Evaluation Of Multi-target Immunosuppressive Therapy In The Treatment Of Refractory Idiopathic Membranous Nephropathy

Background and objectives:Idiopathic membranous nephropathy(IMN)is currently considered to be an organ-specific autoimmune podocyte disease.The treatment of idiopathic membranous nephropathy includes general supportive therapy,immunosuppressive therapy,and the prevention of complications.Immunosuppressant medications are an important option for the patients with IMN that can't spontaneously remit with supportive therapy.The immunosuppressive medications for IMN mainly include corticosteroids,alkylating agents,antimetabolites,calcineurin inhibitors,rituximab,adrenocorticotropic hormone and so on.The 2012 Kidney Disease: Improving Global Outcomes(KDIGO)Clinical Practice Guideline for Glomerulonephritis provides guidance for the treatment of IMN.A number of studies proved the efficiency of immunosuppressant.Combinations of corticosteroid with alkylating agents or calcineurin inhibitor(CNI)have been proved to be effective to induce remission of IMN with persistent heavy proteinuria.However,there are still 30% IMN patients refractory or dependent to immunosuppressant.The Research Group on Progressive Renal Disease sponsored by the Ministry of Health Labor and Welfare of Japan reported that 10 to 12% of the cases with idiopathic nephrotic syndrome were classified into refractory nephrotic syndrome and that the most common cause in adults is idiopathic membranous nephropathy(40%).Therefore,the treatment of refractory idiopathic membranous nephropathy is very important.The aim of our study was to evaluate the efficacy of multi-target therapy in the treatment of refractory idiopathic membranous nephropathy,and to provide a treatment method for refractory idiopathic membranous nephropathy.Methods:A total of 516 patients with IMN diagnosed by renal biopsy were enrolled through the department of nephrology of the first affiliated hospital of Zhengzhou University between January 2011 to January 2016.We excluded: 136 cases of irregular follow-up,63 cases treated with supportive therapy,14 cases with eGFR? 60ml·min-1·(1.73m2)-1,8 cases with severe abnormal liver function,27 cases with abnormal glucose metabolism,11 cases with severe pulmonary infection,185 cases with remission after receiving immunosuppressive therapy.Consequently,there was a total of 72 patients with refractory idiopathic membranous nephropathy were enrolled,with an average age of(44.7 ± 10.5)years.There were 49 men and 23 women in our study.These patients were treated with corticosteroids combined with tacrolimus and mycophenolate mofetil.Record their baseline characteristics and clinical indicators during the follow-up,which include systolic blood pressure(SBP),diastolic blood pressure(DBP),white blood cell(WBC),hemoglobin(Hb),platelet(Plt),blood glucose(Glu),cholesterol(TCHO),triglyceride(TG),serum albumin(Alb),serum creatinine(Scr),24 hours urine protein(24-UP),estimated glomerular filtration rate(eGFR),serum FK506 concentrations and adverse events.Analysis the changes of the clinical indicators,to evaluate the efficacy of multi-target therapy in the treatment of refractory idiopathic membranous nephropathy.Results: 1 The baseline CharacteristicsA total of 72 patients were enrolled in this clinical study with an average age of(44.7 ± 10.5)years.Fifty-six patients(77.8%)with positive anti-phospholipase A2 receptor.Before receiving multi-target therapy,the average of 24 hours urine protein was 5.02(3.52,6.85)g,the serum albumin was(27.61±7.02)g / L,the serum creatinine was(86.22 ± 13.89)mmol / L,the estimated glomerular filtration rate was(87.06 ± 18.62)ml·min-1·(1.73m2)-1.2 Therapeutic regimen before receiving multi-target therapyForty-two patients(58.4%)had been treated with one therapeutic regimen and thirty patients(41.6%)had been treated with two regimens.3 Changes of clinical indicators during follow-up3.1 The 24 hours urine protein showed a downward trend.After 1 month treatment,the 24h-UP was lower than before(P<0.05).And after 2?3?6?8?10?12 months treatment,the 24h-UP were 3.75(2.14,5.15)g?3.09(1.05,4.87)g?1.38(0.23,3.43)g?0.84(0.19,2.87)g?0.49(0.12,2.28)g and 0.29(0.07,1.48)g respectively,which were significantly lower than prior treatment(P<0.01).3.2 The serum albumin showed an upward trend.After 1 month treatment,the serum albumin was higher than prior treatment(P<0.05).And after 2?3?6?8?10?12 months treatment,the serum albumin were(31.18±5.40)g/L?(34.96±5.39)g/L?(37.86±4.03)g/L?(38.25±3.67)g/L?(39.92±3.64)g/L?(41.39±4.78)g/L respectively,which were significantly higher than prior treatment(P<0.01).3.3 At the end of the tenth month,the triglyceride was lower than before(P <0.05),and at the end of the twelfth month,the cholesterol and triglycerides were lower than before(P <0.05).3.4 The levels of white blood cell,hemoglobin,platelet,blood glucose,creatinine and estimated glomerular filtration rate were not significantly difference with berore(P> 0.05).4 Clinical remission4.1 A total of 59 patients achieved remission,and the remission rate was 81.9%(59/72).At the 1st,2nd,3rd,6th,8th,10 th,and 12 th month,there were 15?29?35?55?56?54?53 patients achieved remission respectively.The remission rate was 20.8%?40.3%?48.6%?76.4%?77.8%?75.0% and 73.6%,respectively.At the 1st,2nd,3rd,6th,8th,10 th,and 12 th month,there were 2?6?11?24?29?34?37 patients achieved completely remission,with complete remission rates of 2.8%?8.3%?15.3%?33.3%?40.3%?47.2%?51.4% respectively.4.2 There were 56 patients(77.8%)with serum anti-PLA2 R antibody positive and 16 patients(22.2%)with serum antibody negative.At the 1st,2nd,3rd,6th,8th,10 th,and 12 th month,the remission rates were 17.9%?33.9%?41.1%?73.2%?76.8%?73.2%?73.2% respectively in the positive group.Simultaneously the remission rates were 31.3%?62.5%?75.0%?87.5%?81.3%?81.3%?75.0% respectively in the negative group.There was a significant difference between the two groups during the 2nd,3rd months(P< 0.05).5 RelapseOne patient was lost at the 10 th month of treatment among the 59 patients,and the other 58 patients were followed up regularly.Five patients(8.6%)had a recurrence of proteinuria.One patient relapsed after complete remission and four patients relapsed after partial remission.6 Adverse eventsDuring the follow-up,17 adverse events occured in 11 patients,including 8 cases with tremor(47.1%),5 cases with infection(29.4%),2 cases with hyperglycemia(11.7%),1 cases with elevated serum creatinine(5.9%),1 cases with elevated liver enzymes(5.9%).Among the five infection patients,3 cases(17.6%)were pulmonary infection,1 case(5.9%)was fungal infection and the other one(5.9%)was urinary tract infection.Conclusion:1.The multi-targe immunosuppressive therapy in refractory idiopathic membranous nephropathy patients by FK506 and MMF can obvious reduce urine protein and improve plasma albumin.A high remission rate and less adverse events were observed in this study.It provides a new method for the treatment of refractory idiopathic membranous nephropathy.2.The multi-target immunosuppressive therapy can promptly induce serum anti-PLA2 R antibody-negative patients achieve remission.