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Published ahead of print on January 12, 2005
J Am Soc Nephrol 16: 746-754, 2005
© 2005 American Society of Nephrology
doi: 10.1681/ASN.2004070537
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Clinical Nephrology

Ultradian but not Circadian Blood Pressure Rhythms Correlate with Renal Dysfunction in Children with Chronic Renal Failure

Elke Wühl, Charlotte Hadtstein, Otto Mehls, Franz Schaefer and the ESCAPE Trial Group

Division of Pediatric Nephrology, University Children’s Hospital, University of Heidelberg, Heidelberg, Germany

Address correspondence to: Dr. Franz Schaefer, University Children’s Hospital, Im Neuenheimer Feld 151, 69120 Heidelberg, Germany. Phone: +49-6221-563-2396; Fax: +49-6221-56-4203; E-mail: franz_schaefer{at}med.uni-heidelberg.de


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Appendix
 References
 
Whereas the diurnal fall of BP (dipping) is an important prognostic marker in patients with chronic renal failure (CRF), the integrity of physiologic ultradian (i.e., shorter than 24 h) cardiovascular rhythms in patients with CRF is unknown. Also, the relationship between conventional dipping analysis and Fourier spectral rhythm analysis has not been examined in renal hypertension. The prevalence and dimensions of the circadian and three ultradian (12, 8, and 6 h) cardiovascular rhythms were studied by ambulatory BP monitoring in 214 children (aged 3 to 18 yr) with CRF (stage 2 to 4 chronic kidney disease) and no antihypertensive treatment compared with 938 healthy control subjects, and the relationship of rhythm characteristics to conventional dipping parameters, renal function, proteinuria, and serum electrolytes was assessed. The CRF cohort exhibited significantly reduced amplitudes of the circadian and all ultradian cardiovascular rhythms studied (all P < 0.01). Moreover, all BP and most heart rate rhythms showed significantly delayed acrophases (time of peak; P < 0.01). Whereas conventional BP dipping parameters (day/night difference, day/night ratio) and the 24-h BP amplitude were independent of renal function, the 8-h BP amplitude was positively correlated with GFR (r = 0.3, P = 0.01) and inversely correlated with the urinary protein/creatinine ratio (r = –0.27, P < 0.05), and the 6-h BP amplitude was inversely correlated with proteinuria (r = –0.3, P < 0.02). Children who displayed 24- or 12-h cardiovascular rhythms had significantly lower serum calcium levels than children without these rhythms. In summary, children with CRF display not only blunted circadian but also blunted ultradian cardiovascular rhythms. Ultradian but not circadian rhythms or conventional dipping parameters are quantitatively associated with renal function and proteinuria.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Appendix
 References
 
Diurnal BP variation (nocturnal "dipping") is a well-established phenomenon and a prognostic marker of cardiovascular health in the general population (1). In addition, patients with secondary hypertension (2), autonomic failure (3), and chronic renal failure (CRF) (4) are particularly prone to loss of circadian BP rhythmicity, which also relates to their cardiovascular prognosis (5). In patients with CRF, derangements of diurnal BP rhythmicity have been associated with the degree of renal dysfunction (6), the rate of progression of renal failure (7), and with changes in the autonomic nervous system (5,8).

Assessments of ultradian, i.e., shorter than circadian, cardiovascular rhythmicity has been largely restricted to the variability of continuous intra-arterial BP readings or heart rate (HR) beat-to-beat intervals (9), the latter of which seems to be a useful marker of autonomic nervous activity. In addition to these ultrafast modulations, cardiovascular rhythms with period lengths in the range of hours that are detectable with Fourier analysis of ambulatory blood pressure monitoring (ABPM) profiles exist. We recently detected highly significant 6-, 8-, and 12-h cardiovascular rhythms in the majority of healthy children (10), confirming and extending previous findings in the adult general population (11). The cause of these rhythms is still unclear; whereas some ultradian rhythmicity might be attributed to periodic daily activities such as food intake, they may also reflect periodic autonomic nervous oscillations or ultradian rhythms of endocrine factors that affect vascular tone, such as hormone or serum calcium levels. To date, the qualities of these ultradian cardiovascular rhythms have not been assessed in human disease states.

