PubMed Health⌕ Search

Biomedical subjects

Osamu Hotta

Publications and source records attributed to Osamu Hotta.

At least 19 recordsLinked to original sources
PubMed2007

Significance of glomerular cell apoptosis in the resolution of acute post-streptococcal glomerulonephritis.

BACKGROUND: Glomerular hypercellularity due to resident glomerular cell proliferation and leucocyte infiltration has been described in acute post-streptococcal glomerulonephritis (APSGN). APSGN usually resolves without progression. However, the mechanism of resolution remains to be determined. METHODS: Renal biopsy tissues from 15 patients with APSGN (obtained 1-31 days after disease onset) and five control patients with minor glomerular abnormality were evaluated with respect to glomerular resolution. Apoptotic cells were assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL) as well as by immunostaining of single-stranded DNA (ssDNA). RESULTS: The number of glomerular cells was high in the early-phase of APSGN and decreased over time. No TUNEL+ glomerular cells were found in control subjects, whereas prominent glomerular TUNEL+ cells were observed in APSGN patients, particularly in the early phase of the disease. The number of glomerular TUNEL+ cells decreased exponentially but was still prominent in renal tissue biopsied at 31 days after disease onset. Double staining for ssDNA and glomerular cell markers showed that glomerular apoptotic cells were predominantly mesangium and endothelial cells, with some neutrophils and macrophages. CONCLUSIONS: These results suggest that apoptosis exists in the glomerulus in patients with APSGN from the early to the late stages of the disease and contributes to the resolution of glomerular hypercellularity.

Acute Disease↗
PubMed2006

Deoxyspergualin, an immunosuppressant, in patients suffering from nephropathies with crescent formation: an open-label trial to evaluate safety and efficacy.

BACKGROUND: Crescent formation in glomeruli means an acute active lesion that develops a rapidly progressive course. Therapies using pulse methylprednisolone, oral corticosteroids, and cyclophosphamide are recommended, but no agreement has been reached on the optimal therapy. There have been no controlled trials, because of the severity of this condition and because withholding treatment would become an ethical issue. METHODS: We evaluated the safety and efficacy of deoxyspergualin (DSG), an immunosuppressant, in a multicenter, prospective trial of 44 patients with crescent formation in over 10% of glomeruli, who were randomly placed into groups that received daily doses of 0.1 mg/kg (n = 21) and 0.2 mg/kg (n = 23) of DSG, given by a 1-h infusion for 4 weeks, and who were then monitored for 3 months. All patients received DSG in this open-label prospective study. We evaluated the levels of urinary protein and hematuria, and examined renal function after the DSG treatment. RESULTS: Urinary protein significantly decreased with each dose after starting the DSG administration and this efficacy was sustained for 2 months after the discontinuation of DSG. In the groups receiving 0.1 mg/kg and 0.2 mg/kg, mean urinary protein levels were 2.1 g/day and 2.3 g/day at the initiation of the DSG administration, 1.4 g/day and 1.6 g/day at week 4, and 1.5 g/day and 1.3 g/day at week 12, respectively. Hematuria was markedly improved by a dose of 0.2 mg/kg and was not exacerbated following the termination of DSG. Exacerbation of renal dysfunction, as measured by creatinine clearance, serum creatinine, and blood urea nitrogen was prevented by both doses of DSG. The most common adverse reaction was reversible neutropenia. CONCLUSIONS: Short-term treatment with DSG may be effective and tolerated in patients suffering from nephropathies with crescent formation.

Creatinine↗
PubMed2006

Improvements in treatment strategies for patients with antineutrophil cytoplasmic antibody-associated rapidly progressive glomerulonephritis.

The course of rapidly progressive glomerulonephritis (RPGN) caused by antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is often life-threatening, especially in the elderly when pulmonary involvement and/or severely impaired renal function are present. Corticosteroids and cyclophosphamide are the first-line treatment, but ironically infection, not vascular events such as hemorrhage, caused by the vasculitis itself, is the most common cause of death of RPGN patients. Several new treatment strategies, such as leukocytapheresis (LCAP) and intravenous immunoglobulin (IVIg), have become available during the past decade and these treatments have made it possible to treat high-risk RPGN patients without inducing serious immunosuppressive states. In the present paper we review recent clinical trials of LCAP and IVIg therapy in patients with pauci-immune/ANCA-associated RPGN, and show improved clinical outcomes after using these new treatment strategies in our institution.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed2004

Use of corticosteroids, other immunosuppressive therapies, and tonsillectomy in the treatment of IgA nephropathy.

