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2004 Blackwell Munksgaard Pediatr Transplantation 2004: 8: 496–501 Printed in UK. All rights reserved Pediatric Transplantation Twenty-four-hour ambulatory blood pressure profiles in liver transplant recipients Del Compare ME, DÔAgostino D, Ferraris JR, Boldrini G, Waisman G, Krmar RT. Twenty-four-hour ambulatory blood pressure profiles in liver transplant recipients. Pediatr Transplantation 2004: 8: 496–501.
2004 Blackwell Munksgaard Mónica E. Del Compare1, Daniel D'Agostino1, Jorge R. Ferraris2, Gustavo Boldrini1, Gabriel Waisman3 and Rafael T. Krmar2,3 1 Abstract: Twenty-four-hour ambulatory blood pressure monitoring (ABPM) has proven to have better reproducibility than office blood pressure (BP) and is increasingly used for the study of hypertension in children and adolescents. The aim of our study was to assess 24-h BP profiles and to compare the results of office BP measurements with ABPM in stable liver transplant recipients transplanted before the age of 18 yr. ABPM was performed in 29 patients (nine males, 20 females), aged 3.9–24.8 yr (median 10.8 yr). The investigation was conducted 1.1–11.5 yr (median 5.1 yr) following transplantation. ABPM confirmed hypertension in one out of three office hypertensive patients. Seven patients (24%), whose office BP recordings were within the normotensive range, were reclassified as hypertensive. Non-dippers (n ¼ 17), arbitrarily defined as patients with less than 10% nocturnal fall in BP, were similarly distributed among patients with ambulatory normotension and ambulatory hypertension (v2, p ¼ 0.79). In addition, non-dippers showed a negative correlation between 24-h total urinary albumin excretion and both systolic and diastolic nocturnal decline in BP (Rho ¼ )0.48, p < 0.05 and Rho ¼ )0.86, p < 0.01, respectively). Our study found office BP readings to be poorly representative of 24-h BP profile. Larger studies are needed to confirm our observations as well as to determine whether routine BP measurements in the follow-up of paediatric liver transplant recipients should be based solely on office BP. As long as graft survival in paediatric liver transplant recipients improves, a larger number of patients are exposed to the risks of late complications. In children, arterial hypertension has been reported as one of many post-transplant complications (1). Different mechanisms, including altered vascular reactivity, impaired sodium excretion and glomerular filtration rate, and immunosuppressive agents have been described to contribute to the development of hypertension (2). In addition, compelling clinical evidence indicates that adult liver allograft recipients have a greater risk of cardiovascular events and Abbreviations: ABPM, twenty-four-hour ambulatory blood pressure monitoring; BMI, body mass index; BP, blood pressure; DBP, diastolic blood pressure; SBP, systolic blood pressure. 496 Servicio de Gastroenterolog
a y Transplante Heptico Peditrico, 2Servicio de Nefrolog
a Peditrica,3Unidad de Hipertensin Arterial del Servicio de Cl
nica Mdica, Hospital Italiano, Buenos Aires, Argentina Key words: liver transplantation – hypertension – children – adolescents – ambulatory blood pressure monitoring Rafael Toms Krmar, MD, Department of Pediatrics, Karolinska University Hospital, Huddinge, S-141 86, Stockholm, Sweden Fax: +46 8 58581410 E-mail: rafael.krmar@klinvet.ki.se Accepted for publication 4 January 2004 related mortality than an age- and sex-matched population, pointing out moderate hypertension as a contributing risk factor (3). Even though there are no data showing hypertension as an independent risk factor of premature cardiovascular disease among paediatric liver transplant recipients, there is little reason to think that early diagnosis of hypertension and timely treatment would not have the benefits of BP reduction observed in the general population (4). ABPM has become a very useful tool for evaluation of BP at all ages, providing valuable information about the BP pattern throughout daily activities and sleep (5, 6). Both in adults and in children and adolescents, ABPM has been shown to have better reproducibility and more precise estimation of true BP than office BP recordings (7–9). Data obtained from paediatric clinical studies also show that ABPM is helpful Ambulatory BP profiles in liver transplant