Publications by authors named "Toshiyuki Komiya"

25 Publications

  • Page 1 of 1

Acute Tubulointerstitial Nephritis in Rosai-Dorfman Disease Mimicking IgG4-related Disease.

Intern Med 2021 Sep 18. Epub 2021 Sep 18.

Department of Nephrology, Kansai Electric Power Hospital, Japan.

Rosai-Dorfman-Destombes disease (RDD) is a non-Langerhans cell histiocytosis characterized by the accumulation of histiocytes inside the lymph nodes or extranodally. The association between RDD and IgG4-related disease (IgG4-RD) is discussed. We herein report a case of RDD manifesting as acute tubulointerstitial nephritis mimicking IgG4-RD. The first renal biopsy showed severe tubulointerstitial nephritis with infiltration of S100-positive histiocytes and IgG4-positive plasma cells; storiform fibrosis and obliterative phlebitis were not confirmed. After prednisolone therapy, IgG4-positive cells and S100-positive histiocytes were decreased, but the IgG4/IgG ratio increased despite clinical improvement. These findings indicated extranodal RDD in the kidney presenting as tubulointerstitial nephritis.
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http://dx.doi.org/10.2169/internalmedicine.8046-21DOI Listing
September 2021

Two episodes of acute dyspnea that were induced by COVID-19 in a peritoneal dialysis patient.

CEN Case Rep 2021 Jul 16. Epub 2021 Jul 16.

Department of Nephrology, Kansai Electric Power Hospital, 2-1-7, Fukushima, Fukushima-ku 54, Osaka, 553-0003, Japan.

Dialysis patients have an increased risk of coronavirus disease 2019 (COVID-19)-related mortality. Acute heart failure is a frequent, lethal complication of COVID-19, and it is a risk factor for mortality in hemodialysis patients. Therefore, it is crucial to rapidly distinguish heart failure from COVID-19 pneumonia. Here, we report a case of two episodes of acute dyspnea that were induced by COVID-19 in a peritoneal dialysis (PD) patient. The first episode of acute dyspnea was an exacerbation of heart failure caused by COVID-19 when the patient had a volume overload status due to a peritoneal dialysis catheter malfunction. Heart failure induced by a catheter malfunction was due to omental wrapping, and it was treated with ultrafiltration by hemodialysis and mini-laparotomy. The patient's acute dyspnea was immediately resolved. The second episode of acute dyspnea was caused by COVID-19 pneumonia, which occurred 1 week after the first episode. This case suggests the importance of identifying heart failure and beginning adequate treatment, in COVID-19 patients with PD.
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http://dx.doi.org/10.1007/s13730-021-00629-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284031PMC
July 2021

A novel splice-site mutation of the HNF1B gene in a family with maturity onset diabetes of the young type 5 (MODY5).

Endocrinol Diabetes Metab Case Rep 2020 Sep 23;2020. Epub 2020 Sep 23.

Center for Diabetes, Endocrinology & Metabolism, Kansai Electric Power Hospital, Osaka, Japan.

Summary: Maturity-onset diabetes of the young (MODY) is a form of monogenic diabetes mellitus characterised by early onset and dominant inheritance. Delayed diagnosis or misdiagnosis as type 1 or type 2 diabetes mellitus is common. Definitive genetic diagnosis is essential for appropriate treatment of patients with MODY. The hepatocyte nuclear factor 1-beta (HNF1B) gene is responsible for MODY type 5 (MODY5), which has distinctive clinical features including renal disease. MODY5 should always be considered by clinicians in patients with early onset diabetes and renal anomalies. We report a case of a 30-year-old Japanese male with early-onset diabetes mellitus, renal anomalies and family history of diabetes that was suggestive of MODY5. Renal histology showed no evidence of diabetic nephropathy. Genetic testing revealed a novel heterozygous splice-site mutation of the HNF1B gene in the family members. It was strongly suggested that the mutation could underlie our patient's MODY5.

Learning Points: Genetic diagnosis of MODY is relevant for appropriate treatment. Dominantly inherited early-onset diabetes mellitus with renal cysts suggests MODY5. Scanning the non-coding regions is important for not missing a mutation in HNF1B.
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http://dx.doi.org/10.1530/EDM-20-0092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576636PMC
September 2020

Successful treatment with assisted automated peritoneal dialysis using 4.25% glucose dialysate for an elderly patient with refractory heart failure.

CEN Case Rep 2021 02 15;10(1):121-125. Epub 2020 Sep 15.

Department of Nephrology, Kansai Electric Power Hospital, 2-1-7, Fukushim, Fukushima-ku 54, Osaka, 553-0003, Japan.

