To clarify the vulnerability of juxtamedullary glomeruli and the mesangial function of focal glomerular sclerosis (FGS), rat FGS was studied through two kinds of experimental procedures. In experiment I, tweleve male Sprague-Dawley rats were divided into two groups, glycine overloaded diet and commercial diet groups, five of them unilateral nephrectomy was carried out in each of the groups. Carbon black suspension, 20 mg/100 g of body wt, was injected into rats 24 hours prior to sacrifice and were sacrificed in an age range from 11 months to 21 months. In experiment II, fifteen male rats were also divided into two groups, protamine sulfate and saline groups. In half of them carbon black suspension, 70 mg/100 g of body wt, was administrated weekly intravenously. Either protamine sulfate (6 mg/100 g body wt) or 0.9% saline and sodium heparin (300 U/100 g body wt) were administrated intravenously for 7 days every other one week. Sacrifice of each animals was done from the 35th to 77th experimental day. As a result, 100 glomeruli (50 in the superficial cortex and juxtamedullary zone, each) were observed per section in each of the cases. Segmental glomerular sclerosis and global sclerosis developed in 118 glomeruli out of 1200 glomeruli in experiment I. However, FGS dice not occured in experiment II. Sclerotic glomeruli prominently situated in the zone at hitherto described vulnerability of juxtamedullary glomeruli. By the comparison of segmental sclerosis and non-sclerotic tufts in the damaged glomeruli, carbon particles in the non-sclerotic capillaries were prominent than in the sclerotic lesion in the glomeruli.

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FUT-175, an agent which shows in vitro an inhibitory activity on biologically active cleavages of either Cl or factor B and factor D, was administered daily to rats with nephrotoxic nephritis. Results of the effect of FUT-175 were summarized as follows: 1. For nephritic rats with FUT-175 administration, the level of protein excretion was significantly low against the control nephritic rats which had a marked proteinuria from day 8 to 13 day after the nephrotoxin injection. 2. An inhibitory effect on proteinuria was dependent on the dose of FUT-175. 3. Glomerular inflammatory changes were mild and only in focal and segmental proliferation in FUT-175 rats, and the control rats showed diffuse proliferative and exudative glomerulonephritis. 4. Immunofluorescent study of both groups showed no difference in IgG and C3 patterns. 5. The level of functinal complement activity, estimated by CH50 revealed no difference between the control and FUT-175 groups.

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Rat BSA nephritis is one of the typical models of experimental glomerulonephritis induced by immune complex mechanism. The activation of complement at the site of immune deposition and resultant leukocytic infiltration were considered as important to mediate the glomerular inflammation. FUT-175, which is reported to have in vitro inhibitory effect on biologically active forms of either Cl or factor B and factor D, was given to rats with nephritis, and clinical and histological data were compared with those of nephritic rats without medication. Many rats with FUT-175 administration tended to show that: 1. Urinary excretion of protein was low, and serum creatinine and urea nitrogen were not elevated. 2. Glomerular histology was mild. 3. Immunofluorescent study disclosed less deposition of immune complexes in glomeruli, yet rats showed elevated levels of the antibody against BSA and higher counts of PFC. 4. Complement function, as measured by CH50, was not significantly differed from that of control nephrotic rats. These results suggest that FUT-175 has some effects on the course of rat BSA nephritis.

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We measured serum levels of immune complexes in glomerulonephritis and SLE using Clq deviation test, and investigated the relationship between immune complexes and complement components at various clinical stages. Immune complexes were detected in 53% of the patients with membranoproliferative glomerulonephritis and 61% of the patients with SLE. Immune complex levels in the serum were well correlated with the changes in complement profiles as well as clinical status. Marked reduction of serum immune complex levels was observed after prednisolone therapy in some patients with these renal diseases. On the other hand immune complexes were absent or trace in amount in the patients with membranous glomerulonephritis and acute glomerulonephritis. These results support the conception that these glomerulonephritis may be produced by in situ immune complex formation.

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To examine a role of the kidney in guanidinoacetic acid (GAA) metabolsim, we studied changes of serum GAA level in anephric patients in comparison with those in patients with chronic renal failure under conservative therapy or maintenance hemodialysis (HD) therapy. An experimental study using rabbits with two different models of acute renal failure was also carried out. In patients under conservative therapy the serum GAA level showed a tendency to decrease inversely with the elevation of serum urea-N level, giving a significant coefficient (r= -0.390 ; p<0.05). On the contrary, in patients under HD therapy serum GAA level did not decrease in spite of the elevation of serum urea-N level. Four anephric patients under HD showed a similar level of serum GAA to the other HD patients. When L-arginine with a daily dose of 30 mM was orally given for two days during HD interval, the predialysis level of serum GAA increased to a higher level than before arginine load in the two anephric patients. when the same dose of L-methionine was given for two days during HD interval, the predialysis level of serum GAA was found to decrease. These responses in the anephric patients were not different to those in two non-nephrectomized HD patients following these amino acid loadings. In experimental renal failure rabbits, the serum levels of urea-N, creatinine, guani-dinosuccinic acid and methylguanidine increased significantly 48 hours after the operation of bilateral nephrectomy or bilateral ureter ligation. On the contrary, serum GAA level showed to decrease 6 hours after these operations and then remained unchanged even after following 48 hours. No difference in serum GAA level was found between the nephrectomized and the ureter ligated rabbits. GAA level in blood samples obtained from portal vein was higher than in peripheral artery of the nephrectomized rabbits, while the portal vein GAA level of the ureter ligated rabbits was not higher than the artery blood level, The hepatic vein blood GAA level was the lowest in these two models. These results suggest that a defect of the kidney to produce GAA may be compen-sated by other organ (s) in the portal vein system, probably by the pancreas, in the advanced stage of renal failure.

