Mizoribine Research Articles

Safety and Efficacy of Mycophenolate Mofetil Associated With Tacrolimus for Kidney-pancreas and Kidney Transplantation: A Systematic Review and Meta-Analysis of Randomized Studies

IntroductionThis study evaluated the efficacy and safety of mycophenolate mofetil (MMF) associated with tacrolimus (TAC) in patients undergoing kidney-pancreas and kidney transplants, in comparison with cyclosporine (CyA), azathioprine (AZA), everolimus (EVL), sirolimus (SRL), manitimus (MAN), mizoribine (MZR), and enteric-coated mycophenolate sodium (ECMPS) in combination or monotherapy. MethodsA systematic review and meta-analysis of randomized clinical trials was performed. The outcomes comprised acute rejection, graft loss, and adverse events. ResultsThirty studies were included. The main adverse events related to the TAC+MMF scheme were infection (36%; 95%CI: 26%-46%), including cytomegalovirus (CMV) (14%; 95%CI: 8%-20%); anemia (20%; 95%CI: 2%-37%); leukopenia (18%; 95%CI: 3%-33%); nausea (20%; 95%CI: 1%-39%); and diarrhea (26%; 95%CI:13%-40%). TAC+MMF was compared to the schemes AZA+TAC, CyA+AZA, CyA+MMF, CyA+SRL, ECMPS, EVL, MAN+TAC, MMF+SRL, MZR, TAC+AZA, TAC+EVR, TAC+MZR, TAC +SRL and TAC. TAC+MMF was associated with a lower risk of rejection than MMF monotherapy (RD: -0.24; 95%CI -0.46; -0.02). Comparing TAC+MMF with the other regimens, no significant difference was found for graft loss. TAC+MMF was associated with a higher risk of infections than MZR (RD: 0.174; 95%CI: 0.25; 0.323) and TAC monotherapy (RD: 0.07; 95%CI 0.003; 0.138). ConclusionGastrointestinal and hematological adverse events and infections are the most common with TAC+MMF for kidney-pancreas and kidney. TAC+MMF effectively prevents acute cellular rejection, and alternatives with AZA, CyA, SRL, ECMPS, EVL, MAN, and MSR have similar efficacy and safety profiles. TAC monotherapy and MZR may be associated with a lower risk of infections.

Efficacy and Safety of Mizoribine in comparison with Cyclophosphamide for Treatment of Refractory Nephrotic Syndrome: Protocol for a Multi-center, Controlled, Open-label, Randomized Controlled Trial.

Nephrotic syndrome that is resistant to steroidal therapy is termed refractory nephrotic syndrome (RNS), a condition that is associated with an increased risk of end-stage renal disease (ESRD). Immunosuppressants are utilized to treat RNS, however prolonged may lead to significant adverse effects. Mizoribine (MZR) is a novel agent used in long-term immunosuppressive therapy that has few adverse effects, but data on its long-term use in patients with RNS are unavailable. We propose a trial to examine the efficacy and safety of MZR compared to cyclophosphamide (CYC) in Chinese adult patients with RNS. This is a multi-center, randomized, controlled interventional study with a screening phase (1 week) and a treatment phase (52 weeks). This study was reviewed and approved by the Medical Ethics Committees of all 34 medical centers. Patients with RNS consented to participation, and were enrolled and randomized into an MZR group or a CYC group (1:1 ratio), with each group receiving tapering doses of oral corticosteroids. Participants were assessed for adverse effects and collection of laboratory results at 8 visits during the treatment phase on week-4, week-8, week-12, week-16, week-20, week-32, week-44, and week-52 (exit visit). Participants were able to withdraw voluntarily and investigators were required to remove patients when there were safety concerns or deviations from protocol. The study started in November 2014, and was completed in March 2019. A total of 239 participants from 34 hospitals in China were enrolled. Data analysis is completed. The results are waiting to be finalized by Center for Drug Evaluation. The purpose of the current study is to evaluate the efficacy and safety of MZR in comparison with CYC for treatment of RNS in Chinese adult patients with glomerular diseases. It is the longest lasting and largest randomized controlled trial to examine MZR in Chinese patients. The results can help determine whether RNS should be considered as an additional indication for MZR treatment in China. ClinicalTrials.gov Register, NCT02257697. Registered 2014-10-01, https://clinicaltrials.gov/ct2/show/NCT02257697?term=MZR&rank=2.

