Global health, demographic changes (population growth and aging) and environmental destruction, including climate change and natural disasters, are the key challenges we face in the twenty-first century. In terms of global health, understanding the rates and numbers of people who die as well as where, at what age and from what diseases is a crucial step for planning interventions.1 The Global Burden Disease Study, which was launched by the World Bank and the World Health Organization in 1991, provides a comprehensive and internally consistent source of information on the global burden of disease over time.1 The 2010 report ranked chronic kidney disease (CKD) 18th on the list of conditions that cause the most deaths worldwide.2 Its position jumped from 27th in 1990; only HIV/AIDS moved more positions up the list. In addition, the overall increase from 1990 to 2010 in the years of life lost because of premature mortality was the fourth largest in CKD (51%), behind HIV/AIDS (372%), stroke (177%) and diabetes mellitus (70%). Thus, CKD is now recognized as an emerging global health issue.3

CKD prevalence is generally increasing worldwide but varies by region (10–15%). Its clinical features also differ around the globe.3 CKD involves not only end-stage renal disease and cardiovascular disease (CVD) but also cognitive dysfunction, psychological problems and musculoskeletal issues. These issues lead to a substantial loss of health and are costly for health-care systems to manage. Thus, the identification of individuals who are at risk for these complications, followed by appropriate management for their prevention, is clinically important.

High blood pressure (BP), which is both a cause and consequence of CKD, is a leading risk factor for cardiorenal diseases in CKD.3 Compared with office BP (OBP) values measured by a physician or nurse, out-of-OBP values (that is, home or ambulatory BP, especially nocturnal BP), have been shown to precisely predict outcomes in CKD patients. An example is among African Americans with hypertension-related CKD who participated in the trial and cohort phases of the African American Study of Kidney (AASK) Disease: a majority of participants experienced renal events or died despite good OBP control and the use of renin–angiotensin system (RAS) blockers. One potential explanation is the presence of masked hypertension; of those with well-controlled OBP, 70% had either elevated daytime (⩾135/85 mm Hg) or nocturnal (⩾120/70 mm Hg) BP.4 Masked hypertension is not uncommon in CKD.5 Notably, a sleep BP increase or limited nocturnal BP dipping, rather than an awake BP increase, has been shown in CKD. Herein, we summarize evidence regarding the associations of OBP, ambulatory BP and outcomes in CKD populations (Table 1). Although there are some variations in the pattern of ambulatory BP in CKD, more than half of the populations had a high out-of-OBP and a non-dipper/reverse-dipper status at night.

Table 1 Evidence to show associations of OBP, ambulatory BP and outcomes in CKD populations.
Full size table

In the current issue of Hypertension Research, Cha et al.14 strengthened the evidence against the sole use of OBP. Using a nationwide database from Korea (n=1317, mean age, 58 years; 63% men; all with CKD stage 2–4; and median eGFR, 48 ml min−1 per 1.73 m2), they showed the BP control status based on the OBP and the ambulatory BP. All patients were treated with antihypertensive medications, and 25% had diabetic nephropathy. The majority were treated with two types of antihypertensive agents: RAS inhibitors were used in almost all cases (that is, 90%), suggesting that physicians who participated in this study conformed to the guidelines, and calcium-channel blockers were used in 56% of cases. An OBP of <140/90 mm Hg, a daytime BP of <135/85 mm Hg and a nocturnal BP of <120/70 mm Hg were defined as controlled BP. The nocturnal BP dipping status was defined as extreme dipper if the nocturnal fall in BP was ⩾20%, as dipper if the nocturnal fall in BP was between 10 and 20%, as non-dipper if the nocturnal fall in BP was between 0 and 10%, and as reverse dipper if the nocturnal fall in BP was <0%. As a result, the BP classification was as follows: controlled hypertension, 19%; white-coat hypertension, 4%; masked hypertension, 34% and uncontrolled hypertension, 42%. The nocturnal BP dipping status was as follows: extreme-dipper, 15%; dipper, 33%; non-dipper, 35% and reverse dipper, 17%. A direct comparison of the data of Cha’s study with those of the previous reports shown in Table 1 is not feasible, but the authors showed that more than half of CKD patients have high out-of-OBP and abnormal diurnal BP variation. One of the possible explanations for why so many patients (76%) had uncontrolled high BP is that they used, on average, fewer antihypertensive agents (approximately 2.3 agents) than patients in other reports (2.5–3.8 agents).4, 7, 9, 12, 13 As the authors mentioned, the use of diuretics was relatively low (38%). In Asians, the intake of dietary sodium is high,15 which could also contribute to BP elevation, especially when the kidney function is impaired. However, we should continue to pay close attention to kidney function when we consider diuretics as the combination therapy with RAS inhibitors and diuretics, particularly in non-obese hypertensive cases (common in Asians), provides less cardiorenal protection (and may even be harmful in some cases) than does RAS inhibitors together with calcium-channel blockers.16 In contrast to the reports on Caucasians (30%)13 but similar to those on Asians11 and African Americans,4 white-coat hypertension was uncommon in this study.14

