Can endocannabinoids improve life expectancy in dialysis patients?

UCI Health study suggests link to lower mortality rate

Hamid Moradi, MD, UCI Health nephrologist

A UCI Health study has found that long-term dialysis patients with higher levels of natural endocannabinoids have a lower mortality rate, pointing to a potential path for reversing poor life expectancy rates among people with end-stage kidney disease.

UCI Health nephrologist Dr. Hamid Moradi says the findings, published as "Circulating Endocannabinoids and Mortality in Hemodialysis Patients" in the American Journal of Nephrology, have spurred him and fellow researchers to explore ways to increase endocannabinoids in the blood stream. 

Mortality in patients on maintenance hemodialysis remains exceptionally high — 50% of patients die within five years, Moradi says. With end-stage kidney disease increasing rapidly in the United States, an estimated 970,000 people will need dialysis by 2030. He and his fellow nephrologists are determined to change those survival odds. 

“Dialysis patients metabolize energy inefficiently because the treatment is so hard on the body and has so many metabolic complications,” he says. “Patients lose weight and that puts them at greater risk of adverse effects and even death.” 

But obese patients with end-stage kidney disease fare better on long-term dialysis — a contradiction called the “obesity paradox” that has puzzled kidney disease experts. 

“In most diseases, obesity causes complications and worse outcomes,” says Moradi, an associate professor in the UCI School of Medicine’s Division of Nephrology, Hypertension & Kidney Transplantation. “When you look at observational data for patients on maintenance hemodialysis, obese people survive longer while normal weight patients often develop cachexia — a wasting syndrome. They lose weight and muscle mass and ultimately can die sooner when compared to patients with a larger body mass.”

Endocannabinoids are similar to some compounds found in cannabis, but they are produced by the body and help regulate sleep, mood, appetite, memory and many other functions. It is well-established that they play an important role in preserving and storing energy. Their role in end-stage kidney disease and mortality had not been studied.

To explore the relationship, the UCI Health team identified a random group of participants in a separate, ongoing study to analyze differences in dietary factors and nutritional status across racial and ethnic groups in patients receiving treatment at dialysis facilities in Southern California. 

Moradi and his team measured predialysis serum levels of the endocannabinoids 2-arachidonoyl-sn−glycerol (2-AG) in 400 patients and anandamide (AEA) in 436 patients. It is the largest cohort of dialysis patients ever to have their serum endocannabinoid concentrations studied.

Moradi initially thought higher levels of these endocannabinoids would be associated with worse outcomes in dialysis patients. The data proved otherwise. Increased serum 2-AG levels (>32.5 pmol/mL) were associated with a lower risk of mortality. They found no clear association between serum AEA levels and mortality. 

The UCI team theorizes that higher circulating levels of 2-AG and increased endocannabinoid system activity are associated with improved energy production and preservation. This manifests clinically in higher body mass index (BMI) and serum triglycerides, a reduced risk of wasting syndrome and, ultimately, decreased risk of death.

Moradi says larger studies are needed to confirm these hypotheses and to explore potential endocannabinoid pathways to improve survival in long-term dialysis patients.

He has obtained a $100,000 UCI Beall Applied Innovation grant for the next phase of research. The subsequent study will focus on developing a soluble formulation of the 2-AG molecule that can be safely delivered intravenously and then begin testing it in animals.

Thinking longer term, Moradi says, “If we can prove that it is safe for use in humans and it is effective in preventing cachexia and improving survival rates for dialysis patients, the same concepts and therapy may also apply to patients with cancer, advanced heart failure or other inflammatory conditions that are complicated by cachexia and improve their survival rates as well.”

The superior care provided by the nationally and internationally regarded kidney specialists at UCI Health has placed UCI Medical Center among the nation's best hospitals for treating kidney disorders. The department’s excellence is further reflected in its national ranking in the 2020-2021 U.S. News & World Report Top 50 among nephrology programs.

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