Jared James Grantham, MD
Jared James Grantham was born on May 19, 1936 in Dodge City, Kansas, the first child of Jimmie H., a restaurant server and Ista I. Grantham, a beautician. When Grantham was 4 years old the family moved to Pratt, Kansas where his father worked as a milkman and his mother set up a beauty shop in the home. In 1947 the family moved to Johnson, Kansas where his father opened a furniture store. His sister, Ista Annetta, was born in 1950. Grantham attended elementary school in Johnson and participated in basketball, baseball and track. In his freshman year of high school he and his best friend, Donnie Richard, contracted polio. Grantham spent 10 weeks in St. Francis Hospital in Wichita, Kansas recuperating from partial paralysis of both arms and one leg. His friend died of pulmonary failure. Grantham’s appreciation for the compassionate care of nurses and physicians during those troubling times led him to seek a career in medicine. Unable to participate in athletics, he became the athletic trainer for the sports teams and participated in theater and choir groups. During his senior year he received the highest rating in the State of Kansas Male Vocal Contest. He was salutatorian in the Stanton County Community High School graduating class of 1954.
He entered Baker University in the fall of 1954 to begin pre-medical studies with majors in biology and chemistry. At Baker he was elected student body president in his junior year and to Alpha Delta Sigma, an honor scholarship fraternity. He met Carol Elaine Gabbert in the Baker University choir his sophomore year and they were married in the campus church following graduation in 1958. They were blessed with four children, Janeane Marie (Houchin), Jared Taylor, James Aaron and Joel Don . They suffered a grievous loss in 1987 when Joel, a Kansas University sophomore, died in a car-train collision along with three other students.
Grantham was accepted into the University of Kansas School of Medicine in 1958. In the freshman year he met Paul R. Schloerb M.D., a young surgeon who was doing exciting work to measure body fluid compartments and to devise unique means of dialyzing uremic patients. Schloerb assigned Grantham to work with W. H. Tu M.D., and together they performed experiments to define the clearance of magnesium from dogs utilizing the new Kolff Twin-Coil dialysis machine. This work with Grantham as lead author was published in the American Journal of Physiology in 1960. He worked in Schloerb’s laboratory every summer during medical school and during elective time during his internship and residency in the Department of Medicine at the University of Kansas. Grantham was elected to membership in Alpha Delta Sigma, honor medical fraternity, during his junior year of medical school.
In 1964, Grantham petitioned Robert Berliner M.D. for a fellowship at the National Institutes of Health, Bethesda, Maryland. He was assigned to Jack Orloff M.D., Chief of the Laboratory of Kidney and Electrolyte Metabolism and to a project under the supervision of Maurice (Moe) B. Burg, M.D. Burg, a brilliant Staff Investigator and student of Hodgkin and Huxley’s elegant experiments utilizing perfused squid axons, had conceived the idea of perfusing in vitro isolated segments of renal tubule that were buried so deep within the mammalian kidney they were inaccessible to study by classical micropuncture. In what Grantham describes as one of his most exciting years of research, he, Burg and Maurice Abramow M.D., succeeded in dissecting from rabbit kidneys viable segments of proximal and collecting tubules. They studied the absorption of fluid from proximal tubules coupled to the active transport of NaCl, the net secretion of para-amino hippurate, and the net osmotic water absorption mediated by antidiuretic hormone in cortical collecting tubules. These studies opened the mysterious mammalian kidney to detailed exploration. Undaunted by initial skepticism from investigators wedded to the view that renal tubules must be studied in situ to adduce correct physiologic information, the analytic power of isolated tubule method soon persuaded researchers around the world to adopt it. Within two decades, the intrinsic functions of all mammalian renal tubule segments had been defined as well as the rich array of different types of cells within specific tubule segments.
After two years of fellowship at the NIH, Grantham accepted a permanent position as Staff Investigator, a position he held until 1969. At the NIH, Grantham published a seminal paper describing the effects of vasopressin and cyclic AMP to increase the transepithelial permeability to water of isolated perfused mammalian collecting ducts. There followed studies demonstrating that prostaglandins inhibited the hydro-osmotic effect of vasopressin, laying ground work to understand the mechanisms by which the mysterious syndrome of inappropriate antidiuretic hormone secretion appeared in some patients treated with non-steroidal anti-inflammatory agents. In a paper published in the Journal of the Clinical Investigation, Grantham is credited with showing that cortical collecting ducts actively absorb sodium and secrete potassium.
