IJCA-18485; No of Pages 2 International Journal of Cardiology xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Warfarin-related nephropathy: Prevalence, risk factors and prognosis☆ Yajuan Yang, Tong Liu ⁎, Jianping Zhao, Guangping Li Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, China
a r t i c l e
i n f o
Article history: Received 15 June 2014 Accepted 27 July 2014 Available online xxxx Keywords: Warfarin-related Nephropathy Warfarin Anticoagulation Hemorrhage Acute kidney injury
Warfarin has been the most commonly prescribed oral anticoagulant since its approval in 1954 [1]. Warfarin is widely used in the prevention and treatment of deep venous thrombosis and pulmonary embolism, thromboembolism prevention in the patients with atrial fibrillation, prosthetic heart valves and indwelling central venous catheters. It interrupts the synthesis of coagulation factors (II, VII, IX, and X) by inhibiting the vitamin K epoxide reductase (VKOR) and causes disruption of the extrinsic clotting cascade. Warfarin is still underuse in clinical practice especially in China despite the strong evidence of this drug for thromboembolism prevention [2]. This may be due to its narrow therapeutic range, potential interactions with a variety of commonly used drug and food [3], and its propensity to cause hemorrhage. Also, different warfarin-related genotypes were also related to over-anticoagulation and hemorrhagic complications [4]. Warfarin-related nephropathy (WRN) is a recently recognized complication during warfarin anticoagulation therapy, in which excessive warfarinization [international normalized ratio (INR) N 3.0] leads to acute kidney injury (AKI) by causing glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [5,6]. Brodsky et al. [7] was the first to describe this entity through kidney biopsy in a subset of patients with warfarin overdose, hematuria, and AKI, and each biopsy specimen demonstrated the evidence of acute tubular injury, glomerular hemorrhage and renal tubular obstruction by RBC casts. ☆ Financial disclosures: None. ⁎ Corresponding author at: Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, China. Tel.: + 86 22 88328617; fax: +86 22 28261158. E-mail address: [email protected] (T. Liu).
They termed clinical WRN as an episode of unexplained acute renal injury defined as a serum creatinine increase greater than 0.3 mg/dl within one week of an INR measurement greater than 3.0 in a patient being treated with warfarin without clinical evidence of hemorrhage [5,6]. They also established an animal model of WRN, and showed the excessive anticoagulation increased serum creatinine levels and hematuria in the 5/6 nephrectomy rats but not in controls, which resulted in the formation of obstructing tubular RBC casts [8]. However, WRN could be the result of a problem more widespread than complete tubular obstruction by RBCs. Other potential mechanisms may participate in the occurrence of WRN (Fig. 1). First, oxidative stress damage to tubules by RBC, even though the RBC did not obstruct the tubule, could lead to WRN [9]. The patients with chronic kidney disease have reduced plasma antioxidant enzyme activities, such as glutathione peroxidase and catalase, which may contribute to a higher risk of WRN. Other important mechanisms, including atheroembolism [10], interstitial nephritis [11], apoptosis of glomerular endothelial cells [8] and direct effects of warfarin on the glomerulus [12] may also contribute to the development of WRN. Warfarin has been shown to affect glomerular mesangial cells by interfering with the activation of the product of growth arrest-specific gene 6 [11]. This could affect glomerular hemodynamics or aggravate the underlying glomerular disease. Brodsky et al. [5] further investigated the prevalence, risk factors, and consequence of WRN in a large cohort of patients who initiated warfarin therapy during a 5-year period at the Ohio State University Medical Center, WRN occurred in 20.5% of the entire cohort, 33.0% of the CKD cohort, and 16.5% of the non-CKD cohort, which indicated that patients with CKD are at much greater risk of WRN than those without CKD. It suggests that CKD patients may be prone to overanticoagulation as spend less time within the target range, required more frequent adjustments and had higher bleeding risk. Other risk factors for WRN included age, diabetes mellitus, hypertension, and cardiovascular disease. Therefore, WRN may be a common complication of warfarin therapy in high-risk patients, especially in the CKD patients. Recently, An et al. [13] showed WRN developed in 19.3% of the patients having excessive warfarinization. A lower baseline serum albumin, high serum AST at post INR elevation, and heart failure were independent risk factors for WRN. In contrast, atrial fibrillation significantly decreased the risk of WRN. However, neither the presence of CKD nor baseline estimated glomerular filtration rate (eGFR) was an independent risk factor for WRN. The occurrence of WRN also increased long-term mortality in patients with and without CKD. Brodsky et al. [5] reported that one-year mortality was significantly higher in the patients with WRN compared
http://dx.doi.org/10.1016/j.ijcard.2014.07.166 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Yang Y, et al, Warfarin-related nephropathy: Prevalence, risk factors and prognosis, Int J Cardiol (2014), http:// dx.doi.org/10.1016/j.ijcard.2014.07.166
2
Y. Yang et al. / International Journal of Cardiology xxx (2014) xxx–xxx
Fig. 1. Potential mechanisms may participate in the occurrence and development of WRN.
