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Cardiac sympathetic dysautonomia in children with chronic kidney disease
Cardiac sympathetic dysautonomia in children with chronic kidney disease Viviane Parisotto, MD, PhD,a Eleonora Moreira Lima, MD, PhD,b José Maria Penido Silva, MD, PhD,b Marcos Roberto de Sousa, MD, MS,c and Antonio L. Ribeiro, MD, PhDc Background. The pathophysiology of cardiovascular disease (CVD) in chronic kidney disease (CKD) remains uncertain, but autonomic dysfunction seems to be involved. The aim of the study is to investigate the cardiac dysautonomia in uremic pediatric individuals through iodine 123 metaiodobenzylguanidine (MIBG) scintigraphy and heart rate variability (HRV) analysis. Methods and Results. We divided 40 CKD patients (aged 5-21 years) into 4 groups according to the treatment for CKD: conservative (n ⴝ 7), continuous ambulatory peritoneal dialysis (n ⴝ 5), hemodialysis (n ⴝ 13), and kidney transplantation (n ⴝ 15). Planar and tomographic I-123 MIBG images were acquired, and early and late cardiac uptake, cardiac and lung washout, and regional I-123 MIBG uptake were evaluated. Hemodialysis patients showed increased cardiac washout (P ⴝ .002), a heterogeneous pattern of I-123 MIBG distribution (P ⴝ .036), and lower values of the low-frequency (LF) component of HRV (P ⴝ .040). Subjects undergoing continuous ambulatory peritoneal dialysis had reduced lung washout (P ⴝ .030). The cardiac washout correlated positively with parathyroid hormone levels and negatively with creatinine clearance. There was a significant negative association between the LF component and cardiac washout. Conclusions. Uremic cardiac dysautonomia may be characterized by a decreased LF component of HRV, increased I-123 MIBG washout, and a heterogeneous distribution pattern in the left ventricular walls; these abnormalities were not present after kidney transplantation. (J Nucl Cardiol 2008;15:246-54.) Key Words: Chronic kidney disease • cardiac autonomic dysfunction • heart rate variability • iodine 123 metaiodobenzylguanidine • autonomic nervous system Cardiovascular disease (CVD) is a major cause of morbidity and death in patients with chronic kidney disease (CKD).1-3 The pathophysiology of CVD in CKD remains uncertain, but nowadays sympathetic hyperactivity is recognized as an important mechanism involved in humans.4-10 Recent data show that this sympathetic hyperactivity by itself is indeed significant, because it may influence cardiovascular and renal prognosis.4-6,11 From the Services of Nuclear Medicine,a Pediatric Nephrology,b and Cardiology,c Hospital das Clínicas of the Federal University of Minas Gerais, Minas Gerais, Brazil. This study was supported by grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico and Fundação de Amparo à Pesquisa do Estado de Minas Gerais. Received for publication May 28, 2007; final revision accepted Oct 19, 2007. Reprint requests: Viviane Parisotto, MD, PhD, Rua Alameda Serra da Canastra, 284, Nova Lima, 34.000.000, Minas Gerais, Brazil; [email protected]. 1071-3581/$34.00 Copyright © 2008 by the American Society of Nuclear Cardiology. doi:10.1016/j.nuclcard.2008.01.003 246
Several studies have reported a reduction in heart rate variability (HRV) in patients with uremia, and spectral analysis of short-term HRV has suggested that a reduced low-frequency (LF) component may reflect uremic sympathetic abnormality.12,13 Most of these studies have been performed in adults, and data in the pediatric population are scarce.14,15 Indeed, cardiac diseases, due to hypertension, diabetes, and atherosclerosis, are more frequently found in adult CKD patients and may have a role in the pathogenesis of the cardiac dysautonomia observed in these patients. Because young patients usually do not have those complications, the influence of renal dysfunction on cardiac sympathetic innervation may be more accurately studied in the pediatric population. In this study we assessed cardiac sympathetic innervation using iodine 123 metaiodobenzylguanidine (MIBG) imaging and HRV analysis in children with CKD, to evaluate its relationship with renal function and therapy modality. In addition, we assessed whether myocardial I-123 MIBG uptake and washout correlate with HRV.
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METHODS The Committee on Ethics and Research of the Federal University of Minas Gerais approved the protocol of this observational and cross-sectional study, which was conducted at the Pediatric Nephrology Unit of the university-affiliated hospital, in Belo Horizonte, Minas Gerais, Brazil. Informed consent was obtained from each patient. No adverse effects resulting from the diagnostic procedures occurred. The study complies with the Brazilian Health Ministry research guidelines (resolution 196/1996).
Patients The study population consisted of patients ranging in age from 5 to 21 years, who had undergone dialysis or who had undergone kidney transplantation (KTx) at least 4 months previously, with no signs of transplantation rejection, with definite CKD and creatinine clearance of 50 mL/min or less. The underlying cause of uremia included glomerulonephritis, renal tubular dysfunction, and congenital diseases. Exclusion criteria included refusal to be enrolled, diabetes, clinical instability, severe anemia (hemoglobin level ⱕ6 g/dL), and heart disease, including coronary artery disease, heart failure, congenital heart failure, or cardiac arrhythmia, detected on clinical examination or electrocardiography. All patients had a normal left ventricular ejection fraction (LVEF) on echocardiography. The final sample was composed of 40 subjects (median age, 14 years; 62.5% female patients) classified accordingly to treatment modality: conservative (n ⫽ 7), continuous ambulatory peritoneal dialysis (CAPD) (n ⫽ 5), hemodialysis (n ⫽ 13), and KTx (n ⫽ 15). Patients in the KTx group had undergone dialysis before transplantation (at least 4 months before recruitment for the study) and were selected only in the absence of abnormal renal function or complications related to immunosuppressive therapy (eg, diabetes). Of the 40 patients, 35 had systemic hypertension and were using antihypertensive drugs (-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors). The immunosuppressive drugs were maintained.
Procedures All patients underwent the investigative research protocol, which included epidemiologic, clinical, and laboratory data, as well as performance, echocardiography, HRV analysis, myocardial innervation scintigraphy (I-123 MIBG), and myocardial perfusion scintigraphy (technetium 99m tetrofosmin). Hemoglobin, creatinine, and parathyroid hormone (PTH) levels were measured, and creatinine clearance was calculated. LVEF was estimated by echocardiographic study by use of the Simpson rule.16 HRV analysis. We performed a 24-hour ambulatory electrocardiography recording using 3-channel records (Cardios, São Paulo, Brazil) and standard techniques.17 Data were digitized and annotated by use of an automatic arrhythmiadetection algorithm. Beat annotation was revised by visual inspection to detect and correct any errors in QRS labeling.
