Endothelin-like immunoreactivity (ET-LI) was directly measured in the perfusate from the isolated human umbilical vein perfused with Krebs-Ringer solution. The identity of the immunoreactive peptide was confirmed as ET-1 by high-performance liquid chromatography. The rate of release of ET-LI was 86.7±25.9 (SE) fmol during the first perfusion period of 30 min, and it remained stable at least for 4 hours. Calcium ionophore ionomycin, added to the perfusion medium (10^-7-10^-6 M), stimulated the ET-LI release in a dosedependent fashion ; it increased the rate of release by 29.1% and 143.4% over the control at the concentrations of 10^-7 and 10^-6 M, respectively. These results taken together with previous observations of synthesis of ET in cultured vascular endothelium provide direct evidence for local generation and subsequent release of ET from vascular beds of human beings.

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Latent diabetic nephropathy with no complication such as retinopaty and hypertension was treated with Alacepril, an ACE inhibitor. This study enrolled 10 patients with microalbuminuria ranging from 5 mg/day (5 mg/ gCr) to 50 mg/day (30 mg/gCr). Histological changes due to diabetic nephropathy were confirmed by renal biopsy performed in 4 of 10 patients. All the patients were divided into 2 groups; 5 patients were given 25 mg of Alacepril for 6 months and the remaining 5 patients were employed as the control. As the results, the mean blood pressure was decreased from 92.7±9.0 mmHg to 87.3±11.3 mmHg in Alacepril group but these changes were not statistically significant. Microalbuminuria were significantly ddecreased from 17.33±7.82 mg/gCr to 10.43±4.14 mg/gCr during 6 months in the Alacepril group while in the control group, no significant changes were observed in blood pressure and microalbuminuria. Creatinine clearances were not significantly changed in both groups. These findings suggest that Alacepril is useful in improving microalbuminuria of latent diabetic nephropathy.

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To assess the effect of recombinant human erythropoietin (EPO) on renal function, the slopes of the regression lines of the reciprocal of serum Cr versus month (1/Cr) were studied in 8 pre-dialysis outpatients (2.9 ml/min. < Ccr <17.0, 21.4% < Ht <27.9) who had been followed for a period of 19 to 94 months. EPO was initially given 3000-6000 U (133±31 U/Kg/week) once weekly by the intravenous route and was later switched to the dose to achieve a Ht level of 30-35%. Mean Ht increased from 23.6±0.9 to 33.2±1.1%, and quality of life and exercise capacity were significantly improved in all patients. The mean slopes of 1/Cr after EPO (-0.0050±0.0020) were not significantly different from the values before EPO (-0.0064±0.0010). The slopes of 1/Cr were significantly decreased by EPO therapy in three patients observed for more than 17 months, however in one patient, it increased significantly during EPO treatment. There were no signficant differences in the other 4 patients. The renal function at the initiation of EPO in a patient with increased slope of 1/Cr had been the worst, and Ht was mildly increased from 21.4% to 24.1% and the blood pressure did not change significantly. The good effect on renal function observed in 3 patients may, in part, be due to better control of blood pressure and physical condition (including cardiac and immunological function) by the more close follow-up of the patients and the improvement of anemia during the period of EPO therapy. In conclusion, the current study demonstrated that neither EPO nor a increased Ht adversely affect renal function in azotemic pre-dialysis patients except for the patient with severe renal failure. Furthermore, we can expect the good effect of EPO on the renal function in some patients.

