The effect of insulin resistance in the association between obesity and hypertension incidence among Chinese middle-aged and older adults: data from China health and retirement longitudinal study (CHARLS).

Background and aims: Obesity and insulin resistance are well-known important risk factors for hypertension. This study aimed to investigate the mediating effect of the triglyceride-glucose index (TyG) in the association between Chinese visceral obesity index (CVAI) and hypertension among Chinese middle-aged and older adults. Methods: A total of 10,322 participants aged 45 years and older from CHARLS (2011-2018) were included. Baseline data were collected in 2011 and hypertension incidence data were gathered during follow-up in 2013, 2015 and 2018. Multivariate logistic regression models were constructed to investigate the association of CVAI and TyG with the incidence of hypertension. Additionally, mediation analyses were conducted to evaluate the mediating role of the TyG index in the relationship between CVAI and hypertension. Subgroup analysis was also performed. Results: A total of 2,802 participants developed hypertension during the follow-up period. CVAI and TyG index were independently and significantly associated with hypertension incidence. Increasing quartiles of CVAI and TyG index were associated with high hypertension incidence in middle-aged and older adults. The TyG index was identified as a mediator in the relationship between CVAI and hypertension incidence, with a mediation effect (95% confidence interval) was 12.38% (6.75, 31.81%). Conclusion: Our study found that CVAI and TyG were independently associated with hypertension incidence. TyG played a partial mediating effect in the positive association between CVAI and hypertension incidence.

Sinomenine promotes differentiation of induced pluripotent stem cells into immature dendritic cells with high induction of immune tolerance.

BACKGROUND: Immature dendritic cells (imDCs) play an important role in the induction of donor-specific transplant immunotolerance. However, these cells have limitations, such as rapid maturation and a short lifespan in vivo. In previous studies, induced pluripotent stem cells (iPSCs) differentiated into imDCs, and sinomenine (SN) was used to inhibit the maturation of imDCs. AIM: To study the capacity of SN to maintain iPSC-derived imDCs (SN-iPSCs-imDCs) in an immature state and the mechanism by which SN-iPSCs-imDCs induce immunotolerance. METHODS: In this study, mouse iPSCs were induced to differentiate into imDCs in culture medium without or with SN (iPSCs-imDCs and SN-iPSCs-imDCs). The imDC-related surface markers, endocytotic capacity of fluorescein isothiocyanate-Dextran and apoptosis were analyzed by flow cytometry. The effects of iPSCs-imDCs and SN-iPSCs-imDCs on T-cell stimulatory function, and regulatory T (Treg) cell proliferative function in vitro were analyzed by mixed lymphocyte reaction. Cytokine expression was detected by ELISA. The apoptosis-related proteins of iPSCs-DCs and SN-iPSCs-DCs were analyzed by western blotting. The induced immunotolerance of SN-iPSCs-DCs was evaluated by treating recipient Balb/c skin graft mice. Statistical evaluation of graft survival was performed using Kaplan-Meier curves. RESULTS: Both iPSCs-imDCs and SN-iPSCs-imDCs were successfully obtained, and their biological characteristics and ability to induce immunotolerance were compared. SN-iPSCs-imDCs exhibited higher CD11c levels and lower CD80 and CD86 levels compared with iPSCs-imDCs. Reduced major histocompatibility complex II expression, worse T-cell stimulatory function, higher Treg cell proliferative function and stronger endocytotic capacity were observed with SN-iPSCs-imDCs (P < 0.05). The levels of interleukin (IL)-2, IL-12, interferon-γ in SN-iPSCs-imDCs were lower than those in iPSCs-imDCs, whereas IL-10 and transforming growth factor-ß levels were higher (P < 0.05). The apoptosis rate of these cells was significantly higher (P < 0.05), and the expression levels of cleaved caspase3, Bax and cleaved poly(ADP-ribose) polymerase were higher after treatment with lipopolysaccharides, but Bcl-2 was reduced. In Balb/c mice recipients immunized with iPSCs-imDCs or SN-iPSCs-imDCs 7 d before skin grafting, the SN-iPSCs-imDCs group showed lower ability to inhibit donor-specific CD4+ T-cell proliferation (P < 0.05) and a higher capacity to induce CD4+CD25+FoxP3+ Treg cell proliferation in the spleen (P < 0.05). The survival span of C57bl/6 skin grafts was significantly prolonged in immunized Balb/c recipients with a donor-specific pattern. CONCLUSION: This study demonstrated that SN-iPSCs-imDCs have potential applications in vitro and in vivo for induction of immunotolerance following organ transplantation.

