Researchers Database

iwami daiki

    UrologyRenalSurgeryandTransplantation Professor
Last Updated :2021/10/18

Researcher Information


Research funding number

  • 80581115


J-Global ID

Research Areas

  • Life sciences / Immunology
  • Life sciences / Urology

Academic & Professional Experience

  • 2020/04 - Today  Jichi Medical UniversityDivision of Renal Surgery and TransplantationProfessor
  • 2014/04 - 2020/03  Hokkaido University大学病院

Published Papers

  • Iwami D
    International journal of urology : official journal of the Japanese Urological Association 26 (2) 312  0919-8172 2019/02 [Refereed][Not invited]
  • Iwami D, Miura M, Chiba Y, Ota M, Matsumoto T, Hotta K, Sasaki H, Hirose T, Harada H, Shinohara N
    Transplantation proceedings 50 (10) 3478 - 3482 0041-1345 2018/12 [Refereed][Not invited]
  • Hirose T, Hotta K, Iwami D, Harada H, Morita K, Tanabe T, Sasaki H, Fukuzawa N, Seki T, Shinohara N
    Journal of endourology 32 (12) 1120 - 1124 0892-7790 2018/12 [Refereed][Not invited]
  • Iwami D, Aramaki O, Shinohara N, Niimi M, Shirasugi N
    Transplant immunology 50 60 - 67 0966-3274 2018/07 [Refereed][Not invited]
  • Hiroyuki Iwano, Shingo Tsujinaga, Daiki Iwami, Naoya Asakawa, Satoshi Yamada, Toshihisa Anzai
    CASE (Philadelphia, Pa.) 2 (3) 103 - 108 2018/06 [Refereed][Not invited]
  • Hajime Sasaki, Daiki Iwami, Kiyohiko Hotta, Ken Morita, Tomoaki Naka, Nobuo Shinohara
    International Journal of Urology 25 (5) 513 - 514 1442-2042 2018/05 [Refereed][Not invited]
  • Kanae Takahashi, Teruki Yanagi, Shinya Kitamura, Hiroo Hata, Keisuke Imafuku, Daiki Iwami, Kiyohiko Hotta, Ken Morita, Nobuo Shinohara, Hiroshi Shimizu
    Journal of Dermatology 45 (5) e116 - e117 1346-8138 2018/05 [Refereed][Not invited]
  • Nakano K, Iwami D, Yamada T, Morita K, Yasuda K, Shibuya H, Kahata K, Shinohara N, Shimizu C
    Transplantation direct 4 (1) e337  2018/01 [Refereed][Not invited]
  • K. Kawakubo, M. Kuwatani, T. Shimamura, K. Yamashita, R. Goto, M. Watanabe, Y. Koshizuka, N. Kawamura, D. Iwami, K. Hotta, I. Sano, R. Sugiura, S. Kato, N. Shinohara, A. Taketomi, N. Sakamoto
    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 32 (11) 1791 - 1791 0815-9319 2017/11 [Refereed][Not invited]
  • 山崎 健史, 高橋 俊行, 林 麻子, 岡本 孝之, 岩見 大基, 森田 研
    日本小児腎臓病学会雑誌 (一社)日本小児腎臓病学会 30 (1) 90 - 90 0915-2245 2017/04 [Refereed][Not invited]
  • Kiyohiko Hotta, Masayoshi Miura, Yoshiki Wada, Nobuyuki Fukuzawa, Daiki Iwami, Hajime Sasaki, Toshimori Seki, Hiroshi Harada
    INTERNATIONAL JOURNAL OF UROLOGY 24 (4) 314 - 319 0919-8172 2017/04 [Refereed][Not invited]
    ObjectivesTo evaluate the risk for urological complications after kidney transplantation at a single medical center in Japan. MethodsIn the present study, 408 kidney recipients (255 men, 153 women) were enrolled. There were 349 living and 59 deceased donors. The average age of the recipients was 42.513.5years, and the average pretransplant dialysis period was 71.888.2months. Ureteroneocystostomy was carried out on 347 patients, and ureteroureterostomy on 61 patients. We investigated the relationship between pretransplant duration of dialysis and bladder capacity, and examined the risk factors for urological complication. We also evaluated the incidence of vesicoureteral reflux in 191 recipients who underwent ureteroneocystostomy during transplantation. ResultsThe preoperative duration of dialysis therapy showed a significant negative correlation with bladder capacity (R-2=0.33, P<0.001). The overall urological complication rate was 3.4% (14 patients), including urinary leakage (12 patients) and ureteral stricture (two patients). Univariate analysis showed that atrophic bladder, long-term dialysis therapy, deceased donor and ureteroureterostomy were associated with a higher incidence of urological complications (odds ratio 8.05, 4.43, 3.42 and 3.35; P<0.01, P=0.01, P=0.04 and P=0.04, respectively). Furthermore, multivariate analysis showed that atrophic bladder was the only significant factor associated with urological complications (odds ratio 10.37; P=0.01). Among 191 recipients, vesicoureteral reflux was observed in 32 (16.8%). The incidence of vesicoureteral reflux was significantly higher in patients with atrophic bladder. ConclusionsBladder atrophy in renal transplant recipients after long-term dialysis therapy is associated with a higher risk of urological complications.
  • A. Nakamura, D. Iwami, H. Miyoshi, K. Morita, M. Taguri, Y. Terauchi, N. Shinohara, T. Atsumi
    DIABETIC MEDICINE 34 (4) 569 - 576 0742-3071 2017/04 [Refereed][Not invited]
    AimsTo investigate changes in glucose tolerance, insulin secretion and insulin sensitivity in Japanese recipients before and 1 year after renal transplantation. MethodsWe conducted a study of Japanese recipients without diabetes who underwent renal transplantation at Hokkaido University Hospital. A 75-g oral glucose tolerance test was performed before and 1 year after renal transplantation in these recipients. Insulin sensitivity was estimated using the Matsuda index and homeostasis model assessment of insulin resistance (HOMA-IR). Insulin secretion was evaluated based on the insulin secretion sensitivity index-2 (ISSI-2). ResultsOf the 62 renal transplant recipients, 31 were diagnosed as having impaired glucose tolerance before transplantation. Among these 31 recipients, after 1 year, four had developed new-onset diabetes after transplantation, and nine had impaired glucose tolerance. Unexpectedly, 18 changed from impaired to normal glucose tolerance. When these recipients with impaired glucose tolerance were classified into a non-amelioration group and an amelioration group, the ISSI-2 was significantly reduced, with no significant changes in the Matsuda index or HOMA-IR, in the non-amelioration group 1 year after renal transplantation. By contrast, ISSI-2 and Matsuda index values were significantly increased, with no significant changes in HOMA-IR values in the amelioration group. ConclusionsMore than half of Japanese renal transplant recipients with impaired glucose tolerance had normal glucose tolerance 1 year after renal transplantation. These results suggest that an increase in insulin secretion and whole insulin sensitivity was associated with improvement in glucose tolerance in these recipients.
  • D. Iwami, K. Hotta, H. Sasaki, T. Hirose, H. Higuchi, Y. Takada, N. Shinohara
    TRANSPLANTATION PROCEEDINGS 49 (1) 84 - 87 0041-1345 2017/01 [Refereed][Not invited]
    Background. De novo donor-specific antibody (dnDSA), especially against class II HLA, correlates with chronic active antibody-mediated rejection (CAAMR), which eventually leads to graft loss. It would be helpful if we could identify the patients at high risk of dnDSA development in terms of histocompatibility. Structure-based matching strategy assessing mismatched epitopes/eplets by comparing polymorphic amino acid sequences can predict the risk of development of dnDSA and CAAMR. However, it has not been evaluated in Japanese patients whose diversity in HLA is limited. Patients and Methods. We retrospectively studied 55 living related kidney transplant patients and ascertained donor and recipient HLA-A,-B,-DRB1, and-DQB1. The number of mismatched eplets was determined using an algorithm, HLAMatchmaker version 3. The relationship between characteristics of mismatched eplets and development of CAAMR was evaluated. Results. There were 8 patients in the CAAMR group and 47 in the control group. The numbers of mismatched HLAs (3.6 +/- 1.2 in CAAMR and 3.7 +/- 2.0 in control groups), mismatched eplets (32.2 +/- 10.4 in CAAMR and 34.4 +/- 19.8 in control groups), mismatched DRB1 eplets (11.2 +/- 4.3 in CAAMR and 11.5 +/- 7.9 in control groups), and mismatched DQB1 eplets (9.2 +/- 4.3 in CAAMR and 10.5 +/- 7.3 in control groups) were not significantly different. Significantly more patients had at least one highly immunogenic mismatched eplet (62.5% in CAAMR and 25.5% in control groups; P = .024 by chi(2) test). Conclusions. The presence of highly immunogenic mismatched eplets is associated with development of CAAMR.
  • T. Mitsui, K. Morita, D. Iwami, T. Kitta, Y. Kanno, K. Moriya, M. Takeda, N. Shinohara
    TRANSPLANTATION PROCEEDINGS 49 (1) 65 - 67 0041-1345 2017/01 [Refereed][Not invited]
