Complement system takes an important role in the pathogenesis of immune complex glomerulonephritis. In this study the precise changes of serum complement and its deposition in the glomeruli were investigated in the mice models induced with cationized bovine γ-globulin (CBGG). Balb/c mice preimmunized with CBGG were injected intravenously with CBGG three times every 24 hours. Proteinuria and hypoalbuminemia have developed from day 3 until the death on day 9-13 of progressed azotemia. This nephritis resembled to mesangeal proliferative glomerulonephritis histopathologically. Immunofluorescent study revealed granular deposits of CBGG, IgG, A, M and C3 along the glomerular capillary loop. Serum C3 decreased to about 50% of normal controls within 1 hour after challenge of antigen and plasma C3 conversion evaluated by crossed-immunoelectrophoresis, occured in accordance with C3 reduction and then decreased. Immunofluorescent study showed a big difference in the mode of deposition among IgG, CBGG and C3. The most intense deposits of C3 in the glomeruli were seen 12 hours after challenge of CBGG, and then gradually decreased until the next challenge. IgG and CBGG antigen deposited most intesely soon after the challenge of antigen, and gradually decreased. These results led us to conclude that there existed two phases of complement activation in this immune complex induced mice glomerulonephritis; an early phase activation of complement by antigen-antibody complexes in the circulation and later phase activation of complement by immune complexes after deposition of them in situ glomeruli.

抄録全体を表示

Immune complex deposits found on the subepithelial side of the glomerular basement membrane (GBM) are characteristic of membranous glomerulonephritis. In order to clarify the mechanism of subepithelial immune complex deposition, we investigated the manner of localization of preformed immune complexes (IC) composed of native ferritin (NF) and anti NF antibody (aNFab) in a 40-fold antigen great excess using the system of passive serum sickness nephritis of mice. The following results were obtained. (1) The ferritin particles in the GBM of animals given NF alone, as controls, were mainly restricted to the lamina rara interna (LRI) with very few penetrating the entire depth of the GBM. (2) In animals given the IC, greater numbers of ferritin particles were seen, in comparison with the control animals, not only in the lamina densa (LD) but also in the lamina rara externa (LRE). (3) Immunoelectron microscopy (IEM) demonstrated that each NF particule was accompanied by aNFab, which was found to be peroxidase positive material, throughout the GBM. (4) On the grounds that ICs were prepared in Ag great excess, it is suggested that ICs seen in the GBM are composed of a low avidity antibody with a low Ag/Ab ratio, probably Ag₁Ab₁. From these results, it is suggested that circulating ICs are necessary to give rise to IC deposition on the GBM and that NF and aNFab exist together as ICs throughout the GBM. We concluded that subepithelial IC deposits arise from the circulation, and that after GBM trapping, circulating small-sized IC can pass through the LD to reach the subepithelial side of GBM.

抄録全体を表示

In order to investigate whether preformed (circulating) immune complexes (IC) can localize in the Subepithelial side of the glomerular basement membrane (GBM), non-dissociable covalently cross-linked IC (coy. IC) composed native ferritin (NF) and anti NF antibody (aNFab) were preformed in a 2 step reaction using the bifunctional reagent, toluene-2, 4-diisocyanate (TDI) . Molecular weight of coy. IC was about 58×10⁴ dalton, which suggests that the coy. IC was composed of Ag₁Ab₁ lattices. The GBM of mice given coy. IC intravenously showed that deposition of coy. IC was not only in the lamina rara interna but also, with time, in the lamina densa and lamina rara externa. The size of coy. IC and the distribution in the GBM described above were similar to those we studied previously using preformed dissociable NF and aNFab complexes in a 40-fold antigen great excess. From these results, we concluded that preformed immune complex in vitro can pass through the lamina densa as intact IC to give rise to the subepithelial area without dissociation or reformation. That is, the subepithelial IC deposits arise from the trapping of small-sized IC derived from the circulation.

抄録全体を表示

The present study is an attempt to solve the problem of pathogenesis of focal glomerularr sclerosis (FGS), especially in juxtamedullary cortex, we were investigated by measurement of luminal diameters of afferent arterioles (Aff), efferent arterioles (Eff) of numerous glomeruli, arterial cushion (AC), afferent arterioles (AC-aff) at a region of branching arteries from the interlobular arteries, using scanning electron micrographs of methyl methacrylate casts of intrarenal arteries of aminonucleoside nephrotic rats. As regards luminal diameters, Eff were nearly equal Aff in minor glomerular abnormalities (Minor). Nevertheless Eff of glomeruli with segmental sclerosis (FSHS) were smaller than Aff (t-test). AC with FSHS were smaller than ones of Minor, statistically (t-test). The results of these examination, the cushion may be important factor for the regulation of blood flow in sclerotic glomeruli.

