Warfarin related nephropathy in human and experimental animals Sergey Brodsky MD, PhD The Ohio State University, Columbus, OH, USA

 80 -year-old Caucasian male with nausea and vomiting. The baseline Scr was 1.1 mg/dl, but it was 3.9 mg/dl on presentation. Serologies, including ANA, ANCA and paraprotein were negative, complement levels were normal. Urinalysis showed hematuria and proteinuria. Patient was on warfarin therapy for atrial fibrillation. Shortly before the onset of nausea and vomiting, he had an episode of increased INR (5.2 IU). Kidney biopsy was performed after reversal of increased INR

 Warfarin related nephropathy – WRN. Key features of WRN in this cohort:  AKI: Scr 4.3  0.8 mg/dl, baseline 1.3  0.3 mg/dl.  At presentation with AKI, the INR was above the therapeutic range (4.4  0.7)  Kidney biopsy:  acute tubular injury  glomerular hemorrhage (RBC in the Bowman’s space and numerous occlusive RBC casts in tubules).  An underlying kidney disease (mild glomerular immune complex deposits, FSGS, thickened GBM). Outcome: six of nine patients did not recover from AKI

 103 CKD on warfarin therapy with serial measures of INR and SC.  Of these, 49 patients experienced at least one INR>3.0 and had Scr measured before and after the INR.3.0.  18 of these patients (37%) had an unexplained increase in Scr>0.3 mg/dl associated with INR>3.0

WRN patients had increased mortality rate

Why such a common complication of warfarin therapy has been unrecognized until now? 1)We and others have reported single cases of AKI associated with severe warfarin coagulopathy. However, there was no compelling reason to believe that lesser degrees of warfarin coagulopathy could cause AKI. 2)WRN usually occurs early in the course of warfarin therapy. Therefore, at any given time, the prevalence of acute WRN among all warfarin-treated patients is relatively low. 3)WRN is particularly prevalent in patients at high risk for AKI. The presence of WRN was not easily recognized. 4)Nephrologists might be reluctant to perform kidney biopsy to evaluate AKI in patients who require warfarin. 5)Renal pathologists did not recognize WRN because of underlying kidney diseases. ATN and RBC casts were associated with those conditions.

61-y.o. Caucasian female with recently diagnosed DM. Baseline Scr normal. Presented to the hospital after episodes of diarrhea with Scr 3.2 mg/dl. She developed DVT and was started on warfarin. INR was as high as 5. Scr increased up to 6.6 mg/dl within 2 weeks. ANA (1:640), complement levels were normal. IgG

41-y.o. Caucasian female with aortic bifurcation thrombosis, post-bypass graft placement, on warfarin therapy. INR 27 (!). Baseline Scr 1.0 mg/dl, increased to 6.7 mg/dl. Gross hematuria with RBC casts. Complement levels normal. ANA, ANCA negative. Immunofluorescence – negative. Normal GBM thickness.

A B Scr did not increase in control Scr increased in 5/6 NE rats

Warfarin results in glomerular hemorrhage and RBC cast formation in 5/6 NE rats 5/6 nephrectomy rat Patient, WRN B

NAC prevented Scr increase in WRN but not RBC cast formation

Warfarin Glomerular hemorrhage RBC tubular casts ATN Direct effects Oxidative stress Vitamin K dependent

 Thrombin inhibitors (dabigatran etexilate)  Factor Xa inhibitors (rivaroxaban and apixaban). Novel anticoagulants

Dabigatran increases Scr in 5/6NE and results in RBC casts

 WRN may be a part of broader anticoagulant-related nephropathy (ACRN) and is a common (and often overlooked) complication of anticoagulant therapy. Evidence of AKI appears shortly after the INR acutely increases to >3.0. WRN occurs approximately in 33% (CKD) to 16% (no-CKD) of warfarin-treated patients whose INR acutely rises to >3.0. patients with WRN have increased mortality (one-year mortality rate 31.0% versus 18.9% in no-WRN patients). Studies are needed to evaluate different anticoagulants.  An underlying kidney condition is necessary to induce WRN (or ACRN). Coagulopathy may aggravate the existing condition (such as IgA nephropathy, etc) and increase glomerular hemorrhage.  In a kidney biopsy, WRN should be suspected If the patient is on an anticoagulation therapy, if there is a disproportion between the number of RBC tubular casts and the degree of underlying glomerular lesion (such as immune complex mediated GN, IgA nephropathy, etc).  WRN is reproducible in an animal model. Ablative nephropathy (5/6 nephrectomy) in rats mimics serum creatine changes and morphology seen in humans with CKD. Studies of other models of kidney diseases to reproduce WRN are needed. Conclusions:

The Ohio State University: Dr. Lee Hebert Dr. Brad Rovin Dr. Tibor Nadasdy Dr. Anjali Satoskar Dr. Haifeng Wu Kyle Ware New York Medical College Dr. Michael Goligorsky Dr. Jun Chen