    Background. We investigated whether the age of donor kidneys influences the incidence of nocturnal polyuria in patients with successful renal transplantation (RTX). Methods. Eighty-five patients (45 men and 40 women) undergoing RTX (median age, 47 years) were included in this study. Twenty-four-hour bladder diaries were kept for 3 days, and nocturnal polyuria was defined as a nocturnal polyuria index (nocturnal urine volume/24-hour urine volume) of >0.33. Risk factors for nocturnal polyuria were analyzed in patients with RTX by means of the Mann-Whitney U test, chi(2) test, and a logistic regression analysis. Results. End-stage renal disease (ESRD) developed from diabetes mellitus in 16 patients (19%). Sixty-five patients (76%) received pre-transplant dialysis, with a median duration of 5 years. The median serum creatinine level and body mass index at the most recent visit were 1.2 mg/dL and 21.2 kg/m(2), respectively. On the basis of the 24-hour bladder diaries, nocturnal polyuria was identified in 48 patients (56%). A logistic regression analysis revealed that diabetes mellitus as the original disease for ESRD was the only risk factor for nocturnal polyuria (odds ratio, 8.95; 95% confidence interval, 2.01-65.3; P = .0028). The age of donor kidneys at examination did not affect the incidence of nocturnal polyuria (P = .9402). Conclusions. Nocturnal polyuria was not uncommon in patients with successful RTX. Diabetes mellitus as the original disease for ESRD was the only risk factor for nocturnal polyuria, whereas the age of donor kidneys at examination did not affect the incidence of nocturnal polyuria. Thus, nocturnal polyuria is caused by recipient factors but not donor factors.
  • Daiki Iwami, Yayoi Ogawa, Hiromi Fujita, Ken Morita, Hajime Sasaki, Yuichiro Oishi, Haruka Higuchi, Kanako Hatanaka, Nobuo Shinohara
    NEPHROLOGY 21 63 - 66 1320-5358 2016/07 [Refereed][Not invited]
    Cytomegalovirus (CMV) infection is themost common infectious complication following solid organ transplantation. Ganciclovir (GCV)-resistant CMV infection may be fatal, and is difficult to treat while avoiding allograft rejection. A 31-year-old woman received a second ABO-incompatible kidney transplant, from her father. Induction therapy consisted of basiliximab and rituximab followed by maintenance immunosuppression with tacrolimus, mycophenolate mofetil, and methylprednisolone. Her CMV serostatus was D+/R- at second transplant and she received prophylactic low-dose valganciclovir (VGCV). BK polyoma virus nephropathy (BKVN) developed 7 months after transplant concurrent with CMV hepatitis and retinitis. VGCV was increased to a therapeutic dose combined with reduced immunosuppression with minimal methylprednisolone (2mg/day) and everolimus (0.5mg/day). However, pp65 antigenaemia continued to increase for 6 weeks. Her CMV was defined as ganciclovir (GCV)-resistant. Foscarnet was therefore administered and her CMV disease resolved within 2 weeks. Kidney allograft dysfunction developed 9 months after transplant, and graft biopsy showed tubulointerstitial injury with crystal deposition suggesting foscarnet nephrotoxicity, with no findings of BKVN or rejection. Kidney function recovered after cessation of foscarnet and the patient had good graft function 18 months after transplant. This case demonstrates the successful use of foscarnet to treat GCV-resistant CMV infection after ABO-incompatible kidney transplant complicated with BKVN, without acute allograft rejection. This case further highlights the need to establish appropriate management for CMV D+/R- patients to avoid the acquisition of GCV-resistant gene mutations.
  • C. Colin Brinkman, Daiki Iwami, Molly K. Hritzo, Yanbao Xiong, Sarwat Ahmad, Thomas Simon, Keli L. Hippen, Bruce R. Blazar, Jonathan S. Bromberg
    NATURE COMMUNICATIONS 7 12021  2041-1723 2016/06 [Refereed][Not invited]
    Regulatory T cells (Tregs) are essential to suppress unwanted immunity or inflammation. After islet allo-transplant Tregs must migrate from blood to allograft, then via afferent lymphatics to draining LN to protect allografts. Here we show that Tregs but not non-Treg T cells use lymphotoxin (LT) during migration from allograft to draining LN, and that LT deficiency or blockade prevents normal migration and allograft protection. Treg LT alpha beta rapidly modulates cytoskeletal and membrane structure of lymphatic endothelial cells; dependent on VCAM-1 and non-canonical NF kappa B signalling via LT beta R. These results demonstrate a form of T-cell migration used only by Treg in tissues that serves an important role in their suppressive function and is a unique therapeutic focus for modulating suppression.
  • Yanbao Xiong, Sarwat Ahmad, Daiki Iwami, C. Colin Brinkman, Jonathan S. Bromberg
    JOURNAL OF IMMUNOLOGY 196 (6) 2526 - 2540 0022-1767 2016/03 [Refereed][Not invited]
    T-bet is essential for natural regulatory T cells (nTreg) to regulate Th1 inflammation, but whether T-bet controls other Treg functions after entering the inflammatory site is unknown. In an islet allograft model, T-bet(-/-) nTreg, but not induced Treg, failed to prolong graft survival as effectively as wild-type Treg. T-bet(-/-) nTreg had no functional deficiency in vitro but failed to home from the graft to draining lymph nodes (dLN) as efficiently as wild type. T-bet regulated expression of adhesion-and migration-related molecules, influencing nTreg distribution in tissues, so that T-bet(-/-) nTreg remained in the grafts rather than migrating to lymphatics and dLN. In contrast, both wild-type and T-bet(-/-) CD4(+) conventional T cells and induced Treg migrated normally toward afferent lymphatics. T-bet(-/-) nTreg displayed instability in the graft, failing to suppress Ag-specific CD4(+) T cells and prevent their infiltration into the graft and dLN. Thus, T-bet regulates nTreg migration into afferent lymphatics and dLN and consequently their suppressive stability in vivo.
  • Girdhari Lal, Neeraja Kulkarni, Yumi Nakayama, Amit K. Singh, Apoorva Sethi, Bryna E. Burrell, C. Colin Brinkman, Daiki Iwami, Tianshu Zhang, Thomas Hehlgans, Jonathan S. Bromberg
    IMMUNOLOGY LETTERS 170 52 - 63 0165-2478 2016/02 [Refereed][Not invited]
    B cells are known to control CD4T cell differentiation in secondary lymphoid tissues. We hypothesized that IL-10 expression by marginal zone precursor (MZP) regulatory B cells controls the differentiation and positioning of effector and regulatory T cells during tolerization. Costimulatory blockade with donor specific transfusion (DST) and anti-CD4OL mAb in C57BL/6 mice induced tolerance to allogeneic cardiac allograft. B cell depletion or IL-10 deficiency in B cells prevented tolerance, resulting in decreased follicular regulatory CD4(+) T cells (Tfr) and increased IL-21 expression by T follicular helper (Tfh) cells in the B cell and T cell zones. IL-21 acted with IL-6 to induce CCR6(+) Th17 that caused rejection. Deficiency or blockade of IL-6, IL-21, IL-21R, or CCR6 prevented B cell depletion-induced acute cellular rejection; while agonistic mCCL20-Ig induced rejection. Adoptive transfer of IL-10(+/+) MZP in tolerogen treated CD19-Cre(+/-):IL-10(fl/fl) mice rescued the localization of Tfh and Tfr cells in the B cell follicle and prevented allograft rejection. MZP B cell IL-10 is necessary for tolerance and controls the differentiation and position of Th17, Tfh and Tfr cells in secondary lymphoid tissues. This has implications for understanding tolerance induction and how B cell depletion may prevent tolerance. (C) 2016 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.
  • Takahiko Mitsui, Kimihiko Moriya, Ken Morita, Daiki Iwami, Takeya Kitta, Yukiko Kanno, Masayuki Takeda, Nobuo Shinohara
    ANNALS OF TRANSPLANTATION 20 757 - 763 1425-9524 2015/12 [Refereed][Not invited]
    Background: We investigated risk factors for lower urinary tract (LUT) dysfunction and LUT symptoms in patients who successfully underwent renal transplantation (RTX). Material/Methods: Ninety-five patients (54 males and 41 females) undergoing RTX (median age: 45 years old) at Hokkaido University Hospital were included in this study. Uroflowmetry (UFM), postvoid residual urine volume (PVR), and 24-h bladder diaries were performed. We analyzed risk factors for voiding dysfunction, urinary frequency, polyuria, nocturia, and nocturnal polyuria after RTX using logistic regression analysis. Results: End-stage renal disease arose from diabetes mellitus in 18 patients (19%). Pre-transplant dialysis had been carried out in 74 patients. Voiding dysfunction as assessed by UFM and PVR was observed in 24 patients (27%). Based on the 24-h bladder diaries, we identified frequent micturition in 29 patients (35%), polyuria in 44 (54%), nocturia in 30 (37%), and nocturnal polyuria in 46 (56%). A multivariable logistic regression analysis revealed that diabetes mellitus, which may cause autonomic disorders, was a risk factor for voiding dysfunction and nocturnal polyuria. A risk factor for frequent micturition and nocturia was older age at RTX. Being female was a risk factor for polyuria, which suggested that fluid intake in relation to body weight was higher in females. Conclusions: LUT dysfunction and LUT symptoms were not uncommon in patients who successfully underwent RTX. LUT dysfunction and LUT symptoms need to be considered in patients with risk factors such as diabetes mellitus, older age at RTX, and being female, even after successful RTX.
