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NDT Advance Access originally published online on March 19, 2008
Nephrology Dialysis Transplantation 2008 23(9):2873-2878; doi:10.1093/ndt/gfn126
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Longitudinal observations on circadian blood pressure variation in chronic kidney disease stages 3–5

Thomas Elung-Jensen1, Svend Strandgaard2 and Anne-Lise Kamper1

1 Department of Nephrology, Rigshospitalet, University of Copenhagen, Denmark 2 Department of Nephrology, Herlev Hospital, University of Copenhagen, Denmark

Correspondence and offprint requests to: Thomas Elung-Jensen, Department of Nephrology Rigshospitalet, Blegdamsvej 9, 2200 København N, Denmark. Tel: +45-35-45-05-88; Fax: +45-35-45-24-08; E-mail: thomaselungjensen{at}hotmail.com



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. It has been suggested that status as a ‘non-dipper’ determined from 24-h blood pressure (BP) recordings is associated with increased risk of end-organ damage but little is known about the consistency of dipper status in renal patients. The present post hoc analysis evaluated dipper/non-dipper status prospectively in a study on dosage of enalapril in progressive chronic kidney disease (CKD) stages 3–5.

Methods. In 34 patients, 24-h ambulatory BP (A&D TM2421) was measured at baseline and every 4 months for 1 year or until the need for renal replacement therapy. For each BP recording patients were classified as dippers or non-dippers based on the presence or absence of a nighttime reduction in both systolic and diastolic BP > 10%. Antihypertensive treatment aimed at an office BP < 120/80 mmHg. GFR was measured by the plasma clearance of 51Cr-EDTA and albuminuria was determined from 24-h collections.

Results. A total of 125 24-h BP recordings were made. Ten patients were constant dippers and five were constant non-dippers throughout the study whereas nineteen patients changed dipping status apparently at random. When analysing pairs of sequential recordings in the individual patient, non-dipper and dipper status remained unaltered in 25 (27%) and 32 (35%) of comparisons, respectively, whereas it was inconsistent in 34 (38%) of cases. No correlation between dipper status and GFR, decline in renal function, degree of albuminuria or BP level could be demonstrated.

Conclusions. The consistency of circadian BP variation seems to be poor in CKD stages 3–5 and single measurements of 24-h ambulatory BP are therefore probably inadequate for the evaluation of dipping status.

Keywords: ambulatory; blood pressure monitoring; kidney failure; prospective studies



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
Hypertension is a marked risk factor for progression of chronic kidney disease (CKD) and cardiovascular morbidity and mortality. Loss of the physiologic decline in nocturnal blood pressure (BP), termed non-dipping, has been reported to be common in CKD [1–4], and non-dipping has been suggested to be associated with an accelerated loss of renal function [5–8]. A wider use of 24-h BP monitoring as a prognostic tool in CKD has been proposed to obtain more precise information on BP load and diurnal variation in the individual patient [9].

When assessing the importance of non-dipping as a prognostic marker in CKD, the variability of circadian BP patterns in renal patients must be taken into account. Information about this is limited as there are only few longitudinal data. In 30 patients with autosomal dominant polycystic kidney disease and mild renal impairment, Covic et al. found that only 36.6% of patients maintained a stable dipping pattern through three measurements obtained during an observation period of 12 months [10]. A poor reproducibility of circadian variation in BP has also been observed in patients with mild-to-moderate untreated hypertension [11,12], in isolated systolic hypertension [13], in hypertension with left ventricular hypertrophy [14] and in the elderly [15]. Longitudinal data on variation in BP pattern in patients with moderate to severe renal impairment have not been reported previously.

Thus, the aim of the present report is to describe longitudinal observations on ambulatory BP pattern in patients with progressive CKD stages 3–5 (pre-dialysis).



