Hideaki Yamabe

Toll-like receptor 3 ligands induce CD80 expression in human podocytes via an NF-κB-dependent pathway

BACKGROUND Recent studies suggest that CD80 (also known as B7.1) is expressed on podocytes in minimal-change disease (MCD) and may have a role in mediating proteinuria. CD80 expression is known to be induced by Toll-like receptor (TLR) ligands in dendritic cells. We therefore evaluated the ability of TLR to induce CD80 in human cultured podocytes. METHODS Conditionally immortalized human podocytes were evaluated for TLR expression. Based on high expression of TLR3, we evaluated the effect of polyinosinic-polycytidylic acid (polyIC), a TLR3 ligand, to induce CD80 expression in vitro. RESULTS TLR1-6 and 9 messenger RNA (mRNA) were expressed in podocytes. Among TLR ligands 1-9, CD80 mRNA expression was significantly induced by polyIC and lipopolysaccharide (TLR4 ligand) with the greatest stimulation by polyIC (6.8 ± 0.7 times at 6 h, P < 0.001 versus control). PolyIC induced increased expression of Cathepsin L, decreased synaptopodin expression and resulted in actin reorganization which suggested a similar injury pattern as observed with lipopolyssaccharide. PolyIC induced type I and type II interferon signaling, nuclear factor kappa B (NF-κB) activation and the induction of CD80 expression. Knockdown of CD80 protected against actin reorganization and reduced synaptopodin expression in response to polyIC. Dexamethasone, a corticosteroid commonly used to treat MCD, also blocked both basal and polyIC-stimulated CD80 expression, as did inhibition of NF-κB. CONCLUSIONS Activation of TLR3 on cultured human podocytes induces CD80 expression and phenotypic change via an NF-κB-dependent mechanism and is partially blocked by dexamethasone. These studies provide a mechanism by which viral infections may cause proteinuria.

Relationship between Salt Intake, Nitric Oxide and Asymmetric Dimethylarginine and Its Relevance to Patients with End-Stage Renal Disease

Patients with essential hypertension (n = 24) were administered a low-salt diet (2 g NaCl/day), a high-salt diet (20–23 g) and then a low-salt diet for 7 days, and plasma levels of nitrate and nitrite (NOx) and asymmetric dimethylarginine (ADMA) were examined. There was a negative correlation between the percent changes in mean blood pressure and the plasma NOx concentration after salt loading and restriction. The percent change in plasma ADMA concentration was negatively correlated with that in the plasma NOx concentration after salt loading and restriction. In patients with end-stage renal disease (n = 51), the plasma ADMA concentration was positively correlated with the duration of dialysis treatment. The frequency of cardiovascular events was greater in patients with a plasma ADMA level of ≥3 µM than in those with a plasma AMDA level of <3 µM. The results indicate that ADMA is not only a modulator of salt sensitivity in hypertension but also a cardiovascular risk factor in end-stage renal disease.

A randomized open-label comparative study of conventional therapy versus mizoribine onlay therapy in patients with steroid-resistant nephrotic syndrome (postmarketing survey)

BackgroundA previous double-blind 24-week clinical trial of mizoribine (MZ) vs placebo in steroid-resistant primary nephrotic syndrome (SRPNS) showed that MZ was more effective than placebo in reducing the rate of deterioration of renal function. The present study was conducted to evaluate the efficacy and safety of MZ in patients with SRPNS after 2 years’ treatment.MethodsA multicenter randomized open-label controlled trial in patients with SRPNS was conducted as a 2-year prospective postmarketing study.ResultsThere was a significant imbalance in the baseline serum albumin level (s-Alb) between the conventional therapy (CT) and MZ onlay therapy groups. Early dropouts were more frequent in the subset of patients in the CT group having a baseline s-Alb ≤3 g/dl. Therefore, the primary analysis (urinary protein level (UP)-improving effect) was performed using a mixed-effects model, with stratification according to the baseline s-Alb value. The analysis revealed that, in the subset of 34 patients with membranous nephropathy (MN) within the stratum of patients with baseline s-Alb ≤3 g/dl (n = 52), the rate of change (slope of change in the UP level/month), in terms of the log (UP+0.2), was −0.0577 in those allocated to the MZ group and −0.0227 in those allocated to the CT group (P = 0.058). In the stratum of patients with a baseline s-Alb >3 g/dl (n = 97), there were no significant differences in the UP between the two treatment groups. Hence, MZ onlay therapy was not considered to be efficacious in this group of patients. No serious adverse reactions to the drug were observed.ConclusionsThe present study yielded significant results, in that it suggested the possibility that long-term MZ therapy may afford further reduction of the UP, in addition to that obtained following CT, in particular, in MN patients in a severe nephrotic state.

