ABPM vs. office blood pressure to define blood pressure control in treated hypertensive paediatric renal transplant recipients

Transcription

1 Pediatr Transplantation 2007: 11: Copyright Ó 2007 Blackwell Munksgaard Pediatric Transplantation DOI: /j x ABPM vs. office blood pressure to define blood pressure control in treated hypertensive paediatric renal transplant recipients Ferraris JR, Ghezzi L, Waisman G, Krmar RT. ABPM vs. office blood pressure to define blood pressure control in treated hypertensive paediatric renal transplant recipients. Pediatr Transplantation 2007: 11: Ó 2007 Blackwell Munksgaard Abstract: While 24-h ambulatory blood pressure monitoring (ABPM) is an established tool for monitoring antihypertensive therapy in adults, data in children are scarce. We retrospectively analysed whether office blood pressure (BP) is reliable for the diagnosis of BP control in 26 treated hypertensive paediatric renal transplants. office BP was defined as the mean of three replicate systolic and diastolic BP recordings less than or equal to the 95th age-, sex- and height-matched percentile on the three-outpatient visits closest to ABPM. ABPM was defined as systolic and diastolic daytime BP 95th distribution adjusted height- and sex-related percentile of the adapted ABPM reference. Eight recipients (30%) with controlled office BP were in fact categorized as having non-controlled BP by ABPM criteria. Overall, when office BP and ABPM were compared using the Bland and Altman method, the 95% limits of agreement between office and daytime values ranged from )12.6 to 34.1 mmhg for systolic and )23.9 to 31.7 mmhg for diastolic BP, and the mean difference was 10.7 and 3.9 mmhg respectively. Office readings miss a substantial number of recipients who are hypertensive by ABPM criteria. Undertreatment of hypertension could be avoided if ABPM is applied as an adjunct to office readings. Jorge R. Ferraris 1, Lidia Ghezzi 1, Gabriel Waisman 2 and Rafael T. Krmar 3 1 Servicio de Nefrología Pediµtrica, Hospital Italiano, 2 Unidad de Hipertensión Arterial del Servicio de Clínica MØdica, Hospital Italiano, Buenos Aires, Argentina, 3 Division of Paediatrics, Department for Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden Key words: children renal transplantation office blood pressure ambulatory blood pressure blood pressure control Rafael Tomµs Krmar, Division of Paediatrics, Department for Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Huddinge, S Stockholm, Sweden Tel.: Fax: rafael.krmar@klinvet.ki.se Accepted for publication 24 July 2006 In renal transplant recipients, regardless of patient age, hypertension is a common posttransplant complication (1 3) and has been shown to be a risk for both rejection (4) and graft dysfunction (5, 6). In addition, hypertension has been found to contribute to premature cardiovascular disease (7, 8), which accounts for one of the leading causes of graft loss among adult renal transplant recipients (9). As a result, close monitoring of BP has become an important part of post-transplant medical care of adults and children with renal allografts (3, 10). Abbreviations: ABPM, ambulatory blood pressure monitoring; BP, blood pressure. Investigations conducted in adult hypertensive patients, showed that antihypertensive drug therapy based on 24-h ABPM is associated with more sustained BP control and less intensive drug treatment than when pharmacologic therapy is guided upon office BP readings (11, 12). Over the past decade, there has been much focus on ABPM as a potential useful technique for assessing the true BP in children with high risk for hypertension (13), including paediatric renal allograft recipients (14 18). However, evaluating BP control in treated hypertensive children with renal allografts, in whom long-standing hypertension carries a risk of death (19), has elicited few investigations (17, 18). At our institution, ABPM was introduced in 1995 in clinical investigations and thereafter in 24

2 ABPM vs. office BP in paediatric renal transplants patient care as a reference method to better characterize a patient s BP pattern. In this retrospective study, we reviewed our experience using ABPM and sought to assess whether sole use of office BP readings are sufficiently reliable in the diagnosis of BP control in treated hypertensive paediatric renal transplant recipients. Patients and methods Patients Treated hypertensive children and adolescents who regularly attended the Paediatric Renal Transplant Section at Hospital Italiano (Buenos Aires, Argentina), in whom ABPM had been performed as part of a more comprehensive assessment of efficacy of ongoing antihypertensive therapy, were considered to be potentially eligible for inclusion and their records reviewed. Inclusion criteria for further