Ambulatory Blood Pressure Monitoring in Patients With Chronic Kidney Disease and Resistant Hypertension

Abstract

J Clin Hypertens (Greenwich). 2012; 14:611–617. © 2012 Wiley Periodicals, Inc.

The role of ambulatory blood pressure (BP) monitoring (ABPM) has not been well‐studied in patients with chronic kidney disease and resistant hypertension. In a retrospective study of the outpatient chronic kidney disease population, 156 patients with chronic kidney disease and resistant hypertension who had 24‐hour ABPM and clinic BP measurements were identified. Resistant hypertension was defined as uncontrolled clinic BP while taking ≥3 medications including a diuretic or controlled BP while taking ≥4 medications. Within the study group, ambulatory BP <130/80 mm Hg was found in 35.9% of all patients. Only 6.4% had both ambulatory and clinic BP <130/80 mm Hg. Prevalence of white‐coat hypertension, masked hypertension, and sustained hypertension were 29.5%, 5.8%, and 58.3%, respectively. Compared with patients with sustained hypertension, more patients in the white‐coat hypertension group had low nocturnal average systolic BP (defined as nocturnal average systolic BP <100 mm Hg) (17.4% vs 0%) and low 24‐hour average diastolic BP (defined as 24‐hour average diastolic BP <60 mm Hg) (52.2% vs 22%, P<.01). ABPM provides more reliable assessment of BP in patients with chronic kidney disease and resistant hypertension.

Hypertension is a major risk factor in the progression of chronic kidney disease (CKD). ¹ Hypertension occurs in 86% of patients with CKD; however, the proportion of patients who are able to maintain blood pressure (BP) control (<130/80 mm Hg) remains poor at around 13.2%. ² An analysis of the current literature suggests that the severity and control of BP in patients with CKD may not be reliably assessed with clinic BP measurements alone. In fact, ambulatory BP monitoring (ABPM) provides better insight into a CKD patient’s BP than the BP measured in the clinic. ³ , ⁴ , ⁵ , ⁶ In a meta‐analysis of 6 studies in CKD patients, the prevalence of white‐coat hypertension was 18.3%, while the prevalence of masked hypertension was 8.3%. ⁷ A study in African American patients with CKD showed strikingly high prevalence of masked hypertension. ⁸ High prevalence of white‐coat hypertension in patients with CKD likely overestimates the prevalence of uncontrolled hypertension in this patient population. ⁹ This is likely to be true in CKD patients who have resistant hypertension.

The burden of resistant hypertension is high in patients with CKD. In a study from an academic renal clinic in Italy, the prevalence of resistant hypertension was 26%, which increased to 38% at a 6‐month follow‐up. ¹⁰ Given the high prevalence of white‐coat hypertension in patients with CKD, it is unclear how many CKD patients with resistant hypertension truly have resistant hypertension.

The use of 24‐hour ABPM is well described as a method of assessing patients with resistant hypertension in the general population. ¹¹ , ¹² As mentioned above, it has been evaluated as a tool for use in patients with CKD for BP assessment. However, the use of 24‐hour ABPM in patients with both CKD and resistant hypertension has not been well described.

The objective of this study was to determine the prevalence of white‐coat hypertension in CKD patients with resistant hypertension and to assess their clinical and ambulatory BP readings to determine whether 24‐hour ABPM is a more accurate way to assess BP in these patients.

Methods

This is a retrospective study of patients from an outpatient CKD clinic. Patients included in the study were older than 18 years and had both CKD and resistant hypertension. CKD was defined as estimated glomerular filtration rate (eGFR) by the Modification of Diet in Renal Disease (MDRD) <60 mL/min or evidence of kidney damage persistent for more than 3 months per National Kidney Foundation Kidney Disease Outcome Quality Initiative (NFK‐DOQI) guidelines. ¹³ Hypertension was defined as BP >130/80 mm Hg based on NKF‐DOQI guidelines ¹³ and resistant hypertension as uncontrolled clinic BP in patients taking at least 3 antihypertensive medications including a diuretic or clinic BP <130/80 mm Hg in patients taking ≥4 antihypertensive medications. ¹⁴ Only patients who had at least one 24‐hour ABPM followed by a clinic BP recording within 2 weeks were included. Medical records were reviewed to obtain information including age; sex; race; comorbid conditions including history of diabetes mellitus, hyperlipidemia, and coronary artery disease; body mass index; secondary causes of hypertension (ie, renal artery stenosis, obstructive sleep apnea, and primary hyperaldosteronism); serum creatinine; eGFR; urine albumin to creatinine ratio; and antihypertensive medications including diuretics and diuretic dosing.

