In Practice Coronary Artery Calcium Assessment in CKD: Utility in Cardiovascular Disease Risk Assessment and Treatment? Ahmed Bashir, MRCP,1 William E. Moody, BMedSc, MRCP,1,2 Nicola C. Edwards, MRCP, PhD,1,2 Charles J. Ferro, MD, FRCP,3 Jonathan N. Townend, MD, FRCP,1 and Richard P. Steeds, MA, MD, FRCP1 Coronary artery calcification (CAC) is a strong predictor of cardiovascular event rates in the general population, and scoring with multislice computed tomography commonly is used to improve risk stratification beyond clinical variables. CAC is accelerated in chronic kidney disease, but this occurs as a result of 2 distinct pathologic processes that result in medial (arteriosclerosis) and intimal (atherosclerosis) deposition. Although there are data that indicate that very high CAC scores may be associated with increased risk of death in hemodialysis, average CAC scores in most patients are elevated at a level at which discriminatory power may be reduced. There is a lack of data to guide management strategies in these patients based on CAC scores. There are even fewer data available for nondialysis patients, and it is uncertain whether CAC score confers an elevated risk of premature cardiovascular morbidity and mortality in such patients. In this article, we review the evidence regarding the utility of CAC score for noninvasive cardiovascular risk assessment in individuals with chronic kidney disease, using a clinical vignette that highlights some of the limitations in using CAC score and considerations in risk stratification. Am J Kidney Dis. -(-):---. ª 2015 by the National Kidney Foundation, Inc. INDEX WORDS: Chronic kidney disease (CKD); coronary artery calcification (CAC); cardiac computed tomography; cardiovascular; prognosis; review.

CASE PRESENTATION A 52-year-old man with end-stage renal disease (ESRD) secondary to diabetic nephropathy was referred for cardiovascular assessment before listing for kidney transplantation. The patient started hemodialysis therapy in 2005 and underwent transplantation in 2009, but returned to hemodialysis therapy after transplant failure 3 years later. He was an arteriopath, having had bilateral femoral angioplasties in 2011. He had stopped smoking 10 years previously and was receiving treatment for hypertension and hypercholesterolemia. In 2012, he completed a 2-day maximal exercise stress 99m-technetium computed tomography (CT)-attenuated singlephoton emission CT with multislice coronary artery calcification (CAC) scoring (SPECT/CT; Siemens Symbia T16). Although perfusion imaging was normal and gated imaging indicated normal left ventricular (LV) function, CAC score was high (1,300 Agatston units [U]; volume, 1,063 mm3, .90th centile for age and sex; Figs 1 and 2). In view of the high CAC score, he underwent coronary angiography, but this showed only mild diffuse coronary atheroma and no evidence of a flow-limiting stenosis (Figs 3 and 4). Following this, the patient was accepted onto the waiting list for kidney transplantation, but has not yet undergone surgery. Despite remaining on hemodialysis therapy, the patient is asymptomatic with no clinical cardiovascular events after 2 years’ follow-up.

EPIDEMIOLOGY OF CARDIOVASCULAR DISEASE IN CHRONIC KIDNEY DISEASE Chronic kidney disease (CKD) is an underrecognized highly prevalent cardiovascular risk factor affecting 1 in 7 adults.1 Its prevalence is set to increase further as the Western population ages and the incidence of diabetes, hypertension, and obesity escalates. The extreme cardiovascular risk of patients with ESRD is well documented; nearly 40% of all deaths are due to a cardiovascular cause and cardiovascular mortality is Am J Kidney Dis. 2015;-(-):---

20 to 1,000 times higher than in the general population (the younger the patient, the higher the relative risk).2,3 More recently, large population studies have demonstrated that cardiovascular risk increases very early in the natural history of CKD, as soon as estimated glomerular filtration rate (eGFR) decreases to ,75 mL/ min/1.73 m2, when the risk of cardiovascular death far exceeds that of progressing to dialysis therapy.4 The increasing global emphasis placed on the early detection of CKD provides a huge potential opportunity for diagnosis and risk modification of cardiovascular disease. However, the development of risklowering strategies has been hindered because although the epidemiologic link between CKD and cardiovascular disease is strong, the underlying pathophysiologic mechanisms are not yet established. This has major implications when interpreting cardiovascular imaging From the 1Department of Cardiology, Nuffield House, Queen Elizabeth Hospital Birmingham; 2Clinical Cardiovascular Science, School of Clinical & Experimental Medicine, University of Birmingham; and 3Department of Renal Medicine, Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham, United Kingdom. Received October 8, 2014. Accepted in revised form January 7, 2015. Address correspondence to Richard P. Steeds, MA, MD, FRCP, Nuffield House, Queen Elizabeth Hospital, Birmingham, Edgbaston, Birmingham, B15 2TH, United Kingdom. E-mail: rick. [email protected]  2015 by the National Kidney Foundation, Inc. 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2015.01.012 1

Bashir et al

Figure 1. Multidetector computed tomographic images show heavy calcification (arrow) affecting the proximal left anterior descending coronary artery.