analysis were as follows: stable functioning renal graft, defined as the absence of an increase in serum creatinine 20% during the three outpatient visits closest to ABPM, and no change in recipient s medication, including antihypertensive or episode of infection during the same period. In addition, a minimum of 70% valid readings throughout the 24-h period of BP recordings was required for data to be analysed. The analysis of the results was performed retrospectively and the approval for this study was granted by the Ethics Committee at Hospital Italiano (Buenos Aires, Argentina). Methods At each outpatient clinic visit office BP was measured by physicians 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 systolic and diastolic BP respectively. The mean of three replicate BP readings, taken approximately 1 min apart with the recipient in a sitting position after 5 min of rest, was used to determine the recipient s office systolic and diastolic BP. Seated office BP was always measured in the morning and close after the recipients had taken their medication(s), including antihypertensive drugs. ABPM was recorded on the non-dominant arm using an arm cuff of similar size to the one used for office BP and carried out using a validated non-invasive portable oscillometric device (SpaceLabs model 90207; SpaceLabs Inc., Redmond, WA, USA) (20). The recorder was programmed to measure BP every 10 min from 06:00 to 22:00 hours and every 20 min from 22:00 to 06:00 hours. In order to improve the quality of the BP recordings recipients were given tailored instructions on the procedure and encouraged to maintain their usual activities. They were asked to keep still at the time of measurements and to complete a diary of events during the 24-h period, including their awake and asleep times. Nighttime was defined according to the period of nighttime sleep based on recipient s diary. In recipient(s) who reported daytime naps during their ABPM, daytime values were calculated by excluding the period of nap, as previously described (21). The nocturnal percentage changes in mean systolic and diastolic BP were calculated as follows: [(mean daytime ) mean nighttime)/mean daytime] 100. Due to the lack of reference values for office and ambulatory BP in healthy Argentinean children and adolescents, recipientsõ BP readings were compared with other population norms. Consequently, recipient s office BP was related to the individual age-, sex- and height-related percentile of the adapted reference standard (22). Mean ambulatory daytime and nighttime BP values were related to the recipient s adjusted body dimensions- and sex-related percentile for day and night described in the published paediatric normative data for ABPM (23). For analysis purposes, ABPM data from recipients with body height <120 cm were included in the 120-cm group. In the present analysis, Ôcontrolled office BPÕ, i.e. BP within the normotensive range, was defined as the average of three replicate seated systolic and diastolic office BP recordings less than or equal to the 95th age-, sex- and height-matched percentile of the adapted reference standard (22) on the three outpatient visits closest to ABPM. Because these reference values include no measurements of nighttime BP, Ôcontrolled Õ was defined as systolic and diastolic daytime BP 95th distribution adjusted heightand sex-related percentile of the adapted paediatric ABPM reference values (23). On the basis of these definitions, Ônoncontrolled office and daytime Õ, i.e. BP readings within the hypertensive range were defined as systolic and/or diastolic BP values exceeding the 95th percentile of the respective adapted reference standards (22, 23). Systolic and/or diastolic ambulatory nighttime hypertension was defined as mean BP value(s) above the 95th distribution adjusted body dimensions- and sex-related percentile for night (23). According to data derived from healthy children and adolescents (24), non-dippers were arbitrarily defined as those recipients with a percent decline in BP of less than the mean value ) 1 SD (i.e. <7% for systolic BP and/or <14% for diastolic BP respectively). Analysis Results are presented as mean ± SD unless otherwise indicated. Differences between groups were assessed by twosided unpaired t-test for continuous data, and by the analysis of frequency distribution (chi-squared analysis) for categorical variables. The office and daytime mean values were compared by Student s paired t-test. Pearson correlation coefficients were used to investigate the association of office BP with. Comparison of BP recorded by physicians in the office and by ABPM was carried out as suggested by Bland and Altman (25). By applying this approach, the difference between measurements by the two methods can be examined and the discrepancy