Prediction of acute renal allograft rejection by combined HLA-G 14-bp insertion/deletion genotype analysis and detection of kidney injury molecule-1 and osteopontin in the peripheral blood.

INTRODUCTION: Acute renal rejection usually fails to be diagnosed before the increase in the serum creatinine levels, and the resultant damage to the renal tissues occur in varying degrees. We hypothesized that the combined detection of human leucocyte antigen-G (HLA-G) 14-bp insertion/deletion genotypes and kidney injury molecule-1 (KIM-1) and osteopontin (OPN) levels in serum might facilitate the prediction of acute renal allograft rejections in kidney transplant recipients. METHODS: HLA-G 14-bp insertion/deletion genotypes and the serum KIM-1 and OPN levels of 77 kidney transplant recipients were determined and compared before operation and on days 1, 4, and 7 after the operation (32 in acute rejection [AR] group and 45 in stable allograft function [STA] group). These 3 indicators were combined to establish a model for the early prediction of AR. RESULTS: The KIM-1 levels in the serum of patients were significantly higher in the AR group than in the STA group. The area under the receiver operator characteristics (ROC) curve (AUC) of KIM-1 for the prediction of rejection was maximized on the1st day after operation, with a sensitivity of 84.4% and a specificity of 86.7%. The OPN levels in the serum of patients were significantly higher in the AR group than in the STA group only before operation and on the 7th day after operation. The AUC of OPN for the prediction of rejection was maximized on 7th day after operation, with a sensitivity of 68.8% and a specificity of 88.9%. The HLA-G + 14-bp allele frequency was also significantly higher in the AR group than in the STA group. The results of these three indicators were converted into a qualitative method. If any two of the three indicators show as positive, it was diagnosed as acute rejection, and it has the highest ability to predict acute rejection with a sensitivity and specificity of 84.38% and 91.11%, respectively. CONCLUSIONS: The HLA-G 14-bp insertion/deletion genotype and KIM-1 and OPN levels in the patients' serum were significantly different between the AR and STA groups. The power of predicting acute renal allograft rejection could be improved by combined these three biomarkers.

Different roles of bortezomib and ONX 0914 in acute kidney injury.

Proteasome inhibitor bortezomib offers one more option for acute or chronic antibody-mediated rejection after kidney transplantation, but aggravated acute kidney injury (AKI) in some cases early after surgery using bortezomib bring new problem. Here, we evaluated the effects of bortezomib and ONX-0914 on renal tubule injury in a mouse model of ischemia-reperfusion injury. After treated with bortezomib, serum creatinine, usea nitrogen and tubular necrosis significantly increased compared with vehicle-treated mice, but decreased in ONX-0914 group mildly. Infiltration of neutrophil and macrophage were less in bortezomib and ONX-0914-treated mice than vehicle-treated group, and the same was observed on oxidative stress in the kidneys. Furthermore, the apoptosis of renal tubular epithelial cells increased in bortezomib-treated mice' kidneys compared with ONX-0914 and vehicle-treated controls. In vitro HK2 cell experiments also demonstrated the proapoptotic effect of bortezomib. The mRNA expression of several proapoptotic factors increased in kidneys of bortezomib-treated mice. In brief, bortezomib, as a proteasome inhibitor, shows a certain cytotoxicity to renal tubular epithelial cell during ischemia/reperfusion injury (IRI) through increased apoptosis. ONX-0914, as an immunoproteasome inhibitor, showed equal potency on anti-inflammation and oxidative stress relieving compared with bortezomib, while less cytotoxicity. The results render the immunoproteasome is a better target for anti-rejection and protecting kidney function in the field of organ transplantation.