In 1969, he moved to the University of Kansas, School of Medicine to join the Division of Nephrology directed by Darrel Fanestil M.D. where he established the Laboratory of Microsurgery and continued studies of transport in isolated segments of renal tubule. There he devised a method to determine the deformability of apical membranes of collecting duct cells using micropipettes. His first publication at the University of Kansas was a report in Science that vasopressin and cyclic AMP increased the deformability of the apical membrane, the first demonstration of a physical change in the membrane whose water permeability is increased by vasopressin. Shortly after his arrival, Fanestil announced plans to move to the new medical school in La Jolla, California, and invited Grantham to go with him. That opportunity came too soon after a difficult move, and Grantham decided to stay in Kansas where he accepted the directorship of the Division of Nephrology, a position he held until 1995. In the early days of his directorship he was blessed to have working with him exceptionally capable faculty colleagues including Dennis Diederich, M.D., Donald Tucker M.D., Arnold Chonko M.D., and Virginia Savin, M.D. He was fortunate to recruit some extremely able medical students, post-dostoctoral fellows and graduate students to work in his laboratory including Mark Dellesega, David Dworzack, Larry Welling, Robert Porter, Michael Linshaw, Jerry Cohlmia and Richard Huseman.
As Director, he quickly learned that time management was a key to academic survival permitting him to take a full clinical load for 6 months of each year in addition to his administrative responsibilities and the management of two NIH R01 grants. He was the attending physician during the first related living donor kidney transplant and first deceased donor renal transplant at the University of Kansas Medical Center. It is a little known fact that in 1977 he was the clinical discussant of the only Clinical Pathologic Correlation article published in the New England Journal of Medicine that did not originate within the Massachusetts General Hospital.
At the University of Kansas Medical Center, Grantham was promoted to Associate Professor of Medicine in 1972 and to full Professor in 1975. He was appointed University Distinguished Professor in 1996. In 2000 Grantham became the first Director of the Kidney Institute at the University of Kansas Medical Center.
Patti Qualizza, a research assistant, was perhaps the most important of all the laboratory-based personnel Grantham worked with in the early years at KUMC. A gifted artist, Qualizza quickly learned how to dissect and perfuse isolated proximal tubules. Grantham had devised a simple method to measure net tubule fluid absorption by perfusing liquid into one end of a proximal tubule while completely blocking the distal end. In this way net fluid absorption could be quantified easily by measuring the rate at which a small droplet of oil in the perfusion pipet moved toward the tubule. The oil drop would move only if fluid was absorbed by the tubule epithelium. Grantham used this method to study the effects of a new diuretic, metolazone, on the absorption of salt and water by proximal tubules. One day he shared his results on the telephone with Moe Burg who suggested that he needed a control experiment to exclude the possibility that the diuretic was not being secreted into the tubule lumen, thereby slowing absorption by its effect as a poorly reabsorbed solute, rather that directly inhibiting active sodium transport. Together they came up with para-aminohippurate, which was strongly secreted by proximal tubules, as the control compound. Qualizza set up a proximal straight tubule and added PAH to the external medium. Grantham was sitting in an adjacent room discussing a patient matter on the telephone when Qualizza cried out. “Something weird is going on with this tubule, Dr. Grantham. The oil drop is moving backward.” Indeed, the oil droplet was moving backward. The experiment was redone, and the same thing happened. Then, Grantham placed some un-perfused tubules in the PAH medium, and the lumens opened widely, proving that fluid was transported into the lumen by secretion. The next day, Grantham tested the effect of uremic serum, which contains high levels of hippurate, and the same thing happened. In a two-day period in 1972, he and Qualizza had unwittingly discovered a new mechanism for the coupling of fluid transport into kidney tubules through the active transport of anions.
In the excitement of this discovery, Grantham remembered his boyhood friend, Ronnie Wilkerson, who had suffered from polycystic kidney disease, a condition in which kidney tubules swell to the size of oranges in extreme cases. He wondered if the fluid in cysts might be secreted, perhaps by a mechanism similar to that which powerfully secretes PAH. In 1975, Grantham initiated studies to examine the transport characteristics of renal cysts in patients with autosomal dominant polycystic kidney disease (ADPKD). Taking leads from the work of Kenneth Gardner M.D., Andrew Evan Ph.D., Jay Bernstein M.D., and Frank Carone M.D. he conducted studies to determine the tubular origins of cysts, the pathology and pathophysiology of cyst formation and growth and the specific transport mechanisms of mural epithelial cells that comprise the outer boundary of cysts. This work revealed that cysts are in fact neoplastic growths that differ from ordinary tumors by filling with liquid, rather than cells. The cysts were found to develop in a tiny minority of renal tubules even though the defective gene causing the disease was undoubtedly present in all cells within the kidney. He discovered that as the cysts enlarged they separated from the parent tubule, becoming isolated sacs of liquid. Since most of the cysts had no tubule connections, the only way fluid could enter the cyst lumen and accumulate there was by transepithelial secretion, a mechanism Grantham had postulated for cystic disease when he discovered that PAH caused proximal tubules to secrete liquid in 1972. Based upon these findings he developed the hypothesis that the enlargement of individual renal cysts in ADPKD was mediated by autocrine, paracrine and endocrine factors that stimulate cyst epithelial cell proliferation, transepithelial solute and fluid secretion and extracellular matrix remodelling.
