PURPOSE: The increased tolerability of enteric-coated mycophenolate sodium (EC-MPS), compared to mycophenolate mofetil, among kidney transplant recipients has the potential to facilitate cyclosporine (CsA) minimization. Therefore, a prospective trial to determine the optimum EC-MPS dose in CsA-based immunosuppression regimens is necessary. MATERIALS AND METHODS: A comparative, parallel, randomized, open-label study was performed for 140 patients from four centers to compare the efficacy and tolerability of low dose CsA with standard dose EC-MPS (the investigational group) versus standard dose CsA with low dose EC-MPS (the control group) for six months in de novo kidney transplant recipients. Graft function, the incidence of efficacy failure [biopsy-confirmed acute rejection (BCAR), death, graft loss, loss to follow-up], and adverse events were compared. RESULTS: The mean estimated glomerular filtration rate (eGFR) of the investigational group at six months post-transplantation was non-inferior to that of the control group (confidence interval between 57.3 mL/min/1.73m² and 67.4 mL/min/1.73 m², p<0.001). One graft loss was reported in the control group, and no patient deaths were reported in either group. The incidence of BCAR of the investigational group was 8.7%, compared to 18.8% in the control group (p=0.137), during the study period. There were no significant differences (p>0.05) in the incidence of discontinuations and serious adverse events (SAE) between the groups. CONCLUSION: CsA minimization using a standard dose of EC-MPS kept the incidence of acute rejection and additional risks as low as conventional immunosuppression and provided therapeutic equivalence in terms of renal graft function and safety issues.
Adult ; Aged ; Cyclosporine/*administration & dosage ; Female ; Graft Rejection/*prevention & control ; Humans ; Immunosuppressive Agents/*administration & dosage ; Incidence ; Kidney Transplantation ; Male ; Middle Aged ; Mycophenolic Acid/*administration & dosage ; Prospective Studies ; Tablets, Enteric-Coated ; Time Factors

OBJECTIVETo compare the therapeutic effects of prednisone combined with mycophenolate mofetil (MMF) versus cyclosporin A (CsA) in children with steroid-resistant nephrotic syndrome (SRNS).

METHODSThe clinical data of 164 SRNS children who were treated with prednisone combined with MMF or CsA between January 2004 and December 2013 were collected, and the clinical effect of prednisone combined with MMF (MMF group, 112 children) or CsA (CsA group, 52 children) was analyzed retrospectively.

RESULTSAt 1 month after treatment, the CsA group had a significantly higher remission rate than the MMF group (67.3% vs 42.9%; P<0.05). At 3 months after treatment, the CsA group also had a significantly higher remission rate than the MMF group (78.8% vs 63.3%; P<0.05). The 24-hour urinary protein excretion in both groups changed significantly with time (P<0.05) and differed significantly between the two groups (P<0.05). There were no serious adverse events in the two groups.

CONCLUSIONSPrednisone combined with MMF or CsA is effective and safe for the treatment of SRNS in children, and within 3 months of treatment, CsA has a better effect than MMF.

Adolescent ; Child ; Child, Preschool ; Cyclosporine ; administration & dosage ; Drug Therapy, Combination ; Female ; Humans ; Immunosuppressive Agents ; administration & dosage ; Infant ; Male ; Mycophenolic Acid ; administration & dosage ; analogs & derivatives ; Nephrotic Syndrome ; drug therapy ; Prednisone ; administration & dosage ; Retrospective Studies ; Treatment Outcome

BACKGROUNDLupus nephritis (LN) is one of the most serious manifestations of systemic lupus erythematosus. Although there have been substantial improvements in LN treatment over the last decade, the outcome remains unoptimistic in a considerable percentage of patients. The aim of this study was to evaluate the efficacy and safety of mizoribine (MZR), a novel selective inhibitor of inosine monophosphate dehydrogenase, as induction treatment for active LN in comparison with mycophenolate mofetil (MMF) and intravenous cyclophosphamide (CYC).

METHODSNinety patients with active LN were observed. Thirty patients were given MZR orally at the dose of 300 mg every other day. Thirty patients took MMF at 2 g per day in two divided doses. Thirty patients received CYC intravenously 0.5 g every 2 weeks. Therapeutic effects and adverse events (AEs) were evaluated at the end of 24-week treatment. One-way analysis of variance (ANOVA) followed by Dunn's test was applied to compare the difference among the groups. For comparing categorical data between two groups, χ(2) test was employed.

