We investigated the effects of human recombinant Interleukin 2 (hr IL-2) on anionic sites and the permeability of glomerular basement membrane (GBM) in rats using polyethyleneimine (PEI) as a cationic probe. After administration of a massive dose of hr IL-2 (1.7×10⁶u), aninic sites of both lamina rara externa (LRE) and lamina rara interna (LRI) were markedly reduced in number associated with fusion of foot processes. In NTN (nephrotoxic serum nephritis) rats, sacrificed at 14th day after administration of NTS (nephrotoxic serum), moderate reduction of anionic sites in both number and density, particulary along LRE with foot processes fusion, was noted. In NTN rats injected with a small dose of hr IL-2 (6.8×10⁴u) consecutively for 14 days, no significant differences as compared with those of NTN rats were noted. In rats administered only the same doses of hr IL-2, focal loss of anionic sites with fusion of foot processes was recognized as well. Urinary protein excreted in 24 hours was 23.2+ -1.8mg (N=5) in NTN rats, 34.4+ -2.7mg (N=5) in NTN rats+ hr IL-2 rats and 21.3+ -2.3mg (N=5) in rats with only hr IL-2 administration. All these values were significantly more as compared with that of controls, 5.4+ -1.2mg (N=5), (p<0.05). Using a direct method in vivo, protein excretion was increased after administration of hr IL-2 (from 5-10g/m to 20-40g/m). These data suggested that hr IL-2 might be involved in proteinuria associated with reduction of anionic sites in glomeruho-nephritis.

抄録全体を表示

We examined a total of 102 patients with primary glomerular disease about the C3b receptor using immune adherence hemagglutination (IAHA) method, 2 out of 16 patients with minimal change nephrotic syndrome (MCNS) and 2 out of 13 patients with mesangio-capillary glomerulonephritis (MCGN) showed CR1 deficiency on the red blood cells. There was no difference in the prevalence of CR1 deficiency on red blood cells of normal control (1 out of 53, 1.9%) compared to the 102 patients with the primary glomerular disease. We also examined 23 patients with the secondary glomerular disease, 10 out of 17 with lupus nephritis and 1 out of 4 with Henoch Schönlein purpura nephritis (HSP) also showed CR1 deficiency on the red blood cells. Next we examined the CR1 deficiency in the relatives of the 4 patients with the primary glomerular disease and the patient with HSP nephritis, the deficiency or diminution of CR1 was found in 4 families but no deficiency was found in one case (case 1, MCNS). The defective erythrocyte CR1 reaction was persistent even after these patients had gone into remission without case 1. The reaction of CR1 on erythrocyte (case 1) changed parallel with clinical symptoms and laboratory data. These results imply that the defective erythrocyte reaction found in glomerulonephritis might be caused not only through inheritance but also acquirement. In frozen kidney sections, glomerular CR1 was examined, and then compared with the reaction of erythrocyte CR1 in patients. Among the patients whose erythrocyte were negative by IAHA, two patients with MCNS and one with lupus nephritis showed a high reaction of glomerular CRl and the other three patients (MCGN, lupus nephritis, HSP nephritis) showed a low reaction of glomerular CRl. The results indicate that the expression of CR1 on the glomerulus and the erythrocvte are not parallel

抄録全体を表示

It has been known that progressively thickening of glomerular basement membrane (GBM) with age is accompanied by altered function of GBM We studied age-related changes in biochemical components of human GBM. 29 human kidneys without renall disease were obtained from patients with 13-89 years old. The isolation procedure for glomeruli was based on the method of Spiro Purity of the glomerular preparation was checked by phase microscopy and GBM was isolated by sonicatione analyzed amino acid, carbohydrate components and glucosyl-galactosyl-hydroxylysine (GGH) in the GBM. Amino acid analysis indicated a progressively increase in proline, lysine, alanine and valine, and a decrease in 4-hydroxyproline, total hydroxyproline, hydroxylysine and isoleucine, in the GBM with age. There were no changes in other amino acid components.The ratio of hydroxylysine to lysine and the ratio of hydroxyproline to proline were both significantly decreased with age. In the carbohydrate contents of the GBM, mannose and galactosamine were significantly increased, while glucose was decreased with age. There were no changes in fucose, galactose, N-acetyl-neuraminic acid and glucosaminee The GGH showed a significant decrease with age, but the ratio of GGH to hydroxylysine showed no significant changes with age. It was suggested that there was a decrease of collagenous components and a decrease in hydroxylation of proline and lysine with age in GBM.

