Translational Muti-Omics Exploration of Lubiprostone Effect in Chronic Kidney Disease: Insight from a Randomized Clinical Trial

The incidence of chronic kidney disease (CKD) has been increasing, often progressing to end-stage renal disease. Although constipation is a risk factor in CKD patients, the effect of constipation treatment on reducing uremic toxins and renal function remains unknown. To assess the changes in uremic toxins, renal function and safety of a selective chloride channel activator, lubiprostone, in CKD patients with stage IIIb-IV. 150 CKD patients (estimated glomerular filtration rate (eGFR) 25-45 mL/min/1.73 m^2, stage IIIb-IV) were enrolled in a phase II, randomized, multicenter, double-blind, placebo-controlled exploratory study conducted across nine centers in Japan. Patients were randomized in a 2:2:3 ratio for placebo, 8 ug and 16 ug lubiprostone administration for 24 weeks. The primary endpoint was the change in indoxyl sulfate levels from baseline to 24 weeks. Secondary parameters such as other uremic toxins, changes in renal function (blood urea nitrogen (BUN), creatinine (Cr), cystatin C, eGFR estimated with Cr or cystatin C, urinary protein/Cr ratio, slope of the reciprocal of Cr, from baseline to 24 weeks), and defecation frequency were analyzed. Patients (n = 118; median age, 63 years) were divided into three groups: placebo (n = 35), 8 ug (n = 33), and 16 ug (n = 50) lubiprostone. Patients with eGFR 36-45 and 25-35 mL/min/1.73 m^2 were defined as having moderate and severe renal dysfunction, respectively. Lubiprostone did not change the uremic toxins but improved eGFR in the 16 ug group at the end of the trial, and maintained eGFR and eGFR slope. Especially, 8 and 16 ug lubiprostone was effective in CKD patients with moderate renal dysfunction. Mild-to-moderate adverse gastrointestinal events were reported in the placebo and 16 ug lubiprostone groups. Multiomics analyses revealed that lubiprostone modulated the gut microbial agmatine pathway and increased circulating polyamine level, resulting in improved renal mitochondrial function. Lubiprostone is a novel and safe therapeutic agent that mitigates renal function decline in patients with CKD.