Prediction of kidney transplant outcome based on different DGF definitions in Chinese deceased donation.

BACKGROUND: Delayed graft function (DGF) is an important complication of kidney transplantation and can be diagnosed according to different definitions. DGF has been suggested to be associated with the long-term outcome of kidney transplantation surgery. However, the best DGF definition for predicting renal transplant outcomes in Chinese donations after cardiac death (DCDs) remains to be determined. METHOD: A total of 372 DCD kidney transplant recipients from June 2013 to July 2017 in the First Affiliated Hospital of Xi'an Jiaotong University were included in this retrospective study to compare 6 different DGF definitions. The relationships of the DGF definitions with transplant outcome were analyzed, including graft loss (GL) and death-censored graft loss (death-censored GL). Renal function indicators, including one-year estimated glomerular filtration rate (eGFR) and three-year eGFR, and were compared between different DGF groups. RESULTS: The incidence of DGF varied from 4.19 to 35.22% according to the different DGF diagnoses. All DGF definitions were significantly associated with three-year GL as well as death-censored GL. DGF based on requirement of hemodialysis within the first week had the best predictive value for GL (AUC 0.77), and DGF based on sCr variation during the first 3 days post-transplant had the best predictive value for three-year death-censored GL (AUC 0.79). Combination of the 48-h sCr reduction ratio and classical DGF can improve the AUC for GL (AUC 0.85) as well as the predictive accuracy for death-censored GL (83.3%). CONCLUSION: DGF was an independent risk factor for poor transplant outcome. The combination of need for hemodialysis within the first week and the 48-h serum creatinine reduction rate has a better predictive value for patient and poor graft outcome.

Beneficial Effect of Moderately Increasing Hypothermic Machine Perfusion Pressure on Donor after Cardiac Death Renal Transplantation.

BACKGROUND: Vascular resistance and flow rate during hypothermic machine perfusion (HMP) of kidneys is correlated with graft function. We aimed to determine the effects of increasing HMP pressure versus maintaining the initial pressure on kidney transplantation outcomes. METHODS: We retrospectively reviewed the data of 76 primary transplantation patients who received HMP-preserved kidneys from 48 donors after cardiac death between September 1, 2013, and August 31, 2015. HMP pressure was increased from 30 to 40 mmHg (1 mmHg = 0.133 kPa) in kidneys with poor flow and/or vascular resistance (increased pressure [IP] group; 36 patients); otherwise, the initial pressure was maintained (constant pressure group; 40 patients). Finally, the clinical characteristics and transplantation outcomes in both groups were assessed. RESULTS: Delayed graft function (DGF) incidence, 1-year allograft, patient survival, kidney function recovery time, and serum creatinine level on day 30 were similar in both groups, with improved flow and resistance in the IP group. Among patients with DGF, kidney function recovery time and DGF duration were ameliorated in the IP group. Multivariate logistic regression analysis revealed that donor hypertension (odds ratio [OR]: 1.43, 95% confidence interval [CI]: 1.02-2.06, P = 0.035), donor terminal serum creatinine (OR: 1.27, 95% CI: 1.06-1.62, P = 0.023), warm ischemic time (OR: 3.45, 95% CI: 1.97-6.37, P = 0.002), and terminal resistance (OR: 3.12, 95% CI: 1.76-6.09, P = 0.012) were independent predictors of DGF. Cox proportional hazards analysis showed that terminal resistance (hazard ratio: 2.06, 95% CI: 1.32-5.16, P = 0.032) significantly affected graft survival. CONCLUSION: Increased HMP pressure improves graft perfusion but does not affect DGF incidence or 1-year graft survival.

