Donor-specific antibodies, glomerulitis, and human leukocyte antigen B eplet mismatch are risk factors for peritubular capillary C4d deposition in renal allografts / 中华医学杂志(英文版)

BACKGROUND@#The complement system plays an important role in the immune response to transplantation, and the diagnostic significance of peritubular capillary (PTC) C4d deposition (C4d+) in grafts is controversial. The study aimed to fully investigate the risk factors for PTC C4d+ and analyze its significance in biopsy pathology of kidney transplantation.@*METHODS@#This retrospective study included 124 cases of kidney transplant with graft biopsy and donor-specific antibody (DSA) testing from January 2017 to December 2019 in a single center. The effects of recipient pathological indicators, eplet mismatch (MM), and DSAs on PTC C4d+ were examined using univariate and multivariate logistic regression analyses.@*RESULTS@#In total, 35/124 (28%) were PTC C4d+, including 21 with antibody-mediated rejection (AMR), eight with renal tubular injury, three with T cell-mediated rejection, one with glomerular disease, and two others. Univariate analysis revealed that DSAs (P < 0.001), glomerulitis (P < 0.001), peritubular capillaritis (P < 0.001), and human leukocyte antigen (HLA) B eplet MM (P = 0.010) were the influencing factors of PTC C4d+. According to multivariate analysis, DSAs (odds ratio [OR]: 9.608, 95% confidence interval [CI]: 2.742-33.668, P < 0.001), glomerulitis (OR: 3.581, 95%CI: 1.246-10.289, P = 0.018), and HLA B eplet MM (OR: 1.166, 95%CI: 1.005-1.353, P = 0.042) were the independent risk factors for PTC C4d+. In receiver operating characteristic curve analysis, the area under the curve was increased to 0.831 for predicting PTC C4d+ when considering glomerulitis, DSAs, and HLA B eplet MM. The proportions of HLA I DSAs and PTC C4d+ in active antibody-mediated rejection were 12/17 and 15/17, respectively; the proportions of HLA class II DSAs and PTC C4d+ in chronic AMR were 8/12 and 7/12, respectively. Furthermore, the higher the PTC C4d+ score was, the more serious the urinary occult blood and proteinuria of recipients at the time of biopsy.@*CONCLUSIONS@#PTC C4d+ was mainly observed in AMR cases. DSAs, glomerulitis, and HLA B eplet MM are the independent risk factors for PTC C4d+.

Early Immunosuppressive Exposure of Enteric-Coated-Mycophenolate Sodium Plus Tacrolimus Associated with Acute Rejection in Expanded Criteria Donor Kidney Transplantation / 中华医学杂志(英文版)

<p><b>Background</b>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.</p><p><b>Methods</b>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) and Tac Cwere measured at the 1 week and the 1 month posttransplant, respectively. The correlation was assessed by multivariate logistic regression.</p><p><b>Results</b>The occurrence rates of BPAR and antibody-mediated rejection were 24.1% and 10.3%, respectively. A low level of MPA-AUC at the 1 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-AUClevel was <30 mg·h·L at the 1 week (15.0% vs. 44.4%) or the Tac Cwas <4 ng/ml at the 1 month posttransplant (33.3% vs. 21.6%). Multivariable logistic regression analysis showed that the MPA-AUC at the 1 week (OR: 0.842, 95% CI: 0.784-0.903) and the Tac Cat the 1 month (OR: 0.904, 95% CI: 0.822-0.986) had significant inverse correlation with BPAR (P < 0.05).</p><p><b>Conclusions</b>Low-level exposure of MPA and Tac Cin the early weeks posttransplant reflects an increased acute rejection risk, which suggested that MPA-AUC <30 mg·h·L and Tac C <4 ng/ml should be avoided in the first few weeks after transplantation.</p>

Predictive Score Model for Delayed Graft Function Based on Hypothermic Machine Perfusion Variables in Kidney Transplantation / 中华医学杂志(英文版)