抄録全体を表示

In this study we examined the role of the complement system in Acute glomerulo nephritis (AGN). Breakdown products of complements (iC3b, C4d and Bb) and Terminal complement complex (TCC, SC5b-9 complex) in plasma samples were measured by ELISA. The microassay plates were coated with monoclonal antibodies which bind specifically to human iC3b, C4d, Bb and SC5b-9 complex. This assay accurately quantitates small amounts of in vivo complement activation. The plasma samples were drawn from patients with AGN and other glomerulonephritis. There were some patients with various glomerulonephritis whose plasma iC3b, C4d and Bb concentrations were higher than those in normal human. However specificity was not found, The ratios iC3b/C3 and C4d/C4 were increased in the early stages of AGN, but plasma Bb concentrations revealed no significant changes. Plasma SC5b-9 complex concentrations were increased in the early stages of AGN. C3c, C3d, C4d and SC5b-9 were found to be localised in the glomeruli of those AGN patients. It is suggestive that in these cases of AGN (especially case 2) complement activation is predominantly mediated through the classical pathway and TCC is formed by this activation. This complement activation in the blood and the renal tissue is presumed to be involved in the initiation and progression of AGN.

抄録全体を表示

A comparative clinico-pathological study was performed on 61 children and 51 adults with IgA nephropathy. Hematuria and/or proteinuria found by chance was the most common initial clinical sign, being observed in 82.0% of the children and 52.9% of the adults (p<0.001). At renal biopsy, hypertension and severe proteinuria were found in 9.8% and 33.3% of the adults and 0 and 14.8% of the children (p<0.05, p<0.05). Elevations of blood urea nitrogen and serum creatinine were found at the time of biopsy in 21.6% and 9.8% of the adults but in none of the children (p<0.001, p<0.05). On histological studies, proliferative changes of the glomerulus were similar in the two groups, and diffuse mesangial proliferation was found in 62.3% of the children and 51.0% of the adults (althogh the difference was not significant). Focal glomerulosclerosis and tubular atrophy were found in 52.9% of the adults and 32.8% of the children (p<0.05). These results suggest that focal glomerulosclerosis with tubular atrophy is correlated with deterioration of renal function, hypertension and age at renal biopsy, and has an important influence on the prognosis of patients with IgA nephropathy.

抄録全体を表示

Serum uric acid (S_UA), creatinine clearance (Ccr), urinary excretion of uric acid (U_UAV) and uric acid clearance (C_UA) were determined in 357 patients with IgA nephritis (IgAN) and 81 patients with membranous nephropathy (MGN) in an attempt to clarify uric acid metabolism in patients with chronic glomerulonephritis, and U_UAV/Ccr and C_UA/Ccr levels were measured to investigate their correlations. As a result, hyperuricemia that could hardly be explained with a decline of Ccr alone was recognized in many cases, since the patients with hyperuricemia exceeding 7.0 mg/100 ml of S_UA registered even as high as 25.5% in IgAN and 33.3% in MGN, whereas those with the Ccr levels higher than 80 ml/min registered 22.3% in IgAN and 38.0% in MGN. Although the S_UA level increased and the U_UAV and C_UA levels decreased along with a decline of Ccr in IgAN, no similar trends were recognized in MGN. When the distribution of U_UAV was studied in the patients with the Ccr levels higher than 80 ml/min, the patients whose U_UAV levels higher than 800 mg/ 24 hrs that suggested excessive uric acid production were markedly as low as 3.9% in IgAN and 3.7% in MGN. Thus, the cause of hyperuricemia could not be attributed to an amount in the uric acid production. On the other hand, the patients whose C_UA levels lower than 6.0 ml/min in the distribution of C_UA that suggested a decrease of uric acid excretion registered 47.4% in IgAN and 63.0% in MGN, respectively, which equally appeared to be a type of lowered excretion in a majority of patients whose hyperuricemia was recognized in IgAN and MGN. The mechanism of the lowered excretion of uric acids from the kidney despite the normal level of Ccr has yet to be clarified.