Multiple-biomarkers provide powerful prediction of early acute renal allograft rejection by combination of serum fractalkine, IFN-γ and IP-10.

Biomarkers are urgently required for predicting rejection so that anti-rejection treatment can be taken early to protect the allograft from irreversible damage. We hypothesized that the combination of circulating fractalkine, IFN-γ and IP-10 might serve as effective biomarkers for predicting early acute renal allograft rejection. We conducted a retrospective study of 87 subjects, who were classified into acute rejection group (ARG; n = 38) and non-rejection group (NRG; n = 49). Serum fractalkine, IFN-γ and IP-10 levels were measured by Luminex. The levels of fractalkine on day 0 and 7th day, IP-10 on 4th and 7th day, and IFN-γ on 7th day in ARG was significantly higher than that in NRG. Kaplan-Meier survival analysis highlighted the higher-levels groups of fractalkine on day 0, 4th and 7th day, IFN-γ on day 0, 1st, 4th, and 7th day and IP-10 on the 4th and 7th day in rejection-free survival probability were significantly lower than low-levels groups. ROC analyses highlight the superiority of fractalkine on day 0, IP-10 on day 0, 4th and 7th day, and IFN-γ on day 0, 1st and 7th day in prediction of acute rejection. We found the combination of fractalkine on day 0, IP-10 on 7th day and IFN-γ on 7th day had the highest AUC (0.866) for predicting rejection with a sensitivity of 86.8% and a specificity of 89.8%. Our findings demonstrated a more powerful prediction of early acute renal allograft rejection during the first month after transplantation by combination of multiple-biomarkers of fractalkine, IFN-γ and IP-10, and the results might help stratify the immunologic risk of acute allograft rejection in recipients.

Early Immunosuppressive Exposure of Enteric-Coated-Mycophenolate Sodium Plus Tacrolimus Associated with Acute Rejection in Expanded Criteria Donor Kidney Transplantation.

BACKGROUND: Immunosuppressive agents are still inefficient in preventing biopsy-proven acute rejection (BPAR) after expanded criteria donor (ECD) kidney transplantation. The aim of this study was to investigate the relationships between early immunosuppressive exposure and the development of BPAR. METHODS: We performed a retrospective study of 58 recipients of ECD kidney transplantation treated with enteric-coated-mycophenolate sodium, tacrolimus (Tac), and prednisone. The levels of mycophenolic acid-area under the curve (MPA-AUC)0-12h and Tac C0were measured at the 1st week and the 1st month posttransplant, respectively. The correlation was assessed by multivariate logistic regression. RESULTS: The occurrence rates of BPAR and antibody-mediated rejection were 24.1% and 10.3%, respectively. A low level of MPA-AUC0-12h at the 1st week posttransplant was found in BPAR recipients (38.42 ± 8.37 vs. 50.64 ± 13.22, P < 0.01). In addition, the incidence of BPAR was significantly high (P < 0.05) when the MPA-AUC0-12hlevel was <30 mg·h-1·L-1 at the 1st week (15.0% vs. 44.4%) or the Tac C0was <4 ng/ml at the 1st month posttransplant (33.3% vs. 21.6%). Multivariable logistic regression analysis showed that the MPA-AUC0-12h at the 1st week (OR: 0.842, 95% CI: 0.784-0.903) and the Tac C0at the 1st month (OR: 0.904, 95% CI: 0.822-0.986) had significant inverse correlation with BPAR (P < 0.05). CONCLUSIONS: Low-level exposure of MPA and Tac C0in the early weeks posttransplant reflects an increased acute rejection risk, which suggested that MPA-AUC0-12h <30 mg·h-1·L-1 and Tac C0 <4 ng/ml should be avoided in the first few weeks after transplantation.

