Morphological and functional studies were made on the Kidneys of rats, in which experimental copper intoxication was induced by feeding 0.2% of copper acetate in drinking water for 12 weeks in one group and for 30 weeks in the other. In the kidneys of copper loaded rats, copper was demonstrated histochemically only in the proximal tubular cells. But light microscopy showed no change in the renal tissue except that a few cells of the proximal renal tubules had some vacuolar degeneration. On the other hand, electron microscopy revealed the partial or total loss of the cristae, some swelling and vacuolization of the mitochondria and the lysosomes containing amorphous or lamella-shaped electron-dense substance in the proximal renal tubular cells. After administration of D-penicillamine, the mitochondrial abnormalities in these cells were eliminated though the lysosomal changes were still recognized in some degree. Urinary protein and glucose, and blood and urinary alpha-amino nitrogen were normal in all examined rats. Blood urea nitrogen and endogenous creatinine clearance were also normal in all. Phenol-sulfonphthalein excretion test resulted in the significant decrease in the intoxicated rats, though after administration of D-penicillamine the rate of the dye excretion was restored. From these experimental results, it would be likely to come to the conclusion that all the renal changes of both morphological and functional respects were located in the proximal renal tubules, and that these changes are similar to those of the patients with Wilson's disease. The reversibility of these changes by D-penicillamine leads to the consideration that the changes seen here were only due to the deposited copper itself, suggesting further that the renal changes in Wilson's disease might be secondary to the copper in the proximal renal tubules.

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An attempt to clarify the mechanism of the glucose intolerance in chronic renal failure was made by studying 38 nondiabetic azotemic patients and 11 normal control subjects . None had a family history of diabetes mellitus and complications such as infection or liver disease. The results were as follows:1) Oral glucose tolerance test: Twenty eight per cent of the azotemic subjects were of the diabetic type, 53% the borderline type and only 19% were normal. Serum IRI levels during OGTT showed a hyper-and delayed-response in the glucose intolerance group.2) Tolbutamide test and glucagon test: A normal response to intravenous tolbutamide and glucagon was noted in the azotemic subjects.3) Intravenous glucose tolerance test: K values in the azotemic subjects were low (mean value 1.3) as compared with that of that of controls (mean value 1.8).4) Insulin sensivity test: Insulin sensitivity index of the azotemic subjects was lower than that of the controls.5) Relationship between glucose intolerance and serum HGH, NEFA, Urea-N and K: There was a rough correlation only between glucose intolerance and Urea-N (r=0.61, p<0 .01).6) Histological findings of the pancreas in the azotemic subjects: No remarkable changes were noted in the Langerhans' islands.7) Alterations in the glucose tolerance after long term dialysis: Improvement of both the glucose intolerance and its IRI response was obtained after the dialysis for 1.5-4 months. These results suggest that the glucose intolerance in chronic renal failure results from decreasedd peripheral insulin activities and the accumulation of certain dialyzable substances in blood is the cause of the insulin insufficiency. No indication was obtained as to the nature of these substances which is to be identified.

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Although the carbohydrate intolerance in renal failure is well documented, its pathogenesis remains unsettled. The present studies were undertaken to elucidate the mechanism of abnormal carboh ydrate intolerance in canal failure, and to evaluate the efficacy of long-term intermittent dialysis. Materials and methods The blood glucose, plasma insulin and plasma growth hormone responses to the intravenous injection of 0.5 g/kg body weight glucose were studied in 55 sujects, divided into 3 groups: 25 patients with azotemia (20 of them were treated with dialysis), 3 normal subjects and 27 patients with slight to moderate impairment of renal function. Results 1) In 14 of 16 azotemic non-dialyzed patients with creatinine clearance under 20ml/min, an abnormal responses to intravenous glucose administration were found (glucose decay constant K<1.5). 2) Abnormal K-values in azotemic subjects progressively improved month by month and almost completely normalized at the end of about 6 months of regular dialysis (peritoneal dialy sis and hemodialysis), twice a week. 3) Plasma growth hormone resposes after intravenous glucose administration were correlated with renal function, and highly azotemic subjects especially, showed a paradoxical rise in 60 to 90 min, after intravenous glucose administration . Cases with improvement of carbohydrate intolerance due to long-term dialysis revealed more abnormal plasma growth hormone responses to glucose administratio n than those with incomplete improvement after short-term dialysis. Conclusions 1) Abnormal carbohydrate intolerance was found in azotemic patients, and its degree was correlated with that of impairment of renal function. 2) The carbohydrate intolernce in azotemic stage was improved in respons to long -term dialysis, no to short-term dialysis. 3) There were no correlations between the factors influencing the glucose intolerance and those influencing the growth hormone responses . The former is thought to be dialyzable, the latter, in contrast, is non-dialyzable.

