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1.
Transplant Proc ; 51(6): 1732-1738, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31301858

RESUMO

Plasma cell-rich acute rejection (PCAR) and antibody-mediated rejection (ABMR), for which a standard treatment has not yet been established, are associated with poor graft survival after kidney transplantation. Here, we report a case series of 3 Japanese patients diagnosed with PCAR accompanied by ABMR. Steroid pulse therapy and rabbit antithymocyte globulin, plasma exchange, intravenous immunoglobulin, and rituximab therapies were sequentially performed in the first case. A graft biopsy after each treatment showed that plasma cell infiltration persisted. Five months after the initiation of rejection therapy, the patient was subjected to bortezomib therapy, which led to the partial elimination of plasma cells from the graft. However, the graft function gradually deteriorated, and hemodialysis treatment was warranted. In the other 2 cases, the patients received the same combination of therapy including bortezomib within a short period. Graft biopsies performed subsequently showed a marked decrease in the number of infiltrated plasma cells, and stabilization of renal graft function was achieved in both cases. Bortezomib, which targets plasma cells, is a potent drug that eliminates infiltrated plasma cells from the graft in PCAR. Thus, in addition to conventional therapy comprising plasma exchange, intravenous immunoglobulin, and rituximab against ABMR, bortezomib may be necessary to administer without any delay to control PCAR.

2.
Int. braz. j. urol ; 45(3): 503-513, May-June 2019. tab, graf
Artigo em Inglês | LILACS-Express | ID: biblio-1012320

RESUMO

ABSTRACT Purpose: The purposes of the present study were to evaluate growth rate of nonfunctioning adrenal incidentalomas (AIs) and their development to hormonal hypersecretion on follow-up. Materials and methods: A retrospective study was conducted from the electronic medical records. A total of 314 patients were diagnosed with adrenal tumors between 2000 and 2016. After excluding patients who had overt adrenal endocrine disorders or whose adrenal tumors were clinically diagnosed as metastatic malignancies, we investigated 108 patients with nonfunctioning AIs including characteristics, the treatment, the way of follow-up and pathology. Results: Fifteen patients received immediate adrenalectomy because of the initial tumor size or patient's preference. Pathological examination revealed malignancy in 2 patients. In the remaining 93 patients, radiological examinations were performed periodically. Tumor enlargement of ≥ 1.0cm was observed in 8.6% of the patients who were followed up as nonfunctioning AIs with a median follow-up period of 61.5 months (range: 4-192). Eleven patients underwent adrenalectomy. On the pathological examinations, all of the tumors, which showed a size increase, were diagnosed as benign tumors. Regarding the followed up patients without adrenalectomy, only 2.4% of the patients had tumor enlargement during the prolonged follow-up. Furthermore, none of the patients developed hormonal hypersecretion or clinical signs such as obesity, glucose intolerance or poorly controlled hypertension. Conclusions: Tumor enlargement of AIs did not correlate with malignancy. The value of repeat radiological and hormonal examinations may be limited in the long-term follow-up of patients whose AIs are not enlarged.

3.
Hepatol Res ; 2019 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-31077507

RESUMO

Hepatitis E virus (HEV) infection has been recognized as an acute condition. However, recent reports have shown that immunocompromised patients, such as those receiving solid-organ transplantation, can develop chronic hepatitis with HEV infection. We report two cases of chronic hepatitis E after kidney transplantation (KT) who were successfully treated with ribavirin monotherapy. Several years after KT, both patients had sustained elevations in the levels of liver enzymes for a period of more than 6 months. Both patients had HEV infection, genotype 3a. Histological studies showed infiltration of inflammatory cells without fibrosis. Treatment included ribavirin monotherapy at a dosage of 600 mg daily for 3 months. One month after therapy initiation, HEV-RNA turned to negative, and remained negative at 24 weeks after ribavirin therapy without severe complications. Although the treatment of chronic hepatitis E is not fully established, ribavirin therapy can be a safe and effective treatment for chronic hepatitis E.

