Comparison Of The Efficacy And Safety Of Tacrolimus Monotherapy VS.Cyclophosphamide/Prednisone Combined Therapy In The Treatment Of Idiopathic Membranous Nephropathy

Objective:Idiopathic membranous nephropathy(IMN)is one of the leading causes ofprimary nephrotic syndrome(NS)in adults.KDIGO guideline recommends a6-month course with alternating monthly cycles of corticosteroids(GC)and alkylating agents as best supporting treatment approach,but serious adverse effects limit its clinical applications.Tacrolimus(TAC)monotherapy in idiopathic membranous nephropathy has already been reported in some small sample clinical trials,but the the difference in long-term efficacy and safety between tacrolimus monotherapy and classical therapy is still unclear.The purpose of this study was to observe the difference in efficacy,recurrence rate and incidence of adverse reactions between TAC monotherapy and cyclophosphamide(CYC)prednisone combined therapy in the treatment of IMN,to explore the possibility of TAC monotherapy.Methods:73 patients with biopsy-proved IMN of recent onset were assigned to the study,among them,46 patients received TAC alone,while 27 received CYC combined with prednisone.TAC was given at 0.05-0.1 mg/kg/d initially divided into 2 equal doses at a 12-hour interval and the dose was adjusted according to the whole blood concentration.The dose of CYC was calculated by 750mg/m~2 body surface area per month,administrated intravenously.Depending on the patient’s tolerance level,the patient was treated 4-6 times a month with 200-400mg infusion each time for a total of 6 months.Then,extend the interval of administration to once every 2-3 months with the cumulative dose not exceeding 10 g.The initial dose of oral prednisone was1 mg/kg/d for 8-12 weeks,then gradually decreased by 5 mg every 2 weeks.When it was reduced to 20 mg/d,the rate of drug reduction should be further slowed down to5 mg each 4 weeks until it was reduced to 10 mg/d and maintained it for a long time.The total course of treatment was 24 months and it is currently under observation until the 12th month.Patients were observed for the treatment efficiency,recurrence and adverse reactions.Results:After 12 months of treatment,both groups showed significant improvement in24h-urinary protein(PRO)and serum albumin(ALB)(P=0.000).During the follow-up,the 6-month total remission rate in TAC monotherapy group was 69.23%and the 12-month total remission rate was 91.89%,the 6-month total remission rate in CYC prednisone combined group was 74.07% and the 12-month was 92.59%,with no significant difference.In terms of adverse reactions,the incidence of infection-related events in TAC monotherapy group was 21.74%,which was significantly lower than that in CYC prednisone combined group(51.85%)(P=0.008).There was also significant difference in the incidence of bacterial infections requiring hospitalization(8.70%VS.29.63%,P=0.008).After 12 months of treatment,the serum uric acid(UA)level showed significant elevation in both two groups(P=0.000),and there was no significant difference in the rising trend between the groups(P=0.266).However,the incidence of UA increased by more than 30%was 50.00%in the TAC monotherapy group vs.11.11%in the CYC prednisone combined group,respectively,with statistical significant difference(P=0.001).Meanwhile,there was no significant difference in the incidence of serum creatinine(CREA)elevation,fasting blood glucose(FBG)elevation,liver function damage,gastrointestinal reactions and other adverse reactions.A total of 5 patients(1 case in TAC monotherapy group and 4 cases in CYC prednisone combined group)had serum CREA level exceeding 133μmol/L.Among them,the patient in the TAC monotherapy group had already entered chronic kidney disease stage 4(CREA 227μmol/L)at the time of admission.After 12 months of treatment,she did not get remission,and renal function gradually deteriorated into chronic kidney disease stage5(CREA 414μmol/L).All 4 patients in the CYC prednisone combined group experienced CREA elevation accompanied by infection of different degrees.After controlling the infection,the renal function could gradually recover,and no patients terminated the medicine due to increased CREA or developed to end stage renal disease(ESRD).After 12 months of observation,a total of 3 patients relapsed,including 2 patients in TAC monotherapy group(1 case in the 6th month and 1 in 9th month)and 1 patient in CYC prednisone combined group(the 6th month).Nostatistical significance was found in difference of recurrence rate(P=0.894).Conclusions:TAC monotherapy is effective and safe,which can serve as an alternative therapeutic regimen for patients with nephrotic IMN.The lack of GC makes TAC monotherapy especially applicable to patients who cannot use GC such as patients with diabetes mellitus,tuberculosis,hepatitis B virus infection and osteoporosis.The long-term effect of TAC needs further research.