“A Vulgar Mechanick can practice what he has been taught or seen done, but if he is in an error, he knows not how to find it out and correct it…. Whereas he that is able to reason nimbly and judiciously about figure, force and motion, is never at rest till he gets over every rub.”
Isaac Newton
May 25, 1694
Medicine has long been regarded as among the most noble of professions, largely because of the power of its practitioners to relieve human suffering. Beyond this empirical wisdom and compassion, medicine has benefited enormously from a grand harvest of biomedical advances sowed and reaped by recent generations of physician-scientists. Their successes have accrued in boundless ways toward improvements in diagnosis and treatment of patients everywhere. Barry M. Brenner, MD, who contributed greatly to these advances as an internationally renowned renal physiologist and clinical nephrologist, and who was never at rest, died on August 6, 2024, at the age of 86 years.
Barry Morton Brenner was born in Brooklyn, NY, on October 4, 1937, the second child to first-generation American parents, Louis and Sarah (Lamm), whose predecessors were farm laborers and garment workers confined to Jewish ghettos in areas known today as Eastern Belarus. In high school, Barry's grades were average at best until his senior year, when he decided that he wanted to pursue a career in medicine. From then on, he adopted a deep work ethic including 15 hours a day, 6–7 days per week study schedules, which enabled him to be the first of his family to graduate from college, which he achieved at Long Island University in 1958 in <3 years, with a BS degree with honors. He was then on to the University of Pittsburgh School of Medicine, graduating first in his class with an MD degree in 1962. During each of his 4 years in medical school, Barry engaged in research, defining enzyme kinetics of a newly discovered 5'nucleotidase in rat liver microsomes, and renal tubule brush border enzyme release into urine following experimental ischemic injury. He later said that those early experiences in research proved determinate for his subsequent career as a medical investigator.
Four years of residency in internal medicine followed at Bronx Municipal Hospital Center, Albert Einstein College of Medicine from 1962 to 1966. During his second year, he got hold of the newly released first edition of Strauss and Welt's Diseases of the Kidney, which he devoured and was especially enthralled with the chapters on renal physiology. He knew then that renal research would be his lifelong lodestar. Barry completed his internal medicine training in 1966, his final year as Chief Resident. He was offered postdoctoral renal fellowships in Boston and New Haven, but instead chose the National Institutes of Health (NIH) where he joined the renowned Laboratory of Kidney and Electrolyte Metabolism with a reputation for excellently conceived and executed laboratory research, led by the famed renal physiologist Robert W. Berliner.
In 3 short years at the NIH, Barry quickly gained fame, first from results of micropuncture studies with Julie Troy and Cleaves Bennett, which immediately cast doubt on the then-current geometry hypothesis, which had been invoked by K. Gertz in Germany and soon thereafter by workers in Dallas, to account for regulation of fluid reabsorption by the renal proximal tubule. Then, in collaboration with fellow coworker Fred Wright, they failed to confirm the increasingly popular belief that overall renal handling of sodium was under the influence of a putative natriuretic hormone. Just 17 months after arriving at the NIH, these negative studies made up the bulk of the presentation delivered by Berliner at an invited State of the Art Lecture in Renal Physiology at the first national meeting of the newly formed American Society of Nephrology (ASN) held in Washington, DC, in November 1967. By the end of the meeting, Brenner's name was well known and job offers began to arrive. However, there were more compelling studies for Barry and Julie to undertake, again centered on mechanisms governing net proximal fluid reabsorption, now by consideration of the role of peritubular capillary Starling forces.
Some promising findings emerged at the NIH, but it was not until 1969 when Barry and Julie established a new laboratory at the Fort Miley VA Hospital overlooking the Golden Gate Bridge in San Francisco, CA, that convincing evidence was obtained. Using a novel servo-null micropipette transducer system that made possible real-time continuously recorded pulse waves of peritubular capillary hydraulic pressures, and simultaneously manipulating prevailing capillary plasma oncotic pressures, they were able to examine how induced changes in transcapillary Starling forces affected net proximal tubule fluid exchange. Within a few months, they confirmed and reported that these peritubular transcapillary forces indeed exerted a regulatory effect on net proximal tubule reabsorption rates. Shortly thereafter, Brenner, with major help from William Deen, a graduate student in Channing Robertson's program in bioengineering at nearby Stanford University, developed and published a rigorous mathematical model to formalize this peritubular control theory, the first of several theories with far-reaching significance formulated by Brenner over his highly creative research career.
