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Q1
Q13
Anticoagulant-Related Nephropathy in Kidney Biopsy: A
Single-Center Report of 41 Cases
Sergey V. Brodsky, Anjali Satoskar, Jessica Hemminger, Brad Rovin, Lee Hebert,
Margaret (Maggie) S. Ryan, and Tibor Nadasdy
Rationale & Objective: In 2009, the first case of
acute kidney injury and occlusive red blood cell
(RBC) tubular casts associated with a high international normalized ratio in a patient receiving warfarin
was identified. This entity, named warfarin-related
nephropathy, was later renamed anticoagulantrelated nephropathy (ARN) after similar cases with
other anticoagulants were described. We provide
our 10-year experience with ARN based on a
single-center kidney biopsy laboratory.
Study Design: The kidney pathology database at
the Ohio State University Wexner Medical Center
(OSUWMC) was searched for native kidney biopsy cases consistent with ARN. Clinical data
were obtained from patient medical records.
Q2
Setting & Participants: Native kidney biopsies
performed between January 1, 2009, and
December 31, 2017, at OSUWMC.
Results: Among 8,636 native kidney biopsies
reviewed at the OSUWMC, there were 41 (0.5%)
patients for whom deterioration in kidney function
could not be explained by kidney biopsy findings
alone if anticoagulation was not considered. There
were 63% men and 95% were white; average age
I
was 62 ± 14 years. Most were on warfarin therapy
(N = 28), although cases were also attributed to
direct-acting anticoagulants (N = 2), antiplatelet
medications (N = 1), heparin or enoxaparin (N = 4),
and disseminated intravascular coagulopathy
(N = 6). Morphologically, there was acute tubular
necrosis and RBC casts. The majority of biopsies
had an underlying glomerular disease and many
patients had positive serologic test results. In all
these cases, the severity of kidney failure, RBC
casts, and hematuria were disproportionate to
glomerular morphologic changes.
Limitations: Selection bias in the decision to
perform a kidney biopsy.
Conclusions: ARN is an uncommon diagnosis
in kidney pathology practice, but it should be
considered when the number of RBC casts is
disproportionate to the severity of glomerular
changes in a kidney biopsy in patients either
receiving anticoagulation therapy or who presented with acute coagulopathy. Our data
suggest
that
anticoagulation
aggravates
underlying glomerular diseases rather than
directly affecting the glomerular filtration barrier.
n 2009, we described the first patient we had identified
who presented with acute kidney injury (AKI) while
being treated with warfarin. The patient had a supratherapeutic international normalized ratio (INR) before the
AKI. Kidney biopsy showed acute tubular necrosis (ATN)
with occlusive red blood cell (RBC) tubular casts.1 The
glomerular changes alone could not explain this severe
glomerular hematuria. After searching our renal pathology
database, 8 other patients with similar clinical presentation
were identified. These patients also were receiving
warfarin therapy with high INRs (>3.0) and had ATN and
glomerular hematuria (defined by RBCs in Bowman space
and RBC tubular casts and acanthocytes in urine sediment)
that were unexplained by other morphology findings.1
This AKI associated with a high INR initially was named
warfarin-related nephropathy.
Two subsequent retrospective studies by our group
described warfarin-related nephropathy in patients both with
and without chronic kidney disease.2,3 Warfarin-related nephropathy was demonstrated in animal models, including a
5/6 nephrectomy rat chronic kidney disease model and in
these experiments, in the setting of anticoagulation with
vitamin K antagonists, animals showed morphologic futures
Complete author and article
information provided before
references.
Correspondence to
S.V. Brodsky (sergey.
brodsky@hotmail.com)
Kidney Med. XX(XX):1-6.
