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The relationship between serum albumin levels and 24-h ambulatory blood pressure monitoring recordings in non-diabetic essential hypertensive patients

Abstract

OBJECTIVES:

The goal of this study was to evaluate the relationship between serum albumin levels and 24-hour ambulatory blood pressure monitoring (24-h ABPM) recordings in non-diabetic essential hypertensive patients.

METHODS:

A total of 354 patients (mean [SD] age: 55.5 [14.3] years, 50% females) with essential hypertension and 24-h ABPM recordings were included. Patient 24-h nighttime and daytime ABPM values, systolic and diastolic dipping status and average nocturnal dipping were recorded. The correlations between serum albumin levels and nocturnal systolic and diastolic dipping were evaluated, and correlates of average nocturnal systolic dipping were determined via a linear regression model.

RESULTS:

Overall, 73.2% of patients were determined to be non-dippers. The mean (SD) levels of serum albumin (4.2 [0.3] g/dL vs. 4.4 [0.4] g/dL, p<0.001) and the average nocturnal systolic (15.2 [4.8] mmHg vs. 0.3 [6.6] mmHg, p<0.001) and diastolic dipping (4.2 [8.6] mmHg vs. 18.9 [7.0] mmHg, p<0.001) were significantly lower in non-dippers than in dippers. A significant positive correlation was noted between serum albumin levels and both systolic (r=0.297, p<0.001) and diastolic dipping (r=0.265, p<0.001). The linear regression analysis revealed that for each one-unit increase in serum albumin, the average nocturnal dip in systolic BP increased by 0.17 mmHg (p=0.033).

CONCLUSION:

Our findings indicate an association between serum albumin levels and the deterioration of circadian BP rhythm among essential hypertensive patients along with the identification of a non-dipper pattern in more than two-thirds of patients. Our findings emphasize the importance of serum albumin levels, rather than urinary albumin excretion, as an independent predictor of nocturnal systolic dipping, at least in non-diabetic essential hypertensive patients with moderate proteinuria.

Hypertension; Serum Albumin; Ambulatory Blood Pressure; Dipping Status; Nocturnal Blood Pressure


INTRODUCTION

Deterioration of the circadian blood pressure (BP) rhythm, particularly a non-dipper circadian BP pattern, represents a risk factor for target organ damage and worsening of cardiovascular and renal parameters in patients with essential hypertension (11. Verdecchia P, Schillaci G, Reboldi G, Franklin SS, Porcellati C. Different prognostic impact of 24-hour mean blood pressure and pulse pressure on stroke and coronary artery disease in essential hypertension. Circulation. 2001;103(21):2579-84, http://dx.doi.org/10.1161/01.CIR.103.21.2579.
http://dx.doi.org/10.1161/01.CIR.103.21....
,22. Hermida RC, Ayala DE, Portaluppi F. Circadian variation of blood pressure: the basis for the chronotherapy of hypertension. Adv Drug Deliv Rev. 2007;59(9-10):904-22, http://dx.doi.org/10.1016/j.addr.2006.08.003.
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).

Ambulatory BP monitoring (ABPM), which provides data regarding changes in BP during daily activities (33. Urbina E, Alpert B, Flynn J, Hayman L, Harshfield GA, Jacobson M, et al. Ambulatory BP monitoring in children and adolescents: Recommendations for standard assessment: A scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee of the Council on Cardiovascular Disease in the Young and the Council for High BP Research. Hypertension. 2008;52(3):433-51, http://dx.doi.org/10.1161/HYPERTENSIONAHA.108.190329.
http://dx.doi.org/10.1161/HYPERTENSIONAH...
), has been considered superior to office measurements of BP because ABPM identifies nocturnal declines in BP levels and has higher consistency with target organ damage, thus predicting cardiovascular morbidity and mortality (44. Metoki H, Ohkubo T, Kikuya M, Asayama K, Obasa T, Hara A, et al. Prognostic significance of night-time, early morning, and daytime blood pressures on the risk of cerebrovascular and cardiovascular mortality: The Ohasama Study. J Hypertension. 2006;24(9):1841-8, http://dx.doi.org/10.1097/01.hjh.0000242409.65783.fb.
http://dx.doi.org/10.1097/01.hjh.0000242...
5. Staessen JA, Thijs L, Fagard R, O’Brien ET, Clement D, de Leeuw PW, et al. Predicting cardiovascular risk using conventional vs ambulatory blood pressure in older patients with systolic hypertension. Systolic Hypertension in Europe Trial Investigators. JAMA. 1999;282(6):539-46, http://dx.doi.org/10.1001/jama.282.6.539.
http://dx.doi.org/10.1001/jama.282.6.539...
6. Pickering TG. The clinical significance of diurnal blood pressure variation: Dippers and nondippers. Circulation. 1990;81(2):700-2, http://dx.doi.org/10.1161/01.CIR.81.2.700.
http://dx.doi.org/10.1161/01.CIR.81.2.70...
7. Verdecchia P, Porcellati C, Schillaci G, Borgioni C, Ciucci A, Battistelli M, et al. Ambulatory blood pressure: an independent predictor of prognosis in essential hypertension. Hypertension 1994;24(6):793-801, http://dx.doi.org/10.1161/01.HYP.24.6.793.
http://dx.doi.org/10.1161/01.HYP.24.6.79...
-88. Pickering TG. Ambulatory blood pressure monitoring in clinical practice. Clin Cardiol. 1991;14(7):557-562.).