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As disorders of the defense mechanism in hemodialysis (HD) patients, impairments of cell-mediated immunity have been known, but no agreement has yet been reached as to the function of their polymorphonuclear leukocytes (PMN). Thus this study was undertaken to determine the phagocytic activity and oxigen radicals production of PMN in patients with chronic renal failure (CRF). It was demonstrated that the phagocytic activity of PMN was significantly decreased in HD patients as compared with that in healthy subjects. A significant correlation was also found between phagocytic activity and FcR-positive cells of PMN in HD patients. It suggested that the FcR status of PMN might play an important role with phagocytic activity in HD patients, and the decrease of FcR-positive PMN affects the drop with phagocytic activity. Hydrogen peroxide production of prepared PMN was not significantly different for CRF patients versus healthy subjects. But in whole blood, the enhanced hydrogen peroxide production was observed in all CRF patients. And it was also demonstrated that PMN hydrogen peroxide production become strikingly enhanced when normal PMN was suspended in plasma from CRF patients. When normal renal function was restored by transplantation, hydrogen peroxide production was normalized. These results strongly suggested that the presence of the hydrogen peroxide production enhancing factor in plasma from CRF patients and the enhanced hydrogen peroxide production were specifically associated with renal dysfunction. In plasma of HD patient treated with the EVAL membrane, we measured the hydrogen peroxide production both before and after dialysis. The plasma of postdialysis showed slightly lower hydrogen peroxide production than that of predialysis in most of patients. It was also demonstrated that the plasma from CAPD patients showed a lower hydrogen peroxide production than that from other CRF patients. These results suggested that the hydrogen peroxide production enhancing factor could be considered as one of so called the middle molecules.

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Low protein diet has been a very important clinical manipulation to delay the progression of chronic renal failure. However very low protein diet (less than 30 g/day) is not popular because of concern about malnutrition due to protein restriction, and the difficulty and trouble in making palatable dish. A 48 year old man with chronic renal failure has been on a 20-30 g protein-restricted diet more than three years with no remarkable defect in his daily life, with adequate nutrition, and with very enjoyable and variable daily menus. The rate of progression of chronic renal failure was markedly slowed. Serum creatinine level was 6.9 mg/dl when he started the diet control and it took more than three years for the creatinine level reached to 15.5 mg/dl with no troublesome clinical findings or symptoms. For successful protein restricted dietary treatment, the following several ideas have been helpful: promoting the patient's understanding of the disease and treatment; abundant use of specifically made low protein, high caloric foods such as starch noodles and rice; adoption of creative menus for the patient; and using a free diet a few days a month. The results indicate that we have to again consider the effect of the very low protein (30-20 g/day) diet in slowing the progression of chronic renal failure without nutritional disturbance or restriction of the patient's palatability.

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We described a patient with the milk-alkali syndrome induced by the ingestion of small amount of milk (200 ml/day) and ice cream (145 g/day) and the administration of small dose of absorbable alkali (magnesium oxide 2.0 g/day) for the treatment of chronic constipation. The present case shows not only triads, i, e., hypercalcemia (s-Ca 14.3 mg/dl), metabolic alkalosis (s-HCO₃^- 37.4 mEq/L), and renal insufficiency (s-Cre 2.3 mg/dl) but also hypernatremia (s-Na 161 mEq/L) and hypertonic dehydration after the frequent episodes of elevated body temperature. The milk-alkali syndrome has been defined as the hypercalcemia with a metabolic alkalosis from a high amount of calcium intake and long term administration of absorbable alkali in any form, usually as calcium carbonate for the treatment of peptic ulcer. As the present case could be distinguished from any other cases previously reported with regard to the amount of calcium (0.4 g/day) and alkali (36 mEq/day) intake and the clinical situations that induced the syndrome, we compared the present case with the previous reports, calculating the amount of calcium and alkali intake from milk and absorbable alkali. After the introduction of the H₂ blockers for peptic ulceration, the most cases with milk-alkali syndrome had provoked by the smaller amount of calcium than previously reported, which were associated with the treatment of relatively large amount of alkali (50-150 mEq/day), suggesting the role of sustained metabolic alkalosis for the development. In the present case the metabolic alkalosis induced by hypertonic dehydration and enhanced by absorbable alkali intake also could cause an increase of renal tubular reabsorption of calcium and a decrease of ionized calcium which might produce increased secretion of parathyroid hormone followed by vitamin D₃ activation and increased Ca absorption from the gut. The metabolic alkalosis might be essential to the development of the milk-alkali syndrome without a high calcium and absorbable alkali intake.