Efficacy and safety of mizoribine in comparison with cyclophosphamide for treatment of lupus nephritis: Protocol for a multi-center, open-label, randomized controlled trial

Background: Monthly intravenous cyclophosphamide (IVCY) is a widely accepted induction therapy for lupus nephritis (LN) because this regimen balances the time needed for renal remission with the risk of adverse events. However, IVCY is associated with numerous severe toxicities. Mizoribine (MZR) was originally used as an antibiotic against Candida albicans, but researchers found it had strong immunosuppressive activity in various animal models. Previous clinical trials also examined the efficacy of MZR as an immunosuppressant, and it has been used for treatment of LN in Japan since 1990. We will conduct a phase 3 study in China to evaluate the efficacy and safety of oral MZR in comparison with standard IVCY in patients with LN. Methods: This study will be a multi-center, randomized, controlled, open-label clinical trial that consists of a screening period (seven days) followed by a treatment period (52 weeks). After screening, all eligible subjects will be randomized to an MZR or IVCY group in a 1:1 ratio. Then, subjects will initially receive methylprednisolone pulse therapy (0.5 g/day) for three days, followed by the study drug (MZR or CY) with oral corticosteroid therapy from visit two (day four). The efficacy and safety of oral MZR in comparison with standard IVCY will be determined. Discussion: This paper describes the protocol of a multi-center, open-label, randomized controlled trial that compares the efficacy and safety of MZR with IVCY for treatment of LN. The results may help determine whether LN should be considered an indication for this drug in China. Trial registration: ClinicalTrials.gov register, NCT02256150. Registered 2014-10-01. The protocol version number is 1.3 (2016-08-30).

Mizoribine combined with steroids and dietary sodium restriction on the treatment of primary membranous nephropathy: a prospective study.

We aimed to initially explore the efficiency and safety of mizoribine (MZR) combined with steroids and dietary sodium restriction on the treatment of primary membranous nephropathy (MN) compared with cyclophosphamide (CPM)-based steroids. Patients with primary MN were enrolled. According to the therapy, they were divided into theMZR combined with steroids and dietary sodium restriction group (N = 30) and CPM-based steroids group (N = 30). Both groups were followed up for 1year to monitor safety and efficacy. Compared with the CPM-based steroids group, theMZR combined with steroids and dietary sodium restriction group had significantly lower daily sodium intake, serum sodium, blood pressure (BP), and 24h urine protein (all P < 0.05). Conversely, plasma albumin and complete remission rate in the MZR group were higher at the 12th follow-up (40.39 ± 5.14g/L vs. 37.63 ± 5.40g/L; 86.67% vs. 66.67%; all P < 0.05). These two groups showed similar adverse events rates (20.00% vs. 26.67%, P = 0.54). This study demonstrates that MZR combined with steroids and dietary sodium restriction is superior to CPM-based steroids in terms of completeremission and 24h urine protein in patients with primary MN.

The Efficacy and Safety of Mizoribine versus Mycophenolate Mofetil for the Treatment of Renal Transplantation: A Systematic Review and Meta-Analysis.

Background Mizoribine (MZR) is widely used in Asia due to its high safety and low cost, and comparative studies of its safety and efficacy with the first-line drug mycophenolate mofetil (MMF) have been carried out. This paper aimed to compare the efficacy and safety of MZR and MMF in immunosuppressive therapy of renal transplantation by meta-analysis. Methods We searched randomized controlled trials (RCTs) comparing MZR versus MMF for renal transplantation in PubMed, Excerpta Medica Database (EMBASE), Cochrane Library, Web of Science, WanFang Database, China National Knowledge Infrastructure (CNKI), and Chinese Biomedical Database (CBM). Articles were assessed for their risk of bias using the Cochrane Collaboration. Forest plots and funnel plots were also performed on the included articles. Results A total of twelve studies with 1103 patients were selected in the analysis. No significant difference were observed between the MZR group and the MMF group for the rate of acute rejection (RR = 1.50, 95% CI 1.11 to 2.01, P = 0.008), patient survival (RR = 1.01, 95% CI 0.99 to 1.03, P = 0.56), graft survival (RR = 1.02, 95% CI 1.00 to 1.04, P = 0.12), leucopenia (RR = 0.69, 95% CI 0.44 to 1.10, P = 0.12), and liver damage (RR = 0.72, 95% CI 0.46 to 1.13, P = 0.15). The MZR group was associated with a lower risk of gastrointestinal disorder (RR = 0.28, 95% CI 0.13 to 0.62, P = 0.002) and cytomegalovirus infection (RR = 0.59, 95% CI 0.42 to 0.84, P = 0.003) but had a higher risk of hyperuricemia (RR 1.79, 95% CI 1.17 to 2.75, P = 0.007). No significant publication bias was observed among included studies. Discussion. MZR is similar to MMF in efficacy, and in terms of safety, MZR has a lower risk of gastrointestinal disorder and cytomegalovirus infection but a higher risk of hyperuricemia.