The limited amount of available data regarding the association between serum albumin levels and circadian BP rhythm indicates a correlation between less BP dipping and low serum albumin levels among the elderly (99. Yasuda G, Shibata K, Hirawa N, Saka S, Iwamoto T. Relationship between serum albumin levels, as a biomarker of nutritional status, and nocturnal decline of blood pressure in elderly patients. Clin Nutr. 2013;32(Supplement 1):S167, http://dx.doi.org/10.1016/S0261-5614(13)60431-8.
http://dx.doi.org/10.1016/S0261-5614(13)...
), hemodialysis patients (1010. Tekçe H, Kürşat S, Bahadır Çolak H, Aktaş G. Effects of nutritional parameters on nocturnal blood pressure in patients undergoing hemodialysis. Ren Fail. 2013;35(7):946-50, http://dx.doi.org/10.3109/0886022X.2013.808144.
http://dx.doi.org/10.3109/0886022X.2013....
), patients with chronic kidney disease (CKD) (1111. Agarwal R, Andersen MJ. Correlates of systolic hypertension in patients with chronic kidney disease. Hypertension. 2005;46(3):514-20, http://dx.doi.org/10.1161/01.HYP.0000178102.85718.66.
http://dx.doi.org/10.1161/01.HYP.0000178...
,1212. Yasuda G, Yamamoto Y, Saka S, Hirawa N. Serum albumin levels, as a biomarker of nutritional Status, influence nocturnal decline of blood Pressure in diabetic patients with chronic kidney Disease (CKD). Clin Nutr. 2014;33(Supplement 1):S66, http://dx.doi.org/10.1016/S0261-5614(14)50166-5.
http://dx.doi.org/10.1016/S0261-5614(14)...
) and hypertensive-naïve or nephrotic, non-diabetic patients (1313. Ando D, Hirawa N, Yasuda G. Hypoalbuminemia and hyperalbuminuria as major factors regulating circadian blood pressure rhythm in normal subjects and non-diabetic patients with early stages of chronic kidney disease. J Hypertens. 2014;3:142, http://dx.doi.org/10.4172/2167-1095.1000142.
http://dx.doi.org/10.4172/2167-1095.1000...
). Notably, the sodium retention and high sodium sensitivity caused by impaired daytime natriuresis have been shown to be associated with a loss of nocturnal decline in BP among patients with essential hypertension to provide compensatory pressure natriuresis during the nighttime (1414. Andoh D, Kobayashi M, Yasuda G, Hirawa N, Saka S, Yatsu K, et al. Loss of nocturnal decline of blood pressure in non-diabetic patients with nephrotic syndrome in the early and middle stages of chronic kidney disease. Hypertens Res. 2009;32(5):364-8, http://dx.doi.org/10.1038/hr.2009.21.
http://dx.doi.org/10.1038/hr.2009.21...
15. Uzu T, Frida KS, Ishikawa K, Nakamura S, Inenaga T, Kimura G. High sodium sensitivity implicates nocturnal hypertension in essential hypertension. Hypertension. 1996;28(1):139-42, http://dx.doi.org/10.1161/01.HYP.28.1.139.
http://dx.doi.org/10.1161/01.HYP.28.1.13...
16. Fujii T, Uzu T, Nishimura M, Takeji M, Kuroda S, Nakamura S, et al. Circadian rhythm of natriuresis is disturbed in non-dipper type of essential hypertension. Am J Kidney Dis. 1999;33(1):29-35, http://dx.doi.org/10.1016/S0272-6386(99)70254-4.
http://dx.doi.org/10.1016/S0272-6386(99)...
-1717. Fukuda M, Munemura M, Usami T, Nakao N, Takeuchi O, Kamiya Y, et al. Nocturnal blood pressure is elevated with natriuresis and proteinuria as renal function deteriorates in nephropathy. Kidney Int. 2004;65(2):621-5, http://dx.doi.org/10.1111/j.1523-1755.2004.00419.x.
http://dx.doi.org/10.1111/j.1523-1755.20...
). Moreover, the mechanism underlying the relationship between serum albumin and nighttime BP decline, the crucial predictor of cardiovascular events through vascular atherosclerosis, has not yet been elucidated (99. Yasuda G, Shibata K, Hirawa N, Saka S, Iwamoto T. Relationship between serum albumin levels, as a biomarker of nutritional status, and nocturnal decline of blood pressure in elderly patients. Clin Nutr. 2013;32(Supplement 1):S167, http://dx.doi.org/10.1016/S0261-5614(13)60431-8.
http://dx.doi.org/10.1016/S0261-5614(13)...
).

Similarly, although numerous recent studies have focused on the relationship between urinary albumin excretion (UAE) and the loss of nocturnal BP decline, which are two notable risk markers of cardiovascular mortality and morbidity as well as end-stage CKD in hypertensive patients (1313. Ando D, Hirawa N, Yasuda G. Hypoalbuminemia and hyperalbuminuria as major factors regulating circadian blood pressure rhythm in normal subjects and non-diabetic patients with early stages of chronic kidney disease. J Hypertens. 2014;3:142, http://dx.doi.org/10.4172/2167-1095.1000142.
http://dx.doi.org/10.4172/2167-1095.1000...
,1818. Bianchi S, Bigazzi R, Baldari G, Sgherri G, Campese VM. Diurnal variations of blood pressure and microalbuminuria in essential hypertension. Am J Hypertens. 1994;7(1):23-9, http://dx.doi.org/10.1093/ajh/7.1.23.
http://dx.doi.org/10.1093/ajh/7.1.23...
,1919. Kohara K, Nishida W, Maguchi M, Hiwada K. Autonomic nervous function in non-dipper essential hypertensive subjects. Evaluation by power spectral analysis of heart rate variability. Hypertension. 1995;26(5):808-14, http://dx.doi.org/10.1161/01.HYP.26.5.808.
http://dx.doi.org/10.1161/01.HYP.26.5.80...
), it remains unclear whether albuminuria is a cause or a consequence of impaired circadian BP rhythm (1313. Ando D, Hirawa N, Yasuda G. Hypoalbuminemia and hyperalbuminuria as major factors regulating circadian blood pressure rhythm in normal subjects and non-diabetic patients with early stages of chronic kidney disease. J Hypertens. 2014;3:142, http://dx.doi.org/10.4172/2167-1095.1000142.
http://dx.doi.org/10.4172/2167-1095.1000...
).

