Nighttime Blood Pressure Fall in Renal Disease Patients

Abstract

Objective. There are controversial reports in the prevalence of abnormal nighttime blood pressure fall in renal patients. It has been evaluated nocturnal BP in renal patients using 24 h blood pressure monitoring (ABPM) in comparison with nontreated control subjects either normotensives or hypertensives. Design and Methods. It has been reviewed 137 ABPM studies performed in renal patients (47.8 ± 15.4 years, 76 men and 61 women). The control group includes 119 subjects without kidney disease, 65 were normotensives, and 49 were hypertensives, aged 46.8 ± 12.1 years, 59 men and 60 women. The ambulatory BP was measured noninvasively for 24 h by the SpaceLabs 90207 device programmed to measure BP every 15 min during daytime and every 20 min during nighttime. The definition of daytime and nighttime was made on the basis of wakefulness and sleep or bed rest periods, obtained from a diary kept by each subject. Results. SBP, but not DBP, was higher (133.9/81.7) in renal disease patients when compared to nonrenal subjects (127.9/80.8, p<0.01). When the control group was split into normotensive and hypertensive patients there were still significant differences, but hypertensives had higher BP than renal disease patients (139.0/89.7, p<0.05). Nocturnal SBP fall in renal disease patients was reduced (5.8%, p<0.001) and so was DBP fall (11.1%, p<0.001) compared with the overall nonrenal patients sample (SBP 10.8; DBP 15.3%). The frequency of nondipper status in renal disease patients (39.6%) was higher than in control patients (18.4%, p<0.001). Nontreated normotensive renal disease patients did not show any difference in either SBP or DBP nighttime fall with respect to control normotensives. Neither do nontreated hypertensive renal patients as compared with control hypertensives. There were not differences between proteinuric and nonproteinuric patients in nocturnal BP fall. The same result was obtained when hypertensive and normotensive nontreated renal patients were compared. The presence of renal failure did not induce a reduction of nocturnal BP fall. Most of treated renal patients were mainly receiving drug therapy during the morning and frequently this was the single daily dose. Conclusions. Altered diurnal rhythm should not be considered as a usual complication of renal disease. Inadequate antihypertensive pharmacotherapy could be related to the abnormalities of nighttime BP fall when it is detected.

• Hypertension
• Renal failure
• Nighttime blood pressure

Introduction

The introduction of ambulatory blood pressure monitoring (ABPM) into clinical investigation has allowed one to study daily BP variations. BP usually falls during sleep time; this behavior is normally distributed in normotensive and hypertensive populations, and is attenuated with age. In many studies nighttime BP values have shown a greater predictive power in term of end-organ damage than daytime BP values.[[1]], [[2]], [[3]], [[4]], [[5]]

As in nonrenal patients, negatives target organs consequences of abnormal daily BP variability have been found in renal cohorts. A faster decline of renal function in predialysis patients has been shown in several kinds of kidney disease.[[6]], [[7]], [[8]], [[9]] Increased left ventricular mass in association with nocturnal hypertension has been reported in predialysis patients and in patients undergoing renal replacement therapy.[[10]], [[11]], [[12]], [[13]] The causes of this phenomena, abnormal nighttime BP reduction, are less known.[[14]]

It has been suggested that abnormal reduction in nocturnal BP is linked to several causes of secondary hypertension.[[15]] Among these causes, decreased fall in BP with sleep has been reported in patients with chronic renal diseases, such as IgA nephropathy,[[7]] and chronic renal failure.[[8]], [[16]], [[17]] But the experience collected is not homogeneous and there are some reports, which fail to find any abnormality of circadian BP rhythm in renal patients.[[11]], [[18]]

The objective of this study has been to confirm the abnormal reduction of BP during sleep in a broad group of patients with several forms renal disease and with (or without) associated renal failure and to investigate the possible causes of this phenomena and, specially, the effect of treatment on this problem.

