Aberrant activation of the intrarenal renin-angiotensin system in the developing kidneys of type 2 diabetic rats.

We have previously reported that intrarenal angiotensin II (Ang II) levels are increased long before diabetes becomes apparent in obese Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats, a model of type 2 diabetes. In this study, we examined the changes in intrarenal renin-angiotensin system (RAS) activity in the developing kidneys of OLETF rats. Ang II contents and mRNA levels of RAS components were measured in male OLETF and control Long-Evans Tokushima (LETO) rats at postnatal days (PND) 1, 5, and 15, and at 4-30 weeks of age. In both LETO and OLETF rats, kidney Ang II levels peaked at PND 1, then decreased during the pre- and post-weaning periods. However, Ang II levels and gene expression of RAS components, including angiotensinogen (AGT), renin, and angiotensin-converting enzyme (ACE), were not significantly different between LETO and OLETF rats. Intrarenal Ang IIcontents further decreased during puberty (from 7 to 11 weeks of age) in LETO rats, bur not in OLETF rats. At 11 weeks of age, kidney Ang II levels, urinary AGT excretion, and mRNA levels of AGT and renin were higher in OLETF rats than in LETO rats, while blood glucose levels were not significantly different between these groups of rats. These data indicate that continued intrarenal expression of Ang II during pubescence contributes to the increases in intrarenal Ang II levels in prediabetic OLETF rats, and is associated with increased intrarenal AGT and renin expression. Inappropriate activation of the intrarenal RAS in the prediabetic stage may facilitate the onset and development of diabetic nephropathy in later life.

Long-term evaluation of nutritional status using dual-energy X-ray absorptiometry in chronic hemodialysis patients.

BACKGROUND: Hemodialysis patients very often suffer from malnutrition with net loss of body muscle and fat stores. Since protein-calorie malnutrition has been considered to be highly associated with increased morbidity and mortality, it is important that the nutritional status is evaluated accurately and that long-term evaluation of the nutritional status is performed to obtain good outcome. PATIENTS AND METHODS: Forty-six patients (28 men and 18 women) undergoing maintenance hemodialysis were studied. Nutritional status of the patients was examined by dual-energy X-ray absorptiometry (DXA) and anthropometry measurements after a hemodialysis session and 4 years after the initial measurement. RESULTS: Percent fat, the ratio of body fat (BF) to weight, determined by DXA correlated positively with body mass index (BMI) calculated from weight and height. There was also a significant positive correlation between lean body mass (LBM) determined by DXA and arm muscle circumference (AMC) calculated using the anthropometric method. In the study period of 4 years, LBM and bone mineral content (BMC) observed at the end point were significantly lower than those at the start. In contrast, BF and %fat at the end point were significantly higher as compared with those at the initial measurement. CONCLUSION: These results indicate that DXA is a reliable method for body composition analysis in chronic hemodialysis patients. Because the detection of early alterations in body composition may provide an early indication of the development of malnutrition, serial evaluation of body composition using DXA should be valid for assessment of the nutritional status.

A new approach for glomerular lesions: evaluation of scanning acoustic microscopy (SAM) for experimental glomerular disease in rats.

Most pathological evaluations using ordinary optical microscopy are usually qualitative and subjective. The beneficial properties of scanning acoustic microscopy (SAM) include not only observation of microstructure but also quantitative measurement of acoustic propagation speed, indicating the tissue elasticity. In this study, we examined the capability of SAM to evaluate pathological findings in glomeruli using anti-Thy.1 glomerulonephritis. Light microscopic observations of the glomeruli showed severe cell proliferation and mesangial matrix expansion at 10 days after induction of glomerulonephritis and, yet, to a lower extent at day 21 with onset of healing. C-mode scanning of SAM enabled imaging of glomerular structure compatible to findings of ordinary light microscopy. In addition, glomerular propagation speed in nephritic rats was significantly increased at day 10, and then decreased at day 21. These results indicate that SAM evaluation may be a new, useful technique for quantitative evaluation of proliferative glomerular lesions.

[An autopsy case of membranous lipodystrophy (Nasu)].

