Prognostic value of dobutamine stress echocardiography for the long-term outcomes in kidney transplant candidates

Introduction

Background

Cardiovascular disease accounts for more than 50% of deaths in individuals with end-stage renal disease (ESRD) (1). While kidney transplantation improves survival compared to patients remaining on dialysis, cardiovascular disease remains the leading cause of death (2-4). This is particularly significant as cardiovascular disease often manifests silently in these patients. Therefore, screening for coronary artery disease (CAD) is crucial in kidney transplant (KT) candidates before surgery.

Rationale and knowledge gap

According to Kidney Disease Improving Global Outcomes (KDIGO), asymptomatic KT candidates at high risk for CAD, such as those with diabetes or poor functional capacity, should undergo noninvasive screening (5). Similarly, the American Heart Association/American College of Cardiology, and American Society of Transplantation also recommend noninvasive testing for patients with known CAD, symptoms suggestive of CAD, or multiple risk factors (6). A large systematic review showed that noninvasive tests such as myocardial perfusion scintigraphy (MPS) and dobutamine stress echocardiography (DSE) can predict future adverse cardiac events in KT candidates and both normal MPS and DSE results are associated with a relatively low risk of future adverse events (7).

Stress tests are widely used in patients with chronic kidney disease (CKD). However, there are several controversial issues regarding the screening of CAD in KT candidates. Previous systematic reviews have demonstrated that noninvasive functional tests have moderate accuracy in predicting obstructive CAD in potential KT candidates (7,8). The ISCHEMIA-CKD (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches-Chronic Kidney Disease) study also showed that patients with CKD and moderate to severe myocardial ischemia who were randomized to invasive treatment had no difference in death or nonfatal myocardial infarction compared to conservative treatment (9). There are also potential risks of screening with invasive procedures, including revascularization, such as contrast-induced nephropathy and access site complications. The management of cardiovascular risk factors post-KT is also important since some of these factors are present prior to transplant, and others occur in the post-transplant period (10). Thus, a significant area still needs to be explored.

A previous study showed that DSE has an additional value for predicting cardiac events during long term follow-up in patients with proven or suspected CAD (11). However, in KT candidates, a prior study has demonstrated the prognostic value in the short and intermediate term of follow-up (7).

Objective

The aim of this study is to evaluate the prognostic value of DSE in predicting the long-term cardiovascular outcomes in KT candidates. We present this article in accordance with the STROBE reporting checklist (available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-174/rc).

Methods

Study population

Between January 2007 and December 2017, 292 patients who underwent DSE at Siriraj Hospital for preoperative evaluation before kidney transplantation were initially included in the study. Patients with incomplete echocardiography studies, incomplete echocardiography data, suboptimal image quality, or no follow-up data were excluded from the study. For patients who underwent DSE more than once, only data from their first DSE were recorded.

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and was approved by the Siriraj Institutional Review Board (SIRB), Faculty of Medicine Siriraj Hospital, Mahidol University (COA No. Si 596/2023). The need for consent was waived by the SIRB due to its retrospective nature and as all personal identifying information was obliterated. To evaluate the predictive value of DSE in long-term outcomes, defined as all-cause mortality, baseline characteristics encompassed demographic information such as age, sex, medical history, comorbidities, medications, and laboratory values, were recorded at the time of DSE. CAD was identified if there was a history of myocardial infarction, coronary revascularization, or presence of significant CAD from previous coronary angiography (left main stenosis ≥50% or major epicardial vessel stenosis ≥70%). Hypertension was defined as a blood pressure of ≥140/90 mmHg and/or use of antihypertensive medication. Hyperlipidemia was defined if total cholesterol value was ≥200 mg/dL or use of cholesterol-lowering medication. Diabetes mellitus was defined when fasting blood glucose level ≥126 mg/dL in more than two tests or when HbA1c level ≥6.5%. Resting echocardiography parameters, which were acquired during standard echocardiography performed at rest, as well as DSE parameters, which were obtained during the stress echocardiography test, test results, and any adverse effects during the procedure were also recorded.

