K Kiyosawa

Japan Red Cross Fukuoka Hospital, Hukuoka, Fukuoka, Japan

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Publications (517)2106.65 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The number of hepatocellular carcinoma (HCC) patients with non-viral etiologies is increasing in Japan. We conducted a nation-wide survey to examine the characteristics of those patients.
    Journal of gastroenterology. 06/2014;
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    ABSTRACT: Natural killer cells play a key role in the immune control of viral infections. Killer immunoglobulin-like receptors (KIRs) regulate natural killer cell activation and inhibition through the recognition of their cognate HLA class I ligands. We assessed the predictive factors of a sustained virological response (SVR) in 200 Japanese patients with chronic genotype 1b hepatitis C who were treated with telaprevir (TVR), pegylated-interferon-α2b (PEG-IFN), and ribavirin (RBV) triple therapy (92 patients) or PEG-IFN/RBV therapy alone (108 patients). Sixteen KIR genotypes, HLA-A, -B and -C ligands, and an interleukin (IL) 28B polymorphism (rs8099917) were analyzed. We observed that triple therapy, white blood cell count, hemoglobin value, hepatitis C viral load, a rapid virological response (RVR), IL28B TT genotype, and KIR3DL1-HLA-Bw4 genotype were associated with an SVR. In multivariate regression analysis, we identified an RVR (P < 0.000001; odds ratio [OR] = 20.95), the IL28B TT genotype (P = 0.00014; OR = 5.53), and KIR3DL1-HLA-Bw4 (P = 0.004, OR = 3.42) as significant independent predictive factors of an SVR. In conclusion, IL28B and KIR3DL1/HLA-Bw4 are independent predictors of an SVR in Japanese patients infected with genotype 1b HCV receiving TVR/PEG-IFN/RBV or PEG-IFN/RBV therapy.
    Human immunology. 06/2014;
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    ABSTRACT: This prospective, non-randomized, multicenter cohort study analyzed the safety and efficacy of a steroid-free immunosuppressive (IS) protocol for hepatitis C virus (HCV)-positive living donor liver transplant (LDLT) recipients in Japan. Of 68 patients enrolled from 13 transplant centers, 56 fulfilled the inclusion/exclusion criteria; 27 were assigned the steroid-free IS protocol (Fr group) and 29 the traditional steroid-containing IS protocol (St group). Serum HCV RNA levels increased over time and were higher in the St group until postoperative day 90 (POD 14, p = 0.013). Preemptive anti-HCV therapy was started in a higher percentage of recipients (59.3%) in the Fr group than in the St group (31.0%, p = 0.031), mainly due to early HCV recurrence. The incidence of HCV recurrence at one yr was lower in the Fr group (22.2%) than in the St group (41.4%; p = 0.066). The incidence of acute cellular rejection was similar between groups. New onset diabetes after transplant, cytomegalovirus infection, and renal dysfunction were significantly less frequent in the Fr group than in the St group (p = 0.022, p < 0.0001, p = 0.012, respectively). The steroid-free IS protocol safely reduced postoperative morbidity and effectively suppressed both the HCV viral load in the early post-transplant period and HCV recurrence in HCV-positive LDLT recipients.
    Clinical Transplantation 04/2012; · 1.63 Impact Factor
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    ABSTRACT: The long-term outcome of patients with autoimmune hepatitis (AIH) in Japan has not been well-defined. The aim of this study was to clarify the outcome of this disease over a long follow-up period compared with that of the general Japanese population as well as that among patients. A total of 203 AIH patients were enrolled for a mean follow-up period of 131 months. All patients were treated with corticosteroids with or without azathioprine. The overall survival of AIH patients was similar to that of the general population in Japan. The prognosis of AIH subgroups divided according to disease severity, sex, incidence of relapse, liver histology, presence of cirrhosis, probable or definite AIH score, antibody to hepatitis B core antigen antibody positivity, or human leukocyte antigen DR4-positivity did not differ greatly among patients. However, the prognosis of patients experiencing two or more relapses was significantly poorer than that of patients with remission or a single relapse both in univariate (P < 0.001) and multivariate (P = 0.020) analyses. The development of liver malignancy was also a possibility among AIH patients with multiple relapses. Severe adverse effects of corticosteroids were rare, even in patients who underwent long-term treatment. CONCLUSION: Repeated relapses of AIH are significantly associated with a poorer long-term prognosis in Japan. AIH patients can expect a similar prognosis to that of the general population, provided they are adequately managed with continuous low doses of immunosuppressive therapy, especially after the first relapse.
