Acute kidney injury (AKI) in patients receiving vitamin K antagonist (VKA) therapy are at increased risk for excessive anticoagulation, according to a recent study published in Nephrology Dialysis Transplantation.

In a retrospective study, Luisa Süfling, MD, and colleagues at Martin-Luther-University Halle-Wittenberg, Germany, identified 100 patients with ongoing VKA therapy who experienced an episode of AKI. In 55 patients (55%), the anticoagulant dose had to be modified or discontinued when AKI occurred. Bleeding complications occurred in 24 patients (24%).

Results showed that 73% of the patients experienced an increase in the international normalized ratio (INR) value during AKI when compared with a reference time point with better renal function.

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On multivariable analysis, female gender, a body mass index below 25 kg/m2, and diabetes mellitus were significantly associated with a particularly elevated risk for overanticoagulation. Older age, chronic heart or liver disease, or preexisting chronic kidney disease did not influence this risk.

“With this study we describe for the first time that acute deterioration of kidney function in patients treated with VKA is associated with a high risk of overanticoagulation,” the investigators wrote.

Causality Not Demonstrated

The study is limited by its respective design, so it is not possible to show causality between AKI and overanticoagulation in VKA-treated patients, the authors wrote. Even though their study is the largest to examine this issue, the case series is quite small, and “we cannot provide pharmacokinetic measurements to confirm the suggested mechanisms. In spite of these limitations, our series may provide grounds for further research and highlight a relevant risk in everyday therapy that is worth being considered when caring for patients with AKI.”

The study population had a mean age of 75.4 years, with more men than women (56% vs 44%). All patients received anticoagulation therapy with phenprocoumon.

Among the 100 patients, AKI was attributed to prerenal volume depletion (43 patients), septic renal failure (22 patients), decompensated heart failure (18 patients), toxic renal damage (11 patients), postrenal obstruction (3 patients), and primary renal disease (3 patients).

Among the 100 patients, 54 patients had INR values above the recommended therapeutic range for their indication at diagnosis of AKI. The findings suggest that much greater attention may be warranted when it comes to coagulation parameters in patients with VKA who also have AKI.

Better Surveillance Needed

“There is no recommendation for dose adjustment of vitamin K antagonists due to kidney impairment, yet patients with AKI and anticoagulation have a higher risk for intracerebral bleedings,” said Jochen Reiser, MD, PhD, professor and chairman of medicine at Rush University in Chicago, Illinois. “The paper brings up a good point, which is the [need for] better surveillance of drugs metabolized in the liver yet influenced by kidney function, for example by affecting plasma protein binding and thus increasing the drug effects.”

Although the analysis was well done, it is not conclusive in part because of the inclusion of a small number of patients, he said, adding that the authors raise an important clinical question about when should anticoagulation drugs be adjusted with high protein binding in situations with impaired kidney function. “This certainly raises awareness, but due to its retrospective nature, its single center set up with [a] small sample size is prone for selection bias and thus not necessarily representative of the general population. It needs to be interpreted with caution,” Dr Reiser said.

Platelet Dysfunction a Possibility

Although causality between higher INR and more bleeding cannot be inferred based on the study’s findings, platelet dysfunction could explain differences in the observed bleeding complications, he said. “The effect of INR measuring and adjustment of anticoagulation into the therapeutic range would need to be studied in a larger, multi-center, randomized, controlled and blinded trial set up to study the relevant outcomes,” Dr. Reiser said. “I do think the paper establishes a need for a more definitive study but at present is not set up or powered to change clinical practice.”

Panduranga Rao, MD, a professor of internal medicine in the department of nephrology at the University of Michigan in Ann Arbor, said the study is clinically relevant because it highlights that clinicians need to monitor for the toxicity of certain drugs patients might be taking at AKI onset. “If one looks at postulated mechanisms, such as inhibition of [the] CYP system of enzymes responsible for drug metabolism in the presence of retained uremic toxins, these observations seem viable,” Dr Rao said.

Anand Srivastava, MD, MPH, assistant professor of medicine in the division of nephrology and hypertension at Northwestern University Feinberg School of Medicine in Chicago, Illinois, said the new study draws attention to an often discussed clinical conundrum about the optimal approach to managing drugs administered to patients with AKI, even if these drugs are classically not metabolized by the kidney.

“The study raises an important issue regarding the management of anticoagulation in patients who develop AKI,” Dr Srivastava said. “An important next step is to figure out why patients who develop AKI are at risk for higher INR values. While the study offers some suggestions, additional studies are needed to determine if these findings are related to changes in dietary patterns, administration of other medications, or another reason that may affect the metabolism of VKA in the setting of AKI.”


Süfling L, Greinert D, Girndt M, et al. Risk of over-anticoagulation during acute kidney injury in patients treated with vitamin K antagonists. Published online January 18, 2021. Nephrol Dial Transplant.  doi:10.1093/ndt/gfab008