Evaluation of white coat hypertension in children: importance of the definitions of normal ambulatory blood pressure and the severity of casual hypertension.

To better describe the phenomenon of white coat hypertension (WCH) in children, we reviewed our single-center experience using ambulatory blood pressure monitoring to determine: 1) how the choice of threshold limits for defining ambulatory hypertension affects the determination of WCH, and 2) whether the severity of casual hypertension predicts the occurrence of WCH. Using the same daytime ambulatory blood pressure (ABP) data from 71 children (age 11.9 3.4 years) with persistently elevated casual blood pressure (BP), the prevalence of WCH was compared using 95th percentile BP limits from the Task Force on High Blood Pressure in Children (TF) and from normative pediatric daytime ambulatory BP (ABP) data. To quantify casual hypertension severity, average clinic BP was divided by the patient-specific TF 95th percentile BP to generate a BP index (ie, BP index of 1.1=10% above 95th percentile). The WCH prevalence was lower by normative ABP criteria than by TF criteria (31% v 59%, P < .001), but did not vary significantly by age, gender, race, or body mass index. Logistic regression showed that higher systolic BP index (P < .001) or diastolic BP index (P < .01) was associated with a lower probability of WCH. Specifically, as systolic BP index increased from 1.0 to 1.2, the estimated probability of WCH decreased from 87% to 15%, respectively. These data suggest that the use of the lower TF limits, derived solely from resting BP measurements, may overestimate WCH prevalence in ambulatory children. In addition, these data confirm in children the finding in adults that WCH is highly prevalent when casual hypertension is borderline or mild, but uncommon when moderate or severe.

Long-term treatment of focal segmental glomerulosclerosis in children with cyclosporine given as a single daily dose.

Cyclosporine (CsA) has been successfully used for treatment of children with focal segmental glomerulosclerosis (FSGS) and nephrotic syndrome (NS) for the last decade. Response rates of 50% to 100% have been reported using twice-daily dosing of 5 to 32 mg/kg/d, achieving trough blood levels of 70 to 500 ng/mL. Treatment has been associated with a high incidence of side effects, including nephrotoxicity, hypertension, gingival hyperplasia, and hirsutism. To determine whether once-daily low-dose CsA could minimize side effects and still induce remission, 21 children with biopsy-proven FSGS and NS, each treated with CsA, 4.6 +/- 0.8 mg/kg/d, with no predetermined target trough blood levels, were studied. Eleven of 21 children (52%) attained complete remission and 5 of 21 children (24%) attained partial remission, for a total response rate of 76%. Mean time to response was 2.8 +/- 0.8 months, and mean duration of therapy was 20.6 +/- 13.7 months. CsA dosage was tapered or stopped in 9 responders; 3 of these patients maintained remission at last follow-up 6 to 13 months later, and 6 patients relapsed at 1.5 to 18.7 months (mean, 8.7 months). Five of these 6 patients responded again when CsA therapy was restarted or the dosage was increased. Twelve of 16 responders were still being administered CsA at last follow-up 11 to 60 months (mean, 24.6 months) later. Five of 21 patients (24%) had no response to CsA during 2 to 27 months of therapy; 4 of these 5 patients developed end-stage renal disease after CsA therapy was stopped. Side effects of CsA therapy were minimal: 1 patient each developed new-onset hypertension or gingival hyperplasia, and no patient had hirsutism or nephrotoxicity. Single daily low-dose CsA appears to be effective for long-term treatment of children with FSGS and NS, with fewer side effects than twice-daily dosing.

Screening for eligibility in the study of antihypertensive medication in children: experience from the Ziac Pediatric Hypertension Study.

BACKGROUND: The FDA Modernization Act has resulted in an increase in pediatric trials of antihypertensive medications. As experience is limited in children to guide the planning of these studies, we reviewed data from the Ziac Pediatric Hypertension Study to determine patterns of early study termination to help future studies. METHODS: For inclusion, subjects aged 6 to 17 years were required to have an average systolic blood pressure (SBP) or diastolic blood pressure (DBP) above the 95th percentile at the last of three visits during 2 weeks of single-blind placebo screening. Early study termination was defined as early termination for any reason. Screening termination was defined as normalization of blood pressure (BP) during the placebo screening phase. RESULTS: Early study termination rate was 27% (38 of 140 subjects). The most common reason was screening termination due to normalization of BP, accounting for 63% of all early study terminations. Among screening termination subjects who completed three screening visits, SBP was higher (P < .001) at visit 1 (129+/-8 mm Hg) than at visit 2 (123+/-7 mm Hg) or visit 3 (121+/-8 mm Hg), but did not differ between visits 2 and 3. Screening termination occurred in 15% with isolated SBP hypertension, and 21% with isolated DBP hypertension. At randomization, 83% had SBP hypertension and 53% had DBP hypertension. CONCLUSIONS: These data suggest that SBP hypertension should be part of inclusion criteria to increase enrollment and reduce the rate of screening termination, and that 1-week placebo screening is necessary and sufficient to minimize inclusion of transiently hypertensive subjects.