between the actual measurements and the mean of the two methods can be assessed. Thus, it is assumed that the smaller the SD the better the agreement between the two methods. Accordingly, the 95% limits of agreement were calculated as the mean difference between ABPM and office measurements ±2 SD, and the average of measurements evaluated by the two methods were plotted against their difference for both systolic and diastolic BP. For statistical analysis purpose, office BP recordings obtained over the three outpatient visits closest in time to ABPM were averaged to give a single value, which was regarded as recipient s office BP. A probability value p < 0.05 was considered statistically significant. Results Twenty-six renal transplant recipients (18 males and eight females) met the inclusion criteria for 25

3 Ferraris et al. the analysis. ABPM was performed at the mean age of 14 ± 3.2 years and a mean interval after transplantation of 3.6 ± 3.3 years (range years). All recipients underwent their first transplantation and received triple immunosuppressive treatments consisting of cyclosporin with mycophenolate mofetil and corticosteroid (n ¼ 9) or deflazacort (n ¼ 3), cyclosporine with azathioprine and corticosteroid (n ¼ 2) or deflazacort (n ¼ 2), tacrolimus with mycophenolate mofetil and corticosteroid (n ¼ 8), and tacrolimus with azathioprine and corticosteroid (n ¼ 2). In 11 recipients, antihypertensive drug therapy was initiated before renal transplantation and within 1 15 months after transplantation in 15 recipients. Nineteen recipients were taking dihydropyridine calcium antagonists (nifedipine n ¼ 13, amlodipine n ¼ 4) or angiotensin-converting enzyme inhibitors (enalapril n ¼ 2). In five additional recipients nifedipine was associated with b-blocker (timolol, n ¼ 2), a-blocker (prazosin, n ¼ 2) or enalapril (n ¼ 1). Two recipients were taking amlodipine with b-blocker (atenolol) or with atenolol and prazosin respectively. Overall, only one recipient experienced an episode of acute rejection before ABPM examination. Eight recipients were categorized as having controlled BP by both office and ambulatory measurements and two recipients as having noncontrolled BP by either office or ambulatory measurement. In eight recipients, BP was controlled when measured by office but not by ABPM, with the opposite observed in three recipients. In five recipients, office BP could not be categorized since their office readings fluctuated in one or two of the three outpatient visits closest in time to ABPM. Recipients were further categorized, according to their ambulatory daytime BP values, as having controlled or non-controlled. The characteristics of both groups of recipients are given in Table 1. There were no differences between the groups regarding age, gender, height, weight, body mass index, estimated glomerular filtration rate, office systolic and diastolic BP, donor source and primary diagnosis for renal failure. There were no differences between recipients with controlled and noncontrolled regarding the time elapsed from the transplantation to ABPM examination, 4.1 ± 3.8 years and 2.9 ± 2.8 years, respectively, p ¼ 0.3. A summary of averages for recipients with controlled and non-controlled is given in Table 2. Although the percentage of successful recordings was higher in the former group, the number of successful readings was Table 1. RecipientsÕ characteristics Variable (n ¼ 12) p-value Age (years) Sex (male/female) 10/4 8/4 0.8 Height (cm)* Weight (kg) BMI (kg/m 2 ) Overweight (n) egfr (ml/min/1.73 m 2 ) à Office SBP (mmhg) Office DBP (mmhg) Pre-transplant dialysis (yes/no) 9/5 8/4 0.9 Donor source (n) Living related Deceased Primary diagnosis (n) Renal hypo/dysplasia Congenital nephropathies Acquired glomerulopathies Values are mean SD unless otherwise indicated. BP, blood pressure; BMI, body mass index; egfr, estimated glomerular filtration rate; SBP, systolic blood pressure; DBP, diastolic blood pressure. *In two recipients with controlled and in four recipients with non-controlled height was <120 cm (range and cm respectively). Overweight was defined by applying the cutoff points for BMI by sex (26). à egfr was calculated according to the modified Schwartz Formula (27). Represents the BP average recorded at clinic over the three outpatient visits closest in time to monitoring. Table 2. Results of monitoring Variable (n ¼ 12) p-value Successful recordings (n) Successful recordings (%) Nocturnal sleep (h) h SBP h DBP Daytime SBP Daytime DBP < Nighttime SBP Nighttime DBP Nighttime fall in SBP (%) Nighttime fall in DBP (%) Values are mean SD. Abbreviations as in Table 1. similar in both groups. As expected from methodological definitions, systolic and diastolic daytime and 24-h BP values were significantly lower among recipients with controlled than recipients with non-controlled. Correlations between the two methods were significantly >0 but <1 for systolic but not for diastolic BP in recipients with both controlled and non-controlled, suggesting that office systolic BP readings might be more 26