    Hepatology 02/2012; 56(2):668-76. · 12.00 Impact Factor
  • Gastroenterology 01/2011; 140(5). · 12.82 Impact Factor
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    ABSTRACT: Immunoglobulin (Ig) G4-associated autoimmune hepatitis (AIH) is a recently identified and possibly new disease entity. However, the epidemiology and clinical features of IgG4-associated AIH remain uncertain. The aim of this study was to determine the prevalence and the clinical, serological, and histological characteristics of IgG4-associated AIH. We examined the clinical features, serum IgG4 concentration, liver biopsy histology, and IgG4-bearing plasma cell infiltration of 60 patients with type 1 AIH and 22 patients with autoimmune pancreatitis. High serum IgG4 concentration (≥ 135 mg/dL) and IgG4-bearing plasma cell infiltration in the liver (≥ 10/high-power fields [HPFs]) were found in 2 of the 60 (3.3%) patients with type 1 AIH. These patients had high serum levels of IgE, giant cell change, and rosette formation in the liver. Although corticosteroid therapy reduced the serum IgG4 concentration and normalized liver enzymes and histology, one patient developed IgG4-related sclerosing cholangitis after 5 years of follow-up. Because IgG4-associated AIH was found in over 3% of Japanese patients with type 1 AIH in our cohort, further studies are needed on this possible new disease entity and its impact on the diagnostic guidelines of AIH.
    Journal of Gastroenterology 01/2011; 46 Suppl 1:48-55. · 3.79 Impact Factor
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    Hepatology 07/2010; 52(1):389-90. · 12.00 Impact Factor
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    ABSTRACT: To evaluate the long-term efficacy of entecavir in nucleoside-naïve chronic hepatitis B patients. One hundred and sixty-seven patients treated with entecavir 0.01mg, 0.1mg or 0.5mg for 24-52weeks in Phase II studies entered rollover study ETV-060 and received entecavir 0.5mg daily. Responses were evaluated among patients with available samples. After 96weeks in ETV-060 (120-148weeks total entecavir treatment time), 88% (127/144) of patients had HBV-DNA <400 copies/ml; 90.1% (128/142) had alanine aminotransferase (ALT) 1x the upper limit of normal (ULN) among those with abnormal baseline ALT; and 26% (32/121) achieved HBe seroconversion among those HBeAg(+) at baseline. A subset of 66 patients received entecavir 0.5mg (approved dose) from Phase II baseline: at week 96 in ETV-060, 83% (48/58) had HBV-DNA <400 copies/ml, 88% (52/59) had ALT 1x ULN, and 20% (10/49) achieved HBe seroconversion. Twenty-one out of 66 patients had paired baseline and on-treatment biopsies: 100% (21/21) and 57% (12/21) demonstrated histologic improvement, and improvement in fibrosis, respectively, over 3years. The 3-year cumulative probability of resistance was 3.3% for all patients and 1.7% for the 0.5mg subset. Long-term entecavir for nucleoside-naïve patients resulted in high rates of virological, biochemical, and histological response, with minimal resistance.
    Journal of Hepatology 06/2010; 52(6):791-9. · 9.86 Impact Factor
  • T. Umemura, K. Kiyosawa, E. Tanaka
    Journal of Hepatology - J HEPATOL. 01/2010; 52.
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    ABSTRACT: The Japanese Liver Transplantation Society presented its first report on donor morbidity in 2003. The Society has been continuing to survey outcomes in living liver donors in Japan. By using a uniform comprehensive medical record review process, data were collected on 3565 living liver donors who had donated grafts by the end of December 2006 at 38 Japanese centers. Preoperative problems were reported in 2 donors, intraoperative problems in 27, and postoperative complications in 270. In total, 299 donors (8.4%) suffered complications related to liver donation. Postoperative complications included biliary complications in 3.0%, reoperation in 1.3%, severe after-effects in two (0.06%), and death (apparently related to donor surgery) in one donor (0.03%). The incidence of postoperative complications in left and right lobe donors was 8.7% and 9.4%, respectively. The accumulated experience indicates a reduction in the incidence of donor complications, especially for right lobe resection. One donor death and two cases of severe after effects related to liver donation have been reported during 18 years of living donor liver transplantation experience in Japan.
