Kouju Kamata

A multicenter cross-sectional study of circulating soluble urokinase receptor in Japanese patients with glomerular disease

Elevated serum-soluble urokinase receptor (suPAR) levels have been described in patients with focal segmental glomerulosclerosis (FSGS) in several different cohorts. However, it remains unclear whether this is the case for Japanese patients and whether circulating suPAR can be clinically useful as a diagnostic marker. To determine this, we measured serum suPAR levels in 69 Japanese patients with biopsy-proven glomerular diseases in a cross-sectional manner. The serum suPAR levels showed a significant inverse correlation with renal function by univariate (R(2) of 0.242) and multivariate (β=0.226) analyses. Even after excluding patients with renal dysfunction, no significant difference in the suPAR levels was detected among the groups. Receiver operating characteristic analysis and measures of the diagnostic test performance showed that suPAR was not a useful parameter for differentiating FSGS from the other glomerular diseases (AUC-ROC: 0.621), although a small subgroup analysis showed that patients with FSGS, treated with steroids and/or immunosuppressants, had significantly lower suPAR levels. Patients with ANCA-associated glomerulonephritis had significantly higher levels of suPAR compared with the other disease groups, which may be owing to their lower renal function and systemic inflammation. Thus, suPAR levels are significantly affected by renal function and have little diagnostic value even in patients with normal renal function.

Effective Antibiotic Treatment of Methicillin-Resistant Staphylococcus aureus-Associated Glomerulonephritis

Background: A new type of glomerulonephritis following a methicillin-resistant Staphylococcus aureus (MRSA) infection has been reported. The purpose of this study is to elucidate the clinicopathological features and the responsiveness to treatment of the disease. Methods: We studied the treatment of 8 patients with glomerulonephritis related to MRSA infection. We observed the eight cases and analyzed clinical features, laboratory findings and histopathological data. Results: On admission, all patients had no renal abnormalities. One to four months after suffering from MRSA infection, severe proteinuria and hematuria developed. Renal biopsy specimens revealed moderate to severe mesangial proliferative glomerulonephritis with various degrees of crescent formation. Immunofluorescence studies showed IgA and C3. Antibiotic therapy was performed in six cases, resulting in successfully reducing the proteinuria in parallel with the decreased activity of MRSA infection in five cases. The other 2 cases received corticosteroid treatment after complete cessation of MRSA infection, but they had a relapse of MRSA infection and later died from sepsis. Conclusions: These results suggested that MRSA-associated glomerulonephritis might respond to antibiotic treatment in most cases. This also indicated that special care must be taken in the application of steroid therapy for the glomerulonephritis with crescents, even though the MRSA infection has gone into an inactive state.

15-Deoxyspergualin "rescue therapy" for methylprednisolone-resistant rejection of renal transplants as compared with anti-T cell monoclonal antibody (OKT3).

A randomized trial with OKT3, an anti—T cell monoclonal antibody or with 15-deoxyspergualin against methylprednisolone-resistant rejection crisis was performed in 25 posttransplant patients immunosuppressed with prednisolone and cyclosporine. At least temporary reversal of rejection was observed in 58.3% of patients treated with 15-deoxyspergualin. This reversal rate may be quite comparable to 61.5% seen in patients treated with OKT3. Adverse effects with 15-deoxyspergualin were related to bone marrow suppression, while those with OKT3 were pyrexia, gastrointestinal symptoms, and herpes infection. In contrast to OKT3, which may act by modulating T cell surface antigen, 15-deoxyspergualin may be effective somewhere in the later stages of the rejection cascade.

Suppressive effect of mizoribine on humoral antibody production in DBA/2 mice

The mode of action of mizoribine (MZR) as a B cell inhibitor was studied using DBA/2 mice. Its in vitro administration significantly delayed the primary response in hemagglutinin production against sheep erythrocytes by suppressing the IgM antibody formation. In vitro plaque-forming cell (PFC) response against both T-dependent and T-independent antigens, such as TNP-SRBC and TNP-Brucella abortus, was dose-dependently suppressed by MZR. Since PFC formation by the T-depleted fraction of splenocytes was likewise suppressed, MZR may inhibit humoral antibody response by directly affecting the B cells (and/or macrophages) as well as by modulating the regulatory T cells. MZR may only act on a certain stage of the cell cycle of B lymphocytes following antigenic stimulation. It may not interfere with the initial antigen recognition or with mature B cells.

