Pediatr Nephrol (2001) 16:517525

IPNA 2001

INVITED REVIEW

J.M. Sorof

Systolic hypertension in children: benign or beware?

Received: 28 September 2000 / Revised: 13 December 2000 / Accepted: 18 January 2001

Abstract 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. Keywords Systolic blood pressure Hypertension Left ventricular mass

Introduction
The historical approach to the evaluation and management of adult hypertension has until recently emphasized
J.M. Sorof Division of Pediatric Nephrology and Hypertension, University of Texas Houston, Medical School, Room 3.124, 6431 Fannin Street, Houston, TX 77030, USA e-mail: jonathan.m.sorof@uth.tmc.edu Tel.: +1-713-5005670, Fax: +1-713-5005680

diastolic blood pressure (DBP) elevation and the presence of diastolic hypertension. This emphasis had led to a view of mild-to-moderate elevation of systolic blood pressure (SBP) and systolic hypertension as benign, or at the least of less clinical importance. This bias was based not on the absence of specific evidence of correlation between SBP elevation and hypertensive morbidity and mortality, but rather on the observation that SBP normally rises with age while DBP does not. As a result, the clinical diagnosis of hypertension was primarily defined using the DBP threshold value of 90 mmHg as the upper limit of normal. Accordingly, the inclusion criteria for most trials of anti-hypertensive medication required subjects to have DBP elevation above this 90 mmHg threshold, regardless of the level of SBP. The prevailing view of adult hypertension has recently undergone a major shift in emphasis toward SBP. This shift is best illustrated by the most recent clinical advisory statement from the Coordinating Committee of the National High Blood Pressure Education Program, urging that SBP become the major criterion for the diagnosis, staging, and therapeutic management of hypertension [1]. This recommendation is based on the emergence of several lines of evidence, primarily in middle-aged and older Americans. These lines of evidence have included data on the epidemiology of systolic and diastolic hypertension, the pathophysiology of adult hypertension, the linkage between BP levels and disease, and the relative benefits of treatment. As part of this advisory, the recommendations specifically state: The use of age-adjusted BP targets is discouraged. The reasons cited in adults for emphasizing SBP are of unclear relevance to the evaluation and management of pediatric hypertension. Clearly, age-adjusted BP targets must be used in children due to the normal agerelated rise in BP throughout childhood. The increased stiffness of large arteries from atherosclerotic disease, identified as one of the major etiological factors for isolated SBP hypertension, is uncommon in children. Furthermore, the low prevalence of overt morbidity or mortality in the majority of hypertensive children has effec-

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tively prevented linkage of treated or untreated mildly to moderately elevated BP with poor outcome. Despite these limitations, an accumulation of data now suggests that SBP elevation is as important a factor in the morbidity of hypertension in children as in adults. The goal of this review is to provide support for this statement by summarizing studies on: (1) the importance of SBP hypertension in adults, (2) the prevalence of SBP hypertension in healthy children, (3) the prevalence of SBP hypertension in hypertensive children, (4) the relationship between SBP and indexed left ventricular (LV) mass in children, and (5) the linkage between SBP hypertension and end-organ injury in children.

Importance of SBP hypertension in adults

The evidence supporting an emphasis on SBP hypertension in adults is multi-faceted, derived from epidemiology, pathophysiology, linkage with disease states, and clinical benefits of treatment. The epidemiology of adult hypertension shows that the prevalence of hypertension increases with age, with SBP hypertension far more common than DBP hypertension. An analysis of the data from Third National Health and Nutrition Examination Survey shows that isolated SBP hypertension is present in 65% of hypertensive adults over the age of 60 years [2]. Long-term evaluation of a cohort of adults from the Framingham study showed that after adjustment for age, sex, and risk factors for cardiovascular disease, patients with borderline isolated systolic hypertension had an excess long-term risk of cardiovascular disease (hazard ratio 1.47) and death from cardiovascular disease (hazard ratio 1.57) compared with normotensive participants [3]. A more recent study confirmed that both elevated SBP and wide pulse pressure are independent cardiovascular risk factors [4]. In this study, DBP was actually inversely related to cardiovascular disease risk in patients over 60 years of age with SBP>120 mmHg. Thus, a patient with BP of 160/70 mmHg is at greater risk of cardiovascular morbidity and mortality than a patient with BP of 160/100 mmHg. In the Multiple Risk Factor Intervention Trial [5], the importance of elevated SBP, independent of DBP, was also clearly demonstrated by the linear relationship that was found between SBP and coronary heart disease death rates at every level of DBP (Fig. 1). These epidemiological data can best be interpreted in the context of the pathophysiology of adult hypertension. In adults, SBP tends to increase with age, whereas DBP tends to increase until age 55 years and then decreases [6]. These age-dependent changes in BP are thought to be primarily due to increasing arterial stiffness from atherosclerotic vascular disease [7]. The increased arterial stiffness causes an enhanced pressure wave during systole that leads to a rapid and profound upstroke in SBP. Conversely, the decreased compliance of the large arteries prevents storage of potential energy in the vessel wall during diastole, and thus a rapid decrease in DBP during LV relaxation. Thus, a disease progression may
Fig. 1 Relationship of systolic and diastolic blood pressure (BP) to death from coronary heart disease in the Multiple Risk Factor Intervention Trial. Data from >316,000 males followed for 12 years

