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• W2595991467 abstract "Studies of nephrotic syndrome show that substitution of calcineurin inhibitors by mycophenolate mofetil (MMF) enables sustained remission and corticosteroid sparing and avoids therapy associated adverse effects. However, controlled studies in patients with steroid resistance are lacking. Here we examined the effect of switching from therapy with tacrolimus to MMF on disease course in an open-label, one-to-one randomized, controlled trial on children (one to 18 years old), recently diagnosed with steroid-resistant nephrotic syndrome, at a referral center in India. Following six months of therapy with tacrolimus, patients with complete or partial remission were randomly assigned such that 29 received MMF while 31 received tacrolimus along with tapering prednisolone on alternate days for 12 months. On intention-to-treat analyses, the proportion of patients with a favorable outcome (sustained remission, infrequent relapses) at one year was significantly lower (44.8%) in the MMF group than in the tacrolimus group (90.3%). The incidence of relapses was significantly higher for patients treated with MMF than tacrolimus (mean difference: 1.05 relapses per person-year). While there was no difference in the proportion of patients with sustained remission, the risk of recurrence of steroid resistance was significantly higher for patients receiving MMF compared to tacrolimus (mean difference: 20.7%). Compared to tacrolimus, patients receiving MMF had a significantly (71%) lower likelihood of a favorable outcome and significantly increased risk of treatment failure (frequent relapses, steroid resistance). Thus, replacing tacrolimus with MMF after six months of tacrolimus therapy for steroid-resistant nephrotic syndrome in children is associated with significant risk of frequent relapses or recurrence of resistance. These findings have implications for guiding the duration of therapy with tacrolimus for steroid-resistant nephrotic syndrome. Studies of nephrotic syndrome show that substitution of calcineurin inhibitors by mycophenolate mofetil (MMF) enables sustained remission and corticosteroid sparing and avoids therapy associated adverse effects. However, controlled studies in patients with steroid resistance are lacking. Here we examined the effect of switching from therapy with tacrolimus to MMF on disease course in an open-label, one-to-one randomized, controlled trial on children (one to 18 years old), recently diagnosed with steroid-resistant nephrotic syndrome, at a referral center in India. Following six months of therapy with tacrolimus, patients with complete or partial remission were randomly assigned such that 29 received MMF while 31 received tacrolimus along with tapering prednisolone on alternate days for 12 months. On intention-to-treat analyses, the proportion of patients with a favorable outcome (sustained remission, infrequent relapses) at one year was significantly lower (44.8%) in the MMF group than in the tacrolimus group (90.3%). The incidence of relapses was significantly higher for patients treated with MMF than tacrolimus (mean difference: 1.05 relapses per person-year). While there was no difference in the proportion of patients with sustained remission, the risk of recurrence of steroid resistance was significantly higher for patients receiving MMF compared to tacrolimus (mean difference: 20.7%). Compared to tacrolimus, patients receiving MMF had a significantly (71%) lower likelihood of a favorable outcome and significantly increased risk of treatment failure (frequent relapses, steroid resistance). Thus, replacing tacrolimus with MMF after six months of tacrolimus