抄録全体を表示

To elucidate the molecular mechanism of the vascular action of atrial natriuretic factor (ANF), we investigated the effect of synthetic rat ANF (atriopeptin III) on intracellular cyclic guanosine-5' : 3'-monophosphate (cGMP) production in vascular smooth muscle cells (VSMC) in culture from rat mesenteric artery, and compared the effect of ANF on cGMP production with that of sodium nitroprusside (SNP) . ANF-stimulated cGMP production rapidly within 2 min, and the production was enhanced by phosphodiesterase inhibitor isobutylmethylxanthine (IBMX). Both ANF and SNP increased the level of intracellular cGMP in a dose dependent manner. The effects of ANF and SNP were additive to each other, and methylene blue inhibited the effect of SNP but not that of ANF. ANF-stimulated cGMP production was not affected by the depletion of extracellular calcium ion (Ca²⁺) or calcium antagonists (verapamil and nifedipine). Preincubation with kallikrein inhibited the stimulatory effect of ANF on cGMP production in a dose dependent manner but not that of SNP. The effect of kallikrein was abolished by serine protease inhibitors, aprotinin and gabexate mesilate (FOY). The cGMP production in response to ANF was greater in renal VSMC than mesenteric VSMC. These results in cultured VSMC suggest the followings: (I) ANF may stimulate cGMP production through the activation of guanylate cyclase, (III) extracellular Ca²⁺ does not affect cGMP production by ANF, (IV) the vascular effect of ANF may possibly be regulated by vascular kallikrein lacolly, and if cGMP is involved in the vascular action of ANF, (V) ANF may have specific vasodilatory effect in renal vascular bed.

抄録全体を表示

Membrane permeability of uremic peak "2a" detected by high performance liquid chromatography (HPLC), was examined. When plasma from uremic patients was ultrafiltrated by using membrane of cut-off molecular weight of 30, 000, uric acid (UA) and creatinine (Cr) passed easily through the membrane, showing permeability of approximately 100%m On the other hand, the permeability of 2a remained at approximately 60%. Difference of permeability of 2a from those of UA and Cr was statistically significant (p<0.01). However, permeability of 2a was increased either by addition of HCl to plasma lowering pH to 2, or by 20 times dilution of plasma by physiological salt solutions. Besides that, 2a in bile juice from uremic patients showed high permeability as well as UA and Cr, Those results strongly suggested that uremic peak "2a" was bounded to protein in plasma though rather weakly and excreted as a free form into bile, Possibility of protein binding of uremic toxins was discussed, The protein binding was presumed to be an important factor in further study on their uremic toxicity and kinetics in relation to clinical symptoms.

抄録全体を表示

To understand the relationships between the gastrointestinal complications and endocrinological abnormalities in patients on hemodialysis, we studied the gastrointestinal symptoms, upper gastrointestinal disorders, and serum hormone levels, including gastrin, motilin, c-parathyroid hormone (c-PTH) and calcitonin in 128 patients on hemodialysis. We were especially interested in any relationships between gastrointestinal bleeding and such abnormalities. 1) The mean serum levels of all four hormones assayed, gastrin, motilin, c-PTH and calcitonin, were significantly higher in patients on hemodialysis than in 10 normal controls. 2) The incidence of gastrointestinal symptoms was significantly higher in patients with severe secondary hyperparathyroidism. In patients with marked hypergastrinemia, the incidence was low. 3) In patients with marked hypergastrinemia, the incidence of occult gastrointestinal hemorrhage was significantly higher than in patients with low serum gastrin level, and that of gross gastrointestinal hemorrhage was lowest. Gross gastrointestinal hemorrhage was significantly more frequent in the patients with advanced secondary hyperparathyroidism. The incidences of occult gastrointestinal hemorrhage and that of gross gastrointestinal hemorrhage were not correlated with serum motilin or calcitonin levels. 4) Marked hypergastrinemia was associated with atrophic gastritis, giant fold and gastric polyps. Patients with erosive gastritis, gastric ulcer, or duodenal ulcer, all of which may cause gross gastrointestinal hemorrage, had low gastrin levels. Serum c-PTH was relatively high in patients with erosive gastritis, hemorrhagic gastritis, duodenal ulcer. We think that highly advahced secondary hyperparathyroidism in patients on hemodialysis with upper gastrointestinal complications is most important clinically of the various endocrinological abnormalities.

