A nationwide analysis of renal and patient outcomes for adults with lupus nephritis in Japan.

BACKGROUND: The prognosis of lupus nephritis (LN) has improved following the introduction of effective immunosuppressive therapy and progress in supportive care. This study examined recent renal and patient prognosis for adults with LN in Japan. METHODS: We conducted a nationwide retrospective cohort study of LN patients who received a renal biopsy between 2007 and 2012 that were registered in the Japan Renal Biopsy Registry. Of 623 registered adults with LN from 25 institutions and their affiliated or community hospitals, 489 were eligible for this study. RESULTS: The median age at renal biopsy was 39 years, and 82.2% of patients were female. Renal biopsies were performed in 348 patients with new-onset LN, 106 with relapse LN, and 35 with refractory LN. The distribution of ISN/RPS 2003 Classes was as follows: I 1.6%; II 5.3%; III (± V) 27.0%; IV (± V) 47.0%; V 18.4%; VI 0.6%. During the median observation period of 63.8 months, 36 patients (7.3%) reached a doubling of serum creatinine or end-stage kidney disease (ESKD), and 28 patients (5.7%) died. The 5 year renal and patient survival rates were 93.9% and 94.7%, respectively. Multivariate analysis revealed body mass index (BMI) and estimated glomerular filtration rate (eGFR) were independent risk factors for a doubling of serum creatinine in ESKD. Age and eGFR were independent risk factors for death. CONCLUSION: Recent prognosis for adults with LN are relatively good in Japan. Risk factors for impaired renal function are BMI and eGFR at renal biopsy, while age and eGFR are risk factors for death.

Immunosuppressive therapy for active IgA nephropathy is effective and safe, even in "elderly" patients.

Proportions of elderly aged ≥65 and ≥75 within Japan will increase to 30 and 20 %, respectively, in 2025, when "Baby-Boom Generations" will reach the age of 75 years. Okabayashi and colleagues report that even in elderly patients with IgA nephropathy (IgAN), immunosuppressive treatment can reduce proteinuria, with no adverse events. Their findings remind us of recent finding from STOP-IgAN study; additional immunosuppressive therapy to intensive supportive care [specifically renin-angiotensin system (RAS) inhibitors (RASi)] did not improve the outcome. If STOP-IgAN makes doctors believe that immunosuppression is not necessary, many patients could lose opportunity to eliminate their kidney disease. Indeed, we have experienced patients with IgAN, who despite hematuria, could not undergo renal biopsy or immunosuppressive treatment at another facility because of low proteinuria, and exhibited advanced lesions in their renal biopsy at our institution. The discrepancy between Okabayashi's and STOP-IgAN study was derived not only from differences in population age (≥60 years vs. 18-70 years). STOP-IgAN excluded the crescentic IgAN, whereas Okabayashi et al. found active manifestations (hematuria, mesangial proliferation, and cellular/fibrocellular crescent). Therefore, immunosuppressive therapy is required even in elderly patients. In STOP-IgAN, RASi were used first, and then immunosuppressive agent was additionally used. RASi has important implications to reduce glomerular capillary pressure and to suppress the intrarenal RAS activity. However, immunosuppressant should be administered initially to cure hematuria. In fact, microscopic-hematuria was resolved in only 16 and 42 % of two-assigned groups in STOP-IgAN, respectively. Okabayashi et al. provided a timely message regarding the significance of immunosuppressive treatment of IgAN.

Identification of chromosome 3q28 and ALPK1 as susceptibility loci for chronic kidney disease in Japanese individuals by a genome-wide association study.

