Cardiorenal syndrome: Pathophysiology, preclinical models, management and potential role of uraemic toxins

Abstract

Cardiorenal syndrome (CRS) describes the primary dysfunction in either the kidney or heart that initiates the combined impairment of both organs. The heart and kidney exert reciprocal control of the respective function to maintain constant blood volume and organ perfusion under continuously changing conditions. The pathophysiology of CRS is not fully understood, but appears to be caused by a complex combination of haemodynamic, neurohormonal, immunological and biochemical feedback pathways. Of these pathways, the contributory role of uraemic toxins that accumulate in CRS has been underexplored. One such toxin, namely indoxyl sulphate, has been found to have direct adverse effects on relevant cardiac cells. Early diagnosis by assessing cardiac and renal injury biomarkers may be critical for timely therapeutic intervention. Such therapies are directed at attenuation of neurohormonal activation, control of elevated blood pressure, correction of anaemia and relief of hypervolaemia. Reduction of non-dialysable uraemic toxins is a further potentially beneficial therapeutic strategy.

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

“…Previous studies that evaluated consequences of combined renal and myocardial damage were mainly focused on cardiac function parameters and on the infarct size. While the majority of studies demonstrated that after myocardial infarction the renal damage is exacerbated and in animals with renal injury the infarct size is greater, others either failed to demonstrate worsening of myocardial infarction after renal damage in 5/6 NX rats, or found that infarct size in 5/6 NX rats was the same as in sham‐operated rats, and cardioprotective effects of ischemic preconditioning were maintained . The latter reports contradicted the common opinion that heart and kidney diseases reciprocally deteriorate their respective outcomes.…”

“…Congestive heart failure (CHF) and chronic kidney disease (CKD) present serious medical problems to millions of patients worldwide, with an incidence increasing over time; the patients with CHF and CKD combined are known to exhibit extremely poor survival prognosis, worse than that of most patients with diagnosed cancers . Previous studies have clearly demonstrated that progression of CHF as well as of CKD is accelerated by hypertension and inappropriately increased activity of the renin‐angiotensin system (RAS), therefore RAS blocking agents are currently applied as a golden standard therapy of CHF and CKD . However, the effectiveness of renoprotective action of RAS inhibition is limited, especially in the advanced phase of CKD .…”

“…The rat with aorto‐caval fistula (ACF) presents a well‐defined model of CHF due to volume overload, characterized by activation of the circulating and intrarenal RAS, cardiac remodeling and signs of failure including congestion; in many respects the model imitates the course of CHF in untreated humans . Despite such suitable features, the model was employed in but few studies which focused mostly on the sex‐based differences in the pattern of global myocardial remodelling, mainly those observed during the compensation phase of CHF …”

Triggering of suicidal erythrocyte death by uremic toxin indoxyl sulfate

“…A further uremic toxins that could contribute to anemia in chronic kidney disease is indoxyl sulfate [39,40], which is at least partially effective by suppression of erythropoietin production [41]. Further effects of indoxyl sulfate include downregulation of Klotho [42], induction of oxidative stress [42,43], up-regulation of NFκB [42], aortic calcification and aortic wall thickening [42], interference with wound repair [44], triggering of cell senescence [42], stimulation of cardiac and renal fibrosis [42,45] and acceleration of renal disease progression [42]. Indoxyl sulfate is generated by colonic microbes [46] and accumulates in blood, if renal excretion is impaired [42].…”

Introduction: Understanding the signalling mechanisms in molecular physiology and diseases

“…9 Deregulation of haemodynamic, neurohormonal, immunological and biochemical feedback pathways has been suggested to be among the factors contributing to the pathogenesis of cardiorenal syndrome (CRS), which is characterized by initial dysfunction in either the kidney or heart that initiates progressive impairment of both organs. Liu et al 10 describe a novel aspect of the role of uraemic toxins that accumulate in CRS with indoxyl sulphate being found to have direct adverse effects on cardiac cells. These studies may suggest a new window of opportunity in the early diagnosis of CRS for the assessment of biomarkers for cardiac and renal injury.…”