Deterioration of Renal Function by Chronic Heart Failure is Associated with Congestion and Oxidative Stress in the Tubulointerstitium

Abstract

OBJECTIVE: We examined the hypothesis that renal congestion is responsible for the decline in renal function in patients with heart failure (HF) via tubulointerstitial inflammation. METHODS: First, in a longitudinal study, we retrospectively examined the relationship between cardiac functions and the decline of renal function during a period of 6.4±3.2 years in 20 patients who had a left ventricular ejection fraction of <40% and an estimated glomerular filtration ratio (eGFR) of <60 mL/min/1.73 m(2). Second, we compared the renal histology in autopsy cases of HF-induced renal dysfunction (HF-RD), cases of nephrosclerosis (NSC) and cases of neither RD nor HF (controls) in a cross-sectional study. Third, we retrospectively examined renal function in HF patients with predominantly right, but not left, ventricular dysfunction. Results eGFR decreased at 9.4±4.6%/year in the cohort of the longitudinal study. The rate of eGFR decline was correlated with blood pressure and with diameter of the inferior vena cava (IVCd) (r=0.5) measured at the initial work-up. Multivariate analysis indicated that the IVCd is an independent determinant of decline of eGFR in HF. In the cross-sectional study, fibrosis, Rac1 expression, protein nitrosylation, and number of CD68-positive cells were increased in the tubulointerstitium in both cases of HF-RD and NSC. Peritubular capillaries in HF-RD were dilated by 35% without any change in density compared with those in the controls. In right sided HF, the reduction of IVCd after treatment was associated with improvement of eGFR. CONCLUSION: Venous congestion may contribute to HF-induced deterioration of renal function by augmenting oxidative stress-mediated inflammation in the tubulointerstitium.