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
Study population
This post hoc study was done on data acquired during a 12-month controlled trial demonstrating that low dosage of enalapril afforded the same degree of renoprotection and BP control as conventional dosage in 40 Caucasian patients with progressive CKD stages 3–5 [16,17]. Thirty-four of these patients, 21 men and 13 women with a median age of 58 (range 23–79) years, had at least two 24-h BP recordings done and were included in the present study; CKD was classified as previously described [15,16]. Seven patients had chronic glomerulonephritis, four had diabetic nephropathy, seven had autosomal dominant polycystic kidney disease and four had chronic tubulo-interstitial nephropathy. The remaining 12 patients were classified as having chronic nephropathy of unknown aetiology. Plasma creatinine values at baseline were between 175 and 700 µM. Before entering the controlled study, all of the patients had been on long-term antihypertensive treatment. The therapeutic goal of the trial was an office BP of 120/80 mmHg. All patients were receiving basic treatment with enalapril and were supplemented with additional antihypertensive treatment as needed to obtain the BP goal [16]. None of the patients were in treatment with immunosuppressives or non-steroidal anti-inflammatory drugs.

All patients gave their written informed consent, and the trial was in adherence with the declaration of the Helsinki guidelines regarding ethical principles for medical research involving human subjects and was approved by the Medical Ethics Committee of Copenhagen County and the Danish Medicines Agency.

Measurements
Ambulatory 24-h BP recordings were done at baseline and thereafter every 4 months during 1 year with the oscillometric method using an automated monitor (A&D, TM 2421). Before fitting the device, BP was measured manually on either arm in the sitting position after 10 min of rest employing a mercury sphygmomanometer and these recordings were used as the office BP measurements. If there was a difference in BP of >10 mmHg, the arm with the highest pressure was to be used for the 24-h monitoring. Care was taken to determine the proper cuff size to be used in the individual patient. The device was programmed to make recordings every 15 min between 07:00 and 23:00 h and every 30 min between 23:00 and 07:00 h. A recording was to be rejected as invalid if >20% of potential daytime or nighttime measurements were absent. Patients were not restricted from pursuing their normal daily activities but to refrain from strenuous sport activities and were also asked to go to bed at normal hours. Salt intake was free.

GFR was measured by the plasma clearance of 51Cr-EDTA as described previously [18]. Urinary albumin excretion was determined from 24-h urine collections and analysed by means of routine clinical chemistry methods.

Statistical analysis
Data are reported as median (range) unless otherwise stated.

Individual progression rates were determined from linear regression plots of GFR versus time applying a repeated measurements analysis (SAS PROC MIXED). Comparisons between groups were done by the Mann–Whitney U-test. All probability values are two-tailed. P values < 0.05 were considered statistically significant.



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
Blood pressure variability
A total of 125 24-h BP recordings were done. Twenty-four patients completed the full protocol. One patient started dialysis during the study period and had only two recordings done. Nine patients had three recordings: one patient received a kidney transplant before the final measurement, one patient was withdrawn due to an adverse event related to the core study and seven patients declined to have the final recording. No recordings had to be discarded due to lack of measurements. Dipping status was based on the presence (dippers) or absence (non-dippers) of a nighttime reduction in both systolic and diastolic BP > 10% compared to daytime measurements [19]. The patients who retained their status throughout the study period were termed constant dippers or constant non-dippers. Patients who changed status during the observation period were categorized as inconstant dippers.

Ten patients (29%) were constant dippers, five (15%) were constant non-dippers and nineteen (56%) were inconstant dippers. The patient with two recordings was an inconstant dipper. The patients who changed dipper status did so at apparently random order: 3 patients changed from dipping to non-dipping, 3 patients changed from non-dipping to dipping and 13 patients changed back and forth during the study period. Exact ratios of nighttime reduction in systolic and diastolic BP in the group of inconstant dippers are given in Figures 1 and 2. As shown, a large number of patients had a considerable variation in reduction ratio during the study period.


Figure 1
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  		Fig. 1 Nighttime reduction in systolic BP as compared to daytime values in 19 patients with CKD stages 3–5 and inconstant dipping status during 12 months of observation. Each line represents one patient. Values below 1.0 represent a fall in nighttime BP and values below 0.9 represent status as a dipper.

 

Figure 2
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  		Fig. 2 Nighttime reduction in diastolic BP as compared to daytime values in 19 patients with CKD stages 3–5 and inconstant dipping status during 12 months of observation. Each line represents one patient. Values below 1.0 represent a fall in nighttime BP and values below 0.9 represent status as a dipper.