Arctigenin: A two-edged sword in ischemia/reperfusion induced acute kidney injury.

Arctigenin (ATG) is one of the main active substances in fruit derived from Arctium lappa L. Previous studies have reported that ATG have antitumor, neuroprotective, antioxidant, antifibrosis and anti-inflammatory functions. However, the actions of ATG in kidney with acute injury following ischemia/ reperfusion (I/R) is still uncertain. In our study, mice were subjected to kidney I/R by having the kidney pedicles clamped and administered with vehicle or ATG (1, 3 or 9 mg/kg/d) via oral gavage for 7 consecutive days prior to I/R. Notably, ATG aggravated kidney I/R injury with the concentration increases. Multiple biochemical assays and histological examination showed ATG significantly alleviated the inflammatory response as reflected by a decreased expression of proinflammatory cytokine, TLR4/MyD88, and NF-κB, along with the infiltration of CD68+ macrophage and CD11b+Gr1+ neutrophil in the kidneys. Meanwhile, ATG alleviated I/R-induced oxidative stress proved by increasing kidney manganese superoxide dismutase and glutathione peroxidase activity but reducing levels of malonaldehyde and inducible nitric oxide synthase. On the contrary, apoptosis was significantly increased in kidneys of ATG-treated mice compared with vehicle-treated controls, especially in tubular cells. There were increased numbers of TUNEL positive cells and increased Bcl-2, Bax, cleaved-caspase-3, and cleaved-caspase-9 expression. The current study demonstrates that pretreatment of ATG aggravates I/R induced acute kidney injury by increasing apoptosis of tubular cells despite reducing infiltrating inflammatory cells and proinflammatory cytokine.

Knockdown of NLRC5 attenuates renal I/R injury in vitro through the activation of PI3K/Akt signaling pathway.

NLRC5, as the largest member of nucleotide-binding domain and leucine-rich repeat (NLR) family, was involved in various physiological processes, such as inflammation, fibrosis, innate immunity and diabetic nephropathy. However, the role of NLRC5 in acute kidney injury remains unclear. The aim of this study was to investigate the role of NLRC5 in human renal proximal tubular epithelial cells (HK-2) exposed to hypoxia/reoxygenation (H/R). Our results demonstrated that the expression of NLRC5 was significantly up-regulated in HK-2 cells exposed to H/R. Knockdown of NLRC5 significantly improved the viability of HK-2 cells exposed to H/R. In addition, knockdown of NLRC5 efficiently inhibited H/R-induced oxidative stress and apoptosis in HK-2 cells. Mechanistically, knockdown of NLRC5 markedly enhanced the activation of PIK3/Akt signaling pathway in H/R-stimulated HK-2 cells. In summary, our findings indicate that knockdown of NLRC5 attenuates renal I/R injury in vitro through the activation of PI3K/Akt signaling pathway.

Comparison of the characteristics of macrophages derived from murine spleen, peritoneal cavity, and bone marrow.

Macrophages have a diverse set of functions based upon their activation states. The activation states, including resting (M0) and polarizing (M1 and M2) states, of macrophages derived from the mouse bone marrow, spleen, and peritoneal cavity (BMs, SPMs, and PCMs, respectively) were compared. We evaluated the macrophage yield per mouse and compared the surface markers major histocompatibility complex (MHC) II and CD86 by flow cytometry. The relative mRNA levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, mannose receptor (MR), and Ym1 in the M0, M1, and M2 states were also compared using real-time polymerase chain reaction (PCR) analysis. Bone marrow yielded the most macrophages with the best homogeneity, but they were polarized toward the M2 phenotype. All three types of macrophages had the capacity to polarize into the M1 and M2 states, but SPMs had a stronger capacity to polarize into M1. The three types of macrophages showed no differences in their capacity to polarize into the M2 state. Therefore, the three types of macrophages have distinct characteristics regardless of their resting or polarizing states. Although bone marrow can get large amounts of homogeneous macrophages, the macrophages cannot replace tissue-derived macrophages.

