An open-label randomized controlled trial of low-dose corticosteroid plus enteric-coated mycophenolate sodium versus standard corticosteroid treatment for minimal change nephrotic syndrome in adults (MSN Study)
2018; Elsevier BV; Volume: 94; Issue: 6 Linguagem: Inglês
10.1016/j.kint.2018.07.021
ISSN1523-1755
AutoresPhilippe Rémy, Vincent Audard, Pierre André Natella, Gaëlle Pellé, Bertrand Dussol, Hélène Leray‐Moragues, Cécile Vigneau, Khedidja Bouachi, Jacques Dantal, Laurence Vrigneaud, Alexandre Karras, Frank Pourcine, Philippe Gatault, Philippe Grimbert, Nawelle Ait Sahlia, Anissa Moktefi, Éric Daugas, Claire Rigothier, Sylvie Bastuji‐Garin, Dil Sahali, Jean‐Claude Aldigier, Pierre Bataille, Bernard Canaud, Dominique Chauveau, Christian Combe, Gabriel Choukroun, Emilie Cornec-Legall, Karine Dahan, Michel Delahousse, Dominique Desvaux, P. Deteix, Antoine Dürrbach, Vincent Esnault, Marie Essig, P Fiévet, T. Frouget, Dominique Guerrot, M. Godin, Annie Gontiers-Picard, Morgane Gosselin, Catherine Hanrotel‐Saliou, Anne-Elisabeth Heng, Antoine Huart, Antoine Humbert, Tomek Kofman, Aurélie Hummel, Philippe Lang, Maurice Laville, Yannick Le Meur, Paolo Malvezzi, Marie Matignon, Rafik Mesbah, Bruno Moulin, Sandrine Muller, Jérôme Olagne, Agathe Pardon, François Provôt, Guillaume Queffeulou, Emmanuelle Plaisier, Quentin Raimbourg, Philippe Rieu, Thomas Stehlé, P Vanhille,
Tópico(s)Systemic Sclerosis and Related Diseases
ResumoFirst-line therapy of minimal change nephrotic syndrome (MCNS) in adults is extrapolated largely from pediatric studies and consists of high-dose oral corticosteroids. We assessed whether a low corticosteroid dose combined with mycophenolate sodium was superior to a standard oral corticosteroid regimen. We enrolled 116 adults with MCNS in an open-label randomized controlled trial involving 32 French centers. Participants randomly assigned to the test group (n=58) received low-dose prednisone (0.5 mg/kg/day, maximum 40 mg/day) plus enteric-coated mycophenolate sodium 720 mg twice daily for 24 weeks; those who did not achieve complete remission after week 8 were eligible for a second-line regimen (increase in the prednisone dose to 1 mg/kg/day with or without Cyclosporine). Participants randomly assigned to the control group (n=58) received conventional high-dose prednisone (1 mg/kg/day, maximum 80 mg/day) for 24 weeks. The primary endpoint of complete remission after four weeks of treatment was ascertained in 109 participants, with no significant difference between the test and control groups. Secondary outcomes, including remission after 8 and 24 weeks of treatment, did not differ between the two groups. During 52 weeks of follow-up, MCNS relapsed in 15 participants (23.1%) who had achieved the primary outcome. Median time to relapse was similar in the test and control groups (7.1 and 5.1 months, respectively), as was the incidence of serious adverse events. Five participants died from hemorrhage (n=2) or septic shock (n=3), including 2 participants in the test group and 3 in the control group. Thus, in adult patients, treatment with low-dose prednisone plus enteric-coated mycophenolate sodium was not superior to a standard high-dose prednisone regimen to induce complete remission of MCNS. First-line therapy of minimal change nephrotic syndrome (MCNS) in adults is extrapolated largely from pediatric studies and consists of high-dose oral corticosteroids. We assessed whether a low corticosteroid dose combined with mycophenolate sodium was superior to a standard oral corticosteroid regimen. We enrolled 116 adults with MCNS in an open-label randomized controlled trial involving 32 French centers. Participants randomly assigned to the test group (n=58) received low-dose prednisone (0.5 mg/kg/day, maximum 40 mg/day) plus enteric-coated mycophenolate sodium 720 mg twice daily for 24 weeks; those who did