The Role of Inflammation and Inflammasome Activation in Human Bile Cast Nephropathy

Bile cast nephropathy is an underdiagnosed cause of acute kidney injury. The precise pathogenesis of bilirubin tubular toxicity remains unknown. The aim of this study is to explore the cellular and molecular pathophysiology of human bile cast nephropathy. Paraffin-embedded sections of renal biopsy tissue from a bile cast nephropathy patient were stained by immunohistochemistry for oxidative stress (4-hydroxynonenal), immune cell subpopulations, including dendritic cells (CD1c), macrophages (CD68) and T cells (CD3), and inflammasome activation by staining for active-caspase-1 and the inflammasome ASC adaptor protein. Quantitative analyses of immunohistochemistry staining were compared to healthy renal cortical tissue. We identified yellow to brown granular casts within the bile cast nephropathy case, consistent with the presence of bile pigment. The presence of bile pigment was associated with strong tubular 4-hydroxynonenal staining intensity, a marker of oxidative stress. Diffuse tubulointerstitial inflammatory cell infiltrate was detected, with elevated CD1c, CD68 and CD3 staining. Foci of inflammasome activity were co-localized with this intense immune cell infiltration, with increased active-caspase-1 and ASC staining. Our findings are the first to suggest that bile casts may lead to oxidative stress and trigger the inflammasome signalling cascade, leading to interstitial inflammation and driving AKI pathobiology. This article is protected by copyright. All rights reserved.