Comparison of the Efficacy and Safety of Tacrolimus and Low-Dose Corticosteroid with High-Dose Corticosteroid for Minimal Change Nephrotic Syndrome in Adults
Authors: Chin Ho Jun , Chae Dong-Wan , Kim Yong Chul , An Won Suk , Ihm ChunGyoo , Jin Dong-Chan , Kim Sung Gyun , Kim Yong-Lim , Kim Yong-Soo , Kim Yoon-Goo , Koo Ho Seok , Lee Jung Eun , Lee Kang Wook , Oh Jieun , Park Jung Hwan , Jiang Hongsi , Lee Hyuncheol , Lee Sang Koo 
Published: November 2020

Significance Statement
Steroid resistance, relapse, and side effects are common issues in use of high-dose steroids as first-line treatment for adult minimal change nephrotic syndrome. Tacrolimus is used as a steroid-sparing immunosuppressant to reduce adverse effects of long-term or repeated steroid treatment, but no large-scale randomized study has compared combined tacrolimus and low-dose steroid with high-dose steroid in treating minimal change nephrotic syndrome in adults. In this open-label randomized trial, the authors found that treatment with tacrolimus plus low-dose steroid was noninferior to high-dose steroid for complete remission at 8 weeks, and that treatment with a maintenance dose of tacrolimus during steroid tapering reduced the relapse rate, with no clinically-relevant safety differences. This indicates that tacrolimus is an effective alternative to high-dose steroids in this disease, although investigation into long-term safety is warranted.

Background
Tacrolimus is used as a steroid-sparing immunosuppressant in adults with minimal change nephrotic syndrome. However, combined treatment with tacrolimus and low-dose steroid has not been compared with high-dose steroid for induction of clinical remission in a large-scale randomized study.

Methods
In this 24-week open-label noninferiority study, we randomized 144 adults with minimal change nephrotic syndrome to receive 0.05 mg/kg twice-daily tacrolimus plus once-daily 0.5 mg/kg prednisolone, or once-daily 1 mg/kg prednisolone alone, for up to 8 weeks or until achieving complete remission. Two weeks after complete remission, we tapered the steroid to a maintenance dose of 5–7.5 mg/d in both groups until 24 weeks after study drug initiation. The primary end point was complete remission within 8 weeks (urine protein: creatinine ratio <0.2 g/g). Secondary end points included time until remission and relapse rates (proteinuria and urine protein: creatinine ratio >3.0 g/g) after complete remission to within 24 weeks of study drug initiation.

Results
Complete remission within 8 weeks occurred in 53 of 67 patients (79.1%) receiving tacrolimus and low-dose steroid and 53 of 69 patients (76.8%) receiving high-dose steroid; this difference demonstrated noninferiority, with an upper confidence limit below the predefined threshold (20%) in both intent-to-treat (11.6%) and per-protocol (17.0%) analyses. Groups did not significantly differ in time until remission. Significantly fewer patients relapsed on maintenance tacrolimus (3–8 ng/ml) plus tapered steroid versus tapered steroid alone (5.7% versus 22.6%, respectively; P=0.01). There were no clinically relevant safety differences.

Conclusions
Combined tacrolimus and low-dose steroid was noninferior to high-dose steroid for complete remission induction in adults with minimal change nephrotic syndrome. Relapse rates were significantly lower with maintenance tacrolimus and steroid compared with steroid alone. No clinically-relevant differences in safety findings were observed.