be established such that the initial SBP and DBP hypertension causes vascular injury and contributes to arteriosclerosis, resulting in decreased vascular compliance, and ultimately evolution into isolated SBP elevation. Therefore, SBP elevation may contribute to the vascular injury associated with hypertension during the early stages of the disease and indicate the presence of agerelated vascular injury during the later stages. The most persuasive argument for the clinical importance of SBP hypertension is presented by the clinical benefits of its treatment. Two independent studies, the Systolic Hypertension in the Elderly Program (SHEP) and the Syst-Eur study, conducted randomized, placebocontrolled trials of anti-hypertensive medications in adults with isolated SBP hypertension [8, 9]. Both studies found similar clinical benefit by reduction in SBP. Specifically, the SHEP study demonstrated that treatment compared with placebo resulted in 27% reduction in the incidence of myocardial infarction, 55% reduction in the incidence of heart failure, and 37% reduction in the incidence of stroke. Thus, the preponderance of evidence showing the two-thirds prevalence of isolated SBP hypertension after age 60 years [2], the increased stiffness of large arteries with aging resulting in isolated SBP hypertension [7], the risk stratification for major complications of hypertension for SBP compared with DBP [3], and the clinical benefits of treatment of isolated SBP hypertension [8, 9] have led to the evolution of SBP into the major criterion for the diagnosis, staging, and treatment of hypertension in adults.

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Prevalence of SBP hypertension in healthy children

One way in which the relative importance of SBP and DBP hypertension in children can be expressed is by determination of their prevalence in an unselected pediatric population. Several screening programs have collected BP data to determine the prevalence of hypertension in an unselected population of school-aged children. Prior to the availability of the normative data from the 1st, 2nd, and Update on the Task Force on Hypertension Control in Children and Adolescents [10, 11] and from pooled data from six European studies of BP in childhood [12], most studies defined pediatric hypertension using adult criteria. One of the earliest and largest studies was by Silverberg et al. [13] in 1975 who performed BP screening on over 15,000 Canadian children. In this study, BP was measured at a single visit with hypertension defined as BP greater than 140/90 mmHg. Using these criteria, the prevalence of hypertension was found to be 6.1% for SBP and 1.8% for DBP, or an approximately threefold higher prevalence of SBP than DBP hypertension. Fixler et al. [14] published the results of a similar screening program in the United States using the same definition of hypertension, but added two subsequent sets of BP measurements in the children found to be hypertensive on initial screening. As expected, the overall prevalence of hypertension was lower after follow-up measurements, decreasing from approximately 9% initially to less than 2% by the third set of measurements. However, similar to the previous study, the prevalence of SBP hypertension (1.2%) was approximately threefold greater than that of DBP hypertension (0.37%). The reliance on adult definitions rather than on currently accepted pediatric definitions of hypertension based on the age-, gender-, and height-specific percentiles from the Task Force data makes the validity of these earlier studies uncertain. A study by Sinaiko et al. [15] in 1989 reported the prevalence of hypertension in approximately 15,000 school children using the age- and gender-specific percentile values from the 2nd Task Force. In contrast to the previous studies, the prevalence of hypertension after two sets of measurements on different visits was only 0.3% for SBP and 0.8% for DBP, a threefold higher prevalence of DBP hypertension. However, a recent pilot study by Sorof et al. (unpublished data) of school-based BP screening among ethnic minority children, using the most current Task Force criteria, revealed a prevalence of SBP hypertension higher than in any previous reports. BP screening performed in 1,659 children, approximately 58% Hispanic and 32% African-American, revealed an overall prevalence of hypertension on initial screen of 17%. Among the children found to be hypertensive, 94% had SBP hypertension compared with 14% who had DBP hypertension. Among children found to be persistently hypertensive on re-screening, the prevalence of SBP hypertension was 97% and the prevalence of DBP hypertension was 18%. These data demonstrate a striking trend toward a predominance of SBP hypertension among ethnic minority children.