DSE

DSE was performed and interpreted in accordance with previously established protocols (12) by cardiologists. At our institution, DSE is performed and interpreted by the junior cardiologists [working experience <5 years, most with National Board of Echocardiography (NBE) certificate], under supervision of senior cardiologists (working experience >15 years, all with NBE certificate). More than 99% of the test interpretations have been consistent among observers. If there is a disagreement in the interpretation between observers, the third senior cardiologist will be consulted for the final interpretation. Regarding the echocardiographic equipment, we use the up-to-date Philips cardiovascular ultrasound. Two-dimensional digitized and videotaped echocardiographic images were acquired at baseline, throughout the stress test, and during recovery.

DSE was performed, starting at 5 mcg/kg/min and increasing to 10, 20, 30 and 40 mcg/kg/min every 3 minutes. If target heart rate (85% of the age-predicted maximal heart rate) and the test endpoints for termination did not reach, intravenous atropine was administered in 0.25-mg increments every 1 minute to a maximum of 2 mg. The endpoints for termination of the test included the achievement of the target heart rate, hypotension, new or worsening wall motion abnormalities, significant arrhythmias, severe hypertension, and intolerable symptoms.

Wall motion analysis was performed utilizing a 16-segment, 4-point scale model of the left ventricle (13). Normal DSE was characterized by the absence of wall motion abnormalities both at rest and during stress. Abnormal DSE in the present study was defined by (I) the presence of inducible ischemia, (II) fixed wall motion abnormalities, (III) biphasic response, or (IV) wall motion abnormalities at rest with sustained improvement during stress (non-ischemic cardiomyopathy). An ischemic response is characterized by the development of a new wall motion abnormality with stress in a segment that has normal wall motion at rest, or by the worsening of function with stress in a segment that has a resting wall motion abnormality (12). Biphasic response was assessed in the segments with resting wall motion abnormalities and defined as an improvement of function during low dose of dobutamine and worsening during high dose. A wall motion abnormality at rest that remains unchanged with stress, or an akinetic segment that becomes dyskinetic, is considered a fixed abnormality and indicative of infarcted myocardium (non-viable) (12). The target heart rate was determined as 85% of the age-predicted maximal heart rate, calculated using the formula 220 minus the age in years (12).

Ejection fraction (EF) and hemodynamic parameters during stress echocardiography were assessed through visual estimation or a modified version of the method described by Quinones et al. (14). Changes in left ventricular end-systolic volume (LVESV) from rest to peak stress were categorized as either normal (decrease in LVESV) or abnormal (increase or absence of a decrease).

The wall motion score index (WMSI) was calculated as the summation of the wall motion scores divided by the number of visualized segments. Delta WMSI represented the difference between the resting WMSI and the peak WMSI.

Clinical follow-up

Follow-up data were collected via electronic medical records and telephone calls. All patients were followed from the date of DSE until the event occurred. Patients who underwent kidney transplantation were recorded and followed up. The primary outcome assessed was all-cause mortality. The life status data were received from the National Health Security Office of Thailand, and the closing date or censoring date was 16 January 2024.

Statistical analysis

Categorical variables were presented as numbers and percentages. Continuous data were expressed as mean ± standard deviation (SD), while continuous variables not following a normal distribution were represented as median and the 25^th and 75^th percentiles. Statistical comparisons between two groups were conducted using the independent t-test for continuous variables and the Mann-Whitney U test when appropriate. Categorical variables were analyzed using the Chi-square test or Fisher’s exact test. Univariable clinical characteristics and echocardiographic parameters of events were calculated using a Cox proportional hazards model. We conducted two multivariable models: (I) Model 1, which included variables with a P value <0.05 from the univariable analysis (using the BACKWARD method), and (II) Model 2, which included factors known or potentially associated with adverse outcomes (7,15,16) in combination with abnormal DSE (using the ENTER method). Regarding the variable selection for the multivariable analysis, those with statistical and clinical importance were included for the analysis in the multivariable models. However, some statistically significant variables were not included in the model because they might not have the clinical significance. Also, some variables [e.g., heart rate, blood pressure, left ventricular ejection fraction (LVEF)] were not included because the absolute mean values of both groups were in the normal range, which did not have any clinical significance. Some variables (e.g., WMSI, resting and stress wall motion abnormality, abnormal DSE) were qualitatively/quantitatively similar to one another and should not be included in the same model of multivariable analysis.

