Risk stratification for renal transplantation: A role for heart rate response?
Risk stratification for renal transplantation: A role for heart rate response?
Matthew Topel 0 1
Leslee J. Shaw 0 1
Joe X. Xie 0
0 Reprint requests: Matthew Topel, MD, Division of Cardiology, Department of Medicine, Emory University School of Medicine , 1462 Clifton Rd. NE, Suite 514, Atlanta , GA 30322; J Nucl Cardiol 1071-3581/$34.00 Copyright 2017 American Society of Nuclear Cardiology
1 Division of Cardiology, Department of Medicine, Emory University School of Medicine , Atlanta, GA , USA
Cardiovascular disease is the leading cause of death
among individuals with end-stage renal disease (ESRD)
and in those who undergo renal transplantation,
accounting for up to 40%-50% of all deaths.1–3 Clinical
risk factors for coronary artery disease (CAD) are more
prevalent in patients with ESRD, and 35%-45% of
patients on dialysis and kidney transplant recipients have
CAD.3,4 Accordingly, the American Heart Association
and American College of Cardiology Foundation (AHA/
ACCF) released a scientific statement in 2012 to define
high-risk clinical features in pre-transplantation patients
and have recommended noninvasive cardiac stress
testing in asymptomatic renal transplant candidates with
three or more risk factors, irrespective of functional
In the general population, noninvasive stress
myocardial perfusion imaging (MPI) is a powerful tool
for risk stratification in patients with an intermediate
pre-test probability of CAD and ischemic heart disease.6
However, its utility in advanced renal disease patients
under consideration for transplantation is less clear.
Small studies have shown that in ESRD patients referred
for kidney transplant, stress MPI has relatively low
sensitivity (67%) and specificity (77%) for detecting
coronary artery disease (C 70% stenosis).7 Diagnostic
challenges with MPI are multifactorial, but likely stem
from several conditions associated with ESRD,
including left ventricular hypertrophy and endothelial
dysfunction, which affect interpretability of perfusion
More recently, several non-perfusion variables
measured during stress MPI have been identified in the
search for added prognostic information, and heart rate
response (HRR) to vasodilator stress has appeared
promising.10 Large retrospective cohorts have shown
that blunted HRR is not only an independent predictor of
cardiovascular events and all-cause mortality, but may
also reclassify up to 20% of individuals when added to
traditional risk factors and MPI results.11,12 The added
prognostic impact of HRR has been reproduced in
patients with ESRD,9 but studies examining the role of
HRR in predicting perioperative or long-term events in
renal transplant patients are lacking.
In this issue of the Journal of Nuclear Cardiology ,
Al Jaroudi and colleagues build upon their previous
findings13 and describe the prognostic utility of blunted
HRR in patients with ESRD undergoing renal
transplantation.14 The authors include 352 consecutive patients
from a single center who received vasodilator stress MPI
during pre-renal transplantation evaluation, of whom 140
(40%) had blunted HRR, defined as a \ 28% change from
baseline to peak heart rate after regadenoson
administration or a \ 20% change after adenosine, based on
previously established cutoffs. Patients were followed for
an average of 3.2 years for the primary endpoint of overall
cardiac death or myocardial infarction (MACE); with
secondary events of MACE within 30 days of surgery
(post-op MACE) and all-cause death. The authors found
that patients with blunted HRR during MPI had an
increased risk of MACE (HR 1.7; CI 1.1-2.6) and post-op
MACE (HR 2.2; CI 1.2-4.0) as compared to those with
normal HRR. This association persisted after adjustment
for AHA/ACCF risk factors,5 gender, baseline heart rate,
summed stress score (SSS), and b-blocker use.