Table 1 Prevalence of systolic blood pressure (SBP) and diastolic blood pressure (DBP) hypertension: pooled data from eight studies from 1978 to 1991 [16] SBP hypertension (%) Black Male 512 years 1317 years Female 512 years 1317 years White Male 512 years 1317 years Female 512 years 1317 years DBP hypertension (%) Ratio of SBP/DBP

4.4 2.9 5.3 4.7 3.3 5.5

3.1 2.7 3.2 4.0 3.8 4.1

1.4 1.1 1.7 1.2 0.9 1.3

4.6 3.2 5.8 4.1 3.9 4.2

3.0 2.9 3.1 3.0 1.9 3.6

1.5 1.1 1.9 1.4 2.1 1.2

These single-center studies are limited by their focus on a single geographic region. A recent multicenter collaborative study on ethnic differences in BP in children by Rosner et al. [16] combined the data from eight large studies from 1978 to 1991 from different geographic regions in the United States. Overall, SBP data on 47,196 children (68,556 visits) and DBP (K5) data on 38,184 children (52,053 visits) were available. Few substantive ethnic differences were found. Using Task Force definitions and after pooling the data from all visits, the overall prevalence of SBP hypertension was 4.4% and the prevalence of DBP hypertension was 3.2%. Further analysis shows that the prevalence of SBP hypertension was higher for virtually every sub-grouping of subjects by race, gender, and age (Table 1). Thus, the prevalence of SBP hypertension in a healthy, unselected, and geographically diverse population of children was approximately 1.4 times that of DBP hypertension. It is important to note however that the reliability of the measurement of DBP has been identified as an important issue in the study of BP in children. In particular, the use of the K4 or the K5 sound to define the auscultatory DBP is controversial and has been found to affect the prevalence of DBP hypertension. Sinaiko et al. [17] compared K4 with K5 in 19,274 children aged 10 15 years and found that the K4K5 difference was 5 10 mmHg in 20%, 1120 mmHg in 11%, and greater than 21 mmHg in 3% of the children. In this study, the choice of K4 or K5 to define DBP changed the prevalence for significant DBP hypertension by 2%3%. Uhari et al. [18] studied 3,012 randomly selected children and found that K4 was absent in a higher percentage of individuals than was K5, leading to the conclusion that reliable and repeatable BP measurements in children are best achieved with K5 as the indicator of DBP. Investigators from the Bogalusa Heart Study evaluated differences between K4 and K5 from 4,633 subjects

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530 years of age and found an overall mean difference between K4 and K5 of 9.95.6 mmHg (meanSD) [19]. Based on the finding that K5 was zero in a relatively high percentage of individuals, they concluded that K4 was the more-reproducible measure of DBP. Biro et al. [20] performed a cross-sectional analysis of BP from 2,379 9-year old children in the National Heart, Lung, and Blood Institute Growth and Health Study (NGHS). Of the 159 subjects potentially classified with elevated DBP, 60% would be classified differently depending on whether K4 or K5 was used to define elevated DBP. Thus, the choice of the onset of K4 or K5 for determining DBP in children may have important implications for comparing studies and determining the relative prevalence of SBP and DBP hypertension.