Twenty‐four–hour ABPM was performed using a Welch Allyn 6100 monitor (Skaneateles Falls, NY), which was validated per the British Hypertension Society protocol. ¹⁵ Cuff size was selected according to arm circumference. BP monitoring was performed on a typical working day during routine antihypertensive therapy. Daytime BP was recorded every 30 minutes and nighttime BP was recorded every hour. Overall 24‐hour average BP, average daytime BP, and average nighttime BP measurements were obtained. ABPM was considered adequate, based on the guidelines of the European Society of Hypertension, ¹⁶ if 14 systolic and diastolic measurements were obtained during the day and 7 during the night.

Clinic BP recordings were obtained by medical assistants trained in measurement of BP per standard guidelines ¹⁷ and using a clinically validated automated upper‐arm BP device. ¹⁸ BP was measured while the patient was sitting comfortably in a chair in a quiet room using an appropriately sized cuff and keeping the patient’s arm at the level of the heart. BP was checked twice, and the average of the two readings was used. Due to the retrospective nature of the study, BP readings on different days were obtained by different medical assistants.

Definitions

A patient was considered to have true uncontrolled resistant hypertension if the 24‐hour ambulatory blood pressure (ABP) was >130/80 mm Hg, regardless of clinic BP. We use the term normotension to refer to controlled resistant hypertension that occurred when both 24‐hour ambulatory and clinic BPs were <130/80 mm Hg. White‐coat hypertension was defined as clinic BP above 130/80 mm Hg and 24‐hour ABP <130/80 mm Hg. Masked hypertension was defined as 24‐hour ABP >130/80 mm Hg and clinic BP <130/80 mm Hg. Sustained hypertension was defined as both 24‐hour ABP and clinic BP >130/80 mm Hg. Dipping status was defined as a night/day systolic BP ratio <0.9. Low systolic BP (SBP) was defined as ambulatory SBP <100 mm Hg, and low diastolic BP (DBP) as ambulatory DBP <60 mm Hg.

The primary outcome measured was the prevalence of white‐coat hypertension and masked hypertension in our cohort of CKD patients with resistant hypertension. In addition, clinical, laboratory, and ambulatory BP characteristics were also compared among different subgroups of patients. The study was approved by the local institutional review board.

Statistical Analysis

Statistical analysis was performed using SPSS 15.0 (IBM, Chicago, IL). Continuous variables were reported as means with standard deviation. Categorical variables were expressed as percentages. Means of two groups were compared using t test for parametric data and Mann–Whitney and Wilcoxon rank sum tests for nonparametric data. To compare means between 4 groups, analysis of variance was used for parametric data and the Kruskal‐Wallis test was used for nonparametric data. Fisher exact test and chi‐square test were used to compare categorical variables. For all tests, P values <.05 were considered statistically significant.

Results

A total of 156 patients who met the criteria for having CKD and resistant hypertension and had one 24‐hour ABPM performed in a CKD clinic were included in the study. Based on 24‐hour ABPM, 35.9% of all patients had their BP at goal (<130/80 mm Hg), while only 12.2% patients had clinic BP at goal. The prevalence of true uncontrolled resistant hypertension was 64.1%. The prevalence of white‐coat hypertension was 29.5%, while the prevalence of masked hypertension was 5.8%. Sustained hypertension (BP >130/80 mm Hg by both clinic and 24‐hour ABPM) was found in 58.3% of patients. Only 6.4% of patients had BP at goal by both clinic and 24‐hour ABPM. The clinical and laboratory characteristics of the study population are shown in Table I and the clinic and 24‐hour ABPM readings of the various subgroups are reported in Table II. The mean 24‐hour ABPM readings were higher in patients with sustained and masked hypertension. Clinic BP readings were higher in patients with white‐coat and sustained hypertension. Patients with masked hypertension had elevated night/day SBP and DBP ratios compared with other subgroups.

Table I.