Membranous lipodystrophy (Nasu) is characterized by polycystic osteodysplasia associated with dementia. We recently experienced a 9th autopsy case in Japan. This 50 year-old male, eldest in the reported autopsied case in Japan, presented bone fracture at 35 year of age and dementia started at 45. His parents were cousins. His sister, died with carcinoma of the bladder at 35, developed marked osteoporosis with multiple pathological fractures and "membrano-cystic" lesions were found in her adipose tissue. The roentgenogram of the patient's long bone revealed radiolucent and cystic areas with irregular boundaries at the metaphyses. Computer tomography of the brain examined during the last 3 years showed slowly progressive brain atrophy. Calcifications of the basal ganglia or low density area in the white matter were not found. Autopsy showed typical "membrano-cystic" lesions in the adipose tissue of the whole body including bone marrow. Brain weighed 1,030 g. There was a mild convolutional atrophy at the frontal lobe. White matter was diffusely atrophic. Demyelination was limited to the frontal lobe, where only small number of perivascular sudanophilic lipid-laden macrophages were found. Fibrillary astrocytes were rather diffusely proliferated, consistent with sclerosing leukoencephalopathy. Many spheroids were found in the frontal and occipital deep white matters, and external capsule. Ultrastructural study of spheroid revealed increased amount of neurofilament, vesicles with free patchy dense materials and degenerated mitochondria, which were consistent with primary axonal degeneration.

[Mechanism mediating hypertension induced by chronic inhibition of nitric oxide synthesis].

Although the inhibition of nitric oxide (NO) synthesis is known to induce systemic hypertension, the underlying mechanisms mediating this type of hypertension are incompletely understood. In the present study we investigated the influence of sodium intake on the pressor effect of long-term administration of the NO synthesis inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 16 mg/dl in drinking fluid for 8 weeks), in conscious Sprague-Dawley rats. Urinary excretion rates of catecholamine during NO synthesis inhibition were also examined. Long-term administration of L-NAME produced a sustained elevation in tail-cuff pressure without altering urine flow, or sodium excretion rate. L-NAME-induced hypertension was accompanied by a decreased urinary excretion of the stable NO metabolites, NO2- and NO3-, and was aggravated when rats drank 0.9% saline in place of tap water. Thus, inhibition of NO synthesis resulted in a rightward shift of the pressure natriuresis relationship and a significant decrease in the slope of this relationship. Urinary excretion of epinephrine and norepinephrine, but not that of dopamine, in L-NAME-treated rats significantly increased within the first week of the study when compared with those observed in control rats. A natriuretic index of the sympathetic nervous system, the ratio of dopamine to norepinephrine excretion, was significantly less in L-NAME-treated rats than in control rats. After 8-week treatment with L-NAME, renal morphologic evaluation revealed significant narrowing and obliteration of the arterioles. L-arginine (2 g/dl in drinking fluid) completely reversed the elevation of blood pressure as well as the decrease in urinary NO2- and NO3- excretion and the increased urinary excretion of catecholamines associated with L-NAME treatment after 3 weeks of concomitant administration. These results suggest that the inhibition of chronic NO synthesis produces sodium-sensitive hypertension and that changes in sympathetic nerve activity may, at least in part, contribute to the sodium sensitivity in this type of hypertension.

[Effect of histamine H2-receptor antagonists on the phosphorus-binding ability of phosphate binders in hemodialysis patients].

We examined the effects of histamine H2-receptor antagonists on the phosphorus binding ability of phosphate binders. Serum calcium, phosphorus, ALP, PTH and arterial blood pH and bicarbonate were measured during treatment with histamine H2-receptor antagonists accompanied by calcium carbonate in sixteen patients undergoing maintenance hemodialysis. Seven patients receiving histamine H2-receptor antagonists without calcium carbonate were selected as controls. In the sixteen patients receiving calcium carbonate, serum calcium, ALP, PTH and arterial blood pH and bicarbonate were not significantly altered during treatment with histamine H2-receptor antagonists, but serum phosphorus levels increased significantly after four (5.6 +/- 1.1 mg/dl) and eight weeks (5.9 +/- 0.8 mg/dl) of treatment as compared with that before treatment (4.8 +/- 1.2 mg/dl). Furthermore, serum phosphorus levels decreased significantly eight weeks after the discontinuation of treatment with histamine H2-receptor antagonists. In the seven control patients there were no statistical differences in serum calcium and phosphorus levels measured before and after treatment with histamine H2-receptor antagonists. In seven other patients receiving histamine H2-receptor antagonists with calcium carbonate, calcium carbonate was replaced with calcium lactate as the phosphate binder after four weeks of treatment with histamine H2-receptor antagonists. With the 4-week administration of histamine H2-receptor antagonists accompanied by calcium carbonate, the serum phosphorus level increased, similarly to that of the first study (from 6.3 +/- 0.9 to 7.1 +/- 0.5 mg/dl). However, with the substitution of calcium lactate, the serum phosphorus level decreased significantly (6.3 +/- 0.2 and 6.0 +/- 0.9 mg/dl after four and eight weeks, respectively, despite continued administration of histamine H2-receptor antagonists). These results suggest that histamine H2-receptor antagonists significantly affect the phosphorus binding ability of calcium carbonate, but not of calcium lactate. Although the exact mechanism remains obscure, one possible explanation may be related to the rise in pH of the gastric juice. Careful observation of changes in the serum phosphorus level is required in hemodialysis patients receiving calcium carbonate and histamine H2-receptor antagonists. Calcium lactate may be useful as a phosphate binder in such hemodialysis patients.

