Glucocorticoid-induced diabetes mellitus: prevalence and risk factors in primary renal diseases.

BACKGROUND/AIMS: In patients with primary renal diseases the current knowledge of hyperglycemia associated with corticosteroid therapy is limited. We therefore examined the prevalence and risk factors of glucocorticoid-induced diabetes mellitus (DM) in primary renal diseases. METHODS: Patients were recruited with primary renal diseases who were started on corticosteroids between April 2002 and June 2005. In patients with DM, an impaired fasting glucose level and/or positive urinary glucose analyses before corticosteroids therapy were excluded. RESULTS: During corticosteroid therapy (initial dose: prednisolone 0.75 +/- 0.10 mg/kg/day), DM was newly diagnosed in 17 (40.5%) of 42 patients. All of the 17 patients were diagnosed as having DM by postprandial hyperglycemia at 2 h after lunch, although they had normal fasting blood glucose levels. Age (OR 1.40, 95% CI 1.06-1.84) and body mass index (OR 1.87, 95% CI 1.03-3.38) were determined as independent risk factors for glucocorticoid-induced DM. CONCLUSION: Over 40% of patients with primary renal disease developed DM during treatment with corticosteroids. A high age and high body mass index are the independent risk factors for glucocorticoid-induced DM. 24-hour urinary glucose analyses and postprandial plasma glucose are useful for detecting glucocorticoid-induced DM.

Diuretics shift circadian rhythm of blood pressure from nondipper to dipper in essential hypertension.

BACKGROUND: Recently, we found that sodium restriction shifted the circadian rhythm of blood pressure from nondipper to dipper in patients with the sodium-sensitive essential hypertension. This study examined whether diuretics can transform the circadian rhythm of blood pressure from nondipper to dipper. METHODS AND RESULTS: We studied 21 patients with essential hypertension during both a baseline period and a period of treatment with hydrochlorothiazide (25 mg daily). The periods lasted 4 weeks each. Twenty-four hour ambulatory blood pressures were measured on the same day of the week at the end of the each period. In nondippers (n=11), but not in dippers (n=10), a significant interaction existed between diuretic therapy and nocturnal fall in systolic and diastolic blood pressure, which indicated that the degree of nocturnal blood pressure fall was affected by diuretic therapy. Nocturnal fall, which was diminished in nondippers, was restored by diuretic therapy with hydrochlorothiazide, indicating that the circadian rhythm of blood pressure shifted from nondipper to dipper patterns. CONCLUSIONS: The present study demonstrated that diuretics can restore nocturnal blood pressure decline in a manner similar to sodium restriction, which suggests that the kidneys and sodium metabolism may play important roles in the genesis of the circadian rhythm of blood pressure. Diuretic-based treatment may have an additional therapeutic advantage of reducing the risk for cardiovascular complications by transforming the circadian rhythm of blood pressure.

High sodium sensitivity implicates nocturnal hypertension in essential hypertension.

We investigated the relationship between sodium sensitivity and diurnal variation of blood pressure in patients with essential hypertension. Twenty-eight inpatients with essential hypertension were maintained on high sodium (12 to 15 g NaCl per day) and low sodium (1 to 3 g NaCl per day) diets for 1 week each. Twenty-four-hour blood pressure and urinary sodium excretion were measured at the end of each diet period, and the sodium sensitivity index was calculated as the ratio of the change in mean arterial pressure to the change in urinary sodium excretion rate by sodium restriction. Patients whose average mean arterial pressure was lowered more than 10% by sodium restriction were assigned to the sodium-sensitive group (n = 16); the remaining patients, whose mean arterial pressure was lowered by less than 10%, were assigned to the non-sodium-sensitive group (n = 12). In the non-sodium-sensitive group, mean arterial pressure and heart rate fell during the nighttime, and average values of systolic, diastolic, and mean arterial pressures during the night were significantly lower than those during the day during both low and high sodium diets. On the other hand, in the sodium-sensitive group, there was no nocturnal fall in mean arterial pressure, and none of the systolic, diastolic, and mean arterial pressure values during the nighttime was different from the respective pressure values during the daytime during either sodium diet. The sodium sensitivity index was positively correlated with the fall in mean arterial pressure during the nighttime during a high sodium diet (r = .55, P < .01). These results indicate that in patients with sodium-sensitive essential hypertension, blood pressure fails to fall during the night. High sodium sensitivity may be a marker of greater risk of renal and cardiovascular complications, as has been found in nondippers, patients whose blood pressure fails to fall during the night.