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Using an HRV program (Spacelabs Burdick, Deerfield, Wis), we calculated the mean 24-hour value of normal R-R intervals (in milliseconds) and 3 time domain measures of HRV: the 24-hour SD of normal R-R intervals (in milliseconds), the 24-hour SD of the 5-minute mean of normal R-R intervals (in milliseconds), and the square root of the mean of the squared differences between adjacent normal R-R intervals (in milliseconds). Spectral analysis of HRV was computed by use of fast Fourier transformation (Burdick HRV software) and was expressed as LF (0.04-0.15 Hz) and high-frequency (0.15-0.40 Hz) components. The LF–to– high-frequency component ratio was also calculated. To minimize nonstationary oscillations of HRV, spectral analysis was performed during sleep, in a 5-minute segment of good quality, and without ectopic beats, close to the lowest heart rate.17 For technical reasons, HRV analysis was not performed in patients in the peritoneal dialysis group. Myocardial innervation scintigraphy (I-123 MIBG). To investigate cardiac autonomic neuropathy in uremic patients, we performed myocardial innervation scintigraphy (I123 MIBG) in all patients after a fasting period. I-123 MIBG was provided by the Institute of Nuclear Energy of the Nuclear Energy Commission of Rio de Janeiro (Instituto de Energia Nuclear da Comissão de Energia Nuclear, Rio de Janeiro, Brazil) and had a specific activity of 27.3 to 212 MBq/mmol (9-60 mCi/mmol). Myocardial images were obtained with a large–field of view, double-head gamma camera (Millennium VG; GE Medical Systems, Milwaukee, Wis) equipped with a low-energy, high-resolution parallel-hole collimator, being interfaced with a dedicated computer system (Entegra; GE Medical Systems). A 20% energy window, centered on the 159-keV photopeak, and a 64 ⫻ 64 matrix were used. After a slow intravenous injection of 74 to 114 MBq I-123 MIBG, early (15 minutes) and late (180 minutes) static acquisitions, at 5 minutes per frame, were performed in the anterior and left oblique anterior views of the chest. After the delay planar image, single photon emission computed tomography (SPECT) was performed with the same equipment and collimator. Sixty projections (40 seconds per frame) were obtained over a 180° arc from the right posterior oblique view, and the images were stored. Transverse slices were reconstructed with a filtered backprojection algorithm, after preprocessing of the projection images with a low-pass filter. Vertical long-axis, short-axis, and horizontal long-axis tomograms were reconstructed from the transverse slices. Myocardial perfusion images were acquired, after injection of 296 MBq Tc-99m tetrofosmin (Myoview; Amersham, Buckinghamshire, England), and 60 projections (20 seconds per frame) were acquired, stored, and processed as recommended by the American Society of Nuclear Cardiology.18 The parameters considered in planar images were early and late cardiac uptake and cardiac and lung washout. A region of interest was drawn over the cardiac region, and other regions of interest were drawn over the upper mediastinum area, middle pulmonary lobe, and hepatic region. The activity ratio of the heart to the mediastinum (early and late uptake) was computed to quantify cardiac I-123 MIBG accumulation. The washout rate (WR) from the myocardial uptake was calculated as
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Table 1. General features of CKD patients according to treatment modality
Group 1 Conservative (n ⴝ 7)
Group 2 CAPD (n ⴝ 5)
Group 3 HD (n ⴝ 13)
Group 4 KTx (n ⴝ 15)
P
Contrasts
14 (12–18)
8.0 (6.0–12)
19 (16–21)
13 (11–14)
⬍.001
C ⫽ KTx ⫽ HD ⬎ CAPD
Age (y) Sex (M/F) Prevalent basic kidney disease RCD (mo) Dialysis (mo) SBP (mmHg) DBP (mmHg) DRUGS (n) Cr (mg/dl)
(0/7) (2/3) (4/9) Congenital diseases Glomerulopathies Glomerulopathies
Hb (G/dL) PTH (pG/dL)
(9/6) Tubulopathies
106 (81–121) — 110 (100–115) 70 (65–75) 1 (0–2) 32 (19–35)
38 (26–53) 38 (26–53) 100 (100–128) 60 (60–79) 2 (0–3) 9.0 (8.5–9.4)
115 (58–135) 52 (17–92) 120 (120–130) 80 (80–90) 1 (0–3) 11.6 (11–12)
83 (60–117) 59 (35–71) 110 (100–110) 66 (40–78) 1 (1–2) 0.8 (0.6–0.8)
.096 .058 .005 .011 .623 ⬍.001
12 (12–13)
11 (11–12)
9.0 (8.0–10)
12 (11–12)
⬍.001
305 (120–433)
341 (279–369)
374 (286–835)
64 (41–97)
.014
C ⫽ KTx ⬍ HD C ⫽ KTx ⬍ HD C ⫽ KTx ⬍ HD ⫽ CAPD C ⫽ KTx ⫽ CAPD ⬎ HD HD ⬎ KTx
RCD D, Renal chronic disease; SBP, systolic blood pressure; DBP, diastolic blood pressure; drugs, number of antihypertensive drugs in use; Cr, creatinine; Hb, hemoglobin; PTH, parathyroid hormone; Group 1, conservative; Group 2: CAPD, continuous ambulatory peritoneal dialysis; Group 3: HD, hemodialysis; Group 4: KTx, kidney transplant.
follows: Washout rate ⫽ (Initial myocardial I-123 MIBG uptake ⫺ Delayed myocardial I-123 MIBG uptake)/Initial I-123 MIBG uptake ⫻ 100.19 The regional I-123 MIBG uptake score was visually determined for each of all 10 myocardial regions (anterior, lateral, inferior, septal, anterolateral, lateroinferior, inferoseptal, anteroseptal, apical, and posterobasal) according to the following 4-point scoring system: 3, markedly reduced; 2, moderately reduced; 1, mildly reduced; and 0, normal.6 Images were not suitable for SPECT analysis in 10 patients, because of intense liver I-123 MIBG activity or abdominal retention (in patients undergoing CAPD). As a consequence, regional I-123 MIBG uptake was assessed only in 30 patients. The regional cardiac uptake (I-123 MIBG) was visually compared with perfusion myocardial images (Tc-99m tetrofosmin) by use of SPECT images (vertical long-axis, short-axis, and horizontal long-axis tomograms). For each segment, the I-123 MIBG image was compared with Tc-99m tetrofosmin patterns and classified as improved, equivalent, or worsened. We did not compare I-123 MIBG/Tc-99m tetrofosmin bull’s-eye images, because of severe interference from liver uptake. All image interpretation was performed by 1 experienced examiner (V.S.P.), who was blinded to clinical information.
Statistical Analysis Descriptive statistics of continuous variables comprised medians and interquartile range. When necessary, mathematical transformation of non-normal or heteroscedastic data was performed to allow subsequent analysis. Comparisons among groups were made by the analysis of variance test, and the
Bonferroni correction was used during multiple comparisons tests. The association between variables was assessed by use of Pearson or Spearman correlation coefficients. P ⬍ .05 was considered significant.
RESULTS The data were analyzed and will be presented via comparisons of patients divided into 4 groups, according to treatment modality: conservative, CAPD, hemodialysis, and KTx. General features of patients from the studied groups are displayed in Table 1. The main cause of chronic kidney disease (CKD) was glomerulonephritis, but congenital disease was prevalent in conservative management patients and renal tubular dysfunction were prevalent in KTx patients. Thirty-five patients were hypertensive, and only five of them had uncontrolled hypertension (⬎percentile 95 [P95]). All of them were taking antihypertensive drugs (-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors), and there was no difference in frequency of medication among groups (P ⫽ .623). The CAPD patients presented with a lower age than the other groups according to the preferential indication for treatment in this age range. These patients had been undergoing dialysis treatment for 38 months (range, 26-53 months), whereas those undergoing hemodialysis had been doing so for 52 months (range, 17-92 months);
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Table 2.
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I-MIBG scintigrams data according to treatment modality
Group 1 Conservative (n ⴝ 7)
Group 2 CAPD (n ⴝ 5)
Group 3 HD (n ⴝ 13)
Group 4 KTx (n ⴝ 15)
Hp/Mp HI/MI
2.2 (1.9–2.3) 2.0 (1.9–2.2)
2.0 (2.0–2.2) 1.9 (1.6–2.0)
2.0 (2.0–2.2) 1.9 (1.8–2.2)
2.0 (1.9–2.2) 2.2 (1.8–2.5)
.654 .227
WR123I-MIBG%
11 (9.0–24)
28 (21–33)
25 (15–27)
12 (6.0–17)
.002
WRp123I-MIBG%
26 (19–38)
16 (8.0–25)
25 (19–28)
28 (22–30)
.030
LVEF%
66 (61–67)
67 (57–80)
61 (51–70)
65 (58–72)
.463
Scintigraphic parameters
P — — G4 ⬍ G3 G1 ⬍ G2 G4 ⬍ G2 G2 ⬍ G1 G2 ⬍ G4 —
Hp/Mp, early 123I-MIBG cardiac uptake; HI/MI, late 123I-MIBG cardiac uptake; WR R123I-MIBG%, 123I-MIBG cardiac washout rate; WRp123IMIBG%, 123I-MIBG pulmonary washout rate; LVEF, left ventricular ejection fraction; Group 1, conservative; Group 2: HD, hemodialysis; Group 3: CAPD, continuous ambulatory peritonealdialysis; Group 4: KTx, kidney transplant.
this was not significantly different from the length of treatment in the KTx group before transplantation, at 59 months (range, 35-71 months) (P ⫽ .058). High levels of systolic blood pressure and PTH were found in hemodialysis patients, who had lower hematocrit levels as well. Early and delayed cardiac uptake estimated by use of the heart-mediastinum ratio by I-123 MIBG planar images was not significantly different among groups (Table 2), but the cardiac washout rate was higher in patients in the hemodialysis group (P ⫽ .002) whereas the lung washout rate was significantly lower in the CAPD patients (P ⫽ .030). Children with CKD, undergoing dialysis, displayed I-123 MIBG kinetic abnormalities despite a normal LVEF. On the other hand, the KTx patients showed a marked improvement in the cardiac I-123 MIBG washout rate as compared with those undergoing hemodialysis, 12% (range, 6%-17%) versus 25% (range, 15%27%) (Figure 1) visualized by planar images (Figure 2), with no change in I-123 MIBG cardiac uptake. A more heterogeneous distribution of I-123 MIBG (score) was found in hemodialysis patients as compared with that in conservative management patients (P ⫽ .037) (Figure 3), and this heterogeneity was characterized by decreased uptake in the inferoapical regions of the left ventricular myocardium (Figure 4). All patients studied showed a low uptake in the septum on the I-123 MIBG images compared with that on Tc-99m tetrofosmin images. The cardiac I-123 MIBG washout rate had a significant positive correlation with PTH levels (correlation Spearman coefficient [rs] ⫽ 0.40, P ⫽ .019) and negative correlation with creatinine clearance (rs ⫽ ⫺0.48, P ⫽ .002) (Figure 5). No significant correlation was observed between the cardiac washout rate and age, gender, or severity of high blood pressure.
