aClinica Medica, Ospedale San Gerardo dei Tintori, Monza, Department of Health Science, University of Milano-Bicocca
bIstituto Auxologico Italiano IRCCS
cIRCCS Multimedica, Sesto San Giovanni, Milano, Italy
Correspondence to Cesare Cuspidi, Istituto Auxologico Italiano, Clinical Research Unit, Viale della Resistenza 23, 20036 Meda, Italy. Tel: +39 0362 772433; fax: +39 0362 772416; e-mail: email@example.com
In this issue of the journal, Kanno et al.  report the findings of a population-based longitudinal study aimed at assessing the value of out-of-office blood pressure (BP) (i.e. 24-h, daytime and night-time BP) in predicting the development of chronic kidney disease (CKD) in 843 participants with preserved renal function at baseline. Before addressing the results of the study in detail, available evidence on this issue and related topics deserve to be considered.
Although the pathogenesis of subclinical organ damage such as left ventricular hypertrophy, carotid atherosclerosis, reduced glomerular filtration rate (GFR) and microalbuminuria/proteinuria in the general population as well as in hypertensive cohorts is not fully understood, a consistent body of evidence indicates that BP levels, as better reflected by out-of-office than by office measurements, in combination with a variety of nonhaemodynamic factors, play a key role in its development . In recent decades, growing interest has been devoted to circadian variations in BP and to nocturnal BP in relation to their association with cardiovascular and renal outcomes [3,4]. A number of studies reported that a blunted day/night BP fall (i.e. nondipping) is related to several unhealthy conditions, including diabetes, metabolic syndrome, obesity, sleep apnoea, renal disease, cardiac and extra-cardiac hypertensive target organ damage as well as to an increased risk of cardiovascular disease [5–7]. This association, however, remains controversial, as other reports failed to demonstrate any difference in intermediate end-points, such as vascular and cardiac target organ damage, and in hard outcomes between dipper and nondipper individuals [8,9]. It is worth noting that a greater prognostic value of absolute nocturnal BP over the dipping/nondipping classification has been recently documented by a large meta-analysis including 25856 hypertensive patients and 9641 normotensive individuals randomly recruited from the population . In both groups, absolute night-time BP was a better predictor of outcomes than daytime, day–night BP ratio and the dipping status.
An updated analysis of the International Database of Ambulatory Blood Pressure involving 8711 individuals from 10 populations showed that isolated nocturnal hypertension (i.e. daytime BP <135/85 mmHg and night-time BP >120/70 mmHg) is associated with a higher risk of total mortality (+29%, P = 0.04) and all cardiovascular events (+38%, P = 0.003) than nocturnal normotension, irrespective of the dipper/nondipper classification .
The loss of the physiologic fall in nocturnal BP has been frequently reported in patients with CKD, and a nondipping status has been suggested to accelerate the decline in renal function . The link between CKD and elevated night-time BP is probably related to multiple factors, including volume-dependent hypertension exacerbated by supine posture, abnormal sodium handling, sympathetic activation and comorbidities such as diabetes and autonomic failure. On the contrary, nocturnal BP elevation secondary to the reduced renal capacity to excrete sodium in CKD may enhance pressure natriuresis and has been postulated to be a compensatory mechanism for the impaired daytime natriuresis. As a consequence, patients with renal dysfunction require a longer time period of treatment before night-time BP falls, as high BP during sleep persists until the excess sodium is excreted into urine .
So far, only a limited number of cross-sectional and longitudinal studies have investigated the independent association between 24-h ambulatory BP and circadian BP rhythm with CKD and renal outcomes. In a pioneering longitudinal study conducted in the mid-1990s, Timio et al.  were able to demonstrate that nondipper hypertensives with CKD had a faster decline in creatinine clearance than their dipper counterparts (0.37 ± 0.26 vs. 0.27 ± 0.09 ml/min per month, P < 0.05). Nondippers also exhibited a greater increase in urinary protein excretion rate than dippers (993 ± 438 vs. 691 ± 222 mg/24 h, P < 0.05). In 322 patients with and without CKD, referred for ambulatory BP monitoring, Davidson et al. documented that GFR was stable among the 137 dippers (mean change 1.3%) but significantly declined among the 185 nondippers (mean change −15.9%) (P < 0.001) after a median follow-up of 3.2 years. Of note, the differences between groups persisted after adjustment for well established predictors of GFR decline. The value of ambulatory BP for prediction of end-stage renal disease (ESRD) and death was assessed in a cohort of 217 veterans with CKD over a follow-up period of 3.5 years . For one standard deviation increase in 24 h ambulatory SBP, the risk of ESRD increased by 3.04 [95% confidence interval (CI) 2.13–4.35] and by 2.20 (95%CI 1.43–3.39) when adjusted for clinic SBP. The nondipping condition was associated with a higher risk of total mortality and of the composite end point of ESRD and death. In a large study including 1085 hospitalized patients, night-time SBP measured by nurses with an automated device was found to be an independent predictor of GFR decline and of the composite death, ESRD or GFR decline ; this was not the case for clinic SBP measured during the daytime. Other reports, however, did not find an independent relationship between night-time BP, altered circadian pattern and renal outcomes. The nondipping status in patients with CKD is associated with older age, lower GFR, proteinuria and serum albumin concentration; all these factors correlate with the progression of kidney disease and the adjustment for such variables has been shown to remove the independent prognostic value of ambulatory BP .
