Ambulatory blood pressure measurements.

Ambulatory blood pressure monitoring (ABPM) has emerged as a valuable clinical and research tool in the assessment of pediatric hypertension. Large databases of 24-hour blood pressure monitorings in healthy children are under development for establishing normal reference values analogous to the Task Force data for casual blood pressure. In the clinical setting, pediatric studies using ABPM to evaluate elevated blood pressure have shown that the prevalence of white coat hypertension in children is similar to that reported in adults. Furthermore, 24-hour blood pressure parameters are correlated with hypertensive end-organ injury such as left ventricular hypertrophy. ABPM has allowed detailed assessment of circadian blood pressure patterns that show early subtle abnormalities in some high-risk groups and normal patterns in other groups previously thought to be at high risk. These studies will assist in the practice of evidence-based medicine regarding pediatric hypertension that will improve the long-term care that pediatricians provide to their patients.

Comparison of the actigraph versus patients' diary information in defining circadian time periods for analyzing ambulatory blood pressure monitoring data.

BACKGROUND: Assessment of 24-h changes in blood pressure is one of the unique features that ambulatory blood pressure monitoring (ABPM) can provide. Most studies agree that sleep/wake periods should be based on patients' actual sleep and wake times. Actual wake and sleep time determinations are often based on patients' diary information. Several publications indicate that actigraphy is, at least, as accurate as activity diary in determining sleep/wake periods. OBJECTIVES: To compare subjects' compliance with actigraphy and diary keeping and to compare actigraphy and diary data in determination of sleep and wake times, mean blood pressures, classification of hypertension, and assessment of nocturnal dipping status. METHODS: We evaluated ABPM studies of 62 subjects. Blood pressure data were obtained using Spacelabs monitors for 24h. Sleep and wake times were determined by both the actigraph and patients' activity diary. RESULTS: In the 62 studies, 56 subjects had successful actigraphy (90%), 44 had activity diary completion (71%), and 38 subjects had both (61%). There was no statistically significant difference between the mean wake and sleep onset using the two methods, but up to 3 hours' difference in wake or sleep onset was noted in some studies. Although the two methods did not significantly affect the calculated systolic blood pressure (SBP) or diastolic blood pressure (DBP) loads in either awake or sleep periods, approximately 55% of the subjects' dipping status was changed when diary information on sleep time was used compared to actigraph. CONCLUSIONS: Our data indicate that in children and young adults, compliance with the actigraph was superior to diary completion and use of the actigraphy method rather than diary information changed the interpretation of some ABPM data. Our study suggested that actigraphy is superior to diary keeping in providing the information needed for appropriate interpretation of some ABPM data.

Reduced variability of neoral pharmacokinetic studies in pediatric renal transplantation.

In adult renal transplant recipients the Neoral area under the curve (AUC) displays less inter- and intra-individual variability than Sandimmune, and those renal transplant recipients with reduced intra-individual variability of the AUC have a lower risk for chronic rejection. As variability of Neoral pharmacokinetic (Pk) parameters has not been investigated in pediatric renal transplant recipients, we retrospectively analyzed 453 Pk profiles in 14 pediatric patients who were switched from Sandimmune to Neoral and compared the inter- and intra-individual variability of the Pk profiles on both formulations. After the switch, we observed less inter- and intra-individual variability of AUC, the 2-h concentration, and the oral clearance. As clearance with both formulations is supposedly equal, the significantly lower intra-individual variability of oral clearance is most likely an effect of less variable absorption. While the lower inter-individual variability of the Pk parameters suggests increased success in keeping cyclosporine concentrations on target, the lower intra-individual variability leads to the hypothesis that with Neoral, a lower incidence of chronic rejection might be achieved.

White coat hypertension in children with elevated casual blood pressure.

