Turning Clinical Uncertainty Into Discovery: The Work of Dr. Matthieu Legrand

Dr. Matthieu Legrand, a physician-scientist in the Department of Anesthesia and Perioperative Care at UCSF, strives to create a careful balance between clinical care and high-level research productivity. Trained in anesthesiology and critical care medicine, Dr. Legrand holds an MD, an MSc, and a PhD in cardiovascular physiology. Before joining UCSF, he worked in Paris, France, where he served as a professor and medical director of two Intensive Care Units.

During his clinical training, Dr. Legrand became increasingly aware of how many decisions in critical care are made under conditions of significant uncertainty. Patients are extraordinarily complex, and the physiologic mechanisms underlying their deterioration are often incompletely understood. These experiences motivated him to pursue a career as a physician-scientist.

“The ability to move between bedside observations and scientific investigation is what initially motivated me to pursue this career path and motivates me to continue,” he says. “I cannot separate my clinical work from my research.”

Dr. Legrand’s research focuses on the pathophysiology and management of organ dysfunction in critically ill patients, particularly acute kidney injury (AKI) and circulatory failure in sepsis and major surgery. At UCSF, he leads and collaborates on clinical trials and translational studies aimed at improving organ protection in critically ill and surgical patients.

His work integrates large clinical datasets, randomized trials, and biomarker-driven approaches to better understand mechanisms of injury and identify therapeutic targets. As Director of Clinical Research for the Department of Anesthesia and Perioperative Care, and in collaboration with the department’s Clinical Research Core, Dr. Legrand also works to support faculty and trainees in designing and executing impactful clinical research projects.

2025 was particularly active. Several of Dr. Legrand’s projects focus on better characterizing biological heterogeneity in critical illness and identifying therapeutic strategies tailored to specific patient profiles. In collaborative proteomic studies across multiple international cohorts of patients with sepsis-associated acute kidney injury, his team identified protein expression patterns that appear to define distinct biological clusters of patients. These clusters were associated with different clinical trajectories and may ultimately help guide targeted therapies.

In parallel, his clinical trial work has continued to examine optimal vasopressor strategies in septic shock and whether different blood pressure targets can improve outcomes.

Dr. Legrand’s research has also explored the impact of commonly used cardiovascular therapies on outcomes in surgical and critically ill patients. His work demonstrated that SGLT2 inhibitors (oral medications that treat type 2 diabetes by forcing the kidneys to remove excess glucose through urine rather than reabsorbing it into the blood) are associated with organ protection—particularly in reducing acute kidney injury—in surgical patients, with findings published in JAMA Surgery. In another study published in JAMA Cardiology with Justine Tang, MD, a T32 fellow in the department, his team showed that baseline cardiovascular risk does not significantly affect postoperative outcomes when continuing RAAS (Renin-Angiotensin-Aldosterone System) inhibitors –medications that manage high blood pressure, heart failure, and chronic kidney disease by blocking hormones that constrict blood vessels and increase fluid retention before surgery.

His group also published the results of a randomized clinical trial evaluating iloprost for refractory septic shock with hypoperfusion. Iloprost is a synthetic prostaglandin (prostacyclin) analogue that acts as a vasodilator to widen blood vessels, improve circulation, and prevent blood clots. The study, published in the American Journal of Respiratory and Critical Care Medicine, found no improvement in outcomes—challenging long-held assumptions about the role of microcirculation in septic shock resuscitation.

Meanwhile, the team is conducting the multicenter VEGA-2 trial comparing phenylephrine and norepinephrine for preventing acute kidney injury during surgery. Eight centers have already opened for enrollment, with two additional sites expected to join in the spring of 2026. The study reflects the strong collaboration and commitment of faculty across the UCSF Department of Anesthesia and Perioperative Care.

One common misconception in critical care research, Dr. Legrand notes, is that therapies are broadly effective for most patients. In reality, there is substantial biological and physiological variability among patients.

“Two patients who appear clinically similar may have very different underlying mechanisms driving their illness,” he explains. “This partly explains why many interventions show mixed results in trials. A large part of our work is understanding which treatments affect outcomes and which patients are most likely to benefit.”

To address these questions, his team analyzes biological phenotypes as well as clinical and physiological characteristics using advanced statistical approaches in large clinical trials such as VEGA-2.

For residents and fellows interested in bridging clinical practice with academic research, Dr. Legrand emphasizes the importance of mentorship and collaboration.

“Academic research is rarely an individual endeavor, and working within a supportive network is essential,” he says. “Find a mentor you enjoy working with. Maintain close ties to clinical practice, because many of the most important research questions arise directly from patient care. And work hard—there is no alternative.”

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Outside the hospital, Dr. Legrand spends time with his wife, Anne, and their three children, Chloe, Marius, and Celeste, as well as their dog, Skye, and cat, Tigrou. He also practices Wado-ryu karate and enjoys biking and skiing. Through his work as a clinician, researcher, and mentor, Dr. Legrand continues to foster a culture of curiosity and collaboration—encouraging the next generation of physician-scientists to turn questions at the bedside into discoveries that improve care for critically ill patients.