Yoshifumi Hamasaki

The University of Tokyo, Tōkyō, Japan

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Publications (22)88.22 Total impact

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    ABSTRACT: Although membranous nephropathy (MN) is a commonly observed cause of post-transplant glomerulonephritis, distinguishing de novo from recurrent MN in kidney allograft is often difficult. Phospholipase A2 receptor (PLA2R) staining is useful for diagnosing recurrent MN in allografts similarly to idiopathic MN in native kidney. No specific treatment strategy has been established for MN, especially when accompanied with HCV infection in kidney transplant recipients. This report describes a 66-year-old man who was diagnosed as having PLA2R positive membranous nephropathy accompanied with already-known IgA nephropathy and HCV infection 26 years after kidney transplantation conducted between identical twins. PLA2R was detected along capillary loops, implying that this patient is affected by the same pathogenic mechanism as idiopathic MN, not secondary MN associated with other disorders such as HCV infection. The patient successfully achieved clinical remission after steroid therapy. © 2015 Asian Pacific Society of Nephrology.
    Nephrology 07/2015; 20 Suppl 2(S2):101-4. DOI:10.1111/nep.12458 · 2.08 Impact Factor
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    ABSTRACT: Experimental evidence has clarified distant organ dysfunctions induced by AKI. Crosstalk between the kidney and heart, which has been recognized recently as cardiorenal syndrome, appears to have an important role in clinical settings, but the mechanisms by which AKI causes cardiac injury remain poorly understood. Both the kidney and heart are highly energy-demanding organs that are rich in mitochondria. Therefore, we investigated the role of mitochondrial dynamics in kidney-heart organ crosstalk. Renal ischemia reperfusion (IR) injury was induced by bilateral renal artery clamping for 30 min in 8-week-old male C57BL/6 mice. Electron microscopy showed a significant increase of mitochondrial fragmentation in the heart at 24 h. Cardiomyocyte apoptosis and cardiac dysfunction, evaluated by echocardiography, were observed at 72 h. Among the mitochondrial dynamics regulating molecules, dynamin-related protein 1 (Drp1), which regulates fission, and mitofusin 1, mitofusin 2, and optic atrophy 1, which regulate fusion, only Drp1 was increased in the mitochondrial fraction of the heart. A Drp1 inhibitor, mdivi-1, administered before IR decreased mitochondrial fragmentation and cardiomyocyte apoptosis significantly and improved cardiac dysfunction induced by renal IR. This study showed that renal IR injury induced fragmentation of mitochondria in a fission-dominant manner with Drp1 activation and subsequent cardiomyocyte apoptosis in the heart. Furthermore, cardiac dysfunction induced by renal IR was improved by Drp1 inhibition. These data suggest that mitochondrial fragmentation by fission machinery may be a new therapeutic target in cardiac dysfunction induced by AKI. Copyright © 2015 by the American Society of Nephrology.
    Journal of the American Society of Nephrology 02/2015; DOI:10.1681/ASN.2014080750 · 9.34 Impact Factor
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    ABSTRACT: IntroductionTissue inhibitor of metalloproteinase-2 (TIMP-2) is an emerging acute kidney injury (AKI) biomarker. We evaluated the performance of urinary TIMP-2 in an adult mixed ICU by comparison with other biomarkers that reflect several different pathways of AKI.Methods This study prospectively enrolled 98 adult critically ill patients who had been admitted to the adult mixed ICU. Urinary TIMP-2 and N-acetyl-ß-D-glucosaminidase (NAG), and plasma neutrophil gelatinase-associated lipocalin (NGAL), interleukin-6 (IL-6), and erythropoietin (EPO) were measured on ICU admission. We evaluated these biomarkers¿ capability of detecting AKI and its severity as determined by the Kidney Disease Improving Global Outcomes (KDIGO) serum creatinine criteria and of predicting in-hospital mortality. The impact of sepsis, the leading cause of AKI in ICUs, was also evaluated.ResultsWe found AKI in 42 (42.9%) patients. All biomarkers were significantly higher in AKI than in non-AKI. In total, 27 (27.6%) patients developed severe AKI. Urinary TIMP-2 was able to distinguish severe AKI from non-severe AKI with the area under the receiver operating characteristic curve (AUC-ROC) of 0.80 (95% confidence interval 0.66 to 0.90). A total of 41 one (41.8%) cases were complicated with sepsis. Although plasma NGAL and IL-6 were increased by sepsis, urinary TIMP-2 and NAG were increased not by sepsis but by the presence of severe AKI. Plasma EPO was increased only by septic AKI. In-hospital mortality was 15.3% in this cohort. Urinary TIMP-2 and NAG, and plasma NGAL were significantly higher in non-survivors than in survivors, although plasma IL-6 and EPO were not. Among the biomarkers, only urinary TIMP-2 was able to predict in-hospital mortality significantly better than serum creatinine.Conclusion Urinary TIMP-2 can detect severe AKI with performance equivalent to those of plasma NGAL and urinary NAG with an AUC-ROC value higher than 0.80. Furthermore, urinary TIMP-2 was associated with mortality. Sepsis appeared to have only a limited impact on urinary TIMP-2, in contrast to plasma NGAL.
