Treatment of Refractory Nephrotic Syndrome

摘要

Background:Childhood idiopathic Nephrotic Syndrome (NS) presents with proteinuria of more than 40mg/m2/h，hypoalbuminemia<2.5g/dL，hypercholesterolemia and edema. Around 90%of NS are steroid sensitive and are managed with corticosteroids. However around 60%of patients become steroid dependent or have frequent relapses and around 10%do not respond to corticosteroid therapy and are considered steroid resistant，therefore requiring the addition of second line immunosuppresants to control the disease process.
　　Managing patients with difficult to treat nephrotic syndrome remains a challenge as no proper guidelines are available. Clinicians and researchers are still trying to find the perfect drug which can be used to successfully treat NS. Some drugs have been found to have moderate success however many patients relapses after stopping the immunosuppressant and at the same time they have to deal with the numerous adverse effects due to long term medication use and disease process.
　　This study is an attempt to show the use and efficacy of immunosuppressive agents in our hospital.
　　Purpose:In this study，comparison was done between the demographics of frequently-relapsing (FRNS)，steroid-dependent (SDNS) and steroid resistant (SRNS) nephrotic syndrome. Immunosuppressive agents are recommended for the management of children with FRNS，SDNS and SRNS. We aimed to evaluate the frequency and efficacy of the immunosuppressive agents in the treatment of Refractory Nephrotic Syndrome in our hospital. The results of this research may guide future line of treatment endeavoured clinically.
　　Materials and methods:A retrospective analysis was done of pediatric cases over a period of 55 months，starting from January 2012 to July 2016，who presented to the Second Affiliated hospital of Dalian Medical University. A total of 50 cases were found. Patients were categorized in the control group and case group. The control group consisted of non-relapsing steroid sensitive nephrotic syndrome. Cases group were divided into Group 1 consisting of SDNS and FRNS;and Group 2 consisting of SRNS. Patients were treated with Prednisone，Pulse methylprednisone，Mycophenolate Mofetil，Cyclophosphamide and Tacrolimus either as single，double or triple combination therapy. Treatment was considered effective if complete or partial remission was achieved.
　　The statistical software used was SPSS version 17.0. Mann-Whitney U test was used to compare between the quantitative data of the 2 groups and Non-parametric T-test was used to compare for any statistical significance in the frequency of immunosuppressive agents used between the 2 groups. Chi-square，Fisher’s exact test，was used to check for the correlation between the qualitative variables and to check for any statistical significance in the efficacy of the immunosuppressive agents used.
　　Results:
　　1. Non-parametric T-test:In group 1，the most used immunosuppressant was MMF 16(80%)，followed by CYP-14(70%) and FK-506-1(5%);In group 2，the most frequent was MMF-5(100%)，followed by CYP-3(60%) and FK-506-1(20%)，used either as first line or second line of therapy. The drugs in the 2 groups were comparable to each other.
　　2. Chi-square (Fisher’s exact test):In the SDNS and FRNS the percentage of patients who had a good response to mycophenolate mofetil，cyclophosphamide and tacrolimus were 68.75%，71.4%and 100%respectively，with p=1.000. With MMF and CYP，a minimum of 6 month long remission was achieved in 13 patients;remission was sustained for a maximum of 14 months in 4 patients. Tacrolimus was used in 1 patient with SDNS and histopathology FSGS and more than 6 month long remission was achieved with combination therapy of prednisone，MMF and TAC. In the SRNS，the percentage of patients who had a good response to mycophenolate mofetil，cyclophosphamide and tacrolimus were 80%，67%and 100%with p=1.000. MMF and CYP was effective in achieving remission for a minimum of 8 month. Good control was achieved with Tacrolimus for more than 8 month. On using combination therapy of Tacrolimus，MMF and alternate day prednisone，remission was sustained for longer periods (30 months) in our patient. p-value indicated that the difference in response to the two drugs used，MMF and CYP was statistically non-significant (p=1.000) in both groups.
　　3. The adverse effects due to treatment with immunosuppressive agents/or disease were cushingoid facies (100%)，followed by infections (60%)，neutropenia (46%) and gastric irritations (20%).
　　Conclusion:
　　1. Cyclophosphamide used in combination with Mycophenolate Mofetil and prednisone was effective in bringing a minimum of 6 month long remission in the SDNS and FRNS;and a minimum of 8 month long remission in the SRNS group.
　　2. Remission was achieved in the SDNS group (biopsy result–FSGS)，with Tacrolimus in combination with Mycophenolate Mofetil and low dose steroids，which was sustained for more than 6 months.
　　3. Tacrolimus was effective in bringing an 8 month long remission in SRNS which when combined with Mycophenolate Mofetil and alternate day prednisone was effective in sustaining remission for a period of 30 months.