therapy for steroid-resistant nephrotic syndrome in children is associated with significant risk of frequent relapses or recurrence of resistance. These findings have implications for guiding the duration of therapy with tacrolimus for steroid-resistant nephrotic syndrome. The management of patients with steroid-resistant nephrotic syndrome is challenging, with variable response to immunosuppression and risks of adverse effects and progressive renal damage.1Zagury A. Oliveira A.L. Montalvão J.A. et al.Steroid-resistant idiopathic nephrotic syndrome in children: long-term follow-up and risk factors for end-stage renal disease.J Bras Nefrol. 2013; 35: 191-199Crossref PubMed Scopus (51) Google Scholar, 2Straatmann C. Ayoob R. Gbadegesin R. et al.Treatment outcome of late steroid-resistant nephrotic syndrome: a study by the Midwest Pediatric Nephrology Consortium.Pediatr Nephrol. 2013; 28: 1235-1241Crossref PubMed Scopus (21) Google Scholar, 3Gipson D.S. Chin H. Presler T.P. et al.Differential risk of remission and ESRD in childhood FSGS.Pediatr Nephrol. 2006; 21: 344-349Crossref PubMed Scopus (111) Google Scholar Therapy is aimed at inducing and maintaining complete or partial remission,4Kidney Disease Improving Global Outcomes (KDIGO) Workgroup on clinical practice guideline for glomerulonephritisMethods for guideline development.Kidney Int Suppl. 2012; 2: 243-251Abstract Full Text Full Text PDF Google Scholar, 5Colquitt J.L. Kirby J. Green C. et al.The clinical effectiveness and cost effectiveness of treatments for children with idiopathic steroid-resistant nephrotic syndrome: a systematic review.Health Technol Assess. 2007; 11: 1-93Crossref Scopus (25) Google Scholar the most important predictor of long-term outcome,6Troyanov S. Wall C.A. Miller J.A. et al.Focal and segmental glomerulosclerosis: definition and relevance of a partial remission.J Am Soc Nephrol. 2005; 16: 1061-1068Crossref PubMed Scopus (218) Google Scholar while avoiding medication-related adverse effects. Although recent randomized clinical trials (RCTs) confirm that calcineurin inhibitors (CNIs) are the therapy of choice,7Gulati A. Sinha A. Gupta A. et al.Treatment with tacrolimus and prednisolone is preferable to intravenous cyclophosphamide as the initial therapy for children with steroid-resistant nephrotic syndrome.Kidney Int. 2012; 82: 1130-1135Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, 8Choudhry S. Bagga A. Hari P. et al.Efficacy and safety of tacrolimus versus cyclosporine in children with steroid-resistant nephrotic syndrome: a randomized controlled trial.Am J Kidney Dis. 2009; 53: 760-769Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 9Hodson E.M. Willis N.S. Craig J.C. Interventions for idiopathic steroid-resistant nephrotic syndrome in children.Cochrane Database Syst Rev. 2010; 11: CD003594PubMed Google Scholar, 10Ponticelli C. Rizzoni G. Edefonti A. et al.A randomized trial of cyclosporine in steroid-resistant idiopathic nephrotic syndrome.Kidney Int. 1993; 43: 1377-1384Abstract Full Text PDF PubMed Scopus (285) Google Scholar, 11Lieberman K.V. Tejani A. A randomized double-blind placebo controlled trial of cyclosporine in steroid-resistant idiopathic focal segmental glomerulosclerosis in children.J Am Soc Nephrol. 1996; 7: 56-63PubMed Google Scholar, 12Cattran D.C. Appel G.B. Hebert L.A. et al.A randomized trial of cyclosporine in patients with steroid-resistant focal segmental glomerulosclerosis. North America Nephrotic Syndrome Study Group.Kidney Int. 1999; 56: 2220-2226Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar consensus is lacking on the optimal duration of treatment. Guidelines suggest continuing therapy with CNIs for 1 year or longer in patients who show complete or partial remission.13Kidney Disease Improving Global Outcomes (KDIGO) Glomerulonephritis Work GroupKDIGO Clinical Practice Guideline for Glomerulonephritis. Steroid-resistant nephrotic syndrome in children. Kidney Int.Suppl. 