Correspondence 2. Hoenig MP, Shapiro E, Hladik GA. Lessons learned from the ASN renal educator listserv and survey. Clin J Am Soc Nephrol. 2013;8(6):1054-1060. Received February 3, 2015. Accepted in revised form February 4, 2015. Originally published online February 21, 2015. Ó 2015 by the National Kidney Foundation, Inc. http://dx.doi.org/10.1053/j.ajkd.2015.01.011
RESEARCH LETTER Dobutamine Stress Cardiac MRI for Assessment of Coronary Artery Disease Prior to Kidney Transplantation To the Editor: Cardiovascular disease is the leading cause of death in end-stage kidney disease following successful kidney transplantation.1 The accuracy of noninvasive cardiac stress testing versus coronary angiography in detecting significant coronary artery disease (CAD) prior to kidney transplantation is inadequate.2-4 Dobutamine stress cardiac magnetic resonance (DSCMR) imaging offers highly accurate, prognostically relevant results in detecting inducible myocardial ischemia.5,6 We performed a diagnostic test study to evaluate the utility of DSCMR for identifying significant CAD prior to potential kidney transplantation, using angiography as the reference test. Subject to informed consent, we recruited consecutive patients with CKD older than 18 years referred by their treating nephrologists for CAD assessment prior to consideration of kidney transplantation. Referral occurred when the risk of cardiovascular disease was thought to be sufficiently high to necessitate exclusion prior to listing for transplantation. Ethics approval was obtained from our local human research ethics committee, with adherence to the Declaration of Helsinki. Patients with symptomatic CAD or LVEF , 35% were excluded and referred directly for coronary angiography. Patients also were excluded if MR imaging or dobutamine administration was contraindicated. Participants underwent standard assessment of cardiac structure and function using a 1.5-T Siemens Avanto MR imaging scanner. Images at rest were acquired during expiratory breath holding with retrospectively electrocardiography-gated TrueFISP sequences. Intravenous dobutamine infusion was per a standard weight-based protocol: 3-minute doses of 10, 20, 30, then 40 mg/kg/min (with atropine up to 1.2 mg if required) until achievement of $85% of maximum predicted heart rate (220 2 age [beats/min]) to achieve a diagnostic test. Patients were excluded from analysis if they were unable to reach the required heart rate. b-Blockers were withheld for 48 hours before DSCMR, and there were no adverse outcomes from this. Standard termination criteria for dobutamine were applied.7 Regional wall motion was assessed at each dose increment. Ischemia was defined as at least one segment showing deterioration in segmental wall motion score of at least one grade.8 An example of a positive DSCMR is shown in Fig S1. Following DSCMR, patients underwent standard invasive coronary angiography by common femoral arterial access. Coronary artery stenoses were considered clinically significant if visually estimated to be $70% of luminal diameter. Offline analysis of angiographic stenosis severity was performed by 2 independent experienced observers. Reporters of coronary angiography and DSCMR were blinded to the reciprocal test results. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of a diagnostic DSCMR (index 808
Table 1. Baseline Demographics of Patients With a Diagnostic DSCMR and Diagnostic Coronary Angiography Included Patients (n 5 47) Age, y Male sex Indigenous Australian Overweight (BMI 5 25-29.9 kg/m2) Obese (BMI $ 30 kg/m2) Hypertension Diabetes mellitus Hyperlipidemia History of smoking Known previous myocardial infarction Past PCI Past coronary artery bypass grafting History of stroke Baseline LVEF, % Baseline RWMAs on cardiovascular MR History of peripheral vascular disease Renal replacement therapy Previous kidney transplant b-Blocker therapy
57.6 6 7.7a 35 (75%) 7 (15%) 21 (45%) 11 (23%) 40 (85%) 19 (40%) 17 (36%) 13 (28%) 2 (3%) 2 (3%) 2 (3%) 4 (9%) 65.0 6 10.5a 17 (36%) 6 (13%) 45 (96%) 7 (15%) 17 (36%)
Abbreviations: BMI, body mass index; LVEF, left ventricular ejection fraction; PCI, percutaneous coronary intervention; RWMA, regional wall motion abnormality; SD, standard deviation. a Mean 6 SD.
