Seventy-two patients with MPGN type 1 on whom a total 125 renal biopsies were conducted were examined. Since histological findings of MPGN type 1 vary with the treatment and the natural course of the disease, it was fact convenient to describe the disease by subtyping. That is, the findings were divided into mesangial prolif erative GN, (slight, moderate) (post or pre MPGN type 1) ; chronic, focal ; acute, focal, chronic, diffuse (slight, non-lobular, moderate); acute, diffuse (endocapillary, moderate, marked); lobular and end stage, The histological criteria for each stage were shown. Histological changes and serum complement titers and others of 24 patients whose clinical course were clear and in whom more than two renal biopsies were performed were shown in figure, and the necessity of such histological subtyping for the study of MPGN type 1 were also discussed.

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Rat glomeruli were isolated by sequential sieving of gently mashed renal cortex and cultured in Eagle's minimal essential medium, supplemented with 20% of fetal calf serum. The first outgrown cells propagated surrounding the explanted glomeruli within 4-6 days. These cells, considered to be of epithelial origin, were named as E cells, because, D-amino acid oxidase specifically present in epithelial cells, was detected histochemically in these cells, and also because they had some morphological characterristics; numerous microvilli on the cell surfaces and junctional complexes between the adjacent cells. In two weeks, another types of cells (M cells) predominated over E cells. Only M cells tolerated subcultures. In M cells, D-amino acid oxidase was not detected, but fibronectin was stained in fibrillar fashion by immunofluorescent technique. This stainning fashion of fibronectih and the presence of microfilament in M cells suggested that these cells are of mesangial origin. Antibody to the antigen derived from subcultured M cells reacted restrictively with the mesangium in vitro. Absorbed with isolated glomerular basement membrane (GBM), the antibody still reacted with mesangium. The injection of the heterologous antibody induced immunologicai reaction with the mesangium and GBM of the rat. However, host (rat) IgG was localized restrictively in the mesangium. Slight but significant mesangial hypercellularity and increase of albuminuria were observed in rats receiving the injections of the antibody. Deposition of host C3 was not seen throughout the observation periods. It is suggested that the antibody to the subcultured M cells may be directed to the antigen specific to the mesangium.

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We investigated the distribution of anionic site in glomerular basement membrane of experimental nephritic rats and normal control rats using ruthenium red (RR) known as a cationic probe. Experimental nephritic rats were obtained from three models : nephrotoxic serum nephritis (NTN), daunomycin nephrosis (DMN) and glycoprotein nephritis (GP). The urinary protein excretion of three experimental models (NTN: 62.9±49.3 mg/day, DMN. 255.9±62.7 mg/day, GP: 388.2±96.7 mg/day) were significantly increased compared with control rats (9. 5±4.6 mg/day). When the kidneys were perf used with aldehyde fixative containing RR in normal rats, small RR-stained particles were observed along lamina rara externa on elecron microscopy. In NTN rats, on the contrary, irregular distribution of reduced numbers of RR-stained particles were seen in lamina rara externa of glomerular basement membrane. Characteristic findings of DMN rats were the fusion of foot processes and irregularly arranged RR-stained particles. Histological feature of GP rats were membranous nephropathy, and RR-stained particles were located mainly around subepitherial deposits and lamina rara in this type of nephritic rats, though a very few particles were within dense deposits. According to these observation, it is suggested that the irregularity and reduced numbers of polyanions in glomerular basement membrane might be responsible for the mechanism of the increase of urinary protein excretion.

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Prognosis of 103 patients (65 males and 38 females) with acute renal failure due to 72 medical, 27 surgical and 4 obstetrical causes was examined. Mean age was 49.9±1.9 (mean±SEM). Iatrogenic factors, defined as the administration of aminoglycoside antibiotics, contrast media or other nephrotoxic drugs, and postoperation, accounted for 61.2% of the 103 episodes of acute renal failure. Ninety nine patients except 4 obstetrical cases were devided into 3 groups. The first group was consisted of acute renal failure alone (28 cases), the second one with acute renal failure complicating other organ damage later (23 cases). The third group was consisted of acute renal failure with other organ damage from its onset (48 cases). The mortality rate was 3.6% in the first group, 34.8% in the second group and 68.8 % in the third group. Overall mortality in 99 patients was 42.4% and compatible with the other reports. Solitary acute renal failure at the onset and solitary acute renal failure with one organ damage after the onset revealed relatively good prognosis, however, those with more than one organ damage at the onset and two and more organ damage after the onset showed very high mortality. Oliguric acute renal failure due to medical causes had poor prognosis if they had severe liver damage defined by total bilirubin above 3 mg/dl and GPT above 100 U/L. However, postoperative oliguric patients had overall poor prognosis and did not show the similar result as those with medical causes, because they were already complicated with other severe organ damage. This study suggests that the mortality of acute renal failure depends on the cause of acute renal failure, whether it is oliguric or nonoliguric and, moreover, depends on whether the patients with acute renal failure is complicated with other organ damage.

