Ambulatory Blood Pressure and Endothelial Dysfunction in Patients with Autosomal Dominant Polycystic Kidney Disease

Abstract

Cardiovascular problems are a major cause of morbidity and mortality in patients with autosomal dominant polycystic kidney disease (ADPKD). Endothelial dysfunction (ED), which is an early manifestation of vascular injury, has been shown in patients with ADPKD. However, the association between ambulatory blood pressure and ED has not been investigated in these patients. Forty-one patients with ADPKD having well-preserved renal function were included in the study. Ambulatory blood pressure monitoring was performed in all patients. Patients were divided into dipper and non-dipper groups. Endothelial function of the brachial artery was evaluated by using high-resolution vascular ultrasound. Endothelial-dependent dilatation was expressed as the percentage change in the brachial artery diameter from baseline to reactive hyperemia. The mean 24-hour systolic blood pressure was similar in both groups (125.5 ± 10.7 mmHg in dippers and 121.2 ± 14.3 in non-dippers, p > 0.05). There was also no significant difference between the mean 24-hour diastolic blood pressures in both groups (82.3 ± 9.6 mmHg in dippers and 77.1 ± 8.6 mmHg in non-dippers, p > 0.05). The nocturnal fall rate in systolic blood pressure was 11.1 ± 1.2% in dippers and 0.98 ± 0.9% in non-dippers (p = 0.001). The nocturnal fall rate in diastolic blood pressure was 14.0 ± 0.9% in dippers and 3.8 ± 0.8% in non-dippers (p = 0.001). Endothelial-dependent dilatation was significantly higher in dippers compared to non-dippers (6.22 ± 4.14% versus 3.57 ± 2.52%, p = 0.025). Non-dipper patients with ADPKD show significant ED, which has an important impact on cardiovascular morbidity and mortality.

Keywords:

• ambulatory blood pressure
• autosomal dominant polycystic kidney disease
• dipper
• endothelial dysfunction
• non-dipper

INTRODUCTION

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease, responsible for 5–10% of end-stage renal disease.[1] Cardiovascular problems are a major cause of morbidity and mortality in patients with ADPKD.[2] Endothelial dysfunction (ED), an early manifestation of vascular injury, has been shown in both hypertensive and normotensive patients with ADPKD.[3],[4]

Ambulatory blood pressure predicts cardiovascular events better than does clinic blood pressure.[5],[6] A lack of nocturnal blood pressure fall (non-dipping) is a good predictor of cardiovascular prognosis.[7] Hypertensive patients with ADPKD have significantly less decline in nocturnal blood pressure compared to patients with essential hypertension.[8] The clinical importance of this finding and its association with cardiovascular injury has not been widely investigated in these patients. The aim of this study was to investigate the association between ambulatory blood pressure and ED in patients with ADPKD.

SUBJECTS AND METHODS

Forty-one patients with ADPKD were included in the study, 12 male and 29 female. The mean age of the patients was 37.6 ± 8.1 years. The diagnosis of ADPKD was reached by the ultrasonographic criteria described by Ravine et al.[9] All of the patients had family history of ADPKD. Glomerular filtration rate (GFR) was calculated by the Cockroft-Gault formula. All patients had GFR greater than 60 mL/min/1.73 m².

Subjects affected by diabetes mellitus, established cardiovascular disease, or other chronic diseases that could affect endothelial function, or had a family history of hyperlipidemia or premature atherosclerosis, were excluded. Biochemical markers of thyroid and liver functions were within normal range in all subjects. Thirteen of the patients were smokers, and twenty-six of the patients received antihypertensive treatment.

The study protocol was approved by the institutional medical ethics committee, and written informed consent was obtained from all subjects included in the study.

Systolic and diastolic blood pressures were measured on the right arm of subjects in an upright sitting position after at least five minutes of rest using a sphygmomanometer with appropriate cuff size. Two readings were recorded for each individual. The average of two readings was defined as the subject's clinical blood pressure. Hypertension was defined as systolic blood pressure ≥140 and/or diastolic blood pressure ≥90 mm Hg in the sitting position or taking antihypertensive drugs.