 
To describe changes in dipping status in more detail, we analysed pairs of sequential recordings in each individual patient. That is, any measurement was compared with the following one, resulting in a total of 91 paired comparisons. By this analysis, dipping status remained unaltered in 62% and changed in 38% of cases, respectively. Changes from dipping to non-dipping status or vice versa had the same frequency, 20% and 18%, respectively.

Blood pressure levels and heart rate
Median office BP, daytime and nighttime 24-h BP and the heart rate in constant dippers, constant non-dippers and inconstant dippers are shown in Tables 1 and 2.


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  		Table 1 Office BP (mmHg) in 34 patients with CKD stages 3–5

 

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  		Table 2 Blood Pressure (mmHg) and heart rate (HR) obtained from 24-h recordings in 34 patients with CKD stages 3–5

 
At baseline, systolic office BP was significantly higher in the constant non-dippers than in the other two groups. During the rest of the study there were no differences in office BP between the groups (Table 1). No significant differences in daytime 24-h BP were demonstrated between the groups and furthermore there were no significant differences between office BP and daytime 24-h BP at any time throughout the study (Table 2). Nighttime BP was significantly lower in the constant dippers as compared to the constant non-dippers, in keeping with the definition of the group.

In recordings showing a nightly fall in BP of >10%, the median change in systolic pressure was –15 (–10 to –26)% and the median change in diastolic pressure was –18.5 (–10 to –31) %. In the 56 recordings without a systolic and diastolic nighttime dip, the median change in systolic and diastolic pressure was –5 (–13 to +6)% and –7 (–24 to +3)%, respectively. There was no correlation between the BP level and dipping status.

The heart rate did not differ between the groups, neither during the day nor during the night (Table 2).

Antihypertensive treatment
All patients were treated with enalapril in high or low dosage according to the protocol of the controlled study [16]. There was no significant correlation between enalapril dosage and dipping status. The use of loop diuretics did not differ between the groups, 80–100% of patients in each group were treated with furosemide and no other diuretics were prescribed. The uses of beta blockers and calcium antagonists tended to be highest in the constant non-dipper patients. However, the size of the material, particularly the small number of constant non-dippers, does not allow for statistical analysis on this finding.

Glomerular filtration rate, end-stage renal failure and albuminuria
At baseline, median GFR was 17 (8–35) ml/min/1.73 m2. The median change in GFR during the study was –5 (–15 to +6) ml/min/year including all patients. No correlation between dipping status and aetiology of renal disease, baseline GFR or decline in renal function could be demonstrated. When analysing the dataset in a cross-sectional fashion, no significant correlation between GFR and diurnal change in either systolic or diastolic BP could be found.

Two patients reached end-stage renal failure (ESRF) during the study; one constant dipper patient received a kidney transplant and one inconstant dipper patient started dialysis.

At baseline, the median 24-h urinary albumin excretion was 0.72 (0.08–13.12) g in the constant dippers, 1.07 (0.13–3.0) g in the constant non-dippers and 0.39 (0.01–3.39) g in the inconstant dippers (NS for comparisons between groups). After 12 months of observation, albumin excretion was 0.88 (0.03–5.91), 1.0 (0.84–1.15) and 0.44 (0.01–3.91) g/day in the three groups, respectively (NS). No significant correlation between albumin excretion and diurnal change in either systolic or diastolic BP could be found.



   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
The present longitudinal observations show that during the progression of advanced CKD changes in the circadian BP pattern in the individual patient are very frequent. Thus, during a median observation period of 12 months with 24-h BP recordings every 4th month, only 34% of patients maintained a stable dipping status: 29% were constant dippers and 5% were constant non-dippers. In the remaining 56% of patients, the nocturnal BP drop changed between being preserved or attenuated in an apparently random fashion. Similar results have been demonstrated in a prospective study of 30 patients with autosomal dominant polycystic kidney disease and mild renal impairment, where dipping pattern changed in more than half of the patients during a 12-month observation period [10]. This variation in diurnal BP pattern seems to limit the value of single 24-h BP measurements as a prognostic tool in CKD patients.