to those without WRN. Furthermore, An et al. [13] found that the actual mortality rates were 42.8% in the WRN group, 26.3% in the non-WRN group, which corresponded well with previous studies that reported that AKI was associated with an increased risk for long-term mortality after several years of follow-up. The potential strategies for the prevention and treatment of WRN were still under investigation. In a recent study [14] in which 5/6 Nephrectomy as a validated rat model, co-treatment with warfarin and vitamin K prevented formation of tubular RBC casts and acute tubular injury in 5/6NE animals, suggesting that WRN can be treated by vitamin K administration. Ware et al. [9] showed that N-acetylcysteine ameliorated WRN in the 5/6 nephrectomy rats through its antioxidant effects. They deemed that antioxidants prevented the increase in transforming growth factor (TGF)-1, restored neuronal nitric oxide synthase expression in the kidney, and delay progression of glomerular sclerosis in 5/6 nephrectomy rats. This work suggests that glomerular hematuria is a necessary but not sufficient explanation for the AKI in WRN. The major mechanism of the AKI in WRN maybe tubular obstruction by RBC casts with increased renal oxidative stress. In the face of the patients on systemic anticoagulation therapy, physicians should keep in mind the severity of complication of WRN and carefully monitor coagulation parameters and kidney function in the patients with warfarin therapy. Anticoagulants should be stopped, if possible, or decreased while macroscopic hematuria is present, as excessive warfarin anticoagulation seems to increase the risk of WRN. Future well-designed, prospective, and large cohort studies on WRN along with the experimental studies were urgently needed to clarify the major mechanisms, long-term prognosis, prevention and treatment of WRN.
References [1] Wardrop D, Keeling D. The story of the discovery of heparin and warfarin. Br J Haematol 2008;141(6):757–63. [2] Wang C, Yang Z, Wang C, et al. Significant underuse of warfarin in patients with nonvalvular atrial fibrillation: results from the china national stroke registry. J Stroke Cerebrovasc Dis 2014;23(5):1157–63. [3] Ge B, Zhang Z, Zuo Z. Updates on the clinical evidenced herb–warfarin interactions. Evid Based Complement Alternat Med 2014;2014:957362. [4] Yang J, Chen Y, Li X, et al. Influence of CYP2C9 and VKORC1 genotypes on the risk of hemorrhagic complications in warfarin-treated patients: a systematic review and meta-analysis. Int J Cardiol 2013;168(4):4234–43. [5] Brodsky SV, Nadasdy T, Rovin BH, et al. Warfarin-related nephropathy occurs in patients with and without chronic kidney disease and is associated with an increased mortality rate. Kidney Int 2011;80(2):181–9. [6] Rizk DV, Warnock DG. Warfarin-related nephropathy: another newly recognized complication of an old drug. Kidney Int 2011;80(2):131–3. [7] Brodsky SV, Satoskar A, Chen J, et al. Acute kidney injury during warfarin therapy associated with obstructive tubular red blood cell casts: a report of 9 cases. Am J Kidney Dis 2009;54(6):1121–6. [8] Ware K, Brodsky P, Satoskar AA, et al. Warfarin-related nephropathy modeled by nephron reduction and excessive anticoagulation. J Am Soc Nephrol 2011;22(10): 1856–62. [9] Ware K, Qamri Z, Ozcan A, et al. N-acetylcysteine ameliorates acute kidney injury but not glomerular hemorrhage in an animal model of warfarin-related nephropathy. Am J Physiol Renal Physiol 2013;304(12):F1421–7. [10] Moll S, Huffman J. Cholesterol emboli associated with warfarin treatment. Am J Hematol 2004;77(2):194–5. [11] Kapoor KG, Bekaii-Saab T. Warfarin-induced allergic interstitial nephritis and leucocytoclastic vasculitis. Intern Med J 2008;38(4):281–3. [12] Yanagita M. Gas6, warfarin, and kidney diseases. Clin Exp Nephrol 2004;8(4):304–9. [13] An JN, Ahn SY, Yoon CH, et al. The occurrence of warfarin-related nephropathy and effects on renal and patient outcomes in Korean patients. PLoS ONE 2013;8(4): e57661. [14] Ozcan A, Ware K, Calomeni E, et al. 5/6 nephrectomy as a validated rat model mimicking human warfarin-related nephropathy. Am J Nephrol 2012;35(4): 356–64.
Conflicts of interest None.
