The present study was designed to clarify the effects of TJ-8117 on apoptosis in the glomeruli of 5/6 nephrectomized rats. TJ-8117 (400 mg/kg/day), captopril (50 mg/kg/day) and nicardipine (50 mg/kg/day) were administered as drinking water from the 56th day after renal ablation, and continued throughout the experiment. All rats were sacrificed at 13 weeks and renal tissues were removed to quantify histopathological and apoptotic parameters in glomeruli. TJ-8117 inhibited proteinuria, matrix index and decrease in the number of total cells in glomeruli of nephrectomized rats. In addition, the increase in apoptotic body and DNA fragmentation was significantly inhibited in the TJ-8117-treated group. Captopril and nicardipine failed to inhibit both parameters. In 400 mg/kg of the TJ-8117 treated group, the number of Bcl-2 positive cells in the glomeruli was elevated compared with the 5/6 nephrectomized control group. In addition, the number of Bax positive cells in the TJ-8117 group was significantly suppressed in a dosedependent manner. These results suggest that TJ-8117 may inhibit apoptosis in the late stage of this model by suppressing matrix accumulation and progression of glomerulosclerosis. The apoptosis-preventing effect may be mediated by decreased expression of Bax in the glomerular cells.

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Renal lesions of rats induced by antibodies to cultured rat glomerular epithelial cells (GEC) and mesangial cells (GMC) were studied. Antibodies to cultured rat GEC and GMC were produced by immunization of rabbits with GEC and GMC respectively. The rats injected with anti GEC antibody showed a small amount of urinary protein, glomerular deposition of rabbit IgG and subepithelial dense deposits observed by electron microscopy. Proteinuria was suppressed in the rats in which complement was depleted with cobra venom factor. Western blot analysis demonstrated a band of 200 KD in GEC lysates reacted with anti-GEC antibody. The rats injected with anti-GMC antibody showed little urinary protein, glomerular deposition of rabbit IgG and mesangial dense deposits. Western blot analysis demonstrated two bands of 43 and 14 KD in GMC lysates reacted with anti-GMC antibody. These data showed that the injection of anti GEC antibody or anti-GMC antibody induced similar lesions to passive Heymann nephritis and anti Thy 1.1 nephritis. This study suggested that antigenicity of structural glomerular cells is important as the antigens of glomerulonephritis.

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The relationship between blood pressure (BP) and nitric oxide (NO) in two-kidney, one-clip renovascular hypertensive rats (2K1C) was investigated . Although urinary NO₂^- + NO₃^- (NOx) excretion (U_NOXV) increased 2 weeks after surgery(2W-2K1C), U_NOXV decreased 4 weeks after surgery (4W-2K1C) compared with that of the control. UNOXV levels were restored 2 weeks after unclipping (U2K1C). BP and U_NOXV did not change in 2K1C after treatment with L-arginine (Arg-2K1C). Aorta from 4W-2K1C and Arg -2K1C showed significantly decreased relaxation responses to acetylcholine (Ach), but Ach-induced relaxation of aorta in U2K1C returned to control-level responses. De-endothelialized aorta from 4W-2K1C, Arg-2K1C, and U2K1C had significantly decreased relaxation responses to lipopolysaccharide. These data suggest that : (1) transient increase of NO synthesis is accompanied by elevation of BP, but long-term elevation of BP decreases NO synthesis in endothelium and smooth muscle cells ; (2) L-arginine supplement has no effect on the development of hypertension and on NO production by endothelium and smooth muscle cells in 2K1C.

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We investigated the hemodynamic, renal, and hormonal effects of cyclosporin A (CyA) treatment (6 mg/kg per day) for 4 weeks in 12 patients with nephrotic syndrome (8 women ; 4 men, aged 36-66 years, 3 cases of focal glomerular sclerosis ; 9 cases of membranous nephropathy). To evaluate the effects of CyA on the diurnal variation of blood pressure (BP), 24-h non-invasive BP monitoring was performed using model ABPM-630 (Nihon Colin, Tokyo, Japan) before and during CyA treatment. As indices of hemodynamics, intra-arterial pressure was monitored and cardiac output was measured by the dyedilution technique using a cuvette at 0 and 4 weeks after treatment. CyA ameliorated urinary protein excretion and hypoproteinemia from 3.5±0.9 to 2.2±0.7 g/day, and serum protein concentration from 4.9±0.2 to 5.5±0.2 g/d/ after 4 weeks'treatment. Endogenous creatinine clearance, 24-h urinary sodium excretion, and plasma renin activity decreased significantly at 1 week. CyA treatment raised casual BP from 122±4/75±2 to 140±5/87±3 mmHg after 1 week and to 146±4/90±2 mmHg after 4 weeks. Before treatment 24-h ambulatory BP monitoring showed BP reduction at night (116±5/68±3 mmHg) compared to the daytime (124±5/75±2 mmHg). The diurnal variation of BP disappeared during CyA treatment ; mean daytime and nighttime pressures were 135±4/81±2, 132±5/80±3 mmHg at 1 week and 139±5/83±3, 131±6/80±3 mmHg at 4 weeks, respectively. On hemodynamic study, a 4-week treatment with CyA increased mean arterial pressure from 91±3 to 104±3mmHg, total peripheral resistance index from 2.1±0.1 to 2.5±0.1×10³ dyne ⋅ sec ⋅ cm^-5 ⋅ m², and unchanged heart rate and cardiac index. Serum Mg concentration decreased from 2.1±0.1 to 1.7±0.1 mg/dl. These results suggest that CyA-induced hypertension is characterized by the loss of nocturnal decline in blood pressure, which is accompanied by volume retention after 1 week and systemic vasoconstriction after 4 weeks.

