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Saudi Journal of Kidney Diseases and Transplantation
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CASE REPORT  
Year : 2020  |  Volume : 31  |  Issue : 6  |  Page : 1403-1406
Anticoagulant-related nephropathy: A case report


1 Department of Medicine, Hospital Pulau Pinang, Pulau Pinang, Malaysia
2 Diagnostic Laboratory Services Department, Universiti Kebangsaan Malaysia Medical Center, Kuala Lumpur, Malaysia
3 Nephrology Unit, Department of Internal Medicine, Hospital Pulau Pinang, Pulau Pinang, Malaysia

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Date of Web Publication29-Jan-2021
 

   Abstract 


Anticoagulant-related nephropathy (ARN) is a recently described disease entity which is an underdiagnosed complication of anticoagulation. Despite widespread usage of anticoagulants, ARN is not commonly reported. We report a case of a 64-year old man with biopsy-proven ARN who presented with over anticoagulation and acute chronic kidney injury while on warfarin therapy for his left lower limb deep-vein thrombosis. Various investigations were performed and renal biopsy confirmed the diagnosis of anticoagulant-related nephropathy.

How to cite this article:
Lee KT, Kammal WS, Kong BH. Anticoagulant-related nephropathy: A case report. Saudi J Kidney Dis Transpl 2020;31:1403-6

How to cite this URL:
Lee KT, Kammal WS, Kong BH. Anticoagulant-related nephropathy: A case report. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2021 May 12];31:1403-6. Available from: https://www.sjkdt.org/text.asp?2020/31/6/1403/308356



   Introduction Top


Oral anticoagulants are widely used in the management of thromboembolic disorders. Despite development of new class of anticoagulants, known as a direct-acting oral anticoagulant, warfarin is still the most prescribed oral anticoagulant in the prevention and treatment of thromboembolism. Warfarin is not without shortcomings; it has a narrow therapeutic range, requires close monitoring, and carries a significant risk of bleeding, which is higher among patients with renal impairment.

Warfarin-related nephropathy or anticoagulant related nephropathy is a newly recognized cause of acute kidney injury (AKI) caused by over anticoagulation. The diagnosis is confirmed histologically by the presence of glomerular hemorrhage and tubular injury due to obstruction with red blood cell casts.[1]


   Case Report Top


A 64-year-old man was admitted to the medical ward as he was found to be over anticoagulated during clinic follow-up, with international normalized ratio (INR) of 4.3. He was started on warfarin two months previously for left lower limb deep-vein thrombosis. Other medical histories included diabetes mellitus, hypertension, gout, and chronic kidney disease (CKD). He was on tablet gliclazide 80 mg BD, felodipine 10 mg BD, metoprolol 50 mg BD, furosemide 40 mg BD, and warfarin 3 mg OD. Otherwise, he was asymptomatic with no bleeding tendency. However, he was found to have acute exacerbation of CKD with rapid deterioration of renal profile during admission. His baseline creatinine was 206 μmol/L and increased more than two fold (471 μmol/L) with progressive worsening during admission. Further investigations were performed to look for causes of AKI. Urine examination revealed microscopic hematuria and proteinuria, with 24-h urine protein of 2.54 g. Renal ultrasound showed no evidence of urinary calculi or obstruction. Autoimmune workup for antinuclear antibody, anti-double stranded DNA antibody, and anti-neutrophil cytoplasmic antibody was normal. The complement levels were normal. Hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus serology were all nonreactive.

Warfarin was withheld since admission, and subsequently, he was bridged with subcutaneous low-molecular weight heparin. His kidney function progressively deteriorated without any obvious cause. Blood investigation trends are as summarized in [Table 1]. During admission, he developed sepsis due to catheter-related infection. A decision to perform renal biopsy was taken; however, it was delayed for a period of time even after warfarin was withheld due to sepsis and prolonged INR. Histological examination showed one glomerulus with global sclerosis. The remaining glomeruli showed mild mesangial hypercellularity. No crescent was identified. There was evidence of tubular injury with intraluminal red cell casts. Perl’s stain highlighted hemosiderin deposition within tubular epithelium, features which were consistent with anticoagulant-related nephro-pathy (ARN) [Figure 1]. Immunofluorescence was performed which showed two sclerotic glomeruli and no deposit. Immunohisto-chemistry and electron microscopy were not performed due to limited resources in our center. He was discharged home after normalization of INR. However, his kidney function failed to return to baseline, with creatinine hovering at 700–720 μmol/L. He was given follow-up in the nephrology clinic and counseled for possibility of renal replacement therapy if no renal recovery. However, the patient defaulted subsequent follow-up.
Figure 1: (a) Acute tubular injury with intraluminal red cell casts (white arrow) seen (H&E stain, ×400). (b) Hemosiderin deposition (black arrow) is present within the tubular epithelium (Perls stain, ×400).