Prevalence of SBP hypertension in hypertensive children

Although levels of BP and the prevalence of pediatric hypertension appear to be increasing [21, 22], a growing majority of primary care providers have no experience with the non-pharmacological or pharmacological treatment of hypertension in children [23], and most refer children with elevated clinic BP for subspecialty evaluation. For this reason, most pediatric hypertension studies have been performed in a referral-based patient population. While such studies allow the accumulation of adequate patient numbers to allow meaningful investigation, they must also be interpreted cautiously since they may suffer from referral bias compared with studies of patients identified by routine BP screening. A study by Sorof and Portman [24] reported the prevalence of SBP and DBP hypertension in 115 children referred by primary care providers for persistent casual BP elevation. All patients underwent 24-h ambulatory BP monitoring (ABPM) as part of the initial diagnostic assessment. Among the entire patient group, the prevalence of hypertension by ABPM criteria was 44% for SBP and 23% for DBP. Among the patients with documented casual hypertension in the hypertension clinic, the prevalence of hypertension was 95% for SBP and 35% for DBP. Thus, similar to the unselected screening population, the prevalence of SBP hypertension in this selected referral population was higher than that of DBP hypertension. The 1997 Food and Drug Administration Modernization Act has resulted in a substantial increase in pediatric trials of anti-hypertensive medications [25]. One of the first of these studies was the Ziac Pediatric Hypertension Study, a multicenter study conducted through subject recruitment from 22 centers in the United States and Brazil that care for children with hypertension [26]. The study consisted of a 2-week single-blind screening placebo phase prior to randomization to treatment or placebo. To qualify for randomization, subjects were required to have an average sitting systolic and/or diastolic blood pressure above the Task Force 95th percentile at the last visit of

Fig. 2 Hypertension status at screening enrollment visit and at randomization visit after successful placebo screening. SBP only isolated systolic hypertension, DBP only isolated diastolic hypertension, SBP and DBP both systolic and diastolic hypertension, neither neither systolic nor diastolic hypertension

the screening placebo phase. One hundred and forty children were initially screened for the study, and 110 children qualified for randomization (Fig. 2). At the initial screening visit, 71% of subjects had systolic hypertension (isolated or in combination with DBP hypertension) and 51% had diastolic hypertension (isolated or in combination with SBP hypertension). At randomization, 83% had systolic hypertension and 53% had diastolic hypertension. Among the randomized patients, the prevalence of isolated SBP hypertension was 47% compared with a prevalence of isolated DBP hypertension of only 17%. Again confirming the data from the unselected screening population, SBP hypertension was more common than DBP hypertension in children specifically referred for evaluation and treatment of elevated BP. There is evidence to suggest in children that the presence of both SBP and DBP hypertension may actually indicate a higher likelihood of secondary than primary hypertension. Flynn [27] performed ABPM on two groups of children: 15 primary hypertensives (no identified underlying etiology) and 27 secondary hypertensives (documented secondary forms of hypertension). The study found that the percentage of DBP readings greater than the 95th percentile during both daytime and nocturnal periods was significantly higher in the secondary hypertensives. Nathwani et al. [28] studied 62 patients with Turner syndrome and found that 21% had mean systolic and 17% mean diastolic 24-h ABPM measurements above the 95th percentile for age and sex. Although the presence of underlying cardiorenal disease was not found to have a significant effect on BP, a high percentage of the Turner syndrome patients did have a detectable cardiac abnormality (24%), renal abnormality (42%), or raised plasma renin activity (52%). In several studies of pediatric renal transplant recipients, the prevalence of DBP hypertension by either casual or ABPM criteria ranged from 57% to 59% [29, 30, 31]. Sorof et al. [32] specifically compared the results of ABPM between otherwise healthy children referred for evaluation of hypertension and children after renal transplantation.

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The prevalence of SBP hypertension was similar in both groups (72% vs. 76%, P=NS). In contrast, the prevalence of DBP hypertension was significantly lower in the referral patients than in the transplant patients (26% vs. 55%, P<0.01). Thus, the presence of DBP hypertension, albeit not an absolute indicator, should raise concern for the possibility of secondary forms of hypertension.

