Limited information is available on anticoagulant‐related nephropathy (ARN). We therefore reviewed the Japanese Adverse Drug Event Report database to investigate kidney injury (KI) in patients ...administered warfarin or direct oral anticoagulants (DOACs) and sought to clarify the risk factors for ARN. KI risk in warfarin users was associated with male sex (odds ratio OR, 1.70; 95% confidence interval CI, 1.35–2.13; P < .01) and age ≥80 years (OR, 1.35; 95% CI, 1.07–1.72; P = .01). KI risk in DOAC users was associated with body weight ≥80 kg (OR, 1.60; 95% CI, 1.01–2.53; P = .04) and use of dabigatran (OR, 1.61; 95% CI, 1.09–2.37; P < .01). Our findings suggest that risk factors for ARN differ between warfarin and DOACs and that these risk factors may be associated with bleeding risk. Therefore, the risk of ARN may be decreased by better managing bleeding risk in patients taking anticoagulants.
Anticoagulant related nephropathy (ARN) is the result of glomerular hemorrhage in patients on systemic anticoagulation therapy or underlying coagulopathy. Red blood cells (RBC) that passed through ...the glomerular filtration barrier form RBC casts in the tubules, increase oxidative stress and result in acute tubular necrosis (ATN). The mechanisms of ARN still not completely discovered. Plasminogen activator inhibitor-1 (PAI-1) plays a significant role in the maintenance of coagulation homeostasis. We developed an animal model to study ARN in 5/6 nephrectomy (5/6NE) rats. The aim of this study was to elucidate the role of PAI-1 in the ARN pathogenesis. 5/6NE rats were treated per os with warfarin (0.75 mg/kg/day) or dabigatran (150 mg/kg/day) alone or in combination with PAI-1 antagonist TM5441 (2.5, 5.0 and 10 mg/kg/day). TM5441 in a dose dependent manner ameliorated anticoagulant-induced increase in serum creatinine in 5/6NE rats. Anticoagulant-associated increase in hematuria was no affected by TM5441. The levels of reactive oxygen species (ROS) in the kidneys were in a dose-dependent manner decreased in 5/6NE rats treated with an anticoagulant and TM5441. Our data demonstrates that PAI-1 may reduce ARN by decreasing ROS in the kidneys. Glomerular hemorrhage is not affected by anti-PAI-1 treatment. These findings indicate that while symptoms of ARN can be reduced by PAI-1 inhibition, the main pathogenesis of ARN – glomerular hemorrhage – cannot be prevented.
Background:
We have previously demonstrated that excessive anticoagulation with warfarin or dabigatran may result in acute kidney injury with red blood cell (RBC) tubular casts in some patients with ...chronic kidney disease, and this condition was named anticoagulant-related nephropathy (ARN). 5/6 nephrectomy (5/6NE) rats treated with warfarin or dabigatran reproduce the main pathologic features of human ARN. We had reported that 5/6NE C57BL/6 mice only partially develop ARN with increased serum creatinine and hematuria but no RBC tubular casts in the kidney.
Objectives:
The aim of this study was to investigate whether ARN can develop in 5/6NE 129S1/SvImJ mice.
Methods:
5/6NE was performed in 129S1/SvImJ mice. Three weeks after 5/6NE, mice were treated with warfarin (1.0 and 1.5 mg/kg/day) or vehicle for 7 days. Serum creatinine, hematuria, and prothrombin time (PT) were monitored daily. Renal morphology was evaluated at the end of the studies.
Results:
Treatment with warfarin resulted in PT elevation 2 to 3 folds from baseline (1.0 mg/kg/day warfarin) and 4 to 5 folds from baseline (1.5 mg/kg/day warfarin) by day 7. Serum creatinine and hematuria elevated by day 7 in a dose-dependent manner. Histologically, 2 of 8 (25%) 5/6NE mice had RBCs in the tubules, and there was acute tubular epithelial cell injury in all warfarin-treated 5/6NE 129S1/SvImJ mice.
Conclusions:
Our findings suggest that 129S1/SvImJ mouse strain is a more suitable murine model to study ARN than C57BL/6 mouse strain.
The aim of this study was to report the prevalence and mortality associated with anticoagulant-related nephropathy (ARN) through a systematic review of the literature.