Because IgA nephropathy (IgAN) was originally regarded as a benign condition, the indication of corticosteroids or other immunosuppressive therapies have been highly restricted because of potential side effects, and such drugs have been used for a specific subgroup of patients with IgAN, taking the risk/benefit ratio into consideration. During the last decade, however, with the recognition that the overall long-term prognosis of IgAN is a nonbenign condition, more aggressive treatments, including high-dose corticosteroids, various immunosuppressive agents, and tonsillectomy, have been used for wider subgroups of patients with IgAN. Moreover, recent studies have suggested that clinical remission as well as histopathologic regression of the nephropathy could be obtained by such treatments if treatment is initiated in its relatively early stage. Thus, the possibility has now been raised that the goal of treatment for patients with IgAN will shift from "slowing the progression of nephropathy" to "remission of nephropathy."

Adrenal Cortex Hormones↗
PubMed2004

Tonsillectomy combined with steroid pulse therapy: a curative therapy for IgA nephropathy.

As IgA nephropathy (IgAN) was originally regarded as a benign condition, the indication of corticosteroids has been highly restricted because of their side effects, and has been used for a specific subgroup of IgAN patients with consideration of the risk/benefit ratio. During the last decade, however, with the recognition that the overall long-term prognosis of IgAN is a non-benign condition, more aggressive treatments, including high dose corticosteroids and tonsillectomy, have been used for a wider subgroup of patients with IgAN. Since 1988, we have treated IgAN patients with steroid semi-pulse therapy combined with tonsillectomy. Over 500 patients with IgAN have been treated with this treatment protocol, and a high percentage of patients enter clinical remission, i.e. free from urinary abnormalities if the combination therapy was initiated in its early stage. Through these experiences we think the goal of treatment of IgAN patients should be changed from "slowing the progression of nephropathy" to "clinical remission".

Glomerulonephritis, IGA↗
PubMed2004

Clinical observation of palatine tonsils with IgA nephropathy.

We have previously reported that clinical remission could be achieved by combination therapy consisting of steroid pulse therapy and tonsillectomy in patients with IgA nephropathy. However, there is no consensus as to the indications for tonsillectomy in IgA nephropathy (IgAN) patients. To clarify whether there is any correlation between characteristics of removed palatine tonsils and clinical remission rate, we evaluated the relationships between the remission rate of urinary abnormalities and characteristics of 186 IgAN patients (aged 11-65 years) with mild or moderate renal pathology and their tonsils. Remission of proteinuria was observed in 134 patients (72%) and remission of hematuria was observed in 111 patients (60%). There was no significant difference in remission rate of either proteinuria or hematuria in terms of the past history of recurrent tonsillitis, episodes of synpharyngitic gross hematuria, pus plugs in the tonsillar lacunae, size of tonsils, age and the results of tonsillar provocation tests. Our findings suggest that it is very difficult to predict the efficacy of tonsillectomy and steroid pulse therapy based on the gross appearance of tonsils, the tonsillar provocation test or clinical episodes of tonsillitis. Moreover, contraindication of tonsillectomy for aged IgAN patients is not always justified.

Adolescent↗
PubMed2004

Role of mast cells in the development of renal fibrosis: use of mast cell-deficient rats.