Few reports have shown the clinical features of high out-of-OBP (particularly nocturnal BP) and abnormal diurnal BP variation in CKD. Of note, these BP alterations are not always proportional to the reduction in the renal function. Aging, diabetes, greater proteinuria, less physical activity and frequent nocturia have been reported to be associated with less nocturnal BP dipping in CKD.4, 11, 13 In the study by Cha et al.,14 diabetes nephropathy, pre-existing CVD, and greater proteinuria were most prevalent in reverse dippers. In contrast to the findings of AASK,4 female gender and lower body mass index became more prevalent as the extent of nocturnal BP dipping decreased. Because of the cross-sectional nature of this study,14 a cause-effect association cannot be inferred. That is, less nocturnal BP dipping in CKD may be a marker of poor health rather than a cause of it. To determine whether high nocturnal BP or abnormal diurnal BP variation in CKD is a reversible risk factor, interventional studies are required. In this point, a recent study (n=661; mean age, 59 years; 60% men; eGFR, 66–67 ml min−1 per 1.73 m2) indicated that a progressive decrease in nocturnal systolic BP during follow-up was most significantly associated with a reduction in composite CVD in CKD patients (hazard ratio: 0.86, 95% confident interval: 0.77–0.96; P<0.001, for every 5-mm Hg decrease in nocturnal systolic BP), whereas decreases in daytime systolic BP were not.17

Other possible mechanisms of high nocturnal BP and/or less nocturnal BP dipping in CKD include high sympathetic nerve activity, sleep disturbances and expanded extracellular volume status as well as enhanced salt sensitivity.5, 18 These associations can also be applied to non-CKD. Neither Cha’s study nor previous reports4, 6, 7, 8, 9, 11 compared ambulatory BP in those with CKD and without CKD; therefore, whether the pathophysiologies of nocturnal BP alterations differ in the presence of CKD remains uncertain. In addition, ethnic-based comparison data on ambulatory BP in CKD are limited. Generally, African Americans are thought to experience high nocturnal BP and less nocturnal BP dipping than Caucasians,19 which may be explained by genetic factors (for example, salt sensitivity, nitric oxide and natriuretic peptide) and by physiological, behavioral or environmental factors (e.g., socioeconomic status). The AASK showed a substantially high prevalence of reverse-dippers (39%) among African American CKD patients. In the future, we need to elucidate the mechanisms that give rise to ethnic disparities in nocturnal BP regulation that can lead to race-specific targets for CVD prevention. Thus, international collaborative studies in this field are warranted.

Although abnormal diurnal BP variation is frequently accompanied by high nocturnal BP, the prognostic value of each is not identical. In elderly hypertensive patients, high nocturnal systolic BP was associated with an increased risk for stroke regardless of CKD presence.10 In contrast, a reverse-dipping pattern was associated with a higher stroke risk only in those with CKD. This point should be realized by obtaining the follow-up data for Cha’s study.14

There are still some questions raised by Cha’s study. First, as the authors mentioned, the time of the ingestion of antihypertensive agents is unknown. Although the findings are still controversial, the administration of antihypertensive agents at bedtime rather than after waking-up may be more effective in lowering nocturnal BP or restoring nocturnal BP dipping in CKD patients.17 Second, the authors did not assess sleep quality or nocturia, which could influence nocturnal BP in CKD. Third, despite the usefulness of ambulatory BP monitoring (ABPM) for predicting outcomes in CKD, there are still some caveats associated with ABPM, such as cost, time and relative cumbersomeness. To overcome these difficulties, some newly developed, programmed home BP measurement devices that can measure nocturnal BP automatically have been developed.18 More evidence, including cost-benefit analyses, is warranted to justify the clinical significance of ABPM in CKD patients.