Chiari Kojima

Dynamic Observation of Mechanically-Injured Mouse Femoral Artery Reveals an Antiinflammatory Effect of Renin Inhibitor

Objective—The renin-angiotensin-aldosterone system (RAS) plays a central role in atherosclerosis. To investigate the effects of a direct renin inhibitor aliskiren on vascular inflammation, we conducted leukocyte adhesion assays in vivo and in vitro using a novel real-time imaging system. Methods and Results—Aliskiren (10 mg/kg/d) or PBS was administered to C57BL/6 mice (6–7 weeks of age; Oriental Yeast, Tokyo, Japan) for 2 weeks via an osmotic pump. Blood pressure was not significantly changed in the 2 groups throughout the experimental period. A perivascular cuff injury was then introduced to the femoral artery and real-time intravital microscopic observation was conducted 24 hours after injury. The number of adherent leukocytes was elevated in the injured mice without aliskiren (43.8±9.3/10−2 mm2), whereas that was significantly reduced in the mice with aliskiren (18.4±4.4, P<0.05). Treatment of human umbilical vein endothelial cells (HUVECs) with aliskiren significantly reduced the adhesion of THP-1 cells to TNF-&agr;–activated HUVECs (P<0.05). Interestingly, TNF-&agr;–induced renin activity and angiotensin II production in HUVECs were also blunted by aliskiren. Furthermore, exogenous renin and angiotensin II abrogated the aliskiren-mediated reduction of THP-1 cell adhesion to HUVECs. Conclusions—Our in vivo and in vitro findings indicate a pivotal role for renin inhibition in vascular inflammation independent of blood pressure.

Effect of Single-Dose Rituximab on Primary Glomerular Diseases

Background: A paradigm shift from such toxic ‘nonspecific’ therapies to selective immunomodulating regimens is necessary for glomerular diseases. Rituximab, which acts by inhibiting CD20-mediated B cell proliferation and differentiation, could be effective in the treatment of nephrotic syndrome as shown in recent reports. Design: To assess the effects of rituximab in patients with primary glomerular diseases, including minimal-change disease, immunoglobulin A (IgA) nephropathy, focal segmental glomerulonephritis, membranous nephropathy and membranoproliferative glomerulonephritis, we performed a prospective trial of the effects of single-dose rituximab therapy in 24 patients. We prospectively evaluated the serum and urinary biochemical parameters before and after 6 months of therapy. Results: In all of the patients studied, depletion of CD19 and CD20 cells was noted, with significant reduction in the degree of proteinuria from 3.7 ± 3.4 g/day at baseline to 1.3 ± 2.0 g/day at 6 months after the drug administration (p = 0.002). However, no significant changes of the serum creatinine, urinary RBC sediment, serum CD4/8 or serum IL-4 levels were observed at 6 months after the drug administration. In subjects with IgA nephropathy, while depletion of CD19 and CD20 cells was noted, no significant change in the severity of proteinuria was observed at 6 months after the drug administration as compared with the level at the baseline. Conclusion: For the treatment of primary glomerular diseases, the use of a single dose of rituximab is demonstrated with no serious adverse events. Further study of the mechanism of action of rituximab in successfully treated patients could encourage new perspectives in the treatment of primary glomerular diseases.

Angiotensin-Converting Enzyme Inhibitor Attenuates Monocyte Adhesion to Vascular Endothelium through Modulation of Intracellular Zinc

To elucidate an anti-inflammatory role of angiotensin-converting enzyme inhibitors (ACEIs) in cardiovascular disease, we studied the effect of ACEIs in monocyte adhesion to endothelial cells and underlying molecular mechanisms. Treatment of human monocytic THP-1 cells with monocyte chemoattractant protein-1 (MCP-1; 100 ng/ml; 10 min) significantly increased their adhesion to human umbilical vein endothelial cells (HUVECs) under flow condition (P < 0.001). Preincubation of THP-1 cells with imidaprilat (50 nM; 4 h), an active metabolite of imidapril, reduced MCP-1-triggered THP-1 cell adhesion (P < 0.01). Similar effects were obtained with experiments using human peripheral monocytes (P < 0.05). MCP-1 activated protein kinase C (PKC)α in THP-1 cells, resulting in the up-regulation of α4 and β2 integrin. Imidaprilat attenuated MCP-1-induced PKC activation and integrin up-regulation in THP-1 cells. Imidaprilat also inhibited THP-1 cell adhesion induced by phorbol 12-myristate 13-acetate (PMA), a potent PKC activator. In attempt to elucidate the mechanisms for the modulation of PKC activity by imidaprilat, we found that MCP-1 or PMA increased labile zinc in THP-1 cells, which was canceled by imidaprilat. Indeed, zinc/pyrithione activated PKC and increased THP-1 cell adhesion. Zinc chelator as well as PKC inhibitor inhibited these processes, suggesting the role for labile zinc in PKC activation and THP-1 cell adhesion. Imidaprilat attenuated zinc/pyrithione-induced PKC activation and THP-1 cell adhesion. These data suggest that ACEI reduces MCP-1 or PMA-triggered monocyte adhesion to activated HUVECs by modulating labile zinc in monocytes. Our findings may point out a novel anti-inflammatory mechanism of ACEIs in atherogenesis.