As the importance of the neuroendocrine origins of hypertension in early CRF are increasingly understood (12,13), it is tempting to speculate that abnormalities in the sympathetic tone could affect not only circadian and minute-to-minute fluctuations of BP and HR but also ultradian cardiovascular rhythmicity even in mild to moderate renal failure. Such potential abnormalities may be more readily detectable in children, in whom ultradian rhythms seem to be more prominent than in adults (10).

Here, we investigated for the first time circadian and ultradian cardiovascular rhythmicity by Fourier analysis in a large cohort of children with stage 2 to 4 chronic kidney disease. The aim was both to describe any abnormalities and to relate them to clinical parameters. To place these findings into context of previous research, an additional aim was to elucidate the relationship between Fourier rhythms and more established indices of BP variation.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Appendix
 References
 
Study Design
Children who were between 3 and 18 yr of age and were screened for participation in the ESCAPE trial were eligible for inclusion in this study. ESCAPE is a multicenter, randomized controlled, trial that investigates the effect of strict BP control and angiotensin-converting enzyme inhibition on the progression of CRF in pediatric patients with high normal BP or hypertension (14). CRF is defined as chronic kidney disease (CKD) stage 2 and upward according to the Kidney Disease Outcomes Quality Initiative (K/DOQI) classification (15). For the present study, only children who were not on antihypertensive medication were analyzed to exclude drug-induced changes in circadian and ultradian BP rhythmicity. An additional entry criterion was the availability of good quality ABPM readings (see below).

Twenty-four-hour ambulatory BP monitoring was performed in each patient in the absence of antihypertensive medication. The profiles were obtained either at the start of the run-in period (–6 month time point of ESCAPE trial) or before medication assignment after a 2-month angiotensin-converting enzyme inhibitor washout period (month 0 of ESCAPE trial). Simultaneously with the ABPM, a full clinical examination that included Tanner staging and routine biochemical tests including a full blood count, serum calcium, and renal and liver function tests were performed by standard laboratory techniques. GFR was determined from 24-h creatinine clearance by a modified Jaffé reaction, whereas proteinuria was expressed as the protein/creatinine ratio in spot urine using the Coomassie method. Written informed consent was given by all parents, and informed consent or assent from the patients was given as appropriate. The study protocol was designed in adherence to the declaration of Helsinki and approved by the ethical committees at each of the 33 participating centers.

Control subjects aged 5 to 18 yr were taken from a large multicenter trial of the German Working Group on Pediatric Hypertension designed to establish ABPM normative values (16). Again, only those without medication that might influence BP and with good-quality ABPM were included.

BP Recordings and Analysis
ABPM recordings were taken every 15 to 20 min during the day and every 30 to 60 min during the night with a standard oscillometric monitor (Spacelabs 90207) for both groups. Quality criteria for Fourier analysis were a minimum recording length of 22 h and no gaps greater than 2 h.

Fourier analysis (17) for the circadian (24 h) and three ultradian (12, 8, and 6 h) harmonic cosine rhythms was performed using the ABPM-fit software (18). For each rhythm identified with a significance of P < 0.05 by least-square analysis, an amplitude (half the distance between the maximum and minimum values of the cosine curve, in mmHg) and an acrophase (time of maximum, in hours after midnight) were calculated. Finally, an overall Fourier curve was calculated as the sum of all rhythms that achieved statistical significance and characterized by the peak-trough difference (PTD).

For conventional BP analysis, dipping was calculated as the absolute difference between mean daytime (8 a.m. to 8 p.m.) and nighttime (midnight to 6 a.m.) mean arterial pressure (MAP), as well as the ratio of mean daytime/mean nighttime MAP (same time periods). Nondipping was defined as the absence of a nocturnal BP fall of at least 10%, i.e., a day/night ratio <1.1. Therefore, the nocturnal BP fall was calculated in several ways: First as the absolute difference between mean daytime and mean nighttime MAP (dipping), second as the ratio of the two (D/N ratio), third as the circadian amplitude, and finally as the PTD of the overall Fourier curve (circadian plus ultradian rhythms combined). For definition of children with "normal" and "abnormal" amplitudes or acrophases, the age-specific 10th and 90th percentiles of the control population were used; we have previously described these in detail (10).

Statistical Analyses
Data were stored and analyzed with SAS (SAS Institute, Cary, NC). Categorical variables, such as the prevalence of a given rhythm, were compared using the {chi}2 test. Group comparison was performed with the Wilcoxon two-sample test and the Kruskal-Wallis test in case of multiple groups. P < 0.05 was considered significant. Correlation coefficients were calculated using Spearman rank-order correlation.

