Circadian rhythm of urinary potassium excretion during treatment with an angiotensin receptor blocker

475909JRA15410.1177/1470320313475909Journal of the Renin-Angiotensin-Aldosterone SystemOgiyama et al. 2013 Original Article Circadian rhythm of urinary potassium excretion during treatment with an angiotensin receptor blocker Journal of the Renin-Angiotensin- Aldosterone System 2014, Vol. 15(4) 509 514 The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalspermissions.nav DOI: 10.1177/1470320313475909 jra.sagepub.com Yoshiaki Ogiyama, Toshiyuki Miura, Shuichi Watanabe, Daisuke Fuwa, Tatsuya Tomonari, Keisuke Ota, Yoko Kato, Tadashi Ichikawa, Yuichi Shirasawa, Akinori Ito, Atsuhiro Yoshida, Michio Fukuda and Genjiro Kimura Abstract Introduction: We have reported that the circadian rhythm of urinary potassium excretion (U K V) is determined by the rhythm of urinary sodium excretion (U Na V) in patients with chronic kidney disease (CKD). We also reported that treatment with an angiotensin receptor blocker (ARB) increased the U Na V during the daytime, and restored the non-dipper blood pressure (BP) rhythm into a dipper pattern. However, the circadian rhythm of U K V during ARB treatment has not been reported. Materials and methods: Circadian rhythms of U Na V and U K V were examined in 44 patients with CKD undergoing treatment with ARB. Results: Whole-day U Na V was not altered by ARB whereas whole-day U K V decreased. Even during the ARB treatment, the significant relationship persisted between the night/day ratios of U Na V and U K V (r=0.56, p<0.0001). Whole-day U K V/ U Na V ratio (p=0.0007) and trans-tubular potassium concentration gradient (p=0.002) were attenuated but their night/ day ratios remained unchanged. The change in the night/day U K V ratio correlated directly with the change in night/day U Na V ratio (F=20.4) rather than with the changes in aldosterone, BP or creatinine clearance. Conclusions: The circadian rhythm of U K V was determined by the rhythm of U Na V even during ARB treatment. Changes in the circadian U K V rhythm were not determined by aldosterone but by U Na V. Keywords Circadian rhythm, urinary potassium excretion, sodium, angiotensin receptor blocker, chronic kidney disease Introduction It has been established that there is a circadian rhythm in the rate of urinary potassium excretion (U K V). 1 4 Recently, we have reported that the circadian rhythm of U K V is associated with the urinary sodium excretion rate (U Na V) in patients with chronic kidney disease (CKD), who are not treated with antihypertensive agents. 5 Meanwhile, we have postulated that the diminished renal sodium excretion capability caused sodium retention during the day, and facilitated the nocturnal pressure-natriuresis (i.e. non-dipper circadian blood pressure (BP) rhythm). 6 8 In fact, treatment with an angiotensin receptor blocker (ARB) increased the U Na V during the daytime, lowered the sodium balance compared to the baseline and shifted the circadian BP rhythm from a non-dipper to a dipper pattern, similarly to the action of diuretics. 9,10 In the present study we evaluated the change in the circadian rhythm of U K V during treatment with an ARB in patients with CKD, and determined whether the circadian rhythm of the U K V changes in association with the U Na V during ARB treatment. Materials and methods Patients To be eligible for the study, patients had to fulfill the following criteria: diagnosed as having CKD according to Department of Cardio-Renal Medicine and Hypertension, Nagoya City University Graduate School of Medical Sciences, Japan Corresponding author: Michio Fukuda, Department of Cardio-Renal Medicine and Hypertension, Nagoya City University Graduate School of Medical Sciences, Nagoya, 467-8601, Japan. Email: m-fukuda@med.nagoya-cu.ac.jp

510 Journal of the Renin-Angiotensin-Aldosterone System 15(4) the Kidney Disease Outcomes Quality Initiative (K/DOQI) criteria, 11 a pre-treatment office BP >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, 12 14 and no contra-indications for treatment with ARB. Exclusion criteria were: (a) diabetic nephropathy, (b) nephrotic syndrome, (c) receiving antihypertensive agents or diuretics and (d) change in the dose of glucocorticoids or immunosuppressive agents within two months because these could influence the circadian BP rhythm or renal function. 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 with our previous report. 