  • Girdhari Lal, Yumi Nakayama, Apoorva Sethi, Amit K. Singh, Bryna E. Burrell, Neeraja Kulkarni, C. Colin Brinkman, Daiki Iwami, Tianshu Zhang, Jonathan S. Bromberg
    TRANSPLANTATION 99 (9) 1817 - 1828 0041-1337 2015/09 [Refereed][Not invited]
    Background. Blocking CD40-CD40L costimulatory signals induces transplantation tolerance. Although B-cell depletion prevents alloantibody formation, nonhumoral functions of B cells in tolerance have not been well characterized. We investigated whether specific subsets of B cell or B cell-derived interleukin (IL)-10 contribute to tolerance. Methods. Wild type C57BL/6, or B cell-specific interleukin (IL)-10(-/-) (CD19-Cre(+/-)::IL-10(fl/fl)) mice, received vascularized BALB/c cardiac allografts. BALB/c donor-specific splenocyte transfusion and anti-CD40L monoclonal antibody were used as tolerogen. B cells were depleted with antimouse CD20 monoclonal antibody. Various B-cell subsets were purified and characterized by flow cytometry, reverse transcription polymerase chain reaction, and adoptive transfer. Results. B-cell depletion prevented costimulatory blockade-induced allogeneic tolerance. Costimulatory blockade increased IL-10 in marginal zone precursor (MZP) B cells, but not other subsets. In particular, costimulatory blockade did not change other previously defined regulatory B-cell subsets (Breg), including CD5(+)CD1d(hi) Breg or expression of TIM1 or TIM4 on these Breg or other Breg cell subsets. Costimulatory blockade also induced IL-21R expression in MZP B cells, and IL-21R(+) MZP B cells expressed even more IL-10. B-cell depletion or IL-10 deficiency in B cells prevented tolerance in a cardiac allograft model, resulting in rapid acute cardiac allograft rejection. Adoptive transfer of wild type MZP B cells but not other subsets to B cell-specific IL-10 deficient mice prevented graft rejection. Conclusions. CD40 costimulatory blockade induces MZP B cell IL-10 which is necessary for tolerance. These observations have implications for understanding tolerance induction and how B cell depletion may prevent tolerance.
  • Bryna E. Burrell, Kristi J. Warren, Yumi Nakayama, Daiki Iwami, C. Colin Brinkman, Jonathan S. Bromberg
    TRANSPLANTATION 99 (6) 1119 - 1125 0041-1337 2015/06 [Refereed][Not invited]
    Background. Trafficking and differentiation of naive CD4+ and regulatory Tcells (Treg) within the lymph node (LN) are integral for tolerance induction. The LN is comprised of stromal fibers that dictate lymphocyte migration and LN structure, organization, and microanatomic domains. Distribution of the stromal fiber ER-TR7 changes within the LN after antigenic challenge, but the contributions of ER-TR7 to the resulting immune response remain undefined. We hypothesized that these stromal fiber structural changes affect T cell fate and subsequently allograft survival. Methods. C57BL/6 mice were left naive (untreated) or made immune or tolerant (donor-specific BALB/c splenocyte transfusion -/+ anti-CD40L monoclonal antibody), or made tolerant and received anti-ER-TR7 monoclonal antibody. Donor-specific T-cell migration was visualized by adoptive transfer of carboxyfluorescein diacetate, succinimidyl ester-labeled TEa T cell receptor transgenic CD4+ cells. Immunohistochemistry was performed on LNs to detect stromal fiber distribution, structure, CCL21 presence, and Treg and donor-specific cell location relative to high endothelial venules (HEV). Naive, tolerant, and tolerant + anti-ER-TR7 mice received BALB/c heterotopic cardiac allografts and graft survival was monitored. Results. The ER-TR7 distribution changed after the induction of tolerance vs. immunity. Treating tolerant mice with anti-ER-TR7 altered HEV basement membrane structure and the distribution of CCL21 within the LN. These differences were mirrored by changes in the migration of naive and Treg cells within and surrounding the HEV. AntiER- TR7 prevented tolerance induction and resulted in allograft inflammation and rejection. Conclusions. These results identify ER-TR7 as an important component of LN structure in tolerance and a direct target for immune modulation.
  • Daiki Iwami, C. Colin Brinkman, Jonathan S. Bromberg
    TRANSPLANTATION 99 (4) 668 - 677 0041-1337 2015/04 [Refereed][Not invited]
    Background. Circulation of leukocytes via blood, tissue and lymph is integral to adaptive immunity. Afferent lymphatics form CCL21 gradients to guide dendritic cells and T cells to lymphatics and then to draining lymph nodes (dLN). Vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 (VEGFR-3) are the major lymphatic growth factor and receptor. We hypothesized these molecules also regulate chemokine gradients and lymphatic migration. Methods. CD4(+) T cells were injected into the foot pad or ear pinnae, and migration to afferent lymphatics and dLN quantified by flow cytometry or whole mount immunohistochemistry. Vascular endothelial growth factor receptor 3 or its signaling or downstream actions were modified with blocking monoclonal antibodies (mAbs) or other reagents. Results. Anti-VEGFR-3 prevented migration of CD4+ Tcells into lymphatic lumen and significantly decreased the number that migrated to dLN. Anti-VEGFR-3 abolished CCL21 gradients around lymphatics, although CCL21 production was not inhibited. Heparan sulfate (HS), critical to establish CCL21 gradients, was down-regulated around lymphatics by anti-VEGFR-3 and this was dependent on heparanase-mediated degradation. Moreover, a Phosphoinositide 3-kinase (PI3K)alpha inhibitor disrupted HS and CCL21 gradients, whereas a PI3K activator prevented the effects of anti-VEGFR-3. During contact hypersensitivity, VEGFR-3, CCL21, and HS expression were all attenuated, and anti-heparanase or PI3K activator reversed these effects. Conclusions. Vascular endothelial growth factor C/VEGFR-3 signaling through PI3K alpha regulates the activity of heparanase, which modifies HS and CCL21 gradients around lymphatics. The functional and physical linkages of these molecules regulate lymphatic migration from tissues to dLN. These represent new therapeutic targets to influence immunity and inflammation.
  • Kristi J. Warren, Daiki Iwami, Donald G. Harris, Jonathan S. Bromberg, Bryna E. Burrell
    JOURNAL OF CLINICAL INVESTIGATION 124 (5) 2204 - 2218 0021-9738 2014/05 [Refereed][Not invited]
    Lymph nodes (LNs) are integral sites for the generation of immune tolerance, migration of CD4(+) T cells, and induction of Tregs. Despite the importance of LNs in regulation of inflammatory responses, the LN-specific factors that regulate T cell migration and the precise LN structural domains in which differentiation occurs remain undefined. Using intravital and fluorescent microscopy, we found that alloreactive T cells traffic distinctly into the tolerant LN and colocalize in exclusive regions with alloantigen-presenting cells, a process required for Treg induction. Extracellular matrix proteins, including those of the laminin family, formed regions within the LN that were permissive for colocalization of alloantigen-presenting cells, alloreactive T cells, and Tregs. We identified unique expression patterns of laminin proteins in high endothelial venule basement membranes and the cortical ridge that correlated with alloantigen-specific immunity or immune tolerance. The ratio of laminin alpha 4 to laminin alpha 5 was greater in domains within tolerant LNs, compared with immune LNs, and blocking laminin alpha 4 function or inducing laminin alpha 5 overexpression disrupted T cell and DC localization and transmigration through tolerant LNs. Furthermore, reducing alpha 4 laminin circumvented tolerance induction and induced cardiac allograft inflammation and rejection in murine models. This work identifies laminins as potential targets for immune modulation.
  • Tatsu Tanabe, Ken Morita, Hiromi Fujita, Kanako Hatanaka, Yayoi Ogawa, Takayuki Hirose, Hajime Sasaki, Daiki Iwami, Kiyohiko Hotta, Katsuya Nonomura
    CLINICAL TRANSPLANTATION 27 9 - 13 0902-0063 2013/11 [Refereed][Not invited]
