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.

            Anticoagulant-related nephropathy (ARN) just might be the most common kidney problem that clinicians have never seen. Here is the story of its emergence and why it deserves attention.

ARN is a recently discovered cause of AKI and possibly, progressive CKD as well. It occurs in patients receiving oral anticoagulant therapy, namely warfarin or a novel oral anticoagulant (NOAC; either a direct thrombin inhibitor or a factor Xa inhibitor). The first reports of ARN involved two unrelated cases in which the patients experienced unexplained AKI and gross hematuria while receiving warfarin. After reversal of their international normalized ratio (INR), which was in the INR=range at presentation, the patients underwent renal biopsy, which showed unexplained profuse glomerular haemorrhage.

The glomeruli, however, were unremarkable, except for idiopathic thin glomerular basement membrane (GBM) in one patient and idiopathic thick GBM in the other patient. As we previously reported, patients with abnormally thin or abnormally thick GBM (and no other glomerular abnormalities) can experience bouts of spontaneous gross hematuria. We reasoned that the AKI in these herald patients would likely be a rare occurrence, because it would require the concurrence of an extremely high INR in a patient with an unusual GBM abnormality.

One key question is whether all patients who receive chronic anticoagulant therapy are susceptible to ARN. Although supra therapeutic anticoagulation seems to be essential to inducing ARN, it is likely that a second factor is required. That second factor seems to be either a substantially reduced number of nephrons (resulting in over perfusion of the surviving glomeruli and glomerular hypertension that renders them vulnerable to glomerular hemorrhage or acute damage to the glomeruli, allowing the glomeruli to bleed profusely under conditions of over anticoagulation.

CONCLUSION

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