OBJECTIVE: We reviewed our experience using ambulatory blood pressure monitoring (ABPM) in children referred to a hypertension clinic to determine the frequency of pediatric white coat hypertension (WCH). STUDY DESIGN: WCH was defined by 3 different diagnostic criteria: (1) mean 24-hour blood pressure (BP) less than Task Force-defined 95th percentile, (2) mean 24-hour BP less than 95th percentile from pediatric normative ABPM data, and (3) mean 24-hour BP less than ABPM 95th percentile and BP load (percentage of BP readings during 24-hour period exceeding the 95th percentile) less than 25%. RESULTS: Clinic BP values were available in 67 otherwise healthy children who underwent ABPM; 51 had confirmed clinic hypertension by Task Force criteria. WCH frequency in these 51 patients with the stated criteria was 53%, 45%, and 22%, respectively. Elevated BP load was found in 52% (12/23) of patients with normal mean BP. CONCLUSION: These results suggest that many children referred for casual BP elevation have WCH even by strict diagnostic criteria. ABPM may help differentiate WCH from persistent hypertension, thereby avoiding unnecessary diagnostic evaluation and identifying children most likely to benefit from early intervention.

Evaluation and management of proteinuria and nephrotic syndrome in children: recommendations from a pediatric nephrology panel established at the National Kidney Foundation conference on proteinuria, albuminuria, risk, assessment, detection, and elimination (PARADE).

OBJECTIVE: The development of this review article evolved from a National Kidney Foundation consensus conference on recent advances in the importance of evaluating and treating proteinuria. From this conference, a series of recommendations for the evaluation of adults with proteinuria was published. Because specific pediatric aspects of the problem were outside the scope of the original National Kidney Foundation publication, an ad hoc committee of 6 pediatric nephrologists who were active participants in the National Kidney Foundation conference was established to provide primary care physicians with a concise, up-to-date reference on this subject. METHODS: The recommendations that are given represent the consensus opinions of the authors. These are based on data from controlled studies in children when available, but many of the opinions are, by necessity, based on uncontrolled series in children or controlled trials performed in adults, because controlled trials in children have not been performed to evaluate many of the treatments described. RESULTS AND CONCLUSIONS: These recommendations are intended to provide primary care physicians with a useful reference when they are faced with a young child or teenager who presents with proteinuria, whether this is mild and asymptomatic or more severe, leading to nephrotic syndrome.

Use of anti-hypertensive medications and post-transplant renal allograft function in children.

Post-transplant hypertension is a common occurrence in children. The relative effect of this hypertension on renal allograft function is uncertain. Examining the accumulated data for pediatric renal transplant recipients at our institution from monthly visits for up to three years, we determined whether the use of anti-hypertensive medications (anti-HTN medications) was associated with allograft dysfunction. Monthly clinical data included height, weight, serum creatinine, cyclosporin A (CsA) trough levels, number of acute rejection episodes, and number of anti-HTN medications. Estimated glomerular filtration rate (eGFR) was calculated monthly for each patient using the Schwartz formula. Time post-transplant was grouped into 6-month intervals. One thousand three hundred and sixty-three monthly data sets from 6 months (n = 76 patients) to 3 yr post-transplant (n = 47 patients) were analyzed. Overall mean eGFR was 75 mL/min/1.73 m2 at 6 months and 54 mL/min/1.73 m2 at 3 yr. A lower eGFR was found at all post-transplant time intervals for patients receiving anti-HTN medications compared with those who were not (p < 0.01). This lower eGFR was found at some but not all times post-transplant when patients were grouped by donor type or history of acute rejection episodes and analyzed separately. Mean CsA trough levels were higher at all post-transplant time intervals in patients receiving anti-HTN medications (p < 0.05). While a causal relationship between post-transplant hypertension and graft dysfunction cannot be established from this study, we conclude that the need for anti-HTN medications is associated with worse allograft function.

Comparison of arbitrary definitions of circadian time periods with those determined by wrist actigraphy in analysis of ABPM data.

