Methods and potential biomarkers for the evaluation of endothelial dysfunction in chronic kidney...

Journal of the American Society of Hypertension 4(3) (2010) 116–127

Review Article

Methods and potential biomarkers for the evaluation of endothelialdysfunction in chronic kidney disease: A critical approach

Simona M. Hogas, MDa, Luminita Voroneanu, MDa, Dragomir N. Serban, MD, PhDb,Liviu Segall, MD, PhDa, Mihai M. Hogas, MDb, Ionela Lacramioara Serban, MD, PhDb,

and Adrian Covic, MD, PhD, FRCPa,*aNephrology Clinic at ‘‘C. I. Parhon’’ University Hospital, ‘‘Gr. T. Popa’’ University of Medicine and Pharmacy, Iasi, Romania; and

bPhysiology Department, ‘‘Gr. T. Popa’’ University of Medicine and Pharmacy, Iasi, Romania

Manuscript received October 22, 2009 and accepted March 11, 2010

Abstract

The impressive cardiovascular morbidity and mortality of chronic kidney disease (CKD) patients is attributable in a significantproportion to endothelial dysfunction (ED), arterial stiffness, and vascular calcifications. Abnormal vascular reactivity inthese patients is more pronounced compared with other high-risk populations, but remains undiagnosed in the usual clinicalsetting. We briefly review the most important causes and risk factors of ED, oxidative stress, and inflammation related toarterial stiffness. We describe the main methods of ED investigation and the importance of using potential biomarkerstogether with classic techniques for a more comprehensive assessment of this condition. These methods include evaluationof: forearm blood flow by plethysmography, skin microcirculation by laser Doppler, and flow-mediated vasodilation byDoppler ultrasound imaging. Applanation tonometry is an easy-to-handle tool that allows a clinically reliable assessmentof arterial stiffness and is also useful in quantifying endothelium-dependent and -independent vascular reactivity. We alsodiscuss the diagnostic and therapeutic impact of new markers of ED in the CKD population. Improvement of endothelialfunction is an important challenge for clinical practice, and there are relatively few therapeutical strategies available. There-fore, a combined biomarker and bedside investigational approach could be a starting point for developing optimal therapeutictools. J Am Soc Hypertens 2010;4(3):116–127. � 2010 American Society of Hypertension. All rights reserved.Keywords: Vascular reactivity; arterial stiffness; cardiovascular risk factors; inflammation.

patients.1 Although ‘‘classic’’ CV risk factors are present
Introduction
Cardiovascular (CV) disease is the main cause ofmorbidity and mortality in chronic kidney disease (CKD)

Supported by the Romanian Ministry of Education andResearch, via CNCSIS and UEFISCSU: plan PN2, programIDEI, section PCE, research grant ID-1156 (2007–2010).Presented at the International Symposium ‘‘Works and Views inEndothelium-Dependent Vasodilation’’ (Iasi, Romania, 13–14May 2009). Dragomir N. Serban, Mihai M. Hogas, and IonelaLacramioara Serban are members of the Cell Physiology & Phar-macology Unit at the Center for Study and Therapy of Pain,‘‘Gr. T. Popa’’ University of Medicine and Pharmacy, Iasi,Romania.

Conflict of interest: none*Corresponding author: Adrian Covic, MD, PhD, FRCP, Head of

Nephrology Clinic at ‘‘C. I. Parhon’’ University Hospital, ‘‘Gr. T.Popa’’ University of Medicine and Pharmacy, Bd. Carol I, Nr. 50,700503 Iasi, Romania. Tel: þ40-721-280246; fax:þ40-232-210940.

E-mail: [email protected]

1933-1711/$ – see front matter � 2010 American Society of Hypertendoi:10.1016/j.jash.2010.03.008

and unusually frequent in this population, excessive andaccelerated CV disease cannot be explained by these alone.2

Such factors, including arterial hypertension, dyslipidemia,and diabetes, contribute to endothelial dysfunction (ED).3

Recent evidence suggests that oxidative stress and inflamma-tion are the key players for the pathogenesis of ED and‘‘accelerated atherosclerosis’’ in CKD patients.4,5 (Thereader should note that the term endothelial dysfunctionwas used in this review merely with its generic meaning offunctional disturbance of the endothelium, which circum-scribes the more precise significance of this term [eg,‘‘decreased bio-availability of endothelium-derived nitricoxide,’’ which is accompanied by reduced vasodilatationvs. vasoconstriction, prothrombotic perturbations in coagu-lation and fibrinolysis, abnormal smooth muscle cell prolifer-ation, deficient repair mechanisms, etc.]) Any strategyconsidered for reduction of the CV risk in CKD patientsmust be directed toward restoring normal endothelialfunction or preventing the aggravation of preexisting ED.