test) for detection of a $70% angiographic coronary stenosis (reference test) were calculated. A c2 test was used to compare differences between included and excluded participants. P , 0.05 was considered statistically significant. Statistical analyses were performed using SPSS, version 21.0. From May 2008 through March 2014, a total of 62 patients were enrolled and had DSCMR followed within 1 week by invasive coronary angiography: 47 (76%) participants had a diagnostic DSCMR, while all had diagnostic coronary angiography. Baseline demographics of the 47 patients who had diagnostic index and reference tests are shown in Table 1. Of these, 12 (26%) patients had clinically significant CAD on coronary angiography. All these patients had positive DSCMR scans (sensitivity, 100% [Table 2]). There were 4 further positive DSCMR scans in the absence of angiographically-significant CAD (specificity, 89%; PPV, 75%). Thirty-one participants had negative DSCMR studies, all without angiographically-significant CAD, with no false negatives (NPV, 100%). Fifteen patients (24% of the cohort) did not have a diagnostic DSCMR and were excluded from analyses. Eight patients (13%) were unable to achieve target heart rates despite maximum dobutamine and atropine doses. Five patients (8%) had significant claustrophobia, 1 (2%) patient had severe hypertension, and another had severe dizziness following dobutamine administration. No significant difference was observed between the incidence of significant angiographic CAD between the included diagnostic DSCMR (12/47; 26%)
Table 2. Diagnostic Accuracy of DSCMR (Index Test) Versus Invasive Coronary Angiography (Reference Test)
Positive DSCMR Negative DSCMR
Significant CAD
No Significant CAD
12 0
4 31
Note: Sensitivity, 100% (95% CI, 74%-100%); specificity, 89% (95% CI, 73%-97%); PPV, 75% (95% CI, 48%-93%); NPV, 100% (95% CI, 89%-100%).
Am J Kidney Dis. 2015;65(5):806-809
Correspondence and excluded nondiagnostic DSCMR groups (6/15; 40%): P 5 0.8. Thirty-one of 62 (50%) enrolled patients had diagnostic negative DSCMR scans, with 100% NPV. Hence, we predict that DSCMR in routine pre–kidney transplantation CAD assessment in high-risk asymptomatic patients could obviate the need for invasive angiography in approximately half of patients. It must be acknowledged that a visual estimate of angiographic severity is imprecise.9 Furthermore, a diagnostic study was achieved in only 76% of patients and therefore DSCMR does not provide a noninvasive screening solution for all high-risk candidates. This diagnostic test study to our knowledge is the first to assess the accuracy of diagnostic DSCMR in chronic kidney failure and has demonstrated a high degree of accuracy compared to invasive coronary angiography in potential kidney transplantation candidates. We believe that greater use of DSCMR would reduce the need for invasive coronary angiography in the pretransplantation setting. Benjamin K. Dundon, MBBS,1,2,3 Anthony D. Pisaniello, MBBS1,4 Adam J. Nelson, MBBS,1,2 Murilo Maia, MBBS2 Karen S.L. Teo, MBBS,1,2 Stephen G. Worthley, MBBS1,2,4 Patrick T. Coates, MBBS,1,2 Graeme R. Russ, MBBS1,2 Randall J. Faull, MBBS,1,2 Kym Bannister, MBBS1,2 Matthew I. Worthley, MBBS1,2,4 1 University of Adelaide, Australia 2 Royal Adelaide Hospital, Australia 3 Monash Health, Australia 4 South Australian Health and Medical Research Institute, Australia Corresponding author: [email protected]
Acknowledgements We thank Ms Kerry Williams and Mr Ben Koschade for tireless help and professionalism in undertaking the DSCMR studies. Support: BKD was supported by postgraduate research scholarships from National Health and Medical Research Council/National Heart Foundation of Australia and the Cardiac Society of Australia and New Zealand. MIW is supported by a South Australian Health Practitioner Fellowship. The funders had no role in study design, collection, analysis, and interpretation of data; writing the report; or the decision to submit the report for publication. Financial Disclosure: The authors declare that they have no other relevant financial interests. Contributions: Research idea and study design: MIW, BKD, SGW; data acquisition: BKD, ADP, MM, AJN, KS-LT, SGW; data analysis/interpretation: ADP, MIW, BKD; statistical analysis: ADP, MIW; supervision or mentorship: MIW, SGW; collaboration: PTC, GRR, RJF, KB. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. MIW takes responsibility that this study has been reported honestly,
Am J Kidney Dis. 2015;65(5):806-809
accurately, and transparently; that no important aspects of the study have been omitted, and that any discrepancies from the study as planned have been explained.
