In our study, the negative clinic–awake SBP difference (i.e., masking) was more pronounced with age over 60 years and with tacrolimus use (versus cyclosporine). In the general population, one study found age to be a risk factor for masked HTN [
38]; other studies, however, found that the clinic-awake difference increases (i.e., more positive) with age [
25] and thus elderly have more white-coat effect [
39]. Tacrolimus use was found in other studies [
40,
41] in association with lower clinic BP. We suggest that this association may not be true with regards to ambulatory BP and may thus lead to underestimation (and under-treatment) of BP in tacrolimus-treated patients evaluated using clinic measurements alone. However, we have not pre-specified subset analyses based on age and calcineurin inhibitor regimen, and patients receiving cyclosporine were scarce, and thus results are not conclusive.
As a result of the negative clinic-awake BP difference in our patients, masked HTN was uncovered much more commonly than white coat HTN. This finding is sensitive to clinic HTN definitions. The ACC/AHA and KDIGO-adopted lower clinic BP thresholds amplify the prevalence of sustained HTN on account of masked HTN and that of white coat HTN on account of normotension. Overall, KDIGO/ACC/AHA guideline cutoffs lead to more agreement between clinic- and ABPM awake-based determinations than JNC 8 cutoffs (69% vs. 47%).
Review of the literature with regards to ΔBP in kidney transplantation
Previous studies have also shown negative clinic-ambulatory BP differences in renal transplant populations, albeit of lesser extent. However, in several other studies opposing results have been noted. These previous studies differ one from another in patients’ age, clinic BP and ABPM methods and in exclusion criteria (Table
6).
Table 6clinic-awake SBP and DBP differences from previous studies
| 98 | 55 | −3.5 | −7.2 | all study measurements | no comparison | unstable BP | new center |
| 113 | 44 | −9 | −6.4 | | no comparison | uncontrolled hypertension | |
| 172 | 46 | −1 | −1 | monitoring day only | no comparisona | | |
| 260 | 47 | + 6 | 0 | after ABPM, mean 3.7 years | no comparison | | |
| 87 | 38 | + 6 | + 4.5 | | no difference in dipping | comorbidities | |
| 244 | 53 | + 3.6 | + 2.5 | measurement within 5 days | no effect on ABPM values | | higher clinic BP levels |
| 49 | 35 | + 3–12 | + 6–8 | clinic and 1st and last ABPM measurements | FK only | | |
| 868 | 53 | + 7 | + 1 | absent data | no comparison | | reduced GFR |
| 94 | 55 | + 4 | + 1 | | Lower PP with FK | | higher clinic BP levels |
In a study of 98 patients from New-Zealand [
30], the mean differences between clinic SBP and DBP and average 24 h SBP and DBP were − 3.5 mmHg and − 7.2 mmHg, respectively. These values are also negative, but they are less negative than the current study's values. There are several explanations for this difference: (1) In this study, clinic SBP was compared to 24 h BP, which was lower than awake BP. (2) The clinic BP was measured as an average of all the measurements in the study period, apparently including measurements that were done after (and may have been affected by) the ABPM. (3) The study was conducted at a research center, with which the patients were not familiar. (4) Patients with unstable BP levels (not defined) were not included. In a 113-patient Turkish study [
32], the mean differences between clinic SBP and DBP and average awake SBP and DBP were − 9.0 mmHg and − 6.4 mmHg, respectively. Patients with uncontrolled HTN (not defined) were excluded. Lastly, in 172 Italian patients, the clinic – awake SBP and DBP differences were − 1 mmHg [
42]; clinic BP was measured only in the monitoring day.
On the other hand, in a 260-patient Italian study, the clinic – awake SBP and DBP differences were + 6 and 0 mmHg, respectively [
43]. The clinic measurements in the Italian study were done after the ABPM, a fact that could has influenced the results, and the clinic BP was measured as the mean of BP measurements within a mean period of 3.7 years. In another 87-patient Turkish study, the clinic – awake SBP and DBP differences were + 6 and + 4.5 mmHg, respectively [
29]; however, several exclusion criteria have been used in this Turkish study (history of diabetes mellitus, heart failure, ischemic heart disease, cardiomyopathy, or significant valvular heart disease; hemoglobin level < 10 g/dL; and serum creatinine level > 1.5 mg/dL). Among 244 Canadian patients, the clinic – awake SBP and DBP differences were + 3.6 and + 2.5 mmHg, respectively [
28]. In this Canadian study, one clinic measurement was recorded, obtained within 5 days of ABPM (not mentioned if before or after the ambulatory monitoring). More importantly, the average clinic BP in the Canadian study was 137/79 mmHg, higher than the value in our study. Higher clinic BP levels are associated with less negative clinic – awake BP differences (Fig.