Ambulatory blood pressure monitoring (ABPM) was performed in all patients over a 24-h period by the oscillometric method using a fully automatic non-invasive recorder (Spacelabs 90207, Redmond, Washington, USA). The monitor was programmed to measure blood pressure and heart rate at 20 min intervals between 07.00 and 22.59 and at 30 min intervals between 23.00 and 06.59. The patients were advised to pursue their usual daily activities; none was on night-shift duty, and they all slept during the night. All data were transferred into a software program. Patients showing a nocturnal fall of ≥10% in systolic blood pressure were considered dippers.

Venous blood samples for the biochemical analyses were taken after an overnight fast between 8 PM and 8 AM. Urinary albumin excretion (UAE) was detected in 24-h urine samples.

Echocardiographic examination was performed using a Vingmed System Five, Norway echocardiographic system equipped with 2.5-MHz transducers (Vingmed Sound, Norway). M-Mode and two-dimensional measurements were performed in accordance with methods recommended by the American Society of Echocardiography.[10],[11] Cardiac mass was calculated by means of the formula derived by Devereux and Reichek.[12] Left ventricular hypertrophy (LVH) was defined as left ventricular mass index (LVMI) >125 g/m² for males and >110 g/m² for females.

Brachial Artery Measurements

Endothelium-dependent dilatation (EDD) of the brachial artery after transient ischemia, a noninvasive method to assess endothelial function, was performed according to methods defined by Celermajer et al.[13] using a high-resolution ultrasound machine (Vingmed System Five, Oslo, Norway). All of the subjects abstained from smoking and caffeine-containing drinks for at least 12 hours before testing. The subjects were kept in a supine position for 10 minutes in the stable room temperature between 20–25°C. To best visualize the brachial artery, the arm was immobilized comfortably in the extended position, and the brachial artery was scanned in the longitudinal section 3 to 5 cm above the antecubital fossa by using a 10-MHz high-resolution linear-array transducer. After optimal transducer positioning, the skin was marked for reference for later measurements, and the arm was kept in the same position throughout the study.

All measurements of brachial artery internal diameter were assessed at the end-diastole (timed by the QRS complex) and calculated as the average of measurements obtained during three consecutive cardiac cycles. After baseline measurements of the brachial artery were recorded, the cuff was inflated to 200 mm Hg (or 50 mm Hg higher than systolic blood pressure) for five minutes to create forearm ischemia. Subsequently, the cuff was deflated, and arterial diameter was measured 60 seconds after deflation. EDD was expressed as the percentage of change in brachial artery diameter from baseline to after reactive hyperemia.

All measurements were performed by a single investigator blinded to clinical and biochemical data of the patients and recorded on VHS videotape for subsequent off-line analysis. Intraobserver variability for brachial artery measurements was 3%.

Statistical Analyses

All statistical analyses were performed using the SPSS program, version 11.0 (SPSS Inc., Chicago, Illinois, USA) for Windows XP. Numerical variables were given as mean ± standard deviation. The Mann-Whitney U test was used for the comparison of different groups with abnormally distributed variables. Student's t-test was used for unpaired data, after confirmation by the Kolmogorov-Smirnov test that the data were normally distributed. Pearson correlation coefficient was used to describe correlations between EDD and other variables; a p value below 0.05 was considered statistically significant.

RESULTS

Age, gender, body mass index, hemoglobin, glucose, renal function, lipid parameters, and clinical systolic and diastolic blood pressure were similar in dipper and non-dipper patients with ADPKD (see Table 1). According to clinic blood pressure measurement, fourteen patients were hypertensive in dippers and twelve patients were hypertensive in non-dippers. Thirteen patients were administered angiotensin-converting enzyme (ACE) inhibitors; three patients, calcium channel blockers (CCBs); five patients, angiotensin-receptor blockers (ARBs); five patients, a combination of ACE inhibitors and CCBs; and three patients, beta blocker in groups. No statistically significant difference in antihypertensive use was present between the two groups. Two patients in dipper and two patients in non-dipper groups were using statin.

