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Cardiovascular Biomarkers in CKD: Pathophysiology and Implications for Clinical Management of Cardiac Disease

      Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with all forms of chronic kidney disease (CKD). The underlying pathological state is caused by a complex interplay of traditional and nontraditional risk factors that results in atherosclerosis, arteriosclerosis, and altered cardiac morphological characteristics. This multifactorial disease introduces new challenges in predicting and treating patients with CVD sufficiently early in the course of CKD to positively alter patient outcome. Asymptomatic individuals with progressive CVD are a group of patients that deserve focused attention because early detection and intervention may provide the best opportunity for improved outcome. However, identifying CVD in asymptomatic patients with CKD or end-stage renal disease remains a significant hurdle in the management of these patients. Recently, a number of cardiovascular biomarkers were identified as predictors of patient outcome in individuals with CVD and, with additional research, may be used to guide the early diagnosis of and therapy for CVD in patients with CKD. This review examines the pathophysiological characteristics and potential clinical role of these novel cardiovascular biomarkers in risk stratification, risk monitoring, and selection of preventive therapies for patients with CKD.

      Index Words

      CHRONIC KIDNEY DISEASE (CKD) associated with a decrease in glomerular filtration rate (GFR) confers a markedly increased risk for developing cardiovascular disease (CVD), accelerating the presence of existing CVD, and having an overall worse clinical prognosis. This was shown in people without known preexisting CVD,
      • Go A.S.
      • Chertow G.M.
      • Fan D.
      • McCulloch C.E.
      • Hsu C.-Y.
      Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.
      those with cardiovascular risk factors,
      • Ruilope L.M.
      • Salvetti A.
      • Jamerson K.
      • et al.
      Renal function and intensive lowering of blood pressure in hypertensive participants of the Hypertension Optimal Treatment (HOT) Study.
      • Mann J.F.
      • Gerstein H.C.
      • Pogue J.
      • Bosch J.
      • Yusuf S.
      Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril The HOPE randomized trial.
      and individuals experiencing a cardiovascular event.
      • Shlipak M.G.
      • Heidenreich P.A.
      • Noguchi H.
      • Chertow G.M.
      • Browner W.S.
      • McClellan M.B.
      Association of renal insufficiency with treatment and outcomes after myocardial infarction in elderly patients.
      • Anavekar N.S.
      • McMurray J.J.V.
      • Velazquez E.J.
      • et al.
      Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction.
      Patients with end-stage renal failure have profoundly increased age-specific mortality rates that are 20 to 50 times greater than in the general population, and 51% of these deaths are caused by CVD.
      • Excell L.
      • McDonald S.
      Deaths.
      The increased cardiovascular risk in patients with CKD is explained in part by the high prevalence of traditional cardiovascular risk factors, such as hypertension, diabetes mellitus, and dyslipidemia. These risk factors also contribute to the progression of CKD. However, use of traditional risk factors in risk prediction scores results in underestimation of CVD risk in patients with CKD, including patients with decreased GFR,
      • Sarnak M.J.
      • Coronado B.E.
      • Greene T.
      • et al.
      Cardiovascular disease risk factors in chronic renal insufficiency.
      patients receiving dialysis,
      • Longenecker J.C.
      • Coresh J.
      • Powe N.R.
      • et al.
      Traditional cardiovascular disease risk factors in dialysis patients compared with the general population The CHOICE Study.
      • Cheung A.K.
      • Sarnak M.J.
      • Yan G.
      • et al.
      Atherosclerotic cardiovascular disease risks in chronic hemodialysis patients.
      and renal transplant recipients.
      • Kasiske B.L.
      • Chakkera H.A.
      • Roel J.
      Explained and unexplained ischemic heart disease risk after renal transplantation.
      This underestimation is explained by a number of factors. First, CVD in patients with CKD is a broader entity than coronary heart disease and also includes left ventricular hypertrophy (LVH), vascular calcification, and congestive heart failure.
      • Foley R.N.
      • Parfrey P.S.
      • Sarnak M.J.
      Clinical epidemiology of cardiovascular disease in chronic renal disease.
      Second, the attributable risk of a specific factor is determined in part by its frequency within the population studied, but many coronary risk factors are more prevalent in patients with CKD than the populations from which prediction scores were derived. Third, some traditional risk factors show a relationship to outcomes opposite those of the general population, a phenomenon termed “reverse epidemiology.”
      • Kalantar-Zadeh K.
      • Block G.
      • Humphreys M.H.
      • et al.
      Reverse epidemiology of cardiovascular risk factors in maintenance dialysis patients.
      Finally, patients with CKD have nontraditional, or “uremia-related,” risk factors; conditions or biochemical abnormalities that occur more frequently (or exclusively) in patients with CKD and confer an increased risk for CVD (Table 1). These factors are important because they contribute to abnormal left ventricular morphological characteristics and vascular stiffness in addition to coronary heart disease. Microalbuminuria is an important predictor of progression of renal disease
      • Mogensen C.E.
      • Christensen C.K.
      Predicting diabetic nephropathy in insulin-dependent patients.
      and cardiovascular and noncardiovascular mortality.
      • Hillege H.L.
      • Fidler V.
      • Diercks G.F.H.
      • et al.
      Prevention of Renal and Vascular End Stage Disease (PREVEND) Study Group
      Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population.
      However, it is not discussed further in this review because we limit our discussion to cardiovascular biomarkers measured in serum.
      Table 1Risk Factors for CVD Specific to Patients With CKD or That Occur More Frequently or With Greater Levels in Patients With CKD
      Abnormal biochemistryFactors causing LVH
       Microalbuminuria/proteinuria Volume overload
       Mineral metabolism and vascular calcification Anemia
       Homocysteine Salt and water retention
       Thrombogenic factors Arteriovenous fistula
       Other “uremic toxins”Pressure overload
      Pathological processes Hypertension
       Inflammation Arteriosclerosis/vascular stiffening
       Oxidative stress Aortic stenosis
       Endothelial dysfunctionRenal transplant–specific factors
       Malnutrition Acute rejection
       Sympathetic nervous system overactivity Immunosuppression
      As shown by the underestimation of traditional risk factors and plethora of nontraditional risk factors, evaluation of nontraditional risk factors may enhance the ability of clinicians to stratify and manage cardiovascular risk in patients with all forms of CKD.