Moreover, given the inverse relationship between serum and urinary albumin levels, the presence of albuminuria concomitant with a loss of nighttime BP decline has been found to inevitably cause hypoalbuminemia in patients with non-diabetic nephropathy or glomerulonephritis (1313. Ando D, Hirawa N, Yasuda G. Hypoalbuminemia and hyperalbuminuria as major factors regulating circadian blood pressure rhythm in normal subjects and non-diabetic patients with early stages of chronic kidney disease. J Hypertens. 2014;3:142, http://dx.doi.org/10.4172/2167-1095.1000142.
http://dx.doi.org/10.4172/2167-1095.1000...
). Therefore, the present study was designed to evaluate the relationship between serum albumin levels and 24-h ABPM recordings in non-diabetic essential hypertensive patients.

MATERIALS AND METHODS

Study population

This retrospective single-center study included 354 patients (mean [SD] age: 55.5 [14.3] years, 50% females) with a diagnosis of essential hypertension who received follow-up care, including 24-h ABPM recordings, at our clinic between 2013 and 2015. The patients were divided into 4 groups based on serum albumin levels: quartile 1 (Q1; serum albumin <4.1 g/dL), quartile 2 (Q2; serum albumin ≥4.1<4.4 g/dL), quartile 3 (Q3; serum albumin ≥4.4<4.6 g/dL) and quartile 4 (Q4; serum albumin ≥4.6 g/dL).

Patients with thyroid function disorders, secondary hypertension, diabetes mellitus, chronic liver disease, acute infection or sleep disorders were excluded from the study.

The study was conducted in full accordance with local Good Clinical Practice (GCP) Guidelines and current legislation, and permission for the use of patient data for publication purposes was obtained from our institutional ethics committee.

Study parameters

Data regarding patient demographics, body mass index (BMI; kg/m2), antihypertensive medication history, urinalysis (proteinuria [gr/24 h]) and blood biochemistry findings (urea [mg/dL]; creatinine [mg/dL]; e-GFR [mL/min], uric acid [mg/dL], sodium [mmol/L], potassium [mmol/L], calcium [mg/dL], phosphorus [mg/dL], CaxP product, intact parathormone [PTH; pg/mL], hemoglobin [g/dL], total cholesterol [mg/dL], triglycerides [mg/dL], low-density lipoprotein cholesterol [LDL-c; mg/dL], high-density lipoprotein cholesterol [HDL-c; mg/dL], albumin [g/dL] and ferritin [ng/mL]) were obtained from the medical records of each patient. The 24-h, nighttime and daytime ABPM values of systolic and diastolic BP; systolic and diastolic dipping status (% of dippers and non-dippers); and average amount of nocturnal dipping were recorded in all patients. Blood biochemistry findings, BMI and antihypertensive treatment were evaluated with respect to dipping status (dippers vs. non-dippers), whereas 24-h ABPM recording and average nocturnal dipping were evaluated with respect to quartiles of serum albumin levels (Q1-4) and dipping status. The correlation between serum albumin levels and nocturnal systolic and diastolic dipping was evaluated, and correlates of average nocturnal systolic dipping were determined via a linear regression model with age; serum levels of albumin, creatinine and hemoglobin; and 24-h urinary protein levels as the variables.

Serum albumin levels were measured with an ECLIA test performed using a Cobas E601 analyzer (Roche Diagnostics, MA, USA).

ABPM recordings

A portable noninvasive recording device (Model 90217A-1, Spacelabs, Hertford, United Kingdom) was used to record 24-h ABPM values. All patients were graded according to overall, nighttime and daytime systolic and diastolic BP levels. The 24-h ABPM values were obtained via BP readings set at 20-minute intervals (06:00 AM – 24:00 PM) and at 30-minute intervals (24:00 PM – 06:00 AM). The patients were asked to continue with their normal daily routine and to record the times at which they went to sleep and awakened. The data were transferred to a computer and loaded into ABPM report management system software for the final analysis using the ABPM-FIT program (University of Heidelberg, Germany, version 2.2). For each 24-h measurement, the mean systolic and diastolic BP levels were evaluated separately for the daytime and nighttime periods. Daytime and nighttime arterial hypertension were diagnosed according to the ESH/ESC guidelines (2020. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M, et al. 2013 ESH/ESC Practice Guidelines for the Management of Arterial Hypertension. Blood Press. 2014;23(1):3-16, http://dx.doi.org/10.3109/08037051.2014.868629.
http://dx.doi.org/10.3109/08037051.2014....
) (daytime: systolic BP ≥140 mmHg and/or diastolic BP ≥90 mmHg; nighttime: systolic BP >120 mmHg and diastolic BP >70 mmHg). The non-dominant arm was the site of cuff placement for ABPM. The ambulatory monitor had to agree with a mercury column sphygmomanometer to within 7 mmHg, and patients with failure of ≥25% of BP recordings on a daily basis were not included in the final analysis.

Definitions of dippers and non-dippers

Time in bed was measured based on a diary maintained by the patients that documented the exact times of getting into and arising from bed. The average BP for the time in bed (termed nighttime BP) was calculated from the ambulatory monitoring data. The daytime BP was defined as the BP during the remainder of the 24-h period. The percentage decline in the nighttime BP was calculated as follows: 100 X (1 - mean nighttime systolic BP / mean daytime systolic BP). Patients with a decline in nighttime BP of less than 10% were considered non-dippers (77. Verdecchia P, Porcellati C, Schillaci G, Borgioni C, Ciucci A, Battistelli M, et al. Ambulatory blood pressure: an independent predictor of prognosis in essential hypertension. Hypertension 1994;24(6):793-801, http://dx.doi.org/10.1161/01.HYP.24.6.793.
http://dx.doi.org/10.1161/01.HYP.24.6.79...
).