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Long-term CAPD may develop peritoneal fibrosis, which is thought to be related to permanent loss of ultrafiltration capacity and sclerosing peritonitis. In CAPD patients, we examined the serum (P-) and effluent (D-) levels of type III procollagen N-peptide (P III P) and hyaluronate (HA), which are expected to change concomitantly with a local increase in submesothelial extracellular matrix of the peritoneum. We selected 40 CAPD patients (age : 46.3±11.3 years, time on CAPD : 33.6±26.2 months), who were not suffering from chronic liver disease, any inflammatory disease, nor peritonitis during the previous month. P-P III P, P-HA, D-P III P, and D-HA were measured by PET (values after 4-hour dwelling). D/P ratios (P III P 0.330±0.137, HA 5.68±6.44) suggested that their source was from the peritoneum. Although neither P-P III P nor log P-HA value had a significant correlation with age nor time on CAPD, both had significantly positive correlations (p=0.0009, 0.0005, respectively) with time on total dialysis (including hemodialysis). D-P III P did not have a significant correlation with age nor time on total dialysis but had a significantly positive correlation (p=0.0098) with D/P-creatinine. Although log D-HA had significantly positive correlations with time on CAPD and time on total dialysis (p=0.0007, 0.0051, respectively), time on CAPD was first entered (F=16.5) and time on total dialysis was removed (F to enter ; 4) by stepwise regression analysis. In conclusion, a local increase in extracellular matrix of the peritoneum in CAPD patients, indicated by increases in P III P and HA in the effluent, may be related to higher peritoneal permeability and a longer duration of PD.

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We reported a 27-year-old man who developed nephrotic syndrome 12 months after a bone marrowtransplantation from his HLA-identical sister for chronic myelocytic leukemia. Anti-nuclear antibodies had been serially investigated after the bone marrow transplantation. They were detected in his serum 5 months before the appearance of proteinuria, but he tested negative at the onset of nephrotic syndrome. Histological analysis of the renal biopsy revealed subepithelial and subendothelial immune deposits in the glomerular basement membrane with increased mesangial matrix and cells. These findings suggested immune complex glomerulonephritis due to chronic graft-versus-host disease (GVHD) after bone marrow transplantation. In murine experimental chronic GVHD, antinuclear antibodies, which generate immune complexes that deposit or form in the kidney have been detected.

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A 47-year-old woman was admitted on because of edema of the lower extremities.She had been suffering from RA for about 20 years and underwent total kneereplacements 5 years previously. On admission, nephrotic syndrome and rapidly progressive glomerulonephritis had developed in association with ileus, melena, diarrhea, dyspnea and hemoptysis. She showed a high titer of serum rheumatoid factor (357.0IU/ml) and amyloid A protein (83.9μg/ml) with positive antinuclear antibodies (homogeneous and speckled patterns). However, anti -neutrophil cytoplasmic autoantibody (ELISA), immune complexes and anti -glomerular basement membrane antibody (ELISA) were negative. Renal biopsy showed microscopic PN overlapping A-type positive amyloidosis. Although the maintenance of hemodialysis was necessary, aggressive immunosuppressive therapy with steroid pulse therapy and frequent plasma exchange provided a rapid improvement of systemic symptoms possibly due to vasculitis. We suggested that in this case, massive necrotizing crescentic glomerulonephritis with systemic arteritis developed on the basis of secondary amyloidosis due to rheumatoid arthritis. In such a case, even if various serum autoantibodies and immune complexes were negative, plasma exchange was suggested to be effective to remove not only pathogenic autoantibodies but also various serum inflammatory cytokines which may be related with severe vasculitis and glomerulitis, in addition to aggressive steroid therapy which may suppress the invasion of inflammatory cells producing these cytokines.