4.
Urol Int ; 102(4): 462-467, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30917379

RESUMO

BACKGROUND: The management of febrile urinary tract infection (fUTI) in patients with vesicoureteral reflux (VUR) is crucial to prevent renal scarring. Continuous antibiotic prophylaxis (CAP) is the most widely used initial treatment for VUR. However, the optimal duration of CAP is still unclear. We aimed to clarify an appropriate patient population and the optimal timing to discontinue CAP. METHODS: We reviewed the records of 247 patients with primary VUR between January 2000 and December 2015. Seventy-two patients who discontinued CAP despite persistent VUR were enrolled. Kaplan-Meier method and Cox proportional hazard model was used in statistical analysis. RESULTS: Following the discontinuation of CAP, fUTI developed in 25 patients after a median of 9 months (range 0-81). VUR resolved spontaneously in 9 out of 47 patients without recurrence during follow-up. Multivariate analysis showed bilateral VUR and duration of CAP of less than 1 year after the last fUTI were significant risk factors for recurrence. CONCLUSION: Among the risk factors examined, patients administered CAP for less than 1 year after the last fUTI and those with bilateral VUR had significantly more frequent recurrence. Our study suggests that the administration of CAP for more than 1 year after the last fUTI is beneficial in avoiding recurrent fUTI.

5.
Int Braz J Urol ; 45(3): 503-513, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30785700

RESUMO

PURPOSE: The purposes of the present study were to evaluate growth rate of nonfunctioning adrenal incidentalomas (AIs) and their development to hormonal hypersecretion on follow-up. MATERIALS AND METHODS: A retrospective study was conducted from the electronic medical records. A total of 314 patients were diagnosed with adrenal tumors between 2000 and 2016. After excluding patients who had overt adrenal endocrine disorders or whose adrenal tumors were clinically diagnosed as metastatic malignancies, we investigated 108 patients with nonfunctioning AIs including characteristics, the treatment, the way of follow-up and pathology. RESULTS: Fifteen patients received immediate adrenalectomy because of the initial tumor size or patient's preference. Pathological examination revealed malignancy in 2 patients. In the remaining 93 patients, radiological examinations were performed periodically. Tumor enlargement of ≥ 1.0cm was observed in 8.6% of the patients who were followed up as nonfunctioning AIs with a median follow-up period of 61.5 months (range: 4-192). Eleven patients underwent adrenalectomy. On the pathological examinations, all of the tumors, which showed a size increase, were diagnosed as benign tumors. Regarding the followed up patients without adrenalectomy, only 2.4% of the patients had tumor enlargement during the prolonged follow-up. Furthermore, none of the patients developed hormonal hypersecretion or clinical signs such as obesity, glucose intolerance or poorly controlled hypertension. CONCLUSIONS: Tumor enlargement of AIs did not correlate with malignancy. The value of repeat radiological and hormonal examinations may be limited in the long-term follow-up of patients whose AIs are not enlarged.


Assuntos
Corticosteroides/sangue , Neoplasias das Glândulas Suprarrenais/diagnóstico por imagem , Neoplasias das Glândulas Suprarrenais/metabolismo , Hormônio Adrenocorticotrópico/sangue , Neoplasias das Glândulas Suprarrenais/patologia , Adrenalectomia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Valores de Referência , Estudos Retrospectivos , Estatísticas não Paramétricas , Fatores de Tempo , Tomografia Computadorizada por Raios X , Carga Tumoral
6.
Transpl Int ; 31(10): 1164-1177, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29722117

RESUMO

We have previously reported that co-transplantation of the kidney with vascularized donor thymus from α-1,3-galactosyltransferase gene knockout pigs with an anti-CD154 with rituximab-based regimen led to improved xenograft survival in baboons with donor-specific unresponsiveness. However, nephrotic syndrome emerged as a complication in which the glomeruli showed mild mesangial expansion with similarities to minimal change disease (MCD) in humans. Since MCD is associated with CD80 expression in glomeruli and elevated urinary excretion, we evaluated a potential role for CD80 in xenograft nephropathy. Study 1 confirmed high urinary CD80 excretion in nephrotic animals with renal xenografts showing CD80 expression in glomeruli. In Study 2, baboons receiving xenografts received CTLA4-Ig once a week from the second postoperative week or no CTLA4-Ig. The non-CTLA4-Ig group developed severe proteinuria with modest mesangial expansion with high urinary excretion of CD80 and documented CD80 expression in glomerular podocytes. All of the recipients in non-CTLA4-Ig groups had to be euthanized before POD 60. In contrast, CTLA4-Ig group showed a marked reduction in proteinuria and survived significantly longer, up to 193 days. These results demonstrate that anti-CD80 targeted therapy represents a promising strategy for reduction of proteinuria following renal xeno-transplantation with improved survival.