Proteinuria data were log-transformed to improve clarity of the graphs. Because of the use of rank-order correlation, the correlation coefficients remain identical. Normal values for height and BMI for the calculation of SD scores (SDS) were taken from Prader et al. (19) and Schaefer et al. (20), respectively. SDS for daytime and nighttime BP were calculated using the LMS tables of Wühl et al. (21).

Data on proteinuria were available for 152 children and on GFR were available in 167 children. The rate of GFR decline was estimated by linear regression of an average of 6.3 creatinine clearance values covering a mean period of 1.6 yr around the time point of assessment.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Appendix
 References
 
Patient Characteristics
Of 252 CRF patients without antihypertensive medication, 214 (85%) fulfilled the desired quality criteria for Fourier analysis. Of theses, 61% were male and 57% were prepubescent. Underlying diseases were renal hypo- and dysplasias in 79%, acquired glomerulopathies in 13%, and hereditary or other congenital nephropathies in 8% of patients. According to the K/DOQI classification (15), 26% of children had CKD class 2, 45% had CKD class 3, 22% had CKD class 4, and 3% had CKD class 5. Further patient characteristics are given in Table 1.


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  		Table 1. Patient characteristicsa

 
Of 1141 healthy school children, 938 (82%) fulfilled the ABPM quality criteria. Characteristics of this group are given in the second column of Table 1. More detailed demographic data have been described previously (16). Despite a similar age distribution in the two groups, children with CRF were significantly smaller and lighter and had higher BP than healthy children (all P < 0.001).

Nocturnal BP Fall (Dipping)
Children with CRF had less dipping (12.4 ± 6.2 versus 15.1 ± 6.2 mmHg; 21 versus 10% nondippers), lower D/N ratios (1.16 ± 0.08 versus 1.22 ± 0.1), smaller circadian amplitudes (8.5 ± 3.2 versus 10.5 ± 3.5 mmHg), and smaller PTD (22.4 ± 8.1 versus 26.4 ± 9.7 mmHg) than the control subjects (all P < 0.0001). However, there was no correlation of either absolute BP level or the nocturnal fall of BP or HR measured by any of the four methods to GFR, serum creatinine, GFR decline, proteinuria, or serum calcium in the CRF group. As an illustration, the circadian amplitude plotted against GFR and proteinuria is shown in the first column of Figure 1.



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  		Figure 1. Relationship of various BP parameters to GFR and proteinuria illustrated as scatter plots of rhythm parameters to GFR and log protein/creatinine ratio. Regression lines are only shown if there was significant correlation. MAP, mean arterial pressure. *Indicates statistical significance. BP, blood presssure.

 
There was moderate agreement between the various conventional methods of assessing nocturnal BP fall and Fourier rhythms. Table 2 shows the overlap between dipping status and the size of circadian amplitude for healthy and CRF children. Among healthy children, the sensitivity of nondipping for predicting the absence of circadian rhythmicity was 53%, with a specificity of 95%; for predicting an absent or blunted circadian rhythm, the sensitivity was 40% and specificity was 97%. In the CRF group, sensitivity for predicting the absence of circadian rhythmicity was greater (81%) as a result of the higher incidence of rhythm abnormalities, but specificity for detecting absent circadian rhythmicity was slightly lower at 85%.


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  		Table 2. Agreement between dipping status (>10% nocturnal fall of MAP) with presence and size of the circadian MAP amplitude for 938 healthy children and 214 CRF patients

 
Fourier Analysis
Prevalence of Fourier Rhythms.
Circadian BP rhythmicity was detected in an equally high fraction (90%) of children with CRF and healthy children. However, the prevalence of circadian rhythmicity with a normal amplitude was significantly lower at 62% in CRF children compared with control subjects (72%; P = 0.005). Before the onset of puberty, CRF patients were slightly less likely to display circadian HR rhythmicity (91 versus 97% in healthy control subjects; P = 0.01). In contrast to this subtle difference, the prevalence of 12-h rhythmicity was markedly elevated in the CRF group for BP in both prepubescent (54 versus 26%; P < 0.0001) and pubescent (64 versus 46%; P = 0.001) patients as well as for HR in prepubescent children (61 versus 36%; P < 0.0001). There was also a trend toward more prevalent 8- and 6-h BP and HR rhythmicity in the CRF children compared with control subjects, but this was significant only for 8-h BP rhythms in the group of pubescent children (35 versus 24%; P = 0.02).