BACKGROUND: Recent clinical studies have shown that the number of interstitial mast cells increases in various types of renal disease and correlates well with the magnitude of interstitial fibrosis. The present study was conducted to assess the role of mast cells in renal fibrosis by examining an experimental glomerular disease. METHODS: A rat model of chronic glomerular disease, puromycin aminonucleoside-nephrosis, was induced in mast cell-deficient (Ws/Ws) and normal (+/+) rats. RESULTS: The area of interstitial fibrosis was widely distributed at 6 weeks in both groups of rats; however, unexpectedly, the area of interstitial fibrosis was greater in Ws/Ws rats than in +/+ littermates. Biochemical analysis of the hydroxyproline content confirmed the more severe fibrosis in the Ws/Ws rats. The number of mast cells increased in both Ws/Ws and +/+ rats, concomitant with the development of interstitial fibrosis, but was confirmed to be lower in Ws/Ws than in +/+ rats. There were no differences in the numbers of interstitial macrophages and T lymphocytes between the two groups. Reverse transcription-polymerase chain reaction analysis of cytokine expression revealed that the level of mRNA for transforming growth factor-beta (TGF-beta), a potent profibrotic cytokine, was higher in Ws/Ws rats. In addition, heparin, one of the major components of mast cells, inhibited the expression of TGF-beta mRNA in rat fibroblasts in culture. CONCLUSION: These results suggest that mast cells do not play a major role in the pathogenesis of interstitial fibrosis in puromycin aminonucleoside nephrosis. Rather, they might be protective or ameliorative in this model through the inhibition of TGF-beta production by heparin, and possibly in other models and also in humans.

Animals↗
PubMed2004

Predictive value of urinary micro-cholesterol (mCHO) levels in patients with progressive glomerular disease.

BACKGROUND: Trace amounts of lipids are present in the urine of patients with glomerular disease, raising the possibility that the excess lipids reabsorbed by tubule cells may be toxic to these cells. In the present study, we assessed the prognostic value of micro-cholesterol (mCHO) levels in patients with chronic glomerular disease. METHODS: The urinary mCHO levels of healthy subjects and patients with chronic kidney disease were measured by the enzymatic cholesterol cycling (ECC) method with a minimum detection level of 0.10 x 10(-3) mmol/L. First, the urinary mCHO levels of healthy subjects and 320 patients with various glomerular diseases with proteinuria >1000 mg/gCr were measured. Second, correlations of urinary mCHO levels with those of various other molecules, including albumin, IgG, IgM, transferrin, phospholipid, alpha1-microglobulin (alpha1MG), Apo A1, Apo A2, and Apo B, and urinary fatty body counts, were determined. Third, urinary mCHO, total protein (TP), albumin, and N-acetyl-beta-D-glucosaminidase (NAG) levels were measured longitudinally over 12 months (20.5 +/- 5.8 months) in 68 nondiabetic patients with impaired renal function [serum creatinine (Cr) > or = 1.5 mg/dL]. Correlations of the concentrations of urinary parameters in the initial 3-month period with the slopes of the reciprocal of creatinine versus time for the entire follow-up period were assessed by the ROC method and multiple regression analysis. RESULTS: Urinary mCHO levels of the healthy subjects were 0.06 to 0.72 mg/gCr for males and 0.16 to 2.34 mg/gCr for females. Urinary mCHO levels in subjects with minimal change nephrotic syndrome were significantly lower than those in the patients with other glomerular diseases with massive proteinuria. Urinary mCHO levels correlated significantly with Apo A1 and Apo A2 levels, but not with urinary Apo B levels, in the latter subjects. The correlation coefficient of urinary fatty body counts (a marker of lipoprotein loading tubulopathy) with mCHO was higher than those with TP, albumin, IgG, IgM, and alpha1MG. The urinary mCHO elevation was significantly greater in patients who had a nonselective index of proteinuria than in those with a highly or moderately selective index. In nondiabetic patients with impaired renal function, the urinary mCHO level had a higher predictive value for rapid decline of renal function than TP, albumin, or NAG. CONCLUSION: The urinary cholesterol level corresponds to the magnitude of urinary HDL excretion, and correlates with the degree of lipoprotein loading tubulopathy. Measurement of urinary mCHO by the ECC method is a simple and useful tool for predicting progression of chronic glomerular disease.

Acetylglucosaminidase↗
PubMed2003

Analysis of an expanded width of albumin fraction by cellulose acetate membrane electrophoresis in IgA nephropathy urine before treatment.

