Even mild reversible myocardial perfusion defects predict mortality in patients evaluated for kidney transplantation

Even mild reversible myocardial perfusion defects predict mortality in patients evaluated for... Abstract Aims The value of single-photon emission tomography (SPECT) in patients with severe chronic kidney disease is controversial, and the implications of SPECT finding with lower level of ischaemia are unknown. We assessed the prognostic value of SPECT in patients evaluated for kidney transplantation. Methods and results Five hundred and forty-eight patients underwent SPECT as a part of routine evaluation for kidney transplantation. During the median follow-up of 43.7 months (IQR 22.4–68.4 months), 112 patients (20.4%) died, 49 of cardiovascular (CV) causes (8.9%). In comparison to those with no perfusion defects, mild perfusion abnormalities (1%–9.9%) had an adjusted Cox hazard ratio (HR) of 1.80 [95% confidence interval (95% CI) 1.02–3.17, P = 0.041] for all-cause mortality, while large perfusion defects (≥10%) demonstrated an HR of 2.20 (95% CI 1.38–3.50, P = 0.001). A competing risk analysis produced a similar prognostic capacity for CV mortality. SPECT also offered incremental prognostic impact with two reclassification methods. Revascularization was performed clearly more often on patients with severely than mildly abnormal or normal SPECT (28.0%, 4.3%, and 1.3%, respectively, P < 0.001). However, revascularization was not linked with better survival. Patients with a normal SPECT received a kidney transplant more often than patients with a mildly or severely abnormal SPECT (50.5%, 36.2%, and 36.6%, respectively, P = 0.010). Conclusion Myocardial ischaemia in SPECT is clearly linked with mortality in patients screened for kidney transplantation. Contrary to populations with coronary artery disease, even a mild perfusion defect in SPECT predicts poor prognosis in this patient population. The finding deserves further attention in forthcoming trials. myocardial perfusion imaging , kidney transplantation , prognosis , SPECT Introduction Evidence for the value of myocardial perfusion imaging with single-photon emission tomography (SPECT) in evaluating the function and viability of the myocardium and the prognosis of ischaemic heart disease is extensive.1,2 SPECT thus plays an important role in the diagnosis and management of coronary artery disease (CAD) in international guidelines, being particularly suitable in the diagnosis of stable CAD as it can reveal defective myocardial perfusion before exercise electrocardiogram (ECG) abnormalities are visible. A normal perfusion scan does not rule out CAD but it makes an occlusion of clinical significance improbable. Renal dysfunction is a major risk factor for CAD, with cardiovascular (CV) deaths constituting a major part of the mortality in patients receiving a kidney transplant.3,4 Therefore, the assessment of CV risk before kidney transplantation is important. Previous findings, mostly based on a small number of patients, concerning the role of SPECT in evaluating the CV risk of these patients are controversial. Some studies have found SPECT inadequate for the diagnosis of CAD5–7 while others have deemed it valuable in predicting the risk of CV morbidity in patients with severe chronic kidney disease (CKD).8–10 Furthermore, very little is known about the possible association between the severity of SPECT-identified ischaemia and mortality in this patient group. The objective of this study was to determine the prognostic value of SPECT in the pre-transplant cardiac evaluation of kidney transplant candidates. Particularly, we investigated how the severity of SPECT finding is linked to all-cause- and CV mortality in these patients. In addition, our secondary objective was to examine whether coronary revascularization affected survival in this patient population. Methods Data collection During the study period (2004–2013), 564 patients with end-stage renal disease were screened with SPECT as a part of a routine pre-transplant cardiac evaluation in Helsinki University Central Hospital. If a patient underwent SPECT more than once, only the most recent SPECT preceding the transplantation was chosen. Sixteen patients were excluded because their perfusion scans were technically insufficient or the finding remained ambiguous. In total, 548 patients constituted the study population. The clinical data were collected from the prospective SPECT registry and from the Finnish Registry for Kidney Diseases, which has an estimated coverage of 97–99% of all patients in renal replacement therapy in Finland. All patients gave their written consent when entering the registry. The study was performed in accordance with the Declaration of Helsinki. We received the appropriate approval needed for the registry study as well as the overall approval from our institution to perform the study. Guidelines for cardiac screening of kidney transplant candidates European renal best practice transplantation guidelines recommend different screening methods for kidney transplant candidates according to their CV risk profile.11 The known CV risk factors are age (>50 years), diabetes, previous CV disease or familial history of CV disease. Non-invasive stress imaging, such as SPECT, is recommended for high-risk patients or those with a positive or inconclusive stress tolerance test. Coronary angiography is only recommended for patients with ischaemic results from non-invasive cardiac investigations.11 The local Helsinki University Central Hospital guidelines, which remained unchanged during the enrolment period for the present analysis, emphasize the role of SPECT in the detection of CAD in patients evaluated for kidney transplantation. If the patient has no risk factors and the ECG, thorax X-ray and echocardiography results are normal, no further cardiac investigations are recommended. Coronary angiography prior to SPECT is performed only on patients with angina pectoris symptoms or previous cardiac events. Therefore, most kidney transplant candidates first undergo an evaluation with SPECT. Follow-up and endpoints Patients were followed until death or the end of the follow-up period on 15 September 2013. The primary endpoint in this study was death with CV mortality as the secondary endpoint. Imaging and stress protocol The stress protocol was performed as a symptom-limited exercise stress test for 59% of the kidney patients. The isotope used for SPECT imaging was thallium in 73% and technetium in 27% of the cases. Patients unable to exercise according to the standard protocol underwent a pharmacologic stress test: adenosine in 17%, dipyridamole in 8% and dobutamine in 7% of the cases. Nine per cent of the patients had a stress test combining exercise and a pharmacological agent. The isotope was administered 1 min before the end of the infusion in the dobutamine protocol, or at the end of the third minute of the infusion in the adenosine and dipyridamole protocols. The isotope was injected 1 min before the end of exercise. The SPECT scans were operated with a Toshiba dual-head gamma camera from 2004 to 2010, after which Siemens C-Clear dual-head gamma camera was employed. A gated scan was performed for 96%, and a non-gated scan for 4% of the patients. Attenuation correction was performed in 12% of the cases. Imaging interpretation The clinical analysis of the SPECT images was performed by an experienced cardiologist. All the abnormal images were further examined by two experienced cardiologists. Images technically inapplicable to quantitative analysis were excluded. For quantitative analysis, the perfusion defect was considered significant if the reduction in regional thallium (or technetium) uptake was >40% in the inferior segment or >30% in any of the other segments.12 The percentage of ischaemic myocardium was obtained by calculating the area of the perfusion defect in the reversibility image by using the ImageJ software (National Institutes of Health, Bethesda, MD, USA). We decided to use the 10%-threshold to separate mild and severe ischaemia because previous studies have suggested that revascularization enhances the survival only in patients with >10% area of ischaemic myocardium in SPECT.13 Since mild defects predicted mortality similarly to severe SPECT findings, we did a subanalysis where we divided the mildly abnormal SPECT findings to minimal (1–4.9%) and moderate (5.0–9.9%). The relative difference between stress and rest images was analysed from the bull’s eye display. Fixed perfusion defects were also documented. Statistical analysis Continuous data were expressed as median with interquartile range (IQR) and categorical data as percentages. The Mann–Whitney U and χ2 tests were used to assess between-group differences in the distributions of continuous and categorical variables, respectively. A Cox regression model was used to evaluate the capacity of the levels of ischaemia in SPECT to predict mortality. Fixed perfusion defects were included in additional models without ischaemic SPECT findings; these were not in the same model due to collinearity. Other covariates included in the analyses were age, sex, the type, and duration of dialysis before SPECT, smoking, angina pectoris, and diabetes. As future kidney transplantation and coronary revascularization based on the ischaemic SPECT findings were potentially major modifiers of the risk, they were included as dummy covariates in additional models. The proportionality assumption was checked for the main analyses based on correlations of survival rankings with Schoenfeld residuals; the covariates fulfilled this criterion. Regarding CV mortality, a competing risk analysis with proportional subdistribution hazards regression was performed. The ability of the SPECT finding to reclassify patients into new risk categories were assessed with continuous net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Statistical analyses were performed with SPSS release 22.0 for Windows (SPSS Inc., Chicago, IL, USA) and R (version 3.1.1, R Foundation for Statistical Computing, Vienna, Austria; packages cmprsk and PredictABEL). All statistical tests used an alpha level of 0.05. Results Baseline characteristics The prevalence of risk factors for CAD was high in the study population (Table 1). During the median follow-up of 43.7 months (IQR 22.4–68.4 months), 112 patients (20.4%) died, 49 of whom of CV causes (8.9%). The surviving patient group more rarely had kidney disease due to diabetes, or anginal symptoms, a previous myocardial infarction or coronary artery bypass grafting (CABG), congestive heart failure, and peripheral arterial disease than those who died (Table 1). The survivors were also less often present smokers or in haemodialysis, and their duration of dialysis before SPECT was shorter. As expected, the surviving population received a kidney transplant more often than the ones who died. A clear majority of SPECT scans, 386 (70.4%) out of 548, were deemed as normal, with 43 (7.8%) minimally, 26 (4.7%) moderately, and 93 (17.0%) severely abnormal perfusion findings. 