Masked hypertension in renal transplant recipients

Abstract

Purpose: Arterial hypertension is a risk factor affecting graft function in renal transplant recipients (RTRs). In pediatric RTRs, high prevalence of masked and nocturnal hypertension was reported. Most of the RTRs had a history of hypertension and some of them were normotensive at outpatient visits whereas home blood pressure (BP) levels were higher. Masked hypertension (MHT) is defined as a normal office BP but an elevated ambulatory BP. Previous reports have demonstrated the detrimental role of MHT in clinical outcomes in hypertensive patients. However, the true prevalence of MHT in RTRs is yet to be defined. Methods: A total of 113 RTRs (mean age 44 ± 16 years, 72 males, 41 females) with normal office BP (< 140/90 mmHg) were enrolled to the study from the outpatient renal transplantation clinic. Ambulatory BP monitoring (ABPM) was performed in all participants for a 24-h period. Average daytime BP values above 135 mmHg systolic and 85 mmHg diastolic were defined as MHT. Results: The prevalence of MHT in our cohort was 39% (n = 45). Fasting glucose and C-reactive protein levels were higher in patients with MHT compared with normal BP group (p = 0.02 and p = 0.04, respectively). RTRs with deceased donor type had higher prevalence of MHT than RTRs with living donor (40% vs 19%, p = 0.003). In multivariate analysis, deceased donor type could predict the MHT independent of age, gender, office systolic BP level, diabetes mellitus, serum creatinine, C-reactive protein, and glucose levels (OR = 3.62, 95% CI 1.16–11.31, p = 0.03). Conclusion: We demonstrated an increased prevalence of MHT in a typical renal transplant cohort. In addition, transplantation from a deceased donor may be a predictor of MHT. The prevalence of MHT may help to explain high rate of cardiovascular events in RTRs. Therefore, routine application of ABPM in RTRs may be plausible, particularly in RTRs with deceased donor type.

Key Words::

• ambulatory blood pressure monitoring
• masked hypertension
• renal transplant recipients

Introduction

Cardiovascular disease is the most common cause of death in renal transplant recipients (RTRs) (1). Post-transplant hypertension is a risk factor for cardiovascular disease and chronic allograft dysfunction (2,3). The most common causes of post-transplant hypertension include native kidneys left in place, treatment with corticosteroids and calcineurin inhibitors, graft dysfunction and obesity (4).

Ambulatory blood pressure monitoring (ABPM) may be more informative regarding the intensity of BP elevation than clinic measurements following renal transplantation (5). Moreover, ABPM has been shown to correlate better with target organ damage than isolated clinic blood pressure (BP) readings (6). Masked hypertension (MHT) is defined as normal BP in the physician's office but an elevated BP when measured out of the clinic (7). The reported MHT prevalence in a healthy population was 8% for children and adolescents and 19% for adults (8,9). Because office BP would have misled in 15–37% of hypertensive RTRs as being normotensive, this suggests that the true prevalence of MHT is probably high in this population (10,11). The prevalence of MHT was studied in pediatric renal transplant population (12). The true prevalence of MHT in adult patients has not been investigated well. In a recent study, the prevalence of MHT in RTRs was found to be 21% according to home BP monitoring (13). Thus, we aimed to determine the prevalence of MHT in RTRs using ABPM, a more sensitive method, and also, to examine the predictors of MHT in a cohort of RTRs.

Methods

A total of 113 patients (mean age 44 ± 16 years, 72 males and 41 females) with stable renal graft function were included in the study. Office and ambulatory BP measurements were performed in all participants. Study protocol was approved by the local ethic committee. All patients gave written and oral consent for participation in the study. RTRs with previous graft rejection and uncontrolled hypertension were excluded from the study. In addition, RTRs with duration of transplantation < 1 year and whose plasma immunosuppressive medication levels under therapeutic range were also excluded.

Office blood pressure measurement

All study participants underwent a thorough physical examination and office BP measurements were undertaken. Seated office BP was measured by auscultation method with a mercury sphygmomanometer (ERKA D-83646 Bad Tölz, Kallmeyer Medizintechnik GmbH & Co., KG, Germany). An appropriate cuff size was chosen for each subject. After at least 5 min of rest, the BP was measured twice at 1-min intervals. The average of the readings was determined as office BP. Patients were classified as hypertensive according to the JNC VII criteria if systolic BP (SBP) exceeded 140 mmHg or diastolic BP (DBP) exceeded 90 mmHg and these were excluded from the study (14).

