Pioneers in
kidney
research
BY CJ Janovy
with PKD and whose daughter also had the disease. He and Grantham
started the Polycystic Kidney Research Foundation (now the PKD
Foundation), which now funds more than $2 million in grants and has
leveraged an additional $30 million per year in federal support for PKD
research. (Like Calvet, Grantham is a winner of the International Society
of Nephrology’s Kaplan Prize. He has also won the American Society of
Nephrology’s Homer Smith Award, the association’s highest honor, as
well as its John P. Peters Award for substantial research achievements and
sustained achievements.)
cell proliferation and cyst-filling fluid secretion in animal models. By 2005,
the first patients were enrolled in studies.
PKD is not the world’s most common kidney disease – approximately
600,000 people in the U.S. have it, out of the 26 million American adults
who have chronic kidney disease. But it is one of the most common
life-threatening genetic diseases – more widespread than cystic fibrosis,
muscular dystrophy, hemophilia and sickle cell anemia combined.
Harr’s father and grandfather came from generations of people who
didn’t talk about their medical problems.
For people who have inherited the mutated PKD gene, cysts probably
begin growing in their kidneys before they are born, Calvet says. But
patients can be symptom-free for years. “By ultrasound, you would see
a person in their 20s or 30s who has many cysts but the kidney will function normally for years,” he says. “Patients can have these huge kidneys,
carrying this weight and this mass. They can be uncomfortable but their
kidneys still function.”
Alan Yu, M.D., and James Calvet. Ph.D.
When James Calvet, Ph.D., came to work at the University of Kansas
Medical Center in 1981, he didn’t know anything about the kidney.
Calvet’s background was genetics and cell biology. He’d just finished
postdoctoral studies at the Worcester Foundation for Experimental Biology
in Massachusetts, where he had been researching the mechanisms of gene
expression and ribonucleic acid (RNA) structures in cultured cells – the
HeLa cells made famous in Rebecca Skloot’s bestselling “The Immortal
Life of Henrietta Lacks”.
“I was one of the people growing liters and liters of those cells,” says
Calvet, now a professor in KU’s Department of Biochemistry and
Molecular Biology. Watching as newly synthesized RNAs turned into
messenger RNAs, he eventually discovered new ways to determine how
RNA works without extracting it from cells. It had nothing specifically to
do with the kidney.
Three decades later, however, Calvet would be recognized as an
international authority on kidney research. In April 2011, at a ceremony
in Vancouver, British Columbia, he was awarded the Lillian Jean Kaplan
International Prize, given by the International Society of Nephrology and
the Polycystic Kidney Disease Foundation to scientists who have increased
understanding of polycystic kidney disease (PKD), leading to new
treatments and the promise of a cure.
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When he arrived at KU, Calvet found himself among physician scientists
who had helped establish the field of nephrology.
The chair of Calvet’s department, Kurt Ebner, Ph.D., introduced him
to Jared Grantham, M.D., who had been among the first to develop an
essential understanding of the kidney’s components during a research
fellowship at the National Institutes of Health in the early 1960s. Back
then, the kidney was largely a mystery; Grantham helped establish that
the fist-size organ is made of a million little tubules, each about the size
of a human hair, processing 50 gallons of plasma to produce 1½ quarts of
urine every day. He discovered that each tubule had different parts that
modified the fluid pushed into it, pumping out glucose, for example, or
amino acids, sodium chloride or water.
During an experiment in the early 1970s, Grantham found that what
should have been an inert chemical normally found in urine caused the
tubule to secrete fluid, bringing water back into the tubule instead of
absorbing it. No one had seen this secretion mechanism.
By the early 1980s, Grantham’s work had caught the attention of Joseph
Bruening, a Kansas City real estate developer whose wife was on dialysis
Among the patients now on tolvaptan trials is Nicole Harr, 45, who was
diagnosed with PKD about 10 years ago.
“When I was diagnosed I was really worried because my dad and my
grandfather both had PKD and they both passed away at around 57 years
old,” Harr says. “My dad was very, very ill at the end of his life.”
“I knew what PKD was, but just basically that you had cysts on your kidneys and eventually your kidneys don’t work,” she says. Harr educated
herself and sought specialists, ultimately finding Franz Winklhofer, M.D.,
an associate professor of nephrology in the KU School of Medicine, who
suggested that she take part in the tolvaptan trial.
As part of the study, Harr makes regular visits for blood and urine tests
and has an MRI scan once a year. She hopes that tolvaptan is slowing the
progression of her disease, though she can’t tell for certain whether it is.
But she has other reasons for taking part in the study.
When he turned his attention toward kidney research, Calvet wanted to
know what it was about mutations in PKD genes that led to PKD growth.
“I have two children. I don’t know whether they have PKD or not, but I
want to do whatever I can do to help with the research.”
Examining the behavior of cells in culture, Calvet and his colleagues
determined that the intracellular second-messenger molecule known as
cyclic AMP was causing fluid secretion at the same time as it was driving a cell-proliferation gene called BRAF, which is normally inhibited
by calcium. “We determined that, in PKD, cyclic AMP can stimulate cell
proliferation when it normally does the opposite. We think that’s the difference between normal cells and PKD cells. We can take normal cells and
just by lowering calcium artificially we can switch them to PKD cells.” To
confirm the finding, Darren Wallace, Ph.D., an associate professor in the
Department of Internal Medicine’s Nephrology Division, took cells from
patients’ cystic kidneys and returned them to normal by adding calcium
back to the cells. “It’s a pretty foundational discovery,” Calvet says.
KU scientists are trying to solve some of the world’s biggest kidney
problems. Their research helped attract the Kidney Institute’s new director,
Alan Yu, M.D., who came to KU last year from Keck School of Medicine
at the University of Southern California. Yu is also the new director of the
medical center’s Division of Nephrology and Hypertension.
Having broken down the complex processes of abnormal cell growth and
fluid secretion in the kidneys, KU scientists have begun to develop drugs
targeted to both processes.
“Jared Grantham was a transport physiologist when that was pretty much
all that was done in kidney research, and he made a seminal discovery in
how we make urine,” Yu says.
The most promising drug for PKD therapy – developed as a result of
research initially at KU – is now in clinical trials.
Now, Yu says, scientists have moved on to solving the 3-D structure of
proteins so they can design drugs that work.
Vincent Gattone, Ph.D., patented the use of a drug called tolvaptan for
treating PKD while he was a professor of anatomy and cell biology at KU
Medical Center from the mid-1980s until 2000. Gattone is now at Indiana
University School of Medicine.
“If tolvaptan works,” he adds, “it’s the first clinical treatment of PKD. We
are right on the doorstep of finding a treatment. It would be revolutionary
to have any drug that could work for this disease.”
“One of the relatively common problems in those with PKD or any of the
renal cystic diseases is an inability to concentrate urine,” Gattone explains.
“I was interested in the basis for that.” Gattone essentially figured out a
way to lower levels of cyclic AMP in the kidney so that it decreases both
“KU has a fantastic reputation for kidney clinical care and research,” Yu
says. “It’s definitely one of the top kidney programs in the country.”
His own work as a transport physiologist – understanding how compounds such as salt and water pass across the membrane junctions
between cells – complements the work historically done at KU, he says.
Calvet says a drug doesn’t have to eradicate PKD in order for it to work.
“It just has to slow down the process. If we could change the trajectory of
the disease, essentially a patient’s kidneys would outlive them.”
Contact CJ Janovy at [email protected]
SUMMER 2012
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