Chronic kidney disease (CKD) is frequently associated with a progressive decrease in glomerular filtration rate (GFR), which leads to end-stage renal disease (ESRD). The number of patients with CKD as well as ESRD is increasing markedly worldwide, with poor outcomes and high cost. Cardiovascular disease (CVD) is closely associated with CKD and ESRD and is well shown as the leading cause of morbidity and mortality in the patients with CKD, most notably those on ESRD or dialysis (1). The prevalence of concomitant coronary artery disease (CAD), left ventricular hypertrophy (LVH), congestive heart failure (CHF), cardiac arrhythmia (most commonly atrial fibrillation), and valvular/vascular calcification are increased in CKD patients. Recently, the term, cardiorenal syndrome (CRS) has been introduced in an attempt to emphasize the interaction between the cardiovascular and renal systems in acute or chronic disease settings (2). CRS is a pathophysiological condition in which combined cardiac and renal dysfunction amplifies the progression of failure of the individual organs and has an extremely bad prognosis. It is more than simultaneous cardiac and renal disease. It is now necessary for us to expand our knowledge regarding its pathogenesis, prevention, and potential treatment.
The term ‘biomarker’ (biological marker) was first introduced in 1989 as a Medical Subject Heading (MeSH) term, and the definition was further standardized by the National Institutes of Health working group in 2001 as ‘a characteristic that is objectively measured and evaluated as ‘an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention’. According to its pathophysiological characteristics and/or clinical use, biomarkers can be classified into different types: antecedent index (risk factor), screening index, diagnostic index, staging index, prognostic index, and therapeutic monitoring index . A large number of biomarkers have been evaluated in CVD, and biomarkers pertinent to the CKD/ESRD and cardiovascular interface defined as renocardiovascular biomarkers are shown in Table. From the perspective of pathophysiology, they are classified into 1) neurohormones, 2) metabolic hormones/peptides, 3) cardiac injury markers, 4) oxidative stress markers, 5) matrix-related markers, 6) inflammatory markers, 7) renal markers and 8) mineral and bone disorder (MBD) hormones/markers.
1) Neurohormones include natriuretic peptides, renin-angiotensin-aldosterone, cathecolamines, endothelin-1 and arginine vasopressin (AVP). They are activated locally/systemically, and play causative roles in CVD/CKD progression. Recently, reliable immunoassays for stable precursor fragments of atrial natriuretic peptide (MR-proANP), adrenomedullin (MR-proADM), endothelin-1 (CT-proET-1), and AVP (copeptin) have been tested in the clinical setting with more encouraging results available (3).
B-type natriuretic peptide (BNP) and its amino-terminal fragment (NT-proBNP) have become established as the most ideal markers of HF so far available (4). Arginine vasopressin (AVP) is an antidiuretic and vasoconstrictive hormone that is released from the hypothalamus in response to changes in plasma osmolality and hypovolemia that are upregulated in CHF (5). Copeptin is the stable C-terminal part of proAVP, which is released with AVP after hemodynamic or osmotic stimuli. It emerges to be a more reliable marker for HF and is also released into the circulation early after MI onset, and may aid in rapid diagnosis (6). The plasma level of adrenomedulin is elevated in patients with hypertension and HF and it may play a protective role in various CVDs. MR-proADM, which is relatively more stable, is used to explore the prognostic power for HF related deaths, suggesting better predictability than the natriuretic peptides (7). Although the level was affected by renal function, it may be useful for HF risk stratification independently of renal function (8).
2) Hormonal derangements at the level of the hypothalamic-pituitary axis (thyroid hormone, adrenocorticotropic hormone, cortisol etc.) are often seen with the CKD or CVD. Recent evidences suggest the implication of such hormone disorders in the genesis of CKD or CVD and may be considered as research topics for clues in the complex relationship of CKD and CVD (9). Serum adiponectin is inversely linked to obesity, impaired glucose homeostasis, dyslipidemia and hypertension and has been suggested as a possible marker of CVD in the general population. Although hyperadiponectinemia is a common phenomenon in CKD and is considered to have similar beneficial effects on metabolic risk in this patient group, many recent studies have unexpectedly shown that high, rather than low, concentrations predict mortality (10). Leptin is an anorexigenic hormone, secreted in proportion of fat mass, with additional effects on the regulation of inflammation, CV system, immunity, hematopoiesis and bone metabolism (11). Hyperleptinemia, frequently observed in CKD patients, may play a key role in the pathogenesis of complications associated with CKD such as cachexia, protein energy wasting, chronic inflammation, insulin resistance, CV damages and bone complications. Leptin may be also involved in the progression of renal disease through its pro-fibrotic and pro-hypertensive actions. (12).
...(download the rest of the essay above)