    Critical care (London, England) 12/2014; 18(6):716. DOI:10.1186/s13054-014-0716-5 · 4.48 Impact Factor
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    ABSTRACT: Cardiovascular disease is a frequent cause of death in peritoneal dialysis patients. Biocompatible peritoneal dialysis solutions with neutral pH have been anticipated to reduce cardiovascular disease more than conventional peritoneal dialysis solutions with low pH, but it remains unclear which factors at peritoneal dialysis initiation increase cardiovascular risk in patients using biocompatible peritoneal dialysis solutions. This study was undertaken to investigate which clinical factors at peritoneal dialysis initiation, including peritoneal transport status, are associated with cardiovascular event in patients using biocompatible peritoneal dialysis solution. This retrospective cohort study of peritoneal dialysis patients using biocompatible solutions with neutral pH assessed relations of clinical parameters at peritoneal dialysis initiation to cardiovascular event during the subsequent five years. Of 102 patients who started peritoneal dialysis, cardiovascular event occurred in 18. Age, history of cardiovascular disease before peritoneal dialysis initiation, hemoglobin, serum albumin, C-reactive protein, peritoneal permeability defined by the ratio of dialysate to plasma creatinine concentration at 4 hr (D/Pcre) in peritoneal equilibration test (PET), number of patients in each PET category defined by D/Pcre, and peritoneal protein clearance significantly differed between patients with and without cardiovascular event. For patients divided according to PET category using Kaplan–Meier method, the group of high average to high peritoneal transporters exhibited significantly high incidence of cardiovascular event and mortality compared with the groups of low and low-average peritoneal transporters (Log rank; p = 0.0003 and 0.005, respectively). A Cox proportional hazards model showed independent association of PET category classification with cardiovascular event. Peritoneal permeability expressed as PET category at peritoneal dialysis initiation is an independent cardiovascular risk factor in peritoneal dialysis patients using biocompatible peritoneal dialysis solution with neutral pH. Greater peritoneal permeability at peritoneal dialysis initiation might reflect subclinical vascular disorders.
    BMC Nephrology 11/2014; 15(1):173. DOI:10.1186/1471-2369-15-173 · 1.69 Impact Factor
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    ABSTRACT: Hyperinsulinemia can contribute to hypertension through effects on sodium transport. To test whether the stimulatory effect of insulin on renal proximal tubule sodium transport is preserved in insulin resistance, we compared the effects of insulin on abdominal adipocytes and proximal tubules in rats and humans. Insulin markedly stimulated the sodium-bicarbonate cotransporter (NBCe1) activity in isolated proximal tubules through the phosphoinositide 3-kinase (PI3-K) pathway. Gene silencing in rats showed that while insulin receptor substrate (IRS)1 mediates the insulin effect on glucose uptake into adipocytes, IRS2 mediates the insulin effect on proximal tubule transport. The stimulatory effect of insulin on glucose uptake into adipocytes was severely reduced, but its stimulatory effect on NBCe1 activity was completely preserved in insulin-resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rats and patients with insulin resistance. Despite widespread reduction of IRS1 and IRS2 expression in insulin-sensitive tissues, IRS2 expression in the kidney cortex was exceptionally preserved in both OLETF rats and patients with insulin resistance. Unlike liver, acute insulin injection failed to change the expression levels of IRS2 and sterol regulatory element-binding protein 1 in rat kidney cortex, indicating that regulatory mechanisms of IRS2 expression are distinct in liver and kidney. Thus, preserved stimulation of proximal tubule transport through the insulin/IRS2/PI3-K pathway may play an important role in the pathogenesis of hypertension associated with metabolic syndrome.Kidney International advance online publication, 29 October 2014; doi:10.1038/ki.2014.351.