Statistical analysis

The statistical analysis was performed using IBM SPSS Statistics (IBM Corp. Released 2012, IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp). A Chi-square (χ2) test was used for comparisons of categorical data. Student’s t-test was used for the analysis of parametric variables. Comparisons of albumin quartile groups were performed via one-way ANOVA. Spearman’s correlation analysis was performed to determine the relationship between serum albumin levels and dipping status, and correlates of average nocturnal systolic dipping were determined via a linear regression model with age; serum levels of albumin, creatinine and hemoglobin; and 24-h urinary protein levels as the variables. The data were expressed as the means (SD), percentages (%) and 95% confidence intervals (CIs), as appropriate. P<0.05 was considered statistically significant.

RESULTS

Baseline characteristics and 24-h ABPM recordings in dippers vs. non-dippers

Among the 354 patients, 95 (26.8%) were determined to be dippers, and 259 (73.2%) were non-dippers. No significant differences were noted between the dippers and non-dippers in terms of patient characteristics, BMI, antihypertensive medication or overall 24-h or daytime systolic and diastolic ABPM recordings. Compared with dippers, the non-dippers had significantly higher mean (SD) nighttime systolic (152.3 [23.9] mmHg vs. 130.8 [17.6] mmHg, p<0.001) and diastolic BP (82.3 [15.9] mmHg vs. 71.8 [11.7] mmHg, p<0.001), whereas they had significantly lower average nocturnal systolic (0.3 [6.6] mmHg vs. 15.2 [4.8] mmHg, p<0.001) and diastolic dipping (4.2 [8.6] mmHg vs. 18.9 [7.0] mmHg, p<0.001) (Table 1).

Table 1
Baseline characteristics and 24-h ambulatory blood pressure monitoring recordings in dippers vs. non-dippers.

Compared with dippers, the non-dippers had significantly lower mean (SD) serum albumin levels (4.2 [0.3]vs. 4.4 [0.4] g/dL, p<0.001); otherwise, the two groups had similar laboratory results, including proteinuria (Table 2).

Table 2
Laboratory findings in dipper and non-dipper patients.

24-h ABPM recordings according to quartiles of serum albumin levels

The serum albumin quartiles Q1, Q2, Q3 and Q4 included 71 (20.1%), 100 (28.2%), 78 (22.0%) and 105 (29.7%) patients, respectively. Compared to the patients in Q1, the ABPM recordings of the other groups revealed significantly lower values as follows: mean (SD) 24-h systolic BP in Q2 (157.8 [19.0] mmHg vs. 148.7 [19.6] mmHg, p<0.005) and Q4 (157.8 [19.0] mmHg vs. 149.6 [20.0] mmHg, p<0.05); 24-h diastolic BP in Q2 (89.1 [15.2] mmHg vs. 81.6 [11.5], p<0.01); daytime diastolic BP in Q2 (89.8 [15.1] mmHg vs. 83.3 [12.0] mmHg, p<0.05); nighttime systolic BP in Q2, Q3 and Q4 (158.6 [23.1] mmHg vs. 143.8 [22.5] mmHg, 145.7 [27.9] mmHg and 141.3 [21.6] mmHg, respectively; p<0.001 for each); and nighttime diastolic BP in Q2, Q3 and Q4 (87.0 [17.5] mmHg vs. 76.0 [12.1] mmHg, 78.6 [16.4] mmHg and 78.3 [15.0] mmHg, respectively; p<0.001 for each) (Table 3).

Table 3
24-h Ambulatory blood pressure monitoring recordings according to quartiles of serum albumin levels.

Average nocturnal systolic and diastolic dipping according to quartiles of serum albumin levels

Compared with the patients in serum albumin quartile Q1, the patients in Q3 and Q4 had significantly higher mean (SD) nocturnal systolic dipping (-0.36 [8.42] mmHg vs. 4.79 [9.89] mmHg and 7.16 [8.78] mmHg, respectively; p<0.001 for each), and the patients in Q4 had significantly higher nocturnal diastolic dipping (3.48 [10.32] mmHg vs. 11.14 [10.25] mmHg, p<0.01) (Table 4, Figure 1).

Table 4
Average nocturnal systolic and diastolic dipping according to quartiles of serum albumin levels.
Figure 1
Average nocturnal dipping according to quartiles of serum albumin levels.

Q1: serum albumin <4.1 g/dL; Q2: serum albumin ≥4.1<4.4 g/dL; Q3: serum albumin ≥4.4<4.6 g/dL; Q4: serum albumin ≥4.6 g/dL.


Correlation between serum albumin levels and nocturnal dipping

Significant positive correlations were noted between serum albumin levels and both systolic (r=0.297, p<0.001) and diastolic dipping (r=0.265, p<0.001) (Table 5 andFigure 2).

Table 5
Correlations between serum albumin levels and nocturnal dipping.
Figure 2
Receiver operating characteristic-curve analysis for sensitivity, specificity and cut-off values of the relationship between serum albumin levels and systolic dipping.

Linear regression analysis of correlates of average nocturnal systolic dipping

The linear regression analysis revealed that for each one-unit increase in serum albumin, the average nocturnal dip in systolic BP increased by 0.17 mmHg (p=0.033), even after adjustments for age, serum creatinine, serum hemoglobin and 24-h urinary protein levels (Table 6).

Table 6
Linear regression analysis of correlates of average nocturnal systolic dipping.

DISCUSSION

Our findings in a retrospective cohort of essential hypertensive patients revealed lower serum albumin levels in non-dippers than dippers. Moreover, lower average nocturnal dipping and thus higher nocturnal systolic and diastolic ABPM values were observed in patients with lower (<4.1 g/dL) serum albumin levels. Along with the positive correlation between albumin levels and average nocturnal systolic and diastolic dipping, a decrease in serum albumin was shown to be an independent predictor of lower average nocturnal systolic dipping.