      Cardiovascular Biomarkers

      An ideal cardiovascular biomarker is a substance that is easily measurable; has levels elevated in disease states, but not in health; and is detectable sufficiently early in a disease process to allow diagnosis and effective therapy to occur before permanent organ dysfunction occurs.
      • Morrow D.A.
      • de Lemos J.A.
      • Sabatine M.S.
      • Antman E.M.
      The search for a biomarker of cardiac ischemia.
      In patients with CKD, such a cardiovascular biomarker may be used for a number of purposes: (1) identification of asymptomatic patients at greatest risk early in the course of renal disease, allowing early institution of preventive therapies; (2) definition of symptomatic patients at very high risk for cardiovascular events or death who may benefit from secondary preventive measures and more intensive cardiac investigation and management; (3) assessment of CVD in patients considered for renal transplantation; (4) surveillance of patients for whom cardiac disease may silently progress, who wait for years on renal transplant waiting lists; and (5) application of preventive measures in a targeted way that addresses many of the nontraditional risk factors.
      Cardiovascular biomarkers studied in patients with CKD are listed in Table 2 and discussed next in the context of the pathophysiological process they represent and potential clinical significance. The anatomy and complex interactions of these processes are shown in Fig 1.
      Table 2Cardiovascular Biomarkers Summarized by CKD Stage According to Whether They Were Shown to Predict Cardiovascular Outcomes
      Cardiovascular BiomarkerΔ in CKDCKD Stages 3-5 Not on DialysisPeritoneal DialysisHemodialysisRenal TransplantationRCT to Δ
      Endothelial dysfunction
       ADMAM, CVE
      • Zoccali C.
      • Bode-Boger S.
      • Mallamaci F.
      • et al.
      Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease A prospective study.
       HomocysteineCVE
      • Jungers P.
      • Chauveau P.
      • Bandin O.
      • et al.
      Hyperhomocysteinemia is associated with atherosclerotic occlusive arterial accidents in predialysis chronic renal failure patients.
      CVE
      • Ducloux D.
      • Bresson-Vautrin C.
      • Kribs M.
      • Abdelfatah A.
      • Chalopin J.M.
      C-Reactive protein and cardiovascular disease in peritoneal dialysis patients.
      M,
      Mortality relationship only in patients without inflammation.34 Conversely, low, rather than high, homocysteine level predicted mortality in another study.33
      • Ducloux D.
      • Klein A.
      • Kazory A.
      • Devillard N.
      • Chalopin J.-M.
      Impact of malnutrition-inflammation on the association between homocysteine and mortality.
      CVM,
      • Mallamaci F.
      • Zoccali C.
      • Tripepi G.
      • et al.
      Hyperhomocysteinemia predicts cardiovascular outcomes in hemodialysis patients.
      • Ducloux D.
      • Klein A.
      • Kazory A.
      • Devillard N.
      • Chalopin J.-M.
      Impact of malnutrition-inflammation on the association between homocysteine and mortality.
      CVE
      • Mallamaci F.
      • Zoccali C.
      • Tripepi G.
      • et al.
      Hyperhomocysteinemia predicts cardiovascular outcomes in hemodialysis patients.
      CVE
      • Ducloux D.
      • Kazory A.
      • Chalopin J.-M.
      Predicting coronary heart disease in renal transplant recipients A prospective study.
      No
      • Wrone E.M.
      • Hornberger J.M.
      • Zehnder J.L.
      • McCann L.M.
      • Coplon N.S.
      • Fortmann S.P.
      Randomized trial of folic acid for prevention of cardiovascular events in end-stage renal disease.
      • Zoungas S.
      • McGrath B.P.
      • Branley P.
      • et al.
      Cardiovascular morbidity and mortality in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in chronic renal failure A multicenter, randomized, controlled trial.
      Vascular calcification
       AHSGM, CVM
      • Stenvinkel P.
      • Wang K.
      • Qureshi A.R.
      • et al.
      Low fetuin-A levels are associated with cardiovascular death Impact of variations in the gene encoding fetuin.
      Endothelial monocyte recruitment
       MCP-1
       Selectins
       ICAM-1M
      • Stenvinkel P.
      • Lindholm B.
      • Heimburger M.
      • Heimburger O.
      Elevated serum levels of soluble adhesion molecules predict death in pre-dialysis patients Association with malnutrition, inflammation, and cardiovascular disease.
       VCAM-1
      Inflammation
       CRPM, CVM
      • Menon V.
      • Greene T.
      • Wang X.
      • et al.
      C-Reactive protein and albumin as predictors of all-cause and cardiovascular mortality in chronic kidney disease.
      M, CVE
      • Ducloux D.
      • Bresson-Vautrin C.
      • Kribs M.
      • Abdelfatah A.
      • Chalopin J.M.
      C-Reactive protein and cardiovascular disease in peritoneal dialysis patients.
      M,
      • Zimmermann J.
      • Herrlinger S.
      • Pruy A.
      • Metzger T.
      • Wanner C.
      Inflammation enhances cardiovascular risk and mortality in hemodialysis patients.
      • Iseki K.
      • Tozawa M.
      • Yoshi S.
      • Fukiyama K.
      Serum C-reactive protein (CRP) and risk of death in chronic dialysis patients.
      • Yeun J.Y.
      • Levine R.A.
      • Mantadilok V.
      • Kaysen G.A.
      C-Reactive protein predicts all-cause and cardiovascular mortality in hemodialysis patients.
      CVM
      • Zimmermann J.
      • Herrlinger S.
      • Pruy A.
      • Metzger T.
      • Wanner C.
      Inflammation enhances cardiovascular risk and mortality in hemodialysis patients.
      • Yeun J.Y.
      • Levine R.A.
      • Mantadilok V.
      • Kaysen G.A.
      C-Reactive protein predicts all-cause and cardiovascular mortality in hemodialysis patients.
      CVE,
      • Ducloux D.
      • Kazory A.
      • Chalopin J.-M.
      Predicting coronary heart disease in renal transplant recipients A prospective study.
      M, CVM
      • Varagunam M.
      • Finney H.
      • Trevitt R.
      • et al.
      Pretransplantation levels of C-reactive protein predict all-cause and cardiovascular mortality, but not graft outcome, in kidney transplant recipients.
       IL-6CVM
      • Shlipak M.G.
      • Fried L.F.
      • Cushman M.
      • et al.
      Cardiovascular mortality risk in chronic kidney disease Comparison of traditional and novel risk factors.
      M,
      • Kimmel P.L.
      • Phillips T.M.
      • Simmens S.J.
      • et al.
      Immunologic function and survival in hemodialysis patients.
      • Rao M.
      • Guo D.
      • Perianayagam M.C.
      • et al.
      Plasma interleukin-6 predicts cardiovascular mortality in hemodialysis patients.
      CVM
      • Panichi V.
      • Maggiore U.
      • Taccola D.
      • et al.
      Interleukin-6 is a stronger predictor of total and cardiovascular mortality than C-reactive protein in haemodialysis patients.
      • Rao M.
      • Guo D.
      • Perianayagam M.C.
      • et al.
      Plasma interleukin-6 predicts cardiovascular mortality in hemodialysis patients.
       TNF-αM
      • Kimmel P.L.
      • Phillips T.M.
      • Simmens S.J.
      • et al.
      Immunologic function and survival in hemodialysis patients.
       FibrinogenCVE
      • Descamps-Latscha B.
      • Witko-Sarsat V.
      • Nguyen-Khoa T.
      • et al.
      Advanced oxidation protein products as risk factors for atherosclerotic cardiovascular events in nondiabetic predialysis patients.
      CVE
      • Enia G.
      • Panuccio V.
      • Mallamaci F.
      • Tripepi G.
      • Mandalari A.
      • Zoccali C.
      Fibrinogen and calcium × phosphate product are predictors of cardiovascular events in the CAPD population.
      M,
      • Zoccali C.
      • Mallamaci F.
      • Tripepi G.
      • et al.
      Fibrinogen, mortality and incident cardiovascular complications in end-stage renal failure.
      • Koch M.
      • Kutkuhn B.
      • Grabensee B.
      • Ritz E.
      Apolipoprotein A, fibrinogen, age, and history of stroke are predictors of death in dialysed diabetic patients A prospective study in 412 subjects.
      CVM,
      • Koch M.
      • Kutkuhn B.
      • Grabensee B.
      • Ritz E.
      Apolipoprotein A, fibrinogen, age, and history of stroke are predictors of death in dialysed diabetic patients A prospective study in 412 subjects.
      CVE
      • Zoccali C.
      • Mallamaci F.
      • Tripepi G.
      • et al.
      Fibrinogen, mortality and incident cardiovascular complications in end-stage renal failure.
       Serum amyloid A
      Oxidative stress
      Two RCTs showed a decrease in composite CVE end points with antioxidant therapy (not decreasing a specific cardiovascular biomarker level).118,119
       F2-Isoprostanes
       PlasmalogenCVM
      • Stenvinkel P.
      • Diczfalusy U.
      • Lindholm B.
      • Heimburger O.
      Phospholipid plasmalogen, a surrogate marker of oxidative stress, is associated with increased cardiovascular mortality in patients on renal replacement therapy.
       Advanced oxidation protein productsCVE
      • Descamps-Latscha B.
      • Witko-Sarsat V.
      • Nguyen-Khoa T.
      • et al.
      Advanced oxidation protein products as risk factors for atherosclerotic cardiovascular events in nondiabetic predialysis patients.
      Sympathetic overactivity
       Neuropeptide YCVE
      This study was predominantly hemodialysis patients, but included some peritoneal dialysis patients.
      • Zoccali C.
      • Mallamaci F.
      • Tripepi G.
      • et al.
      Prospective study of neuropeptide Y as an adverse cardiovascular risk factor in end-stage renal disease.
       NorepinephrineM, CVE
      • Zoccali C.
      • Mallamaci F.
      • Parlongo S.
      • et al.
      Plasma norepinephrine predicts survival and incident cardiovascular events in patients with end-stage renal disease.
      Glycosylation of proteins
       AGEsM
      • Roberts M.A.
      • Thomas M.C.
      • Fernando D.
      • Macmillan N.
      • Power D.A.
      • Ierino F.L.
      Low molecular weight advanced glycation end products predict mortality in asymptomatic patients receiving chronic haemodialysis.
      • Wagner Z.
      • Molnar M.
      • Molnar G.A.
      • et al.
      Serum carboxymethyllysine predicts mortality in hemodialysis patients.
      Bone marrow function
       HemoglobinM, CVE
      • Li S.
      • Foley R.N.
      • Collins A.J.
      Anemia, hospitalization, and mortality in patients receiving peritoneal dialysis in the United States.
      M
      • Robinson B.M.
      • Joffe M.M.
      • Berns J.S.
      • Pisoni R.L.
      • Port F.K.
      • Feldman H.I.
      Anemia and mortality in hemodialysis patients Accounting for morbidity and treatment variables updated over time.
      M, CVM
      • Rigatto C.
      • Parfrey P.
      • Foley R.
      • Negrijn C.
      • Tribula C.
      • Jeffery J.
      Congestive heart failure in renal transplant recipients Risk factors, outcomes, and relationship with ischemic heart disease.
      No
      • Levin A.
      • Djurdjev O.
      • Thompson C.
      • et al.
      Canadian randomized trial of hemoglobin maintenance to prevent or delay left ventricular mass growth in patients with CKD.
      • Parfrey P.S.
      • Foley R.N.
      • Wittreich B.H.
      • Sullivan D.J.
      • Zagari M.J.
      • Frei D.
      Canadian European Study
      Double-blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease.
      • Strippoli G.F.M.
      • Craig J.C.
      • Manno C.
      • Schena F.P.
      Hemoglobin targets for the anemia of chronic kidney disease A meta-analysis of randomized, controlled trials.
       EPCs
      Platelet activation
       sCD40L
      Left ventricle stretch
       BNP-32CVE
      CVEs were hospitalizations for heart failure.
      • Takami Y.
      • Horio T.
      • Iwashima Y.
      • et al.
      Diagnostic and prognostic value of plasma brain natriuretic peptide in non–dialysis-dependent CRF.
      M,
      • Zoccali C.
      • Mallamaci F.
      • Benedetto F.A.
      • et al.
      Cardiac natriuretic peptides are related to left ventricular mass and function and predict mortality in dialysis patients.
      CVM
      • Naganuma T.
      • Sugimura K.
      • Wada S.
      • et al.
      The prognostic role of brain natriuretic peptides in hemodialysis patients.
      • Cataliotti A.
      • Malatino L.S.
      • Jougasaki M.
      • et al.
      Circulating natriuretic peptide concentrations in patients with end-stage renal disease Role of brain natriuretic peptide as a biomarker for ventricular remodeling.
      • Zoccali C.
      • Mallamaci F.
      • Benedetto F.A.
      • et al.
      Cardiac natriuretic peptides are related to left ventricular mass and function and predict mortality in dialysis patients.
       NT-proBNP1-76M
      • Anwaruddin S.
      • Lloyd-Jones D.M.
      • Baggish A.
      • et al.
      Renal function, congestive heart failure, and amino-terminal pro-brain natriuretic peptide measurement Results from the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) Study.
      Myocardial necrosis
       cTnTM
      • Wood G.N.
      • Keevil B.
      • Gupta J.
      • et al.
      Serum troponin T measurement in patients with chronic renal impairment predicts survival and vascular disease A 2 year prospective study.
      M, CVM
      • Duman D.
      • Tokay S.
      • Toprak A.
      • Duman D.
      • Oktay A.
      • Ozener I.C.
      Elevated cardiac troponin T is associated with increased left ventricular mass index and predicts mortality in continuous ambulatory peritoneal dialysis patients.
      M, CVM,
      • Khan N.A.
      • Hemmelgarn B.R.
      • Tonelli M.
      • Thompson C.R.
      • Levin A.
      Prognostic value of troponin T and I among asymptomatic patients with end-stage renal disease A meta-analysis.
      CVE
      • Iliou M.C.
      • Fumeron C.
      • Benoit M.O.
      • et al.
      Prognostic value of cardiac markers in ESRD Chronic Hemodialysis and New Cardiac Markers Evaluation (CHANCE) Study.
       cTnIM
      • Apple F.S.
      • Murakami M.M.
      • Pearce L.A.
      • Herzog C.A.
      Predictive value of cardiac troponin I and T for subsequent death in end-stage renal disease.
      • Boulier A.
      • Jaussent I.
      • Terrier N.
      • et al.
      Measurement of circulating troponin Ic enhances the prognostic value of C-reactive protein in haemodialysis patients.
       Miscellaneous
       AdiponectinCVE
      Low levels predicted events.
      • Zoccali C.
      • Mallamaci F.
      • Tripepi G.
      • et al.
      Adiponectin, metabolic risk factors, and cardiovascular events among patients with end-stage renal disease.
       RelaxinM
      In males only.
      • Hocher B.
      • Ziebig R.
      • Krause R.
      • et al.
      Relaxin is an independent risk factor predicting death in male patients with end-stage kidney disease.
       IL-8M, CVM
      • Panichi V.
      • Taccola D.
      • Rizza G.M.
      • et al.
      Interleukin-8 is a powerful prognostic predictor of all-cause and cardiovascular mortality in dialytic patients.
       Pregnancy-associated plasma protein ACVE
      • Lauzurica R.
      • Pastor C.
      • Bayes B.
      • Hernandez J.M.
      • Romero R.
      Pretransplant pregnancy-associated plasma protein-a as a predictor of chronic allograft nephropathy and posttransplant cardiovascular events.
      NOTE. Only studies in which a relationship was significant after adjustment in multivariate analyses for other important factors are included. Direction of change in cardiovascular biomarker levels with stage of CKD is listed in the second column and whether therapy to decrease levels of the specific marker is of proven benefit is listed in the last column.
      Abbreviations: M, all-cause mortality; CVM, cardiovascular mortality; CVE, cardiovascular events; Δ, change in cardiovascular biomarker level.
      low asterisk Mortality relationship only in patients without inflammation.
      • Ducloux D.
      • Klein A.
      • Kazory A.
      • Devillard N.
      • Chalopin J.-M.
      Impact of malnutrition-inflammation on the association between homocysteine and mortality.
      Conversely, low, rather than high, homocysteine level predicted mortality in another study.
      • Kalantar-Zadeh K.
      • Block G.
      • Humphreys M.H.
      • McAllister C.J.
      • Kopple J.D.
      A low, rather than a high, total plasma homocysteine is an indicator of poor outcome in hemodialysis patients.
      Two RCTs showed a decrease in composite CVE end points with antioxidant therapy (not decreasing a specific cardiovascular biomarker level).
      • Boaz M.
      • Smetana S.
      • Weinstein T.
      • et al.
      Secondary Prevention With Antioxidants of Cardiovascular Disease in Endstage Renal Disease (SPACE) Randomised placebo-controlled trial.
      • Tepel M.
      • van der Giet M.
      • Statz M.
      • Jankowski J.
      • Zidek W.
      The antioxidant acetylcysteine reduces cardiovascular events in patients with end-stage renal failure A randomized, controlled trial.
      This study was predominantly hemodialysis patients, but included some peritoneal dialysis patients.
      § CVEs were hospitalizations for heart failure.
      Low levels predicted events.
      In males only.
      Figure thumbnail gr1
      Fig 1Schema showing various pathophysiological processes that give rise to the cardiovascular biomarkers listed in and some of the organ systems involved. Multiple interactions between processes are illustrated.