Cellulose acetate membrane electrophoresis with colloidal silver stain re-vealed that the width of the albumin fraction in IgA nephropathy (IgAN) urine before treatment was significantly expanded. This phenomenon was not shown in IgAN urine after treatment or in non-IgAN urine. There was a reverse correlation between the width of the albumin fraction and the albumin con-centration in IgAN urine. By immuno-fixation, Tamm-Horsfall protein (THP) was located in the same position as the albumin band in IgAN urine before treatment; however, in the urine of a healthy subject it was located in the same position as alpha(1)-globulin. By ELISA, the THP-albumin complex concentration in IgAN urine before treatment was significantly higher than in the other two diseases. The width of the albumin fraction and the sodium ion concentra-tion of the urine were significantly correlated. The THP/albumin ratio in IgAN urine before treatment was significantly higher than in the other two groups. This suggests that the characteristic expanded width of albumin found by immunofixation indicates a THP-albumin complex, and that the sodium concentration of urine is involved in the formation of this complex.

Albuminuria↗
PubMed2003

Cellulose acetate membrane electrophoresis in the analysis of urinary proteins in patients with tubulointerstitial nephritis.

Urinary proteins from 14 patients with tubulointerstitial nephritis were analyzed by cellulose acetate membrane electrophoresis. Urinary total protein concentrations were measured, and urinary 15 proteins (prealbumin, albumin, alpha(1)-microglobulin, alpha(1)-antitrypsin, alpha(2)-macroglobulin, haptoglobin, retinol binding protein, transferrin, beta(2)-microglobulin, IgA, IgG, kappa- and lambda-light chains, cystatin C, and lysozyme) were identified by the use of a rapid and highly sensitive colloidal silver staining reagent suited for use with cellulose acetate membranes, as reported previously by Matsuda et al. (J Clin Lab Anal 15:171-174, 2001; Clin Chem47:763-766, 2001) and Hiratsuka et al. (J Clin Lab Anal 10:403-406, 1996). We also analyzed urinary total protein concentration and urinary protein fractions according to the presence of acute or nonacute interstitial nephritis. In addition, the relationship between urinary protein fraction and complications of interstitial nephritis was analyzed. The goal of this work was to find a useful index for the diagnosis of tubulointerstitial nephritis.

Acute Disease↗
PubMed2003

Resolution of typical lipoprotein glomerulopathy by intensive lipid-lowering therapy.

Lipoprotein glomerulopathy (LPG), characterized by glomerular lipoprotein thrombi, presumably composed of abnormal apolipoprotein E (apoE), leads to a progressive decline in renal function and eventually results in end-stage renal failure. A successful treatment for LPG has not yet been established. The authors treated a 36-year-old woman with LPG and exhibiting a nephrotic syndrome using an intensive lipid-lowering therapy consisting of fenofibrate (300 mg), niceritrol (750 mg), ethyl-icosapentate (1,800 mg), and probucol (500 mg). After the start of treatment, a remarkable decrease in urinary protein excretion and improvement in the hyperlipidemia were obtained; proteinuria was no longer detected 11 months after the initiation of treatment. A second biopsy performed 11 months after the initiation of treatment showed the complete disappearance of the lipoprotein thrombi that had been observed in a diffuse and global manner in the first renal biopsy. These findings suggest that typical LPG could be regressed if the abnormal lipoproteinemia is controlled sufficiently.

Adult↗
PubMed2003

15-Deoxyspergualin in patients with refractory ANCA-associated systemic vasculitis: a six-month open-label trial to evaluate safety and efficacy.

The combination of cyclophosphamide (CYC) and oral corticosteroids is effective in the majority of patients with antineutrophil cytoplasmic antibody-associated vasculitis (AASV), but it carries substantial risk of drug-related morbidity and mortality. New regimens are desired, especially in refractory cases. The immunosuppressant 15-deoxyspergualin (DSG) is effective in experimental autoimmune disease and transplantation as well as in acute kidney transplant rejection in humans. To assess the efficacy and safety of DSG, an open label multicenter trial was conducted in patients with AASV who were either unresponsive or had contraindications for standard immunosuppressants. Included were 19 cases of Wegener granulomatosis and one case of microscopic polyangiitis. Nine of them had received CYC shortly before study entry without apparent therapeutic success. DSG (0.5 mg/kg per d) was given for 2 to 3 wk until the WBC count dropped to 3000/ micro l followed by a rest until at least a WBC of 4000/ micro l was reached again. This was repeated up to six cycles. During the study, no other immunosuppressants besides steroids were allowed. Disease improvement during treatment with DSG was achieved in 70% of cases (six cases of complete remission; eight cases of partial remission). Leucopenia occurred in each patient in a regular pattern during the cycles and was transient without exception. No mortality or septicemia was observed. Mild to moderate infections mainly in the respiratory tract were observed but resolved under adequate treatment without sequel. It is concluded that treatment with DSG is successful in patients with refractory Wegener granulomatosis under careful monitoring of WBC count.

