Sex‐linked differences in the course of chronic kidney disease and congestive heart failure: a study in 5/6 nephrectomized Ren‐2 transgenic hypertensive rats with volume overload induced using aorto‐caval fistula

The role of hypertension and the renin‐angiotensin system (RAS) in sex‐related differences in the course of chronic kidney disease (CKD) and congestive heart failure (CHF) remain unclear, especially when the two diseases are combined. In male and female Ren‐2 transgenic rats (TGR), a model of hypertension with activation of endogenous RAS, CKD was induced by 5/6 renal mass reduction (5/6 NX) and CHF was elicited by volume overload achieved by creation of an aorto‐caval fistula (ACF). The primary aim of the study was to examine long‐term CKD‐ and CHF‐related mortality, especially in animals with CKD and CHF combined, with particular interest in the potential sex‐related differences. The follow‐up period was 23 weeks after the first intervention (5/6 NX). We found, first, that TGR did not exhibit sexual dimorphism in the course of 5/6 NX‐induced CKD. Second, in contrast, TGR exhibited important sex‐related differences in the course of ACF‐induced CHF‐related mortality: intact female TGR showed higher survival rate than male TGR. This situation is reversed in the course of combined 5/6 NX‐induced CKD and ACF‐induced CHF‐related mortality: intact female TGR exhibited poorer survival than male TGR. Third, the survival rate in animals with combined 5/6 NX‐induced CKD and ACF‐induced CHF was significantly worsened as compared with rat groups that were exposed to ‘single organ disease’. Collectively, our present results clearly show that CKD aggravates long‐term mortality of animals with CHF. In addition, TGR exhibit remarkable sexual dimorphism with respect to CKD‐ and CHF‐related mortality, especially in animals with combined CKD and CHF.