Background@#Hypothermic machine perfusion (HMP) is being used more often in cardiac death kidney transplantation; however, the significance of assessing organ quality and predicting delayed graft function (DGF) by HMP parameters is still controversial. Therefore, we used a readily available HMP variable to design a scoring model that can identify the highest risk of DGF and provide the guidance and advice for organ allocation and DCD kidney assessment.@*Methods@#From September 1, 2012 to August 31, 2016, 366 qualified kidneys were randomly assigned to the development and validation cohorts in a 2:1 distribution. The HMP variables of the development cohort served as candidate univariate predictors for DGF. The independent predictors of DGF were identified by multivariate logistic regression analysis with a P < 0.05. According to the odds ratios (ORs) value, each HMP variable was assigned a weighted integer, and the sum of the integers indicated the total risk score for each kidney. The validation cohort was used to verify the accuracy and reliability of the scoring model.@*Results@#HMP duration (OR = 1.165, 95% confidence interval [CI]: 1.008-1.360, P = 0.043), resistance (OR = 2.190, 95% CI: 1.032-10.20, P < 0.001), and flow rate (OR = 0.931, 95% CI: 0.894-0.967, P = 0.011) were the independent predictors of identified DGF. The HMP predictive score ranged from 0 to 14, and there was a clear increase in the incidence of DGF, from the low predictive score group to the very high predictive score group. We formed four increasingly serious risk categories (scores 0-3, 4-7, 8-11, and 12-14) according to the frequency associated with the different risk scores of DGF. The HMP predictive score indicates good discriminative power with a c-statistic of 0.706 in the validation cohort, and it had significantly better prediction value for DGF compared to both terminal flow (P = 0.012) and resistance (P = 0.006).@*Conclusion@#The HMP predictive score is a good noninvasive tool for assessing the quality of DCD kidneys, and it is potentially useful for physicians in making optimal decisions about the organs donated.

Beneficial Effect of Moderately Increasing Hypothermic Machine Perfusion Pressure on Donor after Cardiac Death Renal Transplantation / 中华医学杂志(英文版)

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.

Predictive Score Model for Delayed Graft Function Based on Easily Available Variables before Kidney Donation after Cardiac Death / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>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.</p><p><b>METHODS</b>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.</p><p><b>RESULTS</b>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).</p><p><b>CONCLUSIONS</b>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.</p>

Polyglycolic Acid Fibrous Scaffold Improving Endothelial Cell Coating and Vascularization of Islet / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>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.</p><p><b>METHODS</b>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.</p><p><b>RESULTS</b>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.</p><p><b>CONCLUSIONS</b>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.</p>

Preventive effect of poria cocos on acute rejection of renal transplantation in rats / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To study the effect of Poria cocos (Pcs) in preventing acute rejection of rats after renal transplantation and its mechanism.</p><p><b>METHODS</b>Rat orthotopic renal transplantation model was performed with Wistar rat as donor and SD rat as donee. All donees were divided into 4 groups, 10 in each group, before transplantation. They were treated respectively with normal saline 5 mL x kg(-1) x d(-1) (A), Pcs 25 mg x kg(-1) x d(-1) (B), Pcs 50 mg x kg(-1) x d(-1) (C) and ciclosporin A (CsA) 5 mg x kg(-1) x d(-1) (D) by intragastric administration. The renal allograft survival time (ST) was recorded, and the serum levels of creatinine (SCr), interleukin-2 (IL-2), gamma-interferon (gamma-IFN), CD4+, CD8+ lymphocytes percentage, CD4+/CD8+ ratio, as well as the pathologic changes were observed one week after transplantation.</p><p><b>RESULTS</b>ST of the renal graft in Groups C and D was significantly longer with pathologic change evidently less than those in Groups A and B (P<0.01), and the ST in Group C was shorter that in Group D (P<0.05). Changes of renal function and urine volume were identified to the pathological change of graft, the initiating time of renal dysfunction was later in Groups C and D than that in Groups A and B. Serum levels of IL-2, IFN-gamma and CD4+ percentage in Group C were significantly lower than those in Groups A and B, but higher than those in Group D respectively (P<0.05 or P<0.01), while CD8+ percentage in Group C was significantly lower than that in Group A (P<0.05), but insignificantly different to that in Groups B and D (P>0.05).</p><p><b>CONCLUSION</b>Pcs shows good dosage-dependent effect in suppressing acute rejection of renal transplantation, but the effect is inferior to that of CsA.</p>

Clinical application and exploration on mechanism of action of Cordyceps sinensis mycelia preparation for renal transplantation recipients / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To retrospectively study and analyse the immune regulatory effect of Bailing Capsule (BLC, a dry powder preparation of Cordyceps sinensis mycelia) on patients after renal transplantation, its influences on various systems of organism, and to explore its possible acting mechanism.</p><p><b>METHODS</b>In accordance with the entry criteria, 67 recipients of renal homo-allograft were assigned to two groups. The 42 cases in the control group were treated with mycophenolate mofetil (MMF) plus cyclosporine A (CsA), or tacrolimus (FK506) plus prednisone (Pred); the 25 in the treated group treated with the chemotherapy the same as in the control group plus BLC. They were followed up for 48 weeks by checking up blood routine, urine routine, hepatic and renal function, total serum protein, serum albumin, uric acid, etc., and the dosage of immunoinhibitory used was recorded periodically.</p><p><b>RESULTS</b>Comparison showed no significant difference in graft survival rate, occurrence of reject reaction and renal function recovery between the two groups; but levels of urinary erythrocytes and leucocytes, blood alanine transaminase, aspartate amino transferase, uric acid, total bilirubin, direct bilirubin, as well as the incidence of infection were significantly lower, and serum total protein and albumin were significantly higher in the treated group (all P < 0.01); moreover, counts of erythrocyte and leukocyte from 12 to 48 weeks, T-lymphocyte from 4 to 48 weeks after transplantation were significantly higher in the treated group (P < 0.05 and P < 0.01), and the recovery appeared earlier, the dosage of CsA or FK506 used 12 weeks after operation was significantly lower in the treated group than in the control group (P < 0.05, P < 0.01).</p><p><b>CONCLUSIONS</b>BLC could effectively protect liver and kidney, stimulate hemopoietic function, improve hypoproteinemia, as well as reduce the incidence of infection and the dosage of CsA and FK506 used, etc. Therefore, it is a useful drug for immunoregulation after organ transplantation.</p>

