Disease Markers
Volume 2015 (2015), Article ID 586569, 16 pages
http://dx.doi.org/10.1155/2015/586569

Research Article

Cardiovascular Biomarkers in Chronic Kidney Disease: State of Current Research and Clinical Applicability

Luis D’Marco,¹ Antonio Bellasi,2,3 and Paolo Raggi4,5

¹Unidad Avanzada de Investigación y Diagnostico Ecográfico y Renal, Clínica Puerto Ordaz, Puerto Ordaz, Venezuela
²U.O.C. di Nefrologia e Dialisi, Ospedale Sant’Anna, Azienda Ospedaliera Sant’Anna, Como, Italy
³Department of Health Sciences, University of Milan, Milan, Italy
⁴Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB, Canada
⁵Department of Radiology, Emory University, Atlanta, GA, USA

Received 15 December 2014; Revised 15 March 2015; Accepted 18 March 2015

Academic Editor: Shih-Ping Hsu

Copyright © 2015 Luis D’Marco et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

The high incidence of cardiovascular events in chronic kidney disease (CKD) warrants an accurate evaluation of risk aimed at reducing the burden of disease and its consequences. The use of biomarkers to identify patients at high risk has been in use in the general population for several decades and has received mixed reactions in the medical community. Some practitioners have become staunch supporters and users while others doubt the utility of biomarkers and rarely measure them. In CKD patients numerous markers similar to those used in the general population and others more specific to the uremic population have emerged; however their utility for routine clinical application remains to be fully elucidated. The reproducibility and standardization of the serum assays are serious limitations to the broad implementation of these tests. The lack of focused research and validation in randomized trials rather than ad hoc measurement of multiple serum markers in observational studies is also cause for concern related to the clinical applicability of these markers. We review the current literature on biomarkers that may have a relevant role in field of nephrology.

1. Introduction

The very high incidence of cardiovascular disease (CVD) events and premature mortality in patients with chronic kidney disease (CKD) [1], with a sharp increase in risk as glomerular filtration rate (GFR) declines below 60 mL/min/1.72 m² [2], offers a rationale for better risk stratification in this population. Several traditional risk factors and factors more closely related to loss of renal function (anemia, oxidative stress, inflammation, and bone mineral disorders) contribute to the high incidence of cardiovascular complications seen in patients with CKD. Whether biomarkers help improve the identification of patients at risk of cardiovascular events has been at the core of extensive research in the general population and in patients with CKD [3]. This approach predicates that an accurate assessment of cardiovascular risk at an early stage would facilitate more aggressive and focused treatment of those in greater need of preventive measures with the goal to reduce event rates. In this review, we focus on established and emerging laboratory biomarkers for the assessment of risk in CKD and compare them to their use in the general population.

2. Natriuretic Peptides

The natriuretic peptides are a family of hormones that play a major role in sodium and body volume homeostasis; specifically they control natriuresis, vasodilatation, and diuresis [4]. Three major natriuretic peptides have been identified: atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). They all share a common 17-amino-acid ring structure and have actions that are targeted at protecting the cardiovascular system from the effects of volume overload [5]. While ANP is preferentially produced in and secreted by the atria, BNP is produced by the ventricular myocardium in response to ventricular stretching and wall stress [6]. CNP, derived primarily from endothelial cells, is also synthesized by the myocardium. Upon ventricular myocyte stretch, pre-proBNP is enzymatically cleaved to proBNP and released as active BNP hormone (amino acids 79–108) or an inactive fragment, NT-proBNP (amino acids 1–76, released in a 1 : 1 ratio).

Natriuretic peptides, in particular BNP and NT-ProBNP, have been investigated as biomarkers in several conditions and an increase in their serum levels has been associated with degree of left ventricular dysfunction, severity of congestive heart failure symptoms, and ultimately a poor prognosis in community-based and general population studies [7–11]. Furthermore, NT-proBNP is a good marker for prediction of first cardiovascular events in the population, as well as the risk of stroke in patients with atrial fibrillation [12, 13]. NT-proBNP has a longer half-life and thus its levels may be more stable (less affected by acute stress) than BNP. Both BNP and NT-proBNP are eliminated only to a small degree during a hemodialysis session [14], and NT-proBNP appears to accumulate to a larger degree during dialysis [15, 16]. Several studies have confirmed that both BNP and NT-proBNP are useful markers of cardiovascular risk in CKD patients. In general, they have been shown to correlate with the severity of heart failure and left ventricular dysfunction and to be useful in guiding the management of heart failure in CKD. Plasma BNP concentrations increase progressively with decreasing renal function, and this relationship remains present when patients are subdivided into systolic and diastolic heart failure () [17]. In a prospective evaluation of 213 CKD nondialysis patients, Vickery and coworkers demonstrated that NT-proBNP (≥89 pmol/L, HR 2.5, ) and high-sensitivity C-reactive protein ( mg/L, HR 1.9, ) were independently associated with increased all-cause mortality [3]. Similar findings were reported in dialysis patients [18]. Additionally, NT-proBNP, but not BNP, was an independent predictor of death in a heart failure population with eGFRs < 60 mL/min/1.73 m² [19].

BNP was prospectively studied as a biomarker of cardiovascular events in CKD patients in a community-based study in Japan [20]. The investigators collected baseline plasma BNP, serum creatinine, and urinary protein levels from 9625 patients. The risk of cardiovascular events was significantly higher in participants with the highest BNP serum levels. In a study of 134 hemodialysis patients Sommerer et al. found that plasma levels of NT-proBNP were elevated in 100% and cardiac troponin T (cTNT) levels in approximately 40% of asymptomatic patients [21]. Both increased NT-proBNP and cTNT were strongly associated with an adverse cardiovascular outcome (overall there were 23 deaths due to myocardial infarction and sudden cardiac death). In a prospective cohort study of 230 patients undergoing chronic peritoneal dialysis, Wang et al. reported that NT-pro-BNP was an independent risk marker of congestive heart failure, death, or a combined end-point including death and other adverse cardiovascular outcomes [22] (odds ratios varied between 4.25 and 9.1 for the fourth compared to the 1st quartile of NT-pro-BNP). The authors concluded that in chronic peritoneal dialysis patients NT-pro-BNP adds prognostic information beyond that contributed by left ventricular hypertrophy, systolic dysfunction, and other conventional risk factors. Finally, NT-pro-BNP is a predictor of mortality in CKD patients independent of volume overload and dialysis modality [23, 24].

3. Cardiac Troponin T

Troponin (TN) T, I, and C are components of the contractile apparatus of striated muscle. Specific forms of troponins T and I are present in the heart muscle, namely, cTNT and cTNI. cTNI is exclusively expressed in cardiomyocytes and is released into the circulation after myocardial cell damage. Increased levels of troponins are detectable 3–12 h after myocardial injury, with the concentration being in direct proportion to the extent of injury [5]. The serum levels return to the normal range after 5–14 days from injury, which is 4 times longer than for the creatine kinase myocardial band isoenzyme (CK-MB) fraction, probably because of sustained release of structurally-bound protein from disintegrating myofibrils [25].

cTNT is cardiac specific and is not present in the serum following nonmyocardial muscle damage. The levels of cTNT are commonly increased among patients with renal dysfunction in the absence of acute myocardial infarction [26]. Although the exact mechanism is unknown, several studies suggested that increased levels of troponins are associated with increased risk of coronary artery disease (CAD) and death in predialysis populations [27]. Several explanations, although controversial, have been proposed to understand cTNT elevation in uremic patients. Among them are increased left ventricular wall stress, acute or chronic volume overload, silent plaque rupture in the presence of diffuse coronary atherosclerosis, and apoptosis of cardiomyocytes [28, 29]. The prevalence of elevated cTNT plasma levels prior to hemodialysis sessions varies between 20% and 53%. A serum level of cTNT > 0.01 microg/L is relatively common (28,2%) in patients with CKD stage 3-4 [26]. A cohort of 847 dialysis patients was followed in a multicenter study in the Netherlands between 1997 and 2001. After an average follow-up of two years patients with baseline cTNT levels between 0.05 and 0.10 microg/L showed a hazard ratio for all-cause death of 2.2 (95% CI, 1.7 to 2.8) compared with patients with levels below 0.05 microg/L [30]. For those with levels greater than 0.10 microg/L (11%), the hazard ratio rose to 3.3 (95% CI, 2.5 to 4.5). In this investigation there was no significant difference in risk of events between patients receiving hemodialysis or peritoneal dialysis and between patients with high and low residual renal function. Cardiac TNT was used as a marker to identify occult obstructive coronary artery disease (CAD) in 142 patients at the start of their renal replacement therapy [31]. Of 60 asymptomatic patients at the time of evaluation, 35 (43.8%) had obstructive CAD and 27 had multivessel CAD as assessed by invasive coronary angiography. On stepwise logistic regression analyses cTNT was an independent predictor of asymptomatic multivessel CAD (sensitivity and specificity of cTNT to predict multivessel CAD: 92.6% and 63.6%, resp.). Several publications have further supported the value of cTNT as a predictor of unfavorable CAD events in CKD populations [32–34]. cTNT and cTNI were found to be equivalent in differentiating short-term prognosis in patients with CKD suffering a non-ST-segment elevation myocardial infarction [35]. In summary, cTNT may be helpful to detect asymptomatic CAD, especially multivessel disease, and as a predictor of mortality in CKD patients. However, as for several other markers, the variability of the test both day to day and from one laboratory to the other may limit the ability to issue widely applicable guidelines on the use this biomarker in CKD.