sion. All rights reserved.

mailto:[email protected]

117S.M. Hogas et al. / Journal of the American Society of Hypertension 4(3) (2010) 116–127

Risk Factors for ED in CKD: Central Role ofInflammation and Nitric Oxide Deficit

CKD patients often have both an acute and a chronicinflammatory status, which increases the morbidity andmortality risk.5 The causes of the highly prevalent stateof inflammation in CKD are multiple, including decreasedrenal function, chronic volume overload, comorbidities,and intercurrent clinical events, factors associated withthe dialysis procedure, and genetic factors.6 C-reactiveprotein (CRP) was initially suggested to be merelya biomarker, but accumulating evidence shows that circu-lating CRP appears to be also a mediator of atherogenesisand inflammation.7,8 In vitro experiments reveal that CRPdecreases both basal and stimulated release of nitric oxide(NO), by potently downregulating transcription of endothe-lial nitric oxide synthase.9 In human subjects, an inverserelationship between CRP and endothelium-dependent vas-oreactivity has been described.10 There is also strong andconsistent evidence that acute phase reactants, such asCRP and cytokines such as tumor necrosis factor (TNF)-a and interleukins (IL-1, IL-6), are independently associ-ated with death and atherosclerosis in stage 5 CKDpatients.11

NO is one of the most important vasodilating substancesreleased by the endothelium. Besides that, NO inhibits growthand inflammation and has antiaggregant effects on platelets.12

Decreased NO has often been reported in the presence ofimpaired endothelial function. This decrease may resultfrom reduced endothelial nitric oxide synthase activity underthe action of endogenous or exogenous inhibitors, or becauseof diminished availability of its substrate, L-arginine, and alsofrom decreased bioavailability of NO because of its inactiva-tion by many substances, including reactive oxygen species.13

Evidence is accumulating that CKD is a state of NO deficiencysecondary to decreased kidney NO production or increasedbio-inactivation of NO, primarily by reactive oxygen species14

and inflammation mechanisms and mediators, such as CRP.11

Hemodialysis is associated with hemodynamic instability,repetitive myocardial ischemia, which, in the absence of coro-nary artery disease, may be due to coronary microvasculardysfunction.15

ED, Atherosclerosis, and Arteriosclerosis

ED is a sine qua non condition of atherogenesis. Athero-sclerosis is a complex process that may be initiated byvarious insults to the vascular endothelium. Subsequently,atherosclerosis develops because of continuous damage ofthe vascular endothelium, leading to advanced ED, whichultimately influences the outcome of patients at CVrisk.16 Factors involved in the arterial damage in stage 5CKD patients span from CKD-related CV risk factorssuch as anemia and mineral and bone disease abnormalitiesto emerging risk factors such as hyperhomocysteinemia,

adiponectin, leptin, visfatin, micro-inflammation, and accu-mulation of asymmetric dimethyl-arginine (ADMA), anendogenous inhibitor of NO synthetase.17,18

Systemic disorders of mineral and bone metabolism thatoccur in CKD are characterized by abnormalities of boneturnover, mineralization, volume, and growth as well asvascular calcification.19 Vascular calcifications are notonly the consequence of simple calcium-phosphate deposi-tion/precipitation in the vessel walls, but also are muchmore of an active biological process.20 At the same time,there is a direct bone-arterial crosstalk as a consequenceof direct association between calcium load and aortic stiff-ness in CKD patients, particularly in those with adynamicbone disease.21

There is now evidence that confirms endothelium as animportant regulator of arterial elasticity. Basal endoge-nous NO generation decreases arterial stiffness inanimals22 and humans.23 In contrast, endothelin 1, inconcentrations similar to those observed in the plasmaof patients with CKD, enhances arterial stiffness.24

Vascular calcifications contribute to arterial stiffness,and studies have demonstrated that the presence ofvascular calcification in large arteries25 and in coronaryarteries26 is closely correlated with increased arterialstiffness in stage 5 CKD patients.

