# Anticoagulant related nephropathy

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2020 · $349,200

## Abstract

Project Summary
 Anticoagulant related nephropathy (ARN) is a novel clinical entity that we have identified. ARN is an
umbrella term to describe a form of acute kidney injury (AKI) that is associated with excessive anticoagulation
in patients receiving warfarin and other anticoagulants. We have described the clinical characteristics of ARN
in patients using warfarin and have shown that patients with pre-existing chronic kidney disease (CKD) are
especially vulnerable to ARN. Furthermore, we and others have shown that ARN also occurs with direct oral
anticoagulants, such as dabigatran and apixaban. Because the use of anticoagulants is common in patients
with CKD and it is difficult to control anticoagulation in patients with impaired renal function, thus a large
number of patients are at risk for ARN. The postulated mechanism of this AKI, based on kidney biopsies
from patients and modeling the disease in rats with CKD, is that the coagulopathy, induced by
supratherapeutic anticoagulation, results in glomerular filtration barrier (GFB) injury, glomerular hemorrhage
with subsequent tubular epithelial cell injury and AKI. We propose that the pathogenesis of ARN is dependent
on glomerular hemorrhage, which is multifactorial in origin and includes multiple “hits” to the GFB. A “first hit”
(e.g. glomerular hyperfiltration/hyperperfusion, mild immune complex deposition, etc.) makes the GFB more
vulnerable to supratherapeutic anticoagulation (“second hit”). We hypothesize that the main mechanism of the
anticoagulant-induced GBF injury is related to decreased thrombin activity and is mediated via the loss of
(patho)physiologically-required thrombin-mediated protease-activated receptor-1 (PAR-1) signaling in the
glomerular endothelial cells. Indeed, all classes of oral anticoagulants currently used in the clinical practice
reduce physiologic thrombin activity. We have demonstrated that 5/6 nephrectomy is a suitable animal model
to study ARN. Using this model, we will determine the role of diminished thrombin activity and PAR-1 signaling
in the pathogenesis of GFB injury. Because complete thrombin deficiency is embryonically lethal, we will test
the role of diminished thrombin activity by using 5/6 nephrectomy in thrombin knockdown mice. Next, we will
examine the role of glomerular hyperfiltration/hyperperfusion in the pathogenesis of ARN. We will use
pharmacologic manipulations of glomerular filtration in 5/6 nephrectomy thrombin knockdown mice and test
whether changes in glomerular filtration accelerate or mitigate ARN. Finally, the role of oxidative stress in the
pathogenesis of tubular injury in ARN will be studied by pharmacologic interventions in 5/6 nephrectomy rats.
At the conclusion of these Specific Aims we expect to understand the molecular mechanisms of ARN and
whether ARN can be prevented or the severity of AKI diminished. In summary, this project will provide
information critical to the appropriate design of clinical trials to mitigate ARN, whic...

## Key facts

- **NIH application ID:** 9856453
- **Project number:** 5R01DK117102-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** SERGEY BRODSKY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $349,200
- **Award type:** 5
- **Project period:** 2019-02-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9856453

## Citation

> US National Institutes of Health, RePORTER application 9856453, Anticoagulant related nephropathy (5R01DK117102-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9856453. Licensed CC0.

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