High-Dose Versus Standard-Dose Manidipine for Albuminuria Reduction in Hypertensive Patients With Chronic Kidney Disease: A Triple-Blind, Randomized, Placebo-Controlled Trial

Abstract Background Albuminuria predicts CKD progression and cardiovascular risk. Randomized evidence on manidipine dose escalation in CKD is limited. We evaluated the efficacy and safety of increasing manidipine from 20 to 40 mg/day in hypertensive adults with albuminuric CKD. Methods This single-center, randomized, placebo-controlled trial was conducted in Thailand. Adults aged 35–80 years with hypertension, eGFR ≥ 30 mL/min/1.73 m², persistent UACR > 30 mg/g, and background manidipine 20 mg/day were randomized 1:1 to add-on manidipine 20 mg/day (total 40 mg/day) or matching placebo for 6 months. Participants, treating investigators, outcome assessors, and the statistician responsible for the final analysis were masked to treatment allocation. The primary outcome was a ≥ 30% reduction in UACR from baseline to 6 months, analyzed in all randomized participants using non-responder imputation and Pearson’s chi-square test. Results Ninety-four participants were randomized (46 high-dose; 48 standard-dose); five had no post-baseline assessments. The primary outcome occurred in 32/46 (69.6%) and 15/48 (31.3%) participants, respectively (risk ratio, 2.23; 95% CI, 1.40–3.53; risk difference, 38.3 percentage points; 95% CI, 19.6–57.0; P < 0.001). In the observed-case modified intention-to-treat population, the baseline-adjusted geometric mean ratio for high-dose versus standard-dose UACR at 6 months was 0.48 (95% CI, 0.31–0.74; P = 0.001). No statistically significant between-group differences were observed in blood pressure or kidney function. Among 89 participants with post-baseline safety data, adverse events occurred in 10/44 (22.7%) versus 5/45 (11.1%) (risk difference, 11.6 percentage points; 95% CI, − 4.2 to 27.2; P = 0.167); ankle edema occurred in 18.2% versus 8.9%. One high-dose participant discontinued study medication because of an adverse event; no serious adverse events occurred. Conclusions Escalating manidipine from 20 to 40 mg/day increased the probability of achieving a ≥ 30% UACR reduction and lowered UACR at 6 months. The albuminuria effect was observed without statistically significant between-group differences in blood pressure or kidney function, although blood-pressure lowering may have contributed. Adverse events were numerically more frequent with high-dose therapy. Larger, longer-term trials are needed to clarify safety and clinical kidney or cardiovascular benefit. Clinical trial registration: Thai Clinical Trials Registry, TCTR20260411008. Retrospectively registered on 11 April 2026.