Material and Methods

One hundred and thirty-seven 24 h ABPM studies performed in renal disease patients not undergoing any kind of renal replacement therapy have been reviewed. Causes of nephropathy are shown in Table 1. They were 76 men and 61 women. Mean age was 47.8 ± 15.4 years. Proteinuria, plasmatic creatinine, and creatinine clearance (calculated through 24 h urine collection) was recorded in all patients. Ninety-six patients were receiving antihypertensive treatment. Twenty-five nontreated patients were normotensives in ABPM (averaged 24h BP <130/80 mmHg) and 16 patients rendered hypertensives. Mean plasmatic creatinine was 1.45 ± 0.78 mg/dL. Mean creatinine clearance was 74.1 ± 39.5 mL/min. Seventy patients have proteinuria higher than 500 mg/day, 22 microalbuminuria (30–300 mg/day), and 23 showed normal urinalysis.

Table 1. Causes of nephropathy

Glomerulonephritis	22
Interstitial nephritis	44
Cystic disease	10
Diabetic nephropathy	11
Vascular nephropathy	32
Other/unknown	18

The control group includes 119 patients without kidney problems, with a mean age 46.8 ± 12.1 years. They were 59 men and 60 women (differences are not significant). In the control group, sixty-five patients were normotensives (mean age 44.8 ± 11.0 years, 31 men, and 34 women) and 49 subjects were hypertensives (mean age 47.9 ± 12.2 years, 25 men, and 24 women). Secondary hypertension and renal disease were ruled out by routine clinical and laboratory examinations. No one patient was receiving antihypertensive treatment.

The ambulatory BP was measured noninvasively for 24 h by the SpaceLabs 90207 device programmed to measure BP every 15 min during daytime and every 20 min during nighttime. The definition of daytime and nighttime was made on the basis of wakefulness and sleep or bed rest periods, obtained from a diary kept by each subject. On the day of ambulatory monitoring, the subjects followed their usual activity, which implied a wide variety of social and manual activity levels, but only if compatible. The arm cuff was positioned on the nondominant upper limb. The subjects were asked to refrain from movement and to keep their upper limb immobile during each measurement. Mean number of measures was 75.4. Records containing less than 50 measures were excluded for evaluation.

In every subject 24 h ambulatory BP mean, daytime BP, and nighttime BP means were calculated. We considered subjects without kidney disease to have hypertension if their 24 h BP was ≥135 mmHg systolic or ≥85 mmHg diastolic. Nighttime normal values were SBP <120 mmHg and DBP <80 mmHg. Nighttime blood pressure fall was expressed as percentage: (Daytime BP-NightTime BP)*100/DaytimeBP. Accepted normal value was >10%.

A computer program performed statistical evaluation. ANOVA test was used to compare continuous data of multiple groups, when the result was significant a direct comparison between every two groups was performed through Scheffe test. t Student test was used to directly compare two samples. Chi square text was used to compare noncontinuous variables. All values are expressed as the mean ±1 SD.

Results

Twenty-four hour averaged BP, nighttime BP, and systolic and diastolic BP nocturnal fall are shown in Table 2. SBP, but not DBP, was higher in renal disease patients as compared to nonrenal subjects (p<0.01). When the control group was split into normotensive and hypertensive patients (see Table 2) there were still significant differences, but hypertensives had higher BP (systolic and diastolic) than renal disease patients (p<0.05).

Table 2. All renal disease patients

Group	24 h SBP	24 h DBP	SBP fall	DBP fall
Renal disease	133.9 ± 18.8	81.7 ± 12.7	5.8 ± 8.5	11.1 ± 9.7
Control:	127.9 ± 13.9b	80.8 ± 9.4	10.8 ± 8.4a	15.3 ± 9.4a
Normotensive	118.3 ± 7.2b	74.3 ± 5.6a	10.8 ± 9.0a	15.7 ± 9.9b
Hypertensive	139.0 ± 11.1c	89.7 ± 6.4a	10.3 ± 7.4c	14.3 ± 8.4c

SBP and DBP expressed as mmHg. SBP and DBP nighttime fall expressed as percentage.

^ap<0.001.

^bp<0.01.

^cp<0.05. ANOVA test.

Nocturnal SBP fall in renal disease patients was reduced (p<0.001) and so was DBP fall (p<0.001) compared with the overall nonrenal patients sample. The difference still exists when the first group was separately compared with normotensives or hypertensives without renal disease (see Table 2). The frequency of nondipper status in renal disease patients was higher than in control patients (p<0.001), but this difference did not exist when the comparison was made with control hypertensives (Fig. 1).