       Endothelial Dysfunction

       Asymmetric Dimethylarginine

      Generation of nitric oxide by nitric oxide synthase is important in the regulatory function of the endothelium. Asymmetric dimethylarginine (ADMA), a substance synthesized by methylation of arginine residues in proteins and released as these proteins are hydrolyzed within cells, inhibits nitric oxide synthase, decreasing nitric oxide levels. Assays for ADMA are not widely available, and methods include high-performance liquid chromatography, liquid chromatography-mass spectrometry, gas chromatography-mass spectrometry, and enzyme-linked immunosorbent assay (ELISA).
      • Schulze F.
      • Wesemann R.
      • Schwedhelm E.
      • et al.
      Determination of asymmetric dimethylarginine (ADMA) using a novel ELISA assay.
      As a cardiovascular biomarker, elevated ADMA levels predict acute coronary events in the general population.
      • Valkonen V.P.
      • Paiva H.
      • Salonen J.T.
      • et al.
      Risk of acute coronary events and serum concentration of asymmetrical dimethylarginine.
      ADMA accumulates in patients with CKD
      • Vallance P.
      • Leone A.
      • Calver A.
      • Collier J.
      • Moncada S.
      Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure.
      because of both decreased renal excretion and decreased enzymatic hydrolysis.
      • Kielstein J.T.
      • Frolich J.C.
      • Haller H.
      • Fliser D.
      ADMA (asymmetric dimethylarginine) An atherosclerotic disease mediating agent in patients with renal disease?.
      In patients on hemodialysis therapy, ADMA level predicts both all-cause mortality and cardiovascular events
      • Zoccali C.
      • Bode-Boger S.
      • Mallamaci F.
      • et al.
      Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease A prospective study.
      and correlates positively with left ventricular mass index and negatively with ejection fraction.
      • Zoccali C.
      • Mallamaci F.
      • Maas R.
      • et al.
      Left ventricular hypertrophy, cardiac remodeling and asymmetric dimethylarginine (ADMA) in hemodialysis patients.
      Treatment with l-arginine may overcome inhibition of nitric oxide synthase by ADMA, and this has been studied in patients with CKD with varying results.
      • Bennett-Richards K.J.
      • Kattenhorn M.
      • Donald A.E.
      • et al.
      Oral l-arginine does not improve endothelial dysfunction in children with chronic renal failure.
      • Clarkson P.
      • Adams M.R.
      • Powe A.J.
      • et al.
      Oral l-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults.
      Inhibitors of the renin-angiotensin system, metformin, and thiazolidinediones also may decrease ADMA levels.
      • Zoccali C.
      Asymmetric dimethylarginine (ADMA) A cardiovascular and renal risk factor on the move.

       Homocysteine

      Homocysteine is a sulfhydryl-containing amino acid generated by metabolism of dietary methionine. Potential proatherogenic effects of homocysteine include: (1) oxidative stress, (2) alteration in endothelial antithrombotic mechanisms, and (3) direct damage to the vascular matrix.
      • Welch G.N.
      • Loscalzo J.
      Homocysteine and atherothrombosis.
      Automated immunofluorescence assays are available for measurement of plasma total homocysteine.
      In observational studies, elevated homocysteine levels confer increased risk for vascular disease in the general population.
      Homocysteine Studies Collaboration
      Homocysteine and risk of ischemic heart disease and stroke A meta-analysis.
      However, randomized controlled trials (RCTs) of patients with CVD risk factors
      The Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators
      Homocysteine lowering with folic acid and B vitamins in vascular disease.
      • Bonaa K.H.
      • Njolstad I.
      • Ueland P.M.
      • et al.
      NORVIT Trial Investigators
      Homocysteine lowering and cardiovascular events after acute myocardial infarction.
      treated with folate, vitamin B6, and vitamin B12 to decrease homocysteine levels do not show a decrease in cardiovascular events despite effective decreases in total plasma homocysteine levels in the treatment group.
      Total homocysteine levels increase as GFR decreases, and renal metabolism, rather than clearance, is the major mechanism.
      • Hankey G.J.
      • Eikelboom J.W.
      Homocysteine and vascular disease.
      In patients with CKD stages 3 and 4, elevated homocysteine levels had no relationship to all-cause or cardiovascular mortality after adjustment for GFR,
      • Menon V.
      • Sarnak M.J.
      • Greene T.
      • et al.
      Relationship between homocysteine and mortality in chronic kidney disease.
      although a significant association was shown in an earlier study.
      • Jungers P.
      • Chauveau P.
      • Bandin O.
      • et al.
      Hyperhomocysteinemia is associated with atherosclerotic occlusive arterial accidents in predialysis chronic renal failure patients.
      Both positive
      • Mallamaci F.
      • Zoccali C.
      • Tripepi G.
      • et al.
      Hyperhomocysteinemia predicts cardiovascular outcomes in hemodialysis patients.
      and negative
      • Kalantar-Zadeh K.
      • Block G.
      • Humphreys M.H.
      • McAllister C.J.
      • Kopple J.D.
      A low, rather than a high, total plasma homocysteine is an indicator of poor outcome in hemodialysis patients.
      associations between elevated homocysteine levels and cardiovascular outcomes were reported in the dialysis population. This may occur because elevated homocysteine level is associated with all-cause and cardiovascular mortality only in the subgroup of patients without biochemical evidence of inflammation and malnutrition.
      • Ducloux D.
      • Klein A.
      • Kazory A.
      • Devillard N.
      • Chalopin J.-M.
      Impact of malnutrition-inflammation on the association between homocysteine and mortality.
      Two RCTs using folic acid, 15 mg/d, to decrease plasma total homocysteine levels failed to show a decrease in clinical end points in patients undergoing peritoneal dialysis and hemodialysis.
      • Wrone E.M.
      • Hornberger J.M.
      • Zehnder J.L.
      • McCann L.M.
      • Coplon N.S.
      • Fortmann S.P.
      Randomized trial of folic acid for prevention of cardiovascular events in end-stage renal disease.
      • Zoungas S.
      • McGrath B.P.
      • Branley P.
      • et al.
      Cardiovascular morbidity and mortality in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in chronic renal failure A multicenter, randomized, controlled trial.
      Predialysis patients (15%) were included in 1 study.
      • Zoungas S.
      • McGrath B.P.
      • Branley P.
      • et al.
      Cardiovascular morbidity and mortality in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in chronic renal failure A multicenter, randomized, controlled trial.
      Homocysteine levels are increased in renal transplant recipients
      • Juskowa J.
      • Bartlomiejczyk J.
      • Paczek L.
      • et al.
      Total homocysteine as a risk factor for vascular disease in renal transplant recipients.
      and predict cardiovascular events.
      • Ducloux D.
      • Kazory A.
      • Chalopin J.-M.
      Predicting coronary heart disease in renal transplant recipients A prospective study.
      A large trial of decreasing homocysteine levels to decrease cardiovascular events is underway in this population (http://www.clinicaltrials.gov/ct/show/NCT00064753?order=1).

       Vascular Calcification

       Fetuin A

      Fetuin A (α2-Heremans Schmid glycoprotein [AHSG]) is a circulating inhibitor of vascular calcification,
      • Ketteler M.
      • Bongartz P.
      • Westenfeld R.
      • et al.
      Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis A cross-sectional study.
      a process that is not just precipitation of calcium and phosphate, but that also involves transformation of vascular smooth muscle cells to osteoblast-like cells expressing bone proteins and undergoing mineralization.
      • Giachelli C.M.
      Vascular calcification mechanisms.
      Commercially available indirect ELISA kits are used to measure AHSG.
      • Ketteler M.
      • Bongartz P.
      • Westenfeld R.
      • et al.
      Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis A cross-sectional study.
      Outcome studies of the general population are lacking, but in hemodialysis patients, AHSG level correlates inversely with inflammation (C-reactive protein [CRP] level), and for both hemodialysis and peritoneal dialysis patients, low levels predict cardiovascular events and mortality, but not after adjustment that includes indices of inflammation and nutrition.
      • Ketteler M.
      • Bongartz P.
      • Westenfeld R.
      • et al.
      Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis A cross-sectional study.
      • Wang A.Y.-M.
      • Woo J.
      • Lam C.W.-K.
      • et al.
      Associations of serum fetuin-A with malnutrition, inflammation, atherosclerosis and valvular calcification syndrome and outcome in peritoneal dialysis patients.
      In patients with stage 5 CKD before starting dialysis therapy, low AHSG levels predict all-cause and cardiovascular mortality, even after adjusting for indices of inflammation and nutrition.
      • Stenvinkel P.
      • Wang K.
      • Qureshi A.R.
      • et al.
      Low fetuin-A levels are associated with cardiovascular death Impact of variations in the gene encoding fetuin.
      Achievement of target ranges of calcium, phosphate, parathyroid hormone, and calcium-phosphate product through manipulation of diet, phosphate-binding drugs, and dialysis regimens is the current basis of prevention. These biochemical indices have been studied in relation to cardiovascular outcomes.
      • Block G.
      • Hulbert-Shearon T.
      • Levin N.
      • Port F.
      Association of serum phosphorus and calcium × phosphate product with mortality risk in chronic hemodialysis patients A national study.
      • Stevens L.A.
      • Djurdjev O.
      • Cardew S.
      • Cameron E.C.
      • Levin A.
      Calcium, phosphate, and parathyroid hormone levels in combination and as a function of dialysis duration predict mortality Evidence for the complexity of the association between mineral metabolism and outcomes.
      Low AHSG levels may identify patients who will receive the greatest benefit from stricter or lower target levels of calcium and phosphate, achieved by using novel dialysis regimens (short daily or nocturnal dialysis), noncalcium phosphate binders, or calcimimetic drugs.

       Monocyte Recruitment to the Endothelium

      Monocyte recruitment to the endothelium occurs early in the development of atherosclerotic plaques.
      • Ross R.
      Atherosclerosis—An inflammatory disease.
      Monocytes adhere to the endothelium through soluble vascular cell adhesion molecule 1 (VCAM-1), soluble intercellular adhesion molecule 1 (ICAM-1), E- and P-selectin, and diapedese into the tunica intima along a chemoattractant gradient provided by monocyte chemoattractant protein 1 (MCP-1).
      • Libby P.
      Inflammation in atherosclerosis.
      ELISA kits are available commercially for these cardiovascular biomarkers.
      The association of these cardiovascular biomarkers and cardiac outcomes has been variable in the general population.
      • Hwang S.-J.
      • Ballantyne C.M.
      • Sharrett A.R.
      • et al.
      Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases The Atherosclerosis Risk in Communities (ARIC) Study.
      • Malik I.
      • Danesh J.
      • Whincup P.
      • et al.
      Soluble adhesion molecules and prediction of coronary heart disease A prospective study and meta-analysis.
      • Ridker P.M.
      • Hennekens C.H.
      • Roitman-Johnson B.
      • Stampfer M.J.
      • Allen J.
      Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men.
      • Ridker P.M.
      • Buring J.E.
      • Rifai N.
      Soluble P-selectin and the risk of future cardiovascular events.
      • de Lemos J.A.
      • Morrow D.A.
      • Sabatine M.S.
      • et al.
      Association between plasma levels of monocyte chemoattractant protein-1 and long-term clinical outcomes in patients with acute coronary syndromes.
      In patients with CKD, P-selectin level increases with increasing quintiles of cystatin C, a measure of renal function,
      • Landray M.J.
      • Wheeler D.C.
      • Lip G.Y.
      • et al.
      Inflammation, endothelial dysfunction, and platelet activation in patients with chronic kidney disease The Chronic Renal Impairment in Birmingham (CRIB) Study.
      and both ICAM-1 and VCAM-1 levels increase as GFR decreases.
      • Knight E.L.
      • Rimm E.B.
      • Pai J.K.
      • et al.
      Kidney dysfunction, inflammation, and coronary events A prospective study.
      Patients on hemodialysis therapy have significantly greater ICAM-1, VCAM-1, and MCP-1 levels than controls.
      • Papayianni A.
      • Alexopoulos E.
      • Giamalis P.
      • et al.
      Circulating levels of ICAM-1, VCAM-1, and MCP-1 are increased in haemodialysis patients Association with inflammation, dyslipidaemia, and vascular events.
      In patients on hemodialysis therapy, ICAM-1 level is associated with worse survival.
      • Papagianni A.
      • Kalovoulos M.
      • Kirmizis D.
      • et al.
      Carotid atherosclerosis is associated with inflammation and endothelial cell adhesion molecules in chronic haemodialysis patients.
      • Stenvinkel P.
      • Lindholm B.
      • Heimburger M.
      • Heimburger O.
      Elevated serum levels of soluble adhesion molecules predict death in pre-dialysis patients Association with malnutrition, inflammation, and cardiovascular disease.
      The clinical application of these markers requires additional evaluation.

       Inflammation

      Inflammation clearly is important in atherosclerosis.
      • Ross R.
      Atherosclerosis—An inflammatory disease.
      • Libby P.
      Inflammation in atherosclerosis.
      Cardiovascular biomarkers of inflammation include adhesion molecules (discussed previously), cytokines, acute-phase reactants, and white blood cells.
      • Pearson T.A.
      • Mensah G.A.
      • Alexander R.W.
      • 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.
      Serum albumin is a negative acute-phase reactant that also is a measure of nutritional status and is not discussed further.