2012; 2: 172-176Google Scholar, 14Samuel S. Bitzan M. Zappitelli M. et al.Canadian Society of Nephrology Commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis: management of nephrotic syndrome in children.Am J Kidney Dis. 2014; 63: 354-362Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar, 15Gulati A. Bagga A. Gulati S. et al.Indian Society of Pediatric NephrologyManagement of steroid resistant nephrotic syndrome.Indian Pediatr. 2009; 46: 35-47PubMed Google Scholar Adverse effects associated with therapy, including glucose intolerance and acute and chronic nephrotoxicity,16Sinha A. Sharma A. Mehta A. et al.Calcineurin inhibitor induced nephrotoxicity in steroid resistant nephrotic syndrome.Indian J Nephrol. 2013; 23: 41-46Crossref PubMed Scopus (22) Google Scholar, 17Hamasaki Y. Yoshikawa N. Nakazato H. et al.for Japanese Study Group of Renal Disease in ChildrenProspective 5-year follow-up of cyclosporine treatment in children with steroid-resistant nephrosis.Pediatr Nephrol. 2013; 28: 765-771Crossref PubMed Scopus (35) Google Scholar, 18Roberti I. Vyas S. Long-term outcome of children with steroid-resistant nephrotic syndrome treated with tacrolimus.Pediatr Nephrol. 2010; 25: 1117-1124Crossref PubMed Scopus (54) Google Scholar argue for switching to less toxic agents to maintain CNI-induced remission. The lack of renal, hemodynamic, and metabolic adverse effects with mycophenolate mofetil (MMF), the prodrug of mycophenolic acid, is an important consideration in preferring this agent over CNIs when treating difficult cases of nephrotic syndrome.9Hodson E.M. Willis N.S. Craig J.C. Interventions for idiopathic steroid-resistant nephrotic syndrome in children.Cochrane Database Syst Rev. 2010; 11: CD003594PubMed Google Scholar Multiple case series show that therapy with MMF is effective and safe in reducing the frequency of relapses and cumulative corticosteroid requirement in patients with steroid-dependent nephrotic syndrome.19Bagga A. Hari P. Moudgil A. Jordan S.C. Mycophenolate mofetil and prednisolone therapy in children with steroid-dependent nephrotic syndrome.Am J Kidney Dis. 2003; 42: 1114-1120Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar, 20Afzal K. Bagga A. Menon S. et al.Treatment with mycophenolate mofetil and prednisolone for steroid dependent nephrotic syndrome.Pediatr Nephrol. 2007; 22: 2059-2065Crossref PubMed Scopus (65) Google Scholar, 21Fujinaga S. Ohtomo Y. Hirano D. et al.Mycophenolate mofetil therapy for childhood-onset steroid dependent nephrotic syndrome after long-term cyclosporine: extended experience in a single center.Clin Nephrol. 2009; 72: 268-273PubMed Google Scholar, 22Gellermann J. Querfeld U. Frequently relapsing nephrotic syndrome: treatment with mycophenolate mofetil.Pediatr Nephrol. 2004; 19: 101-104Crossref PubMed Scopus (84) Google Scholar, 23Barletta G.M. Smoyer W.E. Bunchman T.E. et al.Use of mycophenolate mofetil in steroid-dependent and -resistant nephrotic syndrome.Pediatr Nephrol. 2003; 18: 833-837Crossref PubMed Scopus (84) Google Scholar, 24Al-Akash S. Al-Makdama A. Mycophenolate mofetil in children with steroid-dependent and/or frequently relapsing nephrotic syndrome.Ann Saudi Med. 2005; 25: 380-384PubMed Google Scholar Two RCTs comparing MMF with cyclosporine showed that patients receiving therapy with MMF had more relapses25Dorresteijn E.M. Kist-van Holthe J.E. Levtchenko E.N. et al.Mycophenolate mofetil versus cyclosporine for remission maintenance in nephrotic syndrome.Pediatr Nephrol. 