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  Table of Contents  
CASE REPORT
Year : 2018  |  Volume : 28  |  Issue : 5  |  Page : 378-381
 

Warfarin-related nephropathy


1 Department of Nephrology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
2 Department of Pathology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India

Date of Web Publication10-Sep-2018

Correspondence Address:
D. S. B Raju
Department of Nephrology, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad - 500 082, Telangana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijn.IJN_3_17

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  Abstract 


Warfarin-related nephropathy also referred to as anticoagulant-related nephropathy (ACRN) is a type of acute kidney injury (AKI) that may be caused by excessive anticoagulation with warfarin and other anticoagulants. Despite the well-described histological entity, the clinical course and approach to ACRN in patients requiring life-long anticoagulation are however not well described in the literature. We report a 50-year-old Indian woman who was on prolonged anticoagulant therapy post-mitral valve replacement. She presented with AKI, and renal biopsy was suggestive of ACRN. Steroids were given and her creatinine levels reached within the normal range in 2 weeks. A presumptive diagnosis of ACRN should be made if a severe warfarin coagulopathy is present and if other causes of AKI have been excluded, in patients with chronic anticoagulant therapy. Renal function should be monitored regularly in patients who are on anticoagulant therapy.


Keywords: Acute kidney injury, anticoagulant-related nephropathy, corticosteroids, mitral valve replacement, warfarin


How to cite this article:
Golla A, Goli R, Nagalla V K, Kiran B V, Raju D, Uppin M S. Warfarin-related nephropathy. Indian J Nephrol 2018;28:378-81

How to cite this URL:
Golla A, Goli R, Nagalla V K, Kiran B V, Raju D, Uppin M S. Warfarin-related nephropathy. Indian J Nephrol [serial online] 2018 [cited 2018 Dec 16];28:378-81. Available from: http://www.indianjnephrol.org/text.asp?2018/28/5/378/234065





  Introduction Top


Acute kidney injury (AKI) resulting from glomerular hemorrhage has been described in patients with underlying kidney disease in the absence [1],[2],[3] and presence [4],[5] of coagulopathy (international normalized ratio [INR] of 6–9 range). More recently, AKI has been described among patients without underlying kidney disease and with more modest elevations of INR.[6] The recognition of a characteristic histologic lesion that was associated with the clinical presentation of otherwise unexplained AKI in the setting of over-anticoagulation led to the term “anticoagulant-related nephropathy.” We report a case of AKI with biopsy-proven anticoagulant-related nephropathy (ACRN) in a patient with mechanical heart valve where the anticoagulant therapy cannot be withheld.


  Case Report Top


A 50-year-old Indian female, who underwent mitral valve replacement for chronic rheumatic heart disease with severe mitral stenosis with left atrial appendicular clot, was on tablet acenocoumarol (Acitrom) 1 mg, tablet Ecosprin (aspirin) 75 mg, tablet Lanoxin (digoxin) 0.125 mg post mitral valve replacement for 2 years. She was on regular follow-up every 2 months and the dose of acenocoumarol was increased to 2 mg after 6 months. Her creatinine levels were within normal limits and INR within the therapeutic range. She had sudden abdominal distension with fever 1 year later and was diagnosed to have small bowel obstruction for which laparotomy with adhesiolysis was done. Tablet acenocoumarol 1 mg was started again postoperatively, which was increased to 2 mg in the next 6 months. Her creatinine levels were 0.9 and INR was within the therapeutic range. She had been on regular follow-up and was asymptomatic for a period of 1 year. She presented to us with the complaints of multiple episodes of non projectile, non-bilious vomiting following food intake and persistent high-colored urine for the past 1 month. There was no history of exertional dyspnea, chest pain, palpitations, and skin rashes. The patient did not complain of decreased urine output, dysuria, or pyuria. She was not a known diabetic or hypertensive. There was no significant past history with similar complaints. On physical examination, she was well nourished and moderately built, no evidence of pallor, pulse rate was 80 beats/min, and blood pressure was 110/60 mmHg. The patient had epigastric tenderness on abdominal palpation. Serum creatinine was 4.7 mg/dl, a 4-fold increase from her serum creatinine levels 6 months back, and INR was 4.70 (out of the therapeutic range) with dysmorphic red blood cells (RBCs) and casts in the urine. The provisional diagnosis of AKI in the background of anticoagulation was made and investigated further.

