Defining the Natural History of Uremic Cardiomyopathy in ... · he term chronic kidney disease (CKD) en-compasses all renal disease states from the earliest stages through to end-stage

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STATE-OF-THE-ART PAPERS

Defining the Natural History of UremicCardiomyopathy in Chronic Kidney Disease
The Role of Cardiovascular Magnetic Resonance
Nicola C. Edwards, PHD, William E. Moody, MBCHB, Colin D. Chue, MBCHB, Charles J. Ferro, MD,Jonathan N. Townend, MD, Richard P. Steeds, MA, MD

JACC: CARDIOVASCULAR IMAGING CME

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From the Birmingham Cardio-Renal Group, University of Birmingham and Q

United Kingdom. Dr. Chue has received an unrestricted educational grant

Genzyme Corporation. All other authors have reported that they have no re

disclose.

Manuscript received April 21, 2013; revised manuscript received September

CME Objective for This Article: After reading this article the reader should

understand: 1) the prevalence and clinical importance of cardiovascular

disease across all stages of chronic kidney disease (1 to 5); 2) the role and

limitations of different imaging modalities to characterize the various

phenotypes of uremic cardiomyopathy; and 3) the application of recent

advances on echo and cardiac magnetic resonance which provide addi-

tional insight into the causes and consequences of myocardial disease in

chronic kidney disease.

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Ragavendra R. Baliga, MD, has reported that he has no relationships

to disclose.

Author Disclosures: Dr. Chue has received an unrestricted educational

grant, as well as lecture and advisory board fees, from Genzyme Corpo-

ration of Cambridge, Massachusetts. All other authors have reported that

they have no relationships relevant to the contents of this paper to

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Expiration Date: June 30, 2015

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3, 2013, accepted September 5, 2013.

http://dx.doi.org/10.1016/j.jcmg.2013.09.025

http://imaging.onlinejacc.org

Edwards et al. J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 7 , N O . 7 , 2 0 1 4

Use of Cardiac Magnetic Resonance in Chronic Kidney Disease J U L Y 2 0 1 4 : 7 0 3 – 1 4

704

Defining the Natural Histor
y of UremicCardiomyopathy in Chronic Kidney Disease
The Role of Cardiovascular Magnetic Resonance

ABSTRACT

Chronic kidney disease (CKD) is an under-recognized, highly prevalent cardiovascular (CV) risk factor affecting 1 in

7 adults. Large epidemiological studies have clearly established a graded association between the severity of CKD and CV

event rates. Although patients with end-stage renal disease who are undergoing dialysis are at greatest CV risk, the

disease process is evident in the early stages of CKD with glomerular filtration rates as high as 75 ml/min/1.73 m2. Indeed,

these patients are at least 6 times more likely to die of CV disease than to reach end-stage CKD. Thus, the major impact of

CKD on the population and the healthcare budget is not that of providing renal replacement therapy but the cost of death

and disability from premature CV disease.

Although end-stage CKD is characterized by a clustering of conventional atherosclerotic risk factors, it has little

association with CV event rates. This is reflected in disproportionate levels of sudden cardiac death, heart failure,

and stroke, rather than myocardial infarction. Thus it appears that nonatherosclerotic processes, including left ven-

tricular hypertrophy and fibrosis, account for most of the excess CV risk. Over the past decade, the use of cardiac

magnetic resonance in CKD has brought about an improved understanding of the adverse CV changes collectively

known as uremic cardiomyopathy. The unique ability of cardiac magnetic resonance to provide a comprehensive

noninvasive examination of cardiac structure and function, arterial function, myocardial tissue characterization

(T1 mapping and inversion recovery imaging), and myocardial metabolic function (spectroscopy) is ideally suited

to characterize the phenotype of CV disease in CKD and to provide insight into the mechanisms leading to

uremic cardiomyopathy. Concerns relating to an association between gadolinium contrast agents and nephrogenic

systemic fibrosis in dialysis recipients have led to the use of lower doses and lower-risk gadolinium agents that

appear to minimize this risk. (J Am Coll Cardiol Img 2014;7:703–14) © 2014 by the American College of Cardiology

Foundation.

SEE PAGE 729
T he term chronic kidney disease (CKD) en-
compasses all renal disease states fromthe earliest stages through to end-stage

renal disease (ESRD) requiring renal replacementtherapy (Table 1). Although the cardiovascular riskof patients with ESRD is extreme, the major burdenlies in early-stage CKD, which is highly prevalent.Early-stage CKD affects 10% to 16% of adultsin developed nations with a prevalence that isincreasing rapidly as the population ages and as ratesof obesity, diabetes, and hypertension continue torise (1). Although most of the original studies exam-ining cardiovascular disease in CKD focused on pa-tients with ESRD, more recent large studies havedemonstrated that cardiovascular risk increases veryearly in the natural history of CKD, probably at aglomerular filtration rate (GFR) level of approximately75 ml/min/1.73 m2 when serum creatinine may stillbe within the normal range (2). The risk of cardio-vascular death in early-stage CKD far exceeds therisk of progressing to dialysis; therefore, treatmentshould be focused at least as much on reducing this

risk as on reducing the rate of progression of renaldisease.