6 10 Overall, 44 patients with CKD (29 men and 15 women; aged 17 75 years with a mean age of 43±17 years; body mass index: 23.1±3.1 kg/m 2 ; body weight: 62.6±11.0 kg) were enrolled consecutively after providing informed consent. Study protocol The subjects received nutritional instructions to eat a regular sodium diet containing <8 g/day of salt for at least four weeks before enrollment. Twenty-four hour ambulatory BP monitoring (ABPM) and urinary sampling were performed on the last day of a seven-day hospitalization period, during which subject diets included 7.0 and 1.3 2.0 g/day of sodium chloride and potassium, respectively. The diet provided 30 50 g protein per day. The subjects were asked to get up at 6:00 and to start bed-rest at 21:00. Throughout the study period, no additional medications or changes in the dosages of concomitant drugs were allowed. After the baseline examinations, the participants received single daily doses of an ARB, olmesartan, in the morning. The dose of olmesartan medoxomil was increased to the highest possible dose (2.5 40 mg/day) in order to attain the daytime BP goal <130/80 mmhg or 125/75 mmhg if proteinuria was greater than 1 g/day. 12,13 BP was monitored noninvasively every 30 min using a validated automatic device (model ES-H531, Terumo, Tokyo, Japan) with a standard BP cuff (240 mm long and 130 mm wide; Japanese Industrial Standards) on the last day of a seven-day hospitalization period at the baseline and eight weeks after treatment with olmesartan. The BP values were not considered valid for analysis, if data were missing continuously for 2 h, or if the patients awoke during the night and had difficulty falling asleep again. Mean arterial pressure (MAP) was calculated as diastolic BP plus one-third of the pulse BP. Daytime BP was calculated as the average of the 30 readings between 6:00 21:00, and the night-time BP was the average of the remaining 18 readings. The night/day MAP ratio was obtained as the ratio of the above averages as an indicator of the circadian BP rhythm. Nocturnal hypertension was defined as a night-time BP of >120/70 mmhg and the non-dipper BP rhythm defined as a night/day MAP of >0.9. Urinary samples were collected for both daytime (6:00 21:00) and night-time (21:00 6:00) to estimate the circadian rhythm of urinary excretion rates of sodium (U Na V, mmol/hr) and potassium (U K V, mmol/hr). In particular, an increase in U K V/U Na V ratio is known to reflect the effect of aldosterone on renal tubular reabsorption of Na and secretion of K at the primary sites of potassium secretion. 15 The trans-tubular potassium concentration gradient (TTKG) was calculated as follows: 16 TTKG = (U K /P K )/(U osm /P osm ) Where, U K, P K, U osm and P osm were the urine and serum potassium concentration, and urine and serum osmolality, respectively. The collected urine samples were combined to calculate the 24 h creatinine clearance (C Cr, ml/min), which was used as a measure of glomerular filtration rate. The adequacy of 24 h urine collection was judged by the amount of urinary creatinine excretion: for men aged <50 years, 18.5 25.0; for women aged <50 years, 16.5 22.4; for men aged 50 years, 15.7 20.2; and for women aged 50 years, 11.8 16.1 mg/kg body weight/day, respectively. Incomplete or excessive urine collection in either the daytime or night-time samples were judged on the basis of the night/day ratio of the urinary creatinine excretion rate <0.5 or >2.0. Blood samples were collected only once at 6:00, which was the marginal point between the daytime and night-time. To evaluate plasma renin activity (PRA), and plasma aldosterone concentration (PAC), blood samples were centrifuged at 3000 rpm for 10 min at 4 C, and were frozen immediately and stored at 35 C until assay. PRA and PAC were then determined using radioimmunoassay at an external analysis center (SRL, Inc., Hachioji, Japan). Statistical analysis The results are expressed as the mean±standard deviation (SD). Data distribution was tested using the Kolmogorov- Smirnov test, and variables that were not normally distributed were analyzed after log-transformation. The differences in parameters between baseline and ARB treatment were examined using the Student s t-test for paired samples. Correlations among variables were evaluated by the least-squares method. Relationships between the changes in the variables were analyzed by linear regression through the origin. Stepwise forward multiple regression analysis was also applied to identify the factors that contributed independently to the decreases in night/day U K V ratio by ARB. p-values <0.05 were considered statistically significant.