4. C-Reactive Protein

Systemic inflammation plays a major role in the development of atherosclerosis leading to coronary heart disease. C-reactive protein (CRP), an acute phase reactant, is an established marker of systemic inflammation in the general population and patients with CKD [36–38]. Elevated CRP levels, when measured using highly sensitive assays (hsCRP), are predictive of future coronary events in the general population [39]; currently a serum level of hsCRP >3 mg/L is considered a marker of high risk for events [40]. Although the clinical utility of hsCRP in CKD is still under debate, a few studies reported a significant association between hsCRP and all-cause mortality in end-stage renal failure at concentrations varying between 1 and 3 mg/L [18, 41, 42]. Apple et al. followed prospectively 399 CKD stage 5 patients in whom they measured several biomarkers. They reported that hsCRP, cTNT, and cTNI were independent predictors of death after a 2-year follow-up. NT-proBNP was only predictive when analysed as a categorical variable but not as a continuous variable [18]. Snaedal et al. measured hsCRP serially in a three-month observational study of 228 prevalent hemodialysis patients [43]. They reported that median and mean serial CRP levels were associated with an increased hazard ratio for all-cause death (1.013; 95% confidence interval, 1.004 to 1.022 and 1.012; 95% confidence interval, 1.004 to 1.020, resp.). Of interest, 13% of the patients enrolled had persistently low hsCRP levels (<5 mg/L), 19% had CRP levels > 10 mg/L, and 68% demonstrated fluctuating values. Hence, in the majority of hemodialysis patients, hsCRP is a “moving target” depending on a variety of inflammatory stimuli in the individual patient. This observation may be prognostically important. In fact, Nascimento et al. reported that the mortality rate in 180 hemodialysis patients followed for 21 months after 4 sequential measurements of CRP was significantly higher in patients with persistently elevated levels (34% death rate) than in those with low (8%) or intermittently elevated (14%) CRP levels [44]. Of note, the mortality rate was not statistically different between patients with low and intermittently elevated CRP levels. In another prospective observational study of 402 patients receiving peritoneal dialysis the investigators reported a 1.4% increase in mortality for each 1 mg/L increase in hsCRP level after 2 years of follow-up [45]. There are also conflicting reports on the value of CRP in CKD. Kanwar et al. measured troponin T and I and hsCRP in a cohort of 173 prevalent hemodialysis patients divided into 2 groups according to clinical characteristics: patient with CAD or CAD equivalent status (peripheral arterial disease and diabetes) and patients without any relevant prior cardiovascular history [46]. Prior history of CAD or CAD risk-equivalence was strongly predictive of mortality and hsCRP did not add to the risk stratification of these patients. On the contrary, both troponin T and I added incremental prognostic information. In the lower-risk patients hsCRP was predictive of mortality while troponins were not. In a study by Honda et al. where hsCRP, IL-6 serum albumin, and fetuin A were measured in 176 prevalent hemodialysis patients, hsCRP was found to be a good predictor of malnutrition but a weaker predictor of CVD and mortality than IL-6 [47]. Overall, hsCRP may be useful as an additional piece of information to assess risk in CKD patients, but its value needs to be carefully considered in the context of several limitations. There is likely a substantial difference in the significance of hsCRP elevation in predialysis and dialysis patients. In fact, exposure to dialysis membranes, even modern biocompatible membranes, and vascular access infections are associated with marked cytokine and hsCRP release; these events do not obviously take place in predialysis patients. hsCRP levels may be modulated by the concurrent use of statins. The actual risk may differ in patients with persistently elevated as opposed to intermittently elevated CRP levels. Finally the predictive value of hsCRP may be enhanced by combining its measurement with that of several other markers of risk [48].

5. Adiponectin

Recent research has focused on visceral adipose tissue as a source of inflammation and adipocytokines secretion. Adiponectin (APN) is a protein secreted by adipocytes and has anti-inflammatory and antiatherogenic activities and enhances insulin-sensitivity [49, 50]. APN likely exerts its antiatherosclerotic activities by suppressing the release of proinflammatory cytokines such as TNF-α and IL-6 and stimulating the release of anti-inflammatory cytokines such as IL-10 [51, 52] and via enhancement of insulin sensitivity. Low APN levels have BEEN observed in patients with obesity, the metabolic syndrome, diabetes mellitus, CAD, and essential hypertension. In contrast, plasma levels of APN in patients with CKD are increased up to threefold the physiological levels [53–55], most likely due to reduced clearance or catabolism [56]. In the general population low APN levels have been associated with the development of cardiovascular disease [57, 58]. A few observational studies linked APN to adverse cardiovascular outcomes in patients with CKD [59, 60]. Becker and coworkers evaluated 227 nondiabetic patients with CKD and 76 healthy subjects of similar age, sex, and body mass index [61]. After a mean follow-up of 54 months, they concluded that, despite higher serum levels than in control subjects, relatively low plasma APN levels were predictive of cardiovascular events among patients with mild to moderate CKD. Similarly, Zoccali et al. reported that plasma APN levels were 2.5 times higher () among dialysis patients ( μg/mL) than among healthy subjects ( μg/mL), but the APN levels were lower among the dialysis patients who developed cardiovascular complications than those who remained event free [62]. The increased risk of cardiovascular events in CKD patients with lower APN concentrations () relative to other CKD patients was unchanged after adjusting for multiple traditional and CKD-specific risk factors. Each 1 μ/mL increase in APN concentration was associated with a 3% reduction in risk of cardiovascular events.

In contrast, a subanalysis of the modification of diet in renal disease (MDRD) database performed in 820 patients with CKD showed a direct correlation between increased APN plasma concentration and the relative risk of cardiovascular mortality [63]. In multivariable adjusted Cox models, 1 μ/mL increase in APN was associated with a 3% (hazard ratio 1.03; 95% CI 1.01 to 1.05; ) increased risk of all-cause and 6% (hazard ratio 1.06; 95% CI 1.03 to 1.09; ) increased risk of cardiovascular mortality. A potential explanation for these apparently conflicting data is the reported association between increased APN concentrations and poor nutritional status in CKD [64]. However, the existence of a link between higher APN levels and increased cardiovascular risk in CKD remains to be clarified. In view of the bidirectional association of APN with events, its role as a useful marker of cardiovascular risk in CKD remains uncertain pending accumulation of further evidence.

6. Leptin

Leptin is a single-chain 16-kDa protein whose production is under the control of the obese (ob) gene. It is a neurotransmitter entirely produced in adipocytes, with the fundamental function of controlling appetite, regulating food intake, and energy expenditure [65]. Leptin is also a proinflammatory cytokine and is predominantly cleared from the circulation by the kidneys via a combination of glomerular filtration and tubular degradation [66]. Leptin levels increase in proportion to insulin levels, glucocorticoids, cytokines, and obesity [67]. In humans leptin is an anorectic agent and decreases appetite by decreasing the level of neuropeptide Y, a potent stimulator of food intake, and increasing alpha-melanocyte-stimulating hormone (alpha-MSH), an inhibitor of food intake, respectively [68, 69]. In healthy subjects and patients with type 2 diabetes mellitus, weight loss has been shown to be accompanied by a reduction in leptin serum concentration [70, 71]. These data suggest that high leptin concentrations are a component of the metabolic syndrome and may have a role in increasing the cardiovascular risk of these patients. Leptin levels are significantly elevated in patients with CKD, particularly in those undergoing dialysis compared with nondialysis patients [72, 73]. Besides decreased renal clearance other factors affect leptin levels in CKD. Metabolic acidosis reduces the release of leptin from adipocytes and uremic factors of unclear origin reduce leptin gene expression in adipocytes probably as a negative feedback due to decreased elimination [74, 75].

Leptin is believed to have proatherogenic effects that include the development of hypertension, oxidative stress, endothelial dysfunction, inflammation, and proliferation of vascular smooth muscle cells [64, 76]. High leptin levels induce activation of the sympathetic nervous system both via central and peripheral mechanisms. Several studies linked increased leptin and early markers of arterial disease such as increased carotid intima media thickness and decreased arterial distensibility [77–79]. Aguilera et al. described an association of serum levels of leptin with elevated lipids concentration and LVH in a small peritoneal dialysis cohort [80]. In a small size cohort of kidney transplant recipients () there was a positive association between elevated serum leptin levels and increased peripheral arterial stiffness [79].

At this time there are sparse and conflicting data on the role of leptin as a marker of risk in CKD. Scholze et al. reported an association of leptin serum levels with cardiovascular events in 71 prevalent hemodialysis patients followed for 83 months [81]. The serum level of leptin was significantly lower in patients who died from cardiovascular complications (4.7 ± 9.4 microg/L, ) than in survivors (7.7 ± 7.8 microg/L; ; ). Additionally, survival was shorter in patients with leptin concentrations below the median (<2.6 microg/L). Two other studies reported that leptin did not add incremental prognostic value for all-cause mortality and cardiovascular morbidity in 101 hemodialysis patients followed for a period of 4 years [82] and 181 patients followed for 3 years [83]. Hence, the value of leptin as a marker of risk remains unclear in CKD.

7. Fibroblast Growth Factor 23 and Klotho

It has long been recognized that secondary hyperparathyroidism (SHPT) is a consequence and a complication of CKD. The global syndrome that involves bone and vascular disease has been aptly termed CKD-mineral bone disorder (CKD-MBD) [84]. SHPT is a complex process that involves numerous steps such as vitamin D deficiency, hypo- and/or hypercalcemia, and hyperphosphatemia. Phosphorus levels were believed to be under the direct control of the parathyroid glands until the fairly recent discovery of a new hormone called fibroblast growth factor 23 (FGF-23). FGF-23 is a 32-kD protein secreted by bone osteocytes; its primary function is to promote phosphaturia by suppressing the expression of sodium-phosphate cotransporters NaPi-2a and NaPi-2c in the proximal tubule [85, 86]. In addition, FGF-23 acts as a counter-regulatory hormone for vitamin D by blocking the generation of 1,25(OH)2D both through inhibition of the renal 1α-hydroxylase enzyme and through the stimulation of the 24-hydroxylase enzyme that is responsible for the degradation of both the 25(OH)D and 1,25(OH)2D metabolites [87]. Klotho acts as a coreceptor for FGF-23 and its presence appears to be mandatory to induce FGF-23-specific signaling pathways in the kidney, parathyroid glands, and other tissues [88, 89]. Once Klotho is shed from the cell by proteolytic cleavage, it is released in the circulation and serves as a phosphaturic and hypocalciuric hormone independent of FGF-23 [90].

However, it has been postulated that FGF-23 may also operate via Klotho independent mechanisms. In the acute kidney injury (AKI) setting, FGF-23 elevation may precede creatinine elevation and phosphate metabolism impairment [91]. Whether this is due to inflammation or a decrease in Klotho in response to acute uremia needs further elucidation.

Like phosphorus, PTH, and vitamin D, FGF-23 has been independently associated with risk of all-cause death in dialysis and CKD patients, heart failure, cardiovascular events, and death in the general population [92, 93]. A cross-sectional study in 177 patients with mild to moderate CKD submitted to coronary angiography found that FGF-23 increases early in the course of CKD and, as shown for other bone metabolism hormones (PTH, Fetuin A), it is an independent predictor of CAD severity after adjusting for traditional risk factor [94]. Seiler et al. measured plasma FGF-23 levels in 149 CKD patients not receiving dialysis [95]. Patients were stratified according to the median baseline FGF-23 levels (>104 versus ≤104 rU/mL) and were followed for an average of 4.8 ± 0.9 years till the first occurrence of a cardiovascular event. At baseline, patients with more advanced CKD demonstrated higher FGF-23 serum levels. Traditional cardiovascular risk factors and prevalent cardiovascular disease did not differ between groups. Fifty patients experienced a cardiovascular event during follow-up. Compared to CKD patients with an FGF-23 level below the median, those with levels above the median experienced a higher rate of events [HR 2.49 (95% CI 1.40–4.39); ]. In the Chronic Renal Insufficiency Cohort (CRIC), a graded and independent association between high levels of FGF-23 and CKD progression, congestive heart failure, and atherosclerotic events (myocardial infarction, stroke, and peripheral vascular disease) was documented among 3860 CKD 2–4 patients [96, 97]. Serum levels of FGF-23 were measured in 13,448 subjects with preserved renal function (mean eGFR was 97 mL/min per 1.73 m²) enrolled in the atherosclerosis risk in communities study (ARIC) [98]. The investigators documented that among patients with an FGF-23 serum level in the top quintile (>54.6 pg/mL) compared to those in the versus first quintile (<32.0 pg/mL) the risk of ESRD increased 2-fold (HR 2.1, 95% CI: 1.31–3.36, ) independent of numerous confounders. In the Heart and Soul study the investigators measured FGF-23 in 833 outpatients with stable CAD and no CKD [99]. During a follow-up of 6 years, 220 patients died and 182 suffered a CVD event. After adjusting for traditional risk factors, patients in the highest tertile of FGF-23 concentrations demonstrated a 2-fold greater risk of death (HR, 2.15 [95% CI, 1.43 to 3.24]) and CVD events (HR, 1.83 [CI, 1.15 to 2.91]).