7.
Nihon Hinyokika Gakkai Zasshi ; 109(1): 14-19, 2018.
Artigo em Japonês | MEDLINE | ID: mdl-30662046

RESUMO

(Background) Long-term care is necessary for normal growth and development of pediatric recipients of kidney transplants. We report on our experience with pediatric kidney transplantation (KTx) during the past 19 years. (Methods) We retrospectively analyzed the data from 26 recipients who received KTx between 1996 and 2014 at Niigata University Hospital (one patient underwent two consecutive KTx during the designated period). All recipients were 16 years old or younger at the time of KTx. (Results) The graft survival rates at 1, 5, and 10 years after transplantation were 96%, 96%, and 88%, respectively. Three recipients lost the renal graft function due to graft thrombosis, antibody mediated rejection and steroid resistant rejection. Drug non-adherence was associated with rejection episodes, which led to the increasing of estimated glomerular filtration rate (eGFR) level. In addition, renal graft function was related to the growth after KTx. Eighteen recipients graduated from high school during follow-up periods and 17 recipients obtained employment. (Conclusion) Interventions promoting adherence should be implemented among pediatric recipients and parents to optimize graft survival and growth after KTx. Successful KTx contributed the high rate of social participation and employment after pediatric KTx.


Assuntos
Rejeição de Enxerto/prevenção & controle , Transplante de Rim , Insuficiência Renal/cirurgia , Adolescente , Fatores Etários , Criança , Pré-Escolar , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/epidemiologia , Feminino , Rejeição de Enxerto/epidemiologia , Rejeição de Enxerto/terapia , Sobrevivência de Enxerto , Humanos , Japão , Transplante de Rim/mortalidade , Masculino , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/terapia , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de Tempo , Cooperação e Adesão ao Tratamento , Resultado do Tratamento , Cálculos Ureterais/epidemiologia , Cálculos Ureterais/terapia
8.
Nihon Hinyokika Gakkai Zasshi ; 109(2): 68-73, 2018.
Artigo em Japonês | MEDLINE | ID: mdl-31006744

RESUMO

(Backgrounds) The efficacy of bortezomib for chronic antibody mediated rejection (CAMR) after kidney transplantation is still obscure. (Materials and methods) CAMR were persisted in 5 recipients who were treated with plasma exchange, low dose of IVIG, steroid pulse therapy, and rituximab. 1.3 mg/m2 of bortezomib was administered on days 1, 4, 8, 11. Serum creatinine (sCr) levels, anti-HLA antibodies, and histology were analyzed. (Results) Stable sCr levels were obtained in 3 out of 5 recipients. No one lost renal graft function during follow-up periods. Anti-HLA class I antibodies were significantly decreased after bortezomib treatment, however anti-HLA class II antibodies were not changed. Histology showed no improvement at 6 months after bortezomib administration. Two recipients whose sCr levels increased during follow-up had already had interstitial fibrosis and tubular atrophy (IF/TA) in histology before bortezomib treatment. (Conclusions) The use of bortezomib after IF/TA could be detected in histology may not contribute to stabilize renal graft function in CAMR.


Assuntos
Anticorpos , Bortezomib/administração & dosagem , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/terapia , Antígenos HLA/imunologia , Transplante de Rim , Adolescente , Adulto , Bortezomib/uso terapêutico , Criança , Doença Crônica , Feminino , Rejeição de Enxerto/tratamento farmacológico , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Falha de Tratamento , Adulto Jovem
9.
Transplantation ; 101(2): 316-321, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27232934

RESUMO

BACKGROUND: Successful xenotransplantation will likely depend, in part, on the induction of immunological tolerance, because the high levels of immunosuppression otherwise required would likely have unacceptable side effects. Rapid clearance of administered porcine hematopoietic stem cells by primate macrophages has hampered previous attempts to induce tolerance through mixed hematopoietic chimerism across a pig-to-primate barrier. Phagocytosis is normally inhibited by binding of cell surface protein CD47 to macrophage signal regulatory protein α receptors. However, pig CD47 has previously been shown to be ineffective in transducing signals through primate signal regulatory protein α. METHODS: Mobilized peripheral blood hematopoietic cells from transgenic swine expressing high or low levels of human CD47 were infused into conditioned baboons at 3 time points over a 9-week period. Xenogeneic peripheral blood chimerism was assessed after each infusion. Split thickness skin grafts from the hematopoietic cell donor swine were placed on recipients 5 weeks after the last cell infusion and 7 weeks after the discontinuation of all immunosuppression to test immune response. RESULTS: The level and duration of transient chimerism were substantially greater in baboons receiving hematopoietic cells from a pig expressing high levels of human CD47. Skin graft survival on high CD47 recipients was prolonged as well, in 1 case showing no signs of rejection at least 53 days after placement. CONCLUSIONS: Prolongation of transient porcine chimerism via transgenic expression of human CD47 in a primate model is associated with an immune modulating effect, leading to markedly prolonged survival of donor swine skin xenografts that may be applicable to clinical solid organ xenotransplantation.


