Association of morning blood pressure surge with chronic kidney disease progression in patients with chronic kidney disease and hypertension

Abstract Blood pressure (BP) usually rise from being asleep to awake, which is named the morning blood pressure surge (MBPS). Researches have reported that elevated MBPS was related with CV events, incident CKD in hypertensive patients. However, there have been no studies that have investigated the association between MBPS and renal or heart outcomes in patients with CKD and hypertension, in these patients, the MBPS is much lower because of high prevalence of night hypertension and reduced BP dipping. In this prospective two‐center observational study, we enrolled patients with CKD and hypertension and the 24 h ambulatory blood pressure monitoring (ABPM) was conducted in all patients. Time to total mortality, CKD progression and CV events was recorded; Finally, a total of 304 patients were enrolled and 94 (30.9%) of them had elevated MBPS. After a follow‐up for median 30 months, 23 (7.6%), 34 (11.2%), and 95 (31.3%) patients occurred death, CKD progression and new‐onset CV events, respectively. The Cox regression analysis suggested the elevated MBPS was a strong predictor of CKD progression (HR 2.35, 95%CI 1.2 ‐4.63, p = .013), independent of morning BP, while no associations were found between elevated MBPS and CV events (HR 1.02, 95%CI 0.66 ‐1.57), as well as death (HR 1.08, 95%CI 0.46 ‐2.55). In conclusion, we provided the first evidence that elevated MBPS was an important risk factor of CKD progression in patients with CKD and hypertension. Appropriate evaluation and management of MBPS may be helpful to postpone CKD progression.

is an automatic and non-invasive instrumentation which constitutes a method of BP assessment. The ABPM can provide not only the BP data throughout the day but also the BP variability, BP circadian pattern, etc. 8 BP circadian pattern is generally characterized by a fall during sleep and a surge in the morning, a rise in BP from being asleep to awake is named the MBPS, which can be calculated from ABPM data. 9,10 As reported in previous studies, elevated MBPS was associated with CV events in patients with hypertension. [11][12][13] Furthermore, some researchers have found that the elevated MBPS was a risk factor for incident CKD and kidney function deterioration. A cross-sectional study enrolling 823 CKD patients showed that elevated MBPS was an independent risk factor for poor renal function, independent of a nondipping pattern, and BP level 14 ; another prospective study confirmed that elevated MBPS was associated with incident CKD and decline in estimated glomerular filtration rate (eGFR) in hypertensive patients. 15 However, to best of our knowledge, no studies have addressed the predictive value of MBPS to CV events and CKD progression in patients with hypertension and CKD. In this population, patients had high prevalence of night hypertension and non-dipping BP, 16,17 which may result in a small MBPS. Under this situation, it is unclear if MBPS is associated with an increased risk for CV events and CKD progression.
To investigate the relationship between MBPS and prognosis in CKD patients with hypertension, we conducted this two-center prospective longitudinal cohort study.

Outcomes
The primary outcome was CKD progression, which was defined as a composite of progression to ESRD, or eGFR decline ≥ 50%. The secondary outcome included (1) death; (2) CV events, which defined as a fatal or nonfatal newly occurred CV disease, including coronary heart disease, myocardial infarction, heart failure, stroke, angina pectoris, whichever occurred first. Patients were followed up by checking the electronic databases in the hospital and phone calls; the follow up was from the day of ABPM, until December 2020, death, or CKD progression, and censored on the date they had the last clinic visit or phone answering. . The proportional hazards (PH) assumption was tested by assessing the log-minus-log plots of survival. Hazard Ratios (HRs), 95% confidence intervals (CIs) were calculated and a two-tailed p value < .05 was considered statistically significant.

