Masked hypertension and chronic kidney disease

Masked hypertension is the most uncertain hypertension phenotype often leading to diagnostic failure and undertreatment [1]. Traditionally masked hypertension has been defined as the presence of normal office (O) blood pressure (BP) at the time of consultation, but elevated out-of-office BP levels either on ambulatory (ABPM) or home BP monitoring (HBPM) [2,3]. In patients already on antihypertensive treatment, masked hypertension is referred to as masked uncontrolled/resistant hypertension (MUCH), that is, when OBP is normalized, but out-of-office BP levels remain elevated despite of treatment [2,3]. The 2013 ESH/ESC Guidelines were the first to recommend considering treatment of masked hypertension, because of its clinical significance and the accumulated evidence showing the overall negative impact of masked hypertension on cardiovascular prognosis (i.e. which is close to that of sustained hypertension) [4–11]. The recent 2017 United States Guidelines have made a step forward by recommending that such cases should be identified among untreated and treated individuals and treatment decisions be based on out-of-office BP (ambulatory or home) [12]. These recommendations appear to be of particular relevance in African Americans, who are characterized by a higher prevalence of nocturnal hypertension and nondipping BP pattern, and thus represent a special population for investigating masked hypertension. African Americans are known to have higher levels of OBP and prevalence of hypertension than whites, which starts earlier and is associated with higher cardiovascular risk [13,14]. Population studies implementing ABPM have also indicated higher average 24-h BP levels and variability in African Americans compared with whites, as well as a higher prevalence of masked and nocturnal hypertension, nondipping BP profile, and also of renal damage [15,16]. In a recent report of the Jackson Heart Study (JHS), individuals with masked hypertension showed a significantly higher risk of cardiovascular disease [CVD; hazard ratio (HR) of 2.49, 95% confidence interval (CI) 1.26–4.93] compared with their counterparts without masked hypertension [17]. Evidence on the relationship between masked hypertension and renal dysfunction has also been provided for African American populations, in the frame of the African American Study of Kidney Disease Cohort (AASK) in which masked hypertension (defined as clinic BP <140/90 mmHg with daytime ABP ≥135/85 mmHg or night-time ABP ≥120/70 mmHg) was present in 70% of individuals with apparent clinic BP control, and was more frequently associated with organ damage (i.e. left ventricular hypertrophy and proteinuria) [18]. However, none of the studies mentioned above evaluated the prognostic value of masked hypertension for incidence and progression of CKD in a general population of African Americans. In addition, despite the several studies reporting on the association between masked hypertension and the presence of renal impairment, there is very limited evidence from prospective cohorts investigating the predictive value of masked hypertension for development and progression of renal dysfunction. The article by Mwasongwe et al.[19] published in the current issue of Journal of Hypertension provides further evidence on the clinical relevance of masked hypertension for development and progression of renal dysfunction in the frame of the JHS. This prospective cohort, composed exclusively of individuals from African American origin, evaluated the association of any form of masked hypertension (normal clinic BP with elevated daytime and/or night-time and/or 24-h ABP) with very rapid kidney function decline (RKFD, and incident CKD. Overall, after a median follow-up of 8 years, masked hypertension was associated with increased odds for incident CKD [odds ratio (OR) 1.95; 95% CI 1.04–3.67] but not with RKFD, and in fully adjusted models, no association reached statistical significance. Interestingly, when masked daytime, night-time, and 24-h hypertension were analyzed separately, only the association of masked night-time hypertension with incident CKD was statistically significant after adjustment for age, sex, education, eGFR and UACR (OR 1.86; 95% CI 1.01–3.42). However, again in this analysis, significance was lost after full adjustment. Although the results of the study by Mwasongwe et al. do not consistently support the independent association between masked hypertension and incidence/progression of CKD, its results should be interpreted on the background of the population being studied. A previous report of the JHS, addressing normality values for ambulatory BP in blacks suggested adoption of normality thresholds for these individuals over 24 h, daytime and night-time [20], which are higher than those currently recommended by available hypertension guidelines (24-h SBP/DBP ≥130/80 mmHg, daytime SBP/DBP ≥135/85 mmHg, night-time SBP/DBP ≥120/70 mmHg) [2,21]. Defining masked hypertension on the basis of higher ABP normality thresholds for African Americans (rather than those proposed by current Hypertension Guidelines) might have allowed a better assessment of the actual impact of masked hypertension for renal dysfunction in the population of the present study. The work by Mwasongwe et al. has also provided relevant information regarding the diagnostic approach to masked hypertension and has some merits that should be mentioned. At variance from most previous studies reporting on the association between masked hypertension and kidney disease, which were small, of cross-sectional nature, or focusing on specific populations with diabetes or receiving antihypertensive treatment, the present report of the JHS was conducted in the frame of a large community-based cohort (n = 651) followed over 8 years. More importantly, although most previous studies addressing the association of masked hypertension with renal disease were conducted in populations with established CKD or on hemodialysis (in whom BP values are highly variable resulting in frequent BP reclassification) [22–24], in the present study baseline renal function was preserved in all participants (eGFR ≥60 ml/min per 1.73 m2), which allowed authors to properly evaluate the relationship between masked hypertension and incidence of CKD. A crucial aspect of the present report of the JHS is the higher than expected prevalence of masked hypertension reaching 52.7%, and also the fact that this was higher for night-time than daytime ABP whenever evaluated separately. Such a prevalence is by far higher than that reported for general populations and is even higher than the masked hypertension prevalence reported for African Americans with established CKD in previous studies, in spite of the fact that prevalence of masked hypertension is known to be higher in CKD patients [22,25]. Moreover, at variance from most previous reports in which masked hypertension was defined on the basis of daytime ABP only, the study by Mwasongwe et al. defined masked hypertension as proposed by current European ABPM guidelines [2], by taking into account daytime, night-time and 24-h ABP and defining masked hypertension when any of them was elevated together with normal clinic BP. When considering the relative prevalence of different forms of masked hypertension, when separately considered in the study by Mwasongwe et al. (i.e. daytime masked hypertension 29.9%; night-time masked hypertension 48.1%; and 24-h masked hypertension, 33.7%), it is clear that masked hypertension would have been greatly overlooked in a large number of participants (i.e. about 37%) if its diagnosis had been based on daytime ABP values only as the 2017 US guidelines recommend. The overall high prevalence of masked hypertension in the present study is indeed largely explained by the extremely high prevalence of night-time masked hypertension, which is not surprising if the alterations of the diurnal BP profile reported for African American populations are considered. For instance, in a previous report of the JHS study, nocturnal decline in ambulatory BP was much smaller (7.6/13.5%, systolic/diastolic) compared with that reported in other populations, for example, in the IDACO study (14.4/17.8%). These data are in line with previous reports showing nocturnal hypertension, masked hypertension, and the nondipping BP pattern to be more common in blacks in comparison with whites, suggesting that in African Americans, nocturnal hypertension is a major determinant of masked hypertension and often the only determinant (18% of them were reported to display isolated nocturnal hypertension) [15,16]. The results of the study by Mwasongwe et al. might have been also influenced by some issues related to OBP and ABP measurement methodology. Regarding OBP measurement, researchers used the Hawksley random zero sphygmomanometer, which is known to be inaccurate [26]. In addition, the investigators calibrated the Hawksley random zero sphygmomanometer against an oscillometric device, which is an inadequate reference method [27] and certainly did not improve (and might even have introduced further bias) the accuracy of OBP evaluation. Regarding ambulatory BP measurement, either for research or clinical purposes, an ABPM is expected to provide at least 70% of valid measurements (with a minimum of ≥20 valid awake and seven valid asleep readings) [2,3]. However, in this study, a smaller number of valid ABP readings was accepted (up to 10 daytime and 5 night-time readings). Although this approach aimed to maximize the number of participants to be enrolled in this study, as suggested by a previous report of the IDACO study, a lower number of valid BP measurements, in particular at night, might have reduced the reproducibility of ABPM recordings, potentially leading to misclassification of some participants’ masked hypertension status. In addition, the