Figure 3. Coronary angiography shows a patent left anterior descending artery with no flow-limiting disease.

studies in patients with CKD and in particular for quantifying CAC using cardiac CT, which forms the basis of discussion for this review.

Epidemiologic data suggest that not only are a significant proportion of deaths in CKD cardiovascular in origin, but the majority of deaths are due to sudden cardiac death, arrhythmia, congestive heart failure, or stroke, with relatively few from vasculo-

occlusive events such as myocardial infarction.1 Although there is a clustering of conventional risk factors for atherosclerosis, including hypertension and diabetes mellitus, these perform poorly in predicting cardiovascular event rates.5,6 An inverse relationship has been demonstrated between conventional risk factors such as total cholesterol level, obesity, and even hypertension and cardiovascular mortality in ESRD.7 Consistent with these observations, reducing cardiovascular risk in this population remains a challenge; for example, in SHARP (Study of Heart

Figure 2. Multidetector computed tomographic images show heavy calcification (arrow) affecting the proximal right coronary artery.

Figure 4. Coronary angiography shows a patent right coronary artery with minor atheroma but no flow-limiting disease.

PATHOPHYSIOLOGY OF CARDIOVASCULAR DISEASE IN CKD

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Coronary Artery Calcification in CKD

and Renal Protection), decreasing low-density lipoprotein cholesterol levels reduced atherothrombotic events but had no effect on overall survival.8 The extreme rates of LV hypertrophy, dilatation, and fibrosis in CKD and their robust association with an adverse cardiovascular prognosis offer alternative targets for intervention. In a recent cross-sectional echocardiographic study of 3,487 US patients, the CRIC (Chronic Renal Insufficiency Cohort) group reported the prevalence of LV hypertrophy to be as high as 32%, 48%, 57%, and 75% for eGFR categories $ 60, 45 to 59, 30 to 44, and ,30 mL/min/1.73 m2, respectively.9 Imaging modalities restricted to the identification of coronary artery disease (CAD) therefore are likely to underestimate cardiovascular risk if they do not take into account changes in LV structure and function. Table 1 describes the accuracy of the different noninvasive methods for assessing CAD. Vascular disease in CKD results from 2 distinct but coexisting pathologic processes, that is, atherosclerosis and arteriosclerosis.10 The prevalence of atherosclerosis is high in CKD and probably reflects a combination of endothelial damage mediated by reactive oxygen species, activation of the reninangiotensin-aldosterone system, and elevated levels of inflammatory mediators.3 In the general population, it is well established that the amount of coronary calcification correlates closely with the amount of atherosclerosis, and this forms the basis for the use of scoring as the most effective method of improving risk prediction beyond clinical variables.11 In CKD, coronary calcification is more common than in ageand sex-matched controls, and atherosclerotic plaques have higher calcium content compared with those in patients without CKD, which are mostly fibroatheromatous.3 Accelerated atherosclerosis leads to an increased prevalence of ischemic heart disease, stroke, and peripheral vascular disease. Arteriosclerosis is a diffuse disease of the media (without intimal change) characterized by medial thickening and calcification, leading to increased arterial stiffness and, in effect, accelerated aging of the vasculature.10 One of the major consequences is increased rigidity of the thoracic aorta, such that the vessel becomes less able to accommodate the ejected cardiac stroke volume, resulting in increased afterload. Consistent with this, Chue et al12 demonstrated that lower mean femoral z score and the presence of aortic calcification in patients with stage 3 nondiabetic CKD are associated independently with increased LV mass. Arteriosclerosis also leads to loss of the “cushioning effect” that a normal aorta has on pulsatile ejection of blood from the heart.13 This not only increases the risk of subendocardial ischemia by supply and demand imbalance related to low diastolic perfusion pressure, but also exposes the heart, brain, Am J Kidney Dis. 2015;-(-):---

