From Cardiorenal Syndrome to Chronic Cardiovascular and Kidney Disorder: A Conceptual Transition

Abstract

The association between cardiac and kidney dysfunction has received attention over the past two decades. A putatively unique syndrome, the cardiorenal syndrome, distinguishing five subtypes on the basis of the chronology of cardiac and kidney events, has been widely adopted. This review discusses the methodologic and practical problems inherent to the current classification of cardiorenal syndrome. The term "disorder" is more appropriate than the term "syndrome" to describe concomitant cardiovascular and kidney dysfunction and/or damage. Indeed, the term disorder designates a disruption induced by disease states to the normal function of organs or organ systems. We apply Occam's razor to the chronology-based construct to arrive at a simple definition on the basis of the coexistence of cardiovascular disease and CKD, the chronic cardiovascular-kidney disorder (CCKD). This conceptual framework builds upon the fact that cardiovascular and CKD share common risk factors and pathophysiologic mechanisms. Biological changes set in motion by kidney dysfunction accelerate cardiovascular disease progression and vice versa . Depending on various combinations of risk factors and precipitating conditions, patients with CCKD may present initially with cardiovascular disease or with hallmarks of CKD. Treatment targeting cardiovascular or kidney dysfunction may improve the outcomes of both. The portfolio of interventions targeting the kidney-cardiovascular continuum is in an expanding phase. In the medium term, applying the new omics sciences may unravel new therapeutic targets and further improve the therapy of CCKD. Trials based on cardiovascular and kidney composite end points are an attractive and growing area. Targeting pathways common to cardiovascular and kidney diseases will help prevent the adverse health effects of CCKD.

Figure 1

Evolution of kidney function (GFR) and the associated risk of cardiovascular disease. As kidney function worsens, the fully adjusted cardiovascular events increase progressively to be 3.14 times higher than the standard risk in patients with stage G5 CKD. The graph is derived from figures reported by Go et al.; metabolic, traditional, and environmental risk factors are early cardiovascular and kidney disease triggers. These include a sedentary lifestyle, overnutrition, obesity, type 2 diabetes, hypertension, and environmental pollution and noise. Subsequently, as the GFR declines, traditional risk factors have a gradually reduced effect. This trend is mirrored by the progressive rise of risk factors set in motion by CKD and the cardiorenal cross-talk (see main text). Environmental risk factors continue to impinge on cardiovascular and kidney outcomes across kidney dysfunction progression. Nontraditional risk factors include inhibitors of the nitric oxide system and several other factors that impinge upon nitric oxide synthesis, such as AGEs; hyperphosphatemia; FGF23; PTH; low 1,25 vitamin D; and the anti-aging vasculoprotective factor Klotho. Progressive sympathetic overactivity is critical in cardiovascular and kidney diseases because it is the parallel activation of the renin–angiotensin–aldosterone system. Compounds generated in the gut microbiota exert proinflammatory actions and impinge upon cardiovascular and kidney diseases. Inflammation and fibrosis, and dysregulated autophagy are intimately linked to these alterations and are fundamental for cardiovascular and kidney damage. This process is bidirectional because cardiac ischemia engenders kidney damage and accelerates CKD progression by inflammatory mechanisms. At the same time, venous congestion and left ventricular dysfunction may lower the GFR (see also main text). AGE, advanced glycosylation end product; FGF23, fibroblast growth factor 23; PTH, parathyroid hormone.