Chinese Renal Allograft Recipients Research Articles

Tacrolimus and Diabetes in Kidney Transplantation: The Impact of Cyp3a5 Gene Polymorphism

To explore the correlation between single nucleotide polymorphisms (SNPs) of CYP3A4 rs2740574 and CYP3A5 rs776746 and post-transplant diabetes mellitus (PTDM) in Chinese renal allograft recipients treated with tacrolimus. A total of 244 patients treated with tacrolimus were included in this study, wherein DNA sequencing was detected through fluorescence in situ hybridization, and SNP genotyping was performed. Among the 244 patients, 44 (18%) developed PTDM. The PTDM group exhibited higher preoperative body mass index and fasting plasma glucose levels, with higher creatinine values one year after surgery. The CYP3A4 rs2740574 genotype was found to be unique in its homozygous AA form. For CYP3A5 rs776746, the genotypes were distributed as follows: 28 (11.5%) cases with AA, 101 (41.4%) cases with AG, and 115 (47.1%) cases with GG, respectively (P=.042). The AA genotype showed a statistically significant difference from both AG and GG genotypes. Furthermore, the A allele of CYP3A5 rs776746 was found to be associated with an increased risk for PTDM development. The occurrence of tacrolimus-related PTDM is associated with body mass index, fasting plasma glucose levels, and CYP3A5 genotype before renal transplantation. Post-transplant diabetes mellitus is correlated with unfavorable long-term renal graft function, whereas the expression of the CYP3A5 rs776746 gene is linked to an elevated risk of PTDM.

Influence of Calcineurin Inhibitors and Genetic Polymorphism of Transporters on Enterohepatic Circulation and Exposure of Mycophenolic Acid in Chinese Adult Renal Allograft Recipients.

There is significant enterohepatic circulation (EHC) during the disposition of mycophenolic acid (MPA). The aim of this study was to elucidate factors influencing the EHC of MPA in Chinese adult renal allograft recipients. After 2weeks of therapy with mycophenolate mofetil or enteric-coated mycophenolate sodium, blood samples were collected from 125 patients at 0 to 12hours post-administration and MPA concentrations were determined. The influence of calcineurin inhibitors (CNIs) and genetic polymorphisms on MPA exposure and EHC was studied. The Shapley additive explanations method was used to estimate the impact of various factors on the area under the plasma drug concentration-time curve (AUC0-12h ) for MPA. An extreme gradient boosting (XGboost) machine learning-based model was established to predict AUC0-12h . Results showed that the dose-normalized AUC6-12h (dn-AUC6-12h ) of MPA was significantly lower in patients co-administered with cyclosporine (CsA) than in patients co-administered with tacrolimus (TAC) (P<.05). For patients co-administered with TAC, patients with ABCC2 C-24TCC or SLCO1B1 T521CTT genotypes had significantly higher values of dn-AUC6-12h (P<.05). Patients with SLCO1B3 334T/699G alleles had significantly lower dn-AUC6-12h values than homozygotes (P<.05). By introducing body weight, age, and EHC-related factors, including co-administered CNIs and genetic polymorphism of drug transporters, as covariates in the XGboost machine learning model, the prediction performance of AUC0-12h for MPA in Chinese adult renal allograft recipients can be improved.

Establishment of a Liquid Chromatography-Tandem Mass Spectrometry Method for the Determination of Immunosuppressant Levels in the Peripheral Blood Mononuclear Cells of Chinese Renal Transplant Recipients.

Monitoring immunosuppressant levels, such as mycophenolic acid (MPA), cyclosporin A (CsA), and tacrolimus (TAC), in peripheral blood mononuclear cells (PBMCs) could be useful in organ transplant patients administered individualized therapy. The authors developed a liquid chromatography-tandem mass spectrometry assay technique to simultaneously determine immunosuppressant levels in PBMCs and assess their pharmacokinetics in Chinese renal allograft recipients. PBMCs were isolated from the whole blood of 27 Chinese renal transplant patients using Ficoll-Paque Plus solution, and cell number was determined; acetonitrile treatment for protein precipitation, and gradient elution was performed on an Agilent Eclipse XDB-C18 column (3.5 μm, 2.1 × 100 mm) with mobile phase: water and methanol (containing 2 mM ammonium formate); flow rate: 0.3 mL·min. The calibration curves of MPA, CsA, and TAC had a linear range (ng·mL): 0.098-39.2 (r = 0.9987), 0.255-102 (r = 0.9969), and 0.028-11.2 (r = 0.9993), respectively. The extraction effects, matrix effects, and mean relative recovery of these immunosuppressants were 70.4%-93.2%, 72.7%-96.5%, and 90.1%-112.4%, respectively. The within-day and between-day coefficients of variation were <15%. The AUC0-12 of MPA in PBMCs correlated well with those in plasma. The level of MPA, CsA, and TAC in PBMCs might be more stable during dosing interval. The derived liquid chromatography-tandem mass spectrometry assay is suitable for simultaneously monitoring different immunosuppressants in PBMCs. Pharmacokinetic of MPA, CsA, and TAC displayed considerable interindividual variability. Intracellular monitoring of immunosuppressants may facilitate individualized therapy for renal allograft recipients.