抄録全体を表示

In the present study, two protocols were used to assess possible role of renal kallikrein-kinin system and sodium balance in the development of hypertension in young spontaneously hypertensive rats (SHR). In the first protocol, daily excretion of urinary kallikrein and systolic blood pressure were measured in the 5-week-old SHRs on regular diet or on sodium loading with 1% NaCl solution for drinking water for up to 3 weeks. In the second protocol, chronic effect of aprotinin, a reversible inhibitor of kallikrein and other serine proteases, on the development of hypertension was studied in young SHRs on regular diet or on sodium loading with 1% NaCl. Subcutaneous injection of aprotinin (100, 000 units/kg/day) or vehicle as controls was continued every 12 hours for up to 2 weeks. Daily systolic blood pressure in the rats was monitored by an indirect tail cuff method. Kallikrein was determined by its kininogenase activity, and the generated kinins were radioimmunologically measured. Urinary kallikrein excretion and renal kallikrein content were significantly increased in SHRs on sodium loading compared to those in SHRs on regular diet. However, chronic sodium loading with 1% NaCl did not affect the progressive development of hypertension in young SHRs. Aprotinin did not affect the development of hypertension in young SHRs on regular diet or on sodium loading, although aprotinin decreased significantly urinary excretion of kallikrein and renal kallikrein content on both conditions.Therefore present results indicate that reduced renal kallikrein-kinin system may not be involved in the development of hypertension in young SHRs on regular diet and on sodium loading. Additionally, it is reconfirmed that sodium is not a main determinant of the progressive development of hypertension in young SHRs.

抄録全体を表示

In order to clarify the role of second messengers that is to say cyclic AMP and cyclic GMP on the pathogenesis of essential hypertension (EH), plasma concentrations of cyclic AMP, cyclic GMP, norepinephrine, epinephrine, and renin activity were measured in 30 normal subjects, 45 patients with EH and 7 patients with chronic renal failure (CRF) without hypertension. EH was divided into three groups of low, normal and high renin subgroups. There was no significant difference of plasma norepinephrine concentration (PNE) among normal subjects (N), EH and CRF, but PNE in low renin group (LREH) was slightly lower, and in high renin group was slightly higher than that in N. Plasma epinephrine concentration (PE) in EH was within the normal limit as well as that in CRF. Plasma cyclic AMP concentration (cAMP) in LREH was significantly lower than that in N (p<0.02, LREH; 12.3±3.3 pmol/ml, N : 21.0±8.9 pmol/ml), and that in CRF (44.6±34.2 pmol/ml) was higher than in N. Plasma cyclic GMP concentration (cGMP) of LREH was significantly lower than in N (p<0, 05, N : 5.0±2.7 pmol/ml, HREH: 3.5±1.9 pmol/ml), and cGMP in CRF (10.7±9.1 pmol/ml) was slightly higher than in N. There was a significant correlation between cAMP and cGMP in both N and in EH (N:r=0.68, p<0.001; EH:r=0.37, p<0.02).These results suggest that hypofunction of β-adrenergic receptor activity may exist in LREH, and that parasympathetic hypotonicity may participitate in the pathogenesis of HREH.