Effect of mizoribine on lupus nephropathy of New Zealand black/white F1 hybrid mice

Therapeutic trials with mizoribine (MZR), an imidazole nucleoside immunosuppressant, on experimental lupus nephropathy of NZB/W F1 mice resulted in the following. The MZR treatment, 20 mg per kilogram of body weight every other day, starting at 14 weeks of age, caused a significantly prolonged survival time of mice with a mean life span of 54.3 +/- 4.2 weeks, compared with the untreated controls, who had a mean survival time of 38.1 +/- 2.9 weeks (P less than 0.01). In addition, MZR suppressed the elevation of serum anti-DNA antibody titers, the spontaneous development of splenomegaly, and the histological development and progression of glomerulonephritis observed in untreated animals. Although no definite explanation is available at present to explain how MZR caused decreased anti-DNA antibody production and delay in the development of glomerulonephritis in these animals, it is suggested that it acts by directly suppressing the hyperfunctioning B cells of lupus mice. MZR may prove to be a promising immunosuppressant for the treatment of human lupus, in view of its lesser side effects such as bone marrow suppression or hepatotoxicity.

Effects of valsartan on progression of kidney disease in Japanese hypertensive patients with advanced, predialysis, chronic kidney disease: Kanagawa Valsartan Trial (KVT).

Suppression of the renin–angiotensin system is known to slow progression of chronic kidney disease (CKD). However, few trials have been performed with Japanese patients. This study investigated whether the angiotensin receptor blocker (ARB) valsartan would delay the progression of kidney disease more effectively than conventional treatment in Japanese hypertensive patients with advanced, predialysis CKD. In a multicenter, randomized, open-label trial, 303 patients with hypertension and CKD with serum creatinine levels ⩾2.0 mg dl−1 were assigned to receive either conventional therapy plus valsartan (valsartan add-on group) or conventional therapy without ARB (control group). The primary outcome was a change in serum creatinine levels. Changes in urinary protein levels and time to onset of renal events were analyzed as secondary end points. There were no between-group differences in blood pressure during the study. Changes in serum creatinine and urinary protein levels did not differ between the groups. However, the rate of renal events, including doubling of serum creatinine levels or end-stage renal disease, was significantly lower in the valsartan add-on group than in the control group. The addition of valsartan decreased the risk by 42.6% after adjustment for baseline variables. The addition of valsartan to conventional therapy significantly slowed the rate of renal function decline and delayed the need for renal replacement therapy in Japanese hypertensive patients with advanced CKD.

Role of cyclooxygenase-2 in the development of interstitial fibrosis in kidneys following unilateral ureteral obstruction in mice

Unilateral ureteral obstruction (UUO) induced tubulointerstitial fibrosis in kidneys mimics the pathogenesis of chronic kidney diseases and is considered a suitable model for studying the mechanisms leading to fibrosis. To study the role of cyclooxygenase-2 (COX-2) in kidney fibrosis, we investigated whether a selective COX-2 inhibitor, celecoxib, affected renal interstitial fibrosis during UUO in mice. To induce UUO, the left proximal ureter was ligated in male C57BL/6 mice. The mice were fed a diet with or without celecoxib from the day of UUO induction. Following UUO, the renal pelvis was observed to be dilated and the kidney cortex was significantly thinner than that of sham-operated mice. Immunofluorescent staining of type I, III, and IV collagen in UUO kidneys revealed that interstitial collagen deposition was significantly increased in the celecoxib-treated group. Expression of type I, III, and IV collagen in UUO kidneys was also significantly higher in the celecoxib-treated group than in the vehicle-treated group. In the celecoxib-treated group, mRNA levels of TGF-β/FGF-2 were also significantly higher than those in the vehicle-treated group. The present study demonstrates that COX-2 plays a protective role against fibrosis in UUO kidneys and suggests that supplementation of COX-2 products, such as PG analogues, will be a good option for preventing interstitial fibrosis.

