Correction to: Basiliximab versus rabbit antithymocyte globulin as induction therapy for living-related renal transplantation: a single-center experience.

In the original publication, incorrect grant number was included in the Acknowledgements text as 'This study (article) was supported by Natural Science Foundation Y16H050011 of Zhejiang Province, China'. The correct acknowledgement section is given here.

Macrophage-to-Myofibroblast Transition Contributes to Interstitial Fibrosis in Chronic Renal Allograft Injury.

Interstitial fibrosis is an important contributor to graft loss in chronic renal allograft injury. Inflammatory macrophages are associated with fibrosis in renal allografts, but how these cells contribute to this damaging response is not clearly understood. Here, we investigated the role of macrophage-to-myofibroblast transition in interstitial fibrosis in human and experimental chronic renal allograft injury. In biopsy specimens from patients with active chronic allograft rejection, we identified cells undergoing macrophage-to-myofibroblast transition by the coexpression of macrophage (CD68) and myofibroblast (α-smooth muscle actin [α-SMA]) markers. CD68+/α-SMA+ cells accounted for approximately 50% of the myofibroblast population, and the number of these cells correlated with allograft function and the severity of interstitial fibrosis. Similarly, in C57BL/6J mice with a BALB/c renal allograft, cells coexpressing macrophage markers (CD68 or F4/80) and α-SMA composed a significant population in the interstitium of allografts undergoing chronic rejection. Fate-mapping in Lyz2-Cre/Rosa26-Tomato mice showed that approximately half of α-SMA+ myofibroblasts in renal allografts originated from recipient bone marrow-derived macrophages. Knockout of Smad3 protected against interstitial fibrosis in renal allografts and substantially reduced the number of macrophage-to-myofibroblast transition cells. Furthermore, the majority of macrophage-to-myofibroblast transition cells in human and experimental renal allograft rejection coexpressed the M2-type macrophage marker CD206, and this expression was considerably reduced in Smad3-knockout recipients. In conclusion, our studies indicate that macrophage-to-myofibroblast transition contributes to interstitial fibrosis in chronic renal allograft injury. Moreover, the transition of bone marrow-derived M2-type macrophages to myofibroblasts in the renal allograft is regulated via a Smad3-dependent mechanism.

Biomarkers for Early Diagnosis of Acute Kidney Injury: Current Progress and Clinical Prospects.

Acute kidney injury (AKI) is one of the most common complications in critically ill patients, resulting in high morbidity and mortality. AKI usually occurs after major surgery, severe infection or drug-induced nephrotoxicity and is associated with prolonged hospital stays, increased costs and adverse clinical outcomes. The diagnosis of AKI is currently based on decreased glomerular filtration rate (GFR) and urine output, and increased serum creatinine. Novel biomarkers are required for early identification of patients with AKI to allow timely therapy and improve patient outcomes. With the advent of proteomics and genomics techniques, a vast array of biomarkers are now available in clinical practice.

Basiliximab versus rabbit antithymocyte globulin as induction therapy for living-related renal transplantation: a single-center experience.

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.

Effect of BIX-01294 on H3K9me2 levels and the imprinted gene Snrpn in mouse embryonic fibroblast cells.

Histone H3 lysine 9 dimethylation (H3K9me2) hypermethylation is thought to be a major influential factor in cellular reprogramming, such as somatic cell nuclear transfer (SCNT) and induction of pluripotent stem cells (iPSCs). The diazepin-quinazolin-amine derivative (BIX-01294) specifically inhibits the activity of histone methyltransferase EHMT2 (euchromatic histone-lysine N-methyltransferase 2) and reduces H3K9me2 levels in cells. The imprinted gene small nuclear ribonucleoprotein N (Snrpn) is of particular interest because of its important biological functions. The objective of the present study was to investigate the effect of BIX-01294 on H3K9me2 levels and changes in Snrpn DNA methylation and histone H3K9me2 in mouse embryonic fibroblasts (MEFs). Results showed that 1.3 µM BIX-01294 markedly reduced global levels of H3K9me2 with almost no cellular toxicity. There was a significant decrease in H3K9me2 in promoter regions of the Snrpn gene after BIX-01294 treatment. A significant increase in methylation of the Snrpn differentially methylated region 1 (DMR1) and slightly decreased transcript levels of Snrpn were found in BIX-01294-treated MEFs. These results suggest that BIX-01294 may reduce global levels of H3K9me2 and affect epigenetic modifications of Snrpn in MEFs.