    Calcineurin inhibitors (CNIs) have considerably improved renal allograft survival. However, their chronic use has various adverse effects, including hypertension, hyperlipidemia, and nephrotoxicity. We conducted a retrospective study of kidney transplant recipients using a CNI withdrawal protocol. Eleven of 13 patients who had stable graft function on triple-drug therapy including a cyclosporine (CsA) were enrolled in this study. The dose of CsA was reduced by 20% every two wks until complete withdrawal. The mean period between the baseline and last biopsies was 97 (range: 21-123) months. No patient had an acute rejection episode during follow-up. Progression of interstitial fibrosis and tubular atrophy was seen in five and six cases, respectively. Arteriolar hyalinosis improved in three cases, but worsened in four. No patient lost his graft during the study. The mean serum creatinine level was 1.30 +/- 0.26 mg/dL at baseline and stable for 10 yr after elimination (1.26 +/- 0.11 mg/dL). At the end of the study, four of the eleven patients had reduced their antihypertensive drugs, and one patient had stopped hyperlipidemia treatment. CNI withdrawal can be implemented safely in stable renal transplant recipients and might lead to improved patient outcomes. Additional specific evidence of CNI nephrotoxicity should be elucidated.
  • C. Colin Brinkman, Bryna E. Burrell, Daiki Iwami, Yumi Nakayama, Kristi J. Warren, Yanbao Xiong, Jonathan S. Bromberg
    CURRENT OPINION IN ORGAN TRANSPLANTATION 18 (4) 393 - 401 1087-2418 2013/08 [Refereed][Not invited]
    Purpose of reviewThe mechanisms of tolerance induction and maintenance remain incompletely understood and have yet to be translated to clinical practice. Advances in imaging techniques have allowed precise examination of cell interactions in the lymph node, often in real time. Herein we review evidence that lymph node structure is dynamic and controls the character of the immune response in a multistep, multiplayer dance. T-cell responses in particular can be initiated or influenced in regions beyond the canonical T-cell zone. We propose that the cortical ridge is one such region required for induction and maintenance of tolerance.Recent findingsLymph node domains are more complex than T-cell and B-cell zones. Different domains are important for different types of immune responses. These domains are in part defined by dynamic, malleable physical structures that guide cell interactions and influence immune outcomes.SummaryFurther probing as to how lymph node stromal cells and fibers interact with and determine the character of immune responses should yield fundamental insights into tolerance and immunity. Manipulation of lymph node structure and associated unique cell types and molecules may allow therapeutic interventions in the tolerogenic process.
  • K. Morita, T. Seki, D. Iwami, H. Sasaki, N. Fukuzawa, K. Nonomura
    TRANSPLANTATION PROCEEDINGS 44 (6) 1795 - 1799 0041-1345 2012/07 [Refereed][Not invited]
    Background. Spontaneous rupture risk of a renal artery aneurysm (RAA) is extremely low. Indications for surgical repair of RAA remain uncertain. Objective. Long-term outcomes of conservative therapy and surgical repair were evaluated. Patients. The study included 58 patients (17 males, 41 females) who were diagnosed with RAA during the last 21 years. Median age at the time of diagnosis was 62 (19-85) years, and the median follow-up 69 months (range 3-216). Methods. The patients were divided into two groups, conservative group (n = 30) who had been followed with blood pressure control, and treatment group (n = 29), who underwent an intervention. Results. Multiple efferent aneurysmal branches were observed in seven conservative and 16 treatment cases (P = .002). The median maximum diameter of the aneurysm was lower in the conservative than the treatment group (15 versus 25 mm, P = .005). Two conservative group cases showed increases in aneurysm size during follow-up. The hypertensive state showed essentially no change in either group during the follow-up. Renal function decreased with age similarly both in conservative and treatment groups. Conclusions. Our conservative management criteria for RAA are justifiable and even too strict.
  • Daiki Iwami, Hiroshi Harada, Hiroaki Usubuchi, Kiyohiko Hotta, Toshimori Seki, Masaki Togashi, Yuichiro Fukasawa
    BMC NEPHROLOGY 13 38  1471-2369 2012/06 [Refereed][Not invited]
    Background: Conditions associated with high intraglomerular filtration pressure can cause secondary focal segmental glomerulosclerosis (FSGS). Unilateral renal artery stenosis (RAS) or its occlusion results in FSGS-like changes and the nephrotic syndrome in the contralateral kidney due to hyperfiltration. However, it has been rarely reported that stenosis of a renal arterial branch can result in FSGS-like changes in a different portion in the same kidney allograft. Case presentation: A 60-year-old male kidney recipient developed allograft dysfunction after angiotensin II receptor blockade for hypertension 4 months after transplantation. It was proven that one of two arterial branches of the graft was markedly stenotic. Graft dysfunction improved after percutaneous transluminal arterioplasty (PTA), however; the stenosis recurred and massive proteinuria developed 5 months later. Graft biopsy showed ischemic changes in the region fed by the stenotic artery branch and in contrast FSGS-like changes in the region fed by the other branch. His clinicopathological manifestation including massive proteinuria almost normalized after the repeat PTA. Conclusion: Here we report a case of secondary FSGS of a kidney allograft due to severe RAS of a branch of the same kidney, in which clinical and pathological improvement were confirmed after radiological intervention. When moderate to severe proteinuria appear, secondarily developed FSGS as well as primary (recurrent or de novo) FSGS should be taken into account in kidney transplant recipients.
  • Daiki Iwami, Hiroshi Harada, Ken Morita, Koji Oba, Nobuyuki Fukuzawa, Kiyohiko Hotta, Hajime Sasaki, Chihoko Miyazaki, Katsuya Nonomura
    Transplantation 93 (10) 1013 - 6 0041-1337 2012/05 [Refereed][Not invited]
    BACKGROUNDS: The deep inferior epigastric artery (DIEA), which feeds the lower rectus abdominis muscle (lower RAM), is usually transected in kidney transplantation. In this study, we investigated whether preservation of DIEA can prevent lower RAM atrophy. METHODS: Two hundred and forty-five kidney transplant recipients (150 men and 95 women) were enrolled in the study (mean age 39.9 years) and were divided into two groups according to whether DIEA was transected (group A, n = 175) or preserved (group B, n = 70). The extent of lower RAM atrophy calculated in computed tomography (performed 1 year after transplantation) and incidence of lower RAM atrophy were compared between the two groups. The most predictive factors for lower RAM atrophy were assessed using a multivariate logistic regression model. RESULTS: The extent of lower RAM atrophy was significantly lower in group B (15.0 ± 18.5%) than that in group A (38.9 ± 25.4%, P = 0.003). The incidence of lower RAM atrophy was less prevalent in group B (20.0%) compared with that in group A (62.9%, P < 0.001). The sacrifice of DIEA was the only independent predictive factor for lower RAM atrophy (P < 0.001). CONCLUSIONS: Preservation of DIEA during kidney transplant can prevent lower RAM atrophy.
  • H. Harada, M. Nakamura, K. Hotta, D. Iwami, T. Seki, M. Togashi, T. Hirano, C. Miyazaki
    TRANSPLANTATION PROCEEDINGS 44 (3) 672 - 675 0041-1345 2012/04 [Refereed][Not invited]
    Background. Successful kidney transplantation (KT) can theoretically reconstitute body composition of a patient with chronic kidney disease (CKD). However, the practical changes have not been well documented. We evaluated changes in body composition among candidates before and 1 year after KT. Methods. We enrolled 37 male and 18 female kidney recipients eligible for comparison of their body mass index (BMI), body composition, and lipid metabolism before and 1 year after KT. Twenty-one patients had been induced with a calcineurin inhibitor, mycophenolate mofetil, steroid, and basiliximab, and 34 others underwent steroid withdrawal on postoperative day 3. The body composition was analyzed using bioelectrical impedance. We also analyzed changes in BMI and lipid profiles. Results. There was no significant change in BMI (21.4 +/- 3.1 vs 21.7 +/- 3.5 kg/m(2)). Regarding body composition, the water level decreased significantly (61.2 +/- 4.9% vs 58.3 +/- 5.3%; P < .05). In contrast, fat significantly increased (16.4 +/- 6.7% vs 20.3 +/- 7.1%; P < .05). More interestingly, successful KT significantly decreased the muscle and bone mass at 1 year after KT (37.3 +/- 5.1% vs 34.8 +/- 4.7%; 16.3 +/- 2.1% vs 15.2 +/- 2.1%; respectively; P < .05). Serum lipid profiles of total cholesterol, low-density lipoprotein cholesterol, and triglyceride worsened after KT. Comparing the 2 protocols, there was no difference in any item. Conclusions. Care must be taken even after successful KT to avoid dyslipidemia, which is a risk factor for cardiovascular disease. Well programmed dietary and/or exercise protocols to prevent muscle atrophy and fat gain should be considered even after successful KT.
