Increased renal expression and urinary excretion of TLR4 in acute kidney injury associated with cirrhosis

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Abstract
Background: Patients with cirrhosis frequently develop renal dysfunction, a proportion of who do not fulfill criteria for hepatorenal syndrome (HRS). We hypothesized that the kidneys in these patients would exhibit histological and biomarker evidence of kidney injury. We looked specifically for TLR expression as they may mediate kidney injury.Methods: Sixty seven subjects (6); alcoholic cirrhosis: compensated (9), acute deterioration of alcoholic cirrhosis (52)] were included. Renal dysfunction was defined as a creatinine of >133 μmol/L and/or according to the AKI network criteria. Urinary biomarkers, KIM‐1, πGST, αGST and a novel biomarker, urinary TLR4 were measured. Renal biopsies were also available from eight other alcoholic cirrhosis patients (three non‐HRS renal dysfunction; five HRS) that were stained for TLR4 and caspase‐3.Results: Fourteen patients developed renal dysfunction, amongst these three had type 2 HRS. KIM‐1, πGST and αGST were higher in patients with acute deterioration of cirrhosis compared with patients with compensated cirrhosis, but did not differ between those with and without renal dysfunction. Urinary TLR4 was significantly higher in patients with renal dysfunction associated with infection/inflammation. Kidney biopsies from non‐HRS renal dysfunction patients showed tubular damage with evidence of increased tubular expression of TLR4, and caspase‐3. Minor changes were observed in HRS patients.Conclusions: The data provide proof of concept that renal dysfunction in patients with cirrhosis with superimposed inflammation is associated with significant tubular injury and apoptosis and with increased renal expression and urinary excretion of the TLR4, suggesting a potential role of TLR4 as mediator of renal injury.
Funding Information
  • MRC, UK
  • Egyptian fellowship
  • Marie Curie Fellowship

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