not achieve complete remission after week 8 were eligible for a second-line regimen (increase in the prednisone dose to 1 mg/kg/day with or without Cyclosporine). Participants randomly assigned to the control group (n=58) received conventional high-dose prednisone (1 mg/kg/day, maximum 80 mg/day) for 24 weeks. The primary endpoint of complete remission after four weeks of treatment was ascertained in 109 participants, with no significant difference between the test and control groups. Secondary outcomes, including remission after 8 and 24 weeks of treatment, did not differ between the two groups. During 52 weeks of follow-up, MCNS relapsed in 15 participants (23.1%) who had achieved the primary outcome. Median time to relapse was similar in the test and control groups (7.1 and 5.1 months, respectively), as was the incidence of serious adverse events. Five participants died from hemorrhage (n=2) or septic shock (n=3), including 2 participants in the test group and 3 in the control group. Thus, in adult patients, treatment with low-dose prednisone plus enteric-coated mycophenolate sodium was not superior to a standard high-dose prednisone regimen to induce complete remission of MCNS. MCNS is a glomerular disease of immune origin, characterized by massive proteinuria occurring in the absence of glomerular inflammatory lesions or Ig deposits.1Sahali D. Sendeyo K. Mangier M. et al.Immunopathogenesis of idiopathic nephrotic syndrome with relapse.Semin Immunopathol. 2014; 36: 421-429Crossref PubMed Scopus (34) Google Scholar, 2Colucci M. Corpetti G. Emma F. Vivarelli M. Immunology of idiopathic nephrotic syndrome.Pediatr Nephrol. 2018; 33: 573-584Crossref PubMed Scopus (61) Google Scholar MCNS has a higher incidence in children than in adults, but is nevertheless a frequent cause of nephrotic syndrome (NS) in adults, accounting for 10% to 25% of cases. Until now, the relative low prevalence of this glomerular disease has been a barrier to adequately powered studies, and current data guiding treatment decisions in adult patients are limited and often extrapolated from pediatric studies. In children, 4 weeks of daily treatment with oral steroids has been shown to be associated with complete remission (CR) of the NS (classified as steroid-sensitive) in approximately 80% of pediatric cases.3Gipson D.S. Massengill S.F. Yao L. et al.Management of childhood onset nephrotic syndrome.Pediatrics. 2009; 124: 747-757Crossref PubMed Scopus (206) Google Scholar, 4Elie V. Fakhoury M. Deschenes G. et al.Physiopathology of idiopathic nephrotic syndrome: lessons from glucocorticoids and epigenetic perspectives.Pediatr Nephrol. 2012; 27: 1249-1256Crossref PubMed Scopus (38) Google Scholar Nevertheless, no prospective study has yet accurately assessed the incidence of steroid-responsiveness in adults with MCNS after 4 weeks of oral steroid treatment.5Hogan J. Radhakrishnan J. The treatment of minimal change disease in adults.J Am Soc Nephrol. 2013; 24: 702-711Crossref PubMed Scopus (90) Google Scholar, 6Beck L. Bomback A.S. Choi M.J. et al.KDOQI US commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis.Am J Kidney Dis. 2013; 62: 403-441Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar Furthermore, the optimal duration of treatment for achieving CR in adults remains to be determined. Kidney Disease Improving Global Outcomes (KDIGO) guidelines based on limited data from old trials comparing steroid therapy with placebo, and from retrospective observational studies, advise a single daily dose (1 mg/kg) of oral steroids for at least 4 weeks for initial episodes of MCNS in adults, with prolongation to a maximum of 16 weeks if CR is not achieved.7Radhakrishnan J. Cattran D.C. The KDIGO practice guideline on glomerulonephritis: reading between the (guide)lines–application to the individual patient.Kidney Int. 2012; 82: 840-856Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar, 8Black D.A. Rose G. Brewer D.B. Controlled trial of prednisone in adult patients with the nephrotic syndrome.Br Med J. 1970; 3: 421-426Crossref PubMed Scopus (178) Google Scholar, 9Imbasciati E. Gusmano R. Edefonti A. et al.Controlled trial of methylprednisolone pulses and low dose oral prednisone for the minimal change nephrotic syndrome.Br Med J (Clin Res Ed). 