2008; 23: 2013-2020Crossref PubMed Scopus (90) Google Scholar, 26Gellermann J. Weber L. Pape L. et al.Gesellschaft für Pädiatrische Nephrologie (GPN). Mycophenolate mofetil versus cyclosporin A in children with frequently relapsing nephrotic syndrome.J Am Soc Nephrol. 2013; 24: 1689-1697Crossref PubMed Scopus (114) Google Scholar but a higher mean glomerular filtration rate (GFR) at follow-up.26Gellermann J. Weber L. Pape L. et al.Gesellschaft für Pädiatrische Nephrologie (GPN). Mycophenolate mofetil versus cyclosporin A in children with frequently relapsing nephrotic syndrome.J Am Soc Nephrol. 2013; 24: 1689-1697Crossref PubMed Scopus (114) Google Scholar Results of the efficacy of treatment with MMF in patients with steroid-resistant nephrotic syndrome are less satisfactory. Case series suggest that therapy with MMF and corticosteroids might induce remission in such patients.27de Mello V.R. Rodrigues M.T. Mastrocinque T.H. et al.Mycophenolate mofetil in children with steroid/cyclophosphamide-resistant nephritic syndrome.Pediatr Nephrol. 2010; 25: 453-460Crossref PubMed Scopus (38) Google Scholar, 28Li Z. Duan C. He J. et al.Mycophenolate mofetil therapy for children with steroid-resistant nephrotic syndrome.Pediatr Nephrol. 2010; 25: 883-888Crossref PubMed Scopus (41) Google Scholar In a National Institutes of Health–funded RCT, the combination of MMF and oral dexamethasone was found comparable to cyclosporine in patients with steroid-resistant focal segmental glomerulosclerosis (FSGS).29Gipson D.S. Trachtman H. Kaskel F.J. et al.Clinical trial of focal segmental glomerulosclerosis in children and young adults.Kidney Int. 2011; 80: 868-878Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar Other reports suggest that add-on therapy with MMF enabled remission in 20% to 50% patients refractory to treatment with CNIs and corticosteroids.30Nikibakhsh A.A. Mahmoodzadeh H. Karamyyar M. et al.Treatment of steroid and cyclosporine-resistant idiopathic nephrotic syndrome in children.Int J Nephrol. 2011; 2011: 930965Crossref PubMed Google Scholar, 31Jang H.R. Jung H.W. Lee Y.J. et al.Combination treatment with corticosteroid, cyclosporine A, and mycophenolate in refractory nephrotic syndrome.Clin Nephrol. 2011; 75: 511-517Crossref PubMed Scopus (2) Google Scholar, 32Hibino S. Uemura O. Nagai T. et al.Three year outcome of childhood idiopathic nephrotic syndrome under a unified immunosuppressive protocol.Pediatr Int. 2015; 57: 85-91Crossref PubMed Scopus (13) Google Scholar Finally, retrospective case series show that MMF enables CNI- and corticosteroid-free remission in some patients with CNI dependence and/or toxicity.33Gellermann J. Ehrich J.H. Querfeld U. Sequential maintenance therapy with cyclosporin A and mycophenolate mofetil for sustained remission of childhood steroid-resistant nephrotic syndrome.Nephrol Dial Transplant. 2012; 27: 1970-1978Crossref PubMed Scopus (34) Google Scholar, 34Sinha A. Bhatia D. Gulati A. et al.Efficacy and safety of rituximab in children with difficult-to-treat nephrotic syndrome.Nephrol Dial Transplant. 2015; 30: 96-106Crossref PubMed Scopus (57) Google Scholar, 35Fujinaga S. Ohtomo Y. Umino D. et al.A prospective study on the use of mycophenolate mofetil in children with cyclosporine-dependent nephrotic syndrome.Pediatr Nephrol. 