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A 45-years-old woman with rheumatoid arthritis(RA)who developed nephrotic syndrome and aucute renal failure was reported. She first noticed polyarthritis in and was diagnosed as RA. Since her RA was not controlled with nonsteroidal anti-inflammatory drugs (NSAID). she started taking prednisolone 10 mg daily and received 100 mg of D-penicillamine from October 1990 with improvement of the RA. In March 1991, she noticed edema of the face and legs, at which time massive proteinuria and hematuria were first noted. Because of her nephrosis, she was referred to our hospital for further evaluation. Laboratory investigations revealed 24-hour urine proteinuria of 37 g, serum creatinine, 2.7 mg/dl, blood urea nitrogen, 43.5 mg/dl, total protein, 4.1 g/dl, albumin, 1.5 mg/d/, and total cholesterol, 600 mg/dl. The rheumatoid factor and anti-nuclear antibody were positive. Renal biopsy showed focal segmental glomerulosclerosis (FSGS). Her nephrotic syndrome and renal dysfunction recovered after the administration of prednisolone at 60 mg/day. The possible pathogenesis of FSGS in patients with RA was discussed.

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A 25-year-old woman complained of anasarca and was admitted to on the presumptive diagnosis of nephrotic syndrome with 10.7 g of 24 hour urinary protein. At first, lupus nephritis with antiphospholipid antibody syndrome was suspected because of prolongation of APTT, existence of lupus anticoagulant and elevation of serum anticardiolipin antibody titer (IgM) in addition to positive ANA, lymphocytopenia and the biologically false positive test for syphilis (BFPTS) . On day 28 of hospitalization, renal biopsy findings revealed severe endocapillary cell damage, such as swelling and proliferation of endothelial cells, fragmentation and double contour of the basement membrane walls, which were located only in the capillary lumens with a few thrombi. Immunofluoresent micrography revealed the absence of specific immunoglobulin or complement deposit. Therefore, the diagnosis of lupus nephritis was negated as these findings were suggestive of characteristic glomerulopathy due to primary antiphospholipid antibody syndrome. She was treated initially with oral prednisolone 60 mg and intravenous infusion of heparin 20, 000 units daily. Moreover, cyclophosphamide 750 mg was administered intravanously as pulse therapy on day 13 as her serum level of CH₅₀ had fallen suddenly, and hemodialysis was necessary because her renal function had deteriorated and she was suffering from cough and orthopnea with overhydratin. After the combined therapy, BFPTS disappeared and APTT returned to the normal range ; dialysis treatment was not required further after the 4th hemodialysis. Thereafter, renal function improved and complete remission of nephrotic syndrome was obtained. This patient was a case of primary antiphospholipid antibody syndrome in which endothelial cell damage was located exclusively in the capillary lumens and pulse cyclophosphamide therapy in addition to prednisolone and anticoagulant was effective. We present this instructive case to promote understanding of the pathogenesis of primary antiphospholipid antibody syndrome.

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In 1993, Vanherweghem and his associates reported cases of rapidly progressive renal interstitial fibrosis in young women who were administered a slimming regimen including Chinese herbs. Subsequently, similar cases have been reported. In Japan, especially in the Kansai area, several cases of Chinese herbs nephropathy have already been reported. We experienced a patient suffering from Chinese herbs nephropathy(CHN), and further detected aristolochic acids from the Chinese herbs taken by the patient. Aristolochic acids are known to be causative agents of CHN. The danger of CHN should be noted as soon as possible and drugs containing aristolochic acids should be prohibited.

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Background: We investigated the relationships between bone mineral density (BMD) and bone metabolic markers in 41 Japanese women (age range, 23 to 85 years; mean, 61; SD, 16) undergoing hemodialysis, and the relationship between BMD and daily physical activity with nutritional state in those patients.Method: The patients were divided into a group with hyperparathyroidism (intact parathyroid hormone [PTH] <300 pg/mL, n = 9) and a group without hyperparathyroidism (intact PTH < 300 pg/mL, n = 32). Total BMD and spinal BMD (regional evaluation) were measured using dual-energy X-ray absorptiometry. We determined serum concentrations of intact PTH, osteocalcin (bone Gla protein) and alkaline phosphatase as markers of bone formation, and serum tartrate-resistant acid phosphatase (TRAP) as a marker of bone resorption. Mean energy expenditure per day was measured by calorie counters worn by the patients, and serum levels of total protein, albumin, cholesterol, ferritin, and blood urea nitrogen were measured as indices of nutritional status.Results: In the group without hyperparathyroidism, 9 patients had a spinal BMD < 0.85 g/cm2 and were considered to be at risk for bone fracture. In this group, a significant correlation was observed between total BMD and TRAP (r = -0 .52, p = 0.004). Age, duration of hemodialysis, dry body weight, energy expenditure per day, and serum total protein levels were correlated with total BMD and spinal BMD, using multiple regression analysis (p< 0.0001).Conclusions: In patients with low BMD, the bone turnover tended toward bone resorption rather than formation, without strong influence by parathyroid function. Energy expenditure showed a strong relationship to the total BMD (r = 0.32, F =18.5), which appeared to improve bone turnover.

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