BACKGROUND: Although genome-wide association studies (GWASs) have implicated several genes in the predisposition to chronic kidney disease (CKD) in Caucasian or African American populations, the genes that confer susceptibility to CKD in Asian populations remain to be identified definitively. We performed a GWAS to identify genetic variants that confer susceptibility to CKD in Japanese individuals. METHODS: 3851 Japanese individuals from three independent subject panels were examined. Subject panels A, B, and C comprised 252, 910, and 190 individuals with CKD and 249, 838, and 1412 controls, respectively. A GWAS for CKD was performed in subject panel A. RESULTS: Five single nucleotide polymorphisms (SNPs) at chromosome 3q28, ALPK1, FAM78B, and UMODL1 were significantly (false discovery rate<0.05) associated with CKD by the GWAS. The relation of these five SNPs and of an additional 22 SNPs at these loci to CKD was examined in subject panel B, revealing that rs9846911 at 3q28 was significantly associated with CKD in all individuals and that rs2074381 and rs2074380 in ALPK1 were associated with CKD in individuals with diabetes mellitus. These three SNPs were further examined in subject panel C, revealing that rs2074381 and rs2074380 were significantly associated with CKD. For subject panels B and C combined, rs9846911 was significantly associated with CKD in all individuals and rs2074381 and rs2074380 were associated with CKD in diabetic individuals. CONCLUSIONS: Chromosome 3q28 may be a susceptibility locus for CKD in Japanese individuals, and ALPK1 may be a susceptibility gene for CKD in such individuals with diabetes mellitus.

Impact of an angulated aorto-septal relationship on cardio-cerebrovascular outcomes in patients undergoing hemodialysis.

Aortic and valvular calcification are well-known risk factors for cardio-cerebrovascular events in patients undergoing hemodialysis. We investigated the clinical impact of an angulated aorto-septal angle as a result of aortic elongation due to aortic calcification on cardio-cerebrovascular outcomes in patients undergoing hemodialysis. We investigated 306 patients (mean age 65.4 years, 68% male) who underwent pre-scheduled routine echocardiography between April and September 2018. The angle between the anterior wall of the aorta and the ventricular septal surface (ASA) was quantified. We determined aortic and mitral valve calcification scores based on calcified cardiac changes; the aortic and mitral valve scores ranged between 0-9 and 0-6, respectively. The primary endpoint was a composite including cardio-cerebrovascular events and cardio-cerebrovascular death. The mean duration of dialysis among the patients in this analysis was 9.6 years. The primary endpoint was observed in 54 patients during the observational period (median 1095 days). Multivariable Cox proportional hazards analyses identified left ventricular ejection fraction (per 10% increase: hazard ratio [HR] 0.67; 95% confidential interval [CI] 0.53-0.84, P = 0.001), left ventricular mass index (per 10 g/m2 increase: HR 1.14; 95% CI 1.05-1.24, P = 0.001), ASA (per 10 degree increase: HR 0.69; 95% CI 0.54-0.88; P = 0.003), and aortic valve calcification score (HR 1.15; 95% CI 1.04-1.26, P = 0.005) as independent determinants of the primary endpoint. Kaplan-Meier analysis showed a higher incidence of the primary endpoint in patients with ASA <119.4 degrees than those with ASA ≥119.4 degrees (Log-rank P < 0.001). An angulated aorto-septal angle is an independent risk factor for cardio-cerebrovascular events and cardio-cerebrovascular death in patients undergoing hemodialysis.

Non-A Blood Type Is a Risk Factor for Poor Cardio-Cerebrovascular Outcomes in Patients Undergoing Dialysis.