Assuntos
Antígeno CD47/metabolismo , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Transplante de Células-Tronco de Sangue Periférico , Transplante de Pele/métodos , Animais , Animais Geneticamente Modificados , Antígeno CD47/genética , Antígeno CD47/imunologia , Sobrevivência Celular , Rejeição de Enxerto/imunologia , Xenoenxertos , Humanos , Masculino , Papio , Transplante de Pele/efeitos adversos , Sus scrofa/genética , Fatores de Tempo , Quimeras de Transplante , Tolerância ao Transplante
10.
BMC Cancer ; 16: 332, 2016 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-27225190

RESUMO

BACKGROUND: Recruitment of cofactors in the interaction of the androgen receptor (AR) and AR ligands plays a critical role in determining androgenic/antiandrogenic effects of the AR ligand on signaling, but the functions of key cofactors, including nuclear receptor coactivator (NCOA), remain poorly understood in prostate cancer cells treated with AR ligands. METHODS: We examined prostate cancer cell lines LNCaP and VCaP expressing mutated and wild-type ARs, respectively, to clarify the significance of NCOAs in the effect of antiandrogens. Hydroxyflutamide showed antagonistic activity against VCaP and an agonistic effect on LNCaP. Bicalutamide served as an antagonist for both. We analyzed mRNA transcription and protein expression of NCOAs in these cells pretreated with dihydrotestosterone and thereafter treated with the mentioned antiandrogens. Transcriptional silencing of candidate NCOAs and AR was performed using small interfering RNA (siRNA). Cell proliferation was evaluated with MTT assay. RESULTS: LNCaP treated with bicalutamide showed an about four-fold increase in the expression of NCOA2 mRNA compared to those pretreated with dihydrotestosterone alone (P <0.01). In VCaP pretreated with dihydrotestosterone, transcriptions of NCOA2 and NCOA7 were slightly increased with bicalutamide (1.96- and 2.42-fold, respectively) and hydroxyflutamide (1.33-fold in both). With Western blotting, the expression of NCOA2 protein also increased in LNCaP cells treated with bicalutamide compared with that in control cells pretreated with dihydrotestosterone alone. Following silencing with siRNA for NCOA2, PSA levels in media with LNCaP receiving bicalutamide were elevated compared with those in non-silencing controls (101.6 ± 4.2 vs. 87.8 ± 1.4 ng/mL, respectively, P =0.0495). In LNCaP cells treated with dihydrotestosterone and bicalutamide, NCOA2-silencing was associated with a higher proliferation activity compared with non-silencing control and AR-silencing. CONCLUSION: NCOA2, which has been thought to be recruited as a coactivator, possibly plays a corepressive role in AR of prostate cancer cells when treated with antiandrogens, suggesting its potential as a therapeutic target.


Assuntos
Antagonistas de Androgênios/farmacologia , Di-Hidrotestosterona/farmacologia , Coativadores de Receptor Nuclear/genética , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/genética , Anilidas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Flutamida/análogos & derivados , Flutamida/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Mutação , Nitrilos/farmacologia , Coativadores de Receptor Nuclear/metabolismo , Neoplasias da Próstata/genética , Compostos de Tosil/farmacologia
11.
Xenotransplantation ; 22(6): 468-75, 2015 Nov-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26589781

RESUMO

UNLABELLED: Since α-1,3-galactosyltransferase knockout (GalT-KO) pigs became available, there has been an increasing interest in non-Gal natural antibody (nAb)-mediated xenograft rejection. To better understand mechanisms of non-Gal nAb-mediated rejection, a simple small animal model without gene manipulation would be extremely valuable. Here, we tested whether the Chinese tree shrew (CTS), which is a small-sized mammal that is phylogenetically close to primates, could serve as a model for discordant xenograft rejection. METHODS: Study 1: Expression of α-Gal antigens in hearts and kidneys of CTSs and rats was assessed by IB4 lectin binding. Presence of anti-Gal and anti-non-Gal IgM and IgG nAb in CTS sera was tested by FACS using Gal+ and GalTKO PBMC as well as BSA-ELISA. Study 2: Rat hearts were transplanted into CTS recipients (group 1, n = 7), and CTS hearts were transplanted in rats [n = 10; seven received no immunosuppression (group 2) and three received FK506 + leflunomide (group 3)]. RESULTS: Study 1: Both CTSs and rats had α-Gal expression in hearts and kidneys. ELISA showed CTSs do not have anti-Gal nAb, and flow cytometry indicated CTSs have anti-non-Gal IgM and IgG nAb in serum. Study 2: Rat hearts in CTSs were uniformly rejected within 35 mins, while CTS hearts in rats continued beating until day 5 without immunosuppression, and up to day 8 with immunosuppression. CONCLUSION: Rat-to-CTS heart transplantation is a discordant xenotransplant model, CTS-to-Rat heart transplantation is a concordant xenotransplant model. CTSs are valuable small animals to study mechanisms and strategies to avoid non-Gal nAb-mediated xenograft rejection.