Figure 1. I-123 MIBG cardiac washout rate according to treatment modality.
The 24-hour SD of normal R-R intervals, the 24hour SD of the 5-minute mean of normal R-R intervals, the square root of the mean of the squared differences between adjacent normal R-R intervals, and the mean 24-hour value of normal R-R intervals did not significantly differ in the 4 groups, but the LF component was significantly lower in the hemodialysis patients than in the others (P ⫽ .040). On the other hand, no significant improvement was observed after KTx (Table 3). The LF component showed a weak and negative correlation with cardiac MIBG kinetics (r ⫽ ⫺0.36, P ⫽ .034) (Figure 6). Moreover, we could not find a significant correlation between cardiac MIBG uptake and any other HRV indices.
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A WR
123
I = 12%
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B WR
123
I = 45%
Figure 2. Early and late planar images (I-123 MIBG) in patients with normal washout rate (WR) (12%) (A) and abnormal washout rate (45%) (B).
Figure 3. Regional myocardial uptake score (I-123 MIBG) according to therapeutic modality.
DISCUSSION This study showed that the CKD pediatric patients undergoing dialysis had abnormalities in the cardiac autonomic nervous system characterized by the following: (1) a rapid I-123 MIBG cardiac washout rate; (2) a heterogeneous I-123 MIBG distribution in the left ventricular myocardium; (3) a slow I-123 MIBG clearance from the lung, especially those undergoing CAPD; and (4) a decrease in the LF component of HRV analysis (patients undergoing hemodialysis). In addition, patients who underwent KTx recovered the I-123 MIBG cardiac innervation pattern observed in those undergoing conservative treatment, suggesting the reversal of autonomic abnormalities. To our knowledge, this is the first published study that used I-123 MIBG scintigraphy for evaluating the cardiac sympathetic neuropathy in children with CKD in a Western country. At variance with other diseases, in which sympathetic cardiac innervation has been extensively studied by use of I-123 MIBG scintigraphy, only few reports exist on this technique in CKD patients,4-6,20,21 all
Figure 4. Scintigraphic pattern showing heterogeneous distribution of material (I-123 MIBG) through left ventricle walls (bottom rows) as compared with homogeneous pattern found in perfusion images (Tc-99m tetrofosmin) (top rows).
of them in adults and authored by Japanese researchers. Our results are, in general, concordant with those previously published, extending the observations previously reported to a Western pediatric population with CKD. The increased I-123 MIBG cardiac washout rate was previously described by Kurata et al,4 who demonstrated that the I-123 MIBG cardiac washout rate was significantly higher in patients undergoing dialysis (44% ⫾ 23%) than in control subjects (7% ⫾ 11%). Further studies confirmed those findings: Miyanaga et al6 reported values of 43% ⫾ 14% for patients without congestive heart failure, and Kurata et al5 studied 211 patients with CKD and found I-123 MIBG cardiac washout values of 32% ⫾ 23% and, in a subsequent study,21 reported values of 46% ⫾ 21% in CKD patients and 5% ⫾ 8% in control subjects. Unfortunately, those numerical values are not comparable, because each study used a different methodology to estimate the I-123 MIBG cardiac washout rate.22 Several mechanisms have been proposed for increased cardiac I-123 MIBG clearance rates, such as
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Figure 5. Scatter plots of cardiac washout values (WR) (I-123 MIBG) with creatinine clearance (in milliliters per minute) (logarithm-transformed [lnClCr]) (n ⫽ 39; rs ⫽ 0.40; 95% confidence interval ⫽ 0.10 a 0.64; P ⫽ .019) (A) and serum PTH levels (pG/dL) (logarithm-transformed [lnPTH]) H (n ⫽ 40; rs ⫽ ⫺0.48; IC95% ⫽ 0.10 a 0.64; P ⫽ .002) (B).
Table 3. HRV analysis indexes according to treatment modality
Variable SDNN SDANN rMSSD NNm lnHF lnLF lnLF/HF
Group 1 (n ⴝ 7)
Group 3 (n ⴝ 13)
Group 4 (n ⴝ 15)
147.50 (88.00–186.25) 126.00 (78.25–157.50) 47.00 (23.75–65.00) 747.00 (674.00–826.25) 7.38 (6.50–8.09) 7.02 (6.46–7.82) 0.20 (⫺0.83–0.23)
111.00 (90.50–146.50) 94.00 (77.00–135.50) 29.00 (21.00–49.00) 677.00 (627.00–828.50) 5.70 (4.55–7.26) 6.05 (4.67–6.69) ⫺0.14 (⫺1.09–0.53)
97.00 (89.00–129.00) 82.00 (73.00–113.00) 47.00 (21.00–53.00) 669.00 (636.00–742.00) 7.52 (6.39–7.95) 6.03 (5.73–7.45) ⫺0.36 (⫺1.17–0.07)
P .146 .213 .270 .274 .104 .040 .686
G3 ⬍ G1
SDNN, 24-hour standard deviation (SD) of normal RR intervals, in ms; SDANN, 24-hour SD of the 5-min mean of normal RR intervals, in ms; rMSSDI, the square root of the mean of the squared differences between adjacent normal RR intervals, in ms; NNm, mean 24-hour value of normal RR intervals, in ms; LnLF, normal logarithm of low frequency component; LnHF, normal logarithm of high frequency component; LF/HF, normal logarithm of low-to-high frequency component ratio; Group 1, conservative; Group 3: CAPD, continuous ambulatory peritoneal dialysis; Group 4: KTx, kidney transplant.
decreased neuronal uptake of MIBG, rapid MIBG clearance, and increased MIBG release from cardiac sympathetic neurons. A decrease in the neuronal uptake of MIBG is not likely in this case, because extraneuronal uptake is poor in humans and we used low doses of I-123 MIBG with a high specific activity.11,23 A rapid MIBG clearance may be a result of elevated norepinephrine concentrations, a measurement not performed in our study. Nonetheless, very high norepinephrine levels, as observed in pheochromocytoma, are necessary to inhibit the neuronal uptake, a fact that had not been described in CKD.4,5 At variance, strong evidence exists that the activation of efferent sympathetic nerve discharge occurs in patients with CKD undergoing dialysis,4,20,21 suggesting that the increased cardiac sympathetic nerve activity is the most probable mechanism for the rapid MIBG clearance observed in the children studied. Indeed, the increased I-123 MIBG washout rate observed in dialysis patients had a significant positive correlation with PTH
levels and a negative correlation with the creatinine clearance and, thus, parallels renal function deterioration. It should be stressed that the dialysis, by itself, could not be the cause of the increased I-123 MIBG washout rate. Iodine MIBG is a relatively stable radiopharmaceutical that is primarily excreted in the urine, and it is not removed by dialysis, probably because of strong protein binding.24 A slower clearance of radioactivity from the blood would produce a reduced rate of cardiac washout in patients with CKD and dialysis and could not be related to the increased rate observed in our sample. Moreover, we found that the cardiac washout rate increases proportionally with the decrease in creatinine clearance (Figure 5), independently of the therapy modality for the CKD. This study also demonstrated a slow I-123 MIBG washout rate from the lung in the CAPD patients, which is markedly different from those under conservative management. Different reports have suggested that pro-
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Figure 6. Scatter plots of cardiac washout values (WR) (I-123 MIBG) with LF component (lnLF) F (n ⫽ 34; r ⫽ ⫺0.36; 95% confidence level ⫽ ⫺0.63 a ⫺0.03; P ⫽ .034).
