ESPN 54th Annual Meeting

ESPN 2022


 
Shiga toxin targets the podocyte in Haemolytic Uraemic Syndrome (HUS) resulting in glomerular endothelial cell complement dysregulation
EMILY BOWEN 1 JENNY HURCOMBE 1 FERN BARRINGTON 1 LINDSAY KEIR 1 LOUISE FARMER 1 ABIGAIL LAY 1 EVA LARKAI 1 GAVIN WELSH 1 MOIN SALEEM 1 RICHARD COWARD 1

1- UNIVERSITY OF BRISTOL
 
Introduction:

Haemolytic uraemic syndrome (HUS) is a thrombotic microangiopathy (TMA) that has a predilection to present in the kidney. It is a triad of microangiopathic haemolytic anaemia, thrombocytopenia, and acute kidney injury. In 90% of cases, HUS follows gastroenteritis secondary to infection with Shiga toxin (Stx) producing bacteria such as Escherichia coli. Stx HUS is the leading cause of acute kidney injury in children with a mortality of 5%. However, the precise pathophysiological mechanisms following Stx infection leading to TMA remain poorly understood. Here we show that the podocyte is a key initiator in Shiga toxin HUS, which could explain why the glomerulus is the prime target of systemic Shiga toxin driven infection.

Material and methods:

To demonstrate that the podocyte Shiga toxin receptor (Gb3) is sufficient to trigger the development of HUS, we used conditional gene targeting to engineer human Gb3 expression specifically in the podocytes of adult mice (PodGb3).

 

Results:

PodGb3 mice developed HUS (thrombocytopenia, haemolytic anaemia and uraemia p<0.05) at day 10 following intraperitoneal Stx. Renal histology demonstrated glomerular TMA; with intracapillary thrombus formation seen on electron microscopy. Immunofluorescence demonstrated an increase in glomerular fibrinogen deposition and C3b vs. controls. Additionally, glomerular expression of complement regulator Factor H was significantly reduced in PodGb3 mice, rendering them more susceptible to complement attack. Furthermore, C5 inhibition was found to rescue the Shiga toxin HUS phenotype.

Conclusions:

Together, these observations provide compelling evidence for the importance of podocyte to glomerular endothelial cell cross-talk within the kidney in the development of Shiga toxin associated HUS and suggest a possible therapeutic role for complement inhibition in patients with this devastating disease.