The present study by Al Jaroudi et al. is an
important addition to existing literature and
demonstrates the potential value of this easily acquired
measure, HRR, in improving risk stratification in CKD
and pre-transplant patients, a population for whom many
diagnostic and prognostic challenges exist. Frequently,
patients with advanced renal disease are asymptomatic
despite a high burden of underlying cardiovascular
disease. Conversely, many cardiac symptoms such as
angina or dyspnea lack sensitivity and specificity for
severe CAD in patients with ESRD,15 and general
guidelines for perioperative cardiac risk assessment16 do
not specifically address or account for the complex,
heterogeneous clinical milieu of transplantation
Despite these issues, the prognostic value of MPI in
this patient population appears robust—abnormal
findings on stress MPI are associated with adverse
outcomes.9,17 A recent post-hoc analysis of clinical trial
data showed that an abnormal MPI (SSS C 4) was
associated with a nearly twofold increase in risk for
cardiac death or MI among patients with ESRD,
consistent with several other studies.18–21 Unfortunately,
this report also highlights a significant shortcoming of
MPI in high-risk ESRD patients, as lower risk patients
with a normal MPI still had an approximate 5% annual
rate of cardiovascular death or MI.18 To this end, Al
Jaroudi et al. reported that the association between
blunted HRR and MACE remained significant even in
patients with a normal stress MPI (HR 1.8; CI 1.1-3.0),
as well as in subgroups of patients with few clinical
CAD risk factors. As such, HRR may be a useful adjunct
to the traditional evaluation of CAD risk and MPI
findings by improving discrimination of ESRD patients
at risk for future events following transplantation
irrespective of baseline risk.
Several important questions remain regarding the
use of HRR, and stress MPI in general, when evaluating
pre-renal transplant candidates. Although a blunted
HRR appears to identify higher risk patients with ESRD
who undergo renal transplantation, studies on the benefit
of revascularization prior to renal transplant have not
been promising. For instance, Kim et al., performed
gated SPECT on 215 asymptomatic patients with ESRD
at the time of dialysis initiation. Of the 165 patients
deemed high-risk by clinical risk factors, perfusion
defects were present in nearly half of all patients.
Although ischemia was predictive of adverse
cardiovascular events (HR 2.1; CI 1.1-4.2), high-risk
individuals who were revascularized fared no better than
those who were medically managed (HR 0.6; CI
Similarly, results from multiple large clinical trials
such as COURAGE or BARI-2D have shown no added
benefit of revascularization over medical therapy for
patients in the general population with stable CAD.23,24
Importantly, patients with advanced renal disease,
including renal transplant recipients, were excluded
from these studies. An ancillary study of the ongoing,
multicenter randomized controlled ISCHEMIA
(International Study of Comparative Health Effectiveness
with Medical and Invasive Approaches) trial,
ISCHEMIA-CKD (ClinicalTrials.gov Identifier:
NCT01985360), seeks to provide new insight on this
matter for patients with renal disease. With a target
enrollment of approximately 1,000 patients, the
objective of ISCHEMIA-CKD is to compare an initial
strategy of optimal medial therapy (OMT) vs
revascularization plus OMT among stable patients with at least
moderate ischemia on stress testing and advanced CKD
(eGFR \ 30 or on dialysis) for a primary composite
endpoint of death or nonfatal MI through 4 years of
follow-up. Results from ISCHEMIA-CKD may help
elucidate the role of stress MPI in guiding
revascularization in patients with renal dysfunction. Future studies
will be needed to determine whether the use of HRR can
further discriminate patient subsets that would benefit
Alternatively, perhaps HRR, in combination with
MPI, can also be used to guide post-transplant
management of CAD risk factors. Renal transplant patients
have a high prevalence of cardiovascular risk factors as
up to 90% have hypertension, 70% have dyslipidemia,
and 50% have diabetes.25 In particular, the presence of
diabetes has been strongly associated with risk of
allcause mortality (HR 1.6) and MACE (HR 1.8) in renal
transplant candidates.26,27 Given that cardiac autonomic
dysfunction from poorly-controlled or long-standing
diabetes has been implicated in the pathophysiology of
blunted HRR,28 integrating HRR into the
pre-transplantation evaluation may help identify patients who
may benefit from more aggressive diabetic therapies and
strict glucose control.