The clinical impact of ABO blood type on cardio-cerebrovascular outcomes in patients undergoing dialysis has not been clarified. A total of 365 hemodialysis patients participated in the current study. The primary endpoint was defined as a composite including cardio-cerebrovascular events and cardio-cerebrovascular death. The primary endpoint was observed in 73 patients during a median follow-up period of 1182 days, including 16/149 (11%) with blood type A, 22/81 (27%) with blood type B, 26/99 (26%) with blood type O, and 9/36 (25%) with blood type AB. At baseline, no difference was found in the echocardiographic parameters. Multivariable Cox regression analyses revealed that blood type (type A vs. non-A type; hazard ratio (HR): 0.46, 95% confidence interval (95% CI): 0.26-0.81, p = 0.007), age (per 10-year increase; HR: 1.47, 95% CI: 1.18-1.84), antiplatelet or anticoagulation therapy (HR: 1.91, 95% CI: 1.07-3.41), LVEF (per 10% increase; HR: 0.78, 95% CI: 0.63-0.96), and LV mass index (per 10 g/m2 increase; HR: 1.07, 95% CI: 1.01-1.13) were the independent determinants of the primary endpoint. Kaplan-Meier curves also showed a higher incidence of the primary endpoint in the non-A type than type A (Log-rank p = 0.001). Dialysis patients with blood type A developed cardio-cerebrovascular events more frequently than non-A type patients.

Salt sensitivity and nondippers in chronic kidney disease.

High salt-sensitivity and nondipper blood pressure (BP) rhythm are highly associated with each other, because both are caused by impaired renal sodium excretion capability. We proposed that nocturnal hypertension and resultant pressure natriuresis could compensate for daytime sodium retention. If so, high BP may continue until sodium is sufficiently excreted at night. In fact, it takes longer for the night-time BP to fall in patients with more severe renal dysfunction. The time appears to be an essential component of the nondipper BP rhythm and, therefore, we defined the duration as the dipping time. Also, renal function was the sole determinant of a nocturnal BP dip other than age, sex, or BMI. Furthermore, we reported that diuretic therapy or dietary salt restriction, which can prevent sodium retention, restored the circadian BP rhythm into a dipper pattern. Large-scale studies are needed to explore whether these interventions can decrease the risks.

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.

Low birth weight and end-stage renal disease: demographic analysis by region in Japan.

UNLABELLED: BACKGROUND We have previously shown regional differences in the incidence of end-stage renal disease (ESRD)within Japan, which is ethnically homogenous, suggesting that non-genetic factors may contribute to the differences.We examined regional distribution in the incidence of low birth weight (LBW), a surrogate for low nephron number,in our search for an explanation. METHODS: Each year, the Ministry of Health, Labour and Welfare of Japan and the Japanese Society for Dialysis Therapy report the number of LBW babies and patients initiating maintenance dialysis in each prefecture of Japan,respectively. In this study, we calculated the annual incidences of LBW and ESRD in 11 regions of Japan over a 24-year period from 1984 to 2007. RESULTS: There were distinct regional differences in the annual incidences of both LBW and ESRD (p<0.0001).These regional distributions persisted despite consistent increases (p<0.0001) in incidences of both LBW and ESRD during the study period. Compared with the reference group consisting of 3 regions with the lowest LBW incidence, the odds ratios for ESRD (95% confidence interval) of the 5 regions with intermediate LBW incidence and the 3 regions with the highest LBW incidence are 1.09(1.05­1.14) and 1.29 (1.22­1.35), respectively. The annual incidence of LBW was positively correlated with annual incidence of ESRD in their regional distribution across 11 regions (r = 0.66, p = 0.03). CONCLUSIONS: The present study, relating regional distribution between LBW and ESRD dynamics in a nationwide population of Japan, revealed that the marked regional differences in the incidence of ESRD within Japan could be explained by a similar regional distribution in the incidence of LBW.

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.

Geographic differences in the increasing ESRD rate have disappeared in Japan.

BACKGROUND: We 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. METHODS: Each 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. RESULTS: Increasing 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. CONCLUSIONS: The increasing ESRD rate is slowing in Japan, and its geographic differences, previously observed, have disappeared.

Association of a genetic variant of BTN2A1 with chronic kidney disease in Japanese individuals.