While attending a kidney research symposium in Munich, Germany, in 1970, a local investigator mentioned to Barry that his team had found a unique strain of Wistar rats that regularly displayed cherry-red aneurysms on their renal cortical surfaces. He was further told that they had no interest in pathophysiology and offered to ship a dozen to him if he was interested in their further study. Brenner immediately accepted, believing that these cherry-red spots were likely to be glomeruli, not often found on the surface of rat kidneys. When he retrieved the box of rats at Lufthansa Cargo at San Francisco International Airport, he counted 11 rats, whereas the shipping manifest read 12! A small hole in the mesh cover was the presumed exit route, and fearing that this escapee might gnaw through the plane's critical wiring, Dr. Brenner forbade his family and friends from ever flying Lufthansa!
The next day, Barry and Julie prepared two of these rats for micropuncture study, confirmed that several cortical red spots were present on the surface of each of the four kidneys examined, and went on to record hydraulic pressures of 42–46 mm Hg using their sensitive servo-null technique. They confirmed by histology that these were normal glomeruli and promptly transferred the remaining nine rats, dubbed “Munich-Wistar,” to a local rat breeding facility. When an adequate colony size was reached, Barry, Julie, and postdoctoral fellow Terry Daugharty began a systematic study of glomerular hemodynamics, confirming that glomerular pressures average 45 mm Hg or slightly less than half of mean aortic pressure. These glomerular pressure values were far below estimates calculated by Dr. Domingo M. Gomez, now recognized as containing erroneous mathematical assumptions. Their first landmark study “Dynamics of Glomerular Ultrafiltration in the Rat” was accepted without revision by the editors of the Journal of Clinical Investigation.
Brenner invited William Deen and Channing Robertson to help formulate a mathematical model to describe the ultrafiltration process, which, along with two other articles on glomerular dynamics, appeared in American Journal of Physiology in 1971. Five other publications also soon appeared, dealing with glomerular autoregulation, determination of the ultrafiltration coefficient, and response to ischemic injury. In a successful collaboration with Dr. Richard Glassock, two models of immune glomerular injury with attendant proteinuria were established in Munich-Wistar rats, which allowed for a detailed examination of the alterations in glomerular dynamics resulting in the decline of both single-nephron and whole-kidney GFR observed in experimental glomerulonephritis. On the basis of the results of these eight early studies, Brenner theorized that the ultrafiltration process normally results from a relatively low glomerular transcapillary hydraulic pressure gradient, acting on a high intracapillary plasma flow rate, to produce a correspondingly high net filtration rate. The high net flux was made possible by the high permeability of the glomerular capillary wall to water and small solutes and a correspondingly large glomerular capillary filtration surface area. Renal ischemia was shown to reduce GFR by lowering glomerular pressures and intracapillary blood flow, whereas immune-mediated glomerular injury reduced the ultrafiltration coefficient primarily by loss of filtering surface area.
Normally during glomerular filtration, circulating large molecules present in the blood stream are nearly completely restricted from crossing glomerular capillary walls. It had been recognized for some time that the restricted moieties exceeded a size-selective barrier, thought to be housed in the slit diaphragms located between epithelial cell (podocyte) interdigitations situated on the urinary surface of the filtering capillary wall. Using tritiated polydisperse neutral dextrans, the Brenner team probed this sieving process and found unexpectedly that a neutral (uncharged) dextran of 36 Å (consistent with the molecular size of serum albumin) was restricted from crossing the glomerular wall far less than albumin. Insofar as albumin in physiological solutions carries a net negative charge, studies were soon performed substituting anionic dextran for uncharged neutral dextran. Under these conditions, filtration rates of albumin and 36 Å anionic dextran were identical. These results allowed Brenner to theorize that a charge-selective barrier existed in the glomerular capillary wall, perhaps generated by high concentrations of highly anionic heparin sulfate in the wall. Together, charge and size selectivity allow for a very high rate of ultrafiltration while simultaneously preventing transcapillary loss of vital serum proteins. Not surprisingly, cationic dextrans were then found to cross the glomerular walls with less restriction than anionic or neutral molecular forms, that is, cationic >neutral >anionic. When the glomerular wall was injured immunologically, intrinsic wall size and charge selectivity were both greatly diminished, thus explaining reduced GFR and enhanced leakage of circulating macromolecules, predominantly albumin but also larger immunoglobulins, into the urine (clinical proteinuria).