and kidneys to higher fluctuating systolic pressures precipitating microvascular damage and contributing to increased risks of heart failure, arrhythmia, stroke, and further kidney damage.14 Both atherosclerosis and arteriosclerosis result in deposition of calcium within the coronary arteries, but at different sites within the arterial wall. CT calcium scoring (using current standard techniques) is not able to distinguish between intimal (atherosclerotic) and medial (arteriosclerotic) deposition, which in theory may result in different cardiovascular insults (acute coronary syndromes and myocardial infarction vs LV hypertrophy and cardiac failure). In the general population, the location of coronary calcification does not correspond to the site of a stenosis and is simply a marker of intimal atherosclerotic burden. Therefore, as exemplified by our clinical vignette, it is possible to observe a very high Agatston score in the absence of a significant luminal stenosis on coronary angiography. Disturbed mineral metabolism with resulting hyperphosphatemia has been suggested to contribute to the increased vascular calcification observed in CKD.15 Increased serum phosphorus and increased calcium-phosphorus product levels predict cardiovascular mortality in dialysis patients.15,16 The National Kidney Foundation currently recommends that phosphate-binding agents be used to treat hyperphosphatemia in patients with CKD stages 3 to 5 and 5D and that the choice of agent should take into account factors including CKD stage, the presence of other components of CKD mineral-bone disease, the side-effect profile, and other associated medical therapies.17 It also is suggested that the dose of calcium-based phosphate binder and/or the dose of calcitriol or vitamin D analogue be restricted in the presence of persistent or recurrent hypercalcemia (class I, level of evidence B), arterial calcification (II C), adynamic bone disease (II C), and persistently low serum parathyroid hormone levels (II C).

CAC IN THE GENERAL POPULATION Electron-beam CT was introduced in the late 1980s before multidetector CT began to emerge in the late 1990s18; both applications enable the acquisition of images of thin slices of the heart and coronary arteries during diastole through the use of electrocardiogram gating. Although electron-beam CT use has declined, noncontrast multidetector CT is a lowradiation-exposure technique that can accurately determine the presence or absence of CAC, which usually is quantified using the Agatston method.19 This produces a CAC score as a product of the within-slice CAC plaque area and a plaque-specific density factor of 1, 2, 3, or 4, summed for all cardiac CT slices. The density factor reflects increasing 3

Bashir et al Table 1. Accuracy of Noninvasive Methods for Assessing Coronary Artery Disease General Population67-69 CKD Stages 4-5D70-72 Imaging Modality

Sensitivity Specificity Sensitivity Specificity

Exercise ECG

68%

77%

50%-65%

Exercise stress echo

85%

81%

Dobutamine stress echo

82%

84%

Exercise SPECT

87%

73%

75%-85% 76%-93% - No radiation - No iodine contrast - Additional information on myocardial structure and function 60%-87% 78%-94% - No radiation - No iodine contrast - Additional information on myocardial structure and function 70%-85% 61%-88% - Noninvasive - No iodine contrast - Wide availability - Excellent NPV

Adenosine SPECT

89%

75%

70%-85%

Cardiac MRI: vasodilator stress (first-pass contrastenhanced perfusion) Cardiac MRI: dobutamine stress-induced wall motion abnormalities

84%

85%

No data

89%

84%

No data

CT coronary angiography

Adenosine PET

69%-100% 74%-97% No data

89%

86%

No data

30%

Advantages

-

Low cost Wide availability No radiation No iodine contrast

Limitations

- Low sensitivity and specificity in CKD - Nondiagnostic in patients with LBBB, paced rhythm, and digoxin therapy - Often impossible in CKD patients with comorbid conditions and impaired effort tolerance - Reduced specificity in females - Operator dependent - Suboptimal acoustic windows in up to 20%

- Operator dependent - Suboptimal acoustic windows in up to 20% - Adverse response to dobutamine in up to 1% - False positives due to attenuation artefacts caused by high body mass index - Lower sensitivity in females with lower body surface area - Radiation exposure 75%-80% - Noninvasive - False positives due to - No iodine contrast attenuation artefacts caused - Wide availability by high body mass index - Excellent NPV - Lower sensitivity in females with lower body surface area - Radiation exposure No data - Low interobserver variability - Risk of nephrogenic systemic fibrosis - No radiation - Not widely available - Noniodinated contrast - Limited long-term data - Additional information - 5%-10% of patients are intolerant on ventricular structure of MRI scanner and function No data - Low interobserver variability - Risk of nephrogenic - No radiation systemic fibrosis - Noniodinated contrast - Not widely available - Limited long-term data - Additional information on ventricular structure - 5%-10% of patients are intolerant and function of the MRI scanner - Adverse response to dobutamine in up to 1% No data - Combined negative - Contrast nephropathy calcium score and - Decreased specificity due CT coronary angiography to blooming artefact and has excellent NPV effect of calcification - Radiation exposure - Limited long-term data No data - High sensitivity for - Not widely available detection of ischemia - Radiation and myocardial viability - Limited long-term data - High cost