Al Jaroudi et al. demonstrated the promise of HRR
for risk stratification in patients with ESRD prior to
renal transplantation; however, several steps remain
before it is established as a critical component of risk
stratification among these high-risk patients. Prospective
validation across several institutions would improve the
generalizability of HRR in this population. Additionally,
definitions of normal and abnormal HRR in the literature
are variable,29 and although these definitions may be
population- and/or vasodilator-specific, future studies
should address this question prior to clinical utilization.
Finally, how can we best integrate the prognostic
information gained from HRR? Can we use HRR to
determine which transplant candidates should undergo
revascularization prior to surgery? Or should we use
HRR to tailor medical therapy and more aggressively
manage comorbid cardiovascular risk factors? These
questions represent the paucity of evidence available on
risk detection and clinical management of ESRD
patients. Given the clinical benefit afforded by kidney
transplantation and the relative scarcity of kidney
donors,3 we look forward to additional studies to expand
the available high quality evidence targeting risk
detection and potential improvement in patient
outcomes based on imaging-guided care.
1. Briggs JD . Causes of death after renal transplantation . Nephrol Dial Transpl 2001 ; 16 : 1545 - 9 .
2. Kasiske BL . Epidemiology of cardiovascular disease after renal transplantation . Transplantation 2001 ; 72 : S5 - 8 .
3. Saran R , Robinson B , Abbott KC , Agodoa LY , Albertus P , Ayanian J , et al. US Renal Data System 2016 annual data report: Epidemiology of kidney disease in the United States . Am J Kidney Dis 2017 ; 69 : A7 - 8 .
4. Cai Q , Mukku VK , Ahmad M. Coronary artery disease in patients with chronic kidney disease: A clinical update . Curr Cardiol Rev 2013 ; 9 : 331 - 9 .
5. Lentine KL , Costa SP , Weir MR , Robb JF , Fleisher LA , Kasiske BL , 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: Endorsed by the American Society of Transplant Surgeons, American Society of Transplantation, and National Kidney Foundation . Circulation 2012 ; 126 : 617 - 63 .
6. Shaw LJ , Hage FG , Berman DS , Hachamovitch R , Iskandrian A . Prognosis in the era of comparative effectiveness research: Where is nuclear cardiology now and where should it be ? J Nucl Cardiol 2012 ; 19 : 1026 - 43 .
7. Wang LW , Fahim MA , Hayen A , Mitchell RL , Baines L , Lord S , et al. Cardiac testing for coronary artery disease in potential kidney transplant recipients . Cochrane Database Syst Rev 2011 ; 12 : CD008691 .
8. Hakeem A , Bhatti S , Chang SM . Screening and risk stratification of coronary artery disease in end-stage renal disease . JACC Cardiovasc Imaging 2014 ; 7 : 715 - 28 .
9. Golzar Y , Doukky R. Stress SPECT myocardial perfusion imaging in end-stage renal disease . Curr Cardiovasc Imaging Rep 2017 . doi: 10 .1007/s12410-017-9409-1.
10. Bajaj NS , Singh S , Farag A , Stephanie EH , Heo J , Iskandrian AE , et al. The prognostic value of non-perfusion variables obtained during vasodilator stress myocardial perfusion imaging . J Nucl Cardiol 2016 ; 23 : 390 - 413 .
11. Hage FG , Dean P , Iqbal F , Heo J , Iskandrian AE . A blunted heart rate response to regadenoson is an independent prognostic indicator in patients undergoing myocardial perfusion imaging . J Nucl Cardiol 2011 ; 18 : 1086 - 94 .
12. Iqbal FM , Al Jaroudi W , Sanam K , Sweeney A , Heo J , Iskandrian AE , et al. Reclassification of cardiovascular risk in patients with normal myocardial perfusion imaging using heart rate response to vasodilator stress . Am J Cardiol 2013 ; 111 : 190 - 5 .
13. AlJaroudi W , Campagnoli T , Fughhi I , Wassouf M , Ali A , Doukky R . Prognostic value of heart rate response during regadenoson stress myocardial perfusion imaging in patients with end stage renal disease . J Nucl Cardiol 2016 ; 23 : 560 - 9 .