Ogiyama et al. 511 Table 1. Clinical variables before and during the ARB treatment. Variables Baseline ARB p value P Na meq/l 142±2 142±2 0.2 P K meq/l 4.2±0.4 4.3±0.5 0.2 PRA ng/ml/h 1.2±0.8 8.7±10.3 <0.0001 PAC pg/ml 101±64 84±56 0.09 C cr ml/min 90±47 74±39 0.0002 SBP 24 h mmhg 127±18 116±19 <0.0001 Day mmhg 129±18 119±18 <0.0001 Night mmhg 123±22 108±21 <0.0001 Night/day 0.95±0.10 0.90±0.07 0.0003 DBP 24 h mmhg 78±12 71±12 <0.0001 Day mmhg 80±13 74±12 <0.0001 Night mmhg 75±12 65±12 <0.0001 Night/day 0.94±0.10 0.88±0.08 0.0003 MAP 24 h mmhg 94±13 84±13 <0.0001 Day mmhg 96±13 89±13 <0.0001 Night mmhg 91±14 80±14 <0.0001 Night/day 0.95±0.10 0.89±0.07 <0.0001 V 24 h ml/d 1430±660 1350±640 0.3 Day ml/h 62.3±34.5 61.2±33.1 0.8 Night ml/h 54.1±28.3 47.8±25.0 0.1 Night/day 1.05±0.57 0.88±0.39 0.05 U osm 24 h mosm/kgh 2 O 451±237 460±226 0.8 Day mosm/kgh 2 O 465±258 469±234 0.9 Night mosm/kgh 2 O 486±267 468±242 0.7 Night/day 1.14±0.54 1.06±0.38 0.4 U Na V 24 h mmol/d 108±46 119±35 0.07 Day mmol/h 4.7±2.4 5.5±2.0 0.01 Night mmol/h 4.1±2.0 3.9±1.6 0.4 Night/day 1.05±0.62 0.80±0.42 0.002 U K V 24 h mmol/d 32±12 28±9 0.003 Day mmol/h 1.5 ±0.6 1.3±0.4 0.04 Night mmol/h 1.1±0.4 0.9±0.4 0.0002 Night/day 0.85±0.38 0.69±0.26 0.002 U K V/ U Na V 24 h mmol/d 0.33±0.16 0.25±0.09 0.0007 Day mmol/h 0.36±0.21 0.26±0.10 0.0005 Night mmol/h 0.31±0.15 0.25±0.11 0.005 Night/day 0.98±0.61 1.02±0.43 0.7 U osm V 24 h mosm/d 530±180 515±160 0.3 Day mosm/kgh 2 O/h 22.8±9.0 23.4±8.6 0.5 Night mosm/kgh 2 O/h 20.8±7.6 18.0±5.9 0.002 Night/day 1.00±0.39 0.83±0.28 0.001 TTKG 24 h 4.3±1.1 3.7±0.9 0.002 Day 4.6±1.3 3.9±1.0 0.005 Night 3.8±1.2 3.2±1.0 0.002 Night/day 0.88±0.34 0.85±0.24 0.5 Ccr: creatinine clearance; P Na and P K : serum concentrations of sodium and potassium; PAC: plasma aldosterone concentration; PRA: plasma renin activity; SBP, DBP and MAP: systolic, diastolic, and mean arterial blood pressures; TTKG: trans-tubular potassium concentration gradient; U osm : urine osmolality; U Na V and U K V: urinary excretion rates of sodium and potassium, U osm V: urinary osmolar excretion rate; V: urine volume. Results Baseline characteristics The demographics of the study participants are shown in Table 1. At baseline, the average whole-day SBP, DBP and MAP were 127±18, 78±12 and 94±13 mmhg, respectively. Twenty-five out of 44 patients had nocturnal hypertension (>120/70 mmhg). 12,13 Thirty-two patients (73%) exhibited the non-dipper type of circadian BP rhythm. The average C Cr was 90±47 ml/min. The number of subjects with CKD

512 Journal of the Renin-Angiotensin-Aldosterone System 15(4) Figure 1. Relationship between the night/day ratios of urinary excretion of sodium and potassium before and during treatment with angiotensin receptor blocker (ARB). The night/day urinary potassium excretion (U K V) ratio correlated directly with night/ day urinary sodium excretion (U Na V) ratio before and during treatment with the ARB. U K V and U Na V; urinary excretion rates of potassium and sodium (mmol/h), respectively. Open circles with thin line and closed circles with thick line indicate before and during ARB treatment, respectively. stages 1, 2, 3, 4 and 5, according to the Kidney Disease Outcomes Quality Initiative criteria, were 24, 7, 6, 5, and 2, respectively. Whole-day U Na V and U K V were 108±46 and 32±12 mmol/day, respectively. Night/day ratios of U Na V and U K V were 1.05±0.62 and 0.85±0.38, respectively. Interestingly, 23 out of 44 patients (48%) had night/day U Na V ratios >1.0, whereas 12 patients (27%) had night/day U K V ratio of >1.0. Consistent with our previous report, 5 the night/day U K V ratio exhibited an inverse relationship with C Cr (r= 0.33, p=0.03), and correlated directly with night/ day U Na V ratio (r=0.58, p<0.0001, Figure 1). Whole day U K V/U Na V correlated directly with whole day TTKG (r=0.73, p<0.0001). Effects of ARB As shown in Table 1, the ARB decreased the night/day ratios of SBP, DBP, MAP, U Na V and U K V. During the treatment with ARB, 20 subjects (45%) exhibited the non-dipper BP rhythm. Specifically, among 32 patients whose circadian BP rhythm was non-dipper at baseline, the BP rhythm restored into dipper pattern in 14 patients but remained non-dipper in 18 patients. On the other hand, among 12 patients whose circadian BP rhythm was dipper at baseline, 10 patients remained dippers and two patients turned into non-dippers. Whole-day U Na V was not altered by ARB, reflecting the constant amount of sodium intake. On the other hand, whole-day values of U K V were decreased. ARB significantly decreased both daytime and night-time U K V and increased daytime U Na V but night-time U Na V was unchanged. Consequently, ARB