32.4% of patients with mild reversible ischaemia and 36.6% of patients with severe ischaemia also had a scar in the SPECT imaging. Table 1 Baseline characteristics for all the patients and divided by the survival   All  Dead  Alive  P-value  Age, median (IQR)  58 (49–65)  59.5 (51–66)  57.5 (48–64)  0.056  Male sex  62.6  67.9  61.2  0.197  Diabetic nephropathy  38.3  60.7  32.6  <0.001  BMI, median (IQR)  25.8 (22.7–29.6)  25.6 (22.0–30.0)  25.9 (22.9–29.5)  0.388  Angina pectoris  6.6  15.2  4.4  <0.001  Previous AMI  9.3  19.6  6.2  <0.001  Previous CABG  10.8  20.2  7.9  <0.001  LVH  30.6  27.7  31.5  0.475  Decompensation  2.4  5.2  1.5  0.036  ASO  10.6  22.7  6.6  <0.001  Dyslipidaemia + diet  27.0  12.9  31.2  0.002  Dyslipidaemia + medication  56.9  63.4  55.0  0.135  Previous stroke  8.7  13.1  7.3  0.064  Medication for high blood pressure  89.5  86.8  90.3  0.305  Previous smoker  43.9  52.9  41.2  0.055  Present smoker  17.5  30.4  14.2  <0.001  Haemodialysis  58.2  67.0  56.0  0.035  Creatinine (µmol/L), median (IQR)  617 (488–751)  599.5 (441–703)  632 (499–766)  0.160  Duration of dialysis, median (IQR)  2.6 (0.0–13.8)  5.3 (1.2–29.4)  2.2 (0.0–8.9)  <0.001  SPECT normal (<1%)  70.4  51.8  75.2  <0.001  SPECT minimally abnormal (1–4.9%)  7.8  7.1  8.0  <0.001  SPECT moderately abnormal (5–9.9%)  4.7  8.0  3.9  <0.001  SPECT severely abnormal (>10%)  17.0  33.0  12.8  <0.001  Fixed perfusion defect  11.0  26.5  9.4  <0.001  PCI after SPECT  4.2  10.2  3.6  0.028  CABG after SPECT  2.0  2.0  2.0  0.986  Kidney transplantation  46.4  18.8  53.4  <0.001    All  Dead  Alive  P-value  Age, median (IQR)  58 (49–65)  59.5 (51–66)  57.5 (48–64)  0.056  Male sex  62.6  67.9  61.2  0.197  Diabetic nephropathy  38.3  60.7  32.6  <0.001  BMI, median (IQR)  25.8 (22.7–29.6)  25.6 (22.0–30.0)  25.9 (22.9–29.5)  0.388  Angina pectoris  6.6  15.2  4.4  <0.001  Previous AMI  9.3  19.6  6.2  <0.001  Previous CABG  10.8  20.2  7.9  <0.001  LVH  30.6  27.7  31.5  0.475  Decompensation  2.4  5.2  1.5  0.036  ASO  10.6  22.7  6.6  <0.001  Dyslipidaemia + diet  27.0  12.9  31.2  0.002  Dyslipidaemia + medication  56.9  63.4  55.0  0.135  Previous stroke  8.7  13.1  7.3  0.064  Medication for high blood pressure  89.5  86.8  90.3  0.305  Previous smoker  43.9  52.9  41.2  0.055  Present smoker  17.5  30.4  14.2  <0.001  Haemodialysis  58.2  67.0  56.0  0.035  Creatinine (µmol/L), median (IQR)  617 (488–751)  599.5 (441–703)  632 (499–766)  0.160  Duration of dialysis, median (IQR)  2.6 (0.0–13.8)  5.3 (1.2–29.4)  2.2 (0.0–8.9)  <0.001  SPECT normal (<1%)  70.4  51.8  75.2  <0.001  SPECT minimally abnormal (1–4.9%)  7.8  7.1  8.0  <0.001  SPECT moderately abnormal (5–9.9%)  4.7  8.0  3.9  <0.001  SPECT severely abnormal (>10%)  17.0  33.0  12.8  <0.001  Fixed perfusion defect  11.0  26.5  9.4  <0.001  PCI after SPECT  4.2  10.2  3.6  0.028  CABG after SPECT  2.0  2.0  2.0  0.986  Kidney transplantation  46.4  18.8  53.4  <0.001  The comparison was made between the two survival groups. Values are percentages with the exception of age, BMI, creatinine value, and duration of dialysis. AMI, acute myocardial infarction; ASO, arteriosclerosis obliterans; BMI, body mass index; CABG, coronary artery bypass graft; LVH, left ventricular hypertrophy; PCI, percutaneous coronary intervention; SPECT, single-photon emission tomography. Table 1 Baseline characteristics for all the patients and divided by the survival   All  Dead  Alive  P-value  Age, median (IQR)  58 (49–65)  59.5 (51–66)  57.5 (48–64)  0.056  Male sex  62.6  67.9  61.2  0.197  Diabetic nephropathy  38.3  60.7  32.6  <0.001  BMI, median (IQR)  25.8 (22.7–29.6)  25.6 (22.0–30.0)  25.9 (22.9–29.5)  0.388  Angina pectoris  6.6  15.2  4.4  <0.001  Previous AMI  9.3  19.6  6.2  <0.001  Previous CABG  10.8  20.2  7.9  <0.001  LVH  30.6  27.7  31.5  0.475  Decompensation  2.4  5.2  1.5  0.036  ASO  10.6  22.7  6.6  <0.001  Dyslipidaemia + diet  27.0  12.9  31.2  0.002  Dyslipidaemia + medication  56.9  63.4  55.0  0.135  Previous stroke  8.7  13.1  7.3  0.064  Medication for high blood pressure  89.5  86.8  90.3  0.305  Previous smoker  43.9  52.9  41.2  0.055  Present smoker  17.5  30.4  14.2  <0.001  Haemodialysis  58.2  67.0  56.0  0.035  Creatinine (µmol/L), median (IQR)  617 (488–751)  599.5 (441–703)  632 (499–766)  0.160  Duration of dialysis, median (IQR)  2.6 (0.0–13.8)  5.3 (1.2–29.4)  2.2 (0.0–8.9)  <0.001  SPECT normal (<1%)  70.4  51.8  75.2  <0.001  SPECT minimally abnormal (1–4.9%)  7.8  7.1  8.0  <0.001  SPECT moderately abnormal (5–9.9%)  4.7  8.0  3.9  <0.001  SPECT severely abnormal (>10%)  17.0  33.0  12.8  <0.001  Fixed perfusion defect  11.0  26.5  9.4  <0.001  PCI after SPECT  4.2  10.2  3.6  0.028  CABG after SPECT  2.0  2.0  2.0  0.986  Kidney transplantation  46.4  18.8  53.4  <0.001    All  Dead  Alive  P-value  Age, median (IQR)  58 (49–65)  59.5 (51–66)  57.5 (48–64)  0.056  Male sex  62.6  67.9  61.2  0.197  Diabetic nephropathy  38.3  60.7  32.6  <0.001  BMI, median (IQR)  25.8 (22.7–29.6)  25.6 (22.0–30.0)  25.9 (22.9–29.5)  0.388  Angina pectoris  6.6  15.2  4.4  <0.001  Previous AMI  9.3  19.6  6.2  <0.001  Previous CABG  10.8  20.2  7.9  <0.001  LVH  30.6  27.7  31.5  0.475  Decompensation  2.4  5.2  1.5  0.036  ASO  10.6  22.7  6.6  <0.001  Dyslipidaemia + diet  27.0  12.9  31.2  0.002  Dyslipidaemia + medication  56.9  63.4  55.0  0.135  Previous stroke  8.7  13.1  7.3  0.064  Medication for high blood pressure  89.5  86.8  90.3  0.305  Previous smoker  43.9  52.9  41.2  0.055  Present smoker  17.5  30.4  14.2  <0.001  Haemodialysis  58.2  67.0  56.0  0.035  Creatinine (µmol/L), median (IQR)  617 (488–751)  599.5 (441–703)  632 (499–766)  0.160  Duration of dialysis, median (IQR)  2.6 (0.0–13.8)  5.3 (1.2–29.4)  2.2 (0.0–8.9)  <0.001  SPECT normal (<1%)  70.4  51.8  75.2  <0.001  SPECT minimally abnormal (1–4.9%)  7.8  7.1  8.0  <0.001  SPECT moderately abnormal (5–9.9%)  4.7  8.0  3.9  <0.001  SPECT severely abnormal (>10%)  17.0  33.0  12.8  <0.001  Fixed perfusion defect  11.0  26.5  9.4  <0.001  PCI after SPECT  4.2  10.2  3.6  0.028  CABG after SPECT  2.0  2.0  2.0  0.986  Kidney transplantation  46.4  18.8  53.4  <0.001  The comparison was made between the two survival groups. Values are percentages with the exception of age, BMI, creatinine value, and duration of dialysis. AMI, acute myocardial infarction; ASO, arteriosclerosis obliterans; BMI, body mass index; CABG, coronary artery bypass graft; LVH, left ventricular hypertrophy; PCI, percutaneous coronary intervention; SPECT, single-photon emission tomography. Coronary angiography/revascularization and kidney transplantation Only 112 patients went to angiography after the SPECT imaging. The angiographic finding was abnormal in 53.6% of the cases. The percentage of normal angiographic findings in patients with normal, mild, or severe SPECT images were 74.4, 35.3, and 26.9%, respectively. Patients with normal, mild, or severe SPECT findings had a multivessel disease in 20.9, 41.2, and 48.1% of the cases, respectively. Revascularization, either by percutaneous coronary intervention (PCI) or CABG, was performed infrequently in the whole study population. Patients with severely abnormal SPECT finding underwent revascularization clearly more often than the other patients (Table 2). As many as 254 patients (46.4%) proceeded to kidney transplantation. Patients with a normal SPECT scan were more likely to receive a kidney transplant than others. Table 2 Mortality, revascularizations, and kidney transplantations stratified by the level of ischaemia in SPECT   SPECT finding     Normal (<1.0%)  Mild (1.0–9.9%)  Severe (≥10.0%)  P-value    n = 386  n = 69  n = 93    Death, n (%)  58 (15.0)  17 (24.6)  37 (39.8)  <0.001  CV death, n (%)  22 (5.7)  10 (14.5)  17 (18.3)  <0.001  PCI, n (%)  4 (1.0)  1 (1.4)  18 (19.4)  <0.001  CABG, n (%)  1 (0.3)  2 (2.9)  8 (8.6)  <0.001  Transplantation, n (%)  195 (50.5)  25 (36.2)  34 (36.6)  0.010    SPECT finding     Normal (<1.0%)  Mild (1.0–9.9%)  Severe (≥10.0%)  P-value    n = 386  n = 69  n = 93    Death, n (%)  58 (15.0)  17 (24.6)  37 (39.8)  <0.001  CV death, n (%)  22 (5.7)  10 (14.5)  17 (18.3)  <0.001  PCI, n (%)  4 (1.0)  1 (1.4)  18 (19.4)  <0.001  CABG, n (%)  1 (0.3)  2 (2.9)  8 (8.6)  <0.001  Transplantation, n (%)  195 (50.5)  25 (36.2)  34 (36.6)  0.010  Table 2 Mortality, revascularizations, and kidney transplantations stratified by the level of ischaemia in SPECT   SPECT finding     Normal (<1.0%)  Mild (1.0–9.9%)  Severe (≥10.0%)  P-value    n = 386  n = 69  n = 93    Death, n (%)  58 (15.0)  17 (24.6)  37 (39.8)  <0.001  CV death, n (%)  22 (5.7)  10 (14.5)  17 (18.3)  <0.001  PCI, n (%)  4 (1.0)  1 (1.4)  18 (19.4)  <0.001  CABG, n (%)  1 (0.3)  2 (2.9)  8 (8.6)  <0.001  Transplantation, n (%)  195 (50.5)  25 (36.2)  34 (36.6)  0.010    SPECT finding     Normal (<1.0%)  Mild (1.0–9.9%)  Severe (≥10.0%)  P-value    n = 386  n = 69  n = 93    Death, n (%)  58 (15.0)  17 (24.6)  37 (39.8)  <0.001  CV death, n (%)  22 (5.7)  10 (14.5)  17 (18.3)  <0.001  PCI, n (%)  4 (1.0)  1 (1.4)  18 (19.4)  <0.001  CABG, n (%)  1 (0.3)  2 (2.9)  8 (8.6)  <0.001  Transplantation, n (%)  195 (50.5)  25 (36.2)  34 (36.6)  0.010  Survival analysis Even a mildly (1%–9.9%) abnormal