Supplementary Material Figure S1: Images from a study patient with inducible ischemia show a typical biphasic response to dobutamine. Note: The supplementary material accompanying this article (http://dx.doi.org/10.1053/j.ajkd.2015.02.319) is available at www.ajkd.org
References 1. Lentine KL, Costa SP, Weir MR, et al. 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;60:434-480. 2. Bart BA, Cen YY, Hendel RC, et al. Comparison of dobutamine stress echocardiography, dobutamine SPECT, and adenosine SPECT myocardial perfusion imaging in patients with end-stage renal disease. J Nucl Cardiol. 2009;16:507-515. 3. Worthley MI, Unger SA, Mathew TH, Russ GR, Horowitz JD. Usefulness of tachycardic-stress perfusion imaging to predict coronary artery disease in high-risk patients with chronic renal failure. Am J Cardiol. 2003;92:1318-1320. 4. Wang LW, Fahim MA, Hayen A, et al. Cardiac testing for coronary artery disease in potential kidney transplant recipients: a systematic review of test accuracy studies. Am J Kidney Dis. 2011;57:476-487. 5. Kelle S, Egnell C, Vierecke J, et al. Prognostic value of negative dobutamine-stress cardiac magnetic resonance imaging. Med Sci Monit. 2009;15:MT131-MT136. 6. Wahl A, Paetsch I, Gollesch A, et al. Safety and feasibility of high-dose dobutamine-atropine stress cardiovascular magnetic resonance for diagnosis of myocardial ischaemia: experience in 1000 consecutive cases. Eur Heart J. 2004;25:1230-1236. 7. Nagel E, Lehmkuhl HB, Bocksch W, et al. Noninvasive diagnosis of ischemia-induced wall motion abnormalities with the use of high-dose dobutamine stress MRI: comparison with dobutamine stress echocardiography. Circulation. 1999;99:763-770. 8. Paetsch I, Jahnke C, Wahl A, et al. Comparison of dobutamine stress magnetic resonance, adenosine stress magnetic resonance, and adenosine stress magnetic resonance perfusion. Circulation. 2004;110:835-842. 9. Fischer JJ, Samady H, McPherson JA, et al. Comparison between visual assessment and quantitative angiography versus fractional flow reserve for native coronary narrowings of moderate severity. Am J Cardiol. 2002;90:210-215. Received February 8, 2015. Accepted in revised form February 10, 2015. Originally published online February 26, 2015. Ó 2015 by the National Kidney Foundation, Inc. http://dx.doi.org/10.1053/j.ajkd.2015.02.319
809
RESEARCH LETTER Dobutamine Stress Cardiac MRI for Assessment of Coronary Artery Disease Prior to Kidney Transplantation To the Editor: Cardiovascular disease is the leading cause of death in end-stage kidney disease following successful kidney transplantation.1 The accuracy of noninvasive cardiac stress testing versus coronary angiography in detecting significant coronary artery disease (CAD) prior to kidney transplantation is inadequate.2-4 Dobutamine stress cardiac magnetic resonance (DSCMR) imaging offers highly accurate, prognostically relevant results in detecting inducible myocardial ischemia.5,6 We performed a diagnostic test study to evaluate the utility of DSCMR for identifying significant CAD prior to potential kidney transplantation, using angiography as the reference test. Subject to informed consent, we recruited consecutive patients with CKD older than 18 years referred by their treating nephrologists for CAD assessment prior to consideration of kidney transplantation. Referral occurred when the risk of cardiovascular disease was thought to be sufficiently high to necessitate exclusion prior to listing for transplantation. Ethics approval was obtained from our local human research ethics committee, with adherence to the Declaration of Helsinki. Patients with symptomatic CAD or LVEF , 35% were excluded and referred directly for coronary angiography. Patients also were excluded if MR imaging or dobutamine administration was contraindicated. Participants underwent standard assessment of cardiac structure and function using a 1.5-T Siemens Avanto MR imaging scanner. Images at rest were acquired during expiratory breath holding with retrospectively electrocardiography-gated TrueFISP