Dobutamine Stress Echocardiography in the Diagnosis of Asymptomatic Ischemic Heart Disease in Patients With Chronic Kidney DiseasedReview of Literature and Single-Center Experience b, J. Górnyc, J. Kozakd, K. Oniszczukd, L. Gromadzin skif, B. Januszko-Giergielewicza,*, A. Dębska-Slizie n e e a b K. Dorniak , M. Dudziak , P. Malinowski , and B. Rutkowski a Department of Transplantation, Provincial Specialist Hospital, Olsztyn, Poland; bClinic of Nephrology, Transplantology, and Internal sk, Gdan sk, Poland; cDepartment of Cardiology, Provincial Specialist Hospital, Olsztyn, Poland; Medicine, Medical University of Gdan d Ultrasonography and Fine Needle Biopsy Laboratory, Provincial Specialist Hospital, Olsztyn, Poland; eDepartment of Cardiac sk, Gdan sk, Poland; and fUniversity Clinical Hospital, University of Diagnostics, 2nd Chair of Cardiology, Medical University of Gdan Warmia and Mazury, Olsztyn, Poland
ABSTRACT Background. Coronary artery disease (CAD) may be present in kidney transplant (KT) candidates without the presence of CAD clinical symptoms. This study joins an ongoing discussion about appropriate noninvasive diagnostic approaches for ischemic heart disease (IHD) assessment and patient selection for revascularization procedures. The aim of this study was to evaluate the role of dobutamine stress echocardiography (DSE) in IHD diagnosis in initially asymptomatic maintenance hemodialysis (HD) patients. Methods. Forty HD patients aged 52.4 2.0 years, were studied for 2.5 years. At inclusion, they were free of both symptoms and history of IHD. Standard electrocardiography (ECG), chest X-ray, standard echocardiography, DSE, 24-hour Holter ECG, and Doppler ultrasonography (carotids and lower extremities) were performed. Results were analyzed according to a predefined diagnostic algorithm. Results. DSE yielded negative results in all patients. Left ventricular (LV) ejection fraction 60%, LV hypertrophy, and Holter ECG silent ischemia features were noticed in 15%, 70%, and 10% of patients, respectively. Atherosclerotic lesions in lower extremities and carotid arteries were present in 50% and 37.5% of patients, respectively. During the follow-up, 9/40 patients died, including 6 cardiovascular (CV) deaths: 2 with intermediate and 4 with high CV risk according to the proposed algorithm. Conclusions. In asymptomatic KT candidates, not only DSE, but also other noninvasive tests (eg, echocardiography and Doppler ultrasonography of the carotid and peripheral arteries) along with a detailed profile of the remaining CV risk factors should be performed and analyzed. Defined composition of risk factors and particular changes in noninvasive tests may be an indication for coronary angiography.
T
HE PRESENCE of classic and chronic kidney disease (CKD)especific risk factors for ischemic heart disease (IHD) [1] renders CKD patients as a population at high risk for cardiovascular (CV) complications and sudden cardiac death [2e4]. CKD also predisposes the patient to developing autonomic neuropathy involving cardiac and vascular innervation [5e8]. Altered mechanisms of angina perception may be one of the consequences, and indeed, asymptomatic ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 47, 295e303 (2015)
IHD is a predominant form of IHD (up to 75%) in this patient population [9]. In outpatient kidney clinics and dialysis facilities, the selection process for kidney transplantation (KT) frequently *Address correspondence to Beata Januszko-Giergielewicz, _ MD, PhD, Provincial Specialist Hospital, Zołnierska 18, 10-561 Olsztyn, Poland. E-mail: [email protected] 0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2014.11.034
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involves asymptomatic high-CV-risk CKD patients. Noncardiac surgery such as KT is typically related to a degree of risk for CV complications for the recipient. American cardiovascular societies (American College of Cardiology [ACC]/ American Heart Association [AHA]), however, do not recommend routine screening for the “low-risk” asymptomatic population of KT candidates. Therefore, the question arises concerning the “low-risk” CKD patient definition. As already mentioned [2e4,9], all CKD patients are unequivocally considered to be at an increased risk, with their CV status equivalent to that of diabetic patients without CKD. An appropriate noninvasive diagnostic approach to screening asymptomatic KT candidates for the presence of IHD is an additional problem. The issues described above clearly point to an urgent necessity for the development of a universal and uniform diagnostic algorithm that would provide a safe “diagnostic sieve” to prevent post-KT CV events. On the other hand, care should be taken to avoid adoption of too strict selection criteria that would unnecessarily defer the decision regarding KT in, or disqualify, potential recipients who might otherwise benefit from the procedure. Finally, the question arises of what the best management strategy is for patients with coronary artery stenoses identified in the course of the diagnostic workup, ie, which patients should be treated interventionally and which patients would benefit from conservative treatment. Last but not least, there is the question of what impact these strategies might have on another chance for KT. These unresolved questions have been on the agenda at numerous meetings of leading working groups of European and international societies for the past 10 years [10]. In high-risk patients in whom noncardiac surgery is planned, ACC/AHA recommend noninvasive stress testing to assess CV risk. These tests include treadmill exercise, dobutamine stress echocardiography (DSE), dipyridamole stress echocardiography, and single-photon-emission computerized tomography with dipirydamole [11]. However, the DECREASE II study did not demonstrate the postoperative benefits of such preventive measures and incited concern among experts as to whether this noninvasive strategy would not result in KT delay. The usefulness of cardiac noninvasive stress testing before noncardiac surgery was studied by Wijeysundera et al in a retrospective cohort study in Ontario, Canada [12]. In 8.9% of the studied patients, stress tests were performed before surgery: exercise treadmill stress test, exercise or dobutamine stress echocardiography, or perfusion scintigraphy with exercise or dipyridamole infusion. End points included 1-year postoperative mortality and length of hospital stay. The meta-analysis demonstrated that noninvasive stress testing is a justified strategy in patients with intermediate or high risk of postoperative CV complications (ie, patients with 1 risk factor, such as IHD, diabetes, chronic heart failure [CHF], carotid artery disease, or CKD). Thus, data from studies concerning this issue are unequivocal, expert consensus is currently lacking, and no larger multicenter studies on the population of CKD patients have been carried out that might provide reliable algorithms for preoperative management.
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DSE has been proposed among stress tests recommended for this patient population [13,14]. This modality was expected to serve as a universal diagnostic tool for noninvasive IHD detection in CKD patients, because a pharmacologic stressor (dobutamine) is used instead of physical exercise. DSE is currently the most commonly used type of stress test [15,16]. Indications for DSE are summarized in Table 1 [14,16]. Most common indications include a patient’s inability to exercise and electrocardiography (ECG) alterations at rest rendering exercise ECG interpretation difficult. DSE can also be used in patient groups where high false positive rates can be expected: asymptomatic patients with diabetes, CKD, and peripheral artery disease (PAD) [15,17]. Its sensitivity and specificity for IHD detection are quite satisfactory (76%e92% and 72%e89%, respectively) [17,18]. Taking into account that IHD detection in CKD patients can be challenging (eg, atypical, uninterpretable ECG tracing, alterations in radiotracer distribution on scintigraphy, inability to achieve target rate during exercise testing owing to comorbidities), DSE seems to be a valuable alternative among all the noninvasive tests [12,14e16,18,19]. However, high false negative rates of DSE in CKD patients have been reported. Therefore, the question of whether DSE is an appropriate diagnostic modality in CKD patients remains unresolved. In the present paper, we present the results obtained by our team, including a 10-year analysis of this issue, and prospective follow-up results. Our results are discussed in the context of expert opinions published in the literature. The aim of this study was to assess the usefulness of DSE for IHD diagnosis in asymptomatic patients receiving hemodialysis (HD) and to place that in the context of available literature concerning this controversial issue. MATERIAL AND METHODS Inclusion Criteria Forty patients receiving chronic HD (aged 52.4 2.0 years) in the Dialysis Facility of the Provincial Specialist Hospital in Olsztyn, Poland, were examined. Time on dialysis at inclusion ranged from 4 months to 23 years (average 5.21 0.85 years). All patients were prospectively followed for 2.5 years. Exclusion criteria included clinical symptoms or history of IHD and history of stroke or transient ischemic attack (TIA). Other exclusion criteria included infection, active bleeding, neoplasm, or mental disorders precluding patient cooperation.