Table 1 Characteristics and laboratory parameters of the patients

	Dipper (n = 20)	Non-dipper (n = 21)	p value
Age (years)	37.5 ± 7.6	37.6 ± 8.9	0.9
Gender (M/F)	7/13	5/16	0.4
Body mass index (kg/m^2)	25.0 ± 4.1	25.3 ± 4.5	0.8
Smokers (n)	7	6	0.6
Clinic SBP (mm Hg)	140 ± 20	135 ± 15	0.2
Clinic DBP (mm Hg)	90 ± 10	85 ± 15	0.1
GFR (mL/min/1.73m^2)	97.2 ± 21.5	98.8 ± 23.4	0.8
Glucose (mg/dL)	88.5 ± 7.5	90.7 ± 8.5	0.3
Triglyceride (mg/dL)	116.9 ± 65.5	129.6 ± 81.5	0.5
Cholesterol (mg/dL)	189.8 ± 27	183.8 ± 35.8	0.7
Hemoglobin (g/dL)	13.2 ± 0.9	13.3 ± 0.7	0.9
LVMI	109 ± 34	104 ± 33	0.7

Abbreviations: GFR = glomerular filtration rate, SBP = systolic blood pressure, DBP = diastolic blood pressure, LVMI = left ventricular mass index.

The mean 24-hour systolic blood pressure was similar in both groups (125.5 ± 10.7 mm Hg in dippers and 121.2 ± 14.3 in non-dippers, p > 0.05). There was also no significant difference between the mean 24-hour diastolic blood pressures in both groups (82.3 ± 9.6 mm Hg in dippers and 77.1 ± 8.6 mm Hg in non-dippers, p > 0.05). The mean 24-hour pulse rate was similar in both groups. The mean daytime systolic blood pressure was higher in dippers but not statistically significant than non-dippers. The mean daytime diastolic blood pressure was significantly lower in non-dippers (p = 0.005). The mean nighttime systolic blood pressure was higher in non-dippers, although this was not statistically significant. There was no significant difference between the mean nighttime diastolic blood pressures in both groups (see Table 2). The nocturnal fall rate in systolic blood pressure was 11.1 ± 1.2% in dippers and 0.98 ± 0.9% in non-dippers (p = 0.001). The nocturnal fall rate in diastolic blood pressure was 14.0 ± 0.9% in dippers and 3.8 ± 0.8% in non-dippers (p = 0.001).

Table 2 Data from ambulatory blood pressure measurements of the subjects

	Dipper (n = 20)	Non-dipper (n = 21)	p value
Mean 24-hour SBP (mm Hg)	125.5 ± 10.7	121.2 ± 14.3	0.15
Mean 24-hour DBP (mm Hg)	82.3 ± 9.6	77.1 ± 8.6	0.08
Mean 24-hour pulse rate	77 ± 6	76 ± 10	0.49
Mean daytime SBP (mm Hg)	129.8 ± 11.3	122.1 ± 13.5	0.01
Mean daytime DBP (mm Hg)	86.1 ± 10.1	77.0 ± 9.2	0.005
Mean nighttime SBP (mm Hg)	115.4 ± 9.2	120.8 ± 16.8	0.35
Mean nighttime DBP (mm Hg)	74 ± 8.4	74.4 ± 9.3	0.92

Abbreviations: SBP = systolic blood pressure, DBP = diastolic blood pressure.

The UAE was 45.6 ± 40.2 mg/24 h in the dipper group and 36.5 ± 22.2 mg/24 h in the non-dipper group (p > 0.05). There was also no significant difference in LVMIs in both groups (109.1 ± 34.6 g/m² in dippers versus 104.3 ± 33.4 g/m² in non-dippers). Four patients (20%) in the dipper group and seven patients (33.3%) in the non-dipper group had LVH (p > 0.05).