Figure 1. The prevalence of nondipper status was higher in renal patients (39.6%) compared with control normotensives (14.1%, p<0.001) but not when compared with control hypertensives (24.5%, NS). Differences between these latter groups are not significant.

Nontreated normotensive renal disease patients did not show any difference in either SBP or DBP nighttime fall with respect to control normotensives (Table 3). Neither do nontreated hypertensive renal patients as compared with control hypertensives (Table 3). There were no differences in the prevalence of nondipper status (Fig. 2).

Figure 2. When only nontreated renal patients were included (nondipper prevalence, 23.9%) no significant differences could be found between these patients and control normotensives (14.1%) and hypertensives (24.5%).

Table 3. Nontreated renal patients

Group	24 h SBP	24 h DBP	SBP fall	DBP fall
Renal disease	128.4±15.3b	81.1±13.0b	9.3±6.6	14.5±8.2
Normotensive	117.±6.7	72.0±5.8	10.8±6.0	16.3±7.2
Hypertensive	143.2±9.7a	90.5±12.9	7.0±6.7a	11.3±8.9
Control
Normotensive	118.6±7.9	73.9±5.6	10.6±8.3	16.0±9.2
Hypertensive	137.8±10.2	89.0±6.2	10.3±6.9	14.7±7.9

SBP and DBP expressed as mmHg. SBP and DBP nighttime fall expressed as percentage.

^ap<0.05 (t Student test) vs. control hypertensives.

^bp<0.001 vs. control hypertensives and control normotensives. Differences between normotensives are not significant.

There were no differences between proteinuric and nonproteinuric patients in nocturnal BP fall. The same result was obtained when hypertensive and normotensive nontreated renal patients were compared. The presence of renal failure (plasmatic creatinine higher than 1.4 in men or 1.2 in women or creatinine clearance lower than 70 mL/min) did not induce a reduction of nocturnal BP fall. All values are shown in Table 4.

Table 4. Influence of proteinuria, renal failure, and hypertension in nontreated patients

	24 h SBP	24 h DBP	SBP fall	DBP fall
Proteinuria	130.9±13.0	83.9±10.8	7.9±6.2	11.7±7.7
No proteinuria	126.8±16.0	80.4±14.4	10.1±7.2	16.2±8.4
Renal failure	132.2±14.9	85.3±12.3	8.6±6.0	11.5±6.8
Normal function	125.9±14.5	79.5±13.3	9.6±7.5	16.4±8.8
Hypertensive	141.8±12.6a	93.2±11.9a	8.6±7.2	12.0±9.3
Normotensive	119.5±7.9	74.2±6.9	9.6±6.7	16.0±7.4

SBP and DBP expressed as mmHg. SBP and DBP nighttime fall expressed as percentage.

^ap<0.001 vs. normotensives. Other differences are not statistically significant.

Most treated renal patients were mainly receiving drug therapy during the morning and frequently this was the single daily dose (Fig. 3). Mean number of drugs taken were 2.19 in the morning, 0.26 in the afternoon, and 0.54 at night.

Figure 3. There is a clearcut difference in the number of patients who took antihypertensive drugs only in the morning. In addition to this situation, the number of drugs taken in the morning is also higher in the patients with multiple daily doses.

Discussion

The clinical use of ambulatory blood pressure measurement has allowed for a number of phenomena in hypertension to be more clearly identified than is possible with other methods of blood pressure measurement.[[1]], [[2]], [[3]], [[4]] Ambulatory blood pressure measurement is the only noninvasive blood pressure measuring technique that permits measurement of blood pressure during sleep. Nocturnal blood pressure levels are independently associated with end-organ damage, over and above the risk associated with daytime values. It has also been shown that absence of nocturnal “dipping” of blood pressure to lower levels than during the day is associated with target organ involvement either in renal patients or in subjects without renal disease.[[5]], [[6]], [[7]], [[8]], [[9]], [[10]], [[11]], [[12]], [[13]], [[14]]

ABPM in this group of renal patients did not show any consistent association between kidney disease and abnormal nocturnal BP fall when confident factors such as antihypertensive treatment were excluded. For the same range of BP normotensive patients with and without renal disease showed a rather similar decrease in BP during sleep time. Neither hypertension, nor proteinuria, nor renal failure could be related to abnormal BP reduction in nontreated patients with kidney disease.