SPECT scan was a clear predictor of both classes of mortality (Table 3 and Figure 1). Other significant covariates linked with a poorer prognosis were age, smoking, and, particularly, diabetes as the cause of kidney disease. Interestingly, sex was not a determinant in the mortality risk. Table 3 Adjusted regression analyses of all-cause (Cox) and CV mortality (competing risk)   All-cause mortality   Cardiovascular mortality     RR  95% CI   P-value  RR  95% CI   P-value      Lower  Upper      Lower  Upper    SPECT mild  1.80  1.02  3.17  0.041  2.65  1.27  5.55  0.010  SPECT severe  2.20  1.38  3.51  <0.001  2.33  1.13  4.81  0.022  Sex  1.33  0.88  2.00  0.179  1.40  2.65  0.74  0.310  Age  1.05  1.03  1.07  <0.001  1.05  1.01  1.80  0.009  Present smoker  3.04  1.95  4.74  <0.001  2.69  1.36  5.32  0.005  Angina pectoris  1.10  0.62  1.96  0.736  1.07  0.43  2.66  0.890  Duration of dialysis  1.00  1.00  1.01  0.167  1.00  1.00  1.01  0.110  Diabetic nephropathy  3.48  2.32  5.22  <0.001  2.91  1.62  5.21  <0.001  Haemodialysis  1.17  0.79  1.75  0.437  1.01  0.57  1.82  0.960    All-cause mortality   Cardiovascular mortality     RR  95% CI   P-value  RR  95% CI   P-value      Lower  Upper      Lower  Upper    SPECT mild  1.80  1.02  3.17  0.041  2.65  1.27  5.55  0.010  SPECT severe  2.20  1.38  3.51  <0.001  2.33  1.13  4.81  0.022  Sex  1.33  0.88  2.00  0.179  1.40  2.65  0.74  0.310  Age  1.05  1.03  1.07  <0.001  1.05  1.01  1.80  0.009  Present smoker  3.04  1.95  4.74  <0.001  2.69  1.36  5.32  0.005  Angina pectoris  1.10  0.62  1.96  0.736  1.07  0.43  2.66  0.890  Duration of dialysis  1.00  1.00  1.01  0.167  1.00  1.00  1.01  0.110  Diabetic nephropathy  3.48  2.32  5.22  <0.001  2.91  1.62  5.21  <0.001  Haemodialysis  1.17  0.79  1.75  0.437  1.01  0.57  1.82  0.960  SPECT mild denotes reversible perfusion defect of 1–9.9% and SPECT severe ≥10.0%. Table 3 Adjusted regression analyses of all-cause (Cox) and CV mortality (competing risk)   All-cause mortality   Cardiovascular mortality     RR  95% CI   P-value  RR  95% CI   P-value      Lower  Upper      Lower  Upper    SPECT mild  1.80  1.02  3.17  0.041  2.65  1.27  5.55  0.010  SPECT severe  2.20  1.38  3.51  <0.001  2.33  1.13  4.81  0.022  Sex  1.33  0.88  2.00  0.179  1.40  2.65  0.74  0.310  Age  1.05  1.03  1.07  <0.001  1.05  1.01  1.80  0.009  Present smoker  3.04  1.95  4.74  <0.001  2.69  1.36  5.32  0.005  Angina pectoris  1.10  0.62  1.96  0.736  1.07  0.43  2.66  0.890  Duration of dialysis  1.00  1.00  1.01  0.167  1.00  1.00  1.01  0.110  Diabetic nephropathy  3.48  2.32  5.22  <0.001  2.91  1.62  5.21  <0.001  Haemodialysis  1.17  0.79  1.75  0.437  1.01  0.57  1.82  0.960    All-cause mortality   Cardiovascular mortality     RR  95% CI   P-value  RR  95% CI   P-value      Lower  Upper      Lower  Upper    SPECT mild  1.80  1.02  3.17  0.041  2.65  1.27  5.55  0.010  SPECT severe  2.20  1.38  3.51  <0.001  2.33  1.13  4.81  0.022  Sex  1.33  0.88  2.00  0.179  1.40  2.65  0.74  0.310  Age  1.05  1.03  1.07  <0.001  1.05  1.01  1.80  0.009  Present smoker  3.04  1.95  4.74  <0.001  2.69  1.36  5.32  0.005  Angina pectoris  1.10  0.62  1.96  0.736  1.07  0.43  2.66  0.890  Duration of dialysis  1.00  1.00  1.01  0.167  1.00  1.00  1.01  0.110  Diabetic nephropathy  3.48  2.32  5.22  <0.001  2.91  1.62  5.21  <0.001  Haemodialysis  1.17  0.79  1.75  0.437  1.01  0.57  1.82  0.960  SPECT mild denotes reversible perfusion defect of 1–9.9% and SPECT severe ≥10.0%. Figure 1 View largeDownload slide Adjusted survival curves (Cox) for all-cause mortality according to the level of ischaemia detected in SPECT. Figure 1 View largeDownload slide Adjusted survival curves (Cox) for all-cause mortality according to the level of ischaemia detected in SPECT. In a subanalysis where the mildly abnormal SPECT findings were divided into minimal (1%–4.9%) and moderate (5.0%–9.9%) findings, a moderately abnormal SPECT scan was a numerically stronger predictor of all-cause and CV mortality [hazard ratio (HR) 3.02, 95% confidence interval (95% CI) 1.47–6.18, P = 0.003 and HR 3.51, 95% CI 1.28–9.61, P = 0.015, respectively] than a minimally (HR 1.22, 95% CI 0.57–2.62, P = 0.61 and HR 2.11, 95% CI 0.88–5.07, P = 0.095, respectively) or severely abnormal SPECT finding (HR 2.18, 95% CI 1.36–3.47, P = 0.001 and HR 2.33, 95% CI 1.13–4.81, P = 0.022, respectively)—when compared with patients with a normal finding in SPECT. Fixed perfusion defects were also linked with both all-cause and CV mortality (HR 1.89, 95% CI 1.16–3.08, P = 0.011 and HR 2.40, 95% CI 1.19–4.86, P = 0.015, respectively). Fixed and reversible perfusion defects were not included in the same model due to collinearity. As the future interventions PCI, CABG, and kidney transplantation are expected modifiers of mortality risk, we constructed regression models with those as additional covariates. Nevertheless, the SPECT finding retained an essentially unchanged prognostic capacity. Reception of the transplant was the strongest predictor of a favourable prognosis. Subsequent PCI was linked with higher mortality (HR 3.28, 95% CI 1.72–6.26, P < 0.001) but not CV death (HR 2.35, 95% CI 0.82–6.75, P = 0.113), while CABG had a neutral effect for both all-cause and CV mortality (HR 1.05, 95% CI 0.31–3.54, P = 0.933 and HR 0.57, 95% CI 0.07–4.45, P = 0.591, respectively). Adding the SPECT finding (no/mild/severe) to the all-cause mortality model with all the other covariates already present offered an incremental prognostic impact with both reclassification methods: NRI 0.133 (95% CI 0.041–0.225), P = 0.005 (Table 4); IDI 0.022 (95% CI 0.006–0.038), P = 0.009. Using the four-stage instead of the three-stage SPECT finding improved the results even slightly more. Similar analyses with CV mortality as the endpoint produced comparable results. Table 4 Reclassification table comparing models without and with the SPECT finding   Model with SPECT finding     Reclassified     Initial model  <10%  10%…<20%  20%…<60%  ≥60%  Increased risk  Decreased risk  Net correctly reclassified  Patients alive at the end of the follow-up        <10%  144  15  0  0  26  45  4.4%   10%…<20%  25  102  10  0         20%…<60%  0  19  113  1        ≥60%  0  0  1  6        Patients dead at the end of the follow-up        <10%  7  2  0  0  17  7  8.9%   10%…<20%  2  13  9  0         20%…<60%  0  4  60  6        ≥60%  0  0  1  8          Model with SPECT finding     Reclassified     Initial model  <10%  10%…<20%  20%…<60%  ≥60%  Increased risk  Decreased risk  Net correctly reclassified  Patients alive at the end of the follow-up        <10%  144  15  0  0  26  45  4.4%   10%…<20%  25  102  10  0         20%…<60%  0  19  113  1        ≥60%  0  0  1  6        Patients dead at the end of the follow-up        <10%  7  2  0  0  17  7  8.9%   10%…<20%  2  13  9  0         20%…<60%  0  4  60  6        ≥60%  0  0  1  8        Table 4 Reclassification table comparing models without and with the SPECT finding   Model with SPECT finding     Reclassified     Initial model  <10%  10%…<20%  20%…<60%  ≥60%  Increased risk  Decreased risk  Net correctly reclassified  Patients alive at the end of the follow-up        <10%  144  15  0  0  26  45  4.4%   10%…<20%  25  102  10  0         20%…<60%  0  19  113  1        ≥60%  0  0  1  6        Patients dead at the end of the follow-up        <10%  7  2  0  0  17  7  8.9%   10%…<20%  2  13  9  0         20%…<60%  0  4  60  6        ≥60%  0  0  1  8          Model with SPECT finding     Reclassified     Initial model  <10%  10%…<20%  20%…<60%  ≥60%  Increased risk  Decreased risk  Net correctly reclassified  Patients alive at the end of the follow-up        <10%  144  15  0  0  26  45  4.4%   10%…<20%  25  102  10  0         20%…<60%  0  19  113  1        ≥60%  0  0  1  6        Patients dead at the end of the follow-up        <10%  7  2  0  0  17  7  8.9%   10%…<20%  2  13  9  0         20%…<60%  0  4  60  6        ≥60%  0  0  1  8        Discussion Ischaemic findings and prognosis The SPECT finding is a robust indicator of prognosis among candidates for kidney transplantation. The result is in line with some of the previous studies. A recent systematic review suggested that SPECT and dobutamine stress echocardiography were at least as good as coronary angiography in predicting CV mortality in kidney transplant candidates (10 studies, 1902 patients) or major adverse CV events (19 studies, 2689 patients). Regarding all-cause mortality (11 studies, 1564 patients), however, coronary angiography seemed more prognostic than SPECT (relative risk ratio 0.69, P = 0.03).14 A decade-old meta-analysis, partly based on the same studies as the review by Wang et al., assessed the prognostic value of SPECT (8 studies including 555 patients) and stress echocardiography in evaluating the risk of CV events in kidney transplant candidates. Abnormal results in these perfusion studies significantly increased the relative risk of myocardial infarction or cardiac death.8 These reviews, however, did not factor in whether the mortality was determined by the severity of ischaemia in SPECT. While most of the relevant studies are clearly small in terms of the number of patients, there are a few exceptions. A study that presented predictors of all-cause mortality in kidney transplant candidates, consisted of a total of 3698 patients, 2207 of whom were screened with SPECT based on risk stratification. Abnormal SPECT (reversible or fixed perfusion defect) was associated with a lower survival rate, with no difference in the predictive value of fixed or reversible perfusion defects. Angiographically diagnosed CAD did not predict mortality.10 Another study reported 962 kidney transplant patients, 749 of whom were initially screened with SPECT. An abnormal SPECT finding (ischaemia, scar, or cardiomyopathy) had a statistically non-significant trend for predicting 5-year mortality when adjusted for baseline characteristics.15 In a recent study with 892 patients evaluated with SPECT before kidney transplantation, an abnormal SPECT finding was associated with an increased risk of CV events or death only in patients with one risk factor (age >50, diabetes, or CV