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BackgroundThe Y-AIDA study was designed to investigate the renal- and home blood pressure (BP)-modulating effects of add-on dapagliflozin treatment in Japanese individuals with type 2 diabetes mellitus (T2DM) and albuminuria.MethodsWe conducted a prospective, multicenter, single-arm study. Eighty-six patients with T2DM, HbA1c 7.0–10.0%, estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73 m2, and urine albumin-to-creatinine ratio (UACR) ≥ 30 mg/g creatinine (gCr) were enrolled, and 85 of these patients were administered add-on dapagliflozin for 24 weeks. The primary and key secondary endpoints were change from baseline in the natural logarithm of UACR over 24 weeks and change in home BP profile at week 24.ResultsBaseline median UACR was 181.5 mg/gCr (interquartile range 47.85, 638.0). Baseline morning, evening, and nocturnal home systolic/diastolic BP was 137.6/82.7 mmHg, 136.1/79.3 mmHg, and 125.4/74.1 mmHg, respectively. After 24 weeks, the logarithm of UACR decreased by 0.37 ± 0.73 (P P P P = 0.0079 for systolic BP,P = 0.0415 for diastolic BP). Furthermore, the reduction in UACR after 24 weeks significantly correlated with an improvement in home BP profile, but not with changes in other variables, including office BP. Multivariate linear regression analysis also revealed that the change in morning home systolic BP was a significant contributor to the change in log-UACR.ConclusionsIn Japanese patients with T2DM and diabetic nephropathy, dapagliflozin significantly improved albuminuria levels and the home BP profile. Improved morning home systolic BP was associated with albuminuria reduction.Trial registrationThe study is registered at the UMIN Clinical Trials Registry (UMIN000018930;http://www.umin.ac.jp/ctr/index-j.htm). The study was conducted from July 1, 2015 to August 1, 2018.

The carotid bulb has a high density of baroreceptors that play an important role in maintaining blood pressure. We hypothesized that atherosclerosis of the carotid bulb would reflect the severity of orthostatic hypotension more accurately than would atherosclerosis of other carotid artery segments.This cross-sectional study included 198 non-diabetic adults. We measured the cardio-vascular ankle index as an index of arterial stiffness, intima-media thickness in each carotid artery segment (internal carotid artery, carotid bulb, distal and proximal portions, respectively, of the common carotid artery) as a measure of atherosclerosis, and heart rate variability as a measure of cardiac autonomic function. The sit-to-stand test was used to assess severity of orthostatic hypotension.Intima-media thickness of the carotid bulb was correlated with orthostatic systolic blood pressure change (r = -0.218, p = 0.002), cardio-ankle vascular index (r = 0.365, p0.001) and heart rate variability parameters. Multivariate regression analysis revealed that among all of the segments, only intima-media thickness of the carotid bulb was an independent predictor of orthostatic systolic blood pressure change (p = 0.022).Atherosclerosis of the carotid bulb was associated with severity of orthostatic hypotension, arterial stiffening and cardiac autonomic dysfunction than that of other carotid artery segments.

Few studies have examined how renin–angiotensin system inhibitors (RASI) delay dialysis initiation in patients with advanced chronic kidney disease (CKD). We conducted a retrospective survey to examine this subject. We reviewed the records of patients with advanced CKD for the 60-month period before dialysis initiation between 1990 and 2015. Patients were classified based on the decade of dialysis initiation into the 1990s, 2000s, and 2010s groups. The rates of antihypertensive medications administered were assessed. The rate of decline of renal function was evaluated by the slope of reciprocal serum creatinine (SRSC). Multiple regression analyses were conducted to evaluate factors contributing to renoprotection. The duration of RASI administration was longer in the 2010s than in 2000s and 1990s. Both diabetic and non-diabetic patients had lower SRSC in the 2010s compared to the 2000s. In the 2010s, the rate of RASI administration during the 60-month pre-dialysis period showed an initial rise followed by a downward trend, although the rates of administration of the other classes of antihypertensives increased continuously. Multivariate regression analyses identified age, blood pressure, diuretics, α-blockers, α-methyldopa and RASI as independent predictors of SRSC in the 2010s. The rate of RASI administration correlated with serum potassium concentration. Our findings suggest that in the 2010s, RASI with other antihypertensive agents contributed to renoprotection in advanced CKD patients, but they were underused because of the concern over hyperkalemia. In real-world clinical practice, physicians may feel great hesitation in using RASI in patients with advanced CKD.

It remains unclear whether the abnormal circadian blood pressure (BP) rhythm in non-diabetic chronic kidney disease (CKD) is related to hypoalbuminemia. We evaluated relationships between circadian BP rhythm and serum albumin concentration (SAC) and also examined autonomic nervous activities. Non-diabetic CKD patients with proteinuria (n = 197; 105 men, 92 women; aged 47.0 ± 13.3 years; estimated glomerular filtration rate ≥30 ml/min) were divided into nephrotic syndrome (NS: n = 46, SAC ≤ 30 g/l), hypoalbuminemia (n = 65, 30

In the 'Millennium Genome Project', we identified ATP2B1 as a gene responsible for hypertension through single-nucleotide polymorphism analysis. The ATP2B1 gene encodes the plasma membrane calcium ATPase isoform 1, which contributes to the maintenance of intracellular calcium homeostasis by removing calcium ions.Since ATP2B1 knockout mice are reported to be embryo-lethal, we generated systemic heterozygous ATP2B1 null (ATP2B1(+/-)) mice, and evaluated the implication of ATP2B1 in blood pressure.ATP2B1(+/-) mice revealed significantly higher SBP as measured by a radiotelemetric method. Phenylephrine-induced vasoconstriction was significantly increased in vascular rings from ATP2B1(+/-) mice, and the difference in this contraction disappeared in the presence of a nitric oxide synthase (NOS) inhibitor. Vasorelaxation to acetylcholine was significantly attenuated in vascular rings from ATP2B1(+/-) mice. In addition, cultured endothelial cells of ATP2B1(+/-) mice showed that the phosphorylation (Ser-1177) level of endothelial NOS protein was significantly lower, and nitric oxide production in endothelial cells and aorta was lower compared with those in control mice. In contrast, neural NOS expression in vascular smooth muscle cells from ATP2B1(+/-) mice and control mice were not significantly different.These results suggest that decreased ATP2B1 gene expression is associated with impaired endothelial NOS activity and nitric oxide production, and the ATP2B1 gene plays a crucial role in the regulation of blood pressure.