Cardiovascular Diagnostic Workup Cardiovascular diagnostic workup included standard 12-lead ECG, chest X-ray, echocardiography, DSE, 24-hour Holter ECG recording, and duplex ultrasonography of the carotid and peripheral arteries. These tests were performed before the middle HD session of the HD cycle of 3 sessions per week, 1 session every other day. Cardiovascular work-up was performed in the Department of Cardiology and duplex ultrasonography assessment of peripheral arteries in the Ultrasonography Laboratory of the Provincial Specialist Hospital in Olsztyn. Echocardiography was performed with the use of a GE-Vingmed System 5 echocardiographic device equipped with a 2.5e3.5-MHz transducer. The following M-mode parameters were measured: left
DOBUTAMINE STRESS ECHOCARDIOGRAPHY Table 1. Indications for Dobutamine Stress Test [14,16] Ischemic heart disease (IHD) diagnosis in patients unable to exercise disability musculoskeletal disorders preventing exercise peripheral artery disease metabolic polineuropathy (chronic kidney disease, diabetes) low exercise capacity Abnormal resting electrocardiography (ECG), rendering exercise ECG uninterpretable premenopausal women arterial hypertension Prognostic evaluation in postemyocardial infarction patients (detection of hibernating myocardium) Patient selection for revascularization (myocardial viability assessment) Assessment of IHD treatment effect (medical as well as interventional) Risk assessment of cardiovascular complications prior to noncardiac surgery Assessment of left ventricular systolic reserve in patients with significant left ventricular systolic dysfunction Pre-procedure assessment in patients with aortic stenosis and significant left ventricular systolic dysfunction Drug cardiotoxicity assessment
ventricular end-diastolic dimension (LVEDD [cm]), diastolic interventricular septum thickness (IVS [cm]), diastolic posterior wall thickness (PWTd [cm]), and left ventricular ejection fraction (LVEF [%], Teicholz method). Left ventricular mass (LVM [g]) was calculated according to Penn’s formula: i h LVM ¼ 1:04 ðIVS þ LVEDD þ PWTdÞ3 LVEDD3 13:6ðgÞ
Left ventricular mass index (LVMI) was calculated as follows: LVMI ¼ LVM=BSA g m2 DSE was performed with the use of a GE Vingmed System 5 equipped with a 2.5e3.5-MHz transducer, compliant with high imaging quality standards. The study was conducted according to the laboratory’s standard protocol, with an initial dose of 5 mg/kg/min that was gradually increased by 10 mg/kg/min every 3 minutes up to the maximum dosage of 40 mg/kg/min. Regional wall motion abnormalities were assessed in each of the 16 segments of LV myocardium. DSE was performed by a cardiologist with extensive experience in conducting DSE, in cooperation with another experienced echocardiographer from the same center. Twenty-four-hour Holter ECG recording was performed with the use of a Cardio ID Digital Holter Recorder. Ischemic episodes were diagnosed when the ST-segment depression of 1 mm lasted 1 minute and was separated from another episode by an interval of 1 minute. Duplex ultrasonography results were analyzed with the use of an arithmetic code of carotid [20] and peripheral arteries [21] as demonstrated in Table 2.
Assessment of Patient’s CV Status Absence of typical angina was confirmed by the patient’s history and assessment according to the Canadian Cardiovascular Society classification. The lack of previous IHD events was confirmed based on the patient’s medical record. Symptoms consistent with TIA were
297 Table 2. Arithmetic Code Adopted for Statistical Calculations Corresponding to Degrees of Vessel Narrowing According to Threshold Values Used in Duplex Ultrasonography [20,21] Lower extremity arteries 0dno stenosis 1dstenosis 50% of the vessel lumen 3dtotal occlusion Carotid arteries 0dno stenosis 1dstenosis 70% of the vessel lumen 4dtotal occlusion
excluded based on neurologic examination, and history of cerebrovascular events (stroke, TIA) was excluded based on medical records. Peripheral artery atherosclerosis was evaluated by means of duplex ultrasonography. The stage of heart failure was assessed according to the New York Heart Association (NYHA) functional classification. Systolic heart failure was recognized based on LVEF 60%. The presence of 10 selected IHD risk factors in patients on HD was assessed by a dedicated patient questionnaire. Each risk factor was assigned 1 point, to be summed up in each patient (0e10 score). The risk factors included in the score are listed in Table 3.
Statistical Analysis The results were analyzed with the use of Excel and Statistica PL software. Quantitative variables are presented as range, mean, SD, and SEM. Correlation coefficients describing relations between variables are summarized in tables, with their levels of statistical significance noted in a separate column. Combined effect of several variables on selected parameter values were assessed by means of correlation and multivariate linear regression analyses. The results are presented including regression function along with its goodnessof-fit to the adopted model, ie, multiple correlation index R or R2, F value, and corresponding significance level.
RESULTS Patient Characteristics
CKD etiology in the study group included chronic glomerulonephritis (n ¼ 10), diabetic nephropathy (n ¼ 4), hypertensive nephropathy (n ¼ 3), chronic tubulointerstitial nephritis (n ¼ 2), systemic disorders (n ¼ 2), polycystic kidney disease (n ¼ 1), nephrolithiasis (n ¼ 1), and congenital nephropathy (n ¼ 1). A high rate of unknown CKD etiology was noted (n ¼ 16; 40%), and these may include unrecognized cases of hypertensive and atherosclerotic nephropathy. Comorbidities included peripheral arterial occlusive disease (20%), CHF with reduced LVEF 60% (15%), diabetes (12.5%), arterial hypertension (45%), and other (32.5%). In 65% of patients, 3e6 IHD risk factors were identified, and patients with >6 and >3 risk factors were equally distributed and each amounted to 15% of the study group. Patients received HD 3 times per week; mean HD time was 12 > 0.18 h/wk. Mean values of the remaining study group characteristics were as follows: Kt/V 1.04 0.06, hemoglobin 10.4 0.2 g/dL, C-reactive protein 1.61 0.38 mg/d, albumin 3.73
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Table 3. Questionnaire for Summation Score (1e10) of Ischemic Heart Disease (IHD) Risk Factors in Chronic Kidney Disease (CKD) Patients Nonmodifiable
Modifiable
CKD-related
Age, sex Family history Diabetes Arterial hypertension Smoking Lipids
Overweight/Obesity Anemia Fluid overload Calcium-phosphate metabolism
F >65 y; M >55 y Premature IHD HbA1C >140/90 mm Hg or on treatment Total cholesterol >200 mg/dL LDL-C >135 mg/dL HDL-C 150 mg/dL BMI >25 kg/m2 Hemoglobin 3% PTH >200 pg/mL Calcium-phosphate product >55
yes yes yes yes yes yes
no no no no no no
yes yes yes yes
no no no no
Abbreviations: LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; BMI, body mass index; PTH, parathyroid hormone.