disease). Patients with more risk factors already had a high-CV risk that was not increased by the abnormal SPECT result. Patients with no risk factors had a low mortality and event rate despite the SPECT result.16 According to our local guidelines, patients with very low CV risk were not screened with SPECT and thus not included in the present study. Grades of ischaemia and prognosis Hachamovitch et al.13 have demonstrated in an unselected CAD population that revascularization offers survival benefit over medical therapy for patients with more than 10% of ischaemic myocardium in SPECT. Due to the lack of studies in applicable patient population, the extrapolated result of unselected patients has directed the treatment guidelines for patients with severe CKD as well. Our study is the first to report that even perfusion defects of 5–9.9% are a harbinger of death. A perfusion defect as low as 1.0–4.9% had a tendency for predicting CV mortality. Interestingly, patients with a severely abnormal SPECT scan did not have a poorer mortality prognosis than patients with a moderately abnormal finding. The only prior study regarding the association between the severity of SPECT findings and mortality in kidney transplant candidates had remarkably high cut-off points for the levels of ischaemia. Namely, Venkataraman et al.17 reported a stepwise worsening of the survival curve for mild to moderate (5–20%) and large (>20%) perfusion defects in 150 patients evaluated for kidney transplantation. In patients with various stages of renal function, some studies have reported the incremental prognostic value of the SPECT-diagnosed severity of ischaemia. One study included 7348 patients with renal function varying from normal to severe CKD requiring dialysis, and demonstrated that SPECT summed stress score (SSS) and summed difference score (SDS) added a modest incremental prognostic value for all-cause mortality when adjusted for baseline characteristics, glomerular filtration rate (GFR), and ejection fraction.18 Another study reported 1652 predominantly male (97%) patients with different stages of renal function (CKD defined as GFR < 60 mL min−1 1.73−2). Mildly abnormal (SSS 4–8, which represents 5–10% of ischaemic myocardium13) and moderately to severely abnormal (SSS ≥8) SPECT findings were associated with higher incidence of all-cause- and CV mortality in all degrees of renal function when compared with normal SPECT findings. This trend was even stronger in patients with more severe CKD.19 However, these studies included dispersed populations with patients whose kidney function ranged from normal to severe CKD. The reclassification methods NRI and IDI represent the portion of a population that is accurately reclassified when the new test, such as, SPECT, is applied. In our data, both measures demonstrated positive impact of adding SPECT to the prognostic models. As Table 4 indicates, a net 4.4% of the individuals alive and 8.9% of those dead at the end of the follow-up were correctly reclassified when the clinical model was updated by the addition of the SPECT finding. IDI is somewhat more abstract in the interpretation as it is based on discrimination slopes. In our data, the discrimination slope was 2.2% points higher with than without the SPECT findings. These are quite similar or even higher values published earlier for SPECT among patients with known or suspected CAD.20 To our knowledge reclassification methods have not been previously used to assess the predictive value of SPECT imaging in patients evaluated for kidney transplantation or patients in dialysis. In the present analysis, kidney transplantation was strongly associated with better survival. Forty-five per cent of the entire study population received a kidney transplant. Patients with a normal SPECT finding received a kidney transplant significantly more often than did patients with ischaemic findings. Therefore, cardiac evaluation seems to direct the clinical decision-making of transplantation. Higher transplantation rates probably partly explain the lower mortality in patients with a normal SPECT finding. PCI after SPECT was linked with an even higher risk of all-cause mortality, which is probably confounded by indication. Interestingly, CABG was not associated with worse survival; previous studies have indeed suggested that CABG could offer survival benefit over PCI in patients with severe CKD.21–23 A prospective study evaluating whether SPECT-guided CABG would further improve the prognosis in these patients should be launched. Strengths and limitations Our data contain all the patients who underwent SPECT as a pre-transplant screening test for a kidney transplant during the study period in Helsinki University Central Hospital. Analysing all-cause and CV mortality separately gave more information about the prognosis of this patient group. Importantly, our analyses included reclassification measures, which further strengthen the robustness of the results. However, the number of patients with a mild or moderate perfusion defect was small. In addition, we did not have a control group. Patients with a normal SPECT finding received a kidney transplant more often and this could influence the results. However, we included kidney transplantation as a covariate in the analyses to handle the confounding. Conclusion An ischaemic finding in SPECT is a strong predictor of all-cause- and CV mortality in kidney transplant candidates. Contrary to data from CAD patients, even perfusion defects of <10% are associated with elevated mortality in this patient group. This finding deserves further attention in forthcoming trials. Conflict of interest: None declared. References 1 Brown KA. Prognostic value of thallium-201 myocardial perfusion imaging. A diagnostic tool comes of age. Circulation  1991; 83: 363– 81. Google Scholar CrossRef Search ADS PubMed  2 Underwood SR, Anagnostopoulos C, Cerqueira M, Ell PJ, Flint EJ, Harbinson M et al.   Myocardial perfusion scintigraphy: the evidence. Eur J Nucl Med Mol Imaging  2004; 31: 261– 91. Google Scholar CrossRef Search ADS PubMed  3 Briggs JD. Causes of death after renal transplantation. Nephrol Dial Transplant  2001; 16: 1545– 9. Google Scholar CrossRef Search ADS PubMed  4 Sarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton B, Hamm LL et al.   Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation  2003; 108: 2154– 69. Google Scholar CrossRef Search ADS PubMed  5 Wang LW, Fahim MA, Hayen A, Mitchell RL, Lord SW, Baines LA 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– 87. Google Scholar CrossRef Search ADS PubMed  6 De Lima JJ, Wolff Gowdak LH, de Paula FJ, Ianhez LE, Franchini Ramires JA, Krieger EM. Validation of a strategy to diagnose coronary artery disease and predict cardiac events in high-risk renal transplant candidates. Coron Artery Dis  2010; 21: 164– 7. Google Scholar CrossRef Search ADS PubMed  7 Welsh RC, Cockfield SM, Campbell P, Hervas-Malo M, Gyenes G, Dzavik V. Cardiovascular assessment of diabetic end-stage renal disease patients before renal transplantation. Transplantation  2011; 91: 213– 8. Google Scholar CrossRef Search ADS PubMed  8 Rabbat CG, Treleaven DJ, Russell JD, Ludwin D, Cook DJ. Prognostic value of myocardial perfusion studies in patients with end-stage renal disease assessed for kidney or kidney-pancreas transplantation: a meta-analysis. J Am Soc Nephrol  2003; 14: 431– 9. Google Scholar CrossRef Search ADS PubMed  9 Chew CG, Unger S, Shakib S. Value of myocardial perfusion imaging in renal transplant evaluation. Nephrology  2013; 18: 376– 81. Google Scholar CrossRef Search ADS PubMed  10 Hage FG, Smalheiser S, Zoghbi GJ, Perry GJ, Deierhoi M, Warnock D et al.   Predictors of survival in patients with end-stage renal disease evaluated for kidney transplantation. Am J Cardiol  2007; 100: 1020– 5. Google Scholar CrossRef Search ADS PubMed  11 European Renal Best Practice Transplantation Guideline Development Group. ERBP guideline on the management and evaluation of the kidney donor and recipient. Nephrol Dial Transplant  2013; 2: ii1– 71. 12 Berger BC, Watson DD, Taylor GJ, Craddock GB, Martin RP, Teates CD et al.   Quantitative thallium-201 exercise scintigraphy for detection of coronary artery disease. J Nucl Med  1981; 22: 585– 93. Google Scholar PubMed  13 Hachamovitch R, Hayes SW, Friedman JD, Cohen I, Berman DS. Comparison of the short-term survival benefit associated with revascularization compared with medical therapy in patients with no prior coronary artery disease undergoing stress myocardial perfusion single photon emission computed tomography. Circulation  2003; 107: 2900– 7. Google Scholar CrossRef Search ADS PubMed  14 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. Google Scholar CrossRef Search ADS PubMed  15 Kahn MR, Fallahi A, Kim MC, Esquitin R, Robbins MJ. Coronary artery disease in a large renal transplant population: implications for management. Am J Transplant  2011; 11: 2665– 74. Google Scholar CrossRef Search ADS PubMed  16 Galvao D, Lima JJ, Wolff Gowdak LH, de Paula FJ, Franchini Ramires JA, Bortolotto LA. The role of myocardial scintigraphy in the assessment of cardiovascular risk in patients with end-stage chronic kidney disease on the waiting list for renal transplantation. Nephrol Dial Transplant  2012; 27: 2979– 84. Google Scholar CrossRef Search ADS PubMed  17 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. Google Scholar CrossRef Search ADS PubMed  18 Al-Mallah MH, Hachamovitch R, Dorbala S, Di Carli MF. Incremental prognostic value of myocardial perfusion imaging in patients referred to stress single-photon emission computed tomography with renal dysfunction. Circ Cardiovasc Imaging  2009; 2: 429– 36. Google Scholar CrossRef Search ADS PubMed  19 Hakeem A, Bhatti S, Dillie KS, Cook JR, Samad Z, Roth-Cline MD et al.   Predictive value of myocardial perfusion single-photon emission computed tomography and the impact of renal function on cardiac death. Circulation  2008; 118: 2540– 9. Google Scholar CrossRef Search ADS PubMed  20 Candell-Riera J, Ferreira-Gonzalez I, Marsal JR, Aguade-Bruix S, Cuberas-Borros G, Pujol P et al.   Usefulness of exercise test and myocardial perfusion-gated single photon emission computed tomography to improve the prediction of major events. Circ Cardiovasc Imaging  2013; 6: 531– 41. Google Scholar CrossRef Search ADS PubMed  21 Reddan DN, Szczech LA, Tuttle RH, Shaw LK, Jones RH, Schwab SJ et al.   Chronic kidney disease, mortality, and treatment strategies among patients with clinically significant coronary artery disease. J Am Soc Nephrol  2003; 14: 2373– 80. Google Scholar CrossRef Search ADS PubMed  22 Hemmelgarn BR, Southern D, Culleton BF, Mitchell LB, Knudtson ML, Ghali WA. Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease (APPROACH) Investigators. Survival after coronary revascularization among patients with kidney disease. Circulation  2004; 110: 1890– 5. Google Scholar CrossRef Search ADS PubMed  23 Chang TI, Shilane D, Kazi DS, Montez-Rath ME, Hlatky MA, Winkelmayer WC. Multivessel coronary artery bypass grafting versus percutaneous coronary intervention in ESRD. J Am Soc Nephrol  2012; 23: 2042– 9. Google Scholar CrossRef Search ADS PubMed  Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Heart Journal – Cardiovascular Imaging Oxford University Press