Predictive Score Model for Delayed Graft Function Based on Easily Available Variables before Kidney Donation after Cardiac Death.

BACKGROUND: How to evaluate the quality of donation after cardiac death (DCD) kidneys has become a critical problem in kidney transplantation in China. Hence, the aim of this study was to develop a simple donor risk score model to evaluate the quality of DCD kidneys before DCD. METHODS: A total of 543 qualified kidneys were randomized in a 2:1 manner to create the development and validation cohorts. The donor variables in the development cohort were considered as candidate univariate predictors of delayed graft function (DGF). Multivariate logistic regression was then used to identify independent predictors of DGF with P < 0.05. Date from validation cohort were used to validate the donor scoring model. RESULTS: Based on the odds ratios, eight identified variables were assigned a weighted integer; the sum of the integer was the total risk score for each kidney. The donor risk score, ranging from 0 to 28, demonstrated good discriminative power with a C-statistic of 0.790. Similar results were obtained from validation cohort with C-statistic of 0.783. Based on the obtained frequencies of DGF in relation to different risk scores, we formed four risk categories of increasing severity (scores 0-4, 5-9, 10-14, and 15-28). CONCLUSIONS: The scoring model might be a good noninvasive tool for assessing the quality of DCD kidneys before donation and potentially useful for physicians to make optimal decisions about donor organ offers.

Polyglycolic Acid Fibrous Scaffold Improving Endothelial Cell Coating and Vascularization of Islet.

BACKGROUND: Improving islet graft revascularization has become a crucial task for prolonging islet graft survival. Endothelial cells (ECs) are the basis of new microvessels in an isolated islet, and EC coating has been demonstrated to improve the vascularization and survival of an islet. However, the traditional method of EC coating of islets has low efficiency in vitro. This study was conducted to evaluate the effect of a polyglycolic acid (PGA) scaffold on the efficiency of islet coating by ECs and the angiogenesis in the coated islet graft. METHODS: A PGA fibrous scaffold was used for EC coating of islet culture and was evaluated for its efficiency of EC coating on islets and islet graft angiogenesis. RESULTS: In in vitro experiments, we found that apoptosis index of ECs-coating islet in PGA group (27% ± 8%) was significantly lower than that in control group (83% ± 20%, P < 0.05) after 7 days culture. Stimulation index was significantly greater in the PGA group than in the control group at day 7 after ECs-coating (2.07 ± 0.31 vs. 1.80 ± 0.23, P < 0.05). vascular endothelial growth factor (VEGF) level in the PGA group was significantly higher than the coating in the control group after 7 days culture (52.10 ± 13.50 ng/ml vs. 16.30 ± 8.10 ng/ml, P < 0.05). Because of a tight, circumvallated, adhesive and three-dimensional growth microenvironment, islet cultured in a PGA scaffold had higher coating efficiency showing stronger staining intensity of enzyme than those in the control group after 14 days of culture following ECs-coating. For in vivo study, PGA scaffold significantly prolonged the average survival time of EC-coated islet graft after transplantation compared with control group (15.30 ± 5.60 days vs. 8.30 ± 2.45 days, P < 0.05). The angiogenesis and area of survived grafts were more in the PGA group compared with the control group by measuring the mean microvessel density (8.60 ± 1.21/mm2 vs. 5.20 ± 0.87/mm2, P < 0.05). In addition, expression of VEGF and tyrosin-protein kinase receptor (Tie-2) gene increased in PGA scaffold group than that in control group by real-time reverse transcription-polymerase chain reaction analysis. CONCLUSIONS: These results demonstrate that the efficiency of EC coating of islets was successfully increased by culturing ECs on a PGA scaffold. This method enhances the function, survival, and vascularization of isolated islets in vitro and in vivo.