       C-Reactive Protein

      The best-studied cardiovascular biomarker of inflammation is CRP, an acute-phase reactant produced predominantly by hepatocytes under the control of interleukin 6 (IL-6).
      • Jialal I.
      • Devaraj S.
      • Venugopal S.K.
      C-Reactive protein Risk marker or mediator in atherothrombosis?.
      Possible proatherogenic effects of CRP include activation of the complement system, binding to low-density lipoprotein (LDL) and very-LDL, and stimulation of tissue factor.
      • Arici M.
      • Walls J.
      End-stage renal disease, atherosclerosis, and cardiovascular mortality Is C-reactive protein the missing link?.
      High-sensitivity CRP is recommended to measure cardiovascular risk caused by inflammation based on its stability, availability (including automated methods), and coefficient of variation less than 10% in the 0.3- to 10-mg/L range.
      • Pearson T.A.
      • Mensah G.A.
      • Alexander R.W.
      • 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.
      There is unequivocal evidence in the general population that elevated CRP levels predict future cardiac events.
      • Danesh J.
      • Wheeler J.G.
      • Hirschfield G.M.
      • et al.
      C-Reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease.
      Inflammation commonly accompanies CKD because of decreased renal clearance of proinflammatory cytokines, comorbid conditions (inflammatory renal diseases, diabetes), and dialysis-related factors (exposure to dialysis membranes, prosthetic materials).
      • Kalantar-Zadeh K.
      • Ikizler T.A.
      • Block G.
      • Avram M.M.
      • Kopple J.D.
      Malnutrition-inflammation complex syndrome in dialysis patients Causes and consequences.
      Abdominal obesity, which is increasing in the end-stage renal disease population
      • Kramer H.J.
      • Saranathan A.
      • Luke A.
      • et al.
      Increasing body mass index and obesity in the incident ESRD population.
      and is a risk factor for ESRD,
      • Hsu C.-Y.
      • McCulloch C.E.
      • Iribarren C.
      • Darbinian J.
      • Go A.S.
      Body mass index and risk for end-stage renal disease.
      also may contribute to elevated CRP levels. Both truncal fat mass
      • Axelsson J.
      • Rashid Qureshi A.
      • Suliman M.E.
      • et al.
      Truncal fat mass as a contributor to inflammation in end-stage renal disease.
      and waist circumference
      • van Ree R.M.
      • de Vries A.P.J.
      • Oterdoom L.H.
      • et al.
      Abdominal obesity and smoking are important determinants of C-reactive protein in renal transplant recipients.
      correlate significantly with CRP levels in predialysis patients and renal transplant recipients, respectively. In patients with CKD not requiring dialysis, CRP level increases as GFR decreases,
      • Muntner P.
      • Hamm L.L.
      • Kusek J.W.
      • Chen J.
      • Whelton P.K.
      • He J.
      The prevalence of nontraditional risk factors for coronary heart disease in patients with chronic kidney disease.
      • Panichi V.
      • Migliori M.
      • De Pietro S.
      C-Reactive protein and interleukin-6 levels are related to renal function in predialytic chronic renal failure.
      • Pecoits-Filho R.
      • Heimburger O.
      • Barany P.
      • et al.
      Associations between circulating inflammatory markers and residual renal function in CRF patients.
      although this relationship was not shown with cystatin C.
      • Landray M.J.
      • Wheeler D.C.
      • Lip G.Y.
      • et al.
      Inflammation, endothelial dysfunction, and platelet activation in patients with chronic kidney disease The Chronic Renal Impairment in Birmingham (CRIB) Study.
      Patients undergoing hemodialysis have significantly greater CRP levels than controls.
      • Zimmermann J.
      • Herrlinger S.
      • Pruy A.
      • Metzger T.
      • Wanner C.
      Inflammation enhances cardiovascular risk and mortality in hemodialysis patients.
      There are multiple associations with CRP levels and CVD outcomes in patients with CKD. It is associated with increased mortality across the full spectrum of CKD.
      • Ducloux D.
      • Kazory A.
      • Chalopin J.-M.
      Predicting coronary heart disease in renal transplant recipients A prospective study.
      • Zimmermann J.
      • Herrlinger S.
      • Pruy A.
      • Metzger T.
      • Wanner C.
      Inflammation enhances cardiovascular risk and mortality in hemodialysis patients.
      • Menon V.
      • Greene T.
      • Wang X.
      • et al.
      C-Reactive protein and albumin as predictors of all-cause and cardiovascular mortality in chronic kidney disease.
      • Ducloux D.
      • Bresson-Vautrin C.
      • Kribs M.
      • Abdelfatah A.
      • Chalopin J.M.
      C-Reactive protein and cardiovascular disease in peritoneal dialysis patients.
      • Iseki K.
      • Tozawa M.
      • Yoshi S.
      • Fukiyama K.
      Serum C-reactive protein (CRP) and risk of death in chronic dialysis patients.
      • Yeun J.Y.
      • Levine R.A.
      • Mantadilok V.
      • Kaysen G.A.
      C-Reactive protein predicts all-cause and cardiovascular mortality in hemodialysis patients.
      An increase in CRP level during a hemodialysis session predicts increased mortality risk,
      • Korevaar J.C.
      • van Manen J.G.
      • Dekker F.W.
      • de Waart D.R.
      • Boeschoten E.W.
      • Krediet R.T.
      NECOSAD Study Group
      Effect of an increase in C-reactive protein level during a hemodialysis session on mortality.
      and measured just before renal transplantation, CRP level predicts death and cardiovascular mortality, but not graft survival.
      • Varagunam M.
      • Finney H.
      • Trevitt R.
      • et al.
      Pretransplantation levels of C-reactive protein predict all-cause and cardiovascular mortality, but not graft outcome, in kidney transplant recipients.
      Aspirin and statin therapy modify both CRP level and CVD risk associated with CRP level in the general population.
      • Ridker P.M.
      • Cushman M.
      • Stampfer M.J.
      • Tracy R.P.
      • Hennekens C.H.
      Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men.
      • Ridker P.M.
      • Rifai N.
      • Clearfield M.
      • et al.
      Air Force/Texas Coronary Atherosclerosis Prevention Study Investigators
      Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events.
      Statins decrease CRP levels in patients on dialysis therapy,
      • Vernaglione L.
      • Cristofano C.
      • Muscogiuri P.
      • Chimienti S.
      Does atorvastatin influence serum C-reactive protein levels in patients on long-term hemodialysis?.
      • Ikejiri A.
      • Hirano T.
      • Murayama S.
      • et al.
      Effects of atorvastatin on triglyceride-rich lipoproteins, low-density lipoprotein subclass, and C-reactive protein in hemodialysis patients.
      • Chang J.W.
      • Yang W.S.
      • Min W.K.
      • Lee S.K.
      • Park J.S.
      • Kim S.B.
      Effects of simvastatin on high-sensitivity C-reactive protein and serum albumin in hemodialysis patients.
      and angiotensin-converting enzyme inhibitors decrease CRP levels in patients with stages 3 to 5 CKD,
      • Oberg B.P.
      • McMenamin E.
      • Lucas F.L.
      • et al.
      Increased prevalence of oxidant stress and inflammation in patients with moderate to severe chronic kidney disease.
      but the clinical benefit of decreasing CRP levels has not been shown.

       Interleukin 6

      IL-6 stimulates secretion of CRP from the liver, MCP-1 from macrophages, and adhesion molecules and cytokines from endothelial cells.
      • Rattazzi M.
      • Puato M.
      • Faggin E.
      • Bertipaglia B.
      • Zambon A.
      • Pauletto P.
      C-Reactive protein and interleukin-6 in vascular disease Culprits or passive bystanders?.
      Cellular sources of IL-6 include monocytes, fibroblasts, endothelial cells, and adipocytes.
      • Stenvinkel P.
      • Barany P.
      • Heimburger O.
      • Pecoits-Filho R.
      • Lindholm B.
      Mortality, malnutrition, and atherosclerosis in ESRD What is the role of interleukin-6?.
      Adipocyte production explains the associations of abdominal obesity and CRP levels in the previous section. IL-6 ELISA kits are available commercially, and in the general population, prediction of cardiovascular events is inconsistent.
      • Ridker P.M.
      • Rifai N.
      • Stampfer M.J.
      • Hennekens C.H.
      Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men.
      • Ridker P.M.
      • Hennekens C.H.
      • Buring J.E.
      • Rifai N.
      C-Reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women.
      • St-Pierre A.C.
      • Cantin B.
      • Bergeron J.
      • et al.
      Inflammatory markers and long-term risk of ischemic heart disease in men A 13-year follow-up of the Quebec Cardiovascular Study.
      • Pai J.K.
      • Pischon T.
      • Ma J.
      • et al.
      Inflammatory markers and the risk of coronary heart disease in men and women.
      IL-6 level increases as creatinine clearance decreases,
      • Panichi V.
      • Migliori M.
      • De Pietro S.
      C-Reactive protein and interleukin-6 levels are related to renal function in predialytic chronic renal failure.
      correlates negatively with GFR,
      • Panichi V.
      • Migliori M.
      • De Pietro S.
      C-Reactive protein and interleukin-6 levels are related to renal function in predialytic chronic renal failure.
      • Pecoits-Filho R.
      • Heimburger O.
      • Barany P.
      • et al.
      Associations between circulating inflammatory markers and residual renal function in CRF patients.
      and is significantly greater in hemodialysis patients than age-matched healthy controls.
      • Kato A.
      • Odamaki M.
      • Takita T.
      • Maruyama Y.
      • Kumagai H.
      • Hishida A.
      Association between interleukin-6 and carotid atherosclerosis in hemodialysis patients.
      IL-6 was associated with cardiovascular death in elderly persons with a GFR less than 60 mL/min (<1.00 mL/s)
      • Shlipak M.G.
      • Fried L.F.
      • Cushman M.
      • et al.
      Cardiovascular mortality risk in chronic kidney disease Comparison of traditional and novel risk factors.
      and with mortality
      • Kimmel P.L.
      • Phillips T.M.
      • Simmens S.J.
      • et al.
      Immunologic function and survival in hemodialysis patients.
      • Bologa R.M.
      • Levine D.M.
      • Parker T.S.
      • et al.
      Interleukin-6 predicts hypoalbuminemia, hypocholesterolemia, and mortality in hemodialysis patients.
      • Panichi V.
      • Maggiore U.
      • Taccola D.
      • et al.
      Interleukin-6 is a stronger predictor of total and cardiovascular mortality than C-reactive protein in haemodialysis patients.
      • Rao M.
      • Guo D.
      • Perianayagam M.C.
      • et al.
      Plasma interleukin-6 predicts cardiovascular mortality in hemodialysis patients.
      and cardiovascular mortality
      • Panichi V.
      • Maggiore U.
      • Taccola D.
      • et al.
      Interleukin-6 is a stronger predictor of total and cardiovascular mortality than C-reactive protein in haemodialysis patients.
      • Rao M.
      • Guo D.
      • Perianayagam M.C.
      • et al.
      Plasma interleukin-6 predicts cardiovascular mortality in hemodialysis patients.
      in patients undergoing hemodialysis. IL-6 level was superior to CRP level in predicting outcomes in patients receiving hemodialysis
      • Panichi V.
      • Maggiore U.
      • Taccola D.
      • et al.
      Interleukin-6 is a stronger predictor of total and cardiovascular mortality than C-reactive protein in haemodialysis patients.
      and patients starting either hemodialysis or peritoneal dialysis therapy.
      • Honda H.
      • Qureshi A.R.
      • Heimburger O.
      • et al.
      Serum albumin, C-reactive protein, interleukin 6, and fetuin a as predictors of malnutrition, cardiovascular disease, and mortality in patients with ESRD.