  • K. Hotta, H. Harada, H. Sasaki, D. Iwami, N. Fukuzawa, K. Morita, T. Seki, M. Togashi, K. Nonomura
    TRANSPLANTATION PROCEEDINGS 44 (3) 684 - 686 0041-1345 2012/04 [Refereed][Not invited]
    Purpose. Successful kidney transplantation (KTx) can ameliorate bodily damage caused by end-stage renal disease (ESRD). Arterial stiffness (AS) is one of the critical factors that shorten the survival of patients due to cardiovascular events. KTx may reduce AS as well; however, this has not been investigated well. We therefore conducted a retrospective study using noninvasive pulse wave velocity (PWV), which is a useful index of aortic damage. Patients and methods. Fifty-eight consecutive kidney recipients (34 men, 24 women) were enrolled in this study. Mean age at transplantation was 40.5 +/- 12.3 years and the dialysis period was 73.1 +/- 95.8 months. The brachial-ankle PWV was measured preoperatively and 6 months postoperatively. First, we investigated the relationship between the PWV and the other parameters related to AS. Second, we studied the pre- to posttransplant change in PWV to evaluate the amelioration of AS after successful KTx. Results. PWV showed significant positive correlations with age, systolic blood pressure (BP), diastolic BP, and abdominal aortic calcification index. After successful KTx, PWV significantly decreased (P < .01). In addition, systolic and diastolic BP significantly decreased (P < .01 and P < .05, respectively). Conclusion. Successful KTx ameliorates AS in ESRD patients. This might explain the improved cardiovascular prognosis of ESRD patients who undergo KTx.
  • Qi Zhang, Masateru Uchiyama, Xiangyuan Jin, Daiki Iwami, Nozomu Shirasugi, Toshiaki Watanabe, Masanori Niimi
    SURGERY 150 (5) 923 - 933 0039-6060 2011/11 [Refereed][Not invited]
    Background. The Japanese herbal medicine Tokishakuyaku-san (TJ-23) has been used to treat neurodegenerative, immune, and respiratory tract diseases, as well as many gynecologic disorders, with few adverse effects. This study investigated the effect of TJ-23 on alloimmune responses in a murine model of cardiac allograft transplantation. Methods. CBA mice underwent transplantation of a C57BL/6 heart and received oral administration of 2 g/kg per day of TJ-23 or 1 of 16 other commonly used Japanese herbal medicines from the day of transplantation until 7 days afterward. An adoptive transfer study was conducted to determine whether regulatory cells were generated. Histologic and cell proliferation studies, cytokine measurements, and flow cytometry analyses were also performed. Results. Of the 1 7 herbal medicines studied, only TJ-23, given in a dose of 2 g/kg per day, induced significantly prolonged allograft survival (median survival time [MST], > 100 days). TJ-23 also suppressed proliferation of splenocytes and production of interleukin-2, interleukin-6, and interferon-gamma. Adoptive transfer of either whole splenocytes or CD4(+) or CD4(+) CD25(+) cells from TJ-23-treated allograft recipients resulted in indefinite survival of allografts in naive secondary recipients (MST > 100 days). Flow cytometry studies showed that the CD4+ CD25(+) forkhead/winged-helix (FOXP3)(+) regulatory cell population was increased in transplant recipients given TJ-23. Conclusion. TJ-23 induced hyporesponsiveness to fully allogeneic cardiac allografts and generated C)4 CD25(+) regulatory cells in our model. (Surgery 2011;150: 923-33.)
  • Daiki Iwami, Katsuya Nonomura, Nozomu Shirasugi, Masanori Niimi
    INTERNATIONAL IMMUNOPHARMACOLOGY 11 (3) 384 - 389 1567-5769 2011/03 [Refereed][Not invited]
    Dietary intake of omega-3 polyunsaturated fatty acids (PUFAs) has been found to affect inflammation and metabolism, and many researchers have shown that omega-3 PUFAs provide benefits in immunologic and metabolic disorders. These effects were assumed to result mainly from a modification in the production of inflammatory mediators and the suppression of inflammatory leukocytes. Among PUFAs, eicosapentaenoic acid (EPA), a component of fish oil, apparently has the most potent effect. Recently, much research has focused on regulatory T cells (Tregs) as controllers of immune responses not only to self-antigens but also to non-self-antigens, including donor alloantigens. Therefore, induction of antigen-specific Tregs may be an attractive strategy for managing autoimmune diseases and transplant rejection. Peroxisome proliferator-activated receptor gamma (PPAR gamma), a ligand-activated nuclear receptor that regulates lipid and glucose metabolism. can be activated by thiazolidinediones, fatty acids, and eicosanoids, including EPA. PPAR gamma was recently found to have immunoregulatory effects, and a PPAR gamma agonist inhibited immune responses in a rat model of autoimmune disease. Furthermore, in a murine model, one high dose of purified EPA given the day of transplantation induced marked prolongation of cardiac allograft survival in a dose-dependent manner. These findings suggest that EPA induced Tregs by means of a PPAR gamma-dependent mechanism. This review describes the immunomodulatory effects of PUFAs, especially EPA, and summarizes recent research that may have implications for the development of therapies for autoimmune diseases and transplant rejection that are based on induction of Tregs. (c) 2010 Elsevier B.V. All rights reserved.
  • Daiki Iwami, Qi Zhang, Osamu Aramaki, Kenjiro Matsuno, Katsuya Nonomura, Nozomu Shirasugi, Masanori Niimi
    TRANSPLANTATION 91 (4) 413 - 424 0041-1337 2011/02 [Refereed][Not invited]
    Background. We previously showed that pretreatment with intratracheal delivery (ITD) of alloantigen induced prolonged cardiac allograft survival and generated regulatory cells in mice. In this study, we examined the role of alveolar macrophages (AM) in our ITD model. Methods. Some CBA mice were given ITD of C57BL/6 splenocytes and underwent transplantation of C57BL/6 hearts 7 days later. In others, AM were depleted with clodronate-loaded liposomes 3 days before ITD. In adoptive transfer studies, whole splenocytes were obtained from ITD-treated CBA mice and administered to naive CBA secondary recipients, which were given C57BL/6 hearts immediately afterward. Interleukin-10 concentrations in bronchoalveolar lavage fluid were assessed by enzyme-linked immunosorbent assays. Immunohistologic and flow cytometric studies were performed after ITD. Results. C57BL/6 splenocytes given by ITD were ingested by AM in 2 days and undetectable in paratracheal lymph nodes or spleen tissue. CBA mice given ITD of C57BL/6 splenocytes had markedly prolonged allograft survival (median survival time [MST], 86 days), whereas naive CBA mice rejected allografts acutely (MST, 8 days). AM-depleted, ITD-treated mice also rejected allografts (MST, 5.5 days). Naive secondary recipients given adoptive transfer of splenocytes from ITD-treated mice had prolonged allograft survival (MST, > 100 days), whereas secondary recipients given adoptive transfer of splenocytes from AM-depleted, ITD-treated mice rejected the grafts (MST, 15.5 days). Interleukin-10 expression in bronchoalveolar lavage fluid was down-regulated in AM-depleted mice compared with naive mice. Conclusions. AM have an important role in the induction of regulatory cells in our model of ITD of alloantigen.
  • Daiki Iwami, Hiroshi Harada, Kiyohiko Hotta, Masayoshi Miura, Toshimori Seki, Masaki Togashi, Tetsuo Hirano
    CLINICAL TRANSPLANTATION 24 66 - 69 0902-0063 2010/07 [Refereed][Not invited]
    A 32-yr-old female patient, who had been suffering from diffuse crescentic glomerulonephritis and a consequent end-stage renal disease, successfully underwent living-related ABO-incompatible kidney transplantation after a desensitization therapy including anti-CD20 monoclonal antibody. Forty-six months after the transplantation, the recipient became pregnant. At the 17th gestational week, the patient was admitted for the management of pregnancy-induced hypertension and aggressive deterioration of kidney graft function. At the 21st gestational week, the patient lost her kidney graft and was re-induced into regular hemodialysis. The patient was also suffering from progressive hemolytic anemia, thrombocytopenia, and neurologic symptoms with decreased activity of von Willebrand factor-cleaving protease, a disintegrin-like and metalloprotease with thrombospondin type 1 motifs 13 (ADAMTS13). From these findings and a kidney allograft biopsy, the patient was diagnosed as thrombotic thrombocytopenic purpura concurrent with acute T-cell-mediated rejection. The patient immediately underwent plasma exchange as well as steroid pulse therapy. Despite these treatments, thrombocytopenia and intrauterine growth retardation progressed. The patient underwent a caesarian section at the 24th gestational week. Consequently, her platelet count recovered drastically. However, the patient lost her neonate five d after giving a birth, and the patient's graft function had never recovered.