0.08 g/dL, total calcium 9.2 0.2 mg/dL, phosphate 6.7 0.3 mg/dL, and parathyroid hormone 279.5 40.8 pg/mL. Lipid fractions and the remaining parameters are presented in Table 4. Drug treatment included angiotensin-converting enzyme inhibitors in 16 patients (40%), b-blockers in 21 patients (52.5%), and statins in 14 patients (35%). Test Results
ECG tracing was entirely normal in 65% of patients. In 35% of patients ECG was abnormal, in 7 cases unspecific STsegment depression (>1 mm below the isoelectric line) was present in 2 leads, and in 1 patient ST-segment elevation in precordial leads V2eV3 was noted. Chest X-ray revealed LV enlargement in the majority of patients, with no pulmonary congestion. In 1 patient, enlarged cardiac silhouette with features of pulmonary congestion was evident. Pulmonary emphysema was noted in 2 patients. Echocardiography demonstrated LVEF 60% in 15% of patients (Table 5) and LVH in 70% (Table 6). In 5 patients, LVEF was 40%e60%, and in 1 patient LVEF was 25%. LVH (based on LVMI M3 116 g/m2 and K3 104 g/m2) was found in as many as 70% of patients (Table 6). In all of the study patients (40/40), DSE was negative. In the majority of patients, b-blockers could not be discontinued before the stress test, owing to the exaggerated hypertensive effect. One patient was excluded from the program because of a sustained hypertensive reaction during dobutamine infusion. In another patient with persistent hypotension observed at the time of dialysis as well as between dialysis sessions, the dobutamine effect was reduced. Adverse reactions during dobutamine infusion included tachycardia and anxiety that subsided soon after the infusion was stopped. In 2 cases, additional HD sessions were performed to achieve normal blood pressure values before the test. No serious adverse events were noted during the infusion. On 24-hour Holter ECG, in 10% of patients findings consistent with silent ischemia (SI) were noted, and in 30% supraventricular ectopic beats were observed (Table 7).
Duplex ultrasonography results revealed atherosclerotic lesions in the lower extremities in 20 patients (50%), including 4 patients (10%) with stenoses >50%. Regarding carotid arteries, 15 patients (37.5%) had evident atherosclerotic lesions, as did the 4 cases (10%) with stenoses >50%. In 3 patients (16.7%), asymptomatic severe carotid artery stenosis was found, with reduction of the vessel lumen >75%. These results are presented in Table 8. Because the DSE result was negative for 100% of patients in whom multiple abnormalities were found on cardiovascular diagnostic work-up, and multiple CV risk factors were present, the algorithm we propose for cardiac assessment before KT does not include DSE as a noninvasive diagnostic tool. The algorithm is based on modified literature data and our own results [18,22,23] (Fig 1). Risk groups were defined as low, intermediate, and high according to the combination of risk factors including age, sex, cardiovascular history, diabetes, risk score (Table 3), and time on dialysis. Long-Term Follow-Up
During the 2.5-year follow-up, KT was performed in 13/40 patients, and 9/40 died, including 6 CV deaths. Of the 6 CV Table 4. Mean Values of Selected Parameters in the Study Group Parameters
Kt/V Hemoglobin (g/dL) Albumin (g/dL) C-reactive protein (mg/dL) Total cholesterol (mg/dL) Triglycerides (mg/dL) HDL-cholesterol (mg/dL) LDL-cholesterol (mg/dL) Calcium (mg/dL) Phosphate (mg/dL) Calcium-phosphate product (mg2/dL2) PTH (pg/mL) Abbreviations as in Table 3.
Mean Values
1.04 10.4 3.73 1.61 181.8 163 44.2 101.7 9.2 6.7 61.10 279.5
0.06 0.2 0.08 0.38 6.4 13.3 2.3 4.8 0.2 0.3 2.60 40.8
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Table 5. Left Ventricular Ejection Fraction (LVEF) Values in the Study Group LVEF (%)
Patients (n) Patients (%)
20
21e40
41e60
61
Total
d d
1 2.5
5 12.5
29 72.5
40 100.0
Note. Minimum LVEF was 31%, maximum 84%.
deaths, 2 patients were intermediate and 4 high risk according to the proposed algorithm (Fig 1). Taking into account that these patients were asymptomatic and that DSE was negative, coronary angiography was not performed for any of them. All of the CV deaths were sudden cardiac deaths. DISCUSSION
In our study group of 40 HD patients at high CV risk, with a high estimated mortality rate and a high proportion of patients aged >55 years (38%), DSE did not allow for an adequate selection of patients requiring further CV evaluation. The remaining CV tests performed (ECG, chest X-ray, echocardiography, duplex ultrasonography of the carotid and peripheral arteries, and evaluation of the remaining CV risk factors), confirmed that this group is highly burdened with comorbidities, advanced atherosclerosis, high LVH rate, multiple cumulated CV risk factors, and potential chronic HD complications. High mortality rates in the study group (22.9%) should also be a matter of concern. This is consistent with United States statistical data, where the annual mortality rate for HD patients is one of the highest, w23.5% [24,25], with 50% due to CV mortality [26]. With advanced age, diabetes and its complications, IHD, PAD, and respiratory disorders become more prevalent. Therefore, negative DSE results for the entire study group seem to be in contrast to the cardiac risk status and vascular changes demonstrated. The role of DSE in CV evaluation of asymptomatic CKD patients on HD is therefore debatable. However, this modality remains recommended for CV assessment in this specific population of KT candidates [27e31]. Sharma et al demonstrated sensitivity and specificity of DSE for obstructive IHD detection of 88% and 94%, respectively [30]. On the other hand, there are reports suggesting high false negative rates of this test in CKD patients, even though the underlying cause was not elucidated. Gang et al demonstrated a low sensitivity of DSE (66%) for coronary artery stenoses >70% on angiography [32]. This can be related to endogenous cardiac depressants that were identified in this patient population, drug therapy inhibiting the sympathetic nervous system, the presence of LVH, and sympathovagal neuropathy, potentially blunting a direct cardiac response to dobutamine [7]. Exercise ECG is a standard and most appropriate diagnostic tool for IHD and silent ischemia diagnosis in the general population [33], but it is rarely used in CKD patients [13,30,34]. High rates of false negative or nondiagnostic results remain a
problem. Potential causes include insufficient workload, low exercise capacity of the subjects, limitations related to musculoskeletal changes, severe comorbidities, and drug effects. Test interpretation of patients with branch blocks is an important issue, potentially influencing false positive rates [34]. On the other hand, at earlier stages of CKD (2e3) and/or in younger patients, exercise testing can still be useful, although target heart rate may be occasionally difficult to achieve on a treadmill owing to b-adrenolytic treatment [34]. In line with available literature data, our study confirmed that standard ECG has little value in IHD diagnosis in CKD patients on HD [35,36]. Resting ECG in asymptomatic CKD patients remains a screening tool that does not allow for the diagnosis of many important conditions and should always be regarded as an introduction to extensive cardiovascular work-up. There are, however, several single-center cohort studies of asymptomatic “low-risk” CKD patients (age 50%, 50%e70%, >70% lumen narrowing have been proposed, depending on vessel morphology, number of arteries involved, symptoms, and medical history. There is also inconsistency regarding indications for specific treatment methods (conservative, interventional, or coronary artery