The effect of donor-recipient gender mismatch on short- and long-term graft survival in kidney transplantation: a systematic review and meta-analysis.

BACKGROUND: There is no limitation of gender matching in renal transplantation. This study was intended to evaluate its effect on short- and long-term graft survival. METHODS: PubMed, the Web of Knowledge, Medline, the Cochrane Library, and two additional Chinese databases were searched. The data were then abstracted and meta-analyzed. RESULTS: 14 studies involving 445 279 patients were included. Each study reported data on the four gender matches (male donor-male recipient, MDMR; male donor-female recipient, MDFR; female donor-male recipient, FDMR; female donor-female recipient, FDFR). The pooled risk ratios (RRs) for 0.5-, 1-, 2-, 3-, 5-, and 10-yr graft survival rates showed that the FDMR group had the worst outcomes, and when recipients were female, short-term graft survival was worse, but long-term graft survival was better. The differences between groups changed with time. CONCLUSIONS: FDMR patients showed poor graft survival. The female recipients had worse short-term graft survival but the best long-term graft survival. This study introduces an important consideration into donor-recipient matching in renal transplantation.

[Clinical study of single-dose of recombinant humanized anti-CD3 monoclonal antibody injection in kidney transplant recipients].

OBJECTIVE: To evaluate short-term and long-term safety of using single-dose escalation of recombinant humanized anti-CD3 monoclonal antibody (OKT3) in kidney transplantation recipients. METHODS: A total of 29 recipients of cadaveric kidney transplant from June 2008 to December 2008 were sequently assigned to receive single-dose intravenous injection of OKT3 with different doses of 2.5 mg (n = 9), 5.0 mg (n = 10) and 10.0 mg (n = 10) at Days 7 - 14 post-operation. Meanwhile, a control group was established by selecting kidney transplant recipients, who did not participate in the trial in the same period. All patients were followed up for at least 2 years. During this period, liver function, kidney function, hemoglobin and other biochemical indicators were monitored and adverse events recorded over time. RESULTS: No obvious first dose effect was observed, except low heat (7/29), chills (4/29), mild liver damage (2/29), upper respiratory tract infection and headache (1/29) across all doses. Other adverse reactions were mild, unrelated with doses. The 2-year patients/grafts survival rates of treatment group and control group were 100%/100%, and 100%/97%, respectively. The incidence of acute rejection confirmed by renal biopsy was 6.9% (2/29) and 10.0% (3/30) in treatment group and control group, respectively. The incidence of lung infection was 10.3% (3/29) and 13.3% (4/30), respectively. The values of serum creatinine at 1 week and 3, 6, 12, 24 months showed no statistically significance in two groups (all P > 0.05). CONCLUSION: It is safe to use single-shot OKT3 intravenously in kidney transplant recipients. The recombinant humanized OKT3 may be an effective immunosuppressive agent with milder toxicity for solid organ transplantation.

[Conversion from calcineurin inhibitors to sirolimus in chronic allograft nephropathy: a 4-year prospective study].