Residual renal function preservation in patients with renal failure has been shown to be related to better outcomes not only in the pre-dialysis phase but also after hemodialysis initiation. However, the effect of factors such as antihypertensive agents on residual renal function preservation has not been investigated adequately in prevalent hemodialysis patients. This study examined factors related to the rate of residual renal function preservation in 1-year hemodialysis patients who had residual renal function. We enrolled 191 consecutive maintenance hemodialysis patients who underwent hemodialysis for 1 year and maintained a urine output of more than 200 mL/day, to assess residual renal function loss. The rate of residual renal function loss was 19.9%. Multivariate analysis using residual renal function as the dependent variable revealed significant independent relationships with renin-angiotensin system inhibitor use (hazard ratio, 0.438; P = 0.027), history of cardiovascular disease (hazard ratio, 2.475; P = 0.024), and rate of weight gain between dialysis sessions (hazard ratio, 1.348; P = 0.013). No relationship was observed with calcium channel blocker use. Renin-angiotensin system inhibitor use, rate of body weight gain between dialysis sessions, and cardiovascular diseases are independently associated with residual renal function preservation in patients with residual renal function after 1 year of hemodialysis. A further intervention study is required to investigate whether treatment with renin-angiotensin system inhibitors and suppression of body weight gain preserves residual renal function for a longer time in hemodialysis patients.

We reported previously that ATP2B1 was one of the genes for hypertension receptivity in a large-scale Japanese population, which has been replicated recently in Europeans and Koreans. ATP2B1 encodes the plasma membrane calcium ATPase isoform 1, which plays a critical role in intracellular calcium homeostasis. In addition, it is suggested that ATP2B1 plays a major role in vascular smooth muscle contraction. Because the ATP2B1 knockout (KO) mouse is embryo-lethal, we generated mice with vascular smooth muscle cell-specific KO of ATP2B1 using the Cre-loxP system to clarify the relationship between ATP2B1 and hypertension. The KO mice expressed significantly lower levels of ATP2B1 mRNA and protein in the aorta compared with control mice. KO mice showed significantly higher systolic blood pressure as measured by tail-cuff method and radiotelemetric method. Similar to ATP2B1, the expression of the Na + -Ca 2+ exchanger isoform 1 mRNA was decreased in vascular smooth muscle cells of KO mice. However, ATP2B4 expression was increased in KO mice. The cultured vascular smooth muscle cells of KO mice showed increased intracellular calcium concentration not only in basal condition but also in phenylephrine-stimulated condition. Furthermore, phenylephrine-induced vasoconstriction was significantly increased in vascular rings of the femoral artery of KO mice. These results suggest that ATP2B1 plays important roles in the regulation of blood pressure through alteration of calcium handling and vasoconstriction in vascular smooth muscle cells.

Small dense low-density lipoprotein (LDL) plays an important role in glomerular injury through conversion to an oxidatively modified form of LDL. However, few studies have evaluated the effects of antilipidemic agents on the LDL particle size and renal function in hyperlipidemic patients with nondiabetic nephropathy.This study was a randomized crossover trial comparing the effects of atorvastatin (10 mg/day) and probucol (500 mg/day) administered for 24 weeks in 31 patients (urinary albumin excretion 0.3-2.0 g/day and creatinine clearance30 mL/min/1.73 m (2) ). Lipid parameters, mean LDL particle diameter, creatinine clearance, and urinary albumin to creatinine excretion ratio were measured before and during treatment periods.Atorvastatin and probucol significantly reduced the serum total cholesterol and LDL cholesterol concentrations. When stratified by mean baseline LDL particle size at 25.5 nm, atorvastatin increased (p0.05) LDL particle size from 24.6 +/- 0.5 to 25.2 +/- 0.9 nm only in the25.5 nm (pattern B) group, whereas probucol decreased (p0.05) LDL size from 24.8 +/- 0.9 to 24.2 +/- 0.9 nm in the pattern B group and from 25.9 +/- 0.5 to 24.6 +/- 0.8 nm in theor=25.5 nm (pattern A) group. No significant differences in urinary albumin/creatinine excretion ratio and creatinine clearance were observed in both groups during treatment.Only atorvastatin improved the LDL-subtype distribution in hyperlipidemic patients with nondiabetic nephropathy, although both agents exhibited no renoprotective action, suggesting that the effects on LDL-subtype distribution do not directly lead to renoprotection.

Although obesity is recognized to be a risk factor for chronic kidney disease (CKD), few studies have reported the association between obesity and CKD in the young population. We investigated the relationship between obesity and renal function including proteinuria in young Japanese.This cross-sectional study consisted of 16,031 men and 5,746 women aged from 20 to 39 years who received health examinations. The subjects were stratified into four age groups (20-24, 25-29, 30-34, and 35-39 years) or into four groups based on the number of risk factors (hypertension, hyperglycemia, dyslipidemia, and hyperuricemia). The relationship between obesity and risk factors and the relationship between obesity and estimated glomerular filtration rate (eGFR) were analyzed.There were no significant differences in eGFR between obese and nonobese groups, except in the male 35-39 years age group. Body mass index (BMI) in both men and women increased with increase in number of risk factors (P0.001). Multivariate analysis revealed that hypertension, hyperglycemia, dyslipidemia, and hyperuricemia were independently associated with obesity. Obesity and the risk factors were independently associated with proteinuria.The present study indicated that obesity was an independent risk factor for proteinuria in healthy subjects younger than 40 years of age. The other risk factors were independently associated with obesity. These findings suggest that obesity causes proteinuria concomitantly with other risk factors such as hypertension, diabetes, and dyslipidemia in young adults.

