Masayuki Takasugi

Optimal dialysis improves uremic pruritus

The authors analyzed data on 59 hemodialyzed patients who did not have significant disorders of calcium and phosphate metabolism and found that more than 60% suffered from disabling pruritus possibly related to chronic uremia. Both biochemical correlates of the prevalence of pruritus and dialysis efficacy calculated by urea kinetics were investigated. Significantly higher values of blood urea nitrogen and plasma beta 2-microglobulin just before the dialysis session were observed in pruritic patients with lower dialysis efficacy estimated by Kt/V urea and normalized protein catabolic rate (nPCR). After 3 months without changing the dialysis prescriptions, 16 patients with a mean Kt/V urea and a normalized protein catabolic rate (nPCR) of 1.28 and 1.22 g/kg/d, respectively, experienced significant reductions in the degree of pruritus estimated by the pruritic score, from 12.6 +/- 5.1 to 6.3 +/- 3.2. Twenty-two patients with a mean Kt/V urea and an nPCR of 1.09 and 1.01, respectively, continued to have severe pruritus (score: 12.3 +/- 4.7 to 12.7 +/- 6.4). In 9 of 22 patients with prolonged severe pruritus, dialysis efficacy was heightened with an increase in dialyzer membrane area of more than 0.3 m2. Seven of nine patients with increased dialysis prescriptions had significant reductions of the mean pruritic score, from 12.6 +/- 4.8 to 6.3 +/- 2.4, which inversely related to the significant increase of Kt/V urea from 1.05 +/- 0.25 to 1.24 +/- 0.33; among patients whose dialysis prescriptions were not changed, only one had a significant reduction in score. The authors concluded that higher dialysis efficacy with good nutritional state reduces the prevalence and degree of pruritus in hemodialyzed patients.

Adrenomedullin-sensitive receptors are preferentially expressed in cultured rat mesangial cells

By using cultured rat mesangial cells, we compared the effects on cyclic nucleotide levels of adrenomedullin with those of the structurally related peptides, calcitonin gene-related peptide (CGRP) and amylin. Adrenomedullin potently increased cAMP levels 7-fold in a time- and concentration-dependent manner. Its EC50 was 3 x 10(-9) M. CGRP was less potent (2-fold) with an EC50 of 10(-7) M, and amylin had no effect on cAMP levels. All three peptides failed to increase cGMP levels. Treatment of cells with near maximal concentrations of adrenomedullin (10(-7) M) and CGRP (10(-6) M) had no additive effect on cAMP levels. Human adrenomedullin-(22-52)-NH2, a putative adrenomedullin receptor antagonist, inhibited the production of cAMP elicited by adrenomedullin (IC50: 7 x 10(-8) M) and CGRP (IC50: 5 x 10(-8) M). Human CGRP-(8-37), a CGRP receptor antagonist, conversely, reduced the cAMP elevation caused by these peptides with a lower potency (IC50: 10(-6) M for both peptides). This demonstrated that human adrenomedullin-(22-52)-NH2 was a more effective antagonist for adrenomedullin- and CGRP-specific receptors than human CGRP-(8-37). Results suggest that receptors sensitive to adrenomedullin are preferentially expressed in cultured rat mesangial cells. Immunohistochemical study showed almost no immunoreactive adrenomedullin and CGRP, if any, in the cells. Adrenomedullin may regulate mesangial function as either a paracrine or circulating hormone via a cAMP- but not a cGMP-dependent mechanism.

Effects of nifedipine on platelet function.

Effects of nifedipine on platelet aggregation were studied both in vitro and in vivo. From in vitro experiments, nifedipine inhibited platelet aggregation in a dose-dependent manner. The inhibition by nifedipine (final concentration 10 micrograms/ml) on epinephrine-induced and collagen-induced platelet aggregation was more than 90%, greater than that on adenosine diphosphate (ADP)-induced aggregation. The consumption ratio of small platelets (less than or equal to 6.4 fL) was higher than that of large platelets (greater than 6.4 fL), suggesting that nifedipine inhibits the aggregation of large platelets more effectively. Changes in the effects of nifedipine on platelet aggregation associated with exercise were also studied in six healthy volunteers. While platelet aggregability increased after exercise without administration of nifedipine, it was inhibited 90 minutes after the drugs administration (10 mg). The inhibition of collagen-induced and ADP-induced (2 microM) aggregation by nifedipine was particularly significant.