Amplitudes and Acrophases.
Children with CRF had smaller amplitudes than healthy control subjects for all rhythms studied (see Table 3 and Figure 2). Blunting of amplitudes was more pronounced for the BP than for the HR rhythms. Acrophase timing was also markedly altered in the CRF cohort. All MAP acrophases were significantly delayed in patients, whereas HR acrophases occurred later for the 6- and 8-h rhythm, as well as for the 24-h rhythm in pubescent children (P < 0.0001; Table 3). Although there were significant correlations of the circadian with all three ultradian amplitudes in the control group (r = 0.21 to 0.28, all P < 0.003), among patients, it correlated only weakly with the 12-h amplitude (r = 0.20, P < 0.04) and not to the 8- or 6-h amplitudes.


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  		Table 3. Distribution of rhythm parameters for CRF cohort versus control subjectsa

 


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  		Figure 2. MAP and heart rate (HR) amplitudes of chronic renal failure patients (each + represents an individual patient) plotted over the reference ranges (vertical lines of the box from left to right represent 5th, 25th, 50th, 75th, and 95th percentiles in the control group).

 
Correlates of Fourier Rhythms.
BP level.
The circadian BP amplitude was correlated to the all-day BP level in patients (r = 0.27, P < 0.005) and marginally so in control subjects (r = 0.11, P < 0.002). However, amplitudes of the 8- and 6-h ultradian rhythms showed no correlation to mean 24-h or day- or nighttime BP levels (and their SDS) in either the patient or the control group. The 8-h acrophases were correlated positively (r = 0.36 P < 0.001) and the 6-h acrophases inversely with mean 24-h MAP (r = –0.31, P < 0.05) in the patients but not in the control subjects. In both the control and the patient groups, children who displayed a given circadian or ultradian BP rhythm had a higher BP level by 1 to 2 mmHg than those who did not; however, this achieved statistical significance only for the 12- and 6-h rhythms in the control subjects (P < 0.0001 and P = 0.02, respectively).

Renal function.
The prevalence and amplitude of circadian cardiovascular rhythmicity in the CRF cohort was independent of renal function and the type of underlying renal disease. However, children with abnormally late 24-h BP acrophase (>90th percentile) had a lower GFR (25 ± 15 versus 36 ± 18 ml/min per 1.73 m2; P < 0.01) than those with acrophases in the normal range. Moreover, the lack of a circadian BP rhythm was associated with a faster decline of GFR (median, –10.8 ml/min per 1.73 m2/yr; interquartile range, 13.0 ml/min per 1.73 m2/yr) compared with –4.9 ml/min per 1.73 m2/yr (interquartile range, 19.8 ml/min per 1.73 m2/yr) in children with conserved 24-h rhythmicity (P < 0.05), despite similar 24-h MAP (85.1 ± 10.6 versus 87.3 ± 7.9 mmHg; P = 0.35).

All ultradian BP rhythms were related to renal function; generally, advanced CRF was associated with small ultradian BP amplitudes. The correlation of the short ultradian but not of the circadian BP amplitudes to GFR and proteinuria is illustrated in Figure 1. The 6-h BP amplitude was closely correlated with proteinuria (r = –0.39, P = 0.018). Accordingly, children with an abnormally small 6-h BP amplitude (<10th percentile) had significantly greater proteinuria (16 ± 8 versus 7 ± 5 urinary protein/creatinine ratio; P < 0.0005). Similarly, the 8-h BP amplitude correlated positively with GFR (r = 0.3, P = 0.018) and inversely with proteinuria (r = –0.27, P < 0.05). Also, there was a trend for children with small 12-h BP amplitudes (<10th percentile) to have a lower GFR (31 ± 17 versus 40 ± 23; P = 0.08) compared with those in the normal range. The ultradian rhythms of HR showed borderline correlations with renal function, e.g., the 12-h HR amplitude was correlated with GFR (r = –0.20, P = 0.05).

