International Journal of HypertensionVolume 2012 (2012), Article ID 178078, 6 pagesdoi:10.1155/2012/178078

Clinical Study

Ambulatory Arterial Stiffness Index Is Higher in Hypertensive Patients with Chronic Kidney Disease

Ronaldo Altenburg Gismondi,1,2 Mario Fritsch Neves,¹ Wille Oigman,¹ and Rachel Bregman³

¹Department of Clinical Medicine, Rio de Janeiro State University, Rio de Janeiro, RJ, Brazil²Departamento de Clínica Médica, Hospital Universitario Pedro Ernesto, Avenue 28 de Setembro 77, Sala 329, Vila Isabel, 20551-030 Rio de Janeiro, RJ, Brazil³Nephrology Division, Rio de Janeiro State University, Rio de Janeiro, RJ, Brazil

Received 7 January 2012; Revised 28 February 2012; Accepted 28 February 2012

Academic Editor: Agostino Virdis

Copyright © 2012 Ronaldo Altenburg Gismondi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Ambulatory arterial stiffness index (AASI) is a parameter obtained from ambulatory blood pressure monitoring (ABPM) that correlates with clinical endpoints. The aim of this study was to compare AASI in nondiabetic hypertensive patients with and without chronic kidney disease (CKD). Subjects with systemic arterial hypertension (SAH, ) with normal renal function, aged 40 to 75 years, were compared to hypertensive patients with CKD () presenting estimated glomerular filtration rate (eGFR) <60 mL/min by MDRD formula. ABPM was carried out in all patients. In CKD group, eGFR was 35.3 ± 2.8 ml/min. The mean 24-hour systolic and diastolic blood pressure (BP) was similar in both groups. AASI was significantly higher in CKD group ( versus , ), positively correlated to age (, ) and pulse pressure (, ) and negatively correlated to nocturnal BP fall (, ). These findings indicate the presence of stiffer vessels in CKD hypertensive patients.

1. Introduction

Epidemiological and observational studies indicate hypertension as a major cause of chronic kidney disease (CKD) [1]. In fact, hypertension and CKD are strongly connected because hypertension is both a cause and a consequence of CKD [2]. Hypertensive patients with CKD present higher morbidity and mortality rates when compared with those with normal renal function [3, 4]. Additionally, high blood pressure is a predictor of decline of glomerular filtration rate (GFR), and conversely, adequate blood pressure control contributes to preserve renal function [5–7].

Vascular changes are commonly observed in CKD patients, including reduced arterial elasticity observed in patients with end-stage renal disease [8, 9]. Fibroelastic intimal thickening, increased extracellular matrix, enhanced collagen density, and vascular calcification seem to contribute to stiffer arteries in CKD patients [10, 11]. It has been demonstrated that vascular stiffness may predict adverse cardiovascular outcomes [12, 13]. Current gold standard for vascular stiffness evaluation is the pulse wave velocity (PWV) which requires complex equipment and therefore is not commonly used in clinical practice [14]. Recently, a new parameter named ambulatory arterial stiffness index (AASI) was proposed for this evaluation [15, 16]. This index is derived from the regression slope of the diastolic on systolic blood pressure, using all of the readings during ambulatory blood pressure monitoring (ABPM).

It has already been reported that AASI presents good correlation with target organ damage and glomerular filtration rate (GFR) in essential hypertension [17–20]. Moreover, AASI may also correlate with cardiovascular events and mortality [21, 22]. On the other hand, there have been few studies investigating this index in hypertensive patients with different stages of CKD. The aim of our study was to evaluate the AASI in nondiabetic hypertensive patients with CKD and in those with normal renal function.

2. Methods

A case-control study involving 60 consecutive patients with primary hypertension was carried out in our institution. Thirty patients were recruited from the CKD outpatient clinic. Hypertensive patients with CKD, aged 40 to 75 years and estimated glomerular filtration rate (eGFR) <60 mL/min by the Modification of Diet in Renal Disease (MDRD) equation [23], were included (CKD group). Other 30 patients matched by age (±2 years) and gender with the CKD patients were selected from the hypertension outpatient clinic at the same institution. These patients presented systemic arterial hypertension (SAH group) and serum creatinine less than 1 mg/dL. Exclusion criteria were diabetes mellitus, hypertriglyceridemia (>400 mg/dL), urinary albumin-to-creatinine ratio (UACR) >1000 mg/g, acute renal failure, renal replacement therapy, regular use of anti-inflammatory drugs, and history of myocardial infarction or cerebrovascular disease in the last 6 months. The local Ethics Committee has previously approved the study protocol, and all participants gave written informed consent.