longed pulmonary retention of I-123 MIBG may not only be related to pulmonary congestion but is frequently caused by pulmonary endothelial dysfunction or pulmonary sympathetic nervous system overactivity,25-28 although the role of those mechanisms in our CAPD patients was not determined in the study. We observed a heterogeneous I-123 MIBG distribution in the left ventricular myocardium (SPECT images), a phenomenon that was previously reported in CKD5 and in other conditions, such as heart failure.29 There is a marked reduction of uptake in the inferior wall and apex, which is more intense than expected as a result of physiologic variations.19,30 The heterogeneous distribution of myocardial I-123 MIBG uptake may reflect the regional heterogeneity of tissue norepinephrine concentration and sympathetic innervation, which has been reported to be associated with increased sympathetic activity, as in heart failure, and with an increased risk of sudden cardiac death.23,30 Another main finding of the study is the reduction in the LF component of HRV in the frequency domain that was demonstrated in hemodialysis patients. Other HRV indices, more affected by vagal influences, did not differ among groups. A reduction in the HRV indices was demonstrated in CKD patients in earlier reports4-6,21 and might be considered to result from many comorbidities present in CKD patients, such as congestive heart failure, diabetes mellitus, coronary heart disease, and hypertension. In our sample, as well as in some previous studies,6,19,20,31 we excluded patients with heart failure, diabetes mellitus, or coronary heart disease, and HRV reduction could not be ascribed to these conditions. Moreover, hypertension was present in almost all patients and could not be the cause of the
abnormality, which seems to be primarily related to progressive renal dysfunction and, probably, the resultant sympathetic hyperactivity. Although the LF component is frequently reported as a marker of sympathetic activity,17,32 a reduction in the LF component has been described in conditions in which persistent sympathetic activation exists, such as heart failure.33 In severe heart failure, LF components of both electrocardiographic R-R interval and resting muscle sympathetic nerve activity are markedly reduced, suggesting a central autonomic regulatory impairment with important prognostic implications.34 KTx patients have shown a slower I-123 MIBG cardiac washout rate when compared with those undergoing dialysis, although they had been submitted to the same period of dialysis treatment before transplantation. Their I-123 MIBG cardiac washout rate was quite similar to that observed in the conservative patient group, suggesting recovery of autonomic function after KTx. Although Kurata et al21 had previously reported the restoration of normal sympathetic I-123 MIBG patterns after KTx in patients with CKD in 2004, our study is the first to suggest this phenomenon in children. The LF component of HRV did not increase in transplanted children, when compared with those undergoing dialysis. Indeed, they have shown that the improvement in cardiac sympathetic innervation, assessed by myocardial kinetics, may be not be accompanied by HRV changes at the same time, suggesting that the scintigraphy method is either an earlier marker or a more sensitive method to diagnose cardiac autonomic dysfunction.14 All of these findings, obtained by use of both cardiac sympathetic scintigraphy and Holter-derived HRV analysis, point toward a pathophysiologic mechanism com-
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mon to the sympathetic hyperactivity, which could cause the rapid cardiac and slow pulmonary washout rates, the heterogeneous I-123 MIBG distribution in the left ventricular myocardium, and the reduced LF component of HRV variability. In our patients almost all HRV and I-123 MIBG variables had no significant correlation with clinical background such as age, hematocrit level, hemoglobin level, serum electrolyte level, and echocardiographic LVEF. Considering that patients with CVD (including those with asymptomatic depressed LVEF) or diabetes were excluded from the study, the cardiac sympathetic abnormalities could not be attributed to the presence of comorbidities. Indeed, the increased I-123 MIBG washout rate observed in dialysis patients had a significant positive correlation with PTH levels and a negative correlation with creatinine clearance. Moreover, a negative correlation was observed between the LF component of HRV analysis and the I-123 MIBG cardiac washout rate, linking scintigraphic and electrocardiographic phenomena, as previously described by other authors.20 Nonetheless, a perfect correlation between them is not expected, considering that HRV analysis and I-123 MIBG kinetics reflected different aspects of cardiac autonomic control—that is, sympathetic/vagal versus isolated sympathetic, sinus node versus whole left ventricular myocardium, and postsynaptic versus presynaptic events. In fact, these 2 methods seem to be complementary in the evaluation of heart autonomic control. Cardiovascular morbidity and death importantly influence the life expectancy of patients with CKD, and an activated sympathetic nervous system is one of the factors that can adversely affect prognosis independently of its effect on blood pressure.35,36 Indeed, high sympathetic activity has been considered an emerging cardiovascular risk factor in CKD,37 and both MIBG imaging and HRV analysis may have a role in recognizing patients with sympathetic overactivity and a higher risk of cardiovascular complications, an appealing hypothesis that deserves to be tested. Concerning the possibility of clinical use of the MIBG imaging method in young patients with CKD, it is important to stress that the risk related to the radiation exposure in this situation is quite low and comparable to other examinations routinely performed in CKD children. Considering that each patient received 2 to 3 mCi (74-111 MBq), the maximum effective equivalent dose was 1.55 mSv, in the same range of the exposure resulting from intravenous urography (1.58 mSv) and only slight higher than the effective equivalent dose from computed tomography (1.11 mSv). This maximum dose is also proportional to the effective equivalent dose of 5.5 mSv used in adults (with injection of 10 mCi), considering that our patients have a median age of 14 years and
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body surface area of 1.14 m2. It must be stressed that, in children, the calculation of the effective equivalent dose should also consider the tissue immaturity and the greater proximity of the organs, including between the gonads and the target organ. This study has several limitations. We did not access the cardiac presynaptic sympathetic activity using the gold standard method, the measurement of cardiac norepinephrine spillover with norepinephrine labeled to tricio (3H-norepinephrine), because it is not available in our country. Plasma norepinephrine levels were not measured. We did not have a control group, because the use of radioactive material in healthy children is not allowed. Moreover, we could only suggest that cardiac dysautonomia was reversed by renal transplantation, because we did not compare patients studied before and after the procedure. Nonetheless, none of these limitations could jeopardize our main conclusions, and there is robust evidence that cardiac sympathetic abnormalities occur early in CKD, mainly attributed to uremia. Conclusions Children undergoing dialysis displayed many sympathetic abnormalities, including a rapid cardiac I-123 MIBG washout rate, slow pulmonary I-123 MIBG washout rate, heterogeneous I-123 MIBG distribution, and reduced values of the LF component of HRV. These abnormalities, which probably reflected increased sympathetic activity, were detected in the absence of major comorbidities, regardless of the LVEF depression and were related to the severity of renal impairment. In KTx patients cardiac I-123 MIBG washout rate values and regional myocardial uptake scores diminished, paralleling renal function normalization, suggesting that sympathetic functional recovery occurred after KTx. Acknowledgment The authors have indicated they have no financial conflicts of interest.
References 1. Sarnak MJ, Levey AS. Cardiovascular disease and chronic renal disease: a new paradigm. Am J Kidney Dis 2000;35(Suppl 1): S117-31. 2. Kohlhagen J, Kelly J. Prevalence of vascular risk factors and vascular disease in predialysis chronic renal failure. Nephrology (Carlton) 2003;8:274-9. 3. Frankel A, Brown E, Wingfield D. Management of chronic kidney disease. BMJ 2005;330:1039-40. 4. Kurata C, Wakabayashi Y, Shouda S, Okayama K, Yamamoto T, Ishikawa A, et al. Enhanced cardiac clearance of iodine-123-MIBG in chronic renal failure. J Nucl Med 1995;36:2037-43.