Electronic searches were ...conducted in the Medline and EMBASE databases, and manual searches were performed in the reference lists of the identified studies. The studies were selected by two independent researchers, first by evaluating the titles and abstracts and then by reading the complete texts of the identified studies. Case series, cross-sectional studies, cohort studies and case-control studies reporting the prevalence and factors associated with ARN were selected. The methodological quality was assessed using the Newcastle-Ottawa scale. Meta-analyses of the prevalence of ARN and 5-year mortality using the random effects model were performed when possible. Heterogeneity was assessed using the
statistic.
Five studies were included. Prevalence of ARN ranged from 19% to 63% among the four included cohort studies. Meta-analysis of these resulted in high heterogeneity
96%, summary effect 31%; 95% confidence interval (CI) 22-42%. Subgroup meta-analysis yielded an ARN prevalence of 20% among studies that included patients with fewer comorbidities (
12%; 95% CI 19-22%). In a direct comparison, meta-analysis of the 5-year mortality rate between anticoagulated patients who had experienced ARN and anticoagulated patients without ARN, patients with ARN were 91% more likely to die (risk ratio = 1.91; 95% CI 1.22-3;
87%). Risk factors for ARN that were reported in the literature included initial excessive anticoagulation, chronic kidney disease, age, diabetes, hypertension, cardiovascular disease and heart failure.
ARN studies are scarce and heterogeneous, and present significant methodological limitations. The high prevalence of ARN reported herein suggests that this entity is underdiagnosed in clinical practice. Mortality in patients with ARN seems to be high compared with patients without this condition in observational studies.
Anticoagulant-related nephropathy (ARN) was initially described in patients on warfarin (as warfarin-related nephropathy) and recently in those using dabigatran. Herein, we report clinical history ...and kidney biopsy findings in a patient on apixaban (Eliquis). Initiation of treatment with apixaban resulted in aggravation of preexisting mild acute kidney injury (AKI). A few days after apixaban therapy, the patient became oligoanuric, and kidney biopsy showed severe acute tubular necrosis with numerous occlusive red blood cell casts. Only one out of 68 glomeruli with open capillary loops had small segmental cellular crescent. Therefore, there was major discrepancy between the degree of glomerular injury and the glomerular hematuria. Considering that the onset of this AKI was associated with apixaban treatment initiation, we propose that this patient had ARN associated with factor Xa inhibitor (apixaban), which has not previously been described. Monitoring of kidney function is recommended after initiation of anticoagulant therapy.
We experienced a case in which improving the renal damage caused by warfarin‐related nephropathy took a long time. It is important to follow up for a long time after the initiation of dialysis due to ...warfarin‐related nephropathy.
We experienced a case in which improving the renal damage caused by warfarin‐related nephropathy took a long time. It is important to follow up for a long time after the initiation of dialysis due to warfarin‐related nephropathy.
Anticoagulant-related nephropathy (ARN) was initially described in patients on warfarin (as warfarin-related nephropathy) and recently in those using dabigatran. Herein, we report clinical history ...and kidney biopsy findings in a patient on apixaban (Eliquis). Initiation of treatment with apixaban resulted in aggravation of preexisting mild acute kidney injury (AKI). A few days after apixaban therapy, the patient became oligoanuric, and kidney biopsy showed severe acute tubular necrosis with numerous occlusive red blood cell casts. Only one out of 68 glomeruli with open capillary loops had small segmental cellular crescent. Therefore, there was major discrepancy between the degree of glomerular injury and the glomerular hematuria. Considering that the onset of this AKI was associated with apixaban treatment initiation, we propose that this patient had ARN associated with factor Xa inhibitor (apixaban), which has not previously been described. Monitoring of kidney function is recommended after initiation of anticoagulant therapy.
Abstract
Anticoagulant-related nephropathy (ARN) is a clinical syndrome of acute kidney injury in patients taking vitamin K antagonists or direct oral anticoagulants. It is associated with increased ...mortality and there is no specific treatment. We report the case of a 78-year-old man on dabigatran who developed macroscopic haematuria and acute kidney injury 2 weeks after mitral valve repair, reaching a peak creatinine of 415 µmol/L from a normal baseline, which was successfully treated with one course of idarucizumab. This case illustrates the efficacy of an anticoagulant reversal agent for the treatment of ARN.
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