Comparative efficacy and safety of mizoribine and mycophenolate mofetil for treating systemic lupus erythematosus: a retrospective cohort study.

Background:Mizoribine (MZR) is an immunosuppressive agent that selectively inhibits inosine monophosphate dehydrogenase; its actions are considerably similar to those of mycophenolate mofetil (MMF). This study aimed to clarify whether MZR can be a good treatment option for systemic lupus erythematosus (SLE) and to compare the efficacy and safety of MZR and MMF in patients with active SLE.Methods:We retrospectively compared the efficacy, continuation rate, and safety of MZR (52 patients) and MMF (31 patients) after adjusting for stabilized inverse probability of treatment weighting based on propensity scores. The efficacy endpoints were as follows: cumulative incidence of lupus low disease activity state (LLDAS) or remission attainment and flares and change in prednisolone dose over 2 years. Drug continuation rates were defined as the time from drug initiation to discontinuation for any cause, owing to the lack of efficacy, or owing to adverse events. The safety endpoint was the frequency of adverse events.Results:Overall, 25 (48.1%) and 13 (25.0%) patients in the MZR group and 18 (58.1%) and 15 (48.3%) in the MMF group achieved LLDAS and remission during the follow-up period, respectively; thus, the cumulative incidence of LLDAS and remission attainment of the two groups was similar after adjustment. Prednisolone dose was steadily reduced in both the groups, and the change in prednisolone dose was nearly identical between the two groups. Drug discontinuation rate due to adverse events and the frequency of all adverse events and infections were higher in the MMF group than in the MZR group, albeit without significance after adjustment.Conclusion:MZR is as effective as MMF in controlling SLE activity. The adverse events of MZR, whose profile differs from MMF, are comparable to or less than those of MMF. MZR may be a valuable option as an immunosuppressive agent for SLE, as well as MMF.

Conversion from mycophenolate mofetil to mizoribine in the early stages of BK polyomavirus infection could improve kidney allograft prognosis: a single-center study from China

BackgroundSome studies have suggested mizoribine (MZR) could inhibit the replication of BK polyomavirus (BKPyV). The purpose of this study was to explore whether conversion from mycophenolate mofetil (MMF) to MZR in the early stages of BKPyV infection can improve kidney allograft prognosis.MethodsTwenty-one kidney transplant recipients with BKPyV viruria/viremia and ten with BK polyomavirus-associated allograft nephropathy (BKPyVAN) received MZR conversion therapy were retrospectively identified. The clearance rate of urine and blood BKPyV DNA, change of serum creatinine (SCr), uric acid (UA), hemoglobin (HB), white blood cell (WBC), lymphocyte ratio, platelet (PLT), routine urinalysis, panel reactive antibody (PRA), and gastrointestinal disorders during follow-up of the 2 groups were evaluated and compared.ResultsAfter MZR conversion therapy, the clearance rate of urine and blood viral load in BKPyV viruria/viremia group were 85.7 and 100 %, while that in BKPyVAN were 40 and 87.5 %, respectively. Stable SCr were observed in all cases of BKPyV viruria/viremia group, while that of BKPyVAN was only 40 % (P < 0.001) and one even progressed to end-stage renal disease. The results of routine urinalysis in the two groups showed no significant changes before and after MZR conversion therapy. However, in BKPyV viruria/viremia group, four cases developed acute rejection and one had positive PRA-II but no donor specific antibody, requiring conversion back to MMF. Hyperuricemia was the common adverse effect of MZR.ConclusionsConversion from MMF to MZR could help clear BKPyV infection. As compared to BKPyVAN, patients who underwent initiation of MZR conversion therapy in the early stages of BKPyV infection maintained stable allograft function. Prospective studies with larger sample size are needed to ascertain this preliminary finding.

