Kazuhide Suyama

Serum SP-D levels as a biomarker of lung injury in respiratory syncytial virus bronchiolitis

To evaluate whether SP‐D concentration is a useful biomarker of the severity of respiratory syncytial virus (RSV) bronchiolitis, we determined SP‐D concentrations in patients with RSV bronchiolitis with or without chronic heart disease. We enrolled 52 patients who had been diagnosed with RSV bronchiolitis and required admission to the hospital at the Department of Pediatrics of Fukushima Medical University School of Medicine from 2004 through 2005. These patients were divided into two groups: Group 1 consisted of patients without any underlying disease and Group 2 consisted of patients with chronic heart disease. These patients were assigned to one of three categories. Stage A consisted of patients without oxygen dosage, Stage B of patients who required oxygen dosage, and Stage C of patients required artificial respiration. We evaluated baseline characteristics, clinical features, and serum SP‐D concentration in Group 1, Group 2, and a control group (healthy infants without infection). Mean serum SP‐D concentrations in patients with RSV bronchiolitis were higher than those in the control group (125.8 ± 49.3 and 44.2 ± 20.1 ng/ml, respectively). Mean serum SP‐D concentration was also higher in Group 2 than in Group 1 patients (160.4 ± 56.4 and 112.3 ± 39.4 ng/ml, respectively). Mean serum SP‐D concentrations were higher in Stage C than in Stages A or B patients, and mean serum SP‐D concentrations were higher in Stage B than in Stage A. These findings suggest that serum SP‐D is associated with the severity of RSV bronchiolitis and that it may be a useful biomarker for the severity of RSV bronchiolitis. Pediatr Pulmonol. 2011; 46:18–22.

Induction of transcription factor AP-2 by cytokines and prostaglandins in cultured mesangial cells.

Background/aims: Activator protein-2 (AP-2) is an important transcription factor for activation of growth- and inflammatory-associated genes. To detect AP-2 in the mesangium, the expression level of AP-2 was examined in cultured mesangial cells in response to various cytokines and prostaglandins. The level was also observed in kidney tissue samples obtained from patients with proteinuria and from a rat nephrosis model. Methods: AP-2 was immunohistochemically detected with a specific antibody. The expression level was analyzed by immunoblotting. Human tissue samples were obtained from patients with proteinuria. Kidney samples were also obtained from rats with puromycin aminonucleoside-induced nephrosis. Results: Pro-inflammatory cytokines, such as IL-6, IL-1 and IL-2, but not TNF-α, induced AP-2 expression in a time- and dose-dependent manner in cultured mesangial cells. PGE2 and PGI2 also induced AP-2 expression, while PGF2α failed to induce this protein. High expression levels of AP-2 were observed in different cell types including mesangial cells of kidney samples from patients with proteinuria. Similar results were obtained from the rat nephrosis model. Conclusion: These findings demonstrate that the primary cytokines induce AP-2 protein in mesangial cells. AP-2 may act as a transcription factor to produce additional cytokines and growth-associated gene products, suggesting an important role for AP-2 for the function of mesangial cells in glomerular disorders.

Efficacy of recombinant human soluble thrombomodulin for childhood hemolytic uremic syndrome

Recombinant human soluble thrombomodulin (rhTM) is a promising therapeutic natural anticoagulant and is used clinically for the treatment of disseminated intravascular coagulation (DIC). Herein is reported the cases of two HUS children treated with rhTM. The patients were diagnosed as having typical HUS on the basis of thrombocytopenia, hemolytic anemia, acute renal failure, and the detection Escherichia coli 0157. I.v. rhTM was started as an anti‐coagulant drug. At 2 days after the first treatment in both patients, fibrin/fibrinogen degradation products and d‐dimer levels were significantly decreased, and there was a subsequent slight improvement in thrombocytopenia, and a decrease in serum lactate dehydrogenase level. Urinary protein excretion gradually diminished and a decrease in serum creatinine level was observed. The patients did not require dialysis therapy. The present results suggest that rhTM may be a safe and effective treatment for DIC complicated with HUS in children.

Two patients with focal segmental glomerulosclerosis complicated by cyclosporine-induced reversible posterior leukoencephalopathy syndrome.

