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Huang H.-F.,Zhejiang University | Huang H.-F.,Zhejiang University of Science and Technology | Huang H.-F.,Kidney Disease Immunology Laboratory | Huang H.-F.,Key Laboratory of Multiple Organ Transplantation | And 20 more authors.
International Urology and Nephrology | Year: 2016

Purpose: To compare the long-term effects of the interleukin-2 receptor antagonist basiliximab versus rabbit antithymocyte globulin as an induction therapy for living-related renal transplantation. Methods: This is a prospective, open-label, nonrandomized, controlled study including 213 cases of renal transplant. Immunosuppressive therapy containing calcineurin inhibitors, mycophenolate mofetil and steroids was applied in all cases. The interleukin-2 receptor antagonist group (IL2Ra group) included 108 cases with 20 mg basiliximab induction on Day 0 and Day 4. The other 105 cases comprised the rabbit antithymocyte globulin group (rATG group) with 1.0 mg/kg/day ATG induction from Day 0 to Day 4. The primary endpoint was biopsy-proven acute rejection. Other endpoints included delayed graft function (DGF), graft loss and death. Results: All patients were followed up for 3 years. Acute rejection rates in the IL2Ra group and the ATG group were 5.6 and 3.8 % (P = 0.781), and the differences in the DGF rates, graft loss and death were insignificant between groups. All-cause infection rates in the IL2Ra and rATG groups were 26.9 and 43.8 % (P = 0.010). Urinary tract infections were more common in the rATG group than in the IL2Ra group (15.2 vs 6.5 %, P = 0.040). Specific viral infection rates were significantly different (18.1 % in rATG group vs 8.3 % in IL2Ra group, P = 0.035). Conclusions: IL2Ra and rATG had no significant differences as induction therapies during the perioperative period of living-related renal transplantation, according to acute rejection rates, DGF rates, graft loss, 1- and 3-year patient/graft survival rates. However, the incidence of infection, especially of urinary tract infection and specific viral infection, was higher in rATG-induced patients. © 2016, Springer Science+Business Media Dordrecht.


Lu X.,Zhejiang University | Lu X.,Kidney Disease Immunology Laboratory | Lu X.,Key Laboratory Of Multiple Organ Transplantation | Lu X.,Key Laboratory of Nephropathy | And 36 more authors.
Experimental and Clinical Transplantation | Year: 2014

Objectives: To evaluate the effect of isogeneic CD4+CD25+ regulatory T cells on cardiac allograft tolerance in heterotopic heart transplant from Balb/c to C57BL/6 mice. Materials and Methods: Isogeneic and allogeneic CD4+CD25+ regulatory T cells were obtained from pregnant C57BL/6 mice crossed with male Balb/c mice and from regular Balb/c mice. Recipient C57BL/6 mice were treated with sublethal radiation (2 Gy) and an infusion of isogeneic CD4+CD25+ regulatory T cells, allogeneic CD4+CD25+ regulatory T cells, or phosphate-buffered saline alone 1 day before a Balb/c-to-C57BL/6 heterotopic heart transplant. At 10 days after the transplant, cardiac allografts and the sera of recipients were evaluated with histology and cytokine analysis. Splenocytes of recipients were collected to determine chimerism on the day of the cessation of allograft heartbeat. Results: Mice that received an infusion of isogeneic CD4+CD25+ regulatory T cells had significantly greater mean median survival time, greater degree of chimerism, decreased levels of cytokines (monokine induced by interferon γ, interleukin 6, interleukin 10, and regulated upon activation, normal T cell expressed and secreted protein), and decreased lymphocytic infiltration than did mice that received phosphate-buffered saline alone. The effects on allograft tolerance were stronger in mice that received the isogeneic than the allogeneic CD4+CD25+ regulatory T cells. Conclusions: Isogeneic CD4+CD25+ regulatory T cells may establish cardiac allograft tolerance by inducing mixed chimerism and suppressing immune responses. Infusion with isogeneic CD4+CD25+ regulatory T cells combined with radiation (sublethal dose, 2 Gy) may establish allograft tolerance in mice. Therefore, further study is warranted because isogeneic CD4+CD25+ regulatory T cells may have therapeutic benefits. © Başkent University 2014 Printed in Turkey. All Rights Reserved.


