Lubiprostone in chronic kidney disease: Insights into mitochondrial function and polyamines from a randomized phase 2 clinical trial
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.
Authors
- Yotaro Matsumoto (ORCID: https://orcid.org/0000-0001-8498-1341)
- Yoshifumi Ubara (ORCID: https://orcid.org/0000-0003-2322-8203)
- Tetsuhiro Tanaka (ORCID: https://orcid.org/0000-0002-2238-4215)
- Takafumi Toyohara (ORCID: https://orcid.org/0000-0001-7655-3005)
- Kensei Taguchi (ORCID: https://orcid.org/0000-0002-5555-1809)
- Katsuhiko Asanuma (ORCID: https://orcid.org/0009-0005-4536-4873)
- Kei Fukami (ORCID: https://orcid.org/0000-0002-5583-3996)
- Sayaka Mizutani (ORCID: https://orcid.org/0000-0003-4168-6195)
- Tsuneo Konta (ORCID: https://orcid.org/0000-0001-7681-6469)
- Takuji Yamada (ORCID: https://orcid.org/0000-0002-9622-1849)
- Tomoyoshi Soga (ORCID: https://orcid.org/0000-0001-9502-2509)
- Shinji Fukuda (ORCID: https://orcid.org/0000-0001-5161-9880)
- Junichiro James Kazama (ORCID: https://orcid.org/0000-0001-7710-2660)
- Shun Watanabe (ORCID: https://orcid.org/0000-0001-6506-2606)
- Ryota Kujirai (ORCID: https://orcid.org/0009-0002-3600-7442)
- Mitsuharu Matsumoto (ORCID: https://orcid.org/0000-0002-0378-3077)
- Chitose Suzuki (ORCID: https://orcid.org/0009-0002-8242-4984)
- Yasutoshi Akiyama (ORCID: https://orcid.org/0000-0002-0211-7793)
- Hirofumi Kashiwagi
- Takashi Yokoo (ORCID: https://orcid.org/0000-0003-1838-7998)
- Shun Itai (ORCID: https://orcid.org/0009-0001-4939-478X)
- Takaaki Abe (ORCID: https://orcid.org/0000-0003-3170-4660)
- Yuji Naito (ORCID: https://orcid.org/0000-0001-5443-788X)
- Hidetaka Tokuno (ORCID: https://orcid.org/0000-0002-3973-092X)
- Atsushi Komatsuda (ORCID: https://orcid.org/0000-0003-1477-8131)
- Takeya Sato (ORCID: https://orcid.org/0000-0003-2409-1819)
- Tomoko Kasahara (ORCID: https://orcid.org/0000-0003-4109-2362)
- Eikan Mishima (ORCID: https://orcid.org/0000-0002-3706-2745)
- Yusuke Suzuki (ORCID: https://orcid.org/0000-0002-4077-9747)
- Yoshiaki Ogata (ORCID: https://orcid.org/0000-0002-8953-5372)
- Yoshiyasu Tongu (ORCID: https://orcid.org/0009-0005-9085-0563)
- Chiharu Kawabe
- Takehiro Suzuki (ORCID: https://orcid.org/0000-0002-1476-0794)
- Masaaki Nakayama (ORCID: https://orcid.org/0000-0002-7686-8899)
- Yoshihisa Tomioka
- Satoru Sanada (ORCID: https://orcid.org/0000-0002-7063-424X)
- Kôichi Kikuchi
- Marina Urasato
Institutions
- Kurume University (JP)
- Yamagata University (JP)
- Jikei University School of Medicine (JP)
- Fukushima Medical University (JP)
- University of Tsukuba (JP)
- Chiba University (JP)
- Kyoto Prefectural University (JP)
- Kanagawa Institute of Technology (JP)
- Tohoku University (JP)
- Akita University (JP)
- Keio University (JP)
- Juntendo University (JP)
- Kyoto Prefectural University of Medicine (JP)
- St. Luke's International Hospital (JP)
- Tohoku University Hospital (JP)
- Tohoku Medical and Pharmaceutical University Hospital (JP)
- Megmilk Snow Brand (Japan) (JP)
- Sendai Shakai Hoken Hospital (JP)
- Toranomon Hospital (JP)
- National Institute of Technology, Tsuruoka College (JP)
- Tohoku Medical and Pharmaceutical University (JP)
Publication Details
- Journal
- Science Advances
- Published
- 2025-08-29
- DOI
- https://doi.org/10.1126/sciadv.adw3934
- Citations
- 2
- Primary Topic
- Dialysis and Renal Disease Management
- Type
- article
- Field-Weighted Citation Impact
- 2.86