Ambulatory blood pressure monitoring

All participants underwent ABPM using an ambulatory monitor (Tracker NIBP2, Del Mar Reynolds Ltd., Hertford, UK). The device measured BP every 15 min from 07:00 to 22:00 h and every 30 min from 22:00 to 07:00 h. Monitors were calibrated against a mercury sphygmomanometer on five occasions at the beginning of each session, and monitoring practice was in accordance with the respective guidelines (15). BP was measured in the non- dominant arm and appropriate cuff size was chosen for each patient. Each BP reading was edited by a computer and rejected if the SBP was < 80 mmHg or > 250 mmHg or if the DBP was < 40 mmHg or > 140 mmHg. The readings of the ambulatory BP device were checked against those obtained with the sphygmomanometer before putting on and after the wearing of the ABPM device. Recordings for each subject were accepted if more than 80% of the raw data were valid. The following parameters were analyzed: systolic 24-h ABP, diastolic 24-h ABP, systolic daytime ABP, diastolic daytime ABP, systolic night-time ABP, diastolic night-time ABP, systolic early morning ABP, diastolic early morning ABP. Average day time BP value above 135 mmHg of SBP and 85 mmHg of DBP was considered as MHT (16). Dipping was defined as a 10% drop in mean SBP and DBP between daytime and night-time. Non-dipping was defined as a decline of less than 10% of daytime SBP (17).

Demographic and laboratory parameters

Donor age and type, and medications of the patients were recorded (Table I). Body weight, height and body mass index (BMI) calculated as weight (kg) divided by height (m²), were determined in all subjects. Blood samples were drawn on admission and analyzed by the hospital clinical laboratory. Fasting blood samples were obtained for glucose and lipid measurements. In addition, C-reactive protein (CRP), white blood cell count (WBC), hemoglobin and creatinine levels were measured. Second early morning urine samples were collected. Urine sodium and creatinine were measured by an auto-analyzer (BM2250, JEOL Ltd., Tokyo, Japan). Creatinine was measured by an enzymatic method. Glomerular filtration rate (GFR) was calculated using the Cockcroft–Gault formula (18). Estimated 24-h urinary sodium excretion was calculated with the Kawasaki's equation (19). Daily NaCl consumption was calculated that the sodium value transferred into value of NaCI intake using the following formula: NaCI value (g/day) = Na (mmol/day)×(23/1.000)×(58/23), where intake of 1 mmol of Na corresponds to an intake of 58.5 mg of NaCl.

Table I. Demographic, laboratory and clinical parameters of patients with masked hypertension (MHT) and sustained normal blood pressure (SNBP).

	MHT (n = 45)	SNBP (n = 68)	p
Age (years)	40 ± 11	41 ± 11	0.73
BMI (kg/m^2)	26 ± 5	26 ± 4	0.86
Gender (% males)	67	63	083
Office SBP (mmHg)	124 ± 13	121 ± 11	0.26
Office DBP (mmHg)	78 ± 8	78 ± 7	0.81
Laboratory parameters
Total cholesterol (mmol/l)	203 ± 51	197 ± 38	0.47
Triglyceride (mmol/l)	179 ± 95	176 ± 88	0.87
LDL-cholesterol (mmol/l)	117 ± 40	113 ± 34	0.59
HDL-cholesterol (mmol/l)	46 ± 13	49 ± 24	0.46
Fasting glucose (mmol/l)	104 ± 24	95 ± 16	0.02
Hemoglobin (g/dl)	13.0 ± 2.3	13.1 ± 1.9	0.49
Creatinine (mg/dl)	1.16 ± 0.36	1.29 ± 0.41	0.09
GFR, ml/min	71 ± 22	70 ± 18	0.85
Sodium excretion (mmol/day)	172 ± 55	178 ± 60	0.65
24-h NaCl intake (g/day)	10.0 ± 3.0	10.2 ± 3.5	0.66
C-reactive protein, mg/dl	14.7 ± 7.4	7.1 ± 6.5	0.04
Renal tx parameters
Donor age (years)	44 ± 15	44 ± 11	0.89
Months after tx (mean± SD)	37 ± 21	48 ± 30	0.35
Donor type, LD/DD (n, %)	27/18 (60/40)	55/13 (81/19)	0.002
Medications
RAS inhibitors (n, %)	6 (13)	13 (19)	0.29
β-Blockers (n, %)	9 (20)	15 (22)	0.81
Calcium antagonists (n, %)	29 (64)	35 (51)	0.31
Immunosuppressants (%)	100	100	–
Steroids (%)	100	100	–
Comorbidities
CAD (n)	0	1	0.57
Diabetes (n, %)	7 (16)	7 (10)	0.38
Hypertension (n, %)	26 (58)	35 (52)	0.33

BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; LDL, low-density lipoprotein; HDL, high-density lipoprotein; GFR, glomerular filtration rate; Renal tx, renal transplantation; LD, living donor; DD, deceased donor; RAS, renin–angiotensin system; CAD, coronary artery disease. Bold values indicates statistically significant values.