    Kidney International 10/2014; 87(3). DOI:10.1038/ki.2014.351 · 8.56 Impact Factor
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    ABSTRACT: Small-vessel vasculitis is a life-threatening autoimmune disease that is frequently associated with anti-neutrophil cytoplasmic antibodies (ANCAs). Conventional immunotherapy including steroids and cyclophosphamide can cause serious adverse events, limiting the efficacy and safety of treatment. Eicosapentaenoic acid (EPA), a key component of fish oil, is an omega-3 polyunsaturated fatty acid widely known to be cardioprotective and beneficial for vascular function. We report two elderly patients with systemic ANCA-associated vasculitis (AAV) in whom the administration of EPA in concert with steroids safely induced and maintained remission, without the use of additioal immunosuppressants. To explore the mechanisms by which EPA enhances the treatment of AAV, we employed SCG/Kj mice as a spontaneous murine model of AAV. Dietary enrichment with EPA significantly delayed the onset of crescentic glomerulonephritis and prolonged the overall survival. EPA-derived anti-inflammatory lipid mediators and their precursors were present in the kidney, plasma, spleen, and lungs in the EPA-treated mice. Furthermore, a decrease in ANCA production and CD4/CD8-double negative T cells, and an increase in Foxp3(+) regulatory T cells in the lymph nodes of the kidney were observed in the EPA-treated mice. These clinical and experimental observations suggest that EPA can safely support and augment conventional therapy for treating autoimmune small-vessel vasculitis.
    Scientific Reports 09/2014; 4:6406. DOI:10.1038/srep06406 · 5.58 Impact Factor
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    ABSTRACT: Background: Perioperative complication of end-organ injury including acute kidney injury (AKI) is a frequent and severe problem for patients undergoing left ventricular assist device (LVAD) implantation. This study evaluated an emerging AKI biomarker, plasma neutrophil gelatinase-associated lipocalin (NGAL), in a LVAD implantation cohort. Methods and results: Of 31 LVAD implantation patients enrolled to this study, 17 (55%) patients were diagnosed as having AKI. Six AKI patients showed severe AKI requiring renal replacement therapy (RRT). Plasma NGAL values in the AKI-with-RRT group (n=6) were significantly higher than that in other patients, although the AKI-without-RRT (n=11) group showed a similar level of plasma NGAL to that of the non-AKI group (n=14). Multiple logistic regression analysis revealed that plasma NGAL measured at pre-operation and central venous pressure at pre-operation and 12 h after surgery independently discriminated against postoperative RRT requirement. In the AKI-with-RRT group, plasma NGAL decreased before termination of RRT in 4 patients who eventually showed renal recovery, although no decline of plasma NGAL was observed in 2 patients who showed no recovery of renal function. Removal of blood NGAL by continuous hemodiafiltration was shown to be 70-75% lower than that of creatinine. Conclusions: Measurement of perioperative plasma NGAL is useful for predicting severe AKI requiring RRT and renal recovery in patients who have had LVAD implantation surgery. Further investigation is necessary to confirm these findings because this study examined a low number of patients.
    Circulation Journal 06/2014; 78(8). DOI:10.1253/circj.CJ-14-0008 · 3.94 Impact Factor
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    ABSTRACT: Acute lung injury and acute kidney injury are severe complications in critically ill patients and synergistically increase mortality in intensive care units. Organ cross-talk between the kidney and the lung has been implicated recently as amplifying injury in each organ. Here we sought to identify a possible mechanism of acute kidney injury-induced acute lung injury using a mouse bilateral nephrectomy model. Toll-like receptor 4 (TLR4)-mutant C3H/HeJ mice were more resistant to lung injury including neutrophil infiltration, increased neutrophil elastase activity, and vascular permeability caused by bilateral nephrectomy compared with TLR4-wild-type C3H/HeN mice 6 h after surgery. High-mobility group protein B1 (HMGB1) is one agonist for TLR4. Its blood concentrations were increased significantly by bilateral nephrectomy. Blockade of HMGB1 by neutralizing antibody reduced neutrophil infiltration in TLR4-wild-type C3H/HeN but not in TLR4-mutant C3H/HeJ mice. However, HMGB1 blockade in a renal ischemia reperfusion model reduced pulmonary neutrophil infiltration independent from TLR4. Thus, an enhanced HMGB1-TLR4 pathway contributes to lung injury induced by bilateral nephrectomy and the other HMGB1-dependent pathway exists in pulmonary neutrophil infiltration caused by renal ischemia reperfusion. Targeting the HMGB1-TLR4 pathway might enable development of a new therapeutic strategy to improve the outcomes of severely ill patients with both acute lung and acute kidney injury.Kidney International advance online publication, 19 March 2014; doi:10.1038/ki.2014.62.
