The Severe Cardiorenal Syndrome

Abstract

In this thesis we investigated the interactions between heart and kidneys in disease in a longitudinal and integrative fashion. We developed two different rat models of the Severe Cardiorenal Syndrome and studied the effects of different interventions on progression of cardiorenal failure and on structural and functional outcome. In Part I we propose the Cardiorenal Connection (CRC) as a pathophysiological model in which the cardiorenal connectors interact and synergize to cause accelerated cardiovascular damage in the SCRS. The connectors are: (1) an imbalance between nitric oxide (NO) and reactive oxygen species (ROS), (2) activation of the sympathetic nervous system (SNS) (3) activation of the renin-angiotensin system (RAS), and (4) induction of inflammation. In Part II we describe the development of a model of combined chronic kidney disease (CKD) and heart failure (HF), and found evidence of bi-directional organ damage and the effect of interventions targeted at the CRC. We found that pre-existent CKD aggravated cardiac dilatation after MI that was associated with worsened cardiac diastolic and systolic function, and mortality. Conversely, the ensuing HF exacerbated glomerular damage in CKD rats, which was not associated with worsening of creatinine clearance or proteinuria. Blockade of all cardiorenal connectors with angiotensin receptor blockade and beta-blockade, systemic supplementation of NO, and anti-oxidant and anti-inflammatory therapy had significant beneficial effects on cardiorenal outcome: cardiac systolic function was preserved, glomerular damage was ameliorated, and tubulointerstitial damage was almost completely reversed. Blockade of 3 or 1 cardiorenal connectors resulted in a similar upholding of systolic function but had less effect on renal injury. We further described increased cardiac hepcidin expression in rats with SNX or CL, as well as in the combination. In contrast, liver hepcidin expression was not affected by both single insults but down-regulated in combined SNX and CL. Part III describes investigations into the role of nitric oxide (NO) in cardiac dysfunction in CKD. Low dose NO synthase (NOS) inhibition during CKD induced worsened proteinuria, severe cardiac dysfunction and reduced systemic NO production as compared to rats with CKD alone and controls treated with a similar dose of NOS inhibition. Furthermore, the increased protein excretion, the cardiac dysfunction and the low NO production after cessation of NOS inhibition. The mild hemodynamic effects of low dose NOS inhibition observed in controls were fully reversible. The findings of the previous study strongly suggested a causal link between NO availability and cardiac function. We investigated the effect of systemic NO supplementation with the tolerance-free NO donor molsidomine (MOLS) as a rescue therapy. MOLS significantly improved diastolic and systolic heart function, with mild effects on cardiac loading conditions and LVH, and no effects on cardiac fibrosis. Creatinine clearance and tubulo-interstitial injury improved, but no effect was seen on proteinuria. Expression of nNOS was increased compared to controls in this model of the SCRS. We assessed the effect of selective nNOS blockade in baseline and under beta-adrenergic stimulation and found that nNOS derived NO supports diastolic relaxation in CRS rats, but does not modulate the impaired beta-adrenergic response