Besides these relationships with amplitude size, renal function showed some associations with the timing of ultradian cardiovascular rhythms. The 8-h BP acrophase was inversely correlated with GFR (r = –0.24, P < 0.05) and positively with proteinuria (r = 0.26, P < 0.05). Accordingly, children with abnormally late 8-h acrophase (>90th percentile) had a lower GFR (40 ± 17 versus 51 ± 22 ml/min per 1.73 m2; P = 0.01) and greater proteinuria (18 ± 17 versus 9 ± 10 urinary protein/creatinine ratio; P < 0.05). Moreover, 8-h BP acrophase tended to be inversely associated with the rate of GFR decline (r = –0.25, P = 0.05). The timing of the 12-h HR acrophase was also correlated with proteinuria (r = 0.23, P < 0.05).

Serum calcium.
Children who displayed a circadian or a 12-h cardiovascular rhythm had significantly lower serum calcium than children who did not exhibit the respective rhythm. Mean serum total calcium levels and significance levels for the respective groups are given in Table 4. In patients with conserved circadian BP rhythmicity but reduced 24-h amplitude, serum calcium was intermediate compared with patients without rhythmicity and those with normal amplitude (Figure 3). To exclude that these differences were secondary to the weak but significant correlation of serum calcium with age (r = –0.14, P = 0.04) and serum protein levels (r = 0.18, P = 0.02), we computed multiple regression models to predict the occurrence of rhythmicity with serum calcium, age, and serum protein as independent variables. In each case, serum calcium was the most potent predictor of rhythmicity (partial R2 for 24-h BP rhythm, 0.034; 12-h BP rhythm, 0.023; 24-h HR rhythm, 0.023; 12-h HR rhythm, 0.044), whereas age achieved only marginal significance for the 12-h HR rhythm (partial R2, 0.018) and serum protein did not qualify as an independent predictor. Finally, for the 12-h rhythm, there was a negative correlation of the BP acrophase to serum calcium (r = –0.20, P < 0.05).


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  		Table 4. Mean total serum calcium levels (in mmol/L) in children with and without circadian and 12-h BP and HR rhythms

 


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  		Figure 3. Mean serum calcium levels (±SEM) of children without a circadian rhythm compared with those with blunted (below the 10th percentile) and normal circadian amplitudes (above the 10th percentile).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Appendix
 References
 
In this study, we observed distinct abnormalities in both circadian and ultradian cardiovascular rhythmicity in children with mild to moderate CRF. Although there is no previous description of ultradian parameters in renal disease, there are a variety of different findings regarding circadian BP rhythmicity in CRF. Lingens et al. (22) found that children with renal diseases before the onset of CRF had normal prevalence of circadian rhythmicity, whereas Nakamura et al. (23) described a reduced prevalence of circadian rhythmicity on cosinor analysis in 24 children with varying degrees of CRF. In that cohort, amplitudes were blunted in children who did not receive antihypertensive medication, but there was no significant alteration of the circadian acrophase. In our study, children with CRF also had significantly blunted circadian amplitudes and additionally delayed acrophases, in accordance with a previous study in adults (4). However, whereas the fraction of children with normal circadian amplitude was reduced, the overall detection rate of circadian BP rhythmicity was unchanged.

Studies that have used conventional dipping analyses in children with intact renal function have revealed blunted dipping in patients with renal scars secondary to reflux or recurrent urinary tract infection (24) but not in a cohort with solitary kidneys (25). That conventional dipping analyses in children report less consistent findings is in line with our description of only moderate agreement between the conventional dipping status and the presence of a circadian amplitude. However, agreement between the two methods was better when the size of the amplitude rather than just the presence of the circadian rhythm was considered.

As to ultradian rhythms, again there were clear alterations of both BP and HR in CRF. It is interesting that in the CRF patients, ultradian rhythms tended to be more prevalent but when present were markedly blunted and "delayed" as evidenced by reduced amplitudes and later acrophases in comparison with normal children. The increased prevalence of ultradian rhythms may be a consequence of the higher overall BP levels in the patient group. We previously observed that healthy children with ultradian rhythmicity have higher overall BP levels than individuals without (10); this effect seemed to be quantitatively similar in the CRF children studied here, although statistical significance was not reached in this smaller cohort. Increased 12-h rhythmicity is also seen together with an increase in BP in very old age (26) and has been linked to primary hypertension in adults with endothelial dysfunction as well as in spontaneously hypertensive rats (27,28).