High sodium sensitivity and glomerular hypertension/hyperfiltration in primary aldosteronism.

OBJECTIVE: To assess sodium sensitivity and glomerular haemodynamics in patients with primary aldosteronism. DESIGN AND METHODS: Two-week studies were performed in six patients with primary aldosteronism whose diagnosis had been confirmed by histology of the removed adrenal adenoma. Patients were fed normal or sodium-restricted diets for 1 week each and renal clearance measured during the normal sodium diet. Pressure-natriuresis relationships were drawn by plotting the urinary sodium excretion on the y-axis as a function of the systemic mean arterial pressure on the x-axis. RESULTS: The extrapolated x-intercept of the pressure-natriuresis curve was 118 +/- 9 mmHg. The sodium sensitivity, which corresponds to the reciprocal of the slope, was augmented to 0.111 +/- 0.013 mmHg/mmol per day, and the reduction in mean arterial pressure by sodium restriction was 11 +/- 2%. As we had reported previously, the difference between the mean arterial pressure (137 +/- 5 mmHg) with the normal-sodium diet and the x-intercept was assumed to be the effective filtration pressure across the glomerular capillary walls (18.2 +/- 2.0 mmHg). By dividing the glomerular filtration rate (128 +/- 10 ml/min per 1.73 m2) by the effective filtration pressure, the whole kidney ultrafiltration coefficient in these patients was estimated to be 0.127 +/- 0.021 ml/s per mmHg, which was approximately normal. The glomerular capillary pressure was calculated to be 54 +/- 2 mmHg. CONCLUSION: Compared with non-sodium-sensitive essential hypertension patients (n = 18) whose glomerular filtration rate and capillary hydraulic pressure were 84 +/- 3 ml/min per 1.73 m2 and 47 +/- 1 mmHg, the sodium sensitivity of blood pressure in patients with primary aldosteronism was augmented, and both glomerular hyper-filtration and glomerular capillary hypertension were observed. We confirmed that the glomerular haemodynamic characteristics in primary aldosteronism are typical of those expected for sodium-sensitive hypertension caused by enhanced tubular sodium reabsorption.

Changes in the circadian rhythm of blood pressure in primary aldosteronism in response to dietary sodium restriction and adrenalectomy.

OBJECTIVE: Recently, we found that sodium restriction restored the circadian rhythm of blood pressure from non-dippers to dippers in patients with a sodium-sensitive type of essential hypertension. In the present study, we investigated the effects of sodium restriction on the circadian blood pressure rhythm in patients with primary aldosteronism, a typical sodium-sensitive form of secondary hypertension. DESIGN AND METHODS: We performed 24 h blood pressure monitoring in eight patients with primary aldosteronism due to unilateral adenoma (Conn's syndrome) during normal-sodium (7-12 g/day of NaCl) and low-sodium (1-3 g/day) diets, and after adrenalectomy. RESULTS: Sodium restriction lowered the 24 h mean arterial pressure from 116+/-14 to 109+/-12 mmHg (P< 0.01). During a normal-sodium diet, there was no change in systolic, diastolic and mean arterial pressures during the night-time compared with the daytime. In contrast, during a low-sodium diet, all night-time pressure values were significantly lower than those in the daytime. After adrenalectomy, the night-time pressures in patients on a normal-sodium diet were lower than those of the daytime. The nocturnal mean arterial pressure fall was increased by sodium restriction and adrenalectomy. CONCLUSIONS: These results indicate that the circadian rhythm of blood pressure was disturbed in patients with primary aldosteronism who maintained a relatively high sodium intake. Both adrenalectomy and sodium restriction restored a nocturnal dip in blood pressure in primary aldosteronism. Therefore, sodium restriction affects the circadian blood pressure rhythm in sodium-sensitive types of hypertension, not only in primary hypertension, but also in secondary hypertension.