    Transplantation 08/2009; 88(1):110-4. · 3.78 Impact Factor
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    ABSTRACT: Entecavir (ETV) is a potent nucleoside analogue against hepatitis B virus (HBV), and emergence of drug resistance is rare in nucleoside-naive patients because development of ETV resistance (ETVr) requires at least three amino acid substitutions in HBV reverse transcriptase. We observed two cases of genotypic ETVr with viral rebound and biochemical breakthrough during ETV treatment of nucleoside-naive patients with chronic hepatitis B (CHB). Case 1: A 44-year-old HBeAg-positive man received ETV 0.1 mg/day for 52 weeks and 0.5 mg/day for 96 weeks consecutively. HBV DNA was 10.0 log(10) copies/ml at baseline, declined to a nadir of 3.1 at week 100, and rebounded to 4.5 at week 124 and 6.7 at week 148. Alanine aminotransferase (ALT) level increased to 112 IU/l at week 148. Switching to a lamivudine (LVD)/adefovir-dipivoxil combination was effective in decreasing HBV DNA. Case 2: A 47-year-old HBeAg-positive man received ETV 0.5 mg/day for 188 weeks. HBV DNA was 8.2 log(10) copies/ml at baseline, declined to a nadir of 2.9 at week 124, and then rebounded to 4.7 at week 148 and 6.4 at week 160. ALT level increased to 72 IU/l at week 172. The ETVr-related substitution (S202G), along with LVD-resistance-related substitutions (L180M and M204V), was detected by sequence analysis at week 124 in both case 1 and case 2. ETVr emerged in two Japanese nucleoside-naive CHB patients after prolonged therapy and incomplete suppression and in one patient after <0.5 mg of dosing. ETV patients with detectable HBV DNA or breakthrough after extended therapy should be evaluated for compliance to therapy and potential emergence of resistance.
    Hepatology International 06/2009; 3(2):403-10. · 2.64 Impact Factor
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    ABSTRACT: Alcoholic liver disease (ALD) is one of the leading causes of cirrhosis and yet efficient therapeutic strategies are lacking. Polyenephosphatidylcholine (PPC), a major component of essential phospholipids, prevented alcoholic liver fibrosis in baboons, but its precise mechanism remains uncertain. We aimed to explore the effects of PPC on ALD using ethanol-fed peroxisome proliferator-activated receptor alpha (Ppara)-null mice, showing several similarities to human ALD. Male wild-type and Ppara-null mice were pair-fed a Lieber-DeCarli control or 4% ethanol-containing diet with or without PPC (30 mg/kg/day) for 6 months. PPC significantly ameliorated ethanol-induced hepatocyte damage and hepatitis in Ppara-null mice. These effects were likely a consequence of decreased oxidative stress through down-regulation of reactive oxygen species (ROS)-generating enzymes, including cytochrome P450 2E1, acyl-CoA oxidase, and NADPH oxidases, in addition to restoration of increases in Toll-like receptor 4 and CD14. PPC also decreased Bax and truncated Bid, thus inhibiting apoptosis. Furthermore, PPC suppressed increases in transforming growth factor-beta1 expression and hepatic stellate cell activation, which retarded hepatic fibrogenesis. PPC exhibited anti-inflammatory, anti-apoptotic, and anti-fibrotic effects on ALD as a result of inhibition of the overexpression of ROS-generating enzymes. Our results demonstrate detailed molecular mechanisms of the anti-oxidant action of PPC.
    Journal of Hepatology 05/2009; 50(6):1236-46. · 9.86 Impact Factor
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    ABSTRACT: Hepatoprotective therapies that include regular glycyrrhizin injections (GIs) are beneficial for chronic hepatitis C patients, but are sometimes insufficient for normalizing serum alanine aminotransferase (ALT) levels. Here, we evaluated whether the addition of minor bloodletting, named petit phlebotomy (PP), prior to each GI could further reduce serum ALT concentrations in such patients. Seventy-six hepatitis C virus (HCV)-infected patients receiving regular GI, with persistently abnormal serum ALT levels, were randomly divided into GI + PP and GI groups and monitored for 12 months. PP was performed before every GI to a total 60 ml of blood a week. The primary PP endpoint was a serum ferritin level of less than 20 ng/ml. PP was suspended upon reaching the endpoint, but was resumed as needed. The efficacy of the addition of PP was evaluated by measuring changes in serum ALT levels. Two patients in each group dropped out because of the appearance of hepatocellular carcinoma. The remainder completed the 12-month treatment with no serious adverse events. Serum ALT and ferritin levels were significantly decreased in the GI + PP group (from 67 +/- 34 to 44 +/- 14 U/l and from 163 +/- 127 to 25 +/- 21 ng/ml, respectively, both P < 0.001), but these changes were not seen in the GI group. Although 20 patients in the GI + PP group had compensated cirrhosis, no significant reductions in serum albumin concentrations were observed. The addition of PP is effective and safe for improving serum aminotransferase levels in HCV-infected patients receiving regular GI, even in those with compensated cirrhosis.