2007; 22: 71-76Crossref PubMed Scopus (68) Google Scholar The aim of this RCT was to examine whether early use of MMF could be substituted for tacrolimus in maintaining tacrolimus-induced remission in children with idiopathic steroid-resistant nephrotic syndrome. Of 126 patients with steroid-resistant nephrotic syndrome screened, 92 were enrolled to receive 6 months of tacrolimus therapy at a dose of 0.10 ± 0.01 mg/kg per day (Figure 1). Seventy-two patients (78.3%) showed complete or partial remission of proteinuria after median (interquartile range) of 3 (2–4) months and 2 (1–3) months of enrollment, respectively. Thirty-two patients were not randomized because of nonresponse (N = 16, 17.4%), nephrotoxicity (N = 2, 2.4%), and early closure of the study in September 2014 (N = 8, 8.7%) (Figure 1). Sixty patients achieving complete (N = 37, 61.7%) or partial (N = 23, 38.3%) remission after therapy with tacrolimus for 186.4 ± 51.2 days were randomized to receive tacrolimus (N = 31) or MMF (N = 29) for 1 year. The baseline features of enrolled patients who were or were not randomized were similar (Supplementary Table S1). Interim analysis of the first 25 patients per group in September 2014 showed a favorable outcome in 10 patients (40%) receiving MMF compared with 22 (88%) receiving tacrolimus. The difference in proportions (−48%, 95% confidence interval [CI] −71% to −25%, P = 0.0005) prompted the decision to stop further enrollment and randomization. Of the 60 patients randomized, 56.7% had minimal change disease and 46.7% had initial resistance. Before randomization, 18 enrolled patients had steroid-sensitive relapses while receiving therapy with tacrolimus. Characteristics of the randomized patients at enrollment (data not shown) and at randomization (Table 1) were similar. After randomization, patients received tacrolimus at a dose of 0.12 ± 0.04 mg/kg per day or MMF at 800.2 ± 149.8 mg/m2 (32.2 ± 8.8 mg/kg) per day. All patients received the allocated intervention and were included in the intention-to-treat analysis. One girl receiving MMF who was in sustained partial remission did not return for follow-up after 8 months.Table 1Characteristics of patients in the 2 groups at randomizationMycophenolate mofetil (N = 29)Tacrolimus (N = 31)Boys, no. (%)21 (72.4)23 (74.2)Minimal change disease/FSGS, no. (%)17 (58.6)/12 (41.4)17 (54.8)/14 (45.2)Initial resistance, no. (%)13 (44.8)15 (48.4)If late resistance, previous frequent relapses, no. (%)13 (81.3)9 (56.3)Age at onset of nephrotic syndrome, mo42 (26–58)50 (24–79)Age at steroid resistance, mo59 (44–103)59 (37–106)Age at randomization, mo67.5 (53–112.4)66.6 (44.5–115.8)At randomization Duration of enrollment, d193 (187–209.5)194.5 (187–212.5) Complete remission/partial remission18 (62.1)/11 (37.9)19 (61.3)/12 (38.7) Time to remission, d77 (46–129)97 (34–192) Steroid-sensitive relapses during enrollmentaVariables are given as both mean ± SD and median (interquartile range).0.45 ± 0.69; 0 (0, 1)0.26 ± 0.44; 0 (0, 1) Prednisolone during enrollment, mg/kgaVariables are given as both mean ± SD and median (interquartile range).107.4 ± 45.2; 92.7 (75.6–135.5)100.2 ± 39.5; 88.3 (75.3–136.7) Creatinine, mg/dl0.50 ± 0.120.48 ± 0.12 eGFR, ml/min per 1.73 m292.4 (77.3–123.5)96.3 (81.9–118.7) Albumin, g/dl4.30 ± 0.494.23 ± 0.48 Cholesterol, mg/dl152 (124–193)157 (134–187) Urine spot protein to creatinine, mg/mg0.1 (0.03–0.30)0.2 (0.03–0.46)SD scores Weight−1.31 (−2.46 to −0.14)−1.28 (−1.93 to −0.16) Height−2.05 (−2.70 to −0.90)−1.66 (−2.9 to −0.76) Body mass index1.16 (−0.10 to 1.75)0.94 (−0.51 to 1.81) Systolic blood pressure0.86 (0.2–1.39)1.39 (0.61–2.15) Diastolic blood pressure0.73 (0.18–1.31)0.81 (0.19–1.60)eGFR, glomerular filtration rate; FSGS, focal segmental glomerulosclerosis.Continuous data expressed as mean ± SD or median (interquartile range) based on their distribution. All P > 0.1.a Variables are given as both mean ± SD and median (interquartile range). Open table in a new tab eGFR, glomerular filtration rate; FSGS, focal segmental glomerulosclerosis. Continuous data