These results are contradictory with some previous reports on nighttime BP patterns in renal disease patients, which founded abnormal reductions of BP in these subjects.[[7]], [[8]], [[16]], [[17]] There are scanty reports about nocturnal blood pressure fall in renal patients previously to begin hemodialysis. Farmer et al. studied a group of 26 diabetic nephropathy patients to evaluate the influence of nondipper status on chronic renal failure progression but they did not include a control group of non-renal patients, so, differences about nocturnal BP drop could not be analyzed.[[9]] In a previous report of a rather shorter sample of renal patients without control group we found a decreased nighttime BP fall.[[17]]

The biggest study is a retrospective analysis of a total of 480 ambulatory blood pressure recordings in 380 patients with underlying renal disease.[[8]] Patients came from nephrology outpatient clinics, dialysis units (hemodialysis and peritoneal dialysis), and from renal transplant receptors. Fifty patients with essential hypertension, matched for age, gender, and race were the control group. Excluding the patients undergoing renal replacement therapy there were 259 ABPM recordings in renal patients with plasmatic creatinine ranging from less than 110 µmol/L to more than 600 µmol/L. This group includes patients receiving antihypertensive treatment. The prevalence of abnormal sleep-related BP rhythm in those subjects with essential hypertension was 30% (15/50), while in those patients with underlying renal disease and normal plasma creatinine (<110 mmol/L it was 53% (39/74, p<0.01). Our results closely resemble those found in this study. Renal patients have reduced nocturnal BP fall and an increased prevalence of nondipper patients. But in our study, the difference disappears when patients undergoing antihypertensive treatment were not taken into account. Patients without treatment did not show differences when compared with controls, as were in the report of Stefanski et al. where patients were not taken any antihypertensive treatment.[[11]]

In this latter report, 20 untreated patients with biopsy-proven primary chronic glomerulonephritis (GN) who had casual blood pressure below 140/90 mm Hg and normal GFR by inulin clearance were analyzed. Patients were compared with normotensive healthy controls that were matched for BMI, gender, and age. Renal patients have higher 24 h BP and nighttime BP than control subjects, but there was no difference of mean nocturnal BP fall between both groups,[[11]] as in our results when only nontreated patients were taken into account and results were adjusted to blood pressure levels. Another study with 17 patients with mesangial proliferative glomerulonephritis did not find disturbed circadian BP rhythm in these patients.[[18]] Two more studies showed a relationship between renal disease and abnormal BP nocturnal fall only when chronic renal failure was present.[[19]], [[20]]

Antihypertensive treatment seems to play a main role in the differences found. In the study of Farmer et al. the patients with essential hypertension received 1.4 antihypertensives as a mean dose, but those with renal disease only 1.1 anti-hypertensives.[[8]] We have not compared the number of antihypertensives received in each group, but the timetable of doses has been analyzed. Most of the patients were receiving a once daily morning dose or, when receiving multiple doses, most of them were administered in the morning. A smaller group of patients were taking drugs in the afternoon or at night. It seems likely that, at least partially, the abnormalities in BP fall during sleep in renal patients could be attributed to the lack of distribution of drug doses along the day.

We have not found any relationship between altered nocturne BP drop and renal function, but the severity of renal failure was mild and in the biggest part of the sample. In other studies the difference in prevalence of nocturnal dipping reached statistical significance once plasma creatinine rose above 400 mmol/L and this threshold could explain this different result.[[8]] The lack of relationship of proteinuria with abnormal nocturnal BP fall is coincident with other studies of patients with glomerulonephritis.[[19]], [[20]]

In conclusion, altered diurnal rhythm should no longer be considered as a usual complication of renal disease, even when renal failure is present. Inadequate antihypertensive pharmacotherapy could be related to the abnormalities of nighttime BP fall when it is detected. To distribute the dose of antihypertensive drugs along the day might be needed in renal patients to avoid changes in nighttime BP rhythm.