 Clinical, Laboratory Characteristics and Medications Use in All Sub‐Groups of Patients With CKD and Resistant Hypertension

	Sustained Hypertension N=91	White Coat Hypertension N=46	Masked Hypertension N=9	Normotension N=10	P value
Age (years)	71.3±10.5	70.5±12.8	73.1±9.1	67.1±11.9	.6
Males (%)	48.4	39.1	33.3	40	.3*
Caucasians (%)	79.1	91.3	77.8	80	.1*
Diabetes mellitus (%)	40.7	34.8	33.3	30	.1*
Hyperlipidemia (%)	76.9	54.3	88.9	60	<.01*
BMI above 30 (%)	31.9	17.4	11.1	30	.07*
Coronary artery disease (%)	22	10.9	11.1	20	.12*
Renal artery stenosis (%)	9.9	4.3	22.2	0	.34*
Obstructive sleep apnea (%)	8.8	6.5	11.1	0	.75*
Primary hyperaldosteronism (%)	2.2	0.7	0	0	1.0*
Mean serum creatinine (mg/dL)	1.6±0.6	1.5±0.5	1.4±0.3	1.5±0.5	.9
Mean eGFR (mL/min/BSA)	44.1±15.9	44.3±14.9	45.4±10	47.8±20.7	.9
Urine albumin/Cr ratio (g/g)	0.6±1.1	0.7±2.2	0.8±1.2	0.1±0.1	.6
No. of BP medications	4.1±1.0	3.7±0.8	4.2±1.1	4.5±1.5	.5
Diuretics (%)	100	100	100	100
Thiazide diuretic (%)	83.5	84.8	88.9	90	.85*
Mean HCTZ dose (mg)	23.8±6.1	24.7±7.3	21.8±5.7	25	.66
Loop diuretic (%)	16.5	15.2	11.1	10	.85*
Mean furosemide dose (mg)	58.7±44.3	54.3±51.2	100	80	.8
ACE‐I/ARB (%)	67	71.7	77.8	90	.6*
Renin inhibitors (%)	23.1	17.4	11.1	10	.4*
Calcium channel blockers (%)	49.5	32.6	33.3	40	.06*
Beta blockers (%)	69.2	52.2	88.9	60	.05*
Centrally acting alpha 2 agonist (%)	34.1	30.4	44.4	30	.7*
Vasodilators (%)	25.3	13	22.2	40	.09*
Alpha blockers (%)	26.4	23.9	33.3	20	.7*
Spironolactone (%)	7.7	10.9	11.1	20	.5*

P values with asterisk * are calculated for the sustained hypertension vs the white‐coat hypertension group.

Table II.

 Clinic BP and 24‐hour ABPM Readings in All Sub‐Groups of Patients With CKD and Resistant HTN

	Sustained Hypertension N=91	White Coat Hypertension N=46	Masked Hypertension N=9	Normotension N=10	P value
Mean 24‐hour systolic ABP (mm Hg)	147.3±12.9	120.1±7.4	143.1±9.8	119.8±4.0	<.01
Mean 24‐hour diastolic ABP (mm Hg)	67.8±11.2	59.3±7.4	65.8±6.4	61.1±11	<.01
Mean daytime systolic ABP (mm Hg)	148.4±13.3	122.3±8.1	140.2±9.5	122.5±4.9	<.01
Mean daytime diastolic ABP (mm Hg)	69±11.6	61±8	65.2±6.9	63.2±12.8	<.01
Mean night time systolic ABP (mm Hg)	142.5±16.2	111.8±11.4	151.6±17.6	111.7±4.8	<.01
Mean night time diastolic ABP (mm Hg)	63.8±11.7	53.8±6.9	66.6±7.3	55.4±7.1	<.01
Mean 24 hours heart rate	65.3±8.7	66.7±10.7	64.9±10.7	68.5±8.9	.7
Mean night/day systolic BP	0.96±0.09	0.91±0.1	1.1±0.1	0.9±0.6	<.01
Mean night/day diastolic BP	0.92±0.09	0.88±0.1	1.0±0.12	0.9±0.1	<.01
Mean clinic systolic blood pressure (mm Hg)	160.5±19.3	156.0±19.2	120.8±6.6	119.6±6	<.01
Mean clinic diastolic blood pressure (mm Hg)	76.9±14.8	78.4±12.8	62.7±7.9	66.1±13.9	<.01

In patients with white‐coat and sustained hypertension, clinic SBP, 24‐hour ambulatory, day, and night SBP distributions are shown in Figure 1. Clinic DBP, 24‐hour ambulatory DBP, day, and night DBP box plots for patients with sustained and white‐coat hypertension are shown in Figure 2. When compared with the sustained hypertension group, a significant proportion of patients with white‐coat hypertension had low 24‐hour average DBP, defined as DBP <60 mm Hg (52.2% vs 22%, P<.01). Day and nighttime average DBP readings <60 mm Hg were also significantly more common in patients with white‐coat hypertension compared with the sustained hypertension group (47.8% vs 22%, P<.01 for day DBP and 76.1% vs 40.7%, P<.01 for night DBP). Nighttime average SBP was low (defined as SBP <100 mm Hg) in 17.4% of patients with white‐coat hypertension compared with no patients in the sustained hypertension group. There were no patients with low 24‐hour or daytime average SBP in either group.