Please cite this article as: Yang Y, et al, Warfarin-related nephropathy: Prevalence, risk factors and prognosis, Int J Cardiol (2014), http:// dx.doi.org/10.1016/j.ijcard.2014.07.166
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Warfarin-related nephropathy: Prevalence, risk factors and prognosis☆ Yajuan Yang, Tong Liu ⁎, Jianping Zhao, Guangping Li Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, China
a r t i c l e
i n f o
Article history: Received 15 June 2014 Accepted 27 July 2014 Available online xxxx Keywords: Warfarin-related Nephropathy Warfarin Anticoagulation Hemorrhage Acute kidney injury
Warfarin has been the most commonly prescribed oral anticoagulant since its approval in 1954 [1]. Warfarin is widely used in the prevention and treatment of deep venous thrombosis and pulmonary embolism, thromboembolism prevention in the patients with atrial fibrillation, prosthetic heart valves and indwelling central venous catheters. It interrupts the synthesis of coagulation factors (II, VII, IX, and X) by inhibiting the vitamin K epoxide reductase (VKOR) and causes disruption of the extrinsic clotting cascade. Warfarin is still underuse in clinical practice especially in China despite the strong evidence of this drug for thromboembolism prevention [2]. This may be due to its narrow therapeutic range, potential interactions with a variety of commonly used drug and food [3], and its propensity to cause hemorrhage. Also, different warfarin-related genotypes were also related to over-anticoagulation and hemorrhagic complications [4]. Warfarin-related nephropathy (WRN) is a recently recognized complication during warfarin anticoagulation therapy, in which excessive warfarinization [international normalized ratio (INR) N 3.0] leads to acute kidney injury (AKI) by causing glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts [5,6]. Brodsky et al. [7] was the first to describe this entity through kidney biopsy in a subset of patients with warfarin overdose, hematuria, and AKI, and each biopsy specimen demonstrated the evidence of acute tubular injury, glomerular hemorrhage and renal tubular obstruction by RBC casts. ☆ Financial disclosures: None. ⁎ Corresponding author at: Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, China. Tel.: + 86 22 88328617; fax: +86 22 28261158. E-mail address: [email protected] (T. Liu).
They termed clinical WRN as an episode of unexplained acute renal injury defined as a serum creatinine increase greater than 0.3 mg/dl within one week of an INR measurement greater than 3.0 in a patient being treated with warfarin without clinical evidence of hemorrhage [5,6]. They also established an animal model of WRN, and showed the excessive anticoagulation increased serum creatinine levels and hematuria in the 5/6 nephrectomy rats but not in controls, which resulted in the formation of obstructing tubular RBC casts [8]. However, WRN could be the result of a problem more widespread than complete tubular obstruction by RBCs. Other potential mechanisms may participate in the occurrence of WRN (Fig. 1). First, oxidative stress damage to tubules by RBC, even though the RBC did not obstruct the tubule, could lead to WRN [9]. The patients with chronic kidney disease have reduced plasma antioxidant enzyme activities, such as glutathione peroxidase and catalase, which may contribute to a higher risk of WRN. Other important mechanisms, including atheroembolism [10], interstitial nephritis [11], apoptosis of glomerular endothelial cells [8] and direct effects of warfarin on the glomerulus [12] may also contribute to the development of WRN. Warfarin has been shown to affect glomerular mesangial cells by interfering with the activation of the product of growth arrest-specific gene 6 [11]. This could affect glomerular hemodynamics or aggravate the underlying glomerular disease. Brodsky et al. [5] further investigated the prevalence, risk factors, and consequence of WRN in a large cohort of patients who initiated warfarin therapy during a 5-year period at the Ohio State University Medical Center, WRN occurred in 20.5% of the entire cohort, 33.0% of the CKD cohort, and 16.5% of the non-CKD cohort, which indicated that patients with CKD are at much greater risk of WRN than those without CKD. It suggests that CKD patients may be prone to overanticoagulation as spend less time within the target range, required more frequent adjustments and had higher bleeding risk. Other risk factors for WRN included age, diabetes mellitus, hypertension, and cardiovascular disease. Therefore, WRN may be a common complication of warfarin therapy in high-risk patients, especially in the CKD patients. Recently, An et al. [13] showed WRN developed in 19.3% of the patients having excessive warfarinization. A lower baseline serum albumin, high serum AST at post INR elevation, and heart failure were independent risk factors for WRN. In contrast, atrial fibrillation significantly decreased the risk of WRN. However, neither the presence of CKD nor baseline estimated glomerular filtration rate (eGFR) was an independent risk factor for WRN. The occurrence of WRN also increased long-term mortality in patients with and without CKD. Brodsky et al. [5] reported that one-year mortality was significantly higher in the patients with WRN compared
http://dx.doi.org/10.1016/j.ijcard.2014.07.166 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Yang Y, et al, Warfarin-related nephropathy: Prevalence, risk factors and prognosis, Int J Cardiol (2014), http:// dx.doi.org/10.1016/j.ijcard.2014.07.166
2
Y. Yang et al. / International Journal of Cardiology xxx (2014) xxx–xxx
Fig. 1. Potential mechanisms may participate in the occurrence and development of WRN.
