Warfarin-related nephropathy occurs in patients with and without chronic kidney disease and is associated with an increased mortality rate

Abstract

An acute increase in the international normalized ratio (INR; a comparison of prothrombin time to monitor the effects of warfarin) over 3 in patients with chronic kidney disease (CKD) is often associated with an unexplained acute increase in serum creatinine (SC) and an accelerated progression of CKD. Kidney biopsy in a subset of these patients showed obstruction of the renal tubule by red blood cell casts, and this appears to be the dominant mechanism of the acute kidney injury. We termed this warfarin-related nephropathy (WRN), and previously reported cases of WRN only in patients with CKD. We now assess whether this occurs in patients without CKD, its risk factors, and consequences. In 15,258 patients who initiated warfarin therapy during a 5-year period, 4006 had an INR over 3 and SC measured at the same time; however, the large data set precluded individual patient clinical assessment. A presumptive diagnosis of WRN was made if the SC increased by over 0.3 mg/dl within 1 week after the INR exceeded 3 with no record of hemorrhage. WRN occurred in 20.5% of the entire cohort, 33.0% of the CKD cohort, and 16.5% of the no-CKD cohort. Other risk factors included age, diabetes mellitus, hypertension, and cardiovascular disease. The 1-year mortality was 31.1% with compared with 18.9% without WRN, an increased risk of 65%. Thus, WRN may be a common complication of warfarin therapy in high-risk patients and CKD doubles this risk. The mechanisms of these risks are unclear.

Figure 1. International normalized ratio (INR) and changes in serum creatinine (SC) levels associated with INR increase ≥3.0 in patients with and without warfarin-related nephropathy (WRN)

Panel a shows that the INR for the first episode of INR >3.0 was significantly higher in WRN patients than the no-WRN patients for cohort 5 (all patients) and for the no-CKD (chronic kidney disease) subset but not the CKD subset. Panel b shows the changes in SC for cohort 5, stratified by the patient’s status as WRN (square) or no WRN (circle). The mean SC±₁ s.d. is shown for the following intervals: 0–3 months before and at the onset of INR >3.0 (arbitrarily shown as 1 month before and at the onset of INR >3.0), 0–6 days after the INR >3.0 (arbitrarily shown as 6 days after the onset of INR >3.0), and 2–4 months after the INR >3.0 (arbitrarily shown as 3 months after the INR >3.0). The format for panels c and d is the same as that of panel b, except that panel c shows the no-CKD cohort and panel d shows the CKD cohort. As shown, mean SC increased significantly at onset of INR >3.0 in the WRN cohorts and tended to remain elevated 3 months later. SC values were available for all patients within 6 days after the INR >3.0. For the period 0–3 months after the INR >3.0, SC values were available for 1917 of 2780 (69%) of the surviving no-CKD and 611 of 722 (85%) of the surviving CKD patients. Longer-follow-up data are not shown because they were not consistently available across the indicated cohorts. To convert SC in mg/dl to mol/l, multiply by 88.4. *P<0.05 compared with no-WRN group, ^#P<0.05 compared with 0–3 months before INR >3.0. IU, international unit.

Figure 2. Histograms of the international normalized ratio (INR) and changes in serum creatinine (SC) distributions in patients with and without warfarin-related nephropathy (WRN)

Panels a, c, and e show the distribution of changes in SC (delta SC) in all patients (cohort 5, panel a), patients without WRN (no WRN, Panel c), and WRN patients (Panel e). Panels b, d, and f show the distribution of INR in all patients (cohort 5, panel b), patients without WRN (no WRN, panel d), and WRN patients (panel f). IU, international unit.