1985; 291: 1305-1308Crossref PubMed Scopus (63) Google Scholar, 10Coggins C.H. Adult minimal change nephropathy: experience of the collaborative study of glomerular disease.Trans Am Clin Climatol Assoc. 1986; 97: 18-26PubMed Google Scholar, 11Fujimoto S. Yamamoto Y. Hisanaga S. et al.Minimal change nephrotic syndrome in adults: response to corticosteroid therapy and frequency of relapse.Am J Kidney Dis. 1991; 17: 687-692Abstract Full Text PDF PubMed Scopus (66) Google Scholar, 12Nakayama M. Katafuchi R. Yanase T. et al.m.Am J Kidney Dis. 2002; 39: 503-512Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar, 13Mak S.K. Short C.D. Mallick N.P. Long-term outcome of adult-onset minimal-change nephropathy.Nephrol Dial Transplant. 1996; 11: 2192-2201Crossref PubMed Scopus (106) Google Scholar, 14Tse K.C. Lam M.F. Yip P.S. et al.Idiopathic minimal change nephrotic syndrome in older adults: steroid responsiveness and pattern of relapses.Nephrol Dial Transplant. 2003; 18: 1316-1320Crossref PubMed Scopus (71) Google Scholar, 15Waldman M. Crew R.J. Valeri A. et al.Adult minimal-change disease: clinical characteristics, treatment, and outcomes.Clin J Am Soc Nephrol. 2007; 2: 445-453Crossref PubMed Scopus (288) Google Scholar, 16Nolasco F. Cameron J.S. Heywood E.F. et al.Adult-onset minimal change nephrotic syndrome: a long-term follow-up.Kidney Int. 1986; 29: 1215-1223Abstract Full Text PDF PubMed Scopus (197) Google Scholar, 17Shinzawa M. Yamamoto R. Nagasawa Y. et al.Comparison of methylprednisolone plus prednisolone with prednisolone alone as initial treatment in adult-onset minimal change disease: a retrospective cohort study.Clin J Am Soc Nephrol. 2014; 9: 1040-1048Crossref Scopus (23) Google Scholar When we designed our trial, only 1 retrospective study including a limited number of adult patients (n = 28) had estimated the CR rate at 4 weeks. It showed that the CR rate reached 48% within 4 weeks of treatment with steroids at a dose of 1 mg/kg/d.11Fujimoto S. Yamamoto Y. Hisanaga S. et al.Minimal change nephrotic syndrome in adults: response to corticosteroid therapy and frequency of relapse.Am J Kidney Dis. 1991; 17: 687-692Abstract Full Text PDF PubMed Scopus (66) Google Scholar Adverse effects are common in patients treated with prolonged and/or repeated courses of steroids. They include insomnia, hyperphagia, lipodystrophy, diabetes, infections, and bone and digestive complications.18Morin C. Fardet L. Systemic glucocorticoid therapy: risk factors for reported adverse events and beliefs about the drug. A cross-sectional online survey of 820 patients.Clin Rheumatol. 2015; 34: 2119-2126Crossref Scopus (26) Google Scholar Hence, although oral steroids remain the option of choice for first-line treatment in adult patients with MCNS, alternative treatments are required because the optimal time for achieving CR on steroids remains unclear and patients frequently experience adverse effects due to steroid toxicity. Several immunosuppressive agents have been tested, and mycophenolate mofetil (MMF), which is less toxic than cyclosporine A, tacrolimus, or cyclophosphamide, has recently emerged as a promising therapeutic option for the treatment of steroid-dependent or frequently relapsing NS in children and adults.19Hogg R.J. Fitzgibbons L. Bruick J. et al.Mycophenolate mofetil in children with frequently relapsing nephrotic syndrome: a report from the Southwest Pediatric Nephrology Study Group.Clin J Am Soc Nephrol. 