Note: Pooled estimates for sensitivity and specificity are limited to studies that defined coronary artery stenosis using a reference threshold of $70% stenosis on coronary angiography. Abbreviations: CKD, chronic kidney disease; CT, computed tomography; ECG, electrocardiogram; echo, echocardiography; LBBB, left bundle branch block; MRI, magnetic resonance imaging; NPV, negative predictive value; PET, positron emission tomography; SPECT, single-photon emission computed tomography.

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Coronary Artery Calcification in CKD

categories of Hounsfield units (HU) and thus the Agatston score is weighted upward for greater CAC density. Individual CAC scores often are interpreted with reference to percentiles of calcification by age and sex; CAC increases with advancing age and generally is higher in men.20 In the general population, a CAC score of zero has a very high negative predictive value for cardiovascular events. Close correlation between CAC score and overall atherosclerotic plaque burden has been quantified using intravascular ultrasonography.21 It is this anatomic extent of atherosclerosis that is the most important determinant of prognosis, not the capability of identifying a discrete stenosis.22 The extent of coronary calcification is directly proportional to increased cardiovascular event rates, and CAC scores . 100 (or .75th percentile) indicate high cardiovascular risk. A metaanalysis by Pletcher et al showed that for a CAC score between 1 and 100, the relative risk of major adverse cardiovascular events doubles (hazard ratio [HR], 2.1), but the risk then is 3- to 17-fold higher for an Agatston score above this range.13 More recently, data from 6,814 intermediate-risk participants from the MESA (Multi-Ethnic Study of Atherosclerosis) cohort suggested that CAC score not only independently predicts incident cardiovascular disease, but also provides superior discrimination over other novel risk markers, including brachial flow–mediated dilatation, carotid intima-media thickness, and high-sensitivity C-reactive protein level.23 In summary, multidetector CT is a sensitive noninvasive technique to detect and quantify CAC (and therein burden of atheroma) and a useful tool to predict cardiovascular risk in the general population. Although effective in risk prediction, prospective outcomes data from trials in which individuals are randomly assigned to undergo or not undergo coronary calcium scanning are required to firmly establish whether CAC imaging ultimately results in reduced coronary events, provides improved clinical outcomes, and is cost-effective.24 Currently, CAC score is used most often to aid treatment decisions in those at intermediate risk.

GFR (P , 0.05); patients with stage 3 CKD had a mean Agatston score 693 U higher than that of controls (P , 0.001).26 The CRIC investigators found a graded relationship between severity of CKD and CAC score independent of conventional risk factors for atherosclerosis.27 Kramer et al28 found a similar association between CKD stages 3 to 5 and increasing CAC scores and postulated that this relationship may be substantially stronger among diabetic patients. Recently, Russo et al29 confirmed that diabetic patients with coexistent CKD had a higher prevalence, greater extent, and more rapid progression of CAC. Although numerous studies have demonstrated increased prevalence and severity of CAC in patients requiring renal replacement therapy,30-36 data regarding the correlation between CAC score and angiographic CAD in CKD of any severity are conflicting.30,37,38 In a study of 46 patients either on dialysis therapy or after kidney transplantation, Haydar et al30 demonstrated a strong relationship between an electron-beam CT–derived CAC score and extent of atheroma on diagnostic coronary angiography, calculated by adding the percentage stenosis of the most severe lesion in each coronary artery. Mean CAC score in patients with an abnormal coronary angiogram was 2,870 6 418 U, but in this ESRD population, even those with a normal coronary angiogram had a mean CAC score of 559 6 255 U (P 5 0.001). An association between elevated CAC score and obstructive CAD was confirmed in CKD stage 3 (n 5 69), but again, with a substantially higher cutoff CAC score for prediction of significant CAD (140 U; sensitivity, 73%; specificity, 70%) compared with controls (n 5 653) with eGFRs $ 60 mL/min/1.73 m2 (50 U; sensitivity, 75%; specificity, 75%).39 These data undermine the utility of CAC scoring in CKD because a major use of scoring in the general population is to exclude significant coronary disease. In summary, data from studies of CAC scoring specific to patients with CKD suggest that: (1) many patients have an elevated CAC score and (2) even a moderate CAC score may not be associated with significant CAD.

