Kidney Res Clin Pract. 2026;45(2):220-231.

Evaluating the Safety and effectivenesS in adult KorEaN patients treated with Tolvaptan for management of autosomal domInAnt poLycystic kidney disease (ESSENTIAL): final report.

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제1저자 박혜인조, 김영철 · 교신저자 오윤규

PMID 39384353 PMC12990202 DOI 10.23876/j.krcp.24.067 IF 3.5 신장내과

소속 (20)

Department of Internal Medicine, Hallym University Kangnam Sacred Heart Hospital, Seoul, Republic of Korea.
Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
Department of Internal Medicine, Hallym University Chuncheon Sacred Heart Hospital, Chuncheon, Republic of Korea.
Department of Internal Medicine, Keimyung University Dongsan Hospital, Daegu, Republic of Korea.
Department of Internal Medicine, The Catholic University of Korea, Seoul St. Mary's Hospital, Seoul, Republic of Korea.
Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea.
Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
Department of Internal Medicine, Kosin University Gospel Hospital, Busan, Republic of Korea.
Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
Department of Internal Medicine, Kangbuk Samsung Hospital, Seoul, Republic of Korea.
Department of Internal Medicine, Gangnam Severance Hospital, Seoul, Republic of Korea.
Department of Internal Medicine, Severance Hospital, Seoul, Republic of Korea.
Department of Internal Medicine, Inje University Busan Paik Hospital, Busan, Republic of Korea.
Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea.
Department of Internal Medicine, Hallym University Sacred Heart Hospital, Anyang, Republic of Korea.
Department of Internal Medicine, Hanyang University Seoul Hospital, Seoul, Republic of Korea.
Department of Diagnostic Radiology, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China.
Department of Internal Medicine, National Medical Center, Seoul, Republic of Korea.
Department of Internal Medicine, SMG-SNU Boramae Medical Center, Seoul, Republic of Korea.

Abstract

BACKGROUND Tolvaptan, a selective vasopressin V2 receptor antagonist, was first approved by the Korean Ministry of Food and Drug Safety in 2015 as a treatment option for autosomal dominant polycystic kidney disease (ADPKD). To prescribe tolvaptan safely and effectively, we designed the phase 4 clinical trial among Korean ADPKD patients with chronic kidney disease stages 1 to 3.

METHODS A total of 117 Korean patients aged 19 to 50 years with rapidly progressing ADPKD were enrolled in the study. Tolvaptan was prescribed for 24 months with the maximum tolerable dose up to 120 mg/day. The primary outcome was the incidence of treatment-emergent adverse events (TEAEs) including hepatic adverse events. The secondary outcomes were the annual mean percent change of total kidney volume (TKV) and the annual mean change of estimated glomerular filtration rate (eGFR).

RESULTS A total of 489 TEAEs occurred in 106 patients (90.6%). A total of 17 cases of hepatic adverse events (14.5%) occurred during the study period and mostly within the first 18-month period. However, liver enzymes were normalized after drug discontinuation. Although it was not statistically significant, patients with a previous history of liver disease as well as those with mild elevation of liver enzyme showed a higher frequency of hepatic adverse events. Compared with the predicted value from the calculation, tolvaptan attenuated both TKV growth and eGFR decline rate.

CONCLUSION Although the incidence of hepatic adverse events was higher in Korean ADPKD patients compared to the previous studies, tolvaptan can be prescribed safely and effectively using meticulous titration and 1-month interval monitoring.

Keywords

Autosomal dominant polycystic kidneyChemical and drug induced liver injuryDrug-related side effects and adverse reactionsGlomerular filtration rateTolvaptanTreatment outcome

Figures

**Figure 1.** Study design. This was a multicenter, single-arm, open-label, phase 4 clinical trial to evaluate the safety and effectiveness of tolvaptan among Korean patients with rapidly progressive autosomal dominant polycystic kidney disease (ADPKD). Subjects who met inclusion criteria through a screening period up to 8 weeks underwent a 4-week titration period to check tolerability to tolvaptan treatment. The subjects received tolvaptan for 2 years with the maximum tolerable dose of 120 mg per day. Subjects followed the specified procedures at each regular visit. Whether the subjects completed a 2-year administration of drug or not, all patients were subjected to the last follow-up visit (visit 26) to confirm the safety and effectiveness of tolvaptan treatment. CKD, chronic kidney disease; FU, follow-up; TKV, total kidney volume, W, week.

**Figure 2.** The safety profile of tolvaptan among Korean patients with autosomal dominant polycystic kidney disease. (A) A total of 489 treatment-emergent adverse events (TEAEs) occurred in 90.6% of the subjects during the 2 years of study period. Nearly half of the TEAEs occurred within 6 months of the study. (B) A total of 17 hepatic adverse events (14.5%) occurred during the study period. Most of the cases occurred within the first 18 months. Arrows means the time to the first adverse drug reaction related liver injury.

**Figure 3.** Incidence of hepatic adverse events according to subgroups. (A) Patients with a medical history of liver disease showed a higher tendency of hepatic adverse events with marginal statistical significance (33.3% vs. 12.4%, p = 0.07). (B) Patients with elevated liver enzymes before taking tolvaptan demonstrated a higher tendency of hepatic adverse events without statistical significance (26.1% vs. 11.7%, p = 0.10). (C) There was no difference in hepatic adverse events according to Mayo imaging classification (p = 0.14). (D) There was no difference in hepatic adverse events according to chronic kidney disease (CKD) stages (p = 0.84). ALT, alanine aminotransferase; AST, aspartate aminotransferase; TEAE, treatment-emergent adverse events; ULN, upper limit of normal.

**Figure 4.** Effect of tolvaptan upon TKV and eGFR. (A) The mean annual growth rate (AGR) of TKV among tolvaptan-treated patients was 4.5% ± 0.5%. The tolvaptan effect to attenuate kidney growth was the largest at the end point of titration (–2.3% ± 1.0%) and decreased thereafter (1.2% ± 1.2% at 1 year and 8.6% ± 1.5% at 2 years). (B) The on-treatment effect was calculated using the annual eGFR decline rate from the completion of the tolvaptan titration period to the end of the treatment visit (3.0 ± 0.39 mL/min/1.73 m²/yr). (C) The off-treatment effect was calculated using the annual eGFR decline rate from baseline to the follow-up visit (–3.09 ± 0.38 mL/min/1.73 m²/yr). A linear mixed model with log₁₀-transformed as TKV data and (date of MRI visit – date of MRI visit at baseline) / 365.25 as time. B, baseline; eGFR, estimated glomerular filtration rate; FU, follow-up; M, month; MRI, magnetic resonance imaging; SE, standard error; TKV, total kidney volume; W, week.

그림 출처: PubMed Central 공개 논문 (PMC12990202)

Conflict of interest statement

Conflicts of interest . Tae-Hyun Yoo is the Editor-in-Chief, and Seungyeup Han is an Associate Editor of Kidney Research and Clinical Practice. Soo Wan Kim was an Associate Editor at the time of submission and review. They were not involved in the review process of this article. All authors have no other conflicts of interest to declare.

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