Even mild reversible myocardial perfusion defects predict mortality in patients evaluated for kidney transplantation

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Abstract

Abstract Aims The value of single-photon emission tomography (SPECT) in patients with severe chronic kidney disease is controversial, and the implications of SPECT finding with lower level of ischaemia are unknown. We assessed the prognostic value of SPECT in patients evaluated for kidney transplantation. Methods and results Five hundred and forty-eight patients underwent SPECT as a part of routine evaluation for kidney transplantation. During the median follow-up of 43.7 months (IQR 22.4–68.4 months), 112 patients (20.4%) died, 49 of cardiovascular (CV) causes (8.9%). In comparison to those with no perfusion defects, mild perfusion abnormalities (1%–9.9%) had an adjusted Cox hazard ratio (HR) of 1.80 [95% confidence interval (95% CI) 1.02–3.17, P = 0.041] for all-cause mortality, while large perfusion defects (≥10%) demonstrated an HR of 2.20 (95% CI 1.38–3.50, P = 0.001). A competing risk analysis produced a similar prognostic capacity for CV mortality. SPECT also offered incremental prognostic impact with two reclassification methods. Revascularization was performed clearly more often on patients with severely than mildly abnormal or normal SPECT (28.0%, 4.3%, and 1.3%, respectively, P < 0.001). However, revascularization was not linked with better survival. Patients with a normal SPECT received a kidney transplant more often than patients with a mildly or severely abnormal SPECT (50.5%, 36.2%, and 36.6%, respectively, P = 0.010). Conclusion Myocardial ischaemia in SPECT is clearly linked with mortality in patients screened for kidney transplantation. Contrary to populations with coronary artery disease, even a mild perfusion defect in SPECT predicts poor prognosis in this patient population. The finding deserves further attention in forthcoming trials. myocardial perfusion imaging , kidney transplantation , prognosis , SPECT Introduction Evidence for the value of myocardial perfusion imaging with single-photon emission tomography (SPECT) in evaluating the function and viability of the myocardium and the prognosis of ischaemic heart disease is extensive.1,2 SPECT thus plays an important role in the diagnosis and management of coronary artery disease (CAD) in international guidelines, being particularly suitable in the diagnosis of stable CAD as it can reveal defective myocardial perfusion before exercise electrocardiogram (ECG) abnormalities are visible. A normal perfusion scan does not rule out CAD but it makes an occlusion of clinical significance improbable. Renal dysfunction is a major risk factor for CAD, with cardiovascular (CV) deaths constituting a major part of the mortality in patients receiving a kidney transplant.3,4 Therefore, the assessment of CV risk before kidney transplantation is important. Previous findings, mostly based on a small number of patients, concerning the role of SPECT in evaluating the CV risk of these patients are controversial. Some studies have found SPECT inadequate for the diagnosis of CAD5–7 while others have deemed it valuable in predicting the risk of CV morbidity in patients with severe chronic kidney disease (CKD).8–10 Furthermore, very little is known about the possible association between the severity of SPECT-identified ischaemia and mortality in this patient group. The objective of this study was to determine the prognostic value of SPECT in the pre-transplant cardiac evaluation of kidney transplant candidates. Particularly, we investigated how the severity of SPECT finding is linked to all-cause- and CV mortality in these patients. In addition, our secondary objective was to examine whether coronary revascularization affected survival in this patient population. Methods Data collection During the study period (2004–2013), 564 patients with end-stage renal disease were screened with SPECT as a part of a routine pre-transplant cardiac evaluation in Helsinki University Central Hospital. If a patient underwent SPECT more than once, only the most recent SPECT preceding the transplantation was chosen. Sixteen patients were excluded because their perfusion scans were technically insufficient or the finding remained ambiguous. In total, 548 patients constituted the study population. The clinical data were collected from the prospective SPECT registry and from the Finnish Registry for Kidney Diseases, which has an estimated coverage of 97–99% of all patients in renal replacement therapy in Finland. All patients gave their written consent when entering the registry. The study was performed in accordance with the Declaration of Helsinki. We received the appropriate approval needed for the registry study as well as the overall approval from our institution to perform the study. Guidelines for cardiac screening of kidney transplant candidates European renal best practice transplantation guidelines recommend different screening methods for kidney transplant candidates according to their CV risk profile.11 The known CV risk factors are age (>50 years), diabetes, previous CV disease or familial history of CV disease. Non-invasive stress imaging, such as SPECT, is recommended for high-risk patients or those with a positive or inconclusive stress tolerance test. Coronary angiography is only recommended for patients with ischaemic results from non-invasive cardiac investigations.11 The local Helsinki University Central Hospital guidelines, which remained unchanged during the enrolment period for the present analysis, emphasize the role of SPECT in the detection of CAD in patients evaluated for kidney transplantation. If the patient has no risk factors and the ECG, thorax X-ray and echocardiography results are normal, no further cardiac investigations are recommended. Coronary angiography prior to SPECT is performed only on patients with angina pectoris symptoms or previous cardiac events. Therefore, most kidney transplant candidates first undergo an evaluation with SPECT. Follow-up and endpoints Patients were followed until death or the end of the follow-up period on 15 September 2013. The primary endpoint in this study was death with CV mortality as the secondary endpoint. Imaging and stress protocol The stress protocol was performed as a symptom-limited exercise stress test for 59% of the kidney patients. The isotope used for SPECT imaging was thallium in 73% and technetium in 27% of the cases. Patients unable to exercise according to the standard protocol underwent a pharmacologic stress test: adenosine in 17%, dipyridamole in 8% and dobutamine in 7% of the cases. Nine per cent of the patients had a stress test combining exercise and a pharmacological agent. The isotope was administered 1 min before the end of the infusion in the dobutamine protocol, or at the end of the third minute of the infusion in the adenosine and dipyridamole protocols. The isotope was injected 1 min before the end of exercise. The SPECT scans were operated with a Toshiba dual-head gamma camera from 2004 to 2010, after which Siemens C-Clear dual-head gamma camera was employed. A gated scan was performed for 96%, and a non-gated scan for 4% of the patients. Attenuation correction was performed in 12% of the cases. Imaging interpretation The clinical analysis of the SPECT images was performed by an experienced cardiologist. All the abnormal images were further examined by two experienced cardiologists. Images technically inapplicable to quantitative analysis were excluded. For quantitative analysis, the perfusion defect was considered significant if the reduction in regional thallium (or technetium) uptake was >40% in the inferior segment or >30% in any of the other segments.12 The percentage of ischaemic myocardium was obtained by calculating the area of the perfusion defect in the reversibility image by using the ImageJ software (National Institutes of Health, Bethesda, MD, USA). We decided to use the 10%-threshold to separate mild and severe ischaemia because previous studies have suggested that revascularization enhances the survival only in patients with >10% area of ischaemic myocardium in SPECT.13 Since mild defects predicted mortality similarly to severe SPECT findings, we did a subanalysis where we divided the mildly abnormal SPECT findings to minimal (1–4.9%) and moderate (5.0–9.9%). The relative difference between stress and rest images was analysed from the bull’s eye display. Fixed perfusion defects were also documented. Statistical analysis Continuous data were expressed as median with interquartile range (IQR) and categorical data as percentages. The Mann–Whitney U and χ2 tests were used to assess between-group differences in the distributions of continuous and categorical variables, respectively. A Cox regression model was used to evaluate the capacity of the levels of ischaemia in SPECT to predict mortality. Fixed perfusion defects were included in additional models without ischaemic SPECT findings; these