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Abstract
Objective Routine screening for cardiovascular disease before kidney transplantation remains controversial. This study aims to compare cardiac testing rates in patients with end-stage renal disease, referred and not referred for transplantation, and assess the impact of testing on transplant wait times.
Methods This is a retrospective cohort study of 22 687 end-stage renal disease patients from 2011 to 2022, within an integrated health system. Cardiac testing patterns, and the association between cardiac testing and transplant wait times and post-transplant mortality were evaluated.
Results Of 22 687 patients (median age 66 years, 41.1% female), 6.9% received kidney transplants, and 21.0% underwent evaluation. Compared with dialysis patients, transplant patients had a 5.6 times higher rate of stress nuclear myocardial perfusion imaging with single-photon emission (rate ratio (RR) 5.64, 95% CI 5.37 to 5.92), a 6.5 times higher rate of stress echocardiogram (RR 6.51, 95% CI 5.65 to 7.51) and 16% higher cardiac catheterisation (RR 1.16, 95% CI 1.06 to 1.27). In contrast, revascularisation rates were significantly lower in transplant patients (RR 0.46, 95% CI 0.36 to 0.58). Transplant wait times were longer for patients who underwent stress testing (median 474 days with no testing vs 1053 days with testing) and revascularisation (1796 days for percutaneous intervention and 2164 days for coronary artery bypass surgery). No significant association was observed with 1-year post-transplant mortality (adjusted OR 1.99, 95% CI 0.46 to 8.56).
Conclusions This study found a higher rate of cardiac testing in dialysis patients evaluated for kidney transplants. Cardiac testing was associated with longer transplant wait time, but no association was observed between testing and post-transplant mortality.
- Diagnostic Imaging
- Outcome Assessment, Health Care
- Atherosclerosis
Data availability statement
Data may be obtained from a third party and are not publicly available. The datasets generated and/or analysed during the current study are not publicly available due to their being the property of Kaiser Foundation Health Plan, but are available to interested collaborators in the context of a formal collaboration approved by the Kaiser Permanente Southern California Institutional Review Board for the Protection of Human Subjects.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Recent studies suggest cardiac stress testing for potential kidney transplant candidates may be of low value.
WHAT THIS STUDY ADDS
Compared to dialysis patients, patients undergoing kidney transplant evaluation had a significantly higher rate of stress testing.
Transplant wait times were longer for patients who underwent stress testing, and no association was observed between stress testing and post-transplant mortality.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Minimising unnecessary cardiac testing could streamline and enhance the efficiency of the pretransplant evaluation process. The current system could benefit from a re-evaluation, followed by a comprehensive overhaul and adoption of standardised processes.
Introduction
Coronary artery disease is a significant cause of morbidity and mortality in kidney and liver transplant candidates.1 Cardiac stress testing is used routinely in asymptomatic kidney transplant candidates to screen for occult coronary artery disease. However, the benefit of routine use of cardiac testing to improve clinical outcomes remains unclear. Studies performed outside of the transplant setting failed to show screening for coronary artery disease in asymptomatic individuals improves survival.2–4 Given the absence of data regarding the benefit of cardiac testing, there is substantial variability among transplant centres.5 6 Many US programmes do not have a standardised protocol for pretransplant cardiac evaluation.6–8 Screening frequency and modality are often left to the discretion of local clinicians. In 217 US facilities, the use of stress testing in the 18 months preceding transplant ranged from 11% to 96%.8
Clinical practice guidelines from national societies vary widely regarding which patients to screen, how frequently screening should be performed and which screening modality to use.9 A recent cohort study showed that pretransplant coronary artery disease testing was not associated with a reduction in early post-transplant death or acute myocardial infarction,10 suggesting that many transplant candidates may safely avoid unnecessary cardiac testing. Cardiac stress testing often leads to additional downstream testing and procedures, such as revascularisation with stenting or coronary artery bypass surgery (CABG), which may cause a delay in organ transplantation.6 Whether cardiac testing leads to lengthened pretransplant evaluation and prolonged wait times has not been well studied. The goal of this study is to describe the pattern of cardiac testing in a cohort of kidney transplant patients and to evaluate the association between cardiac testing and transplant wait time.