Effectiveness and safety of mizoribine for the treatment of IgG4-related disease: a retrospective cohort study

Abstract Objective Patients with IgG4-related disease (IgG4RD) usually require steroid-sparing agents due to relapse with tapering glucocorticoids (GC). We aimed to determine the efficacy and safety of mizoribine (MZR) among IgG4RD patients. Methods We retrospectively reviewed records of IgG4RD patients at Immuno-Rheumatology Center in St. Luke’s International Hospital, Tokyo, Japan. Patients treated with MZR were classified into the MZR group, and those treated with GC alone or with other immunosuppressants were included in the control group. Disease exacerbation, GC dose, IgG-IgG4 titre and adverse events were evaluated using univariate analyses, including the Kaplan–Meier method. The Cox proportional hazard model was used to evaluate risk factors for disease exacerbation. Results A total of 14 and 29 cases were included in the MZR and control group. Multiple organ involvement (three or more organs) was significantly more frequent in the MZR group [10 (71.4%) vs 9 (31.0%), P= 0.021]. Kaplan–Meier analysis revealed a significant reduction inexacerbation in patients with multiple organ involvement (P&amp;lt; 0.001) but not in total (P= 0.42). The adjusted hazard ratios of MZR use and multiple organ involvement for exacerbation were 0.34 (95%CI 0.12–1.01; P = 0.052) and 3.51 (95%CI 1.29–9.51; P= 0.014). The cumulative GC dose (mg per year, interquartile range) tended to be lower in the MZR group [1448 (1003–1642) vs 2179 (1264–3425); P= 0.09]. Conclusion MZR decreased disease exacerbation among IgG4RD patients with multi-organ involvement and showed a steroid-sparing effect. MZR could be a treatment option for IgG4RD.

Effect of mizoribine pulse therapy in adult membranous nephropathy.

Membraneous nephropathy (MN) is one of the complicated kidney diseases associated with proteinuria. Mizoribine (MZR) is an emerging treatment option for nephrotic syndrome; however, its dosage and administration are yet lack of consensus. This study aims to evaluate the efficacy and safety of high-dose MZR pulse therapy for adult membraneous nephropathy. Sixty patients with membraneous nephropathy were recruited, and assigned to two treatment groups. One group received conventional treatment of steroid combining with cyclophosphamide (CPM), the other group received steroid combining with high-dose MZR pulse administration. Both groups were followed up for 1 year. Treatment efficacy and side effects were measured regularly. Fifty-nine patients completed the treatment courses. There was no significant difference in demographic and disease conditions prior to treatment between two treatment groups. Both groups showed significant decrease of urine proteins and increase of serum albumin levels after treatments with no severe side effects. After 6months of treatment, MZR group has 71% reduction (compared to 74.4% reduction in CPM group) in urine protein compared to baseline after adjusting for age and gender. 89.7% of patients in CPM and 93.3% in MZR groups had partial/ complete remission after 12months. This study demonstrated satisfactory safety and efficacy of high-dose mizoribine pulse administration combining with steroid treatment for adult patients with membranous nephropathy.

Comparative Study of Mizoribine and Mycophenolate Mofetil Combined with a Calcineurin Inhibitor-Based Immunosuppressive Regimen in Patients with Alternative Donor Hematopoietic Cell Transplantation.