The autoimmune markers including anti-dsDNA antibodies, ANCA, and antinuclear antibodies were negative. The ultrasonography showed bilateral normal sized kidneys. Non-contrast computerized tomography confirmed bilateral normal-sized kidneys with no calculi, hydronephrosis, or retroperitoneal fibrosis. Renal biopsy was planned after switching over to heparin and achieving the therapeutic INR. Post biopsy, she was switched over to warfarin, and the target INR of 2 was achieved. The histology suggested acute tubulointerstitial nephritis with RBC casts [Figure 1] and the immunofluorescence studies were negative. The patient was started on steroids. All the clinical investigations are shown in [Table 1].
Figure 1: Renal biopsy findings: tubules show intraluminal red cell casts. Interstitium shows infiltrate of lymphocytes and neutrophils

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Table 1: Laboratory findings according to clinical phase and time

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  Discussion Top


The diagnosis of ACRN should be suspected among patients who present with AKI in the setting of excessive anticoagulation and hematuria. A definitive diagnosis is made by renal biopsy. Incidence of AKI in the largest cohort of warfarin using patients was 20.5% overall and 33% in patients with a history of chronic kidney disease (CKD). Moderate or severe coagulopathy induced by warfarin or other anticoagulants, especially if INR >4 and CKD, is the strongest risk factor for ACRN, and in these cases, prognosis is also worse than those without CKD. Other independent predictors of AKI risk in these patients were age, diabetes mellitus, heart failure, hypertension, and glomerulonephritis particularly with nephrotic syndrome.[6],[7],[8] Kidney biopsy in a subset of these patients showed obstruction of the renal tubule by RBC casts, and this appears to be the dominant mechanism of AKI.[6]

The initiating event in the pathogenesis of ACRN appears to be glomerular hemorrhage, caused by excessive anticoagulation due to warfarin or other anticoagulants.[9] Glomerular hemorrhage results in the formation of obstructing RBC casts within the renal tubules. Obstructing intraluminal RBC casts are the most conspicuous histologic feature of ACRN in the tissue obtained from patients who have undergone biopsy [10] and in animal models.[11] The major histologic feature of ACRN is the obstruction of renal tubules (mainly distal) by RBC casts [Figure 1].[10] Even though disruption of the glomerular filtration barrier is the main pathophysiological event, the molecular mechanism is poorly determined. Proteinase-activated receptors which are activated by thrombin have trophic effect on endothelium; however, its role in the pathogenesis of ACRN is yet to be determined.[12] The glomeruli show little or no abnormalities by immunofluorescence, light, or electron microscopy.

The management of warfarin-related nephropathy (WRN) in patients requiring prolonged anticoagulation poses a management dilemma. Alternative to warfarin, other anticoagulants such as dabigatran (direct thrombin inhibitor) and rivaroxaban, apixaban, and edoxaban (direct-activated factor X inhibitors) are being increasingly used. However, their renal safety is not established. In the literature, two cases of dabigatran-related nephropathy were reported.[13],[14] Although RE-LY study showed that dabigatran was associated with smaller reductions in glomerular filtration rate compared to warfarin, its clinical significance is not clear, and most importantly, this study excluded those patients with estimated GFR (eGFR) of <30 ml/min, which is the strongest risk factor for ACRN.[15]

Brodsky et al. published a data of 9 patients of WRN. A total of 3 patients had complete renal recovery and 6 patients had partial/no renal recovery. All the three patients who recovered had normal eGFR 3 months before biopsy, and in the remaining 6 patients, eGFR was lower than normal. In our case, patient had normal baseline serum creatinine (0.9 mg/dl) before increasing warfarin dose, probably this could be the reason for complete renal recovery.[10]

The role of steroids is not clear in WRN. The anti-inflammatory effect of steroids may be useful in mitigating the onset of interstitial fibrosis as a consequence of WRN. Temporary interruption of anticoagulation may ameliorate glomerular bleeding and result in stabilization of the renal function.[16] We administered steroids in the present case and it should be tested in the future studies.


