Sleep-time Blood Pressure Determined by Home and Ambulatory Monitoring As Potential Prognostic Factor for Chronic Kidney Disease (CKD) Progression, Mortality, and Cardiovascular Morbidity in Patients with Advanced CKD

Hypertension is very common in patients with chronic kidney disease (CKD); its prevalence increases with diminished estimated glomerular filtration rate (eGFR), reaching an estimated 86% in patients with end-stage kidney disease (ESKD). On the other hand, hypertension leads to kidney and other target-organ damage, through its burden of mechanical and oxidative stress on vascular walls.

As in the past, current hypertension guidelines continue to recommend wake-time office blood pressure (BP) measurement (OBPM) as the primary mode of diagnosing hypertension and establishing therapeutic goals. Nonetheless, many of them now advocate ambulatory BP (ABP) monitoring (ABPM) of adult patients to confirm the OBPM-based diagnosis of hypertension because of the well-documented significantly better value of ABPM-derived parameters relative to wake-time OBPM in prognosticating cardiovascular disease (CVD) risk, a relevant finding also well documented in patients with CKD. Unfortunately, ABPM is seldom applied in clinical practice, and when it is, there is no consensus as of yet exactly how to properly apply it, e.g., how frequent to sample BP and for how long, and also what parameter(s) to use for making accurate diagnosis. Most guidelines propose around-the-clock ABPM to derive for diagnostic purpose either the 24h or the "daytime" systolic (SBP) and diastolic BP (DBP) means that typically are defined according to fixed clock time durations established by default by the manufacturers of the measuring devices or set a priori by investigators as opposed to biologically meaningful ones based on the actual clock times of the beginning and end of the activity and sleep spans of each patient to derive accurate individualized awake and asleep BP means and dipping pattern.

Contrary to the recommendation of the most recently published hypertension guidelines to rely on the "daytime" or 24h ABP means to diagnose hypertension when ABPM is performed, multiple prospective outcome trials and meta-analyses substantiate CVD events are much better predicted by the asleep BP mean. CVD risk is additionally predicted by an attenuated sleep-time relative SBP decline - non-dipper (sleep-time relative SBP decline <10%) or riser (sleep-time relative SBP decline <0%) 24h SBP profile. Thus, the elevated asleep SBP mean and blunted sleep-time relative SBP decline (non-dipping) constitute joint significant CVD risk factors, independent of the wake-time OBPM or the awake or 24h ABP means. The importance of the asleep SBP mean for making the diagnosis and prognosis of CVD risk is exemplified by a meta-analysis of the original databases of nine cohorts representing in total 13,844 hypertensive patients. It found that the wake-time office SBP as well as ABPM-derived awake and asleep SBP means were all significantly associated with elevated CVD risk when each variable was analyzed individually; however, when all three SBP measurements were simultaneously included into the survival model, only the asleep SBP mean remained as the independent BP-derived predictor of CVD events.

The differential relevance of several ABPM-derived parameters, compared with the wake-time OBPM, as potential risk markers of CVD morbidity and mortality has been further assessed in the thus far largest reported primary care-based ABPM-based investigation, the Hygia Project, established in 2007 as a multicenter research network - currently comprised of 40 primary care facilities and 292 clinical investigators - designed to incorporate ABPM as routine procedure to diagnose and manage hypertension, assess efficacy of BP-lowering treatment, and evaluate patient CVD and other medical risks. Between 2008 and 2018, participating primary-care physicians - properly trained and certified in the proper application of ABPM and the conduct of procedures of the investigative protocol - referred in total 21,963 primary care patients for 48h ABPM annually, or more frequently when the ABP of treated hypertensive patients remained uncontrolled, i.e., ≥135/85 or ≥120/70 mmHg for, respectively, the awake and asleep SBP/DBP means and those having compelling clinical conditions of elevated CVD risk, including diabetes, CKD, and past major CVD event. During the median follow-up of 6.3 years, 1,830 individuals experienced the main CVD-outcome of CVD death, myocardial infarction, coronary revascularization, heart failure, ischemic stroke, or hemorrhagic stroke. Corroborating and extending previously reported findings - based upon an initial analysis of the data of the Hygia Project cohort of 18,078 individuals that had been recruited up to 2015 - Cox proportional-hazard analyses revealed the asleep SBP mean to be the most significant single BP marker of CVD risk, independent of absence/presence of hypertension therapy at baseline, upon-waking vs. at-bedtime treatment-time, diagnosis of influential morbidities of diabetes or CKD, age, and sex. The joint contribution with the asleep SBP mean to CVD risk was significant only for diminished sleep-time relative SBP decline but not for the wake-time OBPM or the awake or 24h ABP means, such that at any given asleep SBP level, non-dipper individuals showed significantly greater CVD risk than did dipper ones.

A blunted sleep-time BP decline, which is characteristic of the non-dipper/riser 24h BP pattern, is common in patients with CKD. Nonetheless, the reported prevalence of sleep-time hypertension and non-dipping in CKD in different studies is highly inconsistent and, thus, its exact prevalence and associated potential clinical relevance are uncertain. Among other factors, this might be due to differences in the studied populations (treated or untreated patients at differing stages of CKD), relatively small sample sizes, definition of awake and asleep periods by arbitrary fixed clock-hour spans, and frequent reliance only on a single, low-reproducible, 24h ABPM evaluation per participant. Moreover, most previous investigations have evaluated the 24h BP pattern of patients with CKD exclusive of proper comparison to those without CKD.