OBJECTIVE: To evaluate the safety and effect of sirolimus (SIR) substitution for calcineurin inhibitors (CNI) in chronic allograft nephropathy (CAN). METHODS: A prospective, open-label and non-randomized comparative study was performed in 74 kidney recipients from January 2004 to June 2006 with a diagnosis of CAN at a baseline estimated glomerular filtration rate (eGFR) of 30 - 60 ml×min(-1)·(1.73 m(2))(-1). Patients in the SIR group (n = 36) received SIR at 12 hours after a cessation of CNI. For those in the CNI group (n = 38), a cyclosporine (CsA)-based immunosuppressive regimen was prescribed in 30 patients and a tacrolimus (FK506)-based regimen in another 8 patients. All patients were maintained under a high level of mycophenolate mofetil and followed up for 4 years to evaluate the renal function, eGFR, blood routines, blood lipids and liver function, etc. RESULTS: The renal function and eGFR profiles of the SIR group improved significantly after substitution. The baseline eGFR was (40 ± 7) ml×min(-1)·(1.73 m(2))(-1) in the SIR group versus (38 ± 6) ml×min(-1)·(1.73 m(2))(-1) in the CNI group (P > 0.05). In SIR group, the levels of eGFR were higher than those in the CNI group at months 3, 12, 24, 36 and 48 (all P < 0.05). For the endpoint of serum creatinine doubling, the 4-year survival was 75.0% in the SIR group versus 50.0% in the CNI group (P = 0.03). There were 2 cases of acute rejections, 1 proteinuria, 1 pneumonia in the SIR group while 2 patients in the CNI group dropped out as a result of acute rejections (P > 0.05). The total bilirubin value of all the patients decreased significantly but serum cholesterol and triglyceride levels increase significantly after conversion (all P < 0.05). CONCLUSION: The substitution of SIR for CNI is both safe and effective in renal transplant recipients with CAN. And a conversion from CNI to SIR may improve the graft survival.

[Effect of donor bone marrow transfusion on renal allograft function in kidney transplant patients].

OBJECTIVE: To investigate the effect of donor bone marrow transfusion on kidney function in renal allograft recipients. METHODS: From May 1999 through May 2004, 74 cadaver renal transplant patients received postoperative donor bone marrow transfusion (DBMT group), the clinical outcomes were compared with 74 non-infused renal transplant recipients (control group). Both groups received the renal allograft from the same donor and were given equivalent immunosuppressant. The immunosuppressive regimen included tacrolimus/CiclosporinA, mycophenolate mofetil, and prednisolone maintenance. Patients were followed up for 24 to 108 months (mean 69.5 months). RESULT: The serum creatinine concentrations of DBMT group at 1,2 and 3 y after operation were (105 + or - 23.9)micromol/L,(107.5 + or - 32.4) micromol/L and (115 + or - 26.6)micromol/L; those of control group were (114.7 + or - 28)micromol/L,(116.5 + or - 27.6)micromol/L and (125 + or - 32.6)micromol/L,respectively. Glomerular filtration rate (GFR) of DBMT group at 1,2 and 3 y after operation were (70.2 + or - 24.4)ml/min, (74.3 + or - 24.1)ml/min and (73.5 + or - 22.4)ml/min; those of control group were (62.4 + or - 15.8)ml/min, (63.9 + or - 18.7)ml/min and (61.9 + or - 20.3)ml/min. After 5 year-follow-up,the prevalence of proteinuria in DBMT group was 50% (37/74),that was 77% (57/74) in control group (P<0.01). Only 3/74 DBMT recipients had biopsy-proven chronic rejection, whereas 12/74 showed chronic rejection in the controls (P<0.05). CONCLUSION: In kidney transplant recipients DBMC infusions may improve the long-term graft survival.

[Influence of pre-transplant serum level of soluble CD30 on the long-term survival rates of kidney transplant recipients and grafts].

OBJECTIVE: To investigate the influence of pre-transplant sCD30 level on the long-term survival rates of kidney transplant recipients and grafts among Chinese. METHODS: A retrospective cohort of 707 patients undergoing cadaver renal transplants between Dec.1998 and Aug 2003, 467 males and 240 females, aged 40 +/- 11, with their blood samples preserved was studied. The plasma levels of sCD30 were determined by ELISA. RESULTS: The 5-year graft survival/functional rates of the high sCD30 group were 77.7% +/- 3.5%/85.0% +/- 3.2%, significantly lower than those of the low and intermediate groups, 84.7% +/- 2.1%/98.9% +/- 1.1% and 88.1% +/- 2.9%/95.1% +/- 1.6% respectively (all P < 0.05). The 5-year recipient survival rate of the intermediate sCD30 group was 92.4% +/- 1.6%, higher than those of the low and high sCD30 groups, 84.7% +/- 3.9% and 87.1% +/- 2.7% respectively with a significant difference between the intermediate and high sCD30 groups (P = 0.032). CONCLUSIONS: Pre-transplant serum level of sCD30 reflects the immune status. Recipients with high sCD30 are prone to rejection while those with low sCD30 are prone to infections.

