Clinical Observation Of Quadruple Immunosuppressive Regimen In The Treatment Of BK Virus Infection In Renal Transplant Patients In Renal Transplant Patients

ObjectiveTo clarify the status of BK virus infection in kidney-transplantation patients in Qilu Hospital of Shandong University,evaluate the effect of the quadruple immunosuppression therapy based on Mizoribine in the treatment of BK virus infection in renal transplantation patients compared with Leflunomide and provide some guidance for the reasonable selection of the antiviral treatment for BK virus infection after renal transplantation.MethodsIn this retrospective study we gathered clinical data from patients who operated renal transplantation in our center of renal transplantation in Qilu Hospital of Shandong University between January 2016 and December 2019.The load of BK virus in plasma and urine of patients was detected periodically after renal transplantation since 2016.Once the BK virus appeared in the sample of plasma or urine,we reduce the dose of EC-MPS(0.72g/day to 0.36 g/day)and add Leflunomide(20 mg/day)or Mizoribine(100 mg/day)in the original immunosuppressive therapy including prednisolone(Pred),enteric-coated mycophenolate sodium(ES-MPS)vast majority of cases tacrolimus(Tac),or alternatively,Cyclosporine A(CsA),respectively.The decrease and clearance of BK viremia and viruria were observed and analyzed from January 2016 to December 2019.The patients were followed up with routine examination items weekly for the first 3 months after the renal transplantation,biweekly for the third to the sixth months,monthly for the sixth month to the first year,and bimonthly after the first year.During this period,if patients feel uncomfortable at any time,patients need to check physical condition to the hospital.Our routine examination items include:blood routine examination,urine routine examination,liver function,kidney function,blood glucose,blood lipid,blood biochemistry,uric acid,drug concentration(FK506、CsA、Mizoribine etc).All the tests were processed by the Clinical laboratory in Qilu Hospital of Shandong University.The results are expressed as the mean±standard deviation(SD)or percentages.Student’s t-test,Fisher’s exact test and the Chi square test were used for statistical analysis based on the distribution of our data.We used the nonparametric Wilcoxon rank sum test for group comparisons in the SPSS program(version 17.0;SPSS,Inc,Chicago,IL,USA).The threshold of statistical significance was established at p<0.05 for all tests.ResultsIn our center,Leflunomide and Mizoribine were used to treat BKV successively.In general,the therapeutic regimen of Leflunomide was applied from 2016 to 2017,and the regimen of Mizoribine was applied after 2017.The comparison between the two groups retrospectively showed that Mizoribine had better effect on treatment for BK virus infection in renal transplant recipients.The initial search identified 195 patients and 27 of whom met the inclusion criteria with BK viruria and viremia,including 8 in the Leflunomide group and 19 in the Mizoribine group.Two patients with BK viruria and viremia were excluded because of insufficient documentation of the BK load from serum in the medical record in the period after initiation of Mizoribine.162 patients failed inclusion criteria,as they had no infection of BK virus(127)or only infection of BK virus in the urine(41).Of the 27 patients included,two third were men(18/27)and the basic demographic data of the two groups were not statistically different.Most patients were maintained on a standard immunosuppression regimen made up of tacrolimus,corticosteroids and mycophenolate mofetil.Two of the enrolled subjects were administrated Cyclosporine A at the last three months of the Mizoribine follow-up patients with viremia.One patient experienced nausea after taking Leflunomide,but continued treatment despite the side effect.Medication compliance for Leflunomide can be judged from the prescription,which is performed well.Mizoribine was generally well tolerated and no patients in our study experienced apparent adverse effects.After treatment,of the 8 and 19 cases in the Leflunomide and Mizoribine groups,3(37.5%)and 15(78.9%)were cured,3(37.5%)and 4(21.1%)experienced improvement,and 2(25.0%)and 0 were ineffective,with the total improvement rate being 75%and 100%and the total curative rate being 37.5%and 78.9%,respectively.When we compared the total clearance rate of BK virus between the Leflunomide group and Mizoribine group,we found that the load of viremia was significantly lower in the both groups.When we subdivided our total data of clearance rate of BK virus in serum into its two composite categories,we found that the clearance rate of BK virus in the Mizoribine group were significantly decreased compared with Leflunomide group(Wilcoxon Rank Sum test,W=76.5,P=0.023).We also compared estimated glomerular filtration Rate(eGFR),serum uric acid and the concentration of Tacrolimus in serum after the conversion of regime and found no significant differences.We also found no significant statistical difference for BK virus in urine between the two groups after the conversion of regime.Conclusion1.The positive rate of BK virus in urine and blood was 34.9%and 14.9%respectively in the kidney transplantation center.2.The quadruple immunosuppressive regimen(Tacrolimus/Cyclosporine A+Prednisolone+Enteric-coated mycophenolate sodium+Mizoribine)can provide appropriate immunosuppressive intensity after renal transplantation.There is no drug-related rejection in our center of renal transplantation and the patients are well tolerated.3.Compared with Leflunomide regimen,Mizoribine regimen(Tacrolimus/Cyclosporine A+Prednisolone+Enteric-coated mycophenolate sodium+Mizoribine)can better control the development of BK viremia after renal transplantation,so as to control BK virus associated nephropathy(BKAVN).This study recommends a quadruple immunosuppressive regimen based on Mizoribine for the treatment of BK virus infection after renal transplantation.