Refractory heart failure is a major cause of mortality and hospitalization, and peritoneal dialysis (PD) is one of the options for controlling volume overload. Although high glucose dialysate enables a large amount of ultrafiltration, the use of 4.25% glucose dialysate is generally avoided, because high glucose exposure leads to peritoneal damage. Here, we describe a patient who was successfully treated with assisted automated PD using 4.25% glucose dialysate for refractory heart failure. An 84-year-old woman developed heart failure due to severe mitral regurgitation with a low left-ventricular ejection fraction of 30%, and also developed progressive kidney deterioration. She had been refractory to diuretics and repeatedly hospitalized. PD was started to treat refractory heart failure. Since it was difficult for her to change the dialysis bags by herself, assistance with her PD from her family was needed. The use of 4.25% glucose dialysate markedly increased ultrafiltration and improved her condition. In addition, automated PD (APD) using 4.25% glucose dialysate enabled her family to have a break from PD once every 4 days. Thereafter, she had no episodes of hospitalization due to heart failure for approximately 18 months after her discharge.
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http://dx.doi.org/10.1007/s13730-020-00533-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829289PMC
February 2021

Brachiocephalic Vein Occlusion from a Tunneled Hemodialysis Catheter.

Intern Med 2019 11 10;58(22):3339-3340. Epub 2019 Jul 10.

Department of Nephrology, Kansai Electric Power Hospital, Japan.

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http://dx.doi.org/10.2169/internalmedicine.3354-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911745PMC
November 2019

A case of nephrotic syndrome showing contemporary presence of apolipoprotein E2 homozygote glomerulopathy and membranous nephropathy-like findings modified by apolipoprotein E Toyonaka.

Clin Nephrol Case Stud 2018 30;6:45-51. Epub 2018 Nov 30.

Division of Nephrology, Kansai Electric Power Hospital.

A 79-year-old man was admitted to our hospital for proteinuria due to nephrotic syndrome. Renal biopsy revealed focal sclerosis and foam cell infiltration in the glomerulus. In addition, electron microscopic findings (EM) revealed peculiar electron-dense deposits (EDDs) in both sides of the glomerular basement membrane. Although subepithelial deposits had spike formation highly resembling those seen in membranous nephropathy (MN), immunoglobulins and complements were not identified by immunofluorescence study, and microbubbles appeared in high magnification of EM different from the immune disease. The analysis of apolipoprotein (Apo) E showed an elevated concentration of plasma ApoE. The phenotype, genotype, and DNA sequence studies revealed homozygous ApoE2/2 and a novel missense mutation called ApoE Toyonaka (Ser197Cys). This case may confirm the independent responsibility of ApoE2/2 and ApoE Toyonaka for ApoE2 homozygote glomerulopathy and MN-like EDD findings, respectively.
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http://dx.doi.org/10.5414/CNCS109509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287602PMC
November 2018

An integrative study of the genetic, social and environmental determinants of chronic kidney disease characterized by tubulointerstitial damages in the North Central Region of Sri Lanka.

J Occup Health 2014 18;56(1):28-38. Epub 2013 Dec 18.

Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University.

Objectives: Previous investigations on chronic kidney disease of unknown etiology characterized by tubulointerstitial damages (CKDu) in the North Central Region (NCR) of Sri Lanka have supported the involvement of social, environmental and genetic factors in its pathogenesis.

Methods: We conducted a social-environmental-and-genetic epidemiology study on a male population in NCR to investigate the genetic and environmental contributors. We recruited 311 case-series patients and 504 control candidates. Of the 504 control candidates, 218 (43%) were eliminated because of the presence of hypertension, proteinuria, high HbA1c, high serum creatinine or high alpha-1 microglobulin in urine.

Results And Discussion: None of 18 metals measured (μg//) in urine, including Cd, As and Pb, showed significantly higher concentrations in cases compared with controls. As speciation results showed that 75-80% of total urinary As was in the form of arsenobetaine, which is non-toxic to humans. None of the metal concentrations in drinking water samples exceeded guideline values. A genome-wide association study (GWAS) was conducted to determine the genetic contributors. The GWAS yielded a genome-wide significant association with CKDu for a single nucleotide polymorphism (SNP; rs6066043; p=5.23 × 10(-9) in quantitative trait locus analysis; p=3.73 × 10(-9) in dichotomous analysis) in SLC13A3 (sodium-dependent dicarboxylate transporter member 3). The population attributable fraction and odds ratio for this SNP were 50% and 2.13. Genetic susceptibility was identified as the major risk factor for CKDu. However, 43% of the apparently healthy male population suffers from non-communicable diseases, suggesting their possible influence on CKDu progression.
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http://dx.doi.org/10.1539/joh.13-0172-oaDOI Listing
December 2014

[Case of pseudohypercreatininemia associated with monoclonal IgM gammopathy].