Cytomegalovirus (CMV) infection and graft-versus-host disease (GVHD) remain the major causes of nonrelapse mortality (NRM) in patients following alternative donor hematopoietic stem cell transplantation (HCT). Mizoribine (MZR) showed an anti-CMV effect in addition to its immunosuppressive effect in patients with renal transplantation. In this study, we aimed to evaluate the efficacy and safety of MZR combined with a calcineurin inhibitor (CNI) as a method of prophylactic immunosuppression in recipients following alternative donor HCT. Eighty patients were enrolled in the study and randomized to the MZR (n=40) or MMF (n=40) cohort before transplantation conditioning. Analyses involved a comparison of the outcomes between the 2 cohorts, as well as risk analyses of early nonrelapse mortality (NRM) and severe CMV infection. In contrast to MMF, MZR was associated with a lower but statistically nonsignificant median CMV DNA peak load (P=.075), significantly fewer episodes of persistent/refractory infection (odds ratio [OR], .12), and a lower failure rate of CMV treatment (OR, .82), but a significantly higher rate of hyperuricemia (OR, 2.75). Transplantation efficacy was comparable in the 2 cohorts regarding engraftment, the development of secondary poor graft function and GVHD, and the estimated OS and PFS. The 1-year NRM of the MZR cohort did not differ from that of the MMF cohort, whereas the rate of 1-year NRM caused by viral infections was reduced in the MZR cohort and was of borderline statistical significance (P=.05). In the multivariate analysis, lower doses of CD34+ cells in grafts (hazard ratio [HR], 3.65) and persistent/refractory CMV infections (versus no CMV infection: HR, 7.31; versus CMV infection that was not persistent/refractory: HR, 4.46) were predictors of increased 1-year NRM. The use of MMF (versus MZR cohort: OR, 11.54) and grade II-IV acute GVHD (OR, 15.32) were independent risk factors for developing persistent/refractory CMV infection. When combined with CNIs, MZR functioned well in terms of both immunosuppression and reduced severity of CMV infection; however, further studies are warranted to verify its use as a potential immunosuppressant for alternative donor HCT.

Efficacy and Safety of a Quadruple Regimen Compared with Triple Regimens in Patients with Mycophenolic Acid-Related Gastrointestinal Complications After Renal Transplantation: A Short-Term Single-Center Study

BackgroundAt present, there is no ideal conventional triple regimen that can effectively treat gastrointestinal (GI) complications in patients after kidney transplantation. We aimed to investigate the efficacy and safety of a quadruple regimen including standard-dose tacrolimus, low-dose enteric-coated mycophenolate sodium (EC-MPS), low-dose mizoribine (MZR), and corticosteroids, compared with regimens containing standard-dose tacrolimus, corticosteroids, plus either low-dose EC-MPS or standard-dose MZR in patients with mycophenolic acid (MPA)-related GI complications after renal transplantation.Material/MethodsBetween August 2016 and October 2018 in Qilu Hospital of Shandong University, 115 living donor kidney transplant recipients with MPA-related GI complications were enlisted in a single-center, prospective, randomized, control study. Thirty-six recipients were assigned to the low-dose EC-MPS plus low-dose MZR group, 37 recipients were assigned to the low-dose EC-MPS group, and 39 recipients were assigned to the standard-dose MZR group. We analyzed the Gastrointestinal Symptom Rating Scale (GSRS), estimated glomerular filtration rate (eGFR), graft rejection, serum creatinine, human leukocyte antigen (HLA) antibody, and the occurrence of adverse events among the 3 groups.ResultsCompared with baseline, gastrointestinal symptoms improved significantly in all 3 groups. The reduction in mean subscale scores from baseline to month 3 was more significant in the standard-dose MZR group compared with the other 2 groups. The low-dose EC-MPS plus low-dose MZR group had better renal function. The incidence of graft rejection and cytomegalovirus (CMV) and polyomavirus BK (BKV) infection, as well as the incidence of hyperuricemia, in the low-dose EC-MPS plus low-dose MZR group were all significantly reduced.ConclusionsThis quadruple regimen may be equivalent to regimens containing standard-dose tacrolimus, corticosteroids plus either low-dose EC-MPS or standard-dose MZR in improving GI symptoms after kidney transplant, and is also advantageous for kidney function, graft rejection, and the rates of adverse events.