RESULTSEarly responses at week 12 were achieved by 73.3%, 90.0%, and 96.7% in MZR, MMF, and CYC groups, respectively. There was no significant difference in the complete remission rates (22.7%, 24.0%, and 25.0%, respectively) or overall response rates (68.2%, 72.0%, and 75.0%, respectively) among the three groups at week 24. The most prominent drop-down of Systemic Lupus Erythematosus Disease Activity Index scores was observed in MMF or CYC group, and the decline of health assessment questionnaire scores in MZR or MMF group was more prominent than that in the CYC group at week 12. Serum complement 3 (C3) or C4 levels were elevated in all groups after the treatments. CYC was more effective in inhibiting anti-double-stranded DNA antibody, while MZR was more effective in inhibiting antinuclear antibody. The incidences of AEs in patients treated with CYC were significantly higher than those in patients treated with MZR or MMF (24.2% for CYC vs. 3.3% for MZR, and 2.6% for MMF, P = 0.01).

CONCLUSIONSMZR is well tolerated and has an effect similar to MMF in the induction therapy of active LN. MZR may serve as an alternative approach for LN patients.

Administration, Intravenous ; Adolescent ; Adult ; Aged ; Cyclophosphamide ; administration & dosage ; therapeutic use ; Enzyme Inhibitors ; administration & dosage ; therapeutic use ; Female ; Humans ; Immunosuppressive Agents ; administration & dosage ; therapeutic use ; Lupus Nephritis ; drug therapy ; Male ; Middle Aged ; Mycophenolic Acid ; administration & dosage ; therapeutic use ; Ribonucleosides ; administration & dosage ; therapeutic use ; Treatment Outcome ; Young Adult

OBJECTIVETo investigate the clinical characteristics, renal pathology, treatment and prognosis of children with atypical hemolytic uremic syndrome associated with H factor antibody.

METHODFour children less than 18 yr of age admitted from Nov. 2010 to May 2011 in Peking University First Hospital were included. They all met the criteria for atypical hemolytic uremic syndrome and with positive serum anti factor H antibody. They aged from 5 to 11 yr. Data on clinical manifestations, renal pathology, treatment and prognosis were analyzed.

RESULTAll of the 4 cases had gastrointestinal symptoms such as vomiting, abdominal pain, or abdominal distension. None of them had diarrhea. Two children had hypertension. One child had episodes of convulsion. One child had history of atypical hemolytic uremic syndrome. All of them had low serum complement C3. Three of them had low serum factor H (38.0, 88.4, 209.4 mg/L). All of them had serum antibody to factor H (1: 7 068, 1: 1 110, 1: 174, and 1: 869). Three of them received renal biopsy, all of them showed thrombotic microangiopathy. All of them were treated with steroid combined with mycophenolate mofetil. Two children received plasma exchange. They were followed up for 8 to 29 months. The renal function became normal and proteinuria relieved in all of them. The serum factor H concentration increased to 405.8, 155.8 and 438.4 mg/L, respectively. The titer of anti factor H antibody decreased to 1: 119, 1: 170, 1: 123, and 1: 674, respectively.

CONCLUSIONGastrointestinal symptom is common in children with atypical hemolytic uremic syndrome associated with H factor antibody. Hypocomplementemia was observed in all of them. Steroid combined with mycophenolate mofetil seemed to be effective for them. The monitoring of serum factor H and antibody to factor H may help diagnosis and treatment.

Atypical Hemolytic Uremic Syndrome ; Autoantibodies ; blood ; immunology ; Child ; Child, Preschool ; Complement Factor H ; immunology ; Creatinine ; blood ; Female ; Hemolytic-Uremic Syndrome ; drug therapy ; immunology ; pathology ; Humans ; Kidney ; pathology ; physiopathology ; Kidney Function Tests ; Male ; Mycophenolic Acid ; administration & dosage ; analogs & derivatives ; therapeutic use ; Plasma Exchange ; Prednisolone ; administration & dosage ; therapeutic use ; Prognosis ; Retrospective Studies

OBJECTIVETo determine the optimal dose range (therapeutic window) of mycophenolate mofetil (MMF) for preventing acute graft rejection following renal transplantation.