sequences. Intravenous dobutamine infusion was per a standard weight-based protocol: 3-minute doses of 10, 20, 30, then 40 mg/kg/min (with atropine up to 1.2 mg if required) until achievement of $85% of maximum predicted heart rate (220 2 age [beats/min]) to achieve a diagnostic test. Patients were excluded from analysis if they were unable to reach the required heart rate. b-Blockers were withheld for 48 hours before DSCMR, and there were no adverse outcomes from this. Standard termination criteria for dobutamine were applied.7 Regional wall motion was assessed at each dose increment. Ischemia was defined as at least one segment showing deterioration in segmental wall motion score of at least one grade.8 An example of a positive DSCMR is shown in Fig S1. Following DSCMR, patients underwent standard invasive coronary angiography by common femoral arterial access. Coronary artery stenoses were considered clinically significant if visually estimated to be $70% of luminal diameter. Offline analysis of angiographic stenosis severity was performed by 2 independent experienced observers. Reporters of coronary angiography and DSCMR were blinded to the reciprocal test results. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of a diagnostic DSCMR (index 808
Table 1. Baseline Demographics of Patients With a Diagnostic DSCMR and Diagnostic Coronary Angiography Included Patients (n 5 47) Age, y Male sex Indigenous Australian Overweight (BMI 5 25-29.9 kg/m2) Obese (BMI $ 30 kg/m2) Hypertension Diabetes mellitus Hyperlipidemia History of smoking Known previous myocardial infarction Past PCI Past coronary artery bypass grafting History of stroke Baseline LVEF, % Baseline RWMAs on cardiovascular MR History of peripheral vascular disease Renal replacement therapy Previous kidney transplant b-Blocker therapy
57.6 6 7.7a 35 (75%) 7 (15%) 21 (45%) 11 (23%) 40 (85%) 19 (40%) 17 (36%) 13 (28%) 2 (3%) 2 (3%) 2 (3%) 4 (9%) 65.0 6 10.5a 17 (36%) 6 (13%) 45 (96%) 7 (15%) 17 (36%)
Abbreviations: BMI, body mass index; LVEF, left ventricular ejection fraction; PCI, percutaneous coronary intervention; RWMA, regional wall motion abnormality; SD, standard deviation. a Mean 6 SD.
test) for detection of a $70% angiographic coronary stenosis (reference test) were calculated. A c2 test was used to compare differences between included and excluded participants. P , 0.05 was considered statistically significant. Statistical analyses were performed using SPSS, version 21.0. From May 2008 through March 2014, a total of 62 patients were enrolled and had DSCMR followed within 1 week by invasive coronary angiography: 47 (76%) participants had a diagnostic DSCMR, while all had diagnostic coronary angiography. Baseline demographics of the 47 patients who had diagnostic index and reference tests are shown in Table 1. Of these, 12 (26%) patients had clinically significant CAD on coronary angiography. All these patients had positive DSCMR scans (sensitivity, 100% [Table 2]). There were 4 further positive DSCMR scans in the absence of angiographically-significant CAD (specificity, 89%; PPV, 75%). Thirty-one participants had negative DSCMR studies, all without angiographically-significant CAD, with no false negatives (NPV, 100%). Fifteen patients (24% of the cohort) did not have a diagnostic DSCMR and were excluded from analyses. Eight patients (13%) were unable to achieve target heart rates despite maximum dobutamine and atropine doses. Five patients (8%) had significant claustrophobia, 1 (2%) patient had severe hypertension, and another had severe dizziness following dobutamine administration. No significant difference was observed between the incidence of significant angiographic CAD between the included diagnostic DSCMR (12/47; 26%)
Table 2. Diagnostic Accuracy of DSCMR (Index Test) Versus Invasive Coronary Angiography (Reference Test)
Positive DSCMR Negative DSCMR
Significant CAD
No Significant CAD
12 0
4 31
Note: Sensitivity, 100% (95% CI, 74%-100%); specificity, 89% (95% CI, 73%-97%); PPV, 75% (95% CI, 48%-93%); NPV, 100% (95% CI, 89%-100%).