Nihon Jinzo Gakkai Shi 2013 ;55(7):1340-4

Department of Nephrology & Dialysis, Tazuke Kofukai Foundation, Medical Research Institute, Kitano Hospital, Osaka, Japan.

An 80-year-old man with well controlled hypertension for eight years and monoclonal IgM gammopathy was referred to our hospital in May 2010 due to persistent elevation of serum creatinine(s-Cr). At our hospital, urine and blood tests showed no abnormal findings as BUN and Cr were 15.0 mg/dL and 0.91 mg/dL, respectively. In contrast the referring hospital had obtained values of 10.4 mg/dL and 4.8 mg/dL, respectively. This discrepancy was replicated when s-Cr was measured in another sample from this patient using the enzyme assay kits employed by the referring hospital and our hospital. High-performance liquid chromatography (HPLC), which is the standard method for measuring s-Cr, gave a value in the normal range. After removing high molecular weight proteins (>3,000 D)from the serum sample, the s-Cr levels measured with the respective kits were similar. Since elevation of s-Cr was linked to that of IgM at the referring hospital, we diagnosed the patient as having pseudohypercreatininemia with monoclonal IgM gammopathy.
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January 2014

[A case of hypomagnesemia linked to refractory hypokalemia and hypocalcemia with short bowel syndrome].

Nihon Jinzo Gakkai Shi 2012 ;54(8):1197-202

Division of Nephrology and Dialysis, Kitano Hospital, The Tazuke Kofukai Medical Research Institute, Osaka, Japan.

We report a case of a 59-year old Japanese woman with short bowel syndrome, whose hypokalemia and hypocalcemia were successfully treated with magnesium (Mg) supplementation. Two years previously, she underwent Mile's operation for advanced rectal cancer, which could have been the cause of subsequent extensive resection of the small intestine by strangulation. After serial resection, she gradually developed chronic diarrhea and anorexia. Three weeks before admission, she developed general fatigue and tetany, and was hospitalized at another hospital. On admission, her serum K and Ca were 2.5 mEq/L and 4.3 mg/dL, respectively, hence regular fluid therapy containing potassium (K) and calcium (Ca) was provided following admission. However, her hypokalemia and hypocalcemia persisted, and she also displayed renal dysfunction and thereafter was transferred to our department for further evaluation and treatment. Since the laboratory tests revealed severe hypomagnesemia (0.4 mg/dL), we started intravenous Mg supplementation together with fluid therapy containing K and Ca. After the combination therapy, her clinical symptoms and electrolyte disorders were remarkably improved within a week. As Mg is essential for PTH secretion in response to hypocalcemia and to inhibit the K channel activity that controls urinary K excretion, hypomagnesemia can cause hypocalcemia and hypokalemia, which is refractory to repletion therapy unless Mg is administered. Therefore, for patients who present with signs of Mg deficiency, early and accurate diagnosis of Mg deficiency should be made and corrected.
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August 2013

Evaluation of the newly proposed simplified histological classification in Japanese cohorts of myeloperoxidase-anti-neutrophil cytoplasmic antibody-associated glomerulonephritis in comparison with other Asian and European cohorts.

Clin Exp Nephrol 2013 Oct 21;17(5):659-662. Epub 2012 Dec 21.

Safety Control Department, University Hospital, School of Medicine/General, Medical Education Center, Teikyo University, Tokyo, Japan.

The prognostic value of renal biopsy in anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis is widely recognized; however, there is no consensus regarding its pathological classification. Berden et al. proposed a new classification of glomerulonephritis in ANCA-associated vasculitis (AAV) categorized into focal, crescentic, mixed, and sclerotic classes and showed its prognostic value in 100 international multicenter cohorts for 1- and 5-year renal outcomes. In order to evaluate whether this new classification has predictive value and reproducibility in Japanese AAV cases, 87 cohorts with only microscopic polyangiitis in 3 limited centers in Japan were analyzed. In addition, those from Japan, Europe (Berden's cohorts) and China were compared in a recent report.
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http://dx.doi.org/10.1007/s10157-012-0755-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3824231PMC
October 2013

Tubulointerstitial damage as the major pathological lesion in endemic chronic kidney disease among farmers in North Central Province of Sri Lanka.

Environ Health Prev Med 2012 May 13;17(3):213-21. Epub 2011 Oct 13.

Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine, Yoshida-Konoe, Sakyo-ku, Kyoto, Japan.