Statistical analysis

Statistical analyses were performed with the Statistical Package for Social Sciences (SPSS for Windows) software (version 15.0, SPSS Inc., Chicago, IL, USA). The data were expressed as the mean± standard deviation (SD). The distribution of the variables was analyzed with the Kolmogorow–Smirnow test. The relationship between the categorical variables was determined by the chi-square test. Differences between parametric variables of two groups were assessed by Student's t-test. The variables that are significantly different between two groups were included in univariated logistic regression analysis for the detection of the predictors of MHT. A univariated regression model was used separately for each of the following covariates: age, BMI, creatinine, glucose, CRP, office SBP, male gender, diabetes and deceased donor type. Covariates that were significantly associated with or thought to be potential covariates of MHT in univariate model were included in the stepwise multivariate logistic regression analysis (deceased donor type, glucose, CRP and creatinine). A p-value below 0.05 was considered statistically significant.

Results

Patients

The mean age of the patients was 44 ± 16 years. Most of the patients were male (64%). Office SBP and DBP levels were in normal limits (128 ± 16 and 78 ± 8 mmHg, respectively). Renal graft functions were stable in study population (mean creatinine level: 1.19 ± 0.33 mg/dl). The mean 24-h urinary sodium excretion was 175 ± 56 mmol/day. Seventy two percent of the patients received kidney from living donors. Fifty seven percent of patients were prescribed with calcium channel blockers, 21% with beta-blockers and 17% with renin–angiotensin system inhibitors. All RTRs were on low dose steroid treatment while azathioprine was prescribed to 31%, mycophenolate mofetil or mycophenolate sodium to 28%, cyclosporine to 22% and tacrolimus to 68% of the study cohort. Past history of hypertension was present in 52% of the patients, diabetes mellitus in 12% and history of coronary artery disease was present only in one patient.

The main characteristics and laboratory findings of patients with MHT and sustained normal BP (SNBP) are listed in Table I. Only fasting blood glucose and CRP levels were significantly different between the groups (p = 0.02 for glucose and p = 0.04 for CRP). Deceased donor type was significantly more common in MHT group than that of SNBP group (40% vs 19%, p = 0.003) (Table I). Twenty-four hours sodium excretion and daily Na consumption were comparable in both groups (Table I).

Deceased donor versus living donor types

The main features of deceased and living donor groups are depicted in Table II. There was no difference in demographic and laboratory parameters between the groups. Deceased donor group was significantly older than living donor RTRs (45 ± 9 years vs 39 ± 11 years, p = 0.03).

Table II. Demographic and clinical features of renal transplant recipients (RTRs) who received kidney from a deceased (DD) or living donor (LD).

	DD (n = 31)	LD (n = 82)	p
Age (years)	45 ± 9	39 ± 11	0.03
BMI (kg/m^2)	25 ± 4	26 ± 5	0.23
Gender (% males)	45	69	0.08
Office SBP (mmHg)	121 ± 15	123 ± 10	0.22
Office DBP (mmHg)	77 ± 12	78 ± 9	0.46
Creatinine (mg/dl)	1.19 ± 0.45	1.27 ± 0.43	0.44
Donor age (years)	39 ± 15	45 ± 13	0.24
Diabetes (n, %)	4 (11)	10 (13)	0.93
Hypertension (n, %)	21 (58)	38 (50)	0.33
Medications
RAS inhibitors (n, %)	5 (16)	14 (17)	0.58
Beta-blockers (n, %)	4 (13)	21 (26)	0.16
Calcium antagonists (n, %)	19 (61)	42 (51)	0.10
Immunosuppressants (%)	100	100	–
Steroids (%)	100	100	–

BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; RAS, renin–angiotensin system. Bold values indicates statistically significant values.