The coreceptor Klotho has been shown to have direct vascular effects by increasing both production of reactive oxygen species in human vascular smooth muscle cells and NO production in endothelial cells. Klotho deficiency has been associated with oxidative stress and inflammation in ESRD patients [100].

In a large observational study of 804 community-dwelling elderly (age greater than 65 years), plasma Klotho was inversely and independently associated with the risk of all-cause mortality (data adjusted for age, sex, education, body mass index, physical activity, total cholesterol, high-density lipoprotein cholesterol, cognition, 25-hydroxyvitamin D, parathyroid hormone, serum calcium, mean arterial pressure, and chronic diseases). Participants within the lowest tertile of serum Klotho (<575 pg/mL) had a 78% greater risk of death than patients within the highest tertile (>763 pg/mL; hazard ratio: 1.78; 95%; CI 1.20–2.63) [101]. In a cross-sectional study of 956 individuals, Klotho gene polymorphisms were associated with occult coronary artery disease (CAD) (defined as the occurrence of a reversible perfusion defect on nuclear myocardial stress testing) independent of known risk factors for CAD [102]. Recently a significant correlation was reported between severity of CAD and reduced levels of Klotho gene expression in the aorta as well as lower serum levels of soluble Klotho [103]. In a subanalysis of the Heart and Soul study the serum levels of FGF-23 and its coreceptor Klotho lacked an association with left ventricular mass and ejection fraction in the absence of kidney disease [104].

There is no reliable assay to measure Klotho to this date and despite the above findings the evidence to support the utility of FGF-23 and Klotho as markers of risk is still inconclusive; therefore they cannot be recommended for routine clinical use.

8. Fetuin-A and Calciprotein Particles

The alpha 2-Heremans Schmid glycoprotein, also known as Fetuin A, is secreted by hepatocytes in greater concentration during fetal than adult life. It is believed to modulate bone formation and brain development although its full function is still unknown. Fetuin A forms soluble complexes in the circulation with calcium-phosphate crystals. The calcium-phosphate and Fetuin-A complexes form stable particles (less than 100–200 nm in diameter) called calciprotein particles (CPPs) that exist as colloids and do not precipitate [105]. A growing body of evidence suggests that CPPs may be isolated from the serum of patients with CKD but not in healthy individuals; they are further believed to mediate in part the harmful effects associated with chronically elevated phosphate in CKD [106–108]. Unlike inorganic phosphate that stimulates the expression of sodium-phosphate cotransporters across the cellular membrane, CPPs seem to induce cellular responses through an interaction with the plasma membrane and the induction of intracellular messengers but the mechanisms remain to be elucidated. In a cohort of 200 patients suffering from CKD stages 3 and 4, higher levels of CPPs were associated with hyperphosphatemia, increased levels of C-reactive protein, oxidized low density protein, bone morphogenic proteins 2 and 7 as well as a rapid decline in renal function, and a greater aortic pulse wave velocity ((PWV) beta coefficient 0.059, , ) which is known to be a strong predictor of major CV events in CKD patients [107].

The use of CPPs has also been proposed as a simple predictor of the overall uremic milieu propensity for calcification [106]. The clinical validity of such test has been assessed in a recent series of 184 CKD stages 3 and 4 patients. Descending tertiles of T₅₀ (a measure of the calcifying propensity of a patient’s serum) were associated with higher aortic PWV as well as all-cause mortality, independent of several traditional and CKD specific risk factors [109].

Although intriguing, more studies are necessary to further elucidate the role of CPPs as a key mediator of CV damage and as a potential therapeutic target in CKD patients.

9. Wingless (Wnt) Antagonists Inhibitors

Wingless (Wnt) antagonist inhibitors such as sclerostin and Dickkopf-1 (DKK-1) are newly described factors involved in the bone-vascular axis [110]. Wnt activation promotes osteoblast and suppresses osteoclast activity by increasing the ratio of osteoprotegerin (OPG) to receptor activator of nuclear factor-kappaB ligand (RANKL). This leads to bone mineralization and bone turnover downregulation. The Wnt pathway is also involved in vascular and cardiac valve calcification and preliminary data suggest that its overexpression may be identified within ectopic calcification or during calciphylaxis [111, 112]. Reduced Wnt signaling seems to occur in the earliest phases of CKD likely due to the increased expression of Sclerostin and DKK-1 and it may be responsible for accelerated loss of bone mass and strength, uremic resistance to PTH, and increased vascular calcification [110, 113, 114].

Nonetheless, the clinical significance of sclerostin as a marker of risk remains unclear. In a series of 140 patients with CKD stages 2–5D [115], advancing stages of CKD were accompanied by a graded increase in serum levels of sclerostin. At this stage it is unclear whether this is due to reduced renal clearance or increased production in CKD. In the study by Desjardins et al. [115], sclerostin levels were associated with serum levels of phosphate, FGF-23, and IL-6 as well as protein bound uremic solutes such as indoxylsulphate and p-cresyl sulphate and were independent predictors of arterial stiffness and mortality, although they were not associated with vascular calcification. Further adjustments for confounders significantly attenuated the strength of the association of sclerostin with mortality [115].

In a post hoc analysis of 100 prevalent hemodialysis patients, higher levels of serum sclerostin were associated with decreased mortality (age and sex adjusted HR: 0.33, 95% CI 0.15–0.73; ) [116]. After further adjustment for bone specific alkaline phosphatase, serum sclerostin levels dropped out of the multivariable model as a significant variable.

Drechsler and coworkers documented an independent inverse association of sclerostin with cardiovascular (HR 0.29; 95% CI 0.13–0.62) and all-cause mortality (HR 0.39; 95% CI: 0.22–0.68) in 673 hemodialysis patients enrolled in the NECOSAD study [117]. The association tended to lose statistical significance when the observation was prolonged past the first 18 months of dialysis. At the current stage of knowledge, therefore, the role of Wnt signaling inhibitors as markers of risk needs further elucidation and confirmation.

10. Neutrophil Gelatinase-Associated Lipocalin

Neutrophil gelatinase-associated lipocalin (NGAL) is a 25–135 kDa (depending on the tertiary structure of the peptide) member of the lipocalin iron-carrying proteins family [118] and is highly expressed in kidney following ischemic or nephrotoxic injury [119–121]. Although NGAL was originally isolated in neutrophils [122], numerous other tissues express this protein, namely, kidney, liver, and vascular cells (endothelial, smooth muscle cells, and macrophages in atherosclerotic plaques), as well as cardiomyocytes [123–125].

NGAL inhibits the degradation of gelatinase B leading to enhanced proteolytic activity with collagen degradation effects [123]. At steady state, NGAL concentration is negligible (about 20 ng/mL) in both blood and urine [126]. These concentrations likely reflect neutrophils production and renal clearance, the major regulators of NGAL concentration at steady state. As renal function declines, NGAL levels increase and they become markedly increased in chronic dialysis. However, high-flux hemodialysis may significantly remove NGAL from plasma [127].

Identification of increased levels of NGAL in blood and urine in several renal disease states has generated an interest in NGAL as an early marker of acute kidney injury [128]. A recent meta-analysis of 19 studies including 2538 patients from 8 countries summarized the available evidence regarding NGAL as a biomarker [129]. Although data were mainly derived from patients undergoing cardiac surgery, plasma NGAL was a strong predictor of acute kidney injury, initiation of renal replacement therapy, and in-hospital mortality with odds ratios ranging from 8.8 to 18.6 for high versus low NGAL [129].

Although NGAL was associated with progression of CKD after kidney injury in a few reports [130–133], an analysis from the Chronic Renal Insufficiency Cohort (CRIC) questioned its role as a useful biomarker to predict progression [134]. In the CRIC cohort of 3386 patients suffering from CKD 2–4, NGAL was an independent predictor of worsening of CKD (defined as a 50% eGFR decrease or dialysis initiation) but it did not add significantly to the discrimination model suggesting a marginal value of urinary NGAL as a predictor of CKD progression [134].

Investigators from Japan recently reported on the use of NGLA as a marker of CV risk in 88 hemodialysis patients [135]. At the end of 1-year follow-up they recorded 20 events; patients with event had significantly higher levels of NGAL and pro-BNP at study inception than event-free survivors ( versus  ng/mL and versus  pg/mL, for NGAL and proBNP, resp.). After adjustment for confounders each 1 ng/mL increase in NGAL was associated with a 3% (OR: 1.03; 95% CI: 1.01–1.06) increase in the risk of CV events. Patients with simultaneous increase in NGAL and pro-BNP exhibited a 25-fold higher risk of CVD than patients with low NGAL and pro-BNP.

NGAL has been investigated as a prognostic marker in patients suffering from acute heart failure (AHF). Maisel and coworkers evaluated 186 patients admitted via the emergency department with AHF and measured NGAL and BNP [136]. At 30 days, heart failure readmission and death occurred in 29 patients; the NGAL serum level was higher in patients with events (134 versus 84 ng/mL, ) and NGAL was an independent predictor of events in multivariable models (), while BNP was only of borderline significance (). The addition of NGAL to a multivariable-adjusted model lead to a 29.8% net reclassification improvement for prediction of events.

In the Rancho Bernardo Study, NGAL was associated with inflammation, lower HDL-cholesterol levels, and lower creatinine clearance [137]. In this study each standard deviation increase in log-transformed NGAL level was associated with a significant increase in all-cause mortality (HR 1.19; 95% CI: 1.07–1.32), CV death (HR 1.33; 95% CI: 1.12–1.57), and the combined endpoint (HR 1.26; 95% CI: 1.10–1.45).

In summary, the limited available evidence suggests that NGAL is a weak marker of risk for renal function decline but might be a predictor of cardiac event in the setting of HF in patients with and without renal disease. As for other biomarkers, future work will need to define reliable cutoff values in different populations and standardize results arising from different available assays.