2006; 1: 1173-1178Crossref PubMed Scopus (57) Google Scholar, 20Day C.J. Cockwell P. Lipkin G.W. et al.Mycophenolate mofetil in the treatment of resistant idiopathic nephrotic syndrome.Nephrol Dial Transplant. 2002; 17: 2011-2013Crossref PubMed Scopus (74) Google Scholar Two preparations of mycophenolic acid are currently available: the original mycophenolate mofetil formulation (CellCept; Roche Pharma, Basel, Switzerland) and enteric-coated mycophenolate sodium (EC-MPS; Myfortic; Novartis Pharma AG, Basel, Switzerland).21Budde K. Bauer S. Hambach P. et al.Pharmacokinetic and pharmacodynamic comparison of enteric-coated mycophenolate sodium and mycophenolate mofetil in maintenance renal transplant patients.Am J Transplant. 2007; 7: 888-898Crossref PubMed Scopus (92) Google Scholar No randomized trial has yet compared the efficacy of oral steroids alone, at a dose of 1 mg/kg/d, with that of a steroid-sparing regimen, for initial episodes of MCNS in adult patients. We therefore designed a multicenter randomized clinical trial (MSN, Myfortic pour Syndrome Nephrotique) to assess the potential benefits of low-dose steroid therapy (0.5 mg/kg/d) together with EC-MPS relative to conventional treatment (steroids alone at a high dose, 1 mg/kg/d) for the treatment of initial episodes of MCNS in adult patients. The primary endpoint was the CR rate after 4 weeks of treatment. Between November 2009 and June 2014, 117 patients met the inclusion criteria for this study. One of these patients withdrew his consent before randomization. The remaining 116 patients were randomly assigned to either the test group (N = 58) or the control group (N = 58) (Figure 1). At inclusion, 3 patients had received steroids for 1 previous episode of MCNS relapse (1 patient in the test group and 2 in the control group), but all 3 had been off steroids for at least 4 months before inclusion. The baseline characteristics at the time of randomization are summarized in Table 1. They did not differ between the 2 groups. All patients had typical features of NS, with a median albumin concentration of 16.6 gr/l (95% confidence interval [CI]: 13.1–22) and a median proteinuria, as assessed by UPCR, at 896 mg/mmol (95% CI: 558–1362). Nine patients had previously been treated with an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) (2 in the control group and 7 in the test group). MCNS was based on appropriate renal biopsy examination as demonstrated by the mean glomeruli number for light microscopy examination (19.7 per biopsy; range, 9–27) including in all cases juxtamedullary area examination. Diffuse mesangial IgM deposits were found in 13 patients (11.2%). Careful inspection of their initial biopsies did not reveal any features of FSGS.Table 1Baseline characteristics of the 116 adult patients with minimal change nephrotic syndrome included in the MSN trialCharacteristicsTotalN = 116Test groupN = 58Control groupN = 58P valueaP value for the chi-square, Fisher’s exact, or Mann-Whitney test, as appropriate.Age, yr44.3 (31.5–60.3)47.4 (31.3–61.1)41.6 (31.6–55.4)0.28Male65 (56.0)36 (62.1)29 (50.0)0.19Medical history of atopic disease (n = 48/45)31 (33.3)13 (28.9)18 (37.5)0.38Medical history of diabetes mellitus (n = 48/45)9 (9.7)3 (6.7)6 (12.5)0.49Current weight (kg) (n = 57/57)73.5 (64.0–87.0)72.0 (63.0–88.9)74.8 (66.0–86.0)0.49Basal weight (kg) (n = 51/52)68.8 (61.0–80.0)67.0 (61.0–76.0)70.0 (62.0–82.0)0.34Weight minus basis weight (kg) (n = 51/52)4.6 (2.0–7.0)4.6 (2.0–7.0)4.9 (2.0–8.0)0.93Systolic blood pressure (mm Hg) (n = 57/57)129 (119–138)130 (120–132)127 (119–140)0.74Diastolic blood pressure (mm Hg) (n = 57/57)76 (70–83)78 (70–82)75 (68–84)0.65Hemoglobin concentration (g/dl,) (n = 55/55)13.9 (13.0–15.0)14.2 (13.1–15.1)13.7 (12.7–14.9)0.21Platelet count (109/l,) (n = 55/55)287 (238–340)288 (232–342)281 (238–336)0.86Neutrophil count (109/l,) (n = 