recipients to exclude white coat hypertension (10, 11), examine day-to-night BP variability (12, 13), detect elevated night-time BP (14, 15), and to assess responses to antihypertensive treatment (16, 17). Given both the concern that office BP is less representative of average daily BP and the increased risk of developing hypertension after liver transplantation, we aimed to assess BP profiles in stable liver transplant recipients transplanted before the age of 18 yr by using ABPM and to compare results of office BP with ABPM measurements. Patients and methods Between February 2000 and October 2002, stable liver transplant recipients who regularly attended our transplant clinic for their routine clinical visits were considered to be eligible for the present study if they met the following inclusion criteria: (i) liver transplantation performed for more than 1 yr previously; (ii) no acute graft rejection for at least 6 months prior to the study; and (iii) no history of antihypertensive therapy. Since impairment in renal function after liver transplantation has been reported to be associated with more hypertension (18, 19), patients with an estimated glomerular filtration rate <80 mL/min per 1.73 m2 (20) were not considered as qualified for the present study. In addition, as we attempted to compare office BP with ABPM under similar clinical conditions, recent change(s) in immunosuppressive therapy were also considered an exclusion criterion. This study was carried out on an outpatient basis and the analysis of the results was performed retrospectively. The study protocol was approved by the Ethics Committee at our institution. Informed parental consent and, when possible, patient consent were obtained before testing. From a total of 61 potentially eligible patients, 18 were excluded because of chronic renal dysfunction, 12 because of changes in their immunosuppressive therapy, and two because they declined consent. Therefore, our selected study population comprised 29 patients (nine males and 20 females), aged 3.9–24.8 yr (median 10.8 yr), who were investigated 1.1–11.5 yr (median 5.1 yr) following liver transplantation. At the time of the study, all patients except six were younger than 18 yr. Body weight and height ranged between 15.2 and 65 kg (median 38.9 kg) and 99.5 and 176 cm (median 140 cm), respectively. BMI, calculated by dividing the body weight by height squared, ranged from 12.6 to 24.9 kg/m2 (median 18.1 kg/m2). Four of them were regarded as overweight (21). The median value of the estimated glomerular filtration rate was 103.1 mL/min per 1.73 m2 (range 82–176.7 mL/ min per 1.73 m2). Urinary albumin excretion was estimated on the basis of 24-h urine collection and measured by immunoturbidimetric assay. Samples from 24 patients were available for the analysis. The most recent median value of 24-h total urinary albumin excretion was 4.8 mg (range 1.8–56.5 mg). The aetiology of liver disease was biliary atresia in 16 patients, cryptogenic cirrhosis in four, autoimmune hepatitis in two, Wilson’s disease in two, fulminant liver failure in one, neonatal haemochromatosis in one, chronic cholestasis in one, Byler disease in one, and tyrosinaemia in one. Ten patients received their grafts from living-related donors and 19 from cadaveric donors. At the time of the study, 10 patients followed an immunosuppressive protocol based on cyclosporin A alone or associated either with methylprednisone (n ¼ 8), azathioprine (n ¼ 3), methylprednisone and azathioprine (n ¼ 1), mycophenolate mofetil (n ¼ 1), mycophenolate mofetil and methylprednisone (n ¼ 1), or mycophenolate mofetil and azathioprine (n ¼ 1). Four patients received tacrolimus and methylprednisone. Cumulative cyclosporin A and methylprednisone doses ranged between 55.9 and 824 g/m2 (median 173.1 g/m2) and 1.5 and 18.9 g/m2 (median 2.8 g/m2), respectively. Office BP was measured by doctors on different routine clinical visits and determined with a mercury sphygmomanometer on the right arm with cuffs of adequate size. The first and the last Korotkoff sounds (K1 and K5) were taken as SBP and DBP, respectively. The mean of three consecutive BP readings taken approximately 1 min apart, determined with a standard mercury sphygmomanometer with a patient in a sitting position and obtained at our unit by a trained nurse before performing ABPM procedure, was