to those without WRN. Furthermore, An et al. [13] found that the actual mortality rates were 42.8% in the WRN group, 26.3% in the non-WRN group, which corresponded well with previous studies that reported that AKI was associated with an increased risk for long-term mortality after several years of follow-up. The potential strategies for the prevention and treatment of WRN were still under investigation. In a recent study [14] in which 5/6 Nephrectomy as a validated rat model, co-treatment with warfarin and vitamin K prevented formation of tubular RBC casts and acute tubular injury in 5/6NE animals, suggesting that WRN can be treated by vitamin K administration. Ware et al. [9] showed that N-acetylcysteine ameliorated WRN in the 5/6 nephrectomy rats through its antioxidant effects. They deemed that antioxidants prevented the increase in transforming growth factor (TGF)-1, restored neuronal nitric oxide synthase expression in the kidney, and delay progression of glomerular sclerosis in 5/6 nephrectomy rats. This work suggests that glomerular hematuria is a necessary but not sufficient explanation for the AKI in WRN. The major mechanism of the AKI in WRN maybe tubular obstruction by RBC casts with increased renal oxidative stress. In the face of the patients on systemic anticoagulation therapy, physicians should keep in mind the severity of complication of WRN and carefully monitor coagulation parameters and kidney function in the patients with warfarin therapy. Anticoagulants should be stopped, if possible, or decreased while macroscopic hematuria is present, as excessive warfarin anticoagulation seems to increase the risk of WRN. Future well-designed, prospective, and large cohort studies on WRN along with the experimental studies were urgently needed to clarify the major mechanisms, long-term prognosis, prevention and treatment of WRN.
References [1] Wardrop D, Keeling D. The story of the discovery of heparin and warfarin. Br J Haematol 2008;141(6):757–63. [2] Wang C, Yang Z, Wang C, et al. Significant underuse of warfarin in patients with nonvalvular atrial fibrillation: results from the china national stroke registry. J Stroke Cerebrovasc Dis 2014;23(5):1157–63. [3] Ge B, Zhang Z, Zuo Z. Updates on the clinical evidenced herb–warfarin interactions. Evid Based Complement Alternat Med 2014;2014:957362. [4] Yang J, Chen Y, Li X, et al. Influence of CYP2C9 and VKORC1 genotypes on the risk of hemorrhagic complications in warfarin-treated patients: a systematic review and meta-analysis. Int J Cardiol 2013;168(4):4234–43. [5] Brodsky SV, Nadasdy T, Rovin BH, et al. Warfarin-related nephropathy occurs in patients with and without chronic kidney disease and is associated with an increased mortality rate. Kidney Int 2011;80(2):181–9. [6] Rizk DV, Warnock DG. Warfarin-related nephropathy: another newly recognized complication of an old drug. Kidney Int 2011;80(2):131–3. [7] Brodsky SV, Satoskar A, Chen J, et al. Acute kidney injury during warfarin therapy associated with obstructive tubular red blood cell casts: a report of 9 cases. Am J Kidney Dis 2009;54(6):1121–6. [8] Ware K, Brodsky P, Satoskar AA, et al. Warfarin-related nephropathy modeled by nephron reduction and excessive anticoagulation. J Am Soc Nephrol 2011;22(10): 1856–62. [9] Ware K, Qamri Z, Ozcan A, et al. N-acetylcysteine ameliorates acute kidney injury but not glomerular hemorrhage in an animal model of warfarin-related nephropathy. Am J Physiol Renal Physiol 2013;304(12):F1421–7. [10] Moll S, Huffman J. Cholesterol emboli associated with warfarin treatment. Am J Hematol 2004;77(2):194–5. [11] Kapoor KG, Bekaii-Saab T. Warfarin-induced allergic interstitial nephritis and leucocytoclastic vasculitis. Intern Med J 2008;38(4):281–3. [12] Yanagita M. Gas6, warfarin, and kidney diseases. Clin Exp Nephrol 2004;8(4):304–9. [13] An JN, Ahn SY, Yoon CH, et al. The occurrence of warfarin-related nephropathy and effects on renal and patient outcomes in Korean patients. PLoS ONE 2013;8(4): e57661. [14] Ozcan A, Ware K, Calomeni E, et al. 5/6 nephrectomy as a validated rat model mimicking human warfarin-related nephropathy. Am J Nephrol 2012;35(4): 356–64.
Conflicts of interest None.
Please cite this article as: Yang Y, et al, Warfarin-related nephropathy: Prevalence, risk factors and prognosis, Int J Cardiol (2014), http:// dx.doi.org/10.1016/j.ijcard.2014.07.166