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In order to estimate the overall effects of uremia on the metabolism of maltose, the following examinations have been carried out : oral maltose tolerance test (OMTT), intravenous maltose tolerance test (IVMTT) and determination of maltase activities in various organs. 1) In the patients with chronic renal failure, maltose malabsorption was not found on the OMTT in the early morning after overnight fast. 2) In the patients with chronic renal failure, the half life of the plasma maltose on the IVMTT was longer than that of normal controls and there was a significantt negative corelation beween the half life and the creatinine clearance of them. 3) In the rabbits with bilateral nephrectomy, the half life of the plasma maltose on the IVMTT was prolonged immediately after the nephrectomy, but in the rabbits with bilateral ureteral ligation, it was nearly normal at 48 hours after the ligation. 4) In the 5/6 nephrectomized rats, the circadian rhythms of the maltase activities in the small intestine were smaller than those of normal controls. On the other hand in the liver, skeletal muscle and heart muscle, those circadian rhythms were normal. From the clincal and the experimental studies, it is suggested that in renal failure the decrease of the total maltase activities of the kidney plays a most important role in the metabolism of maltose administrated intravenously. The absorption of maltose may be influenced by the abnormality of the circadian rhythm of the maltase activities in the small intestine, but there is no malabsorption of maltose in the early morning after overnight fast in the patients with chronic renal failure.

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The pharmacokinetics of 1-carnitine was investigated in 6 normal subjects, 5 patients with chronic renal failure and 5 chronic hemodialysis patients. One compartment open model was applied to analyse the pharmacokinetics of 1-carnitine following oral admin-istration of 1-carnitine. (1) The time constant of absorption of 1-carnitine was 0.025 which was extremely lower than that of elimination. Therefore, if 1-carnitine was administered orally, it was absorbed very slowly and the raise of serum concentration might be only slight in normal subjects. (2) In patients with chronic renal failure or in those with chronic hemodialysis, the time constant of elimination of 1-carnitine was 0.09 which was clearly lower than that observed in normal subjects. The rates of carnitine synthesis were also reduced in both patient groups, a half or one thirteenth as much as that in normal subjects, respectively. (3) The determination of plasma 1-carnitine level in the patients with chronic hemo-dialysis following the supplemental therapy with 1-carnitine suggested that the administration immediately after dialysis might be most effective and daily admin-istration of 900 mg might be reasonable dose.

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In nine chronic hemodialysis patients, the effects of 7.7±2.5 months of exercise training using walking-jogging program designed for cardiac rehabilitation were studied. The evaluation was obtained through (1) comparing the symptom limited treadmill exercise test before and after training, (2) comparing the exercise intensity and heart rate during early and late training period. (3) comparing hematocrit, BUN and creatinine levels before and after training. Exercise training resulted in an increase in treadmill exercise time from 11.33±2.77 min. to 12.69±1.29 min. (p<0.05), an increase in maximal oxygen comsumption from 19.17±4.2 to 21.5±4.9 ml/kg/min. (p<0.05) and a decrease in heart rate from 139.8±18.5 beats/min. to 134.0±20.9 beats/min. at comarable submaximal work load and heart rate during exercise training did not change in early and late training period, in spite of a significant increase in exercise intensity (p<0.01). With training, hematocrit level increased significantly (p<0.01). These findings suggest that the increased exercise tolerance through exercise training in hemodialysis patients may be due mainly to cardio-vascular improvement.

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Urinary excretions of kallikrein and of prostaglandins (PG) were measured in 58 patients with chronic glomerulonephritis. In addition, the effect of kallidinogenase was studied in 10 patients with chronic glomerulonephritis of hypertensive type. Before and after the oral administration of Kallidinogenase 300 KU/day for 4-8 weeks, the following measurements were carried out; blood pressure, urinary kallikrein and prostaglandins excretion, plasma renin activity, plasma aldosterone concentration and creatinine clearance. 1) In the hypertensive group of chronic glomerulonephritis, daily urinary excretions of kallikrein and PGE2 were significantly lower than those of normotensive group (p<0.005 respectively). There was significantly positive correlation between urinary excretion of kallikrein and that of PGE2 in normotensive group (p<0.01), but not in hypertensive group. 2) In patients with chronic glomerulonephritis of hypertensive type, kallidinogenase significantly reduced systolic and diastolic blood pressure (p<0.001) and increased daily urinary excretions of kallikrein and of PGE2 (p<0.05 respectively). 3) These results suggest that patients with chronic glomerulonephritis of hypertensive type may have decrease in renal kallikrein and PGE2 synthesis.