Assuntos
Modelos Animais de Doenças , Rejeição de Enxerto/imunologia , Transplante de Coração , Xenoenxertos/imunologia , Leucócitos Mononucleares/imunologia , Transplante Heterólogo , Animais , Antígenos/imunologia , Galactosiltransferases/genética , Transplante de Coração/métodos , Imunossupressão/métodos , Ratos , Musaranhos , Suínos , Transplante Heterólogo/métodos
12.
Data Brief ; 4: 180-5, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26217785

RESUMO

Human glomeruli with intermediate (i-GS) and advanced (GS) sclerotic lesions as well as the normal control (Nor) were captured from laser microdissection, digested by trypsin and subjected to shotgun LC-MS/MS analysis (LTQ-Orbitrap XL). The label-free quantification was performed using the Normalized Spectral Index (SI N ) to assess the relative molar concentration of each protein identified in a sample. All the experimental data are shown in this article. The data is associated to the research article submitted to Journal of Proteomics [1].

13.
J Proteomics ; 123: 89-100, 2015 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-25835966

RESUMO

UNLABELLED: Since glomerular sclerosis frequently accompanies various glomerular diseases at the end stages, it is challenging to differentiate ubiquitous biological processes underlying this pathology from those critically involved in specific diseases. Furthermore, in-depth proteomic profile of human glomerular sclerosis remains limited. In this study, human glomeruli with intermediate (i-GS) and advanced (GS) sclerotic lesions, which were excluded from specific renal diseases and assumed to be aging-related, were laser captured from macroscopically normal cortex distant from urological carcinoma, and subjected to label-free quantitative proteomic analysis. We explicate an evident increase of membrane attack complex in i-GS and GS with an up-going tendency, which is accompanied by increasing of inhibitory regulators of alternative and terminal pathways. GO annotation and IPA pathway analysis agree to these results. Proteomic findings are validated by immunohistochemical studies which indicate that alternative and terminal pathways are positively involved in the glomerular sclerosis seen in distinct renal diseases. Furthermore, proteomic analysis also demonstrates remarkable increases of complement factor B in GS and TGF-ß1 in both GS and i-GS. Identification of complement factor B implicates that on-site activation of alternative pathway may occur in injured glomeruli and stepwise increase of TGF-ß1 suggests its contribution to the progression of glomerulosclerosis. BIOLOGICAL SIGNIFICANCE: This study provides in-depth quantitative proteomic profiles of human glomeruli with intermediate and advanced sclerotic lesions. It reveals that the over-expression of alternative and terminal pathway components is significantly involved in human glomerulosclerosis seen in distinct renal diseases. Proteomic identification of the increased TGF-ß1 provides supporting evidence for the role of podocyte apoptosis leading to human glomerulosclerosis.


Assuntos
Via Alternativa do Complemento , Proteínas do Sistema Complemento/fisiologia , Nefropatias/metabolismo , Glomérulos Renais/metabolismo , Urotélio/metabolismo , Idoso , Carcinoma/metabolismo , Carcinoma de Células Renais/metabolismo , Cromatografia Líquida , Fator B do Complemento/metabolismo , Biologia Computacional , Glomerulosclerose Segmentar e Focal/metabolismo , Glomerulosclerose Segmentar e Focal/patologia , Humanos , Imuno-Histoquímica , Neoplasias Renais/metabolismo , Masculino , Pessoa de Meia-Idade , Proteoma , Espectrometria de Massas em Tandem , Fator de Crescimento Transformador beta1/metabolismo , Neoplasias da Bexiga Urinária/metabolismo
14.
Transplantation ; 98(4): 411-8, 2014 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-25243511