55/55)4.3 (3.3–5.7)4.7 (3.6–5.8)3.8 (3.0–5.5)0.08Serum Albumin concentration (g/l)16.6 (13.1–22)15.9 (13–21.2)17.4 (13.3–22.3)0.35Serum Creatinine concentration (μmol/l) (n = 57/58)81 (63–121)81 (60–120)81.5 (64–127)0.54eGFRbGlomerular filtration rate was estimated with the abbreviated modification of diet in renal disease formula, glomerular filtration rate (ml/min per 1.73 m2) = 186.3 × (creatinine [μmol/l] /88.4) – 1.154 × (age [yr]) – 0.203 × 0.742 (if female) × 1.21 (if black). (ml/min per 1.73 m2) (n = 57/58)86.9 (50.7–110)89.0 (54.3–111)83.9 (49.7–108.6)0.32Hemoglobin A1c level (%) (n = 34/43)5.5 (5.1–5.8)5.4 (5.1–5.7)5.5 (5.1–5.9)0.68C-reactive protein concenration (mg/l) (n = 49/41)2.9 (0.9–5.0)3.0 (1.0–6.0)2.0 (0.9–5.0)0.20Hematuria (/ml) (n = 48/50)3000 (416–15900)5000 (40–15,900)1755 (750–15,000)0.96Leukocyturia (/ml) (n = 49/52)5000 (19–20,000)5000 (526–20,000)2000 (12–16,000)0.40Urine protein/creatinine ratio (mg/mmol)896 (558–1362)816 (600–1196)946 (531–1368)0.53Total cholesterol concentration (g/l) (n = 50/53)4.1 (3.2–4.9)4.1 (3.3–4.8)4.1 (3.2–4.9)0.90Triglyceride concentration (mmol/l) (n = 47/53)2.1 (1.5–3.1)2.1 (1.5–3.0)2.2 (1.3–3.5)0.66HDL (g/l) (n = 44/50)0.71 (0.54–0.90)0.69 (0.53–0.87)0.77 (0.57–0.97)0.50LDL (g/l) (n = 42/49)2.8 (1.9–3.5)2.8 (1.8–3.5)2.8 (2.3–3.5)0.85eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol.Categorical variables are expressed as N (%), (n = x/x) indicates the number of patients in each group in cases of missing data; continuous data are presented as medians (interquartile range, Q1–Q3).a P value for the chi-square, Fisher’s exact, or Mann-Whitney test, as appropriate.b Glomerular filtration rate was estimated with the abbreviated modification of diet in renal disease formula, glomerular filtration rate (ml/min per 1.73 m2) = 186.3 × (creatinine [μmol/l] /88.4) – 1.154 × (age [yr]) – 0.203 × 0.742 (if female) × 1.21 (if black). Open table in a new tab eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol. Categorical variables are expressed as N (%), (n = x/x) indicates the number of patients in each group in cases of missing data; continuous data are presented as medians (interquartile range, Q1–Q3). All patients except 1 had received the allocated treatment during the first 4 weeks. No patient was lost to follow-up before evaluation of the primary endpoint, but 2 patients died (1 in each group) (Figure 1). Sixteen (13.8%) patients were lost to follow-up between weeks 4 and 24, including 7 patients from the test group (12.1%) and 9 patients from the control group (15.5%). Sixteen additional patients were lost to follow-up between weeks 24 and 52 (8 in each group). Out of 109 patients for whom data were available at week 4, 65 (59.6%) achieved CR (Table 2). Primary outcome was not available for 5 patients (Figure 1). In the intention-to-treat analysis (imputation of missing data, N = 114), CR rate did not differ significantly between the test group (95% CI: 64.9% [37/57]) and the control group (95% CI: 57.9% [33/57]) (relative risk [RR]: 1.12; 95% CI [0.84–1.50], P = 0.44; absolute risk reduction [ARR]: 7%; 95% CI [–10.8 to 23.8]). Among the 109 patients with available data, CR rate did not also differ significantly between the test (61.5% [32/52]) and the control groups (57.9% [33/57]) (RR: 1.06; 95% CI [0.78–1.44], P = 0.70).Table 2Primary and secondary outcomesTotalTest group (N = 57)Control group (N = 57)P valueaP value of the chi-square or Fisher’s exact test, as appropriate, comparing aprevalence of complete remission (yes vs. no) and bstatus distribution (complete, partial or no remission) between the 2 groups.P valuebP value of the chi-square or Fisher’s exact test, as appropriate, comparing aprevalence of complete remission (yes vs. no) and bstatus distribution (complete, partial or no remission) between the 2 groups.Primary outcome, Week 4 Complete