Adult↗
PubMed2003

Cohort study of advanced IgA nephropathy: efficacy and limitations of corticosteroids with tonsillectomy.

BACKGROUND: Elevated serum creatinine is associated with poor outcome in IgA nephropathy (IgAN). The efficacy and limitations of corticosteroids in advanced IgAN (Cr >or=1.5 mg/dl), however, remains controversial. METHODS: We retrospectively investigated 70 patients with advanced IgAN (Cr >or=1.5 mg/dl) classified into three groups according to their treatment regimens, that is, steroid pulse with tonsillectomy, conventional steroid, and supportive therapy. We evaluated the three groups to elucidate predictors for the endpoints ESRF and doubled serum creatinine from baseline. RESULTS: Steroid pulse with tonsillectomy, conventional steroid and supportive therapy were performed in 30, 25 and 15 patients, respectively. During the mean follow-up period of 70.3 (12-137) months, 41.4% of patients reached ESRF (13.3 vs. 56.0 vs. 73.3%, p < 0.001) and 45.7% doubled serum creatinine from baseline (16.7 vs. 64.0 vs. 73.3%, p < 0.001). The incidence of ESRF in the patients treated by steroid pulse with tonsillectomy was significantly lower than the incidences in the patients treated by conventional steroid and supportive therapy at a baseline creatinine level of 1.5-2 mg/dl, but no statistical difference was observed at a level of >2 mg/dl. The Kaplan-Meier estimated probability of renal survival without ESRF was 89.2, 74.1 and 72.2% at 5 years and 82.8, 51.0 and 45.1% at 8 years, respectively (p = 0.017). The predictors for ESRF, identified in a Cox proportional hazards model, were baseline serum creatinine (p < 0.001) and interstitial infiltrate (p = 0.003). Steroid pulse with tonsillectomy also had a protective effect on the risk of reaching ESRF (p = 0.013). By target cross-stratification, the patients with baseline creatinine of 1.5-2 mg/dl who underwent steroid pulse with tonsillectomy showed a better renal survival rate than the others (p < 0.001). CONCLUSION: Steroid pulse therapy combined with tonsillectomy may be more effective than conventional steroid therapy in patients with a baseline creatinine level of <or=2 mg/dl.

Adrenal Cortex Hormones↗
PubMed2002

Glomerulo-tubular junction stenosis as a factor contributing to glomerular obsolescence in IgA nephropathy.

Periglomerular fibrosis (PF) is an interstitial injury observed in various renal diseases. It is speculated that this lesion, by occluding the glomerulo-tubular junction (GTJ) and causing atubular glomeruli, may result functionally in a reduction of the glomerular filtration rate (GFR) and may be a factor contributing to the progression of renal disease. In the present study, 340 renal biopsy specimens were analysed to determine whether or not there was nephron injury derived from such a mechanism, as well as direct glomerular injury, in IgA nephropathy (IgAN). The patients were divided into five groups according to the degree of glomerular sclerosis. The average age was lower in groups with milder sclerosis and serum creatinine (Cr) was elevated in groups with more severe sclerosis. Because the GTJ was assumed to disappear when an atubular glomerulus was formed, the ratio of the number of glomeruli with discernible GTJ to the total number of glomeruli was evaluated. As glomerular sclerosis progressed, discernible GTJ reduced significantly (p <0.001) and the degree of PF increased significantly (p <0.05). By serial section study in cases with pronounced PF, transitions between the stages of stenosis of the GTJ and atubular glomeruli were observed. It is speculated that the occlusion of the GTJ eventually hyalinizes the glomerulus; in such cases, glomerular obsolescence of the collapse type might be formed. On the other hand, obsolescence of the mesangial proliferative type might be formed in the hyalinization derived from direct glomerular injury. In this context, glomerular obsolescence of the collapse type was observed more frequently and was accompanied by more increased PF than obsolescence of the mesangial proliferative type (p <0.001). These results suggest that in addition to direct glomerular injury, nephron injury derived from interstitial damage of this type plays an important contributory role in the progression of IgAN.

