Warfarin Related Nephropathy: Evidence Based Medicine

Wisit Cheungpasitporn, MD.

PGY-2, Internal Medicine

How can warfarin cause nephropathy?

Abt AB, Carroll LE, Mohler JH.

Department of Pathology, Milton S. Hershey Medical Center, Penn

State Geisinger Health System, Hershey, PA 17033, USA.

• Glomerular hematuria in a pt with excessive warfarin anticoagulation from with underlying structural abnormality of glomerular basement membrane, suspected warfarin-induced glomerular hematuria.

Am J Kidney Dis. 2000 Mar;35(3):533-6.

Thin basement membrane disease and acute renal failure secondary to gross hematuria and tubular necrosis

• Warfarin may induce AKI by causing glomerular hemorrhage and renal tubular obstruction by RBC casts.

Warfarin Related Nephropathy?

Warfarin and AIN

• Nephron. 1989;52(2):196.• Acute renal failure due to hypersensitivity

interstitial nephritis induced by warfarin sodium.

• Volpi A, Ferrario GM, Giordano F, Antiga G, Battini G, Fabbri C, Meroni M, Sessa A.

• Source• Unità Operativa di Nefrologia e Dialisi. Servizio

di Anatomia Patologica. Ospedale di Vimercate, Italia.

• Intern Med J. 2008 Apr;38(4):281-3.

• Warfarin-induced allergic interstitial nephritis and leucocytoclastic vasculitis.

• Kapoor KG, Bekaii-Saab T.

• Source

• The Ohio State University College of Medicine, Columbus, Ohio , USA.

Warfarin and AIN

CONCLUSIONS:Overanticoagulation is associated with faster progression of CKD in a high percentage of patients. Our results indicate the need for prospective trials. Nevertheless, we suggest that our findings are sufficiently compelling at this point to justify extra caution in warfarin-treated CKD patients to avoid overanticoagulation.

37% of CKD pts with elevated INR developed elevated Cr

• “The authors have termed the unexplained increase in Cr associated with INR >3.0, warfarin-related nephropathy (WRN).”

Objective

• To investigate further the prevalence, risk factors, and consequence of WRN, with emphasis on the extent to which WRN develops in CKD compared with no-CKD patients. 

Methods

• Analyzing the de-identified data of consecutive patients who had initiated warfarin therapy during the period of January 2005 to December 2009 at the OSUMC.

Methods

• A multistep algorithm was utilized to identify patients with presumptive WRN.

• The analysis reported here was performed on cohort 5 (the final cohort).

• Cohort 1 (N=15,258): All patients who had warfarin between January 2005 and December 2009

Methods

• Cohort 2 (N=6019). Pts who had at least one episode of INR >3.0 recorded.

(If multiple episodes occurred, used the 1st one for the present analysis)

• Cohort 3 (N=4848). Pts who had Cr within 1 week after the first INR > 3.0.

Methods

• Cohort 4 (N=4816). Pts who had Cr within 3 mths before the 1st abnormal INR >3.0. – Excluded those who had, based on ICD-9

codes, end-stage renal disease or evidence of clinically relevant hemorrhage within the first week after INR >3.0

Methods

Methods

• Cohort 5 (final cohort; N=4006). – This cohort was stratified into CKD or no CKD

using the ICD-9 codes.

Statistical Methods

• The authors checked for the significance of group as a predictor of survival, controlling for the following covariates:– Age at INR spike– CKD– DM and DN– Heart failure – Atrial fibrillation– Glomerulonephritis

Statistical Methods

• The χ 2- tests were used to assess differences in categorical variables between groups; a two-sample t-test was used for age.

• Two-sample t-tests were performed to compare INR between WRN and no WRN as explorative analyses for the overall sample and CKD/non-CKD subgroups.

