Experiments were undertaken to study whether progressive processes of bovine serum albumin (BSA) nephritis in C57BL/B10-BR mice could be prevented by the treatment of Mizoribine (MZR), an immunosuppressant. Crescentic glomerulonephritis could be induced in 22 mice with high reproducibility of 95 per cent by four-times preimmunization of 0.2 mg of BSA every 2 weeks, followed by daily intraperitoneal injections of 50 mg/kg of BSA for 4 weeks (group IV, a control). In 9 mice, intraperitoneal injections of 50 mg/kg of MZR was initiated on 3 days before preimmunization and continued until the final day of the experiment (group I). In 8 mice each, the same treatment with MZR was initiated either before or after daily intraperitoneal injection of BSA and continued until the final day of the experiment (groups II and III). Although anti-BSA antibody titers just before and during daily injection in group I were not suppressed and almost equal to that of a control, the levels of circulating immune complexes (CIC) and urinary protein were significantly lower in group I than those in group IV. Histologically, diffuse intra- and extracapillary proliferation observed in group IV was apperently diminished in group I. In groups II and III, extracapillary proliferation was seen to be diminished, in spite of no decrease in antibody titers, the levels of CIC and urinary protein, and intracapillary hyper-cellularity compared with those of group IV. These results suggest that MZR has a suppressive effect on the progressive processes of immune complexe mediated glomeru-lonephritis, by means of the change in quantity, but not quantity of anti-BSA antibodies, leading to the decrease of CIC levels, especially when used in the early stage of immune reaction.

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Non-immunological factors have been proposed to induce the aggravation and progression of glomerular injury in patients with chronic renal glomerulonephritis. In this experiment, we fed Masugi nephritis rats with various groups of chaw for three to four months after receiving uninephrectomy. We then studied clinically and morphologically each group of rats. The rats fed with chaw containing salt (8%) and protein (24%) showed the highest level of blood pressure (180 mmHg), a moderate incense of proteinuria, and severe glomerular injury. The rats fed with salt in the protein rich (50%) chaw showed a lesser degree of hypertention (160 mmHg) ; however, this group showed the largest amount of proteinuria and the most severe form of glomerular and tubular injury. The sera taken from these rats demonstrated the highest level of DuN (100+17 mg/dl) and Creatinine (1.8±0.2 mg/dl). The rats fed with the protein poor (6%) chaw showed normal blood pressure, a decreasing amount of proteinuria and a mild form of glomerular injury. Lesser and better results of these lesions were obtained in the rats fed with the protein poor chaw containing the essential amino acids. Furthermore, the aggravation of the glomerular injury induced by feeding with salt in the protein rich chaw for 1 month recovered after changing the chew to that of the protein poor chaw containing the essential amino acids; the results also showed a decrease in the amount of proteinuria and a morphological improvement. The results obtained suggest that too much intake of protein and salt lead to the aggravation of glomerular injury, whereas the restriction of protein and salt intake have a protective effect on glomerular injury in patients with chronic glomerulonephritis.

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Antigenicity and nephritogenicity of trypsin-digested and purified renal tubular basement membrane (TBM) antigen from the Lewis (LEW) strain rat was investigated. Immune reactions to TBM antigen in BN, LEW and F₁ hybrid rats were also studied using syngeneic and allogeneic injection systems to evaluate the possible antigenic differences between the two strain rat antigens. Immunization with LEW TBM antigen led to antibody formation against the antigen and induction of tubulointerstitial nephritis (TIN) in BN rats, BALB/c mice with immune deposits and XIII guinea pigs without deposits along the TBM. Circulating anti-LEW TBM antibody could be detected by immunodiffusion and immunofluorescence methods. These data indicates that the LEW rat has nephritogenic antigen on the TBM, though the lack of the antigen in the LEW TBM has been repeatedly reported based on the two lines of results, the failure to detect the TBM by the immunofluorescent technique and to induce TIN in the LEW rat. In comparison of LEW TBM antigen with BN TBM antigen in syngeneic and allogeneic systems, the BN rat was a higher responder to both TBM antigens than the LEW rat. Furthermore, immune response to BN TBM antigen was higher than that to LEW TBM antigen in BN rats. It was indicated that the host immune reaction to TBM antigen along with antigenicity and nephritogenicity of the antigen plays a significant part in induction of TIN.

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The possibility of re-pregnancy in patients having had focal glomerular sclerosis (FGS) and nephrotic syndrome caused by toxemia of pregnancy was studied, Renal biopsy performed in 20 patients with pre-eclampsia, in whom proteinuria of heavier than 1.0 g per day had persisted beyond one month after termination of the gestation, revealed findings compatible with FGS in 7 patients. Six of them achieved complete remission within 4 to 18 months and another patient did incomplete remission type I 12 months after delivery. With intervals of 9 to 29 months 3 patients in complete remission became re-pregnant, but proteinuria or hypertesion did not appear and the patients were able to have a baby with no impairment of renal function. These findings suggest that FGS developed during preeclampsia may follow a favorable clinical course and does not prevent re-pregnancy once complete remission has been achieved.

