In order to elucidate the nature of nephrotoxicity induced by gentamicin and mercuric chloride, morphological and biochemical experiments were performed in rats. The main histological change in gentamicin treated rats was presence of many myelin-like structures in the cytoplasm of the proximal tubular cell. On the other hand, examination of kidneys from rats receiving mercuric chloride revealed many vacuoles in the same location, No marked changes were observed in the plasma membrane and the membranes of organelles, In biochemical study, however, renal tissue concentration of cyclic AMP was decreased, while that of lipoperoxide was increased. These facts suggest that those nephrotoxic substances might attack both the membranes of cellular organelles and the cell surface after their accumulation in organelles, since production of cyclic AMP is dependent upon the activity of adenyl cyclase in cell surface membrane and lipoperoxide is mainly produced from phospholipids present in the endocellular and cell surface membranes.

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Renal glomeruli were isolated from the rats 4 days after injection of nephrotoxic serum. In an early stage of Masugi nephritis, decarboxylation of 1-¹⁴C and 6-¹⁴C-glucose, LDH, G6PDH and 6PGDH activities and glycolysis were investigated in the isolated glomeruli. The ratio of ¹⁴C-1/¹⁴C-6 liberated from labeled glucose was 4.13±0.60 in nephritic glomeruli, while 1.72±0.21 in normal glomeruli. All the enzyme activities mentioned above were significantly increased and glycolysis was accelerated in nephrotic glomeruli. These results indicated that both glycolysic pathway and pentose monophosphate pathway were activated in glomeruli of the rats with Masugi nephritis, and these phenomena may be responsible for the mechanism of repairment in damaged glomeruli.

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In order to assess the significance of .β₂-microglobulin (.β₂-mg) in glomerlar disease, a total of 52 measurements of para-aminohippurate and sodium thiosulfate cleance (C_PAH and C_thio) in 42 patients (22 men and 20 women) with various renal diseases was performed. At the same time, the serum levels and the urinary excretion levels of .β₂-mg were measured. The results were as follows: 1) On double-logarithmic graph, the correlation “r” between C_thio and serum β₂-mg [β₂-mg(s)] was 0.90. The regression line of log C_thio on log .β₂-mg(s) was: log C_thio=-0.85 log .β₂-mg(s)+2.09, with the standard error of estimate of 0.129. 2) The regression slope of log C_thio on log β₂-mg(s) was lower than that of log C_thio on log cr(s)[cr(s): serum creatinine] (p<0.05). The standard error of estimate of log C_thio for log β₂-mg(s) (Se=0.129) was significantly less than that of log C_thio for log cr(s) (Se=0.192)(p<0.01). When production of .β₂-mg was held constant, β₂-mg(s) was supreior to the predicted GFR for cr(s). 3) When serum β₂-mg levels were 4.1 μg/ml or less, increased β₂-mg clearance (>500 μl/min) in patients with glomerular disease was significantly related to fatty degeneration and/or atrophy of proximal tubular cells in the nephron maintaining some filtration functions (<0.01).

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Hartley female guinea pigs, weighing 200g to 250g or 500g, were injected with rat kidney homogenate, the tubular basement membrane (TBM), the F_x1, the liver homogenates and saline in complete Freund's adjuvant and were sacrificed at intervals ranging from 4 to 28 days.No renal lesions were observed in the liver-, F_x1- and saline-injected animals. In guinea pigs weighing 200g to 250g injected with kidney homogenate or TBM, tubulointerstitial nephritis was induced at 14 to 21 days. The lesions were characterized by mononuclear cell infiltrates and tubular cell damage which were observed by light and electron microscopy. However, no immunoglobulin G or C3 deposits along TBM or in the other tissue components were detected.In contrast, in guinea pigs weighing 500g injected with kidney homogenate or TBM, the lesions were characterized by deposition of IgG and C3 along TBM at 14 days, there after tubulo-interstitiall nephritis were developed.Transfer of lymph node cells from kidney-or TBM-injected donor (200g-250g) to irradiated normall recipients resulted in focal interstitial nephritis. However, transfer of irradiated or sonicated lymphh node cells produced no renal lesions. The findings obtained only when young female guinea pigs are used are interpreted as indicating that the tubulo-interstitial lesions results from cell-mediated reactivity against T BM-specific antigens.

