A phase 2 clinical trial has found that lubiprostone, a drug commonly prescribed for chronic constipation, may help slow the decline of kidney function in adults with moderate to severe chronic kidney disease (CKD). The findings were published in Science Advances and suggest that the drug's benefits could be linked to changes in the gut microbiome and improvements in mitochondrial health.
The study involved 118 adults with stage IIIb–IV CKD across nine hospitals in Japan. Participants received either 8 μg/day or 16 μg/day of lubiprostone, or a placebo, over a period of 24 weeks. Researchers primarily measured changes in indoxyl sulfate, a gut-derived uremic toxin, but also tracked other markers such as blood urea nitrogen, creatinine levels, estimated glomerular filtration rate (eGFR), and safety outcomes.
According to the researchers, "Lubiprostone did not significantly change indoxyl sulfate, p-cresyl sulfate, phenyl sulfate, or trimethylamine N-oxide versus placebo at 24 weeks, although a transient reduction in p-cresyl sulfate was observed at week 4 in the 16 μg/day group." However, they noted that signals related to kidney function favored lubiprostone—especially at the higher dose. The eGFR from creatinine increased from baseline for those taking 16 μg/day compared to placebo (least-squares mean difference versus placebo 1.92 ml/min/1.73 m²; P=0.046), and this effect was most pronounced among participants with moderate CKD.
Adverse events were mostly mild to moderate gastrointestinal issues such as diarrhea. Discontinuation rates were similar between treatment and placebo groups.
Multiomics analyses revealed that lubiprostone was associated with increases in certain beneficial gut bacteria and metabolic pathways related to polyamine synthesis. In participants who responded positively to treatment at the higher dose, plasma spermidine levels rose and beneficial bacterial taxa expanded while potentially harmful ones declined.
Mechanistic studies using mice supported these observations: oral spermidine improved kidney markers and mitochondrial function while reducing inflammation-related pathways.
The authors concluded: "Together, these findings suggest that lubiprostone’s kidney effect tracks with a microbiome–polyamine–mitochondrial axis rather than reductions in gut-derived uremic toxins." They added that preserving eGFR without signs of fluid retention supports a biological mechanism beyond hemodynamic effects.
While the study duration was relatively short at 24 weeks and did not show significant reductions in primary uremic toxins, it indicated potential renal benefits for people living with CKD. The researchers emphasized the need for larger and longer trials to confirm these results and determine optimal dosing strategies.
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