Pharmacokinetics of mycophenolic acid in Chinese kidney transplant patients.

To assess the influence of cyclosporin A (CsA) and tacrolimus (FK506) on mycophenolic acid (MPA) and correlation analysis of the pharmacokinetic parameters and patient characteristics, clinical outcome in Chinese kidney transplant recipients, the pharmacokinetics of 1000 mg mycophenolate mofetil (MMF) twice daily was measured by high-performance liquid chromatography (HPLC). PKS (Pharmaceutical Kinetics Software) 1.0.2 software package was used for the calculation of pharmacokinetic parameters. The mean C(max), t(max), and AUC((0-12))were (21.88+/-10.52) microg/ml, (1.20+/-0.95) h, and (52.546+/-13.215) microg.h/ml, respectively. The level of AUC((0-12)) in the FK506 group was significantly higher than that in the CsA group. MPA appeared not to be affected by renal function. MPA AUC((0-12)) showed statistically significant difference according to the patient's gender.

[The influence of early vascular rejection on late rejection in first cadaveric renal transplantation].

OBJECTIVE: To explore the influence of early completely reversal vascular rejection on late rejection. METHODS: The data of 1062 patients who received their first cadaveric transplants between May 1988 and March 2003 were analyzed respectively. The patients were divided into 2 groups: group with vascular rejection occurring within 1 month postoperatively (n = 45), and group without vascular rejection (n = 1017). Follow up was performed for at least 6 months. The influence of demographic characteristics (transplant age, sex), transplant variables (complement dependent cytotoxicity test, cold/warm ischemia time), and post-transplant variables (immunosuppressive agents for the prevention of acute rejection,) were analyzed. RESULTS: There were no differences in the age at transplantation, sex, complement dependent cytotoxicity test, cold/warm ischemia time, immunosuppression agent protocol, and serum creatinine during follow-up between the recipients of these two groups. Late rejection, including acute interstitial rejection, borderline rejection, and chronic rejection, occurring one month after transplantation was 2.22% (1/45) in the vascular rejection group, significantly lower than that of the no vascular rejection group (12.59%, 128/1017, P = 0.034) CONCLUSION: Early completely reversal vascular rejection can reduce the rate of late rejection.

[Completely reversed acute rejection episodes do not influence the long-term renal allograft survival].

