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1.  Quantitative characterization of T-cell repertoire and biomarkers in kidney transplant rejection 
BMC Nephrology  2016;17:181.
T-cell-mediated rejection (TCMR) remains a major cause of kidney allograft failure. The characterization of T-cell repertoire in different immunological disorders has emerged recently as a novel tool with significant implications. We herein sought to characterize T-cell repertoire using next generation sequencing to diagnose TCMR.
In this prospective study, we analyzed samples from 50 kidney transplant recipients. We collected blood and kidney transplant biopsy samples at sequential time points before and post transplant. We used next generation sequencing to characterize T-cell receptor (TCR) repertoire by using illumina miSeq on cDNA synthesized from RNA extracted from six patients’ samples. We also measured RNA expression levels of FOXP3, CD8, CD4, granzyme and perforin in blood samples from all 50 patients.
Seven patients developed TCMR during the first three months of the study. Out of six patients who had complete sets of blood and biopsy samples two had TCMR. We found an expansion of the TCR repertoire in blood at time of rejection when compared to that at pre-transplant or one-month post transplant. Patients with TCMR (n = 7) had significantly higher RNA expression levels of FOXP3, Perforin, Granzyme, CD4 and CD8 in blood samples than those with no TCMR (n = 43) (P = 0.02, P = 0.003, P = 0.002, P = 0.017, and P = 0.01, respectively).
Our study provides a potential utilization of TCR clone kinetics analysis in the diagnosis of TCMR. This approach may allow for the identification of the expanded T-cell clones associated with the rejection and lead to potential noninvasive diagnosis and targeted therapies of TCMR.
PMCID: PMC5117555  PMID: 27871261
T-cell; Kidney transplant; T cell mediated rejection; T cell sequencing
2.  Depression of Complement Regulatory Factors in Rat and Human Renal Grafts Is Associated with the Progress of Acute T-Cell Mediated Rejection 
PLoS ONE  2016;11(2):e0148881.
The association of complement with the progression of acute T cell mediated rejection (ATCMR) is not well understood. We investigated the production of complement components and the expression of complement regulatory proteins (Cregs) in acute T-cell mediated rejection using rat and human renal allografts.
We prepared rat allograft and syngeneic graft models of renal transplantation. The expression of Complement components and Cregs was assessed in the rat grafts using quantitative real-time PCR (qRT-PCR) and immunofluorescent staining. We also administered anti-Crry and anti-CD59 antibodies to the rat allograft model. Further, we assessed the relationship between the expression of membrane cofactor protein (MCP) by immunohistochemical staining in human renal grafts and their clinical course.
qRT-PCR results showed that the expression of Cregs, CD59 and rodent-specific complement regulator complement receptor 1-related gene/protein-y (Crry), was diminished in the rat allograft model especially on day 5 after transplantation in comparison with the syngeneic model. In contrast, the expression of complement components and receptors: C3, C3a receptor, C5a receptor, Factor B, C9, C1q, was increased, but not the expression of C4 and C5, indicating a possible activation of the alternative pathway. When anti-Crry and anti-CD59 mAbs were administered to the allograft, the survival period for each group was shortened. In the human ATCMR cases, the group with higher MCP expression in the grafts showed improved serum creatinine levels after the ATCMR treatment as well as a better 5-year graft survival rate.
We conclude that the expression of Cregs in allografts is connected with ATCMR. Our results suggest that controlling complement activation in renal grafts can be a new strategy for the treatment of ATCMR.
PMCID: PMC4771804  PMID: 26928779
3.  The benefits of cancer screening in kidney transplant recipients: a single‐center experience 
Cancer Medicine  2015;5(2):153-158.
The frequency of malignancy is increasing in kidney transplant recipients. Posttransplant malignancy (PTM) is a major cause of long‐term graft survival inhibition. In this study, we evaluated the frequency and prognosis of PTM at our center and examined the efficacy of cancer screening. Between 1972 and 2013, 750 patients were followed‐up at our center. Annual physical examinations and screenings were performed to detect PTM. We investigated the detail of two distinctive cancer groups: screening‐detected cancers and symptom‐detected cancers. Seventy‐seven PTM were identified during the follow‐up period. The mean age at the initial PTM detection was 43.6 ± 12.8 years. The mean interval from transplantation to cancer diagnosis was 134.5 ± 11.3 months. Among the 77 patients, posttransplant lymphoproliferative disease (PTLD) was the most common cancer (19.5%, 15/77), followed by renal cell carcinoma (15.6%, 12/77). Of the cancer cases, 46.8% (36/77) were detected via screening. The most frequently screening‐detected cancer was renal cell carcinoma of the native kidney and breast cancer (22.2%, 8/36). However, it was difficult to detect PTLD, urothelial carcinoma, and colorectal cancer via screening. Interestingly, Cox proportional regression analyses revealed nonscreened recipients to be a significant prognostic factor for PTM (P < 0.001). This study is the first to report that appropriate screening tests play a key role in early PTM diagnosis and lead to reduce the mortality rate in kidney transplant recipients. These findings support the provision of long‐term appropriate screening for kidney transplant recipients.
