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Written by:
Omar Dodin, MD; Nephrology Fellow, University of Arkansas for Medical Sciences
Umair Ali, MBBS; Nephrology Fellow, University of Arkansas for Medical Sciences
Gerren Hobby, MD; Department of Nephrology, NEA Baptist Clinic
Corina Tedosiu MD; Nephrologist, Bucharest, Romania
Introduction
Hypertension is common in adults with a prevalence of approximately 45% of individuals 18 years of age or older in the United States. A multitude of mechanisms contribute to the development of hypertension, but since Guyton described pressure natriuresis more than 30 years ago, we have been exploring the relationship between sodium balance and blood pressure. Sodium homeostasis is now known to be closely related to blood pressure rhythms during the day and night. This is pertinent to our discussion since higher nocturnal blood pressures are associated with worse cardiovascular outcomes and accumulating evidence shows that sodium excretion is associated with nocturnal dipping. In healthy individuals, sodium excretion typically reaches a maximum during the day and its lowest at night. Conversely, patients with a non-dipping status tend to excrete relatively less sodium during the day which gives them a more flat sodium excretion curve during each 24h period. Although studied in the general population, the 24h blood pressure variation has not yet been characterized in reference to day/night variation in sodium excretion in CKD patients. The current study in Kidney International Reports addresses this research gap by studying the variation in blood pressure patterns in groups of CKD patients depending on their day-to-night ratio of sodium and potassium excretion. With this in mind, let’s dive into the pathophysiology of nocturnal BP dipping.
Pathophysiology
Blood pressure normally follows a dipping pattern during which blood pressure drops by 10-20% during the evening. The rhythm of blood pressure changes is generated endogenously by our circadian rhythm and has a stable pattern that persists even with forced dysyncrony of varying length “days'' or up to 38 hours of continuous wakefulness. This dipping pattern is controlled by the sympathetic nervous system and neurohumoral systems, but is ultimately mediated by heart rate and day-night variations in human activity levels. Interesting work has been published on day patterns of electrolyte excretion and show that diurnal potassium excretion is not affected by food intake or posture.
In a healthy individual, peripheral systemic resistance stays the same during the evening, but heart rate falls. This fall in heart rate lowers the blood pressure, causes a decrease in pressure natriuresis, and leads to a pattern of reduced sodium excretion during nighttime hours as compared to daytime hours. Occasionally though, this dipping pattern is lost, which is is associated with worse cardiovascular outcomes.
The mechanism for the loss in dipping pattern is not yet fully elucidated, although a number of factors seem to be at play. Glomerular filtration rate, urine outputs, and electrolytes excretion are well-known to have diurnal patterns and it’s likely that changes on these factors contribute to a blunted dipping pattern. Obvious factors like getting up to urinate at night have been speculated as a cause for higher nocturnal blood pressures, but other considerations like poor sleep quality and obstructive sleep apnea have also been implicated. Overall, a host of factors are at play, thereby disrupting the delicate rhythm and balance of daily blood pressure patterns.
Over the past several decades, the impact of renal sodium handling has come into focus. An interesting study from 1995 showed that the loss of a dipping status, commonly seen in CKD patients, was restored after kidney transplantation. Two studies, one by Bankir, et al as well as another study by Fujii, et al, showed that hypertensive patients on a high sodium diet with a non-dipper status tend to excrete sodium at a more steady rate during each 24h period compared to those with a dipping status. This change in night-day sodium excretion was shown to be partially ameliorated with a sodium restricted diet. These observations led to the conclusion that defects in renal sodium handling play a role in the loss of nocturnal dipping. The aforementioned studies show an association between electrolyte balance and nocturnal blood pressure, but a big question remains; is this phenomenon also true in the CKD population? This is particularly an important topic considering >80% of CKD patients display a non-dipping status. A 2007 paper showed that sodium and potassium excretion and urine flow rate were higher at nighttime than daytime in CKD patients, but did not relate their ambulatory blood pressure monitoring (ABPM) to dipping status. A 2020 study by Zhang, et al examined the relationship between BP and sodium excretion in CKD patients, but only utilized nocturnal clinic blood pressure rather than the ABPM. To date, no paper has studied the relationship of BP rhythm and sodium excretion patterns in CKD patients utilizing ABPM.
The Study
Design
This is an cross-sectional study of patients with CKD that assesses the relationship between blood pressure patterns and day/night variation in sodium and potassium excretion. The study was performed at a single hospital in China from 2018 until 2022.
Inclusion Criteria
Patients with CKD (defined as eGFR <60mL/min/1.73m2, or with evidence of kidney damage as defined by albuminuria or pathologic or structural abnormalities confirmed by kidney biopsy or imaging).