2.1. Blood Pressure Measurements

Office blood pressure was obtained using an electronic device (model HEM-705CP, Omron Healthcare Inc., IL, USA) and an appropriate sized cuff. Patients were seated for 30 minutes before measurement and refrained from smoking and caffeine ingestion in this period of time. Three readings, one minute apart, were done, and the average of these measurements was defined as the patient clinic blood pressure. The patients underwent 24-hour ABPM in nondominant arm with SpaceLabs 90207 monitor (Spacelabs Inc., Redmond, WA, USA), validated by the British Hypertension Society and the Association for the Advancement of Medical Instrumentation protocol [24]. Readings were taken every 20 minutes during the day and every 30 minutes at night. The patients recorded their sleep and wake times during the monitoring. ABPM was considered adequate if >70% of measurements were successfully obtained. The percentage decline in nocturnal blood pressure was calculated as follows for systolic (SBP) and diastolic (DBP) blood pressures: percentage decline in nocturnal blood pressure = (daytime blood pressure−night-time blood pressure) * 100/daytime blood pressure. The AASI was calculated from 1 minus the regression slope of diastolic pressure on systolic blood pressure. The slope was not forced through the origin.

2.2. Blood and Urine Samples Collection

Fasting venous blood was collected from participants to measure total cholesterol, triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), glucose, creatinine (enzymatic method), and uric acid. The low-density lipoprotein cholesterol (LDL-C) level was calculated by the Friedewald formula (8). eGFR was assessed by modified MDRD equation: eGFR = 0.741 × 175 × Cr −1.154 × age−0.203 (× 0.742 if female). C-reactive protein (nephelometry, BN II, Siemens AG Inc, Munich, Germany) and morning urinary spot albumin and creatinine (nephelometry, Immage, Beckman Coulter Inc, Fullerton, CA, USA) were also measured. The lower detection limit for C-reactive protein was 0.20 mg/L. Values for microalbuminuria were considered normal up to 30 mg/g creatinine.

2.3. Statistical Analyses

Data are presented as mean ± standard error of mean (SEM). For database management and statistical analyses, we used GraphPad Prism software, version 5.0 (GraphPad Software Inc., CA, USA). Chi-squared test (for 2 × 3 tables) or Fisher’s exact test (for 2 × 2 tables) and Student’s t-test were used to compare proportions and means, respectively. Pearson’s correlation coefficients were used to explore associations between examined continuous variables with parametric distribution. Statistical significance was determined by -level of 0.05 on two-sided tests.

3. Results

Baseline clinical characteristics did not differ between the groups. As expected, hemoglobin was significantly lower and serum creatinine and uric acid were significantly higher in CKD group (Table 1). Mean eGFR by MDRD in the CKD group was  mL/min. C-reactive protein and UACR were significantly higher in CKD group (Table 1).

Table 1: Demographic, anthropometric, and laboratory data of hypertensive patients in both groups.

Variable
SAH group
CKD group
P value

Age (years)

0.8786

Men, n (%)
18 (60)
18 (60)
1.0000

Black, n (%)
4 (13)
7 (23)
0.3251

Current smokers, n (%)
5 (17)
4 (13)
0.7232

Previous cerebrovascular disease, n (%)
2 (7)
2 (7)
1.0000

Dyslipidemia, n (%)
14 (47)
13 (43)
0.7091

BMI (kg/m²)

0.3856

Waist-to-hip ratio

0.6881

Hemoglobin (g/dL)

<0.0001

Glucose (mg/dL)

0.2645

Creatinine (mg/dL)

<0.0001

eGFR (mL/min)

<0.0001

Sodium (mg/dL)

0.6317

Potassium (mg/dL)

0.0927

Uric acid (mg/dL)

<0.0001

Triglycerides (mg/dL)