Background. The presence of silent brain infarction (SBI) increases the risk of symptomatic stroke and dementia. The association between SBI and chronic kidney disease (CKD) has not been clarified. Moreover, little is known about what factors are related to SBI in CKD patients and whether the prevalence of SBI differs in CKD stage or cause of CKD. Methods. This is a cross-sectional study. A total of 375 subjects—335 with CKD and 40 with essential hypertension—were included. All subjects underwent magnetic resonance imaging (MRI) of the brain to detect SBI. Glomerular filtration rate (GFR) was estimated using Modification of Diet in Renal Disease equation, and cardiovascular risk factors were examined. Results. The prevalence of SBI was 56.5% in all subjects. Among causes of CKD, hypertensive nephrosclerosis had a strong association with SBI. According to the estimated GFR (eGFR) stage, the more severe the stage of eGFR, the higher the prevalence of SBI (age-adjusted odds ratio [95% confidence interval] for eGFR 30–59, 15–29 and

Sevelamer improves hyperphosphatemia without increasing the calcium load. However, it remains unknown whether sevelamer restores bone metabolism in hemodialysis patients with low bone turnover osteodystrophy and hypoparathyroidism. We investigated the changes in serum intact parathyroid hormone (iPTH) and bone metabolic marker levels after replacing calcium carbonate with sevelamer in these patients. We also conducted stratified analysis based on patient background and multivariate analysis to determine the factors affecting these parameters. During sevelamer replacement therapy, serum calcium and phosphate concentrations, and the calcium phosphate product were measured at 0, 1, 3, and 6 months. Serum iPTH, bone alkaline phosphatase and osteocalcin concentrations were measured at 0 and 6 months. In hemodialysis patients (71 men and 46 women, 63 +/- 12 years old) serum calcium levels and the calcium phosphate product decreased significantly at 1 month. Serum iPTH, bone alkaline phosphatase and osteocalcin levels increased significantly at 6 months. Increases in serum iPTH concentrations were observed in all stratified groups. Significant increases in serum bone alkaline phosphatase and osteocalcin concentrations were found only in the relative hypoparathyroidism group (iPTH levels > or =51.5 pg/mL, the median pretreatment level). Multivariate analysis showed that the factors affecting change in serum iPTH level are baseline serum iPTH, baseline calcium level (> or =9.5 mg/dL), and dialysis duration of 10 years or longer. Sevelamer appears useful for the treatment of hyperphosphatemia in these patients. Particularly, in the relative hypoparathyroidism group, the iPTH secretory response is probably enhanced and bone turnover may have been improved as a result of reducing the calcium load.

Background: Proteinuria and nighttime blood pressure (BP) elevation are notable risk markers of chronic kidney disease and correlate closely with each other. However, daily urinary protein excretion (UPE) always fluctuates. In patients with minimal change nephrotic syndrome (MCNS), serum albumin concentrations (SAC) decrease but fluctuate less than UPE. We evaluated whether SAC is a reliable marker for proteinuria, and compared the relations among circadian BP changes, SAC, and UPE. Methods: In patients with MCNS (12 men and 11 women, 43 ± 18 years), blood and spot urine samples were collected on three consecutive days before treatment, and 24-hour BP was also measured on the three days. Then, an intervention study was conducted in the patients to examine circadian BP changes induced by treatment. Sleeping/waking BP ratio was analyzed as an indicator of circadian BP rhythm. Results: In the three-day measurements before treatment, mean coefficient of variation, an index of dispersion of data, for SAC was 7.4 ± 7.4%, which was markedly lower (p < 0.01) than 35.7 ± 15.4% for UPE. SAC correlated inversely with sleeping/waking systolic and diastolic BP ratios on all three days, whereas UPE did not correlate significantly with sleeping/waking diastolic BP ratio on day 3. Sleeping/waking systolic and diastolic BP ratios were 96 ± 5 and 95 ± 6%, and were higher (p < 0.05) than in healthy subjects (89 ± 8 and 88 ± 10%). Treatment improved hyperproteinuria and hypoalbuminemia, and was accompanied by decreases (p < 0.05) in sleeping and waking systolic/diastolic BP ratio to 91 ± 8 and 89 ± 9%. Conclusion: These findings suggest that reduced SAC in patients with proteinuria is associated with disrupted circadian BP rhythm.

Editor’s comment: The editorial committee of Diabetes Care had some ethical concerns about potentially leaving patients for up to 24 weeks with blood pressure between 140/90 and 200/110 mmHg. After careful consideration, we decided to publish this article for the following reasons. First, the scientific information was considered valid and important. Second, the study was passed by the institutional review board (IRB) of the investigators. The study was passed by their institution at a time when perhaps ethical guidelines were not as stringent. Third, in response to queries by the editorial committee, the investigators pointed out that other hypertension studies initiated at around that time also had similar protocols. The editorial committee then dealt with the general issue of different criteria utilized by different IRBs around the world. Although the editorial committee will continue to be sensitive to decisions by various IRBs, investigators should realize that the more recent, stricter guidelines will also be considered by the editorial committee should ethical concerns be raised in the review process. OBJECTIVE—Few studies have assessed whether 24-h blood pressure control induced by antihypertensive agents improves macroalbuminuria in hypertensive type 2 diabetic patients with overt nephropathy. We evaluated the effects of losartan and amlodipine on 24-h blood pressure, autonomic nervous activity, and albuminuria in these patients. RESEARCH DESIGN AND METHODS—In this open-label, parallel-prospective, randomized study, 44 patients were treated with losartan and 43 with amlodipine for a 12-week titration phase and a maintenance phase for a maximum of 12 weeks. Twenty-four–hour blood pressure and urinary albumin excretion were measured before and during treatment. Simultaneously, power spectral analysis of heart rate was performed to evaluate low frequency (LF) and high frequency (HF) components and LF-to-HF ratios as an index of sympathovagal balance. RESULTS—Losartan decreased (P < 0.001) mean blood pressure from 162/91 to 150/82 mmHg during daytime and from 146/82 to 137/74 mmHg during nighttime (systolic/diastolic). Amlodipine also decreased (P < 0.001) blood pressure from 159/90 to 147/82 mmHg during daytime and from 143/81 to 131/72 mmHg during nighttime. LF and HF components and nighttime-to-daytime ratios for the LF-to-HF ratios did not differ during treatment in two groups, showing no changes in the diurnal autonomic nervous rhythm. Losartan decreased (P < 0.001) 24-h urinary albumin excretion from 810 mg/day (95% CI 780–1,140) to 570 (510–910). Amlodipine, however, did not decrease (P = 0.893) albuminuria (790 mg/day [780–1,170] vs.790 [710–1,260]). CONCLUSIONS—These results suggest that in type 2 diabetes with overt nephropathy, 24-h blood pressure regulation alone is inadequate to reduce macroalbuminuria and additional effects of losartan are crucial for antiproteinuric action.