Lu X.,Zhejiang University | Lu X.,Kidney Disease Immunology Laboratory | Lu X.,Key Laboratory of Multiple Organ Transplantation | Lu X.,Key Laboratory of Nephropathy of Zhejiang Province | And 20 more authors.
Nephrology | Year: 2014

Aim Serum- and glucocorticoid-inducible kinase SGK1 functions as an important regulator of transepithelial sodium transport by activating epithelial sodium channel in renal tubules. Considerable evidence demonstrated that SGK1 was associated with hypertension and fibrosing diseases, such as diabetic nephropathy and glomerulonephritis. The present study was performed to evaluate the role of SGK1 played in immunoglobulin A (IgA) nephropathy. Methods Seventy-six patients of biopsy-proven IgA nephropathy and 33 healthy volunteers were enrolled in this study. All patients and healthy volunteers' urinary and serum samples were tested for SGK1 expression by indirect enzyme-linked immunosorbent assay. Meanwhile all patients' renal tissues were semi-quantified for SGK1 expression by immunohistochemistry assay. The relationships between SGK1 expressions and clinical or pathological parameters were also assessed. Results SGK1 expression was upregulated in urine and renal tubules in patients of Oxford classification T1 and T2, whereas its expression in serum did not increase significantly. Relationship analysis indicated that urinary and tissue SGK1 expressions were associated with heavy proteinuria and renal insufficiency in patients with IgA nephropathy. On the other hand, RAS blockades would reduce the SGK1 levels both in urine and renal tissues. Conclusion These results suggested that urinary SGK1 should be a good indicator of tubulointerstitial damage in patients of IgA nephropathy. SGK1 expressions in urine and renal tissues were associated with the activity of renin-angiotensin-aldosterone system. © 2014 Asian Pacific Society of Nephrology.


Shen J.,Zhejiang University | Shen J.,Kidney Disease Immunology Laboratory | Shen J.,Key Laboratory of Multiple Organ Transplantation | Shen J.,Zhejiang University of Science and Technology | And 42 more authors.
Journal of Pathology | Year: 2016

Podocytes play important roles in the progression of diabetic kidney disease (DKD) and these roles are closely associated with cytoskeletal actin dynamics. N-Methyl-d-aspartate receptors (NMDARs), which consist of two functional NR1 subunits and two regulatory NR2 subunits, are widely expressed in the brain but are also found in podocytes. Here, we found increased NR1 expression in two diabetic mouse models and in podocytes incubated in high glucose (HG). In diabetic mice, knockdown of NR1 using lentivirus carrying NR1-shRNA ameliorated the pathological features associated with DKD, and reversed the decreased expression of synaptopodin and Wilms' tumour-1. In podocytes incubated with HG, NR1 was secreted from the endoplasmic reticulum and this was blocked by bisindolylmaleimide I. NR1 knockdown decreased the cell shape remodelling, cell collapse, bovine serum albumin permeability, and migration induced by HG. After HG incubation, levels of cell division control protein 42 (Cdc42) and its active form increased, and a significantly higher Cdc42-GTP level, increased Cdc42 translocation onto the leading edges, and lower migration ability were found in podocytes with NR1 knockdown. Increases in the number and length of filopodia were found in podocytes with NR1 knockdown but these were abolished by Cdc42-GTP blockade with ML141. In conclusion, the activation of NMDARs plays an important role in DKD by reducing Cdc42-GTP activation. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Jiang H.,Zhejiang University | Jiang H.,Kidney Disease Immunology Laboratory | Jiang H.,Key Laboratory Of Multiple Organ Transplantation | Liang L.,Zhejiang University | And 29 more authors.
Oncotarget | Year: 2016

IgA nephropathy(IgAN) is the most common primary glomerular disease in China. Primary infections always occur before IgAN. However, the pathology of IgAN is still unclear. Previously we found that LL37, a protein secreted by senescent cells, was specific for the progression of IgAN, and also played a role in the neutrophil function. So we hypothesized that the infiltration of neutrophils, inflammation factors, and aging markers, which were modulated by functional networks, induced the immune response and renal injury. RNA-Sequencing (RNA-seq) can be used to study the whole transcriptome and detect splicing variants that are expressed in a specific cell type or tissue. We separate glomerulus from the renal biopsy tissues. After RNA extraction, the sequences were analyzed with Illumina HiSeq 2000/2500. 381 genes with differential expression between the IgAN patients and the healthy controls were identified. Only PLAU, JUN, and FOS were related to DNA damage, telomere dysfunction-induced aging markers, neutrophil function and IgA nephropathy. The networks showed the possibility of these genes being connected. We conclude that DNA damage and telomere dysfunction could play important roles in IgA nephropathy. In addition, neutrophils are also important factors in this disease. The networks of these markers showed the mechanism pathways that are involved in the duration of the occurrence and progression of IgA nephropathy and might be a new therapeutic opportunity for disease treatment.