Epidemiological studies suggest that most cardio-vascular deaths that occur in ESRD are attributableto sudden cardiac death, arrhythmia, or congestiveheart failure, and relatively few deaths result fromcoronary artery disease and myocardial infarction(3). Although traditional cardiovascular risk factorsare more common in patients with CKD, thesefail to account for the elevated risk. This findingsuggests that the mechanistic processes drivingcardiovascular disease in CKD may differ from thosein the general population (Table 2). Nonatheromatousprocesses such as arteriosclerosis, arterial stiffening,and abnormalities of cardiac structure appear to pre-dominate and could explain why standard cardio-vascular disease–modifying drugs such as statinshave failed to have the same impact on car-diovascular mortality in CKD as they do in thegeneral population (4). Thus, detection of these

TABLE 1 Cardiovascular Risk Odds Ratio According to Stage of CKD*

StageEstimated GFR

(ml/min/1.73 m2)Cardiovascular Risk

(Odds Ratio)

1 >90† Dependent on degree of proteinuria

2 30–89† 1.5

3 30–59 2–4

4 15–29 4–10

5 <15 10–50

ESRD Dialysis 20–1000

*The increase in risk in comparison with people free from chronic kidney disease (CKD) depends onthe age of the population studied: the younger the subject, the higher the relative risk. Micro-albuminuria increases the cardiovascular risk by an additional 2- to 4-fold. †Evidence of functionalor structural kidney abnormalities for $3 months defined as abnormal renal biopsy, markers ofrenal damage (persistent proteinuria, albuminuria, hematuria) or structural renal abnormality onimaging studies. Adapted with permission from Schiffrin et al. (50).

ESRD ¼ end-stage kidney disease; GFR ¼ glomerular filtration rate.

ABB R E V I A T I O N S

AND ACRONYMS

AD = aortic distensibility

CKD = chronic kidney disease

CMR = cardiac magnetic

resonance

eGFR = estimated glomerular

filtration rate

ESRD = end-stage renal

disease

Gd = gadolinium

GFR = glomerular filtration

rate

LGE = late gadolinium

enhancement

LV = left ventricular

LVH = left ventricular

hypertrophy

NSF = nephrogenic systemic

fibrosis

TTE = transthoracic

echocardiography

UC = uremic cardiomyopathy

J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 7 , N O . 7 , 2 0 1 4 Edwards et al.J U L Y 2 0 1 4 : 7 0 3 – 1 4 Use of Cardiac Magnetic Resonance in Chronic Kidney Disease

705

abnormalities of cardiac and vascular structure andfunction is pivotal in the diagnosis, risk stratification,and monitoring of cardiovascular disease in CKD(Table 3).

REDEFINING UREMIC CARDIOMYOPATHY

WITH CARDIAC MAGNETIC RESONANCE

In the 1980s, echocardiographic studies identifiedcommon adverse changes in cardiac structure andfunction associated with ESRD that were oftentermed uremic cardiomyopathy (UC) (5). The presenceof these abnormalities, including left ventricularhypertrophy (LVH), left ventricular (LV) dilation,and LV systolic dysfunction, is associated withworse cardiovascular outcome (6). The role of trans-thoracic echocardiography (TTE) in diagnosis andsurveillance of heart disease in CKD is howeverlimited by the wide variability in assessment ofLV mass and lack of tissue characterization. WhereLV volumes are subject to change, for example in pa-tients undergoing dialysis, interoperator variabilitybecomes unacceptable (as high as 40.1 � 22.1 g com-pared with 2.4 � 4.6 g using CMR) (7). Although itis possible to standardize the performance of TTE toa specific time period after dialysis, TTE consistentlyoverestimates LV mass. Almost 48% of patients withLVH can be reclassified as normal when assessedusing CMR criteria (Fig. 1) (8).