All statistical tests were 2-tailed, and all P values of <0.05 were considered to indicate statistical significance. Cumulative probability of event-free survival was calculated using the Kaplan-Meier method. The log-rank test was used to compare Kaplan-Meier survival curves. Censoring (patients who had not experienced the outcome by the close of the study) was included in the survival group. The statistical analysis was performed using IBM SPSS Statistics for Windows, version 20.0 (IBM Corp., Armonk, NY, USA).

The sample size was calculated based on a previous study by Bergeron et al., which demonstrated that the 3-year survival rate of patients with CKD who had normal DSE was 72%, while those with abnormal DSE had a survival rate of 47.8% (15). The estimated sample size for two proportions with independent samples, with a power of 90% and an alpha of 0.05, was 255.

Results

Patient characteristics

The study population comprised 269 patients. Figure 1 shows the study flow chart. The baseline characteristics of the study population are listed in Table 1. The mean age was 51.3±8.1 years old, with 58.7% being male. All patients were in CKD stage 5 with a mean estimated glomerular filtration rate (eGFR) of 6.48±3.39 mL/min/1.73 m², and 91.4% were on dialysis. Thirty-four (12.6%) patients had abnormal DSE results, including 14 (5.2%) with myocardial ischemia and 20 (7.4%) with non-ischemic cardiomyopathy. Table 2 demonstrates the baseline characteristics of patients with abnormal and normal DSE. There were no significant differences in characteristics between the two groups except that patients with abnormal DSE underwent invasive coronary angiography and revascularization more often than those with normal DSE (P<0.001 for both). Sixty-three patients (23%) underwent kidney transplantation after DSE, with a median time interval of 1.7 years (interquartile range: 0.7, 3.8) between DSE and transplantation.

Figure 1 Study flow chart.

Echocardiographic characteristics

Table 3 demonstrates the echocardiographic characteristics of the study population. Resting LVEF was 64.3%±8.4% and resting regional wall motion abnormality was present in 32 patients (11.9%). The average WMSI at rest was 1.07±0.3. During stress, an increase in LVEF and a decrease in WMSI were observed (stress LVEF 74.5%±10.7%; stress WMSI 1.04±0.2). Abnormal stress LVESV was observed in 16 (5.9%) patients. There were some minor adverse effects of DSE, including nausea, headache, palpitations, chest pain, and dyspnea. These effects were temporary and did not require hospitalization (Table 3).

Patient outcomes

In patients with abnormal DSE, 14 had inducible myocardial ischemia and 20 had non-ischemic cardiomyopathy. After DSE, of the 14 patients with inducible myocardial ischemia, 13 underwent invasive coronary angiography, and 11 underwent coronary revascularization [percutaneous coronary intervention (PCI) =8, coronary artery bypass graft (CABG) =3]. Patients with non-ischemic cardiomyopathy received guideline-directed medical therapy.

During the median follow-up period of 7.6 (4.5, 10.1) years, 129 (48%) patients died. The baseline and echocardiographic characteristics of deceased patients, compared to those of surviving patients, are listed in Tables 1,3, respectively. Compared to surviving patients, deceased patients were predominantly male (65.9% vs. 52.1%, P=0.02), with no significant differences in other baseline characteristics, including age, comorbidities, or medications. A significantly higher percentage of surviving patients had undergone kidney transplantation after DSE compared to deceased patients (31.4% vs. 14.7%, P=0.001).

In terms of echocardiographic parameters, patients with abnormal DSE had a significantly higher mortality rate than those with normal DSE (73.5% vs. 44.2%, P=0.003). Deceased patients demonstrated lower resting and stress LVEF (resting LVEF 62.2%±9.9% vs. 66.2%±6.0%; stress LVEF 71.9%±12.6% vs. 77.0%±7.6%, both P<0.001) than those who survived. Deceased patients also had a higher prevalence of resting regional wall motion abnormality (16.2% vs. 7.8%, P=0.003) as well as a higher resting WMSI (1.12±0.33 vs. 1.03±0.17, P=0.004). Figure 2 demonstrates Kaplan-Meier survival analysis, showing that patients with abnormal DSE had significantly higher mortality compared to patients with normal DSE (log-rank P=0.003).

