CIRCADIAN RHYTHM OF URINARY POTASSIUM EXCRETION
IN PATIENTS WITH CKD
Toshiyuki Miura1, Michio Fukuda1, Takehiro Naito1, Hiroyuki Togawa1,
Ryo Sato1, Yuji Sasagawa1, Tatsuya Tomonari1, Yoko Kato1,
Masashi Mizuno1, Minamo Ono1, Tadashi Ichikawa1,
Yuichi Shirasawa1, Akinori Ito1, Atsuhiro Yoshida1 and Genjiro Kimura1
1Department of Cardio-Renal Medicine and Hypertension
Nagoya City University Graduate School of Medical Sciences
Mailing Proofs to:
Michio Fukuda, M.D.
Department of Cardio-Renal Medicine and Hypertension
Nagoya City University Graduate School of Medical Sciences
Mizuho-ku, Nagoya 467-8601, Japan
TEL: +81-52-853-8221, FAX: +81-52-852-3796
E-mail:
Running Title:
Circadian rhythm of urine K
ABSTRACT
Aims: We previously reported in patients with chronic kidney disease (CKD) that the circadian rhythms of blood pressure (BP) and urinary sodium excretion were both impaired into non-dipper pattern as renal function deteriorated. However, the circadian rhythm of urinary potassium excretion has not been studied in relation to renal dysfunction.
Methods: BP and urinary excretion rates of sodium (UNaV) and potassium (UKV) were evaluated for daytime and night-time to estimate their circadian rhythms in 83 subjects with CKD.
Results: As renal function deteriorated, night/day ratios of UNaV and UKV were both increased. Night/day ratio of UKV was positively correlated with night/day ratio of UNaV (r=0.60, p<0.0001). Multiple regression analysis (R2=0.37, p<0.0001) identified that night/day ratio of UKV was determined independently by the night/day ratio of UNaV (r=-0.55, p<0.0001), rather than renal function or night/day ratio of BP.
Conclusions: Circadian rhythm of natriuresis was regulated by renal function and night/day ratio of BP. On the other hand, the circadian rhythm of urinary potassium excretion was primarily determined by neither renal function nor BP, but was correlated with that of urinary sodium excretion.
Key words
blood pressure – circadian rhythm – chronic kidney disease –
urinary sodium – urinary potassium
INTRODUCTION
Kidneys play an important role in maintaining homeostasis of body fluid volume, blood pressure (BP) and solute composition including electrolytes in extracellular compartment. We reported that the circadian rhythms of BP and urinary sodium excretion were both shifted from dipper to non-dipper patterns as renal function deteriorated [1,2]. Recently, we have postulated that reduced renal capacity to excrete sodium into urine causes nocturnal BP elevation, i.e., non-dippers, to compensate for diminished daytime natriuresis by enhancing pressure-natriuresis during the night [3-5]. We propose that it is the kidney and sodium to mainly determine the circadian rhythm of BP [3-5]. In contrast to sodium, circadian rhythm of urinary potassium excretion is seldom evaluated. Therefore, in this study we examined the relationship between the circadian rhythm of potassium excretion and the rhythms of natriuresis and BP in patients with chronic kidney disease (CKD).
METHODS
Subjects
Eighty-three patients with CKD (44 men and 39 women; aged 16 to 80 with the mean of 46±18 years; body mass index: 22.6±4.0 kg/m2; body weight: 59.5±13.7 kg) were studied at Nagoya City University Hospital after 5 patients were excluded because of the incomplete or excessive urine collection of either daytime or night-time on the basis of the night/day ratio of urinary excretion rate of creatinine <0.5 (n=4) or >2 (n=1) [6]. CKD was defined according to the Kidney Disease Outcomes Quality Initiative (K/DOQI) criteria [7]. No patient with diabetic nephropathy, polycystic kidney disease, nephrotic syndrome or arrhythmia was included. Patients under usage of antihypertensive agents or diuretics were excluded. Forty-eight subjects exhibited their office BP exceeding 130/80 mmHg (or 125/75 mmHg if proteinuria was greater than 1 g/day), which was the goal of the antihypertensive therapy for CKD patients recommended by the current guidelines [8,9]. All participants were consecutively enrolled after informed consent given. The study was approved by the ethics review committee of Nagoya City University Graduate School of Medical Sciences, and was conducted in accordance with the Declaration of Helsinki, as we previously published [1,2,10].