AIM: Although recent genetic studies suggested that several genetic variants increase the risk for chronic kidney disease (CKD), the genes that underlie genetic susceptibility to this condition remain to be identified definitively. We showed that the C→T polymorphism (rs6929846) of BTN2A1 and A→G polymorphism (rs2569512) of ILF3 were significantly associated with myocardial infarction in Japanese individuals by a genome-wide association study. The purpose of the present study was to examine a possible association of these polymorphisms (rs6929846, rs2569512) with CKD in Japanese individuals. METHODS: A total of 7542 Japanese individuals from two independent populations were examined: Subject panel A comprised 971 individuals with CKD (estimated glomerular filtration rate (eGFR) <60 mL/min 1.73 m(-2)) ) and 2269 controls (eGFR ≥60 mL/min 1.73 m(-2) ); and subject panel B comprised 1318 individuals with CKD and 2984 controls. RESULTS: The χ(2) test revealed that rs6929846 of BTN2A1, but not rs2569512 of ILF3, was significantly related to the prevalence of CKD both in subject panels A (P = 0.0383) and B (P = 0.0477). Multivariable logistic regression analysis with adjustment for covariates revealed that the C→T polymorphism (rs6929846) of BTN2A1 was significantly associated with the prevalence of CKD in subject panels A (P = 0.0422; recessive model; odds ratio, 2.36) and B (P = 0.0386; dominant model; odds ratio, 1.21) with the T allele representing a risk for this condition. CONCLUSION: Our results suggest that BTN2A1 may be a susceptibility gene for CKD in Japanese individuals.

Trans-species polymorphism of the Mhc class II DRB-like gene in banded penguins (genus Spheniscus).

The Major Histocompatibility Complex (Mhc) class II DRB locus of vertebrates is highly polymorphic and some alleles may be shared between closely related species as a result of balancing selection in association with resistance to parasites. In this study, we developed a new set of PCR primers to amplify, clone, and sequence overlapping portions of the Mhc class II DRB-like gene from the 5'UTR end to intron 3, including exons 1, 2, and 3 and introns 1 and 2 in four species (20 Humboldt, six African, five Magellanic, and three Galapagos penguins) of penguin from the genus Spheniscus (Sphe). Analysis of gene sequence variation by the neighbor-joining method of 21 Sphe sequences and 20 previously published sequences from four other penguin species revealed overlapping clades within the Sphe species, but species-specific clades for the other penguin species. The overlap of the DRB-like gene sequence variants between the four Sphe species suggests that, despite their allopatric distribution, the Sphe species are closely related and that some shared DRB1 alleles may have undergone a trans-species inheritance because of balancing selection and/or recent rapid speciation. The new primers and PCR assays that we have developed for the identification of the DRB1 DNA and protein sequence variations appear to be useful for the characterization of the molecular evolution of the gene in closely related Penguin species and might be helpful for the assessment of the genetic health and the management of the conservation and captivity of these endangered species.

A case series of favorable vessel dilatation using a nitinol scoring element-equipped helical balloon catheter (AngioSculpt®).

OBJECTIVE: Although percutaneous transluminal angioplasty is an effective therapy against vascular access failure in hemodialysis patients, recurrent stenosis imposes enormous burden for hemodialysis patients. A nitinol scoring element-equipped helical balloon catheter (AngioSculpt®) has been altered the landscape for treating several vascular diseases. It is not, however, fully elucidated whether AngioSculpt for advanced vascular access stenosis, difficult to expand by conventional balloons, successfully provides bailout angioplasty. Here, we report our cases whose intradialytic venous pressure significantly improved after percutaneous transluminal angioplasty without any serious adverse complications using AngioSculpt. PATIENTS AND METHODS: Among patients undergoing hemodialysis in Masuko Memorial Hospital, 16 cases with resistant and recurrent vascular access stenosis underwent AngioSculpt (diameter 6 mm, total length 4 cm) angioplasty. We simultaneously measured the average venous pressures during hemodialysis before and after percutaneous transluminal angioplasty. RESULTS: The average outflow vessel stenosis rate was 73.0 ± 11.3% before AngioSculpt intervention. Fully enlarged vessels were observed by expanding vessels at maximum pressure of 14 atm in all cases without any complications including vascular ruptures. Their intradialytic venous pressures decreased from 181.8 ± 39.2 mmHg to 150.5 ± 39.3 mmHg ( p < 0.0001). CONCLUSION: AngioSculpt may provide a promising option for treating hemodialysis patients with severely advanced vascular access stenosis, who would otherwise need repeated vascular access surgeries and/or conventional percutaneous transluminal angioplasties.