METHODSThe trough concentration of MMF (MPA-C0) at 12 h after oral administration of the drug (two doses daily given at an interval of 12 h) was monitored in 110 renal transplant recipients within a month, in 2-3 months, and over 4 months after the transplantation using EMIT method. The occurrence of acute graft rejection and drug toxicity were observed in all the patients during the one-year follow-up.

RESULTSs The incidence of acute graft rejection after transplantation was 13.64% (15/110) in these patients. Drug toxicity and complications occurred in 32.73% (36/110) of the patients, including 12 cases with reduced white blood cell counts, 10 with MMF cid-associated diarrhea, 10 with infection, 4 with liver function damage. Acute rejection was successfully reversed after methylprednisolone treatment and drug toxicity was managed by corresponding treatment and adjustment of MMF dose. No deaths or graft removal occurred in these patients. The ROC curve showed that a MPA-C0 of 1.40-2.80 mg/L was optimal in preventing acute rejection after the transplantation and reducing adverse drug effects.

CONCLUSIONMonitoring MPA-C0 and individualized MMF dosing help to prevent acute graft rejection, reducing drug toxicity and complications, and improving graft survival rate after renal transplantation.

Graft Rejection ; drug therapy ; prevention & control ; Graft Survival ; Humans ; Immunosuppressive Agents ; administration & dosage ; therapeutic use ; Kidney Transplantation ; Methylprednisolone ; Mycophenolic Acid ; administration & dosage ; analogs & derivatives ; therapeutic use ; Survival Rate ; Time Factors

It is reported that a conversion from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPS) relieves gastrointestinal (GI) symptom burden and improves health-related quality of life (HRQoL). However, it is unclear whether renal transplant recipients using tacrolimus receive the same benefit from the conversion. In this prospective, multi-center, open-label trial, patients were categorized into two groups by their GI symptom screening. Equimolar EC-MPS (n=175) was prescribed for patients with GI burdens; those with no complaints remained on MMF (n=83). Gastrointestinal Symptom Rating Scale (GSRS) and Gastrointestinal Quality of Life Index (GIQLI) were evaluated at baseline and after one month. Patients and physicians completed Overall Treatment Effect (OTE) at one month. EC-MPS-converted patients had worse GSRS and GIQLI scores at baseline than MMF-continued patients (all P<0.001). Significant improvements in GSRS and GIQLI scores were observed for EC-MPS-converted patients at one month, but MMF-continued patients showed worsened GSRS scores (all P<0.05). OTE scale indicated that EC-MPS patients improved in overall GI symptoms and HRQoL more than MMF patients did (P<0.001). In tacrolimus-treated renal transplant recipients with GI burdens, a conversion from MMF to EC-MPS improves GI-related symptoms and HRQoL.
Adolescent ; Adult ; Aged ; Female ; Gastrointestinal Diseases/*chemically induced ; Graft Rejection/drug therapy ; Humans ; Immunosuppressive Agents/administration & dosage/*adverse effects/therapeutic use ; Kidney Failure, Chronic/therapy ; *Kidney Transplantation ; Male ; Middle Aged ; Mycophenolic Acid/administration & dosage/*adverse effects/*analogs & derivatives/therapeutic use ; Quality of Life ; Questionnaires ; Tablets, Enteric-Coated ; Tacrolimus/therapeutic use

The paper is aimed to establish an artificial neural network (ANN) for predicting mycophenolic acid (MPA) area under the plasma concentration-time curve (AUC) in renal transplantation recipients. 64 Chinese renal transplantation recipients receiving mycophenolate mofetil (MMF) were investigated. 10 timed samples were drawn at different days after transplantation. Plasma MPA concentration was determined by HPLC method and area under curve over the period of 0 to 12 h (AUC(0-12 h)) was calculated using the linear trapezoidal rule. ANN was established after network parameters were optimized using momentum method in combination with genetic algorithm. Furthermore, the predictive performance of ANN was compared with that of multiple linear regression (MLR). When using plasma MPA concentration of 0, 0.5, 2 h after MMF administration to predict MPA AUC(0-12 h), mean prediction error and mean absolute prediction error were -1.53% and 9.12%, respectively. Accuracy and precision of prediction by ANN were superior to that of MLR prediction, and similar results could be found when using plasma MPA concentration of 0, 0.5 h to predict MPA AUC(0-12h). The accuracy and precision of ANN prediction were superior to that of MLR prediction, and ANN can be used to predict MPA AUC(0-12 h).
Administration, Oral ; Adolescent ; Adult ; Aged ; Area Under Curve ; Drug Monitoring ; methods ; Female ; Humans ; Immunosuppressive Agents ; administration & dosage ; pharmacokinetics ; Kidney Transplantation ; Linear Models ; Male ; Middle Aged ; Mycophenolic Acid ; administration & dosage ; analogs & derivatives ; blood ; pharmacokinetics ; Neural Networks (Computer) ; Young Adult