Methods
This is a retrospective cohort study using electronic medical records from Kaiser Permanente Southern California (KPSC) to identify adults referred for kidney transplant evaluation. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology reporting guideline.11 Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Data source
KPSC is an integrated healthcare delivery system that provides care to more than 4.8 million members in Southern California, USA. Members enrol through the Kaiser Foundation Health Plan for comprehensive health insurance, including prescription drug benefits. The membership is ethnically and socioeconomically diverse and is representative of the general population of California.12 Comprehensive medical information, which includes demographics, administrative, pharmacy, laboratory and healthcare utilisation data from ambulatory and inpatient encounters, is prospectively captured electronically through clinical and administrative databases and from the electronic health record.
Study cohort
Adults ages 18 and above referred for kidney transplant evaluation between 1 January 2011 and 31 December 2022, were identified using an internal registry. Patients who received renal replacement therapy during this period were identified from electronic medical records and claims data using Current Procedural Terminology (CPT) codes and from a KPSC internal dialysis registry. The date of kidney transplant referral was used as the index date. For patients on renal replacement therapy, the first dialysis date was used as the index date. Patients who were not KPSC members or had less than 1 year of membership were excluded. Patients listed for dual organ heart-kidney or liver-kidney transplant were excluded. Patients were categorised into three groups: (1) ‘transplanted’: patients who have undergone kidney transplantation; (2) ‘evaluation’: patients referred for kidney transplant evaluation but have not received kidney transplantation either because they were declined, died while waiting or still undergoing evaluation during the study period; and (3) ‘dialysis’: patients on renal replacement therapy but has not been referred for kidney transplantation.
Patient demographic characteristics, including age, sex, race and ethnicity, were collected from the electronic health record. Race and ethnicity were self-reported and categorised into mutually exclusive groups, including Hispanic regardless of race and the following non-Hispanic groups: Asian or Pacific Islander, black, white and other (defined as Native American or Alaska Native and multiple or other races and ethnicities). Medical comorbidities were identified using International Classification of Diseases, Ninth Revision or International Classification of Diseases, Tenth Revision (ICD-10) codes. Household income was estimated using the provided home address and the corresponding neighbourhood information. Patients were followed until they reached the study endpoint (all-cause death or kidney transplantation) or the end of the study period (31 August 2023).
Exposures and outcomes
Cardiac procedures were identified using CPT codes. These included transthoracic echocardiogram (TTE), stress echocardiogram (SE), stress nuclear myocardial perfusion imaging with single-photon emission CT (MPI), cardiac catheterisation (LHC), percutaneous coronary intervention and CABG. Cardiac stress testing included MPI or SE. The number of cardiac procedures completed during the evaluation period was tallied. For the transplanted group, the evaluation period was defined as the interval between the transplant referral date and the transplant surgery date. For the evaluation group, the evaluation period was defined as the transplant referral date to the date of death, date when their candidacy was declined by the transplant centre, termination of KPSC health plan enrolment or the end of study, whichever came first. For the dialysis group, the evaluation period was defined as the dialysis start date to termination of KPSC health plan enrolment, date of death or the end of study, whichever came first.
The primary outcome was transplant wait time, which was defined as the time of referral for transplant evaluation to transplantation surgery. Secondary outcomes included all-cause mortality and rates of cardiac testing. Mortality data was extracted from a mortality data file that included integrated death information from multiple sources, including insurance plan administrative records, Social Security Administrative death master files and hospital death records.
Statistical analysis
Descriptive statistics were used to examine covariate distribution. Continuous variables were summarised and reported in medians with IQRs or means with SD. Categorical variables were reported as counts and percentages. Differences in categorical data between groups (transplanted, evaluation and dialysis) were compared by the χ2 tests. Differences in continuous data were compared using the Student’s t-test or the Wilcoxon rank-sum test.