A glutathione S-transferase inducer from papaya: rapid screening, identification and structure-activity relationship of isothiocyanates.

We have developed a simple system for rapid detection and measurement of glutathione S-transferase placental form (GSTP1) that detoxify polycyclic aromatic hydrocarbons using the cultured rat normal liver epithelial cell line, (RL34) cells. Survey of fruit extracts for GST inducing ability identified both papaya and avocado as significant sources. Benzyl isothiocyanate (BITC) was isolated from papaya methanol extract as a principal inducer of GST activity. Further, the GST inducing ability of a total of 20 isothiocyanates (ITCs) and their derivatives was investigated. Some ITCs showed significant induction, and BITC was one of the most potent inducers among all compounds tested in the present study. The modification of isothiocyanate group (-NCS) or introduction of substituent group to the alpha-carbon modifies GST induction. Moreover, a significant correlation (P<0.01, r=0.913) between the GST activity enrichment and GSTP1 protein induction by ITCs was observed. We also indicated that phenethyl ITC and nitrophenyl ITC, potently inducing GST activity, but not inactive benzyl isocyanate, are potential inducers of intracellular reactive oxygen intermediates (ROIs). Our system of GSTP1 induction is appropriate for the chemical research such as screening and identification of novel type of inducers as well as the structure-activity relationship studies, providing mechanistic insight into essential structural elements for GSTP1 induction.

Prediction of coronary artery disease and cardiac events using electrocardiographic changes during hemodialysis.

Hemodialysis (HD) patients have a high rate of cardiac morbidity and mortality. Both symptomatic and silent ischemic heart disease may occur frequently during HD because HD simultaneously reduces coronary artery oxygen delivery while increasing myocardial oxygen demand. The purpose of the present study is to prospectively evaluate the usefulness of a significant ST depression induced by HD for the diagnosis of coronary artery disease (CAD) and as the predictor of subsequent cardiac events in HD patients. Sixty-one patients undergoing chronic HD (50 men, 11 women; mean age, 61 years) admitted for such cardiac symptoms as chest pain (n = 43), arrhythmia (n = 5), or heart failure (n = 13) were studied; 38 patients had CAD by coronary angiography. Electrocardiograms performed during HD showed an additional depression (>/=1.0 mV) of the ST segment in 18 patients (positive-ST group), but not in 43 patients (negative-ST group). The incidence of CAD was significantly greater in the former (100%) than in the latter group (46%). A prospective follow-up was performed for 21 +/- 2 months, and cardiac events occurred in all positive-ST group patients and in 21 negative-ST group patients. Event-free survival was poorer in the positive-ST group (P < 0.0001). A Cox proportional hazards model identified the significant ST depression as an independent risk factor for cardiac morbidity (P < 0.05), but not for all-cause mortality. ST depression during HD is useful to diagnose CAD in symptomatic patients and is considered an important prognosticator of subsequent cardiac events.

Circadian rhythm of natriuresis is disturbed in nondipper type of essential hypertension.

