Oxidative stress and inflammasome activation in human rhabdomyolysis-induced acute kidney injury.

Acute kidney injury (AKI) is a life-threatening complication of rhabdomyolysis. The pathophysiological mechanisms of rhabdomyolysis-induced AKI (RIAKI) have been extensively studied in the murine system, yet clinical translation of this knowledge to humans is lacking. In this study, we investigated the cellular and molecular pathways of human RIAKI. Renal biopsy tissue from a RIAKI patient was examined by quantitative immunohistochemistry (Q-IHC) and compared to healthy kidney cortical tissue. We identified myoglobin casts and uric acid localised to sites of histological tubular injury, consistent with the diagnosis of RIAKI. These pathological features were associated with tubular oxidative stress (4-hydroxynonenal staining), regulated necrosis/necroptosis (phosphorylated mixed-lineage kinase domain-like protein staining) and inflammation (tumour necrosis factor (TNF)-α staining). Expression of these markers was significantly elevated in the RIAKI tissue compared to the healthy control. A tubulointerstitial inflammatory infiltrate accumulated adjacent to these sites of RIAKI oxidative injury, consisting of macrophages (CD68), dendritic cells (CD1c) and T lymphocytes (CD3). Foci of inflammasome activation were co-localised with these immune cell infiltrate, with significantly increased staining for adaptor protein ASC (apoptosis-associated speck-like protein containing a caspase activation and recruitment domain) and active caspase-1 in the RIAKI tissue compared to the healthy control. Our clinical findings identify multiple pathophysiological pathways previously only reported in murine RIAKI, providing first evidence in humans linking deposition of myoglobin and presence of uric acid to tubular oxidative stress/necroptosis, inflammasome activation and necroinflammation.

Role of inflammation and inflammasome activation in human bile cast nephropathy.

Bile cast nephropathy (BCN) is an underdiagnosed cause of acute kidney injury (AKI). The precise pathogenesis of bilirubin tubular toxicity remains unknown. The aim of this study is to explore the cellular and molecular pathophysiology of human BCN. Paraffin-embedded sections of renal biopsy tissue from a BCN patient were stained by immunohistochemistry (IHC) 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 adaptor protein, ASC (apoptosis-associated speck-like protein containing a caspase activation and recruitment domain). Quantitative analyses of IHC staining were compared to healthy renal cortical tissue. We identified yellow to brown granular casts within the BCN 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. SUMMARY AT A GLANCE The report suggests that bile casts may lead to oxidative stress and trigger the inflammasome signalling cascade, leading to interstitial inflammation and driving bile cast nephropathy pathobiology.