Results

• Identification of the Study Patients in the Ohio State University Medical Center Information Warehouse Database

Results

• Cohort 5 (N=4006)– 821 pts with presumptive WRN (increase in

Cr ≥0.3 mg/dl within 1 week of INR >3.0, 20.5% of cohort 5)

– 3185 pts with no WRN (no increase in Cr≥0.3 mg/dl within 1 week of INR >3.0, 79.5% of cohort 5).

Results

• INR and Sequential Changes in Cr and Estimated GFR in WRN Patients Compared With No-WRN Patients

Figure 1

4.444.15

4.574.13

4.22 4.222.75±1.65

1.17±0.71

1.80±1.24

1.13±0.67

P<0.0001

2.45±1.57

1.01±0.49

P<0.0001

1.52±1.08

1.00±0.51

3.25±1.67

1.79±1.09

P<0.0001

2.29±1.33

1.65±0.94

Figure 2

Figure 3

eGFR calculated byCKD-EPI Creatinine Equation

Results

• Baseline Clinical Characteristics of the WRN Patients and the No-WRN Patients

Figure 4

Hematuria and WRN

Results

Concurrent Medication and WRN

Survival Rate and WRN

Results

Figure 5

73%

58%

P<0.00181.1%

68.9%

P= 0.049

P=0.064

3.65, 95% CI 2.81-4.75

Non-significant levels

6months

Controlling for covariates; age, CKD, DM, heart falure, GN

3.19, 95% CI 2.45-4.15

Hazard ratio for death

• Of the 4006 patients who experienced an INR >3.0, 20.5% developed presumptive WRN

• Among the CKD patients, the incidence of presumptive WRN was 33%, which is comparable to the 37% incidence of WRN that previously reported in warfarin-treated CKD patients.

• Among the no-CKD patients, the incidence of presumptive WRN was 16.5%.

Discussion

• Why such a common complication of warfarin therapy has been unrecognized until just recently?

• Before this study, there was no compelling reason to believe that lesser degrees of warfarin coagulopathy could cause AKI.

• WRN usually occurs early in the course of warfarin therapy. Thus, at any given time, the prevalence of acute WRN among all warfarin-treated patients is relatively low.

Discussion

• Why such a common complication of warfarin therapy has been unrecognized until just recently?

• The risk of WRN is particularly great in high-risk

patients who have multiple risk factors for AKI.

• Nephrologists might be reluctant to perform a kidney biopsy in patients receiving warfarin.

Discussion

Limitation

• A retrospective study in which the testing protocol was not prespecified. Thus, this work suffers from ascertainment bias.

• Study required Cr by 1 week after the onset of INR >3.0. Frequent measurement of Cr is more likely in sicker patients. Thus, this study may have identified the sickest patients with INR >3.0.

• No consistent testing of proteinuria around the time of the INR spike. ?proteinuria itself was a risk factor for WRN.

Summary

• To clearly establish the risk factors for WRN and its consequences will require a prospective study. The authors suggest that the present work provides compelling reasons to proceed with the prospective study.

Implications for practice

• Warfarin may induce AKI – glomerular hemorrhage and renal tubular

obstruction by RBC casts– ?AIN (2 case reports)

• Watch more carefully in INR>3.0 pts.– ?Mechanical valve replacement pts.

• ?WRN and mortality rate

Implications for research

• Prospective study

• Retrospective study– Control group (patients who are not on

warfarin)– Confounding factors– Definition of AKI; RIFLE vs. AKIN criteria– Drugs interaction with warfarin

RIFLE vs. AKIN criteria

• The RIFLE criteria was put forward by the Acute Dialysis Quality Initiative (ADQI) in 2005. 

• The AKIN "Acute Kidney Injury Network" criteria were published in 2007 after a meeting in the Netherlands comprised of multiple experts on AKI.

AKIN Criteria

Special Thanks to:

• Dr. Zoltick ; my EBM preceptor

• Dr. Knight ; my statistic teacher and fly fishing master

eGFR calculated byCKD-EPI Creatinine Equation