Heli Xiang

Hypoxic preconditioning advances CXCR4 and CXCR7 expression by activating HIF-1α in MSCs.

Recent evidence indicated that sublethal hypoxic preconditioning (HP) of bone marrow-derived mesenchymal stem cells (MSCs) before transplantation could ameliorate their capacity to survive and engraft in the target tissue through yet undefined mechanisms. In this study, we demonstrated that HP (3% oxygen) induced the high expression of both chemokine stromal-derived factor-1 (SDF-1) receptors, CXCR4 and CXCR7, in MSCs. HP also improved in vitro migration, adhesion and survival of MSCs. Although SDF-1-induced migration of HP-MSCs was only abolished by an anti-CXCR4 antibody, both CXCR4 and CXCR7 were responsible for elevated adhesion of HP-MSCs. Moreover, CXCR7 but not CXCR4 was essential for the resistance to oxidative stress of HP-MSC. In addition, HP also evoked an increase in expression of hypoxia-inducible factor-1 (HIF-1α) and phosphorylation of Akt. The chemical inducers of HIF-1α, desferrioxamine (DFX) and cobalt chloride (CoCl₂), induced upregulation of CXCR4 and CXCR7 expression in MSCs under normoxic conditions. Contrarily, blockade of HIF-1α by siRNA and inhibition of Akt by either wortmannin or LY294002 abrogated upregulation of HP-induced CXCR4 and CXCR7 in MSCs. Collectively, these findings provide evidence for a crucial role of PI3K/Akt-HIF-1α-CXCR4/CXCR7 pathway on enhanced migration, adhesion and survival of HP-MSCs in vitro.

Allograft rejection-related gene expression in the endothelial cells of renal transplantation recipients after cytomegalovirus infection.

ObjectiveTo explore the effects of cytomegalovirus (CMV) infection on rejection-related gene expression in the endothelial cells of renal transplantation recipients.MethodsEndothelial cells (ECs) were cultured and stimulated by a variety of factors: A, normal control group; B, inactivated human cytomegalovirus (HCMV) infection group; C, HCMV infection group; D, HCMV supernatant infection group; and E, ganciclovir HCMV group. Expression of intercellular adhesion molecule-1 (ICAM-1) and major histocompability complex (MHC) class I and class II antigens was detected by flow cytometry (FCM) and immunohistochemistry.ResultsWe found characteristic CMV-infected ECs in this study. There were no significant differences among groups A, B and D (P>0.05). Although the expression levels of ICAM-1 were not significantly different between groups C and E (P>0.05), the ICAM-1 expression in these two groups was significantly higher than that in group A (P<0.05). ICAM-1 expression was detected in groups C and E, while there was no expression in groups A, B and D. Furthermore, there was no significant difference of ICAM-1 mRNA expression between groups C and E (P>0.05). Human leucocyte antigen (HLA)-ABC expression was detected in all the groups, while HLA-DR expression was only detected in groups C and E. There were no significant differences of HLA-ABC and HLA-DR expression among groups A, B and D (P>0.05). However, the HLA-ABC and HLA-DR expression levels in groups C and D were higher than those of the remaining groups previously reported (P<0.05). Meanwhile, the HLA-ABC and HLA-DR expression levels in group E were lower than those of group C (P<0.05).ConclusionCMV could up-regulate the expression levels of ICAM-1 and MHC antigens, which was closely related to allograft rejection.

Long-term follow-up of co-administration of diltiazem and cyclosporine in Chinese kidney transplant recipients.

Background: Co-administration of diltiazem and cyclosporine A (CsA) in kidney transplant recipients shows improvement of renal transplantation outcomes. Methods: We respectively analyzed 1531 kidney transplant recipients treated by different immunosuppressive therapy schemes from 1986 to 2003. They were divided into three groups depending on their immunosuppressive therapy schemes: control group with a standard triple therapy without use of diltiazem; study group I with the combination of diltiazem and the standard triple therapy but slightly low CsA; study group II with combination of diltiazem and a modified standard triple therapy but lower CsA. The CsA blood concentrations, posttransplant complications, and long-term survival in the three groups were compared. Results: The results showed that the patient and allograft survival in the study group II was 69.9 and 65.1%, respectively, significantly higher than that in the control group (50.7 and 47.6%). Occurrence of hepatotoxicity and nephrotoxicity episodes was higher in the control group than those in the study group I and the study group II. The incidence of acute rejection in the control group was 30.3% (23/76), similar to 28.0% (184/657) in study group I, but statistically significantly higher than 7.6% (61/798) in the study group II. Conclusion: Combination of diltiazem and CsA in the kidney allograft recipients tends to reduce the CsA oral dosage, improve patient survival, and decrease the occurrence of hepatotoxicity and nephrotoxicity.