1b).
In a 49-patient Indian study, the clinic – awake SBP and DBP differences were positive at 2, 4, 6, and 9 months after transplantation [
26]; however, the mean age of the participants in the Indian study was 35 years, and the methodology of clinic BP measurement was different (it was calculated as a mean of a clinic measurement, the first ABPM measurement and the last ABPM measurements). In a Spanish multicenter study (868 patients), the clinic – awake SBP and DBP differences were + 7 and + 1 mmHg, respectively [
27]; however, kidney transplant recipients with Scr > 2.5 mg/dL or with eGFR < 30 ml/min/1.73m
2 were not included, and description of clinic and ABPM measurement methodology is lacking. In a 94-patient Italian study, the clinic – awake SBP and DBP differences were + 4 and − 1 mmHg, respectively [
7]. A possible explanation for this difference is that in this Italian study the clinic BP was 150/86 mmHg on average, and in our study higher clinic BP measurements associated with less negative delta values, as mentioned previously (Fig.
1b).
As in our study, the tendency for a negative clinic–awake BP difference has been observed in other (non-transplant) CKD populations. In an US cross-sectional study on 1492 CKD patients, the differences between clinic and ambulatory awake SBP and DBP were − 5.9 and − 6.4 mmHg, respectively [
44]. In a Japanese study [
45], masked HTN was more prevalent than white coat HTN among stage 3–5 CKD patients.
In addition to the clinic-awake discrepancy, nocturnal measurements have revealed that 83% of our patients have sleep HTN. This finding is in line with previous results (69% [
42], 71% [
30]). Also, only 23% of the patients in our study were normal dippers. This too is similar to previous findings (21% [
7], 32% [
29], 14% [
27], 27% [
46]). High rates of non-dipping have also been shown in liver transplant patients, treated with cyclosporine or tacrolimus [
47], and in cyclosporine treated heart transplant recipients [
48]. In our study, a non-dipping pattern was associated with tacrolimus use, even after adjustment for diabetes, time since transplantation and age. Low hemoglobin levels were linked to lower SBP and DBP dipping ratio; this finding is consistent with data from the general population [
49]. As compared with BP dipping, heart rate dipping during sleep, an independent predictor of mortality [
50], was relatively preserved in our patients.
In the absence of significant relationships with age, diabetes and BMI, the elevated magnitude of BP masking and non-dipping observed in our patients is possibly a consequence of disturbed volume status, as has been shown for tacrolimus treatment [
51], and derangements in autonomic nervous system activity. Also, in as much as anxiety and stress may be involved in the white-coat BP response [
52], it is tempting to speculate that for a kidney transplant patient in a routine visit, the kidney transplant clinic constitutes a comforting environment, with familiar fellow patients and more importantly staff, with whom not rarely a patient may have more than a decade long familiarity (being that kidney transplant physicians and nurses also care for dialysis and pre-dialysis patients). Thus, hypertension may be masked in the kidney transplant clinic much more often than a white coat response is elicited.
Limitations
Recruitment of participants was performed predominantly by their transplant nephrologists, possibly leading to referral biases toward patients who their physicians thought them to have indications for ABPM. Also, clinic BP measurements were not done in a uniform manner: 5 of 7 physicians used aneroid sphygmomanometry, while two relied on oscillometric measurements taken by the clinic nurse. Only one measurement was typically recorded in each visit. Our study has no dedicated control group, although we did use parallel information from our institution’s general ABPM dataset for perspective. Our study’s relatively small size (76 patients who take different antihypertensive medications) is a limitation too, and caution is advised in interpreting some results also due to their post-hoc nature.
On the other hand, our study’s strength is in examining the clinic-awake BP difference as a continuous variable, and therefore independent of hypertension definitions. To our knowledge, it is the first study that describes diurnal-based BP differences between immunosuppressant regimens, thus generating hypothesis for further studies.