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Clinicopathologic features of the kidney in five patients with Wegener's granulomatosis were presented. Renal biopsy specimens were examined by means of light, electron and immunofluorescence microscopy. Two cases were male and three were female. The age at the time of biopsy ranged from 19 to 64 years old. All cases complicated upper respiratory tract lesions, but no one had significant pulmonary symptomes. Proteinuria and/or hematuria on urinalysis were observed in all cases. Put no one showed deterioration of renal functions. None had macroscopic hematuria and nephrotic syndrome, The renal lesions of two patients were characterized by focal destructive glomerulitis with thrombosis and one of them demonstrated a marked periglomerular inflammatory cell infiltration and destruction of the Bowmann's capsule. Electron microscopical studies demonstrated segmental sclerosis and collapse of glomerular capillaries with complete fusion of epithelial foot process in the segmental lesions. But no electrondense deposits were detected in the basement membrane area of these biopsy specimens, The cases who showed active glomerular lesions such as marked periglomerular inflammatory cell infiltrations and destruction of the Bowmann's capsule, ended after deterioration of renal function instead of various therapies. But the remaining cases showed almost normal and/or inactive lesions and had no more renal impairments besides of continuing mild urinary abnormalities. In these cases, therapeutic effects was supposed to be confirmed histologically. Renal lesions is one of the most important factors which define the prognosis of Wegener's granulomatosis, so the degree of histological changes are supposed to correlate with the prognosis. Early histological examination of renal lesions in Wegener's granulomatosis is utmost important for certification of the prognosis and selection of appropriate treatments.

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Renal biopsy specimens from 86 children with IgA nephropathy (47 boys, 33 girls) were reviewed and classified into 4 groups according to the sites of IgA deposition by immunofluorescent microscopy (IF) and localization of electron dense deposits (EDD) by electron microscopy (EM) followed by comparison with clinical features. In the 285 cases studied by IF, the total incidence of this disease was 28.1%. Seventyfive percent of children were discovered by mass-screening urinalysis. Gross hematuria attack occurred in 65% and elevated serum IgA levels were discovered in 16% of patients. Transient azotemia and hypertension were the major presenting features in 4% and 8% of children, respectively. Only 4% of children presented nephrotic syndrome (s-Albumin<2.5 g/dl) and IF study revealed capillary wall immunoglobulin deposition and electronmicroscopically EDD were observed along the glomerular basement membrane (GBM). Combined therapy with immunosuppressive, anticoagulants and antiplatelet drugs was more efficacious for the group with capillary wall immune deposits and GBM EDD than the group without these changes. In the group with mesangial deposits alone, minimal glomerular alterations, focal segmental proliferative glomerulonephritis (GN) and diffuse proliferative GN (DPGN, slight) were predominant light microscopic findings and urinary abnormalities were slight to mild. On the other hand, the group with capillary wall deposits often demonstrated DPGN (moderate to severe) with extracapillary proliferation and severe urinary abnormalities. During a mean follow-up of 45 months, none of the children had progressed to endstage renal disease except for one boy, being introduced to hemodialysis 9 years after discovery of proteinuria. According to these results, the histological findings closely par-alleled both the clinical features and courses. Immune deposits along the capillary walls and the glomerular basement membrane alterations would seem to be an useful prognostic indicator of the course of IgA nephropathy in children.

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Renal biopsy specimens from 23 rebiopsied children with IgA nephropathy (15 boys, 8 girls) were reviewed and classified into 4 groups according to the sites of IgA deposition by Immunofluorescent microscopy (IF) and localization of electron dense deposits by electron microscopy (EM) followed by comparison with clinical features. In the group with mesangial deposits alone repeat biopsy specimens obtained after intervals ranging from 1 year to 2 years showed few correlation to urinalysis findings but persisting mesangial proliferative glomerulonephritis and mesangial deposition of IgA. During a mean follow-up period of 5 years and 1 month imparired renal function was not observed despite abnormal urinalysis, so it is highly possible that this group takes a good clinical course. In the group with capillary wall deposits detected by IF and EM subsequent biopsy findings often demonstrated the increase of chronicity index stated as one of the poor prognostic factors. Therefore it is necessary for this group to be treated aggressively with a close observation on clinical progression to end stage renal failure. Repeat biopsy specimens from 3 children still showed measangial deposition of IgA 6, 9 months and 1 year and 7 months after clinical resolution respectively. Histological improvement after combined therapy with immunosuppressive, anticoagulants and antiplatelet drugs occurred more frequently in the group with capillary deposition especially with higher scores of activity index. On the other hand the group with mesangial deposition alone or advanced sclerotic lesion showed no remarkable improvement. One case with progression to terminal renal failure revealed development of mesangial sclerosis, an increase of percentage of glomeruli showing crescent formation, the glomerular basement membrane changes, tubulointerstitial changes as well as vascular changes.