  • Daiki Iwami, Qi Zhang, Hisashi Ueta, Osamu Aramaki, Kenjiro Matsuno, Katsuya Nonomura, Nozomu Shirasugi, Masanori Niimi
    AMERICAN JOURNAL OF TRANSPLANTATION 10 362 - 362 1600-6135 2010/04 [Refereed][Not invited]
  • Qi Zhang, Toshio Nakaki, Daiki Iwami, Masanori Niimi, Nozomu Shirasugi
    TRANSPLANTATION 88 (12) 1360 - 1370 0041-1337 2009/12 [Refereed][Not invited]
    Background. Ursodeoxycholic acid (UDCA) has been used to treat patients with cholestatic and autoimmune liver diseases. Several studies have addressed whether UDCA can inhibit graft rejection in experimental and clinical transplantation, but the results have varied. We investigated the effect of UDCA and the mechanism of its effect on alloimmune responses in a murine model of cardiac transplantation. Methods. CBA mice underwent transplantation of a C57BL/10 heart and received a single dose of UDCA. Survival times of the allografts were recorded. An adoptive transfer study was conducted to determine whether regulatory cells were generated. The effects on graft survival of adding FK506 or cyclosporine A (CyA) to UDCA treatment were assessed. Histologic, cell proliferation, and cytokine assessments were performed. Results. CBA recipients given UDCA (25 mg/kg) had indefinite allograft survival (median survival time [MST], > 100 days). UDCA also suppressed proliferation of splenocytes and production of interleukin (IL)-2, IL-6, and interferon-gamma, and up-regulated IL-10 production. Adoptive transfer of either whole splenocytes or CD4(+) cells from UDCA-treated allograft recipients resulted in indefinite survival of allografts in naive secondary recipients (MST, > 100 days). Adoptive transfer of CD4(+)CD25(+) cells from UDCA-treated recipients significantly prolonged allograft survival in naive secondary recipients (MST, >80 days). FK506 (0.1 mg/kg/day) was compatible with the induction of indefinite allograft survival by UDCA, whereas CyA (10 mg/kg/day) abrogated the effect of UDCA. Conclusion. UDCA induced unresponsiveness to fully allogeneic cardiac allografts and generated CD4(+)CD25(+) regulatory cells in Our model. FK506, but not CyA, was compatible with UDCA treatment.
  • Qi Zhang, Daiki Iwami, Osamu Aramaki, Shuji Yakubo, Ko Nishimura, Atsushi Ishige, Kenji Watanabe, Kenjiro Matsuno, Nozomu Shirasugi, Masanori Niimi
    TRANSPLANTATION 87 (12) 1787 - 1791 0041-1337 2009/06 [Refereed][Not invited]
    Sairei-to (TJ114), a 12-component Japanese herbal medicine, is used to treat immune-related diseases. We investigated the effects of oral administration of TJ114 in a murine model of cardiac transplantation with fully mismatched allografts. Untreated CBA mice rejected C57BL/6 hearts acutely (median survival time [MST], 7 days), whereas survival of allografts from mice given TJ114 was significantly prolonged (MST > 100 days). Secondary CBA recipients of C57BL/6 hearts also had prolonged allograft survival (MST > 100 days) after adoptive transfer of whole or CD4(+) splenocytes from primary CBA allograft recipients given TJ114. None of the individual components of TJ114 prolonged allograft survival, suggesting that its effects require administration of the combination agent. In mixed leukocyte Cultures, proliferation of splenocytes from TJ114-treated CBA recipients was markedly suppressed compared with that of splenocytes from untreated mice, and interferon-gamma production was significantly reduced. Thus, in our model, TJ114 treatment induced hyporesponsiveness to cardiac allografts and generated CD4(+) regulatory cells.
  • D. Iwami, Q. Zhang, O. Aramaki, K. Nonomura, N. Shirasugi, M. Niimi
    AMERICAN JOURNAL OF TRANSPLANTATION 9 (6) 1294 - 1307 1600-6135 2009/06 [Refereed][Not invited]
    Fish oil, which is rich in eicosapentaenoic acid (EPA), has been found to have immunomodulatory effects. We examined whether administration of purified EPA affected survival of fully mismatched murine cardiac allografts. Hearts from C57BL/10 (H-2(b)) mice were transplanted into CBA (H-2(k)) recipients treated with one intraperitoneal dose of purified EPA the day of transplantation. Untreated CBA recipients and recipients given 0.1 g/kg of EPA rejected C57BL/10 hearts (median survival time [MST], 8 and 13 days, respectively). With a 1.0 g/kg dose of EPA, graft survival was markedly prolonged (MST > 100 days). To determine whether regulatory cells were generated, naive mice (secondary recipients) underwent adoptive transfer of splenocytes from EPA-treated primary recipients and cardiac allograft transplantation. Adoptive transfer of whole, CD4(+) and CD4(+)CD25(+) splenocytes from EPA-treated recipients induced indefinite survival in secondary recipients. Flow cytometry showed that the CD4(+)CD25(+) cells were Foxp3(+). In reverse transcriptase-polymerase chain reaction (RT-PCR) studies, the expression of peroxisome proliferator-activated receptor gamma (PPAR gamma) mRNA was upregulated by EPA treatment. A PPAR gamma antagonist abrogated the prolongation of graft survival induced by EPA treatment (MST, 13 days). Thus, in our model, purified EPA induced prolonged survival of fully mismatched cardiac allografts and generated regulatory T cells dependent on PPAR gamma activation.
  • D. Iwami, H. Harada, M. Miura, T. Seki, M. Togashi, T. Hirano
    TRANSPLANTATION PROCEEDINGS 41 (5) 1951 - 1953 0041-1345 2009/06 [Refereed][Not invited]
    A 40-year-old woman who had been suffering from type II diabetes mellitus and consequent end-stage renal disease underwent living related kidney transplantation. The graft renal artery was anastomosed to the right internal iliac artery (end-to-end). Postoperative renoscintigraphy demonstrated normal graft perfusion. The serum lactate dehydrogenase level increased abruptly at postoperative day 15 and digital subtraction angiography disclosed graft artery thrombosis. Despite an intervention using a metallic coil stent, the rapid formation of thrombus occluded the graft artery completely. In an emergent surgical operation, the graft was nephrectomized carefully and irrigated after extensive thrombectomy. The graft was reimplanted by using an internal iliac artery graft. After three consecutive hemodialysis treatments, the patient's kidney graft functioned well. She has been in good health with stable graft function for 3 years after the operation.
  • Ken Morita, Daiki Iwami, Kiyohiko Hotta, Naohiko Shimoda, Masayoshi Miura, Yoshihiko Watarai, Sakurako Hoshii, Katsuyuki Obikane, Taiji Nakashima, Satoshi Sasaki, Katsuya Nonomura
    PEDIATRIC TRANSPLANTATION 13 (2) 200 - 205 1397-3142 2009/03 [Refereed][Not invited]
    The aim of the current study was to evaluate long-term outcomes of pediatric live kidney transplantation in patients with genitourinary anomalies relative to those with primary kidney diseases. The study included 35 pediatric patients who received a live kidney transplantation during the last 25 yr (28 males, six females). Median age at the time of transplantation was nine yr (range 1-15 yr), and the median follow-up period was 151 months (range 6-239 month). The patients were divided into two groups. The urological group (n = 14) included patients with primary obstructive/reflux nephropathy. The renal group (n = 20) included patients with primary renal disorders. Differences between groups in graft survival, clinical course, and final graft function were evaluated. Original diseases represented in the urological group included five cases with primary VUR and eight cases with secondary VUR. Diseases in the renal group included eight cases with bilateral hypo-dysplastic kidney, three cases with focal/segmental glomerular sclerosis, two cases with membranous proliferative glomerulonephritis, two cases with congenital nephrotic syndrome and five cases with other forms of chronic nephritis. Ten of 14 cases in the urological group, relative to six of 20 in the renal group, were preemptive. Median age at transplantation was 7.5 or 10 yr old, respectively, in the urological or renal group. Twelve kidney recipients in the urological group had also undergone other urinary surgeries, including upper urinary tract drainage, ureteroneocystostomy, augmentation cystoplasty, endoscopic incision of posterior-urethral valve, urethroplasty, etc. Cumulative post-operative complications occurred in nine or 16, respectively, in the urological or renal group. The acute rejection free and overall graft survival were similar in both groups. One patient in the urological group lost his graft while six patients in the renal group lost their grafts. Thus, the post-transplant clinical outcome of pediatric transplantation in patients with urological anomalies is comparable to that of recipients with primary renal disease. Appropriate urinary tract reconstruction and management is essential to reduce the risk of graft dysfunction because of urinary problems.