Figure 1.

 Box plots of clinic, 24‐hour, day, and night systolic blood pressure (SBP) readings in patients with white‐coat (n=46) and sustained hypertension (HTN) (n=91). P value <.01.

Figure 2.

 Box plots of clinic, 24‐hour, day, and night diastolic blood pressure (DBP) readings in patients with white‐coat (n=46) and sustained hypertension (HTN) (n=91). P value <.01.

Although patients with sustained hypertension had both clinic and 24‐hour ABP readings >130/80 mm Hg, clinic BP readings were significantly higher than 24‐hour ABP readings in this group of patients. The mean clinic SBP was 160.5±19.3 mm Hg compared with mean 24‐hour ambulatory SBP of 147.3±12.9 mm Hg (P<.01). The mean clinic DBP (76.9±14.8 mm Hg) was also significantly higher compared with the mean 24‐hour ambulatory DBP (67.8±11.2 mm Hg) (P<.01).

The percentage of dippers and nondippers in each group of patients is shown in Figure 3. All patients with masked hypertension were nondippers and nearly 78% of patients with sustained hypertension were nondippers.

Figure 3.

 Percentage of nondippers and dippers in patients with white‐coat hypertension (HTN) (n=46), sustained HTN (n=91), masked HTN (n=9), and normotension (n=10). P value <.01 for sustained HTN vs white‐coat HTN.

Discussion

Resistant hypertension is common in patients with CKD and is associated with reduced renal survival. ¹⁰ Although 24‐hour ABPM has been studied both as a diagnostic and prognostic tool in patients with CKD and hypertension, we evaluated its use in patients with CKD and resistant hypertension, which to our knowledge has not been reported previously. In our patient population, only 12.2% patients had BP at goal using clinic BP measurements. However, with 24‐hour ABPM, the percentage of patients with BP at goal increased to 35.9%. This implies that clinic BP measurement alone underestimates BP control in patients with CKD and resistant hypertension and may potentially mislabel some patients with resistant hypertension.

In our patient population of CKD and resistant hypertension, the prevalence of white‐coat hypertension was 29.5%. Previous studies that evaluated ABPM in CKD patients showed similar results. In a study by Minutolo and associates, ⁶ the prevalence of white‐coat hypertension was 31.5%. Anderson and colleagues ³ reported that 28% to 30% of patients had white‐coat hypertension as measured by clinic BP. In a meta‐analysis by Bangash and colleagues, ⁷ the average weighted prevalence of white‐coat hypertension from all studies was 18.5% and among patients who had hypertension on the basis of clinic BP, prevalence of white‐coat hypertension was 30.0%. However, compared with our patient population, the patients in these studies did not exclusively have resistant hypertension. Thus, our data confirm that even CKD patients with resistant hypertension have a significantly higher prevalence of white‐coat hypertension, and 24‐hour ABPM can be an important tool to identify these patients.

We also showed that in patients with sustained hypertension, both SBP and DBP were significantly high when measured in the clinic compared with 24‐hour ABPM. The average burden of medications in this subgroup was 4.1±1.0. These patients will likely need additional medications to achieve their target BP. However, if only clinic BP is used for follow‐up, patients may end up requiring more medications than actually needed to achieve goal BP. In patients with sustained hypertension, follow‐up 24‐hour ABPM may help in optimizing antihypertensive therapy to avoid an unnecessary increase in medication burden.

