Patients
This study was approved by the institutional ethics review board (‘medisch ethische toetsingscommissie’ of the University Medical Center Groningen, chaired by professor WA Kamps, protocol number 2008/133, date of approval June 1, 2008). All included patients gave their written informed consent for participation in this study. Patient information was anonymised and de-identified before data analysis.
Between May 2010 and December 2013 a total of 18 consecutive patients (13 males and five females) with stage 5 CKD were prospectively included. Diagnosis of CKD was based on serum levels of creatinine, and subsequent estimated glomerular filtration rate (eGFR), the latter determined by the Modification of Diet in Renal Disease method [12]. Included were patients aged > 18 years who had no history of CAD and were asymptomatic for present CAD, had no history of Parkinson’s disease or dementia with Lewy bodies, were not currently using tricyclic antidepressant agents which could interfere with 123I-labelled meta-iodobenzylguanidine (123I-MIBG) uptake, and were expected to start HD within the next 6 months. All patients underwent laboratory tests at baseline. Electrocardiograms in pre-HD and during chronic HD were retrieved from the digital patient chart.
123I-MIBG scintigraphy for cardiac sympathetic innervation and 99mTc-tetrofosmin scintigraphy for myocardial perfusion imaging were performed before the start of HD and 6 months after the start of HD. Patients who showed CAD in pre-HD were not excluded from the study to investigate the progression of CAD during maintenance HD. All scans were performed on interdialytic days: a non-weekend day before or after an HD day. Consensus reading on myocardial perfusion scans was performed during general patient care board meetings. All scans were reviewed by an experienced nuclear medicine physician (RHJAS, with > 20 years experience), and cardiologist (RAT, with > 20 years experience).
For 123I-MIBG imaging, nine age-matched normal volunteers were scanned, each on one occasion, to collect a healthy control database. All subjects were in good health, i.e. they did not suffer from known (current or previously treated) hypertension, heart disease, diabetes mellitus, or renal impairment and did not use medication.
Haemodialysis
Patients were dialyzed three times per week. All patients were on bicarbonate dialysis with a low-flux polysulfone hollow-fiber dialyser F8 (Fresenius Medical Care, Bad Hamburg, Germany). Blood flow and dialysate flow rates were 250–350 ml/min and 500 ml/min, respectively. Dialysate temperature was 36.0 or 36.5 °C. Dialysate composition was sodium 139 mmol/l, potassium 1.0 or 2.0 mmol/l, calcium 1.5 mmol/l, magnesium 0.5 mmol/l, chloride 108 mmol/l, bicarbonate 34 mmol/l, acetate 3.0 mmol/l and glucose 1.0 g/dl.
123I-MIBG scintigraphy
Scintigraphy was performed after blockade of thyroid uptake of free 123I by iodine-potassium iodide (Lugol’s solution). After a 15-min resting period, subjects were injected with 185 MBq (5 mCi) 123I-MIBG (General Electric Healthcare Medical Diagnostics, Eindhoven, The Netherlands) by an intravenous catheter. At 15 min (early image) and 4 h (late image) after tracer administration, a 10-min static anterior view of the chest was acquired using a Symbia S gamma camera (Siemens Medical System, Knoxville, Tennessee, USA) with a medium-energy low-penetration parallel-hole collimator [13]. A 15% energy window centred on 159 keV, a 256 × 256 matrix size and a 1.45 zoom factor were used. According to guidelines for 123I-MIBG scintigraphy, the use of β-adrenoceptor blocking agents (β-blockers) was not discontinued [13].
For planar images, left ventricle (LV) activity was measured over the raw static image using a region of interest along the contour of the LV. A second region of interest was placed over the upper mediastinum [13]. The heart-to-mediastinum ratio (HMR) was measured three times, and the average of measurements was taken into account. Late HMR < 2.0 was considered as a sign of cardiac sympathetic innervation abnormalities [13]. Data were also compared with our local normal database.
99mTc-tetrofosmin SPECT
Adenosine stress 99mTc-tetrofosmin (250 MBq, 6.8 mCi) and rest 99mTc-tetrofosmin (750 MBq, 20 mCi) electrocardiographically gated single-photon emission computed tomography (SPECT) were performed in consecutive order in a 1-day protocol to analyse myocardial ischaemia. Patients were asked to withdraw caffeine-containing beverages and/or food 24 h before the examination. 99mTc-tetrofosmin SPECT studies were obtained 1 h after tracer administration using a dual-headed gamma camera, equipped with low-energy high-resolution collimators (Symbia T16 gamma camera, Siemens Medical System, Knoxville, Tennessee, USA), electrocardiographic gating, and low-dose computed tomography for attenuation correction. All data from the 99mTc-tetrofosmin SPECT studies were reformatted to obtain short-axis, horizontal and vertical long-axis sections. Data were analyzed and displayed in a 17-segment polar map using the Quantitative Perfusion SPECT application, a commercially available gated cardiac software package developed by the Cedars-Sinai Medical Center (Los Angeles, CA, USA) [14]. Average counts per segment were obtained from the 17 segments and the measured counts were normalized to the segment with the highest average counts.
Statistical analysis
Baseline descriptive statistics are presented as mean ± standard deviation or median (range) for continuous variables and numbers with percentages for categorical variables as required. We evaluated differences between the two study groups using the χ2 test and Fisher exact test for categorical data and the Student t-test and Mann–Whitney U test for continuous data, according to whether data were normally distributed. Furthermore, a two-way ANOVA with Bonferroni correction for multiple comparison was performed to analyse the differences in study groups over time. In all analyses, p < 0.050 was considered statistically significant. Statistical analysis was performed using the SPSS package version 22 (IBM Corp., Armonk, NY, USA).