Several factors, including uremic toxins, hyperphospha-temia, increased oxidative stress, and inflammation, maygenerate vascular smooth muscle cells phenotypic transfor-mation into osteoblast-like cells. These osteoblast-like cellsare capable of producing bone matrix proteins, which maysubsequently regulate mineralization. After mineralizationis initiated, increased calcium/phosphate load fromadynamic or hyperdynamic bone, secondary hyperparathy-roidism, or excessive calcium intake may accelerate theprocess, whereas serum fetuin A and others calcificationinhibitors may be protective (Figure 1).27 Osteoprotegerin(OPG), a member of the TNF-a receptor superfamily,inhibits osteoclastogenesis, osteoclast activation, andformation of osteoclast-like cells in arteries and atheroscle-rotic plaques. Elevated OPG levels have been interpreted asa failed compensatory mechanism trying to counteract theongoing calcification process; however, because OPGproduction and expression are highly regulated by severalinflammatory cytokines,28 it could also be speculated thatincreased OPG levels in CKD may in part be a consequenceof systemic inflammation.29 Arterial calcifications may leadto arterial wall stiffness, with increased pulse wave velocity(PWV).30 Arterial stiffness may contribute to vessel walldamage and atherosclerosis.31,32

It has recently been reported that the presence of vascularcalcifications in stage 5 CKD patients is associated withincreased stiffness of large elastic-type arteries, such asthe aorta and common carotid artery. Progression of CKDmay be associated with the presence and extent of abdom-inal aortic calcification, and a high level of calcification

Figure 1. Association between arterial stiffness and vascularcalcifications (Ca � P – blood serum calcium-phosphateproduct).

118 S.M. Hogas et al. / Journal of the American Society of Hypertension 4(3) (2010) 116–127

may be associated with de novo CV events.33 However,animals in which CKD was induced experimentally, oroccurred naturally, develop medial calcification, but notatherogenic/intimal calcification.34 In a recent study, Peli-sek et al35 investigated retrospectively the histology ofcarotid plaques from patients with high-grade internalcarotid artery stenosis undergoing carotid endarterectomy.Comparison of plaque morphology was performed on 41patients with CKD. Patients with CKD had a significantlyhigher percentage of total calcification and unstable andruptured plaques as a consequence of enhanced calcifica-tion and reduced collagen fibers in plaques.35 In CKDpatients, changes in the intrinsic properties of the arterialwall (arterial remodeling) promote the increase of arterialstiffness and accelerate atherosclerosis, creating a viciouscircle.36

In vivo Direct Assessment of Endothelial Function

An important armamentarium for the clinical evaluationof ED has been available for many years. Recentlyproposed potential ED biomarkers should be correlatedwith the instrumental methods for a better assessment of

endothelial function and aiming at the development ofnew therapeutic strategies.

Invasive Methods

Quantitative angiography, combined with intracoronaryinfusion of an endothelium-dependent vasodilator (sero-tonin or bradykinin), is used for direct quantification ofendothelial function in coronary arteries, allowingconstruction of dose-response curves for both endothelialagonists and antagonists.37 In a much more invasive proce-dure, dilatation of coronary resistance vessels to induceincreases in shear stress in the upstream epicardial arteriescan be achieved by metabolic stimuli such as exercise orpacemaker stimulation (or by selective infusion of adeno-sine or papaverine into the midportion of the epicardialartery). Quantitative angiography is considered to be the‘‘gold standard’’ for early detection of ED in the coronaryarteries, but has the disadvantage of being invasive (with allinherent risks of coronary catheterization) and also expen-sive; thus, it cannot be used as a screening test in theCKD population.38

Noninvasive Methods

Flow-mediated Dilation

Evaluation of flow-mediated dilation (FMD) by ultra-sound is widely used to study ED in coronary artery disease,hyperlipidemia, arterial hypertension, and diabetes, allconsidered as major CV risk factors. Irrespective of its cause,hyperemia in a vascular bed leads to a coordinated responsein the upstream feeding arteries (ie, FMD), which is cruciallydependent on endothelium activation by shear stress andlargely mediated by NO. The current procedure for measure-ment of FMD in humans involves ultrasound evaluation ofthe brachial artery dilatation during the reactive hyperemiathat follows a brief compressive ischemia of the forearm.38