Rates of cardiac testing and the corresponding 95% CIs were calculated per 100 patient-years, for each patient group (transplanted, evaluation and dialysis), and for each test type. Rate ratios (RRs) and corresponding 95% CIs were estimated using Poisson regression models. A box plot was used to compare wait time between groups; the IQRs are shown for all data. Cumulative incidence curves for the groups with or without stress testing were estimated using the Kaplan-Meier method. Multivariable Cox proportional hazard regression analyses were performed to evaluate the association between stress testing and the likelihood of kidney transplantation during the transplant evaluation period. The proportional hazard assumption was assessed using Schoenfeld residuals. Adjusted HRs (aHRs), corresponding 95% CIs and p values were reported. To evaluate the association between pretransplant cardiac testing and post-transplant mortality, multivariable logistic regression modelling was constructed. Multivariable regression models were adjusted for the following variables: age, sex, race/ethnicity, hypertension, heart failure, diabetes, dyslipidaemia, atrial fibrillation, myocardial infarction, pacemaker, chronic lung disease and liver disease. All p values were two-sided. P<0.05 was considered statistically significant. Analyses were conducted using Stata V.17/MP V.17.0 (StataCorp, College Station, TX) or SAS V.9.4 (SAS Institute).
Results
Study population
The study cohort comprised 22 687 patients divided into three groups: (1) 1573 (6.9%) who underwent kidney transplantation; (2) 4753 (21.0%) referred for evaluation but had not undergone transplant either because they were declined, died while waiting, or were still undergoing evaluation during the study period; and (3) 16 361 (72.1%) on renal replacement therapy and had not been referred for transplant evaluation. Median (IQR) age was 66 (55, 75) years, 9328 (41.1%) were women, 6168 (27.2%) self-identified as non-Hispanic white, 4520 (19.9%) non-Hispanic black, 8669 (38.2%) Hispanic and 3093 (13.6%) Asian. Table 1 shows their baseline characteristics. Compared with dialysis patients, patients evaluated for or who underwent transplant were younger and had a lower prevalence of comorbidities, including diabetes, heart failure, coronary artery disease and atrial fibrillation.
Baseline characteristics
Cardiac testing patterns
Cardiac testing counts during the observation period are shown in online supplemental table 1. Cardiac testing included TTE, SPECT-MPI, SE and cardiac catheterisation (online supplemental table 1). Some patients in the transplanted group underwent multiple testing during the transplant evaluation period: 28.6% had two SPECT-MPIs, 12.1% had three SPECT-MPIs and 7.9% had four or more SPECT-MPIs. A few transplanted patients had more than six TTEs, SPECT-MPIs or SEs during the transplant evaluation period (online supplemental figure 1).
Supplemental material
Cardiac testing rates and RRs are shown in table 2. Patients who underwent kidney transplant evaluation, regardless of whether they eventually underwent transplantation, had significantly higher rates of non-invasive cardiac testing and invasive cardiac catheterisation. Compared with dialysis patients not referred for transplant evaluation, patients who underwent transplant had a 5.6 times higher rate of SPECT-MPI (RR 5.64, 95% CI 5.37 to 5.92) and a 6.5 times higher rate of SE (RR 6.51, 95% CI 5.65 to 7.51). Rate of cardiac catheterisation was 16% higher (RR 1.16, 95% CI 1.06 to 1.27). In contrast, the rate of revascularisation was significantly lower in patients who had kidney transplants (RR 0.46, 95% CI 0.36 to 0.58).
Cardiac testing rates per 100 person-years of observation time and rate ratios
Time from referral to transplantation
Among patients who underwent kidney transplants, the time from referral for transplant evaluation to eventual transplantation was calculated for patients who underwent different types of cardiac testing. The median time from referral to transplant was 474 days for patients who did not undergo any stress testing and 1053 days for those who had either an SE or SPECT-MPI (table 3). Patients who underwent cardiac catheterisation had a longer wait time of 1687 days. Revascularisation with percutaneous cardiac intervention or CABG further prolongs the wait time to 1796 days and 2164 days, respectively (figure 1). Patients who underwent transplant from a living donor had a shorter wait time compared with deceased donor transplant. However, even among living donor transplants, the wait time was higher in those who underwent stress testing (412 days without testing, compared with 574 days with testing) (table 3).