Am J Kidney Dis. 2015;65(5):806-809
Correspondence and excluded nondiagnostic DSCMR groups (6/15; 40%): P 5 0.8. Thirty-one of 62 (50%) enrolled patients had diagnostic negative DSCMR scans, with 100% NPV. Hence, we predict that DSCMR in routine pre–kidney transplantation CAD assessment in high-risk asymptomatic patients could obviate the need for invasive angiography in approximately half of patients. It must be acknowledged that a visual estimate of angiographic severity is imprecise.9 Furthermore, a diagnostic study was achieved in only 76% of patients and therefore DSCMR does not provide a noninvasive screening solution for all high-risk candidates. This diagnostic test study to our knowledge is the first to assess the accuracy of diagnostic DSCMR in chronic kidney failure and has demonstrated a high degree of accuracy compared to invasive coronary angiography in potential kidney transplantation candidates. We believe that greater use of DSCMR would reduce the need for invasive coronary angiography in the pretransplantation setting. Benjamin K. Dundon, MBBS,1,2,3 Anthony D. Pisaniello, MBBS1,4 Adam J. Nelson, MBBS,1,2 Murilo Maia, MBBS2 Karen S.L. Teo, MBBS,1,2 Stephen G. Worthley, MBBS1,2,4 Patrick T. Coates, MBBS,1,2 Graeme R. Russ, MBBS1,2 Randall J. Faull, MBBS,1,2 Kym Bannister, MBBS1,2 Matthew I. Worthley, MBBS1,2,4 1 University of Adelaide, Australia 2 Royal Adelaide Hospital, Australia 3 Monash Health, Australia 4 South Australian Health and Medical Research Institute, Australia Corresponding author: [email protected]
Acknowledgements We thank Ms Kerry Williams and Mr Ben Koschade for tireless help and professionalism in undertaking the DSCMR studies. Support: BKD was supported by postgraduate research scholarships from National Health and Medical Research Council/National Heart Foundation of Australia and the Cardiac Society of Australia and New Zealand. MIW is supported by a South Australian Health Practitioner Fellowship. The funders had no role in study design, collection, analysis, and interpretation of data; writing the report; or the decision to submit the report for publication. Financial Disclosure: The authors declare that they have no other relevant financial interests. Contributions: Research idea and study design: MIW, BKD, SGW; data acquisition: BKD, ADP, MM, AJN, KS-LT, SGW; data analysis/interpretation: ADP, MIW, BKD; statistical analysis: ADP, MIW; supervision or mentorship: MIW, SGW; collaboration: PTC, GRR, RJF, KB. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. MIW takes responsibility that this study has been reported honestly,
Am J Kidney Dis. 2015;65(5):806-809
accurately, and transparently; that no important aspects of the study have been omitted, and that any discrepancies from the study as planned have been explained.
Supplementary Material Figure S1: Images from a study patient with inducible ischemia show a typical biphasic response to dobutamine. Note: The supplementary material accompanying this article (http://dx.doi.org/10.1053/j.ajkd.2015.02.319) is available at www.ajkd.org
References 1. Lentine KL, Costa SP, Weir MR, et al. 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;60:434-480. 2. Bart BA, Cen YY, Hendel RC, et al. Comparison of dobutamine stress echocardiography, dobutamine SPECT, and adenosine SPECT myocardial perfusion imaging in patients with end-stage renal disease. J Nucl Cardiol. 2009;16:507-515. 3. Worthley MI, Unger SA, Mathew TH, Russ GR, Horowitz JD. Usefulness of tachycardic-stress perfusion imaging to predict coronary artery disease in high-risk patients with chronic renal failure. Am J Cardiol. 2003;92:1318-1320. 4. Wang LW, Fahim MA, Hayen A, et al. Cardiac testing for coronary artery disease in potential kidney transplant recipients: a systematic review of test accuracy studies. Am J Kidney Dis. 2011;57:476-487. 5. Kelle S, Egnell C, Vierecke J, et al. Prognostic value of negative dobutamine-stress cardiac magnetic resonance imaging. Med Sci Monit. 2009;15:MT131-MT136. 6. Wahl A, Paetsch I, Gollesch A, et al. Safety and feasibility of high-dose dobutamine-atropine stress cardiovascular magnetic resonance for diagnosis of myocardial ischaemia: experience in 1000 consecutive cases. Eur Heart J. 2004;25:1230-1236. 7. Nagel E, Lehmkuhl HB, Bocksch W, et al. Noninvasive diagnosis of ischemia-induced wall motion abnormalities with the use of high-dose dobutamine stress MRI: comparison with dobutamine stress echocardiography. Circulation. 1999;99:763-770. 8. Paetsch I, Jahnke C, Wahl A, et al. Comparison of dobutamine stress magnetic resonance, adenosine stress magnetic resonance, and adenosine stress magnetic resonance perfusion. Circulation. 2004;110:835-842. 9. Fischer JJ, Samady H, McPherson JA, et al. Comparison between visual assessment and quantitative angiography versus fractional flow reserve for native coronary narrowings of moderate severity. Am J Cardiol. 2002;90:210-215. Received February 8, 2015. Accepted in revised form February 10, 2015. Originally published online February 26, 2015. Ó 2015 by the National Kidney Foundation, Inc. http://dx.doi.org/10.1053/j.ajkd.2015.02.319
809
