Lubiprostone May Offer Renoprotection in CKD

A multicenter, randomized phase 2 clinical trial reported that lubiprostone, a medication typically prescribed for chronic constipation, preserved renal function over 24 weeks in patients with stage IIIb-IV chronic kidney disease (CKD), despite no significant change in gut-derived uremic toxins. The study, published in Science Advances, suggests that lubiprostone achieves this effect not by directly altering uremic toxin levels, but by modulating the gut microbiota and enhancing renal mitochondrial function.¹

Constipation frequently accompanies CKD and is linked to accelerated eGFR decline and increased progression to end-stage disease.² Patients with CKD also exhibit gut microbiota dysbiosis with associated "leaky gut" barrier impairment.3

The LUBI-CKD TRIAL screened 150 patients and randomized 118 to placebo (n = 35), lubiprostone 8 µg/day (n = 33), or 16 µg/day (n = 50).¹ Baseline characteristics were balanced: mean age 63 years, 34.5% women, all Asian; moderate and severe CKD were roughly equally represented (55 vs 61 patients). Prior use of ACE inhibitors/ARBs, SGLT2 inhibitors, MR antagonists, and GLP-1 agonists was comparable across arms.

The primary endpoint, change in serum indoxyl sulfate (IS) from baseline to week 24, was not significantly affected by lubiprostone. The same was true for other uremic toxins (phenyl sulfate, p-cresyl sulfate, and TMAO), which showed no significant alteration at the study's conclusion. However, despite the neutral toxin profile, renal function outcomes improved, demonstrating a significant and dose-dependent preservation of estimated glomerular filtration rate. In the 16-µg lubiprostone group, the estimated glomerular filtration rate based on serum creatinine (eGFRCr) was preserved in the 16 μg group between baseline and the 24-week endpoint, with an LSM change of 0.37 ml/min per 1.73 m² compared to -1.55 ml/min per 1.73 m² in the placebo group (P = .046), with improvements observed as early as week 8.

In subgroup analyses, patients with moderate CKD showed preservation of eGFRCr slope at both 8 µg and 16 µg. Conversely, cystatin C, cystatin C-based eGFR, and its slope did not change, and urinary protein excretion was unchanged. Blood urea nitrogen improved in the 16-µg arm (LSM difference vs placebo -2.90 mg/dl, P = .02).

No new safety findings were observed and were consistent with lubiprostone's known gastrointestinal profile. Diarrhea occurred in 12.1% of patients on 8 µg and 16% on 16 µg. Discontinuations due to adverse events were 8% with 16 µg, 5.7% with placebo, and 0% with 8 µg; differences were not statistically significant.

To understand the mechanism behind these observed renoprotective effects, the researchers conducted a comprehensive Mechanistic analysis, integrating targeted metabolomics, 16S rRNA sequencing, and shotgun metagenomics. This analysis revealed that in responders (patients in the 16 μg arm who showed eGFR improvement), lubiprostone modulated the gut microbial agmatine pathway and increased plasma spermidine levels, correlated with improved eGFR and mitochondrial function.Increases in beneficial genera, such as Blautia, Roseburia, and Akkermansia, were noted, alongside higher fecal expression of agmatine deiminase (aguA), an enzyme important for polyamine synthesis.

While the study's limitations include modest sample size, relatively short 24-week duration, and focus on Japanese patients, it suggests that lubiprostone preserves renal function in stage IIIb-IV CKD, likely through the polyamine-mitochondrial axis, independent of uremic toxins. This reframes the long-standing paradigm linking constipation treatment and toxin removal with kidney protection, suggesting that therapies targeting gut microbiota and mitochondrial health may hold new promise for slowing CKD progression.

References

1. Watanabe S, Nakayama M, Yokoo T, et al; LUBI-CKD TRIAL Investigators. Lubiprostone in chronic kidney disease: Insights into mitochondrial function and polyamines from a randomized phase 2 clinical trial. Sci Adv. 2025;11(35):eadw3934. doi:10.1126/sciadv.adw3934
2. Sumida K, Dashputre AA, Potukuchi PK, et al. Laxative use and change in estimated glomerular filtration rate in patients with advanced chronic kidney disease. J Ren Nutr. 2021l;31(4):361-369. doi:10.1053/j.jrn.2020.08.005
3. suji K, Uchida N, Nakanoh H, Fukushima K, Haraguchi S, Kitamura S, Wada J. The gut-kidney axis in chronic kidney diseases. Diagnostics. 2024;15(1):21. doi:10.3390/diagnostics15010021