Chronic kidney disease of uncertain etiology (CKDu) in North Central Province of Sri Lanka has become a key public health concern in the agricultural sector due to the dramatic rise in its prevalence and mortality among young farmers. Although cadmium has been suspected as a causative pathogen, there have been controversies. To date, the pathological characteristics of the disease have not been reported. Histopathological observations of 64 renal biopsies obtained at Anuradhapura General Hospital from October 2008 to July 2009 were scored according to Banff 97 Working Classification of Renal Allograft pathology. The correlations between the histological observations and clinical parameters were statistically analyzed. Interstitial fibrosis and tubular atrophy with or without nonspecific interstitial mononuclear cell infiltration was the dominant histopathological observation. Glomerular sclerosis, glomerular collapse, and features of vascular pathology such as fibrous intimal thickening and arteriolar hyalinosis were also common. Although hypertension was identified as one of the common clinical features among the cases, it did not influence the histopathological lesions in all the cases. This study concludes that tubulointerstitial damage is the major pathological lesion in CKDu. Exposure(s) to an environmental pathogen(s) should be systematically investigated to elucidate such tubulointerstitial damage in CKDu.
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http://dx.doi.org/10.1007/s12199-011-0243-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3348245PMC
May 2012

Risk factors associated with disease progression and mortality in chronic kidney disease of uncertain etiology: a cohort study in Medawachchiya, Sri Lanka.

Environ Health Prev Med 2012 May 1;17(3):191-8. Epub 2011 Sep 1.

Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Background: The alarming rise in the prevalence of chronic kidney disease of uncertain etiology (CKDu) among the low socioeconomic farming community in the North Central Province of Sri Lanka has been recognized as an emerging public health issue in the country.

Methods: This study sought to determine the possible factors associated with the progression and mortality of CKDu. The study utilized a single-center cohort registered in 2003 and followed up until 2009 in a regional clinic in the endemic region, and used a Cox proportional hazards model.

Results: We repeatedly found an association between disease progression and hypertension. Men were at higher risk of CKDu than women. A significant proportion of the patients in this cohort were underweight, which emphasized the need for future studies on the nutritional status of these patients.

Conclusions: Compared with findings in western countries and other regions of Asia, we identified hypertension as a major risk factor for progression of CKDu in this cohort.
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http://dx.doi.org/10.1007/s12199-011-0237-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3348239PMC
May 2012

[Ischemic tubulointerstitial injury].

Nihon Jinzo Gakkai Shi 2011 ;53(4):625-8

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October 2011

A case of acute rejection with adenovirus infection after ABO-incompatible kidney transplantation.

Clin Transplant 2009 Aug;23 Suppl 20:27-30

Kidney Disease Center, Nagoya Daini Red Cross Hospital, Nagoya, Japan.

We report clinical and histopathologic findings of a case of acute rejection with adenovirus infection after kidney transplantation. A 63-yr-old woman with end-stage renal disease caused by lupus nephritis received an ABO-incompatible living kidney transplantation from her husband. On the 7th post-operative day (POD), she had fever, hematuria, and bladder irritation. Although she was treated with an antibiotic, the symptoms were not improved. We diagnosed adenovirus infection as positive with the urine shell vial method and blood PCR analysis. Cyclophosphamide was interrupted and immunoglobulin therapy was performed. However, urine output decreased and serum creatinine levels increased. An episode biopsy was performed on POD 20. We diagnosed acute antibody-mediated rejection. She was treated with plasma exchange for acute rejection and antiviral drug (rivabirin) for active adenovirus infection. However, the renal graft dysfunction was deemed irreversible and the renal graft was removed on POD 34. The graftectomy specimen showed acute rejection and acute tubular necrosis with adenovirus infection.
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http://dx.doi.org/10.1111/j.1399-0012.2009.01005.xDOI Listing
August 2009

[Combining the use of dipstick protein and specific gravity accurately predicts pathological proteinuria in Japan].

Nihon Jinzo Gakkai Shi 2008 ;50(7):934-41

Division of Nephrology and Dialysis, Department of Medicine, Kitano Hospital, Japan.

Unlabelled: Dipstick urine analysis is the most common and convenient examination in routine health care. The criteria for abnormal proteinuria is a level of more than (+). However, the interference of urine concentration should be considered in the judgement.

Objective: The purpose is to demonstrate the effect of the combined use of specific gravity (SG) in the dipstick judgement to evaluate pathological proteinuria in Japanese people.

Methods: The hospital laboratory database of Kitano hospital was searched for urine samples, for patients consulted at our nephrology department from Oct. 2004 to Sep. 2005 (n=1767), and simultaneously assayed for dipstick proteinuria(DSP), SG, urinary protein, urine creatinine (UC) and urinary protein-creatinine ratio (UPC ratio). To generate a model table, samples were stratified according to DSP and SG values. A DSP versus SG matrix (5 x 6)was created, and then all 30 cells were color-coded by the pathological proteinuria proportion (white: < 5%, gray: 5-95%, black: <95%).