Limited sampling strategy for the estimation of the area under the concentration-time curve for ganciclovir in Chinese adult renal allograft recipients.

Valganciclovir (VGCV) treatment is recommended for the prevention of cytomegalovirus (CMV) infection in renal allograft recipients. The aim of the present study is to investigate the pharmacokinetic characteristics of ganciclovir (GCV) after administration of VGCV in Chinese adult renal allograft recipients and estimate the exposure to GCV using limited sampling strategy (LSS). Forty Chinese renal allograft recipients were given 450 mg or 900 mg VGCV daily. Blood samples were drawn before treatment and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 h after 5 days of VGCV therapy, and the plasma concentrations of VGCV and GCV were determined using a liquid chromatography-mass spectrometry assay. The major pharmacokinetic parameters for GCV and VGCV were determined using a noncompartmental assay. Multiple stepwise linear regression analysis was conducted to establish a model equation for the estimation of the GCV AUC0-24 h in Chinese patients using LSS. In the 450 and 900 mg groups, the Cmax for VGCV was 0.2 ± 0.10 and 0.4 ± 0.16 mg/L, respectively; the Cmax for GCV was 4.2 ± 1.1 and 8.6 ± 1.6 mg/L, respectively; and the AUC0-24 h for GCV was 28.4 ± 8.4 and 60.7 ± 17.5 mg·h/L, respectively. For the establishment of LSS models, 40 patients were divided into the training group (n = 24) and validation group (n = 16). The model equations used for the calculation of AUC0-24 h for GCV were established in the training group by using multiple linear regression assay. Equations including AUC = 8.1 + 29.7 × C0 + 5.7 × C4 (r2 = 0.91) and AUC = - 0.4 + 11.0 × C0 + 2.1 × C2 + 13.7 × C8 (r2 = 0.98) were acceptable. The %MPE and %MAPE values obtained from the validation group for the two model equations were 5.89 ± 14.5% and 12.1 ± 9.53%, and - 1.30 ± 4.40% and 3.28 ± 3.11%, respectively. The LSS models that included C0 and C4 or C0, C2, and C8 in the estimation of AUC0-24 h for GCV had favorable performance and can be used for therapeutic drug monitoring in the prevention of CMV infection using VGCV in Chinese renal allograft recipients.

Population Pharmacokinetics and Bayesian Estimation of Mycophenolic Acid Exposure in Chinese Renal Allograft Recipients After Administration of EC‐MPS

The aim of the present study is to establish a population pharmacokinetic (PPK) model of mycophenolic acid (MPA) and limited sampling strategy models for the estimation of MPA exposure in Chinese adult renal allograft recipients following oral administration of enteric coated mycophenolate sodium (EC-MPS). A total of 74 sets of full pharmacokinetic profiles and 47 sets of MPA-sparing samples were collected from 102 renal transplant recipients who received oral EC-MPS. The MPA concentration was determined by an enzyme-multiplied immunoassay technique, and the pathophysiologic data were recorded. The PPK model was constructed using nonlinear mixed-effects modeling, and the limited sampling strategy models for MPA were established by using multiple regression analysis and the maximum a posteriori Bayesian assay based on 2 to 4 sampling time points following EC-MPS administration. The pharmacokinetics of MPA were best described by a 2-compartment model with a first-order absorption process and a lag time of absorption. The clearance of MPA was 12.3 ± 1.14 L/h. Comedicating with cyclosporine A was found to have a significant impact on the clearance/bioavailability of MPA (P < .01). Sampling strategies consisted of plasma concentration at 1.5, 2, 4 (C1.5-C2-C4) hours and 1.5, 2, 4, 6 (C1.5-C2-C4-C6) hours after EC-MPS administration were shown to be suitable for the estimation of the MPA area under the concentration-time curve in these patients. The PPK model was acceptable and can describe the pharmacokinetics of MPA in Chinese renal transplant recipients administered EC-MPS. The area under the concentration-time curve of MPA in Chinese renal transplant recipients could be estimated through a limited sampling strategy method, based on which individualized immunosuppressive regimens could be designed.