Interferon-gamma enhances superoxide production in human mesangial cells via the JAK-STAT pathway.

Immune reactive cytokines, such as interferon (IFN)-gamma, have multiple effects in glomerulonephritis. Superoxide anions (O(2)(-)), which are associated with the progression of glomerulonephritis, are mainly generated by nicotinamide adenine dinucleotide phosphate (reduced form) NAD(P)H oxidases. We determined the effects of IFN-gamma on O(2)(-) production, phosphorylation of signal transducer and activator of transcription (STAT)-1alpha, and the mRNA and protein expressions of p22phox and Nox1, components of NAD(P)H oxidases, in human mesangial cells (HMCs). Significant increases in O(2)(-) production with IFN-gamma were completely abolished by the flavin-containing enzyme inhibitor, diphenyleneiodonium (10 micromol/l), and the Janus-activated kinase (JAK)2 inhibitor, AG490 (100 micromol/l). Phosphorylated STAT-1alpha was detected after 5 min of IFN-gamma stimulation using Western blot analysis, and binding to the gamma-activating site was observed from 30 min to 4 h, thereafter by electrophoretic mobility shift assay (EMSA). Super-shift analysis in EMSA revealed that the main transcription factor was STAT-1alpha. IFN-gamma significantly increased the expression of p22phox mRNA and protein, although expression was inhibited by AG490. These data suggest that IFN-gamma stimulates O(2)(-) production in HMCs via the JAK-STAT pathway and NAD(P)H oxidase.

[Clinical studies in five cases of Swyer-James syndrome].

We encountered five patients with Swyer-James syndrome. All were men, and ranged in age from 20 to 70 years (mean, 41 years). Their chest X-ray films showed left unilateral hyperlucency. Examinations revealed bilateral involvement in 3 cases and irregularity of involved regions in 2 cases. Chest CT scans revealed the distribution and severity of affected regions in greater detail than did other radiologic exams. Delayed clearance of xenon is a sign of air trapping, which is characteristics of this syndrome. Thus, 133Xe inhalation scintigrams were useful to detect air trapping, especially when mediastinal shift was not apparent on chest X-ray films. Bronchial damage is believed to cause this syndrome, and the present findings support this view. It is noteworthy that all five of these patients were men, and that in all five the affected lung was on the left. Moreover, although "respiratory tract infection is considered to be a very important" factor, many patients had no history of airway infection in childhood. Thus, some congenital factor or factors may contribute to the development of this syndrome.

A trial of quantitative classification of surgical stress.

The severity of various surgical stresses was classified quantitatively on the basis of degree of adrenocortical stimulation by ACTH-Z. Urinary 17-OHCS (total, free and individual fractions) were dtermined in sixteen patients who underwent various operations and were injected some doses of ACTH-Z. The following quantitative classification of surgical stress was possible. In the group of ureterolithotomy and pyeloithotomy, the severity of operative stress appeared to be equivalent to the adrenocortical stimulation caused by injection of 0.125 mg to 0.25 mg of ACTH-Z. The severity in the group of ureterotomia externa was nearly the same as that in the above group. In the group of nephrectomy by oblique incision, the severity of stress appeared to correspond to the stimulation by injection of 0.25 mg or more of ACTH-Z. The group of total nephroureterectomy with partial cystectomy showed the severity which would correspond to the degree of stimulation by injection of about 0.5 mg ACTH-Z, and the group of transperitoneal nephrectomy, by injection of 0.25 mg to 0.5 mg of ACTH-Z.

Prognostic significance of long ventricular pauses in athletes.

The long-term prognosis of athletes with long ventricular pauses has been unknown. In this study, thirty highly-trained cross-country skiers and 24 age-matched controls underwent 24 h Holter monitoring to detect the duration of the longest ventricular pause (LVP), and we followed the athletes for more than 3 years to evaluate prognostic significance of prolonged LVP. The LVPs of the athletes averaged 2.2 +/- 0.6 sec (range 1.3-3.4), which were significantly longer than those, 1.6 +/- 0.3 sec, of the controls. In the athletes, 20 cases (66.7%) had LVPs more than 2 sec, and 5 (16.7%) showed LVPs longer than 3 sec. During 3 years follow-up, no athletes had symptoms of near syncope, syncope or death under continued heavy training. Our study suggested that athlete with prolonged ventricular pause, even of 3 sec or more, did not have a different clinical risk than those without long pauses.