RESUMO

BACKGROUND: Recent survivals of our pig-to-baboon kidney xenotransplants have been markedly shorter than the graft survivals we previously reported. The discovery of high levels of porcine cytomegalovirus (pCMV) in one of the rejected xenografts led us to evaluate whether this reduction in graft survival might be because of the inadvertent introduction of pCMV into our α1,3-galactosyltransferase gene knockout swine herd. METHODS: Archived frozen sections of xeno-kidney grafts over the past 10 years were analyzed for the presence of pCMV, using real-time polymerase chain reaction. Three prospective pig-to-baboon renal transplants using kidneys from swine delivered by cesarean section (C-section) and raised in isolation were likewise analyzed. RESULTS: Kidney grafts, from which 8 of the 18 archived samples were derived were found to be pCMV-negative, showed a mean graft survival of 48.3 days and were from transplants performed before 2008. None showed signs of disseminated intravascular coagulopathy and were lost because of proteinuria or infectious complications. In contrast, 10 of the archived samples were pCMV positive, were from kidney transplants with a mean graft survival of 14.1 days, had been performed after 2008, and demonstrated early vascular changes and decreased platelet counts. Three prospective xenografts from swine delivered by C-section were pCMV negative and survived an average of 53.0 days. CONCLUSIONS: Decreased survivals of α1,3-galactosyltransferase gene knockout renal xenografts in this laboratory correlate temporally with latent pCMV in the donor animals and pCMV in the rejected xeno-kidneys. Transmission of pCMV to swine offspring may be avoided by C-section delivery and scrupulous isolation of donor animals.


Assuntos
Infecções por Citomegalovirus/complicações , Rejeição de Enxerto/etiologia , Transplante de Rim/efeitos adversos , Animais , Feminino , Galactosiltransferases/fisiologia , Sobrevivência de Enxerto , Molécula 1 de Adesão Intercelular/análise , Masculino , Papio hamadryas , Suínos , Tolerância ao Transplante , Transplante Heterólogo
15.
Transplantation ; 98(4): 419-26, 2014 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-25243512

RESUMO

BACKGROUND: Various durations of survival have been observed in the xenotransplantation of life-supporting α-1,3-galactosyltransferase knockout (GalT-KO) porcine kidneys into nonhuman primates. Although others have demonstrated loss of GalT-KO-transplanted kidneys within 2 weeks, we have reported an average survival of 51 days with the cotransplantation of the kidney and vascularized thymus and an average of 29 days with the kidney alone. To determine the factors responsible for this difference in survival time, we performed xenogeneic kidney transplantations into cynomolgus monkeys with an anti-CD40L-based regimen using two different strains of GalT-KO swine, one derived from MGH miniature swine and the other obtained from Meji University. MATERIALS AND METHODS: Eight cynomolgus moneys received GalT-KO kidneys. Three kidney grafts were from Massachusetts General Hospital (MGH)-Nippon Institute for Biological Science (NIBS) GalT-KO pigs and five GalT-KO grafts were from MEIJI GalT-KO swine. All cynomolgus recipients were treated identically. RESULTS: Recipients of kidneys from the MGH GalT-KO kidneys swine, produced by nuclear transfer in Japan, survived an average of 28.7 days, whereas recipients of MEIJI GalT-KO kidneys swine survived an average of 9.2 days. Among the differences between these two groups, one potentially revealing disparity was that the MEIJI swine were positive for porcine cytomegalovirus, whereas the MGH-derived swine were negative. CONCLUSION: This is the first study comparing renal xenotransplantation from two different sources of GalT-KO swine into nonhuman primates at a single center. The results demonstrate that porcine cytomegalovirus may be responsible for early loss of GalT-KO swine kidney xenografts.


Assuntos
Galactosiltransferases/fisiologia , Transplante de Rim , Animais , Anticorpos/sangue , Creatinina/sangue , Infecções por Citomegalovirus/transmissão , Feminino , Rim/patologia , Macaca fascicularis , Masculino , Suínos , Transplante Heterólogo
16.
Transpl Immunol ; 31(3): 134-9, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25240733