were not in the same model due to collinearity. Other covariates included in the analyses were age, sex, the type, and duration of dialysis before SPECT, smoking, angina pectoris, and diabetes. As future kidney transplantation and coronary revascularization based on the ischaemic SPECT findings were potentially major modifiers of the risk, they were included as dummy covariates in additional models. The proportionality assumption was checked for the main analyses based on correlations of survival rankings with Schoenfeld residuals; the covariates fulfilled this criterion. Regarding CV mortality, a competing risk analysis with proportional subdistribution hazards regression was performed. The ability of the SPECT finding to reclassify patients into new risk categories were assessed with continuous net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Statistical analyses were performed with SPSS release 22.0 for Windows (SPSS Inc., Chicago, IL, USA) and R (version 3.1.1, R Foundation for Statistical Computing, Vienna, Austria; packages cmprsk and PredictABEL). All statistical tests used an alpha level of 0.05. Results Baseline characteristics The prevalence of risk factors for CAD was high in the study population (Table 1). During the median follow-up of 43.7 months (IQR 22.4–68.4 months), 112 patients (20.4%) died, 49 of whom of CV causes (8.9%). The surviving patient group more rarely had kidney disease due to diabetes, or anginal symptoms, a previous myocardial infarction or coronary artery bypass grafting (CABG), congestive heart failure, and peripheral arterial disease than those who died (Table 1). The survivors were also less often present smokers or in haemodialysis, and their duration of dialysis before SPECT was shorter. As expected, the surviving population received a kidney transplant more often than the ones who died. A clear majority of SPECT scans, 386 (70.4%) out of 548, were deemed as normal, with 43 (7.8%) minimally, 26 (4.7%) moderately, and 93 (17.0%) severely abnormal perfusion findings. 32.4% of patients with mild reversible ischaemia and 36.6% of patients with severe ischaemia also had a scar in the SPECT imaging. Table 1 Baseline characteristics for all the patients and divided by the survival   All  Dead  Alive  P-value  Age, median (IQR)  58 (49–65)  59.5 (51–66)  57.5 (48–64)  0.056  Male sex  62.6  67.9  61.2  0.197  Diabetic nephropathy  38.3  60.7  32.6  <0.001  BMI, median (IQR)  25.8 (22.7–29.6)  25.6 (22.0–30.0)  25.9 (22.9–29.5)  0.388  Angina pectoris  6.6  15.2  4.4  <0.001  Previous AMI  9.3  19.6  6.2  <0.001  Previous CABG  10.8  20.2  7.9  <0.001  LVH  30.6  27.7  31.5  0.475  Decompensation  2.4  5.2  1.5  0.036  ASO  10.6  22.7  6.6  <0.001  Dyslipidaemia + diet  27.0  12.9  31.2  0.002  Dyslipidaemia + medication  56.9  63.4  55.0  0.135  Previous stroke  8.7  13.1  7.3  0.064  Medication for high blood pressure  89.5  86.8  90.3  0.305  Previous smoker  43.9  52.9  41.2  0.055  Present smoker  17.5  30.4  14.2  <0.001  Haemodialysis  58.2  67.0  56.0  0.035  Creatinine (µmol/L), median (IQR)  617 (488–751)  599.5 (441–703)  632 (499–766)  0.160  Duration of dialysis, median (IQR)  2.6 (0.0–13.8)  5.3 (1.2–29.4)  2.2 (0.0–8.9)  <0.001  SPECT normal (<1%)  70.4  51.8  75.2  <0.001  SPECT minimally abnormal (1–4.9%)  7.8  7.1  8.0  <0.001  SPECT moderately abnormal (5–9.9%)  4.7  8.0  3.9  <0.001  SPECT severely abnormal (>10%)  17.0  33.0  12.8  <0.001  Fixed perfusion defect  11.0  26.5  9.4  <0.001  PCI after SPECT  4.2  10.2  3.6  0.028  CABG after SPECT  2.0  2.0  2.0  0.986  Kidney transplantation  46.4  18.8  53.4  <0.001    All  Dead  Alive  P-value  Age, median (IQR)  58 (49–65)  59.5 (51–66)  57.5 (48–64)  0.056  Male sex  62.6  67.9  61.2  0.197  Diabetic nephropathy  38.3  60.7  32.6  <0.001  BMI, median (IQR)  25.8 (22.7–29.6)  25.6 (22.0–30.0)  25.9 (22.9–29.5)  0.388  Angina pectoris  6.6  15.2  4.4  <0.001  Previous AMI  9.3  19.6  6.2  <0.001  Previous CABG  10.8  20.2  7.9  <0.001  LVH  30.6  27.7  31.5  0.475  Decompensation  2.4  5.2  1.5  0.036  ASO  10.6  22.7  6.6  <0.001  Dyslipidaemia + diet  27.0  12.9  31.2  0.002  Dyslipidaemia + medication  56.9  63.4  55.0  0.135  Previous stroke  8.7  13.1  7.3  0.064  Medication for high blood pressure  89.5  86.8  90.3  0.305  Previous smoker  43.9  52.9  41.2  0.055  Present smoker  17.5  30.4  14.2  <0.001  Haemodialysis  58.2  67.0  56.0  0.035  Creatinine (µmol/L), median (IQR)  617 (488–751)  599.5 (441–703)  632 (499–766)  0.160  Duration of dialysis, median (IQR)  2.6 (0.0–13.8)  5.3 (1.2–29.4)  2.2 (0.0–8.9)  <0.001  SPECT normal (<1%)  70.4  51.8  75.2  <0.001  SPECT minimally abnormal (1–4.9%)  7.8  7.1  8.0  <0.001  SPECT moderately abnormal (5–9.9%)  4.7  8.0  3.9  <0.001  SPECT severely abnormal (>10%)  17.0  33.0  12.8  <0.001  Fixed perfusion defect  11.0  26.5  9.4  <0.001  PCI after SPECT  4.2  10.2  3.6  0.028  CABG after SPECT  2.0  2.0  2.0  0.986  Kidney transplantation  46.4  18.8  53.4  <0.001  The comparison was made between the two survival groups. Values are percentages with the exception of age, BMI, creatinine value, and duration of dialysis. AMI, acute myocardial infarction; ASO, arteriosclerosis obliterans; BMI, body mass index; CABG, coronary artery bypass graft; LVH, left ventricular hypertrophy; PCI, percutaneous coronary intervention; SPECT, single-photon emission tomography. Table 1 Baseline characteristics for all the patients and divided by the survival   All  Dead  Alive  P-value  Age, median (IQR)  58 (49–65)  59.5 (51–66)  57.5 (48–64)  0.056  Male sex  62.6  67.9  61.2  0.197  Diabetic nephropathy  38.3  60.7  32.6  <0.001  BMI, median (IQR)  25.8 (22.7–29.6)  25.6 (22.0–30.0)  25.9 (22.9–29.5)  0.388  Angina pectoris  6.6  15.2  4.4  <0.001  Previous AMI  9.3  19.6  6.2  <0.001  Previous CABG  10.8  20.2  7.9  <0.001  LVH  30.6  27.7  31.5  0.475  Decompensation  2.4  5.2  1.5  0.036  ASO  10.6  22.7  6.6  <0.001  Dyslipidaemia + diet  27.0  12.9  31.2  0.002  Dyslipidaemia + medication  56.9  63.4  55.0  0.135  Previous stroke  8.7  13.1  7.3  0.064  Medication for high blood pressure  89.5  86.8  90.3  0.305  Previous smoker  43.9  52.9  41.2  0.055  Present smoker  17.5  30.4  14.2  <0.001  Haemodialysis  58.2  67.0  56.0  0.035  Creatinine (µmol/L), median (IQR)  617 (488–751)  599.5 (441–703)  632 (499–766)  0.160  Duration of dialysis, median (IQR)  2.6 (0.0–13.8)  5.3 (1.2–29.4)  2.2 (0.0–8.9)  <0.001  SPECT normal (<1%)  70.4  51.8  75.2  <0.001  SPECT minimally abnormal (1–4.9%)  7.8  7.1  8.0  <0.001  SPECT moderately abnormal (5–9.9%)  4.7  8.0  3.9  <0.001  SPECT severely abnormal (>10%)  17.0  33.0  12.8  <0.001  Fixed perfusion defect  11.0  26.5  9.4  <0.001  PCI after SPECT  4.2  10.2  3.6  0.028  CABG after SPECT  2.0  2.0  2.0  0.986  Kidney transplantation  46.4  18.8  53.4  <0.001    All  Dead  Alive  P-value  Age, median (IQR)  58 (49–65)  59.5 (51–66)  57.5 (48–64)  0.056  Male sex  62.6  67.9  61.2  0.197  Diabetic nephropathy  38.3  60.7  32.6  <0.001  BMI, median (IQR)  25.8 (22.7–29.6)  25.6 (22.0–30.0)  25.9 (22.9–29.5)  0.388  Angina pectoris  6.6  15.2  4.4  <0.001  Previous AMI  9.3  19.6  6.2  <0.001  Previous CABG  10.8  20.2  7.9  <0.001  LVH  30.6  27.7  31.5  0.475  Decompensation  2.4  5.2  1.5  0.036  ASO  10.6  22.7  6.6  <0.001  Dyslipidaemia + diet  27.0  12.9  31.2  0.002  Dyslipidaemia + medication  56.9  63.4  55.0  0.135  Previous stroke  8.7  13.1  7.3  0.064  Medication for high blood pressure  89.5  86.8  90.3  0.305  Previous smoker  43.9  52.9  41.2  0.055  Present smoker  17.5  30.4  14.2  <0.001  Haemodialysis  58.2  67.0  56.0  0.035  Creatinine (µmol/L), median (IQR)  617 (488–751)  599.5 (441–703)  632 (499–766)  0.160  Duration of dialysis, median (IQR)  2.6 (0.0–13.8)  5.3 (1.2–29.4)  2.2 (0.0–8.9)  <0.001  SPECT normal (<1%)  70.4  51.8  75.2  <0.001  SPECT minimally abnormal (1–4.9%)  7.8  7.1  8.0  <0.001  SPECT moderately abnormal (5–9.9%)  4.7  8.0  3.9  <0.001  SPECT severely abnormal (>10%)  17.0  33.0  12.8  <0.001  Fixed perfusion defect  11.0  26.5  9.4  <0.001  PCI after SPECT  4.2  10.2  3.6  0.028  CABG after SPECT  2.0  2.0  2.0  0.986  Kidney transplantation  46.4  18.8  53.4  <0.001  The comparison was made between the two survival groups. Values are percentages with the exception of age, BMI, creatinine value, and duration of dialysis. AMI, acute myocardial infarction; ASO, arteriosclerosis obliterans; BMI, body mass index; CABG, coronary artery bypass graft; LVH, left ventricular hypertrophy; PCI, percutaneous coronary intervention; SPECT, single-photon emission tomography. Coronary angiography/revascularization and kidney transplantation Only 112 patients went to angiography after the SPECT imaging. The angiographic finding was abnormal in 53.6% of the cases. The percentage of normal angiographic findings in patients with normal, mild, or severe SPECT images were 74.4, 35.3, and 26.9%, respectively. Patients with normal, mild, or severe SPECT findings had a multivessel disease in 20.9, 41.2, and 48.1% of the cases, respectively. Revascularization, either by percutaneous coronary intervention (PCI) or CABG, was performed infrequently in the whole study population. Patients with severely abnormal SPECT finding underwent revascularization clearly more often than the other patients (Table 2). As many as 254 patients (46.4%) proceeded to kidney transplantation. Patients with a normal SPECT scan were more likely to receive a kidney transplant than others. Table 2 Mortality, revascularizations, and kidney transplantations stratified by the level of ischaemia in SPECT   SPECT finding     Normal (<1.0%)  Mild (1.0–9.9%)  Severe (≥10.0%)  P-value    n = 386  n = 69  n = 93    Death, n (%)  58 (15.0)  17 (24.6)  37 (39.8)  <0.001  CV death, n (%)  22 (5.7)  10 (14.5)  17 (18.3)  <0.001  PCI, n (%)  4 (1.0)  1 (1.4)  18 (19.4)  <0.001  CABG, n (%)  1 (0.3)  2 (2.9)  8 (8.6)  <0.001  Transplantation, n (%)  195 (50.5)  25 (36.2)  34 (36.6)  0.010    SPECT finding     Normal (<1.0%)  Mild (1.0–9.9%)  Severe (≥10.0%)  P-value    n = 386  n = 69  n = 93    Death, n (%)  58 (15.0)  17 (24.6)  37 (39.8)  <0.001  CV death, n (%)  22 (5.7)  10 (14.5)  17 (18.3)  <0.001  PCI, n (%)  4 (1.0)  1 (1.4)  18 (19.4)  <0.001  CABG, n (%)  1 (0.3)  2 (2.9)  8 (8.6)  <0.001  Transplantation, n (%)  195 (50.5)  25 (36.2)  34 (36.6)  0.010  Table 2 Mortality, revascularizations, and kidney transplantations stratified by the level of ischaemia in SPECT   SPECT finding     Normal (<1.0%)  Mild (1.0–9.9%)  Severe (≥10.0%)  P-value    n = 386  n = 69  n = 93    Death, n (%)  58 (15.0)  17 (24.6)  37 (39.8)  <0.001  CV death, n (%)  22 (5.7)  10 (14.5)  17 (18.3)  <0.001  PCI, n (%)  4 (1.0)  1 (1.4)  18 (19.4)  <0.001  CABG, n (%)  1 (0.3)  2 (2.9)  8 (8.6)  <0.001  Transplantation, n (%)  195 (50.5)  25 (36.2)  34 (36.6)  0.010    SPECT finding     Normal (<1.0%)  Mild (1.0–9.9%)  Severe (≥10.0%)  P-value    n = 386  n = 69  n = 93    Death, n (%)  58 (15.0)  17 (24.6)  37 (39.8)  <0.001  CV death, n (%)  22 (5.7)  10 (14.5)  17 (18.3)  <0.001  PCI, n (%)  4 (1.0)  1 (1.4)  18 (19.4)  <0.001  CABG, n (%)  1 (0.3)  2 (2.9)  8 (8.6)  <0.001  Transplantation, n (%)  195 (50.5)  25 (36.2)  34 (36.6)  0.010  Survival analysis Even a mildly (1%–9.9%) abnormal SPECT scan was a clear predictor of both classes of mortality (Table 3 and Figure 1). Other significant covariates linked with a poorer prognosis were age, smoking, and, particularly, diabetes as the cause of kidney disease. Interestingly, sex was not a determinant in the mortality risk. Table 3 Adjusted regression analyses of all-cause (Cox) and CV mortality (competing risk)   All-cause mortality   Cardiovascular mortality     RR  95% CI   P-value  RR  95% CI   P-value      Lower  Upper      Lower  Upper    SPECT mild  1.80  1.02  3.17  0.041  2.65  1.27  5.55  0.010  SPECT severe  2.20  1.38  3.51  <0.001  2.33  1.13  4.81  0.022  Sex  1.33  0.88  2.00  0.179  1.40  2.65  0.74  0.310  Age  1.05  1.03  1.07  <0.001  1.05  1.01  1.80  0.009  Present smoker  3.04  1.95  4.74  <0.001  2.69  1.36  5.32  0.005  Angina pectoris  1.10  0.62  1.96  0.736  1.07  0.43  2.66  0.890  Duration of dialysis  1.00  1.00  1.01  0.167  1.00  1.00  1.01  0.110  Diabetic nephropathy  3.48  2.32  5.22  <0.001  2.91  1.62  5.21  <0.001  Haemodialysis  1.17  0.79  1.75  0.437  1.01  0.57  1.82  0.960    All-cause mortality   Cardiovascular mortality     RR  95% CI   P-value  RR  95% CI   P-value      Lower  Upper      Lower  Upper    SPECT mild  1.80  1.02  3.17  0.041  2.65  1.27  5.55  0.010  SPECT severe  2.20  1.38  3.51  <0.001  2.33  1.13  4.81  0.022  Sex  1.33  0.88  2.00  0.179  1.40  2.65  0.74  0.310  Age  1.05  1.03  1.07  <0.001  1.05  1.01  1.80  0.009  Present smoker  3.04  1.95  4.74  <0.001  2.69  1.36  5.32  0.005  Angina pectoris  1.10  0.62  1.96  0.736  1.07  0.43  2.66  0.890  Duration of dialysis  1.00  1.00  1.01  0.167  1.00  1.00  1.01  0.110  Diabetic nephropathy  3.48  2.32  5.22  <0.001  2.91  1.62  5.21  <0.001  Haemodialysis  1.17  0.79  1.75  0.437  1.01  0.57  1.82  0.960  SPECT mild denotes reversible perfusion defect of 1–9.9% and SPECT severe ≥10.0%. Table 3 Adjusted regression analyses of all-cause (Cox) and CV mortality (competing risk)   All-cause mortality   Cardiovascular mortality     RR  95% CI   P-value  RR  95% CI   P-value      Lower  Upper      Lower  Upper    SPECT mild  1.80  1.02  3.17  0.041  2.65  1.27  5.55  0.010  SPECT severe  2.20  1.38  3.51  <0.001  2.33  1.13  4.81  0.022  Sex  1.33  0.88  2.00  0.179  1.40  2.65  0.74  0.310  Age  1.05  1.03  1.07  <0.001  1.05  1.01  1.80  0.009  Present smoker  3.04  1.95  4.74  <0.001  2.69  1.36  5.32  0.005  Angina pectoris  1.10  0.62  1.96  0.736  1.07  0.43  2.66  0.890  Duration of dialysis  1.00  1.00  1.01  0.167  1.00  1.00  1.01  0.110  Diabetic nephropathy  3.48  2.32  5.22  <0.001  2.91  1.62  5.21  <0.001  Haemodialysis  1.17  0.79  1.75  0.437  1.01  0.57  1.82  0.960    All-cause mortality   Cardiovascular mortality     RR  95% CI   P-value  RR  95% CI   P-value      Lower  Upper      Lower  Upper    SPECT mild  1.80  1.02  3.17  0.041  2.65  1.27  5.55  0.010  SPECT severe  2.20  1.38  3.51  <0.001  2.33  1.13  4.81  0.022  Sex  1.33  0.88  2.00  0.179  1.40  2.65  0.74  0.310  Age  1.05  1.03  1.07  <0.001  1.05  1.01  1.80  0.009  Present smoker  3.04  1.95  4.74  <0.001  2.69  1.36  5.32  0.005  Angina pectoris  1.10  0.62  1.96  0.736  1.07  0.43  2.66  0.890  Duration of dialysis  1.00  1.00  1.01  0.167  1.00  1.00  1.01  0.110  Diabetic nephropathy  3.48  2.32  5.22  <0.001  2.91  1.62  5.21  <0.001  Haemodialysis  1.17  0.79  1.75  0.437  1.01  0.57  1.82  0.960  SPECT mild denotes reversible perfusion defect of 1–9.9% and SPECT severe ≥10.0%. Figure 1 View largeDownload slide Adjusted survival curves (Cox) for all-cause mortality according to the level of ischaemia detected in SPECT. Figure 1 View largeDownload slide Adjusted survival curves (Cox) for all-cause mortality according to the level of ischaemia detected in SPECT. In a subanalysis where the mildly abnormal SPECT findings were divided into minimal (1%–4.9%) and moderate (5.0%–9.9%) findings, a moderately abnormal SPECT scan was a numerically stronger predictor of all-cause and CV mortality [hazard ratio (HR) 3.02, 95% confidence interval (95% CI) 1.47–6.18, P = 0.003 and HR 3.51, 95% CI 1.28–9.61, P = 0.015, respectively] than a minimally (HR 1.22, 95% CI 0.57–2.62, P = 0.61 and HR 2.11, 95% CI 0.88–5.07, P = 0.095, respectively) or severely abnormal SPECT finding (HR 2.18, 95% CI 1.36–3.47, P = 0.001 and HR 2.33, 95% CI 1.13–4.81, P = 0.022, respectively)—when compared with patients with a normal finding in SPECT. Fixed perfusion defects were also linked with both all-cause and CV mortality (HR 1.89, 95% CI 1.16–3.08, P = 0.011 and HR 2.40, 95% CI 1.19–4.86, P = 0.015, respectively). Fixed and reversible perfusion defects were not included in the same model due to collinearity. As the future interventions PCI, CABG, and kidney transplantation are expected modifiers of mortality risk, we constructed regression models with those as additional covariates. Nevertheless, the SPECT finding retained an essentially unchanged prognostic capacity. Reception of the transplant was the strongest predictor of a favourable prognosis. Subsequent PCI was linked with higher mortality (HR 3.28, 95% CI 1.72–6.26, P < 0.001) but not CV death (HR 2.35, 95% CI 0.82–6.75, P = 0.113), while CABG had a neutral effect for both all-cause and CV mortality (HR 1.05, 95% CI 0.31–3.54, P = 0.933 and HR 0.57, 95% CI 0.07–4.45, P = 0.591, respectively). Adding the SPECT finding (no/mild/severe) to the all-cause mortality model with all the other covariates already present offered an incremental prognostic impact with both reclassification methods: NRI 0.133 (95% CI 0.041–0.225), P = 0.005 (Table 4); IDI 0.022 (95% CI 0.006–0.038), P = 0.009. Using the four-stage instead of the three-stage SPECT finding improved the results even slightly more. Similar analyses with CV mortality as the endpoint produced comparable results. Table 4 Reclassification table comparing models without and with the SPECT finding   Model with SPECT finding     Reclassified     Initial model  <10%  10%…<20%  20%…<60%  ≥60%  Increased risk  Decreased risk  Net correctly reclassified  Patients alive at the end of the follow-up        <10%  144  15  0  0  26  45  4.4%   10%…<20%  25  102  10  0         20%…<60%  0  19  113  1        ≥60%  0  0  1  6        Patients dead at the end of the follow-up        <10%  7  2  0  0  17  7  8.9%   10%…<20%  2  13  9  0         20%…<60%  0  4  60  6        ≥60%  0  0  1  8          Model with SPECT finding     Reclassified     Initial model  <10%  10%…<20%  20%…<60%  ≥60%  Increased risk  Decreased risk  Net correctly reclassified  Patients alive at the end of the follow-up        <10%  144  15  0  0  26  45  4.4%   10%…<20%  25  102  10  0         20%…<60%  0  19  113  1        ≥60%  0  0  1  6        Patients dead at the end of the follow-up        <10%  7  2  0  0  17  7  8.9%   10%…<20%  2  13  9  0         20%…<60%  0  4  60  6        ≥60%  0  0  1  8        Table 4 Reclassification table comparing models without and with the SPECT finding   Model with SPECT finding     Reclassified     Initial model  <10%  10%…<20%  20%…<60%  ≥60%  Increased risk  Decreased risk  Net correctly reclassified  Patients alive at the end of the follow-up        <10%  144  15  0  0  26  45  4.4%   10%…<20%  25  102  10  0         20%…<60%  0  19  113  1        ≥60%  0  0  1  6        Patients dead at the end of the follow-up        <10%  7  2  0  0  17  7  8.9%   10%…<20%  2  13  9  0         20%…<60%  0  4  60  6        ≥60%  0  0  1  8          Model with SPECT finding     Reclassified     Initial model  <10%  10%…<20%  20%…<60%  ≥60%  Increased risk  Decreased risk  Net correctly reclassified  Patients alive at the end of the follow-up        <10%  144  15  0  0  26  45  4.4%   10%…<20%  25  102  10  0         20%…<60%  0  19  113  1        ≥60%  0  0  1  6        Patients dead at the end of the follow-up        <10%  7  2  0  0  17  7  8.9%   10%…<20%  2  13  9  0         20%…<60%  0  4  60  6        ≥60%  0  0  1  8        Discussion Ischaemic findings and prognosis The SPECT finding is a robust indicator of prognosis among candidates for kidney transplantation. The result is in line with some of the previous studies. A recent systematic review suggested that SPECT and dobutamine stress echocardiography were at least as good as coronary angiography in predicting CV mortality in kidney transplant candidates (10 studies, 1902 patients) or major adverse CV events (19 studies, 2689 patients). Regarding all-cause mortality (11 studies, 1564 patients), however, coronary angiography seemed more prognostic than SPECT (relative risk ratio 0.69, P = 0.03).14 A decade-old meta-analysis, partly based on the same studies as the review by Wang et al., assessed the prognostic value of SPECT (8 studies including 555 patients) and stress echocardiography in evaluating the risk of CV events in kidney transplant candidates. Abnormal results in these perfusion studies significantly increased the relative risk of myocardial infarction or cardiac death.8 These reviews, however, did not factor in whether the mortality was determined