Patients with heart failure commonly develop organ dysfunction as a consequence of impaired blood perfusion or non-hemodynamic indirect injury, and often subsequent progression of renal dysfunction is associated with poor clinical prognosis. While neurohormonal system activation, systemic inflammatory reaction, and hemodynamic derangement are considered the central pathology in acute (or Type 1) cardio-renal syndrome (CRS), there is growing evidence that intricate networks of mediators participate in the process of cardio-renal injury. However, current treatment strategies are unable to effectively modulate this complex interplay of mediators in order to reverse true cardio-renal injury. The presence of conglomerated cardio-renal mediators in advanced CRS often hampers clinician efforts to recognize proper causal relationships in CRS progress. Either imprecise decongestive treatment or imperfect biomarker-based assessment of renal function can contribute to undesirable outcomes. Hence, there is a pressing need to gain insights into vulnerable cardio-renal substrates during subclinical stages of CRS rather than to overcome such mediators during overt CRS.