image analysis, kidney sections were stained for fibrin(ogen) and CD41 (marker for platelets), von-Willebrand factor (marker for endothelial cells and platelets), and podocin (marker for podocytes). Electron microscopy (EM) was performed on ultrathin sections from mice and human with HUS. Injection of Stx-2 resulted in an increase of both fibrin and platelets in glomeruli, while administration of 3F8 with Stx-2 reduced both platelet and fibrin to control levels. EM studies confirmed that CD41-positive objects observed by IF were platelets. The increases in platelet number and fibrin levels by injection of Stx-2 are consistent with the generation of platelet-fibrin thrombi that were prevented by 3F8.
Highlights
E. coli associated Hemolytic Uremic Syndrome, the most common cause of acute renal failure in children worldwide, is characterized by the triad of thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury, preceded generally by bloody diarrhea. [1, 2]
We previously demonstrated that injection of
Our previous studies demonstrated the role of the lectin pathway in glomerular thrombi formation in eHUS [20, 21], the composition of thrombi in the affected mouse glomeruli was not delineated
Summary
E. coli associated Hemolytic Uremic Syndrome (epidemic hemolytic uremic syndrome, eHUS), the most common cause of acute renal failure in children worldwide, is characterized by the triad of thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury, preceded generally by bloody diarrhea. [1, 2]. E. coli associated Hemolytic Uremic Syndrome (epidemic hemolytic uremic syndrome, eHUS), the most common cause of acute renal failure in children worldwide, is characterized by the triad of thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury, preceded generally by bloody diarrhea. Acute kidney failure occurs in up to 65% of those who develop eHUS, and many require acute dialysis. Death occurs in 3–5% of those affected, and long-term sequelae, including chronic kidney disease and hypertension, are common [7, 8]. Another form of HUS, atypical HUS (aHUS) is distinct from eHUS, while often has overlapping symptoms. Its frequency is only about one-tenth of eHUS [10]
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