Systolic hypertension in children: benign or beware?

Systolic blood pressure (SBP) has become the major criterion for the diagnosis, staging, and treatment of hypertension in adults, based on the epidemiology and pathophysiology of adult hypertension, linkage between SBP levels and disease, and benefits of treatment of isolated SBP hypertension. Although children do not typically suffer overt hypertensive disease, an accumulation of data suggests that SBP elevation is as important a factor in the morbidity of hypertension in children as in adults. SBP hypertension is more common in children, whether examining an unselected sample of patients by routine screening or a selected sample of referred hypertensive patients. Mild-to-moderate BP elevation in children is associated with increased left ventricular mass (LVM), with SBP more closely linked to LV morphology than diastolic blood pressure (DBP). Furthermore, SBP is associated with increased LVM even in patients with SBP within the "normal" range. Among hypertensive children, the reported prevalence of LVH ranges from 30% to 70%, and LV hypertrophy is more closely related to SBP than to DBP. These data suggest that treatment of hypertension should be directed at normalization of SBP, even when DBP is within the normal range. In addition, trials of anti-hypertensive medications in children should incorporate SBP hypertension into study inclusion criteria.

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.

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.

White coat hypertension in children.

Ambulatory blood pressure monitoring (ABPM) has become more widely used in the assessment of elevated blood pressure in children. The accurate diagnosis of white coat hypertension (WCH) is particularly important in children because detection of elevated blood pressure often results in expensive and invasive diagnostic procedures to detect underlying disease. Recent normative pediatric data have both enhanced our ability to interpret ABPM results in pediatric patients and increased awareness that children suffer from WCH as has already been reported in adults. The few studies of WCH in children report a prevalence ranging from 44-88%, depending on the choice of threshold values for normalcy. When persistent hypertension is confirmed by three blood pressure measurements on three different occasions, ABPM should be performed as part of the initial evaluation. If hypertension is confirmed by ABPM, further evaluation should be tailored to the individual patient depending on the age, severity of hypertension, associated risk factors, and presence of end-organ injury.

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.

Abnormal 24-hour blood pressure patterns in children after renal transplantation.

Hypertension after renal transplantation occurs commonly and is associated with decreased allograft survival. Hypertension is usually diagnosed by casual blood pressure (BP) measurements in the outpatient clinic that may not reflect the overall 24-hour BP pattern. To better describe the pattern of BP in children after renal transplantation, 24-hour ambulatory BP monitoring (APBM) was performed in 42 patients with stable renal function. BP was measured every 20 minutes during the daytime and every 30 minutes at night. Mean patient age was 12.8 +/- 5.2 years, and mean time after transplantation was 34 +/- 36 months. Seventy-six percent of the patients were administered antihypertensive medications. Twenty-four-hour mean systolic BP (SBP) was 127 +/- 11 mm Hg, and diastolic BP (DBP) was 80 +/- 11 mm Hg. Mean 24-hour BP load values (percentage of BP readings > 95th percentile based on Task Force criteria) were 59% for SBP and 50% for DBP, which were significantly elevated compared with healthy children (P < 0.001). An attenuated decline in sleep BP (nondipping) was found in 78% of the patients for SBP and 50% for DBP. Sleep BP exceeded awake BP in 24% of the patients for SBP and 17% for DBP. Boys had a greater SBP load (66% versus 45%; P = 0.03) and DBP load (57% versus 38%; P = 0.04) than girls. These results confirm in children the high prevalence of hypertension by ABPM criteria after renal transplantation and show attenuation of normal sleep BP decreases. These BP disturbances may shorten renal allograft survival and predispose children to long-term hypertensive end-organ damage.

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.

Early initiation of peritoneal dialysis after surgical repair of congenital heart disease.

