The localization and characterization of anionic sites in the glomerular basement membrane were investigated by ultrastructural histochemical methods. The high iron diamine (HID) method and enzyme digestion studies demonstrated the presence of heparan sulfate proteoglycan (HS-PG) in the lamina rara eterna (LRE), but positive staining which was considered to be significant was not obtained in the lamina rara interna (LRI). Colloidal iron staining after neuroaminidase treatment proved that the polyanion of the epithelial and endothelial cell surfaces contained sialic acid. The results obtained suggest that there is a qualitative and/or quantitative difference in anionic substances between the LRE and LRI, and that this difference may contribute to the diversity in charge-associated function of the glomerular basement membrane. The HID method was clearly useful for visualizing HS-PG in the LRE in normal and/or pathologic states.

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The time course of glomerular histological alterations in rat serum sickness nephritis was studied using repeated renal biopsies from the pre-nephritic state to debilitation with nephritis. Parameters in the urine and plasma were also followed. Nephritis was produced by daily i.v. injection of rabbit serum albumin (RSA) 7 weeks after the first immunization. At the 7th week, the biopsy specimens showed hypercellularity with white blood cells in the capillary lumen and swollen glomeruli. Thereafter, thickening of the capillary wall and widening of the mesangium became marked. At the 25th week, the autopsical histology indicated so-called chronic nephritis. Immunofluorescent studies revealed rat IgG and RSA on the capillary wall as a granular pattern and in the mesangial area 7 weeks after the first immunization. Mesangial deposition then increased with time. Electron microscopy demonstrated notable subepithelial dense deposits and fusion of foot processes of epithelial cells in rats with severe proteinuria. Proteinuria developed at the 8th week. The anti-RSA antibody titer increased rapidly from the 2nd week and then gradually decreased from the 12th week. In contrast, the antibody titer in the urine was increased after proteinuria. Severe nephrotic syndrom became manifest at the 10th week.

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The effects of indomethacin (Id) and prostaglandin E₂ (PGE₂) on the proliferative responses of peripheral blood lymphocytes (PBL) from patients with minimal change nephrotic syndrome (MCNS) and lupus nephritis (LN) were studied using various mitogens. In MCNS and LN, the suppressed responses of the PBL to phytohemagglutinin (PHA) were markedly restored when the PBL were added with 10 μg/ml of Id, while the suppressed responses to other mitogens, concanavalin A (Con A), pokeweed mitogen (PWM) and Staphylococcus aureus Cowan I (STA), were not significantly restored. Such restoration of the suppressed PHA responses of the PBL, however, was also unexpectedly observed when the PBL were added with 100 ng/ml of PGE₂ in all the patients with MCNS and most of the patients with LN. From these results, it is suggested that the suppression of the proliferative responses of the PBL to PHA was not caused by PGE₂ in MCNS and LN.

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Autoregressive models have been successfully used in the field of engineering especially for the automatic control of various mechanical systems. Based on the potential usefulness of this approach to spectral analysis for investigating feedback regulations in the body, we attempted to apply it to long term data from patients undergoing chronic hemodialysis. Although usual statistical methods failed to reveal the network relationships of metabolic factors, the present approach clearly demonstrated that a major part of the oscillating movements of the clinical parameters is brought about by homeostatic processes in the body. As a result, a mosaic structure composed of metabolic factors explained the time courses of anemia well in these patients. Also, the present approach enabled us to gain an insight from the frequency domain into the concept of homeostasis in the body. This dynamic view of homeostasis suggests an entirely new field of study in biology and medicine.

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We determined the carbamylated plasma protein, i.e. plasma protein to which urea-derived cyanic acid is bound, in patients with renal failure. Carbamylated plasma protein is influenced by the mean BUN concentratation several days before and after blood sampling. Unlike BUN, etc., carbamylated plasma protein may be an indicator of the mean control of renal failure.

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The effects of a low protein diet and essential amino acid supplementation therapy on the rate of progression of chronic renal failure caused by chronic glomerulonephritis were examined retrospectively in 31 patients. A comparison of the rates of progression of renal failure in the low protein diet group with those in the non-low protein diet group was made using the slopes of regression lines between the reciprocal values of the serum creatinine and time. The mean slope of-5.4×10^-3 dl/mg/ month in the low protein diet group was significantly different from that of -9.9×10^-3 dl/mg/month in the non-low protein diet group. In addition, the influence of the low protein diet therapy on the progression of chronic renal failure was examined in 4 patients who started on the low protein diet therapy in mid-course of the follow-up period. Three of them revealed significantly smaller values of serum creatinine during the low protein diet therapy than those predicted by extrapolation of their respective rates of progression before treatment. The effect of essential amino acid supplementation therapy on the rate of progression of chronic renal failure was studied in 2 patients who changed from a low protein diet to essential amino acid supplementation therapy. The creatinine concentrations under the essential amino acid supplementation therapy increased at a significantly slower rate than predicted during the low protein diet alone. These results suggest that the low protein diet therapy may have slowed the progression of chronic renal failure, and that the essential amino acid supplementation therapy could be more effective for retardation of the progress of chronic renal failure than the low protein diet alone.

