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Warfarin related nephropathy in
human and experimental animals
Sergey Brodsky MD, PhD
The Ohio State University, Columbus, OH, USA
80 -year-old Caucasian male with nausea and vomiting. The baseline Scr was
1.1 mg/dl, but it was 3.9 mg/dl on presentation. Serologies, including ANA,
ANCA and paraprotein were negative, complement levels were normal.
Urinalysis showed hematuria and proteinuria. Patient was on warfarin therapy
for atrial fibrillation. Shortly before the onset of nausea and vomiting, he had an
episode of increased INR (5.2 IU). Kidney biopsy was performed after reversal
of increased INR
Warfarin related nephropathy – WRN. Key features of WRN in this cohort:
AKI: Scr 4.30.8 mg/dl, baseline 1.3 0.3 mg/dl.
At presentation with AKI, the INR was above the therapeutic range (4.40.7)
Kidney biopsy:

acute tubular injury
 glomerular hemorrhage (RBC in the Bowman’s space and numerous occlusive
RBC casts in tubules).
 An underlying kidney disease (mild glomerular immune complex deposits,
FSGS, thickened GBM).
•Outcome: six of nine patients did not recover from AKI
103 CKD on warfarin therapy with serial measures of INR and SC.
Of these, 49 patients experienced at least one INR>3.0 and had Scr measured
before and after the INR.3.0.
 18 of these patients (37%) had an unexplained increase in Scr>0.3 mg/dl
associated with INR>3.0
all patients
Serum Creatinine, mg/dl
5
INR>3.0
4
*
3
2
WRN, n=820
no-WRN, n=3185
*#
*
1
0
-1
0
1
2
3
Time, month
CKD patients
no CKD patients
WRN, n=515
no-WRN, n=2580
INR>3.0
4
3
*
2
*#
*
1
Serum Creatinine, mg/dl
Serum Creatinine, mg/dl
INR>3.0
5
5
WRN, n=305
no-WRN, n=605
4
*
3
*#
2
1
0
0
-1
0
1
Time, month
2
3
-1
0
1
Time (month
2
3
WRN patients had increased mortality rate
no WRN CKD
no WRN no CKD
WRN CKD
WRN no CKD
100
90
80
70
60
50
40
30
20
10
0
0
10
20
30
40
50
60
Why such a common complication of warfarin therapy
has been unrecognized until now?
1) We and others have reported single cases of AKI associated with severe
warfarin coagulopathy. However, there was no compelling reason to believe
that lesser degrees of warfarin coagulopathy could cause AKI.
2) WRN usually occurs early in the course of warfarin therapy. Therefore, at any
given time, the prevalence of acute WRN among all warfarin-treated patients is
relatively low.
3) WRN is particularly prevalent in patients at high risk for AKI. The presence of
WRN was not easily recognized.
4) Nephrologists might be reluctant to perform kidney biopsy to evaluate AKI in
patients who require warfarin.
5) Renal pathologists did not recognize WRN because of underlying kidney
diseases. ATN and RBC casts were associated with those conditions.
61-y.o. Caucasian female with recently diagnosed DM. Baseline Scr normal.
Presented to the hospital after episodes of diarrhea with Scr 3.2 mg/dl. She
developed DVT and was started on warfarin. INR was as high as 5. Scr
increased up to 6.6 mg/dl within 2 weeks. ANA (1:640), complement levels
were normal.
IgG
41-y.o. Caucasian female with aortic bifurcation thrombosis, post-bypass graft
placement, on warfarin therapy. INR 27 (!). Baseline Scr 1.0 mg/dl, increased
to 6.7 mg/dl. Gross hematuria with RBC casts. Complement levels normal.
ANA, ANCA negative.
Immunofluorescence – negative. Normal GBM thickness.
Scr did not increase in control
B
1.50
1.50
5/6 NE 3w + Warfarin
5/6 NE 3w + vehicle
Control
1.25
Serum creatinine, mg/dl
Serum creatinine, mg/dl
A
Scr increased in 5/6 NE rats
1.00
0.75
0.50
0.20 mg/kg/day
0.34 mg/kg/day
1.25
1.00
0.50
0.25
0
2
4
6
8
10
12
Time, days
14
16
18
*
0.75
0.75 mg/kg/day
0.25
*
*
*
*
*
0.20 mg/kg/day
0
2
4
0.34 mg/kg/day
6
8
10
12
Time, days
0.75 mg/kg/day
14
16
18
Warfarin results in glomerular hemorrhage and RBC cast formation in 5/6 NE rats
B
5/6 nephrectomy rat
Patient, WRN
Serum Creatinine, mg/dl
NAC prevented Scr increase in WRN
Warfarin + vehicle
Warfarin + NAC 1 mg/kg
Warfarin + NAC 10 mg/kg
Warfarin + NAC 40 mg/kg
Warfarin + NAC 80 mg/kg
1.25
1.00
5/6 nephrectomy
*
* *
* * *
0.75
*
*
0.50
Warfarin 40 mg/kg/day + NAC
BL
-2 -1
0
1
2
3
4
Time, days
5
6
7
but not RBC cast formation
Direct effects
Vitamin K dependent
Warfarin
Oxidative stress
Glomerular hemorrhage
RBC tubular casts
Oxidative stress
ATN
Novel anticoagulants
 Thrombin inhibitors (dabigatran etexilate)
 Factor Xa inhibitors (rivaroxaban and apixaban).
Dabigatran increases Scr in 5/6NE
3 mg/kg/day
10 mg/kg/day
25 mg/kg/day
50 mg/kg/day
100 mg/kg/day
150 mg/kg/day
Serum Creatinine, mg/dl
1.75
1.50
1.25
*
5/6 NE
1.00
0.75
0.50
Dabigatran
0.25
-1
BL
0
1
2
3
4
Time, day
5
6
7
8
and results in RBC casts
Conclusions:
 WRN may be a part of broader anticoagulant-related nephropathy (ACRN) and is
a common (and often overlooked) complication of anticoagulant therapy. Evidence
of AKI appears shortly after the INR acutely increases to >3.0. WRN occurs
approximately in 33% (CKD) to 16% (no-CKD) of warfarin-treated patients whose
INR acutely rises to >3.0. patients with WRN have increased mortality (one-year
mortality rate 31.0% versus 18.9% in no-WRN patients). Studies are needed to
evaluate different anticoagulants.
 An underlying kidney condition is necessary to induce WRN (or ACRN).
Coagulopathy may aggravate the existing condition (such as IgA nephropathy, etc)
and increase glomerular hemorrhage.
 In a kidney biopsy, WRN should be suspected If the patient is on an
anticoagulation therapy, if there is a disproportion between the number of RBC
tubular casts and the degree of underlying glomerular lesion (such as immune
complex mediated GN, IgA nephropathy, etc).
 WRN is reproducible in an animal model. Ablative nephropathy (5/6
nephrectomy) in rats mimics serum creatine changes and morphology seen in
humans with CKD. Studies of other models of kidney diseases to reproduce WRN
are needed.
The Ohio State University:
Dr. Lee Hebert
Dr. Brad Rovin
Dr. Tibor Nadasdy
Dr. Anjali Satoskar
Dr. Haifeng Wu
Kyle Ware
New York Medical College
Dr. Michael Goligorsky
Dr. Jun Chen