PMCID: PMC4735786  PMID: 26686199
Cancer screening; immunosuppression; kidney transplantation; posttransplant malignancy
4.  Early diagnosis and treatment of breast cancer in Japanese kidney transplant recipients: a single center experience 
SpringerPlus  2015;4:196.
The incidence of malignancies in kidney transplant recipients is increasing. Breast cancer is a common malignancy after kidney transplantation and can be more aggressive in kidney transplant recipients than in the general population. In this study, we evaluated the incidence and prognosis of breast cancer in kidney transplant recipients.
Between 1993 and 2013, 750 kidney transplant patients were followed-up at our center. Since 1999, annual physical examination, mammography, and breast ultrasonography have been performed for such patients. Diagnostic studies, including core needle or mammotome biopsy, were performed for suspected malignancies. Patients with malignant neoplasm were administered the appropriate treatment and followed-up to assess tumor response and symptoms.
Nine patients were diagnosed with breast cancer during the follow-up period. The mean age at the initial detection of the breast cancer was 47.7 ± 8.4 years. The mean interval from transplantation to diagnosis was 148.7 ± 37.1 months. Of the 9 patients, 8 were detected through the screening test; 7 were treated with breast conservative surgery and 1 was treated with modified radical mastectomy. The cancer stages were 0 (n = 2), I (n = 6), and II (n = 1). The incidence of breast cancer tended to be unchanged with time between transplantation and diagnosis, inconsistent with the increase in the duration of immunosuppression.
Annual screening tests are crucial in the early diagnosis of breast cancer. Early treatment of breast cancer can result in an excellent prognosis in kidney transplant recipients.
PMCID: PMC4431989  PMID: 25992308
Breast cancer; Kidney transplantation; Prognosis; Screening
5.  A rare case of spontaneous necrosis of primary renal cell carcinoma 
A 42-year-old woman was referred to our hospital with a chief complaint of asymptomatic gross hematuria. Computed tomography revealed a 4-cm tumour in the left kidney and radical nephrectomy was performed. Microscopically, the tumour was completely necrotic and consisted of nests of cells with abundant cytoplasm and large nuclei. Immunohistochemical analysis indicated complete infarction of the chromophobe renal cell carcinoma. Two years after surgery, the patient remained recurrence-free.
PMCID: PMC4301967  PMID: 25624965
6.  A nonerythropoietic derivative of erythropoietin inhibits tubulointerstitial fibrosis in remnant kidney 
The tissue-protective effects of erythropoietin (EPO) have been extensively investigated, and EPO administration can raise the hemoglobin (Hb) concentration. Recently, we reported that carbamylated erythropoietin (CEPO) protected kidneys from ischemia-reperfusion injury as well as EPO.
To investigate the clinical applications of CEPO, we next evaluated the long-term therapeutic effect of CEPO using a tubulointerstitial model rat. We randomized remnant kidney model rats to receive saline, EPO, or CEPO for 8 weeks.
CEPO- and EPO-treated rats had improved serum creatinine levels compared with saline-treated remnant kidney model rats, although the Hb level was significantly increased in EPO-treated rats. Two-photon microscopy revealed that EPO/CEPO significantly ameliorated tubular epithelial cell damage assessed by endocytosis. In addition, CEPO or EPO protected endothelial cells with a sustained blood flow rate. EPO or CEPO suppressed the number of TUNEL-positive apoptotic cells with weak αSMA staining.
Furthermore, PCR analysis demonstrated that TGF-β and type I collagen expression was attenuated in EPO- or CEPO-treated rats, accompanied by a significant decrease in interstitial fibrosis.
We established a long-term therapeutic approach to protect tubulointerstitial injury with CEPO, and thus, the therapeutic value of this approach warrants further attention and preclinical studies.
PMCID: PMC4108904  PMID: 22678524
Carbamylated erythropoietin; Remnant kidney; Apoptosis; TGF-β
7.  Clinical characteristics and risk factors for septic shock in patients receiving emergency drainage for acute pyelonephritis with upper urinary tract calculi 
BMC Urology  2012;12:4.
Acute pyelonephritis (APN) is a common complication of ureteral obstruction caused by urolithiasis, and it can be lethal if it progresses to septic shock. We investigated the clinical characteristics of patients undergoing emergency drainage and assessed risk factors for septic shock.
A retrospective study was performed of 98 patients (101 events) requiring emergency drainage at our urology department for obstructive APN associated with upper urinary tract calculi from January 2003 to January 2011. Clinical characteristics were summarized, and risk factors for septic shock were assessed by logistic regression analysis.
Objective evidence of sepsis was found in 64 (63.4%) events, and 21 events (20.8%) were categorized as septic shock. Ninety-six patients recovered, but 2 patients died of septic shock. Multivariate analysis revealed that age and the presence of paralysis were independent risk factors for septic shock.
APN associated with upper urinary tract calculi is a severe disease that should be treated with caution, particularly when risk factors are present.
PMCID: PMC3353222  PMID: 22413829

Results 1-7 (7)