by the severity of ischaemia in SPECT. While most of the relevant studies are clearly small in terms of the number of patients, there are a few exceptions. A study that presented predictors of all-cause mortality in kidney transplant candidates, consisted of a total of 3698 patients, 2207 of whom were screened with SPECT based on risk stratification. Abnormal SPECT (reversible or fixed perfusion defect) was associated with a lower survival rate, with no difference in the predictive value of fixed or reversible perfusion defects. Angiographically diagnosed CAD did not predict mortality.10 Another study reported 962 kidney transplant patients, 749 of whom were initially screened with SPECT. An abnormal SPECT finding (ischaemia, scar, or cardiomyopathy) had a statistically non-significant trend for predicting 5-year mortality when adjusted for baseline characteristics.15 In a recent study with 892 patients evaluated with SPECT before kidney transplantation, an abnormal SPECT finding was associated with an increased risk of CV events or death only in patients with one risk factor (age >50, diabetes, or CV disease). Patients with more risk factors already had a high-CV risk that was not increased by the abnormal SPECT result. Patients with no risk factors had a low mortality and event rate despite the SPECT result.16 According to our local guidelines, patients with very low CV risk were not screened with SPECT and thus not included in the present study. Grades of ischaemia and prognosis Hachamovitch et al.13 have demonstrated in an unselected CAD population that revascularization offers survival benefit over medical therapy for patients with more than 10% of ischaemic myocardium in SPECT. Due to the lack of studies in applicable patient population, the extrapolated result of unselected patients has directed the treatment guidelines for patients with severe CKD as well. Our study is the first to report that even perfusion defects of 5–9.9% are a harbinger of death. A perfusion defect as low as 1.0–4.9% had a tendency for predicting CV mortality. Interestingly, patients with a severely abnormal SPECT scan did not have a poorer mortality prognosis than patients with a moderately abnormal finding. The only prior study regarding the association between the severity of SPECT findings and mortality in kidney transplant candidates had remarkably high cut-off points for the levels of ischaemia. Namely, Venkataraman et al.17 reported a stepwise worsening of the survival curve for mild to moderate (5–20%) and large (>20%) perfusion defects in 150 patients evaluated for kidney transplantation. In patients with various stages of renal function, some studies have reported the incremental prognostic value of the SPECT-diagnosed severity of ischaemia. One study included 7348 patients with renal function varying from normal to severe CKD requiring dialysis, and demonstrated that SPECT summed stress score (SSS) and summed difference score (SDS) added a modest incremental prognostic value for all-cause mortality when adjusted for baseline characteristics, glomerular filtration rate (GFR), and ejection fraction.18 Another study reported 1652 predominantly male (97%) patients with different stages of renal function (CKD defined as GFR < 60 mL min−1 1.73−2). Mildly abnormal (SSS 4–8, which represents 5–10% of ischaemic myocardium13) and moderately to severely abnormal (SSS ≥8) SPECT findings were associated with higher incidence of all-cause- and CV mortality in all degrees of renal function when compared with normal SPECT findings. This trend was even stronger in patients with more severe CKD.19 However, these studies included dispersed populations with patients whose kidney function ranged from normal to severe CKD. The reclassification methods NRI and IDI represent the portion of a population that is accurately reclassified when the new test, such as, SPECT, is applied. In our data, both measures demonstrated positive impact of adding SPECT to the prognostic models. As Table 4 indicates, a net 4.4% of the individuals alive and 8.9% of those dead at the end of the follow-up were correctly reclassified when the clinical model was updated by the addition of the SPECT finding. IDI is somewhat more abstract in the interpretation as it is based on discrimination slopes. In our data, the discrimination slope was 2.2% points higher with than without the SPECT findings. These are quite similar or even higher values published earlier for SPECT among patients with known or suspected CAD.20 To our knowledge reclassification methods have not been previously used to assess the predictive value of SPECT imaging in patients evaluated for kidney transplantation or patients in dialysis. In the present analysis, kidney transplantation was strongly associated with better survival. Forty-five per cent of the entire study population received a kidney transplant. Patients with a normal SPECT finding received a kidney transplant significantly more often than did patients with ischaemic findings. Therefore, cardiac evaluation seems to direct the clinical decision-making of transplantation. Higher transplantation rates probably partly explain the lower mortality in patients with a normal SPECT finding. PCI after SPECT was linked with an even higher risk of all-cause mortality, which is probably confounded by indication. Interestingly, CABG was not associated with worse survival; previous studies have indeed suggested that CABG could offer survival benefit over PCI in patients with severe CKD.21–23 A prospective study evaluating whether SPECT-guided CABG would further improve the prognosis in these patients should be launched. Strengths and limitations Our data contain all the patients who underwent SPECT as a pre-transplant screening test for a kidney transplant during the study period in Helsinki University Central Hospital. Analysing all-cause and CV mortality separately gave more information about the prognosis of this patient group. Importantly, our analyses included reclassification measures, which further strengthen the robustness of the results. However, the number of patients with a mild or moderate perfusion defect was small. In addition, we did not have a control group. Patients with a normal SPECT finding received a kidney transplant more often and this could influence the results. However, we included kidney transplantation as a covariate in the analyses to handle the confounding. Conclusion An ischaemic finding in SPECT is a strong predictor of all-cause- and CV mortality in kidney transplant candidates. Contrary to data from CAD patients, even perfusion defects of <10% are associated with elevated mortality in this patient group. This finding deserves further attention in forthcoming trials. Conflict of interest: None declared. References 1 Brown KA. Prognostic value of thallium-201 myocardial perfusion imaging. A diagnostic tool comes of age. Circulation  1991; 83: 363– 81. Google Scholar CrossRef Search ADS PubMed  2 Underwood SR, Anagnostopoulos C, Cerqueira M, Ell PJ, Flint EJ, Harbinson M et al.   Myocardial perfusion scintigraphy: the evidence. Eur J Nucl Med Mol Imaging  2004; 31: 261– 91. Google Scholar CrossRef Search ADS PubMed  3 Briggs JD. Causes of death after renal transplantation. Nephrol Dial Transplant  2001; 16: 1545– 9. Google Scholar CrossRef Search ADS PubMed  4 Sarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton B, Hamm LL et al.   Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation  2003; 108: 2154– 69. 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Prognostic value of myocardial perfusion studies in patients with end-stage renal disease assessed for kidney or kidney-pancreas transplantation: a meta-analysis. J Am Soc Nephrol  2003; 14: 431– 9. Google Scholar CrossRef Search ADS PubMed  9 Chew CG, Unger S, Shakib S. Value of myocardial perfusion imaging in renal transplant evaluation. Nephrology  2013; 18: 376– 81. Google Scholar CrossRef Search ADS PubMed  10 Hage FG, Smalheiser S, Zoghbi GJ, Perry GJ, Deierhoi M, Warnock D et al.   Predictors of survival in patients with end-stage renal disease evaluated for kidney transplantation. Am J Cardiol  2007; 100: 1020– 5. Google Scholar CrossRef Search ADS PubMed  11 European Renal Best Practice Transplantation Guideline Development Group. ERBP guideline on the management and evaluation of the kidney donor and recipient. Nephrol Dial Transplant  2013; 2: ii1– 71. 12 Berger BC, Watson DD, Taylor GJ, Craddock GB, Martin RP, Teates CD et al.   Quantitative thallium-201 exercise scintigraphy for detection of coronary artery disease. J Nucl Med  1981; 22: 585– 93. Google Scholar PubMed  13 Hachamovitch R, Hayes SW, Friedman JD, Cohen I, Berman DS. Comparison of the short-term survival benefit associated with revascularization compared with medical therapy in patients with no prior coronary artery disease undergoing stress myocardial perfusion single photon emission computed tomography. Circulation  2003; 107: 2900– 7. Google Scholar CrossRef Search ADS PubMed  14 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. Google Scholar CrossRef Search ADS PubMed  15 Kahn MR, Fallahi A, Kim MC, Esquitin R, Robbins MJ. Coronary artery disease in a large renal transplant population: implications for management. Am J Transplant  2011; 11: 2665– 74. Google Scholar CrossRef Search ADS PubMed  16 Galvao D, Lima JJ, Wolff Gowdak LH, de Paula FJ, Franchini Ramires JA, Bortolotto LA. The role of myocardial scintigraphy in the assessment of cardiovascular risk in patients with end-stage chronic kidney disease on the waiting list for renal transplantation. Nephrol Dial Transplant  2012; 27: 2979– 84. Google Scholar CrossRef Search ADS PubMed  17 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. Google Scholar CrossRef Search ADS PubMed  18 Al-Mallah MH, Hachamovitch R, Dorbala S, Di Carli MF. 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All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.

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European Heart Journal – Cardiovascular ImagingOxford University Press

Published: Aug 4, 2017

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