SBP and LV morphology in normotensive children

The recommendations regarding the threshold values for defining hypertension in adults are based on the associations between BP values that exceed these thresholds and subsequent morbidity or mortality. These associations are difficult to establish in children since overt morbid events such as stroke, myocardial infarction, and congestive heart failure are rare except in cases of severe hypertension. In the absence of these events, the most extensively investigated surrogate marker of hypertensive morbidity has been the geometry and size of the left ventricle measured by M-mode echocardiography. Several studies have used echocardiography to examine the relationship between BP and the LV in healthy normotensive children. Numerous publications on cardiovascular risk factors and pediatric hypertension have resulted from two large population-based epidemiological studies within single communities: the Bogalusa Heart Study and the Muscatine Study. In one of the Bogalusa studies by Burke et al. [33], M-mode echocardiographic measurements were analyzed in 654 healthy subjects, aged 722 years, whose DBP levels remained in the same height-, race-, and sexspecific decile during two biannual examinations. After adjustment for body size, LV wall thickness and the ratio of LV thickness to chamber size were found to be correlated with SBP. Neither parameter correlated with DBP. Perhaps most importantly, LV wall thickness increased throughout the entire SBP distribution indicating that, even within the normal range of BP in healthy children, higher SBP is associated with increased LV size. A similar Muscatine study by Malcolm et al. [34] investigated the relationship between LV mass and BP in 904 normal patients aged 616 years. A strong positive linear association was found between LV mass and age, weight, height, and both SBP and DBP. Further analysis indicated that age, weight, height, and BP each exerted an independent influence on LV mass. Since age, sex, and height are unalterable, the authors contend that statistical adjustment for these variables is appropriate. However, as weight and BP are modifiable risk factors for cardiovascular disease, the pathological contribution of excess weight and BP should not be masked by statistical adjustments in reference values for LV mass. Daniels et al. [35] examined the relationship of LV mass to lean body mass and fat mass determined by dualenergy X-ray absorptiometry, and BP in 201 subjects aged 617 years old. Age, height, weight, body surface area, sexual maturation, lean body mass, fat mass, SBP,

and DBP were all univariate correlates of LV mass. However, multiple regression analysis revealed that only lean body mass, fat mass, and SBP were statistically significant independent correlates of LV mass, suggesting that all three play an important biological role in determining LV mass. Thus, the results from all these studies indicate a clear independent association between SBP and LV morphology, even in healthy children without known elevation of BP to the hypertensive range. Genetic risk factors for cardiovascular disease in otherwise healthy children may also be important contributing determinants of LV mass index (LVMI). One of the most-important risk factors for hypertension in adulthood is a family history of hypertension. Treiber et al. [36] investigated the association between LVMI and BP in 84 biracial children specifically selected for a family history of hypertension. Significant independent correlates with LVMI were adiposity index, gender (boys were greater), age, and resting SBP. Resting DBP did not correlate with LVMI. These findings in normotensive children with a genetic risk factor for future hypertension indicate that resting SBP is an early determinant of LVMI in children. Hypertension and hypertensive sequelae are far more common in African-Americans than in whites. To determine whether systematic racial differences are related to LVMI in children, Harshfield et al. [37] performed BP assessment and echocardiography in 60 African-American and 40 white normotensive youths. Sex, age, and SBP were independent predictors in the sample as a whole, accounting for 37% of the variance of LVMI. In the black subjects, age and sex were the independent factors, accounting for 43% of the variance of LVMI. In contrast, in white subjects, SBP followed by sodium excretion were independent factors. Thus, SBP overall was an independent correlate of LVMI, with the age-related increase in LVMI important in black but not in white youths. Another high-risk group for complications related to hypertension are children who have undergone surgical repair of aortic coarctation. Eroglu and Oztunc [38] compared ABPM results in 18 normotensive patients who were 9 months to 6 years from aortic coarctation repair with 18 matched controls. Patients had significantly higher mean SBP and more SBP readings above the 95th percentile for age than controls. No significant difference was found in DBP profiles. In addition, LVMI was significantly increased in patients compared with controls. The ability of current BP to predict future LV morphology has also been investigated in healthy children. Papavassiliou et al. [39] assessed the contributions of anthropometric, demographic, and cardiovascular parameters as predictors of LV mass 34 years after the initial examination in 68 children. On the follow-up examination, echocardiographic evaluations were conducted to estimate LV mass and related LV geometry. LVMI and relative wall thickness were both predicted by initial adiposity. The only cardiovascular parameter that predicted LVMI was SBP reactivity to postural change. Kapuku et

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al. [40] performed a similar study in 146 youths on two occasions separated by 2.3 years using both clinic and ambulatory BP. Initial LVMI, weight, gender, resting total peripheral resistance, and SBP response to stress predicted LVMI. In addition, initial ambulatory SBP (24-h, daytime, and nighttime) was positively related to the LVMI measured 2 years later. These data suggest that both enhanced SBP reactivity to stress and elevated resting ambulatory SBP are predictive of future LVMI and, by extension, the development of LVH.