We examined the circadian rhythm of urinary sodium excretion and the effects of sodium restriction on rhythm in both dipper and nondipper types of essential hypertension. Patients (n = 26) with essential hypertension were maintained on relatively high- (10 to 12 g/d of sodium chloride) and low-sodium (1 to 3 g/d) diets for 1 week each. On the last day of each diet, 24-hour blood pressures (BPs) were measured every 30 minutes noninvasively with an automatic device, and on the last 3 days, urinary samples were collected for both daytime (7:00 AM to 9:30 PM) and nighttime (9:30 PM to 7:00 AM). Eight patients were classified as dippers based on a more than 10% reduction in mean arterial pressure (MAP) from daytime to nighttime on a high-sodium diet, and 18 patients were classified as nondippers. A nocturnal decrease in urinary sodium excretion rate (U(Na)V) on the high-sodium diet was observed in dippers (from 7.5 +/- 2.1 during the day to 5.3 +/- 2.5 mmol/h at night; P < 0.0001), but not in nondippers (6.7 +/- 2.1 v 7.6 +/- 2.3 mmol/h; not significant). In nondippers, the night-day ratio of sodium excretion was significantly reduced from 1.2 +/- 0.4 to 0.8 +/- 0.3 (P < 0.003) by sodium restriction; at the same time, the night-day ratio of MAP was reduced from 0.98 +/- 0.04 to 0.93 +/- 0.05 (P < 0.05). In dippers, the night-day ratios of MAP and U(Na)V were not affected by sodium restriction, and both ratios remained constant at less than 1. Before sodium restriction, the night-day ratio of sodium excretion correlated with that of MAP (r = 0.78; P < 0.0001), whereas there was no significant correlation (r = -0.05) after sodium restriction. These findings showed that the circadian rhythm of renal sodium excretion differed between the two types of essential hypertension. The enhanced nocturnal natriuresis and diminished nocturnal BP fall on a high-sodium diet, recognized in nondippers, were both normalized by sodium restriction, resulting in circadian rhythms with nocturnal dips in U(Na)V and BP.

Cardiovascular complications in patients with primary aldosteronism.

Primary aldosteronism (PA) is widely believed to be a relatively benign form of hypertension associated with a low incidence of vascular complications. However, several recent studies showed that cardiovascular complications were not rare in PA. PA is known as one of the most typical forms of sodium-sensitive hypertension. Recently, we found that the sodium sensitivity of blood pressure was a marker for greater risk for cardiovascular complications, especially stroke, in patients with essential hypertension. Therefore, we investigated cardiovascular complications in 58 patients with PA confirmed to be Conn's adenoma. Cardiovascular complications were found in 34% of 58 patients. Coronary artery disease was found in only one patient (1.7%), as angina pectoris. Stroke was found in nine patients (15.5%), four patients (6.9%) with cerebral infarctions and five patients (8.6%) with cerebral hemorrhages. Proteinuria and renal insufficiency were found in 14 (24.1%) and 4 (6.9%) patients, respectively. The incidence of cerebral infarction and renal insufficiency was greater in men than women. The prevalence of proteinuria was greater in patients with than without stroke (P = 0.03) among those aged older than 40 years. These results indicated that cardiovascular complications, especially stroke and proteinuria, were common in patients with PA, and proteinuria might be an indicator for stroke as target-organ damage.

Interaction between hypertension and other cardiovascular risk factors in survival of hemodialyzed patients.

The interaction of hypertension with other cardiovascular risk factors, namely hypercholesterolemia, smoking, and past history of cardiovascular complications, was examined. One hundred and ninety-five hemodialysis patients were followed up for 54.2 +/- 2.3 months, among whom 66 died. In patients with cardiovascular complications, such as ischemic heart disease, cerebrovascular accident, or atherosclerotic obliteration of peripheral arteries, and in patients older than 70 years, blood pressure had no significant effect on the already poor survival. On the other hand, in patients with hypercholesterolemia (> or = 220 mg/dL) and in smokers, elevated systolic blood pressure made the survival significantly worse. These results suggest an interaction between hypertension and other cardiovascular risk factors in hemodialysis patients.

Determinants of circadian blood pressure rhythm in essential hypertension.