Determining blood pressure (BP) values at different daily time periods is a well recognised measure to assess the risk of end-organ damage. However, the use of various definitions of these periods, eg, day vs night, sleep vs wake or arbitrary definitions, makes clinical decisions based on available data difficult. In the present study, we compared BP loads in actual sleep-wake periods to default day-night definition provided by the ambulatory BP monitoring (ABPM) software (day 06.00 to 22.00; night 22.00 to 06.00) as well as to an arbitrary definition of sleep-wake periods in children published in Soergel et al (J Pediatr 1997; 130: 178-184)1 (awake 08.00 to 20.00 and sleep 00.00 to 06.00. We used an actigraphy, an accelerometer, to define the actual sleep-wake periods in 46 patients with essential hypertension who are on various treatment regimens. BP data was obtained by using Spacelabs 90207 monitors for a full 24 h. There were significant differences between actual sleep-wake and default definition for BP load. No similar finding was noted when arbitrary definition was used. The proportion of hypertensives was not significantly different when default and arbitrary definitions were used. Classification of dippers and non-dippers is greatly affected by the definition of sleep interval using the default method. Although some of the misclassifications were not statistically significant, their clinical importance must be considered. Determination of sleep and wake periods for analysis of ABPM data should be based on careful determination of actual periods. Using other definitions may not provide complete information or accommodate for individual variation.

Serial estimation of glomerular filtration rate in children after renal transplant.

Evaluation of serial monthly estimated glomerular filtration rate (eGFR) may be useful for studying pediatric renal allograft outcome. To determine the validity of this approach, we reviewed our single-center experience in pediatric renal transplant recipients to determine the effect of risk factors for renal allograft failure on eGFR. Clinical parameters recorded monthly through 5 years post transplant allowed serial assessment of eGFR. Monthly clinical data included height, weight, serum creatinine, cumulative number of acute rejection episodes, cyclosporine dose, and cyclosporine trough levels. From these data, eGFR was calculated monthly for each patient using the Schwartz formula. Time post transplant was grouped in 6-month intervals and plotted against mean eGFR to compare eGFR in patients grouped by demographic and clinical factors; 1,786 monthly data sets from 6 months post transplant (n=76 patients) to 5 years post transplant (n=25 patients) were analyzed. Overall mean eGFR from 6 months to 1 year was 75 ml/min per 1.73 m(2) and from 4. 5 to 5 years 46 ml/min per 1.73 m(2). eGFR was lower at all time intervals for recipients of cadaver versus living-related donor grafts, and patients with >/=1 versus 0 acute rejections (P<0.01). After 1 year, eGFR was lower in black patients compared with white or Hispanic patients (P<0.01). Cyclosporine dose greater than 5 mg/kg per day was associated with better early and worse late graft function. These results are similar to those reported in multi-center studies using the outcome variable of graft failure and suggest that serial eGFR may be valid as an outcome variable to study chronic renal allograft dysfunction in children.

A limited sampling strategy for the estimation of Neoral AUCs in pediatric patients.

The improved pharmacokinetics of Neoral allows the development of an accurate estimate of the full area under the concentration time curve (AUC) from a limited sampling strategy. As no such strategy has been derived from pharmacokinetic data obtained from children on 12-hourly dosing, and as patient convenience demands shorter sampling times, we derived a limited sampling strategy from 45 AUCs obtained from 19 pediatric renal transplant patients by stepwise forward multiple regression, and prospectively tested them on a separate group of 49 AUCs obtained from 18 pediatric renal transplant patients. Full cyclosporine (CsA) AUCs were obtained from samples drawn pre dose (C0) and at 2, 4, 6, 8 and 12 h post dose (C2, C4, C6, C8, and C12). High-precision predictions of full AUC were obtained based on the formula: AUC = 444 + 3.69 x C0 + 1.77 x C2 + 4. 1 x C4 (mean prediction error +/- SD = 0.3 +/- 6.4%, 95% confidence interval=-1.7% to 1.9%.) In conclusion, CsA exposure in pediatric renal transplant patients on 12-hourly Neoral dosing can be reliably predicted by an early time point-based limited sampling strategy in children. This formula has the advantage of obtaining trough as well as AUC from one brief, convenient sampling period.

Population studies of ambulatory blood pressure monitoring in Brazilian children.