Wait time in days among patients who underwent transplantation
Time from referral to transplantation. Each box represents the distribution of wait time (in days) from referral to transplantation for transplanted patients stratified by cardiac procedures received. Horizontal lines within the boxes indicate median wait time. The bottom and top of each box represent the 25th and 75th percentiles, respectively. The lower whisker indicates the smallest value within 1.5 times below the 25th percentile and the upper whisker indicates the largest value within 1.5 times the IQR above the 75th percentile. Values outside of these thresholds were not displayed. (A) All patients who underwent kidney transplantation. (B) Stratified by deceased donor and living donor. CABG, coronary artery bypass surgery; Cath, catheterisation; PCI, percutaneous coronary intervention; revasc, revascularisation.
The cumulative incidence curve showed the probability of transplantation from the time to referral to transplantation, stratified by stress testing (figure 2). Stress testing was associated with a lower probability of transplantation at all timepoints. Multivariable Cox proportional hazard models were used to estimate the association between cardiac testing and the likelihood of kidney transplant during the transplant evaluation period. Compared with no testing, stress testing was associated with a lower likelihood of transplant at any given time (aHR 0.31, 95% CI 0.33 to 0.48) (online supplemental table 2). Cardiac catheterisation, even without revascularisation, was also associated with a lower likelihood of transplant at any given time (aHR 0.25, 95% CI 0.21 to 0.31). Similar findings were observed for revascularisation including percutaneous revascularisation (aHR 0.16, 95% CI 0.09 to 0.25) and coronary bypass surgery (aHR 0.18, 95% CI 0.12 to 0.25) (online supplemental table 2).
Cumulative incidence curve showing the probability of transplantation from the time of referral to transplant, stratified by stress testing.
Pretransplant cardiac testing and early post-kidney transplant outcomes
The rate of mortality was low in patients who underwent kidney transplants. No significant association was detected between pretransplant stress testing and 1-year mortality post-transplant (adjusted OR 1.99, 95% CI 0.46 to 8.56) (online supplemental table 3).
Discussion
In this cohort study of 22 687 patients with end-stage renal disease on dialysis, 6.9% underwent kidney transplantation. Compared with dialysis patients not referred for transplant evaluation, patients who underwent transplant had a 5.6 times higher rate of SPECT-MPI, a 6.5 times higher rate of SE and a 16% higher rate of cardiac catheterisation. Yet, the rate of significant obstructive coronary artery disease requiring revascularisation was 54% lower in transplant patients. Cardiac stress testing was associated with a significantly longer transplant wait time. Patients who underwent cardiac stress testing waited 579 days longer for transplantation than those who did not.
Kidney transplantation is the preferred treatment option for patients with end-stage renal disease, with transplantation leading to longer life expectancy, improved health-related quality of life and reduced healthcare costs.1 13–15 Patients referred for transplant evaluation undergo extensive pretransplant evaluation, a process that may take many months to complete.16 With cardiovascular disease being the leading cause of morbidity and mortality after kidney transplantation, assessment for cardiac disease is an important component of pretransplant evaluation.1 16
Whether the benefits of screening for coronary artery disease in asymptomatic kidney transplant candidates outweigh the potential risks remains controversial.9 A study using the US Renal Data System showed no association between pretransplant cardiac testing with a reduction in post-transplant death or acute myocardial infarction.10 Cardiac catheterisation of kidney transplant candidates with moderate or severe ischaemia on stress testing did not improve outcomes compared with conservative medical management.5 Yet, pretransplant cardiac testing remains common, with some centres requiring testing in 96% of patients.8 Potential risks associated with testing should be considered. This study showed that compared with no testing, patients who had cardiac stress tests experienced significantly longer transplant wait times. Wait times for those who had cardiac catheterisation or coronary revascularisation were even longer. The longer wait time may be of particular importance in living donor kidney transplants, where cardiac testing may be one of the major barriers to proceeding with transplantation surgery.