11. Plasma Growth Differentiation Factor-15

Plasma growth differentiation factor-15 (GDF-15) is generated as a 40-KDa propeptide from which the NH2-terminus is cleaved and the resulting 30-KDa protein is secreted as active form [138]. GDF-15 has been described as a potential inhibitor of left ventricular hypertrophy [139]. An increase in pre- or afterload in experimental settings induces an increase in plasma GDF-15 possibly through proinflammatory cytokines and oxidative stress-dependent signaling pathways [140, 141]. Several studies have shown that GDF-15 is over expressed in patients suffering from atherosclerotic diseases such as myocardial infarction, stroke, and others types of atherosclerotic disease [142–144]. The literature regarding GDF-15 in patients affected by CKD is limited. Interesting data were derived from the 2,614 participants in the Framingham Offspring study followed for a mean of 9.5 years [145]. The investigators reported that higher plasma levels of GDF-15 were associated with incident CKD (multivariable-adjusted OR 1.9 per 1-unit increase in log-GDF-15, 95% CI 1.6–2.3, ) and a rapid decline in kidney function (OR 1.6, 95% CI 1.3–1.8, ). In a prospective observational study Lajer et al. showed that GDF-15 was an independent predictor of all-cause and cardiovascular mortality (HR 3.6 [95% CI 1.3–10.3]; ) and worsening renal function in 451 patients with diabetic nephropathy [146]. Additionally, a study originally designed to evaluate GDF-15 for prognostication of cardiovascular and cancer morbidity and mortality in 940 older men reported a close association between the highest GDF-15 tertile and decline in renal function [147]. Although this marker is of some interest there is a need for substantially more research in patients with renal failure.

12. Asymmetric Dimethylarginine

As an endogenous inhibitor of nitric oxide (NO) synthases, asymmetric dimethylarginine (ADMA) causes endothelial dysfunction, vasoconstriction, elevation of blood pressure, and aggravation of experimental atherosclerosis [148, 149]. After its release from methylated proteins, circulating ADMA levels are regulated via glomerular filtration and enzymatic degradation by dimethylarginine dimethylaminohydrolase. Originally described by Vallance and colleagues [150], ADMA has been investigated fairly extensively in the CKD population, especially in dialysis. Although the exact mechanism linking ADMA with CVD risk in dialysis patients remains to be clarified, one of the potential mechanisms involves an interaction with the sympathetic nervous system [151, 152]. Inhibition of NO synthesis by ADMA leads to enhanced norepinephrine release from sympathetic nerve endings, whereas sympathetic activation impairs endothelium-dependent NO dilation [153, 154]. Zoccali et al. reported that ADMA is an independent predictor of cardiovascular events (HR: 1.17, 1.04–1.33, ) and mortality (HR 1.26, 95% Cl 1.11–1.41, ) in patients receiving chronic hemodialysis [155]. The same researches showed that ADMA is associated with progression of carotid intima media thickness, cardiac remodeling, and LVH in hemodialysis [156, 157]. In patients with mild to moderate CKD, patients with levels of ADMA above the median () showed a faster decline in renal function (), and their mean time to end-stage renal failure was significantly shorter than in patients with ADMA levels below the median (52.8 months (95% CI 46.9 to 58.8) versus 71.6 months (95% CI 66.2 to 76.9)) [158]. The risk of doubling the serum creatinine level or the need for renal replacement therapy increased by 47% for every 0.1 μmol/L increase in ADMA concentration. In contrast, Busch et al. did not find any predictive role for ADMA in a heterogeneous group of patients suffering from CKD [159].

13. Paraoxonase 1

Paraoxonase 1 (PON1) is a 354-amino acid HDL-associated enzyme and has been shown to reduce the susceptibility of LDL to peroxidation [160]. This activity may provide antiatherogenic protection.

Juretić et al. reported a significantly lower concentration of PON1 in 69 patients receiving chronic hemodialysis compared to 145 controls [161]. Similarly, Dirican and coworkers found PON1 levels to be significantly lower in predialysis () and hemodialysis () patients compared to controls () [162]. Serum PON1 activity correlated inversely with serum urea and Cr levels. Subsequently, Saeed et al. showed that PON1 serum level was the best predictor of carotid IMT in a small cohort of predialysis and hemodialysis patients [163]. Sztanek et al. showed that the serum PON1 concentration was lower in patients who had undergone renal transplant () and those receiving chronic hemodialysis () than in controls (, ) [164]. They further described a significant correlation with other biomarkers associated with cardiovascular risk such as homocysteine () and ADMA (). Recent evidence suggests that optimization of renal replacement therapy may produce an increase in PON1 activity, due in part to removal of PON1 inhibitors by high efficiency dialysis [165].

14. Conclusions

It is very unlikely that any marker will have sufficient reproducibility, predictive power, and ease of accessibility to be embraced as the single best marker for prediction of untoward events in CKD. More likely and logically, a combination of biomarkers may provide useful prognostic information. Markers may also become useful as a guide for therapy to select the patient most likely to respond to an intervention with a more individualized approach. However, several methodological issues must be addressed before the routine use of serum biomarkers can be implemented. The close correlation between different biomarkers likely reflects the complexity of the pathophysiological processes leading to CVD in CKD. Although an integrated approach seems reasonable, large ad hoc observational studies should define the most parsimonious approach to risk prediction to avoid unnecessary and expensive testing in different clinical settings. In this regard, the lack of standardization for different assays and the use of cohort specific cutoff values to define high versus low risk subjects do not allow for a reliable comparison of different studies. Validation of cutoff values (external validation) as well as definition of the inter- and intraassay variability for each commercially available assay is a priority to understand how to use the information derived from different biomarkers. Most of all, however, biomarkers must be easy to use and understand to become tools the practicing physician can implement daily. Although promising, available data (Table 1) on serum biomarkers for risk prediction are currently insufficient to recommend their routine use for prognostication and as a guide to therapy in CKD patients.

Table 1: Summary of evidence on the use of serum biomarkers for CV risk prediction in CKD.

Biomarker
Metabolism
Prediction
Clinically useful for

Production
Accumulation in CKD
Dialysis
Putative mechanism(s) involved
Outcome
Risk stratification
Guide therapy

Natriuretic peptides

Atrial natriuretic peptide (ANP)
Atrial myocardium
Yes
Dialyzable only to a small degree
Marker of left ventricular dysfunction, severity of CHF in both general and CKD populations
All-cause mortality in CKD and dialysis patients. Sudden cardiac death and MI in dialysis patients
Useful
Useful (for CHF)

B-type natriuretic peptide (BNP)
Ventricular myocardium

C-type natriuretic peptide (CNP)
Endothelial cells/myocardium

Cardiac troponins

Troponins T, I, and C
Striated muscle
Yes
Increased in dialysis patients
Released after cardiac injury (cTNT)
Predicts CAD and death in CKD and dialysis patients
Useful
No data

Cardiac troponin I (cTNI)
Cardiomyocytes

Cardiac troponin T (cTNT)
Cardiomyocytes

C-reactive protein

C-reactive protein (CRP)
Liver-acute phase reactant
?
Increases during dialysis
Marker of systemic inflammation
Predicts CAD, all-cause mortality
Not useful if used alone
Not useful

Adiponectin

Adiponectin (APN)
Adipocytes
Yes
? Influenced by nutritional status
Anti-inflammatory and antiatherogenic activities, enhances insulin-sensitivity. Associated with malnutrition
Cardiovascular events, all-cause mortality
Not useful, influenced by nutritional status
Not useful, influenced by nutritional status

Leptin

Leptin
Adipocytes
Yes, glomerular filtration and tubular degradation
Increased levels influenced by insulin resistance, metabolic acidosis, and uremic toxins
Anorectic agent associated with cIMT and arterial stiffness
Inverse association with cardiovascular events?
Not useful
Not useful

Fibroblast growth factor 23 (FGF-23)

Fibroblast growth factor 23
Osteocytes
Yes
Increased levels, though low molecular weight and dialysable
Suppresses renal tubular phosphate reabsorption, 1,25OH vitamin D activation and increases 1,25HO vitamin D degradation and possibly iPTH secretion
Associated with ESRD occurrence, CKD progression, LVH, CHF, and atherosclerotic events, all-cause mortality
Useful
No data

Klotho

Klotho
Produced in different tissues: endothelial cells, parathyroid glands, renal tubular cells, and VSMC
Not known
Not known
FGF-23 coreceptor (see FGF-23 actions); ROS and NO production
Oxidative stress, vascular calcification, and all-cause mortality
No data
No data

Fetuin A and Calciprotein Particles

Fetuin-A/Calciprotein Particles
Hepatocytes/serum
Yes
?
Fetuin A forms soluble complexes in the circulation with calcium and phosphate crystals to avoid their precipitation.
Mortality. CKD progression
May be useful
No data; may become useful

Wnt inhibitors

Sclerostin 
Osteocytes
Yes 
Increased in dialysis patients
Inhibitors of Wnt pathway. Increase bone mass and reduce bone turnover
Mortality? CKD-MBD?
No data
No data

Dickkopf-1
(DKK-1)
?
?
?

Neutrophil gelatinase-associated lipocalin (NGAL)

NGAL
Several tissues
Inversely associated with creatinine clearance
?
Suppresses gelatinase B inactivation leading to proteolytic activity and collagen degradation
Acute Kidney Injury, CKD progression, CV events, and mortality
Useful
No data

Plasma growth factor-15 (GDF-15)

GDF-15
?
?
?
Potential inhibitor of left ventricular hypertrophy, overexpressed in atherosclerotic disease
Incident CKD, all-cause and CV mortality
No data
No data

Asymmetric dimethylarginine (ADMA)

ADMA
?
Renal clearance
Increased in dialysis patients
Impairs endothelium dependent NO dilatation
cIMT, LVH, CV events, renal function decline, and mortality
Useful
No data

Paraoxonase 1 (PON1)

PON1
?
Inversely associated with creatinine clearance
Reduced in dialysis patients. Optimal RRT may produce an increase in PON1
HDL-associated enzyme and has been shown to reduce the susceptibility of LDL to peroxidation
cIMT, CV events
No data
No data

CHF: congestive heart failure; CAD: coronary artery Disease; cIMT: carotid intima media thickness; iPTH: intact parathyroid hormone; LVH: left ventricular hypertrophy; VSMC: vascular smooth cells; CKD-MBD: chronic kidney disease mineral bone disorder; Wnt: wingless pathway.

