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Evidence base in Warfarin related nephropathy
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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