Yuichi Shirasawa

Patients With Renal Dysfunction Require a Longer Duration Until Blood Pressure Dips During the Night

We have postulated that the diminished renal capacity to excrete sodium causes nocturnal blood pressure (BP) elevation, which enhances pressure natriuresis in compensation for impaired daytime natriuresis. If such a mechanism holds, high BP during sleep at night may continue until excess sodium is sufficiently excreted into urine. This study examined whether the duration, defined as “dipping time,” until nocturnal mean arterial pressure began to fall to <90% of daytime average became longer as renal function deteriorated. Ambulatory BP measurements and urinary sodium excretion rates were evaluated for daytime and nighttime to estimate their circadian rhythms in 65 subjects with chronic kidney disease. Dipping time showed an inverse relationship with creatinine clearance (Ccr; &rgr;=−0.61; P<0.0001) and positive relationships with night/day ratios of mean arterial pressure (&rgr;=0.84; P<0.0001) and natriuresis (&rgr;=0.61; P<0.0001), both of which were also inversely correlated with Ccr (mean arterial pressure: r=−0.58, P<0.0001; natriuresis: r=−0.69, P<0.0001). When divided into tertiles by Ccr (mL/min), hazard ratios of nocturnal BP dip adjusted for age, gender, and body mass index were 0.37 (95% CI: 0.17 to 0.79; P=0.01) for the second tertile (Ccr: 50 to 90) and 0.20 (95% CI: 0.08 to 0.55; P=0.002) for the third tertile (Ccr: 5 to 41) compared with the first tertile (Ccr: 91 to 164). These findings demonstrate that patients with renal dysfunction require a longer duration until BP falls during the night. The prolonged duration until BP dip during sleep seems an essential component of the nondipper pattern of the circadian BP rhythm.

Angiotensin II type 1 receptor blocker, olmesartan, restores nocturnal blood pressure decline by enhancing daytime natriuresis.

Objective We have shown that as renal function deteriorated, night-time fall in both blood pressure and urinary sodium excretion were diminished. We have also reported that sodium intake restriction and diuretics both normalized circadian blood pressure rhythm from nondipper to dipper patterns. In this study, we investigated whether an angiotensin II receptor blocker, olmesartan, could restore night-time blood pressure fall. Methods Twenty patients with chronic kidney disease (13 men, seven women; mean age 44.8 ± 18.1 years; BMI 22.9 ± 3.5 kg/m2) were studied. At baseline and 8 weeks after the treatment with olmesartan medoxomil (10–40 mg/day), 24-h blood pressure monitoring and urinary sampling for both daytime (0600–2100 h) and night-time (2100–0600 h) were repeated to compare the circadian rhythms of blood pressure and urinary sodium excretion. Results The 24-h mean arterial pressure was lowered by olmesartan, while urinary sodium excretion remained unchanged. On the other hand, daytime urinary sodium excretion was increased from 4.8 ± 2.2 to 5.7 ± 2.1 mmol/h, while night-time urinary sodium excretion tended to be reduced from 3.9 ± 1.7 to 3.4 ± 1.6 mmol/h. Night/day ratios of mean arterial pressure (0.98 ± 0.1 to 0.91 ± 0.08; P = 0.01) and urinary sodium excretion (0.93 ± 0.5 to 0.68 ± 0.4; P = 0.0006) were both decreased. Olmesartan enhanced night-time falls more in mean arterial pressure (r = 0.77; r2 = 0.59; P < 0.0001) and urinary sodium excretion (r = 0.59; r2 = 0.34; P = 0.007), especially in patients whose baseline night-time falls were more diminished. Conclusions These findings demonstrated that olmesartan could restore night-time blood pressure fall, as seen with diuretics and sodium restriction, possibly by enhancing daytime sodium excretion. Since nocturnal blood pressure is a strong predictor of cardiovascular events, olmesartan could relieve cardiorenal load through normalization of circadian blood pressure rhythm besides having powerful ability to block the renin–angiotensin system.

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.