Adult↗
PubMed2002

Regression of IgA nephropathy: a repeat biopsy study.

Histological cure of immunoglobulin A (IgA) nephropathy has been reported only rarely in adults. To elucidate the reversibility of established IgA nephropathy, we performed a repeat biopsy study. A second biopsy was performed in 35 patients with IgA nephropathy in whom hematuria, an essential finding of IgA nephropathy, had disappeared (proteinuria also had disappeared in 23 patients) after a treatment protocol involving high doses of methylprednisolone and tonsillectomy. The interval between the first and second biopsy was 18 to 138 months (mean, 77.1 months). Mean serum creatinine level was 1.11 +/- 0.35 (SD) mg/dL (range, 0.6 to 1.9 mg/dL) at the time of the first biopsy and 0.96 +/- 0.24 mg/dL at the time of the second biopsy. Mesangial proliferation was significantly reduced in second-biopsy specimens (mesangial proliferation score: first-biopsy specimens, 2.49 +/- 0.74; second-biopsy specimens, 0.91 +/- 0.89; P < 0.001). Acute inflammatory glomerular lesions, such as endocapillary proliferations, glomerular tuft necrosis, and cellular crescents, were present in 32 patients in first-biopsy specimens, whereas these were no longer present in any of the second-biopsy specimens. Although no significant difference in percentage of globally sclerotic glomeruli was observed between the first and second biopsy specimens, the percentage of segmentally sclerotic glomeruli was significantly lower in second-biopsy specimens (P < 0.001). Interstitial mononuclear cell infiltration was markedly reduced in second-biopsy specimens (P < 0.001). The area of renal cortex affected by interstitial fibrosis and/or edema was significantly reduced in second-biopsy specimens (first-biopsy specimens, 21.4% +/- 20.3%; second-biopsy specimens, 9.6% +/- 11.7%; P < 0.01). The distribution of IgA mesangial deposits had diminished in most patients, and no IgA deposits were seen in second-biopsy specimens from 8 patients. These findings indicate that mesangial proliferation and interstitial changes in IgA nephropathy are reversible to a considerable extent. A histological cure may be obtainable in a considerable proportion of patients, especially if treatment is initiated at a relatively early stage.

Adult↗
PubMed2002

Leukocyte accumulation and changes in extra-renal organs during renal ischemia reperfusion in mice.

Multiorgan failure is a life threatening complication in patients with ischemic acute renal failure (ARF). However, little is known about the underlying multiorgan system cellular immunity in ischemic ARF. We therefore studied the dynamics of cells accumulating in the kidneys and other organs in mice and analyzed the characteristics of the accumulated cells. We prepared a unilateral renal ischemia/reperfusion injury (IRI) model in C57BL/6 or C3H/He mice. At 1 to 3 hours after renal ischemia, increased accumulations of neutrophils and intermediate T cells were observed in the clamped kidney, but the same phenomena were also observed in the nonclamped kidney, liver, and spleen. After 24 hours, these cell numbers had returned to preischemic levels, but remained elevated for a longer period in the clamped kidney. The intermediate T cells that accumulated in the kidney and liver in the IRI mice expressed higher Vbeta chains specific to forbidden clones than in the control mice. Moreover, the accumulated intermediate T cells in the IRI liver had cytotoxic activity against both tumor cells and syngeneic thymocytes. In the clamped kidney, the accumulated intermediate T cells had less cytotoxic activity against tumor cells; however, the expression of the Fas ligand (FasL) increased, indicating a cell-mediated tissue injury via the Fas/FasL system. Histopathologically, an influx of neutrophils and lymphocytes was observed not only in the clamped kidney but also in the hepatic sinusoids concomitantly with liver dysfunction. These findings indicate that a systemic cellular immune response, including intermediate T cells, affects multiple organs during ischemic ARF, which may play an important role in the development of multiorgan failure.

Alanine Transaminase↗