During 7 extremely productive years in San Francisco, Barry rose to full Professor and was actively recruited to join many other medical institutions, including Yale, Stanford, Boston University, and two of Harvard's major teaching and research hospitals, Beth Israel and Peter Bent Brigham. In May 1976, 5 months before his 39th birthday, he chose the Brigham as Director of the newly established Laboratory of Kidney and Electrolyte Physiology and as the Samuel A. Levine Professor of Medicine at Harvard Medical School. In 1979, he became Director of the Renal Division at the Brigham, a position he held until 2001, when he was appointed as Director Emeritus at the newly renamed Brigham and Women's Hospital and as the Samuel A. Levine Distinguished Professor of Medicine at Harvard Medical School.
It was in Boston that Barry, Julie, and several other researchers who came with him from San Francisco began to more fully explore the renal response to injury. In experiments in Munich-Wistar rats involving graded reductions in renal mass, the normally relatively low glomerular capillary hydraulic pressure of approximately 45 mm Hg was shown to rise progressively as more and more kidney mass was removed, generally to a maximum of approximately 55–60 mm Hg with 75% ablation. Over 6 or 8 weeks after ablation, urine protein was found to increase and samples of renal tissue showed focal and segmental glomerular sclerosis and tubule atrophy, lesions similar to those seen in patients with progressive kidney disease. Until the 1980s, little was known to slow this progressive and unrelenting nephron loss after partial renal ablation. In the early 1980s, Roberto Zatz in Brenner's group demonstrated that despite high-grade renal ablation, the feeding of a low-protein diet reversed the adaptive glomerular hypertension and reduced the proteinuria and histologic evidence of glomerular and tubule injury. Furthermore, they showed that systemic BP lowering with then-available antihypertensive agents (hydralazine, reserpine, hydrochlorothiazide) failed to lower glomerular pressures in rats and, not surprisingly, failed to afford renal protection. Just at that time, angiotensin-converting enzyme (ACE) inhibitors were introduced, which Brenner saw as offering a more promising renal protective mechanism of action, namely, to selectively reduce postglomerular, not preglomerular arteriolar resistance, the latter seen by him to be the undesirable renal target of most prescribed antihypertensives. Instead, in 1986, Brenner predicted that ACE inhibitors would likely reverse glomerular hypertension since these drugs would prevent the action of angiotensin II to cause selective efferent arteriolar vasoconstriction. In studies with Sharon Anderson in Munich-Wistar rats, Brenner's theory was confirmed. As with dietary protein restriction, exposure of rats to ACE inhibitors after high-grade renal mass ablation did indeed reverse glomerular hypertension and largely prevented further renal functional or structural loss. Thus, the potential for a clinically effective drug to offer renal protection was suggested.
Clinical confirmation of this renal protective effect of the first US Food and Drug Administration–approved ACE inhibitor, captopril, came from results of a randomized clinical trial of type 1 diabetic patients by Lewis and coworkers in 1991. Soon thereafter, Brenner led a similar randomized clinical trial (RENAAL) and reported significant renal and cardiovascular benefits in type 2 diabetic patients using the new angiotensin receptor blocker losartan. These drugs were quickly promoted in treatment guidelines, and their use by physicians was widely adopted for diabetic patients and soon extended to patients with almost every form of progressive kidney disease worldwide. The “Brenner hypothesis” was coined to represent the maladaptive tradeoff occurring when glomerular pressures rise after early nephron loss and lead in turn to further nephron loss, often resulting in end stage kidney failure and need for life-sustaining renal replacement dialysis or transplantation. Once again in modern medicine, investigator-initiated bench research led to novel insights applicable to clinical practice. The widely held belief that CKD progresses inexorably to renal failure was soon discarded, and millions of patients have since been able to be maintained with clinically stable kidney disease.