Effects of cilostazol on serum lipid concentrations and plasma fatty acid composition in type 2 diabetic patients with peripheral vascular disease.

Abstract. Cilostazol is an anti-thrombotic and vasodilating agent, reported to have both anti-thrombotic and cerebral vasodilating effects. We investigated the effects of cilostazol on serum lipid concentrations and plasma fatty acid composition in type 2 diabetic patients with peripheral vascular disease. The serum concentrations of total cholesterol, triglycerides, high-density lipoprotein-cholesterol, lipoprotein (a), remnant-like particles-cholesterol, apolipoproteins, and plasma fatty acid composition were measured in 17 diabetic patients with peripheral vascular disease before and 1, 3, and 6 months after administration of cilostazol (200 mg/day). Serum triglyceride concentrations were significantly decreased after cilostazol (from 1.31±0.17 mmol/l to 0.86±0.07 mmol/l at 6 months, P<0.01). Plasma docosahexaenoic acid levels were significantly increased after cilostazol (4.11±0.26% to 4.94±0.26% at 6 months, P<0.01). Our findings show that cilostazol can induce some beneficial changes in serum lipid profile and plasma fatty acid composition.

Glomerular deposition of hepatitis C virus in membranoproliferative glomerulonephritis.

Hideaki Yamabe, MD, Second Department of Internal Medicine, Hirosaki University School of Medicine, 5 Zaifucho, Hirosaki 036 (Japan) References Johnson RJ, Gretch DR, Yamabe H, et al: Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. N Engl JMed 1993;28:465-470. Yamabe H, Johnson RJ, Gretch DR, et al: Hepatitis C virus infection and membranoproliferative glomerulonephritis in Japan. J Am SocNephrol 1995;6:220-223. Doutrelepont JM, Adler M, Willems M, et al: Hepatitis C infection and membranoproliferative glomerulonephritis. Lancet 1993;341:317. Misiani R, Vicari O, Bellavita P, et al: Hepatitis C virus in renal tissue of patients with glomerulonephritis. Nephron 1994;68:400. Dear Sir, Membranoproliferative glomerulonephritis (MPGN) associated with hepatits C virus (HCV) infection has been recently reported [1] and its prevalence may be very high in primary MPGN [2]. This disease is clinically characterized by nephrotic syndrome, active HCV infection, frequent existence of cryoglobulinemia and hypocomple-mentemia and its pathogenesis is assumed to be caused by immune complex including HCV [1,2]. However, the glomerular deposition of HCV has not yet been demonstrated because the amount of HCV may be very small. We tried to detect the glomerular HCV deposition in this disease. Freezed kidney specimens obtained by renal biopsy in 6 patients were examined for glomerular HCV detection. Polyclonal rabbit antibody to HCV core antigen, which was provided by Dr. K. Shimotohno (National Cancer Center, Tokyo, Japan), was used as first antibody in the indirect immunofluorescence techniques. FITC-conjugated goat anti-rabbit IgG (Organon Teknika Co., Durham, N.C., USA) was used as second antibody. Negative control consisted of staining with normal rabbit serum or antibody to HCV absorbed with HCV core antigen, followed by FITCconjugated goat anti-rabbit IgG. Glomerular HCV deposition was observed in 2 of 6 patients with granular manner along the capillary wall and in the mesangium (fig. 1). Doutrelepont et al.

IgA Nephropathy and Henoch-Schönlein Purpura Nephritis with Anterior Uveitis

Two patients with IgA nephropathy and a patient with Henoch-Schönlein purpura nephritis each associated with anterior uveitis are described. As anterior uveitis accompanying IgA nephropathy improved, renal manifestations were relieved. The patient with Henoch-Schönlein purpura nephritis suffered from not only anterior uveitis but also keratitis. It is suggested that immune mechanisms which induce IgA nephropathy may play a role in the development of anterior uveitis and keratitis.

