Setsuko Kuroda

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 Conns 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.

Prevalence of Renal Artery Stenosis in Autopsy Patients With Stroke

BACKGROUND AND PURPOSE Atherosclerotic renal artery stenosis commonly exists as one manifestation of more generalized atherosclerosis. It is a progressive but potentially curable disorder. Thus, information on renal artery involvement in atherosclerotic diseases could be important. We investigated the prevalence of renal artery stenosis in autopsied patients with stroke over 40 years of age. METHODS From 2167 consecutive autopsy patients who died between 1980 and 1997, we studied 346 cases of mean age of 69+/-11 years with clinical evidence of stroke. RESULTS Atherosclerotic renal artery stenosis (>/=75% luminal area narrowing) was found in 36 patients (10.4%). Patients with renal artery stenosis were older and had worse renal function. Renal artery stenosis was found in 14.7%, 28.6%, and 23.9% of patients with hypertension, renal insufficiency, and aortic aneurysm, respectively. Extracranial carotid artery stenosis (>50% luminal area narrowing) was found in 101 patients (29.2%). Of the 346 stroke patients, 256 had a history of brain infarction. In patients with brain infarction, renal artery stenosis was found in 31 (12.1%) and carotid stenosis was found in 81 (33.6%). Patients with carotid artery stenosis were more likely to have renal artery stenosis than patients without carotid artery stenosis (24.4% versus 5.9%, P<0.0001). Multiple logistic regression analysis identified renal insufficiency, hypertension, female gender, and presence of carotid artery stenosis as independent predictors of renal artery stenosis in patients with brain infarction. CONCLUSIONS These data reveal that atherosclerotic renal artery stenosis is common in patients with stroke, especially in those with brain infarction.

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.

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 (Conns 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.

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.

Exacerbation of Renal Failure due to Hypothyroidism in a Patient with Ischemic Nephropathy

A case of acute-on-chronic renal failure in a 70-year-old woman with ischemic nephropathy and primary hypothyroidism is presented. Her renal function became progressively worse as the level of serum creatinine increased from 283 to 628 µmol/l (3.2–7.1 mg/dl) within 8 months. Her thyroid function had been normal before the exacerbation of renal failure, but it was markedly reduced with a marked elevation of serum thyroid-stimulating hormone. Thyroid hormone replacement therapy resulted in rapid improvement of the renal function to 159 µmol/l (1.8 mg/dl) of serum creatinine. The development of primary hypothyroidism seemed to worsen the already impaired renal function in this case. We suggest the assessment of thyroid function in patients with unexplained deterioration of renal failure.

The Role of Kinins and Atrial Natriuretic Peptide on the Renal Effects of Neutral Endopeptidase Inhibitor in Rats

To further elucidate the natriuretic mechanisms of neutral endopeptidase 24.11 (NEP) inhibition, we employed a new specific NEP inhibitor, UK 73967 (UK), with or without a specific kinin receptor antagonist, Hoe 140 (Hoe), in Sprague-Dawley rats, and evaluated the renal NEP, kinins and plasma ANP simultaneously. There were no significant changes in urinary NEP, kinins, urine volume (UV) or urinary sodium excretion (UNaV) with vehicle treatment in anesthetized normotensive rats. Infused UK (10 mg/kg) significantly decreased NEP, and increased kinins, UV and UNaV. There was not a significant difference in plasma ANP between the vehicle and UK groups. Simultaneous administration of Hoe (20 nmol/kg) canceled the increases of UV and UNaV caused by UK. From these results, we conclude that inhibition of NEP may exaggerate the contribution of renal kinins to the renal water-sodium metabolism and overcome the contribution of ANP on that metabolism at least in normotensive rats.

The impact of elevation of serum uric acid level on the natural history of glomerular filtration rate (GFR) and its sex difference

BACKGROUND The impact of elevation of the serum uric acid level (SUA) on the natural history of glomerular filtration rate (GFR) remains controversial. METHODS If elevation of SUA is a result, rather than a cause, of a decline in GFR, the relationship between SUA and GFR should be the same in the same population over years except for shifts by age-dependent reduction of GFR. We tested this hypothesis using data from two cohorts and a group of allopurinol-treated patients. RESULTS In Cohort 1 consisting of urban residents aged 40.6 ± 9.0 years (n = 3 446), SUA was inversely correlated with estimated GFR (eGFR) in both men and women, and the slope of the SUA-eGFR relationship was steeper in women than in men. The slopes of the regression lines became significantly steeper after a 6-year interval in both sexes, and the change in the slope was larger in women. A similar sex difference in the SUA-eGFR relationship and 6-year change in the slope were observed in Cohort 2 consisting of rural town residents aged 61.7 ± 12.2 years (n = 404). Multiple regression analyses showed that explanatory factors of eGFR after a 6-year interval were age and SUA at baseline in both cohorts, and partial regression coefficients of SUA were more negative in women than in men. The SUA-eGFR relationship in allopurinol-treated patients (n = 346, 63.5 ± 13.3 years old) was similar to that in Cohort 2. CONCLUSIONS The results indicate that elevation of SUA accelerates the yearly decline in eGFR and that women are more susceptible to urate-induced decline in eGFR.

The pathophysiological role of digitalis-like substance in essential hypertension.

In order to investigate the role of digitalis-like substance in patients with essential hypertension, levels of plasma digitalis-like substance were measured in nine normotensive, 12 normal-renin and seven low-renin essential hypertensive subjects. The level of plasma digitalis-like substance was determined by using two different methods, the digoxin radio-immunoassay established by our laboratory and Na+,K+-ATPase inhibitory activity (modified Hamlyns method). There was a significant positive correlation between plasma immunoreactive digitalis-like substance and Na+,K+-ATPase inhibitory activity in plasma samples. Both values were significantly higher in hypertensives than in normotensives. Moreover, Na+,K+-ATPase inhibitory activity was significantly higher in low-renin hypertensives than in normal-renin hypertensives or normotensives. These findings suggest (1) digoxin radio-immunoassay may be able to determine the level of plasma digitalis-like substance; (2) digitalis-like substance is increased in essential hypertensives, especially in low-renin hypertensives; (3) the level of digitalis-like substance might be related to plasma renin activity, and mediated by a change in plasma volume; and (4) the activity of the digitalis-like substance may contribute to the pathophysiology of essential hypertension.