Despite this reclassification, abnormalities of car-diac structure or function are still frequent when CMRis performed in ESRD. In a pivotal study of 134 pa-tients who had been undergoing renal replacementtherapy for an average duration of 12 months, CMRwith gadolinium (Gd) contrast agents was performedon the post-dialysis day or at dry weight for perito-neal dialysis (9). The most frequent abnormalitydetected was LVH (72%), with comparatively lowrates of LV dilation (11%) and LV systolic dysfunction(8%). The importance of an accurate, volume-independent measure of cardiac mass is paramount,given that LVH is a strong independent risk factorfor mortality, cardiac arrhythmia, and heart failurein patients undergoing dialysis (10). However, thecategorization of patients as having LVH is not abiological dichotomy; LV mass is a continuous vari-able with a graded relationship with cardiovascularrisk. This is reflected by improved cardiovascularoutcomes with LV mass regression when both LVmass and blood pressure are within the “normalrange” and serves to emphasize the role of CMR inaccurately quantifying LV mass (11). Indeed, previousechocardiographic studies attributed the reduction inmortality following active treatment of anemia (12)

and renal transplantation to a reductionin LV mass (13). When such studies wererepeated using serial CMR, however, regres-sion of LV mass with renal transplantationwas not confirmed (14). These negative find-ings on CMR cast doubt on the reversibility ofLV mass in ESRD and serve to refocus treat-ment to the earlier phases of CKD, whenprevention of LVH may be more successful.

The features of UC have been describedcomprehensively in cross-sectional studiesof patients with ESRD, but far less isknown about the onset or natural history ofsuch changes in early-stage CKD. In a cross-sectional echocardiographic study of 3,487U.S. patients, Park et al. (15) reported preva-lence rates of LVH of 32%, 48%, 57%, and 75%for estimated GFR (eGFR) categories $60, 45to 59, 30 to 44, and <30 ml/min/1.73 m2,respectively. This apparent linear associationbetween the severity of CKD and increasedLV mass was demonstrated using measure-ment of cystatin C to estimate GFR, which has
the advantage of being independent of muscle mass.Although no such graded relationship has beenconfirmed using CMR, the rates of increased LV massare similar to those seen in cross-sectional CMRstudies involving more than 200 patients withstages 2, 3, and 4 CKD without a history of diabetesor cardiovascular disease (16,17). Edwards et al. (17)reported that one-third of patients had significantlyelevated LV mass despite a mean GFR of 51 ml/min/m2 compared to sex- and age-matched controlsubjects. These data are important in emphasizingthat adverse cardiac structural changes occur earlyin the course of CKD when creatinine is frequentlynear normal and before biochemical changes ofuremia are present. Unfortunately, longitudinal data

TABLE 2 Key Studies Using CMR to Characterize Potential Mechanisms of Uremic Cardiomyopathy

Cellular Mechanism Study Population Study Type Outcomes First Author (Ref. #)

Renin-angiotensin-aldosterone system

Aldosterone andangiotensin II

CRIB-2 study,nondiabeticCKD stage 2–4(n ¼ 112)

Randomizedcontrolledtrial

After 40 weeks of treatment, significant reductionsin both LV mass on CMR and PWV were seen inthe spironolactone group

Edwards et al. (21)

CKD stage 2–4(n ¼ 70)

Cross-sectional Excretion of urinary mineralocorticoids in CKDpredicts LVMI on CMR; this relationship isnot present in hypertension and supportsaltered regulatory RAAS mechanisms(aldosterone escape)

McQuarrie et al. (52)

Mineral bone disease

Bone density/aorticcalcification

Nondiabetic CKDstage 3(n ¼ 120)

Cross-sectional LV mass was highest in patients with low bonedensity and aortic calcification

Chue et al. (24)

Calcium ESRD onhemodialysis(n ¼ 246)

Observational Calcium phosphate product independently predictedLVMI and LVH; other key predictors werepre-dialysis SBP and end-diastolic LV volumes

Patel et al. (18)

Phosphate Nondiabetic CKDstage 2–4(n ¼ 208)

Cross-sectional Serum phosphate was independently associatedwith LV mass

Chue et al. (16)

Nondiabetic CKDstage 3(n ¼ 120)

Randomizedcontrolled trial

After 40 weeks, there were no differences betweensevelamer and placebo groups with regard to LVmass, systolic and diastolic function, or pulsedwave velocity

Chue et al. (52)

FGF-23 Diabetic, IgAnephropathyCKD stage 3–4(n ¼ 48)

Cross-sectional FGF-23 was elevated and was an independentpredictor of LVH in CKD but not in essentialhypertension

Stevens et al. (22)

Vitamin D PRIMO study, CKDstage 2–4(n ¼ 227)

Randomizedcontrolledtrial

Therapy for 48 weeks with active vitamin D didnot reduce LV mass on CMR imaging or improveLV diastolic function on echocardiography

Thadhani et al. (25)

Purine metabolism

Uric acid CKD stage 3 withLVH (n ¼ 53)


After 9 months of treatment, allopurinol significantlyreduced LVMI and improved augmentation indexand endothelial function by FMD independent of achange in BP; changes in FMD and proteinuriawere both independent predictors for a changein LVMI