Another potential harm of testing is radiation exposure.17 We observed that rates of SPECT-MPI were 5.6 times higher in transplanted patients compared with those on dialysis despite being younger and having fewer cardiovascular risk factors. A substantial proportion of these patients had multiple SPECT-MPI during the transplant evaluation period. Yet, the rate of significant obstructive coronary artery disease requiring revascularisation was very low, suggesting that the vast majority of patients who underwent testing may not have needed the test.
Non-invasive cardiac testing procedures may trigger a cascade of downstream testing procedures that are invasive and associated with potential complications.18–20 Other potential harm includes treatment burden associated with multiple tests, financial consequences to patients and anxiety from waiting for test results.21 Some physicians characterise the transplant evaluation process as ‘rigid, demanding, and opaque’ over which they have little control.22
Reducing unnecessary cardiac testing may help move the system one step closer to a more streamlined evaluation process. For example, in kidney transplant candidates without known heart disease who report no cardiac symptoms and are deemed low risk based on their cardiac risk factors, deferring cardiac testing may be the preferred approach and may significantly reduce their wait time. For patients who have previously had a normal cardiac stress test, it may be advisable to avoid regular repeat testing unless new symptoms emerge. In patients with known coronary artery disease who are asymptomatic, it may be reasonable to focus on optimising medical therapy instead of immediately opting for coronary revascularisation. The current system could benefit from a reevaluation, followed by a comprehensive overhaul and adoption of standardised processes.
Limitations
Several limitations to this study should be acknowledged. First, we did not have clinical details, such as patient symptoms and physical examination findings, to determine the intentions behind cardiac testing and whether the tests were clinically appropriate. However, the lower rate of revascularisation and higher rate of testing despite having fewer cardiac risk factors in the transplant group suggest overutilisation. Second, the low rate of post-transplant mortality limits the power to detect a difference in post-transplant outcomes related to cardiac testing. Third, the observational nature of this study precludes interpreting the association between stress testing with longer wait time as causation, given possible confounding by indication. Fourth, all patients in this study were insured and had access to care from an integrated healthcare system in the USA, so findings may not be generalisable to uninsured populations and populations outside of the USA.
Fifth, in rare instances, a patient may require urgent transplantation due to the inability to maintain dialysis access. In such cases, the short wait time was driven by factors unrelated to cardiac testing. Within our study cohort, urgent status would only be assigned in life-threatening situations where all possible options for vascular and peritoneal access, including permcath placement, had been exhausted and no further access was attainable. Given the extreme rarity of these situations, we do not expect them to affect the main findings of our study.
Conclusions
The rate of cardiac testing was significantly higher in patients with end-stage renal disease evaluated for transplantation. Testing was associated with a significantly longer waiting time to transplant, with no difference in post-transplant outcomes. These results suggest the need to develop a more evidence-based, individualised, streamlined and efficient approach to pretransplant cardiac testing.
Data availability statement
Data may be obtained from a third party and are not publicly available. The datasets generated and/or analysed during the current study are not publicly available due to their being the property of Kaiser Foundation Health Plan, but are available to interested collaborators in the context of a formal collaboration approved by the Kaiser Permanente Southern California Institutional Review Board for the Protection of Human Subjects.
Ethics statements
Patient consent for publication
Ethics approval
Ethics approval was obtained from the Kaiser Permanente Southern California Institutional Review Board (protocol number 13594) with a waiver of informed consent based on 45 CFR §46.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors M-SL designed the study, analysed and interpreted the data, drafted, finalised and approved the article. CB, JO, RE, WC, JK, AS and RLL interpreted the data, and revised and approved the article. Y-LW prepared, analysed and interpreted the data, and revised and approved the article. MSL was the guarantor of this work.
Funding This research was supported by a grant from the Regional Research Committee of Kaiser Permanente Southern California, RRC grant number: KP-RRC-20230401.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.