CAC IN CKD

PROGNOSTIC UTILITY OF CORONARY CALCIUM SCORE IN CKD

Despite there being more than 1,000 studies of CAC score in the general population, data for the incidence, prevalence, and prognosis of CAC in nondialysis CKD are limited (Table 2). Nondialysis patients with CKD have an increased incidence of CAC compared with controls, but less than that observed in patients with ESRD.25 In a crosssectional study of 544 patients, mean Agatston scores were 175 U higher in patients with stage 2 CKD compared with healthy controls with a normal

A multitude of small studies in patients with ESRD have shown that the extent of CAC correlates with factors affecting calcium and phosphate metabolism, including osteoprotegerin, fetuin, and markers of myocyte damage such as troponin T.40-42 There also are data that indicate a high CAC score is associated with an adverse prognosis in dialysis-dependent patients, although these studies contain relatively small numbers. The evidence for an independent association of CAC score with cardiovascular mortality in CKD

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Bashir et al Table 2. Key Observational Studies Evaluating CAC in CKD Study

Study Design

Na

Study Population

Study End Points

End-Stage Renal Disease 93 ESRD on HD CAC and EAT

Gauss et al58 (2014)

Cross-sectional

Karohl et al53 (2013)

Cross-sectional

Jug et al59 (2013)

Cross-sectional

48 ESRD

CAC and CCTA

de Bie et al60 (2013)

Longitudinal

70 ESRD on HD

CAC, CCTA

Shimoyama et al43 (2012)

Longitudinal

200 ESRD on HD

CAC, mortality

Nguyen et al61 (2007)

Cross-sectional

281 Kidney transplant recipients

CAC and aortic calcification

Ferramosca et al62 (2006)

Cross-sectional

46 Nondiabetic predialysis CKD stages 4-5

CAC and MPS

Sharples et al37 (2004)

Cross-sectional

18 ESRD on dialysis

CAC and coronary angiography

Goodman et al34 (2000) Braun et al33 (1996)

Cross-sectional

39 ESRD on HD

CAC

Longitudinal

49 ESRD on HD

CAC

Yiu et al39 (2013) Cross-sectional

411 CKD stages 4-5D

CAC and EAT

Mild to Moderate CKD 69 Moderate CKD (eGFR, 30- CAC and CCTA 59 mL/min/1.73 m2)

Study Findings

Epicardial fat volume correlated with BMI, age, and smoking but not CAC, suggesting other mechanisms may influence the genesis of coronary calcification Fixed or reversible myocardial perfusion defects found in only 41 (10%) patients listed for transplantation; multivariate logistic regression showed CAC score was an independent predictor of abnormal stress perfusion test results (OR, 1.24 [95% CI, 1.071.43]; P 5 0.005). ESRD associated with a high burden of calcification; the diagnostic association between CAC and atherosclerotic lesions was strong (area under the curve, 0.77 vs 0.80; P 5 0.57) Despite high CAC, .90% of segments on CCTA were deemed interpretable; significant CAD ($50% stenosis) associated with all-cause mortality at 2-y follow-up Cox proportional hazard analysis adjusted for age and HD duration demonstrated all-cause and CV mortality of group 1 (0-105 U) was significantly lower compared with groups 2 (110-1,067 U) and 3 (.1,067 U) CAC was detected in 81%; independent predictors included age, male sex, smoking, dialysis duration, and history of multiple transplantations In patients with total CAC score . 300 or .100 U in a single coronary artery, only half had a perfusion defect CAC score of zero had an NPV of 88% for significant luminal stenosis on invasive coronary angiography; no correlation found between degree of vessel stenosis and CAC score for individual coronary arteries CAC is highly prevalent (88%) in young patients (20-30 y old) with ESRD CAC was 2.5- to 5-fold higher in ESRD compared with controls and higher in hypertensive patients; CAC inversely correlated with bone mass in HD patients In patients with moderate CKD, ROC analysis suggested optimal CAC cutoff value to diagnose obstructive CAD was 2.8-fold higher than in patients without significant CKD