4 ABPM vs. office BP in paediatric renal transplants Table 3. Correlation coefficients between office SBP and DBP and respective readings Variable (n ¼ 12) r* p-value* r p Office SBP 24-h SBP Daytime SBP Nighttime SBP Office DBP 24-h DBP Daytime DBP Nighttime DBP Abbreviations as in Table 1. *Data are values of correlation coefficients r and p respectively. accurate than diastolic readings in predicting daytime BP values (Table 3). In terms of nighttime BP values, no significant difference was observed between the two groups. The percentage nighttime drop in both systolic and diastolic BP was found to be higher in recipients with non-controlled, Table 2. Overall, nighttime hypertension was identified in 16 of 26 recipients, systolic and diastolic nighttime hypertension in 12, and diastolic nighttime hypertension in four recipients respectively. daytime BP and nighttime hypertension, i.e. poor 24-h BP control of hypertension, was found in six recipients and isolated nighttime hypertension in 10 recipients. Dipping status is summarized in Table 4. When daytime vs. office BP values were compared in the entire group, only daytime systolic BP was statistically different than that obtained by office measurements (125.1 ± 11.1 mmhg vs ± 14.7 mmhg; p < for systolic BP, and 75.7 ± 9.4 mmhg vs ± 11.6 mmhg; p ¼ 0.1 for diastolic BP respectively). Agreement between the two methods of measurements according to the Bland and Altman method is shown in Fig. 1. For systolic and Table 4. Dipping status Dipping status (n ¼ 12) p-value Dipper (n) Systolic non-dipper (n) Diastolic non-dipper (n) Systolic and diastolic non-dipper (n) Non-dipping status is defined as a per cent decline in BP of less than the mean value ) 1 SD, i.e. <7% for systolic BP and/or <14% for diastolic BP respectively (24). diastolic BP, the mean difference was 10.7 and 3.9 mmhg, respectively, and the 95% limits of agreement of the difference were )12.6/ 34.1 mmhg for systolic and )23.9/31.7 mmhg for diastolic BP respectively. Discussion This study conducted through our retrospective review of ABPM usage as a method of reference in treated hypertensive paediatric renal transplant recipients establishes that almost one-third of the test group, in whom BP appeared to be controlled according to office BP recordings, were in fact non-controlled by ABPM criteria. In previous paediatric studies, the prevalence of non-controlled ranged from 45% to 82%, 14 of 31 recipients (18) and 18 of 22 recipients (17) respectively. However, it is noteworthy that these results cannot be deemed comparable as the latter study defined noncontrolled from normative data for office BP readings instead of ABPM references values as defined in the former and our study. In addition, contrary to the current investigation, both studies defined non-controlled by analysing mean daytime and nighttime values together. Moreover, these studies did not report on the agreement between office- and ambulatory-based definitions of BP control as presented here. Despite these discrepancies in data analysis, our investigation, similar to the previous studies, shows that ABPM is a useful tool for assessing true responders to antihypertensive therapy. Of note, in our study the BP threshold for defining non-controlled office BP was arbitrarily set at systolic and/or diastolic BP >95th age-, sex- and height-matched percentile of the adapted reference standard (22). This limit, as it has been comprehensively discussed in the literature, is a statistical rather an outcome-based definition as cardiovascular events secondary to arterial hypertension are extremely rare in the paediatric population. Furthermore, there are so far no available prospective paediatric data showing that long-term antihypertensive therapy, either by lowering BP to less than 95th or 90th percentile, may preclude or reverse hypertensive end-organ damage as evaluated by means of surrogate markers of cardiovascular disease, i.e. structural or functional abnormalities regarded as early markers of hypertension sequelae. In comparison with earlier reports (14 18), we also identified a large number of recipients with nighttime hypertension, which like distorted circadian BP rhythm cannot be detected by office 27