In the subgroup of patients with white‐coat hypertension, a significant proportion of patients have low average ambulatory BPs, especially nocturnal BPs. In patients with white‐coat hypertension, 17.4% had nocturnal systolic hypotension and 76.1% had nocturnal diastolic hypotension. Similar findings have been reported in other studies. For example, in a study of elderly patients with CKD, 21% patients had hypotensive episodes as measured with 24‐hour ABPM. ¹⁹ Similarly, Minutolo and colleagues ⁶ reported that 14.1% of white‐coat hypertensive patients had nocturnal systolic hypotension. Our findings are significant since in the general population, particularly in elderly patients, low DBP (especially <60–65 mm Hg) has been potentially associated with adverse cardiovascular events and stroke. ²⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁵ In CKD patients, even low normal SBP (<110–120 mm Hg) has been found to be associated with increased mortality, ²⁶ adverse cardiovascular outcomes, ²⁷ stroke, ²⁸ and worsening renal function. ²⁹ , ³⁰ It is possible that in our white‐coat hypertensive patients, antihypertensive treatment based on clinic BP alone may have led to nocturnal hypotension in these patients. Peralta and colleagues ³¹ has shown that antihypertensive therapy in CKD patients may lead to diastolic hypotension. Thus, 24‐hour ABPM monitoring may possibly help in tailoring antihypertensive therapy to avoid hypotension in such patients.

In our study of CKD patients with resistant hypertension, the prevalence of masked hypertension was 5.8%. In a study by Minutolo and colleagues, ⁶ the prevalence of masked hypertension was 5.9% in all hypertensive patients with CKD. In a meta‐analysis, ⁷ the prevalence of masked hypertension ranged from 4.7% to 31.3%, and the average weighted prevalence of masked hypertension was 8.3%. However, in the African American Study of Kidney Disease (AASK) cohort, ⁶ the prevalence of masked hypertension was strikingly high at 70%. Variation between our results and those of the AASK cohort can be explained by racial differences and by the fact that only patients with resistant hypertension were included in our study. The majority of our study population had to have uncontrolled clinic BP to meet study inclusion criteria, with exception of patients who had controlled BP while taking ≥4 medications. For this reason, the true prevalence of masked hypertension in CKD patients may only be detected by including all patients regardless of whether they have hypertension or not by clinic BP.

The prevalence of white‐coat and masked hypertension will also depend on cutoff values applied to clinic and ambulatory BP to define these terms and characteristics of a study population. ⁷ , ³² Using a higher threshold BP of 140/90 mm Hg will likely result in a lower prevalence of white‐coat hypertension and a higher prevalence of patients with controlled BP. Significant heterogeneity has been noticed in the thresholds of clinic and ambulatory BPs included in previous studies of CKD patients. ⁷ In our study, we used a threshold of 130/80 mm Hg for both clinic and ambulatory BPs. We used this cutoff for two reasons. First, a BP threshold of 130/80 mm Hg was selected based on the recommended guidelines for BP control in CKD patients. ¹ , ³³ In addition, 24‐hour systolic ABP >130 mm Hg does appear to have prognostic value, as SBP above this threshold was associated with an increased cumulative risk of end‐stage renal disease (ESRD) ³⁴ and adverse cardiovascular events. ³⁵ However, a threshold BP of 130/80 mm Hg for CKD patients has been challenged in recent literature. ³⁶ In another study of ABPM prognosis in CKD patients, adverse cardiovascular and renal events were associated with different thresholds for day and nighttime SBP (SBP >135 mm Hg for daytime and SBP >125 mm Hg for nighttime). ³⁷ We agree with others in that threshold values for clinic and ambulatory BPs in patients with CKD need to be standardized. ⁷ , ⁹ , ³²

Study Limitations

The major limitation of our study is that it is retrospective in nature. In clinical practice, patients with normal clinic BPs may not undergo 24‐hour ABPM, thus potentially resulting in under‐reporting of the prevalence of normotension and masked hypertension. In addition, we didn’t conduct long‐term follow‐up studies to evaluate the prognostic significance of ABPM in these patients.

Conclusions

Our study shows that 24‐hour ABPM provides a more reliable assessment of BP in patients with CKD and resistant hypertension. Nearly 30% of CKD patients have white‐coat hypertension. When compared with clinic BP readings, patients with sustained hypertension have lower mean ambulatory BP and a significant proportion of white‐coat hypertension patients actually have low ambulatory BP readings. This potentially suggests a role of ABPM in optimizing antihypertensive therapy to prevent hypotension in this patient population and warrants further study. In addition, the role of 24‐hour ABPM in predicting mortality, ESRD, and cardiovascular events in CKD patients with resistant hypertension should be studied further.

Acknowledgments and disclosures:  The authors report no specific funding in relation to this research and no conflicts of interest to disclose.