OBJECTIVETo identify the factors responsible for the inter-individual variations in the dosage/concentration of tacrolimus in renal transplant recipients.

METHODSThis study involved renal transplant recipients receiving immunosuppressive therapy with the tacrolimus, mycophenolate and prednisone regimen after the operation. The gender, age, height, body weight, tacrolimus dosage, hormone dosage, diarrhea, blood lipids, liver function, renal function, albumin, and hematocrit of the patients were recorded at different time points, namely in early stage (3, 7, 14, and 30 days postoperatively, 118 cases), at 3 months (103 cases), 6 months (75 cases) and over one year (119 cases) after the operation. The concentrations of tacrolimus and gene polymorphisms at CYP3A5, MDR1 3435, MDR1 2677 and MDR1 1236 were also determined in these patients. Multiple linear regression was used for analysis of these factors with tacrolimus concentration/dosage*body surface area as the independent variable.

RESULTSPatients in early stage following renal transplantation showed rather poor fitting of the stepwise regression model, which increased obviously 3 months after the operation and further increased till reaching a stable level at 6 months. Multiple factors were found to affect tacrolimus concentration/dosage in the early postoperative stage, during which period these factors underwent drastic variations and became stable 3 months later. In terms of pharmacogenomics, the major factors affecting tacrolimus concentration/dosage included MDR1 3435, MDR1 2677 and MDR1 1236 polymorphisms, which vastly varied between the patients early after the operation. Of these polymorphic sites, CYP3A5 produced only minor effects on tacrolimus concentration/dosage, and was not included as an active factor until the stable phase (over 1 year) following the transplantation; MDR1 3435 was found to be the predominant factor affecting tacrolimus metabolism in the stable phase. Age, liver function, albumin and hematocrit were found to be positively correlated to the independent variable tacrolimus concentration/dosage*body surface area, and identified as important factors responsible for the intra-individual variation of tacrolimus dosage/concentration.

CONCLUSIONThe variations in the factors affecting tacrolimus dosage/concentration after renal transplantation are consistent with the clinical features of the patients, and these factors vary with the postoperative stages. Pharmacogenomic factors produce the most conspicuous effect on tacrolimus dosage/concentration, and agents that may interfere with tacrolimus metabolism should be avoided after the operation. Age, liver function, albumin and hematocrit are also important factors responsible for the variation of tacrolimus dosage/concentration.

ATP Binding Cassette Transporter, Sub-Family B ; ATP-Binding Cassette, Sub-Family B, Member 1 ; genetics ; Adult ; Cytochrome P-450 CYP3A ; genetics ; Dose-Response Relationship, Drug ; Female ; Graft Rejection ; genetics ; prevention & control ; Humans ; Immunosuppressive Agents ; administration & dosage ; Kidney Transplantation ; Male ; Mycophenolic Acid ; administration & dosage ; analogs & derivatives ; Pharmacogenetics ; Polymorphism, Genetic ; Postoperative Period ; Prednisone ; administration & dosage ; Tacrolimus ; administration & dosage