In contrast, the size of the ultradian BP amplitudes was not consistently correlated with mean BP, suggesting that ultradian amplitude changes may arise primarily as a consequence of CRF rather than of hypertension per se. In a very recent study in adults with primary hypertension, Perez-Lloret et al. (29) also suggested that rhythm disturbances may be independent of hypertension but rather aggravated during the course of the disease by unknown factors. Although this question has not been addressed systematically, it is tempting to speculate on several pathophysiologic possibilities. Muscle sympathetic nerve activity, for example, correlates with daytime BP variability in healthy men (8), and sympathetic nerve overactivity is a hallmark of CRF that occurs early in the course of disease (13). Irregular BP fluctuations caused by an increased sympathetic nervous tone may cause increased "noise" in the dynamic BP patterns, which may lead to apparently blunted amplitudes of the physiologic regular ultradian oscillations of BP. Alternatively, the function of a putative central nervous pacemaker generating ultradian rhythms could be affected directly in CRF.

It is interesting that in our cohort there was no correlation of either circadian Fourier or conventional dipping parameters to renal function that was described in one adult study (6). In contrast, however, we observed a relationship of the ultradian BP rhythms to both proteinuria and GFR. This may suggest that ultradian rhythms are more sensitive indicators of disturbed BP regulation in renal failure than circadian rhythms. This hypothesis is supported by a recent report suggesting that the component of BP variability that is independent of nocturnal dipping has a stronger relationship to end-organ damage than overall BP variability. Bilo et al. (30) showed that in treated hypertensive patients, the SD of all-day BP was superior in predicting left ventricular mass index after adjustment for the day/night BP fall.

Alternatively, circadian and ultradian rhythms may be generated by different physiologic mechanisms or influenced by a different pathogenic effect of CRF. Differential regulatory mechanisms for circadian and ultradian rhythms are also suggested by the lack of correlation between circadian and ultradian amplitudes in our study, as well as evidence from spontaneously hypertensive rats (31). It seems that, whereas circadian BP variation is known to be associated with favorable outcome, ultradian BP variability is more associated with diseased states. Although this kind of analysis may seem technically challenging and is not routinely available in clinical practice at the moment, we hope that our findings and the freely available easy-to-use software will stimulate further research in this area. The clinical role of ultradian rhythms in predicting the poor cardiovascular outcome of patients with childhood-onset CRF remains to be elucidated in prospective trials.

HR rhythms showed analogous abnormalities to BP rhythms, albeit somewhat less pronounced. Changes in HR rhythmicity did not correlate to renal function. Therefore, the question arises whether HR changes are driving or driven by BP changes. Alternatively, it cannot be excluded that both reflect differing patterns of daily physical activity in children with CRF. However, this seems unlikely in view of the similar sociocultural background of patients and control subjects as well as the mild to moderate degree of renal failure that uncommonly interferes with physical activity. Also, a variety of evidence from adults with pacemakers or biventricular assist devices, pregnant women, and spontaneously hypertensive rats suggests that regulation of BP and HR rhythmicity involves separate physiologic mechanisms (31–34). For example, early pharmacologic experiments by Parati at al. (35) clearly demonstrated in human volunteers that decreased HR variability per se does not lead to a decrease of BP variability.

A decreased beat-to-beat HR variability has been shown to be an adverse prognostic marker for cardiovascular outcome in myocardial infarction and heart failure as well as in end-stage renal disease (36–39). The abnormalities of longer ultradian rhythms on noncontinuous monitoring detected for the first time in this study raise the possibility that these more easily accessible rhythms may also be influenced by the autonomic nervous system and may even have prognostic significance.

It is interesting that children with lacking 24- or 12-h rhythms or abnormally small BP amplitudes were characterized by consistently higher serum calcium levels. Serum calcium explained approximately 4% of the total variability in BP amplitudes, independent of differences in age, serum protein levels, or vitamin D treatment. This observation is in line with findings in a large study in healthy Belgian men, in which a negative regressor effect of serum calcium on both overall and 8-h systolic amplitude was found in a multiple regression model (11). The stepwise increase of serum calcium levels of children with normal, blunted, and absent circadian amplitudes in our study suggests a link between serum calcium and BP rhythmicity. The mechanisms underlying this link remain speculative; they may involve alterations of smooth muscle excitability, circadian and/or ultradian rhythms of PTH secretion, or the recently detected circadian fluctuations of responsiveness to vitamin D (40).