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The ACTH-Cortisol axis was studied in chronic renal failure (12 undialysed patients, Ccr below 5 ml/min and 17 dialysed patients). Basal plasma cortisol and ACTH levels were 14.7±1.2μg/dl, 41.4±11.6 pg/ml respectively in undialysed patients and 14.3±1.3μg/dl, 48.6±7.5 pg/ml respectively in dialysed patients. Both hormone levels were within normal range except 1 dialysed patient. The cortisol levels to rapid ACTH stimulation test (250μg ACTH, iv) in both groups increased approximately 10 μg/dl or more. Therefore, we suggest that the patients with chronic renal failure have normal function of adrenal cortex. After the administration of 1 mg dexamethasone orally at midnight as the method of examining negative feedback mechanism, both patients had normal or almost normal suppression of cortisol and ACTH level. But, quarter of patients in each group demonstrated abnormal diurnal rhythm of plasma cortisol and ACTH at 900 hour, 1700 hour. Dialysed patients showed normal cortisol response (Max. ΔCortisol 12.8±1.6μg. dl) to insulin (0.1 U/kg, iv) induced hypoglycemia as a stress test compared with normal controls (Max. ΔCortisol 9.0±0.8 μg/dl). While, undialysed patients showed low cortisol response (Max. ΔCortisol 5.9±1.7μg/dl). And there were no correlation between the Max. ΔCortisol and T. P., BUN, CRN, Uric Acid, Ca and the grade of hypoglycemia. Therefore, it is certain that the failure of secretion of corticotropin releasing factor in hypothalamus or of ACTH secretion in pituitary gland exists in undialysed patients. From these results that there may be impairment of CNS-Hypothalamo-Pituitary Axis in chronic renal failure and this disturbance can be recovered considerably but not perfectly by adequate long term hemodialysis, it was considered that some uremic toxin or dialysable substance associated with uremia itself may be responsible for its abnormality of cortisol and ACTH secretion.

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The kidney volumes of twenty seven patients who had been undergoing hemodialysis for more than four years and four patients with kidney transplants were estimated using computed tomography. Kidney volumes were found to have increased after nine or more years of hemodialysis, but remained unchanged during the first six years. Acquired cystic disease of the kidney (ACDK) was found in nineteen patients (57.6%) and the longer the duration of hemodialysis, the more common it was, with all the patients who had been receiving dialysis for over nine years suffering from it. One patient with ACDK also had a renal cell carcinoma. Separating ACDK cases, and non-ACDK cases, it was found that kidney volume and duration of dialysis were directly proportional, but in the ACDK cases, the relationship (gradient) was positive, and in the non-ACDK cases, it was negative. The average kidney volume of the four patients' own kidneys after kidney transplantation was 29.1 ml/m², there were no cases of ACDK, with the one case of ACDK before transplantation having cleared up. There was no correlation between hematocrit and kidney volume.

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Renal blood distribution on dogs was measured using with a new 5 channel hydeogen gas edectrode. A few results were obtained as follows. 1) Cortical blood distribution devided into 4 zones and medullary blood distribution were measured simultanously. Renal blood flow in secound zone to the outest zone in renal cortex were the highest, the values of them were 1.71±0.39 ml/min⋅g and revealed good agreement with flow rate measured using with magnetic flow meter. 2) The medullary flow was 0.31±0.11 ml/min⋅g, and they were dependent on urine flow. The hydrogen clearance of renal medulla inereased followed by the increase of urine flow. 3) Desaturation times after the stop of hydrogen gas administration had a close relation to local blood flow rate. Desaturation of C-2, in which measured the highest blood flow, appeared first, and the medullary desaturation delayed most of all.