(Continued)

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Coronary Artery Calcification in CKD Table 2 (Cont’d). Key Observational Studies Evaluating CAC in CKD Study

Study Design

Dwivedi et al50 (2013)

Longitudinal

Russo et al29 (2013)

Longitudinal

Na

Study Population

Study End Points

5,572 eGFR ,30-.90 mL/min/ CCTA, mortality 1.73 m2; from CONFIRM study

341 CKD stages 2-5

Serial CAC

He et al63 (2012) Cross-sectional 2,018 eGFR 20-70 mL/min/ 1.73 m2; from the CRIC Study

CAC

Joosen et al64 (2012)

Cross-sectional 2,038 Mild to moderate CKD (eGFR 30-.90 mL/min/ 1.73 m2)

CCTA

Budoff et al27 (2011)

Cross-sectional 1,908 eGFR 20-70 mL/min/ 1.73 m2; from the CRIC Study

CAC

Cho et al65 (2010)

Cross-sectional 4,297 CKD stages 1-3a

CAC and CCTA

Ix et al66 (2008)

Cross-sectional 6,749 Mild to moderate CKD; from the MESA cohort

CAC, cystatin C

Kramer et al28 (2005)

Cross-sectional

CAC

Russo et al25 (2004)

Cross-sectional

211 CKD stages 1-5; from the Dallas Heart Study

85 Moderate CKD (eGFR 33 6 16 mL/min)

CAC

Study Findings

Over a median follow-up of 19 mo, multivariate Cox proportional hazards models revealed that decreased kidney function (HR, 2.29; 95% CI, 1.65-3.18), CAD severity (HR, 1.81; 95% CI, 1.31-2.51), and abnormal LVEF (HR, 4.16; 95% CI, 2.45-7.08) were independent predictors of all-cause mortality Prevalence, extent, and progression of CAC was greater in diabetic CKD vs nondiabetic CKD patients Abnormal calcium and phosphate metabolism, insulin resistance, and declining kidney function were associated with increasing prevalence of high CAC independent of traditional risk factors Coronary plaques with .70% luminal stenosis were more prevalent in both mild (OR, 1.67; 95% CI, 1.16-2.40) and moderate (OR, 2.36; 95% CI, 1.35-4.13) CKD compared with patients with normal kidney function (both P , 0.01); however, this relationship was not independent of traditional risk factors There was a strong and graded relationship between lower eGFR and increasing CAC that remained significant after adjustment for traditional risk factors The presence of proteinuria, rather than eGFR, was an independent risk factor for CAD and CAC score . 100 U There was a strong association of reduced kidney function with CAC but this was attenuated completely after correction for traditional risk factors There was an independent association between moderate CKD (stages 3-5) and CAC but this relationship was not evident in early-stage CKD (stages 1-2) CAC is more prevalent in moderate CKD compared with healthy controls

Abbreviations: BMI, body mass index; CAC, coronary artery calcification; CAD, coronary artery disease; CCTA, coronary computed tomography angiography; CI, confidence interval; CKD, chronic kidney disease; CRIC, Chronic Renal Insufficiency Cohort; CONFIRM, Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry; CV, cardiovascular; EAT, epicardial adipose tissue; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; HD, hemodialysis; HR, hazard ratio; LVEF, left ventricular ejection fraction, MESA, Multi Ethnic Study of Atherosclerosis; MPS, myocardial perfusion stress test; NPV, negative predictive value; OR, odds ratio; ROC, receiver operating characteristic; U, Agatston unit. a Number in study cohort with CKD.

is contradictory. In a small study of 59 patients on hemodialysis therapy, CAC score did not appear to predict 2-year survival.36 In a second single-center study of patients on long-term hemodialysis therapy, those with a low CAC score below the median 200 U (50 patients) had no difference in unadjusted relative risk of death compared with those with a score above Am J Kidney Dis. 2015;-(-):---

the median (54 patients).41 More recently, Shimoyama et al43 showed that CAC score predicted the prognosis of 200 hemodialysis patients at 7 years’ follow-up independently of age and dialysis therapy duration. Much lower cardiovascular mortality was demonstrated in patients with the lowest CAC scores (group 1, 0-105 U, 3.0%; group 2, 110-1,067 U, 7