Table 2 Comparison of hypertensive patients based on left ventricular hypertrophy (LVH) (BMI body mass index, ABPM ambulatory blood pressure monitoring, LVM left ventricular mass, LVMI left ventricular mass index) Normal LV (n=7) Demographics Age (years) Height (cm) Weight (kg) BMI (kg/m2) Clinic BP (mmHg) SBP DBP ABPM mean BP (mmHg) SBP DBP Echocardiography data LVM LVMI LVH (n=15) P value

13.22.5 15711 6625 268

15.21.6 16710 8319 297

0.03 NS NS NS

SBP and end-organ damage in hypertensive children

It has been recognized for many years that severe hypertension in children is associated with significant risk of short-term morbidity and mortality. In one of the earliest studies published in 1967, Still and Cottom [41] described the morbidity and mortality of severe hypertension in children with 55 patients with DBP greater than 120 mmHg and cardiomegaly by examination or LV hypertrophy by echocardiography. The presenting signs in these patients were papilledema in 36%, seizures in 22%, and facial palsy in 6%. The mortality rate was 56%. A more recent study by Daniels et al. [42] systematically investigated 88 children with mild-to-moderate hypertension (either SBP or DBP greater than the 90th percentile) for evidence of target organ injury. Retinopathy was found in 50% of patients, glomerular hyperfiltration in 49%, and LV hypertrophy in 36%. These more-recent data suggest that target organ injury does occur in children with even moderate BP elevation. Several studies of children with mild-to-moderate hypertension by casual BP criteria have specifically investigated the degree and prevalence of hypertensive cardiac alterations. Laird and Fixler [43] studied 50 adolescents with moderately elevated BP and 50 matched normotensive control subjects. Echocardiograms showed that mean LV wall thickness and LVMI were significantly greater in the hypertensive than in control subjects. Culpepper et al. [44] examined children prone to hypertension as evidenced by BP between the 75th and 95th percentiles for age. Average BPs in 27 children with borderline hypertension were 137/89 mmHg compared with 110/68 mmHg for the 26 controls. LV wall thickness and LV mass were significantly greater in the borderline hypertensive group than in the controls. Daniels et al. [45] studied 104 children and adolescents with BP persistently greater than the 90th percentile for age and sex who had no known cause of BP elevation. LV hypertrophy (defined as LVMI greater than the pediatric 95th percentile) was found in 38.5% of patients. Resting SBP was a significant univariate correlate with LVMI, while DBP was not. Multiple regression showed that independent correlates of LVMI were male sex, body mass index, sodium intake, age, and SBP at maximal exercise. ABPM has emerged as a technology that addresses several of the limitations associated with casual BP mea-

1389 694

1509 7913

0.01 NS

1266 705

13611 7610

0.04 NS

11227 283

21255 469

<0.001 <0.001

surements, such as the intermittent nature of casual measurements, the lack of both wake and sleep assessment, and the possibility of white coat hypertension. An increasing number of studies of hypertensive children and adolescents have used ABPM as an investigational tool to determine the association between BP and hypertensive end-organ damage. Chamontin et al. [46] studied 49 young adults (less than 20 years of age) with a history of childhood hypertension detected at a routine school physical examination and 49 young adults with BP greater than the 97.5 percentile. All subjects underwent measurement of ambulatory wake BP by oscillometric monitoring, a 15-min period of oscillometric BP monitoring in clinic, and measurement of clinic office BP with a standard mercury sphygmomanometer. Significant correlates of LVMI were ambulatory wake SBP and mean oscillometric SBP. LVMI did not correlate with office SBP, and did not correlate with any DBP parameter. Belsha et al. [47] performed ABPM and M-mode echocardiography in 33 normotensive and 29 untreated mildly hypertensive adolescents. The prevalence of LV hypertrophy in the hypertensive group was 34%. Overall, sleep SBP correlated most closely with LVMI. Other significant univariate correlates were casual SBP and DBP, and 24-h and wake SBP (r=0.320.40). None of the ambulatory DBP parameters correlated with LVMI. The relationship between ABPM and LVMI has also been investigated in children with secondary forms of hypertension. Matteucci et al. [48] reported that the prevalence of LV hypertrophy in 28 pediatric renal transplant patients was 82%, with a significant correlation between LVMI and both 24-h SBP and maximal exercise systolic BP. A recent study by Sorof et al. [49] specifically compared the relative strength of the relationship between