Abbreviations

95% CI: | 95% confidence interval
ADMA: | Asymmetric dimethylarginine
ANP: | Atrial Natriuretic Peptide
BNP: | B-type natriuretic peptide
CAD: | Coronary artery disease
CHF: | Congestive heart failure
cIMT: | Carotid intima media thickness
CKD: | Chronic kidney disease
CKD-MBD: | Chronic kidney disease mineral bone disorder
CPP: | Calciprotein particles
CRP: | C-reactive protein
cTNI: | Cardiac troponin
CV: | Cardiovascular
CVD: | Cardiovascular disease
DKK-1: | Dickkopf-1
FGF-23: | Fibroblast growth factor 23
GDF-15: | Plasma growth factor-15
HR: | Hazard ratio
iPTH: | Intact parathyroid hormone
LVH: | Left ventricular hypertrophy
NGAL: | Neutrophil gelatinase-associated lipocalin
OR: | Odds ratio
PON1: | Paraoxonase 1
ROC: | Receiver operating characteristic
VSMC: | Vascular smooth cells
Wnt: | Wingless pathway.

Conflict of Interests

There is no conflict of interests to report for any of the authors related to this paper.

References

E. L. Schiffrin, M. L. Lipman, and J. F. E. Mann, “Chronic kidney disease: effects on the cardiovascular system,” Circulation, vol. 116, no. 1, pp. 85–97, 2007.

A. S. Go, G. M. Chertow, D. Fan, C. E. McCulloch, and C.-Y. Hsu, “Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization,” The New England Journal of Medicine, vol. 351, no. 13, pp. 1296–1305, 2004.

S. Vickery, M. C. Webb, C. P. Price, R. I. John, N. A. Abbas, and E. J. Lamb, “Prognostic value of cardiac biomarkers for death in a non-dialysis chronic kidney disease population,” Nephrology Dialysis Transplantation, vol. 23, no. 11, pp. 3546–3553, 2008.

R. G. Fassett, S. K. Venuthurupalli, G. C. Gobe, J. S. Coombes, M. A. Cooper, and W. E. Hoy, “Biomarkers in chronic kidney disease: a review,” Kidney International, vol. 80, no. 8, pp. 806–821, 2011.

Y. Iwanaga and S. Miyazaki, “Heart failure, chronic kidney disease, and biomarkers—an integrated viewpoint,” Circulation Journal, vol. 74, no. 7, pp. 1274–1282, 2010.

Y. Iwanaga, I. Nishi, S. Furuichi et al., “B-type natriuretic peptide strongly reflects diastolic wall stress in patients with chronic heart failure: comparison between systolic and diastolic heart failure,” Journal of the American College of Cardiology, vol. 47, no. 4, pp. 742–748, 2006.

P. A. McCullough, R. M. Nowak, J. McCord et al., “B-type natriuretic peptide and clinical judgment in emergency diagnosis of heart failure: analysis from Breathing Not Properly (BNP) Multinational Study,” Circulation, vol. 106, no. 4, pp. 416–422, 2002.

V. Epshteyn, K. Morrison, P. Krishnaswamy et al., “Utility of B-type natriuretic peptide (BNP) as a screen for left ventricular dysfunction in patients with diabetes,” Diabetes Care, vol. 26, no. 7, pp. 2081–2087, 2003.

A. S. Maisel, P. Krishnaswamy, R. M. Nowak et al., “Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure,” The New England Journal of Medicine, vol. 347, no. 3, pp. 161–167, 2002.

R. Xu, P. Ye, L. Luo et al., “Association between high-sensitivity cardiac troponin T and N-terminal pro-brain natriuretic peptide in a community based population,” Chinese Medical Journal, vol. 127, no. 4, pp. 638–644, 2014.

K. Kara, A. A. Mahabadi, M. H. Geisel et al., “B-type natriuretic peptide: distribution in the general population and the association with major cardiovascular and coronary events—the Heinz Nixdorf Recall Study,” Clinical Research in Cardiology, vol. 103, no. 2, pp. 125–132, 2014.

K. Kara, N. Lehmann, T. Neumann et al., “NT-proBNP is superior to BNP for predicting first cardiovascular events in the general population: the Heinz Nixdorf Recall Study,” International Journal of Cardiology, vol. 183, pp. 155–161, 2015.

Z. Hijazi, J. Oldgren, U. Andersson et al., “Cardiac biomarkers are associated with an increased risk of stroke and death in patients with atrial fibrillation: a randomized evaluation of long-term anticoagulation therapy (RE-LY) substudy,” Circulation, vol. 125, no. 13, pp. 1605–1616, 2012.

H. G. Wahl, S. Graf, H. Renz, and W. Fassbinder, “Elimination of the cardiac natriuretic peptides B-type natriuretic peptide (BNP) and N-terminal proBNP by hemodialysis,” Clinical Chemistry, vol. 50, no. 6, pp. 1071–1074, 2004.

Y. Ishizaka, Y. Yamamoto, M. Tanaka et al., “Molecular forms of human brain natriuretic peptide (BNP) in plasma of patients on hemodialysis (HD),” Clinical Nephrology, vol. 43, no. 4, pp. 237–242, 1995.

P. A. McCullough, T. Omland, and A. S. Maisel, “B-type natriuretic peptides: a diagnostic breakthrough for clinicians,” Reviews in Cardiovascular Medicine, vol. 4, no. 2, pp. 72–80, 2003.

S. Niizuma, Y. Iwanaga, T. Yahata et al., “Impact of left ventricular end-diastolic wall stress on plasma B-type natriuretic peptide in heart failure with chronic kidney disease and end-stage renal disease,” Clinical Chemistry, vol. 55, no. 7, pp. 1347–1353, 2009.

F. S. Apple, M. A. M. Murakami, L. A. Pearce, and C. A. Herzog, “Multi-biomarker risk stratification of N-terminal pro-B-type natriuretic peptide, high-sensitivity C-reactive protein, and cardiac troponin T and I in end-stage renal disease for all-cause death,” Clinical Chemistry, vol. 50, no. 12, pp. 2279–2285, 2004.

C. R. DeFilippi, S. L. Seliger, S. Maynard, and R. H. Christenson, “Impact of renal disease on natriuretic peptide testing for diagnosing decompensated heart failure and predicting mortality,” Clinical Chemistry, vol. 53, no. 8, pp. 1511–1519, 2007.

M. Sakuma, M. Nakamura, F. Tanaka et al., “Plasma B-type natriuretic peptide level and cardiovascular events in chronic kidney disease in a community-based population,” Circulation Journal, vol. 74, no. 4, pp. 792–797, 2010.

C. Sommerer, J. Beimler, V. Schwenger et al., “Cardiac biomarkers and survival in haemodialysis patients,” European Journal of Clinical Investigation, vol. 37, no. 5, pp. 350–356, 2007.

A. Y.-M. Wang, C. W.-K. Lam, C.-M. Yu et al., “N-terminal pro-brain natriuretic peptide: an independent risk predictor of cardiovascular congestion, mortality, and adverse cardiovascular outcomes in chronic peritoneal dialysis patients,” Journal of the American Society of Nephrology, vol. 18, no. 1, pp. 321–330, 2007.

R. Paniagua, M.-D. Ventura, M. Ávila-Díaz et al., “NT-proBNP, fluid volume overload and dialysis modality are independent predictors of mortality in ESRD patients,” Nephrology Dialysis Transplantation, vol. 25, no. 2, pp. 551–557, 2010.

M. Svensson, A. Gorst-Rasmussen, E. B. Schmidt, K. A. Jorgensen, and J. H. Christensen, “NT-pro-BNP is an independent predictor of mortality in patients with end-stage renal disease,” Clinical Nephrology, vol. 71, no. 4, pp. 380–386, 2009.

A. S. Jaffe, L. Babuin, and F. S. Apple, “Biomarkers in acute cardiac disease: the present and the future,” Journal of the American College of Cardiology, vol. 48, no. 1, pp. 1–11, 2006.

S. Kiatchoosakun, D. Sahasthas, C. Wongvipaporn, and C. Pongskul, “Cardiac troponin-T in pre-end stage kidney disease,” Journal of the Medical Association of Thailand, vol. 91, no. 12, pp. 1806–1811, 2008.

C. Sommerer, E. Giannitsis, V. Schwenger, and M. Zeier, “Cardiac biomarkers in haemodialysis patients: the prognostic value of amino-terminal pro-B-type natriuretic peptide and cardiac troponin T,” Nephron—Clinical Practice, vol. 107, no. 3, pp. c77–c81, 2007.

M. C. Iliou, C. Fumeron, M. O. Benoit et al., “Factors associated with increased serum levels of cardiac troponins T and I in chronic haemodialysis patients: chronic haemodialysis and new cardiac markers evaluation (CHANCE) study,” Nephrology Dialysis Transplantation, vol. 16, no. 7, pp. 1452–1458, 2001.

F. Mallamaci, C. Zoccali, S. Parlongo et al., “Troponin is related to left ventricular mass and predicts all-cause and cardiovascular mortality in hemodialysis patients,” The American Journal of Kidney Diseases, vol. 40, no. 1, pp. 68–75, 2002.

B. Havekes, J. G. van Manen, R. T. Krediet, E. W. Boeschoten, J. P. Vandenbroucke, and F. W. Dekker, “Serum troponin T concentration as a predictor of mortality in hemodialysis and peritoneal dialysis patients,” American Journal of Kidney Diseases, vol. 47, no. 5, pp. 823–829, 2006.

T. Hayashi, Y. Obi, T. Kimura et al., “Cardiac troponin T predicts occult coronary artery stenosis in patients with chronic kidney disease at the start of renal replacement therapy,” Nephrology Dialysis Transplantation, vol. 23, no. 9, pp. 2936–2942, 2008.

J. Dierkes, U. Domröse, S. Westphal et al., “Cardiac troponin T predicts mortality in patients with end-stage renal disease,” Circulation, vol. 102, no. 16, pp. 1964–1969, 2000.

M. Goicoechea, S. García De Vinuesa, F. Gómez-Campderá et al., “Clinical significance of cardiac troponin T levels in chronic kidney disease patients: predictive value for cardiovascular risk,” American Journal of Kidney Diseases, vol. 43, no. 5, pp. 846–853, 2004.

C. DeFilippi, S. Wasserman, S. Rosanio et al., “Cardiac troponin T and C-reactive protein for predicting prognosis, coronary atherosclerosis, and cardiomyopathy in patients undergoing long-term hemodialysis,” The Journal of the American Medical Association, vol. 290, no. 3, pp. 353–359, 2003.

C. Melloni, K. P. Alexander, S. Milford-Beland et al., “Prognostic value of troponins in patients with non-ST-segment elevation acute coronary syndromes and chronic kidney disease,” Clinical Cardiology, vol. 31, no. 3, pp. 125–129, 2008.

A. X. Garg, P. G. Blake, W. F. Clark, C. M. Clase, R. B. Haynes, and L. M. Moist, “Association between renal insufficiency and malnutrition in older adults: results from the NHANES III,” Kidney International, vol. 60, no. 5, pp. 1867–1874, 2001.