expressed as mean ± SD or median (interquartile range) based on their distribution. All P > 0.1. At completion of follow-up, the proportion of patients with a favorable outcome, comprising complete and partial remission with or without infrequent steroid-sensitive relapses, was significantly higher with tacrolimus (90.3%) compared with MMF (44.8%) (P = 0.0002) (Table 2). With a mean difference in rates of favorable outcome of −45.5% (95% CI −66.4% to −24.6%) (Table 3), 1 additional favorable outcome was likely for every 2.2 patients treated with tacrolimus.Table 2Outcomes at the end of the studyMycophenolate mofetil (N = 29)Tacrolimus (N = 31)PPrimary outcome: favorable outcome (%)13 (44.8)aIncludes 1 patient lost to follow-up at 8 months after randomization.28 (90.3)0.0002 Sustained complete remission11bIncludes 2 and 4 patients, respectively, in partial remission at randomization.16bIncludes 2 and 4 patients, respectively, in partial remission at randomization. Complete remission with infrequent steroid-sensitive relapses17 Sustained partial remission1aIncludes 1 patient lost to follow-up at 8 months after randomization.1 Partial remission with infrequent steroid-sensitive relapses04Secondary outcomes Treatment failure (%)16 (55.2)3 (9.7)0.0002Recurrence of steroid resistance60Frequent steroid sensitive relapses10cIncludes 3 patients with 2 steroid-sensitive relapses within 6 months of randomization with ≥2 serious adverse events related to relapse.3 No. of relapses by end of studydData shown both as mean ± SD and median (interquartile range, IQR).0.58 ± 0.96; 1 (0–3)0.46 ± 0.76; 0 (0–2)0.086Steroid-sensitive relapsesdData shown both as mean ± SD and median (interquartile range, IQR).1.1 ± 1.3; 1 (0–2)0.8 ± 1.0; 0 (0–2)0.34Steroid-resistant relapsesdData shown both as mean ± SD and median (interquartile range, IQR).0.2 ± 0.4; 0 (0–0)0; 0 (0–0)0.0081 eGFR, ml/min per 1.73 m2, median (IQR)100.1 (87.4–142.2)98.7 (82.3–121.8)0.54eGFR, estimated glomerular filtration rate.a Includes 1 patient lost to follow-up at 8 months after randomization.b Includes 2 and 4 patients, respectively, in partial remission at randomization.c Includes 3 patients with 2 steroid-sensitive relapses within 6 months of randomization with ≥2 serious adverse events related to relapse.d Data shown both as mean ± SD and median (interquartile range, IQR). Open table in a new tab Table 3Estimates of risk ratios and rate differences with 95% confidence limits for therapy-related outcomesOutcomeMycophenolate mofetil (N = 29)Tacrolimus (N = 31)Relative risk or rate ratioMean/% risk differencePFavorable outcome44.8 (28.4, 62.5)%90.3 (74.3, 97.4)%0.50 (0.33, 0.76)−45.5 (−66.4, −24.6)%0.0002Treatment failure55.2 (37.5, 71.6)%9.7 (2.6, 25.7)%5.7 (1.9, 17.6)45.5 (24.6, 66.4)%0.0002 Recurrence of steroid resistance20.7 (9.8, 38.8)%0 (0, 13.1)%20.7 (5.9, 35.4)%0.0095 Frequent relapses35.5 (19.9, 52.7)%9.7 (2.6, 25.7)%3.6 (1.1, 11.7)24.8 (4.6, 45.0)%0.024Occurrence of relapse58.6 (40.7, 74.5)%45.2 (29.2, 62.2)%1.3 (0.8, 2.1)13.5 (−11.6, 38.5)%0.31Incidence of relapses, per person-yr1.8 (1.3, 2.5)0.8 (0.5, 1.2)2.3 (1.4, 3.9)1.1 (0.4, 1.7)0.001Cumulative prednisolone received, mg/kg/d0.5 ± 0.40.3 ± 0.2–0.2 (0.1, 0.4)0.024 Open table in a new tab eGFR, estimated glomerular filtration rate. Similar proportions of patients treated with tacrolimus or MMF showed sustained complete or partial remission at 12 months (54.8% vs. 41.4%, P = 0.30) (Table 2). Figure 2a shows that the time to first relapse was similar in the 2 groups. Because there were 24 relapses over 30.3 person-years in patients receiving tacrolimus compared with 39 relapses during 21.2 person-years in those treated with MMF, therapy with MMF was