The effects of bisoprolol, a selective beta1-blocker, on glucose metabolism by long-term administration in essential hypertension.

Bisoprolol, a beta1-selective beta-blocker, was administered to 13 patients with mild to moderate essential hypertension once daily at doses of 5-10 mg for 24 weeks, and its long-term effects on blood pressure and glucose metabolism were investigated. The systolic, diastolic and mean blood pressures were significantly reduced. At the end of the treatment period, the blood glucose level and hemoglobin A1c were not significantly different from those at baseline. In the glucose tolerance test at the end of the treatment period, the blood glucose and plasma insulin levels after a glucose load of 75 g were not significantly different at any time point, and the sums of each were not significantly different from their baseline levels. Based on these results, bisoprolol appears to be a beta1-selective beta-blocker possessing a satisfactory hypotensive effect without any adverse effects on glucose metabolism for long-term use, and is therefore a safe and useful drug for the treatment of essential hypertension.

[Role of ultrasonography in diagnosis of neutropenic enteritis: a study of 4 cases].

Neutropenic enteritis is a septic or inflammatory disease of the colon. It is usually encountered in patients with hematological malignancy who have undergone chemotherapy, and it presents as fever, diarrhea, and abdominal pain, although the symptoms are not always specific. The diagnostic features of neutropenic enteritis revealed by barium enema, CT and ultrasonography have been reported previously. Here we report 4 cases of neutropenic enteritis in which ultrasound was used for diagnosis, and also for monitoring the clinical course of the disease. Because neutropenic enteritis is rapidly progressive, early diagnosis and therapeutic intervention are required. We believe that ultrasonography is a useful method for examining patients with neutropenic enteritis, being noninvasive, mobile, and providing rapid results in real time, thus aiding early diagnosis and clinical follow-up.

Acute and chronic effects of hyperosmolality on mRNA and protein expression and the activity of Na-K-ATPase in the IMCD.

We investigated acute and chronic effects of hyperosmolality on mRNA and protein expressions of Na-K-ATPase alpha and beta isoforms and Na-K-ATPase activity in the rat inner medullary collecting duct (IMCD). Incubation of IMCD in hypertonic medium for 30 min reduced the Na-K-ATPase activity by 50%. The Na-K-ATPase activity of dehydrated rats measured in isotonic medium was decreased, and incubation in hypertonic medium did not further decrease the activity. Incubation of IMCD in hypertonic medium for 6 h did not change alpha(1) mRNA. In contrast, dehydration decreased alpha(1) subunit mRNA and protein and beta(1) protein expressions without changing beta(1) mRNA. These data show (1) that acute hyperosmolality decreases Na-K-ATPase activity in IMCD without changing alpha(1) and beta(1) mRNA and (2) that 2 days of dehydration decreased Na-K-ATPase activity by reducing alpha(1) and beta(1) proteins. Thus, the mechanisms for the inhibition of the Na-K-ATPase activity in IMCD is different between acute and chronic exposure to hyperosmolality.

Urinary indoxyl sulfate is a clinical factor that affects the progression of renal failure.

We recently demonstrated that indoxyl sulfate is a stimulating factor for the progression of chronic renal failure (CRF). In this study we determined whether the urine or serum levels of indoxyl sulfate are related to the progression rate of CRF in undialyzed uremic patients. Fifty-five CRF patients with a serum creatinine of >2 mg/dl who had not been treated with an oral sorbent (AST-120) were randomly enrolled in the study. We measured the serum and urine levels of indoxyl sulfate, and estimated the recent progression rate of CRF as the slope of the reciprocal serum creatinine versus time (1/S-Cr-time) plot. The mean urinary amount of indoxyl sulfate in the patients was 60 mg/day. Those with indoxyl sulfate urine levels of >60 mg/day had a significantly faster progression rate of CRF than those with <60 mg/day. Especially, those patients with indoxyl sulfate urine levels of >90 mg/day had the highest CRF progression rate and those with indoxyl sulfate urine levels of <30 mg/day had the slowest CRF progression rate. Urinary indoxyl sulfate had a significantly negative correlation with the slope of the 1/S-Cr-time plot. However, the serum level of indoxyl sulfate or the ratio of serum indoxyl sulfate to creatinine was not significantly correlated with the slope of the 1/S-Cr-time plot. In conclusion, high urine levels of indoxyl sulfate are related with a rapid progression of CRF in undialyzed uremic patients. Thus, urinary indoxyl sulfate is one of the clinical factors that affect CRF progression.