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5. Kurata C, Uehara A, Sugi T, Ishikawa A, Fujita K, Yonemura K, et al. Cardiac autonomic neuropathy in patients with chronic renal failure on hemodialysis. Nephron 2000;84:312-9. 6. Miyanaga H, Yoneyama S, Kamitani T, Kawasaki S, Takahashi T, Kunishige H. Abnormal myocardial uptake and clearance of 123I-labeled metaiodobenzylguanidine in patients with chronic renal failure and autonomic dysfunction. J Nucl Cardiol 1996;3(Pt 1):508-15. 7. Kersh ES, Kronfield SJ, Unger A, Popper RW, Cantor S, Cohn K. Autonomic insufficiency in uremia as a cause of hemodialysisinduced hypotension. N Engl J Med 1974;290:650-3. 8. Ewing DJ, Winney R. Autonomic function in patients with chronic renal failure on intermittent haemodialysis. Nephron 1975;15: 424-9. 9. Campese VM, Kogosov E, Koss M. Renal afferent denervation prevents the progression of renal disease in the renal ablation model of chronic renal failure in the rat. Am J Kidney Dis 1995;26:861-5. 10. London GM, Fabiani F, Marchais SJ, De Vernejoul MC, Guerin AP, Safar ME, et al. Uremic cardiomyopathy: an inadequate left ventricular hypertrophy. Kidney Int 1987;31:973-80. 11. Converse RL Jr, Jacobsen TN, Toto RD, Jost CM, Cosentino F, Fouad-Tarazi F, et al. Sympathetic overactivity in patients with chronic renal failure. N Engl J Med 1992;327:1912-8. 12. Cloarec-Blanchard L, Girard A, Houhou S, Grunfeld JP, Elghozi JL. Spectral analysis of short-term blood pressure and heart rate variability in uremic patients. Kidney Int Suppl 1992;37:S14-8. 13. Axelrod S, Lishner M, Oz O, Bernheim J, Ravid M. Spectral analysis of fluctuations in heart rate: an objective evaluation of autonomic nervous control in chronic renal failure. Nephron 1987;45:202-6. 14. Tory K, Sallay P, Toth-Heyn P, Szabo A, Szabo A, Tulassay T, et al. Signs of autonomic neuropathy in childhood uremia. Pediatr Nephrol 2001;16:25-8. 15. Miltenyi G, Tory K, Stubnya G, Toth-Heyn P, Vasarhelyi B, Sallay P, et al. Monitoring cardiovascular changes during hemodialysis in children. Pediatr Nephrol 2001;16:19-24. 16. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr 1989;2:358-67. 17. Crawford MH, Bernstein SJ, Deedwania PC, DiMarco JP, Ferrick KJ, Garson A Jr, et al. ACC/AHA Guidelines for Ambulatory Electrocardiography. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the Guidelines for Ambulatory Electrocardiography). Developed in collaboration with the North American Society for Pacing and Electrophysiology. J Am Coll Cardiol 1999;34:912-48. 18. DePuey EG, Port S, Wackers FJ, Rozanski A, Botvinick EH, Dae MW, et al. Nonperfusion applications in nuclear cardiology: report of a task force of the American Society of Nuclear Cardiology. J Nucl Cardiol 1998;5:218-31. 19. Morozumi T, Kusuoka H, Fukuchi K, Tani A, Uehara T, Matsuda S, et al. Myocardial iodine-123-metaiodobenzylguanidine images and autonomic nerve activity in normal subjects. J Nucl Med 1997;38:49-52.
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20. Kurata C, Shouda S, Mikami T, Wakabayashi Y, Nakano T, Sugiyama T, et al. Comparison of [123I]metaiodobenzylguanidine kinetics with heart rate variability and plasma norepinephrine level. J Nucl Cardiol 1997;4:515-23. 21. Kurata C, Uehara A, Ishikawa A. Improvement of cardiac sympathetic innervation by renal transplantation. J Nucl Med 2004;45: 1114-20. 22. Patel AD, Iskandrian AE. MIBG imaging. J Nucl Cardiol 2002;9: 75-94. 23. Dae MW, De Marco T, Botvinick EH, O’Connell JW, Hattner RS, Huberty JP, et al. Scintigraphic assessment of MIBG uptake in globally denervated human and canine hearts—implications for clinical studies. J Nucl Med 1992;33:1444-50. 24. Tobes MC, Fig LM, Carey J, Geatti O, Sisson JC, Shapiro B. Alterations of iodine-131 MIBG biodistribution in an anephric patient: comparison to normal and impaired renal function. J Nucl Med 1989;30:1476-82. 25. Johnson TS, Young JB, Landsberg L. Norepinephrine turnover in lung: effect of cold exposure and chronic hypoxia. J Appl Physiol 1981;51:614-20. 26. Gillis CN, Pitt BR. The fate of circulating amines within the pulmonary circulation. Annu Rev Physiol 1982;44:269-81. 27. Lee YS. Ultrastructural observations of chronic uremic lungs with special reference to histochemical and X-ray microanalytic studies on altered alveolocapillary basement membranes. Am J Nephrol 1985;5:255-66. 28. Arao T, Takabatake N, Sata M, Abe S, Shibata Y, Honma T, et al. In vivo evidence of endothelial injury in chronic obstructive pulmonary disease by lung scintigraphic assessment of (123)Imetaiodobenzylguanidine. J Nucl Med 2003;44:1747-54. 29. Simmons WW, Freeman MR, Grima EA, Hsia TW, Armstrong PW. Abnormalities of cardiac sympathetic function in pacinginduced heart failure as assessed by [123I]metaiodobenzylguanidine scintigraphy. Circulation 1994;89:2843-51. 30. Gill JS, Hunter GJ, Gane G, Camm AJ. Heterogeneity of the human myocardial sympathetic innervation: in vivo demonstration by iodine 123-labeled meta-iodobenzylguanidine scintigraphy. Am Heart J 1993;126:390-8. 31. Vita G, Bellinghieri G, Trusso A, Costantino G, Santoro D, Monteleone F, et al. Uremic autonomic neuropathy studied by spectral analysis of heart rate. Kidney Int 1999;56:232-7. 32. Lombardi F, Malliani A, Pagani M, Cerutti S. Heart rate variability and its sympatho-vagal modulation. Cardiovasc Res 1996;32: 208-16. 33. Malliani A, Lombardi F, Pagani M. Power spectrum analysis of heart rate variability: a tool to explore neural regulatory mechanisms. Br Heart J 1994;71:1-2. 34. van de Borne P, Montano N, Pagani M, Oren R, Somers VK. Absence of low-frequency variability of sympathetic nerve activity in severe heart failure. Circulation 1997;95:1449-54. 35. Zoccali C, Mallamaci F, Parlongo S, Cutrupi S, Benedetto FA, Tripepi G, et al. Plasma norepinephrine predicts survival and incident cardiovascular events in patients with end-stage renal disease. Circulation 2002;105:1354-9. 36. Neumann J, Ligtenberg G, Klein II, Koomans HA, Blankestijn PJ. Sympathetic hyperactivity in chronic kidney disease: pathogenesis, clinical relevance, and treatment. Kidney Int 2004;65:1568-76. 37. Zoccali C, Mallamaci F, Tripepi G. Traditional and emerging cardiovascular risk factors in end-stage renal disease. Kidney Int Suppl 2003:S105–10.
Several studies have reported a reduction in heart rate variability (HRV) in patients with uremia, and spectral analysis of short-term HRV has suggested that a reduced low-frequency (LF) component may reflect uremic sympathetic abnormality.12,13 Most of these studies have been performed in adults, and data in the pediatric population are scarce.14,15 Indeed, cardiac diseases, due to hypertension, diabetes, and atherosclerosis, are more frequently found in adult CKD patients and may have a role in the pathogenesis of the cardiac dysautonomia observed in these patients. Because young patients usually do not have those complications, the influence of renal dysfunction on cardiac sympathetic innervation may be more accurately studied in the pediatric population. In this study we assessed cardiac sympathetic innervation using iodine 123 metaiodobenzylguanidine (MIBG) imaging and HRV analysis in children with CKD, to evaluate its relationship with renal function and therapy modality. In addition, we assessed whether myocardial I-123 MIBG uptake and washout correlate with HRV.
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METHODS The Committee on Ethics and Research of the Federal University of Minas Gerais approved the protocol of this observational and cross-sectional study, which was conducted at the Pediatric Nephrology Unit of the university-affiliated hospital, in Belo Horizonte, Minas Gerais, Brazil. Informed consent was obtained from each patient. No adverse effects resulting from the diagnostic procedures occurred. The study complies with the Brazilian Health Ministry research guidelines (resolution 196/1996).
Patients The study population consisted of patients ranging in age from 5 to 21 years, who had undergone dialysis or who had undergone kidney transplantation (KTx) at least 4 months previously, with no signs of transplantation rejection, with definite CKD and creatinine clearance of 50 mL/min or less. The underlying cause of uremia included glomerulonephritis, renal tubular dysfunction, and congenital diseases. Exclusion criteria included refusal to be enrolled, diabetes, clinical instability, severe anemia (hemoglobin level ⱕ6 g/dL), and heart disease, including coronary artery disease, heart failure, congenital heart failure, or cardiac arrhythmia, detected on clinical examination or electrocardiography. All patients had a normal left ventricular ejection fraction (LVEF) on echocardiography. The final sample was composed of 40 subjects (median age, 14 years; 62.5% female patients) classified accordingly to treatment modality: conservative (n ⫽ 7), continuous ambulatory peritoneal dialysis (CAPD) (n ⫽ 5), hemodialysis (n ⫽ 13), and KTx (n ⫽ 15). Patients in the KTx group had undergone dialysis before transplantation (at least 4 months before recruitment for the study) and were selected only in the absence of abnormal renal function or complications related to immunosuppressive therapy (eg, diabetes). Of the 40 patients, 35 had systemic hypertension and were using antihypertensive drugs (-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors). The immunosuppressive drugs were maintained.
