Warfarin related nephropathy in human and experimental animals

Sergey Brodsky MD, PhDThe 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 4.30.8 mg/dl, baseline 1.3 0.3 mg/dl.

At presentation with AKI, the INR was above the therapeutic range (4.40.7)

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

-1 0 1 2 30

1

2

3

4

5

*

*

*

Ser

um

Cre

atin

ine,

mg

/dl

Time, month

WRN, n=515 no-WRN, n=2580

INR>3.0

no CKD patients

#

-1 0 1 2 30

1

2

3

4

5

*

*

Ser

um

Cre

atin

ine,

mg

/dl

Time (month

WRN, n=305 no-WRN, n=605

INR>3.0

CKD patients

#

-1 0 1 2 30

1

2

3

4

5

* *

Se

rum

Cre

ati

nin

e,

mg

/dl

Time, month

WRN, n=820 no-WRN, n=3185

INR>3.0

all patients

*

#

0 10 20 30 40 50 600

10

20

30

40

50

60

70

80

90

100 no WRN CKD no WRN no CKD WRN CKD WRN no CKD

WRN patients had increased mortality rate

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.

0 2 4 6 8 10 12 14 16 180.25

0.50

0.75

1.00

1.25

1.50

** *

***

Se

rum

cre

atin

ine

, m

g/d

l

Time, days

5/6 NE 3w + Warfarin 5/6 NE 3w + vehicle

0.75 mg/kg/day0.34 mg/kg/day0.20 mg/kg/day

0 2 4 6 8 10 12 14 16 180.25

0.50

0.75

1.00

1.25

1.50

Control

Se

rum

cre

atin

ine

, m

g/d

l

Time, days

0.75 mg/kg/day0.34 mg/kg/day0.20 mg/kg/day

A B

Scr did not increase in control Scr increased in 5/6 NE rats

Warfarin results in glomerular hemorrhage and RBC cast formation in 5/6 NE rats

5/6 nephrectomy rat Patient, WRN

B

-2 -1 0 1 2 3 4 5 6 7

0.50

0.75

1.00

1.25

5/6 nephrectomy

** *

**

*

*

BL

Ser

um

Cre

atin

ine,

mg

/dl

Time, days

Warfarin + vehicle Warfarin + NAC 1 mg/kg Warfarin + NAC 10 mg/kg Warfarin + NAC 40 mg/kg Warfarin + NAC 80 mg/kg

*

Warfarin 40 mg/kg/day + NAC

NAC prevented Scr increase in WRN but not RBC cast formation

Warfarin

Glomerular hemorrhage

RBC tubular casts

ATN

Direct effects

Oxidative stress

Oxidative stress

Vitamin K dependent

Thrombin inhibitors (dabigatran etexilate)

Factor Xa inhibitors (rivaroxaban and apixaban).

Novel anticoagulants

-1 0 1 2 3 4 5 6 7 80.25

0.50

0.75

1.00

1.25

1.50

1.75 3 mg/kg/day 10 mg/kg/day 25 mg/kg/day 50 mg/kg/day 100 mg/kg/day 150 mg/kg/day

Se

rum

Cre

ati

nin

e,

mg

/dl

Time, day

BL

5/6 NE

Dabigatran

*

Dabigatran increases Scr in 5/6NE and results in RBC casts

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.

Conclusions:

The Ohio State University:Dr. Lee HebertDr. Brad RovinDr. Tibor NadasdyDr. Anjali SatoskarDr. Haifeng WuKyle Ware

New York Medical CollegeDr. Michael GoligorskyDr. Jun Chen