bypass graft) [10,46,47]. Thus, it is evident that dilemmas prevail over firm facts. In our opinion, coronary angiography should be recommended for HD patients not only in cases of positive stress test results, but also for asymptomatic patients with the highest CV risk (based on age, time on HD,
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diabetes) with IHD risk factors present on top of significant abnormalities in the noninvasive tests mentioned previously [48]. Owing to a high rate of false negative results in CKD, stress tests should be interpreted jointly with other noninvasive test results. This is termed the test summation principle in IHD diagnosis [39]. In this context, we proposed the inclusion of duplex ultrasonography in the diagnostic algorithm, allowing for atherosclerosis severity to be taken into account as a marker of CV risk. Similarly, inclusion of 24hour Holter ECG recording, with its additional diagnostic benefit, was proposed. Based on our study results and previous experience, and against current recommendations for CV risk assessment, DSE was not included in the proposed algorithm, because negative DSE results withheld further invasive diagnostic work-up despite significant accumulated abnormalities in the remaining CV tests. It is likely that in the official recommendations for diagnostic evaluation of this patient group, indication for stress testing before coronary angiography will be sustained. However, few data are currently available as to which of the stress modalities is the most effective for this specific patient population. Owing to the increasing availability of coronary angiography, it seems that this procedure would substantially lower perioperative risk when selecting patients for KT. Since the algorithm was introduced in academic centers (Gdansk and Olsztyn, Poland), we have noted decreased rates of perioperative infarctions and coronary events in post-KT patients, especially in diabetics. This has resulted in decreased perioperative CV mortality rates. Greater availability of coronary angiography also reduced the waiting period for noninvasive tests that would eventually fail to provide firm answers as to the patients’ coronary status. It should be mentioned, however, that this is a single-center experience and based on the results derived from a small group of HD patients (as already stated, multicenter studies regarding this issue are currently lacking). Therefore, the algorithm we propose was supported by available data from the literature as well our own clinical experiences. CONCLUSION
The present study did not confirm that DSE could serve as a reliable diagnostic modality for IHD detection in asymptomatic patients receiving HD. Consequently, other noninvasive test results, as described previously, as well as established CV risk factors should be taken into account. In cases of suspected IHD, the “test summation principle” should be applied to the selection of patients for an invasive procedure [39]. Because of frequently atypical or asymptomatic presentation of IHD and difficulties in unequivocal stress testing interpretation (including DSE) in CKD patients, coronary angiography remains the best modality for asymptomatic IHD diagnosis in patients on HD [1]. The present prospective study demonstrated a high clinical utility of the proposed CV risk algorithm for the selection of patients requiring coronary angiography. Given the complexity of this issue, well illustrated by the presented discussion of literature reports, with a wide range of
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researchers’ opinions and various approaches, every initiative aiming at a reliable and effective diagnostic work-up of HD patients before KT is most welcome. SUMMARY
1. DSE did not identify patients requiring further CV diagnostics. 2. In CKD patients, the decision regarding coronary angiography should be based on a variety of noninvasive tests (echocardiography, duplex ultrasonography of both carotid and lower extremity arteries) and an analysis of multiple CV risk factors. 3. In the group of patients prospectively followed, we demonstrated the usefulness of an algorithm for CV risk assessment in asymptomatic patients that would identify patients requiring invasive diagnostics. 4. The population of CKD patients should always be considered to be at increased CV risk, and that risk (low, intermediate, or high) should be further stratified based on a detailed clinical assessment. REFERENCES [1] de Lima JJ, Sabbaga E, Vieira ML, Flavio JP, Ianhez LE, Kriege EM. Coronary angiography is the best predictor of events in kidney transplant candidates compared with noninvasive testing. Hypertension 2003;42:263e8. [2] Foley RN, Parfrey PS, Sarnak MJ. Epidemiology of cardiovascular disease in chronic kidney disease. J Am Soc Nephrol 1998;9(Suppl):16e23. [3] Sarnak MJ, Levey AS. Cardiovascular disease and chronic kidney disease: a new paradigm. Am J Kidney Dis 2000;35(4 Suppl 1):117e31. [4] US Kidney Data System. USRDS 2003 annual data report. Atlas and end-stage kidney disease in the United States. Bethesda, Maryland: National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health; 2003. [5] Converse Jr RL, Jacobsen TN, Toto RD, Charles MT, Cosentino F, Fouad-Tarazi F. Sympathetic overt activity in patients with chronic kidney failure. N Engl J Med 1992;327:1912e8. [6] Esler M, Kaye D. Sympathetic nervous system activation essential hypertension, cardiac failure and psychosomatic heart disease. J Cardiovasc Pharmacol 2000;35(Suppl 4):1e7. [7] Januszko-Giergielewicz B, De˛bska-Slizie n A, Górny J, Gromadzi nski L, Kubiak M, Rutkowski B. Patofizjologia bezobjawowej choroby niedokrwiennej serca u pacjentów z przewlekła˛ choroba˛ nerekefakty i hipotezy. Nefrol Dial Pol 2011;3. [8] Polak G, Manitius J. Autonomiczny układ nerwowy a nadcisnienie te˛tnicze i nerki. Nefrol Dial Pol 1999;3:271e5. [9] Chrusciel B, Stompór T, Sułowicz W, Ziomek K, Szpernal G. Chorobowosc i smiertelnosc wsród chorych dializowanych. Nefrol Dial Pol 1999;3:159e74. [10] Cardiac disease evaluation and management among kidney and liver transplantation candidates. A scientific statement from the American Heart Association and the American College of Cardiology Foundation. J Am Coll Cardiol 2012;5:435e80. [11] Fleisher LA, Beckman JA, Brown KA, Calkins H, Chaikof EL, Fleischmann KE. ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). J Am Coll Cardiol 2007;50:1707e32.