This study was aimed to investigate the therapeutic efficiency and complications after allo-hematopoietic stem cell transplantation (allo-HSCT) with reduced-intensity conditioning regimens in hematologic malignancies. 10 patients (6 CML patients, 2 AML patients, 1 ALL patient and 1 NHL patient) underwent related allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning regimens. The conditioning regimens consisted of "FLU + CY + TBI" basically and was appropriately improved in accordance with status of patients. Cyclosporin A (CsA) and mycophenolate mofetil (MMF) were used to prevent the graft-versus-host disease (GVHD). Detection of bone marrow cells, chromosomes, fused gene, ABO blood group and STR-PCR were used to observe engraftment, relapse, GVHD, transplantation- related complications (TRC) after transplantation and to evaluate patients quality of life. The results showed that the 10 patients successfully accepted the transplantation and their primary diseases were cured. In one patient, severe pulmonary infection happened, and in another one CMV infection occurred. Grade IV of acute GVHD occurred in one case and grade I of acute GVHD in 2 cases, the no chronic GVHD appeared. 5 patients relapsed after transplantation at various time points, the donor lymphocytes infusion (DLI) or drugs rescued these 5 patients. During median follow-up of 5 - 35 months, 2 out of which died, 8 survived, the overall survival rate was 80%, and the survivors live in a high-quality life. In conclusion, the hematopoietic stem cell transplantation with reduced intensity conditioning regimens was feasible with relatively low toxicity for recipients. GVHD and TRC were low, and life quality of patients after transplantation was high. DLI could cure the primary diseases even relapsed after transplantation.
Adult ; Cyclosporine ; administration & dosage ; Female ; Graft vs Host Disease ; prevention & control ; Hematologic Neoplasms ; therapy ; Hematopoietic Stem Cell Transplantation ; methods ; Humans ; Lymphocyte Transfusion ; Male ; Middle Aged ; Mycophenolic Acid ; administration & dosage ; analogs & derivatives ; Transplantation Conditioning ; methods

BACKGROUNDPodocyte has inflammatory role in the development of diabetic nephropathy (DN). Mycophenolate mofetil (MMF), an anti-inflammatory agent, can suppress macrophage infiltration and reduce renal injury in streptozotocin-induced diabetic rats. Angiotensin II receptor blocker (ARB), another renal protecting agent, can decrease podocyte loss in DN. In this study, we detected the expression levels of monocyte chemoattractant protein-1 (MCP-1) and nephrin to evaluate podocyte's role in inflammatory reaction in DN, observe and compare the effect of MMF alone and in combination with valsartan, on preventing podocyte loss in streptozotocin (STZ) induced diabetic rats.

METHODSDiabetic model was constructed in uninephrectomized male Wistar rats by single peritoneal injection of STZ (65 mg/kg). The successfully induced diabetic rats were randomly divided into four groups: diabetes without treatment group (DM), valsartan treated group (DMV), MMF treated group (DMM), and combined therapy group (DMVM). Normal rats of the same sibling were chosen as control (NC). At the end of the 8th week, serum biochemistry, 24-hour urinary protein (UP) and the ratio of kidney weight/body weight (RWK/B) were measured. The rats were sacrificed for the observation of renal histomorphology through light and electron microscope. Nephrin, desmin and MCP-1 levels were detected by semi-quantitative immunohistochemical assays. Real-time quantitative PCR was used to detect the mRNA levels of nephrin and MCP-1.

RESULTSCompared with group NC, serum glucose level, 24-hour UP and RWK/B in group DM were significantly higher (P < 0.01), and the nephrin mRNA level in DM group was significantly lower (P < 0.05). The nephrin mRNA expression levels in group DMV, DMM and DMVM were all higher than that of DM group (P < 0.05) and no significant differences were found among the three treatment groups (P > 0.05). Treatment with MMF, valsartan or their combination could significantly decrease the 24-hour UP and RWK/B, and suppress glomerulosclerosis and interstitial fibrotic lesions in diabetic rats. In diabetic rats, the high expressions of desmin and MCP-1 in kidney were suppressed by valsartan, MMF or their combination.

CONCLUSIONSPodocytes are involved in the inflammatory reaction of diabetic rats. MMF could suppress MCP-1 and desmin expression, enhance nephrin expression, and attenuate proteinuria in diabetic rats. The combined therapy of valsartan and MMF did not show any superiority over monotherapies on renal protection. MMF may have renoprotective effect in early stages of diabetic nephropathy through preventing podocytes loss and anti-inflammatory activity.

Animals ; Chemokine CCL2 ; analysis ; Desmin ; analysis ; Diabetic Nephropathies ; drug therapy ; pathology ; Drug Therapy, Combination ; Immunohistochemistry ; Male ; Membrane Proteins ; analysis ; Mycophenolic Acid ; administration & dosage ; analogs & derivatives ; therapeutic use ; Podocytes ; drug effects ; pathology ; Rats ; Rats, Wistar ; Tetrazoles ; administration & dosage ; therapeutic use ; Valine ; administration & dosage ; analogs & derivatives ; therapeutic use ; Valsartan