Tatsuya Tomonari

Angiotensin receptor blockers shift the circadian rhythm of blood pressure by suppressing tubular sodium reabsorption

Recently, we found that an angiotensin II receptor blocker (ARB) restored the circadian rhythm of the blood pressure (BP) from a nondipper to a dipper pattern, similar to that achieved with sodium intake restriction and diuretics (Fukuda M, Yamanaka T, Mizuno M, Motokawa M, Shirasawa Y, Miyagi S, Nishio T, Yoshida A, Kimura G. J Hypertens 26: 583-588, 2008). ARB enhanced natriuresis during the day, while BP was markedly lower during the night, resulting in the dipper pattern. In the present study, we examined whether the suppression of tubular sodium reabsorption, similar to the action of diuretics, was the mechanism by which ARB normalized the circadian BP rhythm. BP and glomerulotubular balance were compared in 41 patients with chronic kidney disease before and during ARB treatment with olmesartan once a day in the morning for 8 wk. ARB increased natriuresis (sodium excretion rate; U(Na)V) during the day (4.5 ± 2.2 to 5.5 ± 2.1 mmol/h, P = 0.002), while it had no effect during the night (4.3 ± 2.0 to 3.8 ± 1.6 mmol/h, P = 0.1). The night/day ratios of both BP and U(Na)V were decreased. The decrease in the night/day ratio of BP correlated with the increase in the daytime U(Na)V (r = 0.42, P = 0.006). Throughout the whole day, the glomerular filtration rate (P = 0.0006) and tubular sodium reabsorption (P = 0.0005) were both reduced significantly by ARB, although U(Na)V remained constant (107 ± 45 vs. 118 ± 36 mmol/day, P = 0.07). These findings indicate that the suppression of tubular sodium reabsorption, showing a resemblance to the action of diuretics, is the primary mechanism by which ARB can shift the circadian BP rhythm into a dipper pattern.

Is salt intake an independent risk factor of stroke mortality? Demographic analysis by regions in Japan

We reported a remarkable regional difference within Japan in the incidence of end-stage renal disease. Regional differences were also well-known for salt intake, blood pressure (BP), and mortality from stroke, which remains one of the leading causes of death. Noting these regional differences, we examined mutual relationships among salt intake, BP, and stroke mortality in 12 regions of Japan. Data of salt intake, BP, and stroke mortality in 12 regions were collected from National Nutrition Survey (NNS-J), reanalysis of NNS-J, and Vital Statistics of National Population Dynamic Survey (Ministry of Health, Labor and Welfare), respectively. Significant regional differences were found in salt intake (P < .0001), mean arterial BP (P = .0001), and stroke mortality (P < .0001). Although annual changes in these parameters were also significant, their regional differences persisted. Salt intake had positive relationships with both mean arterial BP (r = 0.26, P = .0009) and stroke mortality (r = 0.26, P < .0001) across 12 regions, whereas mean arterial BP was not correlated with stroke mortality. Multiple regression analysis further identified salt intake as an independent factor to increase stroke mortality, but mean arterial BP was not a determinant. Compared with the four regions with lowest salt intake, odds ratios of stroke mortality adjusted by mean arterial BP were 1.04 (95% CI, 1.03-1.06) for the intermediate four regions and 1.25 (95% CI, 1.23-1.27) for the four regions with highest salt intake. These findings suggest that salt intake may have an adverse effect on stroke mortality independently of BP.

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

Introduction: We have reported that the circadian rhythm of urinary potassium excretion (UKV) is determined by the rhythm of urinary sodium excretion (UNaV) in patients with chronic kidney disease (CKD). We also reported that treatment with an angiotensin receptor blocker (ARB) increased the UNaV during the daytime, and restored the non-dipper blood pressure (BP) rhythm into a dipper pattern. However, the circadian rhythm of UKV during ARB treatment has not been reported. Materials and methods: Circadian rhythms of UNaV and UKV were examined in 44 patients with CKD undergoing treatment with ARB. Results: Whole-day UNaV was not altered by ARB whereas whole-day UKV decreased. Even during the ARB treatment, the significant relationship persisted between the night/day ratios of UNaV and UKV (r=0.56, p<0.0001). Whole-day UKV/UNaV 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 UKV ratio correlated directly with the change in night/day UNaV ratio (F=20.4) rather than with the changes in aldosterone, BP or creatinine clearance. Conclusions: The circadian rhythm of UKV was determined by the rhythm of UNaV even during ARB treatment. Changes in the circadian UKV rhythm were not determined by aldosterone but by UNaV.

