Constipation treatment drug suppresses deterioration of chronic kidney disease

A research group led by Professor Takaaki Abe from the Tohoku University Graduate School of Medicine and Dr. Shun Watanabe from the Department of Nephrology and Hypertension, Tohoku University Hospital announced on August 30 that they have confirmed for the first time in the world through a clinical trial that lubiprostone, a chronic constipation treatment drug, suppresses the deterioration of kidney function in patients with chronic kidney disease (CKD). The findings are expected to be applied to the development of new treatments not only for kidney disease but also for various other diseases. The results were published in Science Advances on August 30.

CKD is a disease with high prevalence that occurs due to various factors such as diabetes and hypertension. When it progresses to kidney failure, it causes uremic symptoms and requires dialysis. About 60% of CKD patients also suffer from constipation, and the resulting gut microbiota dysbiosis creates a vicious cycle that further accelerates kidney function decline.

The research group had previously reported that chronic constipation treatment drugs reduce uremic toxins and improve kidney function in CKD experimental animals. Among chronic constipation treatment drugs (laxatives), there are agents with different mechanisms of action, including lubiprostone. It is a new type of drug that promotes intestinal fluid secretion, with confirmed unique protective effects against ischemic intestinal disorders and beneficial gut bacteria-increasing effects.

Therefore, the research group conducted a multicenter collaborative clinical trial (LUBI-CKD TRIAL) involving nine domestic medical institutions from 2016-2019 to verify the renal failure progression suppression effects of lubiprostone, with support from AMED.

The trial was a double-blind, placebo-controlled investigator-initiated trial (phase 2) that evaluated efficacy and safety in 118 male and female patients aged 20 years and older with moderate to severe kidney failure (CKD stage IIIb-IV). They were divided into three groups: lubiprostone 8 µg administration group, 16 µg administration group, and placebo administration group (all for 24 weeks). Subjects included those with or without chronic constipation, and a low-dose formulation (8 µg) not sold domestically was used due to the possibility that laxatives could cause kidney function decline.

As a result, there was no significant difference in changes in indoxyl sulfate (uremic toxin) among the three groups. However, the lubiprostone administration groups maintained eGFR, suggesting a potential effect in suppressing CKD progression. This effect was particularly notable in patients with moderate kidney failure.

To elucidate this mechanism, comprehensive metagenomic analysis and metabolome analysis of gut microbiota were conducted using specimens (blood, urine, feces) from trial participants.

As a result, the researchers found that in the lubiprostone-responsive group, beneficial bacteria carrying the polyamine synthesis enzyme gene (aguA) increased. Correspondingly, the concentration of spermidine, a type of polyamine, increased in the blood.

aguA is an enzyme that works in the pathway that synthesizes spermidine from arginine, and spermidine is known to work to improve mitochondrial function in damaged cells. Indeed, spermidine increased in the lubiprostone-responsive group, and spermidine administration to kidney failure mice improved kidney function and restored mitochondrial morphological abnormalities and dysfunction.

Going forward, the aim is to improve trial efficiency by developing biomarkers that can identify patient groups that will achieve maximum effects.

Watanabe commented: "The gut microbiota-polyamine-mitochondria connection is considered to be a new therapeutic strategy. We hope to bring the results obtained from this research to approval as soon as possible."

Journal Information
Publication: Science Advances
Title: Lubiprostone in chronic kidney disease: Insights into mitochondrial function and polyamines from a randomized phase 2 clinical trial
DOI: 10.1126/sciadv.adw3934