  • Daiki Iwami, Qi Zhang, Hisashi Ueta, Hiroyuki Shirato, Osamu Aramaki, Katsuya Nonomura, Kenjiro Matsuno, Nozomu Shirasugi, Masanori Niimi
    AMERICAN JOURNAL OF TRANSPLANTATION 9 368 - 369 1600-6135 2009 [Refereed][Not invited]
  • Fumihiko Inoue, Qi Zhang, Takurin Akiyoshi, Osamu Aramaki, Daiki Iwami, Kenji Matsumoto, Yuko Kitagawa, Nozomu Shirasugi, Masanori Niimi
    TRANSPLANTATION 84 (10) 1288 - 1297 0041-1337 2007/11 [Refereed][Not invited]
    Background. The effects of histamine on immunologic responses via the histamine receptor 2 (HR2) have been studied, but few investigations explored the immunomodulatory role of histamine in vivo. We examined whether the HR2 antagonist ranitidine affects the alloimmune response in a murine model of cardiac transplantation. Methods. CBA (H-2(k)) recipients were given no treatment or one intravenous injection of ranitidine on the day of transplantation of a heart from C57BL/10 (H-2(b)) donors. Survival of the allografts was recorded. The effect of the ranitidine treatment on cell proliferation and cytokine production was assessed by mixed leukocyte culture and enzyme-linked immunosorbent assays. An adoptive transfer study was conducted to determine whether regulatory cells were generated. The effect on graft survival of adding FK506 to the ranitidine treatment was also examined. Results. CBA recipients given ranitidine (60 mg/kg) had prolonged graft survival (median survival time [MST], 87 days). Ranitidine treatment also suppressed the proliferation of splenocytes and production of interleukin (IL)-2 and up-regulated IL-10 production. Adoptive transfer of splenocytes and CD4(+) cells from ranitidine-treated allograft recipients induced significant prolongation of allograft survival in naive secondary recipients (MST, 71 and > 100 days, respectively). CBA recipients given both ranitidine and FK506 (0.1 mg/kg/day for 14 days) had indefinite survival of cardiac allografts (MST, > 100 days). CBA recipients treated with FK506 alone rejected the allografts (MST, 27 days). Conclusion. In our model, ranitidine treatment induced significantly prolonged survival of fully allogeneic cardiac grafts, generated CD4(+) regulatory cells, and indefinite survival when combined with FK506 (0.1 mg/kg/day).
  • Naohiko Shimoda, Masayoshi Miura, Kanako C. Kubota, Kiyohiko Hotta, Daiki Iwami, Tomoo Itoh, Ken Morita, Yoshihiko Watarai, Katsuya Nonomura
    CLINICAL TRANSPLANTATION 21 13 - 17 0902-0063 2007/07 [Refereed][Not invited]
    Suppression of antibody-mediated rejection (AMR) is mandatory for the acceptance of renal allograft in ABO blood type incompatible and pre-sensitized combinations. The aim of this study was to evaluate the difference in histopathology of AMR between ABO incompatible (ABOI) and pre-sensitized cases. Among 69 kidney recipients who underwent transplant surgery at our institute since 2002, four patients who manifested AMR were included in this study. They initially received quadrant immunosuppressants, tacrolimus, mycophenolate mofetil, methylprednisolone and basiliximab. Two patients received grafts from ABOI donors and the other two received grafts from flow T-cell crossmatch-positive donors. Although satisfying antibody removal was achieved by pre-transplant plasmapheresis, all four cases manifested acute AMR, within two wk post-transplant. Antibody titer and panel reactive antibody increased at the time of AMR. ABOI cases showed slight cellular infiltration. These cases showed diffuse, strong and linear deposition of C4d at peritubular capillaries (PTC). On the other hand, pre-sensitized cases showed more intense cellular infiltration, especially in glomerulus but only faint and focal deposition of C4d at PTC. All four cases were treated with corticosteroid pulse therapy in conjunction with several sessions of plasmapheresis.
  • Masayoshi Miura, Hiroshi Harada, Nobuyuki Fukuzawa, Daiki Iwami, Akihisa Taniguchi, Toshimori Seki, Masaki Togashi, Yayoi Ogawa, Hidetoshi Satoh, Tetsuo Hirano
    Clinical Transplantation, Supplement 19 (14) 54 - 58 1399-6738 2005 [Refereed][Not invited]
    Introduction: Recent immunosuppression with tacrolimus and mycophenolate mofetil has improved the results of renal transplantation. In this study, we analyzed the effect and safety of basiliximab as an induction therapy. Material and methods: Forty-nine kidney recipients were given tacrolimus, mycophenolate mofetil and prednisone (non-Bas group), and 31 recipients were given basiliximab as an induction therapy in addition to the triple immunosuppressants (Bas group). Graft function, incidence of acute rejection (AR), findings of protocol graft biopsy and adverse effects were compared. Results: Serum creatinine within 1 yr post-transplant was comparable between the two groups. Incidence of biopsy-proven AR within 6 months post-transplant was less in the Bas group than in the non-Bas group. Borderline change at 3 months post-transplant was less in the Bas group when compared to the non-Bas group. The frequency and severity of tubulitis were higher in the non-Bas group than in the Bas group. The addition of basiliximab did not increase opportunistic infection, but reduced tacrolimus nephrotoxicity. Conclusion: The addition of basiliximab to the tacrolimus-based triple immunosuppressive regimen enabled us to reduce the doses of immunosuppressants and tacrolimus nephrotoxicity without increasing early rejection or infection. This regimen is safe and effective for application during the early period after renal transplantation. Copyright © Blackwell Munksgaard 2005.
  • M Miura, H Harada, N Fukuzawa, D Iwami, A Taniguchi, T Seki, M Togashi, Y Ogawa, H Satoh, T Hirano
    CLINICAL TRANSPLANTATION 19 54 - 58 0902-0063 2005 [Refereed][Not invited]
    Introduction: Recent immunosuppression with tacrolimus and mycophenolate mofetil has improved the results of renal transplantation. In this study, we analyzed the effect and safety of basiliximab as an induction therapy. Material and methods: Forty-nine kidney recipients were given tacrolimus, mycophenolate mofetil and prednisone (non-Bas group), and 31 recipients were given basiliximab as an induction therapy in addition to the triple immunosuppressants (Bas group). Graft function, incidence of acute rejection (AR), findings of protocol graft biopsy and adverse effects were compared. Results: Serum creatinine within 1 yr post-transplant was comparable between the two groups. Incidence of biopsy-proven AR within 6 months post-transplant was less in the Bas group than in the non-Bas group. Borderline change at 3 months post-transplant was less in the Bas group when compared to the non-Bas group. The frequency and severity of tubulitis were higher in the non-Bas group than in the Bas group. The addition of basiliximab did not increase opportunistic infection, but reduced tacrolimus nephrotoxicity. Conclusion: The addition of basiliximab to the tacrolimus-based triple immunosuppressive regimen enabled us to reduce the doses of immunosuppressants and tacrolimus nephrotoxicity without increasing early rejection or infection. This regimen is safe and effective for application during the early period after renal transplantation.
  • T Kitta, H Kakizaki, D Iwami, K Tanda
    INTERNATIONAL JOURNAL OF UROLOGY 11 (5) 340 - 342 0919-8172 2004/05 [Refereed][Not invited]
    We report on a case of a pure urogenital sinus anomaly presented with bladder distention. A seven-day-old girl with an abdominal distension was referred to the Division of Urology, Hakodate Central Hospital, Hakodate, Japan. A common urogenital sinus without abnormalities in the labium, clitoris or anus was found. A computed tomography (CT) scan documented a distended bladder without hydrometrocolpos or hydroureteronephrosis. Cystography performed at 44 days revealed a large flaccid bladder without ureteral reflux. Urinary management by an indwelling urethral catheter was maintained until 3 months, when an endoscopic examination was performed and a stenotic urethral-type urogenital sinus with low confluence was diagnosed. Parents successfully instituted clean intermittent catheterization as a temporary urinary management, and postvoid residual urine gradually decreased. At 2 years of age, flap vaginoplasty was performed. In an urodynamic study performed postoperatively, the detrusor pressure during voiding was 40-50 cm H2O. The patient maintained spontaneous voiding without consequences. Appropriate urinary care is essential to prevent urological complications in cases with a pure urogenital sinus anomaly.