associated with a higher incidence of relapses (mean difference, 1.05 relapses/person-year; 95% CI 0.39–1.71, P = 0.001) and prednisolone requirement (mean difference, 0.22 mg/kg per day; 95% CI 0.08–0.36, P = 0.024) (Table 3). Treatment failure, significantly more common among patients treated with MMF, was due to frequent relapses (35.7% vs. 9.7%) or recurrence of steroid resistance (20.7% vs. 0%) (Table 2, Table 3). The time to treatment failure was also shorter for patients who received MMF than for those who received tacrolimus (log rank P = 0.0001) (Figure 2b). Compared with patients with late corticosteroid resistance, those with initial resistance were more likely to experience sustained remission (34.4% vs. 64.3%, respectively, P = 0.021) and a favorable outcome (56.3% vs. 82.1%, respectively, P = 0.031). The occurrence of relapse(s) while receiving 6 months of therapy with tacrolimus also predicted treatment failure. Sustained remission was less frequent in those who relapsed during initial therapy with tacrolimus than in those without relapses (22.2% vs. 59.5%, P = 0.008). Similarly, a favorable outcome was less likely in the former compared with the latter patients (44.4% vs. 78.6%, respectively, P = 0.009). The time to treatment failure was shorter for patients with late versus initial resistance (log rank P = 0.031) and for those with, compared with those without, relapse before randomization (P = 0.0042). The relative risk (RR) of a favorable outcome was lower in patients treated with MMF compared with those treated with tacrolimus (unadjusted RR: 0.50, 95% CI 0.33–0.76, P = 0.0002) in the entire population and in subgroups based on the type of steroid resistance, the type of remission at randomization, the occurrence of relapse(s) before randomization, renal histology, and sex (Figure 3a). Similarly, patients receiving MMF had an 8-fold higher risk of treatment failure than those receiving tacrolimus (hazard ratio: 8.0, 95% CI 2.3–27.4, P = 0.001) in the entire population and in various subgroups (Figure 3b). Therapy with MMF was inferior to tacrolimus after adjusting for these parameters (adjusted RR for a favorable outcome: 0.29, 95% CI 0.06–0.79, P = 0.001; adjusted hazard ratio for treatment failure: 14.87, 95% CI 3.87–57.15, P < 0.0001) (Supplementary Table S2). Other factors independently associated with favorable outcome were the presence of initial versus late resistance (adjusted RR: 1.18, 95% CI 1.03–1.21, P = 0.033) and sustained remission during the 6-month initial therapy with tacrolimus (adjusted RR: 1.23, 95% CI 1.06–1.27, P = 0.021). The urine protein-to-creatinine ratio (Up/Uc) at the end of the study was significantly higher in patients treated with MMF compared with patients treated with tacrolimus (P = 0.007) (Supplementary Figure S1A). Proteinuria was stable in the tacrolimus group (median [interquartile range] change in Up/Uc from randomization to the end of the study, 0.004 mg/mg: −0.31 to 0.1 mg/mg), but increased in patients randomized to MMF (0.2 mg/mg [0.01–2.98 mg/mg], P = 0.007) (Supplementary Table S3). Compared with tacrolimus, patients receiving MMF had lower blood levels of albumin (4.2 ± 0.7 vs. 3.6 ± 1.1 g/dl, P = 0.026) and higher cholesterol (147.0 ± 47.8 vs. 228.1 ± 113.3 mg/dl, P = 0.0008) at the end of the study (Supplementary Figure S1B,C). SD scores for weight, height, and body mass index were comparable at the last follow-up (Supplementary Table S3). The estimated GFR (eGFR) was comparable in the 2 groups at the end of the study (P = 0.54) (Table 2), and there was no change during 12 months of therapy in either group (Supplementary Table S3 and Supplementary Figure S1D). Two and 6 months after randomization, 