BACKGROUND: The determination of hypertension in a given population depends on the knowledge of population norms for blood pressure. This is true for both casual blood pressure (CBP) measurements and the newest and most promising technology of ambulatory blood pressure monitoring (ABPM). OBJECTIVE: To design an ambitious multinational co-operative study to determine normal blood pressure data in Brazilian children. METHODS: The study was designed to determine normative data for CBP, using the Task Force technical recommendations for age-, sex- and height-percentile-specific blood pressure values. The proposed procedure is as follows. ABPM will be studied in a random subgroup of individuals, to develop similar normative data. These data will be correlated to CBP measurements and to echocardiographic findings as a measure of end-organ damage. All patients who are diagnosed by CBP measurement to be hypertensive will also be studied by ABPM, and studies of target-organ damage will be performed. Family and medical histories will be evaluated by questionnaire and first-degree relatives will be evaluated for CBP measurement. Hypertensive patients will form a cohort for long-term follow-up. These data will be the foundation for studies of hypertension in Brazilian children.

Technical aspects of blood pressure measurement in pediatric patients.

BACKGROUND: Prolonged hypertension in adults has been associated with end-organ damage, in addition to increased morbidity and mortality. Accurate measurement of blood pressure in pediatric and adult patients is imperative for the appropriate diagnosis of hypertension, so that measures may be instituted to prevent these adverse sequelae. Although intermittent office measurement of blood pressure is practiced in most parts of the world, the technique is fraught with problems. Errors during the actual measurement and difficulties in interpretation of the data are well-studied challenges associated with intermittent blood pressure measurements that have been well studied. Ambulatory blood pressure monitoring offers several advantages over intermittent measurement: blood pressure measurements are available over a prolonged period of time (including the sleep period), measurements are not as dependent on observer biases as are intermittent measurements, and in adults the data appear to correlate well to measures of end-organ damage. In children, the ambulatory blood pressure monitor is well tolerated and accurate. This new technology may offer pediatric specialists the opportunity to identify more accurately the child with increased blood pressure, so that preventive measures can be instituted to reduce the well-known morbidity and mortality associated with hypertension. OBJECTIVE: To review the technical aspects of blood pressure measurement in children, with special attention to the emerging field of ambulatory blood pressure monitoring and its potential use in children.

Stress-induced alterations of blood pressure and 24 h ambulatory blood pressure in adolescents.

OBJECTIVE: To examine the extent to which ambulatory blood pressure was predicted by blood pressure levels exhibited during talking segments of a laboratory protocol and by resting blood pressures in male and female adolescents from three ethnic groups: African, European and Hispanic Americans. DESIGN: This was a laboratory-field study incorporating an experimental study of reactivity of blood pressure during a laboratory protocol and an observational study of 24h ambulatory blood pressure (ABP) monitoring. METHODS: Resting blood pressure, reactivity of blood pressure, 24h ABP, and activity, height, and maturation of a multi-ethnic sample of 373 male and female adolescents aged 11-16 years were measured. A mixed-effects model for repeated measures was the statistical approach, with systolic and diastolic blood pressures as separate, dependent variables. RESULTS: Percentiles of ABP by sex, ethnic group, and height are presented. High and mixed blood pressure reactors in the laboratory had higher levels of 24h ABP and higher levels of blood pressure load during the daytime. African Americans had higher ABP than did European and Hispanic Americans. CONCLUSIONS: Blood pressure measured during laboratory tasks that require talking might be useful as a screening device to identify adolescents with high blood pressures. Further study will be necessary in order to quantify the sensitivity of the laboratory protocol as an indicator of high blood pressure compared with casual measurement of blood pressures. If laboratory patterns of blood pressure could be used to predict which individuals have high levels of blood pressure during the course of daily activities, the laboratory protocol would be a useful screening tool, identifying high-risk individuals.

Comparison of arbitrary definitions of circadian time periods with those determined by wrist actigraphy in analysis of ABPM data.