Membranoproliferative glomerulonephritis related to a streptococcal infection in a girl with IgA deficiency: a case report

BackgroundIgA deficiency associated with glomerulonephritis is rare. In particular, there is no prior report regarding the association between IgA deficiency and membranoproliferative glomerulonephritis (MPGN) in children. Herein, we describe the case of a 5-year-old girl with selective IgA deficiency and MPGN.Case presentationThe patient presented with persisting urinary abnormality and hypocomplementemia following a group A treptococcal infection. Renal biopsy revealed the presence of diffuse mesangial hypercellularity, endocapillary proliferation, and focal thickening of the walls of the glomerular capillaries using light microscopy, with IgG and moderate C3 deposits observed using immunofluorescence. Electron microscopy images revealed nodular deposits in the subendothelial areas, with hump-shaped subepithelial deposits. The pathological diagnosis was confirmed as MPGN. Treatment using oral prednisolone (PSL), mizoribine (MZR), and angiotensin-converting enzyme inhibitors reduced the proteinuria. The PSL dose was gradually tapered, with the low dose of PSL and MZR continued for 4 years. Histological findings were improved on repeated renal biopsy, and PSL and MZR administration was discontinued.ConclusionsWe report a rare case of MPGN related to a streptococcal infection in a child. The clinical presentation included selective IgAD, with several pathological findings and a clinical course typical of glomerulopathy. The patient was successfully treated using multidrug therapy.

Mizoribine treatment in an elderly diabetic patient with antisynthetase-associated interstitial lung disease.

Objective: Immunosuppressive therapy for interstitial lung disease (ILD) is often necessary, but the standard regimen for antisynthetase-associated ILD has not been established.Patient: An 80-year-old man was hospitalized for severely progressive dyspnea. Bilateral interstitial shadows occurred 1 month before the event. Serological findings showed that he had antisynthetase-associated ILD, as identified by strong positivity for anti-aminoacyl-transfer RNA synthetase (ARS) antibody, despite no evidence of myositis. He was treated transiently with noninvasive positive pressure ventilation and steroid-pulse therapy followed by 60 mg/day of oral prednisolone. However, his diabetes mellitus was aggravated by corticosteroid therapy; thus, a combination of low-dose steroid and mizoribine (MZB), which has a low risk of aggravating glucose intolerance, was used.Results: The patient’s clinical symptoms and daily life activities have been well persevered as an outpatient and well maintained with 200 mg of MZB and 10 mg of prednisolone for several months without obvious clinical recurrence and without any remarkable steroid- and MZB-related side effects.Conclusion: The use of MZB appeared to suppress the pathophysiology of anti-ARS antibody-associated ILD.

A case of anti-neutrophil cytoplasmic antibody-associated vasculitis with anti-glomerular basement membrane antibodies that was successfully treated with mizoribine as a safe and effective remission maintenance therapy with prednisolone and plasma exchange

We herein report the case of myeloperoxidase (MPO) anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis with anti-glomerular basement membrane (anti-GBM) antibody positivity that successfully treated with mizoribine (MZR) as an immunosuppressive drug for remission maintenance therapy after the initiation of dialysis in addition to plasma exchange (PE) and glucocorticoid treatment to control the disease condition. A 79-year-old woman developed serious renal dysfunction and pulmonary alveolar hemorrhaging due to MPO–ANCA and anti-GBM antibody double-positive vasculitis. She was started on hemodialysis and was treated with methylprednisolone (m-PSL) pulse therapy with PE, followed by oral prednisolone (PSL). The pulmonary alveolar hemorrhaging disappeared, and both antibody titers immediately decreased but then rose again. Thus, m-PSL pulse therapy performed again in combination with combined with MZR treatment. Her poor renal function was irreversible; however, this therapy decreased both antibody titers, and they did not increase again. The patient developed pancytopenia and hyperuricemia. It was considered likely that these conditions developed in association with MZR treatment. We, therefore, measured the patient’s blood concentration of MZR, and the maintenance dose was finally set at 50 mg after each dialysis session. The patient’s pancytopenia and hyperuricemia improved and PSL could be smoothly tapered. This is the first case report of the use of MZR for remission maintenance therapy in a patient on hemodialysis who was positive for both ANCA and anti-GBM antibodies. The findings suggest that MZR can be used safely and effectively in such cases.

Comparative efficacy of 13 immunosuppressive agents for idiopathic membranous nephropathy in adults with nephrotic syndrome: a systematic review and network meta-analysis

ObjectivesThis study aimed to compare the effectiveness of 13 types of immunosuppressive agents used to treat idiopathic membranous nephropathy (IMN) in adults with nephrotic syndrome.DesignSystematic review and network meta-analysis.Data sourcesPubMed,...

Assessment of factors associated with mizoribine responsiveness in children with steroid-dependent nephrotic syndrome.

