Lubiprostone Slows Kidney Function Decline in Chronic Kidney Disease — Evidence Review

Chronic kidney disease (CKD) patients given the constipation drug lubiprostone experienced a slower decline in kidney function, according to a randomized trial led by researchers at Tohoku University. Existing experimental evidence generally supports this finding, highlighting connections between gut health, constipation, and CKD progression.

• Prior animal studies demonstrate that lubiprostone can improve gut microbiota composition, reduce uremic toxin accumulation, and slow CKD progression, providing a mechanistic basis for the new clinical findings 1.
• Experimental research using organ-on-a-chip and animal models also shows that lubiprostone inhibits pathways involved in kidney fibrosis and restores kidney function, further supporting its potential renal benefits beyond its use as a laxative 2.
• Observational studies confirm constipation is common among CKD patients, especially in advanced stages, and that certain laxatives may carry risks for people with kidney disease—making the identification of a potentially kidney-protective laxative clinically significant 5 3.

Study Overview and Key Findings

Chronic kidney disease is a progressive condition with limited therapeutic options to restore or preserve kidney function. While constipation is a frequent comorbidity in CKD, few studies have explored whether treating constipation can also influence kidney outcomes. This new multicenter randomized controlled trial investigated whether repurposing lubiprostone, a constipation medication, could slow CKD progression. The study is notable for linking gut microbiota modulation and increased spermidine production to improved kidney outcomes, representing a novel therapeutic approach for CKD.

Property	Value
Organization	Tohoku University Graduate School of Medicine
Journal Name	Science Advances
Authors	Professor Takaaki Abe
Population	Individuals with moderate chronic kidney disease
Sample Size	150 individuals
Methods	Randomized Controlled Trial (RCT)
Outcome	Kidney function decline, spermidine production
Results	Lubiprostone slowed kidney function decline compared to placebo.

Literature Review: Related Studies

To contextualize these findings, we searched the Consensus paper database, which includes over 200 million research papers, using the following queries to identify relevant studies:

1. lubiprostone kidney function decline
2. constipation medication kidney protection
3. placebo comparison lubiprostone effects

Below is a summary of the key topics and findings from the related studies:

Topic	Key Findings
What is the relationship between constipation, gut microbiota, and CKD progression?	- Lubiprostone improves gut microbiota composition and reduces uremic toxin accumulation, slowing CKD progression in animal models 1. - Constipation is highly prevalent in CKD patients, especially in advanced stages, and management practices vary 5.
Do constipation medications have direct effects on kidney health?	- Lubiprostone reduces kidney fibrosis and restores kidney function in preclinical models by inhibiting profibrotic and inflammatory pathways 2. - Some laxatives, such as senna, may be nephrotoxic with chronic use, underscoring the importance of safe medication selection in CKD 3.
What is known about the safety and efficacy of lubiprostone and other laxatives in CKD?	- Lubiprostone is effective and well-tolerated for constipation in general and in special populations, but prior to this study, evidence of kidney-protective effects in humans was lacking 8 9 10 11 12. - Other laxatives (lactulose, senna plus ispaghula husk) are similarly effective for constipation in CKD, but their impact on kidney function is unclear 6.
How do changes in the gut–kidney axis impact CKD progression?	- Modulating the gut environment (via lubiprostone or other means) can reduce the production and accumulation of uremic toxins, which are implicated in CKD progression 1. - Restoring beneficial gut bacteria and reducing dysbiosis are potential therapeutic strategies for slowing kidney decline 1 2.

What is the relationship between constipation, gut microbiota, and CKD progression?

Multiple lines of evidence support a link between constipation, gut microbiota dysbiosis, and worsening CKD outcomes. Lubiprostone has been shown in animal models to improve gut microbial composition, reduce the buildup of harmful uremic toxins, and protect against renal damage. Observational studies confirm that constipation is common among CKD patients, particularly in later stages, and that constipation management is a common clinical challenge.

• Lubiprostone alters gut microbiota in CKD models, leading to reduced uremic toxins and improved kidney outcomes 1.
• Constipation prevalence increases with CKD stage, and treatment practices differ based on disease severity 5.
• Both gut dysbiosis and constipation independently contribute to CKD progression, making interventions targeting these pathways clinically meaningful 1 5.
• The new study’s focus on addressing constipation to benefit kidney function aligns with the rationale established in preclinical and epidemiological research 1 5.