Genetic risk factors for post-transplantation diabetes mellitus in Chinese Han renal allograft recipients treated with tacrolimus

BackgroundPost-transplantation diabetes mellitus (PTDM) is a serious metabolic complication after kidney transplantation. The aim of this study was to explore the association of clinical variables and five selected single nucleotide polymorphisms (SNPs) with PTDM in Chinese Han renal allograft recipients taking tacrolimus (TAC). MethodsA total of 129 non-diabetic, primary, Chinese Han renal allograft recipients treated with TAC were enrolled. Five SNPs (CYP3A5 rs776741, rs776746, rs15524, CYP24A1 rs2296241, and PPARG rs1801282) were genotyped and analyzed. ResultsAmong 129 recipients, 17 (13.2%) developed PTDM. Both univariate and multivariate analysis demonstrated that age over 50 years old and CYP24A1 rs2296241 A allele were independently correlated with the development of PTDM, while no significant differences was observed in TAC pharmacokinetics and CYP3A5, PPARG polymorphisms between two groups. ConclusionsPatients with advanced age and CYP24A1 rs2296241 A allele had an increased risk of PTDM after kidney transplantation.

Evaluation of the area under the curve of enteric-coated mycophenolate sodium using a limited sampling strategy in Chinese kidney transplant recipients .

To investigate the area under the curve (AUC) of mycophenolic acid (MPA) in adult Chinese renal allograft recipients receiving concomitant enteric-coated mycophenolate sodium (EC-MPS) and cyclosporine (CsA) during the early post-transplant phase and to develop optimal model equations for estimation of the MPA area under the plasma concentration-time curve from 0 to 12 hours (AUC0-12h) using a limited-sampling strategy (LSS). The present study enrolled 24 Chinese renal recipients treated with EC-MPS, CsA, and corticosteroid, from whom 24 serial blood samples were collected over 12 hours. MPA concentration was evaluated with enzyme multiplied immunoassay technique (EMIT). LSS was developed by multiple stepwise regression analysis using a two-group method (test group, n=12; and validation group, n=12). The MPA predose concentration had a poor correlation with MPA AUC0-12h, and the best equations obtained from the test group were the following: 25.73+0.59 × C1.5 + 0.79 × C2 + 2.03 × C4 (for three time points, r2 = 0.761) and 22.13 + 1.7 × C0.5 + 0.61 × C1.5 + 0.78 × C2 + 1.83 × C4 (for four time points, r2 = 0.853). When these equations were tested in the validation group, there were no significant differences in prediction errors. An LSS using time points at 1.5, 2, and 4 hours or 0.5, 1.5, 2, and 4 hours provides the most accurate and reliable estimation of the MPA AUC0-12h in Chinese adult renal recipients treated concomitantly with EC-MPS and CsA during the early post-transplant phase. .

Limited Sampling Strategy for Mycophenolic Acid in Chinese Kidney Transplant Recipients Receiving Enteric-Coated Mycophenolate Sodium and Tacrolimus During the Early Posttransplantation Phase.

Mycophenolic acid (MPA), a potent immunosuppressant, is widely used in solid organ transplantations. This study aimed to investigate the pharmacokinetics of enteric-coated mycophenolate sodium (EC-MPS) in Chinese adult renal allograft recipients and to generate optimal model equations for estimation of the MPA area under the concentration-time curve from 0 to 12 hours (AUC0-12 h), using a limited sampling strategy (LSS). Serial blood samples were collected over 12 hours from 38 recipients of a primary living-related donor kidney graft treated with EC-MPS, tacrolimus, and corticosteroid. MPA concentrations were evaluated using an enzyme-multiplied immunoassay technique. The LSSs were developed and validated by multiple regression analysis using a 2-group method (test group, n = 19; validation group, n = 19). The best algorithms obtained from the test group were the following: 15.09 + 1.05 × C1.5 + 1.8 × C4 + 4.18 × C6 (for 3 time points, r = 0.902) and 10.44 + 0.7 × C1 + 1.22 × C2 + 1.75 × C4 + 4.36 × C6 (for 4 time points, r = 0.941). When these algorithms were tested in the validation group, there were no significant differences in prediction errors. LSSs using time points of 1.5, 4, and 6 hours or 1, 2, 4, and 6 hours after dose provide effective and reliable estimations of the MPA AUC0-12 h in Chinese renal allograft recipients treated concomitantly with EC-MPS and tacrolimus during the early posttransplantation phase.