Bashir et al

22.4%; group 3, 1,094-1,548 U, 26.9%). In 106 patients who had been on maintenance hemodialysis therapy for an average of 4 years with a mean CAC score of 200 U, CAC score . 200 U was associated with lower survival but with an adjusted relative risk of death for CAC of only 1.001.41 In a further study of 166 patients on maintenance hemodialysis therapy for an average of 2 years, most of whom had severe coronary calcification, CAC score . 400 U identified an increased risk of death independent of demographic data, risk factors, and comorbid conditions.44 Finally, in a secondary analysis of a study in 127 patients starting hemodialysis therapy but already with mean CAC scores much .400 U, risk was approximately 4 times higher in those with CAC scores . 400 U than in those with lower scores.16 There are notable limitations to these data. In each of these studies, most patients had CAC scores that would be considered very high in the general population. Furthermore, these data do not clarify whether performing CAC imaging ultimately results in reduced risk of coronary events, provides improved clinical outcomes, and is cost-effective in the dialysisdependent population. Evidence that CAC scoring predicts outcomes in early and moderate CKD is limited to a single-center study of 225 proteinuric diabetic patients (mean eGFR, 52 mL/min/1.73 m2), showing that patients in the highest quartile of CAC score (.428 U) on electron-beam CT had a 2.5-fold increase in allcause mortality compared with those in the lowest quartile.42 Taken together, these studies indicate that CAC scoring may provide some prognostic data, but whether this improves risk stratification to a useful degree in CKD is questionable. Exercise capacity consistently is one of the best markers of cardiovascular prognosis, particularly when considering perioperative risk during noncardiac surgery, and in our clinical vignette, the workload the patient was able to do on the treadmill may have been the most important result.45

QUESTIONING CALCIUM SCORING IN CKD Although CAC in asymptomatic individuals is an established predictor of future cardiovascular events in the general population, there may be reasons why this association is difficult to confirm in patients with CKD. It recently has been suggested that arterial calcification should be conceptualized in terms of cause: inflammatory (atherosclerotic, mostly intimal), metabolic (CKD, mostly medial), and genetic (eg, pseudoxanthoma elasticum).46 Although this is likely to be an oversimplification because intimal sclerosis can be identified at all stages of CKD in the coronary tree,47 this brings to the fore other important recent findings. Calcified coronary plaques are more stable 8

than weak plaques and are less prone to rupture.48 The current standard method for scoring CAC is the Agatston score, which takes account of area as well as density. However, it has never been established whether upweighting the score to account for increased calcific density is appropriate. A large multicenter publication from the MESA investigators recently has identified that although CAC volume is a strong predictor of cardiovascular events in the general population, high coronary calcium density is protective.49 Similar studies need to be performed in patients with CKD, with its high burden of both calcific coronary atheroma and medial calcification. It is likely that the heavier the degree of medial calcification, the less likely CAC score is to be able to predict obstructive cardiovascular events. The limitation of CAC scoring to identify adverse cardiovascular risk in CKD does not extend to noninvasive CT angiography. A recent multicenter study assessed the prognostic value of coronary CT angiographic measures in 5,572 patients with varying degrees of decreased kidney function.50 Death occurred in only 0.33% of patients without coronary atherosclerosis, 1.82% of patients with nonobstructive CAD, and 2.43% of patients with obstructive CAD. However, interestingly and in accord with the paradigm described earlier, identification of coronary stenosis was a weaker predictor of cardiovascular mortality than ejection fraction (HR, 1.81; 95% confidence interval [CI], 1.31-2.51 for CAD severity vs HR, 4.16; 95% CI, 2.45-7.08 for LV systolic dysfunction). Thus, in our clinical vignette, confirmation of normal LV function was a further strong positive indicator of prognosis. Our patient also had normal perfusion. Recent data confirm the prognostic utility of stress myocardial perfusion scintigraphy in CKD,51 but whether performing CAC scoring in addition to SPECT provides incremental value in predicting adverse cardiovascular events remains unanswered.52,53

CONCLUSIONS Use of CAC scoring in ESRD raises an issue about screening for the assessment of cardiac risk prior to kidney transplantation. Table 3 highlights key consensus recommendations. Although a succession of completely normal test results position the patient at ever lower risk, abnormal test results, whether an electrocardiogram, echocardiogram, CAC score, or SPECT, tend to move the patient through yet more tests and often to coronary angiography prior to kidney transplantation. Although coronary angiography carries low risk in the general population, it is not without risk, particularly in patients with complex comorbid disease including CKD, and the use of intravenous contrast may precipitate a need for Am J Kidney Dis. 2015;-(-):---