    Journal of Gastroenterology 04/2009; 44(6):577-82. · 3.79 Impact Factor
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    ABSTRACT: Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are characterized by a high mortality rate; therefore, ARDS/ALI in humans is a leading cause of morbidity and mortality in critically ill patients. As previously reported, cytokines play a critical role as signaling molecules that initiate, amplify, and perpetuate inflammatory responses on a local and systemic basis, and the polymyxin-B immobilized direct hemoperfusion system (PMX-DHP) is effective for the treatment of ARDS/ALI. Furthermore, another direct hemoperfusion system using the beta2-microglobulin-selective adsorbent column, Lixelle, the direct hemoperfusion treatment (Lixelle-DHP), has been applied in some cases to patients who are affected with systemic inflammatory response syndrome. The aim of this study is to evaluate the therapeutic efficacy of Lixelle-DHP in the treatment of ARDS/ALI. Four patients, aged 67-79 years old (mean 72 +/- 6.2 years), diagnosed with ARDS/ALI were treated with Lixelle-DHP. The P(a)O(2)/fraction of inspired oxygen (F(i)O(2)) ratio (PF ratio) was 90.0 +/- 22.9 before the treatment, and it increased to 129.9 +/- 5.6 at 72 h afterward the start of treatment. Inflammatory cytokines such as interleukin (IL)-1 beta, IL-6, soluble intercellular adhesion molecule 1 (sICAM-1) decreased significantly after the treatment. All patients were still alive after one month. However, while IL-2 had decreased significantly after the treatment, it had returned by the next treatment. It is possible that Lixelle-DHP might be able to improve the PF ratio and mortality rate as a result of decreased cytokines, and it has been suggested that Lixelle-DHP has a beneficial influence in the treatment of ARDS/ALI.
    Therapeutic apheresis and dialysis: official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy 03/2009; 13(1):27-33. · 1.53 Impact Factor
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    ABSTRACT: The original publication is available at www.springerlink.com
    01/2009;
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    ABSTRACT: Primary liver cancer, 95% of which is hepatocellular carcinoma (HCC), is ranked third in men and fifth in women as a cause of death from malignant neoplasms in Japan. The number of deaths and death rate of HCC began to increase sharply in 1975. These numbers peaked at 34,510 and 27.4/100,000, respectively, in 2004, but decreased to 33,662 annual deaths and a 26.7/100,000 death rate in 2006. Although hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are both major causes of HCC, HCV-related HCC represents 70% of all cases. The incidence of HCC without hepatitis B surface antigen (HBsAg) or antibodies to HCV (anti-HCV) accounts for 8%-15% of HCC patients nationwide. Geographically, HCC is more frequent in western than eastern Japan, and death rates of HCC in each prefecture correlate with anti-HCV, but not HBsAg, prevalence. Interferon therapy for chronic hepatitis C reduces the risk of development of HCC, especially among patients with sustained virological response. Further research should focus on the mechanisms of carcinogenesis by HCV and HBV, development of more effective treatments, and establishment of early detection and preventative approaches. Better understanding of HCC unrelated to HCV and HBV, possibly caused by steatohepatitis and diabetes, should also be a major concern in future studies.
    Journal of Gastroenterology 01/2009; 44 Suppl 19:102-7. · 3.79 Impact Factor
  • Kanzo 01/2009; 50(1):38-42.
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    ABSTRACT: Hepatitis B virus (HBV) reactivation in patients with resolved HBV infection was found in 23 (4%) of 552 newly hepatitis B surface antigen-positive patients in Japan. Because one-fourth of cases develop into fulminant hepatic failure and mortality is 100%, management of HBV reactivation in patients with resolved HBV infection should be discussed.
    Clinical Infectious Diseases 09/2008; 47(5):e52-6. · 9.37 Impact Factor
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    ABSTRACT: Aim: Autoimmune hepatitis (AIH) is an organ-specific autoimmune disease characterized by chronic inflammation of the liver. Although the HLA DR4 allele is associated with type 1 AIH in Japanese, the exact genetic etiology of AIH remains undefined. The cytotoxic T-lymphocyte antigen 4 (CTLA4) is an inhibitory receptor expressed by T-cells that acts largely as a negative regulator of T-cell responses, and polymorphisms of CTLA4 have been reported to be associated with susceptibility to various autoimmune diseases. Therefore, we sought to clarify whether CTLA4 single-nucleotide polymorphisms are associated with disease susceptibility in Japanese patients with type 1 AIH. Methods: We genotyped 76 patients with AIH and 100 ethically matched controls for allelic determinants using TaqMan genotyping assays at four polymorphism sites: -1722 and -318 in the promoter; +49 in exon 1 and +6230 in the 3' untranslated region. Results: We observed no difference in the distribution of the alleles, genotypes, or haplotypes between patients and controls. Compared with -1722 C/C patients, -1722 T/T patients were younger (56 vs. 63 years; P = 0.01) and had significantly lower serum levels of aspartate aminotransferase (313 vs. 763 IU/L; P = 0.031) and bilirubin (1.1 vs. 8.6 mg/dL; P = 0.027). Analysis of allelic frequencies revealed no significant difference between patients with and without the HLA DR4 allele. Conclusion: These data suggest that the CTLA4 polymorphism is not associated with susceptibility to type 1 AIH in the Japanese population.
