Department of Internal Medicine, Ruperto Carola University, Heidelberg, Germany
Keywords: antihypertensive treatment; blood pressure; circadian blood pressure; progression of renal failure; renal transplantation
Ambulatory blood pressurewhat is normal?
According to Verdecchia et al. [1], the average awake blood pressure (BP) by ambulatory BP measurement (ABPM) is normally 130/80 mmHg. Values
135/85 mmHg should be considered as diagnostic for the presence of hypertension. Similarly, based on a meta-analysis of numerous studies, Staessen et al. [2] found that the 95th percentile of normal BP values is 130/80 mmHg for average 24-h pressure values and 135/85 mmHg or 120/70 mmHg for day-time and night-time pressure values respectively. A decrease of nocturnal BP by <10% (or according to the more rigorous definition by <15%), is considered as `non-dipping. Although gender and age are expected to affect circadian BP profile, these confounders are not considered in the above preliminary threshold values for untreated patients. No well-documented information is available on target BP values in patients on antihypertensive treatment.
Circadian blood pressure in renal patients
Most [35], but not all [6] authors noted an attenuated nocturnal decline in BP and an increased proportion of `non-dippers even in early renal disease. The proportion of non-dippers is higher in more advanced stages of renal dysfunction. The abnormality is independent of the underlying renal disease [3] and is seen even in individuals with normal excretory renal function [5]. As shown in Table 1, Stefanski et al. [7] examined patients with biopsy-confirmed IgAGN with normal inulin clearance who were compared with age-, gender-, and body mass index (BMI)-matched controls. He found that casual BP was significantly higher in patients than in controls, but the difference was much more pronounced for 24-h BP. The proportion of patients with abnormal nocturnal BP is particularly high when patients reach end-stage renal failure. This was found both in patients on CAPD [8,9] and on haemodialysis [1014]. Patients on long, slow dialysis sessions, who were practically all normotensive during the day-time despite no antihypertensive medication, nevertheless had night-time values and nocturnal ratios for systolic BP and diastolic BP that were higher than the reference values [2], when these patients were examined by ABPM. Though long, slow haemodialysis sessions undoubtedly improve BP control [1013], nevertheless in the study of Mc Gregor et al. [12] only 35% of patients had a normal circadian BP rhythm and the majority had a subnormal decrease or even an increase of night-time BP. Left-ventricular (LV) mass index, which is a known predictor of cardiovascular mortality in dialysis patients, was inversely correlated to the nocturnal decrease in BP (r=-0.54).
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In patients with essential hypertension, non-dipping was related to increased LV mass [16], and failure to respond to antihypertensive medication [27]. In a prospective study it was also related to coronary or cerebrovascular morbidity and mortality [28].
In diabetic patients even without microalbuminuria, the night-time decrease of BP may be blunted [18,20] and in non-microalbuminuric diabetic patients, higher night-time BP values were associated with the development of retinopathy [25]. In microalbuminuric type 1 diabetic patients, a very tight correlation exists between non-dipping and albumin excretion [24], and the same is true in type 2 diabetic patients. At the time of diagnosis of type 2 diabetes, 61% of our patients had a nocturnal decrease of BP by <15%, and 29% of patients a decrease by <10% [26]. This abnormality was related to the presence of microalbuminuria and was progressive with time; after 5 years, the percentage of patients with a blunted night-time decrease, i.e. <15%, had increased to 74% [29].
Why is the circadian blood pressure profile abnormal in renal patients?
Unfortunately, the information in patients with primary renal disease is limited, but there is a wealth of information in diabetes, and this may well be relevant for non-diabetic renal disease as well.
In type 1 [30] and type 2 [31] diabetic patients, non-dippers had higher extracellular volume. Apart from overhydration, impaired function of the autonomous nerve system, particularly of the parasympathetic system, also plays a role. Abolished beat-to-beat variation was noted in type 2 diabetic patients with nephropathy and impaired BP variability by ABPM [31]. According to van Ittersum et al. [32], higher nocturnal systolic BP is related to a blunted decline of heart rate, which pre<!?twb>vents adequate lowering of cardiac output during sleep. The role of autonomous dysinnervation is illustrated by the paradoxical and often major increase of BP at night-time in patients with autonomic failure [33].