14. AlJaroudi W , Anokwute C , Fughhi I , Campagnoli T , Wassouf M , Vij A , et al. The prognostic value of heart rate response during vasodilator stress myocardial perfusion imaging in patients with end-stage renal disease undergoing renal transplantation . J Nucl Cardiol 2017 . doi: 10 .1007/s12350-017-1061-2.
15. Sharma R , Pellerin D , Gaze DC , Gregson H , Streather CP , Collinson PO , et al. Dobutamine stress echocardiography and the resting but not exercise electrocardiograph predict severe coronary artery disease in renal transplant candidates . Nephrol Dial Transpl 2005 ; 20 : 2207 - 14 .
16. Fleisher LA , Fleischmann KE , Auerbach AD , Barnason SA , Beckman JA , Bozkurt B , et al. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines . J Am Coll Cardiol 2014 ; 64 : e77 - 137 .
17. Wang LW , Masson P , Turner RM , Lord SW , Baines LA , Craig JC , et al. Prognostic value of cardiac tests in potential kidney transplant recipients: A systematic review . Transplantation 2015 ; 99 : 731 - 45 .
18. Doukky R , Fughhi I , Campagnoli T , Wassouf M , Ali A . The prognostic value of regadenoson SPECT myocardial perfusion imaging in patients with end-stage renal disease . J Nucl Cardiol 2017 ; 24 : 112 - 8 .
19. Patel AD , Abo-Auda WS , Davis JM , Zoghbi GJ , Deierhoi MH , Heo J , et al. Prognostic value of myocardial perfusion imaging in predicting outcome after renal transplantation . Am J Cardiol 2003 ; 92 : 146 - 51 .
20. Venkataraman R , Hage FG , Dorfman T , Heo J , Aqel RA , de Mattos AM , et al. Role of myocardial perfusion imaging in patients with end-stage renal disease undergoing coronary angiography . Am J Cardiol 2008 ; 102 : 1451 - 6 .
21. Atkinson P , Chiu DY , Sharma R , Kalra PR , Ward C , Foley RN , et al. Predictive value of myocardial and coronary imaging in the long-term outcome of potential renal transplant recipients . Int J Cardiol 2011 ; 146 : 191 - 6 .
22. Kim JK , Kim SG , Kim HJ , Song YR . Cardiac risk assessment by gated single-photon emission computed tomography in asymptomatic end-stage renal disease patients at the start of dialysis . J Nucl Cardiol 2012 ; 19 : 438 - 47 .
23. Boden WE , O'Rourke RA , Teo KK , Hartigan PM , Maron DJ , Kostuk WJ , et al. Optimal medical therapy with or without PCI for stable coronary disease . N Engl J Med 2007 ; 356 : 1503 - 16 .
24. Group TBDS. A randomized trial of therapies for type 2 diabetes and coronary artery disease . N Engl J Med 2009 ; 360 : 2503 - 15 .
25. Neale J , Smith AC . Cardiovascular risk factors following renal transplant . World J Transpl 2015 ; 5 : 183 - 95 .
26. Lim WH , Wong G , Pilmore HL , McDonald SP , Chadban SJ . Long-term outcomes of kidney transplantation in people with type 2 diabetes: A population cohort study . Lancet Diabetes Endocrinol 2017 ; 5 : 26 - 33 .
27. Seoane-Pillado MT , Pita-Fernandez S , Valdes-Canedo F , SeijoBestilleiro R , Pe´rtega-D´ıaz S , Ferna´ ndez-Rivera C , et al. Incidence of cardiovascular events and associated risk factors in kidney transplant patients: A competing risks survival analysis . BMC Cardiovasc Disord 2017 ; 17 : 72 .
28. Bravo PE , Hage FG , Woodham RM , Heo J , Iskandrian AE . Heart rate response to adenosine in patients with diabetes mellitus and normal myocardial perfusion imaging . Am J Cardiol 2008 ; 102 : 1103 - 6 .
29. Andrikopoulou E , Hage FG . Heart rate response to regadenoson: Making the case for its value in clinical practice . J Nucl Cardiol 2016 ; 23 : 575 - 80 .