In keeping with this thread, Brenner went on to recognize that individuals are not all born with an adequate number of nephrons. This circumstance is common among those of low birthweight, usually due to prematurity or suboptimal intrauterine growth as sometimes seen even in full-term infants. Nephrogenesis in utero is largely complete at week 36 of gestation. The endowment of nephrons is, therefore, low in those born prematurely; the deficit is greater, the more premature the infant. In 1988, Brenner and coresearchers Sharon Anderson and Diego Garcia hypothesized that low nephron endowment at birth increases the later-in-life risk of developing systemic hypertension and kidney disease, both the result of the maladaptive consequences of compensatory glomerular hypertension, leading progressively to further reduction in viable nephron number. Other than the Brenner group, the nephrology community in general paid little attention to this novel idea for its first 20 years. The past decade and presently, however, has seen an explosion of interest, ranging from new research into processes and regulation of nephron development in utero, to early and later-life clinical renal outcomes in affected individuals, including those with low birthweight who eventually served as living kidney donors and the kidney transplant recipients who received suboptimally endowed organs. While low birthweight currently seems to be the best available surrogate for nephron number, other more direct approaches are being explored, including nephron number estimates derived from three-axis radiological kidney imaging to extrapolations of total nephron number from kidney biopsy samples subjected to novel glomerular counting techniques. Although many years have passed since this, Brenner's fifth theory was first proposed; he always remained convinced that a low nephron endowment would prove to be the first hit in individuals born too soon or too small and that subsequent hits from acquired hypertension, exposure to nephrotoxins, or other renal challenges would account for the inevitable progressive GFR decline characteristic of patients with CKD.
Over his long and productive career, Dr. Brenner published more than 730 articles and reviews. He served as Editor or Co-editor of 49 books and Editor-in-Chief of Current Opinion in Nephrology and Hypertension from its founding in 1992 until his final days. He was founding Co-editor with the late Dr. Floyd C. Rector of four editions of Brenner & Rector's The Kidney and then as sole Editor of the next four editions before turning all editorial responsibilities to six younger associates now engaged in production of the 12th edition. Dr. Brenner was invited to serve as Visiting Professor at more than 250 institutions and delivered more than 150 Special Lectures, including many Memorial Lectures honoring paragons of yore. He greatly enjoyed rendering service to the greater nephrology and academic community as a member of several Study Sections for the NIH, 26 editorial boards, and innumerable academic committees for Harvard Medical School and Brigham and Women's Hospital. He served as Councilor and President of the American Society of Nephrology and American Society of Hypertension and Vice-President of the American Society for Clinical Investigation and the International Society of Nephrology (ISN). Together as Co-Chairs, Dr. Brenner and Dr. John Dirks traveled the globe as leaders of ISN's Committee on Global Advancement of Nephrology, which brought modern concepts of diagnosis and treatment to practitioners who were hungry for new knowledge throughout the world. This was one of Barry's favorite and devoted responsibilities.
In recognition of his outstanding contributions, Dr. Brenner was elected to membership in many academic and professional societies, including Alpha Omega Alpha, The American Society for Clinical Investigation, Association of American Physicians, American Academy of Arts and Sciences, and Fellow of The American Association for Advancement of Science, The New York Academy of Sciences, and Royal College of Physicians of Great Britain. He was also elected to honorary memberships in many national societies of nephrology or hypertension, including Greece, Czech Republic, India, Argentina, Cuba, South Africa, and Lebanon. Honorary doctorates were conferred from several universities, including his alma maters Long Island University and University of Pittsburgh; University of Paris—Marie et Pierre Curie; Charles University, Prague; and Universidad Complutense, Madrid.