Background. Diabetic patients with moderate to advanced renal failure have severe hypertension and often require multiple antihypertensive agents to control it. Nevertheless, no standardized therapy has been established. This study was designed to examine the safety and efficacy of the biliary-excreted angiotensin converting enzyme inhibitor temocapril in those patients whose blood pressure was not adequately decreased by calcium channel blocker monotherapy. Methods. Twenty-seven patients who did not reach the therapeutic goal of blood pressure (140/90 mm Hg) with amlodipine monotherapy were assigned to receive temocapril (2 mg) and amlodipine (5 mg) for 3 months. Blood samples for hematological and biochemical examinations were taken every month during treatment. Twenty-four-hour urine was collected to measure urinary protein excretion. Trough plasma concentrations and pharmacokinetics were measured during temocapril treatment. Results. Blood pressure was significantly decreased (P < 0.05) from 158 ± 14/91 ± 9 to 148 ± 15/83 ± 8 mm Hg by the addition of temocapril. The peak serum concentration (Cmax) was 86.3 ± 22.7 μg/l at 3.9 ± 1.6 h (Tmax) after administration. Mean area under curve for 0 to 24 h (AUC0–24 h) was 1179 ± 273 μg/l · h. Trough levels showed a steady state. After temocapril therapy, the slope of the reciprocal of creatinine decreased compared with that before the addition of temocapril. Urinary protein excretion significantly decreased from 3100 ± 1100 to 2300 ± 1100 mg/day. There was no significant change in hematological and biochemical data. Conclusions. The present findings suggest that temocapril can be safely used in patients with advanced diabetic nephropathy, and in combination with dihydropyridine calcium channel blockers it decreases blood pressure and effectively retards the aggravation of renal insufficiency for 3 months in those patients.

A 31-year-old woman was diagnosed as having Bartter's syndrome in 1978, although suspicions remained that she had been taking diuretics surreptitiously. Careful observation and repeated urinary drug analyses revealed no clue that she had been taking diuretics, until 20 years later, when the urine samples at last disclosed traces of furosemide. At this time she showed proteinuria, of 2 g/day, and hypercholesteremia. The glomerular filtration rate had decreased to 66 ml/min per 1.73 m2. The 24-h urinary concentrations of β2-microglobulin, N-acetyl-β-d-glucosaminidase (NAG) activity, and other urinary enzymes that are indicators of damage in proximal tubular cells, were increased, showing proximal tubular damage. The function of the loop of Henle was evaluated by a hypotonic saline loading test. The fractional distal chloride reabsorption, an index of the solute conservation rate in the loop of Henle, was 65.4%, which was lower than the normal value (88.9 ± 6.2%). The maximal urinary concentrating ability was 357 mOsm/kg·H2O, and a short ammonium chloride loading test showed impairment in the acidification of the urine. The third renal biopsy specimens showed some obsolescent glomeruli, marked juxtaglomerular cell hyperplasia, intraluminal calcification, interstitial infiltration of lymphocytes with fibrosis, and thickening of arteriolar walls with narrow lumens. Patients often attempt to hide their use of diuretics from medical staff, leading to them to make a misdiagnosis of Bartter's syndrome. Although the patient described here has not experienced life-threatening adverse effects from furosemide abuse, some findings appear to be irreversible, suggesting the deterioration of renal function. Patients should realize that longstanding abuse of diuretics causes not only metabolic abnormalities but also the risk of renal damage.

We conducted a prospective study to assess the effects of doxazosin, as the third agent, on morning and position-related blood pressure (BP) in 77 diabetic patients with chronic kidney disease, who were allocated randomly to doxazosin and diuretics groups. Doxazosin decreased morning BP but diuretics could not decrease pre-awakening diastolic BP. Only doxazosin improved sympathovagal balance. Doxazosin and diuretics decreased standing and sitting BP but only doxazosin improved sympathovagal balance regardless of body positions. Doxazosin did not decrease absolute BP changes shortly after standing. In diabetic patients, doxazosin decreased morning BP through improving sympathovagal balance without causing significant orthostatic hypotension (ClinicalTrials.gov number, NCT00295555).

Regulation of cAMP production in initial and terminal inner medullary collecting ducts.BackgroundThe inner medullary collecting duct (IMCD) is composed of at least two functionally and morphologically distinct segments, the initial (IMCDi) and the terminal (IMCDt) portions. However, most studies of receptor signaling have been performed on cells obtained from the entire inner medulla. The purpose of this study was to determine whether the patterns of receptor-activated cAMP accumulation were different between these segments.MethodsWe measured cAMP accumulation stimulated by vasopressin and isoproterenol, and the effect of epinephrine in freshly dissected IMCDi and IMCDt segments cultured and IMCDi and IMCDt cells in primary culture.ResultsThe maximum response to vasopressin was twofold higher in fresh IMCDt versus IMCDi (P < 0.05), however, it increased in cultured IMCDi by 40% versus fresh cells with no change in the response in fresh versus cultured IMCDt. The maximum response to isoproterenol was small in fresh cells but increased by five- and sixfold, respectively, in cultured IMCDi and IMCDt cells. α2-Adrenoceptor stimulation almost completely inhibited both vasopressin and isoproterenol-stimulated cAMP accumulations in fresh IMCDi and IMCDt cells, but only partially inhibited either accumulation by 34 to 49% in cultured cells.Conclusions(1) IMCDi and IMCDt cells are both subject to vasopressin and α2- and β-adrenergic regulation of adenylyl cyclase activity; (2) the relative influence of β-adrenergic, α2-adrenergic and V2 receptors to affect cAMP accumulation is altered in primary culture versus freshly dissected IMCD segments, suggesting that caution must be exercised in the extrapolation of data from cultured IMCD cells to in vivo models.

