Circadian Variation and Arterial Stiffness in Chronic Kidney Disease and Their Treatment

Chronic kidney disease (CKD) has been recognized as a cause of progression to end-stage renal disease and as a risk of cardiovascular disease.1 Although the risk factors of CKD are diverse, hypertension and arterial stiffness are especially predominant risk factors. A number of studies have discussed the association between hypertension and CKD.2 For the management of hypertension, recent international guidelines recommend not only the measurement of office blood pressure (BP) but also out-of-office BP. The guidelines in Japan have stressed the use of home BP measurement,3 because the use of home BP devices has spread throughout Japan, and there is now an accumulation of evidence regarding the prognostic power of home BP measurement in Japanese hypertensive populations. Both the average BP level and BP variability have been shown to be linked to a risk of cardiovascular events. Although there are various indexes of BP variability, home BP measurement is available to assess 1 index of BP variability, i.e., day-by-day BP variability, which has been associated with cardiovascular events in general and clinical populations independently of the average home BP level.4 We demonstrated that increased day-by-day home BP variability was associated with a decreased estimated glomerular filtration rate in subjects with diabetes among 4,231 individuals in a Japanese general clinical population, and we did not detect this association for the average home BP level.5 The impact of BP variability in individuals with CKD may therefore be important in high-risk populations. Ambulatory BP monitoring has been acknowledged as the gold-standard method for measuring out-of-office BP for the diagnosis and treatment of hypertension. Abnormal circadian BP rhythm and a diminished nocturnal BP fall as assessed by ambulatory BP monitoring have been associated with a risk of target organ damage and cardiovascular events.6 In patients with heart failure, the riser pattern (in which nighttime BP exceeds daytime BP) was associated with a risk of adverse cardiovascular outcomes in heart failure patients with a preserved ejection fraction, but not in those with a reduced ejection fraction.7 Most recently, in our investigation of 6,359 clinical patients with more than 1 cardiovascular risk, we observed that the riser pattern was linked to a cause-specific outcome, which indicated that the riser pattern was specifically associated with the incidence of heart failure independently of nighttime BP compared with the normal circadian BP rhythm (hazard ratio, 2.45; 95% confidence interval, 1.34–4.48).8 Thus, abnormal circadian BP rhythm is an important target for the prevention of organ damage and cardiovascular events. Arterial stiffness has been found to pose a risk of CKD.9 Age and hypertension accelerate the stiffening of large elastic arteries, which leads to a reduction in the buffering capacity of arteries and transmits highly pulsatile pressure and flow stress under the low resistance of renal glomerular capillaries, as a result, CKD is progressed. We have investigated whether a reduction in arterial stiffness as revealed by the pulse wave velocity (PWV) is associated with the reduction in the urinary albumin-to-creatinine ratio, one of the indexes of CKD, independently of the reduction in BP.10 In the combination of 404 treated hypertensive patients with an active treatment group (mainly using doxazosin and atenolol) and a control group, the reduction in urinary albumin-to-creatinine ratio in the subjects with a brachial-ankle PWV <0 cm/s at 6 months of follow-up compared with baseline was higher than in the subjects without this PWV value. This association was admitted independent of the reduction in home BP level. Thus, arterial stiffness would independently contribute for the progression of CKD. The report by Kusunoki et al. published in the American Journal of Hypertension may provide insight into the association between circadian rhythm and arterial stiffness in the severity of CKD.11 In their study of in 184 essential hypertensive patients, Kusunoki et al. investigated the association between the presence of CKD and arterial stiffness represented by aortic BP or PWV throughout a 24-hour period by using an automated oscillometric ambulatory BP monitoring device, which can assess not only brachial BP but also aortic (central) BP and indexes of arterial stiffness (such as the PWV and augmentation index) throughout a 24-hour period. Although their results demonstrated that a diminished nocturnal brachial BP fall was associated with the severity of CKD, interestingly, diminished nocturnal aortic BP and a PWV fall were also each associated with the severity of CKD independently of the degree of the