Barry has also been the recipient of many awards. He is the only individual to receive all three major awards from ASN since its inception, namely 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), as well as establishment of an Endowed Annual Brenner Lecture. He also received the David M. Hume and Donald W. Seldin Awards of the National Kidney Foundation (the United States); Jean Hamburger Award, A.N. Richards Award, Amgen Prize, and Endowed Brenner-Dirks Lecture of the ISN; George E. Brown Memorial Award and Novartis International Award, Council for High Blood Pressure Research of the American Heart Association; MERIT Award, NIH, Richard Bright Award, American Society of Hypertension; Bright, Masugi, Volhard Medal, Japanese Society of Nephrology; Gordon Wilson Medal, American Clinical and Climatological Society; Gold Medal, Fundacion Conchita Rabago di Jimenez, Madrid; and finally and especially meaningful to Dr. Brenner, two Distinguished Alumnus Awards, one from the University of Pittsburgh School of Medicine and the other from the entire University.
Throughout his career, Dr. Brenner enjoyed bedside teaching rounds with medical students, residents, and clinical fellows, using wherever possible concepts taken from renal and cardiovascular physiology to explain observed physical and chemical manifestations of disease. He likewise enjoyed frequent review of data obtained by laboratory fellows, encouraging their interpretations of results, ideas about next experimental steps to be taken, and review of manuscripts in preparation. The influence of his rigorous, exacting, and creative approach to scientific investigation had a profound impact on the trainees and scientists who came within his orbit. Regrettably, space limitations prevent identifying all of Barry's many trainees and more senior collaborators whose contributions he made every effort to extol.
Dr. Brenner leaves a treasure chest of memories in the hundreds of family members, friends, and colleagues who knew him as a considerate, compassionate, and thought-provoking but also somewhat acerbic personality. Despite formidable commitments, he cherished time with Jane, his devoted wife of 64 years; their adult children Robert Brenner, MD, and Jennifer Ash, PhD; Rob's wife Molly and children Elliott and Abigail; and Jen's husband Ron and children Sam and Max. Indeed, nothing brought Barry more joy than spending time with his four grandchildren and engaging and encouraging them as they matured into young adulthood. He cared deeply for his cousins, nieces, nephews, and their extended families. At different stages and ages, there was shared globe-trotting, sailing calamities, fine family meals prepared in turn by outstanding chefs Jane, Molly, and Ron, and always accompanied by choice well-aged wines from Barry's, Rob's, and Ron's thoughtfully collected cellars. Barry could regularly be seen roaming around in various Porsche cabriolets and coupes, from his first Model 912 gift from Jane on his 30th birthday in 1957, to her 14th and final gift auto, a bright Gentian blue metallic 911 Carrera on his 83rd birthday in 2021. Barry was also a serious student of baseball, to the end a fanatical Boston Red Sox fan, but also closely allied to the performances and fates of his other local favorites, Celtics, Bruins, and Patriots. To the end, Barry maintained strong ties via email with many friends and associates, sending and receiving often lengthy expositions on a wide range of topics, including past reminiscences and rants addressing current political sanity and insanity, most often the latter. These conversations evoked comparisons with the salons of yesteryear, a repair not to be forgotten. He enjoyed quoting from Churchill and adopted his habit of ending emails to cronies with the letters KBO, meaning “keep buggering on.”
This depiction of the highly accomplished and wondrously impactful life of Barry Brenner could hardly have been predicted, given the very modest background from which he came. Yet he long held that these seeming limitations were, in fact, empowering as they served to motivate a yeoman work ethic and an undistracted focus to every challenge he chose to meet. The result is more than a half century of uncommon creativity, grand achievement, and several theories that will, even from this early perspective, very likely endure. As illustrated by the life of Newton, quoted earlier, theories if confirmed and accepted widely merge into doctrines, principles, and perhaps even laws. In Brenner's case, they will most certainly provide motivation, opportunity, and direction for generations of young scientists who choose to follow and extend his ambitious pursuits. To him, instead of the familiar sentiment “Rest In Peace,” we think he would prefer our sending him off saying, “Barry, Keep Buggering On!”
Footnotes
Deceased.
Disclosures
Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/JSN/E851.
Funding
None.
Author Contributions
Writing – original draft: Barry M. Brenner, Robert M. Brenner, Richard J. Glassock.
Writing – review & editing: Robert M. Brenner, Richard J. Glassock.