Use of limited sampling strategy for estimating area under concentration-versus-time curve of mycophenolate sodium in renal allograft recipients

To establish a formula for estimating area under the concentration-versus-time curve (AUC) of mycophenolate sodium in Chinese renal allograft recipients with a limited sampling model. A total of 35 renal allograft recipients were recruited from 2010 to 2013 to receive enteric-coated mycophenolate sodium (EC-MPS), calcineurin (CNI) and prednisone as immunosuppressive triple therapy. The serum concentration of mycophenolic acid (MPA) was assayed by enzyme multiplied immunoassay technique (EMIT) at pre-dose (C0), 0.5 (C0.5), 1.0 (C1), 1.5 (C1.5), 2.0 (C2), 3.0 (C3), 4.0 (C4), 6.0 (C6), 8.0 (C8) and 12.0 (C12) h post-dose respectively. Pharmacokinetic parameters of MPA (C0, C12, Cmax, Tmax, AUC0-12 h) were calculated by software WINNOLIN. Simplified formulae for estimation of MPA-AUC in tacrolimus (Tac) group or cyclosporin A (CsA) group were established by multiple stepwise regression analysis. There were variable MPA AUC0-12 h levels between 14 and 67 mg×h/L (mean: 37 ± 14). The MPA trough level (C0) had no correlations with MPA AUC0-12 h (r(2) = 0.090) . The simplified MPA AUC formula for Tac group was AUC = 5.678+1.718×C4+2.853×C6+1.812×C8+3.413×C12 with four sampling points (C4, C6, C8, C12). Estimated AUC with the formula had correlations with AUC0-12 h (r(2) = 0.890). The mean absolute predict error (APE) was 3.45% (0.41%-24.71%) and the proportion of APE above 15% stood at 11.1% (2/18) . In CsA group, the simplified MPA AUC formula was AUC = 7.072+1.525×C3+1.558×C4+ 1.573×C6+2.285×C8. The correlation was r(2) = 0.952, mean APE was 6.50% (0.02%-12.91%) and proportion of APE above 15% stood at 0. The above formulae were observed to have agreement with AUC0-12 h by Bland-Altman analysis. The simplified MPA AUC formulae with 4-point sampling provide an effective approach for estimating full MPA AUC0-12 h in Chinese renal recipients on EC-MPS plus tacrolimus or cyclosporin A.

Evaluation of Mycophenolic Acid Exposure Using a Limited Sampling Strategy in Renal Transplant Recipients

Background/Aims: While there are drug exposure equation models based on limited sampling times for mycophenolate mofetil (MMF), there are few for enteric-coated mycophenolate sodium (EC-MPS), and none that studied Chinese individuals. Our objective is to generate the optimal model equations for estimation of the mycophenolic acid (MPA) area under the plasma concentration-time curve from 0 to 12 h (MPA-AUC_0-12h) with a limited sampling strategy (LSS) for renal transplant recipients receiving EC-MPS. Methods: The pharmacokinetics in 31 Chinese renal allograft recipients treated with EC-MPS in combination with tacrolimus and steroids were determined. The model equations were generated by multiple stepwise regression analysis for estimation of the MPA-AUC. Results: A total of 31 patients with an average age and weight of 37.58 ± 10.9 years and 60.9 ± 10.7 kg, respectively, were included. Mean serum creatinine and glomerular filtration rate were 112.2 ± 17.7 μmol/l and 65.6 ± 14.6 ml/min, respectively. The mean values of AUC_0-12h, pre-dose MPA trough concentration (C₀), maximum concentrations (C_max), and time to reach C_max (T_max) were 61.17 ± 26.39 mg·h/l (range 22.9-123.0 mg·h/l), 4.98 ± 4.65 mg/l (range 0.13-20.04 mg/l), 17.54 ± 10.67 mg/l (range 4.08-42.36 mg/l), and 5.0 ± 2.6 h (range 1.0-10.5 h), respectively. The best predictive equation for estimation of MPA-AUC_0-12h was -3.63 + 8.35 × C₄ + 17.04 × C₇ + 13.74 × C₁₂ (r² = 0.7491), prediction bias (PE%) was 20.9 ± 20.37, and prediction precision (APE%) was 3.66 ± 29.20. Conclusions: This model provides an effective approach for estimation of full MPA-AUC_0-12h in Chinese adult renal allograft recipients treated with EC-MPS and tacrolimus.