Coronary Artery Calcification in CKD Table 3. Consensus Recommendations for Cardiac Risk Assessment in Potential Kidney Transplant Candidates Recommendation

Class

Level of Evidence

A detailed clinical assessment is recommended to identify active cardiac conditions before kidney transplantation A preoperative 12-lead ECG at rest is recommended for kidney transplant candidates with any cardiovascular symptoms or known cardiovascular disease Kidney transplant candidates with LVEF , 50%, evidence of ischemic left ventricular dilation, exerciseinduced hypotension, angina, or demonstrable ischemia in the distribution of multiple coronary arteries should be referred to a cardiologist for evaluation and long-term management according to ACC/AHA guidelines for the general population Noninvasive stress testing may be considered in kidney transplantation candidates without active cardiac conditions in the presence of $3 risk factors irrespective of functional status, eg, diabetes mellitus, prior cardiovascular disease, .1 year on dialysis therapy, left ventricular hypertrophy, age . 60 y, smoking, hypertension, and dyslipidemia The effectiveness of periodic screening of asymptomatic kidney transplantation candidates for myocardial ischemia while on the waiting list is unclear It is reasonable to do preoperative left ventricular function assessment by echocardiography in kidney transplantation candidates There is no evidence in favor of or against repeated left ventricular function surveillance after listing for a kidney transplant It is reasonable to evaluate kidney transplantation candidates with echocardiographic evidence of significant pulmonary hypertension for underlying causes (eg, obstructive sleep apnea, left-sided heart disease) A preoperative 12-lead ECG at rest is reasonable in kidney transplantation candidates without known cardiovascular disease Annual performance of 12-lead ECG after listing for renal transplantation may be reasonable Measurement of cardiac troponins (at the time of evaluation for kidney transplantation) may be considered an additional prognostic marker The usefulness of noncontrast CT calcium scoring and cardiac CT angiography is uncertain for the assessment of pretransplantation cardiovascular risk It may be reasonable for each program to identify a primary cardiology consultant for questions related to potential kidney transplantation candidates

I

C

I

C

I

B

IIb

C

IIb

C

IIa

B

IIb

C

IIa

C

IIa

C

IIb IIb

C B

IIb

B

IIb

C

Abbreviations: ACC, American College of Cardiology; AHA, American Heart Association; CT, computed tomography; ECG, electrocardiogram; LVEF, left ventricular ejection fraction. Adapted from Lentine et al.71

hospitalization and death.54,55 We would advise against invasive coronary angiography in patients with CKD and high CAC scores but good LV function and normal perfusion. In patients capable of exercise with normal LV function and myocardial perfusion, further testing is not warranted and those responsible for transplantation need to be apprised of the data. A summary of key clinical points from the article is included in Box 1.

listing for transplantation if angiography is suspended until dialysis therapy has commenced). Given that preemptive kidney transplantation is the best mode of renal replacement therapy for minimizing cardiovascular risk, this asymptomatic patient capable of exercise on a treadmill with good LV function and Box 1. Clinical Considerations of CAC Scoring in CKD 

CASE REVIEW In our experience, there often is incongruence between the CAC score and findings on cardiac catheterization in patients with advanced CKD. Diagnostic coronary angiography is an invasive procedure with an expected composite rate of major complications including periprocedural stroke, heart attack, or death of w0.1%, although the rate of complications may be higher in patients with CKD.56,57 In addition, invasive angiography adds significant cost to health care, exposes the patient to additional radiation, and the use of intravenous contrast may precipitate the need for dialysis (or delay Am J Kidney Dis. 2015;-(-):---







In patients from the general population with intermediate cardiovascular risk, CAC scoring is useful for predicting events beyond clinical variables In patients with CKD, there is only a weak association between myocardial perfusion on single-photon emission CT and the degree of coronary calcification on non– contrast-enhanced CT There often is incongruence between the CAC score and findings on invasive coronary angiography in patients with CKD The usefulness of CAC score in patients with ESRD being considered for kidney transplantation is questionable, particularly for those with normal LV function and myocardial perfusion

Abbreviations: CAC, coronary artery calcification; CKD, chronic kidney disease; CT, computed tomography; ESRD, end-stage renal disease; LV, left ventricular. 9

Bashir et al

normal perfusion should have been listed without delay. We would advise against invasive coronary angiography in patients with CKD and high CAC scores but good LV function and normal perfusion.

ACKNOWLEDGEMENTS Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests.

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