Nocturnal heart rate rising is a risk factor for poor renal outcomes in patients with chronic kidney disease and hypertension

Abstract The association of heart rate (HR) dipping pattern with renal outcomes in chronic kidney disease (CKD) patients with hypertension has never been investigated. In order to demonstrate if HR dipping pattern is a risk factor for renal outcomes, cardiovascular (CV) diseases, and mortality in hypertensive patients with CKD, we conducted the prospective longitudinal observational study. Patients were divided into three groups according to their nocturnal HR: HR dippers (night–day HR ratio ≤ 0.9), HR non‐dippers (0.9 < night–day HR ratio ≤ 1.0), and HR risers (night–day HR ratio > 1.0). The primary outcome was renal endpoint, a composite outcome of progression to end‐stage renal disease (ESRD) or estimated glomerular filtration rate (eGFR) decline ≥ 50%; the secondary outcomes included poor renal outcomes, CV events, and death. A total of 34 (11.3%) patients reached renal endpoint after a follow‐up of 34 ± 17 months. Both HR non‐dippers and HR risers were predictive to renal endpoint (hazard ratio 2.58, 95% confidence interval (CI) 1.04‐ 6.4, P = .04; hazard ratio 3.95, 95% CI 1.33‐ 11.79, P = .01, respectively), while only HR risers was shown to be correlated with a decline in eGFR≥ 50% (hazard ratio 5.28, 95% CI 1.45–19.16, P < .05), and decline in eGFR (β ‐0.17, 95% CI ‐0.33‐ ‐0.01, P = .04). No predictive value was found for HR dipping pattern to mortality and CV events. In conclusion, our study provided the first evidence that HR non‐dippers, especially risers were a risk factor for poor renal outcomes in hypertensive patients with CKD.


INTRODUCTION
Chronic kidney disease (CKD) is a public health problem, with a 3-18% prevalence in the general population. 1 It has caused a great global burden owing to the high risk of advancing to end-stage renal disease (ESRD), and cardiovascular (CV) complications. [1][2][3] It is vitally imperative to find prognostic factors to help identify early intervention strategies to slow the progression of CKD and improve prognosis of renal diseases.
Heart rate (HR) is a clinically accessible indicator of vital signs and sympathetic activity, 4 which has been reported to be predictive of allcause mortality, cardiovascular disease, and renal outcome. [5][6][7] Similar to blood pressure, HR follows circadian rhythms; that is, it normally decreases by 10-20% at night due to the effect of the parasympathetic system, 8,9 a night HR decline less than 10% from day is defined as the HR non-dippers. 10 Circadian rhythms of heart rate can be obtained by ambulatory blood pressure monitoring(ABPM), and has been recommended to be applied in hypertensive patients by guidelines, because of the better predictability of blood pressure (BP) parameters from ABPM to prognosis compared to office/home BP. [11][12][13] HR non-dippers has been reported to be associated with all-cause mortality at the end of the 1990s by Verdecchia and associates,14 this was later confirmed by a few studies on general or hypertensive patients, which showed that HR non-dippers was related to preclinical cardiac damage, mortality, and CV events. 6,[15][16][17][18] However, to the best of our knowledge, studies on the association of HR dipping pattern with prognosis in CKD patients are very limited. The first study related to HR dipping pattern in CKD patients occurred in 2019, which reported the high prevalence (43.3% in the hypertensive pre-dialysis patients and 77.4% in the hypertensive hemodialysis patients) of nondipping HR in CKD patients 19 ; subsequently, a study conducted by Cui and associates in 2021 demonstrated that non-dipping HR was a prognostic marker of all-cause mortality in CKD patients with stage 5. 20 To further investigate the association of HR dipping pattern with renal and heart outcomes in patients with CKD and hypertension, we conducted this prospective longitudinal observational study.

Definitions
Dipping pattern of BP and HR were calculated with the formula: mean night-day ratio of systolic blood pressure (SBP), diastolic blood pressure (DBP) and HR, patients were diagnosed with normal BP or HR dippers if the night-day ratio was ≤0.9, or non-dippers if the ratio was > 0.9 and ≤1.0, 10,23

Outcomes
The primary outcome was a renal endpoint, which was defined as a December 2020, death, or renal endpoints, and censored on the date they had the last clinic visit or phone answering.
A higher proportion of reaching renal endpoint was associated with HR non-dippers (13.8%) and HR risers (16.7%), versus HR dippers (5.6%) (P < .05); cumulative survival of CKD progression was significantly lower in patients with HR non-dippers (P = .034) and HR risers (P = .01) when compared to HR dippers (shown in Figure 1).
In the Cox regression model, both HR non-dippers (hazard ratio 2.58, 95% CI 1.04-6.4, P < .05) and HR risers at night (hazard ratio 3.95, 95% CI 1.33-11.79, P < .05) were demonstrated to be associated with the renal endpoint, even after adjustment of basic clinical characteristics (arrythmia, use of β blocker, use of calcium channel blocker) (Table 3); however, after further adjustment, HR non-dippers was not predictive to the renal endpoint, while HR risers could still strongly predict the renal endpoint, independent of baseline eGFR, 24h HR and BP dipping (Table 3).
In the further research, both HR non dippers (hazard ratio 2.15, 95% CI 1.13-4.09, P < .05) and risers (hazard ratio 2.65, 95% CI 1.14-6.14, P < .05) showed strong predictive value to a composite renal outcome of ESRD or eGFR decline ≥30% (Table 4). When ESRD, eGFR decline  Figure 2). Conversely, HR nondippers were not shown to be correlated with the relative change rate of eGFR (shown in Figure 2). risers were demonstrated to be negatively associated with the change in eGFR, indicating that nocturnal HR rising from the day level was correlated with more declined eGFR. These data suggest that HR nondipping pattern, especially HR rising pattern, plays a vitally important role in poot renal outcomes in hypertensive patients with CKD.