used to ascertain the patient’s office SBP and DBP. Our procedure for ABPM has previously been described in detail (22, 23). Briefly, ABPM was recorded on the nondominant arm using an arm cuff of similar size to the one used for office BP with a SpaceLabs model 90207 (SpaceLabs, Redmon, WA, USA) oscillometric monitor. The validation of this automatic monitor has been confirmed previously in children (24). The device was programmed to measure BP every 10 min between 6 a.m. and 10 p.m., and every 20 min between 10 p.m. and 6 a.m. Night-time was defined according to the period of night-time sleep based on the patient’s diary. In three patients, who reported a siesta during their ABPM, daytime BP values were calculated by excluding the period of siesta, as previously described (25). At the time of office BP measurements as well as during ABPM, no patient was taking any concurrent medication with the potential to modify BP. For patients under 18 yr (n ¼ 23), office hypertension was defined when at least in two different outpatient visits the mean of three SBP and/or DBP readings exceeded the 95th age-, sex-, and height-matched percentile of the adopted reference standard (26). For patients aged 18 yr or older (n ¼ 6), BP values ‡140 mmHg (SBP) and/or ‡90 mmHg (DBP), also based on the average of three readings measured on two or more office visits, were considered office hypertension (27). In 18 patients, whose heights were between 120 and 185 cm in males and 120 and 175 cm in females, ambulatory systolic and/or diastolic daytime, night-time, or both daytime and night-time hypertension was defined as mean BP values(s) above the 95th height- and sex-related percentile for day and/or night according to Wühl et al. (28). For analysis purposes, five patients with a body height <120 cm (range 99.5–115 cm) were included in the 120-cm group. In patients aged 18 yr or older mean daytime values higher than 135/85 mmHg and higher than 120/75 mmHg during the night were considered ambulatory hypertension (27). The nocturnal percentage changes in mean SBP and DBP were calculated as follows: [(mean daytime ) mean nighttime)/mean daytime] · 100. In the present study, a patient with less than 10% nocturnal falls in SBP and/or DBP was arbitrarily defined as a non-dipper. This classification was derived from studies conducted in adults who reported a 497 Del Compare et al. worse prognosis, in terms of target organ damage, in nondippers than in those with normal day–night BP difference (29–31). The results are expressed as means ± standard deviation, unless otherwise indicated. Statistical tests utilized included Student’s test to assess differences between groupsÕ means for normally distributed variables and the Mann–Whitney U-test for non-normally distributed variables. Test of association between categorical variables was carried out using the chi-squared test. Spearman-Rho correlation coefficient was performed to identify significant associations between 24-h, daytime, night-time systolic and diastolic BP, and dipping, and various variables such as BMI, estimated glomerular filtration rate, 24-h total urinary albumin excretion, cumulative dose of cyclosporin A and methylprednisone, and office systolic and diastolic BP. In all tests, p values <0.05 were considered to indicate statistical significance. Results On the basis of office BP measurements three patients had systolic and diastolic office hypertension. By applying ABPM, two of them were regarded as patients with white coat hypertension, i.e. office BP in the hypertensive range with ambulatory normotension (32), and hypertension was confirmed in the other one. In five patients, whose heights were ‡120 cm, both systolic and diastolic daytime and night-time hypertension was observed in two, isolated systolic and diastolic daytime hypertension in one, and two had isolated night-time hypertension (systolic and diastolic in one, and diastolic in one). In two patients older than 18 yr, systolic daytime and systolic and diastolic night-time hypertension was detected in one, and isolated diastolic daytime hypertension in the other. The percentage of successful BP recordings ranged from 72 to 99% (median 89%) and the total number of readings from 82 to 123 (median 101). According to the ABPM results, we further analysed our population separately in terms of patients with ambulatory