Figure 3. Changes in estimated glomerular filtration rate (eGFR) associated with international normalized ratio (INR) increase ≥3.0 in patients with and without warfarin-related nephropathy (WRN)

eGFR was calculated based on the chronic kidney disease (CKD)-EPI equation. Panel a shows the changes in eGFR for cohort 5, stratified by the patient’s status as WRN (square) or no WRN (circle). The mean eGFR±₁ s.d. is shown for the following intervals: 0–3 months before and at the onset of INR >3.0 (arbitrarily shown as 1 month before and at the onset of INR >3.0), 0–6 days after the INR >3.0 (arbitrarily shown as 6 days after the onset of INR >3.0), and 2–4 months after the INR >3.0 (arbitrarily shown as 3 months after the INR >3.0). The format for panels b and c is the same as that of panel a, except that panel b shows the no-CKD cohort and panel c shows the CKD cohort. As shown, mean eGFR decreased significantly at onset of INR >3.0 in the WRN cohorts and tended to remain reduced 3 months later. eGFR was calculated based on serum creatinine (SC) values, which were available for all patients within 6 days after the INR >3.0. For the period 0–3 months after the INR>3.0, SC values were available for 1917 of 2780 (69%) of the surviving no-CKD and 611 of 722 (85%) of the surviving CKD patients. Longer-follow-up data are not shown because they were not consistently available across the indicated cohorts. *P<0.05 compared with no-WRN group, ^#P<0.05 compared with 0–3 months before INR >3.0.

Figure 4. Changes in the hematuria grade in patients with and without warfarin-related nephropathy (WRN)

Hematuria was graded using a semiquantitative scale of 0 to 3+. Grade 0, no hematuria; 1+, mild hematuria; 2+, moderate hematuria; and 3+, large hematuria. Panel a shows changes in the hematuria grade in the WRN and no-WRN patients. The difference in hematuria grade at 1 week post-INR >3.0 and 0–3 months before the INR >3.0 was calculated, and the percentage of patients whose hematuria grade was changed is shown. Consecutive data were available in only 732 patients. Panel b shows changes in the hematuria grade in the WRN and no-WRN patients at 0–3 months after INR >3.0 and 0–3 months before INR >3.0. Consecutive data were available for only 771 patients. None of the differences shown in panel a or b was significant. a.u., arbitrary unit.

Figure 5. Survival analysis and hazard ratio in patients with and without warfarin-related nephropathy (WRN) and chronic kidney disease (CKD)

Panel a: Kaplan–Meier plot (log-rank P-value <0.0001) for WRN patients (N = 3179, black dotted line) and no-WRN patients (N = 810, black solid line). Panel b: Kaplan–Meier plot (log-rank P-value <0.0001) for patients with WRN and no WRN, stratified by CKD, no-CKD status. Patients with WRN and CKD (black dotted line) had the lowest survival rate. Patients with WRN but no CKD had better survival rates (gray solid line). Patients without WRN, but with CKD had better survival rates compared with WRN patients with CKD (black dashed line). Patients without both WRN and CKD had the best survival rate (black solid line). Panel c: the univariate Cox model with survival as a time-varying covariate was used to estimate the hazard ratio for death in the WRN versus no-WRN cohorts, with 95% confidence intervals (CIs) at selected early time points. Because violation of the assumption of proportional hazards, WRN and no-WRN status was included as a time-varying covariate in the model. As shown, the hazard ratio for death (WRN versus no WRN) was highest within the first week after international normalized ratio (INR) >3.0. Thereafter it decreased progressively until it reached non-significant levels 6 months later. Estimated hazard ratio (solid black line) with 95% CIs (gray lines) is shown. Panel d shows the hazard ratio described in panel c but adjusted for the covariates that were significantly different between the WRN and no-WRN cohorts: age at INR >3.0, CKD, diabetes mellitus, heart failure, atrial fibrillation, and glomerulonephritis. The adjusted hazard ratio is similar to that of the unadjusted hazard ratio. Also, there was no evidence of an interaction between WRN, no-WRN status, and CKD status (P = 0.2102). Estimated hazard ratio (solid black line) with 95% CIs (gray lines) is shown.