Several studies propose that brachial artery FMD measure-ment may represent a surrogate for diagnostic evaluation ofcoronary circulation in patients with evident coronary arterydisease or who are at risk.39,40 A close correlation of endothe-lial function in the human coronary and peripheral vascula-ture has been demonstrated.41 Acute increases in oxidativestress occurring during hemodialysis have also been relatedto impaired brachial artery FMD.38

Forearm Blood Flow

Measurement of the forearm blood flow by strain gaugeplethysmography is a simple noninvasive technique, yieldingresults that are less observer-dependent than ultrasound-based measurements. Endothelial function can be studied byplethysmographic forearm blood flow measurement, eitherafter brachial infusion of endothelium-activating substancesor after a 5-minute compressive ischemia of the distal forearm(percentage change of flow from baseline to maximum during


this reactive hyperemia).42 The method principle is thatobstruction of the venous outflow, without altering arterialinflow, leads to an increase in limb volume that is directlyproportional to the rate of arterial inflow.43

Applanation Tonometry

Applanation tonometry allows noninvasive assessment ofquantitative markers of arterial stiffness, such as aorticPWV and augmentation index, obtained by pulse-waveanalysis, and established as strong independent predictorsof CV morbidity and mortality in patients with CKD.44,45

The pulse wave shape provides information about arterialcompliance and serves as a basis for calculation of augmen-tation index (ie, the ratio between the pulse pressure at thesecond systolic and first systolic peaks), which iscommonly used as a measure of arterial stiffness. Changesin the peripheral pressure waveform (measured by tonom-etry and quantified using augmentation index) induced byb2 adrenoceptor stimulation have been tested for the assess-ment of global endothelial function.46

Laser Doppler Flowmetry

Laser Doppler flowmetry is a new method used to investi-gate endothelial function, at the level of skin microcircula-tion (finger), during postischemic or thermal hyperemia, orafter local application of endothelium-activating substancesby iontophoresis. The method principle is to measure theDoppler shift (ie, the change in light frequency when it is re-flected by the moving blood cells inside microvessels[terminal arterioles, capillary loops, and post-capillaryvenules]). The skin blood flow oscillation appears to berelated to vasomotion; the major components are sponta-neous myogenic, of sympathetic origin, and endothelial-dependent, variable with the frequency domain.47 Theinterest in the study of skin microcirculation using laserDoppler flowmetry in CKD patients arises from the hypoth-esis that skin microvascular function can mirror the state ofother microcirculation territories, including the coronaries.48

Evaluation of endothelium-dependent microvascularreactivity by laser Doppler flowmetry demonstrates thatstage 5 CKD patients are characterized by profound alter-ations in thermal hyperemic responsiveness.49

Iontophoresis

Iontophoresis is based on the principle that electricallycharged drug molecules in solution will migrate acrossthe skin under the influence of a direct low-intensity elec-tric current.50 The delivered quantity of drug depends onthe magnitude and duration of the current applied, and onthe diffusional and electrical characteristics of the skinbarrier. Many studies have evaluated ED in conductancearteries as a surrogate endpoint of coronary arterydisease.51,52 By contrast, connective tissue diseases, suchas systemic sclerosis, involve mostly microvascular

dysfunction, which also frequently complicates otherdiseases, such as diabetes, peripheral artery disease, andrenal failure. Methodological developments presently allowthe evaluation of ED by assessment of microvascular endo-thelial function.53 Recent research demonstrates the benefitof laser Doppler flowmetry for measurement of cutaneousperfusion, as accompanied by iontophoresis of acetylcho-line (ACh) and sodium nitroprusside to evaluate endothelialfunction. ACh and sodium nitroprusside are used togenerate endothelium-dependent and -independent vasodi-lation, respectively. A reduction in vascular response toACh with no concurrent reduction in sodium nitroprussideresponse is indicative of ED.54

Prognostic Value of Endothelium-dependentVasomotor Function

Endothelial function has been defined as an ‘‘excellentbarometer’’ of vascular health and can be used to gaugeCV risk in CKD patients.55 Several studies have evaluatedED using in vivo invasive and noninvasive tests. They haveexplored the reactivity of coronary arteries56–59 and of fore-arm resistance vessels60 after ACh infusion and FMD inbrachial arteries. The evaluation revealed that patientswith ED have a far greater incidence of adverse CV eventsduring follow-up compared with patients with preservedendothelial function. The early occurrence of vasculardysfunction in the course of progressive renal disease leadsto the question of whether vascular function might condi-tion the susceptibility of a healthy individual to renaldamage. The severity of CKD varies considerably amongpatients with similar systemic risk factor profiles, such ashypertension and diabetes, and seems to be also dependenton intrinsic, probably genetically conditioned factors.