Lipoprotein Subfractions Highly Associated With Renal Damage in Familial Lecithin:Cholesterol Acyltransferase Deficiency

Objective— In familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD), deposition of abnormal lipoproteins in the renal stroma ultimately leads to renal failure. However, fish-eye disease (FED) does not lead to renal damage although the causative mutations for both FLD and FED lie within the same LCAT gene. This study was performed to identify the lipoproteins important for the development of renal failure in genetically diagnosed FLD in comparison with FED, using high-performance liquid chromatography with a gel filtration column. Approach and Results— Lipoprotein profiles of 9 patients with LCAT deficiency were examined. Four lipoprotein fractions specific to both FLD and FED were identified: (1) large lipoproteins (>80 nm), (2) lipoproteins corresponding to large low-density lipoprotein (LDL), (3) lipoproteins corresponding to small LDL to large high-density lipoprotein, and (4) to small high-density lipoprotein. Contents of cholesteryl ester and triglyceride of the large LDL in FLD (below detection limit and 45.8±3.8%) and FED (20.7±6.4% and 28.0±6.5%) were significantly different, respectively. On in vitro incubation with recombinant LCAT, content of cholesteryl ester in the large LDL in FLD, but not in FED, was significantly increased (to 4.2±1.4%), whereas dysfunctional high-density lipoprotein was diminished in both FLD and FED. Conclusions— Our novel analytic approach using high-performance liquid chromatography with a gel filtration column identified large LDL and high-density lipoprotein with a composition specific to FLD, but not to FED. The abnormal lipoproteins were sensitive to treatment with recombinant LCAT and thus may play a causal role in the renal pathology of FLD.

Amelioration of circulating lipoprotein profile and proteinuria in a patient with LCAT deficiency due to a novel mutation (Cys74Tyr) in the lid region of LCAT under a fat-restricted diet and ARB treatment

Familial lecithin-cholesterol acyltransferase (LCAT) deficiency is a hereditary disease characterized by an abnormal lipid profile, corneal opacity, anemia and progressive renal disease. We report a patient with complete loss of LCAT activity due to a novel lcat gene mutation of Cys74Tyr in the lid region of LCAT protein. Esterification of cholesterol in this patient was disturbed by disruption of a substrate binding loop of Cys50-Cys74 in LCAT protein. She had progressive renal dysfunction, proteinuria, corneal opacity, anemia and an abnormal lipid profile. Her serum lipids showed a significant increase in abnormal lipoproteins at the original position in agarose gel electrophoresis and VLDL-cholesterol, and a severe decrease in serum HDL-cholesterol. Lipoprotein analyzes also revealed the presence of an abnormal midband lipoprotein, and a maturation disturbance of HDL particles. Renal function and proteinuria improved following the adoption of a fat-restricted diet and administration of an angiotensin II receptor blocker. The abnormal lipoproteins also decreased after this treatment.

Toxicological and immunological evaluation of the immunosuppressant 15-deoxyspergualin in BALB/c mice: an in vivo and in vitro study.

The toxicological aspects as well as the immunosuppressive mechanism of 15-deoxyspergualin (DSP) were studied using BALB/c mice. Five-week-old animals were subcutaneously given phosphate-buffered saline (PBS; Group 1) or DSP at 0.5 (Group 2) to 5.0 mg (Group 4) per kg body weight daily for 1 to 3 months. They were sacrificed to obtain blood for hematology and liver function studies. The spleen, taken simultaneously, was histologically examined, the T cell surface markers of splenocytes were flow cytometrically measured, and their interleukin 2 (IL-2) production induced in vitro by Enterotoxin A (Ent A) was assayed using CTLL cells. Additionally, the in vitro effect of DSP on IL-2 generation and plaque forming cell (PFC) production was studied using splenocytes of non-treated mice. During the 3 months of treatment, the body weight slowly increased in Groups 1 and 2, while the body weight of the 2.5-mg DSP mouse group (Group 3) was significantly lower on days 28 and 56 of treatment compared with Group 1 of the same age (P less than 0.05). The administration of DSP at 5.0 mg/kg (Group 4) caused marked reduction in body weight of the animals. They were sacrificed on day 28 because of their worsening general condition. WBC and RBC counts decreased in Group 3 on days 57 and 93, and the platelet number increased on day 57. A liver function test was not affected by DSP treatment except for an elevated SGOT in Group 4.(ABSTRACT TRUNCATED AT 250 WORDS)