Anticoagulant-Related Nephropathy in Kidney Biopsy: A Single-Center Report of 41 Cases

Abstract

Rationale & Objective In 2009, the first case of acute kidney injury and occlusive red blood cell (RBC) tubular casts associated with a high international normalized ratio in a patient receiving warfarin was identified. This entity, named warfarin-related nephropathy, was later renamed anticoagulant-related nephropathy (ARN) after similar cases with other anticoagulants were described. We provide our 10-year experience with ARN based on a single-center kidney biopsy laboratory. Study Design The kidney pathology database at the Ohio State University Wexner Medical Center (OSUWMC) was searched for native kidney biopsy cases consistent with ARN. Clinical data were obtained from patient medical records. Setting & Participants Native kidney biopsies evaluated between January 1, 2009, and December 31, 2017 at OSUWMC. Results Among 8,636 native kidney biopsies reviewed at the OSUWMC, there were 41 (0.5%) patients for whom deterioration in kidney function could not be explained by kidney biopsy findings alone if anticoagulation was not considered. There were 63% men and 95% were white; average age was 62 ± 14 years. Most were on warfarin therapy (N = 28), although cases were also attributed to direct-acting anticoagulants (N = 2), antiplatelet medications (N = 1), heparin or enoxaparin (N = 4), and disseminated intravascular coagulopathy (N = 6). Morphologically, there was acute tubular necrosis and RBC casts. The majority of biopsies had an underlying glomerular disease and many patients had positive serologic test results. In all these cases, the severity of kidney failure, RBC tubular casts, and hematuria were disproportionate to glomerular morphologic changes. Limitations Selection bias in the decision to perform a kidney biopsy. Conclusions ARN is an uncommon diagnosis in kidney pathology practice, but it should be considered when the number of RBC tubular casts is disproportionate to the severity of glomerular changes in a kidney biopsy in patients either receiving anticoagulation therapy or who presented with acute coagulopathy. Our data suggest that anticoagulation aggravates underlying glomerular diseases rather than directly affecting the glomerular filtration barrier.

Role of glomerular filtration rate‐modifying drugs in the development of anticoagulant‐related nephropathy

“…Pauci‐immune crescentic necrotizing glomerulonephritis was seen in 20% of patients. Only 10% of patients had FSGS and 5% of patients had diabetic glomerulosclerosis (Brodsky et al, 2019). It appears that only two latter kidney diseases had some changes in the GFR, whereas the majority of patients with ARN had a glomerular injury that is related either to immune complexes or other etiologies (ANCA‐associated pauci‐immune crescentic glomerulonephritis).…”

“…However, we demonstrated that the effects of dabigatran on the kidney in regards to the ARN development in rats are similar to those of warfarin (Ryan et al, 2014). Also, dabigatran‐associated ARN currently is the most commonly reported after warfarin‐induced ARN in humans, indicating the importance to investigate anticoagulation with dabigatran (Brodsky et al, 2019). With the development of direct oral anticoagulants (one of those is dabigatran), the proportion of warfarin‐treated patients is decreasing (Wu et al, 2020).…”

“…Anticoagulant-related nephropathy (ARN) has been described over 10 years ago as a complication of anticoagulation therapy first with warfarin and later with dabigatran and other anticoagulants (Brodsky et al, 2009(Brodsky et al, , 2019. An animal model that shows similar kidney funcion changes and morphologic findings as in human ARN was developed (Ozcan et al, 2012;Ware et al, 2011).…”

“…Based on our constantly gaining experience with renal biopsy cases of ARN in humans, different underlying kidney diseases are seen in patients who developed ARN. They include focal segmental glomerular sclerosis (FSGS), diabetic nephropathy, mild immune complex depositions in the glomeruli or glomerular basement membrane abnormalities (Brodsky et al, 2009(Brodsky et al, , 2019. Broad pathologic mechanisms lead to these diseases, but glomerular hyperfiltration/hyperperfusion is seen in many forms of chronic kidney disease, including secondary FSGS, hypertensive nephrosclerosis, and diabetic nephropathy (Apakkan Aksun et al, 2003;Nyberg et al, 1994;Reiser et al, 2014;Savin et al, 2003;Srivastava, 2006).…”

Warfarin: A double-edged sword

“…[4] Preexisting chronic kidney disease (CKD) doubles the incidence of WRN, 33% in CKD and 16.5% in non-CKD population. [56] Out of nine patients analyzed by them, four patients had a complete renal recovery, four became dialysis-dependent, and one developed CKD with no improvement in kidney function 2 months after biopsy. [4]…”