Published online Month X,
XXXX.
doi: 10.1016/
j.xkme.2019.03.002
© 2019 Published by
Elsevier Inc. on behalf of the
National Kidney Foundation,
Inc. This is an open access
article under the CC BYNC-ND license (http://
creativecommons.org/
licenses/by-nc-nd/4.0/).
of warfarin-related nephropathy similar to human disease,
including ATN and glomerular hemorrhage.4,5
Later it was demonstrated that morphologic features
similar to warfarin-related nephropathy may also be seen
in 5/6 nephrectomy rats treated with the direct thrombin
inhibitor dabigatran.6 This observation and clinical data
suggested that such AKI may be associated not only with
vitamin K antagonists, but other agents that predispose to
bleeding. Accordingly, the term “anticoagulant-related
nephropathy” (ARN) is preferred. Since the seminal report
of pathologic features of warfarin-related nephropathy,1
several investigators published case reports and retrospective studies showing AKI in association with different anticoagulants, including multiple case reports and case
series that describe warfarin-related nephropathy,7-12
several reports of dabigatran-associated AKI,13-17 a case
report of AKI in a patient with thrombocytopenia,18 and a
case of biopsy-proven ARN in a patient receiving antiplatelet medications.19
Given the existing data for this newly described entity
and the presence of multiple causes for anticoagulation,
we explored our database of existing kidney biopsies
since our initial description of ARN to describe ARN in
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greater detail, including agents that may predispose to
this unusual cause of AKI.
METHODS
This study was deemed exempt from the need for
informed consent.20 We reviewed The Ohio State University Wexner Medical Center Renal and Transplant Pathology Laboratory Database between January 1, 2009,
and December 31, 2017, for the following key words:
“nephropathy,” “warfarin,” or “anticoagulant,t” or
“coagulation.” Kidney biopsy pathology reports were
deidentified and reviewed along with the clinical history
and list of medications. Criteria for warfarin-related nephropathy (ARN) included history of anticoagulation and/
or coagulopathy, clinical presentation with AKI, and RBC
casts in the kidney biopsy. Slides stained with hematoxylin
and eosin were blindly reviewed by a renal pathologist
(S.V.B.) and the percentage of RBC tubular casts was
evaluated for each individual case. Interstitial fibrosis and
tubular atrophy were estimated using a semiquantitative
scale of 0 to 3 on slides stained with double periodic
acid–Schiff/trichrome stain.21
Statistical analysis was performed using GraphPad Prizm
5.0 software (GraphPad Software). Data are presented as
mean ± standard deviation, unless specified otherwise.
RESULTS
There were 8,636 native kidney biopsy cases in the Renal
Pathology database between January 1, 2009, and
December 31, 2017. We identified 57 kidney biopsy reports that contained the keywords “nephropathy,”
“warfarin,” or “anticoagulant,” or “coagulation.” After
reviewing kidney biopsy pathology reports, clinical history, and medications, 48 (0.6%) patients for whom
deterioration in kidney function could not be explained by
kidney biopsy findings alone if anticoagulation was not
considered were included in the study. Among those, 7
patients had AKI and increased hematuria that were associated with anticoagulation, but kidney biopsies from
those patients did not contain RBC tubular casts, making
the diagnosis of glomerular bleeding uncertain. Because of
the lack of RBC tubular casts in the kidney biopsy specimens, these 7 patients were excluded from further analyses, resulting in a final study population of 41 (0.5%)
patients. Warfarin-related nephropathy (or ARN) was
suggested in >6.3% of native kidney biopsies per year in
the first 4 years of this study (2009-2012), whereas since
2014, such diagnosis was suggested in w4.3% of the
native kidney biopsies, decreasing w33%.
Demographic characteristics and clinical data for these
patients are shown in Table 1 stratified by the cause of
coagulopathy. There were 26 (63%) men, and most patients (95%) were white. Average age of the cohort was
62 ± 14 years. Mean body weight was 103.7 ± 29.3 kg,
mean systolic blood pressure was 130 ± 17 mm Hg, and
mean diastolic blood pressure was 75 ± 11 mm Hg.
Twenty-eight (68%) were receiving warfarin (INR before
AKI was 5.6 ± 6.0), 1 (3%) was receiving combined clopidogrel/aspirin, 4 (10%) were receiving heparin (2,
unfractionated heparin; and 2, enoxaparin), and 2 (5%)
were receiving the factor Xa inhibitor apixaban. Six (15%)
patients did not have records of anticoagulation therapy,
but they had acute coagulopathy (such as disseminated
intravascular coagulation syndrome) at the time of deterioration of kidney function and their biopsy findings were
consistent with ARN.
