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

Abstract

Background and objectives: Minimal change disease is an important cause of nephrotic syndrome in adults. Corticosteroids are first-line therapy for minimal change disease, but a prolonged course of treatment is often required and relapse rates are high. Patients with minimal change disease are therefore often exposed to high cumulative corticosteroid doses and are at risk of associated adverse effects. This study investigated whether tacrolimus monotherapy without corticosteroids would be effective for the treatment of de novo minimal change disease.

Design, setting, participants, & measurements: This was a multicenter, prospective, open-label, randomized, controlled trial involving six nephrology units across the United Kingdom. Adult patients with first presentation of minimal change disease and nephrotic syndrome were randomized to treatment with either oral tacrolimus at 0.05 mg/kg twice daily, or prednisolone at 1 mg/kg daily up to 60 mg daily. The primary outcome was complete remission of nephrotic syndrome after 8 weeks of therapy. Secondary outcomes included remission of nephrotic syndrome at 16 and 26 weeks, rates of relapse of nephrotic syndrome, and changes from baseline kidney function.

Results: There were no significant differences between the tacrolimus and prednisolone treatment cohorts in the proportion of patients in complete remission at 8 weeks (21 out of 25 [84%] for prednisolone and 17 out of 25 [68%] for tacrolimus cohorts; P=0.32; difference in remission rates was 16%; 95% confidence interval [95% CI], -11% to 40%), 16 weeks (23 out of 25 [92%] for prednisolone and 19 out of 25 [76%] for tacrolimus cohorts; P=0.25; difference in remission rates was 16%; 95% CI, -8% to 38%), or 26 weeks (23 out of 25 [92%] for prednisolone and 22 out of 25 [88%] for tacrolimus cohorts; P=0.99; difference in remission rates was 4%; 95% CI, -17% to 25%). There was no significant difference in relapse rates (17 out of 23 [74%] for prednisolone and 16 out of 22 [73%] for tacrolimus cohorts) for patients in each group who achieved complete remission (P=0.99) or in the time from complete remission to relapse.

Conclusions: Tacrolimus monotherapy can be effective alternative treatment for patients wishing to avoid steroid therapy for minimal change disease.

Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_01_16_CJN06180519.mp3.

Keywords: Glomerulonephritis; United Kingdom; adult; humans; lipoid nephrosis; nephrology; nephrotic syndrome; prednisolone; prospective studies; recurrence; remission induction; tacrolimus; treatment outcome.

Graphical abstract

Figure 1.

Study design and study cohort flowchart. Of 55 patients enrolled, 52 were randomized to treatment, and 25 patients in each cohort completed treatment. Two patients in the tacrolimus group did not complete treatment; one patient developed diarrhea and rash 2 days after starting tacrolimus; one patient developed lower respiratory tract infection 8 days into treatment; both were withdrawn from the study to receive nonprotocol treatment. These patients are included in the intention-to-treat analysis and excluded from the per-protocol analysis.

Figure 2.

The proportion of patients achieving complete remission. (A) Complete remission and (B) all remission (complete or partial remission) against weeks from the start of treatment in the prednisolone (gray, solid line) and tacrolimus (black, dashed line) cohorts. The number of patients achieving remission is shown in the table below each graph.

Figure 3.

The proportion of patients who suffered a relapse after complete remission in the prednisolone (gray, solid line) and tacrolimus (black, dashed line) cohorts. The number of patients with relapse after complete remission at 26-week intervals is shown. Two of the patients in remission in the prednisolone group were lost to follow-up at 36 weeks and 40 weeks.

Figure 4.

Changes in mean serum creatinine, median urine protein-to-creatinine ratio, and mean serum albumin from the start of treatment and during follow-up in the prednisolone and tacrolimus treated cohorts. The urine protein-to-creatinine ratio data were nonparametrically distributed.