0.0737

Total Cholesterol (mg/dL)

0.6355

LDL-cholesterol (mg/dL)

0.1489

HDL-cholesterol (mg/dL)

0.0199

C-Reactive protein (mg/L)

0.0338

UACR (mg/g)

0.0002

LVH in ECG, n (%)
1 (4)
4 (13)
0.2216

Data presented as mean ± SEM or n (%). SAH, systemic arterial hypertension; CKD, chronic kidney disease; BMI, body mass index; eGFR, estimated glomerular filtration rate by MDRD equation; LDL, low-density lipoprotein; HDL, high-density lipoprotein; UACR, urinary albumin-creatinine ratio; LVH, left ventricular hypertrophy; ECG, electrocardiogram.

The mean office and ambulatory blood pressure readings were similar in both groups (Table 2), although CKD patients needed to use more antihypertensive drugs ( versus , ) to obtain blood pressure control. When CKD was compared to SAH group concerning antihypertensive treatment, there was no significant difference for diuretics (60% versus 70%), angiotensin converting enzyme inhibitors/angiotensin receptor blockers (86% versus 77%) and beta blockers (40% versus 37%). However, use of calcium channel antagonists was significantly more common in CKD patients (47% versus 23%, ).

Table 2: Office and ambulatory blood pressure parameters of hypertensive patients with normal and impaired renal function.

BP parameters
SAH group
CKD group
P value

AASI, units

0.0400

Office systolic BP, mmHg

0.4452

Office diastolic BP, mmHg

0.5121

Controlled office BP, n (%)
15 (50)
10 (33)
0.2949

24 h systolic BP, mmHg

0.6172

24 h diastolic BP, mmHg

0.6004

24 h Pulse Pressure, mmHg

0.2034

Controlled 24 h BP, n (%)
14 (47)
14 (47)
1.0000

White coat effect, n (%)
6 (20)
3 (10)
0.2859

Daytime systolic BP, mmHg

0.8732

Daytime diastolic BP, mmHg

0.5507

Nocturnal systolic BP, mmHg

0.2707

Nocturnal diastolic BP, mmHg

0.9644

Systolic nocturnal fall, %

0.0588

Diastolic nocturnal fall, %

0.2945

Data are expressed as mean ± SEM or n (%). AASI, ambulatory arterial stiffness index; SAH, systemic arterial hypertension; CKD, chronic kidney disease; BP, blood pressure.

The mean nocturnal systolic blood pressure fall was lower than 10% in both groups (% in CKD versus % in SAH, ). There were 40% of dipper patients, 50% of nondipper, and 10% of reverse dipper in SAH group. On the other hand, CKD group presented 30% of dipping pattern, 40% nondipping, and 30% reverse dipping (Figure 1). Pulse pressure was not different between CKD and SAH groups (54 ± 2 versus 50 ± 2 mmHg, ).

Figure 1: Percentage of nocturnal blood pressure fall patterns as dipper, nondipper, and reverse dipper in chronic kidney disease (CKD) and systemic arterial hypertension (SAH) groups.

The AASI index was significantly higher in CKD patients when compared with SAH group ( versus , ). Correlation tests showed that AASI was positively related to age (, ), pulse pressure (, ) and inversely related to nocturnal blood pressure fall (, ) (Figure 2). AASI did not correlate to UACR, serum creatinine, or eGFR. However, when eGFR was analyzed among all patients, those with eGFR less than 30 mL/min had higher AASI (Figure 3).

(a)

(b)

(c)

Figure 2: Plots of ambulatory arterial stiffness index on age (a), pulse pressure (b), and systolic nocturnal blood pressure fall (c).

Figure 3: Ambulatory arterial stiffness index (AASI) according to estimated glomerular filtration rates (eGFR). Data are presented as mean ± SEM. * versus other groups.