Table 1. Clinical and Demographic Data in Patients With ARN Based on the Anticoagulation Used
Anticoagulation
Demographic and Clinical Data
Age, y
Sex (male/female)
Race (W/AA)
Weight, kgb
Reason for anticoagulation (AF/DVT/APLS)b
Common comorbid conditionsc
Diabetes mellitus
Hypertension
Positive ANCA
SLE
Baseline Scr, mg/dL
Peak Scr at AKI diagnosis, mg/dL
Warfarin/DOAC (n = 30)
61.2 ± 15.6
18/12 (60%/40%)
25/2 (93%/7%)b
99.4 ± 22.5
19/6/2
Othera (n = 11)
65.5 ± 10.8
8/3 (73%/37%)
10/0b
114.6 ± 42.6
1/2/0
4 (13%)
7 (23%)
7 (23%)
1 (3%)
1.29 ± 0.4
4.16 ± 2.0
2 (18%)
2 (18%)
3 (27%)
2 (18%)
1.17 ± 0.4
4.82 ± 2.4
Note: Values expressed as mean ± standard deviation or number (percent).
Abbreviations: AA, African American; AF, atrial fibrillation; AKI, acute kidney injury; ANCA, antineutrophil cytoplasmic antibodies; APLS, antiphospholipid antibody
syndrome; ARN, anticoagulant-related nephropathy; DOAC, direct-acting oral anticoagulant; DVT, deep vein thrombosis; Scr, serum creatinine; SLE, systemic lupus
erythematous; W, white.
a
Other anticoagulation/coagulopathy included 1 patient using antiplatelet medications, 4 using heparin/enoxaparin, and 6 patients with disseminated intravascular
coagulopathy.
b
Data are not available for some patients.
c
Some patients have more than 1 comorbid condition.
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Original Research
Table 2. Histologic Findings in Kidney Biopsies With Diagnosis Suggestive of ARN
Q3
Q9
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Anticoagulation
Q11
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Histologic Findings
Warfarin/DOAC (n = 30)
Othera (n = 11) Q10
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Glomerular lesions
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1 (6%)
IgA-predominant immune complexes in
13 (43%)
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glomeruli (nonmembranous)
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2 (12%)
IgG-predominant immune complexes in
3 (10%)
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glomeruli (nonmembranous)
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4 (24%)
Pauci-immune crescentic glomerulonephritis
4 (13%)
1 (6%)
Focal segmental glomerulosclerosis
3 (10%)
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1 (6%)
Lupus nephritis ISN/RPS class I or II
2 (7%)
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1 (6%)
Diabetic glomerulosclerosis
1 (3%)
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1 (6%)
Other
4 (13%)
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No. of glomeruli in biopsy specimen
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Total
27.9 ± 18.2
37.1 ± 28.7
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Globally sclerotic
3.3 ± 3.3
3.7 ± 4.1
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0.27 ± 0.6 (1%)b
Cellular crescents
1.47 ± 3.0 (4%)b
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IFTAc
1.8 ± 0.5
1.8 ± 0.6
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Tubules with red blood cell casts
20.0 ± 16.6
12.7 ± 9.6
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Abbreviation: ARN, anticoagulant-related nephropathy; DOAC, direct-acting oral anticoagulant; IFTA, interstitial fibrosis and tubular atrophy; IgA, immunoglobulin A;
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ISN/RPS, International Society of Nephrology/Renal Pathology Society.
a
Other anticoagulation/coagulopathy included 1 patient using antiplatelet medications, 4 using heparin/enoxaparin. and 6 with disseminated intravascular coagul300
opathy.
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b
Percentage of glomeruli with open capillary loops.
c
On a semiquantitative scale of 0 to 3: 0 = no IFTA, 1 = 0% to 24% IFTA, 2 = 25% to 49% IFTA, and 3 = 50% to 100% IFTA.