Potential Biomarkers for Assessmentof Endothelial Function

Various potential biomarkers have recently been proposed(Figure 2), which may predict ED, but cannot quantify it, asassessed via the clinical methods described previously. Onceestablished, such biomarkers could detect ED in early stages,when the vascular functional tests are still normal, and theycould also be used for ED screening in high-risk populations.Moreover, they may provide a better understanding of ED; ifcombined with noninvasive clinical evaluation methods, theywould promote a better evaluation of ED, thereby facilitatingthe development of new therapeutic weapons to prevent andreduce endothelial damage.

ADMA

ADMA, a residue of the proteolysis of arginine-methylated proteins, is a potent inhibitor of NO synthesis.ADMA is primarily cleared by the kidney and is found in

Figure 2. Endothelial dysfunction in chronic kidney disease:factors, new markers, therapeutic armamentarium (NO, nitricoxide; ADMA, asymmetric dimethyl-arginine; EMP, endothe-lial microparticles; PTX3, long pentraxin 3; OPG, osteoprote-gerin; ACEI, angiotensin-converting enzyme inhibitors; þ,beneficial influence; �, moderate beneficial influence). Themarkers that have been shown to correlate with endothelialdysfunction as determined by functional tests are indicatedby an asterisk.


elevated circulating levels in CKD because of both decreasedelimination and reduced activity of the enzyme dimethylargi-nine dimethylaminohydrolase.61 Increased plasma levels ofADMA are associated with various clinical conditionsinvolving ED, including hypertension, hypercholesterol-emia, diabetes mellitus, and CV disease.62 High ADMAlevels lead to NO depletion, impaired endothelium-dependent vasodilation, reduced free radical scavenging,and plaque rupture with thrombus formation.63 ADMA iselevated in CKD patients, even before impairment of excre-tory function.62 High ADMA levels are associated with fasterrates of kidney disease progression in patients in the earlierstages of CKD.64 ADMA is also an independent predictorof ED, CV disease, and all-cause mortality in hemodialysispatients.65 High ADMA levels are associated with increasedintima-media thickness, a surrogate marker of atheroscle-rosis.66 Pharmacological interventions aimed at decreasingplasma ADMA have not been conclusive, and no specificADMA-lowering therapies are available. Homocysteine-lowering agents (folic acid, vitamin B6, and vitamin B12)exert an inconstant impact on plasma ADMA concentra-tions.67,68 The effect of statins on ADMA levels is alsounclear. There is only one report showing a significantdecrease in plasma ADMA level after 10 mg of rosuvastatinfor 6 weeks.69 Simvastatin, atorvastatin, and pravastatin hadno significant effect on ADMA level.70 Angiotensin-converting enzyme inhibitors and blockers of angiotensinreceptor blockers seem to lower ADMA, but this has beenshown only in small studies of short duration that requirefurther confirmation.71 Elevated ADMA levels are wellcorrelated with arterial stiffness evaluated by applanationtonometry, but ADMA should not be used as a single marker

of ED, because it has a better prognostic value whencombined with tonometry.72

Endothelial Microparticles

Endothelial microparticles (EMP) displaying increasedplasma levels may represent a specific marker of ED inpatients with CV disease.73 A recent study in childrenwith CKD shows that endothelial damage starts in the earlystages of CKD, with overt ED developing along with theincrease of CV risk factors, which supports EMP as a reli-able marker of subclinical atherosclerosis and arterial stiff-ness.74 EMP impair the release of NO from vascularendothelial cells, as observed in isolated arteries exposedto circulating concentrations of EMP from patients withstage 5 CKD and acute coronary syndromes75,76; EMPalso inversely correlate with FMD in stage 5 CKDpatients.75 Capture assays and flow cytometry can be usedfor detection and evaluation of the cellular origin ofEMP.77 Circulating EMP, mainly those derived from endo-thelial cells, express markers of cellular injury and couldreflect the degree of ED. Although the functional and path-ogenic implications of EMP remain to be firmly estab-lished, elucidation of the mechanisms of EMP generationcould lead to pharmacological manipulation of EMP levelsfor therapeutic purposes.