The article by Kanno et al.  confirms and expands previous evidence on the prognostic relevance of ambulatory BP by showing that night-time BP was significantly related to the risk of CKD and all-cause death, whereas 24-h, day-time, office BP and nondipping pattern were not. Indeed, average night-time BP was the only ambulatory component predictive of both renal outcome (i.e. development of proteinuria and a GFR <60 ml/min per 1.73 m2) and all-cause mortality in Cox's proportional hazard models adjusted for several demographic/clinical variables such as age, sex, major cardiovascular risk factors, antihypertensive treatment, history of previous cardiovascular disease and night-time and daytime BP values. In particular, for one standard deviation increase in night-time SBP (13.3 mmHg), a 21% higher risk of CKD (P < 0.05) and an 18% higher risk of a composite outcome of CKD or all-cause death (P < 0.05) was present. Such an association was also found for night-time DBP: one standard deviation increase in diastolic night-time BP (7.6 mmHg) conferred a similar higher risk of CKD (22%, P < 0.05) and CKD or all-cause mortality (20%, P < 0.05). Furthermore, when the relationship between ambulatory BP and outcomes was investigated by categorizing the participants according to tertiles of night-time SBP, the risk of CKD and all-cause death was approximately 50% greater in the third than in the first tertile. Of note, sex and age-based subanalyses confirmed the findings obtained in the whole population. Some aspects and clinical implications of this study deserve to be further commented. In keeping with previous evidence [10,11], these results indicate that absolute night-time BP level rather than nocturnal BP fall from daytime value is independently related to new-onset CKD. This means that nocturnal BP level but not the extent of night-time BP fall may be regarded as a powerful diagnostic parameter for identifying individuals exposed to a higher risk of incident CKD. It is worth noting that in the study by Kanno et al. , the rate of nocturnal BP decline and the prevalence of the nondipping pattern at baseline did not differ among the individuals who developed CKD as compared with their counterparts with persistent normal renal function. In line with this observation, we have recently shown that in the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) population, both mean nocturnal SBP [relative risk (RR) for each 10 mmHg increase in SBP: 1.15; 95% CI 1.01–1.23, P < 0.0001] and the lowest SBP level (RR for each 10 mmHg increase in SBP: 1.10; 95% CI 1.02–1.19, P = 0.01) were independent predictors of new onset echocardiographic left ventricular hypertrophy; this was not the case for the magnitude of night-time SBP fall (hazard ratio for each 10% decrease in SBP: 0.91; 95% CI 0.80–1.04, P = 0.18) . The lack of a predictive value of day–night BP variations and nondipping status, as shown by both studies [1,19], may be related to the limited reproducibility of circadian BP variations over time as well as to the inaccurate classification of dippers and nondippers on the basis of a single 24-h ABPM. Moreover, a preserved BP fall at night may not necessarily result in a normal night-time BP; in fact, nocturnal hypertension, (i.e. average night-time BP >120/70 mmHg) may occur independently from the dipping status . Finally, the greater relevance of night-time over daytime BP in predicting renal outcome and mortality may be attributed to the superior reproducibility of nocturnal BP as compared with daytime BP, which is markedly influenced by a number of factors including physical activity, job stress and smoking .
Some limitations of the present study should be also acknowledged. First, definition of the CKD phenotype was based on a single determination of serum creatinine for estimation of e-GFR; this may have misclassified renal status in individuals with transient rather than chronic renal dysfunction. Indeed, results from a large Canadian study  have shown that low GFR values at a first determination were confirmed in a subsequent testing performed within at least 30 days in less than 70% of the individuals included in the survey. Second, as recognized by the authors, urinary protein excretion was assessed by a semi-quantitative method by using a dipstick test for spot-urine, which is unable to detect microalbuminuria, an established marker of endothelial dysfunction and renal disease; this methodological approach did not allow identification of individuals with subclinical renal disease and could not provide reliable information on the relationship of this marker of renal organ damage with ambulatory BP. Third, as the results of this study refer to a high-risk Japanese population with a nearly 20% all-cause mortality during a mean follow-up period of 8.2 years, they should not be extended to different clinical settings and ethnic groups.
In conclusion, the study by Kanno et al.  reinforces the concept that nocturnal BP is a strong predictor of both intermediate and hard outcomes, by focusing for the first time on the role of this out-of-office BP component in identifying individuals at a higher risk of new-onset CKD. In a practical perspective, this observation supports the value of ambulatory BP for assessing the risk of CKD in general populations and suggests that targeting nocturnal BP may reduce new-onset renal failure.
Conflicts of interest
The authors report no conflicts of interest.
The authors alone are responsible for the content and writing of the article.
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