Anticoagulant-Related Nephropathy

Abstract

Anticoagulant-related nephropathy (ARN) is a newly recognized form of AKI in which overanticoagulation causes profuse glomerular hemorrhage, which manifests on renal biopsy as numerous renal tubules filled with red cells and red cell casts. The glomeruli show changes, but they are not sufficient to account for the glomerular hemorrhage. We were the first to study ARN, and since then, our work has been confirmed by numerous other investigators. Oral anticoagulants have been in widespread use since the 1950s; today, >2 million patients with atrial fibrillation take an oral anticoagulant. Despite this history of widespread and prolonged exposure to oral anticoagulants, ARN was discovered only recently, suggesting that the condition may be a rare occurrence. This review chronicles the discovery of ARN, its confirmation by others, and our animal model of ARN. We also provide new data on analysis of "renal events" described in the post hoc analyses of three pivotal anticoagulation trials and three retrospective analyses of large clinical databases. Taken together, these analyses suggest that ARN is not a rare occurrence in the anticoagulated patient with atrial fibrillation. However, much work needs to be done to understand the condition, particularly prospective studies, to avoid the biases inherent in post hoc and retrospective analyses. Finally, we provide recommendations regarding the diagnosis and management of ARN on the basis of the best information available.

Keywords: chronic kidney disease; nephropathy; renal biopsy.

Figure 1.

Typical renal biopsy findings in warfarin-related nephropathy. Red blood cells (RBCs) in different compartments of the kidney in patients on warfarin therapy with acute kidney injury. (A) Numerous RBCs and RBC occlusive casts were noticed in tubules and Bowman space. (Hematoxylin and eosin stain; original magnification ×200). (B) Immunohistochemical stain for Tamm-Horsfall protein shows that most RBC casts do not contain Tamm-Horsfall protein. (Arrow) Positively-stained thick ascending loop of Henle. (C) Immunohistochemical stain for cytokeratin AE1/AE3 (arrows, dark brown) highlights distal tubules with occlusive RBC casts. (Counterstain with hematoxylin/eosin; original magnification ×200). (D) Dysmorphic RBCs were noticed in several tubules by means of electron microscopy. (Uranyl acetate, lead citrate stain; original magnification ×3000).

Figure 2.

Changes in serum creatinine (SC) levels associated with an international normalized ratio (INR) increase >3.0 IU in CKD with initial increase in SC that was either ≥0.3 mg/dl (upper curve) or <0.3 mg/dl (lower curve).

Figure 3.

Changes in serum creatinine levels associated with international normalized ratio (INR) increase ≥3.0 in patients whose initial serum creatinine change was either ≥0.3 mg/dl (upper curve) or <0.3 mg/dl (lower curve). In patients with CKD, 33% developed AKI. In patients with no CKD, 16.5% developed AKI. For the cohort as a whole, 20.5% developed AKI. WRN, warfarin-related nephropathy.

Figure 4.

Survival rate in patients with and without warfarin-related nephropathy (WRN). INR, international normalized ratio.

Figure 5.

Suggested management for the anticoagulated patients with atrial fibrillation whose kidney biopsy shows anticoagulant-related nephropathy (ARN). These recommendations pertain to both ARN that is AKI and ARN that is large chronic eGFR loss. NOAC, novel oral anticoagulant.