       Tumor Necrosis Factor α

      Tumor necrosis factor α (TNF-α) is a proinflammatory cytokine produced by macrophages, vascular smooth muscle cells, and endothelial cells
      • Barath P.
      • Fishbein M.C.
      • Cao J.
      • Berenson J.
      • Helfant R.H.
      • Forrester J.S.
      Detection and localization of tumor necrosis factor in human atheroma.
      that stimulates smooth muscle cell production of IL-6.
      • Blake G.J.
      • Ridker P.M.
      Novel clinical markers of vascular wall inflammation.
      TNF-α ELISA kits are available commercially, and elevated levels were reported in patients with heart failure
      • Levine B.
      • Kalman J.
      • Mayer L.
      • Fillit H.M.
      • Packer M.
      Elevated circulating levels of tumor necrosis factor in severe chronic heart failure.
      and associated with coronary events in the general population.
      • Ridker P.M.
      • Rifai N.
      • Pfeffer M.
      • Sacks F.
      • Lepage S.
      • Braunwald E.
      Elevation of tumor necrosis factor-α and increased risk of recurrent coronary events after myocardial infarction.
      TNF-α levels are greater in patients with decreased GFRs
      • Bolton C.H.
      • Downs L.G.
      • Victory J.G.
      • et al.
      Endothelial dysfunction in chronic renal failure Roles of lipoprotein oxidation and pro-inflammatory cytokines.
      and those on hemodialysis therapy.
      • Kimmel P.L.
      • Phillips T.M.
      • Simmens S.J.
      • et al.
      Immunologic function and survival in hemodialysis patients.
      • Bolton C.H.
      • Downs L.G.
      • Victory J.G.
      • et al.
      Endothelial dysfunction in chronic renal failure Roles of lipoprotein oxidation and pro-inflammatory cytokines.
      In patients undergoing hemodialysis, TNF-α levels in 1 study
      • Kimmel P.L.
      • Phillips T.M.
      • Simmens S.J.
      • et al.
      Immunologic function and survival in hemodialysis patients.
      and TNF-α messenger RNA levels, but not TNF-α levels, in another study
      • Futh R.
      • Herder C.
      • Forster S.
      • et al.
      Evaluation of diagnostic relevance of mRNA levels in peripheral blood predictive value for mortality in hemodialysis patients.
      were associated with increased mortality. Antagonists of TNF-α were studied in patients with heart failure.
      • Mann D.L.
      • McMurray J.J.
      • Packer M.
      • et al.
      Targeted anticytokine therapy in patients with chronic heart failure Results of the Randomized Etanercept Worldwide Evaluation (RENEWAL).

       Fibrinogen

      Fibrinogen is produced by hepatocytes and has such inflammatory effects as stimulation of smooth muscle cell proliferation and migration, altered endothelial function, and uptake into atherosclerotic lesions. In hemostasis, fibrinogen influences platelet aggregation and blood viscosity.
      • Ernst E.
      • Koenig W.
      Fibrinogen and cardiovascular risk.
      Assay methods include clotting assays, nephelometry, and immunologic assays and are widely available.
      • Danesh J.
      • Collins R.
      • Appleby P.
      • Peto R.
      Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease Meta-analyses of prospective studies.
      A positive association between fibrinogen levels and cardiovascular events in the general population was shown by using meta-analysis.
      • Danesh J.
      • Collins R.
      • Appleby P.
      • Peto R.
      Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease Meta-analyses of prospective studies.
      Compared with controls, fibrinogen levels are greater in patients with CKD not requiring dialysis
      • Landray M.J.
      • Wheeler D.C.
      • Lip G.Y.
      • et al.
      Inflammation, endothelial dysfunction, and platelet activation in patients with chronic kidney disease The Chronic Renal Impairment in Birmingham (CRIB) Study.
      and those receiving dialysis.
      • Zimmermann J.
      • Herrlinger S.
      • Pruy A.
      • Metzger T.
      • Wanner C.
      Inflammation enhances cardiovascular risk and mortality in hemodialysis patients.
      • Levine B.
      • Kalman J.
      • Mayer L.
      • Fillit H.M.
      • Packer M.
      Elevated circulating levels of tumor necrosis factor in severe chronic heart failure.
      • Bolton C.H.
      • Downs L.G.
      • Victory J.G.
      • et al.
      Endothelial dysfunction in chronic renal failure Roles of lipoprotein oxidation and pro-inflammatory cytokines.
      Fibrinogen levels significantly predict cardiovascular events in patients with CKD before dialysis
      • Descamps-Latscha B.
      • Witko-Sarsat V.
      • Nguyen-Khoa T.
      • et al.
      Advanced oxidation protein products as risk factors for atherosclerotic cardiovascular events in nondiabetic predialysis patients.
      and those undergoing peritoneal dialysis
      • Enia G.
      • Panuccio V.
      • Mallamaci F.
      • Tripepi G.
      • Mandalari A.
      • Zoccali C.
      Fibrinogen and calcium × phosphate product are predictors of cardiovascular events in the CAPD population.
      or hemodialysis.
      • Zoccali C.
      • Mallamaci F.
      • Tripepi G.
      • et al.
      Fibrinogen, mortality and incident cardiovascular complications in end-stage renal failure.
      In patients undergoing hemodialysis
      • Zoccali C.
      • Mallamaci F.
      • Tripepi G.
      • et al.
      Fibrinogen, mortality and incident cardiovascular complications in end-stage renal failure.
      or hemodialysis and peritoneal dialysis patients analyzed together,
      • Koch M.
      • Kutkuhn B.
      • Grabensee B.
      • Ritz E.
      Apolipoprotein A, fibrinogen, age, and history of stroke are predictors of death in dialysed diabetic patients A prospective study in 412 subjects.
      fibrinogen level predicts mortality.

       Serum Amyloid A

      Serum amyloid A protein is a hepatic acute-phase reactant. It may bind to high-density lipoprotein and displace such “protective” apolipoproteins as apolipoprotein A-I and also cause chemotaxis of monocytes. It can be measured by means of nephelometry on commercial platforms. In the general population
      • Ridker P.M.
      • Hennekens C.H.
      • Buring J.E.
      • Rifai N.
      C-Reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women.
      and hemodialysis patients,
      • Zimmermann J.
      • Herrlinger S.
      • Pruy A.
      • Metzger T.
      • Wanner C.
      Inflammation enhances cardiovascular risk and mortality in hemodialysis patients.
      • Ridker P.M.
      • Hennekens C.H.
      • Buring J.E.
      • Rifai N.
      C-Reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women.
      • Tsirpanlis G.
      • Chatzipanagiotou S.
      • Ioannidis A.
      • Moutafis S.
      • Poulopoulou C.
      • Nicolaou C.
      Detection of Chlamydia pneumoniae in peripheral blood mononuclear cells Correlation with inflammation and atherosclerosis in haemodialysis patients.
      associations were described for cardiovascular events and mortality, but these were nullified by adjustment for other factors, including levels of other cardiovascular biomarkers of inflammation.

       Oxidative Stress

      Oxidative stress, the imbalance between generation of oxidant compounds and antioxidant defense mechanisms, leads to oxidation of lipids, carbohydrates, and proteins. Reactive oxygen species decrease nitric oxide levels, stimulate vascular smooth muscle proliferation and migration, and stimulate proinflammatory cytokines.
      • Gordon C.A.
      • Himmelfarb J.
      Antioxidant therapy in uremia Evidence-based medicine?.
      Therefore, there is a strong link with inflammation.
      In patients with CKD, increased oxidant stress may be caused by deficiency of antioxidants and scavenging systems, advanced age, diabetes, inflammation, and exposure to bioincompatible dialysis membranes and fluids.
      • Locatelli F.
      • Canaud B.
      • Eckardt K.-U.
      • Stenvinkel P.
      • Wanner C.
      • Zoccali C.
      Oxidative stress in end-stage renal disease An emerging threat to patient outcome.
      Measurement of oxidative stress requires measurement of the consequences, rather than the oxidants themselves. Lipid peroxidation products (plasma F2-isoprostanes, malonyldialdehyde), advanced oxidation protein products, antibodies to oxidized LDL,
      • Locatelli F.
      • Canaud B.
      • Eckardt K.-U.
      • Stenvinkel P.
      • Wanner C.
      • Zoccali C.
      Oxidative stress in end-stage renal disease An emerging threat to patient outcome.
      protein carbonyl content, protein thiol groups, reduced glutathione,
      • Dursun E.
      • Dursun B.
      • Suleymanlar G.
      • Ozben T.
      Carbonyl stress in chronic renal failure The effect of haemodialysis.
      and phospholipids with antioxidant properties (plasmalogens)
      • Stenvinkel P.
      • Diczfalusy U.
      • Lindholm B.
      • Heimburger O.
      Phospholipid plasmalogen, a surrogate marker of oxidative stress, is associated with increased cardiovascular mortality in patients on renal replacement therapy.
      are all measures of oxidative stress, but none are widely available.
      In patients with coronary heart disease, low levels of the antioxidant glutathione peroxidase 1 in red blood cells were associated with cardiovascular events.
      • Blankenberg S.
      • Rupprecht H.J.
      • Bickel C.
      • et al.
      Glutathione peroxidase 1 activity and cardiovascular events in patients with coronary artery disease.
      However, antioxidant therapy did not reduce cardiovascular events in large RCTs,
      • Yusuf S.
      • Dagenais G.
      • Pogue J.
      • Bosch J.
      • Sleight P.
      Heart Outcomes Prevention Evaluation Study Investigators
      Vitamin E supplementation and cardiovascular events in high-risk patients.
      MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals A randomised placebo-controlled trial.
      including subgroup analysis of patients with decreased GFRs.
      • Mann J.F.
      • Lonn E.M.
      • Yi Q.
      • et al.
      Effects of vitamin E on cardiovascular outcomes in people with mild-to-moderate renal insufficiency Results of the HOPE Study.
      In patients with CKD
      • Oberg B.P.
      • McMenamin E.
      • Lucas F.L.
      • et al.
      Increased prevalence of oxidant stress and inflammation in patients with moderate to severe chronic kidney disease.
      and those receiving dialysis,
      • Danielski M.
      • Ikizler T.A.
      • McMonagle E.
      • et al.
      Linkage of hypoalbuminemia, inflammation, and oxidative stress in patients receiving maintenance hemodialysis therapy.
      levels of cardiovascular biomarkers indicating increased oxidative stress and inflammation were elevated compared with healthy controls. Cardiovascular mortality was predicted by erythrocyte plasmalogen levels in patients with end-stage renal disease,
      • Stenvinkel P.
      • Diczfalusy U.
      • Lindholm B.
      • Heimburger O.
      Phospholipid plasmalogen, a surrogate marker of oxidative stress, is associated with increased cardiovascular mortality in patients on renal replacement therapy.
      and cardiovascular events, by advanced oxidation protein product levels in patients with decreased GFR.
      • Descamps-Latscha B.
      • Witko-Sarsat V.
      • Nguyen-Khoa T.
      • et al.
      Advanced oxidation protein products as risk factors for atherosclerotic cardiovascular events in nondiabetic predialysis patients.
      In patients undergoing hemodialysis, 2 RCTs showed a reduction in composite cardiovascular end points, but not mortality, with vitamin E
      • Boaz M.
      • Smetana S.
      • Weinstein T.
      • et al.
      Secondary Prevention With Antioxidants of Cardiovascular Disease in Endstage Renal Disease (SPACE) Randomised placebo-controlled trial.
      and N-acetylcysteine therapy.
      • Tepel M.
      • van der Giet M.
      • Statz M.
      • Jankowski J.
      • Zidek W.
      The antioxidant acetylcysteine reduces cardiovascular events in patients with end-stage renal failure A randomized, controlled trial.
      This requires additional consideration, and type of antioxidant used may influence any observed outcome.

       Sympathetic Nervous System Activation

      Overactivity of the sympathetic nervous system contributes to end-organ damage in patients with CKD.
      • Koomans H.A.
      • Blankestijn P.J.
      • Joles J.A.
      Sympathetic hyperactivity in chronic renal failure A wake-up call.
      Neuropeptide Y is a cardiovascular biomarker of sympathetic nervous system activation that has a number of cardiovascular effects.
      • Wallerstedt S.M.
      • Skrtic S.
      • Eriksson A.L.
      • Ohlsson C.
      • Hedner T.
      Association analysis of the polymorphism T1128C in the signal peptide of neuropeptide Y in a Swedish hypertensive population.
      It is measured by means of radioimmunoassay after extraction and is not widely available. A genetic polymorphism was associated with cardiovascular events in the general population.
      • Wallerstedt S.M.
      • Skrtic S.
      • Eriksson A.L.
      • Ohlsson C.
      • Hedner T.
      Association analysis of the polymorphism T1128C in the signal peptide of neuropeptide Y in a Swedish hypertensive population.
      Neuropeptide Y levels were elevated in patients with CKD and associated with LVH and systolic dysfunction in patients on dialysis therapy.
      • Zoccali C.
      • Mallamaci F.
      • Tripepi G.
      • et al.
      Neuropeptide Y, left ventricular mass and function in patients with end stage renal disease.
      It predicted cardiovascular events, but not mortality, in these patients.
      • Zoccali C.
      • Mallamaci F.
      • Tripepi G.
      • et al.
      Prospective study of neuropeptide Y as an adverse cardiovascular risk factor in end-stage renal disease.
      Level of plasma norepinephrine, an alternative cardiovascular biomarker of sympathetic overactivity, predicted both mortality and events.
      • Zoccali C.
      • Mallamaci F.
      • Parlongo S.
      • et al.
      Plasma norepinephrine predicts survival and incident cardiovascular events in patients with end-stage renal disease.
      Blockade of the sympathetic nervous system is underused in patients with CKD,
      • Koomans H.A.
      • Blankestijn P.J.
      • Joles J.A.
      Sympathetic hyperactivity in chronic renal failure A wake-up call.
      and this cardiovascular biomarker may identify patients who will benefit most from such therapies.