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SBP or DBP and LVMI in 22 children with documented casual hypertension by Task Force criteria. All patients underwent clinic BP measurement, 24-h ABPM, and M-mode echocardiography. LV hypertrophy (defined as LVMI greater than the 95th percentile from published pediatric data [50]) was found in 68% (15/22) of all patients, and in 75% (12/16) with both casual and ambulatory hypertension. Patients with LV hypertrophy had higher 24-h and casual SBP than those without LV hypertrophy (Table 2). Neither 24-h nor casual DBP differed based on the presence of LV hypertrophy. Univariate analysis showed that LVMI had the strongest correlation with 24-h mean SBP (r=0.61, P<0.01) and did not correlate with 24-h mean DBP. Summary There is little doubt that very young children or children with extreme BP elevation virtually always necessitate a very aggressive management approach. However, the changing epidemiology of pediatric hypertension has made these types of patients increasingly less common in the face of a growing epidemic of childhood obesity, inactivity, and poor dietary habits. The conventional wisdom has been that primary renal disease is the likely cause of the hypertension in children. This is no longer the case. In a large pediatric hypertension practice, the typical patient demographic has evolved into an otherwise healthy adolescent often with some combination of the cardiovascular risk factors of obesity, a family history of hypertension, and an ethnic predisposition to hypertensive disease. In this context, the appropriate level of aggressiveness regarding diagnostic evaluation, the indications for pharmacological treatment, and the target BP values to aim for in response to treatment are not always obvious based on the current literature. Thus, the practice of truly evidence-based medicine remains a challenge for physicians who care for hypertensive children. In adults, the paradigm of essential hypertension has clearly shifted to an emphasis on SBP. SBP hypertension in older patients is more common, is a marker for vascular disease, predicts cardiovascular morbidity and mortality, and when treated results in decreased morbidity and mortality. In children and adolescents, data supporting a similar pattern of disease is emerging. 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. However, prevalence data alone are not sufficient to warrant the same emphasis on SBP as has been recommended in adults. To some extent, a BP value is simply the arbitrary numeric representation of a hemodynamic state that may or may not be pathological. Without linkage of these numeric values to the presence or the risk for the development of specific disease states, physicians are merely treating the number and not the disease. In this regard, studies of pediatric hypertension have been hampered to some extent by the lack of satisfactory

outcome measures, since children with mild or moderate hypertension rarely suffer from hypertension-related mortality or overt morbidity. However, compelling evidence in children suggests that even mild-to-moderate BP elevation is associated with increased LV mass, and that SBP appears to be more closely linked to LV morphology than DBP. This association persists even when controlling for other variables such as age and body habitus. Among patients with hypertension by conventional definition, the reported prevalence of LV hypertrophy defined by pediatric standards ranges from 30% to 70%, and is more closely related to SBP than to DBP. Furthermore, increased LV mass has been associated with SBP even in patients whose SBP falls within the normal range. As a possible explanation for this observation, Goonasekera and Dillon [51] have suggested that, although a child's BP at a single point in time may fall within the population-based range of normality, a previous and undetected pattern of relative increases in BP across percentile lines over time may still effectively render that patient hypertensive. This reasoning further supports the argument for the development of functional rather than statistical definitions of pediatric hypertension. In aggregate, these data indicate that SBP hypertension in children should be considered of primary prognostic significance. This assertion has practical implications. Treatment of hypertension should be directed at normalization of SBP, even when DBP is within the normal range. Trials of anti-hypertensive medications in children should incorporate SBP hypertension into the study inclusion criteria. Future pediatric studies should be aimed at demonstrating regression of LV mass with effective treatment of both SBP and DBP elevation, and at prevention of cardiovascular morbidity by early initiation of such treatment. If physicians who care for hypertensive children seek to promote health that extends beyond the traditional pediatric age range, early recognition and intervention for hypertension clearly must begin in childhood.