4. Discussion

The results of our study demonstrate that hypertensive patients with CKD presented a higher AASI when compared to those with normal renal function. Supporting the concept that AASI is a marker of arterial stiffness, Li et al. described its correlation with pulse wave velocity, central and peripheral augmentation indexes [15]. Moreover, in a cohort of 11,291 patients, Dolan et al. showed that AASI carried prognostic information, as it was a predictor of stroke and cardiac death [16]. In a Japanese study, Kikuya et al. also observed that AASI predicted cardiovascular and stroke mortality over and beyond pulse pressure [25]. Muxfeldt et al. demonstrated that AASI is a predictor of cardiovascular morbidity and mortality in 547 patients with resistant hypertension [21]. Furthermore, some research groups have already reported that AASI presents good reproducibility, with repeatability coefficients close to 60% [26, 27]. Criticizers say that this index is dependent on pulse pressure and dipping pattern and do not provide new information [28, 29]. Schillaci et al. studied 515 untreated hypertensive patients and found that AASI was strongly dependent on the degree of nocturnal blood pressure fall and only weakly related to pulse wave velocity [28]. Similar results were found by Baumann et al. with 112 German hypertensive patients [29].

Some authors have studied the relationship between AASI and renal function among hypertensive patients. Ratto et al. showed that AASI was positively related to urinary albumin excretion and negatively related to estimated creatinine clearance in a population of 168 patients with recently diagnosed hypertension and without drug treatment [30]. Mulè et al. studied 142 hypertensive patients without drug treatment and with serum creatinine less than 1.5 mg/dL and demonstrated that patients with high AASI presented lower GFR [17]. This paper also suggested that AASI was a better predictor of GFR decline than 24 h pulse pressure. In 554 hypertensive patients with and without drug treatment, Garcia-Garcia et al. observed that AASI correlates with eGFR, carotid intima-media thickness, and Cornell voltage-duration product [20].

Ageing is an important factor for arterial stiffening. Elderly people are predisposed to lose arterial elastic laminae and increase collagen deposits in vascular wall [10, 31]. This way, assuming AASI as a marker of vascular stiffness, the relationship between AASI and age is expected. Interestingly, CKD patients tend to have stiffer vessels when compared to age- and blood-pressure-matched patients with normal renal function [31, 32]. Beyond traditional risk factors, such as hypertension and dyslipidemia, uremia seems also play a role to this finding. Mineral metabolism alterations and arterial calcification are probably relevant mechanisms [10, 33]. This may be one hypothesis to explain why AASI was higher in CKD than in SAH group despite similar office and ambulatory blood pressure measurements in the present study. Moreover, patients with the lowest eGFR (stage 4, according to the American National Kidney Foundation [4]) presented higher AASI.

Pulse pressure and nocturnal blood pressure fall are two parameters from ABPM that correlate with arterial stiffness [34, 35]. Lekakis et al. and Jerrard et al. showed that hypertensive patients with nondipper pattern presented stiffer vessels when measured by pulse wave velocity, suggesting a relationship between blunted nocturnal blood pressure fall and reduced arterial elasticity [35, 36]. These findings corroborate with our study, since nocturnal blood pressure fall and pulse pressure were correlated with AASI. Indeed, AASI was different between groups despite similar pulse pressure and dipper status. This emphasizes the importance of calculating AASI after ABPM.

The present study has limitations considering the small sample size. Moreover, it was not prospective and not focused on clinical outcomes. However, our data strongly implies the value of AASI as a noninvasive tool for hemodynamic evaluation of CKD patient and reinforces the role of ABPM in hypertensive patients with renal dysfunction. Increased AASI might be one of the pathophysiological changes observed in CKD patients before the progression to end stage renal disease. More studies are needed to support the clinical usefulness of this parameter, but we propose that the software for ABPM analysis should include AASI value as a marker of cardiovascular risk assessment in the near future.

Conflict of Interests

The authors declare that they have no conflict of interests.

Acknowledgments

This research was partially supported by the Foundation to Support Research at State of Rio de Janeiro (FAPERJ). The authors would like to thank Sergio Franco Laboratory for the measurements of serum C-reactive protein and urinary albumin and creatinine.

References

E. Ritz, “Hypertension: the kidney is the culprit even in the absence of kidney disease,” Kidney International, vol. 71, no. 5, pp. 371–372, 2007.

A. M. Thompson and T. G. Pickering, “The role of ambulatory blood pressure monitoring in chronic and end-stage renal disease,” Kidney International, vol. 70, no. 6, pp. 1000–1007, 2006.