Adiponectin Gene Polymorphisms Are Associated With Posttransplantation Diabetes Mellitus in Chinese Renal Allograft Recipients

Background Posttransplantation diabetes mellitus (PTDM) is a well-recognized renal transplantation complication that is associated with increased graft loss, morbidity, and mortality. Adiponectin gene polymorphisms are associated with type 2 diabetes. However, it remains unknown whether these polymorphisms increase the risk for development of PTDM. Therefore, the aim of this study was to investigate the association between the adiponectin gene polymorphism and the risk of PTDM among Chinese renal allograft recipients. Methods We genotyped 398 unrelated renal allograft recipients without a prior diagnosis of diabetes, including 97 PTDM and 301 without PTDM, for adiponectin gene variants: single nucleotide polymorphisms at position 45 and 276, that is, SNP-45: T/G, SNP-276: G/T, using the polymerase chain reaction-restriction fragment length polymorphism assay. No prisoners or organs from prisoners were used in the study. Results The G allele of SNP-276 was significantly more frequent in PTDM than non-PTDM subjects ( P = .041). For SNP-45 and SNP-276, the incidence of PTDM was significantly higher in patients with the GG genotype than those with the TG and TT genotypes (48.1% vs 21.5% and 23.6% and 30.7% vs 18.5% and 22.8%; ( P = .011 and .024, respectively). Even after adjusting for age and sex, the effects of the SNP-45 genotypes for GG compared to TT (odds ratio [OR] = 3.108, P = .009) and GG compared to TG (OR = 3.620, P = .004) as well as for SNP-276 genotypes GG compared to TG (OR = 2.203, P = .002) and body mass index at transplantation (OR = 1.099, P = .024) remained significant. Conclusions These data suggested that SNP-45 and SNP-276 of the adiponectin gene were significantly associated with an increased risk for PTDM among Chinese renal allograft recipients.

Characteristics of Long-Term Immunosuppressive Therapy in Chinese Pediatric Renal Transplant Patients: A Single-Center Experience

We performed this study to investigate the trend and characteristics of various immunosuppressive regimens as well as their efficacy and safety for long-term survival of Chinese pediatric renal allograft recipients. Methods Thirty-four patients who underwent kidney transplantation between January 1985 and July 2002 had ≥5 years follow up. We retrospectively reviewed the baseline characteristics, patient and kidney survival rates, renal function, immunosuppressive regimens, drug levels, and adverse effects of immunosuppressive medications. Results The 1-, 3-, and 5-year recipient versus graft survival rates were 100% and 97.1%; 91.2% and 88.2%; 85.3% and 82.4%, respectively. The proportions of patients treated with cyclosporine- or tacrolimus-based immunosuppressive regimen at these times were 48.5%/51.5%; 60.0%/40.0%; and 53.6/46.4%. There were no significant differences in the dosages and drug levels after 1 year ( P > .05). The proportions of azathioprine versus mycophenolate mofetil adjunctive therapy were 21.3/78.8%; 23.3%/70%; and 32.1%/60.7%, respectively. Forty percent of the surviving recipients developed complications, including hypertension, hyperlipidemia, gingival hyperplasia, hirsutism, liver dysfunction, herpes zoster, diabetes mellitus or cataracts. Conclusions Cyclosporine or tacrolimus, plus mycophenolate mofetil or azathioprine, and prednisone triple therapies showed promising long-term results with similar efficacy and safety in pediatric renal recipients. Periodic drug level monitoring is required to facilitate individualization of immunosuppressive regimens. Drug doses and levels differed markedly from non-Chinese patients because of the ethnic discrepancy.