diminished nocturnal brachial BP fall (Figure 1). The severity of CKD and the risk factors and treatment of CKD. Abbreviations: BP, blood pressure; CKD, chronic kidney disease; MRA, mineral corticoid receptor antagonist; RAS, renin–angiotensin system; SGLT2, sodium-glucose cotransporter 2. The severity of CKD and the risk factors and treatment of CKD. Abbreviations: BP, blood pressure; CKD, chronic kidney disease; MRA, mineral corticoid receptor antagonist; RAS, renin–angiotensin system; SGLT2, sodium-glucose cotransporter 2. That study’s design was cross-sectional, and thus although the cause-and-effect relationship between a diminished nocturnal PWV fall and CKD remains to be clarified, abnormal circadian rhythm of arterial stiffness might be a novel factor for the severity of CKD. However, there is an important limitation of the Kusunoki et al. study. Several noninvasive devices are available to measure aortic stiffness. A majority of these devices calculate indexes of aortic stiffness such as the central BP or pulse pressure using a transfer function given in the measurement of peripheral BP. Therefore, the indexes of aortic stiffness calculated by these devices are often closely associated with peripheral BP. In the Kusunoki et al. study, the correlation coefficient of 24-hour peripheral systolic BP and 24-hour aortic systolic BP was 0.95.11 Moreover, Huang et al. reported that when they compared the association of cardiovascular events with central and peripheral BP and pulse pressure, they found no significant difference in prognostic power between central and peripheral BP and pulse pressure.12 Further research is needed to determine whether aortic stiffness measured by noninvasive devices is associated with a risk of the progression for CKD, beyond peripheral BP. Optimal BP control is one of the important treatments for the suppression of CKD progression. Although there has been no specific treatment for CKD, the situation has changed. Sodium-glucose cotransporter 2 (SGLT2) inhibitors is one of the hypoglycemic agent. In the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Blood Pressure Trial in Type 2 Diabetes Mellitus Patients), a SGLT2 inhibitor, empagliflozin, significantly reduced the rates of cardiovascular events and adverse renal outcomes.13,14 In the recent Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, canagliflozin added to a renin–angiotensin system blocker demonstrated a 34% relative risk reduction of the renal-specific composite endpoint of end-stage renal disease, a doubling of the creatinine level, or death from renal causes.15 In the recent international DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in CKD) trial, patients with an estimated glomerular filtration rate of 25–75 ml/min/1.73 m2 and a urinary albumin-to-creatinine ratio of 200–5,000 mg/gcre were randomized to control and dapagliflozin (10 mg once daily) groups and followed for a median of 2.4 years. The primary endpoint was a composite of a sustained decline in the estimated glomerular filtration rate of ≥50%, end-stage renal disease, or death from renal or cardiovascular causes.16 The results showed that dapagliflozin significantly reduced the rate of the primary endpoint compared with the control group (hazard ratio, 0.61; 95% confidence interval, 0.51–0.72). There is a possibility that SGLT2 inhibitors specifically reduce nighttime BP and improve arterial stiffness.17,18 Finerenone is a novel, nonsteroidal, selective mineral corticoid receptor (MR) antagonist that has much greater MR selectivity and better MR affinity than any other MR receptor antagonist in vitro. Most recently, in the Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease (FIDELIO-DKD) phase III trial, patients with type II diabetes were randomized to a control group and a group in which finerenone treatment was added to an renin–angiotensin system blocker. Finerenone significantly reduced the rate of the primary endpoint, which was the composite endpoint of the onset of kidney failure, a sustained ≥40% decrease in the estimated glomerular filtration rate from baseline over ≥4 weeks, or renal death.19 Another investigation reported that finerenone reduced aortic stiffness in vivo.20 Since finerenone has a BP reduction effect, further research is needed to determine whether finerenone specifically reduces nighttime BP. Kusunoki et al. demonstrated that an abnormal circadian variation of aortic pressure and arterial stiffness may be predominant risks in the severity of CKD.11 It is challenging to identify the appropriate risk stratification and the optimal treatment while taking into account the finding that aortic pressure and arterial stiffness suppress the progression of CKD, which will result in a reduction of cardiovascular events. The authors declared no conflict of interest.