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The prognostic features in patients with IgA nephropathy who showed severe histopathological changes were described. Fifty five patients with moderate and advanced stages of IgA nephropathy were evaluated. The mean duration of the follow up ranged from 6 to 112 months (mean : 51.2 months). These patients were divided into four groups (Typel-4) according to the mean levels of the slope of the reciprocal of serum creatinine (s-Cr) vs time plot. The histopathological changes of renal specimens, blood pressure, s-Cr, serum IgG, IgA, IgM, C3 levels, PSP (15 min), the degree of proteinuria and hematuria were examined at the time of biopsy. The averages of blood pressure and the amount of proteinuria were examined serially throughout the study period. Proteinuria, s-Cr, PSP (15 min) at the time of biopsy in Type 4 (fulminant type) were significantly increased compared with those in Type 1 (stable type). The average amount of proteinuria were also significantly increased in Type 4. It was suggested that histopathological changes of renal specimen, proteinuria of more than 1.0 g/day, s-Cr of more than 1.5 mg/dl and PSP (15 min) of less than 35% were useful to evaluate the prognosis of patients with IgA nephropathy with severe histopathological changes.

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The reduction of functional renal mass is known to induce the compensatory renal growth. Although the mechanism has not been fully elucidated, the humoral factors are considered to participate in it. In this study, the humoral factors were investigated on the rats, the renal mass of which were reduced by the subtotal ligation of renal arteries lieving one of the third branches of unilateral kidney. The effects of the plasma of uremic rats on the DNA synthesis were measured by the isotopic thymidine incorporation into DNA of renal cortex slice The plasma of uninephrectomized rats produced the stimulation of DNA synthesis, which was inhibited by adding the plasma of subtotally nephrectomized rats. By the dialysis of the uremic plasma with cellophane membrane or by the adsorption with the charcoal adsorbent (AST420), the inhibitory effects were markedly decreased. The uremic toxin fraction 2a obtained with the high performance liquid chromatography exerted the inhibitory effects on the DNA synthesis. The administration of AST-120 orally to the uremic rats reduced the hight of peak 2a and increased the stimulatry effects of the plasma on DNA synthesis. These results indicate that the renal growth factor in the plasma of rats with reduced renal mass is inhibited by the uremic toxins, the elimination of which by the adsorbent could increase the action of the growth factors.

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The mechanisms of the hypotensive action of a sulfonamide diuretic, mefruside (M), were analyzed based on the pressure-natriuresis relationship. A 5-week study was performed in 8 patients with uncomplicated essential hypertension, who were given a regular sodium diet (15-18 g of NaCl/day) in the 1st & 5th weeks, a severe sodium-restricted diet (2 g/day) in the 2nd week. and a mild sodium-restricted diet (7 g/day) in the 3rd & 4th weeks. M (25 mg/day) was administered in the 4 & 5th weeks. Urinary sodium excretion (UNaV) and mean arterial pressure (MAP) were measured at the end of each week, and the pressure-natriuresis curve (PNC), so-called renal function curve, was drawn by plotting UNaV on the ordinate and MAP on the abscissa before and after medication with M. The reciprocal of the slope (1/B: mmHg/mEq/day) was used for analyzing the slope (B: mEq/day/mmHg), because dietary sodium intake was altered primarily and the consequent secondary change in MAP was observed. Before medication, PNC was linear and MAP was changed in consequence of altering sodium intake (1st week: 117±9, 2nd week: 105±7, 3rd week : 109±9 mmHg). But after medication, the change in MAP was very small (4th week : 102±8, 5th week: 104±7 mmHg). M raised the slope of PNC (1/B: 0.048±0.020→0.007±0.015 mmHg/mEq/day, p<0.01), without significantly changing the x-intercept (104±6→101±9 mmHg, NS) of PNC. The rise was greater in patients whose slope had been depressed before medication of M. The hypotensive effect of M on a regular sodium diet (change in MAP from the 1st to the 5th week) correlated positively with the rise in the slope with M (r=0.833, p<0.02), but not with the leftward shift, suggesting that the effect of M is mainly due to its diuretic action, since the slope is determined by glomerulotubular balance. On the other hand, the effect of M on a mild sodium-restricted diet (change in MAP from the 3rd to the 4th weeks) did not correlated with the rise in the slope, but tended to correlate with the degree of the leftward shift of the PNC (r=0.670, p<0.10). Since the x-intercept of the PNC is determined by the renal vascular resistance, the leftward shift may be due to its vasodilating action of M. These results suggest that extreme restriction of the dietary sodium intake is not necessary under the treatment of an antihynertensive diuretic, mefruside.