Kao et al. (53)

Collagen/fibrosis

Collagen turnover CRIB-2 study,nondiabeticCKD stage 2–4(n ¼ 112)


Spironolactone treatment attenuated an increase inPIIINP levels associated with impairment of LVdiastolic function

Edwards et al. (53)

Myocardial fibrosis ESRD on RRT(n ¼ 134)

Observational Subendocardial infarction in 14% was associatedwith conventional CV risk factors; mid-wall diffusefibrosis in 14% associated with LV mass but notconventional atheromatous risk factors

Mark et al. (9)

Continued on the next page



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on LV remodeling during progression of CKD andin response to treatment are scarce.

A key question in relation to the high prevalenceof LVH in CKD is whether this association is purelythe result of elevated blood pressure. Althoughblood pressure may be one important determinant, itdoes not appear to be the sole driving force behindthe development of UC (18). For example, an inde-pendent association exists between urinary proteinexcretion and LV mass on CMR that is also inde-pendent of blood pressure (19). Moreover, the varia-tions in response to different antihypertensiveagents suggest that other, blood pressure–

independent mechanisms are involved (20). Aldo-sterone may be a major driver of this process (21), andmediators of abnormal bone mineral metabolism inCKD may also be important. Serum phosphate levelhas been shown to predict LV mass independently ofrenal function and blood pressure (16,18). This may bemediated by increased arterial stiffness, which iscommon in CKD. Increased levels of the phosphaturichormones fibroblast growth factor 23 (FGF-23) andparathyroid hormone arising from impaired renalexcretion of phosphate are also implicated (22). Theseintermediaries have been shown to induce myocytehypertrophy in vitro and in animal studies (23).

TABLE 2 Continued

Cellular Mechanism Study Population Study Type Outcomes First Author (Ref. #)

Proteinuria

Proteinuria CKD stage 2–4(n ¼ 49)

Observational Spot protein/creatinine ratio and 24-h proteinuriaboth independently predicted LVMI on CMR indiabetic patients; combined with SBP, proteinuriaaccounted for 29% and 23% variation in LV mass,respectively.


CKD stage 2–4(n ¼ 70)

Cross-sectional Proteinuria was a univariate predictor of LVMI; urinaryaldosterone independently predicted proteinuriaand was associated with elevated urinary sodiumlevels (surrogate of dietary sodium intake); thesedata support altered RAAS regulation


Arterial stiffness

CKD stage 5(n ¼ 144)

Observational Aortic distensibility on CMR was negatively correlatedwith LV mass, was lower in patients with nonfatalCV events, and was an independent predictor ofmortality (with SBP and diabetes) over medianfollow-up of 719 days

Mark et al. (43)

ESRD � CAD(n ¼ 35)

Cross-sectional Patients with ESRD without CAD had reduced aorticcompliance to an equivalent level as patientswith severe CAD awaiting coronary bypasssurgery; these data support an alterationin the fibroelastic composition within thearterial wall as a cause for altered arterial-ventricular interaction in ESRD

Zimmerli et al. (42)

NondiabeticCKD stage2–3 (n ¼ 189)

Cross-sectional Aortic distensibility was significantly reduced adifferent levels throughout the thoracic aortacompared with control subjects; the strongindependent predictors were age and GFR,which accounted for 50% of variation in theascending aorta

Chue et al. (44)

The cellular pathophysiological mechanisms promoting uremic cardiomyopathy in ESRD were previously reviewed by Glassock et al. (51). Please see the Online Appendix for additionalreferences.

BP ¼ blood pressure; CAD ¼ coronary artery disease; CKD ¼ chronic kidney disease; CMR ¼ cardiac magnetic resonance; CV ¼ cardiovascular; ESRD ¼ end-stage renal disease; GFR ¼glomerular filtration rate; FGF ¼ fibroblast growth factor; FMD ¼ flow mediated dilatation; IgA ¼ immunoglobulin A; LV ¼ left ventricular; LVH ¼ left ventricular hypertrophy; LVMI ¼ leftventricular mass index, PIIINP ¼ aminoterminal propeptide of type III procollagen; PWV ¼ pulsed wave velocity; RAAS ¼ renin-angiotensin-aldosterone system; RRT ¼ renal replacementtherapy; SBP ¼ systolic blood pressure.


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Finally, experiments in vitro have demonstratedthat high levels of intracellular phosphate activelypromote the osteogenic transformation of vascularsmooth muscle cells and result in vascular calcifica-tion. Consistent with this finding, the presence ofaortic calcification is associated with increased arte-rial stiffness and CMR-measured LV mass (24). Morerecent data, however, assessing the effect of phos-phate binder and vitamin D therapy on LV massregression after 40 and 48 weeks, respectively, instage 3 and 4 CKD, were negative (25).

