Lubiprostone in chronic kidney disease: Insights into mitochondrial function and polyamines from a randomized phase 2 clinical trial.

Yoshiyasu Tongu, Koichi Kikuchi, Chitose Suzuki, Hidetaka Tokuno, Marina Urasato, Ryota Kujirai, Yotaro Matsumoto, Yasutoshi Akiyama, Yoshihisa Tomioka, Shun Itai, Hitomi Kashiwagi, Eikan Mishima, Chiharu Kawabe, Tomoko Kasahara, Yoshiaki Ogata, Takafumi Toyohara, Takeya Sato, Tetsuhiro Tanaka, Takaaki Abe, Junichiro J Kazama, Shun Watanabe, Masaaki Nakayama, Takashi Yokoo, Satoru Sanada, Yoshifumi Ubara, Atsushi Komatsuda, Katsuhiko Asanuma, Yusuke Suzuki, Tsuneo Konta, Kei Fukami, Takehiro Suzuki, Shinji Fukuda, Tomoyoshi Soga, Takuji Yamada, Sayaka Mizutani, Mitsuharu Matsumoto, Yuji Naito, Kensei Taguchi

Journal: Science advances 2025;11(35):eadw3934

PMID: 40880481

View on PubMed

Abstract

Chronic kidney disease (CKD) is a life-threatening condition, and constipation is a progressive risk factor. We evaluated changes in uremic toxins, renal function, and the safety of lubiprostone, a selective chloride channel activator, in patients with CKD. In this phase 2, randomized, double-blind, placebo-controlled trial across nine centers in Japan, 150 patients with stage IIIb-IV CKD received lubiprostone (8 or 16 micrograms) or placebo for 24 weeks. The primary end point was change in indoxyl sulfate levels. Secondary end points included other uremic toxins and renal function markers. Lubiprostone did not alter uremic toxin levels but improved or preserved estimated glomerular filtration rate and its slope in the 16-microgram group. Mild-to-moderate gastrointestinal events occurred in the placebo and 16-microgram groups. Multiomics analysis revealed that lubiprostone modulated the gut microbial agmatine pathway and increased spermidine levels, thereby improving renal mitochondrial function. Lubiprostone is a previously unknown and safe therapeutic option to mitigate renal decline in CKD.

Address: Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8574, Japan.; Division of Nephrology, Rheumatology, and Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8574, Japan.; Department of Nephrology, St. Luke's International Hospital, Chuo-ku, Tokyo 104-8560, Japan.; Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Minato-ku, Tokyo 105-8461, Japan.; Department of Nephrology, Japan Community Health Care Organization Sendai Hospital, Sendai, Miyagi 981-3281, Japan.; Nephrology Center, Toranomon Hospital, Minato-ku, Tokyo 105-8470, Japan.; Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Akita 010-8543, Japan.; Department of Nephrology, Graduate School of Medicine, Chiba University, Chiba, Chiba 263-8522, Japan.; Department of Nephrology, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.; Department of Public Health and Hygiene, Yamagata University School of Medicine, Yamagata, Yamagata 990-9585, Japan.; Department of Nephrology, Fukushima Medical University, Fukushima, Fukushima 960-1295, Japan.; Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan.; Laboratory for Regenerative Microbiology, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.; Gut Environmental Design Group, Kanagawa Institute of Industrial Science and Technology, Kawasaki, Kanagawa 210-0821, Japan.; Transborder Medical Research Center, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.; Metagen Inc., Tsuruoka, Yamagata 997-0052, Japan.; Metagen Theurapeutics Inc., Tsuruoka, Yamagata 997-0052, Japan.; Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan.; Metagen Inc., Tsuruoka, Yamagata 997-0052, Japan.; Metagen Theurapeutics Inc., Tsuruoka, Yamagata 997-0052, Japan.; School of Life Science and Technology, Institute of Science Tokyo, Meguro-ku, Tokyo 152-8550, Japan.; digzyme, Inc., Minato-ku, Tokyo 105-0004, Japan.; Metagen Inc., Tsuruoka, Yamagata 997-0052, Japan.; Dairy Science and Technology Institute, Kyodo Milk Industry Co. Ltd., Hinode-machi, Tokyo 190-0182, Japan.; Department of Human Immunology and Nutrition Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto 602-8566, Japan.; Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan.; Research Institute of Medical Mass Spectrometry, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan.; Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan.; Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8574, Japan.; Laboratory of Oncology, Pharmacy Practice and Sciences, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Miyagi 980-8578, Japan.; Division of Nephrology, Rheumatology, and Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8574, Japan.; Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8574, Japan.; Division of Nephrology, Rheumatology, and Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8574, Japan.; Division of Medical Science, Tohoku University Graduate School of Biomedical Engineering, Sendai, Miyagi 980-9874, Japan.

DOI: 10.1126/sciadv.adw3934

MeSH Terms: Humans, Renal Insufficiency, Chronic, Male, Female, Lubiprostone, Middle Aged, Aged, Mitochondria, Polyamines, Glomerular Filtration Rate, Double-Blind Method, Adult