    Kidney International 03/2014; 86(2). DOI:10.1038/ki.2014.62 · 8.56 Impact Factor
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    ABSTRACT: A selective 5-hydroxytryptamine (5-HT) 2A receptor antagonist sarpogrelate (SG) blocks serotonin-induced platelet aggregation. It has been used clinically for the treatment of peripheral arterial disease. SG might be able to improve chronic ischemia, which contributes to renal fibrosis progression by maintaining renal microcirculation. This study investigated whether SG suppresses renal fibrosis. C57BL/6 mice fed a 0.2% adenine-containing diet for 6 weeks developed severe tubulointerstitial fibrosis with kidney dysfunction. Subsequent SG treatment (30 mg/kg/day) for 4 weeks improved these changes significantly by increasing peritubular blood flow in the fibrotic area, as evaluated by intravital microscopy and decreasing fibrin deposition. Urinary L-type fatty acid-binding protein, up-regulated by renal hypoxia, was also reduced by SG. Additionally, results showed that mRNA expression of plasminogen activator inhibitor-1 (PAI-1), which is known to promote fibrosis by mediating and enhancing TGF-β1 signaling, was suppressed by SG treatment in the kidney. In vitro experiments using cultured murine proximal tubular epithelial (mProx) cells revealed that incubation with TGF-β1 and 5-HT increased PAI-1 mRNA expression; SG significantly reduced it. In conclusion, SG reduces renal fibrosis not only by the anti-thrombotic effect of maintaining peritubular blood flow, but also by suppressing PAI-1 expression in renal tubular cells.
    AJP Renal Physiology 10/2013; 305(12). DOI:10.1152/ajprenal.00151.2013 · 3.25 Impact Factor
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    ABSTRACT: Accumulating evidence of the beyond-glucose lowering effects of a gut-released hormone, glucagon-like peptide-1 (GLP-1), has been reported in the context of remote organ connections of the cardiovascular system. Specifically, GLP-1 appears to prevent apoptosis, and inhibition of dipeptidyl peptidase-4 (DPP-4), which cleaves GLP-1, is renoprotective in rodent ischemia-reperfusion injury models. Whether this renoprotection involves enhanced GLP-1 signaling is unclear, however, because DPP-4 cleaves other molecules as well. Thus, we investigated whether modulation of GLP-1 signaling attenuates cisplatin (CP)-induced AKI. Mice injected with 15 mg/kg CP had increased BUN and serum creatinine and CP caused remarkable pathologic renal injury, including tubular necrosis. Apoptosis was also detected in the tubular epithelial cells of CP-treated mice using immunoassays for single-stranded DNA and activated caspase-3. Treatment with a DPP-4 inhibitor, alogliptin (AG), significantly reduced CP-induced renal injury and reduced the renal mRNA expression ratios of Bax/Bcl-2 and Bim/Bcl-2. AG treatment increased the blood levels of GLP-1, but reversed the CP-induced increase in the levels of other DPP-4 substrates such as stromal cell-derived factor-1 and neuropeptide Y. Furthermore, the GLP-1 receptor agonist exendin-4 reduced CP-induced renal injury and apoptosis, and suppression of renal GLP-1 receptor expression in vivo by small interfering RNA reversed the renoprotective effects of AG. These data suggest that enhancing GLP-1 signaling ameliorates CP-induced AKI via antiapoptotic effects and that this gut-kidney axis could be a new therapeutic target in AKI.