M. G. Shlipak, L. F. Fried, C. Crump et al., “Elevations of inflammatory and procoagulant biomarkers in elderly persons with renal insufficiency,” Circulation, vol. 107, no. 1, pp. 87–92, 2003.

H.-J. Hsu, C.-H. Yen, K.-H. Hsu et al., “Chronic kidney disease stage is a modulator on the association between high-sensitivity C-reactive protein and coronary vasospastic angina,” The Scientific World Journal, vol. 2014, Article ID 852507, 9 pages, 2014.

P. M. Ridker, “Clinical application of C-reactive protein for cardiovascular disease detection and prevention,” Circulation, vol. 107, no. 3, pp. 363–369, 2003.

T. A. Pearson, G. A. Mensah, R. W. Alexander et al., “Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the centers for disease control and prevention and the American Heart Association,” Circulation, vol. 107, no. 3, pp. 499–511, 2003.

F. M. van der Sande, J. P. Kooman, and K. M. Leunissen, “The predictive value of C-reactive protein in end-stage renal disease: is it clinically significant?” Blood Purification, vol. 24, no. 4, pp. 335–341, 2006.

F. Mallamaci, G. Tripepi, S. Cutrupi, L. S. Malatino, and C. Zoccali, “Prognostic value of combined use of biomarkers of inflammation, endothelial dysfunction, and myocardiopathy in patients with ESRD,” Kidney International, vol. 67, no. 6, pp. 2330–2337, 2005.

S. Snaedal, O. Heimbürger, A. R. Qureshi et al., “Comorbidity and acute clinical events as determinants of C-reactive protein variation in hemodialysis patients: implications for patient survival,” American Journal of Kidney Diseases, vol. 53, no. 6, pp. 1024–1033, 2009.

M. M. Nascimento, R. Pecoits-Filho, A. R. Qureshi et al., “The prognostic impact of fluctuating levels of C-reactive protein in Brazilian haemodialysis patients: a prospective study,” Nephrology Dialysis Transplantation, vol. 19, no. 11, pp. 2803–2809, 2004.

S.-H. Liu, Y.-J. Li, H.-H. Wu et al., “High-sensitivity C-reactive protein predicts mortality and technique failure in peritoneal dialysis patients,” PLoS ONE, vol. 9, no. 3, Article ID e93063, 2014.

M. Kanwar, M. Hashem, H. Rosman et al., “Usefulness of clinical evaluation, troponins, and C-reactive protein in predicting mortality among stable hemodialysis patients,” The American Journal of Cardiology, vol. 98, no. 9, pp. 1283–1287, 2006.

H. Honda, A. R. Qureshi, O. Heimbürger et al., “Serum albumin, C-reactive protein, interleukin 6, and fetuin a as predictors of malnutrition, cardiovascular disease, and mortality in patients with ESRD,” The American Journal of Kidney Diseases, vol. 47, no. 1, pp. 139–148, 2006.

C. Zoccali, G. Tripepi, and F. Mallamaci, “Predictors of cardiovascular death in ESRD,” Seminars in Nephrology, vol. 25, no. 6, pp. 358–362, 2005.

F. M. Fisher, M. E. Trujillo, W. Hanif et al., “Serum high molecular weight complex of adiponectin correlates better with glucose tolerance than total serum adiponectin in Indo-Asian males,” Diabetologia, vol. 48, no. 6, pp. 1084–1087, 2005.

M. Bouskila, U. B. Pajvani, and P. E. Scherer, “Adiponectin: a relevant player in PPARγ-agonist-mediated improvements in hepatic insulin sensitivity?” International Journal of Obesity, vol. 29, supplement 1, pp. S17–S23, 2005.

T. Yokota, C. S. R. Meka, T. Kouro et al., “Adiponectin, a fat cell product, influences the earliest lymphocyte precursors in bone marrow cultures by activation of the cyclooxygenase-prostaglandin pathway in stromal cells,” The Journal of Immunology, vol. 171, no. 10, pp. 5091–5099, 2003.

M. C. Wulster-Radcliffe, K. M. Ajuwon, J. Wang, J. A. Christian, and M. E. Spurlock, “Adiponectin differentially regulates cytokines in porcine macrophages,” Biochemical and Biophysical Research Communications, vol. 316, no. 3, pp. 924–929, 2004.

K. Hotta, T. Funahashi, Y. Arita et al., “Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 20, no. 6, pp. 1595–1599, 2000.

J. P. Whitehead, A. A. Richards, I. J. Hickman, G. A. Macdonald, and J. B. Prins, “Adiponectin—a key adipokine in the metabolic syndrome,” Diabetes, Obesity and Metabolism, vol. 8, no. 3, pp. 264–280, 2006.

Z. Dzielińska, A. Januszewicz, A. Więcek et al., “Decreased plasma concentration of a novel anti-inflammatory protein—adiponectin—in hypertensive men with coronary artery disease,” Thrombosis Research, vol. 110, no. 5-6, pp. 365–369, 2003.

N. Komura, S. Kihara, M. Sonoda et al., “Increment and impairment of adiponectin in renal failure,” Cardiovascular Research, vol. 86, no. 3, pp. 471–477, 2010.

M. Kumada, S. Kihara, S. Sumitsuji et al., “Association of hypoadiponectinemia with coronary artery disease in men,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 23, no. 1, pp. 85–89, 2003.

N. Ouchi, M. Ohishi, S. Kihara et al., “Association of hypoadiponectinemia with impaired vasoreactivity,” Hypertension, vol. 42, no. 3, pp. 231–234, 2003.

B. Kollerits, D. Fliser, I. M. Heid, E. Ritz, and F. Kronenberg, “Gender-specific association of adiponectin as a predictor of progression of chronic kidney disease: the Mild to Moderate Kidney Disease study,” Kidney International, vol. 71, no. 12, pp. 1279–1286, 2007.

C. Zoccali and F. Mallamaci, “Adiponectin and leptin in chronic kidney disease: causal factors or mere risk markers?” Journal of Renal Nutrition, vol. 21, no. 1, pp. 87–91, 2011.

B. Becker, F. Kronenberg, J. T. Kielstein et al., “Renal insulin resistance syndrome, adiponectin and cardiovascular events in patients with kidney disease: the mild and moderate kidney disease study,” Journal of the American Society of Nephrology, vol. 16, no. 4, pp. 1091–1098, 2005.

C. Zoccali, F. Mallamaci, G. Tripepi et al., “Adiponectin, metabolic risk factors, and cardiovascular events among patients with end-stage renal disease,” Journal of the American Society of Nephrology, vol. 13, no. 1, pp. 134–141, 2002.

V. Menon, L. Li, X. Wang et al., “Adiponectin and mortality in patients with chronic kidney disease,” Journal of the American Society of Nephrology, vol. 17, no. 9, pp. 2599–2606, 2006.

O. M. Kaisar, D. W. Johnson, J. B. Prins, and N. Isbel, “The role of novel biomarkers of cardiovascular disease in chronic kidney disease: focus on adiponectin and leptin,” Current Cardiology Reviews, vol. 4, no. 4, pp. 287–292, 2008.

P. Stenvinkel, “Leptin—a new hormone of definite interest for the nephrologist,” Nephrology Dialysis Transplantation, vol. 13, no. 5, pp. 1099–1101, 1998.

S. K. Fried, M. R. Ricci, C. D. Russell, and B. Laferrère, “Regulation of leptin production in humans,” Journal of Nutrition, vol. 130, no. 12, pp. 3127–3131S, 2000.

R. V. Considine, M. K. Sinha, M. L. Heiman et al., “Serum immunoreactive-leptin concentrations in normal-weight and obese humans,” The New England Journal of Medicine, vol. 334, no. 5, pp. 292–295, 1996.

D. G. Baskin, J. E. Blevins, and M. W. Schwartz, “How the brain regulates food intake and body weight: the role of leptin,” Journal of Pediatric Endocrinology and Metabolism, vol. 14, no. 6, pp. 1417–1429, 2001.

T. M. Mizuno, S. P. Kleopoulos, H. T. Bergen, J. L. Roberts, C. A. Priest, and C. V. Mobbs, “Hypothalamic pro-opiomelanocortin mRNA is reduced by fasting and [corrected] in ob/ob and db/db mice, but is stimulated by leptin,” Diabetes, vol. 47, no. 2, pp. 294–297, 1998.

M. Mapfei, J. Halaas, E. Ravussin et al., “Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects,” Nature Medicine, vol. 1, no. 11, pp. 1155–1161, 1995.

G. Boden, K. Sargrad, C. Homko, M. Mozzoli, and T. P. Stein, “Effect of a low-carbohydrate diet on appetite, blood glucose levels, and insulin resistance in obese patients with type 2 diabetes,” Annals of Internal Medicine, vol. 142, no. 6, pp. 403–411, 2005.

E. Merabet, S. Dagogo-Jack, D. W. Coyne et al., “Increased plasma leptin concentration in end-stage renal disease,” Journal of Clinical Endocrinology and Metabolism, vol. 82, no. 3, pp. 847–850, 1997.

J. J. Díez, P. Iglesias, M. J. Fernández-Reyes et al., “Serum concentrations of leptin, adiponectin and resistin, and their relationship with cardiovascular disease in patients with end-stage renal disease,” Clinical Endocrinology, vol. 62, no. 2, pp. 242–249, 2005.

D. Teta, A. Bevington, J. Brown, I. Pawluczyk, K. Harris, and J. Walls, “Acidosis downregulates leptin production from cultured adipocytes through a glucose transport-dependent post-transcriptional mechanism,” Journal of the American Society of Nephrology, vol. 14, no. 9, pp. 2248–2254, 2003.

L. Nordfors, F. Lönnqvist, O. Heimbürger, A. Danielsson, M. Schalling, and P. Stenvinkel, “Low leptin gene expression and hyperleptinemia in chronic renal failure,” Kidney International, vol. 54, no. 4, pp. 1267–1275, 1998.

A. Scholze and M. Tepel, “Role of leptin in reverse epidemiology in chronic kidney disease,” Seminars in Dialysis, vol. 20, no. 6, pp. 534–538, 2007.

M. Ciccone, R. Vettor, N. Pannacciulli et al., “Plasma leptin is independently associated with the intima-media thickness of the common carotid artery,” International Journal of Obesity, vol. 25, no. 6, pp. 805–810, 2001.

A. Singhal, I. S. Farooqi, T. J. Cole et al., “Influence of leptin on arterial distensibility: a novel link between obesity and cardiovascular disease?” Circulation, vol. 106, no. 15, pp. 1919–1924, 2002.

M. C. Lee, Y. C. Chen, G. J. Ho, M. H. Shih, K. C. Chou, and B. G. Hsu, “Serum leptin levels positively correlate with peripheral arterial stiffness in kidney transplantation patients,” Transplantation Proceedings, vol. 46, no. 2, pp. 353–358, 2014.