A further aetiological factor may be sleep apnoea, which is common in patients with end-stage renal failure [34,35]. A grotesque case of day-time hypertension, sleep apnoea, and metabolic alkalosis in a haemodialysis patient with sodium bicarbonate abuse illustrates the underlying pathomechanisms [36]. In addition, a link between the known reduction of arterial distensibility and an abnormal circadian BP profile has been documented in dialysed patients [37]; it is unknown whether the increased pulse wave velocity in this study is, at least in part, a consequence of more severe hypervolaemia, causing blood pressure elevation and increased wall stress. This interpretation would be in line with the above findings of a relationship between hypervolaemia and an abnormal circadian BP profile [30,31].
Finally another important confounder is physical activity, which has a definite impact on nocturnal blood pressure and the dipping/non-dipping status [38], but given the notorious reduction in physical activity of renal patients, this is presumably less of a problem in this patient population.
Table 2 summarizes the factors that may play a role in the genesis of an abnormal circadian blood pressure profile in renal patients.
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Does circadian blood pressure profile affect renal prognosis?
Several retrospective studies suggest that non-dipping is associated with more rapid progression of renal disease. Potentially it may even be a cause of accelerated progression, but this remains unproven. Csiky et al. [4] studied patients with IgA nephropathy. Among 55 normotensive patients, an increase in serum creatinine was noted only in those who had been non-dippers at baseline. Similarly, in a retrospective study by Timio et al. [39] renal function was evaluated in 48 hypertensive patients with renal failure. Non-dippers (n=28) had a faster rate of decline of creatinine clearance than dippers (n=20), i.e. 0.37 vs 0.27 ml/min/month, and in parallel proteinuria increased more in non-dippers.
In a retrospective study of diabetic patients [40], Farmer et al. evaluated the rate of decline of creatinine clearance in 26 type 1 or type 2 diabetic patients and found a more rapid decline in non-dippers (-7.9 ml/min/year) compared to dippers (-2.9 ml/min/year).
In the absence of prospective intervention trials it is difficult to be certain, however, that the observed relation is truly causal.
Does the circadian blood pressure profile affect survival?
In patients with essential hypertension, a prospective study [28] showed that ABPM values were highly predictive of coronary and cerebrovascular morbidity and mortality. In haemodialysed patients as well, Tozawa et al. [41] noted that the cumulative rate of all-cause death was significantly correlated to the coefficient of variation of systolic BP. Cox regression analysis showed that the hazard ratio was increased by 1.63 per 1% increase in the coefficient of variation of systolic blood pressure. It is also of concern that reduced BP variability was shown to be predictive of progressive LV dilatation in dialysed patients [42], since LV dilatation is a potent predictor of cardiac death. These observations would be in line with the results of a study in type 2 diabetic patients that crude mortality, unadjusted for confounders, was higher by a factor of 20 in patients in whom the circadian BP rhythm was reversed [43].
Is abnormal BP profile reversible after renal transplantation?
The information on this point is not entirely consistent and one has to be aware of the confounding effects of renal dysfunction, antihypertensive treatment, and immunosuppressive treatment. The latter is particularly true for calcineurin inhibitors.
In a retrospecitve study, Gatzka et al. [44] found normalization of BP after transplantation. In contrast, Baumgart et al. [3] and Farmer et al. [5] as well as ourselves [45] failed to observe normalization. The same was noted in paediatric patients [46,47]. In the latter study, it was interesting that paediatric graft recipients who were normotensive by ABPM had hypertensive systolic blood pressure values in response to the treadmill exercise test, analogous to what is, found in normotensive microalbuminuric type 1 diabetic patients.