Pentraxin 3

Pentraxin 3 (PTX3, long pentraxin) is a recently discov-ered multimeric inflammatory mediator produced bya variety of tissues and cells, including vascular endothelialcells and macrophages.78 PTX3 levels are increased in dial-ysis patients and inversely correlated with glomerular filtra-tion rate in nondialyzed patients with CKD.79 Also,elevated plasma concentrations of PTX3 were found instage 5 CKD patients with inflammation, protein-energywasting, and signs of CV disease.80 Furthermore, PTX3levels are incrementally higher when inflammation andCV disease coexist. Thus, PTX3 can predict mortality,independently of traditional risk factors and short pentraxin(CRP). There is a strong association of PTX3 with vascularcell adhesion molecule 1 and fibrinogen, other markers ofED.81 There are no specific strategies to reduce PTX3 level;however, Yilmaz et al82 recently showed that in type 2 dia-betes patients, PTX3 levels are significantly reduced indirect proportion with proteinuria and ED after 12 weeksof angiotensin-converting enzyme inhibitor treatment.However, there is still no established correlation betweenPTX3 and functionally assessed ED.

Leptin

Leptin is an adipocyte-derived hormone that belongs tothe IL-6 family of cytokines. Leptin is a crucial hormone


for the regulation of food intake and body weight. It alsoplays a role in various processes and organ systems,including glucose homeostasis, hematopoiesis, and thereproductive and CV systems. Leptin acts on peripheraltissues and increases the inflammatory response by stimu-lating the production of TNF-a, IL-6, and IL-12.83 Hyper-leptinemia is common in CKD, particularly in dialysispatients.84 High leptin concentrations have been associatedwith atherogenic lipid profiles in CKD patients, and thismay contribute to the elevated CV risk that has been linkedto hyperleptinemia in these patients.84 Leptin also plays animportant modulator role in endothelial function, but theinvolved mechanisms remain controversial. Leptin deter-mines endothelium-dependent, NO-mediated vasorelaxa-tion, but it may also upregulate inducible NO synthase togenerate large amounts of NO that impair endothelial func-tion and promote atherogenesis by inducing oxidativestress.85 Scholze et al have recently shown that low leptinlevels predict poor outcome in dialysis patients, probablyreflecting the detrimental effects exerted by the state ofenergy wasting and loss of fat mass in these patients.86

Again, there is no established relation between this markerand the degree of ED as determined by functional tests.

Visfatin

Visfatin is a recently identified adipose tissue cytokine,which is synthesized in visceral fat and mimics the effectsof insulin. Visfatin levels are increased in dialysis patients87

and are associated with increased mortality,88 most oftencaused by CV events. Patients with atherosclerosis andmetabolic syndrome have increased visfatin levels.Increased circulating visfatin is associated with endothelialdamage in all stages of CKD, including dialysis patients,independently of inflammation and insulin resistance.89

There is a strong association between circulating levels ofvisfatin and soluble vascular cell adhesion molecule-1(sVCAM-1), a marker of ED. Very recently, Nuskenet al90 found that hemodialyzed patients have an inverseassociation between active serum visfatin and high-density lipoprotein cholesterol, which is a strong inversepredictor of CV events. They concluded that reduced circu-lating high-density lipoprotein cholesterol may hint at anincreased probability of CV events in hemodialyzedpatients with elevated serum visfatin concentrations.90 Ina recent study in type 2 diabetes patients,91 visfatin wasstrongly and inversely associated with FMD.

Osteoprotegerin

OPG, a cytokine that belongs to the TNF receptor super-family, has a wide range of effects on bone metabolism,endocrine function, and the immune system.92 OPG isproduced in many organs, including lungs, kidneys, intes-tine, and bone. Endothelial cells are also a cellular source

of OPG,93 and elevated OPG levels are significantly associ-ated with ED in type 2 diabetes patients.94 High levels ofcirculating OPG are strong predictors of mortality in hemo-dialyzed patients, suggesting that OPG is a CV risk factor,particularly in patients with high CRP levels.95 Increasedserum OPG levels in hemodialyzed patients indicate arte-rial calcification, which leads to increased PWV, withconsequent CV events.96 Increased OPG level is associatedwith ED, but OPG acts as an antiapoptotic factor, prolong-ing endothelial cell survival in vitro.97 In a recent study,Akinci et al found a significant association of OPG withcarotid intima-media thickness in diabetic women.98