CHARACTERIZING THE PATHOGENESIS OF

UREMIC CARDIOMYOPATHY WITH CMR

Characterization of myocardial tissue using Gd-basedcontrast agents is a major strength of CMR and hasbeen applied in CKD to elucidate further the struc-tural changes that are found. In a cross-sectionalstudy, 28% of patients with ESRD had evidence oflate Gd enhancement (LGE), 72% had LVH on CMR,and the average blood pressure of the whole cohort

was 139/81 mm Hg (9). One-half of these patients (14%of the total) had discrete subendocardial LGEindicative of myocardial infarction (Fig. 2A), thepresence of which was associated with a history ofischemic heart disease and conventional cardiovas-cular risk factors including hypercholesterolemia anddiabetes (but not hypertension). The other patientswith LGE had diffuse mid-wall scarring (Fig. 2B),which was associated with greater LV mass but notwith risk factors for coronary atheroma, LV systolicdysfunction, or angiographic coronary artery disease.The etiology of this pattern of fibrosis in CKD remainsunclear. In a smaller study of 24 patients undergoinghemodialysis, LGE was found in 79%, once againdivided not only into an infarct-related pattern butalso into diffuse and focal noninfarct patterns inequal percentages (26). This study differed from thatof Mark et al. by including only patients undergoinghemodialysis and also by studying a high proportionof African-American patients. Although LV mass wasmuch higher in the latter group, both studiesidentified a significant relationship between volume

TABLE 3 Complementary Imaging Techniques Used to Assess the Cardiovascular Features of Uremic Cardiomyopathy

Imaging Features

Imaging Technique: Strengths and Limitations

2D Echocardiography/Ultrasonography Comment Cardiac Magnetic Resonance Comment

LV structure

LV mass M-mode or 2D Increased interstudy and operatorvariabilityLV geometric assumptionsVolume dependentImage quality

Short-axis LV contouring Reference standardHigh reproducibilityNo geometric assumptionsLoad independent

LV dilation M-mode or 2D dimensions or volumes Load dependent Short-axis LV contouring: endocardialsegmentation and summation of disks

High reproducibilityNo geometric assumptionsLoad independent

LV function

Global LV ejection fraction As per LV mass LV ejection fraction As per LV mass

Regional Deformation imaging (strain, torsion) High temporal resolutionAngle independent (Speckle tracking)Strain is load dependentImage quality

Deformation imaging (myocardialtissue tagging)

Reference standardImprovements in tag-tissue contrastand persistenceImproving temporal resolution (15–20 ms)

Longitudinal Long-axis function (tissueDoppler imaging)

High temporal resolutionHeart rate and load dependent

Phase contrast myocardial tissue velocitiesAnnular plane excursion

Lower temporal resolution than echo

Diastolic Transmitral and pulmonary venousDoppler indicesLA volumes (biplane area-length)

High temporal resolutionHeart rate dependentLoad dependentGeometric assumptions

Phase contrast transmitral and pulmonaryvenous flowShort-axis LA contouring

Lower temporal resolution than echoReference standardNo geometric assumptions

Myocardial fibrosis

Integrated backscatter Validation against histological collagencontentAssessment of interstitial fibrosisWide availabilityLow reproducibility

Late gadolinium enhancementT1 mapping

Reference standardHistological validationLimited to detection of coarse scarringUse may be precluded in ESRDDetection of diffuse fibrosisNew noncontrast techniques

Arterial function

Arterial stiffness Aortic distensibility, aortic compliance,b-index on high-definition echo-trackingand ultrasound devicesCarotid-femoral PWV

Noninvasive blood pressuremeasurements for centralhemodynamicsLower spatial resolutionReference standard

Aortic distensibilityPWV

Direct assessmentAssessment of multiple arterial sitesNoninvasive blood pressure measurementsfor central hemodynamics

Endothelialdysfunction

Flow-mediated dilation Reference standardCorrelation with invasive coronaryartery assessment.Complementary assessment offlow-mediated constriction

Brachial artery dilation High spatial resolution, direct quantificationAssessment of central and peripheral arteriesIntegrated assessment of vascular and ventricularfunction in a single examination

2D ¼ 2-dimensional; LA ¼ left atrial; LV ¼ left ventricular; PWV ¼ pulsed wave velocity.

Edwards

etal.