D. E. Weiner, H. Tighiouart, P. C. Stark et al., “Kidney disease as a risk factor for recurrent cardiovascular disease and mortality,” American Journal of Kidney Diseases, vol. 44, no. 2, pp. 198–206, 2004.

A. S. Levey, J. Coresh, K. Bolton et al., “K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification,” American Journal of Kidney Diseases, vol. 39, supplement 1, no. 2, pp. S1–S266, 2002.

M. J. Sarnak, T. Greene, X. Wang et al., “The effect of a lower target blood pressure on the progression of kidney disease: long-term follow-up of the modification of diet in renal disease study,” Annals of Internal Medicine, vol. 142, no. 5, pp. 342–351, 2005.

T. H. Jafar, P. C. Stark, C. H. Schmid et al., “Progression of chronic kidney disease: the role of blood pressure control, proteinuria, and angiotensin-converting enzyme inhibition: a patient-level meta-analysis,” Annals of Internal Medicine, vol. 139, no. 4, pp. 244–252, 2003.

D. Ljuticand and P. Kes, “The role of arterial hypertension in the progression of non-diabetic glomerular diseases,” Nephrology Dialysis Transplantation, vol. 18, supplement 5, pp. v28–v30, 2003.

J. J. Mourad, B. Pannier, J. Blacher et al., “Creatinine clearance, pulse wave velocity, carotid compliance and essential hypertension,” Kidney International, vol. 59, no. 5, pp. 1834–1841, 2001.

P. Gosse and M. E. Safar, “Arterial stiffness and plasma creatinine in untreated hypertensive patients,” American Journal of Hypertension, vol. 18, no. 9, pp. 1140–1145, 2005.

A. P. Guerin, B. Pannier, F. Metivier, S. J. Marchaisand, and G. M. London, “Assessment and significance of arterial stiffness in patients with chronic kidney disease,” Current Opinion in Nephrology and Hypertension, vol. 17, no. 6, pp. 635–641, 2008.

C. D. Chue, J. N. Townend, R. P. Steedsand, and C. J. Ferro, “Republished paper: arterial stiffness in chronic kidney disease: causes and consequences,” Postgraduate Medical Journal, vol. 86, no. 1019, pp. 560–566, 2010.

S. Laurent, P. Boutouyrie, R. Asmar et al., “Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients,” Hypertension, vol. 37, no. 5, pp. 1236–1241, 2001.

T. W. Hansen, J. A. Staessen, C. Torp-Pedersen et al., “Ambulatory arterial stiffness index predicts stroke in a general population,” Journal of Hypertension, vol. 24, no. 11, pp. 2247–2253, 2006.

S. Laurent, J. Cockcroft, L. Van Bortel et al., “Expert consensus document on arterial stiffness: methodological issues and clinical applications,” European Heart Journal, vol. 27, no. 21, pp. 2588–2605, 2006.

Y. Li, J. G. Wang, E. Dolan et al., “Ambulatory arterial stiffness index derived from 24-hour ambulatory blood pressure monitoring,” Hypertension, vol. 47, no. 3, pp. 359–364, 2006.

E. Dolan, L. Thijs, Y. Li et al., “Ambulatory arterial stiffness index as a predictor of cardiovascular mortality in the dublin outcome study,” Hypertension, vol. 47, no. 3, pp. 365–370, 2006.

G. Mulè, S. Cottone, P. Cusimano et al., “Inverse relationship between ambulatory arterial stiffness index and glomerular filtration rate in arterial hypertension,” American Journal of Hypertension, vol. 21, no. 1, pp. 35–40, 2008.

G. Leoncini, E. Ratto, F. Viazzi et al., “Increased ambulatory arterial stiffness index is associated with target organ damage in primary hypertension,” Hypertension, vol. 48, no. 3, pp. 397–403, 2006.

H. Triantafyllidi, S. Tzortzis, J. Lekakis et al., “Association of target organ damage with three arterial stiffness indexes according to blood pressure dipping status in untreated hypertensive patients,” American journal of hypertension, vol. 23, no. 12, pp. 1265–1272, 2010.