Results: SG was positively associated with UC. In the patients, SG < or = 1.005 and DSP(-), 12/70 (17.1%) was > or =300 mg/gCr. Moreover in the patients, both 1.005 < SG < or = 1.010 and DSP(+/-), 21/32 (65.6%) had pathological proteinuria. We confirmed the consistency for this combination table in the urine samples of another 1111 out-patients. Moreover, the area under the curve in DSP(+/-) suggests that the patients whose SG was < or = 1.011 might have pathological proteinuria (sensitivity; 82.1%, specificity; 89.3%).

Conclusion: We recognized that the combination of DSP and SG enhances a more accurate proteinuria judgement. DSP(- approximately +/-) in diluted urine (SG < or = 1.1011) has the potential for pathological proteinuria. Therefore, diluted urine samples should be re-examined.
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January 2009

Nephronophthisis complicated with hepatic fibrosis: an autopsy case with rupture of the splenic artery after renal transplantation.

Clin Exp Nephrol 2008 Feb 5;12(1):82-8. Epub 2008 Jan 5.

Division of Nephrology and Dialysis, Department of Medicine, Kitano Hospital, Tazuke Kofukai Medical Institute, 2-4-20 Ohgimachi, Kita-ku, Osaka 530-8480, Japan.

Nephronophthisis (NPHP) is a disease characterized by a genetic cause of chronic renal failure in children and adolescents, complicated with several extra-renal manifestations such as retinal defect and/or liver fibrosis. Although it is difficult to establish the correct diagnosis, mutations in six genes (NPHP 1-6) have recently been identified. Here we report the case of a 25-year-old male with NPHP with congenital hepatic fibrosis. He showed microscopic hematuria and moderate proteinuria at 20 years. Renal biopsy revealed severe interstitial fibrosis, diffuse tubular atrophy and microcysts at this time with chronic kidney disease stage III (Cr 2.43 mg/dl). C3c was positive in glomeruli in direct immunofluorescent study. Although his mother belongs to a family with polycystic kidney disease, he did not have a novel genetic background of Arg585Cys mutation in exon 8 of the PKD1 gene. Magnetic resonance angiography (MRA) showed typical portal hypertension with spleno-renal shunt caused by biopsy-proven liver fibrosis. Thus, we diagnosed him as having undetermined renal cystic or tubulo-interstitial disease complicated with membranoproliferative glomerulonephritis (MPGN). Renal transplantation was performed in January 2005 after 2 years of dialysis therapy. He was transported to our emergency room because of severe abdominal pain in December 2005. A computed tomographic scan showed massive ascites, which were caused by rupture of the splenic artery. Despite full intensive care including intraluminal coiling of the ruptured aneurysm and extensive blood transfusion, we failed to rescue him on the next day. The autopsy findings revealed severe atrophy of the bilateral kidney with multiple cysts along the cortico-medullary border. Obvious portal hypertension, resulting from congenital hepatic fibrosis, could account for the rupture of the splenic artery with aneurysm formation under pressure/volume overload. This is the first report of a NPHP patient with the complication of hepatic fibrosis emerging from an ADPKD family. As it remains elusive on the phenotype-genotype of the Japanese NPHP population, a registration system of cystic disease of the kidney is required.
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http://dx.doi.org/10.1007/s10157-007-0004-7DOI Listing
February 2008

Clinicopathological influence of obesity in IgA nephropathy: comparative study of 74 patients.

Contrib Nephrol 2007 ;157:90-3

Department of Nephrology, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan.

The pathological role of obesity has rarely been studied in primary glomerular diseases. The purpose of this study is to examine the clinicopathological influence of obesity in IgA nephropathy (IgAN). 74 patients with IgA nephropathy in our institution from October 2000 to January 2004 were retrospectively divided into two groups according to body mass index (BMI): the non-obese group (group N) with BMI < 25 kg/m(2), and the obese group (group O) with BMI > or = 25 kg/m(2). There were 50 patients in group N and 24 patients in group O. Clinical analysis showed no significant difference between these two groups in blood pressure, serum cholesterol, creatinine clearances or grade of hematuria. However, urinary protein excretion and serum creatinine were significantly greater in group O than in group N. Although semiquantitative analysis of light-microscopical findings showed no significant differences in the severity of mesangial proliferation, matrix expansion, glomerulosclerosis or crescent formation, image analysis showed that total glomerular area and tuft area were significantly larger in group O. In addition, ultrastructural study revealed significantly higher glomerular basement membrane thickness in group O. 62 patients (46 patients, group N; 16 patients, group O) were followed in our institution for one year. Urinary protein was significantly decreased only in patients who received steroid in both groups. Although administration of ACE inhibitor or ARB tended to decrease urinary protein in group O, the change was not statistically significant. Our findings indicate that obesity may accelerate the increase of proteinuria in IgAN through ultrastructural modification of the glomerular basement membrane.
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http://dx.doi.org/10.1159/000102309DOI Listing
July 2007

Molecular mechanisms and therapeutic strategies of chronic renal injury: the role of nuclear factor kappaB activation in the development of renal fibrosis.