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FIGURE 1 Assessment of LV Mass in CKD With CMR and Transthoracic Echocardiography

(A) Short-axis stack of a patient with stage 4 chronic kidney disease (CKD) who was diagnosed with left ventricular (LV) hypertrophy on

transthoracic echocardiography (maximum wall thickness, 15 mm; LV mass, 129 g/m2) but within normal limits for sex and age on cardiac

magnetic resonance (CMR) (maximum wall thickness, 12 mm; LV mass, 84 g/m2). (B) Bland-Altman analysis of the difference in LV mass

measured by echocardiography and CMR in patients undergoing hemodialysis. M-mode echocardiography (Echo) significantly overestimates

LV mass relative to CMR as mass increases. MR ¼ magnetic resonance. (B) Adapted with permission from Stewart et al. (8).


709

of LGE and LV mass. The prevalence of LGE in early-stage CKD is unclear, but LGE appears to be far lesscommon. In a cross-sectional study of 100 patientswith stage 2 and 3 CKD but no history ofcardiovascular disease and low levels of risk factors,only 6% had mid-wall diffuse LGE, and 1% hadsubendocardial enhancement consistent with aprevious silent myocardial infarction (27). Unlike thestudies of LGE in ESRD, these patients had normalLV mass, but the predominance of patients withvasculitic disease suggested that inflammation maybe important in this process.

The implication of these studies is that ESRD ischaracterized either by infarct-related scar (driven byatheroma) or by coarse focal scarring that is relateddirectly to the severity of LV hypertrophy. No directhistological verification of the cause of LGE-CMR inCKD has been reported, but the findings are consis-tent with myocardial biopsy results from patientswith ESRD that demonstrate severe myocyte hyper-trophy, myocyte disarray, and extensive interstitialfibrosis (28). These biopsy studies contrast with thehistological findings in arterial hypertension anddiabetes, in which accumulation of type I and type IIIcollagen fibers most commonly results in reactiveinterstitial fibrosis with diffuse distribution withinthe interstitium. Such diffuse fibrosis is often missedon LGE CMR because this technique relies on relative

differences in signal intensities and employs themyocardium with the lowest signal intensity as areference for normality, regardless of the degree offibrosis therein (29). Although LGE is found in somepatients with arterial hypertension, the relationshipbetween the extent of LGE scar and the severity of LVhypertrophy that is observed in CKD is not (30).Newer T1 mapping techniques hold great promise ininvestigating the interactions among hypertension,CKD, and the development of ventricular dysfunctionand subsequent clinical events.

VENTRICULAR FUNCTION IN

UREMIC CARDIOMYOPATHY

Despite the frequency of LVH, focal myocardialfibrosis, and infarct-related disease, overt systolicdysfunction is uncommon in pre-dialysis CKD. In thecross-sectional study of pre-dialysis patients by Parket al. (15), only 8% had systolic dysfunction (definedas an ejection fraction <45%), and no association wasnoted between kidney function (eGFR) or the level ofproteinuria and systolic function in demographic ormultivariate models. This is the same rate as found onCMR in patients undergoing dialysis when using anLV ejection fraction cut-off below 55% (9). At first,this finding appears at odds with the known rates ofsudden cardiac death, arrhythmia, and heart failure,

FIGURE 2 Examples of LGE Imaging in Patients With CKD

(A) An infarct-related pattern of late gadolinium enhancement (LGE) (arrows)

in a patient with stage 3 chronic kidney disease (CKD), without a known his-

tory of coronary heart disease. (B) Non–infarct-related diffuse pattern

(arrows) on LGE in the basal lateral wall of a patient with stage 3 CKD.



710

but on further consideration, it serves to emphasizethe limitations of using ejection fraction to quantifyLV function, particularly in a population exposed tolarge variations in loading conditions.

The application of newer imaging techniques toassess systolic and diastolic function in CKD suggeststhat the extent and severity of functional abnormal-ities were previously underestimated (31). Using tis-sue Doppler echocardiography in 129 patients withESRD (62% undergoing dialysis) with a normal LVmass and without evidence of myocardial ischemiaor overt LV dysfunction (mean LV ejection fraction,59%), Rahkit et al. (31) demonstrated that at leastone marker of reduction in either LV deformation orearly myocardial relaxation velocity was present inall patients. Moreover, these changes independentlypredicted an increase in all-cause mortality andcardiac mortality over 2.4 years of follow-up (31). Asimilar reduction in LV deformation was also evidenton tissue Doppler echocardiography in patients withstage 2 and 3 CKD (32). The advantages of CMR tissuetagging over tissue Doppler echocardiography arewell known, and use of this technique has extendedthese findings. Using spatial magnetization modula-tion tissue tagging, it has been possible to showthat reduction in strain and strain rate is confinednot only to longitudinal myocardial shortening

but also to circumferential contraction in stage 2and 3 CKD, specifically affecting the mid-wall andendocardium compared with control subjects (Fig. 3)(33). The circumferential abnormalities differ fromthose observed with aging, hypertension, and heartfailure with preserved ejection fraction, a findingconfirmed in a study of 98 patients who were receiv-ing maintenance hemodialysis, and may suggest adifferent pathophysiological process in CKD (34).Taken together, these studies suggest that LV functionis abnormal from the early stages of CKD and that re-duction in LV ejection fraction is a late feature of UC.