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As of July 1985, about 2, 000 ESRD patients were on CAPD which was introduced into Japan about 5 years ago. Protein loss with CAPD, which is not seen with HD, can have some beneficial effects and some harmful effects on patients. One of the good effects is an increase in the clearance of guanidine compound (G.C.) which is regarded as a kind of uremic toxin (U.T.). Although most of the G.C. is categorized into small molecular weight substance in the shape of a simple substance, there is some G.C. which is bound to protein and not easily removed by HD. The serum G.C. levels of CAPD patients were mostly lower than the pre-HD serum G.C. levels of HD patients. The results of gel-chromatography using Bio-Gel P10 indicated that the levels of peptide with molecular weights of 200 to 3, 000 were higher in the serum of CAPD patients than in that of HD patients. Analysis of the dialysates showed a higher loss of peptide with the same molecular weight in CAPD than in HD. One of the bad effects of protein loss is related to the loss of GC-globulin (vitamin D binding protein, VDBP) which is bound to vitamin D and its metabolite (VDM). The loss was 710 ng/day of 25 (OH)D and 3.7 ng/day of 1α 25 (OH)₂ D. Such a loss can cause serious effects on the Ca or bone metabolism in the case of a long period on CAPD. There may be other losses in the shape of bound protein, simple hormone and vitamin. It is most important to understand both the good effects and the bad effects of protein loss in CAPD.

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The serum levels and mass transfer of various substances in 15 children undergoing CAPD were studied during a total period of 232 dialysis months (range, 8 to 27 months; average, 15.5 months). The serum UN and Cr levels were kept under fair control, but the UN levels were found to be higher in 10 children weighing less than 20 kg (group A) than in 5 children weighing over 20 kg(group B). The Cr levels were higher in group B than in A. An increase of dialysis cycles of infusion volume was necessary in those with Ccr below 6 L/day/1.73 m² and infusion volume below 40 ml/kg/cycle, 4 exchanges per day (160 ml/kg/day). Smaller children had a higher daily ultrafiltration rate, protein and sodium loss (37.4 ml/kg, 0.27 g/kg and 3.6 mkq/kg respectively) compared to children weighing over 20 kg (10.7, 0.15 and 1.4, respectively). The daily glucose absorption was 3.2 g/kg in group A and 2.2. in group B. In small infants, occasional hypoproteinemia, hyponatremia and hypokaremia were observed, associated with anorexia and vomiting. The serum cholesterol levels showed an increas-ing tendency during 24-month period. Although there was no correlation between the serum calcium levels and Alk-P and PTH-C levels, high Alk-P and PTH-C levels were observed when the serum calcium fell below 10 mg/dl. Based on these results, CAPD appears to represent an useful treatment for children with ESRD.

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Sixteen patients under regular hemodialysis were investigated for their serum osteocalcin (OC) BUN, creatinine, and PTH. To evaluate the effect of lα(OH) D₃ on the serum level of OC, the changes of these parameters following lα(OH)D₃ treatment for 10.2 ±;5.5 months (mean ± SD) were investigated. The mean daily dose was 0.53 ± 0.16 μg/day. OC was increased from 24.6 ± 20.4 ng/ml to 49.7 ± 42.6 ng/ml (p<0.05) after the lα(OH)D₃ treatment. The natural course of hemodialysis and/or less efficient dialysis technique were not responsible for the increase in OC because of the insignificant relation between the OC level and duration of dialysis, and insignificant changes in BUN, creatinine, and PTH levels during the treatment. Significant positive correlations were found between the daily VD dose and the increase in OC level (r=0.513, p<0.02), and the serum OC level (r=0.701, p <0.01) after the VD treatment. These data suggest that long-term treatment with lα(OH)D₃ increases the serum OC level in dialyzed patients, possibly due to improvement of the relative vitamin D deficiency in these patients, followed by an increase of OC synthesis.