Reversible posterior leukoencephalopathy syndrome (RPLS) is a distinctive clinicoradiological entity observed in a variety of clinical settings. Cyclosporine (CyA)-RPLS has been reported in a few patients with focal segmental glomerulosclerosis (FSGS); however, there had been no reports on developed RPLS after the re-administration of CyA treatment. We report two patients with FSGS who developed CyA-induced RPLS and summarize the results of a literature review for similar patients. The two patients with FSGS presented here were a 4-year-old boy and a 9-year-old boy, who presented with steroid-resistant nephrotic syndrome (NS) and were treated with CyA. The first patient developed CyA-induced RPLS at the 7th day after the start of CyA treatment, and the second patient at the 16th day after the re-start of CyA treatment. The two patients complained of a visual disorder and exhibited signs of a disturbance in consciousness and hypertension. Electroencephalography (EEG) examinations revealed a generalized slow wave pattern, and magnetic resonance imaging (MRI) disclosed an area of high signal intensity in the white matter. Subsequently, CyA was discontinued and neurological symptoms improved and recrudescence of RPLS did not occur. Our findings suggest that patients with FSGS and NS who are treated with CyA should be closely monitored for the possible onset of RPLS, presenting as a disturbance in consciousness, visual disturbances and/or convulsions.

Girl with garland-pattern poststreptococcal acute glomerulonephritis presenting with renal failure and nephrotic syndrome.

Complete recovery occurs in more than 95% of children with poststreptococcal acute glomerulonephritis (PSAGN). However, some patients with acute renal failure (RF) or nephrotic syndrome (NS) present with chronic renal insuffi ciency. 1 – 5 In this study, we report a girl with garland-pattern PSAGN who presented with RF and NS and had clinical and histological improvement by plasmapheresis (PP) and methylprednisolone pulse therapy.

Role of Vascular Endothelial Growth Factor and Angiopoietin 1 in Renal Injury in Hemolytic Uremic Syndrome

Background/Aims: The recovery process from renal injury in hemolytic uremic syndrome (HUS) remains obscure. In order to clarify the role of vascular endothelial growth factor (VEGF) and angiopoietin 1 (Ang-1) in the renal recovery from HUS, we produced a model of mild HUS and examined the renal recovery process. Methods: We investigated three groups of mice. Group 1 consisted of mice that received an injection of Shiga toxin 2 (Stx2) and lipopolysaccharide (LPS); group 2 consisted of mice that received an injection of low dose of Stx2 and LPS, and group 3 consisted of control mice. Results: Serum Cr levels in group 1 were greater than those in group 2, and all mice in group 1 died, whereas all mice in group 2 remained alive. Endothelial injury at 24 h in group 1 was higher than in group 2. Electron-microscopic findings demonstrated that the endothelial cells formed immature capillary-like lumina from 7 to 28 days with increases in the expression of CD31-positive cells. Glomerular VEGF expression decreased at 72 h in group 1, but gradually increased in group 2. Glomerular Ang-1 expression peaked from 72 h to 28 days. Ang-1 expression was frequently found in the endothelial cell region of vesicle walls simultaneous with increased CD31-positive staining. Conclusion: Our findings suggest that VEGF and Ang-1 play important roles in the recovery process, particularly in the regeneration of endothelial injury.

Resistance factors for the treatment of immunoglobulin A nephropathy with diffuse mesangial proliferation.

Some patients with severe immunoglobulin A nephropathy (IgAN) are resistant to multi‐drug combination therapy; however, there have been few reports on the risk factors for non‐responsiveness to treatment for severe IgAN. We, therefore, evaluated the risk factors for non‐responsiveness to treatment in cases of severe IgAN.

Successful therapy with tonsillectomy for severe ISKDC grade VI Henoch–Schönlein purpura nephritis and persistent nephrotic syndrome

Henoch–Schönlein purpura (HSP) is a systemic disorder characterized by leukocytoclastic vasculitis involving the capillaries and the deposition of IgA immune complexes. Renal involvement is the principal cause of morbidity and mortality in children with HSP. We report here a 13-year-old girl with Henoch–Schönlein purpura nephritis (HSPN) of International Study of Kidney Disease in Children (ISKDC) grade VI and persistent nephrotic syndrome despite receiving conventional therapy, such as prednisolone, methylprednisolone and urokinase pulse therapy and plasmapheresis (PP). The patient was treated with tonsillectomy, which subsequently decreased proteinuria, induced the disappearance of microscopic hematuria, and improved renal pathological findings. A regimen of methylprednisolone and urokinase pulse therapy plus PP with tonsillectomy may be an effective and useful therapy for some children with severe HSPN children of ISKDC grade VI and persistent nephrotic syndrome.