C-Type Natriuretic Peptide Inhibits Proliferation and Monocyte Chemoattractant Protein-1 Secretion in Cultured Human Mesangial Cells

Background: Mesangial cell proliferation and matrix accumulation are hallmarks of various progressive glomerular diseases. We examined whether C-type natriuretic peptide (CNP) that is known to regulate the proliferation of vascular smooth muscle cells could modulate these pathological processes using human glomerular mesangial cells (GMCs) in culture. Methods: Proliferation of GMCs cultured with different concentrations of CNP-22 for 48 h was determined by a colorimetric assay using a tetrazorium salt. Monocyte chemoattractant protein-1 (MCP-1) and type IV collagen secretion into the culture media by GMCs in the presence or absence of CNP-22 were evaluated by ELISA. Expression of mRNA for natriuretic peptide receptor B (NPR-B), a specific receptor for CNP, was examined by reverse transcription polymerase chain reaction (RT-PCR). Results: CNP-22 (1–10 µM) inhibited serum-induced GMC growth in a dose-dependent manner. The amount of MCP-1 in the culture supernatant was increased approximately 2.4-fold by 5 µg/ml of lipopolysaccharide. This increase was inhibited by CNP-22 at 0.1–1 µM in a dose-dependent fashion. CNP-22 (10 µM) inhibited GMC type IV collagen secretion stimulated by 20 ng/ml of platelet-derived growth factor. Expression of NPR-B mRNA was confirmed in GMCs by RT-PCR. Conclusions: CNP suppresses GMC proliferation and MCP-1 and type IV collagen secretion by GMCs. It may have a therapeutic potential against human proliferative glomerular diseases, especially those with the involvement of monocytes.

Nephrotic syndrome associated with interferon-β-1b therapy for multiple sclerosis

A 43-year-old woman with multiple sclerosis (MS) had nephrotic syndrome 21 months after starting treatment with interferon (IFN)-β-1b (subcutaneous administration). She had taken no drug except for the IFN-β-1b. Because nephrotic syndrome may be induced by IFN therapy, the IFN was stopped. Percutaneous renal biopsy revealed that she had minimal change nephrotic syndrome. As nephrotic-range proteinuria, hypoalbuminemia, and general edema were worsening even 2 weeks after cessation of the drug, oral corticosteroid therapy (prednisolone 40 mg/day) was started. The nephrotic syndrome was treated successfully with prednisolone. The dosage of prednisolone was tapered, without a relapse, and then the corticosteroid therapy was stopped. IFN-β-1b therapy was then resumed, and the patient is in remission for both nephrotic syndrome and MS. Though proteinuria and nephrotic syndrome is a rare adverse effect of IFN-β-1b therapy, physicians treating MS patients with this agent should pay careful attention to new clinical symptoms and laboratory findings.

Lack of Awareness among Future Medical Professionals about the Risk of Consuming Hidden Phosphate-Containing Processed Food and Drinks

Phosphate toxicity is an important determinant of mortality in patients with chronic kidney disease (CKD), particularly those undergoing hemodialysis treatments. CKD patients are advised to take a low phosphate-containing diet, and are additionally prescribed with phosphate-lowering drugs. Since these patients usually seek guidance from their physicians and nurses for their dietary options, we conducted a survey to determine the levels of awareness regarding the high phosphate content in commercially processed food and drinks among medical and nursing students at the Hirosaki University School of Medicine in Japan. For this survey, 190 medical and nursing students (average age 21.7±3 years) were randomly selected, and provided with a list of questions aimed at evaluating their awareness of food and drinks containing artificially added phosphate ingredients. While 98.9% of these students were aware of the presence of sugar in commercially available soda drinks, only 6.9% were aware of the presence of phosphate (phosphoric acid). Similarly, only 11.6% of these students were aware of the presence of phosphate in commercially processed food, such as hamburgers and pizza. Moreover, around two thirds of the surveyed students (67.7%) were unaware of the harmful effects of unrestricted consumption of phosphate-containing food and drinks. About 28% of the surveyed students consume such “fast food” once a week, while 40% drink at least 1∼5 cans of soda drinks/week. After realizing the potential long-term risks of consuming excessive phosphate-containing food and drinks, 40.5% of the survey participants considered reducing their phosphate intake by minimizing the consumption of commercially processed “fast food” items and soda drinks. Moreover, another 48.4% of students showed interest in obtaining more information on the negative health effects of consuming excessive amounts of phosphate. This survey emphasizes the need for educational initiative to raise awareness of the health risks posed by excessive consumption of phosphate additives.

A case of sjögren's syndrome associated with sweet's syndrome

SummaryWe report a case of Sjögrens syndrome whose clinical course had been indolent until the patient presented with Sweets syndrome (acute febrile neutrophilic dermatosis). This patient showed renal failure and renal tubular acidosis. Sweets syndrome resolved within 3 weeks without corticosteroid therapy. Renal biopsy findings were consistent with interstitial nephritis. His renal manifestations responded to corticosteroid therapy and the renal function remained stable during 6 years follow-up without recurrence of Sweets syndrome. Although close association of both syndromes is already known, in our case Sjögrens syndrome may have been exacerbated by occurrence of Sweets syndrome.