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A push/pull HDF system was developed by the authors which effectively and simultaneously eliminates both small and middle molecules. The system involves a fixed-volume ultrafiltration over a fixed time period with dialysis, and a back flush of the same amount of dialyzate to the blood side as dilution fluid in a short time, in repeated fashion. With this procedure, clogging of the pores on the membrane is less marked than in conventional HF, and drip infusion fluid is not necessary as a convection component. Three regular dialysis patients were put on push/pull HDF for 6 months. The restless leg syndrom and skin itchiness were found to be ameliorated with the push/pull HDF treatment. All three patients displayed recovery from anemia and a lowering of serum phosphate concentration.

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In the course of studies on the condition of trypsin treatment for inactive renin detection, we found that the dog renal renin activity was raised by the addition of a commercial bovine serum albumin (BSA) at low concentration. It is possible that BSA modified the renin-substrate reaction rather than mediating the conversion from inactive to active renin. The renin activity was raised not only by the addition of BSA but also by porcine serum albumin, and bovine and porcine gamma globulin at lower concentrations of 0.5% and less. However, at higher concentrations above 1% of these 3 proteins except porcine gamma globulin, the activity became gradually diminished. It is not yet known whether both the accelerating and inhibiting effects depend on these proteins themselves or on impurities.

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The renal histology and some clinical aspects of three patients with Bartter's syndrome are described. In all three cases, the renal function was moderately impaired and the concentrating ability was markedly reduced. Renal biopsy revealed hypertrophy, hyperplasia, and marked hypergranulation of the juxtaglomerular cells. In the medulla and/or medullary rays, nodular structures were observed which contained winding strands and vacuoles, surrounded by collagen fibers and fibroblasts. Some of them contained destroyed tubules with protein casts which leaked out into the interstitium. It is conceivable therefore that these structures were due to the reaction of the interstitium to leakage of the contents of the destroyed tubules. The destruction of the tubules, presumably due to severe and prolonged potassium depletion, might account for the impairment of the concentrating mechanism and might predict the later development of severe renal failure. Indomethacin combined with spironolactone did not raised the serum potassium in our cases.

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Exaggerated natriuresis was observed only in SHR on a standard sodium diet and not in SHR observed on a high sodium diet following acute saline infusion. Inhibition of efferent renal sympathetic nerve activity was also associated with this phenomenon. However, such exaggerated natriuresis was not observed in WKY on either a standard or a high sodium diet with acute saline infusion.

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Angiotensin II analogue (AIIA), 1Sar-8Ile-angiotensin II, was infused intravenously in 39 patients with essential hypertension (EHT, 28 cases) or renovascular hypertension (RVH, 11 cases) on sodium repletion and in 17 of the 39 patients (EHT, 11 cases; RVH, 6 cases) on sodium depletion. There was a significant correlation between the maximum percent change in diastolic blood pressure (DBP) during the first 10 min of AIIA infusion (Immed %DBP) and the percent change in DBP at 60 min after initiation of the AIIA infusion (60 min %DBP) (r=0.83, p<0.01). Furthermore, all patients with an Immed %DBP in excess of 10% except one, who had RVH with a relatively low level of plasma renin activity compared to the other RVH patients, revealed a 60 min %DBPin excess of 5%, which could be considered to represent a pressor response. These findings suggest that when the Immed %DBP exhibits a change in excess of 10%, no further infusion of AIIA is necessary at least in patients with EHT. After sodium depletion, the control PRA increased and not only was the pressor response observed during AIIA infusion on sodium repletion abolished but also a depressor response was recognized in some patients. Most patients with a high level of plasma renin activity showed a null or depressor response irrespective of the sodium balance. Accordingly, it may not be necessary to perform troublesome procedures for sodium depletion in order to increase the frequency of depressor responses on AIIA infusion tests.

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In 230 cases with either primary or secondary glomerular diseases, the intraglomerular fibronectin distribution was investigated by means of a direct immunofluorescence technique. In normal glomeruli and those with only minor abnormalities, fibronectin was distributed restrictively in the mesangial area. The localization of this protein extended to the pericapillary regions in cases with proliferative glomerulonephritis in order of severity off proliferation, irrespective of the glomerular lesions being primary and secondary. Examinations by light microscopy together with those by immunofluorescence suggested that the extension of the fibronectin reflected that of mesangial matrix to the pericapillary wall. In membranous lesions of primary as well as secondary glomerular disease, pericapillary extension of this protein was observed despite the absence of proliferation. The pericapillary fibronectin in this type of glomerular lesion appears to originate from the plasma, caused possibly by an enhanced glomerular permeability as well as the affinity of this protein to the GBM.

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