This study was conducted to examine whether imidaprilat, an active diacid of the angiotensin-converting enzyme (ACE) inhibitor imidapril, preferentially inhibits angiotensin I degradation rather than bradykinin degradation, and whether imidapril is less active than other ACE inhibitors in inducing cough in patients with hypertension. The effect of imidaprilat on the inhibition of pressor response to angiotensin I and augmentation of depressor response to bradykinin was compared with that of enalaprilat and captopril in anesthetized rats. To determine the incidence of cough associated with imidapril, patients with a history of ACE inhibitor-induced dry cough were enrolled in a randomized, open-labeled, crossover trial with two 6-week periods to be treated with imidapril or amlodipine, a calcium-channel blocker. The recurrence of cough was assessed during both treatments. In the animal study, there were no significant differences in the ratio of inhibition of pressor response to angiotensin I and the augmentation of depressor response to bradykinin among the ACE inhibitors. In the cough-challenge trial, a total of 60 patients with hypertension were enrolled in the study. Cough and cough related symptoms recurred in 98.3% of the patients (59/ 60) during imidapril therapy. In contrast, only two patients reported cough during treatment with amlodipine. These results indicate that imidapril has no selectivity in inhibiting angiotensin I- and bradykinin-degradation in rats, and that clinically it is not different from other ACE inhibitors in inducing cough in patients with hypertension.

The present study was conducted to prospectively evaluate whether a new ACE inhibitor, temocapril, could modify urinary microalbumin excretion rate (UAE) in a group of hypertensive outpatients who had no evidence of renal impairment. Sixty-three outpatients (32 men and 31 women; mean age, 59.9 +/- 1.5 yr) with essential hypertension entered the study, all having been treated for at least 6 mo with dihydropyridine calcium-channel blockers (CCBs: nitrendipine, nisoldipine, or amlodipine). Their blood pressures (BPs) had been controlled to adequate levels with the CCBs. None had overt proteinuria (determined by Albustix) or abnormal serum creatinine levels. After 3 mo of baseline observation under the previous treatment, the subjects were randomly divided into two groups. In group A (n = 31), the previously used CCBs were switched to temocapril, 2 to 4 mg once daily for 12 mo, and BP was controlled at a level equivalent to that during CCB treatment. In group B (n = 32), the subjects were maintained on their previous treatment for a further 12 mo. The effect of temocapril on BP appeared to be clinically similar to that of the previously used CCBs, but it significantly decreased UAE as compared with the previous therapy. In group A, UAE decreased significantly (p0.01) from the baseline value of 38.9 +/- 5.1 mg/g creatinine (Cr) to 22.2 +/- 4.2 and 25.3 +/- 5.6 mg/g Cr at the 6th and 12th months of temocapril therapy, respectively. In contrast, in group B UAE was unchanged (baseline 39.8 +/- 6.6 mg/g Cr; 6 mo, 44.6 +/- 6.8; 12 mo, 45.9 +/- 7.7). In group A, 17 of 31 patients (54.8%) had abnormal UAE levels (or = 29.5 mg/g Cr) during previous therapy with CCBs, but 6 mo after switching to temocapril 25 of these patients (80.6%) had normal UAE (29.5 mg/g Cr). In group B, 15 of 32 patients (46.9%) had abnormal UAE levels during the observation period, and these abnormal UAE levels remained unchanged; 17 of the 32 patients (53.1%) had abnormal UAE levels after a further 6 mo of continued CCBs therapy. We conclude that long-term therapy with temocapril may provide renal protection by reducing UAE even in hypertensive patients with no evidence of renal impairment.

We studied the characteristics of bunazosin-sensitive alpha1-adrenoceptors in human renal medullae by using renal-clearance studies and radioligand-binding assay. In 12 patients with hypertension, renal-clearance studies demonstrated that bunazosin significantly increased renal blood flow from 683 +/- 82 (SD) to 829 +/- 103 ml/min (p0.05) and decreased renal vascular resistance from 0.18 +/- 0.02 to 0.14 +/- 0.02 mm Hg/(ml/min) (p0.05), but that prazosin had little effect on renal function. In a radioligand-binding assay, specific, saturable, and stereoselective [3H]bunazosin binding, with a single class of binding sites (Kd = 2.7 +/- 1.4 nM; Bmax = 44 +/- 16 fmol/mg protein; n = 11) was detected in membrane preparations of human renal medullae. The rank order of potency of antagonists that inhibited [3H]bunazosin-binding was bunazosin (Ki in nM = 49)prazosin (57)yohimbine (3,900)propranolol (29,000), and that of agonists, l-norepinephrine (7,400)l-epinephrine (19,000)d-norepinephrine (71,000). The competition curves fit a one-site model. These findings suggest that bunazosin-sensitive alpha1-adrenoceptors exist in human renal medullae and participate in the regulation of renal hemodynamics.

In a previous study we have reported the existence of alpha2- and beta-adrenoceptors in cultured rat inner medullary collecting duct (IMCD) cells. In this report, we examined the effect of epinephrine on intracellular adenosine 3',5'-cyclic monophosphate (cAMP) accumulation and evaluated whether alpha2-adrenoceptors interact with beta-receptors, vasopressin receptors, and prostaglandin (PG) E2 receptors by measuring cAMP generation. Epinephrine stimulated cAMP accumulation in a dose-dependent manner [half-maximal effective concentration (EC50) = 300 nM]. Rauwolscine (10 microM) enhanced epinephrine effects, shifting the dose-response curve for epinephrine to the left (EC50 = 120 nM); however, beta-antagonists inhibited epinephrine-induced cAMP accumulation. Epinephrine (10 microM) inhibited cAMP accumulation maximally induced by isoproterenol (10 microM); this effect was reversed by rauwolscine (10 microM). Epinephrine inhibited vasopressin (100 nM)-induced cAMP accumulation but failed to inhibit PGE2 (10 microM)-induced cAMP accumulation. We conclude that epinephrine acts as an alpha2- and beta-adrenoceptor agonist and that alpha2-adrenoceptors interact with beta-adrenoceptors and vasopressin receptors but not with PGE2 receptors on cAMP accumulation. This suggests that alpha2-adrenoceptors play a physiological role via interaction with different hormone receptors.