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Among the common comorbid conditions, the most glomerular findings, including one with membranous 304
frequent was positive antineutrophil cytoplasmic antibody glomerulonephritis, 1 with fibrillary glomerulone- 305
(ANCA; in 11 (27%) patients, including 7 with peri- phritis, 1 with mild C3-containing deposits, and 2 bi- 306
nuclear ANCA, 2 with cytoplasmic ANCA, 1 with both opsies with no specific glomerular lesions but 307
perinuclear and cytoplasmic ANCA, and 1 with atypical moderately to prominently enlarged glomeruli. All bi- 308
ANCA). Nine (22%) patients had a clinical history of hy- opsies had features of ATN and RBC casts in the tubules 309
pertension, 6 (15%) had diabetes mellitus type 2, and 3 (Fig 1). On average, 18.0% ± 15.0% of tubules had RBC Q4310
(8%) had systemic lupus erythematous. No comorbid casts. Interstitial fibrosis and tubular atrophy were on 311
condition data were available for 2 patients. Serum creat- average moderate (1.8 ± 0.7 on the scale of 0-3). Focal 312
inine levels had increased from 1.25 ± CC mg/dL at mild to moderate active-appearing interstitial 313
baseline to 4.33 ± 1.99 mg/dL at the time of kidney bi314
opsy (Table 1). Before the presentation with AKI, all pa315
tients developed either de novo hematuria (from moderate
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[2+ on dipstick] to gross) or had a significant increase in
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pre-existing hematuria.
318
Histologic findings from kidney biopsies are pre319
sented in Table 2. In general, biopsies contained
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33.4 ± 20.6 glomeruli, with 7.0 ± 3.5 (14%) of those
321
globally sclerosed. Active cellular crescents were seen in
322
1.1 ± 2.7 glomeruli (5% of glomeruli with open capil323
lary loops). All patients with a presumed diagnosis of
324
ARN had some glomerular injury. The most common
325
finding was mild immune complex deposition in
326
glomeruli, which was seen in 22 (53%) patients
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(including 14 [34%] with immunoglobulin A [IgA]328
predominant, 5 (12%) with IgG-predominant de329
posits, and 3 (7%) with nonproliferative (International
330
Society of Nephrology/Renal Pathology Society classes I
331
and II) lupus nephritis. Pauci-immune crescentic Figure 1. Common light microscopy findings in patients with 332
necrotizing glomerulonephritis was diagnosed in 8 anticoagulant-related nephropathy (ARN). In a patient with 333
(20%) patients. Four (10%) patients had focal segmental ARN, red blood cell tubular casts and acute tubular injury are 334
glomerulosclerosis (FSGS), and 2 (5%) had diabetic the common light microscopy morphologic findings. Glomeruli 335
glomerulosclerosis. Five (12%) patients had other usually do not show significant morphologic changes.
336
web 4C=FPO
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inflammatory cell infiltrates were noted in 22 (54%)
kidney biopsies. Histologic findings stratified by the
type of anticoagulation used (warfarin and direct-acting
oral anticoagulants vs others) are presented in Table 2.
Q5
DISCUSSION
Our 10-year study from a single-center pathology laboratory suggests that ARN is an uncommon diagnosis in
kidney pathology practice, but that ARN should be
considered when the number of RBC casts and/or hematuria is disproportionate to the severity of glomerular
changes in a kidney biopsy specimen in patients either
receiving anticoagulation therapy or who presented with
acute coagulopathy. Our data further suggest that ARN
develops in individuals with underlying glomerular diseases rather than directly affecting the glomerular filtration
barrier, while reinforcing that any agent or condition
resulting in coagulopathy may predispose individuals to
ARN.
Our study shows that the prevalence of ARN in kidney
biopsies was low, at w0.5%. Several possibilities may
influence the low prevalence of ARN described here. First,
we do not know how many of the native kidney biopsies
that we received in our renal pathology laboratory are
from patients previously receiving anticoagulation.
Therefore, the percentage of patients on anticoagulation
therapy who developed ARN cannot be evaluated based on
the total number of kidney biopsies. Second, nephrologists
(and radiologists) are reluctant to perform a kidney biopsy
in a patient on anticoagulation therapy; therefore, the true
incidence rate of ARN cannot be determined based on the
kidney biopsy database. Third, with the recognition of
warfarin-related nephropathy (and ARN), the number of
kidney biopsies from patients with AKI on anticoagulation
therapy is decreasing because nephrologists now associate
AKI with anticoagulation and may be less likely to perform
kidney biopsies in such patients.