Treatment of Cytomegalovirus infection after renal transplantation: Experience from a Single Center in China

BACKGROUND We compared the efficacy and safety of 2 different treatments of CMV infection, including asymptomatic CMV replication and CMV disease. MATERIAL AND METHODS 852 renal transplantation recipients, including asymptomatic CMV replication and CMV disease, received antiviral therapies of intravenous acyclovir or comprehensive anti-infection solution, mainly with intravenous ganciclovir. Effect, time, acute allograft rejection, and safety were analyzed during the antiviral therapy RESULTS The total effective rates were higher with ganciclovir in both asymptomatic CMV replication (98.96% vs. 84.90%) and CMV disease (96.29% vs. 50.36%). Ganciclovir significantly shortened antiviral therapy duration in both asymptomatic CMV replication (15.0 ± 2.3 days vs. 16.0 ± 3.4 days) and CMV disease (19.7 ± 3.1 days vs. 21.5 ± 4.0 days). The acute allograft rejection incidences were significantly lower with ganciclovir in both asymptomatic CMV replication (8% vs. 14%) and CMV disease (11% vs. 22%). CMV-IEA was detected in renal grafts of patients with acute rejection. There was more CMV-associated acute rejection using acyclovir than using ganciclovir. Except for the higher incidence of anemia leucopenia and anemia with ganciclovir, the safety profiles of both drugs were similar. CONCLUSIONS Comprehensive anti-infection solution, mainly with intravenous ganciclovir, can effectively treat CMV infection, shorten duration of therapy, and decrease acute rejection. The few adverse effects had negligible effects on use of ganciclovir.

Assessment of different biomarkers provides valuable diagnostic standards in the evaluation of the risk of acute rejection

Acute rejection (AR) is a strong risk factor for chronic rejection in renal transplant recipients. Accurate and timely diagnosis of AR episodes is very important for disease control and prognosis. Therefore, objectively evaluated the immune status of patients is essential in the field of post-transplantation treatment. This longitudinal study investigated the usefulness of five biomarkers, human leukocyte antigen (HLA)-G5 and sCD30 level in sera, intracellular adenosine triphosphate (iATP) release level of CD4(+) T cells, and granzyme B/perforin expression in peripheral blood mononuclear cells (PBMCs) and biopsies, to detect AR and the resolution of biomarkers in a total of 84 cases of renal transplantation. The data demonstrated that recipients with clinical or biopsy proven rejection significantly increased iATP release level of CD4(+) T cells, and elevated sCD30 but lowered HLA-G5 level in sera compared with individuals with stable graft function. Expression levels of granzyme B and perforin were also elevated in PBMCs and graft biopsies of AR patients. Taken together, we identified that upregulation of sCD30, iATP, granzyme B, perforin, and downregulation of HLA-G5 could provide valuable diagnostic standards to identify those recipients in the risk of AR. And iATP may be a better biomarker than others for predicting the graft rejection episode.

Methodology for monitoring cytomegalovirus infection after renal transplantation

Abstract Background: The aim of this study was to evaluate the diagnostic value of different detection methods for cytomegalovirus (CMV) infection after renal transplantation and also to establish a system to monitor therapy for CMV infection. Methods: We retrospectively studied 1516 renal transplant recipients from June 1994 to December 2006. All patients were screened for CMV-DNA. A total of 1402 patients had received CMV-IgG/IgM detection since June 1996 and 660 had received CMV antigen detection since June 2000. Results: A total of 664 (43.8%) recipients developed CMV infection. The sensitivity, specificity and Youden index of the three methods, respectively, were 18.84%, 100% and 0.1884 for ELISA, 91.86%, 82.98% and 0.7484 for PCR, and 88.06%, 96.95% and 0.8501 for the CMV-pp65 antigenemia test. The sensitivity and specificity of the two combined detection methods (CMV-DNA and CMV-pp65) for post-operation CMV infection were 93.49% and 99.06%; the two detection methods had significant dependability (p<0.05) in diagnosis of CMV infection and in evaluation of therapeutic effect of antiviral drugs. Conclusions: Only ELISA can be used as a screening index in order to distinguish whether the donors or recipients are infected with CMV or not. CMV-pp65 antigenemia can help guide clinical therapy for CMV infection. CMV-pp65 and CMV-PCR combined together provide a more effective method to monitor CMV infection and predict its outcome. Clin Chem Lab Med 2009;47:177–81.

Which is more suitable for kidney transplantation at the early post-transplantation phase in China – low dosing or standard dosing of enteric-coated mycophenolate sodium?

To investigate the pharmacokinetics of enteric‐coated mycophenolate sodium (EC‐MPS) and the clinical outcome in kidney transplant recipients in the early post‐transplantation phase. Then explain which regimen is more suitable for Chinese renal transplant recipients.