J Pharmacol Sci 2006 Jan 6;100(1):17-21. Epub 2006 Jan 6.

Department of Urology, Osaka City University Medical School, Osaka, Japan.

Tubulointerstitial fibrosis is a common feature of many progressive renal diseases and is a main determinant that leads to an irreversible loss of renal function. In chronic cyclosporin A nephrotoxicity, we previously reported that inflammatory responses such as macrophage infiltration preceded interstitial fibrosis. This inflammation was accompanied by an elevation in renal nuclear factor kappaB (NF-kappaB) activity. Similar findings were obtained in chronic tacrolimus nephrotoxicity and obstructive nephropathy. Inhibition of NF-kappaB markedly attenuated renal inflammation and interstitial fibrosis in these models. Furthermore, administration of oral adsorbent (Kremezin) significantly attenuated the increase in renal NF-kappaB activity and concomitantly reduced interstitial inflammation and renal fibrosis in chronic renal failure rats. Elimination of indoxyl sulfate by this adsorbent is likely involved in this mechanism since it is known that indoxyl sulfate activates NF-kappaB in renal tubular cells. It is suggested that strategy aiming at NF-kappaB inhibition is important to prevent the progression of renal fibrosis.
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http://dx.doi.org/10.1254/jphs.fmj05003x4DOI Listing
January 2006

Clinical significance of von Willebrand factor in patients with adult dermatomyositis.

Clin Rheumatol 2005 Aug 23;24(4):352-7. Epub 2004 Nov 23.

The Department of Medicine, The Tazuke Kofukai, Medical Research Institute, Kitano Hospital, Ohgimachi, Kita-ku, Osaka, Japan.

Because the clinical significance of von Willebrand factor (vWF), a marker of endothelial injury, has not been well studied in adult patients with dermatomyositis (DM), we evaluated whether plasma vWF levels are useful as an index of disease activity in these patients. We measured plasma vWF antigen levels in 11 patients with active adult DM, 13 patients with inactive DM, and 18 healthy subjects using an enzyme-linked immunosorbent assay. The association of vWF level with clinical condition and muscle-derived enzyme leakage among DM patients was examined using analysis of covariance and logistic regression analysis. Furthermore, we studied the effects of treatment on the vWF antigen level. The mean vWF antigen level was significantly higher in active DM patients than in inactive DM patients and healthy subjects. Higher vWF levels were associated with clinical symptoms, such as general fatigue, fever, and muscle weakness. They were also associated with the levels of aspartate aminotransferase, alanine aminotransferase, and aldolase, but not with those of lactate dehydrogenase and creatine kinase (CK). vWF antigen was correlated with muscle enzymes except for CK. The plasma vWF levels in six patients with active DM significantly decreased after successful corticosteroid treatment. Plasma vWF level may be considered a useful marker of disease activity in adult DM patients.
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http://dx.doi.org/10.1007/s10067-004-1027-zDOI Listing
August 2005

Possible involvement of nuclear factor-kappaB inhibition in the renal protective effect of oral adsorbent AST-120 in a rat model of chronic renal failure.

Int J Mol Med 2004 Jan;13(1):133-8

Department of Nephrology, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno-ku Osaka 545-8585, Japan.

Oral adsorbent, AST-120 removes uremic toxins (such as indoxyl sulfate) and retards the progression of chronic renal failure (CRF). However, its mechanism of action has not been precisely clarified. Since indoxyl sulfate elicits renal tubular nuclear factor-kappaB (NF-kappaB) activation in vitro, the present experiments were conducted to elucidate the involvement of NF-kappaB in the beneficial effects of AST-120 using rats with 3/4 nephrectomy, a model of early-stage CRF. Daily administration of AST-120 was started at 6 weeks after 3/4 nephrectomy and continued for 18 weeks. Sham-operated rats, untreated CRF rats and AST-120-treated CRF rats were compared for NF-kappaB DNA-binding activity, gene expression and renal histology. Systolic blood pressure was increased in CRF rats, and this increase was not affected by AST-120. Blood urea nitrogen, serum creatinine and urinary protein were increased in CRF rats. Although AST-120 attenuated these increases, it did not do so to a statistically significant extent. Indoxyl sulfate, which was accumulated in serum of CRF rats, was significantly eliminated by AST-120. Renal cortical NF-kappaB DNA-binding activity was increased in CRF rats. AST-120 significantly inhibited this increase. Monocyte/macrophage infiltration and increased monocyte chemoattractant protein-1 (MCP-1) mRNA observed in CRF rats were attenuated by AST-120. Furthermore, AST-120 significantly blocked renal fibrosis with concomitant inhibition of transforming growth factor beta1 (TGF-beta1) gene expression. It appeared that AST-120 reduced NF-kappaB activation and possibly the activity of NF-kappaB-dependent pathways of interstitial inflammation including MCP-1 expression and macrophage infiltration. The anti-inflammatory effect of AST-120 mediated via inhibition of NF-kappaB is a possible mechanism by which AST-120 retards the progression of renal fibrosis in CRF.
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January 2004