抄録全体を表示

We have already reported that renal glycine amidinotransferase (GAT) activity decreases in the course of renal damage, however, the inability of the kidney to synthesize guanidinoacetic acid (GAA) may be compensated by the pancreas in a more advanced stage of renal failure, and that in diabetes mellitus, the production of GAA is decreased from the period without renal dysfunction, and the extrarenal production of GAA is also decreased. In order to elucidate the significance of GAA synthesis in the pancreas, the author measured serum concentration of GAA, creative, and the renal and pancreatic GAT activity in control, streptozotocin (STZ) -induced diabetic, insulin-treated diabetic, and ethionineinduced acute pancreatitis rats. The serum GAA concentration was depressed in untreated diabetic rats (21.5±2.5 μg/ dl) compared with the level in controls (85.5±10.1μg/dl), and was restored to control level by insulin treatment (66.±7.3 μg/dl). The renal and pancreatic GAT activities were depressed in untreated diabetic rats compared with the level in controls and the latter was restored (625.2μ 96.2μg/g·tissue/h) by insulin treatment. The positive correlation was observed between pancreatic GAT activity and serum GAA concentration. The serum GAA concentration was significantly higher in acute pancreatitis rats (716.0±223.7 μg/dl) compared with the level in controls, although the renal and pancreatic GAT activities were lower in acute pancreatitis rats compared with the level in controls. These results indicate that in STZ-induced diabetic rats, depressed pancreatic GAT activity was ameliorated by insulin treatment, consequently the level of serum GAA was restored and that GAA might be released from the acinar pancreas, resulting in higher concentration of serum GAA in acute pancreatitis rats. GAA may be synthesized in the acinar pancreas, and insulin can directly regulate the function of acinar pancreas including GAA synthesis.

抄録全体を表示

A sensitive and specific radioimmunoassay for β-endorphin without gel filtration of plasma extracts has been developed by using newly raised antibody. The minimal detectable quanntity was 5 pg, and ED 50 was 23 pg/ml. The crossreactivity of antibody with β-lipotropin was 3.3%, but not showed crossreaction with other fragments of β-lipotropin, β-MSH and ACTH. The inter-assay coefficient of variation was 2.7% to 17.4%, and the intra-assay coefficient of variation was 4.5% to 26.4%, respectively. The mean recovery for unlabeled β-endorphin added to plasma and extracted was 92.1% to 110.4%. Plasma levels of β-endorphin in 40 normal subjects was 14.7±3.1 pg/ml and 14.8±1.1 pg/ml in 10 patients with chronic glomerulonephritis whose renal function was normal. There was no significant difference between the two groups. On the other hand, plasma levels of β-endorphin in 16 patients on maintenance hemodialysis was significantly increased of 56.3±6.3 pg/ml than the other two groups. Physiological role of this high β-endorphinemia in patients on maintenance hemodialysis still remains to be resolved.

抄録全体を表示

In order to assess the roles of vasoconstrictor thromboxane in the antihypertensive action of α₁ adrenoceptor antagonist, we explored the influences of OKY-046, a selective thromboxane inhibitor, on the antihypertensive effects of bunazosin in spontaneously hypertensive rats (SHR). 2-week antihypertensive treatment with bunazosin (0.5 mg/kg/day) did not produce a significant decrease of systolic blood pressure in SHR, as compared to untreated controls. The blood pressure reduction was associated with a decreases of PGI₂/TXA₂ in vascular eicosanoids generation (p<0.02) and an increase of TXA₂ excretion in urine (p<0.05). A combination treatment with OKY-046 almost completely abolished the enhanced TXA₂ generation in the vascular wall and kidney, which was strikingly associated with a potentiation of the blood pressure reduction by bunazosin treatment (176 vs 186 mmHg, p<0.01). Bunazosin directly stimulated TXA₂ biosynthesis in vascular smooth muscle cells in culture in a dose-dependent manner. Thus, these data clearly indicate that bunazosin, a quinazoline derivative, enhances vasoconstrictor TXA₂ system in the vascular wall and kidney possibly through direct actions, which would attenuate the antihypertensive effects of α₁ adrenoceptor antagonism by bunazosin treatment.