The angiotensin II type 1 receptor blocker azilsartan can overwhelm the sympathetic nerve activation stimulated by coadministration of calcium channel blockers.

OBJECTIVE:: In our recent study, non-Gaussianity of heart rate variability (λ25s), an indicator of sympathetic nerve activity, did not change during two-day treatment with the angiotensin II type 1 receptor blocker (ARB) azilsartan. Coadministration of calcium channel blockers (CCBs) might affect the study results. METHODS:: In this subanalysis, 20 patients with chronic kidney disease (14 men; age 61±15 years) were divided into three groups: patients with coadministration of L-type CCB, patients without coadministration of CCB, and patients with coadministration of sympathoinhibitory (L/T- or L/T/N-type) CCB. λ25s was calculated separately in daytime and nighttime. RESULTS:: Daytime λ25s at baseline was higher in patients with L-type CCB coadministration (0.62±0.18, n = 5) compared with those without CCB (0.49±0.13, n = 11) and those with sympathoinhibitory CCB (0.46±0.06, n = 4). The relationship between the changes in daytime λ25s and systolic blood pressure was positive in patients with L-type CCB coadministration, whereas the relationship was inverse in the other two groups. A larger decrease in daytime λ25s was shown in patients with L-type CCB coadministration compared with those in the other two groups. CONCLUSIONS:: CCBs, as well as diuretics, are recommended as second-line antihypertensive agents. Our results suggested that ARBs can overwhelm the activation of sympathetic nerve activity stimulated by coadministration of L-type CCBs.

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.

Regional differences in end-stage renal disease and amount of protein intake in Japan.

OBJECTIVE: We recently showed regional differences in the incidence of end-stage renal disease (ESRD) within Japan, which is generally ethnically homogenous, suggesting that factors other than genetic may contribute to the difference. We examined regional differences in the amounts of dietary nutrient intake, especially protein in our search for an explanation. DESIGN AND SETTING: Annually, the Japanese Society for Dialysis Therapy reports the numbers of patients entering maintenance dialysis in each prefecture of Japan. We used these numbers from 1984 to 2002 to calculate the annual ESRD incidence in each of 12 regions of Japan. The regional differences were analyzed in relation to the amounts of nutrient intake reported annually by National Nutrition Survey in corresponding regions for these 19 years. Each year, approximately 15,000 subjects from 5000 households in randomly selected 300 districts were included to obtain a representative sample of the entire population of Japanese in a manner of age, sex, and body mass matched. RESULTS: There were marked regional differences in the annual ESRD incidence and small regional differences in dietary intake of each nutrient. Multiple regression analysis showed that the annual ESRD incidence was negatively correlated with energy intake (r = -0.65, F = 240, n = 228) and positively correlated with animal protein intake (r = 0.25, F = 30). Across 12 regions in the values averaged for 19 years in each region, however, the incidence of ESRD was negatively correlated only with the amounts of energy intake (r = -0.74, F = 12, n = 12), but not with animal protein (r = 0.07, F = 0.04). CONCLUSION: The present study, relating regional differences between ESRD dynamics and the amounts of nutrient intake in a nationwide population of Japan, revealed that the renal protective effects of dietary restriction of protein, suggested by animal models of progressive nephropathies but yet unproved by large-scale clinical trials, remained unestablished even on a macro level of whole Japan through mapping approaches.

Sodium balance, circadian BP rhythm, heart rate variability, and intrarenal renin-angiotensin-aldosterone and dopaminergic systems in acute phase of ARB therapy.