The association between serum albumin levels and the loss of nocturnal BP decline has been reported in several studies of elderly patients (99. Yasuda G, Shibata K, Hirawa N, Saka S, Iwamoto T. Relationship between serum albumin levels, as a biomarker of nutritional status, and nocturnal decline of blood pressure in elderly patients. Clin Nutr. 2013;32(Supplement 1):S167, http://dx.doi.org/10.1016/S0261-5614(13)60431-8.
http://dx.doi.org/10.1016/S0261-5614(13)...
), hemodialysis patients (1010. Tekçe H, Kürşat S, Bahadır Çolak H, Aktaş G. Effects of nutritional parameters on nocturnal blood pressure in patients undergoing hemodialysis. Ren Fail. 2013;35(7):946-50, http://dx.doi.org/10.3109/0886022X.2013.808144.
http://dx.doi.org/10.3109/0886022X.2013....
), patients with CKD (1111. Agarwal R, Andersen MJ. Correlates of systolic hypertension in patients with chronic kidney disease. Hypertension. 2005;46(3):514-20, http://dx.doi.org/10.1161/01.HYP.0000178102.85718.66.
http://dx.doi.org/10.1161/01.HYP.0000178...
,1212. Yasuda G, Yamamoto Y, Saka S, Hirawa N. Serum albumin levels, as a biomarker of nutritional Status, influence nocturnal decline of blood Pressure in diabetic patients with chronic kidney Disease (CKD). Clin Nutr. 2014;33(Supplement 1):S66, http://dx.doi.org/10.1016/S0261-5614(14)50166-5.
http://dx.doi.org/10.1016/S0261-5614(14)...
) and hypertensive-naïve or nephrotic non-diabetic patients (1313. Ando D, Hirawa N, Yasuda G. Hypoalbuminemia and hyperalbuminuria as major factors regulating circadian blood pressure rhythm in normal subjects and non-diabetic patients with early stages of chronic kidney disease. J Hypertens. 2014;3:142, http://dx.doi.org/10.4172/2167-1095.1000142.
http://dx.doi.org/10.4172/2167-1095.1000...
).

A previous study of the effects of nutritional parameters on nocturnal BP in Turkish hemodialysis patients revealed an association between malnutrition and deterioration in the circadian BP rhythm (1010. Tekçe H, Kürşat S, Bahadır Çolak H, Aktaş G. Effects of nutritional parameters on nocturnal blood pressure in patients undergoing hemodialysis. Ren Fail. 2013;35(7):946-50, http://dx.doi.org/10.3109/0886022X.2013.808144.
http://dx.doi.org/10.3109/0886022X.2013....
). The malnutrition score was positively correlated with nighttime systolic BP, mean nighttime BP and mean 24-h arterial BP as well as with reductions in serum albumin and anthropometric indices (1010. Tekçe H, Kürşat S, Bahadır Çolak H, Aktaş G. Effects of nutritional parameters on nocturnal blood pressure in patients undergoing hemodialysis. Ren Fail. 2013;35(7):946-50, http://dx.doi.org/10.3109/0886022X.2013.808144.
http://dx.doi.org/10.3109/0886022X.2013....
). Therefore, low serum albumin levels and hypervolemia have been suggested to contribute to the association between impaired nutritional status and elevated nighttime BP (1010. Tekçe H, Kürşat S, Bahadır Çolak H, Aktaş G. Effects of nutritional parameters on nocturnal blood pressure in patients undergoing hemodialysis. Ren Fail. 2013;35(7):946-50, http://dx.doi.org/10.3109/0886022X.2013.808144.
http://dx.doi.org/10.3109/0886022X.2013....
).

In another study of 778 subjects including hypertensive naïve non-diabetic subjects (n=231), subjects without proteinuria (n=441) and non-diabetic nephrotic patients (n=37), nighttime BP decline was found to be associated with marked changes in both urinary and serum albumin levels (1313. Ando D, Hirawa N, Yasuda G. Hypoalbuminemia and hyperalbuminuria as major factors regulating circadian blood pressure rhythm in normal subjects and non-diabetic patients with early stages of chronic kidney disease. J Hypertens. 2014;3:142, http://dx.doi.org/10.4172/2167-1095.1000142.
http://dx.doi.org/10.4172/2167-1095.1000...
).

In our study population, non-dipping status was associated with significantly lower serum albumin compared with dipping status and low albumin levels predicted lower average nocturnal systolic dipping. However, no significant correlation was noted between the amount of proteinuria and dipping status and moderate proteinuria was evident in both dipper and non-dipper hypertensive patients.

Serum albumin has been reported to be an independent predictor of loss of nocturnal BP decline even in subjects with no albuminuria or dipstick-positive proteinuria (1313. Ando D, Hirawa N, Yasuda G. Hypoalbuminemia and hyperalbuminuria as major factors regulating circadian blood pressure rhythm in normal subjects and non-diabetic patients with early stages of chronic kidney disease. J Hypertens. 2014;3:142, http://dx.doi.org/10.4172/2167-1095.1000142.
http://dx.doi.org/10.4172/2167-1095.1000...
). In non-diabetic subjects, a significant loss of nighttime BP decline preceding the emergence of massive albuminuria and hypoalbuminemia was normalized following the correction of hyperalbuminuria and hypoalbuminemia (1313. Ando D, Hirawa N, Yasuda G. Hypoalbuminemia and hyperalbuminuria as major factors regulating circadian blood pressure rhythm in normal subjects and non-diabetic patients with early stages of chronic kidney disease. J Hypertens. 2014;3:142, http://dx.doi.org/10.4172/2167-1095.1000142.
http://dx.doi.org/10.4172/2167-1095.1000...
).