The characteristics of relapse in adult-onset minimal-change nephrotic syndrome

BackgroundAlthough minimal-change nephrotic syndrome (MCNS) is highly steroid-responsive, the frequency of relapses in some patients is high, necessitating the administration of repeated courses of prednisolone in high doses. It is, therefore, necessary to identify factors that can predict this increased risk of relapse in some patients in order to establish useful treatment methods to reduce the risk.MethodsTo clarify the factors that might increase the risk of relapses, the data of 82 Japanese adult patients with MCNS receiving treatment at our department were analyzed retrospectively. Of the total, 55 patients (67.1%) experienced relapse after showing an initial response. We divided the patients into two groups; namely, the nonrelapse group (n = 27) and the relapse group (n = 55), and compared the clinico-pathophysiological characteristics between the two groups.ResultsSignificantly increased serum immunoglobulin E (IgE) levels (P = 0.0002) and increased frequency of steroid side effects were observed in the relapse group as compared to the nonrelapse group.ConclusionsTo develop effective therapeutic modalities, it is important to have a thorough understanding of the clinico-pathophysiological characteristics of MCNS patients showing relapse.

Successful therapeutic use of a single-dose of rituximab on relapse in adults with minimal change nephrotic syndrome.

Minimal change nephrotic syndrome (MCNS) usually is considered to have a good renal prognosis, but the frequency of relapses is a therapeutic challenge to physicians. The treatment of patients with multiple relapses remains a matter of controversy, because few controlled studies are available. We report the case of a 25-year-old man who experienced relapses of MCNS. Single-dose rituximab therapy (total dose 500 mg) was given during the fourth relapse. Complete remission occurred 10 days later, when no CD19/20-positive B cells were detected in the blood. This the first report of efficacy of single-dose rituximab therapy to treat multi-relapsing MCNS in an adult patient.

Long-term beneficial effects of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker therapy for patients with advanced immunoglobulin A nephropathy and impaired renal function.

BackgroundThere are few reports analyzing the effects of angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs) on the long-term renal survival of advanced immunoglobulin A nephropathy (IgAN) patients.Patients and methodsIn this retrospective cohort analysis, we divided 66 IgAN patients with an estimated glomerular filtration rate (eGFR) <60 ml/min into three groups: ACEI group (n = 20, treated with ACEIs), ARB group (n = 23, treated with ARBs), and control group (n = 23, treated with antiplatelet agents), and analyzed the clinical and histological background, renal survival rate until the primary endpoint of 50% decrease of eGFR from baseline, and the secondary endpoint of progression to end-stage renal disease, and the risk factors for progression.ResultsThe clinical and histological background without serum IgA and C3 were not significantly different among the three groups. The renal survival rate until the primary and secondary endpoints was significantly higher in the ACEI and ARB groups than in the control group. The independent risk factors for progression were higher mean blood pressure (hazard ratio [HR] 1.76, P = 0.04), higher histological grade (HR 2.54, P = 0.0184) at baseline, and without ACEIs or ARBs (HR 7.09, P = 0.001), but decreased proteinuria and blood pressure. The risk factors with resistance to ACEIs or ARBs were higher blood pressure and lower eGFR at baseline. There was no difference regarding the survival rate and the risk for progression between ACEI s and ARBs.ConclusionACEIs or ARBs were effective for long-term renal survival of advanced IgAN, although proteinuria and blood pressure did not decrease.

Three cases of late-onset oligomeganephronia

Oligomeganephronia is classified as a subgroup of renal hypoplasia, characterized by histopathologic abnormalities which progress to end-stage renal disease (ESRD) by school age. We describe three adult cases of oligomeganephronia who have not yet developed ESRD. We performed a renal biopsy in all of them. The pathological features, consisting of a reduced number of enlarged glomeruli, were diagnostic of oligomeganephronia. It was assumed that the condition had not progressed to ESRD in the patients because the degree of loss of glomeruli may have been milder than that in typical cases of oligomeganephronia.