Application of kushenin on patients with chronic hepatitis C after renal transplantation / 中国结合医学杂志

<p><b>OBJECTIVE</b>To evaluate the efficacy of kushenin in treating patients with chronic hepatitis C after renal transplantation.</p><p><b>METHODS</b>Fifty-five patients were randomly assigned by lottery to the treatment group (29 cases) and control group (26 cases). The same immunosuppression therapy was given to all patients in both groups. Patients in the treatment group were treated with kushenin 0.6 g once a day, while those in the control group were treated with conventional liver protective agents such as vitamins. The treatment duration of both groups was 3 months. The incidences of serious hepatitis and acute rejection reaction, serum biochemistry parameters including indicators of liver and kidney functions, hepatic fibrosis index, and serum HCV-RNA were compared between the two groups.</p><p><b>RESULTS</b>(1) The incidence of serious hepatitis in the treatment group and the control group was 3.45% (1/29 cases) and 11.54% (3/26 cases), respectively, which was insignificantly different between the two groups (P=0.335). (2) The incidence of acute rejection in the treatment group was 6.90% (2/29 cases) and that in the control group was 7.69% (2/26 cases), showing insignificant difference (P=0.335). (3) The differences in serum alanine aminotransferase (ALT), direct bilirubin (DBIL), hyaluronic acid (HA), propeptide collagen type III (PC III), laminin (LN), collagen type IV (Col IV) levels between the two groups were insignificant before transplantation (P>0.05), while the above-mentioned parameters in the treatment group were significantly lower than those in the control group after transplantation (P<0.05). The difference in serum creatinine (SCr) and endogenous creatinine clearance rate (CCr) between the two groups was insignificant before and after transplantation (P>0.05). (4) The negative conversion rate of HCV-RNA in the treatment group was 31.03% (9/29 cases), significantly higher than the value of 11.54% (3/26 cases) in the control group after transplantation (P<0.05). (5) The levels of serum ALT and DBIL in patients with HCV-RNA converted to negative were significantly lower than those with still-positive HCV-RNA (P<0.05).</p><p><b>CONCLUSIONS</b>Kushenin has a certain effect on inhibiting the proliferation of HCV, protecting liver cells, and anti-liver fibrosis. On the other hand, it has no obvious influence on renal allograft function. Thus, the drug is clinically safe and effective for use in treating patients with chronic hepatitis C after renal transplantation.</p>

Directional differentiation of murine CD117+ hemopoietic stem cells into immature dendritic cells and their identification / 南方医科大学学报

<p><b>OBJECTIVE</b>To establish a stable method for obtaining large quantity of highly purified immature dendritic cells (imDCs) in vitro, and identify the morphology, function and surface markers of the cells.</p><p><b>METHODS</b>CD117(+) hemopoietic stem cells (HSCs) were isolated and purified from the bone marrow of healthy C57 mice by magnetic affinity cell sorting. After cell expansion by treatment with stem cell factor (SCF) and interleukin-3 (IL-3), the HSCs were induced for directional differentiation into imDCs by treatment with GM-CSF, IL-4 and IL-10. The imDCs obtained were identified by morphological and functional observation under inverted microscope, scanning electron microscope and transmission electron microscope, followed by detection of the expressions of the surface markers using flow cytometry.</p><p><b>RESULTS</b>After 3, 5 and 7 days of culture in the presence of SCF+IL-3, the cells were expanded by 10.34-/+1.43, 22.65-/+2.71 and 54.39-/+3.08 folds, respectively. The HSCs were successfully induced to differentiate into imDCs with phagocytotic activity. The dendrites of the imDCs were short small, and appearing spinous. The expressions of surface markers were detected from the cells showing the phenotype of CD11c(+), I-A/I-E(low), CD40(-), CD80(-), CD86(-).</p><p><b>CONCLUSION</b>The method described allows steadily acquisition of large quanty of highly purified imDCs and of their effective identification in vitro.</p>