title: Increased renal expression and urinary excretion of TLR4 in acute kidney injury associated with cirrhosis.
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.
authors: Institute of Liver and Digestive Health, Royal Free Hospital, London, UK.
authors: Naina
authors: N
authors: Shah
authors: Fatma E
authors: FE
authors: Mohamed
authors: Maria
authors: M
authors: Jover-Cobos
authors: Jane
authors: J
authors: Macnaughtan
authors: Nathan
authors: N
authors: Davies
authors: Richard
authors: R
authors: Moreau
authors: Valerie
authors: V
authors: Paradis
authors: Kevin
authors: K
authors: Moore
authors: Raj
authors: R
authors: Mookerjee
authors: Rajiv
authors: R
authors: Jalan
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology* / Q000378:metabolism* / Q000652:urine; D000704:Analysis of Variance; D015153:Blotting, Western; D015331:Cohort Studies; D003401:Creatine / Q000097:blood; D005260:Female; D051549:Glutathione S-Transferase pi / Q000652:urine; D005982:Glutathione Transferase / Q000652:urine; D000072596:Hepatitis A Virus Cellular Receptor 1; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000652:urine; D008104:Liver Cirrhosis, Alcoholic / Q000150:complications*; D008297:Male; D008562:Membrane Glycoproteins / Q000652:urine; D008875:Middle Aged; D011991:Receptors, Virus; D051197:Toll-Like Receptor 4 / Q000097:blood / Q000378:metabolism*
chemical_list: C491143:HAVCR1 protein, human; D000072596:Hepatitis A Virus Cellular Receptor 1; D007527:Isoenzymes; D008562:Membrane Glycoproteins; D011991:Receptors, Virus; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; C119995:glutathione S-transferase alpha; D003401:Creatine