Figure 2 A Kaplan-Meier survival analysis shows the mortality rate compared between patients with abnormal and normal DSE. Patients with abnormal DSE exhibited a significantly higher mortality rate compared to those with normal DSE. DSE, dobutamine stress echocardiography.

Univariable and multivariable analyses for the prediction of all-cause mortality

Table 4 shows univariable and multivariable Cox regression analyses for the prediction of all-cause mortality during follow-up. Univariable analysis demonstrated that male gender [hazard ratio (HR) 1.50, 95% confidence interval (CI): 1.04–2.16, P=0.03], resting systolic blood pressure (HR 1.006, 95% CI: 1.00–1.01, P=0.04), abnormal DSE (HR 1.95, 95% CI: 1.25–3.05, P=0.003), higher delta WMSI (HR 2.57, 95% CI: 1.24–5.35, P=0.01), and abnormal stress LVESV (HR 2.05, 95% CI: 1.11–3.82, P=0.02), and post-KT status (HR 0.48, 95% CI: 0.30–0.79, P=0.004) were associated with mortality. In the multivariable analysis Model 1, which included variables with a P value <0.05 from the univariable analysis, male gender and abnormal DSE were independent predictors of mortality [adjusted HR (aHR) 1.65, 95% CI: 1.06–2.20, P=0.02, and aHR 1.88, 95% CI: 1.20–2.93, P=0.006, respectively], while post-KT status emerged as an independent predictor of better outcomes (aHR 0.47, 95% CI: 0.29–0.77, P=0.003). In Model 2, which included known or potential variables associated with adverse outcomes (age, male gender, body mass index, hypertension, diabetes mellitus, known CAD, revascularization following DSE, atrial fibrillation, and the time interval between DSE and kidney transplantation), abnormal DSE remained an independent predictor of mortality (aHR 2.01, 95% CI: 1.20–3.34, P=0.008).

Discussion

Key findings

The main findings of the study revealed that over a mean follow-up period of 7.6 years, KT candidates with abnormal DSE demonstrated a significantly higher mortality rate compared to those with normal DSE results. Male gender and abnormal DSE emerged as independent predictors of mortality. Post-KT status was associated with a favorable long-term prognosis.

In the population of KT candidates, preoperative evaluation is crucial due to their high risk of cardiovascular mortality. Invasive coronary angiography has been proven as the better prognostic and diagnostic tool in KT candidates (17). However, it is invasive, costly, and associated with some serious procedural-related complications. Exercise stress testing is a practical tool, but less accurate due to some limitations in patients with ESRD, such as limited exercise capacity, abnormal resting electrocardiogram, and failure to achieve target heart rate (18).

Explanations of findings and comparison with similar research

Previous studies, including a large systematic review, have indicated that noninvasive tests such as DSE and MPS are as effective as coronary angiography in predicting future adverse cardiac events over the short and intermediate terms of follow-up (7). Moreover, both normal DSE and MPS results are associated with a relatively low risk of future adverse events in KT candidates (7). Additionally, a study by Cai et al. found that in KT candidates, DSE can effectively identify those at low and high risk of major adverse cardiac events (MACE) (19). Another study of Bergeron et al. which included 477 patients with CKD (33% undergoing kidney transplantation) also showed abnormal DSE associated with all-cause mortality (15). However, there is limited data on the prognostic value of long-term mortality.

In our study, 12.6% of the cohort had abnormal DSE. The relatively low rate of abnormal DSE in our study could be explained by the fact that almost all of our population had no known CAD (99.3%), which differs from previous studies. For example, a study by Sharma et al. included 30% with known CAD, contributing to a larger number of abnormal DSE (31%) (20). Similarly, a study by Bergeron et al., which included 31% with known CAD, reported 58% of abnormal DSE (15). However, due to the relatively long follow-up period of our study, the mortality rate was high (48%).