DOBUTAMINE STRESS ECHOCARDIOGRAPHY [12] Wijeysundera DN, Beattie WS, Elliot R, Austin PC, Hux JE, Laupacis A. Noninvasive cardiac stress testing before elective major noncardiac surgery: population based cohort study. BMJ 2010:340. [13] Ali M, Giblin L, Farhad K, O’Kelly P, Hickey D, Little D. Pretransplant cardiac investigation in the Irish kidney transplant populationethe effectiveness of our current screening techniques in predicting cardiac events. Kidney Fail 2004;26:375e80. [14] Utility of echocardiography in the evaluation of coronary artery disease in patients with end-stage kidney disease. Adv Perit Dial 2009;25:129e32. [15] Amstrong WF. Stress echocardiography: introduction, history and methods. Prog Cardiovasc Dis 1997;39:499e522. [16] Pellikka PA, Nagueh SF, Elhendy AA, Abdou A, Sherif F, Kuehl CA. American Society of Echocardiography. American Society of Echocardiography: recommendations for performance, interpretation, and application of stress echocardiography. J Am Soc Echocardiogr 2007;20:1021e41. [17] Ballar RS, Kapadia S, Secknus MA, Rubin D, Arheart K, Marwick TH. Prognosis of patients with vascular disease after clinical evaluation and dobutamine stress echocardiography. Am Heart J 1999;39:469e75. [18] Ga˛sior Z. Echograficzny test obcia˛z_ eniowy z zastosowaniem dobutaminy. In: Echografia obcia˛z_ eniowadstress echo. Wrocław: Volumed; 2000. pp. 15e26. [19] Hennessy TG, Codd MB, Kane G, McCarthy C, McCann HA, Sugrue DD. Dobutamine stress echocardiography in the detection of coronary artery disease; importance of the pre-test likelihood of disease. Am Heart J 1997;134:685e92. [20] Grant EG, Benson CB, Moneta G, Alexandrov AV, Baker JD, Bluth EI. Carotid artery stenosis: gray scale and Doppler US DiagnosisdSociety of Radiologists in Ultrasound Consensus Conference. Radiology 2003;229:340e6. [21] Pellerito JS. Badania ultrasonograficzne w chorobach te˛tnic obwodowychestan na 1998 rok. Med Prakt 2000;1:3e16. [22] De˛bska-Slizie n A, Lizakowski S, Wołyniec W, JanuszkoGiergielewicz B. Kidney Transplantation in dialysis patients with the history of coronary artery bypass grafting and cardiac valve replacement. Transplant Proc 2007;39:45e50. [23] Foley RN, Wang C, Collins AJ. Cardiovascular risk factor profiles and kidney function stage in the US general population: the NHANES III Study. Mayo Clin Proc 2005;80:1270e7. [24] Tsakris D, Jones EH, Briggs JD, Elinder CG, Mehls O, Mendel S. Death within 90 days from starting kidney replacement therapy in the ERA-EDTA Registry between 1990 and 1992. Nephrol Dial Transplant 1999;14:2343e50. [25] US Kidney Data System. 1999 annual data report. Am J Kidney Dis 1999;34(Suppl 1). [26] Perrino GC, Ragni R, Salomone M. Analysis of cause of death in the first and last period of the Piedmontese Dialysis and Transplantation Registry. Minerva Urol Nefrol 1998;50:71e4. [27] Ferreira PA, de Lima VC, Compos FO, Gil MA, Cordovil A, Machado CV. Feasibility, safety and accuracy of dobutamine/atropine stress echocardiography for the detection of coronary artery disease in kidney transplant candidates. Arq Bras Cardiol 2007;88:45e51. [28] Link K, Stewart D, Cooper S, Davis CL. Pre-transplant cardiac testing for kidney-pancreas transplant candidates. Transplantation 2005;80:815e20. [29] Sharma R, Chemla E, Tome M, Mehta RL, Gregson H, Brecker SJ. Echocardiography-based score to predict outcome after kidney transplantation. Heart 2007;93:464e9. [30] Sharma R, Pellerin D, Gaze DC, Gregson H, Streather CP, Collinson PO. Dobutamine stress echocardiography and the resting but not exercise electrocardiograph predict severe coronary artery
303 disease in kidney transplant candidates. Nephrol Dial Transplant 2005;20:2207e14. [31] Sicari R, Nihyoannopoulos P, Evangelista A, Kasprzak J, Lancellotti P, Poldermans D. Stress echocardiography expert consensus statement of European Association of Echocardiography. Eur J Echocardiogr 2008;9:415e37. [32] Gang S, Dabhi M, Rajapurkar MM. Ischemia imagining in type 2 diabetic kidney transplant candidatesdis coronary angiography essential? Nephrol Dial Transplant 2007;22:2334e8. [33] Gianrossi R, Detrano R, Mulvihill D, Lehmann K, Dubach P, Colombo A. Exercise induced ST depression in the diagnosis of coronary artery disease: a meta-analysis. Circulation 1989;80:87e98. [34] Mamcarz A. Test wysiłkowy w diagnostyce niedokrwienia. In: Dłu_zniewski M, editor. Choroba niedokrwienna serca. Warszawa: Akcydens; 1998. pp. 111e24. [35] Abe S, Yoshizawa M, Nakanishi N, Yazawa T, Yokota K, Honda M. Electrocardiographic abnormalities in patients receiving hemodialysis. Am Heart J 1996;131:1137e44. [36] Rayner HC, Pisoni RL, Bommer J, Canaud B, Hecking E, Locatelli F. Mortality and hospitalisation in hemodialysis patients in five European counties: results from the Dialysis Outcomes and Practice Pattern Study (DOPPS). Nephrol Dial Transplant 2004;19: 108e20. [37] Kasiske BL, Malik MA, Herzog CA. Risk-stratified screening for ischemic heart disease in kidney transplant candidates. Transplantation 2005;80:815e20. [38] Foley RN, Parfrey PS, Harnett JD, Kent GM, Mertin CJ, Murray DC. Clinical and echocardiographic disease in patients starting end-stage kidney disease therapy. Kidney Int 1995;47:186e92. [39] Conti CR. Nieme niedokrwienie. In: Yellon DM, Rahimtoola SH, Opie LH, editors. Nowe zespoły niedokrwienne. Gda nsk: Via Medica; 2001. pp. 27e37. [40] Witek P. Nieme niedokrwienie mie˛snia sercowego. Przegla˛d Lekarski 2001;58:127e30. [41] Jogestrand T, Lindqvist M, Nowak J. Diagnostic performance of duplex ultrasonography in the detection of high grade internal carotid artery stenosis. Eur J Vasc Endovasc Surg 2002;23:510e8. [42] Nishimura Y, Okamura Y, Fujiwara K, Sekii H, Yamamoto S, Hatada A. Ultrasonographic measurement of intimamedia thickness of the carotid artery before coronary artery bypass grafting. Surg Today 2005;35:28e30. [43] Dawson DL. Peripheral arterial disease: medical care and prevention of complication. Prev Cardiol 2002;5:119e30. [44] Reddan DN, Szczech LA, Tutle RH, Shaw LK, Jones RH, Schwab SJ. Chronic kidney disease, mortality, and treatment strategies among patients with clinically significant coronary disease. J Am Soc Nephrol 2003;14:2373e80. [45] Rubenstein MH, Harrell LC, Sheynberg BV, Schunkert H, Bazari H, Palacios IF. Are patients with kidney failure good candidates for percutaneous coronary revascularization in the new device era? Circulation 2000;102:2966e72. [46] De Lima JJ, Gowdak LH, de Paula FJ. Treatment of coronary artery disease in hemodialysis patients evaluated for transplanteregistry study. Transplantation 2010;89:845e50. [47] Manske CL, Wilson RF, Wang Y, Thomas W. Atherosclerotic vascular complication in diabetic transplant candidates. Am J Kidney Dis 1997;29:601e7. [48] Yamada S, Ishii H, Takahashii H, Aoyama T, Morita Y, Kasuga H. Prognostic value of reduced left ventricular ejection fraction at start of hemodialysis therapy on cardiovascular and allcause mortality in and-stage kidney disease patients. Clin J Am Soc Nephrol 2010;5:1793e8.
ABSTRACT Background. Coronary artery disease (CAD) may be present in kidney transplant (KT) candidates without the presence of CAD clinical symptoms. This study joins an ongoing discussion about appropriate noninvasive diagnostic approaches for ischemic heart disease (IHD) assessment and patient selection for revascularization procedures. The aim of this study was to evaluate the role of dobutamine stress echocardiography (DSE) in IHD diagnosis in initially asymptomatic maintenance hemodialysis (HD) patients. Methods. Forty HD patients aged 52.4 2.0 years, were studied for 2.5 years. At inclusion, they were free of both symptoms and history of IHD. Standard electrocardiography (ECG), chest X-ray, standard echocardiography, DSE, 24-hour Holter ECG, and Doppler ultrasonography (carotids and lower extremities) were performed. Results were analyzed according to a predefined diagnostic algorithm. Results. DSE yielded negative results in all patients. Left ventricular (LV) ejection fraction 60%, LV hypertrophy, and Holter ECG silent ischemia features were noticed in 15%, 70%, and 10% of patients, respectively. Atherosclerotic lesions in lower extremities and carotid arteries were present in 50% and 37.5% of patients, respectively. During the follow-up, 9/40 patients died, including 6 cardiovascular (CV) deaths: 2 with intermediate and 4 with high CV risk according to the proposed algorithm. Conclusions. In asymptomatic KT candidates, not only DSE, but also other noninvasive tests (eg, echocardiography and Doppler ultrasonography of the carotid and peripheral arteries) along with a detailed profile of the remaining CV risk factors should be performed and analyzed. Defined composition of risk factors and particular changes in noninvasive tests may be an indication for coronary angiography.