5 Ferraris et al. Fig. 1. Comparison of systolic and diastolic daytime ambulatory and office blood pressure according the method of Bland and Altman (SBP, systolic blood pressure; DBP, diastolic blood pressure). BP readings. Thus, in treated hypertensive recipients, ABPM provides additional information on BP control during nighttime. It should be stressed that in the current study there were no differences in nighttime BP values between groups. This might explain the fact that a larger per cent decline in nocturnal BP was observed among recipients with non-controlled daytime compared to recipients with controlled BP. Although the clinical significance of blunted physiological nocturnal fall of BP in paediatric renal transplant recipients, i.e. non-dippers, remains so far unknown (17) it has been suggested to indicate underlying renovascular pathology (14). However, the distinction between dipper and non-dipper recipients as reported in the present investigation remains questionable on the basis of a single ABPM study (28). Although nearly half of our study population was found to have non-controlled daytime it cannot be said that the antihypertensive therapy they received was ineffective as we cannot exclude the possibility that non-adherence to treatment might have contributed to the poor control of BP (29). At our institution, education about non-pharmacological and pharmacological measures is regularly reinforced at every visit. RecipientsÕ parents are usually motivated to play an active role in the follow up, for instance, by reporting side effects that might be related to the medication or if agreeable, by recording BP at home. Due to these measures, we hypothesize that non-compliance would then not account for the difference in BP observed between recipients with controlled and non-controlled. On the other hand, it can also be speculated that if antihypertensive treatment has been based upon ABPM a large number of recipients would have benefit from a better control of BP. The use of office BP recordings still remains the routine screening tool to assess paediatric population for hypertension (22, 30). An important consideration, while interpreting office BP readings obtained by auscultatory methods, is that BP measurements during office visits should be of a high standard as improper BP measurement techniques can result in the overdiagnosis or underdiagnosis of hypertension (22, 30). However, one of the major limitations of BP readings obtained on an intermittent basis is the high variability of BP, i.e. the small number of readings obtained at a clinic visit may not mirror patient s usual BP (31). In this regard, ABPM, by carrying out repeated BP recordings over a 24-h period and without being subject to observer bias, provides more representative values of BP than office recordings (32). For this reason, as office BP and ABPM do not measure the same BP, it is not surprising that a considerable variation among recipients in the magnitude of BP measurements obtained by the two methods was observed (Fig. 1). This observation correlates with a previous study where the long-term reproducibility of ABPM in children with renal allografts was shown to be superior to that of office measurements (28). 28

6 ABPM vs. office BP in paediatric renal transplants Ambulatory BP monitoring also allows the identification of children with white coat hypertension (33), a condition that can lead to overdiagnosis of hypertension and subsequent unnecessary treatment, as well as the opposite phenomenon, i.e. normal office BP but hypertension by ABPM criteria. As a consequence of this, ABPM has been more widely used in the transplant clinic in recent years and has been suggested as a standard method for the diagnosis and therapeutic monitoring of hypertension in paediatric renal recipients (3, 34). However, the latest recommendations for diagnosis, evaluation, and treatment of hypertension in children and adolescents (22) do not indicate ABPM as a clinical tool for the assessment of efficacy of antihypertensive therapy. Our study presents compelling evidence, which shows that if office BP remains as the main method of choice in the assessment of efficacy of antihypertensive treatment, a substantial number of recipients with non-controlled would be missed. In conclusion, we believe that ABPM should be considered as an adjunct to office BP readings to better characterize the recipient s BP pattern. Acknowledgments The authors would like to thank Professor Ulla B. Berg for her critical review of this study. Dr Krmar was supported by grants from the Freemason s Stockholm Foundation for Children s Welfare and the Samariten Foundation. Conflicts of interest None. References 1. Kasiske BL, Anjum S, Shah R, et al. Hypertension after kidney transplantation. Am J Kidney Dis 2001: 43: Baluarte HJ, Gruskin AB, Ingelfinger JR, Stablein D, Tejani A. Analysis of hypertension in children post renal transplantation a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). 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