Procedures All patients underwent the investigative research protocol, which included epidemiologic, clinical, and laboratory data, as well as performance, echocardiography, HRV analysis, myocardial innervation scintigraphy (I-123 MIBG), and myocardial perfusion scintigraphy (technetium 99m tetrofosmin). Hemoglobin, creatinine, and parathyroid hormone (PTH) levels were measured, and creatinine clearance was calculated. LVEF was estimated by echocardiographic study by use of the Simpson rule.16 HRV analysis. We performed a 24-hour ambulatory electrocardiography recording using 3-channel records (Cardios, São Paulo, Brazil) and standard techniques.17 Data were digitized and annotated by use of an automatic arrhythmiadetection algorithm. Beat annotation was revised by visual inspection to detect and correct any errors in QRS labeling.
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Using an HRV program (Spacelabs Burdick, Deerfield, Wis), we calculated the mean 24-hour value of normal R-R intervals (in milliseconds) and 3 time domain measures of HRV: the 24-hour SD of normal R-R intervals (in milliseconds), the 24-hour SD of the 5-minute mean of normal R-R intervals (in milliseconds), and the square root of the mean of the squared differences between adjacent normal R-R intervals (in milliseconds). Spectral analysis of HRV was computed by use of fast Fourier transformation (Burdick HRV software) and was expressed as LF (0.04-0.15 Hz) and high-frequency (0.15-0.40 Hz) components. The LF–to– high-frequency component ratio was also calculated. To minimize nonstationary oscillations of HRV, spectral analysis was performed during sleep, in a 5-minute segment of good quality, and without ectopic beats, close to the lowest heart rate.17 For technical reasons, HRV analysis was not performed in patients in the peritoneal dialysis group. Myocardial innervation scintigraphy (I-123 MIBG). To investigate cardiac autonomic neuropathy in uremic patients, we performed myocardial innervation scintigraphy (I123 MIBG) in all patients after a fasting period. I-123 MIBG was provided by the Institute of Nuclear Energy of the Nuclear Energy Commission of Rio de Janeiro (Instituto de Energia Nuclear da Comissão de Energia Nuclear, Rio de Janeiro, Brazil) and had a specific activity of 27.3 to 212 MBq/mmol (9-60 mCi/mmol). Myocardial images were obtained with a large–field of view, double-head gamma camera (Millennium VG; GE Medical Systems, Milwaukee, Wis) equipped with a low-energy, high-resolution parallel-hole collimator, being interfaced with a dedicated computer system (Entegra; GE Medical Systems). A 20% energy window, centered on the 159-keV photopeak, and a 64 ⫻ 64 matrix were used. After a slow intravenous injection of 74 to 114 MBq I-123 MIBG, early (15 minutes) and late (180 minutes) static acquisitions, at 5 minutes per frame, were performed in the anterior and left oblique anterior views of the chest. After the delay planar image, single photon emission computed tomography (SPECT) was performed with the same equipment and collimator. Sixty projections (40 seconds per frame) were obtained over a 180° arc from the right posterior oblique view, and the images were stored. Transverse slices were reconstructed with a filtered backprojection algorithm, after preprocessing of the projection images with a low-pass filter. Vertical long-axis, short-axis, and horizontal long-axis tomograms were reconstructed from the transverse slices. Myocardial perfusion images were acquired, after injection of 296 MBq Tc-99m tetrofosmin (Myoview; Amersham, Buckinghamshire, England), and 60 projections (20 seconds per frame) were acquired, stored, and processed as recommended by the American Society of Nuclear Cardiology.18 The parameters considered in planar images were early and late cardiac uptake and cardiac and lung washout. A region of interest was drawn over the cardiac region, and other regions of interest were drawn over the upper mediastinum area, middle pulmonary lobe, and hepatic region. The activity ratio of the heart to the mediastinum (early and late uptake) was computed to quantify cardiac I-123 MIBG accumulation. The washout rate (WR) from the myocardial uptake was calculated as
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Table 1. General features of CKD patients according to treatment modality
Group 1 Conservative (n ⴝ 7)
Group 2 CAPD (n ⴝ 5)
Group 3 HD (n ⴝ 13)
Group 4 KTx (n ⴝ 15)
P
Contrasts
14 (12–18)
8.0 (6.0–12)
19 (16–21)
13 (11–14)
⬍.001
C ⫽ KTx ⫽ HD ⬎ CAPD
Age (y) Sex (M/F) Prevalent basic kidney disease RCD (mo) Dialysis (mo) SBP (mmHg) DBP (mmHg) DRUGS (n) Cr (mg/dl)
(0/7) (2/3) (4/9) Congenital diseases Glomerulopathies Glomerulopathies
Hb (G/dL) PTH (pG/dL)
(9/6) Tubulopathies
106 (81–121) — 110 (100–115) 70 (65–75) 1 (0–2) 32 (19–35)
38 (26–53) 38 (26–53) 100 (100–128) 60 (60–79) 2 (0–3) 9.0 (8.5–9.4)
115 (58–135) 52 (17–92) 120 (120–130) 80 (80–90) 1 (0–3) 11.6 (11–12)
83 (60–117) 59 (35–71) 110 (100–110) 66 (40–78) 1 (1–2) 0.8 (0.6–0.8)
.096 .058 .005 .011 .623 ⬍.001
12 (12–13)
11 (11–12)
9.0 (8.0–10)
12 (11–12)
⬍.001
305 (120–433)
341 (279–369)
374 (286–835)
64 (41–97)
.014
C ⫽ KTx ⬍ HD C ⫽ KTx ⬍ HD C ⫽ KTx ⬍ HD ⫽ CAPD C ⫽ KTx ⫽ CAPD ⬎ HD HD ⬎ KTx
RCD D, Renal chronic disease; SBP, systolic blood pressure; DBP, diastolic blood pressure; drugs, number of antihypertensive drugs in use; Cr, creatinine; Hb, hemoglobin; PTH, parathyroid hormone; Group 1, conservative; Group 2: CAPD, continuous ambulatory peritoneal dialysis; Group 3: HD, hemodialysis; Group 4: KTx, kidney transplant.
follows: Washout rate ⫽ (Initial myocardial I-123 MIBG uptake ⫺ Delayed myocardial I-123 MIBG uptake)/Initial I-123 MIBG uptake ⫻ 100.19 The regional I-123 MIBG uptake score was visually determined for each of all 10 myocardial regions (anterior, lateral, inferior, septal, anterolateral, lateroinferior, inferoseptal, anteroseptal, apical, and posterobasal) according to the following 4-point scoring system: 3, markedly reduced; 2, moderately reduced; 1, mildly reduced; and 0, normal.6 Images were not suitable for SPECT analysis in 10 patients, because of intense liver I-123 MIBG activity or abdominal retention (in patients undergoing CAPD). As a consequence, regional I-123 MIBG uptake was assessed only in 30 patients. The regional cardiac uptake (I-123 MIBG) was visually compared with perfusion myocardial images (Tc-99m tetrofosmin) by use of SPECT images (vertical long-axis, short-axis, and horizontal long-axis tomograms). For each segment, the I-123 MIBG image was compared with Tc-99m tetrofosmin patterns and classified as improved, equivalent, or worsened. We did not compare I-123 MIBG/Tc-99m tetrofosmin bull’s-eye images, because of severe interference from liver uptake. All image interpretation was performed by 1 experienced examiner (V.S.P.), who was blinded to clinical information.
Statistical Analysis Descriptive statistics of continuous variables comprised medians and interquartile range. When necessary, mathematical transformation of non-normal or heteroscedastic data was performed to allow subsequent analysis. Comparisons among groups were made by the analysis of variance test, and the
Bonferroni correction was used during multiple comparisons tests. The association between variables was assessed by use of Pearson or Spearman correlation coefficients. P ⬍ .05 was considered significant.
RESULTS The data were analyzed and will be presented via comparisons of patients divided into 4 groups, according to treatment modality: conservative, CAPD, hemodialysis, and KTx. General features of patients from the studied groups are displayed in Table 1. The main cause of chronic kidney disease (CKD) was glomerulonephritis, but congenital disease was prevalent in conservative management patients and renal tubular dysfunction were prevalent in KTx patients. Thirty-five patients were hypertensive, and only five of them had uncontrolled hypertension (⬎percentile 95 [P95]). All of them were taking antihypertensive drugs (-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors), and there was no difference in frequency of medication among groups (P ⫽ .623). The CAPD patients presented with a lower age than the other groups according to the preferential indication for treatment in this age range. These patients had been undergoing dialysis treatment for 38 months (range, 26-53 months), whereas those undergoing hemodialysis had been doing so for 52 months (range, 17-92 months);
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Table 2.