Diuretics or calcium channel blockers (CCBs) are used concomitantly with an angiotensin II receptor blocker (ARB). However, it is not established which ARB-based combination therapy is the most effective and safe. This prospective randomized open-label study compared the efficacy and safety of a fixed-dose tablet of losartan (LST)–hydrochlorothiazide (HCTZ) (n = 99) and LST–amlodipine (AML) (n = 77) in Japanese patients whose hypertension was uncontrolled by ARB monotherapy. Blood pressure changed similarly over the 12-month study period. Only LST–HCTZ significantly increased serum uric acid (SUA) in patients with low baseline SUA (

We report a 54-year-old female patient in whom thyroid storm was improved dramatically by plasma exchange. The patient presented with tachycardia, high fever and pulmonary congestion, in addition to left hemiparalysis and dysarthria. Serum thyroid hormone concentrations were markedly increased and computed tomography showed a fresh cerebral infarct, suggesting that she had thyroid storm precipitated by cerebral infarction. As there was no remarkable improvement even after 24 h of conventional therapy, plasma exchange was carried out using fresh frozen plasma. Consequently, her critical condition improved quickly. The half-life of thyroid hormones is so long that quick improvement is not always achieved even by sufficient doses of antithyroid drugs. Thus, plasma exchange in combination with conventional therapy appears to be effective in relieving the life-threatening state in our patient with thyroid storm precipitated by acute cerebral infarction.

Study background: Albuminuria and nighttime blood pressure (BP) elevation are notable risk markers of chronic kidney disease (CKD). In non-diabetic patients with albuminuria, the effect of albuminuria on nocturnal BP and other risk factors that may disrupt circadian BP rhythm remain unclear. The aim of this study was to evaluate the relationship among albuminuria, serum albumin level and 24-hour BP rhythm in non-diabetic subjects. Methods: This prospective study enrolled 778 subjects (aged 20-80 years, estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2). Main outcome measure was sleeping/waking mean BP (MBP) ratio as an indicator of circadian BP rhythm. First, a cross-sectional study was performed in all individuals showing no proteinuria. Second, a study was done in subjects never treated for hypertension (hypertensive-naive) stratified by urinary albumin excretion. Third, an intervention study was conducted in patients with massive albuminuria and hypoalbuminemia to examine circadian BP changes induced by treatment. Results: In 441 subjects without proteinuria, multivariate regression analyses identified serum albumin, cholesterol level and circadian sympathovagal rhythm as independent predictors of sleeping/waking MBP ratio. Among hypertensivenaive non-diabetic subjects (n=231), sleeping/waking MBP ratio increased with increasing albuminuria and decreasing serum albumin. Of 37 non-diabetic nephrotic patients who underwent treatment, 25 with serum albumin level increased to >3 g/dL showed a significant decrease (P=0.026) in sleeping/waking MBP ratio after treatment, whereas 13 with urinary albumin/creatinine lowered to

Yasuda G, Shionoiri H, Umemura S, Takasaki I, Ishii M. Exaggerated blood pressure response to angiotensin II in patients with Cushing's syndrome due to adrenocortical adenoma. Eur J Endocrinol 1994:131:582–8 ISSN 0804–4643 We studied the roles played by the renin-angiotensin system in inducing hypertension in nine patients with Cushing's syndrome (CS) resulting from adrenocortical adenoma, and compared them with those in patients with primary aldosteronism (PA), renovascular hypertension (RVH) and essential hypertension (EH). In the CS group, each parameter, including serum potassium, plasma renin activity, plasma aldosterone, deoxycorticosterone and corticosterone concentrations, is within the normal range. However, plasma renin activity in the CS group was lower than that in the RVH group but higher than that in the PA group, and plasma aldosterone concentration was lower than that in each RVH or PA group. These findings indicated that the CS group had a different type of hypertension from that in either RVH or PA, in which the renin angiotensin system or mineralocorticoids play an important role in hypertension. Meanwhile, captopril (50 mg) administration either with or without indomethacin pretreatment decreased the mean blood pressure in the CS group, although captopril failed to change it in the PA group or in normal subjects. Furthermore, the pressor response to exogenous angiotensin II in the CS group was higher than that in the RVH or EH group, but was not different from that in the PA group. Thus, the hypertension in patients with CS due to adrenocortical adenoma appears to be mediated through a change in the renin-angiotensin system in the form of exaggerated pressor responses to angiotensin II. G Yasuda, Second Department of Internal Medicine, Yokohama City University School of Medicine, 3-46 Urafune, Minami, Yokohama 232, Japan

1. The localization of alpha-adrenoceptors in the plasma membranes of human kidney were investigated by radioligand binding, using an alpha 1-antagonist, [3H]-bunazosin, and an alpha 2-antagonist, [3H]-rauwolscine. 2. Both the maximum binding (Bmax) and dissociation constant (Kd) of [3H]-bunazosin were greater in the cortex than in the medulla. The Bmax of [3H]-rauwolscine in the medulla was greater than in the cortex. 3. Thus, alpha 1-adrenoceptors appeared to be localized predominantly in the cortex, while the alpha 2-adrenoceptors were mainly present in the medulla of the human kidney.

晩発性皮膚ポルフィリン症 (PCT) が慢性腎不全血液透析患者に合併することが報告されているが本邦では症例は少ない. 慢性腎不全では尿検査からポルフィリン代謝異常を証明することが困難であったことが少ない理由の1つであるが, 本例では特徴的皮膚症状を示し, 糞便中, 透析液中ポルフィリンを分析検討し診断し得た. 症例は慢性糸球体腎炎を原疾患とする慢性腎不全の女性 (37歳) である. 血液透析導入7年後より顔面, 手背の色素沈着, 水疱, 糜爛, 色素脱を伴う小瘢痕を示すようになった. 皮膚生検にてPCTを疑わせた. 本症例と対照として同様の病歴を持つ皮膚症状のない女性慢性腎不全血液透析患者4例を選び, 1日排泄糞便中ポルフィリン量, ダイアライザー; EL201-12R (ethylene vinyl alcohol膜, 膜面積1.2m2, 血液流量200ml/min, 透析液流量500ml/min) 使用時, 透析開始1, 3時間後の透析液中ポルフィリン濃度を測定した. 糞便検査では, 患者は対照に比べ, 高uroporphyrin (URO), 高coproporphyrin (COPRO), 高heptacarboxyporphyrin (HEPTA) 排泄を示した. また, URO/COPRO比, HEPTA/COPRO比はいずれも対照に比べ高値であった. 透析液中URO, COPRO濃度も, 透析開始1, 3時間後いずれも対照と比し高値を示した. これらの結果はPCTにおけるポルフィリン代謝異常に一致し, 慢性腎不全血液透析に合併したPCTと診断した. 本例では, 誘因と考えられる鉄剤, 水酸化アルミニウムゲルの使用中止, 鎮痛剤投与量の漸減, さらにダイアライザーと血液回路を遮光し, 皮膚の日光暴露を極力避けることにより皮膚症状の改善と, 糞便中ポルフィリン比の低下を認めた.