Given that hyperalbuminuria and hypoalbuminemia are inseparable and usually coexisting conditions, it has been considered difficult to evaluate the relationship between serum albumin levels and circadian BP patterns without considering albuminuria (1313. Ando D, Hirawa N, Yasuda G. Hypoalbuminemia and hyperalbuminuria as major factors regulating circadian blood pressure rhythm in normal subjects and non-diabetic patients with early stages of chronic kidney disease. J Hypertens. 2014;3:142, http://dx.doi.org/10.4172/2167-1095.1000142.
http://dx.doi.org/10.4172/2167-1095.1000...
). Our findings indicate that serum albumin levels, rather than albuminuria, are a significant determinant of nighttime BP decline, at least among non-diabetic essential hypertensive patients with moderate proteinuria. Similarly, an increase in serum albumin to >3 g/dL was reported to be associated with a significant decrease in sleeping/waking mean BP in non-diabetic nephrotic patients, whereas lowering urinary albumin/creatinine to <300 mg/g was shown to be ineffective (1313. Ando D, Hirawa N, Yasuda G. Hypoalbuminemia and hyperalbuminuria as major factors regulating circadian blood pressure rhythm in normal subjects and non-diabetic patients with early stages of chronic kidney disease. J Hypertens. 2014;3:142, http://dx.doi.org/10.4172/2167-1095.1000142.
http://dx.doi.org/10.4172/2167-1095.1000...
).

Notably, a disrupted 24-h BP rhythm has been suggested to precede microalbuminuria, whereas it is considered unlikely that microalbuminuria predisposes a patient to pathophysiological alterations that lead to a loss of nocturnal BP decline per se (1313. Ando D, Hirawa N, Yasuda G. Hypoalbuminemia and hyperalbuminuria as major factors regulating circadian blood pressure rhythm in normal subjects and non-diabetic patients with early stages of chronic kidney disease. J Hypertens. 2014;3:142, http://dx.doi.org/10.4172/2167-1095.1000142.
http://dx.doi.org/10.4172/2167-1095.1000...
). These findings imply a potential impact of a greater burden of long-term traditional cardiovascular risk factors, at least in non-diabetic hypertensive patients (1313. Ando D, Hirawa N, Yasuda G. Hypoalbuminemia and hyperalbuminuria as major factors regulating circadian blood pressure rhythm in normal subjects and non-diabetic patients with early stages of chronic kidney disease. J Hypertens. 2014;3:142, http://dx.doi.org/10.4172/2167-1095.1000142.
http://dx.doi.org/10.4172/2167-1095.1000...
).

In fact, a non-dipper circadian BP pattern was shown to be associated with subsequent microalbuminuria (22. Hermida RC, Ayala DE, Portaluppi F. Circadian variation of blood pressure: the basis for the chronotherapy of hypertension. Adv Drug Deliv Rev. 2007;59(9-10):904-22, http://dx.doi.org/10.1016/j.addr.2006.08.003.
http://dx.doi.org/10.1016/j.addr.2006.08...
,2121. Afsar B, Elsurer R. Urinary albumin excretion among nondipper hypertensive patients is closely related with the pattern of nondipping. J Am Soc Hypertens. 2010;4(4):196-202, http://dx.doi.org/10.1016/j.jash.2010.06.004.
http://dx.doi.org/10.1016/j.jash.2010.06...
), which is a well-recognized marker of adverse cardiovascular outcomes in hypertensive subjects (2222. Basi S, Lewis JB. Microalbuminuria as a target to improve cardiovascular and renal outcomes. Am J Kidney Dis. 2006;47(6):927-946, http://dx.doi.org/10.1053/j.ajkd.2006.02.182.
http://dx.doi.org/10.1053/j.ajkd.2006.02...
,2323. Jensen JS, Feldt-Rasmussen B, Strandgaard S, Schroll M, Borch-Johnsen K. Arterial hypertension, microalbuminuria, and risk of ischemic heart disease. Hypertension. 2000;35(4):898-903, http://dx.doi.org/10.1161/01.HYP.35.4.898.
http://dx.doi.org/10.1161/01.HYP.35.4.89...
). Moreover, a close relationship between a diurnal rhythm of BP and albumin excretion has been suggested in patients with essential hypertension (2121. Afsar B, Elsurer R. Urinary albumin excretion among nondipper hypertensive patients is closely related with the pattern of nondipping. J Am Soc Hypertens. 2010;4(4):196-202, http://dx.doi.org/10.1016/j.jash.2010.06.004.
http://dx.doi.org/10.1016/j.jash.2010.06...
).