Bucillamine-induced nephropathy in a child with juvenile rheumatoid arthritis and Kartagener's syndrome

The patient had suffered from swelling and pain bilaterally in the ankle and wrist joints and continued fever at 9 years of age in 1993. He was admitted to a hospital and was diagnosed with JRA and treated with combination of a nonsteroid anti-inflammatory drug (ibuprofen), methotrexate (MTX) and prednisolone. In September 1994, MTX was discontinued and bucillamine (50 mg/day) was prescribed. After 2.5 months, urinalysis revealed proteinuria. Bucillamineinduced renal injury was suspected. Bucillamine was discontinued, but proteinuria persisted. In May 1995, he was referred and admitted to our hospital. On admission, his ankle and wrist joints exhibited contracture bilaterally. Results of laboratory investigation were notable for a platelet count of 52.8 × 104/mm3, C-reactive protein (CRP) level of 1.58 mg/dL and erythrocyte sedimentation rate (ESR) of 28 mm/h. The third component of complement (C3), C4 and 50% hemolyzing dose of complement (CH50) were within normal range, antinuclear antibody was negative and rheumatoid factor was 8 U. Urinalysis revealed proteinuria (210 mg/dL) without hematuria, but with granular casts. The clinical course is shown in Fig. l. Proteinuria was 1.4 g/day and renal function was normal. Chest X-ray revealed situs inversus, with dextrocardia, right aortic arch and a bubble in the stomach below the right hypochondrium. Computerized tomography of the chest and head revealed bronchiectasis and maxillary and sphenoid sinusitis. We diagnosed Kartagener’s syndrome, on the basis of the situs inversus, bronchiectasis and chronic sinusitis. A renal biopsy was performed. On immunofluorescence microscopic examination (IF), the specimen contained six glomeruli; two glomeruli contained linear depositions of IgG along segmental glomerular capillary walls and a little deposition of C3. In four glomeruli examined, no depositions of immunoglobulin or complement were found. In 29 other glomeruli examined, no mesangial cell proliferation or increase in matrix was found. In four of these 29 glomeruli, light microscopy (LM) with Azan stain revealed subepithelial deposits in focal segmental glomeruli (Fig. 2). In two of six glomeruli, subepithelial deposits in glomerular basement membrane (GBM) were observed on electron microscopy (EM). We therefore diagnosed focal membranous glomerulonephropathy (MGN) induced by bucillamine. Pediatrics International (2000) 42, 316–318

The efficacy of recombinant human soluble thrombomodulin for the treatment of shiga toxin associated hemolytic uremic syndrome model mice

BACKGROUND Recombinant human soluble thrombomodulin (rhTM) is a promising therapeutic natural anticoagulant that is comparable to antithrombin, tissue factor pathway inhibitor and activated protein C. In order to clarify the efficacy of rhTM for the treatment of typical hemolytic uremic syndrome (t-HUS), we examined changes in renal damage in t-HUS mice treated with rhTM or vehicle alone. METHODS We used severe and moderate t-HUS mice injected with shiga toxin (Stx) and lipopolysaccharide (LPS). The severe t-HUS mice were divided into two subgroups [an rhTM subgroup (Group A) and a saline subgroup (Group B)] along with the moderate t-HUS mice [an rhTM subgroup (Group C) and a saline subgroup (Group D)]. Groups E and F were healthy mice treated with rhTM or saline, respectively. RESULTS All mice in Group B died at 80-90 h post-administration of Stx2 and LPS whereas all mice in Group A remained alive. Loss of body weight, serum creatinine level, endothelial injury and mesangiolysis scores at 24 h after administration in the t-HUS mice treated with rhTM were lower than those in t-HUS mice treated with saline. The levels of hemoglobin at 6 h and platelet counts at 24 h after administration in Group A were higher than those in Group B. Serum interleukin (IL)-6, IL-1β and tumor necrotic factor (TNF)-α levels at 24 h after administration in Group A were lower than those in Group B. Serum C5b-9 levels at 24 h after the administration and serum fibrinogen degradation product (FDP) at 72 h after the administration of Stx2 and LPS were lower in Group A than in Group B. CONCLUSIONS These results indicate that rhTM might afford an efficacious treatment for t-HUS model mice via the inhibition of further thrombin formation and amelioration of hypercoagulant status.