Several immunosuppressants have been used to treat children with steroid-dependent nephrotic syndrome (SDNS). Mizoribine (MZR) is an immunosuppressant used to maintain remission in children with SDNS, although its effectiveness for treating SDNS remains controversial. Therefore, in this study, we assessed the clinical factors associated with children having SDNS who were successfully treated with MZR. A total of 47 children with SDNS who underwent MZR treatment were retrospectively evaluated. Clinical features including pharmacokinetics after MZR administration were compared between MZR responders and non-responders. The comparison of the two groups revealed no significant differences in age, body weight (BW), daily dose of MZR per BW, serum concentration 2h after administration (C2), peak serum concentration (Cmax), and area under the concentration curve 0-4h after administration (AUC0-4). C2/(single dose/BW), Cmax/(single dose/BW), and AUC0-4/(single dose/BW) were significantly higher in the MZR responders than in the non-responders (all p < 0.01). Receiver operating characteristic analysis revealed that the cutoff values of C2 (single dose/kg), Cmax/(single dose/BW), and AUC0-4/(single dose/BW) were 0.55, 0.58, and 1.37, respectively. MZR is a useful immunosuppressant for treating frequent-relapse NS in children who are susceptible to the drug. The efficacy of MZR may be associated with not only serum concentrations defined by the dosage or absorption efficiency through MZR transporters, but also the susceptibility defined by the expression level and performance of MZR transporters on the target cells.

Efficacy and Safety of a Quadruple Regimen in Patients with Gastrointestinal Complications after Renal Transplantation

Objectives: The aim of this study was to evaluate the efficacy and safety of a quadruple regimen including standard-dose tacrolimus, low-dose enteric-coated mycophenolate sodium (EC-MPS), low-dose mizoribine (MZR), and corticosteroids compared with regimens containing standard-dose tacrolimus, corticosteroids plus either low-dose EC-MPS or standard-dose MZR in patients with mycophenolic acid (MPA)-related GI complications after kidney transplantation. Methods: Between August 2016 and October 2018 in Qilu Hospital of Shandong University, 115 living donor kidney transplantations with MPA-related GI complications were enrolled in a single-center, prospective study. Thirty-six recipients were assigned to the low-dose EC-MPS plus low-dose MZR group. Thirty-seven recipients were assigned to the low-dose EC-MPS group, and thirty-nine recipients were assigned to the standard-dose MZR group. The three groups were compared with the Gastrointestinal Symptom Rating Scale (GSRS), graft rejection, human leukocyte antigen (HLA) antibody, serum creatinine levels, estimated glomerular filtration rate (eGFR), and incidence of adverse effects. Results: A significant improvement in GI symptoms was observed in all three groups compared with baseline. Renal function was better in the low-dose EC-MPS plus low-dose MZR group. The incidence of graft rejection and cytomegalovirus (CMV) and polyomavirus BK (BKV) infection with the incidence of hyperuricemia were all significantly lower in the low-dose EC-MPS plus low-dose MZR group. Conclusions: The quadruple regimen may be not only equivalent to regimens containing standard-dose tacrolimus, corticosteroids plus either low-dose EC-MPS or standard-dose MZR in improving GI symptoms after kidney transplantation but also advantageous for renal function, graft rejection rates, and the incidence of adverse effects. Funding: This study was funded by the Provincial Key Technologies R & D Program of Shandong Province (Grant No. 26010104011025), National Natural Science Foundation of China (Grant No. 81600092), Key Research and Development Plan of Shandong Province (Grant No. 2017GSF218003). Declaration of Interest: The authors declare no competing interests. Ethical Approval: Patients gave their informed consent to be in the study, and the study protocol was approved by the ethics committee of Qilu Hospital of Shandong University, China (2016Qilu Hospital of Shandong University IRB Approval No. 2016041).