Right ventricular function is a powerful indepen-dent predictor of outcome in heart failure in thegeneral population, and some evidence indicates arelationship with outcome in patients with CKD andLV systolic heart failure (35). Studies of the interac-tion between CKD and right ventricular structureand function are limited to patients with ESRDwho have been studied with TTE, mainly by investi-gating the effect on tissue velocity imaging and long-axis function measured by tricuspid annular planesystolic excursion (36). The difficulty in using thesedata in CKD is that such measures are load depen-dent, and the prevalence of pulmonary hypertensionin ESRD may be as high as 60% (37). Assessment ofright ventricular structure and function is a uniquestrength of CMR, and studies are awaited that in-vestigate both cross-sectional change according toseverity of CKD and longitudinal outcome.

ASSESSMENT OF ARTERIAL STIFFNESS BY CMR:

A PRECURSOR TO UREMIC CARDIOMYOPATHY?

CKD is characterized by a high prevalence ofatheroma, but of equal importance is arteriosclerosis.This different arterial disease affects the mediallayer of the arterial wall and is characterized bythickening (increased collagen and smooth musclehypertrophy) and calcification (38). The resultant in-crease in arterial stiffness and loss of arterial disten-sibility exposes the myocardium, brain, and kidneysto higher pressure fluctuations and is a strong pre-dictor of cardiovascular morbidity and mortality inESRD (39). There is a graded increase in arterialstiffness that occurs with advancing stages of CKD(40) and is independent of blood pressure and aging,thus leading investigators to hypothesize that arterialstiffness is intimately linked to UC (41).

To date, most of the data on arterial stiffness inCKD have been derived from applanation tonometrytechniques to measure pulsed wave velocity. CMR,however, allows complete assessment of arterialfunction through measurement of aortic distensibility

FIGURE 3 Examples of CMR Tissue Tagging for Deformation Assessment

(A) Short-axis images in end-diastole, mid-systole, and end-systole with spatial magnetization modulation tissue tagging for assessment of

circumferential deformation using Cardiac Image Modeller software (CIM-Tag; University of Auckland, Auckland, New Zealand). (B) Longitu-

dinal tagging assessment of the left ventricle in a 4-chamber view. CMR ¼ cardiac magnetic resonance.


711

(AD), aortic pulsed wave velocity, and endothelialfunction by brachial artery flow-mediated dilation(Fig. 4). In a small cross-sectional study, 24 patientswho were undergoing dialysis and who did not havecoronary artery disease (angiography or exercisetesting) were compared with age- and sex-matchedpatients who had severe CAD and who were awaitingbypass, as well as with healthy control subjects(42). Aortic compliance in the ascending aorta wasreduced to equivalent levels in patients with ESRDand coronary artery disease. The prognostic impor-tance of reduced AD in ESRD was highlighted in astudy of 144 patients with stage 5 CKD (76% un-dergoing dialysis) (43). Over a median follow-upof 24 months, AD and aortic volumetric arterialstrain (a non–pressure-dependent parameter) wereindependent predictors of combined vascular eventsand mortality, whereas AD also predicted all-causemortality.

AD is reduced early in CKD. In a cross-sectionalstudy of 189 patients with nondiabetic stage 2 to 4CKD, AD in the proximal and descending thoracicaorta was reduced with a graded relationship to eGFR(r ¼ 0.172, p < 0.01) (44). Both age and eGFR inde-pendently predicted AD in the ascending aorta,thereby explaining 50% of variance. Similar trends

were seen in a study in stage 2 and 3 disease in whichAD in the ascending aorta was also inversely corre-lated with LV mass (r ¼ �0.284, p < 0.01). In regres-sion analysis, AD contributed 6% of the variance inLV mass index, and this compared to 2% for GFR and10% for systolic blood pressure (17). These changes inlarge arterial function are thought to be closely linkedto the development of UC: as arterial stiffness in-creases, the loss of AD exposes the myocardium tohigher systolic pressures and greater pressure fluc-tuations (38). Although high systolic pressure in-creases afterload, lower diastolic pressure reducesdiastolic coronary perfusion and promotes coronarymicrovascular ischemia. In health and early CKD,cardiac function is matched to arterial function toensure maximum cardiac efficiency, a relationshipdemonstrated on TTE as the ratio of arterial to ven-tricular elastance (17). Whereas the arterial-to-ventricular coupling ratio is preserved in CKD,absolute levels of arterial and ventricular stiffnessare increased. Thus cardiac reserve is reduced, butat a price: diastolic relaxation is impaired, andleft atrial volumes are elevated (45). Inefficiencyin cardiac energetic metabolism also is found inpatients with ESRD, as measured using phosphorus-31 magnetic resonance spectroscopy (46).