Attenuation of renal fibrosis by proteasome inhibition in rat obstructive nephropathy: possible role of nuclear factor kappaB.

Int J Mol Med 2003 Oct;12(4):587-92

Department of Applied Pharmacology and Therapeutics, Osaka City University Medical School, Osaka 545-8585, Japan.

We previously reported that pyrrolidine dithiocarbamate blocked nuclear factor-kappaB (NF-kappaB) activation and attenuated interstitial inflammation and tubulointerstitial fibrosis in the rat obstructive nephropathy. Since pyrrolidine dithiocarbamate is an anti-oxidant and possesses additional biological properties, present experiment was conducted to clarify further the role of NF-kappaB in the development of tubulointerstitial fibrosis in obstructed kidney using a proteasome inhibitor that blocks NF-kappaB through stabilizing IkappaB, an endogenous inhibitor of NF-kappaB. At 5 days following unilateral ureteral obstruction (UUO) in rats, obstructed kidney exhibited tubulointerstitial fibrosis that was associated with macrophage infiltration. UUO decreased renal cortical IkappaB protein contents with concomitant increases in NF-kappaB DNA-binding activity and gene expression of monocyte chemoattractant protein-1. Administration of PSI, N-benzyloxy-carbonyl-Ile-Glu (O-t-Bu)-Ala-leucinal, a proteasome inhibitor, (3 mg/kg/day, s.c., b.i.d) to UUO rats inhibited proteasome activity and attenuated the changes in IkappaB content, NF-kappaB activity and MCP-1 mRNA expression observed in UUO rats. PSI also decreased macrophage influx and attenuated the development of fibrosis. Furthermore, up-regulated gene expression of pro-fibrogenic molecules observed in the obstructed kidney was attenuated by PSI. These results further support the notion that NF-kappaB plays an important role in the development of renal fibrosis in the obstructive nephropathy.
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October 2003

Activation of transcription factors AP-1 and NF-kappaB in chronic cyclosporine A nephrotoxicity: role in beneficial effects of magnesium supplementation.

Transplantation 2003 Apr;75(7):1040-4

Department of Urology, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno, Osaka 545-8585, Japan.

Background: It has been shown that the transcription factors activator protein (AP)-1 and nuclear factor (NF)-kappaB play a pivotal role in various renal diseases. We aimed to study their activations in chronic cyclosporine A (CsA) nephrotoxicity and evaluate the effect of magnesium (Mg) supplementation and blockade of the renin-angiotensin system (RAS), which are known to ameliorate CsA nephrotoxicity, on these transcription factors.

Methods: CsA (15 mg/kg/day) was administered subcutaneously daily to rats maintained on a low-sodium diet for 7, 14, and 28 days. DNA-binding activities of AP-1 and NF-kappaB in renal cortex were determined by electrophoretic mobility shift assay.

Results: DNA-binding activity of AP-1 and NF-kappaB started to increase at day 14 and further elevated at day 28 by CsA treatment. These activations were markedly attenuated when rats were maintained on a high-Mg diet. In contrast, angiotensin-converting enzyme inhibitor (ACEI) had no effect on CsA-induced AP-1 activation. CsA-induced activation of NF-kappaB was suppressed by ACEI at day 14, whereas such effect could not be observed at day 28.

Conclusions: Renal cortical AP-1 and NF-kappaB DNA binding were activated in chronic CsA nephrotoxicity. These activations were induced largely by means of RAS-independent mechanisms. It is suggested that prevention of CsA-induced DNA-binding activation of these transcription factors is at least in part responsible for the beneficial effects of Mg supplementation on CsA nephrotoxicity.
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http://dx.doi.org/10.1097/01.TP.0000057242.96219.AFDOI Listing
April 2003

[Two cases of systemic lupus erythematosus accompanied by antiphospholipid syndrome nephropathy without immune complex nephritis].