In addition, we recognized 7 patients on anticoagulation therapy who had AKI and significantly
increased hematuria, but the kidney biopsy did not show
RBC casts. Because the kidney biopsy in these patients did
not show RBC casts, although these patients had increased
hematuria, we do not have morphologic evidence of
glomerular hemorrhage; therefore, the diagnosis of ARN
cannot be made with certainty. A sampling error could
occur, but this is less likely because in patients with ARN,
there is an increased number of RBC casts or tubular RBCs
that is disproportional to the glomerular injury or changes
(such as mild immune complex deposition or very focal
crescentic glomerulonephritis). Therefore, AKI in these
patients is probably secondary to other causes. Therefore,
Kidney biopsy findings of numerous tubular RBC
and/or RBC casts and ATN
Diffuse active glomerular disease:
- Active crescentic GN with
cellular crescents
- Immune-complex mediated GN
Focal or inactive glomerular disease:
- Focal crescentic GN with fibrocellular
crescents
- Mild immune-complex mediated GN
- Thin GBM
- LN Class I or II
- FSGS
NOT ARN
Yes
Clinical history of:
- Anticoagulation with warfarin, INR>3.0
- Recently started anticoagulation with DOAC or
other anticoagulants
- DIC or other coagulopathy
Suspect ARN
No
- Possible sampling error
- Unrecognized coagulopathy
- Other conditions
Figure 2. Proposed diagnostic algorithm in patients with suspected anticoagulant-related nephropathy (ARN). If a kidney biopsy
shows numerous red blood cells (RBCs) in tubules or RBC casts without appropriate glomerular injury, clinical history and laboratory
data should be reviewed to exclude excessive anticoagulation with warfarin (international normalized ratio [INR] > 3.0), new onset of
anticoagulation therapy, or coagulopathy (although the current terminology is ARN, our data suggest that patients with underlying
coagulopathy such as disseminated intravascular coagulopathy [DIC] may experience glomerular hemorrhage and ARN-like findings
in the kidney biopsy). Abbreviations: ATN, acute tubular necrosis; DOAC, direct-acting oral anticoagulant; FSGS, focal segmental
glomerulosclerosis; GBM, glomerular basement membrane; GN, glomerulonephritis; LN, lupus nephritis.
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at this moment, the diagnosis of ARN is reserved only for
cases in which an excessive number of RBC casts is present
in a kidney biopsy.
Our data reinforce prior findings that ARN develops in
patients with underlying glomerular diseases. We identified
multiple different pathologic changes in glomeruli. The
spectrum of these changes is broad, from cellular crescents to
glomerular enlargement. The most common pathologic
finding, seen in more than half the biopsies, was mild immune complex deposition in glomeruli. These glomeruli had
mild segmental immune complex deposits (most commonly
IgA, but including some patients with class I or II lupus
nephritis) and did not show significant proliferative lesions
by light microscopy. Therefore, the presence of numerous
RBC tubular casts could not be explained just by these
glomerular findings.
The second most common finding was focal crescentic
glomerulonephritis (usually pauci-immune). Although RBC
tubular casts are a hallmark of crescentic glomerulonephritis,
the number of RBC tubular casts in these patients was significantly higher than the number of glomeruli with crescents,
suggesting that anticoagulation played a role in the formation
of this excessive number of RBC tubular casts. Other glomerular
diseases included FSGS, diabetic glomerulosclerosis, and others
such as membranous glomerulonephritis and C3 deposits.