T
HE PRESENCE of classic and chronic kidney disease (CKD)especific risk factors for ischemic heart disease (IHD) [1] renders CKD patients as a population at high risk for cardiovascular (CV) complications and sudden cardiac death [2e4]. CKD also predisposes the patient to developing autonomic neuropathy involving cardiac and vascular innervation [5e8]. Altered mechanisms of angina perception may be one of the consequences, and indeed, asymptomatic ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 47, 295e303 (2015)
IHD is a predominant form of IHD (up to 75%) in this patient population [9]. In outpatient kidney clinics and dialysis facilities, the selection process for kidney transplantation (KT) frequently *Address correspondence to Beata Januszko-Giergielewicz, _ MD, PhD, Provincial Specialist Hospital, Zołnierska 18, 10-561 Olsztyn, Poland. E-mail: [email protected] 0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2014.11.034
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involves asymptomatic high-CV-risk CKD patients. Noncardiac surgery such as KT is typically related to a degree of risk for CV complications for the recipient. American cardiovascular societies (American College of Cardiology [ACC]/ American Heart Association [AHA]), however, do not recommend routine screening for the “low-risk” asymptomatic population of KT candidates. Therefore, the question arises concerning the “low-risk” CKD patient definition. As already mentioned [2e4,9], all CKD patients are unequivocally considered to be at an increased risk, with their CV status equivalent to that of diabetic patients without CKD. An appropriate noninvasive diagnostic approach to screening asymptomatic KT candidates for the presence of IHD is an additional problem. The issues described above clearly point to an urgent necessity for the development of a universal and uniform diagnostic algorithm that would provide a safe “diagnostic sieve” to prevent post-KT CV events. On the other hand, care should be taken to avoid adoption of too strict selection criteria that would unnecessarily defer the decision regarding KT in, or disqualify, potential recipients who might otherwise benefit from the procedure. Finally, the question arises of what the best management strategy is for patients with coronary artery stenoses identified in the course of the diagnostic workup, ie, which patients should be treated interventionally and which patients would benefit from conservative treatment. Last but not least, there is the question of what impact these strategies might have on another chance for KT. These unresolved questions have been on the agenda at numerous meetings of leading working groups of European and international societies for the past 10 years [10]. In high-risk patients in whom noncardiac surgery is planned, ACC/AHA recommend noninvasive stress testing to assess CV risk. These tests include treadmill exercise, dobutamine stress echocardiography (DSE), dipyridamole stress echocardiography, and single-photon-emission computerized tomography with dipirydamole [11]. However, the DECREASE II study did not demonstrate the postoperative benefits of such preventive measures and incited concern among experts as to whether this noninvasive strategy would not result in KT delay. The usefulness of cardiac noninvasive stress testing before noncardiac surgery was studied by Wijeysundera et al in a retrospective cohort study in Ontario, Canada [12]. In 8.9% of the studied patients, stress tests were performed before surgery: exercise treadmill stress test, exercise or dobutamine stress echocardiography, or perfusion scintigraphy with exercise or dipyridamole infusion. End points included 1-year postoperative mortality and length of hospital stay. The meta-analysis demonstrated that noninvasive stress testing is a justified strategy in patients with intermediate or high risk of postoperative CV complications (ie, patients with 1 risk factor, such as IHD, diabetes, chronic heart failure [CHF], carotid artery disease, or CKD). Thus, data from studies concerning this issue are unequivocal, expert consensus is currently lacking, and no larger multicenter studies on the population of CKD patients have been carried out that might provide reliable algorithms for preoperative management.
GÓRNY ET AL JANUSZKO-GIERGIELEWICZ, DĘBSKA-SLIZIE N,
DSE has been proposed among stress tests recommended for this patient population [13,14]. This modality was expected to serve as a universal diagnostic tool for noninvasive IHD detection in CKD patients, because a pharmacologic stressor (dobutamine) is used instead of physical exercise. DSE is currently the most commonly used type of stress test [15,16]. Indications for DSE are summarized in Table 1 [14,16]. Most common indications include a patient’s inability to exercise and electrocardiography (ECG) alterations at rest rendering exercise ECG interpretation difficult. DSE can also be used in patient groups where high false positive rates can be expected: asymptomatic patients with diabetes, CKD, and peripheral artery disease (PAD) [15,17]. Its sensitivity and specificity for IHD detection are quite satisfactory (76%e92% and 72%e89%, respectively) [17,18]. Taking into account that IHD detection in CKD patients can be challenging (eg, atypical, uninterpretable ECG tracing, alterations in radiotracer distribution on scintigraphy, inability to achieve target rate during exercise testing owing to comorbidities), DSE seems to be a valuable alternative among all the noninvasive tests [12,14e16,18,19]. However, high false negative rates of DSE in CKD patients have been reported. Therefore, the question of whether DSE is an appropriate diagnostic modality in CKD patients remains unresolved. In the present paper, we present the results obtained by our team, including a 10-year analysis of this issue, and prospective follow-up results. Our results are discussed in the context of expert opinions published in the literature. The aim of this study was to assess the usefulness of DSE for IHD diagnosis in asymptomatic patients receiving hemodialysis (HD) and to place that in the context of available literature concerning this controversial issue. MATERIAL AND METHODS Inclusion Criteria Forty patients receiving chronic HD (aged 52.4 2.0 years) in the Dialysis Facility of the Provincial Specialist Hospital in Olsztyn, Poland, were examined. Time on dialysis at inclusion ranged from 4 months to 23 years (average 5.21 0.85 years). All patients were prospectively followed for 2.5 years. Exclusion criteria included clinical symptoms or history of IHD and history of stroke or transient ischemic attack (TIA). Other exclusion criteria included infection, active bleeding, neoplasm, or mental disorders precluding patient cooperation.
Cardiovascular Diagnostic Workup Cardiovascular diagnostic workup included standard 12-lead ECG, chest X-ray, echocardiography, DSE, 24-hour Holter ECG recording, and duplex ultrasonography of the carotid and peripheral arteries. These tests were performed before the middle HD session of the HD cycle of 3 sessions per week, 1 session every other day. Cardiovascular work-up was performed in the Department of Cardiology and duplex ultrasonography assessment of peripheral arteries in the Ultrasonography Laboratory of the Provincial Specialist Hospital in Olsztyn. Echocardiography was performed with the use of a GE-Vingmed System 5 echocardiographic device equipped with a 2.5e3.5-MHz transducer. The following M-mode parameters were measured: left
DOBUTAMINE STRESS ECHOCARDIOGRAPHY Table 1. Indications for Dobutamine Stress Test [14,16] Ischemic heart disease (IHD) diagnosis in patients unable to exercise disability musculoskeletal disorders preventing exercise peripheral artery disease metabolic polineuropathy (chronic kidney disease, diabetes) low exercise capacity Abnormal resting electrocardiography (ECG), rendering exercise ECG uninterpretable premenopausal women arterial hypertension Prognostic evaluation in postemyocardial infarction patients (detection of hibernating myocardium) Patient selection for revascularization (myocardial viability assessment) Assessment of IHD treatment effect (medical as well as interventional) Risk assessment of cardiovascular complications prior to noncardiac surgery Assessment of left ventricular systolic reserve in patients with significant left ventricular systolic dysfunction Pre-procedure assessment in patients with aortic stenosis and significant left ventricular systolic dysfunction Drug cardiotoxicity assessment
ventricular end-diastolic dimension (LVEDD [cm]), diastolic interventricular septum thickness (IVS [cm]), diastolic posterior wall thickness (PWTd [cm]), and left ventricular ejection fraction (LVEF [%], Teicholz method). Left ventricular mass (LVM [g]) was calculated according to Penn’s formula: i h LVM ¼ 1:04 ðIVS þ LVEDD þ PWTdÞ3 LVEDD3 13:6ðgÞ
Left ventricular mass index (LVMI) was calculated as follows: LVMI ¼ LVM=BSA g m2 DSE was performed with the use of a GE Vingmed System 5 equipped with a 2.5e3.5-MHz transducer, compliant with high imaging quality standards. The study was conducted according to the laboratory’s standard protocol, with an initial dose of 5 mg/kg/min that was gradually increased by 10 mg/kg/min every 3 minutes up to the maximum dosage of 40 mg/kg/min. Regional wall motion abnormalities were assessed in each of the 16 segments of LV myocardium. DSE was performed by a cardiologist with extensive experience in conducting DSE, in cooperation with another experienced echocardiographer from the same center. Twenty-four-hour Holter ECG recording was performed with the use of a Cardio ID Digital Holter Recorder. Ischemic episodes were diagnosed when the ST-segment depression of 1 mm lasted 1 minute and was separated from another episode by an interval of 1 minute. Duplex ultrasonography results were analyzed with the use of an arithmetic code of carotid [20] and peripheral arteries [21] as demonstrated in Table 2.