Angiotensin receptor blockers regulate the synchronization of circadian rhythms in heart rate and blood pressure.

Objective: The sympathetic nervous system plays an important role in blood pressure regulation even in the early stages of chronic kidney disease (CKD). Methods: To understand the role of the sympathetic system, we examined the relationship between day/night ratios of both heart rate (HR) and mean arterial pressure (MAP) as well as HR variability (HRV, SD) before and during an 8-week treatment with the angiotensin II receptor blocker (ARB), olmesartan, in 45 patients with CKD. Results: The day/night HR ratio strongly correlated with the day/night MAP ratio before and during ARB treatment. The ratio of [day/night HR ratio] over [day/night MAP ratio] was increased as renal function deteriorated at baseline (r = −0.31, P = 0.04), and it was attenuated (1.10 ± 0.10 to 1.06 ± 0.10; P = 0.04) and became independent of renal function during ARB treatment (r = −0.04, P = 0.8). ARB increased both the day/night HR ratio (1.17 ± 0.09 to 1.21 ± 0.13; P = 0.04) and HRV (10.6 ± 2.9 to 11.7 ± 4.2; P = 0.04), which were lower when baseline renal function deteriorated. Conclusion: The present study indicates that there exists a close correlation in circadian rhythms between HR and MAP in CKD. Synchronization between the two rhythms was progressively lost as renal function deteriorated, and ARB partly restored the synchronization. These findings suggest that the sympathetic nervous system is activated as renal function deteriorates, and ARB may suppress its activation.

Morning hypertension in chronic kidney disease is sustained type, but not surge type.

ObjectiveWe have shown that as renal function deteriorates, the circadian blood pressure (BP) rhythm shifts to a nondipper pattern and the duration until nocturnal BP decline [dipping time (DT)] is prolonged. We investigated whether or not morning hypertension (BP 2 h after awakening >135/85 mmHg) in chronic kidney disease (CKD) was sustained type with a prolonged DT. Materials and methodsTwenty-four-hour BP was monitored in 104 patients with CKD. Fifty-one of 104 participants (group A) did not exhibit morning hypertension. The patients with morning hypertension (group B, n=53) were classified into three groups: group C (n=23), participants who exhibited morning hypertension but did not meet the criteria for the surge or sustained type; group D (n=29), the sustained type (with no night-time BP readings <120/70 mmHg); and group E (n=1), the surge type (systolic BP rises >25 mmHg after awakening). ResultsThe night/day BP ratio and DT were compared among groups A, C, and D because there was only one participant in group E. Night/day ratio of BP and DT were both significantly higher in group D compared with groups A and C. The prevalence of nondippers tended to be higher in group D compared with the other groups (A, 65%; C, 57%; D, 86%, P=0.09). Creatinine clearance was significantly lower in group D compared with groups A and C. ConclusionSustained elevation of night-time BP until the early morning and high night/day ratio of BP may contribute to the high frequency of morning hypertension, which is generally the sustained rather than the surge type in CKD.

Predictors of proteinuria reduction by monotherapy with an angiotensin receptor blocker, olmesartan

