I have a vivid memory of Barry telling me in his special captain's-like home in Nantucket: ‘a simple hypothesis in medicine means nothing unless it can be extended to improve human health’.
Barry Brenner has transformed our understanding of medicine. Throughout his research and groundbreaking ideas, he elucidated some of the key mechanisms of renal function, emphasized the role of glomerular endowment (‘not all of us are born with the same number of nephrons’) in health and disease and laid the foundation for renal medicine and hypertension, as well as the consequences in cardiovascular diseases. Brenner's work spanned fundamental studies of kidney microcirculation, to clinical applications that continue to influence our understanding and treatment of kidney diseases today, to the novel approaches with aldosterone inhibitors and sodium–glucose co-transporter-2 (SGLT2) inhibitors.
After graduating with honours in biology from Long Island University in 1958, completing the program in <3 years, he went on to attend the University of Pittsburgh School of Medicine, where he graduated first in his class and earned the prestigious George Heard Memorial Prize in Medicine. Early on, during his years as a student, he developed a deep passion for research, which he continued to pursue throughout his 4-year residency at the Bronx Municipal Hospital Center, where he focused on renal research. Completing his residency, he joined the Postdoctoral Fellowship Program at the National Institutes of Health (NIH), where he conducted pioneering research in the Laboratory of Kidney and Electrolyte Metabolism. In just 3 years at NIH, he achieved discoveries that challenged established paradigms in renal physiology, and his findings were presented at the first meeting of the American Society of Nephrology, where it became clear to everyone that he was an extraordinary talent destined to make a significant impact in the field. He then moved to the University of California, San Francisco, where he held various roles up to Professor of Medicine and Physiology. He chose to lead the Kidney and Electrolyte Physiology Laboratory of the Harvard Medical School at only 39 years of age. Three years later, in 1979, he was nominated as Director of the Renal Division at Brigham and Women's Hospital, a role he held until 2001.
His exceptional scientific work, evidenced by many hundreds of papers and about 50 books as editor or co-editor, has left an unparalleled legacy that will inspire and serve as a guide for future generations of nephrologists.
No kidney doctor in the world could escape reading the ‘bible’ of nephrology: Brenner and Rector's ‘The Kidney’, the world's foremost textbook of nephrology, of which 11 editions have been published. Barry had read not once, but four times, every page of this monumental book for every edition, and this was the proof of his rigor and dedication.
He served as a member of major societies, including roles as Councillor and Vice-President of the American Society for Clinical Investigation, Councillor and President of the American Society of Nephrology and the American Society of Hypertension, Councillor of the International Society of Nephrology, Councillor and Co-Chairman of the Commission for Global Advancement of Nephrology (COMGAN) of the International Society of Nephrology, Councillor of the American Association of Physicians, Chair of the Section on Medical Sciences of the American Association for the Advancement of Science and Councillor of the Association of American Physicians.
Barry Brenner's early scientific interest focused on the intricate dynamics of fluid reabsorption in the proximal tubule. His work revealed that the forces driving fluid reabsorption in the proximal tubules are governed by Starling forces, i.e. the balance between hydrostatic pressure and oncotic pressure in peritubular capillaries. These findings became foundational knowledge for understanding renal physiology and provided the basis for understanding kidney response to disease conditions. Micropuncture techniques, done with the invaluable help of Julie Troy, allowed Brenner and his colleagues to quantify capillary pressures in rat kidneys, providing a precise framework to understand the variables influencing glomerular filtration rates.
To better clarify the dynamics of this processes, Brenner collaborated with a young biomedical engineer, William Deen, and they developed mathematical models to describe quantitatively the role of the determinants of glomerular ultrafiltration. These models integrated the principles of fluid dynamics with physiological data (glomerular capillary pressure, plasma oncotic pressure and hydraulic permeability of the glomerular capillary membrane), enabling a quantitative analysis of the dynamics of water filtration across the glomeruli.