Assessment of Patient’s CV Status Absence of typical angina was confirmed by the patient’s history and assessment according to the Canadian Cardiovascular Society classification. The lack of previous IHD events was confirmed based on the patient’s medical record. Symptoms consistent with TIA were
297 Table 2. Arithmetic Code Adopted for Statistical Calculations Corresponding to Degrees of Vessel Narrowing According to Threshold Values Used in Duplex Ultrasonography [20,21] Lower extremity arteries 0dno stenosis 1dstenosis 50% of the vessel lumen 3dtotal occlusion Carotid arteries 0dno stenosis 1dstenosis 70% of the vessel lumen 4dtotal occlusion
excluded based on neurologic examination, and history of cerebrovascular events (stroke, TIA) was excluded based on medical records. Peripheral artery atherosclerosis was evaluated by means of duplex ultrasonography. The stage of heart failure was assessed according to the New York Heart Association (NYHA) functional classification. Systolic heart failure was recognized based on LVEF 60%. The presence of 10 selected IHD risk factors in patients on HD was assessed by a dedicated patient questionnaire. Each risk factor was assigned 1 point, to be summed up in each patient (0e10 score). The risk factors included in the score are listed in Table 3.
Statistical Analysis The results were analyzed with the use of Excel and Statistica PL software. Quantitative variables are presented as range, mean, SD, and SEM. Correlation coefficients describing relations between variables are summarized in tables, with their levels of statistical significance noted in a separate column. Combined effect of several variables on selected parameter values were assessed by means of correlation and multivariate linear regression analyses. The results are presented including regression function along with its goodnessof-fit to the adopted model, ie, multiple correlation index R or R2, F value, and corresponding significance level.
RESULTS Patient Characteristics
CKD etiology in the study group included chronic glomerulonephritis (n ¼ 10), diabetic nephropathy (n ¼ 4), hypertensive nephropathy (n ¼ 3), chronic tubulointerstitial nephritis (n ¼ 2), systemic disorders (n ¼ 2), polycystic kidney disease (n ¼ 1), nephrolithiasis (n ¼ 1), and congenital nephropathy (n ¼ 1). A high rate of unknown CKD etiology was noted (n ¼ 16; 40%), and these may include unrecognized cases of hypertensive and atherosclerotic nephropathy. Comorbidities included peripheral arterial occlusive disease (20%), CHF with reduced LVEF 60% (15%), diabetes (12.5%), arterial hypertension (45%), and other (32.5%). In 65% of patients, 3e6 IHD risk factors were identified, and patients with >6 and >3 risk factors were equally distributed and each amounted to 15% of the study group. Patients received HD 3 times per week; mean HD time was 12 > 0.18 h/wk. Mean values of the remaining study group characteristics were as follows: Kt/V 1.04 0.06, hemoglobin 10.4 0.2 g/dL, C-reactive protein 1.61 0.38 mg/d, albumin 3.73
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Table 3. Questionnaire for Summation Score (1e10) of Ischemic Heart Disease (IHD) Risk Factors in Chronic Kidney Disease (CKD) Patients Nonmodifiable
Modifiable
CKD-related
Age, sex Family history Diabetes Arterial hypertension Smoking Lipids
Overweight/Obesity Anemia Fluid overload Calcium-phosphate metabolism
F >65 y; M >55 y Premature IHD HbA1C >140/90 mm Hg or on treatment Total cholesterol >200 mg/dL LDL-C >135 mg/dL HDL-C 150 mg/dL BMI >25 kg/m2 Hemoglobin 3% PTH >200 pg/mL Calcium-phosphate product >55
yes yes yes yes yes yes
no no no no no no
yes yes yes yes
no no no no
Abbreviations: LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; BMI, body mass index; PTH, parathyroid hormone.
0.08 g/dL, total calcium 9.2 0.2 mg/dL, phosphate 6.7 0.3 mg/dL, and parathyroid hormone 279.5 40.8 pg/mL. Lipid fractions and the remaining parameters are presented in Table 4. Drug treatment included angiotensin-converting enzyme inhibitors in 16 patients (40%), b-blockers in 21 patients (52.5%), and statins in 14 patients (35%). Test Results
ECG tracing was entirely normal in 65% of patients. In 35% of patients ECG was abnormal, in 7 cases unspecific STsegment depression (>1 mm below the isoelectric line) was present in 2 leads, and in 1 patient ST-segment elevation in precordial leads V2eV3 was noted. Chest X-ray revealed LV enlargement in the majority of patients, with no pulmonary congestion. In 1 patient, enlarged cardiac silhouette with features of pulmonary congestion was evident. Pulmonary emphysema was noted in 2 patients. Echocardiography demonstrated LVEF 60% in 15% of patients (Table 5) and LVH in 70% (Table 6). In 5 patients, LVEF was 40%e60%, and in 1 patient LVEF was 25%. LVH (based on LVMI M3 116 g/m2 and K3 104 g/m2) was found in as many as 70% of patients (Table 6). In all of the study patients (40/40), DSE was negative. In the majority of patients, b-blockers could not be discontinued before the stress test, owing to the exaggerated hypertensive effect. One patient was excluded from the program because of a sustained hypertensive reaction during dobutamine infusion. In another patient with persistent hypotension observed at the time of dialysis as well as between dialysis sessions, the dobutamine effect was reduced. Adverse reactions during dobutamine infusion included tachycardia and anxiety that subsided soon after the infusion was stopped. In 2 cases, additional HD sessions were performed to achieve normal blood pressure values before the test. No serious adverse events were noted during the infusion. On 24-hour Holter ECG, in 10% of patients findings consistent with silent ischemia (SI) were noted, and in 30% supraventricular ectopic beats were observed (Table 7).