In all these cases, AKI was associated either with
excessive anticoagulation (INR > 3.0) or the initiation of
anticoagulation therapy (such as in patients with heparinor apixaban-associated AKI). Therefore, we propose that
rather than directly affecting the glomerular filtration
barrier, excessive anticoagulation aggravates an underlying
glomerular disease and increases glomerular hematuria,
which leads to the formation of RBC casts and ATN. Several
patients with pauci-immune crescentic glomerulonephritis
did not have clinical symptoms of this disease until they
initiated anticoagulation therapy, but kidney biopsy specimens from these patients showed fibrocellular and fibrous
crescents, indicating chronic disease. In some patients, RBC
casts do not form (or may be not seen in the kidney biopsy
due to sampling issues), but those patients have increased
hematuria, which results in ATN, possibly through
increased oxidative stress.22
Demographically, patients with ARN in our study
population were obese, suggesting that glomerular
hyperfiltration/hyperperfusion plays a significant role in
the pathogenesis of ARN. We modeled ARN in a warfarintreated 5/6 nephrectomy rat model that is characterized by
glomerular hyperfiltration/hyperperfusion.4-6 These animals developed ARN within 3 weeks after the ablative
surgery, much earlier than changes of FSGS could be seen
histologically.4,6
The major limitation of the current study is selection
bias in the decision to perform biopsy on patients with AKI
who are on anticoagulation therapy. Nephrologists are
reluctant to perform biopsy on such patients, and sometimes only other laboratory data (such as positive ANCA
results) may prompt the biopsy decision. However, the
number of biopsies with ARN decreased as the nephrology
and pathology community became more aware that AKI
may be associated with anticoagulation therapy, potentially resulting in an empiric clinical diagnosis without a
kidney biopsy, particularly in individuals with high INRs.
Clinical features of ARN and a suggested algorithm for the
evaluation of patients receiving anticoagulation who present with AKI were recently described by our group.23
In conclusion, ARN is an uncommon diagnosis in renal
pathology practice, but it should be considered when there
is a disproportion between the severity of glomerular
changes and number of RBC casts and/or hematuria in a
kidney biopsy in patients on anticoagulant therapy or who
presented with acute coagulopathy (Fig 2). The glomerular
changes in patients with suspected ARN are insufficient to
explain the occurrence of substantial blood and RBC casts
in tubules, but the high prevalence of underlying
glomerular diseases and obesity suggests that ARN may be
most likely to occur in individuals with pre-existing
glomerular damage increasing their susceptibility to
glomerular bleeding in the setting of systemic anticoagulation or other coagulopathy.
ARTICLE INFORMATION
Authors’ Full Names and Academic Degrees: Sergey V. Brodsky,
MD, PhD, Anjali Satoskar, MD, Jessica Hemminger, MD, Brad Rovin,
MD, Lee Hebert, MD, Margaret (Maggie) S. Ryan, MD, and Tibor
Nadasdy, MD, PhD.
Authors’ Affiliations: Departments of Pathology (SVB, AS, JH, TN)
and Medicine (BR, LH), Ohio State University, Columbus, OH; and
Department of Pathology, Mayo Clinic, Scottsdale, AZ (MSR).
Address for Correspondence: Sergey V. Brodsky, MD, PhD,
Department of Pathology, The Ohio State University, 333 W 10th
Ave, Graves Hall, B078, Columbus, OH 43210. E-mail: sergey.
brodsky@hotmail.com
Authors’ Contributions: Research idea and study design: SVB, LH,
TN; data acquisition: SVB, AS, JH, MR; data analysis/interpretation:
SVB, BR, LH, TN; statistical analysis: SVB; MR, JH; supervision or
mentorship: BR, LH, TN. Each author contributed important
intellectual content during manuscript drafting or revision and
accepts accountability for the overall work by ensuring that
questions pertaining to the accuracy or integrity of any portion of
the work are appropriately investigated and resolved.
Support: This study partially was supported by National Institutes of
Health grant DK117102 to Dr Brodsky. The funder had no role in
study design; data collection, analysis, or reporting; or the
decision to submit for publication.
Financial Disclosure: The authors declare that they have no
relevant financial interests.
Peer Review: Received December 5, 2018. Evaluated by 2 external
peer reviewers, with direct editorial input from the Editor-in-Chief.
Accepted in revised form March 4, 2019.
REFERENCES
1. Brodsky SV, Satoskar A, Chen J, et al. Acute kidney injury
during warfarin therapy associated with obstructive tubular red
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