Their research showed that the high permeability of capillaries to water and small solutes, combined with a large surface area, is crucial for effective glomerular filtration. This combination allows the kidneys to rapidly filter large volumes of plasma water while selectively retaining essential proteins and cells. Brenner's insights were crucial in identifying the structural and functional features that distinguish glomerular capillaries from other vascular beds, advancing the understanding of renal microcirculation. Brenner and Deen's models were groundbreaking, providing a theoretical basis to predict changes in glomerular filtration dynamics and their role in disease condition, including surgical reduction of renal mass as well as immunologically mediated renal disease, the latter in collaboration with Dr Dick Glassock.
Furthermore, by utilizing neutral dextran molecules of graded sizes, Brenner and Deen were able to provide conclusive evidence for the presence of a size-selective filtration barrier in the glomerulus. This barrier permits the passage of small solutes while restricting larger molecules, such as proteins, from crossing into the urine. His studies not only defined the size selectivity of the glomerular barrier, but also demonstrated the importance of negative charges in its function. Brenner found that negatively charged dextran molecules are more effectively retained in the circulation due to the negative charge on the filtration barrier. This research led to the widely accepted model of charge and size selectivity of the glomerular filtration membrane, a concept that is fundamental to understanding the pathophysiology of proteinuria in various diseases of the kidney.
In experiments involving Munich Wistar rats, Barry, again with Julie Troy, demonstrated that a reduction in renal mass leads to compensatory changes so as to increase glomerular capillary pressure. Specifically, he showed that a 75% reduction in renal mass resulted in glomerular capillary pressures rising from 40–45 mmHg to 55–60 mmHg. He concluded that this increase is a maladaptive response that can contribute to further kidney damage, underscoring the concept that nephron loss sets the stage for a vicious cycle of progressive renal injury (commonly considered, both then and now, as the ‘Brenner Hypothesis’).
Brenner and collaborators then explored possible approaches to managing intraglomerular pressure. Their research showed that reducing dietary protein intake in rats effectively lowered intraglomerular pressure, even after substantial renal ablation, suggesting that dietary interventions could influence glomerular haemodynamics. This discovery opened new avenues for dietary management in patients with kidney disease, highlighting the potential of dietary modifications to mitigate kidney damage. As for pharmacological approaches, they documented that conventional antihypertensive agents lower systemic blood pressure without significantly affecting intraglomerular pressures.
The use of angiotensin-converting enzyme (ACE) inhibitors to manage glomerular hypertension paved the way to a completely different story. These studies, done in collaboration with Tom Hostetter, Sharon Andreson and Roberto Zatz, demonstrated that ACE inhibitors could effectively reverse glomerular hypertension by preventing the action of angiotensin II, a potent vasoconstrictor that specifically targets the efferent arteriole of the glomerulus. By reducing the constriction of the efferent arteriole, ACE inhibitors lower glomerular capillary pressure, providing a protective effect against further glomerular injury. Brenner's work on ACE inhibitors has had profound implications for the treatment of glomerular diseases since then and established a novel paradigm for preventing the progression of chronic kidney disease (CKD) in humans, once considered ‘inexorably progressive’, an expression no longer in use after the study of Dr Brenner.
The first major clinical validation of experimental findings was the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study, which investigated the effects of losartan, an angiotensin II receptor blocker (ARB), in patients with type 2 diabetes and nephropathy. The RENAAL study demonstrated that losartan significantly reduced the risk of doubling serum creatinine, end-stage renal disease and death.
This breakthrough not only confirmed the clinical relevance of the ‘Brenner Hypothesis’, but also set the stage for its broader application in nephrology. The principles derived from this hypothesis have been extended to various forms of CKD, beyond diabetic nephropathy. It has led to the widespread use of renin–angiotensin–aldosterone system inhibitors—such as ACE inhibitors and ARBs—as first-line therapies in managing CKD to reduce proteinuria and slow disease progression. Originally developed for the treatment of type 2 diabetes, SGLT2 inhibitors reduce the resorption of sodium and glucose in the proximal tubules and are now widely used to manage CKD. As observed with ACE inhibitors, this class of drugs, which act by lowering intracapillary pressure, improve renal outcomes in both diabetic and non-diabetic patients.