normotension and ambulatory hypertension. Age, BMI, estimated glomerular filtration rate, 24-h total urinary albumin excretion, cumulative time with liver transplant, cumulative dose of cyclosporin A and methylprednisone did not differ between normotensive and hypertensive patients, whereas systolic and diastolic office, 24-h, daytime, and night-time BP values were significantly higher in patients with ambulatory hypertension (Tables 1 and 2). No significant correlation between BMI, estimated glomerular filtration rate, 24-h total urinary albumin excretion, cumulative dose of cyclosporin A and methylprednisone, office systolic and diastolic BP, and 24-h, daytime, and night-time systolic and diastolic BP was observed in hypertensive patients (data not shown). Among patients with ambulatory normotension, a significant relationship was observed only between 24-h, daytime, and night-time systolic BP and office systolic BP (Rho ¼ 0.73, p < 0.01, Rho ¼ 0.75, p < 0.01, and Rho ¼ 0.74, p < 0.01, respectively). Overall, the percentage night-time falls in SBP and DBP were 8.6 ± 4.2 and 16 ± 6, respectively. When patients were analysed according to their ABPM results, there were no statistical differences between patients with ambulatory normotension and ambulatory hypertension in terms of percentage decline in BP during the night-time period (Table 2). The occurrence of a non-dipping pattern was similarly distributed among patients with ambulatory normotension Table 1. Patient characteristics Variables Ambulatory normotension (n ¼ 21) Ambulatory hypertension (n ¼ 8) p Age (yr) Sex (male/female) BMI (kg/m2) GFR (mL/min per 1.73 m2) Total urinary albumin excretion (mg/24 h)* Cumulative time with liver transplant (yr) Office systolic BP (mmHg) Office diastolic BP (mmHg) 12.8 € 7/14 18.5 € 114.1 € 10.2 € 5.6 € 104.3 € 66.7 € 12.9 € 2/6 19.8 € 103.9 € 19.7 € 5.7 € 114.6 € 75.1 € NS NS NS NS NS NS <0.05 <0.05 Immunosuppression Cyclosporin A (n) Methylprednisone (n) Cumulative dose of Cyclosporin A (g/m2)* Cumulative dose of methylprednisone (g/m2)* 17 10 300.5 € 193.8 6.4 € 5.1 Data are mean € s.d. NS, not significant; BP, blood pressure; *Non-normal distributed variables. 498 6.6 3.2 26.6 10.5 2.9 11.5 7.5 5.7 3.1 13.6 19.8 3.4 11.4 10.6 8 4 264.2 € 171.3 6.5 € 3.7 NS NS NS NS Ambulatory BP profiles in liver transplant recipients Table 2. Results of ambulatory blood pressure monitoring Variables Ambulatory normotension (n ¼ 21) Systolic blood pressure (mmHg) 24 h 109.8 € 8.1 Daytime 113.2 € 8.2 Night-time 103.1 € 7.5 Night-time fall in SBP (%) 8.7 € 4 Diastolic blood pressure (mmHg) 24 h Daytime Night-time Night-time fall in DBP (%) 67.5 71.2 59.7 16.1 € € € € 5.8 6.3 5 5.5 Ambulatory hypertension (n ¼ 8) p 126.5 129.9 118 9.1 € € € € 5.8 6 8.3 5.4 <0.0001 <0.0001 <0.0001 NS 80.3 84 70.5 15.8 € € € € 3.2 5.1 5 8.2 <0 .0001 <0 .0001 < 0.0001 NS Data are mean € s.d. NS, not significant; SBP, systolic blood pressure; DBP, diastolic blood pressure. and ambulatory hypertension (12 and five patients, respectively; chi-square, p ¼ 0.79). No significant relationship was observed between dipping and BMI, estimated glomerular filtration rate, 24-h total urinary albumin excretion, and cumulative dose of cyclosporin A and methylprednisone (data not shown). However, when patients were separately analysed as dippers and non-dippers, we observed, among non-dippers, total urinary albumin excretion as the only variable to be significantly correlated with night-time percentage decrease in both SBP and DBP (Rho ¼ )0.48, p < 0.05 and Rho ¼ )0.86, p < 0.01, respectively). Discussion By applying ABPM in a carefully selected population of liver-transplant recipients, we confirmed hypertension in one out of three office hypertensive patients, whereas seven patients (24%), whose office BP recordings were within the normotensive range, were reclassified as hypertensive. In addition, we identified patients with abnormalities of day-to-night variability, which, like isolated night-time hypertension, would not be detected by any casual BP measurements. Our data are consistent with previous paediatric studies, which emphasized that office BP measurements are subject to many errors, showing ABPM to be more reliable than office BP for evaluating a subject for hypertension (8, 9, 33). Furthermore, as it has been reported in previous studies (10, 11), in