Introduction: It is known that reduced glomerular filtration rate (GFR) is a crucial factor to limit the blood pressure lowering effect of antihypertensives. In the present study, we tested whether the effects of monotherapy with an angiotensin receptor blocker (ARB) to lower proteinuria could be restricted by reduced GFR. Materials and methods: Thirty-five renal patients who had albuminuria more than 30 mg/day, but did not have diabetic nephropathy or nephrotic syndrome, were studied before and during eight weeks of monotherapy with ARB, olmesartan. Results: Blood pressure was lowered from 129 ± 18/79 ± 12 to 116 ± 18/72 ± 12 mmHg (p < 0.0001), while albuminuria was reduced from 614±630 to 343±472 mg/day (p < 0.0001). Albuminuria was inversely correlated with GFR both before and during treatment. Albuminuria reduction was enhanced as plasma renin activity (p = 0.047) and dose of olmesartan were increased (p = 0.04). Although the absolute reduction in proteinuria was not correlated with GFR (p = 0.56), the % reduction was significantly proportional with GFR (p = 0.027). Multiple regression analysis demonstrated that 64% of proteinuria reduction could be explained by baseline levels of albuminuria, GFR and renin activity. Conclusions: The reduction in proteinuria by olmesartan may be roughly predicted using baseline GFR and other parameters. These findings clarify that the effect of ARB on proteinuria reduction is restricted by reduced GFR.

Circadian rhythm of urinary potassium excretion in patients with CKD.

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 nighttime 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) revealed 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.

Geographic differences in the increasing ESRD rate have disappeared in Japan

BackgroundWe previously showed that there are marked geographic differences in the incidence of end-stage renal disease (ESRD) within Japan. In addition, the use of renin–angiotensin system inhibitors was found to be inversely correlated with the increasing ESRD rate. It was recently demonstrated that the incidence of ESRD due to diabetic nephropathy is declining in both Europe and USA. Therefore, we investigated the increasing ESRD rate and its geographic difference in Japan.MethodsEach year, the Japanese Society for Dialysis Therapy reports the numbers of patients initiating maintenance dialysis therapy in each prefecture of Japan. We used old (1984–1991) and recent (2001–2008) data to compare the increasing ESRD rate, which was estimated from the slope of the regression line of the annual incidence corrected for population, between the two periods in 11 regions of Japan.ResultsIncreasing ESRD rate almost halved, from 11.1 ± 5.6 to 5.4 ± 0.7/million per year from the old to the recent period. Deceleration of the increasing ESRD rate from the old to the recent period was correlated with the incidence in the old period across 11 regions (r = 0.81, p < 0.003); i.e., the deceleration was greater in the regions where ESRD incidence had been higher. Whereas the increasing ESRD rate was significantly different among regions in the old period, this was not the case in the recent period, resulting in uniformity throughout Japan.ConclusionsThe increasing ESRD rate is slowing in Japan, and its geographic differences, previously observed, have disappeared.

731 Postural decreases in natriuresis can be used to detect diminished renal reserve leading to a non-dipper type of circadian BP rhythm

Objectives: Sodium-sensitivity of the blood pressure (BP) is not easy to determine in clinical scene. We postulated that impaired renal sodium excretion capability enhances sodium-sensitivity of BP,sustaining high nocturnal BP (i.e., non-dippers) to compensate for diminished daytime natriuresis. Activities during the daytime, in which an upright position is maintained for a longer period than night-time, lower the glomerular capillary hydraulic pressure. Therefore, we presume that patients, whose urinary sodium excretion rate (UNaV) is diminished on shifting the body position from supine to upright, exhibit a non-dipper circadian BP rhythm. Design and methods: Twenty-seven subjects with CKD [13 male/14 female, 43 ± 19 years] were asked to lie in a supine position for 1.5 h. The urine excreted during the first 30 min was discarded, and the urine excreted during the remaining 1 h was used to examine supine UNaV (mmol/h). After the supine examination, the subjects kept upright position for 30 min. The urine excreted during the 30 min was used to calculate upright UNaV. During the test, the BP is measured every 15 min with a validated automatic device. The Next day, 24h-ABPM was recorded every 30 min. Results: Night/day BP ratio correlated inversely with the upright/supine ratios of BP (r = -0.38), creatinine clearance (Ccr)(r = -0.48), and UNaV (r = -0.54). Upright/supine UNaV ratio had direct relationships with upright/supine ratio of Ccr (r = 0.84). Multiple regression analysis (r2 = 0.26, p = 0.004) identified the upright/supine UNaV (F = 10.1, p = 0.004) ratio as an independent determinant of night/day BP ratio, rather than upright/supine ratios of MAP, or Ccr. Conclusions: Postural decrease in UNaV can be used to detect diminished renal sodium excretion capability, indicating high sodium-sensitivity leading to non-dipper BP rhythm.