Increased intracellular adenosine triphosphate level as an index to predict acute rejection in kidney transplant recipients.

BACKGROUND: Peripheral blood CD4+ T cell adenosine triphosphate (ATP) release has been reported to be an adjunct tool to evaluate global cellular immune response in solid-organ transplant recipients. However, the correlation between the ATP level and rejection was controversial. The aim of this prospective clinical study was to explore the association between the intracellular ATP level and the occurrence, progression, and treatment of acute rejection (AR) episodes, determine the predicting value of intracellular ATP level for AR in kidney transplant (KT) recipients. PATIENTS AND METHODS: In the period of October 2011 to October 2012, 140 KT recipients were recruited and followed for six months after transplantation. Patients were categorized into stable group and AR group according to their clinical course. Whole blood samples were collected pretransplantation, and at 7, 14, 21, and 28days, and at 2, 3, 4, 5 and 6months post-transplantation. Additional blood samples were obtained from AR patients on the day AR occurred, on the day before and 3 and 7days after intravenous anti-rejection therapy started, and on the day when AR reversed. The intracellular ATP in CD4+ T cells was detected by ImmuKnow Immune Cell Function Assay according to the manufacturer's instruction. The absolute number of CD4+ T cells and the trough levels of tacrolimus and cyclosporine were also measured. RESULTS: The ATP level detected on the day AR occurred (627.07±149.85ng/ml) was obviously higher than that of the stable group (320.48±149.11ng/ml, P<0.05). ATP value decreased to 265.35±84.33ng/m at the end of anti-rejection therapy, which was obviously lower than that measured on the day before the anti-rejection therapy started (665.87±162.85ng/ml, P<0.05). ROC analysis revealed that increased intracellular adenosine triphosphate level showed better sensitivity and specificity than those obtained using single time point detection (89.5% vs 85.0%;95.0% vs 88.9%). The best cutoff value was 172.55ng/ml. A positive correlation between the intracellular ATP level and absolute CD4+ T cell number (r=0.656, P<0.001) was found in the patients with CD4+ T cell counts <200/µl.

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.

Kidney injury molecule-1 and osteopontin: new markers for prediction of early kidney transplant rejection.

BACKGROUND: Kidney injury molecule-1 (KIM-1) and osteopontin (OPN) play important roles in immune regulation. We hypothesized that serum KIM-1 and OPN might serve as biomarkers for predicting early acute rejection after kidney transplantation (KTx). METHODS: We conducted a single-center study of 155 subjects, who were classified into acute rejection group (ARG, n=32), non-rejection group (NRG, n=45) and healthy controls (HC, n=78). Serum KIM-1 and OPN levels were measured by Luminex. RESULTS: The pre-transplant levels of serum KIM-1 and OPN in all KTx recipients were higher than those of HC (P<0.01). Compared with NRG, ARG showed significantly high serum levels of KIM-1 on day 0 (pre-KTx) and on the 1st, 4th, and 7th post-KTx days, and significantly high OPN levels on day 0 and the 7th day. Kaplan-Meier survival analysis showed that the higher levels of KIM-1 on day 0, the 1st and 4th days and OPN on day 0 and the 7th day were significantly associated with the lower probabilities of rejection-free survival. ROC analyses highlight the superiority of KIM-1 on the 1st day and OPN on the 7th day over those on other post-KTx days in prediction of acute rejection episodes. Multivariate logistic analysis revealed that the serum KIM-1 levels on the 1st post-KTx day and the OPN level on the 7th day were independent and powerful predictors of acute rejection episodes. An optimal predictive model was built by combining KIM-1 on the 1st day and OPN on the 7th day, and this model had the highest AUC (0.922). CONCLUSIONS: This study was the first to demonstrate that serum KIM-1 and OPN may be the promising and elegant markers for prediction of early acute kidney allograft rejection.

Impact of HLA-G 14-bp polymorphism on acute rejection and cytomegalovirus infection in kidney transplant recipients from northwestern China.