    Hepatology Research 08/2008; 38(7):689-95. · 2.07 Impact Factor
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    ABSTRACT: The interferon sensitivity determining region (ISDR) of the hepatitis C virus (HCV) and T-helper type 1 and type 2 (Th1/Th2) ratio were analyzed along with other host and viral factors for their ability to predict the response of patients with chronic hepatitis C to pegylated interferon alpha-2b (Peg-IFN) and ribavirin (RBV) combination therapy. A total of 120 chronic hepatitis C patients with genotype 1 HCV and high baseline viral loads who were to undergo combination therapy scheduled for 48 weeks were enrolled. Sustained virologic response (SVR) was achieved in 54 (45%) of the 120 patients. The pretreatment factors significantly associated with SVR by logistic regression analysis were ISDR mutant [odds ratio (OR) = 86.0, P = 0.0008], Th1/Th2 ratio ≤ 15.5 (OR = 9.6, P = 0.0021), body weight 59 kg, and neutrophil count 2,300/μL. A logistic regression model to estimate SVR before combination therapy was constructed using these four factors. Patients fell into three groups when plotted according to estimated and actual SVR rates: actual SVR rate was 91% (32/35) in the high sensitivity group, 41% (15/37) in the intermediate sensitivity group, and 15% (7/48) in the low sensitivity group. Rapid or early virological responses were seen in 80% of patients with high sensitivity and who achieved SVR but were found in only 40% of patients with intermediate or low sensitivity. Null- and very late virological responses were quite rare in the high sensitivity group. In conclusion, a logistic regression model that includes the sequence of ISDR of the HCV, Th1/Th2 ratio, body weight, and neutrophil count can be useful for accurately predicting actual SVR rate before combination therapy. (HEPATOLOGY 2008;48:1753-1760.)
    Hepatology 07/2008; 48(6):1753 - 1760. · 12.00 Impact Factor

Publication Stats

11k Citations
2,106.65 Total Impact Points

Institutions

  • 1999–2014
    • Japan Red Cross Fukuoka Hospital
      Hukuoka, Fukuoka, Japan
  • 1972–2011
    • Shinshu University
      • • Department of Medicine
      • • Division of Gastroenterology
      • • Department of Metabolic Regulation
      • • Department of Internal Medicine I
      Shonai, Nagano, Japan
  • 1991–2010
    • Chiba University
      • Department of Medicine and Clinical Oncology
      Chiba-shi, Chiba-ken, Japan
    • Aizawa Hospital
      Honjō, Saitama, Japan
  • 2009
    • Okayama University
      • Department of Gastroenterology and Hepatology
      Okayama, Okayama, Japan
  • 1998–2007
    • Showa General Hospital
      Edo, Tōkyō, Japan
  • 2005
    • Tokyo Metropolitan Institute of Medical Science
      Edo, Tōkyō, Japan
  • 1983–2004
    • Matsumoto University
      Shonai, Nagano, Japan
  • 2003
    • National Heart, Lung, and Blood Institute
      Maryland, United States
    • Dokkyo Medical University
      Totigi, Tochigi, Japan
  • 2000–2003
    • Baylor College of Medicine
      • • Department of Medicine
      • • Veterans Affairs Medical Center
      Houston, TX, United States
  • 1992–2001
    • The Scripps Research Institute
      • Department of Molecular and Experimental Medicine
      La Jolla, CA, United States
  • 1990–2000
    • Kofu Municipal Hospital
      Kōhu, Yamanashi, Japan
    • Japanese Red Cross
      Edo, Tōkyō, Japan
  • 1997
    • National Eye Institute
      Maryland, United States
  • 1996
    • National Institutes of Health
      Maryland, United States
  • 1994
    • Nihon University
      • Department of Pathology
      Tokyo, Tokyo-to, Japan