CV events and death
Due to the circadian rhythm of the autonomic nervous system, the parasympathetic nervous system is normally dominant at night, causing HR decline. 8,25 Abnormal variation of HR rhythm has very complex pathogenesis, including abnormal circadian gene expression, 26,27 and abnormal neurohumoral system regulation, etc. 28 This will lead to the increment of sympathetic excitability, nocturnal HR elevates consequently, causing a non-dipping pattern of HR. The prevalence of HR non-dipping pattern in our study is relatively high, with the rate of 64.2%. For the reason, the patients we enrolled were those who had both CKD and hypertension, which indicated they might originally have an imbalance of autonomic nervous system resulting in relative dominance of sympathetic nervous system, 9 then the high incidence of HR non-dippers in these participants could be explained.
HR non-dipping pattern have been proved to have effects on physiological and pathological processes of heart and kidney, resulting in preclinical cardiac damage, microalbuminuria, CV complications and even all-cause or CV mortality, as previous studies reported. 8 However, studies on the association of HR dipping pattern with prognosis in CKD patients are very limited. The first study related to the HR dipping pattern in CKD patients occurred in 2019, 19 which reported the incidence of non-dipping HR pattern was higher in hypertensive patients with CKD than that in hypertensive patients without CKD; furthermore, the risk of non-dipping HR increased with the severity of renal insufficiency. 19 As our study illustrated, HR non-dipping pattern Notably, in our study, HR risers were demonstrated to be more associated with poor renal outcomes compared to HR non-dippers. Similar findings can be seen in BP, as some previous studies reported, HR risers were correlated with worse renal function than non-dippers and dippers. 32,33 Our previous study also identified that high prevalence of nocturnal hypertension (65%) and non-dipping BP pattern (90.5%) was associated with CKD progression 34 ; Considering the consistency of mechanism of nocturnal rising BP and HR, it is not surprising that HR risers were found to have a stronger association with poor renal outcomes in this study. HR rising signifies an extreme variation in circa-dian HR rhythm, and a more increment of sympathetic tone than nondippers and dippers, 35 which is often considered as an especially harmful HR phenotype, the same as BP rising. 36 However, there were no studies underlining the predictive value of HR rising pattern previously, our findings need further validation.
In our study, we concluded that HR risers were negatively correlated with the relative change rate of eGFR from baseline (ß coefficient -0.17, 95% CI -0.33--0.01, P < .05) whereas HR non-dippers had no correlation with change rate of eGFR compared to HR dippers ( Figure 2).  17 Some researchers also drew the same conclusions, 29,37 while some others not. 14,38 Our findings are consistent with the latter, no associations were found between HR non-dipping pattern and CV complications. Reasonable explanations for the contradiction may be the differences in the study population, the previous studies mainly enrolled general or hypertensive patients without CKD while our study included patients with hypertension and CKD; in addition, the small sample size and relatively short follow-up time of our study may be the other reasons. Prospective well-designed researches with enough sample size are required.
There are some strengths of our study. Firstly, previous published studies have mostly focused on the association of BP rather than HR dipping pattern with the renal and heart outcomes in CKD patients 33,39 ; the researches on the abnormal circadian rhythm of HR has mainly limited to the general or hypertensive patients without CKD, 8,17,29 our study provides the first evidence on the predictive value of HR dipping pattern to renal and heart outcomes in hypertensive patients with CKD, which may provide a great basis for clinical practice to monitor and manage HR for those CKD patients. Secondly, patients have comprehensive 24-h ambulatory HR data and clinical assessments; furthermore, our research had a very low rate of lost to follow-up (0.66%). These strengths make our research result more reliable.
Our study also has some limitations. First, with only 302 patients included into the study, the sample size is relatively small; second, the median follow-up time is also not long enough with only 34-month. Further prospective studies with larger sample sizes and long follow-up periods are needed in the future.

CONCLUSIONS
Nocturnal HR non-dipping pattern, especially HR rising, was associated with increased risk of renal endpoint, kidney function deterioration and decline in eGFR. The predictive value of HR nondippers for poor renal outcomes disappeared after further adjustment, while that of HR risers remained stable. Circadian rhythm of HR in hypertensive patients with CKD deserves further attention and research.