Controlled trial of falecalcitriol versus alfacalcidol in suppression of parathyroid hormone in hemodialysis patients with secondary hyperparathyroidism.

Active vitamin D3 is extensively used for the treatment of secondary hyperparathyroidism in hemodialysis patients. But it is often impossible to administer enough dose to suppress parathyroid hormone (PTH) level, because of hypercalcemia and hyperphosphatemia. New modalities with higher specificity for PTH suppression are desirable. We conducted a crossover comparative study of falecalcitriol, an active vitamin D3 analog, and alfacalcidol (1alpha[OH]D3). In this study, 25 hemodialysis patients with moderate to severe secondary hyperparathyroidism who had normal serum calcium levels were enrolled. They received daily oral doses of alfacalcidol during an 8-week observation period. Based on serum calcium levels and intact PTH, the subjects were allocated into two groups, and a comparative study was conducted using unmasked crossover design of two drugs x two periods. The dosage of both drugs was adjusted to maintain the initial serum calcium levels, and the relative change (%change) of serum biochemical parameters were compared. Comparison of two drugs in period 1 was taken as primary efficacy evaluation. Reproducibility of drug action was confirmed by comparing the effect of falecalcitriol between period 1 and 2. The percent change of PTH of falecalcitriol was lower than that of alfacalcidol: Those were, respectively, -7.89% and +30.42% for c-terminal PTH (P = 0.022), -4.39% and +38.88% for i-PTH (P = 0.077), and +3.68% and +30.52% for midregion PTH (P = 0.099). The similar changes were observed in the falecalcitriol group during period 2, confirming the reproducibility. Falecalcitriol was found to be superior to alfacalcidol in suppression of PTH levels in patients with moderate to severe secondary hyperparathyroidism when it is administered in equivalent doses that might maintain similar serum calcium levels.

Long-term enalapril therapy in patients with chronic renal failure on a low-protein diet. A prospective randomized comparison with metoprolol.

The effect of enalapril (5-10 mg/day) on the progression of chronic renal failure (CRF) was compared with that of metoprolol (40-120 mg/day) in 28 patients for 24 months in a prospective study. Throughout the study, there was no significant difference between the 2 groups in protein intake and urinary sodium excretion. But there was a significant difference between the 2 groups in diastolic and mean arterial blood pressure at 6 months. In the serum creatinine level, there was a significant difference between the 2 groups at 6, 12, 18, and 24 months. In creatinine clearance, there was a significant difference between the 2 groups at 24 months. In addition, the progression of CRF was significantly faster in the metoprolol group than the enalapril group as estimated from the slope of creatinine clearance (p < 0.05) and the slope of glomerular filtration rate (p < 0.0005). In urinary protein excretion, there was a significant difference between the 2 groups at 6 and 18 months (p < 0.05). These findings indicate that enalapril has a suppressive effect on the progression of CRF and also has an antiproteinuric effect by a mechanism independent of its antihypertensive effect.

[Summer-type hypersensitivity pneumonitis with remarkable obstructive impairment of pulmonary function].

A 57-year-old-man was admitted because of persistent cough and progressive dyspnea over a period of 2 months. Examination revealed wheezing in both lungs, severe hypoxemia, and marked obstructive impairment of pulmonary function. A chest CT scan showed diffuse small nodular lesions with patchy air space opacifications. The patient was initially given a diagnosis of bronchiolitis of unknown cause. He showed marked improvement after treatment with oral prednisolone, but developed fever and dyspnea after returning home. This episode indicated hypersensitivity pneumonitis, a diagnosis supported by findings of increased CD 8 positive T-lymphocytes in bronchoalveolar lavage fluid, and a high titer of serum anti-Trichosporon antibody. Lung biopsy samples obtained under video-assisted thoracoscopy disclosed noncaseating granulomas in terminal and respiratory bronchioles, which resulted in marked narrowing of the lumen. The pathologic changes seemed to be consistent with obstructive impairment of pulmonary function in this patient.

Quasi-steadiness approximation for the two-compartment solute kinetic model.