Research Grants & Projects

  • Development of an algorithm for risk of chronic antibody-mediated rejection after kidney transplant assessed by human leukocyte antigen structure-based histocompatibility
    Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2018/04 -2021/03 
    Author : 岩見 大基, 大野 浩太, 篠原 信雄, 堀田 記世彦
    HLAの三次元構造に注目したStructure-Based Matching Conceptをもとに算出されるミスマッチ(MM) eplet数と腎移植後の慢性拒絶反応(CAMR)との関係については、HLAミスマッチ数よりも高感度にCAMRを予測できるというデータがすでに報告されている。しかしそれらのデータは海外とくに白色人種が多くを占める欧州や多民族国家である米国のものであり、HLAの多様性の低い日本人でのデータを明らかにする必要がある。本研究では実際の腎移植患者の臨床経過とMM eplet特性の関係を解析しCAMR発症リスクの階層化を行うことである。これらの検討は本邦において臓器移植に従事する医師および臓器移植患者に対する貴重な情報となりうると期待される。 研究の方法としては、これまでのHLAの情報をもとにHLAMatchmakerという解析ソフトを用いてMM eplet/epitopeの総数およびその種類を解析する。そして、腎移植後の観察期間ごとにCAMRを発症したCAMR群とCAMR非発症の対照例とに群別し、CAMR発症リスク評価アルゴリズムを作成する。アルゴリズム作成は、MM eplet/epitope特性とCAMR発症との関係について、各観察時点(移植後経過期間)におけるCAMR発症率とMM eplet/epitope特性、臨床データも考慮に入れてCox比例ハザードモデルを用いて解析し、予めCAMR発症リスクを予測するための免疫学的リスク評価アルゴリズムを作成する。 現時点では目標とする症例数が集まっておらず(200組程度)、十分な解析ができていないが次年度中に目標数に達して解析に進めるものと考えている。
  • Development of an immunological monitoring system to predict chronic rejection in kidney transplant recipients.
    Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2018/04 -2021/03 
    Author : 堀田 記世彦, 村上 正晃, 岩見 大基, 篠原 信雄
    腎移植の短期成績は飛躍的に向上していが、長期的にはドナー特異的抗体による慢性抗体関連型拒絶反応(CAMR)により移植腎機能廃絶となる症例が多く、この克服が長期成績の向上に必要不可欠である。しかし、CAMRに対する有効な治療法は未だ確立していない。当研究の目的は、CAMRとなりうる患者を未然にもしくは可能な限り早期に発見する診断法を開発することである。当研究は3つからなり昨年度の研究実績は以下の通りである。 1.パラフィン移植腎生検標本を用いたCAMR早期診断関連遺伝子の検索:経時的に採取したプロトコール移植腎生検のパラフィン切片100検体を共同研究者のマサチューセッツ総合病院に遊走子遺伝子解析中である。 2.慢性抗体関連型拒絶反応(CAMR)早期診断のための尿中バイオマーカーの検索:CAMRの診断となった移植腎生検組織を免疫染色したところ正常腎組織に比べORM1発現の亢進を認めたことから、尿中ORM1に注目した。CAMRと組織学的に正常である患者での尿中ORM1を比較したところCAMR群で尿中ORM1濃度が有意に上昇していた。さらに他の慢性障害である間質の繊維化や尿細管の萎縮(IF/TA)や免疫抑制剤であるカルシニューリン阻害剤の腎毒性の患者群に比べてCAMR群の尿中ORM1の濃度が上昇していることが確認できた。これにより、尿中ORM1が慢性障害の中でもCAMR患者に特異的に上昇している可能性がありバイオマーカーの臨床応用への可能性が見出せた。 3.末梢血リンパ球反応による早期診断法の開発:30症例につきCFSE/MLR assayを行った。結果、腎機能が正常で病理学的にも問題ない患者においてはCD8の反応が認めないが、慢性抗体型拒絶反応の患者ではドナーに対するCD8の反応が認める傾向にあり、CAMRを早期に診断する可能性は見出せた。
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Research Activity start-up
    Date (from‐to) : 2014/08 -2016/03 
    Author : Iwami Daiki
    We established a rat kidney transplant model in which immunosuppressive drugs are unnecessary to exclude the effect of the drugs on reversibility of diabetic lesion in the kidney. In that model, SDT rat as donor and SDT/SDJ F1 rat as recipient were used. SDT rat spontaneously develops diabetes mellitus and diabetes-associated complications such as cataract and diabetic nephropathy resulting in massive proteinuria and renal dysfunction. We also confirmed that SDT/SDJ F1 rat has normal glucose metabolism in oral glucose tolerance test. We underwent 4 cases of successful transplant of SDT kidney with diabetic nephropathy into non-diabetic SDT/SDJ F1 rat. Two recipients out of the 4 were evaluated at 2 weeks after transplant and the other 2 were evaluated at 24 weeks after transplant, however, no obvious amelioration or deterioration was observed pathologically. Our results suggest that reversibility of diabetic nephropathy need to be determined in longer observational period.

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