Elevated plasma OPG may have an important role in thedevelopment of vascular dysfunction in hypothyroidpatients as well.99

Endothelial Progenitor Cells

Endothelial progenitor cells (EPC) are primitive bonemarrow cells that have the ability to mature into endothelialcells and have a physiologic role in the repair of endotheliallesions.100 EPC circulating levels are inversely correlatedwith the degree of ED evaluated by FMD.101 Statin therapymay increase circulating EPC and accelerate reendothelial-ization.102 Erythropoietin also stimulates EPC mobiliza-tion.103 In CKD patients, erythropoietin deficiency isassociated with reduced circulating EPC levels, whichmay partly explain ED in this population.103 Less decreasedEPC levels were found in peritoneal dialysis subjectscompared with hemodialysis subjects, independently ofthe arterial stiffness assessed by tonometry.104 CirculatingEPC count in CKD patients positively correlates withmarkers of vascular injury, such as PWV and the EMPlevel,105 suggesting that vascular lesions could stimulateprogenitor cell mobilization, even in a context of lowEPC induced by CKD.

Soluble TNF-like Weak Inducer of Apoptosis

Soluble TNF-like weak inducer of apoptosis (sTWEAK).sTWEAK is a member of the TNF superfamily, which,through binding to its receptor Fn14, mediates various bio-logic effects, including exacerbation of the inflammatoryresponse and muscle-wasting activation through theubiquitin-proteasome and NF-kB pathways.106 ElevatedsTWEAK plasma levels associated with inflammatorystatus (elevated CRP and IL-6) increase the mortality riskin hemodialysis patients.107 Furthermore, because IL-6induces the production of Fn14, it has been suggestedthat a persistently inflamed state may exacerbate the actionof sTWEAK through increased receptor synthesis.108 Theexact role of this biomarker is still unknown. A recent studyby Yilmaz109 described sTWEAK as a novel biomarker ofendothelial dysfunction in patients with CKD. The studyevaluated ED by FMD in 295 patients with different stages


of nondiabetic CKD and revealed that progression of CKDis accompanied by a gradual reduction in sTWEAK plasmalevel. The study also showed that sTWEAK level directlycorrelates with ED,109 which could be related with theexpression of sTWEAK or its receptor, Fn14, by endothe-lial cells.110,111 Further studies will be necessary to eluci-date the precise role of this biomarker.

Therapy of ED

Improvement of endothelial function is an importantchallenge for both the clinical practice and the researchlaboratory. In some cases, treatment of the underlyingdisease may restore endothelial function. For example,kidney transplantation restores renal function in CKDpatients and may improve ED. In patients with arterialhypertension, reduction of blood pressure does not seemto restore endothelial function112; however, the blockadeof the renin-angiotensin system may improve endothelialfunction in these patients by reducing oxidative stress andinflammation.113 Statins have shown beneficial effects onED,114 which are only partially explained by lipid lowering,because these drugs have pleiotropic anti-inflammatoryeffects and also increase endothelial nitric oxide synthaseexpression in human coronary artery endothelial cells.115

Evidence from both animal and human studies suggestthat fish oil supplements, such as n-3 polyunsaturated fattyacids, eicosapentaenoic acid, and docosahexaenoic acid,have anti-inflammatory properties.116 Moreover, dietarysupplementation with fish oil rich in n-3 polyunsaturatedfatty acids positively impacts vascular function and reducesCV risk in the setting of atherosclerosis.117

More studies will be necessary to find the optimal thera-peutic tools for ED. For now, we should probably focus onreducing the risk factors of ED, aiming to preserve orrestore endothelium health. The control of hypertension,dyslipidemia, and diabetes, but also of oxidative stressand inflammation, might be the major therapeutical targetsin this respect.

Conclusion

Endothelium-dependent arterial vasomotor function isnotoriously abnormal in CKD patients and is intimatelylinked to changes in arterial structure and function.118–120

ED contributes to the initiation and progression of athero-sclerotic disease and could be considered both a majorstep in atherogenesis and an independent vascular riskfactor. Clinical methods for testing endothelial functioncan be used as indicators for vascular damage or disease,and also for other diseases associated with increased oxida-tive stress. Several circulating molecules seem to beinvolved in the regulation of endothelial function andmay serve as biomarkers of ED. The elucidation of their

physiologic and pathogenic roles may lead to new thera-peutic avenues in this area.

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