抄録全体を表示

The effects of intravenous infused magnesium on hemodynamics and renal watersodium metabolism in patients with essential hypertension. The present study aimed to elucidated the effects of intravenous infused magnesium on hemodynamics and renal water-sodium handling in patients with essential hypertension. Mean arterial pressure (MAP), heart rate (HR), urine volume (UV), urinary excretion of sodium (U_NaV), endogenous creatinine clearance (Ccr), fractional excretion of sodium (FE_Na) were measured before and after intravenous infusion of 10% magnesium sulfate (an initial dose: Mg 13.5 mg/m²·BSA/15 min ; a maintainance dose: Mg 2.7 mg/m²·BSA/ 105 min) in 6 normotensive subjects (NT) and 12 mild-to-moderate essential hypertensives (EHT). Following magnesium infusion, serum magnesium concentration (s-Mg) increased and reached the level of about 1.8 times basal value. Significant increases of UV, U_NaV and FE_Na in both NT and EHT, and a similar tendency of Ccr in EHT were observed, while no significant change in MAP nor HR was found in the two groups. The changes in UVNa (ΔU_NaV) was positively correlated with those in FENa (ΔFE_Na) and a similar tendency was shown between JUNaV and change in Ccr (dCcr) in all subjects. While there was no significant percentage change of s-Mg (%Δs-Mg) nor of Ccr (%ΔCcr), those of UNaV (%ΔU_NaV) and FENa (%ΔFF_Na) were significantly greater in EHT. It is concluded from these findings that magnesium infusion produces diuresis and the natriuresis which might result from suppression of renal tubular reabsorpsion of sodium, without any change in systemic hemodynamics in NT and EHT. The pronounced natriuretic response tomagnesium in EHT might contribute to the hypctensive mechanism of magnesium loading in EHT.

抄録全体を表示

We studied the therapeutic effects of human urinary trypsin inhibitor (UTI) in 5 cases with acute renal failure, resulting from traumatic shock in 1 case, post-operative shock in 2 cases, septic shock in 1 case, and dehydration in 1 case. We administerd 300, 000 u/day of UTI intravenously at the initial phase of acute renal failure for 7 days. We measured the activities of urinary N-acetyl-β-D-glucosaminidase (NAG), alanine aminopeptidase (AAP) and the activities of serum β-glucuronidase, PMN-elastase serially. As a control, we also studied same markers in 5 cases with acute renal failure without the administration of UTI. We could obtain the following results. 1) Urinary activities of NAG and AAP were already elevated markedly at the onset phase of acute renal failure. 2) The administration of UTI caused a significant decrease of the activities of NAG and AAP in the urine as compared with those in the controls. 3) The administration of UTI caused also the significant suppression of the activities of β-glucuronidase and PMN-elastase in the serum. These results suggested that UTI has the protective effects on the tubular epithelial cell injuries in cases of acute renal failure.

抄録全体を表示

Three cases presenting with systemic lupus erythematosus (SLE) and minimal change nephrotic syndrome (MCNS) are reported in this paper. All cases were female; they abruptly developed nephrotic syndrome at the age of 30, 11 and 23 years, respectively. In Case 1, the diagnosis of SLE was based on fever, butterfly rash, Raynaud's phenomenon, leukopenia, lymphopenia, hypocomplementemia, a high titer of anti-DNA anti-bodies, positive DNA and LE test, and the presence of anti-nuclear antibodies (speckled pattern). In Case 2, the diagnosis was based on butterfly rash, central nervous system involvement, lymphopenia, hypocomplementemia, a positive LE cell phenomenon, a high titer of anti-DNA antibodies and a positive DNA test. In Case 3, the diagnosis was based on photosensitivity, alopecia, lymphopenia, hypocomplementemia, a high titer of anti-DNA antibodies, a positive DNA test and a positive LE cell phenomenon. In these three cases, initial symptoms were puffy face and pretibial edema which occurred suddenly. These symptoms disappeared completely after either corticosteroid therapy or a combination therapy using corticosteroids and immunosuppressive drugs. These patients took a favorable course andno aggravation was noted in the findings of urinalysis and renal functions. In two of these cases, the diagnostic criteria for SLE were satisfied, but the remaining patient fulfilled only three criteria except for renal disorder. In each of these cases, minor glomerular abnormalities were disclosed by renal histology. It seems likely that SLE was complicated by MCNS in these cases. From these cases, it is suggested that there is a possibility of immunological abnormalities associated with SLE and MCNS.

抄録全体を表示