It has been postulated that the lack of nocturnal blood pressure fall in patients called nondippers is associated with more serious end organ damages by hypertension than in dippers whose blood pressure falls during the night. Recently, we found that sodium restriction shifted circadian rhythm of blood pressure from that of a nondipper to a dipper in patients with essential hypertension. In the present study, we aimed to clarify these important findings from the different approaches, and examined which factors affected the diurnal rhythm of blood pressure. A total of 70 patients with essential hypertension were maintained on high and low sodium diets for 1 week each. Nocturnal fall in mean arterial pressure was calculated in each patient, and, based on multiple regression analysis, independent factors affecting this nocturnal fall were examined. Thirty-eight patients were classified as non-sodium-sensitive, whereas 32 were considered sodium sensitive, based on a >10% change in 24-h mean arterial pressure by sodium restriction. In all 70 patients, sodium sensitivity of blood pressure, as well as an interaction between sodium sensitivity and sodium restriction, were identified as independent factors affecting the nocturnal fall. In sodium-sensitive types, in addition to sodium restriction, glomerular filtration rate was identified, whereas, in non-sodium sensitive types, there was no significant factor. Based on multiple regression analysis, the present study reached the same important conclusion as our previous findings: namely, that the enhanced sodium sensitivity was an independent determinant for the diminished nocturnal fall in essential hypertension and that sodium restriction could restore the nocturnal decline, especially in patients with enhanced sodium sensitivity whose nocturnal decline was diminished. Reduced renal sodium excretory capability may be one of the mechanisms involved in nondipping.

Nipradilol inhibits rat mesangial cell mitogenesis through the activation of soluble guanylate cyclase.

Nipradilol is a beta-adrenoreceptor blocking agent, whose structure contains an NO2 group. Thus, it is possible that it modulates the function of glomerular mesangial cells through the activation of soluble guanylate cyclase. To prove this hypothesis, we examined the effect of nipradilol on soluble guanylate cyclase, intracellular cyclic guanosine monophosphate (cGMP) accumulation, and the mitogenesis of cultured rat glomerular mesangial cells. Nipradilol increased intracellular cGMP accumulation in a dose-dependent manner through the activation of soluble guanylate cyclase. Furthermore, nipradilol inhibited the incorporation of [3H]thymidine into the mesangial cells stimulated by 2.5% fetal bovine serum in a dose-dependent manner. These results indicate that nipradilol may modulate mesangial cell function through an increase in intracellular cGMP resulting from the activation of soluble guanylate cyclase.

Circadian rhythm and postural change in natriuresis in non-dipper type of essential hypertension.

Recently we found that, in non-dipper type of essential hypertensive patients who showed the lack of nocturnal fall in blood pressure, circadian rhythm of urinary sodium excretion rate was disturbed. In the present study we examined whether postural change in natriuresis is also disturbed in non-dippers. Sixteen inpatients with essential hypertension were maintained on a relatively high sodium diet containing 10 to 12 g of NaCl per day for 8 days. On the 7th day of the study period, 24-h ambulatory blood pressures were measured, and 5-7th days urinary samples were collected for both daytime and night-time. On the last day of the study period, patients stood for 2 h and then lay down for 2 h. Urinary volume and excretion rates of creatinine and sodium were measured every hour in both positions. Night-time urinary sodium excretion rate was significantly higher in non-dippers (n = 9) than that in dippers (n = 7). Night/day ratio of mean arterial pressure had a positive relationship with night/day ratio of urinary sodium excretion rate. In non-dippers, but not in dippers, the mean value of U(Na)V during upright position was significantly lower than that during supine position. There was a significantly negative relationship between upright/supine ratio of U(Na)V and night/day ratio of MAP or night/day ratio of U(Na)V. In patients with non-dipper type of essential hypertension, both natriuresis patterns, circadian rhythm and postural change, were disturbed.

Role of insulin resistance in the genesis of sodium sensitivity in essential hypertension.

We recently showed that cardiovascular morbidity was higher in sodium sensitive type of essential hypertension than in the non-sodium sensitive type. It was examined whether sodium sensitivity was associated with insulin resistance, an important atherosclerotic cardiovascular risk factor in essential hypertension. Fifty-three patients with essential hypertension, who had normal (n = 12) and impaired (n = 41) glucose tolerance, were placed on high (12-15 g NaCl/day) and low (1-3 g) sodium diets for 1 week each to determine sodium sensitivity. Fasting plasma glucose and insulin concentrations were measured on a regular sodium diet. The homeostasis model assessment insulin resistance index (fasting glucose [mmol/L] x fasting insulin [mU/L]/22.5) was 1.40+/-0.10 and 1.47+/-0.14 in non-sodium sensitive and sodium sensitive groups. The insulin resistance index was positively correlated with the sodium sensitivity index, while was negatively correlated with fractional excretion of sodium (FE(Na)) obtained during a high sodium diet. In addition, the insulin resistance index had a positive relationship with overall creatinine clearance. Sodium sensitivity index was also negatively correlated with FE(Na) obtained during a high sodium diet. These results showed that insulin resistance might participate in the genesis of sodium sensitivity in essential hypertension by enhancing tubular sodium reabsorption, as reflected in decreased FE(Na) and augmented creatinine clearance. Insulin resistance seemed elevated in sodium sensitive state of essential hypertension, leading to future cardiovascular events.