[A case of Swyer-James syndrome diagnosed at age 70].

A male case of Swyer-James syndrome, who had been followed for bronchiectasis for a long time, detected at age 70 and diagnosed by radiological studies was reported. The movement of his left diaphragm was impaired. Arterial oxygen tension was 68 torr while breathing room air. Pulmonary function tests showed mixed ventilatory impairment, increase of residual volume, and uneven gas distribution, but diffusing capacity was normal with the single breath method. Chest radiograph revealed hyperlucency of the left lung and the right middle lung field. In these areas, pulmonary angiography showed marked hypovascularity and diffuse vascular atrophy, and perfusion and inhalation scans also showed marked decreased perfusion and ventilation. Pulmonary hypertension was not detected by right heart catheterization. Fiberoptic bronchoscopy was performed and showed no abnormality of the left bronchial tree, and bronchography demonstrated diffuse cylindrical bronchiectasis of the left lung with no alveolar filling. He had suffered from chronic sinusitis for a long time, which might suggest that he had sinobronchitis due to congenital abnormality of the airway and this caused continuous respiratory infection, which could cause this syndrome. Including our own case, about 80 cases of Swyer-James' syndrome have been reported in Japan. But only 4 cases were above 70 years of age and all of them were male, and there has been no female cases above age 50. Males predominate over females, and in both sexes the left lung was more commonly affected than the right.

A simple and early prognostic index for acute renal failure patients requiring renal replacement therapy.

Recent advances in technology have not substantially changed the high mortality rate associated with acute renal failure (ARF). To obtain a simple, valid prognostic index, we retrospectively evaluated the relative importance of demographic data, causes (acute insults) of renal failure, and comorbid clinical conditions for the outcome in 102 ARF patients who received renal replacement therapy with an overall mortality rate of 65% (66 of 102). There were no significant differences between survivors and nonsurvivors in age and gender. Mortality according to acute insults was similar to that of the whole population studied. Of the 10 clinical conditions at the time of the first renal replacement therapy, mechanical ventilation (p = 0.0002), cardiac failure (p = 0.0006), hepatic failure (p = 0.003), central nervous system dysfunction (p = 0.005), and oliguria (p = 0.04) were found to be significantly related to mortality by univariate analysis. Furthermore, multivariate analysis demonstrated that only mechanical ventilation, cardiac failure, and hepatic failure were significant risk factors. Survival was directly related to the number of significant variables in univariate analysis: zero, 89% (8 of 9); one, 62% (21 of 34); two, 19% (5 of 27); three, 10% (2 of 20); four, 0% (0 of 8); five, 0% (0 of 4). This simple and early prognostic index, derived from the assessment of clinical conditions which were easily determined at the patient's bedside, could be useful for outcome prediction in ARF patients requiring renal replacement therapy.

The effect of combination therapy with interferon and cryofiltration on mesangial proliferative glomerulonephritis originating from mixed cryoglobulinemia in chronic hepatitis C virus infection.

Cryofiltration, which has developed from double filtration plasmapheresis (DFPP) with a cooling unit, is an on-line technique to remove cryoglobulin. We report on a patient who suffered from progressive edema and renal insufficiency caused by cryoglobulinemic membranoproliferative glomerulonephritis (MPGN), probably due to chronic hepatitis C virus (HCV) infection. To remove cryoglobulins and terminate the HCV infection, we utilized combination therapy with cryofiltration and interferon-alpha injection with corticosteroids. Interferon-alpha was capable of decreasing proteinuria but not diminishing cryoglobulin. Additional cryofiltration could remove cryoglobulin to an undetectable level. This combination therapy was partially successful to reduce proteinuria and prevent the progressive deterioration of renal function. The major adverse effects of this therapy were bleeding and myelosuppression. We conclude that this combination therapy may be effective and should be considered as treatment for cryoglobulinemic MPGN.

Sodium sensitivity and sympathetic nervous system in hypertension induced by long-term nitric oxide blockade in rats.