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L I T E R AT U R E A B S T R A C T S

T. Wang C.L. Yang T. Abbiati P.J. Schultheis G.E. Shull G. Giebisch P.S. Aronson

M. Wada N. Nagano Y. Furuya J. Chin E.F. Nemeth J. Fox

Mechanism of proximal tubule bicarbonate absorption in NHE3 null mice

Am J Physiol (1999) 277:F298F302

Calcimimetic NPS R-568 prevents parathyroid hyperplasia in rats with severe secondary hyperparathyroidism
Kidney Int (2000) 57:5058

NHE3 is the predominant isoform responsible for apical membrane Na(+)/H(+) exchange in the proximal tubule. Deletion of NHE3 by gene targeting results in an NHE3(/) mouse with greatly reduced proximal tubule HCO()(3) absorption compared with NHE3(+/+) animals (P.J. Schultheis, L.L. Clarke, P. Meneton, M.L. Miller, M. Soleimani, L.R. Gawenis, T.M. Riddle, J.J. Duffy, T. Doetschman, T. Wang, G. Giebisch, P.S. Aronson, J.N. Lorenz, and G.E. Shull. Nature Genet. 19:282285, 1998). The purpose of the present study was to evaluate the role of other acidification mechanisms in mediating the remaining component of proximal tubule HCO()(3) reabsorption in NHE3(/) mice. Proximal tubule transport was studied by in situ microperfusion. Net rates of HCO()(3) (J(HCO3)) and fluid absorption (J(v)) were reduced by 54 and 63%, respectively, in NHE3 null mice compared with controls. Addition of 100 microM ethylisopropylamiloride (EIPA) to the luminal perfusate caused significant inhibition of J(HCO3) and J(v) in NHE3(+/+) mice but failed to inhibit J(HCO3) or J(v) in NHE3(/) mice, indicating lack of activity of NHE2 or other EIPA-sensitive NHE isoforms in the null mice. Addition of 1 microM bafilomycin caused a similar absolute decrement in J(HCO3) in wild-type and NHE3 null mice, indicating equivalent rates of HCO()(3) absorption mediated by H(+)-ATPase. Addition of 10 microM Sch-28080 did not reduce J(HCO3) in either wild-type or NHE3 null mice, indicating lack of detectable H(+)-K(+)ATPase activity in the proximal tubule. We conclude that, in the absence of NHE3, neither NHE2 nor any other EIPA-sensitive NHE isoform contributes to mediating HCO()(3) reabsorption in the proximal tubule. A significant component of HCO()(3) reabsorption in the proximal tubule is mediated by bafilomycin-sensitive H(+)-ATPase, but its activity is not significantly upregulated in NHE3 null mice.

Background Secondary hyperparathyroidism (secondary HPT) in chronic renal insufficiency (CRI) is characterized by multiglandular hyperplasia. Methods In this study, we investigated the effects of the calcimimetic NPS R-568 on the parathyroid gland in rats with CRI induced by ligation of the renal arteries and severe secondary HPT induced by dietary phosphorus loading. Six days after surgery, high-phosphorus diet feeding was started, and NPS R-568 was administered to the rats for 56 days either by daily gavage (30 or 100 micromol/kg) or by continuous subcutaneous infusion (20 micromol/kg/day). Results After 54 days, serum PTH levels in vehicle-treated CRI rats were 1019 vs. 104 pg/mL in sham-operated controls. Infusion of NPS R-568 maintained serum PTH at levels comparable with those of sham-operated controls, whereas daily gavage also prevented much of the increase in CRI controls and decreased PTH levels intermittently in a dose-dependent fashion. Parathyroid gland enlargement was caused predominantly by hyperplasia. Total cell number per kg body wt was 3.5-fold higher in vehicletreated CRI rats than in sham-operated controls. Both infusion and high-dose gavage of NPS R-568 completely prevented the increase in parathyroid cell number. Conclusion These results demonstrate that the calcimimetic compound NPS R-568 can prevent both the increase in serum PTH levels and parathyroid hyperplasia in rats with CRI and severe secondary HPT. Moreover, these changes occurred despite decreases in serum 1, 25(OH)2D3 and increases in serum phosphate, suggesting a dominant role for the calcium receptor in regulating parathyroid cell proliferation.

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