The mortality rate of infants who require renal replacement therapy after surgical repair of congenital heart disease has been reported to be 30%-79%. We report our experience with early initiation of continuous manual peritoneal dialysis (CPD) to treat fluid overload in 20 consecutive critically ill children who underwent CPD post cardiotomy. CPD catheters were inserted at the discretion of the cardiothoracic surgeon. CPD was started for evidence of total body fluid overload with inadequate urine output, and stopped when negative fluid balance was achieved and urine output improved. Median age was 10 days (range 3-186 days), mean time to start CPD post-operatively was 22 h (range 5-40 h), and mean duration of CPD was 50 h (range 13-92 h). CPD resulted in mean ultrafiltration of 93 ml/kg per day (range 43-233 ml/kg per day). Net negative fluid balance was 106 ml/kg per day (range 49-273 ml/kg per day). During CPD, the mean number of inotropes decreased from 2.2 to 1.6 (P<0.05) and urine output increased from 2.2 to 3.9 ml/kg per hour (P<0.01). No patient died during CPD or had CPD discontinued due to adverse hemodynamic effects. The overall mortality rate was 20%. We conclude that early initiation of CPD can safely and effectively promote fluid removal in infants after repair of congenital heart disease, with a lower mortality rate than has previously been reported.

Ambulatory blood pressure monitoring in pediatric end-stage renal disease: chronic dialysis and transplantation.

Hypertension is highly prevalent in pediatric patients with end-stage renal disease (ESRD). Ambulatory blood pressure monitoring (ABPM) has been used to characterize the altered circadian blood pressure patterns in ESRD in order to improve our understanding of the blood pressure dysregulation that occurs in these children. In children receiving chronic hemodialysis, 24-h blood pressure load elevation and a high prevalence of non-dipping are reported for both systolic blood pressure (SBP) and diastolic blood pressure ((DBP). When comparing casual and ABPM measurements for diagnosing hypertension, ABPM reclassified approximately one third of patients from normotensive to hypertensive and from hypertensive to normotensive. ABPM has also been used to confirm experimentally that interdialytic weight gain is positively associated with increases in interdialytic blood pressure. In children who have undergone renal transplantation, 24-h blood pressure load elevation and non-dipping are also highly prevalent. A non-dipping pattern in transplant patients may be indicative of underlying renal parenchymal, renovascular disease or effect of medications. The prevalence of left ventricular hypertrophy (LVH) in pediatric patients after transplantation is approximately 20%, and left ventricular mass index (LVMI) is correlated with 24-h, daytime, and night-time ambulatory blood pressure. Since ESRD is a lifetime disease, addressing the high prevalence of hypertension and altered circadian blood pressure patterns in childhood may help prevent cardiovascular morbidity and mortality in early adulthood. Further studies are therefore needed to establish the utility of ABPM for the management of hypertension and prevention of end-organ injury in children with ESRD.

Severe hypertensive sequelae in a child with Seckel syndrome (bird-like dwarfism).

We report a 19-year-old male with Seckel syndrome (bird-like dwarfism) who presents with malignant hypertension associated with hypertensive nephrosclerosis, dilated cardiomyopathy, and a ruptured cerebral artery aneurysm. Although end-organ injury due to chronic hypertension occurs frequently in adults, no previous reports of renal insufficiency due to hypertension exist in children or adolescents. We speculate that this patient may have been particularly prone to hypertensive end-organ injury due to his extreme short stature.

Evaluation and prediction of urea rebound and equilibrated Kt/V in the pediatric hemodialysis population.

The posthemodialysis blood urea nitrogen (BUN) concentration rebounds for 30 to 60 minutes after hemodialysis in adults. Timing of the posttreatment BUN sample has a significant impact on the calculation of Kt/V. Urea rebound and its effect on Kt/V have not been extensively studied in children and adolescents. We evaluated posthemodialysis urea rebound after 46 treatments in 18 pediatric patients with end-stage renal disease. BUN levels were drawn at 30 seconds and 5 and 15 minutes posttreatment. From these values, a logarithmic regression curve was derived that defined percentage of urea rebound (%UR) = -0.254 + 10.9*log(t), (r = 0.79). Using this equation, we estimated BUN, %UR, and Kt/V at equilibration (50 minutes) for each treatment. Estimated mean %UR was 18.7%. Single-pool Kt/V (spKt/V) and estimated double-pool Kt/V (estKt/V) values were significantly different (P < 0.0001). %UR and percentage of difference between spKt/V and estKt/V did not vary as a function of dry weight, body surface area, or K/V. To test the validity of logarithmic extrapolation, additional BUN levels were drawn at 30 seconds and every 10 minutes for 1 hour postdialysis in six patients. Percentage of difference between estKt/V and measured equilibrated Kt/V was 3.6% +/- 1.7%. Our results show %UR has a significant impact on the calculation of Kt/V in children, does not vary with patient size, and is similar to that seen in adults. We have devised an easy and accurate method to predict equilibrated BUN and calculate double-pool Kt/V in children, which requires only an additional 15-minute posttreatment BUN sample.

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.

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.