decreased the night/day ratios of U Na V (1.05±0.62 to 0.80±0.42, p=0.002) and U K V (0.85±0.38 to 0.69±0.26, p=0.0002). Whole day, daytime and night-time values of urine volume (V, ml/h) were not altered by ARB (p=0.3, 0.8 and 0.1, respectively). The night/day ratio of urine volume was also significantly reduced (p=0.05): the ratio correlated directly with that of U K V at baseline (r=0.44, p=0.003), but it did not correlate with night/day U K V ratio during the ARB treatment (r=0.29, p=0.05). Whole day, and daytime values of urinary osmolar excretion rate (U osm V, mosm/h) were not altered by ARB (p=0.3, and 0.5, respectively), whereas night-time U osm V significantly decreased (p=0.002). Even during the ARB treatment, the significant relationship persisted between the night/day ratios of U Na V and U K V (r=0.56, p<0.0001, Figure 1). Whole-day, daytime and night-time values of both U K V/U Na V and TTKG were all attenuated by ARB treatment. Even during the ARB treatment, whole day U K V/U Na V correlated directly with whole day TTKG (r=0.79, p<0.0001). Night/day ratios of both U K V/U Na V and TTKG were unchanged. Multiple regression analysis (R 2 =0.35, p<0.0001) identified that the change in the night/ day ratio of U K V was determined by the change in night/ day U Na V ratio (F=21.3), rather than the changes in aldosterone (F=0.5), C Cr (F=0.9), TTKG (F=1.2), U K V/ U Na V ratio (F=0.4), or the night/day MAP ratio (F=1.3). Discussion The present study demonstrated that the circadian rhythm of U K V was associated with the rhythm of U Na V before and during the treatment with ARB. ARB decreased the U K V/ U Na V and TTKG, indicating that the ARB could diminish the effect of aldosterone on renal tubular reabsorption of Na + and secretion of K + at the primary sites of potassium secretion. However, the change in the night/day ratio of U K V was determined by the change in night/day U Na V ratio, rather than the changes in aldosterone, C Cr, TTKG, U K V/U Na V ratio, or the night/day MAP ratio. Potassium is excreted into urine primarily through secretion from tubular cells rather than filtration across the glomerular capillary wall because almost all of the filtered potassium is reabsorbed passively by the proximal tubule and loop of Henle: and potassium is secreted into urine from the principal cells of the cortical collecting tubules and from the cells in the adjacent connecting segment or outer medullary collecting tubules. 17 Under physiologic conditions, tubular potassium secretion is mediated by aldosterone, the plasma potassium concentration, the distal flow rate and the transepithelial potential difference: in the presence of aldosterone, tubular potassium secretion is enhanced as the delivery of sodium to the distal nephrons is augmented. 18 22 On the basis of these findings, we

Ogiyama et al. 513 examined the U K V/U Na V ratio. The ratio cannot strictly represent the relationship between distal flow and potassium secretion but an increase can roughly indicate the effect of aldosterone on renal tubular potassium secretion. The present study demonstrated that 24 h values of the U K V/U Na V ratio and TTKG were attenuated, indicating that the ARB also reduced the sodium reabsorption via epithelial sodium channels (ENaCs). In fact, ARBs are known to diminish the secretion of adrenal aldosterone, and to decrease the number 23 and activity 24 of ENaCs, independent of circulating aldosterone. Interestingly, during the ARB treatment, the night/day ratio of TTKG and U K V/U Na V were both unchanged and the change in the circadian U K V rhythm was not attributed to the change in U K V/U Na V ratio or TTKG, but was determined by the change in the circadian U Na V rhythm. The present study has some limitations. It was reported that aldosterone can contribute to U K V only under the condition of supraphysiologic levels due to hyperkalemia. 25 In addition, recently, it was reported that dietary potassium intake was sensed in the gut, and an unidentified gut factor is activated to stimulate renal potassium. 26 Dietary potassium was constant and relatively low in this study protocol. Potassium can also be secreted into feces (5 10 mmol/ day) and sweat (0 10 mmol/day). As renal function deteriorates, aldosterone secretion is stimulated independent of angiotensin, 27 resulting in enhanced potassium excretion into feces. 28 Therefore, we could not confirm the amount of potassium intake or total body potassium balance, based solely on the 24 h U K V. During the data collection period, the amount of dietary sodium, potassium and protein were constant for individual subject. 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