ABPM evaluation

The overall prevalence of MHT was 39% (n = 45). Non-dipping (< 10%) was present in 78% of the study cohort. ABP parameters of patients with deceased and living donor type are shown in Table III. Significant differences were found in systolic 24-h ABP, systolic daytime ABP, diastolic daytime ABP, systolic night-time ABP and systolic early morning ABP levels between the groups (Table III).

Table III. Ambulatory blood pressure (ABP) parameters of renal transplant recipients (RTRs) transplanted from deceased (DD) or living donors (LD).

	DD (n = 31)	LD (n = 82)	p
Systolic 24 h ABP (mmHg)	136 ± 18	127 ± 11	0.002
Diastolic 24 h ABP (mmHg)	86 ± 11	82 ± 8	0.05
Systolic daytime ABP (mmHg)	138 ± 17	129 ± 11	0.002
Diastolic daytime ABP (mmHg)	87 ± 11	83 ± 8	0.04
Systolic night-time ABP (mmHg)	134 ± 23	124 ± 13	0.007
Diastolic night-time ABP (mmHg)	82 ± 12	79 ± 10	0.14
Systolic early morning ABP (mmHg)	136 ± 19	126 ± 14	0.004
Diastolic early morning ABP (mmHg)	87 ± 13	82 ± 11	0.10
Non-dipping (%)	20 (64)	68 (82)	0.23

Bold values indicates statistically significant values.

Predictors of masked hypertension

In univariate analysis, deceased donor type and blood glucose level significantly predicted the presence of MHT (Table IV). In stepwise multivariate analysis, only deceased donor type could predict the presence of MHT, independent of age, gender, office systolic BP, diabetes mellitus, creatinine, C-reactive protein and blood glucose levels (OR = 3.62, 95% CI 1.16–11.31, p = 0.03).

Table IV. Predictors of masked hypertension in renal transplant recipients.

Variables	Univariate analysis
	OR (95% CI)	p
Age	0.99 (0.96–1.03)	0.74
BMI, kg/m^2	0.95 (0.85–1.07)	0.41
Creatinine	1.18 (0.98–3.04)	0.09
GFR	1.02 (1.00–1.39)	0.11
Glucose	1.02 (1.00–1.05)	0.02
C-reactive protein	1.03 (0.99–1.08)	0.09
Diabetes	1.39 (0.45–4.27)	0.56
Antihypertensive medications	1.31 (0.52–3.32)	0.57
Male gender	1.17 (0.51–2.69)	0.72
Office SBP	1.02 (0.99–1.06)	0.19
Deceased donor	4.00 (1.59–10.07)	0.003
Stepwise multivariate analysis
Deceased donor	3.62 (1.16–11.31)	0.03
Glucose	1.02 (0.99–1.05)	0.08
C-reactive protein	1.03 (0.99–1.07)	0.08
Creatinine	1.12 (0.98–2.26)	0.06

OR, odds ratio; CI, confidence interval; BMI, body mass index; SBP, systolic blood pressure. Bold values indicates statistically significant values.

Discussion

The primary finding of the present study was that MHT is considerably frequent (39%) in RTRs. The prevalence of deceased donor type was also higher in MHT group (40%). In addition, deceased donor type appeared to be a significant and independent predictor of MHT. ABP parameters were affected in patients transplanted with deceased donor. Nevertheless, the prevalence of non-dipping status in our study cohort was in agreement with the related literature (78%).

Post-transplant hypertension is a risk factor for cardiovascular disease and chronic allograft dysfunction (2,3). Among causes of abnormal BP in renal transplants are reduced vascular compliance (20), autonomic neuropathy (21), latent over hydration, use of erythropoietin (22) and medications (steroids and cyclosporine) (23).

ABPM may be more informative regarding the intensity of BP elevation than clinic measurements following renal transplantation (5). Kanbay et al. (24) have reviewed the importance of ABPM and concluded that ABPM gives a better prediction of clinical outcomes in various patient populations. In 36 RTRs, Kooman et al. (25) showed that office BP may not reflect whole 24-h period adequately, thus ABPM should be considered. Covic and colleagues (26) have suggested twice-yearly ABPM in RTRs. In a pediatric renal transplant population, Seeman et al. (27) have demonstrated that ABPM-guided treatment may improve not only BP control but also modify the rate of change in renal function. They found that transplant recipients who remained hypertensive after ABPM-guided therapy showed significant reduction in graft function compared with those who remained normotensive. The largest data published in this area is the study performed by Haydar et al. (10) in which ABPM was found a more sensitive method for diagnosing hypertension than office BP measurements. In their study, age and GFR were determined as independent predictors of diurnal BP variation.