A Single-dose Daclizumab Induction Protocol in Renal Allograft Recipients: A Chinese Single Center Experience

This study prospectively compared immunoprophylaxis with a single dose of daclizumab versus no induction in kidney transplant recipients treated with a cyclosporine, mycophenolate mofetil, and prednisone-based immunosuppression regimen seeking to observe the impact of a single-dose regimen for prevention of acute rejection among Chinese renal allograft recipients. A total of 118 renal transplant recipients were randomized into a daclizumab induction therapy group (daclizumab group, n = 58) and a no induction group (control group, n = 60). The daclizumab group received a single-dose (1 mg/kg of ideal body weight by intravenous infusion) 2 hours before the operation. There was no induction therapy in the control group. There was no significant difference in the baseline parameters at randomization between the two groups. The mean time to the first episode of acute rejection was 41.2 ± 3.2 days for the daclizumab group versus 11.2 ± 4.6 days for the control group. The number of first biopsy-confirmed acute rejection episodes during the 6-months after transplantation was significantly different in the daclizumab (7,12.1%) versus the control group (14,23.3%; P < .001). At the end of 12 months, patient and graft survivals were 100% in the groups with or without daclizumab. We noted that the incidence of infection, including serious infection was similar, in the daclizumab group to that in the control group, 17.2% and 20.0%, respectively. This study showed that a single-dose of daclizumab effectively prevented acute rejection in Chinese renal allograft recipients.

Pharmacokinetics of Mycophenolic Acid and Estimation of Exposure Using Multiple Linear Regression Equations in Chinese Renal Allograft Recipients

To investigate the pharmacokinetics of mycophenolic acid (MPA) in Chinese adult renal allograft recipients, and to generate the validated model equations for estimation of the MPA area under the plasma concentration-time curve from 0 to 12 hours (AUC(12)) with a limited sampling strategy. The pharmacokinetics in 75 Chinese renal allograft recipients treated with mycophenolate mofetil 2 g/day in combination with cyclosporin and corticosteroids were determined. The MPA concentration was assayed by high-performance liquid chromatography at pre-dose (C(0)) and at 0.5 (C(0.5)), 1 (C(1)), 1.5 (C(1.5)), 2 (C(2)), 4 (C(4)), 6 (C(6)), 8 (C(8)), 10 (C(10)) and 12 (C(12)) hours after dosing on day 14 post-transplant. Patients were randomly divided into: (i) a model group (n = 50) to generate the model equations by multiple stepwise regression analysis for estimation of the MPA AUC by a limited sampling strategy; and (ii) a validation group (n = 25) to evaluate the predictive performance of the model equations. The mean MPA AUC(12) was 52.97 +/- 15.09 mg . h/L, ranging from 24.0 to 102.3 mg . h/L. The patient's age and serum albumin level had a significant impact on the MPA AUC(12). The correlation between the pre-dose MPA trough level (C(0)) and the MPA AUC(12) was poor (r(2) = 0.02, p = 0.33). Model equations 7 (MPA AUC(12) = 14.81 + 0.80 . C(0.5) + 1.56 . C(2) + 4.80 . C(4), r(2) = 0.70) and 11 (MPA AUC(12) = 11.29 + 0.51 . C(0.5) + 2.13 . C(2) + 8.15 . C(8), r(2) = 0.88) were selected for MPA AUC calculation in Chinese patients, resulting in good agreements between the estimated MPA AUC and the full MPA AUC(12), with a mean prediction error of +/-10.1 and +/-6.9 mg . h/L, respectively. In Chinese renal allograft recipients, MPA pharmacokinetics manifest substantial interindividual variability, and the MPA AUC(12) tends to be higher than that in Caucasian patients receiving the same dose of mycophenolate mofetil. Two validated model equations with three sampling timepoints are recommended for MPA AUC estimation in Chinese patients.

Tacrolimus combined with mycophenolate mofetil can effectively reverse C4d-positive steroid-resistant acute rejection in Chinese renal allograft recipients