remission, ITT analysiscAnalysis according to the intent-to-treat principle after imputation of missing data.70 (61.4)37 (64.9)33 (57.9)0.44Remission status (without data imputation)1095257 Complete remission65 (59.6)32 (61.5)33 (57.9)0.70 No complete remission44 (40.4)20 (38.5)24 (42.1)Partial remission10 (9.2)4 (7.7)6 (10.5)0.87No remission31 (28.4)14 (26.9)17 (29.8)Not specifiedeThe not specified status corresponds to patients who were not in complete remission and whose specific status (partial or no remission) was not known at the time of assessment.3 (2.8)2 (3.9)1 (1.8)Secondary outcomesdNo imputation for missing data was performed for secondary endpoints.Week 8964650 Complete remission73 (76.0)38 (82.6)35 (70.0)0.15 No complete remission23 (24.0)8 (17.4)15 (30.0)Partial remission12 (12.5)3 (6.5)9 (18.0)0.22No remission11 (11.5)5 (10.9)6 (12.0)Week 24904644 Complete remission72 (80.0)37 (80.4)35 (79.6)0.92 No complete remission18 (20.0)9 (19.6)9 (20.4)Partial remission7 (7.8)2 (4.4)5 (11.4)0.16No remission9 (10.0)7 (15.2)2 (4.5)Not specifiedeThe not specified status corresponds to patients who were not in complete remission and whose specific status (partial or no remission) was not known at the time of assessment.2 (2.2)0 (0)2 (4.5)Week 52784038 Complete remission57 (73.1)27 (67.5)30 (78.9)0.26 No complete remission21 (26.9)13 (32.5)8 (21.1)Partial remission5 (6.4)3 (7.5)2 (5.3)0.72No remission14 (17.9)8 (20.0)6 (15.8)Not specifiedeThe not specified status corresponds to patients who were not in complete remission and whose specific status (partial or no remission) was not known at the time of assessment.2 (2.6)2 (5.0)0 (0)Complete remission was defined as urine protein-to-creatinine ratio (UPCR) < 30 mg/mmol or trace or negative results on repeat urine albumin dipstick tests, associated with an albumin level > 30 g/l; partial remission was defined as UPCR between 30 and 300 mg/mmol and albumin concentration > 30g/l; no remission was defined as persistent proteinuria (UPCR > 300 mg/mmol) and low albumin concentration (<30 g/l).Categorical variables are expressed as N (%).a,b P value of the chi-square or Fisher’s exact test, as appropriate, comparing aprevalence of complete remission (yes vs. no) and bstatus distribution (complete, partial or no remission) between the 2 groups.c Analysis according to the intent-to-treat principle after imputation of missing data.d No imputation for missing data was performed for secondary endpoints.e The not specified status corresponds to patients who were not in complete remission and whose specific status (partial or no remission) was not known at the time of assessment. Open table in a new tab Complete remission was defined as urine protein-to-creatinine ratio (UPCR) < 30 mg/mmol or trace or negative results on repeat urine albumin dipstick tests, associated with an albumin level > 30 g/l; partial remission was defined as UPCR between 30 and 300 mg/mmol and albumin concentration > 30g/l; no remission was defined as persistent proteinuria (UPCR > 300 mg/mmol) and low albumin concentration (<30 g/l). Categorical variables are expressed as N (%). Overall, 44 patients (40.4%) did not reach the primary endpoint at week 4: partial remission (PR) and no remission were observed in 10 (9.2%) and 31 (28.4%) patients, respectively. The remission status (partial or no remission) was not specified for 3 patients (2.8%). The percentage of patients achieving the combined CR and PR endpoint did not differ between the test and control groups (36/52, 69.2% vs. 39/57, 68.4%, respectively; P = 0.79). At weeks 8 and 24, the distributions of patients according to remission status and CR rate were similar in the 2 groups (Table 2). We then analyzed the specific outcome of the 44 patients who did not reach the primary endpoint at week 4, 20 from the test group and 24 from the control group (Figure 