Sodium retention and high sodium sensitivity were reported to cause a loss of nocturnal BP decline among patients with essential hypertension (1515. Uzu T, Frida KS, Ishikawa K, Nakamura S, Inenaga T, Kimura G. High sodium sensitivity implicates nocturnal hypertension in essential hypertension. Hypertension. 1996;28(1):139-42, http://dx.doi.org/10.1161/01.HYP.28.1.139.
http://dx.doi.org/10.1161/01.HYP.28.1.13...
,1616. Fujii T, Uzu T, Nishimura M, Takeji M, Kuroda S, Nakamura S, et al. Circadian rhythm of natriuresis is disturbed in non-dipper type of essential hypertension. Am J Kidney Dis. 1999;33(1):29-35, http://dx.doi.org/10.1016/S0272-6386(99)70254-4.
http://dx.doi.org/10.1016/S0272-6386(99)...
). Impaired daytime natriuresis has been suggested to be associated with elevations in nocturnal BP to facilitate pressure natriuresis and thus to compensate for the diminished natriuresis during the day (1414. Andoh D, Kobayashi M, Yasuda G, Hirawa N, Saka S, Yatsu K, et al. Loss of nocturnal decline of blood pressure in non-diabetic patients with nephrotic syndrome in the early and middle stages of chronic kidney disease. Hypertens Res. 2009;32(5):364-8, http://dx.doi.org/10.1038/hr.2009.21.
http://dx.doi.org/10.1038/hr.2009.21...
,1616. Fujii T, Uzu T, Nishimura M, Takeji M, Kuroda S, Nakamura S, et al. Circadian rhythm of natriuresis is disturbed in non-dipper type of essential hypertension. Am J Kidney Dis. 1999;33(1):29-35, http://dx.doi.org/10.1016/S0272-6386(99)70254-4.
http://dx.doi.org/10.1016/S0272-6386(99)...
,1717. Fukuda M, Munemura M, Usami T, Nakao N, Takeuchi O, Kamiya Y, et al. Nocturnal blood pressure is elevated with natriuresis and proteinuria as renal function deteriorates in nephropathy. Kidney Int. 2004;65(2):621-5, http://dx.doi.org/10.1111/j.1523-1755.2004.00419.x.
http://dx.doi.org/10.1111/j.1523-1755.20...
). In this regard, given the association between hypoalbuminemia and low plasma oncotic pressure and shifting of sodium and fluid from the intravascular circulation to the extravascular space (1414. Andoh D, Kobayashi M, Yasuda G, Hirawa N, Saka S, Yatsu K, et al. Loss of nocturnal decline of blood pressure in non-diabetic patients with nephrotic syndrome in the early and middle stages of chronic kidney disease. Hypertens Res. 2009;32(5):364-8, http://dx.doi.org/10.1038/hr.2009.21.
http://dx.doi.org/10.1038/hr.2009.21...
), the lower serum albumin levels among non-dipper compared with dipper patients in our study might also be associated with compensatory natriuresis.

However, although 73.0% of the hypertensive patients in our cohort were non-dippers, moderate proteinuria was evident regardless of dipping status.

Nonetheless, it should be noted that a debate continues regarding the common pathogenic mechanisms between UAE and circadian BP, with inconsistent findings regarding the role of a non-dipping pattern in the appearance of unfavorable UAE and regarding the value of absolute BP levels or dipping/non-dipping status in predicting UAE (2121. Afsar B, Elsurer R. Urinary albumin excretion among nondipper hypertensive patients is closely related with the pattern of nondipping. J Am Soc Hypertens. 2010;4(4):196-202, http://dx.doi.org/10.1016/j.jash.2010.06.004.
http://dx.doi.org/10.1016/j.jash.2010.06...
).

As an independent predictor of diabetic nephropathy and impaired renal function (2424. Yokoyama H, Tomonaga O, Hirayama M, Ishii A, Takeda M, Babazono T, Ujihara U, et al. Predictors of the progression of diabetic nephropathy and the beneficial effect of angiotensin-converting enzyme inhibitors in NIDDM patients. Diabetologia. 1997;40(4):405-11, http://dx.doi.org/10.1007/s001250050694.
http://dx.doi.org/10.1007/s001250050694...
) and an indicator of inflammatory process of atherogenesis via its negative correlation with C-reactive protein levels (2525. Zimmermann J, Herrlinger S, Pruy A, Metzger T, Wanner C. Inflammation enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int. 1999;55(2):648-58, http://dx.doi.org/10.1046/j.1523-1755.1999.00273.x.
http://dx.doi.org/10.1046/j.1523-1755.19...
), low serum albumin has been considered to play a key role in systemic vascular damage (1313. Ando D, Hirawa N, Yasuda G. Hypoalbuminemia and hyperalbuminuria as major factors regulating circadian blood pressure rhythm in normal subjects and non-diabetic patients with early stages of chronic kidney disease. J Hypertens. 2014;3:142, http://dx.doi.org/10.4172/2167-1095.1000142.
http://dx.doi.org/10.4172/2167-1095.1000...
). Hypoalbuminemia, even a decrease of only 0.2 g/dL, has been suggested to be closely associated with an increased risk of cardiovascular events (2626. Fung F, Sherrard DJ, Gillen DL, Wong C, Kestenbaum B, Seliger S, et al. Increased risk for cardiovascular mortality among malnourished end-stage renal disease patients. Am J Kidney Dis. 2002;40(2):307-14, http://dx.doi.org/10.1053/ajkd.2002.34509.
http://dx.doi.org/10.1053/ajkd.2002.3450...
,2727. Mehrotra R, Duong U, Jiwakanon S, Kovesdy CP, Moran J, Kopple JD, et al. Serum albumin as a predictor of mortality in peritoneal dialysis: comparisons with hemodialysis. Am J Kidney Dis. 2011;58(3):418-28, http://dx.doi.org/10.1053/j.ajkd.2011.03.018.
http://dx.doi.org/10.1053/j.ajkd.2011.03...
).

The significantly lower nighttime systolic and diastolic BP in the Q2, Q3 and Q4 serum albumin quartiles in our cohort suggest that a decline in albumin levels beyond 4.1 g/dL appears to increase the likelihood of non-dipping status in patients with essential hypertension.

A decrease in serum albumin was shown to be an independent predictor of lower average nocturnal systolic dipping and thus a nocturnal systolic non-dipping pattern, in our cohort. This finding appears to agree with reports that nighttime BP is more closely associated with the albumin-to-creatinine ratio (ACR) compared with daytime and 24-h BP (1313. Ando D, Hirawa N, Yasuda G. Hypoalbuminemia and hyperalbuminuria as major factors regulating circadian blood pressure rhythm in normal subjects and non-diabetic patients with early stages of chronic kidney disease. J Hypertens. 2014;3:142, http://dx.doi.org/10.4172/2167-1095.1000142.
http://dx.doi.org/10.4172/2167-1095.1000...
).