In our study, patients with abnormal DSE had a significantly higher rate of mortality compared to those with normal DSE. Additionally, abnormal DSE emerged as the strongest predictor of mortality from multivariable analysis. These findings are consistent with previous studies. For instance, a study by Tita et al. that included 149 patients undergoing DSE before kidney transplantation demonstrated that abnormal DSE was associated with a 7-fold increased rate of MACE, while patients with negative DSE had a very low rate of MACE (16). In our study, abnormal DSE was an independent predictor of all-cause mortality, unlike cardiovascular risk factors such as diabetes mellitus or hypertension. This finding is consistent with a study by Tita et al., which found that positive DSE, hemoglobin levels less than 11 g/dL post-KT, and calcium channel blocker use post-KT were independent predictors of MACE (16). Similarly, Bergeron et al. demonstrated that the independent predictors of death in patients who underwent kidney transplantation were resting heart rate and any evidence of ischemia during DSE (15). Both studies align with our results, indicating that abnormal DSE is a strong independent predictor of mortality rather than cardiovascular risk factors or comorbidities.

It is well-known that men with CKD have higher cardiovascular risk factors and a higher mortality rate than women (21-23). The study by Ricardo et al. on sex-related disparities in CKD progression found that women had a lower risk of ESRD and death, despite observed sex-related disparities in lifestyle and medical management (22). This was true even after extensive adjustment for sociodemographic characteristics, baseline kidney function, cardiovascular risk factors, medications, and markers of bone mineral metabolism (22). Our study is also consistent with prior studies that found male gender to be a predictor of mortality in KT candidates.

Regarding coronary revascularization before kidney transplantation, a post hoc analysis from ISCHEMIA-CKD study compared outcomes of patients with CAD not listed for kidney transplantation versus those listed according to management strategy. The analysis found that an invasive strategy in KT candidates did not improve outcomes (all-cause mortality or nonfatal myocardial infarction) compared with conservative management and does not support routine coronary angiography or revascularization in patients with advanced CKD and CAD listed for kidney transplantation (24). This highlights that guideline-directed medical therapy, such as statins, antiplatelets, and angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, is the mainstay for managing this population, with limited benefit from routine coronary revascularization. Our study, albeit with a limited number of patients who underwent coronary revascularization before kidney transplantation, did not show an effect on all-cause mortality in either the univariable or multivariable analysis.

Not only consistent with previous studies, but our study also provides additional prognostic value of DSE for long-term outcomes. Despite patients with ESRD having a substantially high rate of mortality in the long term, DSE still emerged as the strongest predictor of adverse outcomes.

Implications and actions needed

DSE can be a valuable tool for long-term risk stratification in KT candidates. Clinicians might consider incorporating this modality into preoperative evaluation protocols to better predict long-term outcomes and potentially improve patient management strategies.

Limitations

This study has some noteworthy limitations. First, the retrospective design rendered it vulnerable to missing or incomplete data and certain biases. Second, not every patient undergoing kidney transplantation is represented in our cohort, which may limit the generalizability of our findings to all patients undergoing kidney transplantation. Third, our study had a relatively limited sample size; however, it successfully demonstrated the prognostic value of DSE. Fourth, while the use of all-cause mortality as the primary outcome serves the purpose of an unbiased and objective endpoint, it is worth noting that there are other nonfatal outcomes, such as myocardial infarction or heart failure, that could be considered as endpoints of interest. Fifth, contrast echocardiography was not performed. Although it provides improvements in endocardial border delineation and aids in detecting perfusion defects, contrast echocardiography is not available at our institution or in Thailand. Lastly, the prevalence of abnormal DSE and patients who underwent kidney transplantation was low, which could be an important confounder of the study. This could be explained by our cohort, which included patients with intermediate risk (young age and low rate of known CAD). However, DSE still demonstrated an independent prognostic value.

Conclusions

Our study provided long-term prognostic value of preoperative DSE in KT candidates. Male gender and abnormal DSE were independent predictors of all-cause mortality, while post-KT status emerged as an independent predictor of better outcomes.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-174/rc

Data Sharing Statement: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-174/dss

Peer Review File: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-174/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-174/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was approved by Siriraj Institutional Review Board (SIRB), Faculty of Medicine Siriraj Hospital, Mahidol University (COA No. Si 596/2023). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The need for consent was waived by the SIRB due to its retrospective nature and as all personal identifying information was obliterated.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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