diagnosis of masked hypertension was based on a single ABPM, without confirmation of the BP status by repetition of the recording [28]. More importantly, for defining OBP (which is known to be much less reproducible than ABP) [29], the authors considered only two BP readings performed on a single occasion, which certainly affected the reliability of masked hypertension classification. Assessment of a condition such as masked hypertension, which is highly dependent also on the degree of blood pressure variability (BPV), would deserve considering more stringent quality criteria for OBP and ABP evaluation, in order to guarantee the reliability and reproducibility of its assessment, as much as possible. Overall, the present report of the JHS reinforces the recommendations given by several hypertension guidelines [2,30,31] that ABPM should be mandatory for the evaluation of almost all participants with elevated BP, and particularly so in African Americans in whom the conventional OBP measurement often fails to demonstrate important hypertension phenotypes. More specifically, the major contribution of this article is that its results emphasize the importance of considering all components of 24 h ABPM for identification of specific BP phenotypes such as masked 24 h and night-time hypertension that cannot be identified by daytime BP measurement only. Focusing on daytime average values only, and sometimes also on the overall 24 h ABP levels only, would lead to ignore possible specific changes in night-time BP, which is known to be the strongest predictor of cardiovascular risk. This may lead to misclassify participants with isolated nocturnal hypertension and/or isolated nocturnal masked hypertension, which are not uncommon in patients with diabetes mellitus, nephropathy, and sleep apnea. This is particularly true in African American populations in whom the hypertension-related cardiovascular disease burden has been shown to be higher and is largely driven by nocturnal BP [13,14]. The growing awareness on the importance of implementing ABPM as a complement to office and home BP measurements for the management of arterial hypertension has led some of the current international guidelines to more strongly support its use, along with its reimbursement, by the healthcare system. The 2017 American guidelines for the prevention, detection, evaluation, and management of high blood pressure in adults, issued with a joint effort by a high number of Scientific Societies, have for the first time strongly considered the use of out-of-office BP monitoring (either ABPM or HBPM), for the diagnostic approach to masked hypertension and MUCH as well as for the long-term follow-up of these conditions, giving specific recommendations for their use in clinical practice [12]. However, it should be emphasized that, at variance from the ESH 2013 and 2014 ABPM guidelines, which clearly recommend to take into account daytime as well as night-time and 24-h ABP for a proper ABPM evaluation (see Fig. 1), the 2011 NICE and 2017 US guidelines recommend the use of daytime ABP only. This implies missing night-time BP, which is the most important component of the 24-h BP profile, particularly in African Americans as demonstrated in the JHS.FIGURE 1: Different forms of masked hypertension (MH, in untreated patients) and masked uncontrolled hypertension (MUCH, in treated patients) identified according to 2013 European Society of Hypertension guidelines on ambulatory blood pressure monitoring.In conclusion, masked hypertension is a high-risk phenotype of hypertension and should not be left undetected, in particular in African Americans. Its diagnosis should be confirmed by repeating office and out-of-office BP measurements using the same or the alternative method (ambulatory or home), and management decisions should consider both office and out-of-office measurements. It should be mentioned, however, that to date no longitudinal outcome trial randomizing participants with masked hypertension (or MUCH in treated individuals) to be managed based either on office or out-of-office BP measurements has been conducted, in order to fully support these recommendations. The ongoing MASTER study (NCT02804074) focusing on MUCH patients, is expected to provide unique information aimed at finally clarifying whether a management strategy based on out-of-office BP measurements might offer a greater benefit in terms of prevention or regression of organ damage and prevention of cardiovascular events than a management strategy based only on office BP readings, thereby assessing the actual value of out-of-office BP monitoring in improving cardiovascular protection. Until such data become available, it would not seem sensible to completely disregard individuals with masked hypertension having elevated home or ambulatory BP (daytime and/or night-time) untreated, just because their BP in the office is normal. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.