Do constipation medications have direct effects on kidney health?

Experimental data suggest that certain constipation medications may have kidney-specific effects beyond their impact on bowel movements. Lubiprostone, in particular, has demonstrated antifibrotic and anti-inflammatory properties in preclinical studies, reducing tubulointerstitial fibrosis and restoring renal function. Conversely, some stimulant laxatives, such as senna, may carry nephrotoxic risks in chronic use, highlighting the importance of medication choice in CKD.

• Lubiprostone inhibits key fibrotic and inflammatory signaling pathways in renal models, leading to improved kidney outcomes 2.
• Senna-based laxatives can cause kidney and liver toxicity in animal models, supporting caution with their chronic use in CKD patients 3.
• The new study provides clinical evidence that lubiprostone, unlike some other laxatives, may protect kidney function in humans with CKD 2 3.
• The identification of a laxative with potential renoprotective effects is a notable advance for CKD management 2.

What is known about the safety and efficacy of lubiprostone and other laxatives in CKD?

Lubiprostone’s efficacy and safety for treating constipation are well established in the general population and in specific groups, such as those with opioid-induced constipation or Parkinson’s disease. However, until now, there was limited evidence regarding its effects on kidney function in people with CKD. Other laxatives, such as lactulose and senna plus ispaghula husk, are also effective for constipation in CKD patients, but their renal effects remain unclear.

• Multiple randomized controlled trials show lubiprostone to be effective and generally well-tolerated for constipation in diverse populations 8 9 10 11 12.
• There is no prior strong evidence that lubiprostone or other laxatives directly slow kidney function decline in humans 8 9 10 11 12.
• The new study fills a gap by offering the first clinical evidence of lubiprostone’s potential kidney-protective effects in CKD patients 8 9 10 11 12.
• Other laxatives used in CKD (e.g., lactulose, senna plus ispaghula husk) have similar efficacy for constipation but unproven impact on kidney function 6.

How do changes in the gut–kidney axis impact CKD progression?

Emerging research highlights the role of the gut–kidney axis in CKD progression. Altering the gut environment—whether through diet, medication, or other means—can reduce the generation and absorption of uremic toxins that contribute to renal decline. Lubiprostone’s ability to improve gut microbiota and increase beneficial metabolites such as spermidine provides a mechanistic explanation for its observed renal benefits in the new study.

• Modifying gut microbiota reduces uremic toxin production, which is implicated in kidney damage and CKD progression 1.
• Lubiprostone’s gut-protective effects are linked with reduced renal fibrosis and improved mitochondrial function in preclinical models 1 2.
• The new study’s findings that lubiprostone increases spermidine and enhances mitochondrial function align with these mechanistic insights 1 2.
• Targeting the gut–kidney axis is a promising and relatively novel approach to slowing CKD progression 1 2.

Future Research Questions

While this study provides promising evidence for lubiprostone’s role in preserving kidney function in CKD, several important questions remain. Larger clinical trials, mechanistic studies, and research addressing safety, patient selection, and long-term outcomes are needed to fully understand the therapeutic potential and limitations of this approach.

Research Question	Relevance
Does lubiprostone have kidney-protective effects in advanced CKD or dialysis patients?	The current study focused on moderate CKD; its effects in patients with more severe disease or on dialysis are unknown. Advanced CKD patients have higher rates of constipation and may respond differently 5.
What are the long-term safety and efficacy profiles of lubiprostone in CKD patients?	Long-term safety and sustained efficacy data are needed, especially since chronic use of some laxatives can be detrimental in CKD 3 5.
Which patient subgroups with CKD are most likely to benefit from lubiprostone?	Identifying biomarkers or clinical features that predict response could enable personalized therapy, as planned in upcoming trials 5.
How does lubiprostone-induced alteration of the gut microbiota mediate renal protection?	Further mechanistic studies are needed to clarify how changes in gut microbiota and metabolites like spermidine translate into kidney benefits 1 2.
Are other constipation treatments similarly effective at slowing CKD progression?	Comparative studies are necessary to determine whether the observed effects are unique to lubiprostone or can be replicated with other agents 6.