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The effects on blood pressure, renin-angiotensin system, kallikrein-kinin system of a new non-sulfhydryl, long acting angiotensin converting enzyme (ACE) inhibitor, MK-421 (enalapril maleate) were observed administering single dose of 10 mg in 8 patients with mild to moderate essential hypertension. A single dose of 10 mg oral MK-421 produced a significant fall in both systolic and diastolic blood pressure from 2 to 24 hours. As could be expected, plasma renin activities (PRA) enhanced up to 24 hours following administration of MK-421. ACE activity in serum decreased markedly to reach levels well below 10n mol/ml/min between 2 and 9 hours after MK-421, and it was still significantly reduced at 24 hours after MK-421. Between 2 and 9 hours after MK-421 had produced significant falls in plasma angiotensin II (ANG II), however, ANG II had returned towards pretreatment values after 24 hours. It was observed no significant change in venous bradykinin levels and in urinary excretion rate of kallikrein, whereas a slight increase was observed in urinary excretion rate of kinins after dosing of 10 mg MK-421. The significant correlations were observed after a single dose of oral MK-421, between the increase in PRA levels and the decrease of mean blood pressure (MBP), between the reduction in ACE activities and the fall in MBP, and also between the decrease in ANG II and the fall in MBP. These results obtained suggest that this new ACE inhibitor (MK-421) has a prolonged duration of action, that it very effectively reduces the blood pressure, ACE activity and ANG II and that it may be effective with once a day regimen in patients with mild to moderate essential hypertension.

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To approach the pathophysiological role of circulating renin, I tried to develop a new simple assay method for plasma renin concentration. The plasma obtained from nephrectomized sheep was semipurified with the ammonium sulfate fractionation and pepstatin aminohexyl-agarose column to use as renin substrate. After the two steps, it was confirmed that sheep renin was almost completely removed from the plasma. For the enzyme reaction, 200μl of human plasma was incubated at 37°C, pH 6. 5, with 800μl of sheep sbstrate (1, 000 ng angiotensin I; ATI), 50μl of 250 mM EDTA and 50μl of 200 mM PMSF. Formed ATI was measured by radioimmunoassay. The linearity of the reaction was observed until at last 5 hours. And the initial velocity was reached to the maximal velocity. These were also true for trypsin activated or acid activated plasma. By this method, PRC and trypsin activated total renin concentration (TRC) inn normal human subjects were 2.9±0.4 and 36.8±6.1 ng ATI/ml/hr, respectively And in the case with renin secreting tumor, there was a difference in the value between PRC by this method and plasma reamn activity by Haber's modification. These results suggest that this method completely satisfied the requirements for determination of PRC or TRC, and also it was very useful for clinical application.

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To assess the effects of angiotensin converting enzyme inhibitors (ACEIs) on renal function and blood pressure, we evaluated the acute effects of 5 mg of MK 421 (MK), 50 mg of SQ 14225 (SQ) and 10 mg of SA 446 (SA) on urinary excretions of sodium and potassium, of kallikrein and kinin and of prostaglandin E (UNaV, UKV, UKa1V UKinV and UPGEV), creatinine clearance (Ccr), plasma renin activity (PRA), plasma aldosterone concentration (PAC) and blood pressure in 13 essential hypertensive patients maintained with 200 mEq of sodium intake. MK, SQ and SA lowered blood pressure significantly by 10.9 mmHg, -13.5 mm Hg and -9.7 mmHg, respectively and induced diuresis and natriuresis whereas no change was found in Ccr. They also induced concomitant increases in UPGEV and UKinV and a decrease in PAC. Increases in UNaV. UPGEV and UKinV, and blood pressure reduction in SA treated group tended to be less than those in other groups whereas there were no difference in the response of PRA among the three groups. Significant positive correlations were found between the change of UKinV and of UNaV in SQ and SA treated groups and were also found between the change of UKinV and of UNaV in SQ and SA treated groups. There was no relationship between basal levels of PRA and the hypotensive effect of MK, SQ and SA, and each ACEI also lowered blood pressure even in low renin groups. These result suggest that other mechanisms than the inhibition of angiotensin II generation, such as a potentiation of bradykinin or enhanced prostaglandin formation, may contribute to their antihypertensive and renal effects.