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The immune process is responsible for many forms of glomerulonephritis in man, but the chracterization of the antigens in glomerular immune complex has been little elucidated. The purpose of this paper is to study the characterization of the immune complex dcposited in glop meruli of membranous nephropathy (M. N.), membranoproliferative glomerulonephritis (MPGN), lupus nephritis, IgA nephropathy and Schöenlein-Henoch purpura (S.H.P.) Nine cases of lupus nephritis, seven cases of MN, two cases of MPGN, seven cases of IgA nephropathy and one case of S.H.P. are studied. Immunof luorescence studies revealed granular IgG deposits of all cases of lupus nephritis, MN and MPGN, and mesangial IgA deposits of all cases of IgA nephropathy and S.H.P. These renal frozen sections are performed dissociation test of IgG from the glomeruli. Renal frozen sections were incubated with human Fr II, human IgG, human IgA, human FxIA, DNA, rabbit Fr II, rat Fr II, and bovine Fr II for 6 hours at room temperature changing in PBS, and then these specimens were stained with FITC-conjugated anti-human IgG or IgA antibody. In all cases of lupus nephritis, MN and MPGN, the IgG deposits in glomeruli disappeared following incubation with human Fr II and human IgG, especially heat aggregated human Fr II. These results suggested that the immune complex deposits in glomeruli of lupus nephritis, MN, and MPGN consisted of the patients own denatured IgG and IgG rheumatoid factor.

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Passive Heymann nephritis (PHN) in rats and one shot serum sickness in rabbits were employed as experimental model to investigate the possible effects of rheumatoid factor (RF) on in vivo and in vitro antigen-antibody reaction (1) The experiments of RF and rats with PHN. Following injection of serum containing RF, all rats with PHN developed severe abnormal proteinuria, comparing rats with PHN combined with normal human serum (NHS) or saline. By immuR nofluorescence (IF), rat IgG, C3 and human IgM along glomerular capillary walls in granular pattern were observed in rats with PHN combined with RF, but only rat IgG and C3 in rats with PHN combined with NHS or saline. By light-microscopy, more abundant exsudative hypercellularity in glomeruli was observed in rats with PHN combined with RF, comparing the less changes in rat with PHN combined with NHS or saline. Moreover, by indirect IF, human IgM (presumably IgM-RF) from serum containing RF was observed in glomeruli of rat with PHN. (2) The experiments of RF and one shot serum sickness (SS) in rabbit. Rabbits with the SS received serum containing RF immediately after development of proteinuria showed severe proteinuria and abundant prolif erative glomerulonephrits, comparing that the rabbits with the SS received the serum containing RF or saline before development of proteinuria showed mild type of GNThese results indicated that the in vivo reaction of immune complexes and RF deposited in glomeruli exaggerate the inf lamatory reaction in glomeruli.

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Twenty-four hemodialized patients with severe anemia (Ht<20%), were treated with a new androgenic steroid, Mepitiostane, orally at the daily doses of 20mg for 4 months. As for anemia, increase of Ht over 3% after the therpy, and decrease of blood transfusion amount with in crease of Ht over 3% were considred to be effective Eighteen out of 22cases (81.8%) responded to Mepitiostane. As for side effects, development of impaired liver function seemed less marked in the course of treatment with Mepitiostane than the other steroids. In the course of the treatment, serum ferritin decreased prominently, therefore iron supplement was recommended during therapy, Serum erythropoietin was fell after the treatment Increase of appetite, body weight and TIBC was observed, meanwhile serum creatinine increased significantly. As a result, Mepitiostane is well effective on anemia with minor side effects.