1. Pharmacological inhibition of nitric oxide (NO) synthesis is known to produce acute and chronic hypertension in many animal species, but the underlying mechanisms mediating the hypertension are not completely understood. In particular, the pathogenetic roles of sodium sensitivity and the sympathetic nervous system in this model of hypertension are controversial. The present study was designed to test the hypothesis that long-term administration of the NO synthesis inhibitor NG-nitro-L-arginine methyl ester (L-NAME) to male Sprague-Dawley rats would produce a sodium-sensitive hypertension and that the enhanced activity of the sympathetic nervous system in this type of hypertension contributes to the sodium sensitivity. 2. NG-Nitro-L-arginine methyl ester was added to drinking fluid for 8 weeks at a concentration of 16 mg/dL. Rats received tap water for the first 4 weeks of the study and were then divided into two groups and placed on either a normal or high sodium intake (ingestion of either tap water or 0.9% NaCl, respectively). Awake systolic blood pressure was measured by the tail-cuff method every week. Urinary excretion rates of the stable NO metabolites and catecholamines during NO synthesis inhibition were examined. 3. Long-term administration of L-NAME produced a marked and sustained elevation in arterial pressure without altering urine flow, or sodium excretion rate. NG-Nitro-L-arginine methyl ester-induced hypertension was accompanied by a decreased urinary excretion of the stable NO metabolites NO2- and NO3- and was aggravated when rats drank 0.9% NaCl in place of tap water. Urinary excretion of adrenaline and noradrenaline, but not dopamine, in L-NAME-treated rats increased significantly within the first week of the study compared with control rats. L-Arginine (2 g/dL in drinking fluid) completely reversed the elevation of arterial pressure as well as the decrease in urinary NO2- and NO3- excretion and the increased urinary excretion of catecholamines associated with L-NAME treatment by 3 weeks of concomitant administration. 4. These results suggest that long-term inhibition of NO synthesis produces a sodium-sensitive hypertension and that changes in sympathetic nerve activity may, at least in part, contribute to the sodium sensitivity in this type of hypertension.

[Corticoids secretion in primary aldosteronism. I. Diurnal variation and the effect of dexamethasone (author's transl)].

For the purpose of studying the metabolism of adrenocortical steroids in primary aldosteronism, diurnal variation and the effect of dexamethasone were examined in four patients. The circadian rhythm of cortisol was observed in plasma aldosterone and corticosterone in all cases in the preoperative state. With regards to plasma progesterone, 17 alpha-hydroxyprogesterone and dehydroepiandrosterone-sulfate, however, no demonstrable change was noted. Dexamethasone was administered to two subjects for 10 days before the operation. As a result, the urinary aldosterone of one subject decreased on the 5th day after the administration but was restored to its original value on the 10th day, while the urinary aldosterone of the other subject did not decrease at all. On the first day after the operation, the value of plasma cortisol was elevated, losing its circadian rhythm. On the 7th day after the operation, the normal circadian rhythm was observed again in plasma cortisol. Plasma aldosterone was reduced to the normal range without any demonstrable changes on the first and 7th days after the operation. On the 30th day after the operation, a slight cortisol-like circadian rhythm was observed. Plasma levels of progesterone, corticosterone, 17 alpha-hydroxyprogesterone and dehydroepiandrosterone-sulfate were almost within the normal range throughout the pre- and post-operative periods. Although plasma progesterone was within the normal range, it tended to be lower in the postoperative state than in the preoperative state.

[Corticoid secretion in primary aldosteronism. II. The renin releasing test and the angiotensin II analog infusion test (author's transl)].

To study the secretion of adrenocortical steroids, the renin releasing test and the angiotensin II analog (1-Sar, 8-Ala-Angiotensin II) infusion test was performed on four subjects with primary aldosteronism. The plasma renin activities of these subjects in the preoperative state were rather low, without any response to the renin releasing test. Plasma aldosterone was, however, significantly high and showed a tendency to declineits value when the subject was in an upright position. In the preoperative state, all the subjects lacked any alterations in plasma renin activity throughout the angiotensin II analog infusion test. Though slight elevations were observed in the blood pressure of three subjects, there was no demonstrable change in plasma aldosterone. In the other subject, though blood pressure did not change, plasma aldosterone exhibited a remarkable rise as did progesterone, 11-deoxycorticosterone and corticosterone. From these data, it was suggested that in the latter subject the aldosterone secretion was sensitive to angiotensin in comparison with ACTH. Three weeks after the operation, it was observed that plasma aldosterone response decreased, while the response of plasma renin activity to the renin releasing test was normal. This is considered to be due to the diminished sensitivity of the glomerulosa of the nonadenomatous adrenal gland to angiotensin. The levels of 17 alpha-hydroxyprogesterone, 11-deoxycorticosterone and corticosterone were almost within the normal range in the pre- and postoperative state. The levels of plasma progesterone and 11-deoxycorticosterone, however, tended to be lower in the postoperative state compared with the preoperative state.