A. Garcia-Garcia, M. A. Gomez-Marcos, J. I. Recio-Rodriguez, et al., “Relationship between ambulatory arterial stiffness index and subclinical target organ damage in hypertensive patients,” Hypertension Research, vol. 34, no. 2, pp. 180–186, 2010.

E. S. Muxfeldt, C. R. L. Cardoso, V. B. Dias, A. C. M. Nascimento, and G. F. Salles, “Prognostic impact of the ambulatory arterial stiffness index in resistant hypertension,” Journal of Hypertension, vol. 28, no. 7, pp. 1547–1553, 2010.

M. Kikuya, J. A. Staessen, T. Ohkubo et al., “How many measurements are needed to provide reliable information in terms of the ambulatory arterial stiffness index the Ohasama study,” Hypertension Research, vol. 34, no. 3, pp. 314–318, 2011.

A. S. Levey, J. P. Bosch, J. B. Lewis, T. Greene, N. Rogersand, and D. Roth, “A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group,” Annals of Internal Medicine, vol. 130, no. 6, pp. 461–470, 1999.

E. O'Brien, N. Atkins, and J. Staessen, “State of the market: a review of ambulatory blood pressure monitoring devices,” Hypertension, vol. 26, no. 5, pp. 835–842, 1995.

M. Kikuya, J. A. Staessen, T. Ohkubo et al., “Ambulatory arterial stiffness index and 24-hour ambulatory pulse pressure as predictors of mortality in Ohasama, Japan,” Stroke, vol. 38, no. 4, pp. 1161–1166, 2007.

G. S. Stergiou, A. Kollias, V. C. Rarra, and L. G. Roussias, “Ambulatory arterial stiffness index: reproducibility of different definitions,” American Journal of Hypertension, vol. 23, no. 2, pp. 129–134, 2010.

D. G. Dechering, M. S. van der Steen, A. Adiyaman et al., “Reproducibility of the ambulatory arterial stiffness index in hypertensive patients,” Journal of Hypertension, vol. 26, no. 10, pp. 1993–2000, 2008.

G. Schillaci, G. Parati, M. Pirro et al., “Ambulatory arterial stiffness index is not a specific marker of reduced arterial compliance,” Hypertension, vol. 49, no. 5, pp. 986–991, 2007.

M. Baumann, L. Dan, J. Nurnberger, U. Heemannand, and O. Witzke, “Association of ambulatory arterial stiffness index and brachial pulse pressure is restricted to dippers,” Journal of Hypertension, vol. 26, no. 2, pp. 210–214, 2008.

E. Ratto, G. Leoncini, F. Viazzi et al., “Ambulatory arterial stiffness index and renal abnormalities in primary hypertension,” Journal of Hypertension, vol. 24, no. 10, pp. 2033–2038, 2006.

A. P. Guerin, B. Pannier, S. J. Marchaisand, and G. M. London, “Arterial structure and function in end-stage renal disease,” Current Hypertension Reports, vol. 10, no. 2, pp. 107–111, 2008.

F. H. Verbeke, M. Agharazii, P. Boutouyrie, B. Pannier, A. P. Guérin, and G. M. London, “Local shear stress and brachial artery functions in end-stage renal disease,” Journal of the American Society of Nephrology, vol. 18, no. 2, pp. 621–628, 2007.

G. M. London, A. P. Guérin, F. H. Verbeke et al., “Mineral metabolism and arterial functions in end-stage renal disease: potential role of 25-hydroxyvitamin D deficiency,” Journal of the American Society of Nephrology, vol. 18, no. 2, pp. 613–620, 2007.

H. Y. Lee and B. H. Oh, “Aging and arterial stiffness,” Circulation Journal, vol. 74, no. 11, pp. 2257–2262, 2010.

J. P. Lekakis, N. A. Zakopoulos, A. D. Protogerou et al., “Arterial stiffness assessed by pulse wave analysis in essential hypertension: relation to 24-h blood pressure profile,” International Journal of Cardiology, vol. 102, no. 3, pp. 391–395, 2005.

P. Jerrard-Dunne, A. Mahmud, and J. Feely, “Ambulatory arterial stiffness index, pulse wave velocity and augmentation index - Interchangeable or mutually exclusive measures?” Journal of Hypertension, vol. 26, no. 3, pp. 529–534, 2008.