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We investigated bone mineral content and factors related to decreased bone mineral content in maintenance hemodialysis patients. Bone mineral contents, ∑GS/D, radius-bone mineral content (R-BMC) and L3-bone mineral density (L3-BMD), were measured with a micro densitometer, a bone mineral analyzer and a dual energy quantative CT scaner, and relative bone mineral contents (%∑GS/D, %R-BMC and % L3-BMD) were calculated respectively. The desferrioaxmine infusion test was carried out for diagnosis of aluminium associated bone disease, and an elevated level of aluminium (Δ aluminium) was observed. There was reverse correlation between ∑GS/D and age in female hemodialysis patients. Serum bone gla protein, alkaline phosphatase and PTH-C levels were high in cases with increased ∑GS/D and who were receiving little medication with activated Vitamin D in maintenance hemodialysis patients. A correlation was observed between Δ aluminium and total medication of aluminium hydroxide-gel. Hemodialysis patients with bone pain had long term hemodialysis, high total medication of aluminium and high aluminium. Relative bone mineral contents (%∑GS/D, %R-BMD) were useful for estimating bone mineral content in hemodialysis patients. Hemodialysis patients were divided in four groups by PTH-C and Δ aluminium levels as follow, 1) normal, 2) aluminium associated bone disease, 3) secondary hyperparathyroidism with aluminium associated bone disease, 4) secondary hyperparathyroidism, These results indicate that secondary hyperparathyroidism, and medication with aluminium may play a role in decreased bone mineral content in hemodialysis patients, and menopause may also be an important factor in female hemodialysis patients.

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It is well known that hypertension (HT) frequently develops in patients with chronic glomerulonephritis (CGN) and that HT contributes to progession of CGN. So, proper antihypertensive therapy is required in hypertensive patients with CGN. However, there is so far no consensus of optimal blood pressure (BP) level to maintain the renal function in these patients. In order to evaluate the BP control level in the patients with renal insufficiency, we investigated the transition of BP and renal function in 22 CGN patients with HT (average age 36.5±9.9 years at the first medical examination, 15 male, 7 female, total 179.5 patient-years), who receive antihypertensive therapy for more than 5 years as outpatients at the second department of internal medicine of Tohoku University Hospital between 1975 and 1990. Renal biopsy had been performed in all these patients for CGN diagnosis. During this period 7 patients came to receive hemodialysis therapy from 5 to 10 (average 7.6±2.1) years after the first medical examination. In one of these 7 patients, the rate of decline in renal function accelerated after child-birth, and one after two years interruption of treatment. The other 13 patients are currently receiving drug treatments at our hospital. As a result, in CGN patients there was an optimal mean BP (MBP) control range, that is, when MBP was controlled in this range, the rate of decline in renal function became slow, but when MBP deviated from this range it became fast (p<0.01). Moreover, this range changed according to the serum creatinine (SCr) concentration level. From our study, the optimal MBP was 1) 100-115 mmHg when SCr was between 1.2 and 1.5 mg/dl 2) 105-115 mmHg when SCr was between 1.5 and 1.7 mg/dl 3) not less than 110 mmHg when SCr was between 1.7 and 2.0 mg/dl. In addition, when MBP was lower than this range, the rate of decline in renal function was faster than when MBP was higher than this range. These results demonstrate that it is able to delay the rate of the progession of CGN, if we control the MBP of CGN patients in optimal MBP range.

