Role of glomerular filtration rate‐modifying drugs in the development of anticoagulant‐related nephropathy

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Abstract

Introduction

Anticoagulant‐related nephropathy (ARN), that was described in humans first as warfarin‐related nephropathy, is characterized by acute kidney injury and red blood cell (RBC) tubular casts in the kidney. 5/6 nephrectomy (5/7NE) rats treated with warfarin or dabigatran show changes in kidney function and morphology that are similar to human disease. The role of glomerular filtration rate (GFR) in the pathogenesis of ARN is not clear. The aim of these studies was to elucidate the role of GFR in the pathogenesis of dabigatran‐induced ARN in 5/6NE rats.

Methods

5/6NE rats were treated per os with 150 mg/kg/day dabigatran alone or with drugs that lower (enalapril, 1.5 mg/kg/day) or increase (albuterol, 4.0 mg/kg/day) GFR for 7 days. Changes in coagulation and kidney function were recorded daily. Kidney morphology was evaluated on day 7 after the treatment.

Results

Dabigatran resulted in activated partial thromboplastin time increase that was not affected by GFR‐modifying drugs. Blood pressure was significantly lower in 5/6NE rats treated with enalapril and dabigatran as compared to dabigatran alone. The GFR was decreased by 35% in enalapril/dabigatran‐ and increased by 26% in albuterol/dabigatran‐treated animals. There were no changes in serum creatinine, hematuria or urinary kidney injury molecule (KIM‐1) levels when GFR‐modifying drugs were added to dabigatran. All dabigatran‐treated animals had RBC casts in the kidney regardless of the GFR modification.

Conclusions

GFR does not play a significant role in the dabigatran‐induced acute kidney injury in 5/6 nephrectomy model in rats. Based in these data, modification of GFR in patients with ARN is not warranted.

Abstract

Changes in the glomerular filtration rate (GFR) do not play a significant role in the development of anticoagulant‐related nephropathy (ARN), at least in the 5/6 nephrectomy rat model. Therefore, treatment with GFR‐modifying drugs does not appear to be beneficial for patients with ARN.

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Most cited references 29

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Warfarin-related nephropathy occurs in patients with and without chronic kidney disease and is associated with an increased mortality rate.

Sergey V Brodsky, Tibor Nadasdy, Brad H Rovin … (2011)

An acute increase in the international normalized ratio (INR; a comparison of prothrombin time to monitor the effects of warfarin) over 3 in patients with chronic kidney disease (CKD) is often associated with an unexplained acute increase in serum creatinine (SC) and an accelerated progression of CKD. Kidney biopsy in a subset of these patients showed obstruction of the renal tubule by red blood cell casts, and this appears to be the dominant mechanism of the acute kidney injury. We termed this warfarin-related nephropathy (WRN), and previously reported cases of WRN only in patients with CKD. We now assess whether this occurs in patients without CKD, its risk factors, and consequences. In 15,258 patients who initiated warfarin therapy during a 5-year period, 4006 had an INR over 3 and SC measured at the same time; however, the large data set precluded individual patient clinical assessment. A presumptive diagnosis of WRN was made if the SC increased by over 0.3 mg/dl within 1 week after the INR exceeded 3 with no record of hemorrhage. WRN occurred in 20.5% of the entire cohort, 33.0% of the CKD cohort, and 16.5% of the no-CKD cohort. Other risk factors included age, diabetes mellitus, hypertension, and cardiovascular disease. The 1-year mortality was 31.1% with compared with 18.9% without WRN, an increased risk of 65%. Thus, WRN may be a common complication of warfarin therapy in high-risk patients and CKD doubles this risk. The mechanisms of these risks are unclear.

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Acute kidney injury during warfarin therapy associated with obstructive tubular red blood cell casts: a report of 9 cases.

G Molnar-Nadasdy, Anjali Satoskar, Alexander Brodsky … (2009)

Acute kidney injury (AKI) during warfarin therapy usually is hemodynamic secondary to massive blood loss. Here, we report pathological findings in kidney biopsy specimens from 9 patients with warfarin overdose, hematuria, and AKI. Kidney biopsy specimens from patients on warfarin therapy with AKI were identified in our database within a 5-year period. Each kidney biopsy specimen was evaluated by using semiquantitative morphometric techniques, and medical history was reviewed for conditions explaining AKI. Biopsy specimens with morphological findings of active glomerulonephritis and active inflammatory lesions were excluded from the study. Biopsy specimens from 9 patients were selected. At presentation with AKI, each patient had an abnormal international normalized ratio (mean 4.4 +/- 0.7 IU) and increased serum creatinine level (mean, 4.3 +/- 0.8 mg/dL). Morphologically, each biopsy specimen showed evidence of acute tubular injury and glomerular hemorrhage: red blood cells (RBCs) in Bowman space and numerous occlusive RBC casts in tubules. Each biopsy specimen showed chronic kidney injury. Six of 9 patients did not recover from AKI. These data suggest that warfarin therapy can result in AKI by causing glomerular hemorrhage and renal tubular obstruction by RBC casts. Our experience suggests that this may be a potentially serious complication of warfarin therapy, especially in older patients with underlying chronic kidney injury.