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Table 1: Summary of blood investigations.

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   Discussion Top


Warfarin therapy requires close monitoring and dose adjustment to keep the INR within the therapeutic range. This may pose a challenge among patients with CKD as they are associated with unstable anticoagulation profile.[2] A study by Limdi et al evaluated the influence of kidney function on warfarin therapy and complications on a prospective cohort of 578 patients. They noted that patients with renal impairment required lower dosages of warfarin, had poorer control of anticoagulation, and were at higher risk for major hemorrhage. Both the risks of over anticoagulation and major hemorrhage were higher, especially among patients with severe CKD.[3]

ARN is an important differential diagnosis in the evaluation of AKI in patients on warfarin therapy, particularly so in the presence of microscopic hematuria. The prevalence of ARN varies significantly according to the risk of the study population and is estimated to be 20.4% based on a recent meta-analysis.[4] Another study done in Korea described that 19.3% of patients having excessive warfarin doses developed ARN.[5] However, ARN is still significantly underdiagnosed and is only recently gaining attention. A few other factors may also contribute to this since ARN occurs mainly in patients with multiple risk factors for AKI, as in our case. It is possible that clinician will attribute the acute on chronic kidney injury to these other factors. In addition, ARN is a diagnosis of exclusion which can only be confirmed by renal biopsy. However, some nephrologists will be cautious in performing a renal biopsy in patients on anticoagulant therapy.

The pathophysiology of ARN is multifactorial. The initiating event is likely attributed to glomerular hemorrhage with disruption of the glomerular filtration barrier. The subsequent formation of inrtraluminal red cell casts causes obstructive injury toward the tubular epithelium. In addition, free hemogloblin which is released by the red blood cells generates reactive oxygen species as well as increases lipid perodixation, which, in turn, generates oxidative stress and direct damage toward the tubular epithelium.[6]

There are dilemmas of management of ARN in patients who required long-term anticoa-gulation, especially on the decision of timing to restart oral anticoagulation. Up to this date, there are no prospective studies or guidelines that specifically guide the management of ARN. Several experimental studies and case reports described the use of N-acetylcysteine[7] and corticosteroids[8] in the management of ARN.


   Conclusion Top


ARN leads to significant morbidity and mortality, especially among patients with CKD. Prompt recognition and diagnosis of ARN is important and should be suspected in patients with unexplained AKI in the presence of over anticoagulation. Our case highlights the importance of monitoring of renal function in patients who are on anticoagulation, especially among patients with CKD.

Conflict of interest: None declared.



 
   References Top

1.
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;54:1121-6.  Back to cited text no. 1
    
2.
Kleinow ME, Garwood CL, Clemente JL, Whittaker P. Effect of chronic kidney disease on warfarin management in a pharmacist-managed anticoagulation clinic. J Manag Care Pharm 2011;17:523-30.  Back to cited text no. 2
    
3.
Limdi NA, Beasley TM, Baird MF, Goldstein JA, McGwin G, Arnett DK, et al. Kidney function influences warfarin responsiveness and hemorrhagic complications. J Am Soc Nephrol 2009;20:912-21.  Back to cited text no. 3
    
4.
De Aquino Moura KB, Prates Behrens PM, Pirolli R, et al. Anticoagulant-related nephro-pathy: Systematic review and meta-analysis. Clin Kidney J 2019;12:1-8.  Back to cited text no. 4
    
5.
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:e57661.  Back to cited text no. 5
    
6.
Brodsky SV. Anticoagulants and acute kidney injury: Clinical and pathology considerations. Kidney Res Clin Pract 2014;33:174-80.  Back to cited text no. 6
    
7.
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: F1421-7.  Back to cited text no. 7
    
8.
Di Maso V, Carraro M, Bevilacqua E, Bucconi S, Artero ML, Boscutti G. Warfarin-related nephropathy: Possible role for the warfarin pharmacogenetic profile. Clin Kidney J 2014;7:605-8.  Back to cited text no. 8
    

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Correspondence Address:
Kee Tat Lee
Department of Medicine, Hospital Pulau Pinang, Pulau Pinang
Malaysia
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DOI: 10.4103/1319-2442.308356

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