Human leukocyte antigen (HLA)-G plays an important role in promoting transplant tolerance and helping human cytomegalovirus (CMV) to subvert host defenses. Strong evidence suggests that HLA-G 14-bp insertion/deletion polymorphism influences the stability of HLA-G mRNAs and levels of protein expression. We hypothesized that HLA-G 14-bp polymorphism of recipients has an influence on the risk of acute rejection (AR) and CMV infection. We investigated the impact of HLA-G 14-bp polymorphism on a total of 363 unrelated Chinese Han individuals who included 42 kidney transplant recipients with AR, 43 recipients with CMV infection, 102 recipients with stable allograft function (STA), and 176 healthy controls (HC). No statistically significant difference was found between all kidney transplant patients and HC (P=0.149). But, our data showed an increased frequency of homozygous genotype +14/+14 bp (P(c)=0.004) and allele +14 bp (P(c)=0.002) in patients with AR when compared with STA, with the odds ratio of 3.17 and 2.28, respectively. Moreover, we found that the frequency of the -14/-14 bp genotype (P(c)=0.008) and the -14 bp allele (P(c)=0.016) was increased in patients with CMV infection when compared with STA, with the OR of 2.66 and 1.96, respectively. Multivariate analysis further demonstrated that HLA-G homozygous +14 bp and -14 bp genotypes were an independent risk factor for allograft rejection and CMV infection, respectively. In conclusion, this study identified an important genetic risk factor for acute allograft rejection, and it was the first to show a significant correlation between HLA-G 14-bp polymorphism and CMV infection after kidney transplantation from northwestern China.

[The influence of rapamycin on BTLA expression of human peripheral blood T lymphocytes].

AIM: To explore the effect of rapamycin (RPM) on the expression of B and T lymphocyte attenuate (BTLA) on human peripheral blood T lymphocytes, providing a experimental basis for application of RPM to organ transplantation and autoimmune diseases. METHODS: Human peripheral blood mononuclear cells were isolated by Ficoll density gradient centrifugation, and then the T cells were isolated from PBMCs with immunomagnetic beads. Concanavalin A (Con A) used to stimulate and activate the human peripheral blood T cells. The proliferation of T cells was detected by MTT colorimetry. The levels of IL-2 and IFN-γ in cell culture supernatant were detected by ELISA. The expression of BTLA on T cells was assayed by Flow cytometry. RESULTS: The expression of BTLA on T cells treated with various concentrations (10-1 000 ng/L) of RPM had no significant difference, while had significant difference (P<0.01) by compared with RPM non-treatment group. ELISA detection manifested that compared with the untreated group different concentrations of RPM could significantly inhibit the IL-2 and IFN-γ secretion and significantly inhibited T lymphocyte proliferation (P<0.01). CONCLUSION: RPM has little effect on expression BTLA, but has stronger inhibition on lymphocyte proliferation and inflammatory cytokines secretion. Suggesting that RPM is suitable for the treated of organ transplant rejection and autoimmune diseases.

Efficacy of Cordyceps sinensis in long term treatment of renal transplant patients.

High doses of cyclosporin A (CsA) can not be used in the long term treatment of kidney allograft recipients primarily due to severe side effects. In the present study, we investigated the potential application of Cordyceps sinensis (CS) in the long term treatment of renal transplant patients. The renal function and survival rates of grafts and patients did not show significantly different between the control group and the treatment group. However, the incidences of complications were significantly lower in the treatment group compared with that in control group with the exception of those showing acute rejection. Furthermore, the dosage and the whole blood trough concentrations of CsA were significantly lower than control group. However, there was no significant difference in the serum level of IL-2 in the two groups. Interestingly, the serum level of IL-10 in the treatment group was significantly higher than that in control group. These data demonstrat that CS may be used in combination with a low dose of CsA in the long term treatment of kideny transplant patients.