Clinical Significance of Natriuretic Peptides and Cyclic GMP in Hemodialysis Patients with Coronary Artery Disease

Background: Plasma concentrations of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and cyclic guanosine monophosphate (cGMP) are suitable markers of ’dry body weight’ (DW) in hemodialysis (HD) patients. However, it is still unknown whether these markers can be applied to patients with renal failure and coronary artery disease (CAD). We examined the reliability of these peptides as volume markers in HD patients with CAD. We also assessed the relationship between natriuretic peptides and indices of left ventricular (LV) function. Methods: Plasma concentrations of ANP, BNP and cGMP were determined before and after HD in patients with CAD (group 1, n = 19, mean age 63 ± 12 years) and were compared with those of patients without cardiac disease (group 2, n = 20, age 61 ± 15 years). Using data obtained by cardiac catheterization, we examined the relationship between natriuretic peptides and indices of LV function in HD patients with CAD. Results: Baseline ANP (244 ± 205 pg/ml), BNP (713 ± 928 pg/ml) and cGMP (29.6 ± 21.6 pmol/ml) were significantly higher in group 1 than in 11 healthy volunteers (18.6 ± 9.9 pg/ml, 7.7 ± 7.6 pg/ml, cGMP 8.9 ± 4.9 pmol/ml, respectively). HD significantly reduced plasma ANP (87 ± 75 pg/ml) and BNP (477 ± 702 pg/ml) although they were still above normal control. HD reduced plasma cGMP (7.2 ± 4.5 pmol/ml) to normal values, suggesting the elimination of cGMP across the dialyzers. Baseline levels of ANP, BNP and cGMP in group 2 were less than those of group 1 but higher than the control. HD reduced natriuretic peptides in group 2 to levels lower than those in post-HD group 1. After HD, there was no significant correlation between reductions in body weight and changes in ANP or BNP. Baseline ANP and BNP levels closely correlated with pulmonary artery pressure, pulmonary artery wedge pressure, left ventricular end-diastolic pressure and left ventricular ejection fraction. A significant correlation was observed between BNP levels and the severity of CAD. Conclusion: ANP, BNP and cGMP seem to be a useful markers for fluid overload but not for DW in HD patients with CAD. Plasma ANP and BNP might be useful markers for left ventricular function.

Adrenomedullin increases cyclic AMP more potently than CGRP and amylin in rat renal tubular basolateral membranes

In rat renal tubular basolateral membranes, the potency to increase cAMP of adrenomedullin (AM), a novel vasorelaxant peptide originally isolated from human pheochromocytoma, was compared with those of calcitonin gene-related peptide (CGRP) and amylin. Although all three peptides raised cAMP in a time- and concentration-dependent manner with a 4-fold increase at 10(-6)-10(-5) M, the EC50 value (10(-9) M) of AM was 100-fold smaller than those of CGRP and amylin. CGRP[8-37], an antagonist for CGRP receptors, attenuated cAMP elevation induced by these peptides with the essentially similar concentration-inhibition curves. These results suggest that the receptors for AM, CGRP and amylin share a common structural homology, and that the receptors sensitive to AM are preferentially expressed in renal tubular basolateral membranes.

Upregulation of the expression of vasopressin gene in the paraventricular and supraoptic nuclei of the lithium-induced diabetes insipidus rat.

The expression of arginine vasopressin (AVP) gene in the paraventricular (PVN) and supraoptic nuclei (SON) was investigated in rats with lithium (Li)-induced polyuria, using in situ hybridization histochemistry and radioimmunoassay. The male Wistar rats consuming a diet that contained LiCl (60 mmol/kg) for 4 weeks developed marked polyuria. The Li-treated rats produced a large volume of hypotonic urine with low ionic concentrations. Plasma sodium concentrations were found to be slightly increased in the Li-treated rats compared with those in controls. Plasma concentration of AVP and transcripts of AVP gene in the PVN and SON were significantly increased in the Li-treated rats compared with controls. These results suggest that dehydration and/or the activation of visceral afferent inputs may contribute to the elevation of plasma AVP and the upregulation of AVP gene expression in the PVN and the SON of the Li-induced diabetes insipidus rat.

Morphological effects of cadmium on proximal tubular cells in rats.

