Role of glomerular filtration rate-modifying drugs in the development of anticoagulant-related nephropathy.

INTRODUCTION: Anticoagulant-related nephropathy (ARN), that was described in humans first as warfarin-related nephropathy, is characterized by acute kidney injury and red blood cell (RBC) tubular casts in the kidney. 5/6 nephrectomy (5/7NE) rats treated with warfarin or dabigatran show changes in kidney function and morphology that are similar to human disease. The role of glomerular filtration rate (GFR) in the pathogenesis of ARN is not clear. The aim of these studies was to elucidate the role of GFR in the pathogenesis of dabigatran-induced ARN in 5/6NE rats. METHODS: 5/6NE rats were treated per os with 150 mg/kg/day dabigatran alone or with drugs that lower (enalapril, 1.5 mg/kg/day) or increase (albuterol, 4.0 mg/kg/day) GFR for 7 days. Changes in coagulation and kidney function were recorded daily. Kidney morphology was evaluated on day 7 after the treatment. RESULTS: Dabigatran resulted in activated partial thromboplastin time increase that was not affected by GFR-modifying drugs. Blood pressure was significantly lower in 5/6NE rats treated with enalapril and dabigatran as compared to dabigatran alone. The GFR was decreased by 35% in enalapril/dabigatran- and increased by 26% in albuterol/dabigatran-treated animals. There were no changes in serum creatinine, hematuria or urinary kidney injury molecule (KIM-1) levels when GFR-modifying drugs were added to dabigatran. All dabigatran-treated animals had RBC casts in the kidney regardless of the GFR modification. CONCLUSIONS: GFR does not play a significant role in the dabigatran-induced acute kidney injury in 5/6 nephrectomy model in rats. Based in these data, modification of GFR in patients with ARN is not warranted.

An unexpected paradox: wall shear stress in the aorta is less in patients with severe atherosclerosis regardless of obesity.

BACKGROUND: Obesity is a widespread condition that is more prevalent in Western countries compared to others. Aortic atherosclerosis (AA) is a condition that frequently has been associated with obesity. An obesity paradox, where morbidly obese decedents had either no or minimal AA compared to nonobese decedents, recently has been described by some of us. The explanation for this almost counterintuitive paradox has yet to be determined, but a number of hypotheses were advanced, including hemodynamic factors producing aortic wall shear stress (WSS). The purpose of the present study was to determine if there was a relationship between AA and WSS, as determined by postmortem measurement of aortic wall diameters. METHODS: Circumferences of the aorta at the levels of the ascending, thoracic and abdominal aorta were measured in 274 consecutive autopsies over 2-year period of time. AA was assessed using a previously described grading scale as either mild or severe. Circumferences were mathematically converted to diameters and WSS was calculated using the Hagen-Poiseuille formula. Two different methods to estimate cardiac output were used, both based on literature methods, one of which was body mass index (BMI) dependent, and the other BMI independent. Univariate and multivariable analyses of the relationship between WSS, age, BMI, gender, race and severity of AA were performed. RESULTS: Of the 274 decedents, 140 had mild and 134 had moderate to severe AA. BMI <35 was associated with moderate to severe AA. WSS was inversely correlated with AA in all these segments of the aorta in each BMI subgroup with the exception of the ascending aorta for decedents with BMI ≤35 kg/m2. Contrary to what we had hypothesized, WSS was not a determinant of the obesity paradox. However, among all the variables analyzed, a history of hypertension, diabetes mellitus and age were significant factors for developing AA (relative risk [RR] 0.35, P = .039; RR 1.51, P = .0006, RR 1.19, P = .0001, respectively). CONCLUSIONS: Our data demonstrate that WSS was unexpectedly lower in decedents with moderate and severe AA as compared to those with mild AA. This observation, which requires further investigations, was seen in all BMI ranges and was confirmed by 2 methods to calculate WSS.

Anticoagulant Related Nephropathy Only Partially Develops in C57BL/6 Mice: Hematuria Is Not Accompanied by Red Blood Cell Casts in the Kidney.

Anticoagulant-related nephropathy (ARN) may develop in patients that are on anticoagulation therapy. Rats with 5/6 nephrectomy treated with different anticoagulants showed acute kidney injury (AKI) and red blood cell (RBC) casts in the tubules similar to ARN in humans. The aim of the current study was to investigate the feasibility of inducing ARN in mice. C57BL/6 5/6 nephrectomy mice were treated with warfarin and dabigatran 3 weeks after ablative surgery for 7 days. Two doses of each anticoagulant were used. All anticoagulants resulted in serum creatinine and hematuria increase. Mortality was 63% in 5.0 mg/kg/day of warfarin but only 13% in 2.5 mg/kg/day of warfarin or in 400 mg/kg/day of dabigatran and 0% in 200 mg/kg/day of dabigatran. In spite of increasing hematuria, RBC tubular casts were not seen in mice treated with any anticoagulant. The 5/6 nephrectomy murine model in C57BL/6 mice only partially reproduced ARN in terms of increasing serum creatinine and hematuria, but there were no RBC tubular casts in the remnant kidney.