We have revealed that even in humans, activated intrarenal renin-angiotensin-aldosterone system (RAAS) enhances tubular sodium reabsorption to facilitate salt sensitivity and nondipper rhythm of blood pressure (BP), and that angiotensin receptor blocker (ARB) could increase daytime urinary sodium excretion rate (UNaV) to produce lower sodium balance and restore nondipper rhythm. However, the sympathetic nervous system and intrarenal dopaminergic system can also contribute to renal sodium handling. A total of 20 patients with chronic kidney disease (61 ± 15 years) underwent 24-h ambulatory BP monitoring before and during two-day treatment with ARB, azilsartan. Urinary angiotensinogen excretion rate (UAGTV, µg/gCre) was measured as intrarenal RAAS; urinary dopamine excretion rate (UDAV, pg/gCre) as intrarenal dopaminergic system; heart rate variabilities (HRV, calculated from 24-h Holter-ECG) of non-Gaussianity index λ25s as sympathetic nerve activity; and power of high-frequency (HF) component or deceleration capacity (DC) as parasympathetic nerve activity. At baseline, glomerular filtration rate correlated inversely with UAGTV (r = -0.47, P = 0.04) and positively with UDAV (r = 0.58, P = 0.009). HF was a determinant of night/day BP ratio (ß = -0.50, F = 5.8), rather than DC or λ25s During the acute phase of ARB treatment, a lower steady sodium balance was not achieved. Increase in daytime UNaV preceded restoration of BP rhythm, accompanied by decreased UAGTV (r = -0.88, P = 0.05) and increased UDAV (r = 0.87, P = 0.05), but with no changes in HRVs. Diminished sodium excretion can cause nondipper BP rhythm. This was attributable to intrarenal RAAS and dopaminergic system and impaired parasympathetic nerve activity. During the acute phase of ARB treatment, cooperative effects of ARB and intrarenal dopaminergic system exert natriuresis to restore circadian BP rhythm.

Pathophysiology of antihypertensive therapy with diuretics.

Recent progress in antihypertensive therapy has widened the selection of drugs, and large clinical trials have attracted attention to newer classes of antihypertensives. Consequently, the use of diuretics as antihypertensive agents has been relatively reduced, particularly since the newer drugs are associated with fewer adverse metabolic reactions. However, diuretics have a specific activity of removing sodium from the body fluid, thereby rendering the blood pressure insensitive to sodium intake, relieving the overload to systemic circulation, and normalizing the circadian rhythm of blood pressure from a non-dipper to a dipper pattern. At low doses, diuretics are known to be as effective as all other antihypertensive agents for reducing nearly all types of cardiovascular events. In this brief review, the indication for thiazide diuretics will be discussed based on the pathophysiology of hypertension and antihypertensive therapy with diuretics mainly from the point of view of sodium metabolism. Low-dose diuretics will continue to be an important agent in the treatment of hypertension, mostly in combination with vasodilators such as modulators of the reninangiotensin system and calcium channel blockers.

Hypothesis on renal mechanism of non-dipper pattern of circadian blood pressure rhythm.

In some patients with sodium sensitive type of hypertension or kidney disease, blood pressure (BP) fails to dip during night and they have been called "non-dipper", whereas those with a normal nocturnal dip are called "dipper". Many investigators reported that non-dippers were certainly exposed to greater risks of cardiovascular complications. We have recently proposed that kidneys play an important role in determining the circadian rhythm of BP, in addition to long-term BP regulation. When sodium intake is high, the defect in sodium excretory capability of kidneys becomes evident, making BP during night elevated, that is non-dipper, in order to compensate for diminished natriuresis during daytime and to enhance pressure-natriuresis during night. Therefore, as renal function deteriorates, longer duration may be required before BP begins to dip during night. Non-dipping may be one mechanism causing cardiovascular events in chronic kidney disease.