Should Reducing Nocturnal Blood Pressure Be a Therapeutic Target in CKD? The Time Is Ripe for a Clinical Outcomes Trial

Ambulatory blood pressure (ABP) monitoring is a noninvasive technique in which blood pressure (BP) is recorded over an extended period of time, typically 24 hours or more, outside of the office setting. As such, it provides information on diurnal BP patterns, which cannot be obtained from either clinic or home measurements. In the general population without chronic kidney disease (CKD), use of ambulatory BP monitoring has been proposed as a means to identify persons with white-coat hypertension, that is, persons at lower risk of cardiovascular disease than suggested by clinic measurements. The opposite might be true for CKD patients. Because of the high prevalence of abnormal diurnal BP patterns in CKD patients, clinic BP may underestimate the risk of cardiovascular disease, as well as the risk of progression of kidney disease. Hence, the likely role of ABP in CKD patients is to identify patients at higher “cardiovascular-kidney risk.”

The normal diurnal pattern of BP is a reduction in nighttime BP of 10% or more compared to daytime BP levels (persons with this pattern are termed “dippers”). Elevated nocturnal BP and an abnormal dipping status are extremely common in patients with CKD.1, 2, 3 One of the earliest studies was by Portaluppi et al who compared age-matched hypertensive patients with and without CKD.2 Mean 24-hour BP was similar in the 2 groups, but those without CKD had a nocturnal systolic pressure BP reduction of 12.7 mm Hg, while those with CKD showed an average increase of 2.7 mm Hg. This lack of decline in nocturnal BP has been confirmed in several other studies.4, 5, 6 In the African American Study of Kidney Disease and Hypertension (AASK), as many as 40% of African American patients with hypertensive CKD had a reversed diurnal pattern, that is, higher nocturnal BP than daytime BP.7

The pathophysiologic mechanisms underlying elevation of BP at night remain uncertain. Activation of the sympathetic nervous system,2, 8 altered sodium balance requiring a higher pressure at night to achieve adequate natriuresis,9 elevated renin and aldosterone levels,10 and decreased endothelial-derived vasodilators have been postulated. High nocturnal BP has also been associated with sleep apnea11 and insulin resistance.12

Although the etiology is uncertain, both abnormal dipping status (nondippers compared to dippers) and higher nighttime BP are associated with greater BP-related target organ damage and higher cardiovascular morbidity and mortality.13, 14 Several cross-sectional studies have shown that high nocturnal BP is associated with proteinuria.15, 16, 17 In prospective studies, elevated nocturnal BP or nondipping BP is associated with incident proteinuria in diabetics,18 more rapid decline in glomerular filtration rate in hypertensive patients with CKD,19 and loss of function in renal allografts.20 In a prospective study of CKD patients, a 1–standard deviation increase in nocturnal systolic BP was associated with a more than 2-fold increase in end-stage renal disease and a 50% higher risk of death. Even in patients with relatively preserved renal function, glomerular filtration rate remained stable among dippers (mean change, 1.3%) but declined among nondippers (mean change, −15.9%) during a median follow-up period of 3.2 years.21

To date, few studies have tested strategies designed to lower nocturnal BP and restore normal diurnal pattern. In hypertensive patients without CKD, use of diuretics22 and shifting the time of medication (valsartan23 and diltiazem24) administration to the evening have been shown to reduce nocturnal BP. In the setting of CKD, 1 study documented that administration of the calcium channel blocker isradipine in the evening lowered nocturnal BP.25

In view of the paucity of available data, the study by Minutolo et al in this issue of AJKD is an important advance. This pre-post, single-arm study addressed the issue of whether shifting the time of drug administration from morning to evening can safely and effectively restore normal circadian pattern in patients with an estimated glomerular filtration rate less than 90 mL/min/1.73 m2 (1.5 mL/s/1.73 m2), a nondipper BP profile (nighttime-to-daytime BP ratio of > 0.9), and controlled daytime BP (<135/85 mm Hg). At baseline, the pattern of antihypertensive medication use was typical of that used in CKD, that is, most patients were on combination therapy. Importantly, the intervention was quite simple. Patients on monotherapy were asked to take their medications in the evening instead of the morning. For those on multiple medications, at least 1 of the medications was taken in the evening.

After 8 weeks, the vast majority of patients (88%) had converted from a nondipper to a dipper profile. Nocturnal BP was lowered by an average of 7 mm Hg without an increase in daytime BP; somewhat surprising is the observation that office BP was also lower after 8 weeks. Results were consistent regardless of the antihypertensive medication. This finding suggests the effective component of the intervention was medication timing rather than a specific drug effect. Of considerable interest is the finding that the intervention, albeit brief, just 8 weeks, reduced proteinuria. Interestingly, the extent of proteinuria reduction correlated with the night-day ratio, not the level of nocturnal BP. No adverse effects were reported.

Despite these intriguing results, the study has some limitations. The core design was a pre-post study without a control arm. Hence, whether the BP changes reflect habituation to the measurement technique is unclear. The patient population was small, just 32 patients, and was a convenience sample of patients referred for ambulatory blood pressure monitoring. It does not reflect the broad spectrum of the CKD patients; for example, only 17% of patients had diabetes. The intervention lasted only 8 weeks; whether the effects persist or diminish over time is unknown. The study tested only 1 intervention. Alternate approaches to lowering nocturnal BP, such as addition of a small dose of an antihypertensive agent in the evening, might likewise be effective. Finally, the racial/ethnic composition of this Italian cohort certainly differs from that of other countries, particularly the United States, where CKD disproportionately affects African Americans. In view of these limitations, replication in other patient populations is warranted.

This paper provides useful, preliminary data to guide the design of a clinical outcome trial. The simple maneuver of switching the time of drug administration from morning to evening appears to safely lower nocturnal BP and restore a normal diurnal BP pattern. The next logical question is whether lowering nocturnal BP can retard the progression of CKD and prevent cardiovascular complications. This is particularly important in the context of recent data which document that hypertensive CKD continues to progress in the setting of recommended BP therapy (an office BP goal of < 130/80 mm Hg and provision of renin-angiotensin-system blocking medication).26 Such findings highlight the urgent need to develop and test novel interventions that retard the progression of CKD. The time is now ripe for a clinical outcomes trial of therapy that lowers nocturnal BP.