抄録全体を表示

It has been reported that salt loading induces blood pressure rise in partially nephrectomized rats. We examined the role of the sympathetic nerve activity in the pathogenesis of this type of hypertension. Male Wistar rats underwent partial nephrectomy (removing 70-80% renal mass). One % of saline was given as drinking water in the experimental animals and tap water was given in the control groups. Blood pressure rose 7 days after the operation and hypertension was maintained for 5 weeks (101.0±1.5 mmHg→174.6±5.1 mmHg). Plasma norepinephrine was increased in acute phase, 10 days after surgery (Experimental group; 0.54±0.09 ng/ml, control group; 0.18±0.02 ng/ml, p<0.01). But plasma norepinephrine was not significantly increased in chronic phase, 5 weeks after surgery (Experimental group; 0.29±0.06 ng/ml, control group; 0.23±0.05 ng/ml, n. s.). Plasma norepinephrine was significantly correlated with plasma sodium in acute phase (r=0, 79, p<0.001). It is suggested that blood pressure elevation induced by salt loading and partial nephrectomy was associated with increased sympathetic nerve activity in its acute phase.

抄録全体を表示

Fifteen patients with idiopathic membranous nephropathy were treated with gammaglobulin (sulfonated or polyethylene glycol treated human gamma-globulin) at a daily dose of 10g for 6 consecutive days. Two of them were treated twice with a one year interval. Follow up periods were 6 months in 3 patients and 12 months in 14 patients in all. After the initiation of the treatment, serum protein and albumin increased significantly, in an accompaniment with clinical improvement in 9 patients (53%) within 2 months and in 12 patients (71%) within 6 months. The OKT4/OKT8 ratio of peripheral blood, estimated serially in 14 patients using the flow cytometry, was initially 2.16±0.18, which was a significantly higher level than that of the controls (1.60±0.10, p<0.01), but decreased to 1.61±0.17 in one month and maintained around same level throughout the period of 6 month observation, showing the ultimate ratio of 1.60±0.15 at the 6th month (p<0.05), whereas it tended to rise one year later (1.77±0.27). These results indicate that the high-dose gamma-globulin administration causes reduction of OKT4/OKT8 ratio in membranous nephropathy and is useful for induction of early remission of the disease.

抄録全体を表示

Effects of long-term treatment with Dilazep on 314 patients with renal disease were studied. Based on the clinical features and renal biopsy findings, 216 patients were diagnosed as chronic glomerulonephritis (CGN), 81 as nephrotic syndrome (NS) and 17 as other renal diseases. All of them received Dilazep 300 mg a day and followed up every 3 months for 2 years. Results of obtained in this study were as follows1. Global improvement rates in patients with CGN and NS were 46.0% and 54.2%, respectively, and 49.1% in all patients.2. Blood pressure, pulse rate and urine volume did not show significant change during the treatment.3. Urine protein was significantly decreased in 3, 6, 12 and 18 months after the treatment. The improvement rates in patients with CGN and NS were 43.4% and 52.5%, respectively, 47.2% in all patients.4. Creatinine clearance was significantly increased in 3, 6, 12, 18 and 24 months after the treatment. The improvement rates in patients with CGN and NS were 29.9% and 33.8%, respectively, 30.7% in all patients.5. As possible adverse reactions, elevation of serum liver enzymes and fever were noted only transiently in 11 of 314 patients studied (3.37%).These results suggest that Dilazep reduces urine protein and improves renal function, indicating that Dilazep has a beneficial effect on CGN and NS.