    Journal of the American Society of Nephrology 10/2013; 24(12). DOI:10.1681/ASN.2013020134 · 9.34 Impact Factor
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    ABSTRACT: Apheresis therapy is used to remove pathogenic antibodies within the recipient blood during ABO-incompatible living related renal transplantation (LRRT). Factor XIII (FXIII) is a coagulating factor. Its deficiency reportedly engenders perioperative bleeding. This study compared apheresis modalities from the perspective of the FXIII level. Cases 1-3 were treated only with double-filtration plasmapheresis (DFPP) without (case 1) or with (cases 2 and 3) fresh frozen plasma (FFP) supplementation. Cases 4 and 5 were treated with simple plasma exchange (PEx) with FFP supplementation for the last session. Cases 1-3 showed a marked (case 1, 8.6%) or moderate (case 2, 26.2%; case 3, 28.4%) decrease in FXIII on the day before the procedure after the last apheresis session, although cases 4 (81.9%) and 5 (66.2%) did not. Case 1 experienced perioperative bleeding. The last session is usually performed the day before the surgical procedure. Therefore, FXIII elimination by DFPP might cause bleeding complications because of its slow recovery. The fact warrants that the last apheresis modality during the course might be PEx from the viewpoint of FXIII depletion.
    Transfusion and Apheresis Science 07/2013; 49(2). DOI:10.1016/j.transci.2013.06.004 · 0.77 Impact Factor
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    ABSTRACT: Non-anticoagulant hemodialysis is conducted occasionally at limited numbers of hospitals on an empirical basis. This study examines the efficacy of polysulfone and vitamin E-bonded polysulfone dialyzer for non-anticoagulant hemodialysis. These dialyzers were assigned one after the other for a vintage hemodialysis patient complicated with uncontrollable bleeding. The patient's vital and console data throughout non-anticoagulant hemodialysis were monitored serially. Both dialyzers were reasonably applicable to hemodialysis without major clotting. The scheduled treatment period was completed. Vitamin E-bonded polysulfone dialyzer was superior to non-anticoagulant hemodialysis based on venous pressure observed during treatment.
    ASAIO journal (American Society for Artificial Internal Organs: 1992) 05/2013; 59(3):284-5. DOI:10.1097/MAT.0b013e318289b975 · 1.52 Impact Factor
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    ABSTRACT: Purpose: Septic acute kidney injury (AKI) shows an unacceptably high mortality rate. Detection of sepsis is important for the clinical management of AKI patients. This study was undertaken to evaluate 2 biomarkers of neutrophil gelatinase-associated lipocalin (NGAL) and endotoxin activity (EA) assay and their combination for detecting sepsis in AKI. Materials and methods: Adult intensive care unit patients consisting of 40 non-AKI, 65 AKI without sepsis, 10 non-AKI with sepsis, and 24 septic AKI were examined in a cross-sectional manner. Plasma NGAL and EA values in whole blood were measured at recruitment. We evaluated whether combining 2 different biomarkers would improve the performance of each biomarker using receiver operating characteristic analysis. Results: Plasma NGAL was significantly higher in septic AKI patients than in the other AKI patients and non-AKI patients, whereas EA values were higher in septic patients than nonseptic patients irrespective of AKI complication. Combination of plasma NGAL and EA value increased the area under the curve of the receiver operating characteristic curve and showed better performance compared with a clinical model consisting of clinically available variables. Conclusion: Combinations of plasma NGAL and EA, which are operating via different pathological pathways, significantly improved their detection performance in complicated conditions of septic AKI.
    Journal of critical care 03/2013; 28(5). DOI:10.1016/j.jcrc.2013.01.009 · 2.00 Impact Factor
  • Transfusion and Apheresis Science 09/2012; 47:S8. DOI:10.1016/S1473-0502(12)70015-0 · 0.77 Impact Factor
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    ABSTRACT: Prerenal acute kidney injury (AKI) is thought to be a reversible loss of renal function without structural damage. Although prerenal and intrinsic AKI frequently coexist in clinical situations, serum creatinine and urine output provide no information to support their differentiation. Recently developed biomarkers reflect tubular epithelial injury; therefore, we evaluated urinary biomarker levels in an adult mixed intensive care unit (ICU) cohort of patients who had been clinically evaluated as having prerenal AKI. Urinary L-type fatty acid-binding protein (L-FABP), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), N-acetyl-β-D-glucosaminidase (NAG), and albumin in patients with prerenal AKI showed modest but significantly higher concentrations than in patients with non-AKI. We also conducted a proof-of-concept experiment to measure urinary biomarker excretion in prerenal AKI caused by volume depletion. Compared with cisplatinum and ischemia-reperfusion models in mice, volume depletion in mice caused a modest secretion of L-FABP and NGAL into urine with more sensitive response of L-FABP than that of NGAL. Although no histological evidence of structural damage was identified by light microscopy, partial kidney hypoxia was found by pimonidazole incorporation in the volume depletion model. Thus, our study suggests that new AKI biomarkers can detect mild renal tubular damage in prerenal acute kidney injury.Kidney International advance online publication, 1 August 2012; doi:10.1038/ki.2012.266.