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It has been postulated that abnormal platelet function may contribute to the occurrence and development of both diabetic macroangiopathy and microangiopathy. On the other hand, platelet-derived growth factor (PDGF) released from a-granules of platelets when the platelets aggregate may play an important role in the occurrence and development of diabetic atherosclerosis. In this article, in order to clarify the role of platelets in diabetes mellitus, we investigated the effects of PDGF on the growth of DALP/c 3T3 cells. In the diabetics complicating coronary artery disease (CAD), whole blood serum (WPS) contaning PDGF significantly promoted DNA synthesis of 3T3 cells compared with the normal controls. Moreover, similar results were obtained in the diabetics with nephropathy of diffuse glomerular lesion over grade 2 and with retinopathy over stage IV. However, plasma derived serum (PDS) less containing PDGF had such little effect on the growth of 3T3 cells in the diabetics with CAD, nephropathy and retinopathy. These results indicate that PDGF may be correlated with the development of microangiopathy as well as macroangiopathy in diabetes mellitus.

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We experienced 3 cases of rheumatoid arthritis (RA) developing glomerulonephritis with crescent formation. All of them, aged over 50 years, had long-term histories of RA with involvement of multiple joints and had never been pointed out the abnormalities of urinary findings. In 2 of them proteinuria with granular casts and pedal edema developed abruptly, accompanying cutaneous vasculitis lesions (skin ulcer and purpura). Serum levels of IgG-rheumatoid factor increased in both patients. Percutaneous renal biopsies were performed and the glomerular involvements were characterized by crescent formation with fibrinoid deposits and mild mesangial proliferation. The percentage of glomeruli affected by crescent formation was 37% and 61%, respectively. The treatment with prednisolone and/or cyclophosphamide led them to clinical improvements of vasculitis and glomerulonephritis. In these cases, glomerulonephritis with crescent formation developed in association with cutaneous vasculitis which suggests that the renal lesion may be regarded as a' complication of rheumatoid vasculitis. The third patient noted general weakness and pedal edema after one month of increasing arthralgia Laboratory investigations showed renal dysfunction and renal biopsy revealed severe crescentic glomerulonephritis with fibrinoid deposits. Despite of prednisolone therapy, renal function was progressively aggravated and maintenance hemodialysis was need. Although it was unclear whether the patients had complicating vasculitis, the increasing symptomes of polyarthritis reflected the active stage of RA, in which vasculitis and other complications were likely to develop. In this case active RA seems likely compared to coincidental development of idiopathic crescentic glomerulonephritis as the cause of the renal lesion. Diffuse or focal crescentic glomerulonephritis may be a part of the spectrum of active RA with vasculitis and this complication may not be as rare as generally considered.

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Uremic peak 2a in high performance liquid chromatography analysis of uremic plasma has already been reported in relation to uremic symptom and progression of renal failure. Inorder to study mechanism of production and excretion of peak 2a, 2a levels in plasma and in urine were compared with those of creatinine (Cr) and guanidino compounds in patients undergoing conservative therapy and hemodialysis, in this paper. With progression of renal failure, 2a levels increased exponentially in plasma, but did not much change in urine. This pattern resembled with that of guanidine, but different from those of Cr, guanidinosuccinic acid (GSA), methyl guanidine (MG) and guanidinoacetic acid (GAA), i. e., Cr, increase in plasma, decrease in urine; GSA and MG, increase both in plasma and urine ; GAA, small change in plasma, decrease in urine. Production of 2a was suggested to increase in renal failure, however its main production organ did not seem to be kidney. Ratio of clearance of 2a to Cr was found to be larger than unity in initial stage of renal failure, indicating existence of tubular excretion of 2a. The ratio rapidly decreased with progression of renal failure. Similar tendency was observed in GSA and GAA, however their clearance ratios to Cr were not correlated with that of 2a, therefore excretion mechanism was thought to be different between 2a and GSA.

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Serum samples from hypocomplementemic MPGN patients with or without C3 nephritic factor (C3NeF) were examined for the nature of C3 splitting factor and the levels of complement component. Totally 10 patients showed the existence of C3 splitting factor, 5 patients were detected C3bBb stabilizing activity (C3NeF) from their sera, other 5 cases were not detected C3NeF activity. Purified IgG from these C3NeF negative cases did not agglutinate the EAC4b3bBb cell except one case and indicated the different pattern of complement profiles from C3NeF positive cases. In C3NeF positive cases, both the pattern of complement profiles and the nature of C3 splitting activity cannot be explained by C3NeF only. These results suggest the variety of mechanism that causes hypocomplementemia in MPGN.

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