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Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation.

T H Hostetter, J Olson, H Rennke … (1981)

Micropuncture studies were performed in three groups of male Munich-Wistar rats 1 wk after surgery: group I, eight control rats that underwent laparotomy and were fed a normal diet; group II, nine rats that underwent right nephrectomy and segmental infarction of five-sixths of the left kidney and were fed a normal diet; and group III, seven rats that underwent the same renal ablative procedure and were fed a low protein diet. Single nephron glomerular filtration rate (SNGFR) was higher in the remnant kidney of group II rats compared with group I rats due to higher average values for mean glomerular transcapillary hydraulic pressure difference (delta P) and initial glomerular plasma flow rate (QA) in group II. Glomeruli in remnant kidneys of group II showed striking alterations in morphology, including epithelial cell protein reabsorption droplets, foot process fusion, and mesangial expansion. Group III rats demonstrated a mean SNGFR not statistically different from that of group I, but significantly less than that of group II rats. This lack of absolute hyperfiltration in remnant glomeruli of group III rats relative to group I obtained because QA and delta P did not increase above values found in group I. The glomerular structural lesions seen in group II were also largely attenuated in group III. These studies demonstrate that alterations in glomerular hemodynamics associated with renal ablation are accompanied by structural lesions and suggest that sustained single nephron hyperfiltration may have maladaptive consequences by damaging remnant glomeruli.

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Author and article information

Contributors

Sergey V. Brodsky:

ORCID: https://orcid.org/0000-0003-4570-5883

sergey.brodsky@osumc.edu

Journal

Journal ID (nlm-ta): Physiol Rep

Journal ID (iso-abbrev): Physiol Rep

Journal ID (doi): 10.1002/(ISSN)2051-817X

Journal ID (publisher-id): PHY2

Journal ID (hwp): physreports

Title: Physiological Reports

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Electronic): 2051-817X

Publication date (Electronic): 11 January 2021

Publication date Collection: January 2021

Volume: 9

Issue: 1 ( doiID: 10.1002/phy2.v9.1 )

Electronic Location Identifier: e14697

Affiliations

[ ¹ ] Department of Pathology The Ohio State University Wexner Medical Center Columbus Ohio USA

[ ² ] Department of Medicine The Ohio State University Wexner Medical Center Columbus Ohio USA

Author notes

[*] [* ] Correspondence

Sergey V. Brodsky, Department of Pathology, The Ohio State University, 333 W 10 ^th Ave, Graves Hall, B078, Columbus, OH 43210, USA.

Email: sergey.brodsky@ 123456osumc.edu

[*]

Authors equally participated in this work.

Author information

Sergey V. Brodsky https://orcid.org/0000-0003-4570-5883

Article

Publisher ID: PHY214697

DOI: 10.14814/phy2.14697

PMC ID: 7798050

PubMed ID: 33427414

SO-VID: d3c44946-a400-4a74-924d-c5e85dd8489d

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

History

Date received : 12 November 2020

Date revision received : 28 November 2020

Date accepted : 29 November 2020

Page count

Figures: 3, Tables: 0, Pages: 7, Words: 4476

Funding

Funded by: NIH NIDDK , open-funder-registry 10.13039/100000062;

Award ID: R01DK117102

Custom metadata

source-schema-version-number 2.0

cover-date January 2021

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.6 mode:remove_FC converted:11.01.2021

Keywords: 5/6 nephrectomy,anticoagulant‐related nephropathy,glomerular filtration rate

Data availability:

Keywords: 5/6 nephrectomy, anticoagulant‐related nephropathy, glomerular filtration rate

Role of glomerular filtration rate‐modifying drugs in the development of anticoagulant‐related nephropathy

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Warfarin-related nephropathy occurs in patients with and without chronic kidney disease and is associated with an increased mortality rate.

Acute kidney injury during warfarin therapy associated with obstructive tubular red blood cell casts: a report of 9 cases.

Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation.

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