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Ten uremic patients maintained stable on regular dialysis treatment participated in a comparison study of 2 hours' biofiltration and 4 hours' bicarbonate hemodialysis with informed consents. In biofiltration, ultrafiltrate was replaced by a solution consisting of Na 145 mEq/l, HCO₃^- 100 and Cl 45 at the infusion rate 2.51/hour. Dialysate composition was Na 130-149 mEq/l, K 1.0, Cl 119, Ca 2.5, Mg 0.5, CH₃COO_-15 and glucose 200 mg/dl. Hemodiafilter was F80, polysulphone, 1.9 m², manufactured by Fresenius Co. Ltd. Blood flow rate was 5 ml/min/kg·body·weight to keep urea index (Kt/V) over 1.0. B-A-B' comparison was designed in which B and B' stand for 4 hours' bicarbonate hemodialysis while A for 2 hours' biofiltration, 3 times per week for 2 months, respectively. It was intended to find out if there are aggravations of clinical parameters in A after B and/or improvements in B' after A in view of evaluation of optimum for 2 hours' biofiltration. One patient was withdrawn from biofiltration at 15th treatment in A because of frequent muscular twitchings. Others finished the whole program, thus making drop-out rate 10%. No significant differences were observed in the following parameters between B and A and between A and B': cardiothoratic ratio, pre-treatment blood pressure, human atrial natriuretic hormone, cardiovascular dynamics, total protein, BUN, serum creatinine, uric acid, β₂ microglobulin, blood counts, blood gas analysis, elctrolytes, alkaline-phosphatase, PTH-C, protein catabolic rate (PCR), lipids and liver functions. Pre-treatment levels of inorganic phosphorus in the blood were significantly decreased from 6.1±0.9 mg/dl in A to 5.0±1.3 in B' (p<0.05, n=9). PCR developed an increasing tendency in A, 1.31±1.3 g/body weight kg/day at the end of 2 months, although within normal range. The results indicate the optimum of 2 hours' biofiltration for uremic patient when treatment is programmed after urea index, Increasing tendnency of PCR must be improved.

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A 10-year-old girl who presented with microscopic hematuria, proteinuria and normal renal function has been followed up for the past two years. At the first examination, renal biopsy revealed focal/segmental lesions accompanying by occaisional necrosis and small crescents. Diagnosis of IgA nephropathy was given by light, electron and immunofluorescent microscopic findings. She started on the treatment with dipyridamol and was followed up for one year without any serious complications. Thereafter, she suddenly developed severe deterioration of renal function (serum creatinine 2.7 mg/dl) with nephrotic syndrome and hypertension. The second renal biopsy done at this time indicated the presence of typical crescentic glomerulonephritis with mesangial proliferation. No vasculitis was noted. She was intensively treated with steroids, anticoagulants and other medication and responded fairly well clinically. The third renal biopsy performed 5 months afterwards demonstrated marked histological improvement, but there was still present mesangial proliferation and varied degrees of sclerotic changes with fibrocellular crescents. Focal interstitial fibrosis and collapsed tubules were also seen. At present, 5 months after the last renal biopsy, she has improved much better and her serum creatinine decreased to 1.9 mg/dl, although proteinuria of 3 g/day still persists. It is suggested that only a small segmental necrosis with crescent formation in IgA nephropathy should be considered as an important indicator of disease activity in the evaluation of prognosis.

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Although the etiology of systemic lupus erythematosus (SLE) is thought to be multifactorial, genetic factors may play some role in its pathogenesis. Supportive of this hypothesis are the studies of identical twins and familial cases of SLE. We describe below a family in which mother and son both developed SLE. The mother was diagnoged as SLE at age 25, and had been treated with prednisolone. In Feburualy, she had massive proteinuria. The onset of the son's disease was at age 13 in, when he noted erythema and photosensitivity. At admission to our hospital in 1989, he had polyarthralgia, proteinuria, positive antinuclear antibody, positive anti-DNA antibody. Both two patients had a same haplotype, HLA A2·BW61(40)·DR9. Two asymptomatic members of this family were also studied, the younger son had positive antinuclear antibody and hypocomplementemia.

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We describe here two patients with rheumatoid arthritis who developed nephrotic syndrome after administration of bucillamine, a novel antirheumatic drug developed in Japan. The nephrotic syndrome occurred after six months'and five months' treatment of bucillamine, respectively. The renal biopsy showed early phase of membranous glomerulonephritis (stage 1) in both patients. The first patient was a 64-year-old man who had received gold therapy for two years, and penicillamine therapy for eight months before bucillamine therapy. The nephrotic syndrome occurred after one year's cessation of the gold therapy and six months' cessation of the penicillamine therapy. The other patient, 57-year-old woman, had no history of gold or penicillamine therapy. Our experience suggests that membranous glomerulonephritis might occur in relation to bucillamine therapy.

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