       Glycosylation of Proteins

      Advanced glycation end products (AGEs) are chemically heterogeneous fluorescent and nonfluorescent compounds that form as a result of nonenzymatic modification of proteins. In the pathogenesis of atherosclerosis, AGEs have receptor-mediated actions on mononuclear phagocytes and smooth muscle and endothelial cells, causing increased expression of cytokines and adhesion molecules.
      • Basta G.
      • Schmidt A.M.
      • De Caterina R.
      Advanced glycation end products and vascular inflammation Implications for accelerated atherosclerosis in diabetes.
      In addition, non–receptor-mediated modification of the extracellular matrix causes vascular stiffness and modification of LDL. This renders it less easily taken up by its receptor and more easily oxidized.
      • Basta G.
      • Schmidt A.M.
      • De Caterina R.
      Advanced glycation end products and vascular inflammation Implications for accelerated atherosclerosis in diabetes.
      The heterogeneous nature of AGEs is mirrored by the variety of methods of measurement. These include immunologic (ELISA)
      • Munch G.
      • Keis R.
      • Wessels A.
      • et al.
      Determination of advanced glycation end products in serum by fluorescence spectroscopy and competitive ELISA.
      and fluorescent methods that measure either protein-bound AGEs
      • Munch G.
      • Keis R.
      • Wessels A.
      • et al.
      Determination of advanced glycation end products in serum by fluorescence spectroscopy and competitive ELISA.
      or low-molecular-weight (LMW) AGEs.
      • Wrobel K.
      • Garay-Sevilla M.E.
      • Nava L.E.
      • Malacara J.M.
      Novel analytical approach to monitoring advanced glycosylation end products in human serum with on-line spectrophotometric and spectrofluorometric detection in a flow system.
      Standardization of methods is required before they become routinely available.
      In patients with diabetes, AGEs were implicated in microvascular and macrovascular complications.
      • Brownlee M.
      Biochemistry and molecular cell biology of diabetic complications.
      In patients with CKD, AGE level correlated with GFR
      • Thomas M.
      • Tsalamandris C.
      • MacIsaac R.
      • et al.
      Low-molecular-weight AGEs are associated with GFR and anemia in patients with type 2 diabetes.
      and was greatest in patients receiving hemodialysis.
      • Busch M.
      • Franke S.
      • Muller A.
      • et al.
      Potential cardiovascular risk factors in chronic kidney disease AGEs, total homocysteine and metabolites, and the C-reactive protein.
      Three previous studies showed no association with cardiovascular outcomes or mortality in patients with CKD.
      • Busch M.
      • Franke S.
      • Muller A.
      • et al.
      Potential cardiovascular risk factors in chronic kidney disease AGEs, total homocysteine and metabolites, and the C-reactive protein.
      • Suliman M.E.
      • Heimburger O.
      • Barany P.
      • et al.
      Plasma pentosidine is associated with inflammation and malnutrition in end-stage renal disease patients starting on dialysis therapy.
      • Schwedler S.B.
      • Metzger T.
      • Schinzel R.
      • Wanner C.
      Advanced glycation end products and mortality in hemodialysis patients.
      Conversely, our group showed an association of elevated LMW AGE fluorescence with all-cause mortality in a 4-year prospective study.
      • Roberts M.A.
      • Thomas M.C.
      • Fernando D.
      • Macmillan N.
      • Power D.A.
      • Ierino F.L.
      Low molecular weight advanced glycation end products predict mortality in asymptomatic patients receiving chronic haemodialysis.
      An important explanation that may account for differences in association with outcomes between our study and others is that our study analyzed the LMW fraction of AGEs in serum, rather than the protein-linked high-molecular-weight AGEs measured in other studies.
      • Busch M.
      • Franke S.
      • Muller A.
      • et al.
      Potential cardiovascular risk factors in chronic kidney disease AGEs, total homocysteine and metabolites, and the C-reactive protein.
      • Suliman M.E.
      • Heimburger O.
      • Barany P.
      • et al.
      Plasma pentosidine is associated with inflammation and malnutrition in end-stage renal disease patients starting on dialysis therapy.
      • Schwedler S.B.
      • Metzger T.
      • Schinzel R.
      • Wanner C.
      Advanced glycation end products and mortality in hemodialysis patients.
      A recent study by Wagner et al
      • Wagner Z.
      • Molnar M.
      • Molnar G.A.
      • et al.
      Serum carboxymethyllysine predicts mortality in hemodialysis patients.
      showed that high levels of the AGE carboxymethyllysine was an independent risk factor for death in patients on hemodialysis therapy. These studies emphasize the importance of clearly defining the biological product measured because this will influence the interpretation of the pathophysiological significance of the putative cardiovascular biomarker.
      AGEs may be a modifiable risk factor because their levels can be decreased by dietary modification (reduction in foods containing products of the Maillard reaction)
      • Uribarri J.
      • Peppa M.
      • Cai W.
      • et al.
      Restriction of dietary glycotoxins reduces excessive advanced glycation end products in renal failure patients.
      and such pharmacological agents as benfotiamine.
      • Hammes H.P.
      • Du X.
      • Edelstein D.
      • et al.
      Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy.
      Inhibitors of the renin-angiotensin system inhibit AGE formation in patient sera in vitro.
      • Miyata T.
      • van Ypersele de Strihou C.
      • Ueda Y.
      • et al.
      Angiotensin II receptor antagonists and angiotensin-converting enzyme inhibitors lower in vitro the formation of advanced glycation end products Biochemical mechanisms.
      In experimental studies, such drugs as aminoguanidine, an inhibitor of AGE formation, and ALT-711, a “cross-link breaker,” had effects on atherosclerotic lesions
      • Forbes J.M.
      • Yee L.T.
      • Thallas V.
      • et al.
      Advanced glycation end product interventions reduce diabetes-accelerated atherosclerosis.
      and cardiac structure and function.
      • Candido R.
      • Forbes J.M.
      • Thomas M.C.
      • et al.
      A breaker of advanced glycation end products attenuates diabetes-induced myocardial structural changes.
      • Herrmann K.L.
      • McCulloch A.D.
      • Omens J.H.
      Glycated collagen cross-linking alters cardiac mechanics in volume-overload hypertrophy.

       Bone Marrow Function

      Erythropoietin deficiency as a result of decreased renal mass in patients with CKD leads to anemia, contributing to uremic symptoms and altered cardiac morphological characteristics. Erythropoietin may be measured by using automated immunoassays,
      • Marsden J.T.
      Erythropoietin—Measurement and clinical applications.
      but measurement of hematocrit or hemoglobin is performed more commonly. Both anemia
      • Robinson B.M.
      • Joffe M.M.
      • Berns J.S.
      • Pisoni R.L.
      • Port F.K.
      • Feldman H.I.
      Anemia and mortality in hemodialysis patients Accounting for morbidity and treatment variables updated over time.
      and dose of erythropoietin used to correct it
      • Zhang Y.
      • Thamer M.
      • Stefanik K.
      • Kaufman J.
      • Cotter D.J.
      Epoetin requirements predict mortality in hemodialysis patients.
      were linked to mortality in observational studies. However, RCTs of patients with decreased GFRs
      • Levin A.
      • Djurdjev O.
      • Thompson C.
      • et al.
      Canadian randomized trial of hemoglobin maintenance to prevent or delay left ventricular mass growth in patients with CKD.
      and patients on hemodialysis therapy
      • Parfrey P.S.
      • Foley R.N.
      • Wittreich B.H.
      • Sullivan D.J.
      • Zagari M.J.
      • Frei D.
      Canadian European Study
      Double-blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease.
      showed that treating patients to greater target hemoglobin levels does not reduce progression of LVH, and a meta-analysis showed poorer survival with greater hemoglobin target levels.
      • Strippoli G.F.M.
      • Craig J.C.
      • Manno C.
      • Schena F.P.
      Hemoglobin targets for the anemia of chronic kidney disease A meta-analysis of randomized, controlled trials.
      Erythropoietin also is an important stimulus for bone marrow–derived endothelial progenitor cells (EPCs). These cells circulate in peripheral blood and contribute to angiogenesis and maintenance of vascular integrity.
      • Rafii S.
      • Lyden D.
      Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration.
      They are measured by using flow cytometry techniques that are not routinely available.
      In patients with coronary artery disease, low EPC levels predicted cardiovascular events and death (but not all-cause mortality).
      • Werner N.
      • Kosiol S.
      • Schiegl T.
      • et al.
      Circulating endothelial progenitor cells and cardiovascular outcomes.
      In patients with CKD not on dialysis therapy (mean creatinine, 5.67 mg/dL [501 μmol/L]), EPC number was less than that in healthy subjects, and in a small number, levels increased after 2 weeks of hemodialysis treatment.
      • de Groot K.
      • Hermann Bahlmann F.
      • Sowa J.
      • et al.
      Uremia causes endothelial progenitor cell deficiency.
      In patients undergoing hemodialysis, EPC levels were reported as low
      • Choi J.H.
      • Kim K.L.
      • Huh W.
      • et al.
      Decreased number and impaired angiogenic function of endothelial progenitor cells in patients with chronic renal failure.
      or elevated,
      • Herbrig K.
      • Pistrosch F.
      • Oelschlaegel U.
      • et al.
      Increased total number but impaired migratory activity and adhesion of endothelial progenitor cells in patients on long-term hemodialysis.
      but in both studies, function was impaired. In renal transplant recipients, EPC numbers were decreased
      • Soler M.J.
      • Martinez-Estrada O.M.
      • Puig-Mari J.M.
      • et al.
      Circulating endothelial progenitor cells after kidney transplantation.
      or unchanged,
      • de Groot K.
      • Bahlmann F.H.
      • Bahlmann E.
      • Menne J.
      • Haller H.
      • Fliser D.
      Kidney graft function determines endothelial progenitor cell number in renal transplant recipients.
      • Steiner S.
      • Winkelmayer W.C.
      • Kleinert J.
      • et al.
      Endothelial progenitor cells in kidney transplant recipients.
      but correlated with graft function.
      • de Groot K.
      • Bahlmann F.H.
      • Bahlmann E.
      • Menne J.
      • Haller H.
      • Fliser D.
      Kidney graft function determines endothelial progenitor cell number in renal transplant recipients.
      It is not known whether EPC levels are related to clinical outcomes, but the systemic delivery of transplantable cells is a potential option for promoting vascular repair.
      • Rafii S.
      • Lyden D.
      Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration.

       Platelet Activation

      Platelet aggregation provides a structural framework for vessel occlusion and thrombosis
      • Prasad K.S.
      • Andre P.
      • Yan Y.
      • Phillips D.R.
      The platelet CD40L/GP IIb-IIIa axis in atherothrombotic disease.
      and is the target of aspirin. Soluble CD40 ligand (sCD40L) is a platelet-derived inflammatory cytokine
      • Henn V.
      • Slupsky J.R.
      • Grafe M.
      • et al.
      CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells.
      that mediates platelet activation and stabilization of platelet aggregates by interactions with platelet glycoprotein IIb/IIIa (GPIIb/IIIa).
      • Prasad K.S.
      • Andre P.
      • Yan Y.
      • Phillips D.R.
      The platelet CD40L/GP IIb-IIIa axis in atherothrombotic disease.
      It promotes expression of multiple proatherogenic mediators, including matrix metalloproteinases, which contribute to plaque rupture.
      • Schonbeck U.
      • Libby P.
      CD40 signaling and plaque instability.
      Commercial ELISA kits are available to measure sCD40L.
      In RCTs studying patients with acute coronary syndromes (ACSs), sCD40L level independently predicted cardiovascular events and death.
      • Varo N.
      • de Lemos J.A.
      • Libby P.
      • et al.
      Soluble CD40L Risk prediction after acute coronary syndromes.
      In patients with CKD, sCD40L levels were increased compared with healthy controls, with the greatest levels in hemodialysis patients.
      • Schwabe R.F.
      • Engelmann H.
      • Hess S.
      • Fricke H.
      Soluble CD40 in the serum of healthy donors, patients with chronic renal failure, haemodialysis and chronic ambulatory peritoneal dialysis (CAPD) patients.
      However, the predictive value in these patients is not yet known.
      In patients with ACSs, antagonists of GPIIb/IIIa reduce cardiovascular events, particularly in those with greater sCD40L levels.
      • Heeschen C.
      • Dimmeler S.
      • Hamm C.W.
      • et al.
      Soluble CD40 ligand in acute coronary syndromes.
      sCD40L levels were decreased by using statins in hyperlipidemic patients without CKD
      • Cipollone F.
      • Mezzetti A.
      • Porreca E.
      • et al.
      Association between enhanced soluble CD40L and prothrombotic state in hypercholesterolemia Effects of statin therapy.
      and patients on peritoneal dialysis therapy
      • Malyszko J.
      • Malyszko J.S.
      • Hryszko T.
      • Mysliwiec M.
      Increased soluble CD40L levels are reduced by long-term simvastatin treatment in peritoneally dialyzed patients.
      and by using clopidogrel in renal transplant recipients administered cyclosporine.
      • Graff J.
      • Harder S.
      • Wahl O.
      • Scheuermann E.-H.
      • Gossmann J.
      Anti-inflammatory effects of clopidogrel intake in renal transplant patients Effects on platelet-leukocyte interactions, platelet CD40 ligand expression, and proinflammatory biomarkers.