Hyperuricemia in Living Donor Kidney Transplantation Patients During Mizoribine Administration Caused Mainly by Changes in Kidney Function

BackgroundAlthough mizoribine (MZR) is used as an immunosuppressant after renal transplantation, the occurrence of hyperuricemia has been reported. The onset of hyperuricemia is often observed within the first several months after surgery. Since MZR is a renal excretion-type drug excreted as an unchanged drug from the kidneys, MZR blood concentrations may rise due to the influence of renal function. We investigated whether the onset of hyperuricemia after MZR administration was associated with the direct effect of a change in renal function. MethodsSerum uric acid (serum UA), serum creatinine (sCr), serum β2-microglobulin (serum β2-MG), and serum cystatin C (serum Cys-C) were measured for about 3 months in 22 subjects. Correlation coefficients were calculated using the change rates of serum UA and sCr (Δ serum UA, Δ sCr), serum UA and serum β2-MG (Δ serum UA, Δ serum β2-MG), and serum UA and serum Cys-C (Δ serum UA, Δ serum Cys-C) at the onset of hyperuricemia. ResultsThe correlation coefficients between Δ serum UA and Δ sCr, Δ serum UA and Δ serum β2-MG, and Δ serum UA and Δ serum Cys-C were 0.723 (P < .001), 0.863 (P < .001) and 0.548 (P < .001), respectively. Further, serum UA and sCr level reached their highest peak on the same day after MZR administration, and the behavior was mostly consistent. ConclusionIt was suggested that hyperuricemia occurred about 3 months after MZR administration due mainly to temporary changes in kidney function.

Usefulness of mizoribine administration in children with frequently relapsing nephrotic syndrome, and the relationship between pharmacokinetic parameters and efficacy: a multicenter prospective cohort study in China.

Mizoribine (MZR) is an immunosuppressant used to treat adult nephropathy. There is little experience with the drug in treating Chinese children with frequently relapsing nephrotic syndrome (FRNS). We investigated the efficacy and safety for treating MZR with FRNS. Furthermore, the relationship between efficacy and serum concentration was investigated. A prospective multicenter observational 12-month study was performedfor evaluating the usefulness of MZR with FRNS. Serum MZR concentration was measured, and the relationships between pharmacokinetic parameters (Cmax, AUC), number of relapses, and urinary protein were evaluated. Eighty-two pediatric patients from four hospitals were treated with MZR and prednisone. MZR treatment significantly reduced the number of relapses and steroid doses. A correlation between pharmacokinetic parameters and relapses was observed, which fits well with the sigmoidal Emax model. Even in the relationship between pharmacokinetic parameters and urinary proteins, it was recognized that there was a threshold in the pharmacokinetic parameters for the therapeutic effect similar to the results obtained with the sigmoidal Emax model. Eleven patients (13.4%) experienced mild adverse events. MZR therapy was effective in reducing the number of relapses and steroid doses. No severe adverse reactions were observed. Therapeutically effective serum concentrations were estimated to be Cmax ≥ about 2μg/mL or AUC ≥ about 10μgh/mL. MZR and steroid treatment were effective and safe for pediatric FRNS.

Conversion From Mycophenolates to Mizoribine Is Associated With Lower BK Virus Load in Kidney Transplant Recipients: A Prospective Study

BackgroundBK virus allograft nephropathy (BKVAN) is a graft-threatening complication after kidney transplantation. Current consensus regarding the prevention of BKVAN is to screen for BK viremia and to treat sustained BK viremia through reducing immunosuppression. This study assessed the effect of conversion from mycophenolates to mizoribine (MZR) on the prevention of BK viremia in kidney transplant recipients. MethodsDe novo kidney transplant recipients were screened for BK viruria. Sustained high levels of BK viruria (>107 copies/mL) were treated by switching from mycophenolates to MZR. The reduction and clearance of BK viruria and viremia were evaluated. ResultsFifty kidney transplant recipients with high levels BK viruria were enrolled, including 11 recipients with BK viremia. After 6 months of MZR therapy, only 3 recipients still had high levels of BK viruria. The clearance rate of BK viremia was 100%. One episode of acute rejection occurred (2.0%) and was reversed by steroid administration. The serum uric acid level of the recipients was similar before and after switching to MZR, but the proportion of recipients receiving uric acid–reducing drugs increased significantly after 3 months of MZR therapy (19/50 vs 31/50; P = .02). No new cases of BK viremia were observed after conversion to MZR. ConclusionConversion from mycophenolates to MZR in kidney transplant recipients with sustained high levels of BK viruria was associated with reduction of BK viruria and clearance of BK viremia. This may be an effective approach to prevent BK viremia and BKVAN.