title: Warfarin-related nephropathy is the tip of the iceberg: direct thrombin inhibitor dabigatran induces glomerular hemorrhage with acute kidney injury in rats.
abstract: BACKGROUND
  Excessive anticoagulation with warfarin can result in acute kidney injury (AKI) by causing glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts in some patients, especially in those with chronic kidney disease (CKD). This condition was described as warfarin-related nephropathy (WRN). Recent evidence suggests that WRN-like syndromes are not confined to anticoagulation with warfarin, but may be seen with other anticoagulants, such as dabigatran. The aim of this study was to investigate dabigatran effects on kidney function in an animal model of CKD and possible pathogenic mechanisms of AKI.
  
  
  METHODS
  Control and 5/6 nephrectomy rats were treated with different doses of dabigatran and protease-activated receptor 1 (PAR-1) inhibitor SCH79797.
  
  
  RESULTS
  Dabigatran resulted in changes in coagulation in rats similar to those in humans at 50 mg/kg/day. Dabigatran resulted in a dose-dependent increase in serum creatinine (Scr) and hematuria in both control and 5/6 nephrectomy rats. SCH79797 also increased Scr and hematuria, more prominent in animals with CKD. Morphologically, numerous RBC tubular casts were seen in 5/6 nephrectomy rats treated with either dabigatran or SCH79797 and only occasional RBC casts in control rats.
  
  
  CONCLUSIONS
  Our data indicate that WRN represents part of a broader syndrome, anticoagulant-related nephropathy (ARN). ARN, at least partially, is mediated via PAR-1. Our findings suggest that not only CKD patients, but other patients as well, are at high risk of developing AKI if the therapeutic range of anticoagulation with dabigatran is exceeded. Close monitoring of kidney function in patients on dabigatran therapy is warranted.
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, OH, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Ryan
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, OH, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Ware
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, OH, USA.
authors.forename: Zahida
authors.initials: Z
authors.lastname: Qamri
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, OH, USA.
authors.forename: Anjali
authors.initials: A
authors.lastname: Satoskar
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, OH, USA.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, OH, USA.
authors.forename: Gyongyi
authors.initials: G
authors.lastname: Nadasdy
authors.affiliation: Department of Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: Brad
authors.initials: B
authors.lastname: Rovin
authors.affiliation: Department of Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: Lee
authors.initials: L
authors.lastname: Hebert
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, OH, USA.
authors.forename: Tibor
authors.initials: T
authors.lastname: Nadasdy
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, OH, USA.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Brodsky
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000150:complications* / Q000473:pathology; D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use; D000991:Antithrombins / Q000009:adverse effects; D001562:Benzimidazoles / Q000009:adverse effects*; D000069604:Dabigatran; D004195:Disease Models, Animal; D006470:Hemorrhage / Q000139:chemically induced* / Q000473:pathology; D007668:Kidney / Q000098:blood supply*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014859:Warfarin / Q000633:toxicity; D015091:beta-Alanine / Q000009:adverse effects / Q000031:analogs & derivatives*
chemical_list: D000925:Anticoagulants; D000991:Antithrombins; D001562:Benzimidazoles; D015091:beta-Alanine; D014859:Warfarin; D000069604:Dabigatran
keywords: acute kidney injury; dabigatran; warfarin-related nephropathy