Lubiprostone in Chronic Kidney Disease: Insights into Mitochondrial Function and Polyamines from a Randomized Phase 2 Clinical Trial
The incidence of chronic kidney disease (CKD) is increasing; it often progresses to end-stage renal disease. Although constipation is a risk factor in patients with CKD, the effect of constipation treatment on reducing uremic toxins and improving renal function remains unknown. We assessed the changes in uremic toxins, renal function, and safety of a selective chloride channel activator, lubiprostone, in patients with CKD having stage IIIb-IV. A total of 150 patients with CKD (estimated glomerular filtration rate (eGFR): 25-45 mL/min/1.73 m2, 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 to receive placebo, 8 ug, or 16 ug lubiprostone for 24 weeks.The primary endpoint was the change in indoxyl sulfate levels from baseline to 24 weeks. Secondary parameters, including other uremic toxins, changes in renal function (blood urea nitrogen, creatinine (Cr), cystatin C, eGFR estimated with Cr or cystatin C, urinary protein/Cr ratio, and the slope of the reciprocal of Cr), 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 values of 36 to 45 and 25 to 35 mL/min/1.73 m2 were classified as having moderate and severe renal dysfunction, respectively. Lubiprostone did not change uremic toxin levels but improved eGFRCr in the 16 ug group at the end of the trial and maintained eGFRCr and eGFR slope. Both 8 ug and 16 ug doses of lubiprostone were effective in patients with CKD having moderate renal dysfunction. Mild-to-moderate adverse gastrointestinal events were reported in the placebo and 16 ug lubiprostone groups. Multi-omics analyses revealed that lubiprostone modulated the gut microbial agmatine pathway and increased circulating polyamine levels, resulting in improved renal mitochondrial function. Lubiprostone is a novel and safe therapeutic agent that mitigates the decline in renal function in patients with CKD (Clinical Trials Registry Number: UMIN000023850).