       Left Ventricular Structure and Function

      The cardiac ventricles produce B-type natriuretic peptide (BNP), a hormone that causes vasodilation, natriuresis, and inhibition of the renin-angiotensin system.
      • Stein B.C.
      • Levin R.I.
      Natriuretic peptides Physiology, therapeutic potential, and risk stratification in ischemic heart disease.
      Before secretion, BNP is cleaved into the active C-terminal end, BNP-32, and the inactive N-terminal end, proBNP1-76.
      • Goetze J.P.
      Biochemistry of pro-B-type natriuretic peptide-derived peptides The endocrine heart revisited.
      There are important physiological differences between these 2 forms of BNP. First, the half-life of BNP-32 is 22 minutes compared with 120 minutes for proBNP1-76.
      • McCullough P.A.
      • Omland T.
      • Maisel A.S.
      B-Type natriuretic peptides A diagnostic breakthrough for clinicians.
      Second, clearances of BNP-32 and proBNP1-76 may differ. BNP-32 is cleared by circulating neutral endopeptidases that open its ring structure and by intracellular enzymatic degradation after receptor-mediated uptake.
      • Panteghini M.
      • Clerico A.
      Understanding the clinical biochemistry of N-terminal pro-B-type natriuretic peptide The prerequisite for its optimal clinical use.
      N-Terminal proBNP1-76 has no ring structure. Renal function has an important influence on levels of both forms of BNP, which increase with advancing stages of CKD.
      • deFilippi C.R.
      • Fink J.C.
      • Nass C.M.
      • Chen H.
      • Christenson R.
      N-Terminal pro-B-type natriuretic peptide for predicting coronary disease and left ventricular hypertrophy in asymptomatic CKD not requiring dialysis.
      • Vickery S.
      • Price C.P.
      • John R.I.
      • et al.
      B-Type natriuretic peptide (BNP) and amino-terminal proBNP in patients with CKD Relationship to renal function and left ventricular hypertrophy.
      Patients with heart failure with a GFR less than 60 mL/min (<1.00 mL/s) have greater BNP-32 levels than those with a greater GFR despite having similar indices of left ventricular function.
      • Tsutamoto T.
      • Wada A.
      • Sakai H.
      • et al.
      Relationship between renal function and plasma brain natriuretic peptide in patients with heart failure.
      It is controversial whether proBNP1-76 is more influenced by GFR than BNP-32
      • Vickery S.
      • Price C.P.
      • John R.I.
      • et al.
      B-Type natriuretic peptide (BNP) and amino-terminal proBNP in patients with CKD Relationship to renal function and left ventricular hypertrophy.
      • McCullough P.A.
      • Sandberg K.R.
      B-Type natriuretic peptide and renal disease.
      or they are influenced similarly.
      • Richards M.
      • Nicholls M.G.
      • Espiner E.A.
      • et al.
      Comparison of B-type natriuretic peptides for assessment of cardiac function and prognosis in stable ischemic heart disease.
      Both BNP-32 and proBNP1-76 can be assayed by using immunoassay techniques on automated platforms.
      Both BNP-32 and proBNP1-76 predict adverse clinical outcomes in community studies,
      • Wang T.J.
      • Larson M.G.
      • Levy D.
      • et al.
      Plasma natriuretic peptide levels and the risk of cardiovascular events and death.
      patients with stable coronary heart disease,
      • Omland T.
      • Persson A.
      • Ng L.
      • et al.
      N-Terminal pro-B-type natriuretic peptide and long-term mortality in acute coronary syndromes.
      and patients with ACSs.
      • Omland T.
      • Persson A.
      • Ng L.
      • et al.
      N-Terminal pro-B-type natriuretic peptide and long-term mortality in acute coronary syndromes.
      • de Lemos J.A.
      • Morrow D.A.
      • Bentley J.H.
      • et al.
      The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes.
      This was independent of left ventricular ejection fraction in 1 study.
      • Omland T.
      • Persson A.
      • Ng L.
      • et al.
      N-Terminal pro-B-type natriuretic peptide and long-term mortality in acute coronary syndromes.
      In patients presenting with dyspnea, both BNP-32 and proBNP1-76 levels detected decreased left ventricular ejection fraction.
      • Richards M.
      • Nicholls M.G.
      • Espiner E.A.
      • et al.
      Comparison of B-type natriuretic peptides for assessment of cardiac function and prognosis in stable ischemic heart disease.
      In patients with CKD not yet requiring dialysis therapy, BNP-32 levels are significantly greater than in hypertensive controls.
      • Takami Y.
      • Horio T.
      • Iwashima Y.
      • et al.
      Diagnostic and prognostic value of plasma brain natriuretic peptide in non–dialysis-dependent CRF.
      In patients undergoing hemodialysis, BNP-32 levels are significantly greater in patients with than without coronary artery disease and greater than in healthy controls.
      • Nishikimi T.
      • Futoo Y.
      • Tamano K.
      • et al.
      Plasma brain natriuretic peptide levels in chronic hemodialysis patients Influence of coronary artery disease.
      • Naganuma T.
      • Sugimura K.
      • Wada S.
      • et al.
      The prognostic role of brain natriuretic peptides in hemodialysis patients.
      • Osajima A.
      • Okazaki M.
      • Kato H.
      • et al.
      Clinical significance of natriuretic peptides and cyclic GMP in hemodialysis patients with coronary artery disease.
      Patients undergoing hemodialysis have greater BNP-32 levels than patients undergoing peritoneal dialysis.
      • Nakatani T.
      • Naganuma T.
      • Masuda C.
      • Uchida J.
      • Sugimura T.
      • Sugimura K.
      Significance of brain natriuretic peptides in patients on continuous ambulatory peritoneal dialysis.
      There is a positive correlation between BNP-32 level and left ventricular mass index and a negative correlation with left ventricular ejection fraction in patients on both dialysis modalities.
      • Nishikimi T.
      • Futoo Y.
      • Tamano K.
      • et al.
      Plasma brain natriuretic peptide levels in chronic hemodialysis patients Influence of coronary artery disease.
      • Naganuma T.
      • Sugimura K.
      • Wada S.
      • et al.
      The prognostic role of brain natriuretic peptides in hemodialysis patients.
      • Nakatani T.
      • Naganuma T.
      • Masuda C.
      • Uchida J.
      • Sugimura T.
      • Sugimura K.
      Significance of brain natriuretic peptides in patients on continuous ambulatory peritoneal dialysis.
      • Mallamaci F.
      • Zoccali C.
      • Tripepi G.
      • et al.
      Diagnostic potential of cardiac natriuretic peptides in dialysis patients.
      • Cataliotti A.
      • Malatino L.S.
      • Jougasaki M.
      • et al.
      Circulating natriuretic peptide concentrations in patients with end-stage renal disease Role of brain natriuretic peptide as a biomarker for ventricular remodeling.
      In patients with CKD not requiring dialysis, BNP-32 level predicts heart failure hospitalization,
      • Takami Y.
      • Horio T.
      • Iwashima Y.
      • et al.
      Diagnostic and prognostic value of plasma brain natriuretic peptide in non–dialysis-dependent CRF.
      and proBNP1-76 level predicts a combined end point of CVD events, progression of kidney disease, and mortality.
      • Carr S.J.
      • Bavanandan S.
      • Fentum B.
      • Ng L.
      Prognostic potential of brain natriuretic peptide (BNP) in predialysis chronic kidney disease patients.
      In patients with a GFR less than 60 mL/min/1.73 m2 (<1.00 mL/s/1.73 m2) presenting with dyspnea, proBNP1-76 level predicts 60-day mortality.
      • Anwaruddin S.
      • Lloyd-Jones D.M.
      • Baggish A.
      • et al.
      Renal function, congestive heart failure, and amino-terminal pro-brain natriuretic peptide measurement Results from the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) Study.
      BNP-32 level is an independent predictor of cardiovascular death
      • Naganuma T.
      • Sugimura K.
      • Wada S.
      • et al.
      The prognostic role of brain natriuretic peptides in hemodialysis patients.
      • Cataliotti A.
      • Malatino L.S.
      • Jougasaki M.
      • et al.
      Circulating natriuretic peptide concentrations in patients with end-stage renal disease Role of brain natriuretic peptide as a biomarker for ventricular remodeling.
      • Zoccali C.
      • Mallamaci F.
      • Benedetto F.A.
      • et al.
      Cardiac natriuretic peptides are related to left ventricular mass and function and predict mortality in dialysis patients.
      and overall mortality
      • Zoccali C.
      • Mallamaci F.
      • Benedetto F.A.
      • et al.
      Cardiac natriuretic peptides are related to left ventricular mass and function and predict mortality in dialysis patients.
      in patients undergoing dialysis. Therefore, such therapies that decrease left ventricular wall tension as a decrease in volume by dialysis treatment, angiotensin-converting enzyme inhibition, or β-blockade potentially are of most value in patients with elevated BNP levels. This remains to be proven.