Tacrolimus (TAC) combined with mycophenolate mofetil (MMF) has been suggested to play a critical role in the reversal of C4d-positive acute humoral rejection (AHR) in renal transplantation, but the efficacy of using only TAC-MMF without immunoadsorption or plasmapheresis has not been investigated. On the other hand, Chinese recipients of renal grafts usually need lower doses of immunosuppressants, and their optimal treatment for acute humoral rejection has not been established. Since 1999, we have used TAC-MMF to treat steroid-resistant acute rejection (AR). C4d staining was retrospectively performed in 32 patients with steroid-resistant AR, and the treatments of 19 patients with C4d-positive steroid-resistant AR were investigated. Thirteen of 19 patients received TAC-MMF treatment only; 11 episodes of rejection in them were reversed (7 completely, 4 partially) and only 2 recipients lost their graft. Another 6 patients received immunoadsorption also. One of them failed to respond and lost her graft. Four of 5 patients treated with immunoadsorption and TAC-MMF recovered (3 completely, 1 partially), but 3 of them had severe pneumonia, a complication rate statistically higher than in patients treated with only TAC-MMF (P<0.05). AR occurring during the first two weeks after transplantation had a statistically better outcome than that occurring later (P = 0.003). Our study suggests that the combination of TAC and MMF is a potentially safe and economic treatment for most Chinese renal allograft recipients with C4d-positive steroid-resistant AR, especially for rejections developing within the first two weeks after transplantation.

Improved clinical outcomes in Chinese renal allograft recipients receiving lower dose immunosuppressants.

The application of potent immunosuppressants has decreased the incidence of acute rejection and increased short- and long-term graft survival; however, these drugs cause a variety of complications. In China, many transplant centers have adopted the immunosuppressive protocols based on the white population, neglecting the differences between the races. The purpose of this study was to explore a suitable immunosuppressive regimen for Chinese renal allograft recipients. Two hundred cadaveric renal allograft recipients who underwent transplantation between July 1999 and October 2001 were observed. Before October 2000, 104 recipients received the conventional dose of immunosuppressants; thereafter, 96 recipients received lower dose treatment. Doses of immunosuppressive agents, the incidence of acute rejection and pulmonary infection, and patient and graft survival rates were compared between the two groups. Doses of mycophenolate mofetil (MMF) and cyclosporine A (CsA) administered in the conventional dose group were significantly higher than in the lower dose group at 3 months posttransplant, as was prednisone at 6 months posttransplant. The incidence of acute rejection and subclinical rejection that was biopsy-proven or diagnosed by clinical manifestations was 17.3% and 19.8%, respectively, in the conventional dose group and the lower dose group within the first 6 months, and no significant difference was noted (P=0.55). The incidence of pulmonary infection, especially severe infection, was much higher in the conventional treatment group (40.1% and 26.9%, respectively) than that in the lower dose group (11.5% and 5.2%, respectively), and the differences were statistically significant (P<0.001). The corresponding 1-year survival rate of patients was 87.4% and 97.9% (P<0.01), and that of renal grafts was 85.5% and 96.9% (P<0.01), for patients receiving conventional dose and lower dose immunosuppressive drugs, respectively. The rate of death with a functioning allograft caused by infection in the conventional dose group was significantly higher than that in the lower dose group (12.5% vs. 0%, P<0.01). The regimen of lower dose MMF, CsA, and prednisone in combination can significantly reduce the incidence of pulmonary infection, especially severe pulmonary infection, without increasing the incidence and severity of allograft rejection.

A long-term study on hyperlipidemia in stable renal transplant recipients.

Hyperlipidemia is a common and important risk factor after renal transplantation, but there is little long-term data on its incidence, pattern, and evolution in stable renal allograft recipients on low dose maintenance immunosuppression. A retrospective study was conducted on all patients who received kidney transplants from April 1, 1990 to March 31, 2000 at a single center, on their serial lipid profile during the first 3 yr after kidney transplantation. A total of 221 (122 male, 99 female; mean age 37.8 +/- 10.0 yr at the time of transplantation) Chinese adult renal allograft recipients were included. A 95.3% of patients were on cyclosporine and prednisolone based immunosuppression. Increases in total cholesterol (TC), low density lipoprotein (LDL), and high density lipoprotein (HDL) were noted, while the level of triglyceride (TG) decreased after renal transplant. The incidence of hypercholesterolemia (defined as TC >/= 6.3 mmol/L or LDL >/= 4.2 mmol/L) within the first year was 28.2 and 20.3%, respectively. The incidence rate decreased significantly in the second (5.4%, p = 0.000 and 6.4%, p = 0.003) and third year (9.5%, p = 0.003 and 4.9%, p = 0.021), but the incidence of patients having a high risk-ratio (defined as TC/HDL >/= 5) remained unchanged (6.9, 4.9 and 10.3% within the first, second, and third year, respectively). Treatment with statin was necessitated in 6.8, 13.6 and 21.7% of the patients at 1, 2, and 3 yr after transplantation, respectively. The prevalence rates of elevated TC and LDL were 18.3 and 18.9% at baseline, 40.6 and 33.3% after 1 yr, 32.8 and 27.3% after 2 yr, and 24.8 and 19.0% after 3 yr, despite treatment. The prevalence of patients with a high risk-ratio was 45.0% at baseline, 30.5% after 1 yr (p = 0.002), 22.6% after 2 yr (p = 0.000) and 21.8% after 3 yr (p = 0.000). Hypercholesterolemia at the time of transplantation was an independent predictor for post-transplant hypercholesterolemia (odds ratio 3.76, 95% confidence interval 1.47-9.62, p = 0.006). Renal transplantation is associated with a characteristic pattern of dyslipidemia, with increased TC, LDL and HDL, and a decrease in TG. Patients with pre-existing hypercholesterolemia were at higher risk for post-transplant hypercholesterolemia. Although the incidence of hypercholesterolemia peaks within the first year after transplantation, this remains a long-term complication in a significant proportion of patients on low dose immunosuppressive medications.

