Warfarin Therapy That Results in an International Normalization Ratio above the Therapeutic Range Is Associated with Accelerated Progression of Chronic Kidney Disease

Abstract

Background/Aims: We had previously reported that acute kidney injury (AKI) in warfarin-treated chronic kidney disease (CKD) patients may occur shortly after an acute increase in the International Normalization Ratio (INR) >3.0 with formation of occlusive red blood casts. Recovery from this warfarin-associated AKI is poor. Here we investigated whether excessive warfarin therapy could accelerate the progression of CKD. Methods: We analyzed serum creatinine (SC) and INR in 103 consecutive CKD patients on warfarin therapy in our Nephrology program from 2005 to the present. Results: Forty-nine patients experienced at least 1 episode of INR >3.0. Of these, 18 patients (37%, Group 1) developed an unexplained increase in SC ≧0.3 mg/dl coincident with INR >3.0 (mean SC increase 0.61 ± 0.44 mg/dl); 31 patients (63%, Group 2) showed stable SC (mean SC change 0.04 ± 0.19 mg/dl). Subsequent CKD progression was accelerated in Group 1, but not in Group 2. The 2 groups were not different with respect to demographics, comorbidities, blood pressure, or therapies. However, African Americans were overrepresented in Group 1 (p = 0.035). 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 justi- fy extra caution in warfarin-treated CKD patients to avoid overanticoagulation.

Pathogenesis of glomerular haematuria

“…AKI could be caused by intratubular obstruction of RBC casts during glomerular haemorrhage, although atheroembolism [81] , interstitial nephritis [82] , and direct effects of warfarin on the glomerulus [83] have been also pointed. The real WRN incidence could be 16% in non-CKD and 37% in CKD patients [84] . There has been described several risk factors for WRN, including: (1) aspirin therapy; (2) drugs that increase glomerular hydrostatic pressure, such as dihydropyridine calcium channel blockers; (3) low serum albumin levels; and (4) concurrent congestive heart failure [85] .…”

N-acetylcysteine ameliorates acute kidney injury but not glomerular hemorrhage in an animal model of warfarin-related nephropathy

“…In humans, WRN is not an uncommon complication of excessive anticoagulation with warfarin. Our retrospective studies show that when the international normalized ratio (INR) acutely exceeds 3.0, 16% of non-CKD patients (6) and 33-37% of CKD patients (5,6) may develop AKI within ϳ1 wk of the INR Ͼ 3.0. Those at greatest risk of WRN have CKD or cardiovascular disease (5,6).…”

“…We named this condition warfarin-related nephropathy (WRN). WRN can have dire consequences, particularly in chronic kidney disease (CKD) patients, whose CKD progression can be accelerated (5,6). In humans, WRN is not an uncommon complication of excessive anticoagulation with warfarin.…”

Warfarin-Related Nephropathy Modeled by Nephron Reduction and Excessive Anticoagulation

“…1 Subsequent analysis of 103 patients with CKD revealed that 37% experienced an unexplained increase in serum creatinine (SC) of Ն0.3 mg/dl within 1 week of an international normalized ratio (INR) Ͼ 3.0. 2 Also, patients with WRN had accelerated progression of CKD, as compared with patients without WRN.…”