Together with James P. Calvet Ph.D., Lawrence Sullivan Ph.D., Billy Hudson Ph.D., Darren Wallace Ph.D.and Tamio Yamaguchi Ph.D.and a host of marvelous senior investigators, graduate students and fellows, Grantham began to fill in the molecular pieces of the cyst puzzle, demonstrating that fluid secretion was driven by increased levels of intracellular cyclic AMP in response to hormones and autacoids, and that cellular proliferation was stimulated by the complementary interaction of epidermal growth factor and cyclic AMP. Fluid secretion was powered by active chloride secretion and cell proliferation was controlled in large measure by stimulation of the mitogen-activated protein kinase pathway.
In 1982, Grantham joined with Joseph Breuning, a Kansas City businessman, who wanted to do something to help his wife and daughter who had polycystic kidney disease. He asked Grantham for a “cafeteria” of ideas, one of which he might choose to support with cash from the recent sale of his real estate business. Grantham decided that rather than use the donor’s funds for his own research more would be gained by catalyzing research in this neglected field throughout the nation. After several meetings, Mr. Bruening agreed to create the Polycystic Kidney Research Foundation as a means to increase awareness of PKD and stimulate more research. From 1982 until 1990 Grantham served as Chairman of the Scientific Advisory Board and from 1990 until 1998 as Chairman of the Board of Trustees of the PKD Foundation. During his term with the Foundation, the annual grant portfolio for polycystic kidney research at the National Institutes of Health grew from less than $100,000 to more than $5,000,000 per year. In addition, the Foundation raised more than $1,000,000 per year from private donors to fund startup grants for new investigators entering the field. The PKD Foundation is widely credited with inspiring the remarkable progress that has been made over the last 20 years in our understanding of polycystic kidney disorders.
Grantham maintained two research grants from the NIH and directed the Nephrology Division in the Department of Medicine at the University of Kansas Medical Center. He continued research in basic renal tubule physiology, discovering, with Darren Wallace, that normal collecting ducts of rat and man had the capacity to secrete chloride and fluid by mechanisms identical to those found in renal cysts. They demonstrated in human cystic tissue that cyclic AMP promoted the transepithelial secretion of chloride and water into the lumen. More recently he and his collaborators have extended the study of cyclic AMP to discover that the nucleotide stimulates the proliferation of cyst epithelial cells and, thereby contributes to acceleration of cyst growth. This work serves as the foundation of a clinical trial that will be initiated in the USA and abroad in 2006 to determine if inhibition of cyclic AMP will diminish the rate of kidney enlargement in patients with PKD.
In addition to his laboratory studies of cyst pathogenesis, Grantham initiated studies of disease progression in patients with ADPKD. Most recently, he implored the NIDDK to perform a study to determine if radiologic imaging of polycystic kidneys was an accurate way to monitor disease progression. This work served as the basis for a large multi-center NIH study of over 200 ADPKD patients that was completed in 2005. This study established that sequential measurements of kidney volume could be used to judge the rate of PKD progression, and thereby serve as an outcome marker in studies to determine the therapeutic efficacy of drugs and special diets before the disease reached end-stage.
Grantham directed the Renal Training Program at the University of Kansas Medical Center for 25 years. Sixty fellows have completed clinical and/or research training 17 of whom have held faculty positions in Schools of Medicine. Grantham was a founding member of the Midwest Transplant Network and served on the Board of Trustees for 10 years. He was the founding editor of The Journal of the American Society of Nephrology which had the highest impact factor of more than 30 Nephrology/Urology titles when he left the editorship after 6 years.
Grantham was the first faculty member of the Kansas University School of Medicine to be elected to membership in the American Society of Clinical Investigation and the Association of American Physicians. He was also elected to membership in the American Clinical and Climatological Association, the American Physiological Society and is a Fellow of the American Association for the Advancement of Science. He served as Program Chairman of the American Society of Nephrology in 1985 and was a member of the Council of the ASN for 10 years as Secretary/Treasurer and JASN editor.
Grantham has received awards, including the Dolph Simons-Higuchi Award in Biomedical Sciences (University of Kansas), the Scientific Councils' Distinguished Achievement Award (American Heart Association), the Award of Merit (American Heart Association), the Distinguished Medical Alumnus Award (University of Kansas School of Medicine), the Homer W. Smith Award (New York Heart Association and American Society of Nephrology), the Laureate Award (American College of Physicians), the Chancellor's Club Research Award (University of Kansas), the President’s Medal Award (American Society of Nephrology), the Jared J Grantham Distinguished Service Award (Polycystic Kidney Research Foundation), the David Hume Award (National Kidney Foundation) the Distinguished Alumnus Award (Baker University) and the Lillian Jean Kaplan Prize for studies of PKD (International Society of Nephrology and Polycystic Kidney Disease Foundation).
In his spare time, when not entertaining his 10 grand children and travelling with Carol, Grantham sings in the church choir, performs occasional vocal solos, and indulges in his newest passion, writing children’s stories. His first book, Ashley and the Mooncorn People, done in collaboration with illustrator Craig Lueck, was published in 2002 and the second, Ashley and the Dollmaker published in 2004, have been warmly received by children and adults though out the USA. His autobiography, “Why I think about urine….and a treatment for polycystic kidney disease” was published in 2014.