We analytically solved the equation of the variable volume, two-compartment solute kinetic model (TCSKM). From the solution, we constructed an expression of weekly concentration profiles developing in the patient's body by routine hemodialyses. Obtained formulas can be used to calculate Kt/V, solute reduction index (SRI), the solute generation rate (G) per unit distribution volume (V), and a mass transfer coefficient (MTC) between the two compartments. To estimate these parameters, the formulas only need three-point data during a dialysis, that is, pre-, one-hour, and post-dialysis solute concentrations instead of four that would otherwise be needed. A 48 hour data point is not required. The weekly concentration profiles can be easily calculated by the formulas. As examples of clinical applications, we calculated Kt/V, G/V, and SRI of urea, Cr, and uric acid using plasma data of 121 hemodialyzed patients. Then the results were compared with the single-compartment solute kinetic model (SCSKM). The obtained mean MTC/V values, that is, 1.08 (1/hr) for urea, 0.53 (1/hr) for Cr, and 1.11 (1/hr) for uric acid, were consistent with the previous works. SCSKM overestimated the mean G/V by 7.1%, 15.9%, and 10.0%, and the mean SRI by 6.7%, 18.6%, and 10.0%, for urea, Cr, and uric acid, respectively. The solute distribution volume ratio of TCSKM to SCSKM, (V)TCSKM/(V)SCSKM, depended on the value of MTC/V and the hemodialysis duration. Using pedometers, we measured the total number of steps the patients took during a week. We found that the total number of steps in a week was significantly correlated with the Cr generation rate (r = 0.285, P < 0.03), but that it was not significantly correlated with the other generation rates (r = 0.204, P > 0.09 for urea, and r = 0.209, P > 0.08 for uric acid). These data suggest that the Cr generation rate is related to the patient's physical activity. We conclude that the formulas can estimate an adequate dialysis prescription for the hemodialyzed patient.

Microlocalization and effects of adrenomedullin in nephron segments and in mesangial cells of the rat.

We examined microlocalization of mRNA coding for adrenomedullin (AM), using reverse transcription-polymerase chain reaction (RT-PCR), and the effects of AM on adenosine 3',5'-cyclic monophosphate (cAMP) generation and water transport in microdissected rat nephron segments. We also examined intraglomerular site of the expression of AM and AM-stimulated cAMP generation in cultured rat mesangial cells (MC). RT-PCR demonstrated the signals for AM mRNA in glomerulus (Glm), cortical collecting duct (CCD), outer medullary collecting duct (OMCD), and inner medullary collecting duct (IMCD) but not in proximal convoluted tubule (PCT) or medullary thick ascending limb (MTAL). AM (10(-7) M) stimulated cAMP generation in Glm >> CCD = IMCD > OMCD but not in PCT or MTAL, which corresponded to the results of the expression of AM mRNA. AM (10(-8) M) slightly increased osmotic water permeability by 24% in perfused terminal IMCD. Northern blot analysis revealed high expression of AM mRNA in MC. AM (10(-7) M) stimulated cAMP generation in MC both in the presence and absence of fetal calf serum, suggesting that AM-dependent cAMP generation was evident both in cycling MC and in quiescent MC. AM may work as a diuretic peptide mainly by increasing glomerular filtration rate via cAMP in MC.

Effects of quinapril hydrochloride in patients with essential hypertension and impaired renal function.

The short-term effects of administration of an angiotensin-converting enzyme (ACE) inhibitor, quinapril hydrochloride (quinapril) (5-10 mg/day), for 12 weeks on blood pressure and renal function were evaluated in 8 patients (60.5 +/- 7.3 years old, mean +/- SD) with mild to moderate essential hypertension and mild impairment of renal function due to nephrosclerosis. Systolic blood pressure and diastolic blood pressure were significantly reduced from 163.0 +/- 4.0 to 132.3 +/- 17.6 mmHg (p < 0.01) and from 98.3 +/- 4.6 to 81.5 +/- 6.4 mmHg (p < 0.001), respectively, before to after treatment. Both renal plasma flow (RPF) and glomerular filtration rate (GFR) were significantly increased in all patients, from 203.9 +/- 33.3 to 245.4 +/- 36.7 ml/min/1.73 m2 (p < 0.01), and from 43.4 +/- 6.4 to 53.5 +/- 4.6 ml/min/1.73 m2 (p < 0.05), respectively. Short-term quinapril administration was beneficial to renal function in patients with essential hypertension and impaired renal function.

Churg-Strauss syndrome associated with necrotizing crescentic glomerulonephritis in a diabetic patient.

We report a patient with Churg-Strauss syndrome-associated rapidly progressive glomerulonephritis concurrent with diabetes mellitus. The patient was a 64-year-old woman who was admitted to our hospital because of a glove and stocking type hypesthesia and numbness, multiple purpurae on both legs, and renal insufficiency with hematuria and proteinuria. Renal biopsy revealed necrotizing crescentic glomerulonephritis accompanied by necrotizing arteritis, marked eosinophilic infiltration of the interstitium, and diffuse and nodular diabetic glomerulosclerosis. Cyclophosphamide and steroid therapy succeeded in improving her neurologic symptoms as well as retarding the deterioration in renal function. No clinical manifestations suggestive of a recurrence of Churg-Strauss syndrome have been observed during the one-year follow-up period.