Duplex ultrasonography results revealed atherosclerotic lesions in the lower extremities in 20 patients (50%), including 4 patients (10%) with stenoses >50%. Regarding carotid arteries, 15 patients (37.5%) had evident atherosclerotic lesions, as did the 4 cases (10%) with stenoses >50%. In 3 patients (16.7%), asymptomatic severe carotid artery stenosis was found, with reduction of the vessel lumen >75%. These results are presented in Table 8. Because the DSE result was negative for 100% of patients in whom multiple abnormalities were found on cardiovascular diagnostic work-up, and multiple CV risk factors were present, the algorithm we propose for cardiac assessment before KT does not include DSE as a noninvasive diagnostic tool. The algorithm is based on modified literature data and our own results [18,22,23] (Fig 1). Risk groups were defined as low, intermediate, and high according to the combination of risk factors including age, sex, cardiovascular history, diabetes, risk score (Table 3), and time on dialysis. Long-Term Follow-Up
During the 2.5-year follow-up, KT was performed in 13/40 patients, and 9/40 died, including 6 CV deaths. Of the 6 CV Table 4. Mean Values of Selected Parameters in the Study Group Parameters
Kt/V Hemoglobin (g/dL) Albumin (g/dL) C-reactive protein (mg/dL) Total cholesterol (mg/dL) Triglycerides (mg/dL) HDL-cholesterol (mg/dL) LDL-cholesterol (mg/dL) Calcium (mg/dL) Phosphate (mg/dL) Calcium-phosphate product (mg2/dL2) PTH (pg/mL) Abbreviations as in Table 3.
Mean Values
1.04 10.4 3.73 1.61 181.8 163 44.2 101.7 9.2 6.7 61.10 279.5
0.06 0.2 0.08 0.38 6.4 13.3 2.3 4.8 0.2 0.3 2.60 40.8
DOBUTAMINE STRESS ECHOCARDIOGRAPHY
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Table 5. Left Ventricular Ejection Fraction (LVEF) Values in the Study Group LVEF (%)
Patients (n) Patients (%)
20
21e40
41e60
61
Total
d d
1 2.5
5 12.5
29 72.5
40 100.0
Note. Minimum LVEF was 31%, maximum 84%.
deaths, 2 patients were intermediate and 4 high risk according to the proposed algorithm (Fig 1). Taking into account that these patients were asymptomatic and that DSE was negative, coronary angiography was not performed for any of them. All of the CV deaths were sudden cardiac deaths. DISCUSSION
In our study group of 40 HD patients at high CV risk, with a high estimated mortality rate and a high proportion of patients aged >55 years (38%), DSE did not allow for an adequate selection of patients requiring further CV evaluation. The remaining CV tests performed (ECG, chest X-ray, echocardiography, duplex ultrasonography of the carotid and peripheral arteries, and evaluation of the remaining CV risk factors), confirmed that this group is highly burdened with comorbidities, advanced atherosclerosis, high LVH rate, multiple cumulated CV risk factors, and potential chronic HD complications. High mortality rates in the study group (22.9%) should also be a matter of concern. This is consistent with United States statistical data, where the annual mortality rate for HD patients is one of the highest, w23.5% [24,25], with 50% due to CV mortality [26]. With advanced age, diabetes and its complications, IHD, PAD, and respiratory disorders become more prevalent. Therefore, negative DSE results for the entire study group seem to be in contrast to the cardiac risk status and vascular changes demonstrated. The role of DSE in CV evaluation of asymptomatic CKD patients on HD is therefore debatable. However, this modality remains recommended for CV assessment in this specific population of KT candidates [27e31]. Sharma et al demonstrated sensitivity and specificity of DSE for obstructive IHD detection of 88% and 94%, respectively [30]. On the other hand, there are reports suggesting high false negative rates of this test in CKD patients, even though the underlying cause was not elucidated. Gang et al demonstrated a low sensitivity of DSE (66%) for coronary artery stenoses >70% on angiography [32]. This can be related to endogenous cardiac depressants that were identified in this patient population, drug therapy inhibiting the sympathetic nervous system, the presence of LVH, and sympathovagal neuropathy, potentially blunting a direct cardiac response to dobutamine [7]. Exercise ECG is a standard and most appropriate diagnostic tool for IHD and silent ischemia diagnosis in the general population [33], but it is rarely used in CKD patients [13,30,34]. High rates of false negative or nondiagnostic results remain a
problem. Potential causes include insufficient workload, low exercise capacity of the subjects, limitations related to musculoskeletal changes, severe comorbidities, and drug effects. Test interpretation of patients with branch blocks is an important issue, potentially influencing false positive rates [34]. On the other hand, at earlier stages of CKD (2e3) and/or in younger patients, exercise testing can still be useful, although target heart rate may be occasionally difficult to achieve on a treadmill owing to b-adrenolytic treatment [34]. In line with available literature data, our study confirmed that standard ECG has little value in IHD diagnosis in CKD patients on HD [35,36]. Resting ECG in asymptomatic CKD patients remains a screening tool that does not allow for the diagnosis of many important conditions and should always be regarded as an introduction to extensive cardiovascular work-up. There are, however, several single-center cohort studies of asymptomatic “low-risk” CKD patients (age 50%, 50%e70%, >70% lumen narrowing have been proposed, depending on vessel morphology, number of arteries involved, symptoms, and medical history. There is also inconsistency regarding indications for specific treatment methods (conservative, interventional, or coronary artery
bypass graft) [10,46,47]. Thus, it is evident that dilemmas prevail over firm facts. In our opinion, coronary angiography should be recommended for HD patients not only in cases of positive stress test results, but also for asymptomatic patients with the highest CV risk (based on age, time on HD,
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diabetes) with IHD risk factors present on top of significant abnormalities in the noninvasive tests mentioned previously [48]. Owing to a high rate of false negative results in CKD, stress tests should be interpreted jointly with other noninvasive test results. This is termed the test summation principle in IHD diagnosis [39]. In this context, we proposed the inclusion of duplex ultrasonography in the diagnostic algorithm, allowing for atherosclerosis severity to be taken into account as a marker of CV risk. Similarly, inclusion of 24hour Holter ECG recording, with its additional diagnostic benefit, was proposed. Based on our study results and previous experience, and against current recommendations for CV risk assessment, DSE was not included in the proposed algorithm, because negative DSE results withheld further invasive diagnostic work-up despite significant accumulated abnormalities in the remaining CV tests. It is likely that in the official recommendations for diagnostic evaluation of this patient group, indication for stress testing before coronary angiography will be sustained. However, few data are currently available as to which of the stress modalities is the most effective for this specific patient population. Owing to the increasing availability of coronary angiography, it seems that this procedure would substantially lower perioperative risk when selecting patients for KT. Since the algorithm was introduced in academic centers (Gdansk and Olsztyn, Poland), we have noted decreased rates of perioperative infarctions and coronary events in post-KT patients, especially in diabetics. This has resulted in decreased perioperative CV mortality rates. Greater availability of coronary angiography also reduced the waiting period for noninvasive tests that would eventually fail to provide firm answers as to the patients’ coronary status. It should be mentioned, however, that this is a single-center experience and based on the results derived from a small group of HD patients (as already stated, multicenter studies regarding this issue are currently lacking). Therefore, the algorithm we propose was supported by available data from the literature as well our own clinical experiences. CONCLUSION
The present study did not confirm that DSE could serve as a reliable diagnostic modality for IHD detection in asymptomatic patients receiving HD. Consequently, other noninvasive test results, as described previously, as well as established CV risk factors should be taken into account. In cases of suspected IHD, the “test summation principle” should be applied to the selection of patients for an invasive procedure [39]. Because of frequently atypical or asymptomatic presentation of IHD and difficulties in unequivocal stress testing interpretation (including DSE) in CKD patients, coronary angiography remains the best modality for asymptomatic IHD diagnosis in patients on HD [1]. The present prospective study demonstrated a high clinical utility of the proposed CV risk algorithm for the selection of patients requiring coronary angiography. Given the complexity of this issue, well illustrated by the presented discussion of literature reports, with a wide range of
GÓRNY ET AL JANUSZKO-GIERGIELEWICZ, DĘBSKA-SLIZIE N,
researchers’ opinions and various approaches, every initiative aiming at a reliable and effective diagnostic work-up of HD patients before KT is most welcome. SUMMARY
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