A patient (32-year-old female) with Cushing's syndrome due to pituitary adenoma and hypertension with hypokalemia is reviewed. Endocrinological studies demonstrated low plasma renin activity, low plasma aldosterone concentration and high plasma deoxycorticosterone concentration. Blood pressure response to exogenous angiotensin II was enhanced. After the withdrawal of cortisol replacement following surgery, her abnormal endocrinological findings, hypertension and serum potassium level returned to normal and her blood pressure response to exogenous angiotensin II was reduced. These results suggest that in this case deoxycorticosterone might have contributed to the development and maintenance of her hypertension accompanied with hypokalemia.

Background Several reports have found that chronic kidney disease (CKD) is an independent risk factor for stroke. However, little is known about whether cerebrovascular disease conversely predicts the outcome of kidney function. In view of the similarities between vascular beds of the kidney and brain, we hypothesized that silent brain infarction (SBI) could reflect the degree of injury in renal small vessels and predict the risk of progression of kidney disease. Study Design Prospective cohort study. Setting & Participants 142 patients with CKD (stages 3-5) admitted to our clinic for education about CKD from January 2006 to July 2007 were recruited and followed up for 2 years. Predictor SBI. Outcomes Composite primary outcomes: doubling of serum creatinine level, development of end-stage renal disease defined as dialysis or transplant, and death from cardiovascular causes. Secondary outcome: rate of decrease in estimated glomerular filtration rate. Measurements Brain magnetic resonance imaging was performed to determine the presence or absence of SBI. Results At baseline, 87 patients had SBI. During follow-up, 43 patients (30.3%) developed the following primary outcomes: doubling of serum creatinine level (8 patients), dialysis therapy (32 patients), and death from cardiovascular causes (3 patients). In crude analysis, the presence of SBI predicted time to primary outcomes ( P = 0.01). A multivariate Cox model confirmed the presence of SBI to be an independent predictor of study outcomes (HR, 2.16; 95% CI, 1.01-4.64; P = 0.04). Estimated glomerular filtration rate decreased more in patients with SBI than in those without SBI (−0.11/y vs −0.06/y relative to baseline value; P = 0.005). Limitations Study size was small. Conclusion We showed that SBI was an important independent prognostic factor for the progression of kidney disease in patients with CKD. Our findings suggest that patients with SBI should be considered a high-risk population for decreased kidney function.

In non-diabetic patients with nephrotic syndrome (NS) at early stages of chronic kidney disease, it remains unclear whether the degree of proteinuria affects the nocturnal blood pressure (BP) dip. We evaluated the relationship among circadian BP rhythm, proteinuria and hypoalbuminemia in these patients. We also evaluated the autonomic nervous activity. Twenty-four-hour BP was measured in NS patients (8 men and 13 women; mean age, 58.5+/-14.8 years) and age- and sex-matched normal subjects (11 men and 13 women; mean age, 54.3+/-18.2 years) as controls. Serum albumin and urinary protein concentrations were measured. Power spectral analysis of the heart rate was performed, and the high frequency (HF) and low frequency (LF) components were calculated as indices of sympathovagal balance. There were no differences in waking BP between the NS and the control groups (131+/-13/78+/-9 vs. 130+/-17/76+/-7 mm Hg; P0.05). However, sleeping BP was significantly higher in the NS group than in the control group (127+/-18/75+/-9 vs. 115+/-14/66+/-7 mm Hg; P0.05). Sleeping/waking BP ratios were higher in the NS group than in the control group (P0.01). In the NS group, these ratios correlated significantly with serum albumin level (r=-0.54, P=0.011 for systolic BP; r=-0.48, P=0.030 for diastolic BP) and urinary protein excretion (r=0.47, P=0.027 for systolic BP; r=0.60, P=0.003 for diastolic BP). Both HF components and LF/HF ratios were not significantly different between the two groups. In non-diabetic NS patients, loss of nocturnal BP reduction correlates with proteinuria and hypoalbuminemia but not with circadian autonomic nervous rhythm.

A single high affinity binding site for an alpha 2-adrenoceptor in human coronary arteries was identified by radioligand binding assay. Human coronary arteries were obtained at autopsy within 6 hours of death. A crude membrane solution was incubated with (3H)-rauwolscine at 25 degrees C for 30 min. The binding of (3H)-rauwolscine was rapidly saturable and reversible. Kd was 1.2 +/- 0.2 (SE) nM and Bmax 22 +/- 3 fmol/mg protein. This is the first study which has shown the presence of an alpha 2-adrenoceptor in human coronary arteries using a radioligand binding assay method.

AIMS Few studies have reported the effect of alpha(1)-adrenergic antagonists on 24-h blood pressure (BP) and sympathetic nervous activity in hypertensive patients with diabetic nephropathy. We assessed the effects of doxazosin on 24-h BP and spectral analysis of heart rate variability in hypertensive Type 2 diabetic patients with macroalbuminuria and compared the results with those in hypertensive Type 2 diabetic patients with normoalbuminuria and non-diabetic patients with essential hypertension. METHODS Thirty-three patients in the macroalbuminuric group, 24 patients in the normoalbuminuric group, and 34 patients with essential hypertension underwent ambulatory BP monitoring before and after doxazosin treatment. Spectral analysis was performed to calculate the high-frequency (HF) components, a marker of parasympathetic nervous activity, and the low-frequency (LF) components, a marker of sympathetic nervous activity. RESULTS Doxazosin decreased waking (from 158 +/- 17/88 +/- 10 to 148 +/- 15/80 +/- 7 mmHg, P = 0.001 for systolic and P < 0.001 for diastolic BP) and sleeping BP (146 +/- 20/79 +/- 10 to 137 +/- 17/72 +/- 9 mmHg, P < 0.001 and P < 0.001) in the macroalbuminuric group, but only decreased waking BP in the essential hypertension group (157 +/- 16/91 +/- 9 to 145 +/- 15/84 +/- 11 mmHg, P < 0.001 and P < 0.001) and normoalbuminuric group (159 +/- 15/89 +/- 9 to 150 +/- 16/82 +/- 10 mmHg, P = 0.014 and P < 0.001). Doxazosin decreased waking (from 1.48 +/- 0.11 to 1.42 +/- 0.12, P = 0.001) and sleeping (1.46 +/- 0.11 to 1.40 +/- 0.13, P = 0.001) LF components [unit: log(ms(2)/Hz)] only in the macroalbuminuric group without changing HF components. The normoalbuminuric and essential hypertension groups showed no differences (P = 0.637 and 0.492) in LF components during sleep. CONCLUSIONS Doxazosin may be an antihypertensive agent that decreases both waking and sleeping BP through inhibiting sympathetic nervous activity in macroalbuminuric diabetes patients.