Indoxyl sulfate and progression of renal failure: effects of a low-protein diet and oral sorbent on indoxyl sulfate production in uremic rats and undialyzed uremic patients.

We have previously demonstrated that indoxyl sulfate is a stimulating factor for the progression of glomerular sclerosis in uremic rats. In this study we determined if a low-protein diet or oral sorbent (AST-120) could reduce the serum and urine levels of indoxyl sulfate in 5/6-nephrectomized uremic rats and undialyzed uremic patients. The uremic rats were treated by fasting or AST-120 for 2 days. The serum and urine levels of indoxyl sulfate dramatically decreased 1-2 days after fasting or AST-120 treatment. We then measured the serum and urine levels of indoxyl sulfate and calculated protein intake from urinary amounts of urea nitrogen using Maroni's equation in 80 undialyzed uremic patients with creatinine clearance less than 30 ml/min. The serum and urine levels of indoxyl sulfate were significantly lower in the patients on a low-protein diet than in those in the normal-protein diet group. Administration of AST-120 significantly decreased serum and urine levels of indoxyl sulfate in 22 undialyzed uremic patients. In conclusion, a low-protein diet or AST-120 reduced the serum and urine levels of indoxyl sulfate, a stimulating factor for glomerular sclerosis, in both uremic rats and undialyzed uremic patients.

Effects of oral adsorbent AST-120 on the progression of chronic renal failure: a randomized controlled study.

This prospective, randomized controlled study was designed to examine the effects of oral adsorbent AST-120 on the progression of chronic renal failure (CRF) in patients on a strict low protein diet (LPD). Twenty-six patients with CRF (serum creatinine 3.0 to 8.6 mg/dl) on a LPD were randomly assigned to a control group (N = 13) or an AST-120 group (N = 13). The 1/Cr slope and creatinine clearance (CCr) slope were used to estimate the progression rate of CRF; uremic toxins, serum and urinary indoxyl sulfate (IS), peak 2a and guanidino substrates (GS) measured by HPLC. Comparisons were made between the baseline observation period for 6 to 12 months and the treatment period (0.6 g/kg/day of LPD alone or concurrent with 6 g/day of AST-120, for the control and the AST-120 groups, respectively) for 12 to 24 months in both groups. Both the 1/Cr slope and CCr slope were significantly lessened in the treatment period only in the AST-120 group. Serum and urinary IS, but neither peak 2a nor GS were significantly decreased in the treatment period only in the AST-120 group. We conclude that AST-120 administration concurrent with LPD may be superior to LPD alone in retarding the progression of CRF by inhibiting accumulation of indoxyl sulfate.

Role of urinary arginine vasopressin in the sodium excretion in patients with chronic renal failure.

Patients with chronic renal failure show almost equal levels of sodium excreted in the urine as healthy subjects through an increase of the fractional excretion sodium (FE(Na)). The mechanisms of this adaptation, however, are unknown. Recently, urinary arginine vasopressin (AVP) has been shown to inhibit the antidiuretic action of plasma AVP in the collecting ducts of rabbits and rats. In this article, the roles of plasma and urinary AVP are examined with other hormones in the sodium excretion of 57 patients with chronic renal disease. The fractional excretion of AVP, plasma atrial natriuretic peptide (ANP) and endothelin-1 (ET-1), urinary ET-1, and FE(ET-1) correlated with the decrease of creatinine clearance (Ccr). Multiple and stepwise regression analyses showed that FE(AVP) is the major dependent determinant for FE(Na) (adjusted r2 = 0.78). These results suggest that the increase of AVP excretion per remaining nephron could be a cause of the increase of FE(Na) in patients with renal failure. Although plasma AVP works as an antidiuretic hormone, urinary AVP serves as an intrinsic diuretic, especially in patients with chronic renal failure.

Accumulation of indoxyl-beta-D-glucuronide in uremic serum: suppression of its production by oral sorbent and efficient removal by hemodialysis.