the present investigation ABPM was also useful in excluding white coat hypertension. Previous larger paediatric studies reported a prevalence of hypertension higher than 20% beyond the first year after liver transplantation (19, 34). Although our findings are in agreement with these results, it should be stressed that in our study the definition of normotension and hypertension was based upon ABPM criteria, which might provide a better representation of BP patterns than office BP. In addition, as in the present study those patients with impaired renal function were not investigated, it may be that the actual prevalence of hypertension in liver transplant patients may be higher than demonstrated in this study which used a selected population of such patients. In the general population, prospective studies pointed out that the information provided by ABPM possesses a superior prognostic value in predicting cardiovascular complications associated with hypertension than office BP measurements (35, 36). Due to the rarity of clinically evident cardiovascular morbidity in hypertensive children, ABPM cannot, as yet, serve as a similar prognostic tool in this young population. In spite of this limitation, studies conducted in young patients with untreated essential hypertension (13) and after renal transplantation (37) found that ambulatory BP values correlate better than office BP with markers of hypertensive organ damage. Furthermore, a prospective study conducted in adolescents with type 1 diabetes has shown that elevated night-time BP was a marker for predicting the development of microalbuminuria (38). As opposed to reports in the adult population, the link between no-dipping status and target organ damage has so far not been well documented in children (13, 39, 40). Almost all of our patients were given drugs that are associated with hypertension after liver transplantation, and these include steroids (2) and cyclosporin A (41). Both drugs have also been implicated in the aetiology of non-dipping status in different clinical settings (42, 43). It is likely, but currently not proven, that blunted nocturnal dipping associated with these immunosuppressive drugs may increase the risk of target organ damage due to a continuing BP load. In our study, we observed that neither cumulative dose of cyclosporin A nor methylprednisone were related either to blunted nocturnal dipping or BP. Our findings are in accordance with previous paediatric renal transplant studies (16, 44), which reported that immunosuppressive therapy did not contribute to the abnormal dipping status. Microalbuminuria, a slight elevation in urinary albumin excretion, is considered a marker of endothelial dysfunction (45) and was found to be an independent predictor of cardiovascular disease (46). A negative association between 499 Del Compare et al. microalbuminuria and nocturnal BP reduction has been observed in non-insulin dependent adult diabetic patients (47). Similarly, in patients with essential hypertension and abnormal dipping patterns of nocturnal BP, the occurrence of microalbuminuria was reported to be more frequent than in patients with a >10% nocturnal BP fall (30, 48). In our analysis, we observed, among non-dippers, that 24-h total urinary albumin excretion was negatively correlated to nocturnal decline in BP. However, it should be noted that our classification of a non-dipper was based on a single ABPM recording. Considering both the limited reproducibility of the circadian BP profile from one occasion to another (12, 49), and that the rate of urinary albumin excretion in our study population was within the normal range in all but five patients (data not shown), our observation must be interpreted with caution, thus making any conclusion regarding the non-dipping status tentative. The major limitations of this study are that the results are based on a single-centre study and on a relatively small number of patients. Our data, however, indicate that a considerable proportion of stable liver paediatric transplants would be misclassified as normotensives, should only office BP measurements be used. Larger studies will be required to confirm our observations as well as to determine whether these patients would be candidates for diagnosis evaluation of suspected target organ damage. 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