6th October 2019. Dr Chee L Khoo
Traditionally, warfarin was the main anticoagulant for stroke prevention in patients with atrial fibrillation and in patients with significant valvular disease. The newer direct oral anti-coagulants (DOACs) are now the main anti-coagulants used instead of warfarin. However, a common limiting factor in the use of the DOACs is renal impairment. We still have come back to good old warfarin in patients whose eGFR is near 30 mL/min/1.73 m2. However, a relatively new entity, warfarin related nephropathy is increasingly being recognised.
The concept of warfarin-related nephropathy was first described by Brodsky et al in 2009 (1). They described acute kidney injury among patients on warfarin therapy associated with biopsy-proven obstructive tubular red blood cell casts. In a retrospective analysis of 1500 patients on warfarin, amongst patients who had an INR > 3.0, 33% of patients with known chronic kidney disease developed warfarin-related nephropathy compared with 16% of patients who did not have chronic kidney disease (2).
In a novel experiment, Ware etal6 found that in rats which underwent a 5/6 partial nephrectomy and received warfarin, increased prothrombin time was associated with significant increase in serum creatinine. Increased prothrombin time in control rats with normal kidneys did not result in serum creatinine levels. It was postulated that renal damage occurred from glomerular haematuria due to occlusive red blood cell casts, which in turn led to acute tubular injury (3).
Research on the mechanism of anticoagulant- related nephropathy is still evolving. It is thought that complex interactions involving heme molecules cause a cascade of oxidative stress and inflammation of the renal tubular epithelium and surrounding interstitium. Anticoagulant-related nephropathy is impacted by a decrease in the number of nephrons. Over-proliferation of the surviving glomeruli and glomerular hypertension render them vulnerable to glomerular haemorrhage (4,5)
Warfarin is not the only anti-coagulant implicated in nephropathy. If heme is involved, the DOACs might also be implicated. Indeed, dabigatran have been reported to “dose-dependent increase in serum creatinine and haematuria in both control groups and 5/6 nephrectomy rats.” (6). Brodsky et al (2017) described a case of apixaban-induced acute kidney injury. Kidney biopsy showed numerous occlusive red blood cell casts, acute tubular necrosis, and red blood cells filling Bowan’s space in multiple glomeruli— the hallmark for anticoagulant-related nephropathy (7).
In the ARISTOTLE trial, amongst patients randomised to apixaban, worsening of eGFR was seen in 20% of patients (8).
Because the DOACs are also implicated, warfarin-related nephropathy is now renamed anti-coagulant nephropathy. Patients with anticoagulant-related nephropathy have had various degrees of renal recovery. Some can achieve normal kidney function, though, unfortunately, most patients require haemodialysis. While it is unclear what the true number of patients is who go on to haemodialysis, one study reported that as many as 66% were dialysis dependent (1).
As the use of anti-coagulants are increasing and most of these patients are managed in primary care, anti-coagulant nephropathy is an important entity to remember.
References:
- Brodsky SV, Satoskar A, Chen J, et al. Acute kidney injury durin gwar farin therapy associated with obstructive tubular red blood cell casts: a report of 9 cases. Am J Kidney Dis. 2009;54 (6):1121-6.
- 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.
- Ware K, Brodsky P, Satoskar AA, et al. Warfarin-related nephropathy modelled by nephron reduction and excessive anticoagulation. J Am Soc Nephrol. 2011;22 (10):1856-62.
- Brodsky SV, Eikelboom J, Hebert LA. Anticoagulant-related nephropathy. J Am Soc Nephrol. 2018;29 (12):2787-93.
- Parikh SV, Haddad NJ, Hebert LA. Retarding progression of kidney disease. Comprehensive Clinical Nephrology Philadelphia: Elsevier. 2014: 931-47.
- Ryan M, Ware K,Qamri Z, et al. Warfarin-related nephropathy is the tip of the iceberg: direct thrombin inhibitor dabigatran induces glomerular haemorrhage with acute kidney injury in rats. Nephrol Dial Transplant. 2014;29 (12):2228-34.
- Brodsky SV, Mhaskar NS,ThiruveediS, et al. Acute kidney injury aggravated by treatment initiation with apixaban:another twist of anticoagulant-related nephropathy. Kidney Res Clin Pract. 2017;36(4): 387-92.
- Ryan M, Ware K, Qamri Z, et al. Warfarin-related nephropathy is the tip of the iceberg:direct thrombin inhibitor dabigatran induces glomerular haemorrhage with acutekidneyinjuryinrats. NephrolDialTransplant. 2014;29(12):2228-34.
- Thomas Oliver, Liann Abu Salman, Brandon Ciaudelli, David A. Cohen. Anticoagulation-Related Nephropathy: The Most Common Diagnosis You’ve Never Heard Of. The American Journal of Medicine (2019) 132:e631-e633