By Mike Beattie
Scientists have discovered key sex-based differences in kidney metabolism reflected in the blood of men and women with diabetes that are associated with the progression and severity of diabetic kidney disease. The researchers have identified a product of cellular metabolism called pyruvate that was found in higher concentrations in female kidney cells, which may explain why some women with diabetes are protected from diabetic kidney disease.
The research team, led by Dr. Sergi Clotet-Freixas and Dr. Ana Konvalinka, published the findings of their study in the journal Science Translational Medicine on March 6, 2024.
Diabetic kidney disease (DKD), also known as diabetic nephropathy, is the most common cause of chronic kidney disease and kidney failure. It is characterized by the gradual loss of kidney function occurring in those living with diabetes. The disease progresses slowly over many years, ultimately leading to end-stage kidney disease. Unfortunately, there are few treatment options available to delay or reduce disease severity, and currently none that can completely prevent it.
Notably, DKD develops and progresses more readily in men compared to women. Previous studies on sex hormone effects in the kidney led Dr. Clotet-Freixas and Dr. Konvalinka to study how metabolism within kidney cells differs among men and women, which had not been previously studied until now.
In the present study, researchers found that men tended to have increased levels of TCA cycle metabolites in the blood and kidney cells, which were associated with the presence and severity of DKD. In contrast, women showed increased levels of pyruvate – an antioxidant metabolite – in the blood and kidney cells. According to the researchers, these heightened pyruvate levels may explain milder DKD in the kidneys of women.
“Our findings suggest that we need to understand whether lowering TCA cycle metabolites and raising pyruvate levels impact the development and progression of DKD,” says Dr. Clotet-Freixas. “We believe this could potentially help prevent disease progression in both men and women living with diabetes.”
Dr. Clotet-Freixas led the study during his postdoctoral training in the laboratory of Dr. Ana Konvalinka, a senior scientist at the University Health Network and an associate professor at the University of Toronto. He collaborated with clinicians and scientists from the University of Manitoba (iCARE Cohort Study) and international partners, such as the GenoDiabMar Cohort Study in Spain, and the GCKD Cohort Study in Germany.
In addition to the findings related to DKD, the study also offered important insights for scientists studying diseases at the cellular level – basic and clinical researchers should consider sex differences when conducting their studies.
“The sex of the cell matters,” says Dr. Clotet-Freixas. “Most animal studies investigating DKD have been conducted only in male animals. Clinical studies have also tended to predominantly include male subjects over female subjects, leading scientists to stumble into results that have the potential to inspire treatments that benefit men more than women. Our latest study highlights the importance of considering the sex of the subjects being studied – whether those are human participants, animal models, or cells on a plate.”
In August 2023, Dr. Clotet-Freixas (pictured above) joined the Hamilton Centre for Kidney Research (HCKR) at St. Joseph’s Healthcare Hamilton, where he is continuing his research on DKD and the importance of sex. He is currently an assistant professor in the department of medicine at McMaster University and an affiliate scientist at The Research Institute of St. Joe’s Hamilton.
“We are very excited that Dr. Clotet-Freixas has joined our group,” says Dr. Joan Krepinsky, a scientist within the HCKR and professor of medicine at McMaster University. “His research focus on how biologic sex influences kidney disease, coupled with his translational approach and analysis of samples from people with DKD, are important and timely expansions of our research capacity. Understanding how biologic sex influences disease may lead to better, more refined treatments for kidney and other disease.”
“The findings that Dr. Clotet-Freixas and his colleagues recently uncovered connecting sex differences with diabetic kidney disease is a major advance in understanding how sex hormones impact kidney function and enhance kidney protection,” said Dr. Richard Austin, Director of the HCKR. “Importantly, this seminal discovery will provide a solid foundation for identifying novel sex-specific factors that could be targeted for the treatment of diabetic kidney disease. We are extremely fortunate that Dr. Clotet-Freixas decided to join our research team at the Hamilton Centre for Kidney Research to further these exciting and clinically relevant studies that will undoubtedly impact patients with diabetic kidney disease.”
The Hamilton Centre for Kidney Research at St. Joe’s brings clinical and biomedical researchers together in one place where the focus is to improve the lives of patients with chronic kidney disease through leading-edge research.