In summary, we have demonstrated marked blunting and delay of the rhythmicity of both BP and HR in pediatric patients with CRF. Changes in ultradian and circadian rhythms seemed to be independent of each other. Also the ultradian BP amplitudes but not the circadian amplitudes or conventional dipping parameters were correlated to indices of renal function, raising the possibility that ultradian rhythms play an independent role in CRF. Current evidence therefore suggests that, whereas normal circadian BP variation is a positive predictor of cardiovascular outcome, ultradian BP variability is more associated with diseased states. Together with the unsuspected finding of a relationship between serum calcium levels and the prevalence of 24- and 12-h rhythms, these findings raise the exciting possibility that rhythm changes picked up on ABPM, rather than more invasive continuous measurements, open a new window into the cardiovascular dysregulation in CRF.


   Appendix
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Appendix
References
 
Participants of the ESCAPE (Effect of Strict Blood Pressure Control and ACE Inhibition on CRF Progression in Pediatric Patients) Trial Group: A. Anarat (Adana); A. Bakkaloglu, F. Ozaltin (Ankara); A. Peco-Antic (Belgrade); U. Querfeld, J. Gellermann (Berlin); P. Sallay (Budapest); D. Drozdz (Cracow); K.-E. Bonzel, A.-M. Wingen (Essen); A. Zurowska, I. Balasz (Gdansk); F. Perfumo, A. Canepa (Genoa); D.E. Müller-Wiefel, K. Zepf (Hamburg); G. Offner, B. Enke (Hannover); O. Mehls, F. Schaefer, E. Wühl, C. Hadtstein (Heidelberg); U. Berg, G. Celsi (Huddinge); S. Emre, A. Sirin, I. Bilge (Istanbul); S. Çaliskan (Istanbul-Cerrahpasa); S. Mir, E. Serdaroglu (Izmir); C. Greiner, H. Eichstädt, S. Wygoda, (Leipzig); K. Hohbach-Hohenfellner (Mainz); N. Jeck, G. Klaus (Marburg); A. Appiani, G. Ardissino, S. Testa (Milano); G. Montini (Padova); P. Niaudet, M. Charbit (Paris); J. Dusek (Prague); A. Caldas-Afonso, A. Teixeira (Porto); S. Picca, C. Matteucci (Rome); M. Wigger (Rostock); M. Fischbach, J. Terzic (Strasbourg); J. Fydryk, T. Urasinski (Szezecin); R. Coppo, L. Peruzzi (Torino); A. Jankauskiene (Vilnius); M. Litwin, M. Abuauba, R. Grenda (Warszawa); K. Arbeiter (Vienna); T.J. Neuhaus (Zurich).


   Acknowledgments
 
Support for this study was obtained from the European Commission (5th Framework Programme, QLG1-CT-2002-00908), the Boehringer Ingelheim Foundation, the Baxter Extramural Grant Program, and Aventis Pharma.

The ABPM-fit software was kindly supplied by the Institute of Pharmacology & Toxicology, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Germany (www.abpm.fit.de).

Parts of this work were presented previously as the following conference abstracts:

Hadtstein C, Wühl E, Mehls O, Schaefer F; ESCAPE-Studiengruppe: Veränderungen zirkadianer und ultradianer kardovaskulärer Rhythmen bei Kindern mit chronischer Niereninsuffizienz. Nieren Hochdruckkrankheiten 2004; 33 (3).

Hadtstein C, Wühl E, Mehls O, Schaefer F; the ESCAPE Trial Group: Alterations in circadian and ultradian cardiovascular rhythms in children with chronic renal failure. Am J Hypertens 17[Suppl]: 98A, 2004.

Hadtstein C, Wühl E, Mehls O, Schaefer F; the ESCAPE Trial Group: Children with chronic renal failure have blunted and delayed rhythms of BP and heart rate. J Hypertens 22[Suppl 2]: S303, 2004.


   Footnotes
 
Published online ahead of print. Publication date available at www.jasn.org.

E.W. and C.H. contributed equally to this work.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Appendix
 References
 

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Received for publication July 9, 2004. Revision received November 19, 2004.


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C. Hadtstein and F. Schaefer
What adult nephrologists should know about childhood blood pressure
Nephrol. Dial. Transplant., August 1, 2007; 22(8): 2119 - 2123.
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