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I-MIBG scintigrams data according to treatment modality
Group 1 Conservative (n ⴝ 7)
Group 2 CAPD (n ⴝ 5)
Group 3 HD (n ⴝ 13)
Group 4 KTx (n ⴝ 15)
Hp/Mp HI/MI
2.2 (1.9–2.3) 2.0 (1.9–2.2)
2.0 (2.0–2.2) 1.9 (1.6–2.0)
2.0 (2.0–2.2) 1.9 (1.8–2.2)
2.0 (1.9–2.2) 2.2 (1.8–2.5)
.654 .227
WR123I-MIBG%
11 (9.0–24)
28 (21–33)
25 (15–27)
12 (6.0–17)
.002
WRp123I-MIBG%
26 (19–38)
16 (8.0–25)
25 (19–28)
28 (22–30)
.030
LVEF%
66 (61–67)
67 (57–80)
61 (51–70)
65 (58–72)
.463
Scintigraphic parameters
P — — G4 ⬍ G3 G1 ⬍ G2 G4 ⬍ G2 G2 ⬍ G1 G2 ⬍ G4 —
Hp/Mp, early 123I-MIBG cardiac uptake; HI/MI, late 123I-MIBG cardiac uptake; WR R123I-MIBG%, 123I-MIBG cardiac washout rate; WRp123IMIBG%, 123I-MIBG pulmonary washout rate; LVEF, left ventricular ejection fraction; Group 1, conservative; Group 2: HD, hemodialysis; Group 3: CAPD, continuous ambulatory peritonealdialysis; Group 4: KTx, kidney transplant.
this was not significantly different from the length of treatment in the KTx group before transplantation, at 59 months (range, 35-71 months) (P ⫽ .058). High levels of systolic blood pressure and PTH were found in hemodialysis patients, who had lower hematocrit levels as well. Early and delayed cardiac uptake estimated by use of the heart-mediastinum ratio by I-123 MIBG planar images was not significantly different among groups (Table 2), but the cardiac washout rate was higher in patients in the hemodialysis group (P ⫽ .002) whereas the lung washout rate was significantly lower in the CAPD patients (P ⫽ .030). Children with CKD, undergoing dialysis, displayed I-123 MIBG kinetic abnormalities despite a normal LVEF. On the other hand, the KTx patients showed a marked improvement in the cardiac I-123 MIBG washout rate as compared with those undergoing hemodialysis, 12% (range, 6%-17%) versus 25% (range, 15%27%) (Figure 1) visualized by planar images (Figure 2), with no change in I-123 MIBG cardiac uptake. A more heterogeneous distribution of I-123 MIBG (score) was found in hemodialysis patients as compared with that in conservative management patients (P ⫽ .037) (Figure 3), and this heterogeneity was characterized by decreased uptake in the inferoapical regions of the left ventricular myocardium (Figure 4). All patients studied showed a low uptake in the septum on the I-123 MIBG images compared with that on Tc-99m tetrofosmin images. The cardiac I-123 MIBG washout rate had a significant positive correlation with PTH levels (correlation Spearman coefficient [rs] ⫽ 0.40, P ⫽ .019) and negative correlation with creatinine clearance (rs ⫽ ⫺0.48, P ⫽ .002) (Figure 5). No significant correlation was observed between the cardiac washout rate and age, gender, or severity of high blood pressure.
Figure 1. I-123 MIBG cardiac washout rate according to treatment modality.
The 24-hour SD of normal R-R intervals, the 24hour SD of the 5-minute mean of normal R-R intervals, the square root of the mean of the squared differences between adjacent normal R-R intervals, and the mean 24-hour value of normal R-R intervals did not significantly differ in the 4 groups, but the LF component was significantly lower in the hemodialysis patients than in the others (P ⫽ .040). On the other hand, no significant improvement was observed after KTx (Table 3). The LF component showed a weak and negative correlation with cardiac MIBG kinetics (r ⫽ ⫺0.36, P ⫽ .034) (Figure 6). Moreover, we could not find a significant correlation between cardiac MIBG uptake and any other HRV indices.
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A WR
123
I = 12%
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B WR
123
I = 45%
Figure 2. Early and late planar images (I-123 MIBG) in patients with normal washout rate (WR) (12%) (A) and abnormal washout rate (45%) (B).
Figure 3. Regional myocardial uptake score (I-123 MIBG) according to therapeutic modality.
DISCUSSION This study showed that the CKD pediatric patients undergoing dialysis had abnormalities in the cardiac autonomic nervous system characterized by the following: (1) a rapid I-123 MIBG cardiac washout rate; (2) a heterogeneous I-123 MIBG distribution in the left ventricular myocardium; (3) a slow I-123 MIBG clearance from the lung, especially those undergoing CAPD; and (4) a decrease in the LF component of HRV analysis (patients undergoing hemodialysis). In addition, patients who underwent KTx recovered the I-123 MIBG cardiac innervation pattern observed in those undergoing conservative treatment, suggesting the reversal of autonomic abnormalities. To our knowledge, this is the first published study that used I-123 MIBG scintigraphy for evaluating the cardiac sympathetic neuropathy in children with CKD in a Western country. At variance with other diseases, in which sympathetic cardiac innervation has been extensively studied by use of I-123 MIBG scintigraphy, only few reports exist on this technique in CKD patients,4-6,20,21 all
Figure 4. Scintigraphic pattern showing heterogeneous distribution of material (I-123 MIBG) through left ventricle walls (bottom rows) as compared with homogeneous pattern found in perfusion images (Tc-99m tetrofosmin) (top rows).
of them in adults and authored by Japanese researchers. Our results are, in general, concordant with those previously published, extending the observations previously reported to a Western pediatric population with CKD. The increased I-123 MIBG cardiac washout rate was previously described by Kurata et al,4 who demonstrated that the I-123 MIBG cardiac washout rate was significantly higher in patients undergoing dialysis (44% ⫾ 23%) than in control subjects (7% ⫾ 11%). Further studies confirmed those findings: Miyanaga et al6 reported values of 43% ⫾ 14% for patients without congestive heart failure, and Kurata et al5 studied 211 patients with CKD and found I-123 MIBG cardiac washout values of 32% ⫾ 23% and, in a subsequent study,21 reported values of 46% ⫾ 21% in CKD patients and 5% ⫾ 8% in control subjects. Unfortunately, those numerical values are not comparable, because each study used a different methodology to estimate the I-123 MIBG cardiac washout rate.22 Several mechanisms have been proposed for increased cardiac I-123 MIBG clearance rates, such as
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Figure 5. Scatter plots of cardiac washout values (WR) (I-123 MIBG) with creatinine clearance (in milliliters per minute) (logarithm-transformed [lnClCr]) (n ⫽ 39; rs ⫽ 0.40; 95% confidence interval ⫽ 0.10 a 0.64; P ⫽ .019) (A) and serum PTH levels (pG/dL) (logarithm-transformed [lnPTH]) H (n ⫽ 40; rs ⫽ ⫺0.48; IC95% ⫽ 0.10 a 0.64; P ⫽ .002) (B).
Table 3. HRV analysis indexes according to treatment modality
Variable SDNN SDANN rMSSD NNm lnHF lnLF lnLF/HF
Group 1 (n ⴝ 7)
Group 3 (n ⴝ 13)
Group 4 (n ⴝ 15)
147.50 (88.00–186.25) 126.00 (78.25–157.50) 47.00 (23.75–65.00) 747.00 (674.00–826.25) 7.38 (6.50–8.09) 7.02 (6.46–7.82) 0.20 (⫺0.83–0.23)
111.00 (90.50–146.50) 94.00 (77.00–135.50) 29.00 (21.00–49.00) 677.00 (627.00–828.50) 5.70 (4.55–7.26) 6.05 (4.67–6.69) ⫺0.14 (⫺1.09–0.53)
97.00 (89.00–129.00) 82.00 (73.00–113.00) 47.00 (21.00–53.00) 669.00 (636.00–742.00) 7.52 (6.39–7.95) 6.03 (5.73–7.45) ⫺0.36 (⫺1.17–0.07)
P .146 .213 .270 .274 .104 .040 .686
G3 ⬍ G1
SDNN, 24-hour standard deviation (SD) of normal RR intervals, in ms; SDANN, 24-hour SD of the 5-min mean of normal RR intervals, in ms; rMSSDI, the square root of the mean of the squared differences between adjacent normal RR intervals, in ms; NNm, mean 24-hour value of normal RR intervals, in ms; LnLF, normal logarithm of low frequency component; LnHF, normal logarithm of high frequency component; LF/HF, normal logarithm of low-to-high frequency component ratio; Group 1, conservative; Group 3: CAPD, continuous ambulatory peritoneal dialysis; Group 4: KTx, kidney transplant.