    Kidney International 08/2012; 82(10). DOI:10.1038/ki.2012.266 · 8.56 Impact Factor
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    ABSTRACT: Fabry disease is a genetic disorder caused by deficient activity of lysosomal enzyme α-galactosidase A (GLA) and end-stage renal disease (ESRD) will be present after accumulation of glycosphingolipids within the kidney. Undiagnosed atypical variants of Fabry disease, which are limited to renal involvement, were found in several ESRD patient populations. On the other hand, unexpectedly high frequencies of male subjects having the c.196G>C nucleotide change (p.E66Q) showing low α-GLA activity have been reported on Japanese and Korean screening for Fabry disease. However, several evidences indicate the c.196G>C is not a pathogenic mutation but is a functional polymorphism. In the present study, high-throughput screening of serum GLA could successfully indentify two Fabry disease patients in a cohort consisted of 1080 male hemodialysis patients. Moreover, our serum assay was able to distinguish two patients with disease-causing genetic mutations (p.G195V and p.M296I) from eight functional variants that showed relatively decreased enzyme activity (p.E66Q). In conclusion, high-throughput serum enzyme assay distinctly identified disease-causing mutants and functional variants of GLA gene in Japanese male hemodialysis patients. In addition, our results underscore the high prevalence of not only undiagnosed Fabry patients but functional variants of p.E66Q among the ESRD population.
    Journal of Human Genetics 06/2012; 57(9):575-9. DOI:10.1038/jhg.2012.68 · 2.46 Impact Factor
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    Norio Hanafusa · Yoshifumi Hamasaki · Kosuke Negishi · Eisei Noiri · Toshiro Fujita
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    ABSTRACT: Hemodialysis removes solutes uniformly according to their molecular weight. During each hemodialysis session, 6–8 g of amino acids are reportedly removed into the dialysate. Little is known about the amount of amino acids removed from those who have undergone intradialytic parenteral nutrition (IDPN).Objective We measured amino acid amounts prospectively during hemodialysis treatment.Methods We used 200 ml of 7.2% amino acid solution (KidminTM), 200 ml of 50% glucose, and 20% of lipid emulsion as IDPN fluid. Blood samples were collected at the beginning and end of each session. The dialysate portion was also collected.ResultsSix patients were included in this study after providing written informed consent. The amount of amino acids removed during hemodialysis sessions was calculated as 9.1±1.4 g, which was less than that infused as IDPN. The profiles of the removed amino acids showed that the amount removed was less than that within IDPN. However, for tyrosine and alanine, hemodialysis treatment removed more amino acids than that infused as IDPN, as well as amino acids that were not IDPN solution constituents. During a 2-week follow-up period, no significant change in amino acid profiles was observed.ConclusionsIDPN entirely supplemented the removed amino acids, although some amino acids were not restored.