There are few reports on the safety and efficacy of long-term treatment with statins in patients with chronic renal disease and hyperlipidemia. We evaluated these subjects treated with fluvastatin.After a 4-week run-in period, a total of 80 patients with diabetic nephropathy or chronic glomerulonephritis were randomly allocated to receive dietary therapy and fluvastatin 20 mg/day (n=39), or dietary therapy alone (n=41) for a period of 48 weeks. Lipid parameters, rhabdomyolysis-related indicators, 24-hour urinary albumin excretion and creatinine clearance were measured. The pharmacokinetics of fluvastatin was examined in 8 patients.Creatinine clearance and 24-hour urinary albumin excretion did not differ between the two groups. The peak serum fluvastatin concentration (Cmax) was 141+/-67 microg/L and the mean AUC0-6 h was 341+/-149 microgh/L. Fluvastatin treatment significantly lowered serum total cholesterol, low-density lipoprotein (LDL) cholesterol and apo-lipoprotein B concentrations by 16%, 25%, and 22%, respectively, compared with patients receiving dietary therapy alone. There were no significant differences in serum triglyceride and high-density lipoprotein (HDL) cholesterol concentrations between the two treatment groups. Serum creatine kinase and aldolase concentrations did not change throughout treatment in both groups.Fluvastatin treatment significantly improved lipid parameters in patients with chronic renal disease. Fluvastatin was well tolerated, with no adverse effects on renal function and no muscular toxicity. However, the drug showed no direct renoprotective effects.

We investigated beta-adrenoceptor subtype(s) expressed in cultured rat inner medullary collecting duct (IMCD) cells. In radioligand binding assay, [125I]iodocyanopindolol bound to IMCD cell membranes, representing a single class of binding sites (dissociation constant = 96.1 pM, maximum binding capacity = 18.2 fmol/mg protein, n = 8). In competition studies, ICI-89406 (beta 1-antagonist) and ICI-118551 (beta 2-antagonist) bound with high affinity, fitting a two-site model. Isoproterenol increased intracellular adenosine 3',5'-cyclic monophosphate (cAMP) accumulation (half-maximal effective concentration = 200 nM). Propranolol completely inhibited isoproterenol-induced cAMP accumulation [half-maximal inhibitory concentration (IC50) = 270 nM]. ICI-89406 and ICI-118551 inhibited cAMP accumulation by 50% (IC50 = 1.5 microM and 1.7 microM, respectively). The combined addition of ICI-89406 and ICI-118551 resulted in a curve indistinguishable from that of propranolol. The beta 1- and beta 2-adrenoceptor mRNAs have been demonstrated using reverse transcription-polymerase chain reaction. In initial and terminal IMCD cells, propranolol (3 microM) inhibited isoproterenol-stimulated cAMP accumulation by 80%, whereas ICI-89406 (3 microM) and ICI-118551 (3 microM) resulted in only partial inhibition (50%). We conclude that both beta 1- and beta 2-adrenoceptors are expressed in initial and terminal IMCD cells in primary culture.

The frequency of hypertriglyceridemia is high in CKD patients, but few medications are available for controlling this lipid parameter when renal insufficiency advances. We evaluated the safety and efficacy of long-term treatment with rosuvastatin, one of the strong statins for hypercholesterolemic control, on lipid abnormalities in patients with CKD stage 3 and above. The protocol consisted of a 4-week run-in period and a 48-week treatment phase with rosuvastatin. Inclusion criteria were CKD stage 3 and above with serum low-density lipoprotein (LDL) cholesterol levels above 100 mg/dL and triglyceride levels above 150 mg/dL. Patients received 2.5 to 5.0 mg rosuvastatin daily. Lipid parameters and myolysis-related indicators were measured. Forty-nine patients (29 men and 20 women aged 61 ± 9 years, serum creatinine levels above 1.5 mg/dL) were enrolled in the study. Rosuvastatin significantly decreased (P〈0.05) serum LDL cholesterol from 163 ± 39 to 126 ± 31 mg/dL and apolipoprotein B from 151 ± 36 to 108 ± 24 mg/dL at 4 weeks and maintained these parameters at low levels. Rosuvastatin also significantly decreased (P = 0.001) serum triglyceride levels from 194 ± 43 mg/dL at baseline to 160 ± 51 mg/dL at 48 weeks. High-density lipoprotein (HDL) cholesterol concentrations did not change from baseline (56 ± 16 mg/dL) to 48 weeks of treatment (57 ± 17 mg/dL). However, LDL/HDL ratio decreased significantly (P = 0.036) from 3.4 ± 0.7 to 2.2 ± 0.9, which approached the target level (2.0). During the rosuvastatin treatment period, serum creatine kinase, aldolase, and myoglobin concentrations did not change. In conclusion, rosuvastatin treatment improved serum triglyceride level as well as the LDL/HDL ratio in hyperlipidemic patients with CKD stage 3 and above, without serious adverse effects, suggesting that rosuvastatin is useful to control not only hypercholesterolemia but also hypertriglyceridemia in CKD patients.

In two patients with Bartter's syndrome proximal tubular function and distal chloride reabsorption were intact on admission; however, chloride reabsorption and distal tubular acidifying capacity decreased in one patient over a period of 10 years. Renal prostaglandin E excretion and urinary and plasma uric acid were in the normal range, but urinary ammonium was significantly elevated during controlled diet. One patient developed ammonium urate nephrolithiasis. In both patients renal biopsy demonstrated lymphocytic infiltration of the interstitial tissue and hypercellularity of the macula densa. Indomethacin treatment improved serum potassium concentration and decreased plasma renin activity, plasma aldosterone concentration, and urinary prostaglandin E but had to be discontinued because of side effects. It is likely that our patients represent a variant form of the syndrome originally described by Bartter.