decreased neuronal uptake of MIBG, rapid MIBG clearance, and increased MIBG release from cardiac sympathetic neurons. A decrease in the neuronal uptake of MIBG is not likely in this case, because extraneuronal uptake is poor in humans and we used low doses of I-123 MIBG with a high specific activity.11,23 A rapid MIBG clearance may be a result of elevated norepinephrine concentrations, a measurement not performed in our study. Nonetheless, very high norepinephrine levels, as observed in pheochromocytoma, are necessary to inhibit the neuronal uptake, a fact that had not been described in CKD.4,5 At variance, strong evidence exists that the activation of efferent sympathetic nerve discharge occurs in patients with CKD undergoing dialysis,4,20,21 suggesting that the increased cardiac sympathetic nerve activity is the most probable mechanism for the rapid MIBG clearance observed in the children studied. Indeed, the increased I-123 MIBG washout rate observed in dialysis patients had a significant positive correlation with PTH
levels and a negative correlation with the creatinine clearance and, thus, parallels renal function deterioration. It should be stressed that the dialysis, by itself, could not be the cause of the increased I-123 MIBG washout rate. Iodine MIBG is a relatively stable radiopharmaceutical that is primarily excreted in the urine, and it is not removed by dialysis, probably because of strong protein binding.24 A slower clearance of radioactivity from the blood would produce a reduced rate of cardiac washout in patients with CKD and dialysis and could not be related to the increased rate observed in our sample. Moreover, we found that the cardiac washout rate increases proportionally with the decrease in creatinine clearance (Figure 5), independently of the therapy modality for the CKD. This study also demonstrated a slow I-123 MIBG washout rate from the lung in the CAPD patients, which is markedly different from those under conservative management. Different reports have suggested that pro-
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Figure 6. Scatter plots of cardiac washout values (WR) (I-123 MIBG) with LF component (lnLF) F (n ⫽ 34; r ⫽ ⫺0.36; 95% confidence level ⫽ ⫺0.63 a ⫺0.03; P ⫽ .034).
longed pulmonary retention of I-123 MIBG may not only be related to pulmonary congestion but is frequently caused by pulmonary endothelial dysfunction or pulmonary sympathetic nervous system overactivity,25-28 although the role of those mechanisms in our CAPD patients was not determined in the study. We observed a heterogeneous I-123 MIBG distribution in the left ventricular myocardium (SPECT images), a phenomenon that was previously reported in CKD5 and in other conditions, such as heart failure.29 There is a marked reduction of uptake in the inferior wall and apex, which is more intense than expected as a result of physiologic variations.19,30 The heterogeneous distribution of myocardial I-123 MIBG uptake may reflect the regional heterogeneity of tissue norepinephrine concentration and sympathetic innervation, which has been reported to be associated with increased sympathetic activity, as in heart failure, and with an increased risk of sudden cardiac death.23,30 Another main finding of the study is the reduction in the LF component of HRV in the frequency domain that was demonstrated in hemodialysis patients. Other HRV indices, more affected by vagal influences, did not differ among groups. A reduction in the HRV indices was demonstrated in CKD patients in earlier reports4-6,21 and might be considered to result from many comorbidities present in CKD patients, such as congestive heart failure, diabetes mellitus, coronary heart disease, and hypertension. In our sample, as well as in some previous studies,6,19,20,31 we excluded patients with heart failure, diabetes mellitus, or coronary heart disease, and HRV reduction could not be ascribed to these conditions. Moreover, hypertension was present in almost all patients and could not be the cause of the
abnormality, which seems to be primarily related to progressive renal dysfunction and, probably, the resultant sympathetic hyperactivity. Although the LF component is frequently reported as a marker of sympathetic activity,17,32 a reduction in the LF component has been described in conditions in which persistent sympathetic activation exists, such as heart failure.33 In severe heart failure, LF components of both electrocardiographic R-R interval and resting muscle sympathetic nerve activity are markedly reduced, suggesting a central autonomic regulatory impairment with important prognostic implications.34 KTx patients have shown a slower I-123 MIBG cardiac washout rate when compared with those undergoing dialysis, although they had been submitted to the same period of dialysis treatment before transplantation. Their I-123 MIBG cardiac washout rate was quite similar to that observed in the conservative patient group, suggesting recovery of autonomic function after KTx. Although Kurata et al21 had previously reported the restoration of normal sympathetic I-123 MIBG patterns after KTx in patients with CKD in 2004, our study is the first to suggest this phenomenon in children. The LF component of HRV did not increase in transplanted children, when compared with those undergoing dialysis. Indeed, they have shown that the improvement in cardiac sympathetic innervation, assessed by myocardial kinetics, may be not be accompanied by HRV changes at the same time, suggesting that the scintigraphy method is either an earlier marker or a more sensitive method to diagnose cardiac autonomic dysfunction.14 All of these findings, obtained by use of both cardiac sympathetic scintigraphy and Holter-derived HRV analysis, point toward a pathophysiologic mechanism com-
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mon to the sympathetic hyperactivity, which could cause the rapid cardiac and slow pulmonary washout rates, the heterogeneous I-123 MIBG distribution in the left ventricular myocardium, and the reduced LF component of HRV variability. In our patients almost all HRV and I-123 MIBG variables had no significant correlation with clinical background such as age, hematocrit level, hemoglobin level, serum electrolyte level, and echocardiographic LVEF. Considering that patients with CVD (including those with asymptomatic depressed LVEF) or diabetes were excluded from the study, the cardiac sympathetic abnormalities could not be attributed to the presence of comorbidities. Indeed, the increased I-123 MIBG washout rate observed in dialysis patients had a significant positive correlation with PTH levels and a negative correlation with creatinine clearance. Moreover, a negative correlation was observed between the LF component of HRV analysis and the I-123 MIBG cardiac washout rate, linking scintigraphic and electrocardiographic phenomena, as previously described by other authors.20 Nonetheless, a perfect correlation between them is not expected, considering that HRV analysis and I-123 MIBG kinetics reflected different aspects of cardiac autonomic control—that is, sympathetic/vagal versus isolated sympathetic, sinus node versus whole left ventricular myocardium, and postsynaptic versus presynaptic events. In fact, these 2 methods seem to be complementary in the evaluation of heart autonomic control. Cardiovascular morbidity and death importantly influence the life expectancy of patients with CKD, and an activated sympathetic nervous system is one of the factors that can adversely affect prognosis independently of its effect on blood pressure.35,36 Indeed, high sympathetic activity has been considered an emerging cardiovascular risk factor in CKD,37 and both MIBG imaging and HRV analysis may have a role in recognizing patients with sympathetic overactivity and a higher risk of cardiovascular complications, an appealing hypothesis that deserves to be tested. Concerning the possibility of clinical use of the MIBG imaging method in young patients with CKD, it is important to stress that the risk related to the radiation exposure in this situation is quite low and comparable to other examinations routinely performed in CKD children. Considering that each patient received 2 to 3 mCi (74-111 MBq), the maximum effective equivalent dose was 1.55 mSv, in the same range of the exposure resulting from intravenous urography (1.58 mSv) and only slight higher than the effective equivalent dose from computed tomography (1.11 mSv). This maximum dose is also proportional to the effective equivalent dose of 5.5 mSv used in adults (with injection of 10 mCi), considering that our patients have a median age of 14 years and
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body surface area of 1.14 m2. It must be stressed that, in children, the calculation of the effective equivalent dose should also consider the tissue immaturity and the greater proximity of the organs, including between the gonads and the target organ. This study has several limitations. We did not access the cardiac presynaptic sympathetic activity using the gold standard method, the measurement of cardiac norepinephrine spillover with norepinephrine labeled to tricio (3H-norepinephrine), because it is not available in our country. Plasma norepinephrine levels were not measured. We did not have a control group, because the use of radioactive material in healthy children is not allowed. Moreover, we could only suggest that cardiac dysautonomia was reversed by renal transplantation, because we did not compare patients studied before and after the procedure. Nonetheless, none of these limitations could jeopardize our main conclusions, and there is robust evidence that cardiac sympathetic abnormalities occur early in CKD, mainly attributed to uremia. Conclusions Children undergoing dialysis displayed many sympathetic abnormalities, including a rapid cardiac I-123 MIBG washout rate, slow pulmonary I-123 MIBG washout rate, heterogeneous I-123 MIBG distribution, and reduced values of the LF component of HRV. These abnormalities, which probably reflected increased sympathetic activity, were detected in the absence of major comorbidities, regardless of the LVEF depression and were related to the severity of renal impairment. In KTx patients cardiac I-123 MIBG washout rate values and regional myocardial uptake scores diminished, paralleling renal function normalization, suggesting that sympathetic functional recovery occurred after KTx. Acknowledgment The authors have indicated they have no financial conflicts of interest.
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