Triple Immunosuppressive Therapy In Children With Steroid Resistant Nephrotic Syndrome:a Prospective And Controlled

Background:Primary nephrotic syndrome (PNS) is a condition in which the glomeruli of the kidney leak protein from the blood into the urine. According to its response to steroid, PNS can be categorized as steroid-resistant nephrotic syndrome (SRNS) and steroid-sensitive nephrotic syndrome (SSNS). Persistent nephrotic syndrome is associated with poor patient-reported quality of life, thromboembolic events, hypertension, peritonitis and other serious infections, persistent dyslipidemia and death. Generally, steroid-resistant nephrotic syndrome is associated with a 50% risk for end-stage renal disease(ESRD) within 5 years of diagnosis if patients do not achieve a partial or complete remission. Refractory nephrotic syndrome(RNS) includes SRNS, steroid-dependent nephrotic syndrome (SDNS) and frequently relapsing nephrotic syndrome (FRNS). The treatment of SRNS patients is still a major challenge that to be overcome.For children with SRNS, calcineurin inhibitors(CNI) are recommended as initial therapy by the KIDGO guideline and the Chinese Association of Pediatric Nephrology. To date, cyclosporine A (CsA) or tacrolimus(TAC) are widely used in clinical practice in children with SRNS. Compared with CsA, TAC has been suggested to have stronger immunosuppressive effects and significantly reduced side-effects. Some patients respond completely to CNI, but it is possible to relapse throughout their subsequent course. Some patients fail to achieve complete or partial remission with combination therapy of steroid and CNI. According to the principle of mulit-target immunosuppress-ive therapy, based on the successful treatment of nephrotic syndrome(NS) patients using multidrug therapy comprising TAC, PDN and MMF/MZR, we think TAC and steroid-based triple immunosuppressive therapy would be an effective and safe therapy to 19 children with SRNS.Objective:The effective therapy for steroid resistant nephrotic syndrome remains uncertain at present, especially in those with calcineurin inhibitor resistant or intolerant nephrotic syndrome. To date, few studies have been reported using multiple combination therapy of immunosuppressive reagents for patients with calcineurin inhibitor resistant or intolerant nephrotic syndrome.Methods:19 consecutive children with steroid-resistant and tacrolimus-resistant (n=10) or tacrolimus-sensitive but frequent relapsing nephrotic syndrome(n=9) were randomly recruited in present study. All of them received futher triple-combination therapy by cyclophosphamide (CTX, n=6), mycophenolate mofetil (MMF, n=6) or leflunomide (LEF, n=7). The short-term remission rate within 6 months, frequent relapse rate and side-effects during 1-year follow-up of triple-combination therapy were evaluated.Results:Compared with previously double-combined therapy of Pre & TAC, short-term remission rate in 19 patients was significantly improved after triple-combination therapy,while the frequent relapse rate in the following 12 months was significantly decreased. Among three different subgroups with CTX, MMF or LEF, no significant difference was found in short-term remission rate and relapse rate within 1 year.Conclusion:Triple-combination therapy with Pre+TAC+CTX/MMF/LEF is effective or short-t erm response and 1-year remission, without significant additional side-effects seen in children with steroid-resistant and tacrolimus-resistant or tacrolimus-sensitive but frequently relapsing nephrotic syndrome. Further study for evaluating long-term effica-cy and safety of triple-combination therapy with Pre+TAC+CTX/MMF/LEF would be necessary for these patients.