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Four urinary enzymes, Leucine aminopeptidase (LAP), γ-Glutamyl-transpeptidase (γ-GTP), β-glucuronidase (β-Gl) and N-acetyl-β-D-gluco-saminidase (NAG), were measured in sixteen patients with chance proteinuria and/or hematuria to evaluate their role in the diagnosis and prediction of glomerular lesion. The measurement of them were obtained from 24 hour urine samples refrigerated at 4°C until testing. We studied six patients with minor glomerular lesions and ten patients with definite glomerular lesions. Urinary levels of these enzymes were increased in some patients with definite glomerular lesions, that is, mesangio-capillary glomerulo-nephritis and IgA-IgG nephropathy. Urinary enzymes assay is simple, and is a useful aid to the early diagnosis of patients with chance proteinuria and/or hematuria. γ-Glutamyl transpeptidase and β-Glucuronidase were of a little value in evaluating glomerular lesions, comparing with Leucine aminopeptidase and N-acetyl-β-D-glucosaminidase.

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The studies were carried out using frozen sections of renal specimens. Glomerular C3b-receptor (C3b-GR) activity (C3b-GRA) was semiquantitatively determined by enumerating C3-coated erythrocytes bound per unit of glomerulas. 1) a) C3b-GRA was enhanced by pretreatment with neuraminidase. b) C3b-GRA was diminished by pretreatment with protamine, whereas it was restored by treatment with heparin after protamine-pretreatment. c) C3b-GRA was more markedly diminished by treatment with protamine after neuraminidase-pretreatment rather than by protamine alonepretreatment. These results suggest that C3b-GR has many characteristics of negatively charged substances which are different from sialic acid. 2) a) In mesangial proliferative glomerulonephritis, C3b-GRA tended to decrease in the patients with diminished renal function and advanced histological changes, but was nearly normal in those with mild abnormalities. b) In membranous glomerulonephritis (MN), C3b-GRA markedly decreased in 75% of the patients, and the decrease in C3b-GRA appeared to be in connection with immune deposits and histological changes of membrane. c) In MN, C3b-GRA markedly decreased in the patients with nephrotic syndrome (NS), whereas C3b-GRA was normal in the patients without NS, suggesting the loss of C3b-GR as glomerular polyanion in MN with NS. d) In contrast to MN with NS, C3b-GRA was normal in minimal change NS. In minimal change NS, C3b-GRA was markedly diminished by protamine-treatment and the decrease in glomerular polyanion was shown with colloidal iron stain. These results suggest that the changes of glomerular polyanion may be different in quality between MN and minimal change NS. On the basis of these data, a role of C3b-GR in glomerulonephritis was discussed in connection with glomerular immune clearance.

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The kallikrein-kinin system has been proposed as one of the major depressor mechanisms which subserve the antihypertensive function. To assess the antihypertensive function of the kallikrein-kinin system of the kidney in renovascular hypertension, male Sprague-Dawley rats were subjected either to shamoperation (Sham-RAC group) or to unilateral renal artery constriction using solid silver clips of 0.25 or 0.20 mm internal diameter to produce benign (BH group) or malignant (MH group) two-kidney, one clip Goldblatt hypertension, respectively. All rats were maintained with low sodium diet for 4 weeks after the clipping. Depressor responses to i. v. bolus injection of kininase II inhibitor, captopril (250 μg) were observed during continuous i. v. infusion of saralasin (10 μg/min) under conscious state. Resting mean arterial pressures of Sham-RAC, BH and MH groups were 97.4±3.3, 137.1±4.4 and 160.0±4.4 mmHg, respectively. Plasma renin activities were determined in Sham-RAC group and MH group, 43.0±9.1 and 120.0±9.4 ng of AI/3h /ml, respectively. aralasin produced consistent depressor responses in all groups of rats. After the depressor effects of saralasin, captopril elicited significant further depressor response in BH group (-15.4±3.2 mmHg), whereas there was no significant depressor effect in Sham-RAC group (-7.5±1.9 mmHg) or H group (-3.8±0.8 mmHg). Rats in BH group were randomly subdevided into two groups, the rats in one group were subjected to unilaterall nephrectomy of unclipped contralateral kidney (BH-Nx group) and the remaining rats were performed sham contralateral nephrectomy (BH-sham-Nx group) under ether anesthesia. Two hours after the operation, the same amount of captopril was injected under saralasin infusion. Whereas sham contralateral nephrectomy did not preclude the significant depressor effect of captopril (-11.4±1.2 mmHg in BH-Sham-Nx group), there was not significant response in BH-Nx group (-1.4±0.2 mmHg). These data suggest that the kallikrein-kinin system is enhanced in benign renovascular hypertension. Contralateral kidney is playing an important role in the increased activity of the system which may be subserving the antihypertensive function, and the development of malignant hypertension is associated with decreased activity of the kallikrein-kinin system.

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