Subjects with MHT have a higher risk of cardiovascular accidents than normotensive subjects (28). MHT is associated with higher left ventricular mass (29). In chronic kidney disease (CKD) population, patients with MHT are more likely progress to end-stage renal disease (ESRD) and die (30). Thus, estimating the prevalence of MHT is of epidemiological as well as of clinical importance. In a meta-analysis, the overall prevalence of MHT in patients with CKD was 8.3% (31). In the Ohasama study, CKD was significantly associated with MHT (15% of prevalence) (32). According to Kuriyama et al. (33), a large percentage of patients with CKD have morning hypertension, which is more common in subjects with MHT and poorly controlled BP. ESRD developed in 22% of the patients with MHT and in none of the patients with white-coat hypertension (30). The data regarding prevalence of MHT in renal transplants are scarce. There are studies with small sample sizes performed in pediatric population. The prevalence of MHT in pediatric kidney transplants was reported as 24% (12). In another pediatric renal transplant population, the prevalence was reported as 38% (34). The first study in adult renal transplants was performed by Beltran et al. (35) who observed a small but important incidence of MHT in RTRs. However, in that study, half of the patients were “poorly controlled hypertensives”. In a recent study, the prevalence of MHT in RTRs was found as 21% (13). In our study, while the patients were “controlled hypertensives”, the prevalence of MHT was higher (39%). Interestingly, estimated 24-h sodium excretion and amount of daily Na consumption were significantly increased in both groups. Several studies have shown that while under an appropriately Na-restricted diet urinary excretion of sodium chloride should not exceed 100 mmol/day (36). Increased Na consumption may contribute to increased prevalence of MHT in the study population.

In our study, we found higher prevalence of deceased donor type in RTRs with MHT. Besides, deceased donor type was an independent predictor of MHT. The impact of donor type was investigated previously and Coles et al. (37) demonstrated that the incidence of hypertension was increased after deceased donor renal transplantation. Similar results were reported by Goldman and colleagues (38) that after living-donor transplants the BP fell but this did not occur after deceased-donor transplants. The possible explanation of these observations might be more ischemic damage after deceased-donor transplantations (38). To the best of our knowledge, this is the first study where the impact of donor type on ambulatory BP parameters was reported. The prevalence of non-dipping in patients with renal transplantation is high, ranging between 60% and 90% (25,39–41). In line with these observations, we also found high frequency of non-dipping in RTRs (78%). In a well-conducted prospective study including 1187 untreated essential hypertensive patients, Verdecchia et al. (42) showed that non-dippers had significantly more cardiovascular events compared with dippers. The association between non-dipping status and CV outcome was even stronger in ESRD (43). In addition, in a small study, Covic and colleagues (44) found that half of non-dipper dialysis patients maintain a permanently abnormal circadian rhythm, despite successful renal transplantation.

Several limitations of this study need to be emphasized:

(1) Pre-transplant data about the diurnal BP variability of the RTRs were not presented.

(2) Echocardiographic evaluation of left ventricular mass, which is an important marker of left ventricular hypertrophy, was not performed.

(3) ABPM is more expensive and cumbersome to apply. However, it has been shown that ABPM is cost-effective both in primary care and special services (45).

(4) Some environmental factors may have affected ABPM such as sleep disturbances, daily activity and postural changes.

(5) The effect of immunosuppressive agents on the MHT has not been adequately studied in this study.

(6) Unfortunately, we did not repeat ABPM in these patients. Therefore, the reproducibility of the ABPM in the studied patients was not presented. However, previous studies demonstrated better reproducibility of ABPM than office BP measurements in hemodialysis patients (46). In a real-life ABPM database, MHT was found to be reasonably reproducible (47). In our study, average of daytime BP measurements was based on the diagnosis of MHT, therefore we think that the reproducibility of MHT was not significantly affected

(7) It is important that both masked hypertensive and normotensive recipients were subjected to all aforementioned limitations. For this reason, we think that all limitations probably affected the results of each group in the same magnitude and direction.

(8) Finally, because primary aim of the study was not examine the relationship between donor types and MHT, the groups were unbalanced according to the donor types.

In conclusion, our results indicate that the prevalence of MHT is tangible in renal transplant population. Regular use of ABPM in RTRs enables detection of MHT so it might be applied regularly in RTRs at least for this purpose. Larger studies are needed to clarify the true prevalence and long-term prognostic significance of MHT in RTRs.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.