Loss of nighttime BP decline has been shown to be a crucial risk marker for vascular atherosclerosis and cardiovascular events and an independent risk factor for overt CV disease (1313. Ando D, Hirawa N, Yasuda G. Hypoalbuminemia and hyperalbuminuria as major factors regulating circadian blood pressure rhythm in normal subjects and non-diabetic patients with early stages of chronic kidney disease. J Hypertens. 2014;3:142, http://dx.doi.org/10.4172/2167-1095.1000142.
http://dx.doi.org/10.4172/2167-1095.1000...
,2828. Kario K, Pickering TG, Matsuo T, Hoshide S, Schwartz JE, Shimada K. Stroke prognosis and abnormal nocturnal blood pressure falls in older hypertensives. Hypertension. 2001;38(4):852-7, http://dx.doi.org/10.1161/hy1001.092640.
http://dx.doi.org/10.1161/hy1001.092640...
29. Kario K. Nondipping in nocturnal blood pressure in diabetes: an indicator of autonomic nervous dysfunction? Am J Hypertens. 2007;20(5):546-7, http://dx.doi.org/10.1016/j.amjhyper.2007.03.004.
http://dx.doi.org/10.1016/j.amjhyper.200...
-3030. Bouhanick B, Bongard V, Amar J, Bousquel S, Chamontin B. Prognostic value of nocturnal blood pressure and reverse-dipping status on the occurrence of cardiovascular events in hypertensive diabetic patients. Diabetes Metab. 2008;34(6 Pt 1):560-7, http://dx.doi.org/10.1016/j.diabet.2008.05.005.
http://dx.doi.org/10.1016/j.diabet.2008....
). Along with the superiority of systolic over diastolic BP non-dipping in the prediction of target organ damage in essential hypertension (3131. Syrseloudis D, Tsioufis K, Lioni L, Andrikou E, Giakoumis M, Kordalis A, et al. The superiority of systolic over diastolic blood pressure non-dipping in the prediction of target organ damage in essential hypertension: implications in dipping definition. J Am Coll Cardiol. 2011;57(14s1):E539-E539, http://dx.doi.org/10.1016/S0735-1097(11)60539-1.
http://dx.doi.org/10.1016/S0735-1097(11)...
), hypertensive nocturnal dippers were reported to exhibit a worse profile than normotensives regarding pulse wave velocity, ACR and hs-CRP (3232. Syrseloudis D, Tsioufis K, Andrikou E, Andrikou I, Mazaraki A, Stefanadi E, et al. The adverse effects of nocturnal hypertension on arterial stiffness and urinary albümin excretion in hypertension. J Am Coll Cardiol. 2010;55(10s1):A60.E571-A60.E571, http://dx.doi.org/10.1016/S0735-1097(10)60572-4.
http://dx.doi.org/10.1016/S0735-1097(10)...
). The identification of serum albumin levels as an independent predictor of nocturnal systolic non-dipping in our cohort supports the idea that serum albumin levels alone may provide sufficient data on systolic non-dipping and, thus, indices of target organ damage and cardiovascular risk (1313. Ando D, Hirawa N, Yasuda G. Hypoalbuminemia and hyperalbuminuria as major factors regulating circadian blood pressure rhythm in normal subjects and non-diabetic patients with early stages of chronic kidney disease. J Hypertens. 2014;3:142, http://dx.doi.org/10.4172/2167-1095.1000142.
http://dx.doi.org/10.4172/2167-1095.1000...
,3131. Syrseloudis D, Tsioufis K, Lioni L, Andrikou E, Giakoumis M, Kordalis A, et al. The superiority of systolic over diastolic blood pressure non-dipping in the prediction of target organ damage in essential hypertension: implications in dipping definition. J Am Coll Cardiol. 2011;57(14s1):E539-E539, http://dx.doi.org/10.1016/S0735-1097(11)60539-1.
http://dx.doi.org/10.1016/S0735-1097(11)...
).

Certain limitations of this study should be considered. First, due to the retrospective single-center design, establishing temporality between cause and effect and generalizing our findings to the overall essential hypertensive population may be difficult. Second, although no significant association was noted between dipping status and the type of hypertensive agents used by patients, we cannot exclude the possibility that the maintenance of treatment during ABPM altered the relationship between BP and the study outcomes. The limited data on surrogate markers of target organ damage and cardiovascular risk in hypertensive subjects is another limitation; the availability of such markers would extend the knowledge achieved in the current study. Despite these limitations, given the paucity of solid information available in this area, our findings represent a valuable contribution to the literature.

In conclusion, our findings indicate an association between serum albumin levels and the deterioration of circadian BP rhythm among essential hypertensive patients, with a non-dipper pattern identified in more than two-thirds of the patients. Our findings emphasize the importance of serum albumin levels, rather than UAE, as an independent predictor of nocturnal systolic dipping, at least in non-diabetic essential hypertensive patients with moderate proteinuria. Larger prospective ABPM studies addressing the relationship between circadian BP rhythm and serum and urinary albumin among hypertensive patients with massive albuminuria or hypoalbuminemia are needed, as are advanced biochemical markers of target organ damage and cardiovascular risk.

AUTHOR CONTRIBUTIONS

Ahbap E, Sakaci T, Kara E and Sahutoglu T designed the study, collected and analyzed the data and wrote the manuscript. Basturk T and Koc Y were involved in designing the study and collecting the data. Sevinc M and Kara E performed the statistical analysis and collected the data. Akgol C, Ucar ZT, Kayalar AO and Bayraktar F collected the data. Unsal A was responsible for final editing of the manuscript.

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    » http://dx.doi.org/10.1161/hy1001.092640
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    » http://dx.doi.org/10.1016/j.diabet.2008.05.005
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    » http://dx.doi.org/10.1016/S0735-1097(10)60572-4

Publication Dates

  • Publication in this collection
    May 2016

History

  • Received
    27 Nov 2015
  • Reviewed
    13 Jan 2016
  • Accepted
    11 Feb 2016
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