FIGURE 4 Examples of Arterial Assessment on CMR

(A) Pulsed wave analysis in the thoracic aorta. The intercept method of the upstroke in the ascending aorta (Asc Ao) and descending aorta (Desc

Ao) are used to calculate transit time between the two sites. Distance is assessed through the midline of the aortic lumen on a sagittal oblique

image. Pulsed wave velocity is calculated as distance/time. (B) Distensibility in the ascending aorta. The maximal and minimal areas are applied

to a formula with simultaneously acquired brachial blood pressure to calculate aortic distensibility. (C) Brachial artery reactivity to hyperemia. A

pressure cuff is applied to the forearm distal to the imaging site, and a surface coil placed is placed above the elbow region. The middle panel

shows high-resolution magnetic resonance imaging aligned perpendicular to the brachial artery (arrow). CMR ¼ cardiac magnetic resonance.



712

CONTRAST-ASSOCIATED NEPHROGENIC

SYSTEMIC FIBROSIS: AN END TO FIBROSIS

RESEARCH IN END-STAGE RENAL DISEASE?

The safety of contrast-enhanced magnetic resonanceimaging using Gd-based agents in CKD was chal-lenged in 2006 when a link between nephrogenicsystemic fibrosis (NSF) and Gd-based contrast agentsemerged from a registry of 355 cases that all occurredin patients with ESRD. Patients with NSF present withindurated plaques and papules on the distal extrem-ities caused by deposition of collagen bundles in thedermis with resultant hardened skin; in 5% cases,this condition progresses to stiffness, joint contrac-tures, and ultimately internal organ involvement(47). No effective treatment is known, although NSFcan be improved by restoration of normal renalfunction. Gd itself is toxic, but these adverse effectsare suppressed in clinical use by encasing it within

a chelator, which may be linear or cyclic. Over time,Gd may dissociate from the chelate, but in subjectswith normal renal function, this happens too slowlyfor tissue to be exposed to the toxic effects of themetal. Most Gd-based contrast agents are renallyexcreted, and the half-life may be increased from90 min with normal renal function to up to 18 to34 hours in ESRD, which may be sufficient forrelease of Gd from linear chelates. The risk of NSFappears to be increased synergistically with a recentproinflammatory event, such as surgery, and withsepsis (48). Risk also depends on the type of contrastagent (most cases have occurred with nonionic linearchelates) and the dose used; the incidence is nearzero at 0.1 mmol/kg regardless of renal function (49).

Following the introduction of a series of Europeanand American guidelines, virtually no new cases ofNSF have been reported in patients either withnormal renal function or CKD (49). Caution is now


713

advised in patients with eGFR <30 ml/min/1.73 m2,and recent assessment of renal function is obligatory.If CMR with Gd-based contrast agents is still thoughtnecessary, low-risk agents (gadobutrol, gadoteridol,and gadoterate) should be used at the lowestpossible dose (0.1 mmol/kg perfusion; 0.1 to 0.2mmol/kg LGE) with early dialysis after imaging.Under these circumstances, the risk of NSF appearsto be very low (47).

CONCLUSIONS

CMR has a proven role in patients with both early-stage and end-stage CKD in defining LV mass andsubclinical and overt ventricular dysfunction and inidentifying the presence of coarse fibrosis. Futureresearch is needed using CMR to confirm the findingsof existing case-control studies with longitudinaloutcome follow-up. It will be important to identifythe impact of LGE fibrosis on outcome, but perhaps

greater opportunity lies with the development ofextracellular volume T1 mapping, which may openthe way to intervention studies to reverse the hugeimpact of cardiovascular morbidity and mortality inthis common condition. As part of this process, ani-mal and human translational work is required toconfirm the histological foundation of cardiovascularfibrosis in CKD.

ACKNOWLEDGMENT S The authors acknowledgethe expertise of Dr. Leeson’s group in Oxford, UnitedKingdom in helping to establish the technique offlow-mediated dilation on CMR in Birmingham.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Nicola C. Edwards, University of Birmingham andQueen Elizabeth Hospital Birmingham, School ofClinical and Experimental Medicine, BirminghamB15 2TT, United Kingdom. E-mail: [email protected].

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KEY WORDS cardiac magnetic resonance,chronic kidney disease, uremiccardiomyopathy

APPENDIX For supplemental references,please see the online version of this article.

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