Baseline characteristics
In this two-center prospective observational cohort study, a total of 304 CKD patients with hypertension were enrolled (210 with non-

Blood pressure indices differentiating elevated MBPS
The ROC curve analysis was conducted using MBPS as a state vari-

DISCUSSION
In this prospective longitudinal cohort study, we firstly investigated the relationship between sleep-trough MBPS and prognosis in CKD stage 1-4 patients with hypertension. In these patients, the MBPS was much lower than that reported previously, but elevated MBPS also showed a significant association with CKD progression independent of morning BP, BP dipping and control of ambulatory BP and office BP. Conversely, the elevated MBPS was not found to be correlated with death and CV events. These data suggests that elevated MBPS  Morning BP and MBPS are distinct but related BP indices, elevated MBPS was often accompanied with high morning BP, our study also showed their close connection. Morning BP could distinguish elevated MBPS well ((AUROC 0.723, 95%CI 0.66-0.78, p < .001) (Figure 1), the optimal morning SBP cut-off for detecting abnormal MBPS was 129 mmHg; furthermore, 53.2% patients in the elevated MBPS group had morning hypertension, versus 28.1% in low MBPS group (Table 2); Therefore, our findings suggest that it is possible to detect abnormally elevated MBPS by monitoring home morning BP if the ABPM was not available.
Although the intimate correlation between morning BP and MBPS existed, and morning hypertension has been reported to be a risk factor of declined kidney function, 26,27 the predictive value of elevated MBPS to CKD progression was independent of morning BP, as well as BP dipping and ambulatory BP/ office BP control, indicating that MBPS held some independent characteristics which were associated with CKD progression. It has previously been observed that elevated MBPS was related to urinary albumin excretion and albumin/creatinine ratio . 28 Albuminuria is an established sign of kidney damage, and indicates an increased risk of kidney and CV disease because of insulin resistance and endothelial dysfunction. 29 Based on present evidences, it is speculated that elevated MBPS rises the glomerular pressure load rapidly in a short time and injures renal vascular endothelium, resulting in poor renal function. 14 Previous studies also reported that elevated MBPS was associated with impaired baroreceptor sensitivity, neurohormonal abnormalities of the renin-angiotensin system and sympa- These cardiovascular damages may affect renal blood perfusion, which is likely to contribute to the CKD progression. However, the underlying mechanisms regarding MBPS and CKD progression are still unclear, further studies are needed.
In this study, we also analyzed the association of elevated MBPS with CV events and death. Elevated MBPS was not found to be an independent predictor of CV events and death, consistent with some previous studies. An analysis of 2051 subjects indicated a weak positive relationship between elevated MBPS and CV events or death, which disappeared after adjustments. 32 Another study in blacks showed that MBPS itself was not associated with increased CV risk and death. 33 However, many studies reported the predictive value of MBPS to CV events in non-CKD patients. 34 probably not associated with an increased risk of death or cardiovascular events. 37 In addition, the differences of study population may be another reason. The study population in this study were patients with stage 1-4 CKD and hypertension while previous studies were mostly hypertensives without CKD.
Our study has some strengths. First, to our knowledge, this is the first prospective study to investigate clinical predictive value of elevated MBPS to CKD progression in patients with CKD and hypertension. Second, this study has high rates of follow-up. There are also some limitations. Only 304 patients were included into this study, the sample is relatively small. And the median follow-up time is 2.5-year, which is not long enough. A larger sample size prospective study with enough follow-up time is needed in the future. Besides, our data were from Chinese population, so it is not sure whether these findings are appropriate for other ethnic groups. Therefore, other validation enrolling other ethnics would be required.
In conclusion, we provided the first evidence that elevated MBPS was an important risk factor of CKD progression in patients with CKD and hypertension. Appropriate evaluation and management of MBPS may be helpful to postpone CKD progression.

CONFLICTS OF INTEREST
The authors declared no potential conflicts of interest concerning the research, authorship, and/ or publication of this article.

AUTHOR CONTRIBUTIONS
Xiang Liu, Ting Zhang, Yi Tang, and Wei Qin: Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND drafting the work or revising it critically for important intellectual content; AND final approval of the version to be published; AND agreement to be accountable for all aspects of the work in ensuring that questions related to the accu-racy or integrity of any part of the work are appropriately investigated and resolved.
Fangming Li, Zhiyao Zheng, and Huan Zhou, Aiya Qin: analysis and acquisition of data; AND drafting the work; AND final approval of the version to be published; AND agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.