Research News

A team of Cleveland Clinic researchers led by Stanley Hazen, MD, PhD, have made a surprising new discovery about trimethylamine N-oxide (TMAO). Their preclinical research shows that targeting the gut microbial pathway can reverse kidney damage in chronic kidney disease (CKD).

The research, published in the Journal of the American Society of Nephrology, builds on previous studies that identify high TMAO levels as a driver of worse kidney disease.

Addressing a major public health problem

CKD is a condition defined by damage to the kidneys and means the organs aren’t functioning as well as they should. As we age, we all slowly lose kidney function. In CKD, the loss of function has become even more significant.

New data supports a previous estimate that there are 850 million people across the world with kidney disease. Of those, 46 million are on kidney replacement therapy, and 1.5 million die each year. That means one person dies from kidney disease every 20 seconds.

Most people with early- and even later-stage CKD experience no outward symptoms at all. Only when kidney function drops to critical levels do toxic waste products and fluid build up and cause symptoms. Treatment of late-stage CKD requires dialysis or transplant. CKD diagnoses are divided into five stages, based on two tests that calculate the kidneys’ filtration rate and measure the amount of protein in a patient’s urine.

The rate of progression through these stages varies and is connected to factors like blood pressure, diabetes, age and race/ethnicity.

There is no cure for CKD. Current treatment options focus on preserving kidney function.

“Regardless of the stage, CKD is a strain on time, money, resources and the body — especially for patients who rely on dialysis or whose only option is to wait for a transplant,” Dr. Hazen says. “We need to find a treatment method that does more than just slow or stop progression.”

Uncovering a contributor to disease progression — and more

Previous clinical and mechanistic research led by Dr. Hazen linked higher TMAO with worse kidney disease and faster decline in kidney function. For example, a seminal 2014 study first linked the gut microbial TMAO pathway to CKD, heightened mortality risk and kidney fibrosis progression. In a 2024 study with over 10,000 community-based subjects and serial TMAO levels, Dr. Hazen's team showed TMAO was linked to an accelerated rate of CKD development and progression.

One unanswered question in the field of CKD research is whether the disease can be reversed. Based on their previous studies about TMAO, the researchers asked: Can lowering TMAO not only halt, but also reverse kidney damage that already exists?

The answer, to the researchers’ surprise, is yes.

In preclinical studies, Dr. Hazen and his team found that blocking the production of TMAO using a therapeutic that specifically targets a gut microbe’s ability to make TMAO resulted in:

• Decreased TMAO levels in the blood
• Halting, and in some cases reversing components of CKD — for example, a striking reduction in the degree of kidney fibrosis (scarring and damage usually considered irreversible)
• Improved kidney function, and lowered levels of several other harmful waste products in the blood called uremic toxins

“Our discovery showed that TMAO is more than just a marker of kidney disease — it’s also a contributor to disease progression and a therapeutic target,” Dr. Hazen says. “The possibility of targeting this gut microbiome pathway and reversing established kidney disease not only challenges what we thought about CKD and fibrosis, it also adds to the benefits we already know about limiting TMAO generation, such as protection from cardiovascular disease. Dietary changes can lower TMAO. This study gives promise for potential interventions in subjects with CKD — to not only preserve, but also improve kidney function.”