    06/2012; 31(2):A34. DOI:10.1016/j.krcp.2012.04.395
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    ABSTRACT: Epidemiological data have suggested that 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) prevent the progression of chronic kidney diseases (CKDs), whereas the precise mechanism explaining in vitro to in vivo is missing. This study is aimed at exploring a new mechanism of action by statins on renal fibrosis, a hallmark of CKD, using mouse renal fibrosis model in vivo and Madin-Darby canine kidney (MDCK) cells expressing USAG-1 in vitro. C57/BL6 mice fed a 0.2% adenine-containing diet for 4 weeks developed renal dysfunction accompanied with severe tubulointerstitial fibrosis. Subsequent simvastatin (SIM) treatment (50 mg/kg per day) for 2 weeks significantly suppressed fibrosis progression. We found that SIM enhanced bone morphogenetic protein-7 (BMP-7)-mediated anti-fibrotic signaling with the reduced expression of uterine sensitization-associated gene-1 (USAG-1), a BMP-7 antagonist produced by renal distal tubular epithelial cells. Therefore, MDCK cells were incubated with transforming growth factor-β1 and showed increased expression of USAG-1 and α-smooth muscle actin; SIM significantly reduced them. SIM significantly increased E-cadherin expression. Gene knockdown experiments using MDCK suggested that homeobox protein Hox-A13 (HOXA13) played a suppressive role in the USAG-1 gene and thus SIM reduced USAG-1 by increasing HOXA13 expression. The data from our study demonstrate that SIM, one of statins, contributes to prevent the progression of renal fibrosis by upregulating BMP-7-mediated anti-fibrotic signaling and that one aspect of crucial efficacies is achieved by regulating HOXA13 and USAG-1. HOXA13-USAG-1 pathway is a newly identified mechanism in renal fibrosis and will be a new therapeutic target for preventing renal fibrosis progression in CKDs.
    Laboratory Investigation 04/2012; 92(8):1161-70. DOI:10.1038/labinvest.2012.71 · 3.68 Impact Factor
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    ABSTRACT: Glomerular infiltration of macrophages is a characteristic alteration of renal pathology in hyperlipidaemic renal injury. Leukotriene B4 (LTB4) is a bioactive eicosanoid and macrophage and has two key enzymes for LTB4 synthesis, 5-lipoxygenase and leukotriene A4 (LTA4) hydrolase. The purpose of this study was to evaluate the role of LTB4 in accelerated hyperlipidaemic renal injury. To induce accelerated hyperlipidaemic renal injury, 8 week old male spontaneously hypercholesterolaemic (SHC) rats were fed with a high cholesterol diet for 6 weeks. LTA4 hydrolase activities in the kidney and urine LTB4 levels were examined. The effects of LTB4 antagonist (ONO-4057) were also evaluated. Urinary protein and LTB4 excretion was increased by a high cholesterol diet for 6 weeks. The scores of glomerular foam cell accumulation and sclerosis, numbers of infiltrated macrophages in glomeruli and interstitial area, LTA4 hydrolase activity in renal cortex were higher in the high cholesterol diet group than the normal diet group. LTB4 antagonist treatment reduced urinary protein and LTA4 activity and attenuated renal pathological changes. These results suggest that LTB4 directly contributes to accelerated hyperlipidaemic renal injury and the therapeutic potential of LTB4 antagonist for renal damage induced by hyperlipidaemia.
    Nephrology 03/2011; 16(3):304-9. DOI:10.1111/j.1440-1797.2010.01387.x · 2.08 Impact Factor
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    ABSTRACT: The diagnostic process of disease detection and the disease management after therapy has been initiated differ from one disease to the next. The process of diagnosing kala-azar has recently been simplified. The time-consuming pathological exam that was formerly needed has been replaced by a convenient blood test. But once treatment has begun, the monitoring of disease activity still relies on clinical findings and laboratory data in endemic areas. In this chapter, we propose the use of the urinary biomarker, fatty-acid-binding protein 1 (FABP1), for monitoring kala-azar disease activity and drug-induced side effects. The FABP1 assay, developed as an enzyme-linked immunosorbent assay, was developed in the form of an immunochromatography (dipstick) urine test in our project for use in areas with a high concentration of kala-azar infection. We expect that the FABP1 dipstick test will prove invaluable as a triage tool and for monitoring the severity of the disease. In addition, we discuss the potential usefulness of urinary interleukin-18, a biomarker for acute kidney injury, in monitoring kala-azar activity. Further studies of this and other recently discovered urinary biomarkers are needed. KeywordsDipstick urine test-Fatty-acid-binding protein 1-Interleukin-18-Kala-azar-Leishmaniasis-Urinary biomarker
    12/2010: pages 69-90;

Publication Stats

158 Citations
88.22 Total Impact Points


  • 2008–2015
    • The University of Tokyo
      • • Department of Nephrology and Endocrinology
      • • Center for 22nd Century Medical and Research
      Tōkyō, Japan
  • 2012
    • Shiga University of Medical Science
      • Department of Surgery
      Ōtu, Shiga Prefecture, Japan