We identified and quantified indoxyl-beta-D-glucuronide in uremic serum and urine to determine the metabolism of indoles including indoxyl sulfate in uremic patients. Serum levels of indoxyl-beta-D-glucuronide were markedly increased in undialyzed uremic patients, in patients on hemodialysis, and in patients on continuous ambulatory peritoneal dialysis. Urinary excretion of indoxyl-beta-D-glucuronide was also increased in undialyzed uremic patients. Urinary indoxyl-beta-D-glucuronide was significantly correlated with serum indoxyl sulfate, indicating that a high serum level of indoxyl sulfate leads to the enhanced synthesis of indoxyl-beta-D-glucuronide. Oral sorbent (AST-120) administration markedly decreased the serum and urine levels of indoxyl-beta-D-glucuronide as well as indoxyl sulfate in the undialyzed uremic patients. Serum indoxyl-beta-D-glucuronide could be efficiently removed by hemodialysis despite its high protein-binding ratio of about 50%. In conclusion, the serum level of indoxyl-beta-D-glucuronide increases in uremic patients due to renal insufficiency and its increased production. The production of indoxyl-beta-D-glucuronide can be suppressed by oral sorbent treatment, and serum indoxyl-beta-D-glucuronide can be efficiently removed by hemodialysis.

Effects of oral adsorbent AST-120 concurrent with a low-protein diet on the progression of chronic renal failure.

This study was designed to examine the effects of oral adsorbent AST-120 on the progression of CRF in patients on strict LPD. Thirteen patients with CRF (serum creatinine: 1.8-8.2 mg/dl) that had been kept on LPD (0.4-0.7 g/kg/day) were enrolled in this study. After LPD alone for 5-24 months, AST-120 (3-6 g/day) was administered concurrently with the LPD for an additional 5-13 months. In 9 of the 13 patients, the slopes of reciprocal creatinine (Cr) vs. time plot linearly declined before AST-120 treatment. After treatment, the slopes of these patients lessened from -0.01 +/- 0.001 to -0.003 +/- 0.001 dl/mg/month (p < 0.01). Because reciprocal Cr did not decline linearly with time before AST-120 treatment in the remaining 4 patients, the slopes of reciprocal Cr could not be compared before and after treatment with AST-120. Seven of the 9 patients had sufficient creatinine clearance (Ccr) data after treatment with AST-120. The decline of Ccr decreased from -0.59 +/- 0.13 to -0.12 +/- 0.12 ml/min/month in these patients. This study has clearly demonstrated that AST-120 compounds the effects of well-controlled LPD on retarding the progression of CRF. AST-120 may remove some uremic metabolite(s) which promote the progression of CRF.

MRA imaging of arterial patency in undialyzed uremic patients with arteriosclerosis obliterans.

Magnetic resonance angiography (MRA) was performed on 13 undialyzed patients with chronic renal failure (CRF) (serum creatinine concentrations: 4.0 +/- 0.6 mg/dL) who were suspected of having arteriosclerosis obliterans (ASO) due to symptoms and/or physical findings. In the 13 patients studied, MRA images of 10 patients exhibited stenosis or occlusion of iliac arteries, femoral arteries, a vertebral artery, or a carotid artery, indicating the presence of ASO. Four asymptomatic patients were diagnosed as having ASO by MRA. MRA showed ASO findings which were exactly the same as those shown by conventional angiography in one patient, suggesting that MRA is in good agreement with conventional angiography for evaluating arterial patency. Our study showed that MRA can reveal arterial patency in patients with CRF. MRA seems to be most suitable for patients with CRF to diagnose ASO, avoiding contrast nephropathy and acute deterioration of renal failure.

Immunohistochemical localization of V2 vasopressin receptor along the nephron and functional role of luminal V2 receptor in terminal inner medullary collecting ducts.

We investigated immunohistochemical localization of V2 vasopressin receptor along the nephron using a specific polyclonal antibody. Staining was observed in some of thick ascending limbs and all of principal and inner medullary collecting duct (IMCD) cells. Not only basolateral but also luminal membrane was stained in collecting ducts, especially in terminal IMCD (tIMCD). To learn the functional role of luminal V2 receptor in tIMCD, we studied the luminal effects of arginine vasopressin (AVP) on osmotic water permeability (Pf), urea permeability (Pu), and cAMP accumulation using isolated perfused rat tIMCD. In the absence of bath AVP, luminal AVP caused a small increase in cAMP accumulation, Pf and Pu, confirming the presence of V2 receptor in the lumen of tIMCD. In contrast, luminal AVP inhibited Pf and Pu by 30-65% in the presence of bath AVP by decreasing cAMP accumulation via V1a or oxytocin receptors and by an unknown mechanism via V2 receptors in the luminal membrane of tIMCD. These data show that V2 receptors are localized not only in the basolateral membrane but also in the luminal membrane of the distal nephron. Luminal AVP acts as a negative feedback system upon the basolateral action of AVP in tIMCD.