Cathelicidin PR-39 peptide inhibits hypoxia/ reperfusion-induced kidney cell apoptosis by suppression of the endoplasmic reticulum-stress pathway

Ischemia/reperfusion injury (IRI) is a major cause of acute kidney damage, which often occurs in deceased donor kidney transplants. Cathelicidin PR-39 peptide possesses anti-inflammatory and wound repair effects through tissue angiogenesis and anti-apoptosis. This study assessed the role of PR-39 in anti-apoptosis in vitro using a lentiviral vector with a kidney specific promoter (KSP) to drive PR-39 expression. Our data revealed that PR-39 peptide was specifically over-expressed in kidney-derived HK-2 cells, but was scarcely detected in non-kidney tissue-derived cells. PR-39 over-expression had a protective role in the hypoxia/re-oxygenation (H/R) treated cells. The anti-apoptotic activity of PR-39 peptide was mediated by the inhibition of caspase-2, caspase-12 and caspase-3 activity in the endoplasmic reticulum (ER) stress-induced apoptotic pathway. It was also revealed that the anti-apoptotic effect of PR-39 peptide was mediated by an apoptosis-related protein, cellular inhibitor apoptosis protein-2 (c-IAP-2). Taken together, the current data demonstrate that PR-39 expression driven by KSP could prevent kidney damage (apoptosis) from IRI via the ER stress-induced apoptotic pathway.

The clinical value of enzyme-multiplied immunoassay technique monitoring the plasma concentrations of cyclosporine A after renal transplantation

The feasibility and the clinical value of the enzyme-multiplied immunoassay technique (EMIT) monitoring of blood concentrations of cyclosporine A (CsA) in patients treated with CsA were investigated after kidney transplantation. The validation method was performed to the EMIT determination of CsA blood concentration, the CsA whole blood ‘trough concentrations (C0) of patients in different time periods after renal transplantation were monitored, and combined with the clinical complications, the statistical results were analyzed and compared. EMIT was precise, accurate and stable, also with a high quality control. The mean postoperative blood concentration of CsA was as follows: <1 month, (281.4 ± 57.9)ng/mL; 2 – 3 months, (264.5 ± 41. 2)ng/mL; 4 – 5 months, (236.4 ± 38. 9)ng/mL; 6 – 12 months, (206.5 ± 32.6)ng/mL; >12 months, (185.6 ± 28.1)ng/mL. The toxic reaction rate of CsA blood concentration within the recommended therapeutic concentration was 14. 1%, significantly lower than that of the none-recommended dose group (37.2%) (P < 0.05); the transplantation rejection rate was 4.4%, significantly lower than that of the none-recommended dose group (22.5%) (P < 0.05). Using EMIT to monitor the blood concentration of CsA as the routine laboratory method is feasible, and is able to reduce the CsA toxicity and rejection significantly, leading to achieving the desired therapeutic effect.

Outcomes of EC-MPS combined with low-dose tacrolimus in DCD kidney transplantation for high-risk DGF recipients

Effective use of immunosuppressive agents to avoid the occurrence of nephrotoxicity and rejection in recipients with delayed graft function (DGF) is a concern for physicians. We investigated the outcomes of treatment with enteric-coated mycophenolate sodium (EC-MPS) in combination with a low-dose of tacrolimus (Tac) in renal transplantation for recipients with a high risk of DGF. We conducted a retrospective study of 61 recipients with a high risk of DGF who were treated with EC-MPS and low-dose Tac. The recipients were separated into a no-DGF group and a DGF group, based on whether DGF actually occurred. The results showed that although EC-MPS and Tac doses were similar in both groups, the percentage of recipients whose mycophenolic acid area under the curve 0–12 h (MPA-AUC0–12 h) was below 30 (mg·h)/L was significantly higher and the Tac trough concentration significantly lower in the DGF group one week after transplantation. Notably, a higher incidence of biopsy-proven acute rejection (BPAR) was found in the DGF group and among all recipients whose MPA-AUC0–12 h was less than 30 (mg·h)/L at one week after transplantation. One-year graft survival, patient survival, allograft function, and the incidence of the most common adverse events were similar in the two groups. In conclusion, the immunosuppressive regime is applicable to Chinese kidney transplant recipients, and early low exposure to EC-MPS was related to acute rejection in the recipients at a high risk of DGF.摘要目的分析心脏死亡供体(DCD)肾移植中移植物功能延迟恢复(DGF)高风险受者应用米芙(EC-MPS) 联合低剂量他克莫司治疗术后1年的有效性及安全性,指导临床用药。创新点对比DGF 高风险受者术后发生DGF 及正常恢复受者的免疫抑制剂药代动力学特征。方法将本中心进行肾移植的61 例DGF 高风险受者按照实际病情纳入DGF 组及正常恢复组,均行米芙联合低剂量他克莫司免疫抑制治疗。对比两组免疫抑制剂血药浓度及预后各项指标。结论DGF 组及正常恢复组间米芙及他克莫司剂量无显著差异。术后1 周DGF 组EC-MPS 血药浓度曲线下面积小于30 (mg·h)/L 的比率显著高于正常恢复组,同时他克莫司谷浓度显著低于正常恢复 组,DGF 组经活检证实的急排反应的发生率显著 高于正常恢复组,术后1 周的EC-MPS 血药浓度曲线下面积低于30 (mg·h)/L 的受者中经活检证实的急排反应的发生率显著高于其他受者。1 年移植物存活率、移植物功能及常见不良反应在两 组间未见明显差异。