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Protein binding of 35S-Furosemide (FM) was measured by ultrafiltration technique in 8 normal subjects (C), 8 nephrotic patients (NS), 9 non-dialysis patients with chronic renal failure (CRF), 12 dialysis patients (HD) and 5 transplanted patients. The percent bound FM was 98.2±0.1% in C, 95.5±0.6% in NS, 95.8±0.5% in CRF and 94.0±0.5% in HD. FM binding was significantly reduced in. NS, CRF and HD (p<0.001). There was a linear relationship between albumin concentration and ratio of bound/unbound FM Therefore, it was considered that the reduced binding in NS was due to hypoalbuminemia. In contrast, it was considered that the reduced binding in uremia was not due to decreased albumin but due to abnormal metabolism in uremia. FM binding, however, was not influenced by pH (6.0-8.0), free fatty acids (0.3-3.0 mEq/L), urea, creatinine, methylguanidine and guanidinosuccinic acid. FM binding in uremic patients was increased slightly but significantly after hemodialysis and ultraf filtrate of uremic plasma contained a few substances which inhibited FM binding. Moreover, FM binding of uremic plasma was normalized by adsorption with synthetic polymers at pH3 After renal transplantation, FM binding was normalized after three to five weeks, whereas serum creatinine was restored to normal within a week. These findings indicated that the reduced binding in uremia was due to unknown substances, “binding inhibitors”, which accumulated in uremia. Since these inhibitors were strongly bound to albumin at physiologic pH, they were only partly dialyzed. Inhibitors were suggested to be excreted not by glomerular filtration but by tubular secretion of the transplanted kidney.

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Factors affecting the intestinal absorption of ⁵⁹Fe in a uremic state were investigated by using the everted gut sacs of renal failure (RF) rats with 30% GFR and normal rats. The duodenal absorption of ⁵⁹Fe was significantly lower in the (RF) rats than in the normal rats, while the colonic absorption of ⁵⁹Fe did not differ between the two groups. The absorption of ⁵⁹Fe in the duodena of the normal rats was significantly lower after the addition of sera from non-dialyzed uremic patients than after the addition of sera from hemodialyzed uremic patients. The absorption of ⁵⁹Fe in the duodena of the normal rats was significantly lower after the addition of sera from uremic patients under hemodialysis (HD) than after the addition of sera from uremic patients under continuous ambulatory peritoneal dialysis (CAPD). The absorpton of ⁵⁹Fe in the duodena of the normal rats was not altered by the separate addition of urea, creatinine, methylguanidine (MG) and guanidinosuccinic acid (GSA), but became significantly lower after the addition of the mixture of these substances.

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Effects of long term treatment of ROD by peroral administration of 1α-D₃ were evaluated. Twenty patients under stable hemodialysis having some signs of hypocalcemia, hyper-alkalinephosphatasemia, radiological bone changes or symptoms like bone fracture or bone pain were followed up about 5 years under daily administration of 1α-D₃. As a control group, 15 hemodialysed patients without clinical sign or symptom of ROD were followed up for the same period. The results obtained were as follows: 1) A dose dependent correction of hypocalcemia and hyperalkalinephosphatasemia was confirmed in all cases under 1α-D₃ treatment. However significant decrease of serum inorganic phosphate and increase of serum magnesium levels were observed only in high dose of 1α-D₃ administration, namely 3.0μg/day. 2) Serum iPTH levels (C-terminal assay) were unstable during three months of 1a-D₃ administrap tion but showed a significant decrease after 23 months. 3) Improvement of radiological bone changes estimated from MCI and from the pattern of subperiosteal bone resorption was clearly demonstrated. However to obtain significant effects on bone radiography, observation of more than three years was needed. Considering the evidence of decreasing tendency of MCI in hemodialysed patients, the early administration of 1α-D₃ might be inevitable. 4) From the evidence of a sharp increase of serum calcinum level and a high probability of hyper calcemia in its high dose administration, 1.Oμg/day in initial dose and stepwise addition of 0.5-1.0μg/day might be more safer. 5) As side effects of 1α-D₃ administration, there were liver function disturbance in 2/20, itching is 3/20 and hypercalcemia in 5/20.

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Within the last six years, 5 examples of red cell antibodies have been found in the sera of 69 patients maintained on chronic hemodialysis . The frequency with which these irregular antibodies were detected was about 7 .2%, and many of the patients who were revealed to have irregular antibodies, had a history of prior transfusion and pregnancies. Since there was no attempt at systematic study, the true incidence may well have been higher. These identified antibodies were anti N, anti Le^b+anti HI mixture, anti Le^a+anti Le^b mixture, anti HI and anti P₁. In the first case, it has been suggested that extracorporeal circulation may induce an unusual degree of antigenecity on red cells. These irregular antibodies appeared to be of much clinical significance as hemodialysis patients may customarily receive blood transfusion and renal transplantation in future. We are planning further investigations in order to find the evidence by which we may discriminate between the roles of blood transfusion and of extracorporeal circulation in the induction of antibodies.

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