Tacrolimus Monotherapy after Intravenous Methylprednisolone in Adults with Minimal Change Nephrotic Syndrome

Abstract

Glucocorticoid treatment is the first choice therapy for adults with minimal change nephrotic syndrome; however, this therapy associates with many adverse effects. Tacrolimus may be an alternative to conventional glucocorticoid therapy. To investigate this possibility, we conducted a prospective, randomized, controlled trial (WHO International Clinical Trials Registry Platform: ChiCTR-TRC-11001454) in eight renal units across China. We randomized enrolled patients with adult-onset minimal change nephrotic syndrome (=119) to receive glucocorticoid therapy or tacrolimus after intravenous methylprednisolone (0.8 mg/kg per day) for 10 days. Patients received a conventional glucocorticoid regimen or tacrolimus monotherapy, starting with 0.05 mg/kg per day (target trough whole-blood level of 4-8 ng/ml) for 16-20 weeks and subsequently tapering over approximately 18 weeks. Remission occurred in 51 of 53 (96.2%; all complete remission) glucocorticoid-treated patients and 55 of 56 (98.3%; 52 complete and three partial remission) tacrolimus-treated patients (=0.61 for remission; =0.68 for complete remission). The groups had similar mean time to remission (=0.55). Relapse occurred in 49.0% and 45.5% of the glucocorticoid- and tacrolimus-treated patients, respectively (=0.71), with similar time to relapse (=0.86). Seven (13.7%) glucocorticoid-treated and four (7.3%) tacrolimus-treated patients suffered frequent relapse (=0.28); five glucocorticoid-treated and two tacrolimus-treated patients became drug dependent (=0.26). Adverse events occurred more frequently in the glucocorticoid group (128 versus 81 in the tacrolimus group). Seven adverse events in the glucocorticoid group and two adverse events in the tacrolimus group were serious. Consequently, tacrolimus monotherapy after short-term intravenous methylprednisolone is noninferior to conventional glucocorticoid treatment for adult-onset minimal change nephrotic syndrome in this cohort.

Randomized, Controlled Trial of Tacrolimus and Prednisolone Monotherapy for Adults with De Novo Minimal Change Disease

“…Relapse rates were similar in our tacrolimus and prednisolone treatment groups and comparable to the 48-76% relapse rates reported in other case series 9,13,14,41 . Our relapse rate is higher than either of the cohorts in the Li et al study 40 . This may also be explained by the use of intravenous methylprednisolone in the Li et al study or to racial differences in relapse rates.…”

“…We recorded equal and relatively few adverse events in both treatment regimens. The study by Li et al recorded a higher rate of total adverse events (209 adverse events in 119 study patients), and did show an increased adverse event frequency in the prednisolone cohort, particularly osteoporosis and new-onset hypertension 40 . Following intravenous methylprednisolone for ten days, the prednisolone treatment regimen used by Li et al provided 1mg/kg oral prednisolone (up to a maximum of 80mg/day) and 22-24 weeks total prednisolone treatment.…”

“…The most comprehensive clinical trial of de novo minimal change disease in adults comes from China. In this, Li et al compared the use of tacrolimus and prednisolone monotherapy in adults with minimal change disease 40 after treatment of all patients with high dose daily intravenous methylprednisolone (0.8mg/kg) for ten days 40 . Notably high remission rates were achieved in both cohorts, more than 90% of both treatment cohorts were in remission by four weeks 40 .…”

“…In this, Li et al compared the use of tacrolimus and prednisolone monotherapy in adults with minimal change disease 40 after treatment of all patients with high dose daily intravenous methylprednisolone (0.8mg/kg) for ten days 40 . Notably high remission rates were achieved in both cohorts, more than 90% of both treatment cohorts were in remission by four weeks 40 . This may be due to initial use of high-dose intravenous corticosteroids in all their patients, but there may also be a difference in response rates between Chinese and UK patients 13,23 .…”

“…Non-inferiority was assessed by estimating the two-sided 95% confidence interval (CI) for the difference in remission rates between the two groups using the Koopman asymptomatic score 38 .We aimed to verify that the lower limit of the 95% CI was not lower than 10% (delta value of -0.1). The expected complete remission rate for patients treated with corticosteroids at eight weeks was estimated at 60% 23 , and tacrolimus at 84% 40 . Allowing for a 10% drop-out rate, we calculated we needed to enrol 52 patients.…”