Figure 1 shows the percentage night-time decrease of systolic pressure in transplanted patients as a function of serum creatinine concentration in 112 patients attending the transplant outpatient clinic during a 3-months period in the Heidelberg clinic (median age 52 years, range 2378; 40 female, 72 male; S-creatinine 1.4 mg/dl; range 0.63.9. Antihypertensive medication was required in 94.5% of the patients and treated systolic BP was positively correlated to the number of antihypertensive agents, BMI, gender, but not serum creatinine and cyclosporin dose. Despite treatment with an average three antihypertensive agents (range 17), normotension according to JNC VI (<130/85 mmHg) was achieved in no more than 22.4% of patients. It is of interest that in patients with simultaneous pancreas/kidney transplants, abnormal 24-h BP control was noted as well [48], although the proportion of patients with post-transplant hypertension has apparently declined with increasing use of tacrolimus and mycophenolate mofetil [49].
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When to measure ambulatory blood pressure and what consequences to draw from the results?
A first important issue is whether or not ABPM measurements are reproducible. In the study of Peixoto et al. [50] ABPM values were significantly less variable than pre- or post-haemodialysis blood pressure values, the coefficient of variation being 7.5%. In contrast, the reproducibility of the decrease in BP during sleep was poor. Up to 43% of the subjects changed the dipping category. This is in good agreement with recent studies of Covic [51], who noted that in patients with autosomal dominant polycystic kidney disease with repetitive ABPM measurements, only 43% maintained the same dipping category. It must be questioned, however, whether in the individual patient the dipping category is the really important aspect. Treating night-time BP as a continuous variable we found much less variability, i.e. in 30 transplanted patients with 2 ABPM measurements, CV was 18% for absolute systolic BP day-time/night-time difference and 19% for MAP. Consequently, the absolute (mmHg) or relative (%) day-time/night-time BP difference values may be clinically much more relevant than the somewhat arbitrary categorization according to dipping status.
It is also important to point out that day-time and night-time do not refer to the actual hours, but to the hours when patients are awake or asleep, since wakefulness rather than local time are relevant for the behaviour of BP.
It may also been questioned whether conventional ABPM for 24 h is sufficient or optimal. Kooman et al. [13] measured pre- and post-dialytic BP and ABPM during the first and second day of the inter-dialytic period. Post-dialytic BP was better related to the inter-dialytic period ABPM than pre-dialytic BP. The difference between the first and second day was not statistically significant, although a rapid increase of BP was found in the hours before dialysis.
Finally, an important consideration is whether white-coat hypertension is an important confounder in patients with diabetic or non-diabetic renal disease, which would render BP measurements other than ABPM unreliable to a certain extent. Nielsen et al. [22] found white-coat hypertension in only 8% of type 1 diabetic patients with microalbuminuria and in 9% of patients with macroalbuminuria; in contrast, white-coat hypertension was found in 23% of diabetic patients with normoalbuminuria. This is in line with our own observations [52] where we found white-coat hypertension in 30% of non-renal patients, but only in 13% of renal patients. The latter observation would argue for the validity of single-point BP measurements, including home BP measurements [53,54]. The disadvantage of the exclusive use of home BP measurements is of course that sleeping time BP cannot be monitored and, as indicated above, it is this observation that may provide clinically relevant information on the quality of BP control in patients on antihypertensive treatment.
What consequences can one draw from ABPM measurements? The observations of a relationship between nocturnal BP and renal disease progression [4,39,40] and the observations of an impact on survival [41,42] are a matter of considerable concern. Although we admit that prospective studies are not available to show that antihypertensive intervention reverses these risks, there is a considerable case for monitoring the abnormality and intervening. This can be done with relative ease by managing the suggested aetiological factors (Table 2) and, if this remains ineffectively, administering an antihypertensive agent with intermediate duration of action at bed time.
Notes
Correspondence and offprint requests to: Professor Dr E. Ritz, Department of Internal Medicine, Bergheimer Str. 58, D-69115 Heidelberg, Germany.
1 Present address: 1st Department of Medicine, 3rd Faculty of Medicine, Charles University, Srobarova 50, 10034 Praa 10, Czech Republic.
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