Study Protocol
The subjects received nutritional instructions to eat a regular sodium diet containing <8 g/day of salt for at least 4 weeks before enrollment. Twenty-four-hour BP monitoring and urinary sampling were performed on the last day of a 7-day hospitalization period, during which their diets included 7.0, 1.3-2.0, and 30-50 g/day of salt, potassium and protein, respectively.
BP was monitored every 30 minutes noninvasively with a validated automatic device (model ES-H531, Terumo), and the subjects were asked to get up at 6:00 and start bed-rest at 21:00. BP values were not considered valid for analysis if data were missing for 2 hours continuously or if the patients awoke during the night and had difficulty falling asleep again. Daytime BP was calculated as the average of the 30 readings between 6:00 and 21:00, and night-time BP was determined as the average of the remaining 18 readings. Mean arterial pressure (MAP) was calculated as diastolic BP plus one third of the pulse BP. Night/day ratio of MAP was obtained as the ratio of the above averages.
Urinary samples were collected for both daytime (6:00 to 21:00) and night-time (21:00 to 6:00) to estimate the circadian rhythm of urinary excretion rates of volume (V, mL/hr), sodium (UNaV, mmol/hr) and potassium (UKV, mmol/hr). These urine collections were combined to calculate 24-hour creatinine clearance (Ccr, mL/min), which was used as a measure of glomerular filtration rate (GFR). Blood samples were collected only once at 6:00.
Statistical analysis
Results are expressed as means ± SD. Correlations among variables were evaluated by the least-squares method. Independent determinants of the night/day ratios of urinary electrolytes excretion rates and that of BP were examined by multiple regression analysis. All statistical analyses were performed using SPSS 15.0J (SPSS, Inc). The p values of <0.05 was considered statistically significant.
RESULTS
The average values of serum creatinine concentration and GFR were 1.7 ± 1.9 mg/dL and 78 ± 45 mL/min, respectively. The number of the subjects in CKD stage 1, 2, 3, 4 and 5 according to Kidney Disease Outcomes Quality Initiative criteria were 35, 18, 13, 9 and 8, respectively. The 24 hour-urinary excretion rates of sodium and potassium were 103 ± 41 and 33 ± 15 mmol/day. The 24 hour-urinary excretion rate of sodium was not correlated with GFR (r=0.19, p=0.08), while that of potassium was directly correlated with GFR (r=0.40, p=0.0002). Serum electrolyte concentrations as well as urinary excretion rates and BP in 24-hour, daytime and night-time values and their night/day ratios are shown in Table 1. The night/day ratios of urinary excretion rates of volume, sodium and potassium were all elevated as GFR was reduced (Figure 1). According to ABPM, the numbers of the hypertensive patients based on the mean values of daytime (>135/85 mmHg), night-time (>120/70 mmHg), and 24-h BP (>130/80 mmHg) were 28, 47, and 35, respectively [8,9]. Night/day ratios of MAP, systolic BP (SBP) and diastolic BP (DBP) were also elevated as GFR was reduced. Night/day ratios of urinary volume, UNaV and UKV were all positively correlated with night/day ratio of MAP (Figure 2), as well as with those of SBP and DBP. Night/day ratio of UKV was positively correlated with night/day ratio of UNaV (r=0.60, p<0.0001).
By multiple regression analysis, night/day ratio of UNaV (R2=0.57, p<0.0001) was determined by GFR (r=-0.32, p=0.0003) as well as the night/day ratios of MAP (r=0.31, p=0.0003) and UKV (r=0.37, p<0.0001). On the other hand, night/day ratio of UKV (R2=0.36, p<0.0001) was determined only by night/day ratio of UNaV (r=0.55, p<0.0001) rather than GFR (r=-0.10. , p=0.4) or night/day ratio of MAP (r=-0.02, p=0.8). Finally, night/day ratio of MAP (R2=0.30, p<0.0001) was determined solely by night/day ratio of UNaV (r=0.51, p=0.0003), but was not by GFR (r=-0.09, p=0.5) or night/ day ratio of UKV (r=-0.03, p=0.8). Similarily, night/day ratio of urinary volume (R2=0.54, p<0.0001) was determined by the night/day ratio of UNaV (r=0.64, p<0.0001) rather than GFR (r=0.02, p=0.8), the night/day ratio of UKV (r=0.11, p=0.3) or MAP (r=0.08, p=0.4).