Nihon Jinzo Gakkai Shi 2002 Dec;44(8):817-22

Department of Nephrology, Osaka City University Graduate School of Medicine, Osaka, Japan.

We report here two interesting cases of systemic lupus erythematosus(SLE) accompanied by antiphospholipid syndrome nephropathy(APSN). These cases satisfied the criteria for SLE established by the American College of Rheumatology 1997 and also satisfied the criteria for antiphospholipid syndrome (APS) established by the Sapporo International Workshop of APS 1998. Both cases had high blood pressure with elevated plasma renin activity, proteinuria and renal dysfunction. Their biopsied renal specimens showed the characteristic findings for APSN, such as mesangial proliferation, double contours, thickening of the capillary loops, and intimal hyperplasia, but there was no evidence for immune complexes in the glomeruli, which were examined by the indirect immunofluorescence methods and the electron microscopy method. These results indicated that their renal dysfunction was caused by APSN, but not by immune complex nephritis. In addition to treatment with prednisolone, they were administered anticoagulants(warfarin, or aspirin, or heparin) for APSN and an angiotensin II receptor blocker, candesartan, for the hypertension. Subsequently, their conditions recovered with the improvement of renal function and hypertension. Our experiences suggest that anticoagulant therapy in addition to corticosteroids offers advantages in the treatment of patients with SLE accompanied by APSN and renal dysfunction.
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December 2002

Role of renin-angiotensin system and nuclear factor-kappaB in the obstructed kidney of rats with unilateral ureteral obstruction.

Jpn J Pharmacol 2002 Dec;90(4):361-4

Department of Urology, Osaka City University, Japan.

The present study was conducted to elucidate the role of oxidative stress and nuclear factor-kappaB (NF-kappaB) in the beneficial effects of angiotensin receptor blockade on obstructive nephropathy. Unilateral ureteral occlusion in rats elicited tubulo-interstitial fibrosis with concomitant macrophage infiltration and increased expression of monocyte chemoattractant protein-1. These changes were accompanied by an induction of renal cortical lipid peroxidation and activation of NF-kappaB. Both an AT(1) antagonist, candesartan, and a NF-kappaB inhibitor, pyrrolidine dithiocarbamate, markedly attenuated these changes and to a similar extent. These results suggest that the beneficial effects of angiotensin blockade are mediated by the inhibition of oxidative stress and subsequent NF-kappaB activation in obstructive nephropathy.
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http://dx.doi.org/10.1254/jjp.90.361DOI Listing
December 2002

Inhibition of nuclear factor-kappaB activation by pyrrolidine dithiocarbamate prevents chronic FK506 nephropathy.

Kidney Int 2003 Jan;63(1):306-14

Department of Urology, Osaka City University, Osaka, Japan.

Background: Chronic tacrolimus (FK506) nephrotoxicity is characterized by renal fibrosis with interstitial inflammation. Since nuclear factor-kappaB (NF-kappaB) plays a key role in chronic inflammatory diseases including renal disease, the present study was conducted to elucidate the role of NF-kappaB in the pathogenesis of chronic FK506-induced nephropathy.

Methods: FK506 (1 mg/kg/day, SC) was administered daily to rats maintained on low sodium diet for 42 days. Some rats were treated with a putative NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC; 100, 200 mg/kg/day, by gavage). The renal function, renal histology, renal NF-kappaB-DNA binding activity and gene expression profile were examined.

Results: FK506 caused a decline in glomerular filtration and induced characteristic renal morphologic changes including arteriolopathy, tubular atrophy and interstitial fibrosis. FK506 markedly activated renal cortical NF-kappaB-DNA binding. PDTC administration inhibited NF-kappaB-DNA binding activity in a dose dependent manner. With higher dose, NF-kappaB-DNA binding activity was decreased to a control level. PDTC had little effect on FK506-induced renal dysfunction. Renal cortical monocyte/macrophage infiltration observed in FK506-treated rats was dramatically suppressed by PDTC. FK506 up-regulated renal cortical gene expression of chemoattractant proteins, monocyte chemoattractant protein-1 (MCP-1) and osteopontin. PDTC significantly blocked MCP-1 gene expression but had no effect on osteopontin gene expression. Tubular atrophy and tubulointerstitial fibrosis, but not arteriolopathy, were significantly attenuated by PDTC. FK506 increased renal mRNA expression of fibrogenic molecules and extracellular matrices that also were attenuated by PDTC treatment.

Conclusions: NF-kappaB plays an important role in mediating cortical monocyte/macrophage infiltration and in the pathogenesis of tubular injury and interstitial fibrosis in experimental FK506-induced chronic nephropathy.
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http://dx.doi.org/10.1046/j.1523-1755.2003.00714.xDOI Listing
January 2003
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