High blood pressure is a risk factor for the development of microalbuminuria in Japanese subjects with non-insulin-dependent diabetes mellitus.

In this study, 52 nonproteinuric Japanese patients with non-insulin-dependent diabetes (NIDDM) were followed from 1985 to 1990 to investigate the rate of development and progression of microalbuminuria and the factors which influence it. In 1985, 34 patients were normoalbuminuric, and 18 patients were microalbuminuric. Five years later, 11 of 34 initially normoalbuminuric patients (32.4%) developed microalbuminuria, and 6 of 18 initially microalbuminuric patients (33.3%) developed overt proteinuria. At the beginning of the study, hypertension existed more frequently in the patients who later developed microalbuminuria (8 of 11, 72.7%) than in the patients who stayed normoalbuminuric (4 of 23, 17.4%). Age-adjusted values of mean blood pressure (+/- SEM) at the beginning of the study in the patients who developed microalbuminuria (98.2 +/- 3.4 mm Hg, n = 11) were significantly higher than those in the patients who stayed normoalbuminuric (87.3 +/- 2.4 mm Hg, n = 23). In six patients who developed overt proteinuria, initial urinary albumin excretion rates (AER) were higher than those in the patients who stayed microalbuminuric, and four patients who presented with initial AER greater than 100 micrograms/min all developed overt proteinuria. These results indicate that, in Japanese patients with NIDDM, the rate of development of microalbuminuria is faster than that reported in Caucasian IDDM, and preexisting hypertension with relatively poor control of blood pressure may be a risk factor for the development of microalbuminuria.

Does the concomitant intra-arterial injection of asialoerythropoietin and edaravone mitigate ischaemic mucosal damage after acute superior mesenteric artery thromboembolism in a rabbit autologous fibrin clot model?

To increase the survival rate of patients with acute superior mesenteric artery thromboembolism (ASMAT) treated by catheter thrombolysis, we examined the effects of delivering edaravone and asialoerythropoietin, agents with tissue-protective activities, using a rabbit autologous fibrin clot ASMAT model. Japanese white rabbits (n=32) were randomly separated into four equal groups. 45 min after introducing autologous fibrin clot, Group U received urokinase and heparin; Group E received urokinase and heparin plus edaravone; Group A received urokinase and heparin plus asialoerythropoietin; and Group EA received urokinase, heparin and edaravone plus asialoerythropoietin via a catheter. The intestines were removed 6 h later and intestinal mucosal damage was scored using the Park's injury score. Survival time was assessed. Average mucosal injury was 5.78+/-1.52 (Group U), 2.88+/-0.72 (Group E), 1.90+/-1.23 (Group A) and 1.18+/-1.25 (Group EA). The degree of mucosal injury was significantly lower in Group EA than in Groups U and E (p<0.05). Conversely, there was no significant difference between Group A and Group EA, or between Group A and Group E. The survival times were 31.50+/-13.30 h (Group U), 51.00+/-24.74 h (Group E), 48.00+/-16.97 h (Group A) and 82+/-51.07 h (Group EA); the difference among the four groups was not significant. In conclusion, the concomitant administration of asialoerythropoietin and edaravone reduced mucosal membrane injury significantly compared with edaravone alone. However, to improve the survival of ASMAT rabbit models, the delivery of an appropriate dose of asialoerythropoietin is required, together with the development of methods to assess peripheral recanalisation.