OBJECTIVE: To assess the influence of times and duration of acute rejection episodes and the effect of antirejection therapy in renal transplantation recipients on the long-term survival of renal allograft. METHODS: The clinical data of 946 patients who received renal transplantation were analyzed to analyze the survival of renal allograts in different conditions: times of rejection episode, time of onset of acute rejection, and effect of antirejection therapy by life table and Wilcoxon test, and to identify the risk factors through Cox regression analysis. RESULTS: During the follow-up with a range of 3 approximately 158 months acute rejection occurred in 172 patients. The 946 cases of kidney transplantation were divided into rejection free group (NAR, n = 774), one time rejection group (1AR, n = 159), and twice and more rejection group (2AR, n = 13) according to the times of rejection. The 1AR group was subdivided into completely reversed group (CAR) and incompletely reversed group (1AR). The 1AR cases were subdivided into early-stage rejection group (EAR, with episode within 90 days after transplantation, n = 112) and late-stage rejection group (LAR, with episode 90 days later transplantation, n = 47) according to the onset time of rejection episode. The five-year survival rate was 70.9% in the AR group (n = 172) and was 93.3% in the NAR group (P < 0.000 1). The ten-year survival rate of renal allografts was 29.8% in the AR group, and was 83.3% in the NAR group (P < 0.000 1). The 5-year survival rate of renal allograft was less than 30% in the 2AR group, significantly lower than those in the NAR and IAR groups (P < 0.000 1 and P< 0.003). The 5-year survival rate of renal allograft was 89.0% in the EAR group, significantly higher than that in the LAR group (48.9%, P < 0.000 1). The 8-year survival rate was 84.3% in the EAR group, significantly higher than that in the LAR group (32.1%, P < 0.000 1). Both the survival rates of renal allograft in the EAR and LAR groups were significantly lower than that in the NAR group (P = 0.025 and P < 0.000 1). The condition had been completely reversed in 95 patients and incompletely reversed in 54 patients, and failed to be improved in 10 patients out of the 159 cases in the IAR group after antirejection therapy. The 5-year survival rate of renal allograft was 93.9% in the CAR group, significantly higher than that in the IAR group (63.1%, P < 0.000 1) but not significantly different from that in the NAR group (P = 0.96). The 8-year survival rate of renal allograft was 89.2% in the CAR group, significantly higher than that in the IAR group (41.4%, P < 0.000 1) but not significantly different from that in the NAR group (P = 0.96). The time of rejection onset was not the main factor effecting survival rate of grafts. The main risk factor influencing the long-term survival of renal allograft was the therapeutic effect after the onset of rejection with a risk rate of 3.14. CONCLUSION: The acutely rejected renal allografts have poor long-term survival. The long-term survival rate of renal allograts with acute rejection that occurs only once and is completely recovered after antirejection therapy is not significantly different from that of the renal allografts in NAR group.

[Diagnosis and therapy of the nutcracker phenomenon: long-term follow-up].

OBJECTIVE: To study the diagnosis of adult nutcracker phenomenon (NCP) and assess the therapeutic value of endovascular stenting (ES) and superior mesentery artery transposition (SMAT) for the treatment of NCP in long-term follow-up. METHODS: Six patients (6 men) aged 16 and 34 years old (mean age, 22.7 +/- 18.0 years) were diagnosed as having NCP using the examination of the doppler ultrasound and/or magnetic resonance of artery/digital radiography (MRA/DSA). Three patients underwent ES and 3 patients received SMAT for the treatment of the NCP patients associated with recurrent gross hematuria and left flank pain. Doppler ultrasound and urine examination were used at pre- and post-operation. RESULTS: In 3 patients who underwent SMAT, the postoperative complications comprised retroperitoneal hematoma necessitating surgical revision (n = 1). Functional disorder of intestine (n = 1) and paralytic ileus (n = 1) that were resolved by conservative management. In 3 patients who experienced ES, 1 patient received surgical revision because the position of stent was not suitable in left renal vein but no other complication took place. During the follow-up of 6 approximately 50 months (mean 24.7 +/- 18.0 months), except that 1 patient's hematuria disappears at rest and reappears after motion while the other 5 patients remain asymptomatic and free of hematuria. The dopplar ultrasound showed the left renal vein diameters of the angel segment between superior mesentery artery and aorta were (0.18 +/- 0.05) cm preoperation and (0.65 +/- 0.17) cm postoperation, P < 0.001; the left renal vein diameters of the portal segment were (0.89 +/- 0.22) cm preoperation and (0.79 +/- 0.20) cm postoperation, P = 0.003; the left renal vein diameter's ratio between portal and angel segment were (4.99 +/- 0.79) preoperation and (1.23 +/- 0.16) postoperation, P < 0.001. CONCLUSIONS: Dopplar ultrasound plays a very important role in the diagnosis of adult NCP. SMAT is an efficient surgical approach to the treatment of the nutcracker phenomenon and is associated with an acceptable risk of complications. But ES is safer and more efficient than SMAT and may represent a valuable approach to lessening the morbidity of surgical procedures. ES is a new therapeutic method for adult NCP.