Twenty-four male rats of the Wistar strain divided into four groups were injected sc with a dose of 0.8, 1.5, and 3.0 mg Cd/kg body wt as CdCl2 in saline, and saline alone to the control rats, three times a week for 3 wk. Cadmium levels of whole kidney homogenate, supernatant (cytosol), precipitate, and metallothionein (MT) fraction were measured. Histological changes of the renal proximal tubules were investigated by optical and electron microscopy. In the kidneys, Cd levels were increased with the increment of Cd dosage; 80–90% of Cd was contained in cytosol, and 55–75% was in MT fraction. Non-MT-Cd reached a maximum in the 1.5 mg Cd group, whereas that of the 3.0 mg Cd group showed some decline. With increasing Cd doses, the size of nuclei and nucleoli in the cells of proximal tubule showed significant enlargement and also an increase in the number of nucleoli on light microscopy. At higher doses, chromatin condensation of the tubular nuclei and vacuolar degeneration of the tubular cells were evident.On electron microscopy, perichromatin granules of the proximal tubular nuclei were increased in number, especially in the rats of Cd 0.8 mg and 1.5 mg/kg groups. As the Cd doses increased, ring-shaped nucleoli were increased in number and nucleolar segregation was observed more clearly. Moreover, in the 3.0 mg/kg Cd group, nuclear indentation and nucleoli containing compact dense granules were observed. In the cytoplasm, there was an increase of lysosomes, myelin bodies, ring-shaped mitochondria, and vesiculation; ultimate changes were degeneration and cell necrosis. The injured cells were heterogenously distributed in each nephron and this heterogeneity was attributed in the difference in Cd content and cell cycle in each cell of the nephron.

Isolated hematuria in adults: IgA nephropathy is a predominant cause of hematuria compared with thin glomerular basement membrane nephropathy.

We examined kidney biopsy specimens obtained from 40 adult patients with isolated hematuria to determine the renal pathology and the incidence of thin glomerular basement membrane nephropathy (TGBMN). Light microscopy showed minor glomerular abnormalities in 26 patients (65%), focal and segmental lesions in 3 patients (8%), and mild diffuse proliferative glomerulonephritis in 11 patients (28%). Immunofluorescence microscopy showed IgA nephropathy (IgA-N) in 16 patients (40%), in whom no progressive lesions were identified. We measured the glomerular basement membrane (GBM) thickness using electron microscopy, and TGBMN was identified in 4 patients (10%). Our results suggest that IgA is a major pathological finding in adult patients with isolated hematuria. GBM thinning does not appear to be a major cause of glomerular hematuria.

Dialysis efficacy and nutritional status in elderly hemodialyzed patients

To examine the effect of dialysis efficacy on nutritional status. Prospective, nonrandomized comparison study over a 24-month period. Sixty-nine chronic hemodialysis patients (36 patients aged over 65 (elderly) and 33 aged under 64 (young). Each group was further divided into three subgroups according to the level of dialysis dose shown by Kt/V urea. The malnutrition index (MI) based on seven nutritional parameters and estimated protein calorie intakes based on urea kinetics were determined. In subgroup 0 (i.e. patients with persistently high Kt/V urea, mean 1.3), the MI improved with time in the young (from 26.8 to 25.2, p < 0.01) but not in the elderly (from 29.2 to 30.4, ns). In subgroup 1 (i.e. patients whose Kt/V urea increased from 1.0 to over 1.3), the MI improved significantly in the young from 28.1 to 25.2 (p < 0.01) concomitantly with an increase in the estimated dietary protein and calorie intakes, but not in the elderly (from 30.3 to 29.9, ns). In subgroup 2 (i.e. patients who had persistent low Kt/V urea, mean 1.0), the MI score further deteriorated in the elderly (from 30.8 to 32.8, p < 0.01) and young (from 28.5 to 30.7, ns). Increasing the dialysis dose as a treatment for malnutrition does not necessarily improve nutritional status in malnourished elderly patients, but it does in young individuals, possibly because of the additional adverse effect of aging on nutrition.

Chlorpropamide alters AVP-receptor binding of rat renal tubular membranes

The effects of chlorpropamide on AVP-receptor binding in rat renal tubular basolateral membranes were investigated utilizing [3H][Arg8]vasopressin (AVP). Our data indicate that chlorpropamide alters AVP-receptor binding in a competitive manner.