2). In the test group, which includes 14 patients with no remission at week 4, we obtained after 4 additional weeks of combined therapy, 5 CR and 3 PR, whereas 3 failed to respond. In addition, 2 patients were lost to follow-up and the outcome was not available in 1. All the test group patients in PR at week 4 (n = 4) were in CR at week 8. For patients in the control group without remission at week 4 (N = 17), 4 further weeks of steroid therapy resulted in CR in 6 cases and PR in 4 cases, while no remission was observed in 5 patients. A similar protocol was used for patients with PR at week 4 (n = 6) and was associated with CR in 1 case and clinical failure in another, while PR persisted in 2 cases. Three patients were lost to follow-up in both groups (2 test and 1 control). One patient without remission at week 4 died between weeks 4 and 8 in the control group. Two of 11 patients without remission after 8 weeks of treatment exhibited IgM mesangial deposits (1 patient in each group). Among the 3 patients with not specified status at week 4, 1 remained nephrotic after 8 weeks of steroid therapy and no data were available at this time assessment in another patient in the test group, while 1 patient achieved PR in the control group (Figure 2). For patients without remission at week 8, EC-MPS was discontinued, while the steroid dose was increased to 1 mg/kg/d in the test group. Four patients of the control group have received 4 supplementary weeks of steroids at the same dose, whereas cyclosporine (CsA) was introduced in the 2 last patients. Fifteen of 65 patients who had achieved the primary endpoint at week 4 relapsed (23.1%) during follow-up without significant difference in relapse rates between the groups (P = 0.39) (Figure 3). One relapse occurred between weeks 4 and 8 in the control group, at the time of weaning off steroids, and 6 relapses occurred between weeks 8 and 24. Eight of the 15 relapses occurred after definitive treatment cessation (between 24 and 52 weeks of follow-up). Steroid dose at the time of relapse was significantly lower in the test group than in the control group (3.5 mg/d [95% CI: 1.7–7.5] and 10 mg/d [95% CI: 8–26], respectively; P = 0.03). The median time to relapse did not differ between the test and control groups (7.1 [95% CI: 6.5–9] and 5.1 months [95% CI: 2.8–8.6], respectively, P = 0.2). At week 24, 72 patients (80%) displayed CR, 7 (7.8%) PR, and 9 (10%) displayed no remission of NS (Table 2). The remission status (partial or no remission) was not specified for 2 patients (2.2%). The CR rates and distributions of patients according to remission status did not differ between the 2 groups. At the end of follow-up (week 52), data were available for 78 patients. Fifty-seven were in CR, and there was no difference in CR rate between both groups (27/40, 67.5% vs. 30/38, 78.9%, test and control groups, respectively; P = 0.26). At this time point, the median estimated glomerular filtration rate was 91.5 ml/min per 1.73 m2 (95% CI: 80.3–107.8) for the overall population (95.9 ml/min per 1.73 m2 [95% CI: 84.6–117.5] in the test group and 88.5 ml/min per 1.73 m2 [95% CI: 80.3–98.6] in the control group, P = 0.15). The frequency of adverse events (AEs) and serious AEs (SAEs) did not differ significantly between the 2 groups (P = 0.54 and P = 0.99, respectively) (Table 3). Twenty-four SAEs were reported, 14 of which (58.3%) were observed in patients from the control group. Two patients died between inclusion and primary outcome evaluation, due to a post-renal biopsy hemorrhage for 1 patient from the test group and hemorrhagic shock related to stomach ulcer for 1 patient from the control group. In addition, 3 patients died during follow-up (52 weeks), all from septic shock: 1 patient from the test group (39 weeks after inclusion) and 2 patients from the control group (8 and 13 weeks after