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Glucose metabolism was studied in 28 adult patients with severe chronic renal insufficiency and influence of hemodialysis was investigated in 21 patients of them. Our data indicated the followings;1) Fasting blood sugar was slightly increased in most cases. All cases showed abnormal curve in oral glucose tolerance test. 40% of those cases was diabetic type and the remaining 60% was border line type of diabetes mellitus.2) 60% of all cases showed hyperresponse reaction in immune reactive insulin of oral glucose tolerance test.3) Free fatty acid was low in comparing with control group at fasting and oral glucose tolerance test.4) The result of tolbutamide test was slightly abnormal.5) Glucagon test showed normal reaction.6) ¹³¹I Insulin disappearance curve was prolonged significantly in comparing with those of diabetic nephropathy.7) After repeated hemodialysis was improved the blood sugar of oral glucose tolerance significantly, but significant change in immune reactive insulin was not observed after the Hemodialysis. Serum immune reactive insulin in most cases was the type of hyperresponse curve. The delaying tendency of free fatty acid was improved at 120 and 130 minute after oral glucose load by hemodialysis.8) It is suggested that the glucose intolerance in uremia is due to the presence of insulin antagonist or antagonists of dialysable form. However, the exact nature of antagonist or antagonists in dialysate is further to be clearified. In order to maintain the normal glucose metabolism in uremia, more than 20 hours of dialysis weekly wity Kiil type of artificial kidney would be required.

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Many studies on pathogenesis of acute renal failure have been previously reported by many investigators. In recent years, some patients of postoperative acute renal failure, which pathogenesis was not clear, have been treated in our clinic. In addition, same cases have been reported in many other institutes. All of them were administrated Kanamycin (IBM) and sodium-alginate before or after operation . I thought that the coindental administration of antibiotics and sodium-alginate effected for renal function and tissus. So, I have experimented on the renal damage in rabbits, which the coincidental administration of antibiotics and sodium-alginate was been done, by light and electron microscopic findings and blood urea nitrogen levels. The results of this experiment were as follows. 1) Acute renal failure was surely produced by the coincidental administration of aminoglycocidal antibiotics (kanamycin (KM), paromomycin (PM), neomycin (NM)), except streptomycin (SM), and sodium-alginte in state of dehydration and postoperation. 2) The grade of renal functional and morphological damage was in order to NM, PM, IBM, and SM. 3) Acute rnal failure was not produced by the coincidental administration of polypeptid antibiotics colimycin (CL) or penicillin and sodium-alginata. 4) Characteristic morphological findings of this acute renal failure were necrosis of proximal convolted tubular cells and in early stage the appearance of PAS positive, high electron dense prectipitate in proximal tubular lumen and the appearance and destruction of lysosome in proximal tubular cells.5) Electron microscopic observations suggested that lysosome played an important role to make the necrosis of proximal tubular cells, and these findings were established 3 hours after the coincidental administration of aminoglycocide antibiotics and sodium-alginate.

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The constant infusion of a small dose of angiotensin II (0.035 μg/kg/min) into the peripheral vein of the conscious dogs disclosed the rapid decrease in GFR, RPF, urine volume, urinary Na excretion (UNaV) and fractional Na excretion, whereas a large dose of angiotensin II (0.2 μg/kg/min) caused diuresis and natriuresis. In the dogs anesthetized with pentobarbital (30 mg/kg), however, even a small dose induced diuresis and natriuresis, and the correlation between the rise blood pressure and UNaV was observed. The direct infusion of small dose of angiotensin II into the renal artery without any change of systemic blood pressure resulted in antidiuresis and antinatriuresis. The simultaneous administration of ethacrynic acid and hydrochlorothiazide has been clarified to induce distal blockade. In that condition, a small dose of angiotensin II brought antidiuresis, and antinatriuresis in the conscious dogs. This indicates the increased Na reabsorption in the proximal tubules during the peripheral infusion of angiotensin II. The redistribution of intrarenal blood flow was asessed by measuring the extraction ratio of ¹³¹I-hippuran, indicating a decrease in total RPF, cortical RPF and non-cortical RPF during infusion of angiotensin II in both the conscious and anesthetized dogs. But its fall was blunted in the latter. Next, we examined the existence of humoral Na excreting factor(s) through the extra-corporeal circulation between the recipient dogs and about 400 ml of blood pool in the bottle drawn from the donor dogs under three different conditions. Blood from tho saline-loaded dogs caused the remarkable natriuresis in the recipient dogs, whereas both the simplly saline-diluted blood of the dehydrated dogs and that of the dogs whose extracellular volume was expanded with saline under the ligation of bilateral renal veins and arteries showed no significant change in urinary Na excretion. These result indicates that angiotensin II has Na-retaining effect on kidney, although Na-excreting effect becomes increasingly marked depending upon an increased dose of angiotensin II and it is also observed by administration of pentobarbital anesthetics. Its principal action site may be proximal tubules. Moreover, it is concluded that blood of saline-loaded dogs contains any humoral Na excreting factor. Its origin may be kidneys.

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