A. Aguilera, M. A. Bajo, F. Rebollo et al., “Leptin as a marker of nutrition and cardiovascular risk in peritoneal dialysis patients,” Advances in Peritoneal Dialysis, vol. 18, pp. 212–217, 2002.

A. Scholze, D. Rattensperger, W. Zidek, and M. Tepel, “Low serum leptin predicts mortality in patients with chronic kidney disease stage 5,” Obesity, vol. 15, no. 6, pp. 1617–1622, 2007.

I. Beberashvili, I. Sinuani, A. Azar et al., “Longitudinal study of leptin levels in chronic hemodialysis patients,” Nutrition Journal, vol. 10, no. 1, article 68, 2011.

Y.-C. Tsai, C.-T. Lee, T.-L. Huang et al., “Inflammatory marker but not adipokine predicts mortality among long-term hemodialysis patients,” Mediators of Inflammation, vol. 2007, Article ID 19891, 5 pages, 2007.

S. Moe, T. Drueke, G. Block, and J. Cannata-andia, “KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD),” Kidney International, vol. 113, pp. S1–S130, 2009.

S. Liu, J. Zhou, W. Tang, X. Jiang, D. W. Rowe, and L. D. Quarles, “Pathogenic role of Fgf23 in Hyp mice,” The American Journal of Physiology—Endocrinology and Metabolism, vol. 291, no. 1, pp. E38–E49, 2006.

H. Segawa, E. Kawakami, I. Kaneko et al., “Effect of hydrolysis-resistant FGF23-R179Q on dietary phosphate regulation of the renal type-II Na/Pi transporter,” Pflugers Archiv, vol. 446, no. 5, pp. 585–592, 2003.

T. Shimada, H. Hasegawa, Y. Yamazaki et al., “FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis,” Journal of Bone and Mineral Research, vol. 19, no. 3, pp. 429–435, 2004.

M. Yamazaki, K. Ozono, T. Okada et al., “Both FGF23 and extracellular phosphate activate Raf/MEK/ERK pathway via FGF receptors in HEK293 cells,” Journal of Cellular Biochemistry, vol. 111, no. 5, pp. 1210–1221, 2010.

V. P. Eswarakumar, I. Lax, and J. Schlessinger, “Cellular signaling by fibroblast growth factor receptors,” Cytokine and Growth Factor Reviews, vol. 16, no. 2, pp. 139–149, 2005.

M. Kuro-O, “Phosphate and klotho,” Kidney International, vol. 79, supplement 121, pp. S20–S23, 2011.

M. Christov, S. S. Waikar, R. C. Pereira et al., “Plasma FGF23 levels increase rapidly after acute kidney injury,” Kidney International, vol. 84, no. 4, pp. 776–785, 2013.

O. M. Gutiérrez, M. Mannstadt, T. Isakova et al., “Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis,” The New England Journal of Medicine, vol. 359, no. 6, pp. 584–592, 2008.

J. H. Ix, M. G. Shlipak, C. L. Wassel, and M. A. Whooley, “Fibroblast growth factor-23 and early decrements in kidney function: the heart and soul study,” Nephrology Dialysis Transplantation, vol. 25, no. 3, pp. 993–997, 2010.

M. Kanbay, M. Nicoleta, Y. Selcoki et al., “Fibroblast growth factor 23 and fetuin A are independent predictors for the coronary artery disease extent in mild chronic kidney disease,” Clinical Journal of the American Society of Nephrology, vol. 5, no. 10, pp. 1780–1786, 2010.

S. Seiler, B. Reichart, D. Roth, E. Seibert, D. Fliser, and G. H. Heine, “FGF-23 and future cardiovascular events in patients with chronic kidney disease before initiation of dialysis treatment,” Nephrology Dialysis Transplantation, vol. 25, no. 12, pp. 3983–3989, 2010.

T. Isakova, P. Wahl, G. S. Vargas et al., “Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease,” Kidney International, vol. 79, no. 12, pp. 1370–1378, 2011.

J. J. Scialla, H. Xie, M. Rahman et al., “Fibroblast growth factor-23 and cardiovascular events in CKD,” Journal of the American Society of Nephrology, vol. 25, no. 2, pp. 349–360, 2014.

C. M. Rebholz, M. E. Grams, J. Coresh et al., “Serum fibroblast growth factor-23 is associated with incident kidney disease,” Journal of the American Society of Nephrology, vol. 26, no. 1, pp. 192–200, 2015.

B. D. Parker, L. J. Schurgers, V. M. Brandenburg et al., “The associations of fibroblast growth factor 23 and uncarboxylated matrix Gla protein with mortality in coronary artery disease: the heart and soul study,” Annals of Internal Medicine, vol. 152, no. 10, pp. 640–648, 2010.

H. J. Oh, B. Y. Nam, M. J. Lee et al., “Decreased circulating Klotho levels in patients undergoing dialysis and relationship to oxidative stress and inflammation,” Peritoneal Dialysis International, vol. 35, no. 1, pp. 43–51, 2015.

R. D. Semba, A. R. Cappola, K. Sun et al., “Plasma klotho and mortality risk in older community-dwelling adults,” Journals of Gerontology—Series A Biological Sciences and Medical Sciences, vol. 66, no. 7, pp. 794–800, 2011.

D. E. Arking, D. M. Becker, L. R. Yanek et al., “KLOTHO allele status and the risk of early-onset occult coronary artery disease,” The American Journal of Human Genetics, vol. 72, no. 5, pp. 1154–1161, 2003.

J. F. Navarro-González, J. Donate-Correa, M. M. de Fuentes, H. Pérez-Hernández, R. Martínez-Sanz, and C. Mora-Fernández, “Reduced Klotho is associated with the presence and severity of coronary artery disease,” Heart, vol. 100, no. 1, pp. 34–40, 2014.

I. Agarwal, N. Ide, J. H. Ix et al., “Fibroblast growth factor-23 and cardiac structure and function,” Journal of the American Heart Association, vol. 3, no. 1, Article ID e000584, 2014.

M. Kuro-o, “Klotho, phosphate and FGF-23 in ageing and disturbed mineral metabolism,” Nature Reviews Nephrology, vol. 9, no. 11, pp. 650–660, 2013.

A. Pasch, S. Farese, S. Gräber et al., “Nanoparticle-based test measures overall propensity for calcification in serum,” Journal of the American Society of Nephrology, vol. 23, no. 10, pp. 1744–1752, 2012.

E. R. Smith, M. L. Ford, L. A. Tomlinson, C. Rajkumar, L. P. McMahon, and S. G. Holt, “Phosphorylated fetuin-A-containing calciprotein particles are associated with aortic stiffness and a procalcific milieu in patients with pre-dialysis CKD,” Nephrology, Dialysis, Transplantation, vol. 27, no. 5, pp. 1957–1966, 2012.

E. R. Smith, E. Hanssen, L. P. McMahon, and S. G. Holt, “Fetuin-A-containing calciprotein particles reduce mineral stress in the macrophage,” PLoS ONE, vol. 8, no. 4, Article ID e60904, 2013.

E. R. Smith, M. L. Ford, L. A. Tomlinson et al., “Serum calcification propensity predicts all-cause mortality in predialysis CKD,” Journal of the American Society of Nephrology, vol. 25, no. 2, pp. 339–348, 2014.

M. G. Vervloet, Z. A. Massy, V. M. Brandenburg et al., “Bone: a new endocrine organ at the heart of chronic kidney disease and mineral and bone disorders,” The Lancet Diabetes and Endocrinology, vol. 2, no. 5, pp. 427–436, 2014.

V. M. Brandenburg, R. Kramann, R. Koos et al., “Relationship between sclerostin and cardiovascular calcification in hemodialysis patients: a cross-sectional study,” BMC Nephrology, vol. 14, no. 1, article 219, 2013.

R. Kramann, V. M. Brandenburg, L. J. Schurgers et al., “Novel insights into osteogenesis and matrix remodelling associated with calcific uraemic arteriolopathy,” Nephrology Dialysis Transplantation, vol. 28, no. 4, pp. 856–868, 2013.

D. Cejka, J. Herberth, A. J. Branscum et al., “Sclerostin and dickkopf-1 in renal osteodystrophy,” Clinical Journal of the American Society of Nephrology, vol. 6, no. 4, pp. 877–882, 2011.

S. Thambiah, R. Roplekar, P. Manghat et al., “Circulating sclerostin and dickkopf-1 (DKK1) in predialysis chronic kidney disease (CKD): relationship with bone density and arterial stiffness,” Calcified Tissue International, vol. 90, no. 6, pp. 473–480, 2012.

L. Desjardins, S. Liabeuf, R. B. Oliveira et al., “Uremic toxicity and sclerostin in chronic kidney disease patients,” Néphrologie & Thérapeutique, vol. 10, no. 6, pp. 463–470, 2014.

L. Viaene, G. J. Behets, K. Claes et al., “Sclerostin: another bone-related protein related to all-cause mortality in haemodialysis?” Nephrology Dialysis Transplantation, vol. 28, no. 12, pp. 3024–3030, 2013.

C. Drechsler, P. Evenepoel, M. G. Vervloet et al., “High levels of circulating sclerostin are associated with better cardiovascular survival in incident dialysis patients: results from the NECOSAD study,” Nephrology Dialysis Transplantation, vol. 30, no. 2, pp. 288–293, 2015.

K. Mori, H. T. Lee, D. Rapoport et al., “Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury,” The Journal of Clinical Investigation, vol. 115, no. 3, pp. 610–621, 2005.

K. Mori and K. Nakao, “Neutrophil gelatinase-associated lipocalin as the real-time indicator of active kidney damage,” Kidney International, vol. 71, no. 10, pp. 967–970, 2007.

K. M. Schmidt-Ott, K. Mori, Y. L. Jau et al., “Dual action of neutrophil gelatinase-associated lipocalin,” Journal of the American Society of Nephrology, vol. 18, no. 2, pp. 407–413, 2007.

R. Hirsch, C. Dent, H. Pfriem et al., “NGAL is an early predictive biomarker of contrast-induced nephropathy in children,” Pediatric Nephrology, vol. 22, no. 12, pp. 2089–2095, 2007.

L. Kjeldsen, A. H. Johnsen, H. Sengelov, and N. Borregaard, “Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase,” The Journal of Biological Chemistry, vol. 268, no. 14, pp. 10425–10432, 1993.

J. B. Cowland and N. Borregaard, “Molecular characterization and pattern of tissue expression of the gene for neutrophil gelatinase-associated lipocalin from humans,” Genomics, vol. 45, no. 1, pp. 17–23, 1997.

A. Friedl, S. P. Stoesz, P. Buckley, and M. N. Gould, “Neutrophil gelatinase-associated lipocalin in normal and neoplastic human tissues. Cell type-specific pattern of expression,” Histochemical Journal, vol. 31, no. 7, pp. 433–441, 1999.

