Myocardial Infarction Enhances Progressive Renal Damage in an Experimental Model for Cardio-Renal Interaction

Abstract

Abstract. Studied were the effects of myocardial infarction (MI) on mild renal function loss in unilateral nephrectomized (UnX) rats. UnX was performed, followed after 1 wk by a variable MI (UnX ϩ MI; n ϭ 24). Rats with only UnX (n ϭ 15) or MI (n ϭ 9) and double sham animals (CON, n ϭ 15) served as controls. Renal outcome was measured by proteinuria and plasma creatinine. Focal glomerulosclerosis (FGS) incidence was evaluated by renal histology. Cardiac function and systolic BP were measured. A division into small and large infarcts after UnX was made a priori, resulting in two groups, one with a mild MI (Ͻ20%; n ϭ 15) and one with a moderate MI (Ͼ20%; n ϭ 9). Mild proteinuria up to 55.5 mg/d was observed in the UnX ϩ mild MI group, whereas proteinuria rose significantly higher to 124.5 mg/d in the UnX ϩ moderate MI group. Incidence of FGS was significantly increased in both UnX ϩ MI groups compared with all other groups. The average MI size was 18%, 17%, and 25% in the MI, UnX ϩ mild MI, and UnX ϩ moderate MI group, respectively. LVP in both UnX ϩ MI groups was correlated with proteinuria, indicative of a cardio-renal interaction. Clinically, these data imply that more patients are at risk for cardiovascular events and that after such an event, their chance of more renal function loss increases. Finding the underlying mechanism will enable improved protection for both kidneys and heart. Recent data from clinical studies have fueled the interest in the interaction between kidney and heart, and in particular the interaction between progressive function loss of both organs. The effect of renal impairment on cardiovascular function has been demonstrated in various studies. Patients with mild to severe renal insufficiency, including those patients starting renal replacement therapy, show an increased prevalence of cardiovascular disease (1-3), and Mann et al. (4) showed that impaired renal function increases the risk of cardiovascular events in the HOPE trial. Hillege et al. (5) found that impaired renal function is a stronger predictor of mortality than impaired cardiac function in advanced chronic heart failure. In addition, microalbuminuria is an independent risk factor for cardiovascular disease (6 -9). Although the mechanism behind the association between compromised renal function and the increased risk for cardiovascular disease remains unknown, it does not appear to involve common risk factors such as hypertension, diabetes, or hyperhomocystinemia (10). Although the effects of renal function impairment on cardiovascular mortality and morbidity have been extensively studied, it is unknown whether the opposite is also true-that is, whether cardiac function affects the outcome of mild renal function loss.The aim of the study presented here was to investigate whether cardiac damage could aggravate a mild state of chronic renal function loss. For this purpose, we used the rat model of unilateral nephrectomy (UnX) as this model shows a very mild state of chronic, mild renal function loss. In this model we introd...

Renal Damage after Myocardial Infarction Is Prevented by Renin-Angiotensin-Aldosterone-System Intervention

“…This study confirms our previous finding that MI induces enhanced progressive renal damage in unilateral nephrectomized rats (11). This detrimental cardiorenal interaction can be attenuated by treatment with either an ACE inhibitor or a VPI, with substantial beneficial effects on kidney and heart.…”

“…In our previous study, we found a trend toward a decrease in natriuretic peptide levels in the group with combined cardiac and renal damage, whereas in the group with only cardiac damage, higher levels were observed (11). From this observation, we hypothesized a role for natriuretic peptides in the deteriorating effect of the cardiorenal interaction.…”

“…At week Ϫ2, all 75 rats underwent right unilateral nephrectomy under anesthesia with 2.0% isoflurane in N 2 O/O 2 (2:1) as described previously (11). At week 0, rats were intubated, ventilated (AIV, Hoek Loos, The Netherlands), and anesthetized using 2.0% isoflurane in O 2 .…”

“…Impaired cardiac function is detrimental to the kidney (cardiorenal interaction), which is less well characterized and only in experimental settings. Recently, we described enhanced progressive renal damage in a model of cardiorenal interaction that was elicited by myocardial infarction (MI) in unilaterally nephrectomized rats (11). The mechanism of this cardiorenal interaction is unclear, but candidate mechanisms are hormonal systems such as the renin-angiotensin-aldosterone-system (RAAS) and the natriuretic peptide system (11).…”

“…Recently, we described enhanced progressive renal damage in a model of cardiorenal interaction that was elicited by myocardial infarction (MI) in unilaterally nephrectomized rats (11). The mechanism of this cardiorenal interaction is unclear, but candidate mechanisms are hormonal systems such as the renin-angiotensin-aldosterone-system (RAAS) and the natriuretic peptide system (11). Both angiotensin-converting enzyme inhibition (ACEi) and neutral endopeptidase (NEP) inhibition (although controversial) have been shown to be protective in progressive function loss of either the kidney or the heart (12)(13)(14)(15).…”