At baseline, the constant non-dippers had a significantly higher office systolic BP. This is not judged to be of importance for the results of the study, as no significant differences in daytime 24-h BP were demonstrated between the groups during the study. However, to achieve constant BP levels, antihypertensive therapy was modified during the study, which might contribute to the observed variation in circadian BP rhythm. The small size of the study does not allow any specific analysis of the relationship between changes in antihypertensive drugs and dipping pattern. The same applies to the absent relationship between office-derived BP and 24-h-derived daytime BP. There was no suggestion of any association between BP pattern and aetiology of renal disease, level of GFR or urinary albumin excretion.

We found no relationship between the constant non-dipping pattern and the faster progression of renal impairment as judged by the rate of decline in GFR. This is at variance with previous studies. In a case-control study, progression rates as judged by creatinine clearance in 48 hypertensive patients with renal insufficiency were faster in the non-dippers than in the dippers [8]. An inverse correlation has been found between estimated creatinine clearance and nightly BP dips in 32 patients with secondary hypertension in a cross-sectional study [4]. In a large cross-sectional study of 480 ambulatory BP recordings in 380 patients with either essential hypertension and normal renal function, secondary hypertension due to kidney disease or on renal replacement therapy, non-dipping was seen in 53% of patients with underlying renal disease and normal creatinine values as compared to the values in 30% of patients with essential hypertension, and the prevalence of non-dipping was gradually increased with worsening of renal function [2]. In a study of 26 patients with diabetic nephropathy, a marked effect of non-dipping on the rate of decline of renal function was shown, as judged by estimated creatinine clearance. Twelve of the patients had repeated ambulatory BP recordings done, in which the diurnal rhythm pattern was retained [7]. Two cohort studies have recently been published. In a retrospective cohort of 322 hypertensive patients without major renal disease referred for ambulatory BP monitoring, 57% were non-dippers. During a median follow-up of 3.2 years, GFR remained stable among dippers but declined among non-dippers. Due to the design of the study, there was no data about BP control during the observation period [6]. In another cohort study of 217 veterans with CKD and an estimated average GFR of 45 ml/min/1.73 m2, a non-dipping frequency of 80% was reported. Thirty-seven percent had diabetic nephropathy and nearly all were on antihypertensive treatment, in most patients including blockers of the renin–angiotensin system. Non-dipping was found to be an independent predictor for ESRF. Interestingly, among the circadian BP parameters, daytime ambulatory BP was the strongest predictor of ESRF and nighttime ambulatory BP, the strongest predictor of total mortality [5].

Several factors might contribute to the discrepancy between these earlier studies and the present. Firstly, previous studies have been cross-sectional [2–4] or retrospective [6, 7]. Secondly, almost all have been based on a single 24-h BP measurement in the individual patient, thereby not taking the frequent inconsistency of dipping status into consideration [2–7]. Another contrast to earlier studies is that we have evaluated the decline in renal function by a more reliable method using sequential direct measurements of GFR, by the 51Cr-EDTA plasma clearance method [16,18] rather than indirect GFR methods [2–4,6–8,20]. On the other hand, the minor number of patients and the length of follow-up are limitations of the present study.

The pathogenesis of the attenuated nightly BP in patients with CKD has not been clarified. An abnormally increased secretion of vasoactive hormones including angiotensin II has been suggested [4]. A possible beneficial influence of RAS blockade was observed in a randomized study of early diabetic nephropathy where reductions in mainly nighttime BP was seen in lisinopril-treated patients as compared with placebo [21]. In the present study all patients were in treatment with an ACE inhibitor; however, the dosing of that was not changed during the study period.

To conclude, we have found limited consistency in the diurnal variation in BP in a longitudinal study of 34 patients with progressive CKD stages 3–5. Consequently, it seems that single 24-h BP recordings do not allow classification of CKD patients as dippers or non-dippers. More studies are needed to establish the prognostic value of diurnal BP variation in this group of patients.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Baumgart P, Walger P, Gemen S, et al. Blood pressure elevation during the night in chronic renal failure, hemodialysis and after renal transplantation. Nephron (1991) 57:293–298.[Web of Science][Medline]
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  7. Farmer CK, Goldsmith DJ, Quin JD, et al. Progression of diabetic nephropathy—is diurnal blood pressure rhythm as important as absolute blood pressure level? Nephrol Dial Transplant (1998) 13:635–639.[Abstract/Free Full Text]
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Received for publication: 23. 9.07
Accepted in revised form: 15. 2.08


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