Warfarin Related Kidney Damage: A Confusing Case of Thrombophlebitis Masquerading as Infection

Abstract

Anticoagulant-related nephropathy (ARN) is a rare, newly recognized cause of acute kidney injury and significant but underdiagnosed complication of anticoagulation therapy. ARN occurs in patients taking oral anticoagulant therapy most often warfarin or a novel oral anticoagulant (NOAC). It is a potentially devastating disorder with serious renal consequences and increased all-cause mortality. Anticoagulant-related nephropathy presents as an acute kidney injury (AKI) in the setting of a supratherapeutic INR with profuse glomerular hemorrhage seen as renal tubules filled with red cells and red cell casts on renal biopsy. Being that millions of Americans are on warfarin, a thorough understanding and awareness of the clinical presentation, diagnosis, and therapeutic interventions are crucial to protecting the renal function, lowering all-cause mortality and optimizing treatment. Our goal is to provide education on a newly recognized form of AKI and significant but underdiagnosed complication of anticoagulation therapy.

Case Presentation

Seventy-eight-year-old gentleman on chronic anticoagulation with warfarin for past medical history significant of three previous venous thromboses (DVT), hypertension, diabetes, and hypercholesterolemia presented to his outpatient primary care physician with one week of progressive right lower extremity erythema, edema, pain and low grade temp of 99F. He described the progressive right lower extremity erythema as initially localized around his knee and distal thigh that expanded to his proximal thigh and groin within 72 hrs. He denied weakness, calf pain, fever, chills, or other signs of systemic inflammation. On physical examination, he had tense, non-pitting edema and erythema from 10 cm distal to the right knee to 5 cm distal to the inguinal fold that was blanchable, warm, and tender to palpation. No open lesions, skin breakdown, posterior calf, or popliteal fossa tenderness. Labs were significant for elevated WBC 15.5 × 10⁹/L, with neutrophilic predominance, creatinine 0.96 mg/dL (baseline) and elevated International Normalized Ratio (INR) of 6.6. Outpatient differential included lymphangitis, cellulitis, or deep vein thrombosis (DVT). Based on lab findings and physical exam, lymphangitis was declared as the primary diagnosis and he was treated with 1 g IM Ceftriaxone during his office visit and prescribed a 10 day course of sulfamethoxazole-trimethoprim 800 to 160 mg and Cefadroxil for 10 days. Of note, 2 weeks prior to presentation of his right lower extremity edema and erythema, he underwent a laparoscopic bilateral inguinal hernia repair with mesh and umbilical hernia repair without mesh and had admitted to being less mobile due to the abdominal discomfort which explains the DVT as it was likely provoked preceding the supratherapeutic INR.

Two days after outpatient assessment, he was admitted to the hospital for worsening right lower extremity edema and erythema with suspected failed outpatient treatment. Initial labs on admission showed an AKI with serum creatinine of 12.88 mg/dL (baseline 0.9 mg/dL), gross hematuria, dysmorphic red blood cells, and significant proteinuria consistent with an acute glomerular nephritis. His hemoglobin had dropped to 6.7 g/dL and his INR was supratherapeutic at 6.9. Bilateral lower extremity ultrasound showed acute deep vein thrombosis (DVT) involving the right gastrocnemius, soleal veins and acute occlusive superficial venous thrombosis (SVT) within the right great saphenous vein (GSV) extending from the mid-calf to within approximately 1.25 cm of the sapheno-femoral junction (SFJ). He was admitted for inpatient treatment.

Further investigation for causes of his acute glomerular nephritis, supratherapeutic INR, AKI, and DVT included C3, C4, ANCA, thrombophilia panel + anticardiolipin IgG/IgM + beta 2 glycoprotein IgG/IgM, ANCA panel, ANA, CK, SPEP, free light chain kappa/lambda, and PNH PI-Linked Antigen were all within normal limits. Based on aforementioned diagnostic findings and lack of alternative explanation for his AKI, gross hematuria and proteinuria, anticoagulation related nephropathy secondary to decreased renal function from outpatient antibiotic regimen, was declared as the cause.

With transitioning his antibiotic regimen to less nephrotoxic alternatives, amoxicillin/clavulanic acid and doxycycline, and administering IV fluids, his creatinine improved significantly within the first 48 h from 12.88 to 2.89 mg/dL. While renal function improved, warfarin was held in the setting of gross hematuria and unstable hemoglobin that required 3 blood transfusions with pRBCs. Vascular medicine was consulted and did not recommend reversal of his INR as there is no evidence that rapid reversal of INR improves outcomes of ARN. With the new antibiotic regimen, improved renal function and holding warfarin, his INR returned to therapeutic range, his Hg stabilized, and he met criteria for discharge with outpatient nephrology follow up. Please see Figure 1 for correlation.

Figure 1.

Showing the correlation between the INR and creatinine progress as the warfarin was held over time.

Discussion

Prompt recognition of ARN is critical, as it is associated with accelerated progression of chronic kidney disease, and significantly increased short-term and long-term all-cause mortality. ¹

ARN is currently defined as AKI without obvious etiology in the setting of an (INR) of >3.0. In the few previously diagnosed cases of ARN, renal biopsies were done to confirm diagnosis. However given the risk of renal biopsies in the setting of an elevated INR, the diagnosis of ARN no longer relies on demonstration of these characteristic pathologic lesions. The underlying molecular mechanism is thought to be warfarin-induced thrombin depletion; however, newer studies have hinted at an alternative mechanism involving reductions in activated protein C and endothelial protein C receptor signaling. ¹

When considering alternative anticoagulation options in the setting of warfarin induce nephropathy and a medically indicated need for prolonged anticoagulation DOAC’s have a less studied consequential reaction on renal function in the setting of decreased surveillance. Differences in the incidence and severity of ARN between patients taking warfarin and those taking novel oral anticoagulants are unknown; a post hoc analysis of routinely reported adverse renal outcomes in clinical trials comparing warfarin and novel oral anticoagulants found no significant difference in the rates of AKI, a prerequisite for ARN. ²

Take Home Message

Anticoagulation-related nephropathy is an often-missed diagnoses that should be considered in the differential diagnosis of any patient receiving anticoagulation with a recent INR of >3.0 presenting with AKI ± hematuria. Presently, the treatment of ARN is supportive and includes returning the INR to a therapeutic range. There is no evidence that rapid reversal of INR limits kidney injury, however it is logical to assume that prolonged periods of INR elevation will result in continued glomerular hemorrhage and additional kidney tubular damage. The best approach to ARN is prevention and early detection. Anticoagulation levels and renal function should be monitored periodically in all patients receiving anticoagulation therapy. Lastly, as warfarin has a number of drug-drug interactions that can cause elevated INRs, close monitoring whenever new medications or other medical interventions are started is essential, especialy when using medications such as trimethoprim-sulfamethoxazole. In antibiotic associated nephritis, typically patients present with rash, fever, and eosinophilia, none of which our patient experienced. Antibiotic associated nephritis is important to consider in patients presenting with anticoagulation-related nephropathy and physical examination, history, and renal biopsy can help further differentiate.