Wang M.,Zhejiang University | Jin Q.,Zhejiang University | Tu H.,Zhejiang University | Mao Y.,Zhejiang University | And 17 more authors.
International Urology and Nephrology | Year: 2011

This study aimed to diagnose renal allograft dysfunction with specific biomarkers by serum proteomic analysis. Surface-enhanced laser desorption/ ionization time-of-flight mass spectrometry (SELDI-TOF MS) and bioinformatics (support vector machine and leave-one cross validation) were used to analyze serum proteome. Enrolled patients included 38 biopsy-proved acute rejection (BPAR), 10 acute tubular necrosis (ATN), 24 subclinical rejection (SCR) and 29 stable control recipients verified by protocol biopsy. A characteristic protein profile can be detected in each renal allograft dysfunction group. BPAR patients were differentiated from stable patients with markers of 9710.1, 4971, 6675.5, 8563.8, 6709.2, 9319 and 4476.7 Da with high sensitivity and specificity. ATN can be clearly distinguished from BPAR and stable control. Subclinical rejection differentiated from stable control with markers of 9193.1, 2759.1, 8464.6 Da. The independent blind test yielded with high specificity and sensitivity for each group. Serum proteome analysis by SELDI-TOF MS combined with bioinformatics in renal allograft dysfunction is valuable and promising. Specific markers were detected in each group. Identification of these proteins may prove useful as diagnostic markers for allograft dysfunction and better to elucidate the mechanism of acute rejection. © 2011 Springer Science+Business Media, B.V.


Wang B.,Zhejiang University | Wang B.,Kidney Disease Immunology Laboratory | Wang B.,Key Laboratory of Multiple Organ Transplantation | He Q.,Zhejiang University | And 13 more authors.
Transplant Immunology | Year: 2012

Aims: In this study, we analyzed the mRNA expression of serine/threonine (Ser/Thr) protein phosphatase 2A (PP2A) in the human leukemic T-cell line Jurkat cells treated with rapamycin, to determine whether rapamycin inhibiting cell viability is accompanied with the change of mRNA expression of PP2A. Methods and results: Jurkat cells were incubated with various concentrations of rapamycin and cultured for different hours. Cell viability was assessed by MTT assay. The mRNA expressions of PP2A subunits were measured by quantitative real-time polymerase chain reaction (PCR). We found that rapamycin had an inhibitory effect on cell viability. IC50 was 343.3. nM at 48. h.We also found rapamycin had a dose and time-dependent effect on the gene expression of PP2A. When setting the concentration of rapamycin 500. nM, the mRNA expressions of PP2A subunits (Aa, Aβ, PR55a, PR55δ, PR61γ, PR70, Ca and Cβ) were declined significantly at 48. h. When treated with various concentrations of rapamycin for 48. h, the mRNA expressions of PP2A subunits were down-regulated in the range from 10. nM to500. nM. Conclusions: Rapamycin inhibiting Jurkat T cells viability may be related to the reduction of PP2A mRNA expressions. © 2011.


Lv R.,Zhejiang University | Lv R.,Key Laboratory of Nephropathy | Lv R.,Kidney Disease Immunology Laboratory | Lv R.,Key Laboratory of Multiple Organ Transplantation | And 20 more authors.
Disease Markers | Year: 2015

Background. C3d is a product of both the classic and the alternative complement cascades; however, few studies have addressed the role of C3d in renal biopsies and its relationship with long-term graft survival rate is not very clear. Methods. 94 patients with biopsy-proven acute rejection episodes were included in the study. We investigated the associations between histological findings, clinical examinations, and outcome. Results. The overall prevalence for C4dPTC and C3dPTC was 42.6% and 29.8%. There was a significant association between C3dPTC and C4dPTC (P < 0.001). C3dPTC and C4dPTC were related with histological types (P = 0.024 and P < 0.001, resp.). The long-term survival rate for C4dPTC positive transplants was lower than that of C4dPTC negative transplants, but it was not statistic significant in our study (P = 0.150). The survival rate of C3dPTC positive group was much lower than the negative group (P = 0.014). Patients with double positives for C4dPTC and C3dPTC exhibited the lowest survival rate significantly different from those of the C3dPTC only and C4dPTC only groups (P = 0.01 and P = 0.0037). Conclusions. This longitudinal cohort study has demonstrated that C3d deposition in the PTC was closely related to renal dysfunction and pathological changes. © 2015 Rong Lv et al.

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