Basal diameter of the brachial artery was 3.44 ± 0.59 in the dipper group and 3.50 ± 0.53 in the non-dipper group, and it was not statistically significant. Endothelial-dependent dilatation was significantly higher in dippers compared to non-dippers (6.22 ± 4.14% versus 3.57 ± 2.52%, p = 0.025; see Figure 1).

Figure 1. Endothelial-dependent dilatation in dipper and non-dipper ADPKD patients.

There was no significant correlation between EDD and LVMI and both 24h systolic and diastolic blood pressure and microalbuminuria. On the other hand, 13 patients were smoking, and there was a significant correlation between EDD and smoking (4.86 ± 3.6 versus 1.6 ± 0.4, p = 0.03).

DISCUSSION

Cardiovascular problems are common in patients with ADPKD.[2] Increased left ventricular mass indexes, biventricular diastolic dysfunction, ED, increased carotid intima-media thickness, and exaggerated blood pressure response during exercise have been reported even in young normotensive patients with ADPKD with well-preserved renal function.[4],[14–21] Ambulatory blood pressure and non-dipping pattern have been shown to be more closely associated with target organ damage and a worsened cardiovascular outcome than clinic blood pressure in patients with essential hypertension.[22] Li Kam Wa et al.[8] have reported that hypertensive patients with ADPKD have significantly less nocturnal fall in blood pressure compared to patients with essential hypertension. Moreover, nocturnal decline in blood pressure is attenuated even in normotensive patients with ADPKD compared to healthy subjects.[19]

The association between ambulatory blood pressure profile and target organ damage has not been widely investigated in patients with ADPKD. It has been demonstrated that ambulatory blood pressure correlates with renal volume and number of renal cysts in children with ADPKD.[23] A significant negative correlation between renal concentrating capacity and ambulatory blood pressure has also been reported in these patients.[24] A significant association between LVMI and 24-hour systolic and diastolic blood pressure has been shown in hypertensive patients with ADPKD.[15] Valero et al.[19] reported that ambulatory blood pressure correlated with left ventricular mass in normotensive patients with ADPKD. However, no difference in LVMI was found between ADPKD dippers and non-dippers in that study.

Endothelial dysfunction, which is an early manifestation of vascular injury, can be detected non-invasively using high-resolution ultrasonography to measure post-ischemic flow-mediated dilation of the brachial artery.[13] Brachial artery ED correlates with coronary ED.[25] A previous study showed significant ED in both hypertensive and normotensive patients with ADPKD with well-preserved renal function, suggesting that cardiovascular involvement starts very early in the course of ADPKD.[4] In the present study, the association between 24-hour blood pressure profile and ED was investigated in patients with ADPKD. Endothelial-dependent dilatation was found significantly less in non-dipper patients with ADPKD compared to the dippers. Moreover, smokers had significantly lower EDD compared to non-smokers.

In the present study, no significant difference in the UAE levels was observed among dipper and non-dipper patients, although they were in the microalbuminuric range. The drugs patients were using may affect the results of UAE; however, no statistically significant difference in antihypertensive use was present between the two groups. Similarly, no significant difference was observed in LVMIs and the rate of LVH among dipper and non-dipper groups, as has been reported previously.[19]

There are some limitations to our study. First, the sample size used in our study was small, although the study was made with a special population. Second, vascular endothelial markers such as nitric oxide and endothelin were not evaluated in the present study.

In conclusion, this study provides evidence that ED, an important early feature of the atherogenic process, may occur in the systemic arteries of non-dipper patients with ADPKD. On this basis, ambulatory blood pressure monitoring is a useful tool in predicting cardiovascular risk in patients with ADPKD. Non-dipping pattern could be considered as an atherosclerotic risk factor in these patients. However, large-scale studies are needed for definitive conclusions.

ACKNOWLEDGMENTS

This study was supported by a grant (2004/3) from the Turkish Kidney Foundation. This study was presented in part at the Annual Meeting of the American Society of Nephrology in Philadelphia, PA, November 8–13, 2005.