A.-L. Hemdahl, A. Gabrielsen, C. Zhu et al., “Expression of neutrophil gelatinase-associated lipocalin in atherosclerosis and myocardial infarction,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 26, no. 1, pp. 136–142, 2006.

J. R. Charlton, D. Portilla, and M. D. Okusa, “A basic science view of acute kidney injury biomarkers,” Nephrology Dialysis Transplantation, vol. 29, no. 7, pp. 1301–1311, 2014.

C. Donadio, “Effect of glomerular filtration rate impairment on diagnostic performance of neutrophil gelatinase-associated lipocalin and B-type natriuretic peptide as markers of acute cardiac and renal failure in chronic kidney disease patients,” Critical Care, vol. 18, no. 1, article R39, 2014.

J. Mishra, M. A. Qing, A. Prada et al., “Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury,” Journal of the American Society of Nephrology, vol. 14, no. 10, pp. 2534–2543, 2003.

M. Haase, R. Bellomo, P. Devarajan, P. Schlattmann, and A. Haase-Fielitz, “Accuracy of neutrophil gelatinase-associated lipocalin (NGAL) in diagnosis and prognosis in acute kidney injury: a systematic review and meta-analysis,” The American Journal of Kidney Diseases, vol. 54, no. 6, pp. 1012–1024, 2009.

J. Mishra, C. Dent, R. Tarabishi et al., “Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery,” The Lancet, vol. 365, no. 9466, pp. 1231–1238, 2005.

T. L. Nickolas, M. J. O'Rourke, J. Yang et al., “Sensitivity and specificity of a single emergency department measurement of urinary neutrophil gelatinase-associated lipocalin for diagnosing acute kidney injury,” Annals of Internal Medicine, vol. 148, no. 11, pp. 810–819, 2008.

A. Viau, K. El Karoui, D. Laouari et al., “Lipocalin 2 is essential for chronic kidney disease progression in mice and humans,” Journal of Clinical Investigation, vol. 120, no. 11, pp. 4065–4076, 2010.

D. Bolignano, A. Lacquaniti, G. Coppolino et al., “Neutrophil gelatinase-associated lipocalin as an early biomarker of nephropathy in diabetic patients,” Kidney and Blood Pressure Research, vol. 32, no. 2, pp. 91–98, 2009.

K. D. Liu, W. Yang, A. H. Anderson et al., “Urine neutrophil gelatinase-associated lipocalin levels do not improve risk prediction of progressive chronic kidney disease,” Kidney International, vol. 83, no. 5, pp. 909–914, 2013.

F. Furuya, H. Shimura, H. Yokomichi et al., “Neutrophil gelatinase-associated lipocalin levels associated with cardiovascular disease in chronic kidney disease patients,” Clinical and Experimental Nephrology, vol. 18, no. 5, pp. 778–783, 2014.

A. S. Maisel, C. Mueller, R. Fitzgerald et al., “Prognostic utility of plasma neutrophil gelatinase-associated lipocalin in patients with acute heart failure: the NGAL EvaLuation Along with B-type NaTriuretic Peptide in acutely decompensated heart failure (GALLANT) trial,” European Journal of Heart Failure, vol. 13, no. 8, pp. 846–851, 2011.

A. Thompson, P. Gao, L. Orfei et al., “Lipoprotein-associated phospholipase A₂ and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies,” The Lancet, vol. 375, no. 9725, pp. 1536–1544, 2010.

M. R. Bootcov, A. R. Bauskin, S. M. Valenzuela et al., “MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-β superfamily,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 21, pp. 11514–11519, 1997.

T. Kempf, M. Eden, J. Strelau et al., “The transforming growth factor-β superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury,” Circulation Research, vol. 98, no. 3, pp. 351–360, 2006.

J. Strelau, M. Böttner, P. Lingor et al., “GDF-15/MIC-1 a novel member of the TGF-beta superfamily,” Journal of Neural Transmission, Supplementum, no. 60, pp. 273–276, 2000.

J. Xu, T. R. Kimball, J. N. Lorenz et al., “GDF15/MIC-1 functions as a protective and antihypertrophic factor released from the myocardium in association with SMAD protein activation,” Circulation Research, vol. 98, no. 3, pp. 342–350, 2006.

D. Schlittenhardt, A. Schober, J. Strelau et al., “Involvement of growth differentiation factor-15/macrophage inhibitory cytokine-1 (GDF-15/MIC-1) in oxLDL-induced apoptosis of human macrophages in vitro and in arteriosclerotic lesions,” Cell and Tissue Research, vol. 318, no. 2, pp. 325–333, 2004.

D. A. Brown, S. N. Breit, J. Buring et al., “Concentration in plasma of macrophage inhibitory cytokine-1 and risk of cardiovascular events in women: a nested case-control study,” The Lancet, vol. 359, no. 9324, pp. 2159–2163, 2002.

T. Kempf, E. Björklund, S. Olofsson et al., “Growth-differentiation factor-15 improves risk stratification in ST-segment elevation myocardial infarction,” European Heart Journal, vol. 28, no. 23, pp. 2858–2865, 2007.

J. E. Ho, S.-J. Hwang, K. C. Wollert et al., “Biomarkers of cardiovascular stress and incident chronic kidney disease,” Clinical Chemistry, vol. 59, no. 11, pp. 1613–1620, 2013.

M. Lajer, A. Jorsal, L. Tarnow, H.-H. Parving, and P. Rossing, “Plasma growth differentiation factor-15 independently predicts all-cause and cardiovascular mortality as well as deterioration of kidney function in type 1 diabetic patients with nephropathy,” Diabetes Care, vol. 33, no. 7, pp. 1567–1572, 2010.

L. Wallentin, B. Zethelius, L. Berglund et al., “GDF-15 for prognostication of cardiovascular and cancer morbidity and mortality in men,” PLoS ONE, vol. 8, no. 12, Article ID e78797, 2013.

M. T. Bedford and S. G. Clarke, “Protein arginine methylation in mammals: who, what, and why,” Molecular Cell, vol. 33, no. 1, pp. 1–13, 2009.

R. H. Böger, R. Maas, F. Schulze, and E. Schwedhelm, “Asymmetric dimethylarginine (ADMA) as a prospective marker of cardiovascular disease and mortality—an update on patient populations with a wide range of cardiovascular risk,” Pharmacological Research, vol. 60, no. 6, pp. 481–487, 2009.

P. Vallance, A. Leone, A. Calver, J. Collier, and S. Moncada, “Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure,” The Lancet, vol. 339, no. 8793, pp. 572–575, 1992.

P. Schwarz, R. Diem, N. J. Dun, and U. Forstermann, “Endogenous and exogenous nitric oxide inhibits norepinephrine release from rat heart sympathetic nerves,” Circulation Research, vol. 77, no. 4, pp. 841–848, 1995.

F. Costa, N. J. Christensen, G. Farley, and I. Biaggioni, “NO modulates norepinephrine release in human skeletal muscle: implications for neural preconditioning,” American Journal of Physiology—Regulatory Integrative and Comparative Physiology, vol. 280, no. 5, pp. R1494–R1498, 2001.

M. L. Hijmering, E. S. G. Stroes, J. Olijhoek, B. A. Hutten, P. J. Blankestijn, and T. J. Rabelink, “Sympathetic activation markedly reduces endothelium-dependent, flow-mediated vasodilation,” Journal of the American College of Cardiology, vol. 39, no. 4, pp. 683–688, 2002.

F. Mallamaci, G. Tripepi, R. Maas, L. Malatino, R. Böger, and C. Zoccali, “Analysis of the relationship between norepinephrine and asymmetric dimethyl arginine levels among patients with end-stage renal disease,” Journal of the American Society of Nephrology, vol. 15, no. 2, pp. 435–441, 2004.

C. Zoccali, S. M. Bode-Böger, F. Mallamaci et al., “Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study,” The Lancet, vol. 358, no. 9299, pp. 2113–2117, 2001.

F. Mallamaci, F. Benedetto, G. Tripepi, L. Malatino, R. Boeger, and C. Zoccali, “Asymmetric dimethylarginine (ADMA) and carotid atherosclerosis in end-stage renal disease,” Journal of Hypertension, vol. 20, p. S140, 2002.

F. Mallamaci, G. Tripepi, G. Bonanno, G. Seminara, P. Fatuzzo, and F. Rapisarda, “Asymmetric dimethylarginine (ADMA), left ventricular hypertrophy and systolic dysfunction in hemodialysis patients,” Journal of the American Society of Nephrology, vol. 13, 2002.

D. Fliser, F. Kronenberg, J. T. Kielstein et al., “Asymmetric dimethylarginine and progression of chronic kidney disease: the mild to moderate kidney disease study,” Journal of the American Society of Nephrology, vol. 16, no. 8, pp. 2456–2461, 2005.

M. Busch, C. Fleck, G. Wolf, and G. Stein, “Asymmetrical (ADMA) and symmetrical dimethylarginine (SDMA) as potential risk factors for cardiovascular and renal outcome in chronic kidney disease—possible candidates for paradoxical epidemiology?” Amino Acids, vol. 30, no. 3, pp. 225–232, 2006.

P. N. Durrington, B. Mackness, and M. I. Mackness, “Paraoxonase and atherosclerosis,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 21, no. 4, pp. 473–480, 2001.

D. Juretić, M. Tadijanović, B. Rekić, V. Simeon-Rudolf, E. Reiner, and M. Baričić, “Serum paraoxonase activities in hemodialyzed uremic patients: cohort study,” Croatian Medical Journal, vol. 42, no. 2, pp. 146–150, 2001.

M. Dirican, R. Akça, E. Sarandöl, and K. Dilek, “Serum paraoxonase activity in uremic predialysis and hemodialysis patients,” Journal of Nephrology, vol. 17, no. 6, pp. 813–818, 2004.

S. A. Saeed, M. Elsharkawy, K. Elsaeed, and O. Fooda, “Paraoxonase-1 (PON1) activity as a risk factor for atherosclerosis in chronic renal failure patients,” Hemodialysis International, vol. 12, no. 4, pp. 471–479, 2008.

F. Sztanek, I. Seres, M. Harangi et al., “Decreased paraoxonase 1 (PON1) lactonase activity in hemodialyzed and renal transplanted patients. A novel cardiovascular biomarker in end-stage renal disease,” Nephrology Dialysis Transplantation, vol. 27, no. 7, pp. 2866–2872, 2012.

A. Gugliucci, E. Kinugasa, H. Ogata, R. Caccavello, and S. Kimura, “Activation of paraoxonase 1 after hemodialysis is associated with HDL remodeling and its increase in the HDL2 fraction and VLDL,” Clinica Chimica Acta, vol. 430, pp. 9–14, 2014.