DISCUSSION
Our study demonstrated that the circadian rhythm of urinary excretion of potassium was essentially paralleled with the rhythm of sodium excretion. Although the circadian rhythm of urinary sodium excretion was determined by both GFR and night/day ratio of BP, multiple regression analysis showed that night/day ratio of urinary potassium excretion was determined solely by night/day ratio of urinary sodium excretion. Neither GFR nor night/day ratio of BP influenced night/day ratio of urinary potassium excretion.
We have postulated that nocturnal BP is elevated in order to compensate for impaired daytime sodium excretion capacity by enhancing pressure-natriuresis during the night, when sodium cannot be excreted sufficiently during daytime [3-5]. In fact, the present study showed that there was a strongly direct correlation between night/day ratio of urinary sodium excretion and night/day ratio of BP during regular sodium intake as shown in the present (Figure 2) and previous studies [11-13], while no correlation existed between these two during low sodium intake as we previously showed [11]. In addition, night/day ratios of BP and urinary sodium excretion were both elevated as GFR was reduced in CKD (Figure 1), as already we reported [1]. Recently, we showed the duration until nocturnal BP fell below 90 % of the daytime averages was prolonged, as GFR was reduced [2]. These findings are all consistent with our hypothesis that nocturnal BP must be elevated in order to enhance urinary sodium excretion during the night. Our previous findings that sodium intake restriction [14] and diuretics [15] normalized circadian BP rhythm from non-dipper to dipper are also consistent with our hypothesis, although these were studied in the different population (essential hypertension) from the present study (CKD). In the present study, we showed that electrolytes such as potassium other than sodium did not play important roles in regulating circadian BP rhythm. Instead, circadian rhythm of urinary potassium excretion was determined mostly by circadian rhythm of urinary sodium excretion.
Night/day ratio of urinary potassium excretion was positively correlated with night/day ratio of urinary sodium excretion and was negatively correlated with GFR as seen in Figure1. As GFR is reduced, aldosterone secretion is stimulated independently of angiotensin [16], resulting in enhanced potassium excretion into feces [17] as well as into urine. This seems the main reason why the amount of urinary potassium excretion was reduced as GFR was reduced in CKD. Nevertheless, the circadian rhythm of urinary potassium excretion was independently correlated only with the rhythm of urinary sodium excretion. The amount of tubular excretion of potassium in the distal tubule and cortical collecting duct, which accounts for most of the total amount of urinary potassium excretion, is determined by the amount of sodium delivery to the nephrons [18]. Since the amount of urinary sodium excretion should be proportional to the amount of sodium delivery to the nephrons [18], it is easy to understand why the amount of urinary potassium excretion is enhanced as urinary sodium excretion is increased. Therefore, circadian rhythms of urinary sodium and potassium excretions were also paralleled, as already expected [19-22].
Multiple regression analysis showed in CKD that GFR influenced only circadian rhythm of natriuresis directly, while the latter influenced all rhythms of BP as well as urinary excretions of potassium and volume. In addition, it should be noted that circadian rhythms of natriuresis and BP, and circadian rhythms of natriuresis and urinary potassium excretion were interacted each other. Therefore, BP and potassium excretion both influenced circadian rhythm of natriuresis. When potassium was delivered to distal nephron more, potassium secretion through renal outer medullary potassium channel was increased [23,24]. Then tubular sodium reabsorption through epithelial sodium channel and sodium/chloride cotransporter might be suppressed in distal nephron [23,24], resulting in more sodium excretion into urine.
In conclusion, this is the first study to our knowledge to demonstrate clearly that in patients with CKD the circadian rhythm of urinary potassium excretion was paralleled with the rhythm of urinary sodium excretion each other, but was not primarily determined by GFR or BP.
ACKNOWLEDGEMENTS
The study is supported by Research Grants for Cardiovascular Diseases (C-2001-5) from the Ministry of Health and Welfare of Japan, as well as Grants from Nagoya City University, Salt Science Research Foundation (No. 04C1), Metabolic Disorders Treatment Research Foundation, Aichi Kidney Foundation and Japan Cardiovascular Research Foundation, and Grant-in-Aid for Scientific Research (B#19390232 & C#17590836) from Ministry of Education, Culture, Sports, Science and Technology of Japan through Japan Society for the Promotion of Science. These funding sources had no role in the design, conduct, analysis or interpretation of the study.
CONFLICT OF INTEREST
None declared.
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