Determining blood pressure (BP) values at different daily time periods is a well recognised measure to assess the risk of end-organ damage. However, the use of various definitions of these periods, eg, day vs night, sleep vs wake or arbitrary definitions, makes clinical decisions based on available data difficult. In the present study, we compared BP loads in actual sleep-wake periods to default day-night definition provided by the ambulatory BP monitoring (ABPM) software (day 06.00-22.00; night 22.00-06.00) as well as to an arbitrary definition of sleep-wake periods in children published in Journal of Pediatrics (Soergel et al, 1997) (awake 08.00-20:00 and sleep 00.00-06.00). We used an actigraph, an accelerometer, to define the actual sleep-wake periods in 46 patients with essential hypertension who are on various treatment regimens. BP data were obtained by using Spacelabs 90207 monitors for a full 24 hours. There were significant differences between actual sleep-wake and default definition for BP load. No similar findings were noted when arbitrary definition was used. The proportion of hypertensives was not significantly different when default and arbitrary definitions were used. Classification of dippers and non-dippers is greatly affected by the definition of sleep interval using the default method. Although some of the misclassifications were not statistically significant, their clinical importance must be considered. Determination of sleep and wake periods for analysis of ABPM data should be based on careful determination of actual periods. Using other definitions may not provide complete information or accommodate for individual variation.

Antihypertensive medication and renal allograft failure: a North American Pediatric Renal Transplant Cooperative Study report.

Hypertension after renal transplantation occurs commonly and, in adults, is associated with decreased graft survival. The North American Pediatric Renal Transplant Cooperative Study database was analyzed to determine: (1) the percent use of antihypertensive (anti-HTN) medication based on donor type, race, age, and acute rejection status; and (2) whether use of anti-HTN medication is associated with higher rates of subsequent graft failure. Data regarding anti-HTN medication use was available in 5251 renal allografts (4821 patients) with >30 d graft function. Posttransplant follow-up data were collected at 30 d, 6 mo, 12 mo, and then annually for 5 yr. At each follow-up, patients were selected for further analysis if the graft was functioning at that visit and subsequent follow-up data were available. Overall, anti-HTN medication use was 79% on day 30 and 58% at 5 yr. At each follow-up, anti-HTN medication use was higher (P < 0.01) for cadaveric donor versus living related donor, blacks versus whites, age >12 versus <12 yr, and > or = 1 versus 0 acute rejection episodes. Anti-HTN medication use at each annual follow-up was associated with significantly higher rates of subsequent graft failure. Multiple regression analysis controlling for all factors associated with increased use of anti-HTN medications revealed a relative risk of graft failure for use of anti-HTN medication of greater than 1.4 (P < 0.001). In recipients of cadaveric allografts, only acute rejection status predicted subsequent graft failure more strongly than use of anti-HTN medications. These data suggest that hypertension after renal transplantation in children, as evidenced by use of anti-HTN medications, is associated with increased rates of subsequent graft failure.

Changing patterns in the histopathology of idiopathic nephrotic syndrome in children.

BACKGROUND: It is widely accepted that minimal change nephrotic syndrome (MCNS) is the most common cause of nephrosis in children. Recent studies have demonstrated an increasing incidence of focal segmental glomerulosclerosis (FSGS) in adults. METHODS: To determine possible changes in the etiology of childhood nephrosis, the clinical charts of 152 pediatric patients diagnosed with idiopathic nephrotic syndrome between 1978 and 1997 were reviewed. Histopathological diagnosis was available in 105 patients. RESULTS: MCNS was present in 35% of all biopsies, whereas FSGS was observed in 31%. Even if we assume that all patients without a histological diagnosis had MCNS (presumptive MCNS), the total incidence of MCNS (biopsy proven + presumptive) in our population was only 55%. We observed a dramatic increase in the incidence of FSGS during recent years. Before 1990, FSGS was diagnosed in 23% of all renal biopsies but increased to 47% afterward (P = 0.02). This pattern was observed in all ethnic groups. In African Americans, there was a trend for an increase in the incidence of FSGS from 38% before 1990 to 69% after 1990. A similar trend was observed in Caucasians (from 20 to 45%) and Hispanics (from 8 to 33%) Hispanics had the highest incidence of MCNS (biopsy proven + presumptive: 73%), followed by Caucasians (53%) and African Americans (37%). The mean age for presentation of nephrotic syndrome in African Americans (8.0 +/- 0.9 years) was higher than in Caucasians (4.1 +/- 0.05) and Hispanics (3.3 +/- 0.5). CONCLUSIONS: Our study showed that the incidence of FSGS in children with idiopathic nephrotic syndrome has increased recently. Furthermore, in African American children. FSGS is the most common cause of nephrotic syndrome. These findings may have significant implications in the management of childhood nephrotic syndrome.