  Conclusion Top


Among patients who develop AKI and are on chronic anticoagulant therapy, a presumptive diagnosis of ACRN should be made if a severe coagulopathy is present and if other causes of AKI have been excluded. Renal biopsy may be warranted in different clinical setting. The most important measure to prevent ACRN is proper adjustment of the anticoagulant dose, especially in the CKD patients, who are more vulnerable to ACRN.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Kincaid-Smith P, Bennett WM, Dowling JP, Ryan GB. Acute renal failure and tubular necrosis associated with hematuria due to glomerulonephritis. Clin Nephrol 1983;19:206-10.  Back to cited text no. 1
    
2.
Clarkson AR, Seymour AE, Thompson AJ, Haynes WD, Chan YL, Jackson B, et al. IgA nephropathy: A syndrome of uniform morphology, diverse clinical features and uncertain prognosis. Clin Nephrol 1977;8:459-71.  Back to cited text no. 2
    
3.
Praga M, Gutierrez-Millet V, Navas JJ, Ruilope LM, Morales JM, Alcazar JM, et al. Acute worsening of renal function during episodes of macroscopic hematuria in IgA nephropathy. Kidney Int 1985;28:69-74.  Back to cited text no. 3
    
4.
Kabir A, Nadasdy T, Nadasdy G, Hebert LA. An unusual cause of gross hematuria and transient ARF in an SLE patient with warfarin coagulopathy. Am J Kidney Dis 2004;43:757-60.  Back to cited text no. 4
    
5.
Abt AB, Carroll LE, Mohler JH. Thin basement membrane disease and acute renal failure secondary to gross hematuria and tubular necrosis. Am J Kidney Dis 2000;35:533-6.  Back to cited text no. 5
    
6.
Brodsky SV, Nadasdy T, Rovin BH, Satoskar AA, Nadasdy GM, Wu HM, 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;80:181-9.  Back to cited text no. 6
    
7.
Brodsky SV, Collins M, Park E, Rovin BH, Satoskar AA, Nadasdy G, et al. Warfarin therapy that results in an international normalization ratio above the therapeutic range is associated with accelerated progression of chronic kidney disease. Nephron Clin Pract 2010;115:c142-6.  Back to cited text no. 7
    
8.
An JN, Ahn SY, Yoon CH, Youn TJ, Han MK, Kim S, et al. The occurrence of warfarin-related nephropathy and effects on renal and patient outcomes in Korean patients. PLoS One 2013;8:e57661.  Back to cited text no. 8
    
9.
Ryan M, Ware K, Qamri Z, Satoskar A, Wu H, Nadasdy G, et al. Warfarin-related nephropathy is the tip of the iceberg: Direct thrombin inhibitor dabigatran induces glomerular hemorrhage with acute kidney injury in rats. Nephrol Dial Transplant 2014;29:2228-34.  Back to cited text no. 9
    
10.
Brodsky SV, Satoskar A, Chen J, Nadasdy G, Eagen JW, Hamirani M, 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;54:1121-6.  Back to cited text no. 10
    
11.
Ozcan A, Ware K, Calomeni E, Nadasdy T, Forbes R, Satoskar AA, et al. 5/6 nephrectomy as a validated rat model mimicking human warfarin-related nephropathy. Am J Nephrol 2012;35:356-64.  Back to cited text no. 11
    
12.
Wheeler DS, Giugliano RP, Rangaswami J. Anticoagulation-related nephropathy. J Thromb Haemost 2016;14:461-7.  Back to cited text no. 12
    
13.
Moeckel GW, Luciano RL, Brewster UC. Warfarin-related nephropathy in a patient with mild IgA nephropathy on dabigatran and aspirin. Clin Kidney J 2013;6:507-9.  Back to cited text no. 13
    
14.
Escoli R, Santos P, Andrade S, Carvalho F. Dabigatran-related nephropathy in a patient with undiagnosed IgA nephropathy. Case Rep Nephrol 2015;2015:298261.  Back to cited text no. 14
    
15.
Böhm M, Ezekowitz MD, Connolly SJ, Eikelboom JW, Hohnloser SH, Reilly PA, et al. Changes in renal function in patients with atrial fibrillation: An analysis from the RE-LY trial. J Am Coll Cardiol 2015;65:2481-93.  Back to cited text no. 15
    
16.
Ware K, Brodsky P, Satoskar AA, Nadasdy T, Nadasdy G, Wu H, et al. Warfarin-related nephropathy modeled by nephron reduction and excessive anticoagulation. J Am Soc Nephrol 2011;22:1856-62.  Back to cited text no. 16
    


    Figures

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    Tables

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