inclusion). The main cause of death in these patients was necrotizing fasciitis and severe community-acquired pneumonia in 2 cases. All observed SAEs are listed in Table 3. Nonfatal or fatal episodes of infection were the most frequent cause of SAEs. Nonfatal infectious episodes consisted in acute pyelonephritis in 3 patients, acute prostatitis in 1 case, viral diarrhea in 2 and an abscess after surgical intervention for carpal tunnel syndrome in the last. New-onset glucose intolerance occurred in 2 patients from the control group, and none of the patients from the test group. Two patients from the control group suffered bone fractures. None of the patients in the test group required an adjustment of EC-MPS dose due to significant changes in blood cell counts.Table 3Adverse events (AEs) and serious adverse events (SAEs) in patients included in the MSN studyAdverse eventsTotal (N = 116)Test group (N = 58)Control group (N = 58)P valuePatients with AEs104 (89.6%)53 (91.4%)51 (87.9%)0.54Patients with SAEs18 (15.5%)9 (15.5%)9 (15.5%)0.99Total number of SAEs241014 Death523Septic shock312Hemorrhagic shock211 Nonfatal SAEsInfectious episodes752Acute kidney injury312New-onset glucose intolerance202Acute pulmonary embolism110Bone fracture202Other nonfatal SAEsDiarrhea202Behavioral disorders110Suspicion of lung cancer101P value of Fisher’s exact test. Open table in a new tab P value of Fisher’s exact test. To date, no randomized prospective trials have been conducted to identify optimal dose or duration of steroid therapy for MCNS in adults as recommended by KDIGO guidelines. In this multicenter clinical trial, we found that low doses of oral steroid therapy plus EC-MPS did not modify the rate of CR or of CR + PR relative to conventional oral steroid therapy alone after 4 weeks of treatment. Similar results were obtained after 8 and 24 weeks of treatment. Our decision to propose daily oral steroid therapy in both groups as a conventional treatment for the first episode of MCNS patients is consistent with current international guidelines.7Radhakrishnan J. Cattran D.C. The KDIGO practice guideline on glomerulonephritis: reading between the (guide)lines–application to the individual patient.Kidney Int. 2012; 82: 840-856Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar Nevertheless, alternative strategies could be considered. Waldman et al., in a retrospective analysis of 95 MCNS patients, found no differences in the time to first remission, CR rate, and relapse rate or incidence of adverse events between patients treated daily with steroids and patients receiving steroids on alternate days.15Waldman M. Crew R.J. Valeri A. et al.Adult minimal-change disease: clinical characteristics, treatment, and outcomes.Clin J Am Soc Nephrol. 2007; 2: 445-453Crossref PubMed Scopus (288) Google Scholar Li et al. recently reported the results of a prospective study comparing tacrolimus monotherapy with prednisone at the dose used here for the control group (1 mg/kg/d).22Li X. Liu Z. Wang L. et al.Tacrolimus monotherapy after intravenous methylprednisolone in adults with minimal change nephrotic syndrome.J Am Soc Nephrol. 2017; 28: 1286-1295Crossref PubMed Scopus (21) Google Scholar They found that more than 90% of patients went into remission (CR or PR) after 4 weeks of steroid treatment, with no significant difference between the 2 groups. Nevertheless, the design of their study differed from ours, because their patients first received 10 consecutive days of i.v. methylprednisone (0.8 mg/kg/d). The difference in remission rate (CR or PR) at week 4 between their study and ours (68.8% for the total population and 68.4% for control group) may therefore reflect the pulses of methylprednisolone treatment administered before the oral steroid treatment. Consistent with this hypothesis, 2 retr
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