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In order to analyse alteration of R-A-A system in normotensive subjects, plasma renin activity (PRA), plasma aldosterone concentration (PAC) and urinary sodium excretion (UNa) were measured in 24 cases at recumbent, and 2 hours, 4 hours upright posture on normal sodium diet, low sodium diet and after spironolactone administration on low sodium diet. The relationships between PRA and UNa, PAC and UNa, PRA and PAC were investigated. The results were as follows. In the relationship between PRA and UNa on normal sodium diet and low sodium diet, PRA increased according as UNa decreased. Normal limits were revealed between the upper limit: y=6.73-1.54 In X and the lower limit: y=1.80-0.30 lnX. Furthermore, after spironolactone administration on low sodium diet, the normal lower limit was y=5.11-1.24 lnX. In the relationship between PAC and UNa, PAC elevated as UNa decreased. Normal limits were revealed between the upper limit: y=10.82+56.99/x and the lower limit: y=5.14+17.79/x. PAC increased as PRA elevated.

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In order to analyse alteration of R-A-A system in hypertensive patients, plasma renin activity (PRA), plasma aldosterone concentration (PAC) and urinary sodium excretion (UNa) were measured in 25 cases at recumbent and 2 hours, 4 hours upright posture on normal sodium diet, low sodium diet and after spironolactone administration on low sodium diet. The relationships between PRA and UNa, PAC and UNa, PRA and PAC were investigated according to results on normotensive subjects. The results were as follows. In the relationship between PRA and UNa, on normal sodium diet and low sodium diet, the low renin hypertensives and the normorenin hypertensives were almost separated by the limit lines of normotensive subjects. After spironolactone administration, the low renin hypertensives were clearly distinguished from the normorenin hypertensives. In the normorenin hypertensives, PAC was almost within the normal limits of normotensive subjects, and in the low renin hypertensives, PAC was generally suppressed.

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Renin in rat aorta was purified by chromatography with DEAF-cellulose and Seph-adex G-200. The molecular weight of reamn was estimated to be 124000 and 72000 on Sephadex G-200 gel filtration. The isozymes, however, migrated as a single band with molecular weight of 71000 on SDS/polyacrylamide gel electrophoresis. These isozymes showed the same optimal pH (7.4) and temperature (37°C), and both the isozymes were completely inhibited by pepstatin (0.2mM), a specific inhibitor of renin. However, the activity of both enzymes did not change with other protease inhibitors (EDTA, 10mM; o-phenanthroline, 10mM; phenylmethylsulphonyl fluoride, 20mM). Renin activity was the highest in the microsomal fraction of the aorta. Renin, widely distributed in subcellular fractions of the aorta, may present in a high-molecular form. It seems likely that renin in arterial wall plays a possible role in the local control of vascular tone by generation of angiotensin II in arterial tissue.

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The antinephritic effects of tiaramide on nephrotic-type and crescentic-type anti-glomerular basement membrane (anti-GBM) nephritis in rats were assessed in comparision with those of indomethacin. In both type nephritis, tiaramide at doses of 50 and 100 mg/kg or indomethacin at a dose of 1.5 mg/kg was given daily orally to rats from the day after injection of anti-GBM serum to the 39th day. In nephritic-type nephritis, tiaramide at 100 mg/kg/day significantly reduced urinary protein excretion and plasma urea nitrogen and cholesterol contents on the 40th day. In light microscopic observation of renal glomeruli on the 40th day, tiaramide at this dose significantly prevented mesangial proliferation and crescent formation and was prone to prevent the adhesion of capillary walls to Bowman's capsule. In crescentic-type nephritis, this drug (100 mg/kg/day) remarkably prevented the crescent formation, adhesion of capillary walls to Bowman's capsule and fibrinoid degeneration on the 40th day, although it showed no apparent effects on biochemical parameters in urine and plasma. This drug also caused anti-hypertensive action with high dose from the 21st day onwards. On the other hand, indomethacin was effective in reducing proteinuria and hypercholesterolemia in both type nephritis. In the case of the nephrotic-type nephritis, these effects of indomethacin appeared more rapidly than those of tiaramide. However, indomethacin showed little effect on histopathological parameters in both models. Thus, tiaramide, unlike indomethacin, also showed a pronounced prevention on histopathological changes in glomeruli. Therefore, tiaramide is greatly expected to have a beneficial effect on various type nephritis in clinical fields.

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