TOPLINE:

A 16-µg dose of lubiprostone, a medication used in the management of constipation, improved or preserved estimated glomerular filtration rate (eGFR) in patients with chronic kidney disease (CKD), particularly those with moderate disease. The effects likely resulted from stimulating gut bacteria to produce spermidine, which enhanced mitochondrial function and protected the kidneys from further damage.

METHODOLOGY: 

• Constipation is common in patients with CKD and correlates with faster eGFR decline and a higher risk for end‐stage renal disease. The use of drugs such as lubiprostone improved renal function in animal models; however, their effects in CKD lack confirmation from randomized trials.
• Researchers conducted a phase 2 clinical trial across nine centers in Japan to evaluate the efficacy and safety of lubiprostone in 118 patients with stage IIIb-IV CKD who were randomly assigned to receive lubiprostone (8 or 16 μg) or placebo for 24 weeks.
• Participants with a persistent eGFR of 25-45 mL/min/1.73 m² for 3 months or more were included, with 55 patients having moderate renal dysfunction and 61 having severe renal dysfunction; 7.8% had diabetic kidney disease.
• The primary endpoint was the change in levels of indoxyl sulfate from baseline to 24 weeks, and secondary endpoints included the suppression of eGFR decline and changes in levels of blood urea nitrogen and urinary protein.
• Comprehensive metabolomics, 16S ribosomal RNA amplicon sequencing, and shotgun metagenome analysis were also conducted to evaluate changes in gut microbiota and metabolic pathways.

TAKEAWAY:

• Lubiprostone improved or preserved eGFR (calculated on the basis of serum creatinine) to a greater extent in the 16 μg group than in the placebo group (P = .0457); these benefits were only observed in patients with moderate renal dysfunction.
• The medication, however, did not lower levels of uremic toxins.
• Diarrhea, an anticipated adverse event, occurred in 12.1% and 16% of patients who received 8 µg and 16 µg lubiprostone, respectively, with no significant difference in discontinuation rates.
• Multiomics analyses showed that lubiprostone reshaped the gut microbiome’s agmatine pathway and increased spermidine levels, which in turn enhanced mitochondrial function and reduced inflammation, potentially preventing further progression of renal failure.

IN PRACTICE:

“Lubiprostone is a previously unknown therapeutic agent for CKD that improves renal function by modulating mitochondrial function. The primary objective of CKD treatment is to improve renal function rather than target surrogate markers, such as uremic toxins or proteinuria/albuminuria,” the authors of the study wrote.

SOURCE:

This study was led by Shun Watanabe, Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine, Sendai, Japan. It was published online on August 29, 2025, in Science Advances.

LIMITATIONS:

The clinical study period was relatively short and involved a small sample size. The renoprotective effects observed were secondary and exploratory endpoints, warranting cautious interpretation. The study was limited to Japanese participants, which restricted generalizability to other ethnic groups or broader CKD populations.

DISCLOSURES:

This study was supported by the Japan Agency for Medical Research and Development Translational Research Network Program and Research on Development of New Drugs, along with grants from other sources. One author had a patent of lubiprostone for CKD in Japan.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.