2 patients had a doubling of the serum creatinine level and a decrease in the GFR to <50 ml/min per 1.73 m2; tacrolimus levels were in the target range and creatinine levels normalized with a decrease in dosage. The frequency of adverse events, including minor infections, corticosteroid toxicity, and biochemical abnormalities, was similar for patients treated with tacrolimus or MMF (Supplementary Table S4). Serious adverse effects, chiefly related to infections or other complications of relapse, showed a higher trend in patients receiving MMF compared with tacrolimus (P = 0.087). Results from this open-label RCT show that a switch from tacrolimus to MMF at 6 months failed to maintain remission in patients with steroid-resistant nephrotic syndrome who had previously achieved complete or partial remission after therapy with tacrolimus. Changing therapy was associated with an approximately 3-fold lower likelihood of a favorable outcome. The corresponding risk of treatment failure, comprising either of frequent relapses or recurrence of steroid resistance, was independently increased almost 15-fold. Compared with 12 months of treatment with tacrolimus, patients receiving MMF showed 2-fold increased incidence of relapses and higher prednisolone use. Tacrolimus also outperformed MMF in patients categorized by sex, histology, and type of remission or resistance. Given the limited data from controlled studies, Kidney Disease Improving Global Outcomes (KDIGO) guidelines suggest that patients with steroid resistance receive therapy with a CNI for at least 12 months (grade of evidence 2C).13Kidney Disease Improving Global Outcomes (KDIGO) Glomerulonephritis Work GroupKDIGO Clinical Practice Guideline for Glomerulonephritis. Steroid-resistant nephrotic syndrome in children. Kidney Int.Suppl. 2012; 2: 172-176Google Scholar The current study supports these guidelines and highlights the benefits of continued treatment with tacrolimus for 18 months. Based on results from prospective studies and RCTs, the combination of a CNI and an alternate-day corticosteroid is the standard of care for patients with steroid-resistant nephrotic syndrome.7Gulati A. Sinha A. Gupta A. et al.Treatment with tacrolimus and prednisolone is preferable to intravenous cyclophosphamide as the initial therapy for children with steroid-resistant nephrotic syndrome.Kidney Int. 2012; 82: 1130-1135Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, 8Choudhry S. Bagga A. Hari P. et al.Efficacy and safety of tacrolimus versus cyclosporine in children with steroid-resistant nephrotic syndrome: a randomized controlled trial.Am J Kidney Dis. 2009; 53: 760-769Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 9Hodson E.M. Willis N.S. Craig J.C. Interventions for idiopathic steroid-resistant nephrotic syndrome in children.Cochrane Database Syst Rev. 2010; 11: CD003594PubMed Google Scholar, 10Ponticelli C. Rizzoni G. Edefonti A. et al.A randomized trial of cyclosporine in steroid-resistant idiopathic nephrotic syndrome.Kidney Int. 1993; 43: 1377-1384Abstract Full Text PDF PubMed Scopus (285) Google Scholar, 11Lieberman K.V. Tejani A. A randomized double-blind placebo controlled trial of cyclosporine in steroid-resistant idiopathic focal segmental glomerulosclerosis in children.J Am Soc Nephrol. 1996; 7: 56-63PubMed Google Scholar, 12Cattran D.C. Appel G.B. Hebert L.A. et al.A randomized trial of cyclosporine in patients with steroid-resistant focal segmental glomerulosclerosis. North America Nephrotic Syndrome Study Group.Kidney Int. 1999; 56: 2220-2226Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar, 13Kidney Disease Improving Global" @default.
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