RESUMO

BACKGROUND: We have previously demonstrated that the juvenile thymus plays an essential role in tolerance induced by both renal transplantation and a short course of calcineurin inhibitors. Aged thymi have a decreased ability to induce tolerance. Luteinizing hormone-releasing hormone (LHRH) is known to pharmacologically rejuvenate the thymus in rodents. In order to develop a clinically applicable regimen of transplantation tolerance in adults, we sought to determine if thymic rejuvenation would occur with LHRH agonism in non-human primates. METHODS AND RESULTS: Thymic rejuvenation was evaluated by magnetic resonance imaging (MRI), histology, as well as in-vitro cellular and molecular tests. Four aged male hamadryas baboons underwent subcutaneous injection of a 3-month depot of Lupron (11.25mg; LI) and were followed for 3 months. Thymi increased volumetrically by MRI. After LI, thymic cellularity markedly increased within the cortical and medullary thymus. Additionally, a significant increase in the CD4(+)/CD45RA(hi+) population in the peripheral blood occurred for 50 days after LI, and flow cytometry of thymic tissue revealed a large increase in the percentage of CD4(+)/CD8(+) cells. TREC assay corroborated enhancement in thymic function. CONCLUSION: These data indicate that LI is associated with thymic rejuvenation in baboons, and further confirm that extrinsic factors play an important role in thymic rejuvenation in a non-human primate model.


Assuntos
Leuprolida/administração & dosagem , Linfócitos T/imunologia , Timo/efeitos dos fármacos , Envelhecimento/imunologia , Animais , Antígenos CD4/metabolismo , Antígenos CD8/metabolismo , Células Cultivadas , Hormônio Liberador de Gonadotropina/agonistas , Tolerância Imunológica , Antígenos Comuns de Leucócito/metabolismo , Leuprolida/farmacologia , Imagem por Ressonância Magnética , Masculino , Papio , Rejuvenescimento , Timo/imunologia , Timo/patologia
17.
Nihon Hinyokika Gakkai Zasshi ; 105(3): 139-43, 2014 Jul.
Artigo em Japonês | MEDLINE | ID: mdl-25158557

RESUMO

A 36-year-old female received protocol biopsy at 1 month after living donor kidney transplantation. At 3 months post-transplantation, presence of a growing cystic mass in the kidney graft which had not been detected preoperatively, was demonstrated by ultrasound and computed tomography. The patient had an abdominal pain around the graft. Percutaneous drainage and sclerotherapy with minocyclin were performed twice, but the cystic mass, nevertheless, became enlarged and the abdominal pain recurred again. Laparoscopic fenestration was then performed. Immunohistochemistry of the cystic mass wall showed that it was CD34 (-), EMA (-), Megalin (-), but D2-40 (+). These results suggested that the cystic mass was derived from lymphatic vessels, which developed into lymphocele in the graft. We concluded that lymphatic vessels could have been injured and obstructed by the protocol biopsy. This is the first report of successful laparoscopic fenestration for lymphocele in the kidney graft.


Assuntos
Transplante de Rim , Linfocele/etiologia , Linfocele/cirurgia , Adulto , Feminino , Humanos , Laparoscopia , Doadores Vivos , Complicações Pós-Operatórias
18.
Int Urol Nephrol ; 46(7): 1441-6, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24526331

RESUMO

PURPOSE: We aimed to examine the influence of donor age on living-donor kidney transplantation (KTx), particularly with regard to long-term graft survival in young recipients with aged kidney grafts. METHODS: Between 1988 and 2012, 287 living-donor KTxs were performed in our center. The recipients were divided into 3 groups according to age in years: under 30 (young), 30-49 (middle-aged), and over 50 (old). The data regarding the influence of kidneys from donors aged over 50 years were retrospectively analyzed. RESULTS: Graft survival at 1, 5, 10, and 15 years was 94.7, 94.7, 90.2, and 75.2%, respectively, in young recipients who received grafts from donors aged under 50 years, and 96.4, 91.9, 65.4, and 41.4%, respectively, in young recipients who received grafts from donors aged over 50 years (P = 0.023). In contrast, there were no significant differences regarding graft survival and donor age in the middle-aged and old recipient groups. Multivariate analysis revealed that young recipient and rejection episode were significant predictors of graft loss in transplantation from older donors. Histological examination revealed significant age-related changes in the grafts before transplant and a significant higher rate of glomerular hypertrophy at the 1-month protocol biopsy in young recipients with aged kidney grafts. CONCLUSIONS: Kidney grafts from older living donors affected long-term graft survival in young recipients. In addition to the damage from rejection, aged kidney grafts, which have less nephron mass, may have a limited capacity to appropriately respond to increases in physiological or metabolic demands of young recipients, leading to a greater reduction in renal function.