       Myocardial Necrosis

      The cardiac troponins detect minimal injury to the myocardium and have markedly influenced the management of patients with ischemic chest pain.
      • Apple F.S.
      • Wu A.H.
      Myocardial infarction redefined Role of cardiac troponin testing.
      Troponins C, I (cTnI), and T (cTnT) are associated with actinomysin of the cardiac and skeletal muscle sarcomere, but only cTnI and cTnT are cardiac specific.
      • Freda B.J.
      • Tang W.H.
      • Van Lente F.
      • Peacock W.F.
      • Francis G.S.
      Cardiac troponins in renal insufficiency Review and clinical implications.
      Assays for cTnI and cTnT are widely available on automated platforms.
      In patients presenting with ACSs, elevated cTnI or cTnT level is associated with a 3-fold risk for death,
      • Heidenreich P.A.
      • Alloggiamento T.
      • Melsop K.
      • McDonald K.M.
      • Go A.S.
      • Hlatky M.A.
      The prognostic value of troponin in patients with non-ST elevation acute coronary syndromes A meta-analysis.
      • Olatidoye A.G.
      • Wu A.H.
      • Feng Y.J.
      • Waters D.
      Prognostic role of troponin T versus troponin I in unstable angina pectoris for cardiac events with meta-analysis comparing published studies.
      and these cardiovascular biomarkers identify patients who benefit from such specific therapies as GPIIb/IIIa antagonists.
      • Heeschen C.
      • Hamm C.W.
      • Goldmann B.
      • Deu A.
      • Langenbrink L.
      • White H.D.
      PRISM Study Investigators
      Troponin concentrations for stratification of patients with acute coronary syndromes in relation to therapeutic efficacy of tirofiban. Platelet Receptor Inhibition in Ischemic Syndrome Management.
      • Hamm C.W.
      • Heeschen C.
      • Goldmann B.
      • et al.
      c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) Study Investigators
      Benefit of abciximab in patients with refractory unstable angina in relation to serum troponin T levels.
      • Newby L.K.
      • Ohman E.M.
      • Christenson R.H.
      • et al.
      Benefit of glycoprotein IIb/IIIa inhibition in patients with acute coronary syndromes and troponin T-positive status The PARAGON-B Troponin T Substudy.
      Thus, the troponins (or creatine kinase-MB) are part of the 7-component Thrombolysis in Myocardial Infarction Risk Score that predicts adverse outcomes in patients with ACSs and also defines patients who benefit most from specific therapies.
      • Sabatine M.S.
      • Antman E.M.
      The Thrombolysis in Myocardial Infarction risk score in unstable angina/non-ST-segment elevation myocardial infarction.
      In asymptomatic patients with CKD, the proportion with elevated troponin levels increases as GFR decreases
      • Abbas N.A.
      • John R.I.
      • Webb M.C.
      • et al.
      Cardiac troponins and renal function in nondialysis patients with chronic kidney disease.
      and is very high in patients on dialysis treatment.
      • Apple F.S.
      • Murakami M.M.
      • Pearce L.A.
      • Herzog C.A.
      Predictive value of cardiac troponin I and T for subsequent death in end-stage renal disease.
      Elevated cTnT level predicts adverse outcomes in asymptomatic patients with decreased GFRs,
      • Abbas N.A.
      • John R.I.
      • Webb M.C.
      • et al.
      Cardiac troponins and renal function in nondialysis patients with chronic kidney disease.
      • Goicoechea M.
      • Garca de Vinuesa S.
      • Gomez-Campdera F.
      • et al.
      Clinical significance of cardiac troponin T levels in chronic kidney disease patients Predictive value for cardiovascular risk.
      • Wood G.N.
      • Keevil B.
      • Gupta J.
      • et al.
      Serum troponin T measurement in patients with chronic renal impairment predicts survival and vascular disease A 2 year prospective study.
      those undergoing hemodialysis,
      • Apple F.S.
      • Murakami M.M.
      • Pearce L.A.
      • Herzog C.A.
      Predictive value of cardiac troponin I and T for subsequent death in end-stage renal disease.
      • Iliou M.C.
      • Fumeron C.
      • Benoit M.O.
      • et al.
      Prognostic value of cardiac markers in ESRD Chronic Hemodialysis and New Cardiac Markers Evaluation (CHANCE) Study.
      • Dierkes J.
      • Domrose U.
      • Westphal S.
      • et al.
      Cardiac troponin T predicts mortality in patients with end-stage renal disease.
      • Ishii J.
      • Nomura M.
      • Okuma T.
      • et al.
      Risk stratification using serum concentrations of cardiac troponin T in patients with end-stage renal disease on chronic maintenance dialysis.
      • Mallamaci F.
      • Zoccali C.
      • Parlongo S.
      • et al.
      Troponin is related to left ventricular mass and predicts all-cause and cardiovascular mortality in hemodialysis patients.
      • Ooi D.S.
      • Zimmerman D.
      • Graham J.
      • Wells G.A.
      Cardiac troponin T predicts long-term outcomes in hemodialysis patients.
      and those undergoing peritoneal dialysis.
      • Duman D.
      • Tokay S.
      • Toprak A.
      • Duman D.
      • Oktay A.
      • Ozener I.C.
      Elevated cardiac troponin T is associated with increased left ventricular mass index and predicts mortality in continuous ambulatory peritoneal dialysis patients.
      • Lowbeer C.
      • Gutierrez A.
      • Gustafsson S.A.
      • Norrman R.
      • Hulting J.
      • Seeberger A.
      Elevated cardiac troponin T in peritoneal dialysis patients is associated with CRP and predicts all-cause mortality and cardiac death.
      In patients undergoing hemodialysis, cTnI level also predicts mortality and cardiovascular events.
      • Apple F.S.
      • Murakami M.M.
      • Pearce L.A.
      • Herzog C.A.
      Predictive value of cardiac troponin I and T for subsequent death in end-stage renal disease.
      • Ishii J.
      • Nomura M.
      • Okuma T.
      • et al.
      Risk stratification using serum concentrations of cardiac troponin T in patients with end-stage renal disease on chronic maintenance dialysis.
      • Boulier A.
      • Jaussent I.
      • Terrier N.
      • et al.
      Measurement of circulating troponin Ic enhances the prognostic value of C-reactive protein in haemodialysis patients.
      • Beciani M.
      • Tedesco A.
      • Violante A.
      • et al.
      Cardiac troponin I (2nd generation assay) in chronic haemodialysis patients Prevalence and prognostic value.
      • Roberts M.A.
      • Fernando D.
      • Macmillan N.
      • et al.
      Single and serial measurements of cardiac troponin I in asymptomatic patients on chronic hemodialysis.
      In a meta-analysis of these studies, elevated cTnT level predicted poorer outcomes, but the lack of standardization of the cTnI assay precluded a conclusion about this cardiovascular biomarker.
      • Khan N.A.
      • Hemmelgarn B.R.
      • Tonelli M.
      • Thompson C.R.
      • Levin A.
      Prognostic value of troponin T and I among asymptomatic patients with end-stage renal disease A meta-analysis.
      Despite the clear association with adverse outcome, the clinical problem of abnormal cardiac troponin levels in asymptomatic patients with CKD remains challenging. An elevated troponin level may be attributed to decrease in GFR, and it is true that both cTnT and cTnI (the former with greater frequency) very frequently are detectable in patients receiving dialysis.
      • Apple F.S.
      • Murakami M.M.
      • Pearce L.A.
      • Herzog C.A.
      Predictive value of cardiac troponin I and T for subsequent death in end-stage renal disease.
      • Ishii J.
      • Nomura M.
      • Okuma T.
      • et al.
      Risk stratification using serum concentrations of cardiac troponin T in patients with end-stage renal disease on chronic maintenance dialysis.
      • Chapelle J.P.
      • Dubois B.
      • Bovy C.
      • Aldenhoff M.C.
      • Gielen J.
      • Rorive G.
      Comparison of plasma cardiac troponins T and I in chronically hemodialyzed patients in relation to cardiac status and age.
      • Fehr T.
      • Knoflach A.
      • Ammann P.
      • Pei P.
      • Binswanger U.
      Differential use of cardiac troponin T versus I in hemodialysis patients.
      • Iliou M.C.
      • Fumeron C.
      • Benoit M.O.
      • 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.
      • Li D.
      • Jialal I.
      • Keffer J.
      Greater frequency of increased cardiac troponin T than increased cardiac troponin I in patients with chronic renal failure.
      • Musso P.
      • Cox I.
      • Vidano E.
      • Zambon D.
      • Panteghini M.
      Cardiac troponin elevations in chronic renal failure Prevalence and clinical significance.
      • Roppolo L.P.
      • Fitzgerald R.
      • Dillow J.
      • Ziegler T.
      • Rice M.
      • Maisel A.
      A comparison of troponin T and troponin I as predictors of cardiac events in patients undergoing chronic dialysis at a Veteran’s Hospital A pilot study.
      The hemodialysis procedure is not a likely explanation for this difference because there is minimal
      • Ooi D.S.
      • House A.A.
      Cardiac troponin T in hemodialyzed patients.
      • Tarakcioglu M.
      • Erbagci A.
      • Cekmen M.
      • et al.
      Acute effect of haemodialysis on serum markers of myocardial damage.
      • Wayand D.
      • Baum H.
      • Schatzle G.
      • Scharf J.
      • Neumeier D.
      Cardiac troponin T and I in end-stage renal failure.
      • Willging S.
      • Keller F.
      • Steinbach G.
      Specificity of cardiac troponins I and T in renal disease.
      or no
      • Tarakcioglu M.
      • Erbagci A.
      • Cekmen M.
      • et al.
      Acute effect of haemodialysis on serum markers of myocardial damage.
      • Willging S.
      • Keller F.
      • Steinbach G.
      Specificity of cardiac troponins I and T in renal disease.
      • Mockel M.
      • Schindler R.
      • Knorr L.
      • et al.
      Prognostic value of cardiac troponin T and I elevations in renal disease patients without acute coronary syndromes A 9-month outcome analysis.
      • Lowbeer C.
      • Stenvinkel P.
      • Pecoits-Filho R.
      • et al.
      Elevated cardiac troponin T in predialysis patients is associated with inflammation and predicts mortality.
      • Farkouh M.E.
      • Robbins M.J.
      • Urooj Zafar M.
      • et al.
      Association between troponin I levels and mortality in stable hemodialysis patients.
      • Tun A.
      • Khan I.A.
      • Win M.T.
      • et al.
      Specificity of cardiac troponin I and creatine kinase-MB isoenzyme in asymptomatic long-term hemodialysis patients and effect of hemodialysis on these cardiac markers.
      change in postdialysis troponin levels. In addition, cTnT levels decrease after restoration of renal function by renal transplantation.
      • Wu A.H.
      • Feng Y.J.
      • Roper L.
      • Herbert K.
      • Schweizer R.
      Cardiac troponins T and I before and after renal transplantation.
      • McNeil A.R.
      Implications of a rapid decrease in serum troponin T levels after renal transplantation.
      However, studies examining elimination of cTnI
      • Ellis K.
      • Dreisbach A.W.
      • Lertora J.L.
      Plasma elimination of cardiac troponin I in end-stage renal disease.
      or levels of both troponins in urine and serum
      • Ziebig R.
      • Lun A.
      • Hocher B.
      • et al.
      Renal elimination of troponin T and troponin I.
      did not show that renal elimination was important. For cTnT, immunoreactive fragments small enough to undergo renal excretion may contribute to increased levels in patients with CKD,
      • Diris J.H.
      • Hackeng C.M.
      • Kooman J.P.
      • Pinto Y.M.
      • Hermens W.T.
      • van Dieijen-Visser M.P.
      Impaired renal clearance explains elevated troponin T fragments in hemodialysis patients.
      although this is controversial.
      • Fahie-Wilson M.N.
      • Carmichael D.J.
      • Delaney M.P.
      • Stevens P.E.
      • Hall E.M.
      • Lamb E.J.
      Cardiac troponin T circulates in the free, intact form in patients with kidney failure.
      The question remains, “Does cardiac troponin level reflect GFR or does the elevated level indicate disturbed cardiac pathological states?” Our studies showed that levels of serial cTnI measured weekly for 2 months in asymptomatic patients undergoing hemodialysis fluctuated significantly.
      • Roberts M.A.
      • Fernando D.
      • Macmillan N.
      • et al.
      Single and serial measurements of cardiac troponin I in asymptomatic patients on chronic hemodialysis.
      Of patients with undetectable cTnI at baseline, 27% subsequently developed at least 1 additional detectable cTnI measure. Of patients with detectable cTnI at baseline, 92% had 1 or more additional detectable cTnI levels. Because these were stable dialysis patients, factors other than GFR must contribute to transiently increased cTnI levels. In another study of patients on hemodialysis treatment, overall cTnT levels increased over time, and patients who had an increase in cTnT level over time were more likely to experience an ischemic heart disease event.
      • Fernandez-Reyes M.J.
      • Mon C.
      • Heras M.
      • et al.
      Predictive value of troponin T levels for ischemic heart disease and mortality in patients on hemodialysis.
      The strong association with adverse outcomes coupled with the known high prevalence of such myocardial abnormalities as LVH, systolic heart failure,
      • Mallamaci F.
      • Zoccali C.
      • Parlongo S.
      • et al.
      Diagnostic value of troponin T for alterations in left ventricular mass and function in dialysis patients.
      and coronary atheroma
      • deFilippi C.R.
      • Tocchi M.
      • Parmar R.J.
      • et al.
      Cardiac troponin T in chest pain unit patients without ischemic electrocardiographic changes Angiographic correlates and long-term clinical outcomes.
      in patients with CKD suggests that 1 of the main contributions of decreased GFR to troponin levels is amplification of a signal from a diseased heart. Thus, increased levels in asymptomatic patients strongly suggest the need to further investigate and treat such abnormalities. However, unlike patients with ACSs, it is not known whether more intensive investigation and treatment of asymptomatic patients on dialysis therapy based on troponin levels will improve outcomes.
      • Lauer M.S.
      Cardiac troponins and renal failure The evolution of a clinical test.

       Other Cardiovascular Biomarkers

      In patients with CKD, many other cardiovascular biomarkers were studied in relation to cardiovascular outcomes and mortality. Examples of cardiovascular biomarkers associated with these outcomes in dialysis patients include such hormones as adiponectin
      • Zoccali C.
      • Mallamaci F.
      • Tripepi G.
      • et al.
      Adiponectin, metabolic risk factors, and cardiovascular events among patients with end-stage renal disease.
      and, in males, but not females, relaxin.
      • Hocher B.
      • Ziebig R.
      • Krause R.
      • et al.
      Relaxin is an independent risk factor p