Comparative Effectiveness of Lubiprostone and Stool Softeners on Risk of Kidney Outcomes in Patients with CKD

Key Points Lubiprostone has been suggested to exert kidney protective effects by improving the gut microbiome in animal studies. This comparative effectiveness study examined the association of lubiprostone (versus softeners) use with kidney outcomes in patients with CKD. Lubiprostone (versus softeners) use was associated with a lower risk of progressive kidney function decline in patients with CKD and constipation. Background Lubiprostone, a chloride channel activator used to treat constipation, has been suggested to exert kidney protective effects by improving the gut microbiome. However, little is known about the comparative effectiveness of lubiprostone versus conventional laxatives on the risk of kidney outcomes in patients with CKD. Methods Among US veterans with CKD and constipation receiving care from the Veterans Administration health care system over 2004–2019, we identified incident users of lubiprostone versus stool softeners (docusate sodium or calcium), excluding combined users of the examined drugs. We used a target trial emulation approach to examine the association of lubiprostone versus stool softener use with a subsequent risk of a composite kidney outcome (incident ESKD, incident eGFR <15 ml/min per 1.73 m 2 , or 57% reduction in eGFR, as primary) and change in eGFR (as secondary). The associations were examined using weighted Cox models for the composite kidney outcome and weighted multinomial logistic regression models for change in eGFR, applying a propensity score-overlap weighting method to minimize confounding by indication. Results Among 52,231 patients who met eligibility criteria, 551 (1%) and 51,680 (99%) were incident users of lubiprostone and stool softeners, respectively. Compared with incident stool softener users, incident lubiprostone users had a significantly lower risk of a composite kidney outcome (hazard ratio [95% confidence interval], 0.70 [0.51 to 0.97]) and lower risk of experiencing more progressive eGFR decline (multinomial odds ratios [95% confidence interval] for eGFR slope <−3 and −3 to <−1 [versus −1 to <0] ml/min per 1.73 m 2 per year, 0.39 [0.23 to 0.68] and 0.73 [0.53 to 1.01], respectively). Conclusions Incident lubiprostone (versus stool softener) use was independently associated with a lower risk of progressive kidney function decline in patients with CKD and constipation. Further studies are needed to refine the comparative effectiveness of different laxative types on kidney outcomes in clinical trials. Podcast This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2025_10_28_CJASNOctober.20.10..mp3