Sirolimus in Kidney Transplantation: A Pilot Study in Chinese Patients

We conducted a pilot open-label study on the use of sirolimus in 10 Chinese patients undergoing kidney transplantation who received triple prophylactic immunosuppression comprising prednisolone, cyclosporine and sirolimus. Sirolimus was given as a 6 mg loading dose followed by 2 mg/day maintenance. All patients achieved target sirolimus trough serum concentrations exceeding 5 ng/mL. Median duration of follow-up was 22 months after transplantation. One patient developed Type Ia acute cellular rejection at 6 months, which responded to pulse steroid therapy. Graft survival was 100% at 12 months and serum creatinine was 131 ± 36 μmol/L at 1 year. Low-density lipoprotein cholesterol and triglyceride levels were significantly increased after 2 months. Eight patients received atorvastatin, which was subsequently discontinued successfully in three patients. Infection was noted in two patients; one died of pneumocystis pneumonia 10 months after transplantation and the other had septicemia from urinary tract infection complicating graft vesicoureteric reflux. Two patients developed lymphocele in the early postoperative period, which resolved spontaneously in one patient and was treated successfully with ethanol sclerotherapy in the other. No patients developed thrombocytopenia or arthralgia. We conclude that sirolimus, when used together with prednisolone and cyclosporine, is well tolerated and effective in Chinese renal allograft recipients, and that hyperlipidemia early after transplantation is the most common adverse effect.

The pharmacokinetics and bioequivalence of Gengraf and Neoral in stable renal transplant recipients

Objective Gengraf capsule, an AB-rated generic cyclosporine for Neoral, has been shown to be bioequivalent in previous studies. The objective of this study was to evaluate the pharmacokinetics and bioequivalence of Gengraf and Neoral in stable Chinese renal allograft recipients Methods In a prospective, open-label, two-period design study, 20 renal allograft recipients receiving stable doses of Neoral were recruited. Subjects continued their Neoral regimen during period I (days 1-14). They were then switched from Neoral on a milligram-for-milligram basis to Gengraf during period II (days 15-28). Four-hour pharmacokinetic parameters (concentration before dosing [Ctrough], maximum blood concentration [Cmax], time to maximum concentration [Tmax], and area under the blood concentration-versus-time curve [AUC0-4]) were taken on days 1, 8, 21, and 28. Biochemical parameters were also evaluated. Results There was no significant difference in the pharmacokinetics of Gengraf (Ctrough, Tmax, Cmax, and AUC0-4) as compared with that of Neoral in stable renal transplant recipients. The bioequivalent capsules were interchangeable with respect to Ctrough, Cmax and AUC0-4. The 90% confidence intervals of the ratio of Ctrough, Cmax, Tmax, and AUC0-4 of Gengraf and Neoral were 0.94 to 1.21 for Ctrough, 0.97 to 1.20 for Cmax, and 0.97 to 1.20 for AUC0-4. Ctrough and C2 remained stable throughout the study without any dosage adjustments. Gengraf was well tolerated, and had a comparable safety profile as Neoral. Conclusion Gengraf are bioequivalent to Neoral. Gengraf is well tolerated and interchangeable with Neoral in stable Chinese renal allograft recipients.