Tacrolimus decreases albuminuria in patients with IgA nephropathy and normal blood pressure: a double-blind randomized controlled trial of efficacy of tacrolimus on IgA nephropathy

Abstract

Background: Treatment remains uncertain for IgA nephropathy patients with mild to moderate proteinuria, for whom anti-hypertensive medication or the RAS blocker is not applicable due to low blood pressure.

Trial design: A double blinded randomized trial.

Methods: The anti-proteinuric effect of tacrolimus was explored for 40 biopsy-proven mild IgA nephropathies for 16 weeks. We randomly assigned patients either to receive tacrolimus or placebo with stratification by using a renin angiotensin system blocker. The primary outcome was the percentage change of final UACR compared to the baseline value (pcUACR).

Results: The mean value of pcUACR at 12-week and 16-week visits (primary outcome) was decreased more in the Tac group compared to the control group (-52.0±26.4 vs -17.3±29.3%, p = 0.001). At each visit, pcUACR was also decreased more in the Tac group compared to the control group. In the Tac group, the pcUACRs were -60.2±28.2%, -62.2±33.9%, -48.5±29.8%, and -55.5±24.0%, and, in the control group, -6.8±32.2%, -2.5±35.9%, -12.7±34.2%, and -21.9±30.6%, at 4-week, 8-week, 12-week, and 16-week visits, respectively. The pre-defined secondary outcomes were better in the Tac group compared to the control group. The frequency of decrease in pcUACR and percentage change of UPCR (pcUPCR) ≥50% at 16 weeks were 65.0% (13/20) and 55.0% (11/20)in the Tac group, and 25.0% (5/20) and 15.0% (3/20), in the control group, respectively (p = 0.025 for pcUACR and p = 0.019 for pcUPCR). However, tacrolimus wasn't effective with a dose of 0.05 mg/kg/day in patients taking ARB. The adverse events were tolerable.

Conclusion: Tacrolimus effectively reduced proteinuria in IgA nephropathy with normal blood pressure. This suggested that tacrolimus could be an alternative to corticosteroid and RAS blocker for IgA nephropathy patients who cannot endure anti-hypertensive medication.

Trial registration: Clinicaltrial.gov NCT1224028.

Trial registration: ClinicalTrials.gov NCT01224028 NCT01224028.

Conflict of interest statement

Competing Interests: This study was supported by Astellas pharma Korea. HJC and SK had another research grant from Astellas pharma Korea and have been conducting a clinical trial. Astellas pharma Korea owns the branded version of the drug being investigated in this study. There are no further patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Study algorithm.

One patient in the control group withdrew at the 8-week visit because of the addition of a prohibited drug in another department, one patient in the Tac group withdrew at day 1 after enrollment because of pregnancy and had taken only 2 mg of tacrolimus, and another patient in the Tac group withdrew at the 4-week visit because of general weakness and myalgia related to medication.

Figure 2. The percentage changes of UACR and UPCR at each visit compared to the baseline level.

2A. Percent changes of UACR. 2B. Percent changes of UPCR. Baseline UACR or UPCR; mean value of UACR or UPCR at screening period and randomization. Final; mean value of UACR at 12 weeks and 16 weeks. The bar in each bar graph is the 95% confidence interval of mean value of the percent change of UACR or UPCR at each visit compared to baseline level. * p-value t-test for percent change of UACR or UPCR between control and Tac groups at each visit.

Figure 3. The frequency of decrease in UACR and UPCR at 16 weeks as secondary outcomes.

Outcome Aa and Ap: frequency of decrease in UACR and UPCR ≥30% at 16 weeks, compared to baseline level. Outcome Ba and Bp: frequency of decrease in UACR and UPCR ≥50% at 16 weeks compared to baseline level, Outcome Ca and Cp: frequency of decrease in UACR and UPCR