抄録全体を表示

Hemolytic uremic syndrome (HUS) is a rare disease in adults, however, in childhood the syndrome is not rarely found and shows usually a benign outcome. Most cases of HUS in adults show a resistance for any therapeutic devices such as anticoagulants or antiplatelet therapy. Maintenance hemodialysis therapy is usually necessary because of the persistance of chronic renal failure. Recently some papers which demonstrated an efficacy of plasmapheresis (PP) therapy for the syndrome, were reported. We report a case of adult HUS treated with PP and antiplatelet therapy. A 37-year-old male patient was admitted for nausea, peripheral edema and oliguria. Seven days prior to the admission he complainted of teethache and headache and received a prescription of antiinflammatory drugs (SEDES®, NOUSHIN®) and an antibiotic (ACROMYCIN®) On admission hemolytic anemia and thrombocytopenia were pointed out in addition to acute renal failure. RBC counts, hemoglobin, hematocrit and platelet counts were 150×10⁴/cmm, 5.1 g/100 ml, 13.8% and 98, 000/cmm, respectively. Some RBCs showed a deformity such as burr cells and helmet cells. Serum LDH lever was 5535 IU/1, BUN, creatinine and potassium concentrations were 201, 21.1 mg/100ml and 7.1 mEq/l. A renal histology done on the 13th day after admission showed thrombi in some interlobular arteries and glomerular capillaries and some glomeruli showed ischemic changes. These findings were compatible with renal changes in HUS. PP therapy was carried out twice using 3, 000 ml of fresh frozen plasma besides blood transfusion and hemodialysis therapy. His renal function was gradually improved, and anemia and thrombocytopenia were also recovered. After a mandibular biopsy which disclosed ameloblastoma, a decrease of urine output, azotemia and anemia appeared again and peripheral platelet counts also decreased, A third PP therapy was carried out, which brought about a recovery of thrombocytopenia. But anemia and renal failure were not recovered and repeated hemodialysis therapy was continued. The recurrence of hemolytic uremic episode following a surgical manipulation to the mandibular ameloblastoma is to suggest that the tumor might have some relation to an etiology of the syndrome, because the syndrome occurred after teethache in the patient. We think PP therapy was effective for the syndrome by means of a removal of some humoral substances released from the tumor which might cccur hemolytic uremic episode.

抄録全体を表示

This paper deals with a case in 8 year-old girl with focal, segmental membranoproliferative glomerulonephritis (MPGN). She was admitted to this hospital with the history of a fever for two weeks because of acute tonsillitis. On admission, laboratory findings disclosed microhematuria, proteinuria, hypocomplementemia, and elevated levels of BUN, serum creatinine and circulating immune complex (CIC). With an antibiotic and conservative therapy, she was recovered from acute renal failure and serum levels of CIC and C3 returned to normal. The first renal biopsy was performed 25 days after the admission, and analysis with light microscopy showed focal, segmental MPGN. Electron microscopy revealed circumferential mesangial interposition and massive subendothelial deposits typical of Type 1 MPGN, and immunofluorescence microscopy showed granular deposits of IgG and C3 along the capillary walls. Thereafter, microhematuria and proteinuria was found to decrease slowly without aggressive treatment for focal, segmental MPGN, and 12 months after the onset of the disease urinalysis revealed negative. A further renal biopsy was performed 17 months after the onset of the disease, and light microscopy revealed mild mesangial proliferative glomerulonephritis. Electron microscopy showed no evidences of MPGN, and immunofluorescence microscopy showed only segmental deposits of C3 along the capillary walls in the weak intensity. On the basis of these observations it was felt that this patient could possively constitute IC induced glomerulonephritis related with bacterial infection.

抄録全体を表示

The case is a 57-years-old man, who was examined with chief complaints of anorexia and lumbago and hospitalized for renal failure of unknown origin together with azotemia and hyperkalemia. Bence-Jones protein λ type confirmed in both the blood and the urine suspected amybid kidney or myeloma kidney. Light and electron microscopic findings of renal biopsy showed tubular degeneration, intratubuloluminal protein cast, syncytium cell and no amyloid deposition. Additional bone marrow aspiration confirmed abundant atypical plasma cells. Thus, the case was diagnosed as Bence-Jones 2 type myeloma kidney. In addition to chemotherapy after several treatments of hemodialysis and plasma exchange, dimethyl sulfoxide was given p. o. and i. v. in hopes of improving renal function via elution of the Bence-Jones protein from the tubular lumen. As a result, decreases in Bence-Jones protein in both the blood and the urine, apparent improvement of renal function and of general conditions were obtained. Since then the patient has been doing well without hemodialysis.

抄録全体を表示