Exclusion Criteria
Age <14 years old
Dialysis
Kidney Transplantation
Acute medical condition within 6 months
Incomplete data of daytime or nighttime sodium or potassium excretion
Study Design
First, the patients were assessed for the presence of comorbidities such as diabetes mellitus, hyperlipidemia, and cardiovascular disease. Blood pressure was assessed via ambulatory blood pressure monitoring (ABPM) which recorded at intervals of 15 and 30 minutes during the daytime and nighttime, respectively. Separate urine collections were obtained for daytime and nighttime. Daytime and nighttime periods were personalized to each patient, but averaged 15 and 9 hours, respectively. Next, the participants were divided into groups based on their patterns of urinary sodium and potassium excretion. These groups were the quartiles, based on the day-to-night ratios of urinary sodium or potassium excretion. A ratio of <1.0, for example, indicates more sodium or potassium excretion during the night as compared to the day.
Quartile 1 (Q1): day-to-night excretion ≤ 1.0
Quartile 2 (Q2): day-to-night excretion 1.01-1.52
Quartile 3 (Q3): day-to-night excretion 1.53-2.52
Quartile 4 (Q4): day-to-night excretion > 2.52
As mentioned above, the normal pattern seen in healthy individuals is higher sodium and potassium excretion during the day as compared to night. These would be patients in quartile 4(Q4). Those in the lower quartile (Q1) have more sodium excretion during the night which has been associated with an attenuated dipping status. Said differently, Q4 is a more normal, healthy pattern of sodium handling and Q1 is a pattern traditionally seen in those with a non-dipping status. Lastly, the authors defined dippers as those with a nocturnal BP decline of ≥ 10%. Those with <10% decline in nocturnal BP were categorized as non-dippers. Those whose blood pressure actually rose during the evening were categorized as risers.
Results
In total, the analysis included 3152 patients with a mean age of 47 years. Of the participants, 57% were men. The patients were divided into quartiles of day-to-night sodium and potassium excretion.
On baseline characteristics, those in Q1 were more likely to be older, have a higher BMI, higher fasting blood glucose, higher percentage of diabetes mellitus, higher chance of CVD, higher albuminuria, higher number of antihypertensive agents, and have a lower eGFR as compared to those in Q4 (Table 1)
The authors then looked at the degree of blood pressure control via different methods of BP measurement according to quartiles (panels A and B of table 1, respectively). For all BP measurement methods, those in Q4 showed better BP control. As expected, participants were more likely to have a dipping pattern and less likely to be “risers” in Q4 compared to Q1 based on both sodium and potassium excretion (panels C and D, respectively).
The overall trend continues as those in Q4 were shown to have lower nighttime SBP and DBP as compared to those in Q1 even when analyzed for day-night ratios of sodium or potassium excretion (figure 2 and table 2) .
Next, the authors explored a multivariate analysis of clinical factors and BP trends amongst the different quartiles (table 3). Even after adjusting for demographic factors, lifestyles, and clinical variables (including DM, blood glucose, CVD, eGFR, antihypertensives, glucocorticoids, immunosuppressive agents, and 24h excretion of sodium and potassium), nighttime SBP and DBP were 6.89 mmHg and 4.25 mmHg higher in Q1 as compared to Q4, respectively. In addition, higher levels of dipping were seen in Q4 vs Q1.
Lastly, table 4 gives us some hard numbers on the urine volume during day and night urine collections as well as sodium and potassium excretion. Keep in mind that on average, the daytime urine collections were around 15h in length and nighttime collections were 9 hours. This makes it notable that in Q1, the nighttime sodium excretion was higher during the night than in the day even despite a much shorter collection time. The opposite is true for those in Q4 whose daytime urine flow rate was 65% higher and the urine sodium excretion was 20% higher as compared to those in Q1.
In sum, we see that those in Q1 exhibit increased nighttime blood pressure and sodium excretion as compared to daytime. Q4 showed the opposite pattern with more nocturnal dipping as well as a drop in sodium excretion.
Conclusion
This is the first study to evaluate the relationship of sodium and potassium excretion with blood pressure trends in CKD patients utilizing ambulatory blood pressure monitoring. A normal dipping pattern in this study was seen most predominantly in Q4 – those with the highest day/night ratio of sodium and potassium excretion. Conversely, those in Q1 excreted more sodium and potassium during the night. This pattern was associated with a 12 mmHg higher nocturnal SBP as compared to Q4. Even though multiple factors are postulated to contribute to higher nocturnal blood pressures, a higher nocturnal BP as well as blunted SBP dipping was observed when adjusting for multiple demographic factors, lifestyles, and clinical variables through a multivariate analysis.
This study adds to our knowledge of electrolyte balance and blood pressure in the CKD population. This study also supports the hypothesis that in those with diminished daytime sodium and potassium excretion, a higher nocturnal blood pressure is necessary to maintain sodium excretion. What remains to be studied is if particular antihypertensive regimens can restore a higher daytime electrolyte excretion and restore a dipping pattern and potentially improve cardiovascular outcomes. Be on the lookout for new studies in this area.
AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.