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The interplay between the heart and the kidney seems complex and multifactorial: cardiac output, regulation of extracellular volume, blood pressure and renal sodium handling are the major parameters that determine the crosstalk between the 2 organs. These basic parameters are controlled through mediators (renin-angiotensin system, endothelin) and the relevant antagonists (natriuretic peptides). Recently, it has been shown that the nitric oxide \/ reactive oxygen species balance, sympathetic nervous system activation and the presence of systemic inflammation aggravate atherosclerosis, promote structural alterations in left ventricular geometry and favor progression of renal disease. Although the prevalence of the CRS is high, major clinical trials for heart failure have only partially addressed this issue. The present review tries to dissect the role of various components of the CRS in a way that could potentially facilitate the implementation of specific therapeutic strategies. The multiple factors that participate in the pathogenesis of this syndrome are studied in detail in an effort to better understand this syndrome and address effectively its various components, since a holistic approach could (ideally) alter the syndrome's course and hence ameliorate the prognosis of the CRS. 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