In the reduction of renal mass model (in the Munich Wistar rat), renal capillary hypertension and disease progression were associated with a reduction of nephron number. These findings were in keeping with another major contribution to nephrology: the role of nephron endowment in health and disease. Barry was intrigued by several observations in the literature that individuals born prematurely or those who experienced intrauterine growth restriction often have fewer nephrons. He hypothesized that this condition predisposes them to an increased risk of developing kidney disease later in life. He proposed the ‘two-hit hypothesis’, where a low nephron number at birth serves as a ‘first hit’. A subsequent ‘second hit,’ such as hypertension, nephrotoxic drug exposure or other renal insults, can then trigger the progression of renal disease. To provide robust experimental and clinical evidence for this idea, Brenner meticulously explored all the literature on the subject; for the last 10 years or so, every night, he was committed to keeping up with reading papers that were published daily, eventually showing a link between the number of nephrons and the development of renal disease later in life. He managed to consult thousands of papers. Collaborating with Andrea Remuzzi and his co-workers, they found experimental proof of this concept, showing that in a substrain of the Munich Wistar rat, a reduced nephron number is associated with the spontaneous development of proteinuria and glomerulosclerosis with age.
In several lectures Brenner emphasized that not all individuals are born with the same number of nephrons, telling the story that surgeons, while looking at a lot of parameters to select the best donor for their recipients, normally do not weigh the kidney, a surrogate of nephron number. Brenner introduced the concept that donors with a low birthweight and a reduced number of nephrons might face greater risks of kidney complications compared with those with a normal nephron endowment. This finding has led to a more nuanced understanding of the risk factors for kidney disease initiation and progression and has informed both clinical practice and public health policies.
His impressive record of scientific, clinical and academic accomplishments has earned him a long list of awards too numerous to mention in full. Notably, he is the only individual to have received three awards from the American Society of Nephrology: the Homer W. Smith Award (for basic science), the John P. Peters Award (for clinical science) and the Robert G. Narins Award (for education and teaching), along with the establishment of an Endowed Annual Brenner Lecture in his honour. Among the other prestigious prizes he has received are Fellow, Royal College of Physicians, London (1998), Jean Hamburger (1999), Amgen (2003), A N Richards (2015) and Life Time Achievement (2016), International Society of Nephrology, Novartis International Prize for High Blood Pressure Research and American Heart Association (2005). He has received honorary degrees from Harvard University (A.M., 1977), Long Island University (D.Sc., 1987), Université de Paris, Pierre et Marie Curie (D. Med. Sci.,1992), Charles University, Prague (Diploma, 1995) and Universidad Complutense, Madrid (2002).
Brenner's comprehensive approach—from basic science to clinical applications—transformed renal medicine and medicine at large. His legacy continues to shape current and future research directions and his impact on the field will endure for years to come. But to truly honour Barry, I must mention what a fantastic lecturer and great teacher he was. He genuinely enjoyed speaking with young doctors and students, as long as they were hardworking, dedicated and brilliant. He was the quintessence of rigor himself, and he expected from his students the same accuracy and dedication to research and clinical medicine that led him.
Barry could be direct and, at times, somewhat unpleasant (those who considered him rude or arrogant surely did not know him), but he could also be the sweetest and most generous person one could ever meet.
Brenner had countless friends, many of whom had the good fortune of being his students and then went on to brilliant careers. He had a deep admiration for the greatest of them all, Don Seldin, admired the intelligence and abilities of Dick Glassock, and was very close to John Dirks, Anita Aperia and David Warnock. One evening, when we were all together at one of the dinners Dr Brenner organized for his intimate friends during the ASN, someone said, ‘Look how much nephrology-oriented brainpower there is in this single room.’ And Barry, who had a sense of humour like no one else, replied, ‘Yes, like when Homer Smith dined alone at home’.
When I learned that Barry was no longer with us, my first thought went to Jane. She was the key person in his life, always by his side in a balanced and discreet way, ready to leave him alone when he was in a bad mood but always ready to give him prompt and right advice. Jane was a steady anchor for him.
Barry had a more profound influence on my personal and professional life than anyone else. The little that my colleagues and I have accomplished in nephrology would not have been possible without him. Barry's spirit will forever hold a special place in my heart.
‘A simple hypothesis in medicine means nothing unless it can be extended to improve human health’. Barry Brenner himself, and his entire research life, embodied this principle.
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