Assuntos
Sobrevivência de Enxerto/fisiologia , Transplante de Rim , Rim/fisiologia , Adulto , Fatores Etários , Humanos , Doadores Vivos , Pessoa de Meia-Idade , Análise Multivariada , Fatores de Risco , Doadores de Tecidos
19.
J Am Soc Nephrol ; 25(4): 737-44, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24459229

RESUMO

We previously reported life-supporting α1,3-galactosyltransferase knockout (GalTKO) thymokidney xenograft survival of >2 months in baboons. However, despite otherwise normal renal function, recipients developed proteinuria with morphologic changes (podocyte effacement), a condition that presents a major obstacle to long-term studies in this model. A recent clinical study showed that rituximab therapy after allogeneic transplant prevented proteinuria possibly associated with loss of sphingomyelin phosphodiesterase acid-like 3b (SMPDL-3b). Here, we demonstrate that rituximab prevents the disruption of pig podocytes in an SMPDL-3b-dependent manner in vitro and the early development of proteinuria after xenogeneic kidney transplantation in baboons. Immunofluorescence showed SMPDL-3b expression in pig glomerular epithelium; immunoprecipitation demonstrated rituximab binding to SMPDL-3b in glomeruli. Culture of isolated pig podocytes with naive baboon sera, which has preformed antipig natural antibodies, reduced SMPDL-3b expression, disrupted podocyte morphology, and decreased podocyte proliferation, whereas pretreatment with rituximab prevented these effects. Six baboons received rituximab before transplantation to deplete B cells and again in the peri-transplant period; 18 baboons treated only before transplantation served as historical controls. The onset of post-transplant proteinuria was significantly delayed in a B cell-independent manner in the animals that received peri-transplant rituximab treatment. Although further optimization of this protocol is required, these data provide intriguing clues to the mechanisms of post-transplant proteinuria in xenogeneic kidney transplantation and a potential strategy for its prevention.


Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Transplante de Rim/efeitos adversos , Proteinúria/prevenção & controle , Animais , Células Cultivadas , Galactosiltransferases/fisiologia , Papio , Podócitos/patologia , Rituximab , Esfingomielina Fosfodiesterase/metabolismo , Suínos , Transplante Heterólogo
20.
Transplantation ; 96(11): 966-74, 2013 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-24056624

RESUMO

BACKGROUND: We have previously reported that Massachusetts General Hospital miniature swine, which had accepted class I-mismatched kidneys long-term after 12 days of high-dose cyclosporine A, uniformly accepted donor-major histocompatibility complex (MHC)-matched kidneys without immunosuppression but rejected donor MHC-matched split-thickness skin grafts by day 25, without changes in renal graft function or antidonor in vitro responses. We have now tested whether this "split tolerance" would also be observed for the primarily vascularized skin of vascularized composite allografts (VCAs). METHODS: Group 1 animals (n=3) received donor MHC-matched VCAs less than 70 days after primary kidney transplant (KTx). Group 2 animals (n=3) received a second donor-matched kidney transplant followed by a donor-matched VCA more than 200 days after primary KTx. RESULTS: Animals in Group 1 lost the epidermis on days 28, 30, and 40, with all other components of the VCAs remaining viable. Histology showed cellular infiltration localized to dermal-epidermal junction. One of three recipients of VCAs in Group 2, accepted all components of the VCA, including epidermis (>200 days). The other two recipients lost only the epidermis on days 45 and 85, with survival of the remainder of the VCA long-term. CONCLUSIONS: All tissues of a VCA are accepted long-term on animals tolerant of class I-mismatched kidneys, with the exception of epidermis, the survival of which is markedly prolonged compared with split-thickness skin grafts but not indefinite. Exposure of tolerant animals to second donor-matched kidneys before VCA increases the longevity of the VCA epidermis, suggesting an increase in the immunomodulatory mechanisms associated with tolerance of the kidney.


Assuntos
Aloenxertos Compostos/transplante , Epiderme/transplante , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Transplante de Rim/efeitos adversos , Complexo Principal de Histocompatibilidade/imunologia , Transplante de Pele/efeitos adversos , Tolerância ao Transplante , Alotransplante de Tecidos Compostos Vascularizados/efeitos adversos , Animais , Aloenxertos Compostos/imunologia , Aloenxertos Compostos/patologia , Ciclosporina/farmacologia , Epiderme/imunologia , Epiderme/patologia , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/efeitos dos fármacos , Histocompatibilidade , Imunossupressores/farmacologia , Suínos , Porco Miniatura , Linfócitos T Reguladores/imunologia , Fatores de Tempo , Tolerância ao Transplante/efeitos dos fármacos
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