Ambulatory blood pressure monitoring and interdialytic weight gain in children receiving chronic hemodialysis.

Volume overload appears to induce hypertension in hemodialysis patients, yet studies of the effect of hydration status on interdialytic blood pressure (BP) have yielded contradictory results. We measured interdialytic BP by ambulatory BP monitoring (ABPM) during inpatient fluid restriction in 12 children receiving chronic hemodialysis to describe the overall BP pattern and to determine the effect of weight gain on BP change. Weight was measured on admission and four times each day. For each weight, casual BP was measured and compared with the mean of 3 hours of ABPM surrounding the weight measurement. Sleep BP decreased from daytime BP by 6% for systolic BP (SBP) and 11% for diastolic BP (DBP). Sleep loads were greater than daytime loads (P < 0.01) for SBP (53% v 28%) and DBP (57% v 27%). Overall, 58% (7 of 12) of the patients had sleep SBP load greater than 50%, and 67% (8 of 12) of the patients had sleep DBP load greater than 50%. Casual and ABPM measurements of BP showed moderate correlations for SBP (r = 0.51) and DBP (r = 0.46) and mean differences between methods of 6.3 +/- 13.2 mm Hg and -1.4 +/- 12.6 mm Hg, respectively. Increases in interdialytic weight were positively associated with increases in SBP (r = 0.41; P < 0.001), and interdialytic BP changes varied closely with corresponding weight changes. We conclude that in children receiving chronic hemodialysis: (1) sleep BP decreases are attenuated and sleep BP loads are elevated, (2) casual BP correlates poorly with ABPM, and (3) interdialytic weight and BP are related.

A limited sampling strategy for the estimation of eight-hour neoral areas under the curve in renal transplantation.

Neoral, the microemulsion formulation of cyclosporine (CsA), demonstrates more consistent bioavailability than the corn oil formulation Sandimmune. Because of Neoral's rapid peak and metabolism, 8-hour dosing has to be used in many pediatric and some adult patients to maintain adequate CsA peak-to-trough ratios. Although the area under the curve (AUC) is considered the best estimate of total drug exposure, it requires repeated blood sampling. Abbreviated AUC profiles yielding excellent estimates of Neoral AUC with twice daily dosing have been described, but no such abbreviated strategy exists for 8-hour dosing. One hundred fifty-two pharmacokinetic profiles in 23 patients were used to derive and prospectively test a limited two-sample strategy to predict Neoral AUCs in pediatric and adult patients on 8-hour dosing regimens of Neoral. The formula was derived from 69 full 8-hour CsA pharmacokinetic profiles in nine children who underwent renal transplantation. Stepwise forward linear and multiple-curve regression techniques assessed the relative importance of single and combination concentration time points to predict AUC. The abbreviated profiles were validated by comparing the mean prediction error for each regression equation. The abbreviated profile calculated by second (C2)- and fourth (C4)-hour levels (AUC = 129 + 1.84 x C2 + 4.39 x C4) correlated well with the full AUC (r2 = 0.96; p < 0001). Mean prediction error was -0.4% +/- 5.48%, and no values fell outside the clinically acceptable 15% prediction error limit. Prospectively applying the formula to 83 AUCs of 14 adults who underwent renal transplantation and were taking Neoral three times a day demonstrated an excellent fit (r2 = 0.93; p < 0.001), with 94% of predicted values falling inside the +/-15% limit. The authors describe the development of a clinically acceptable, limited sampling strategy to predict 8-hour Neoral AUCs in children and adults who underwent renal transplantation.