This month, hundreds of thousands of Americans, and millions of people around the world, have hope that they’ve never had before. And it’s largely because of four decades’ worth of work that’s gone on at Kansas University Medical Center.
Those people are sufferers of polycystic kidney disease, a genetic disorder that causes a person’s kidneys to slowly balloon with fluid-filled cysts over the course of his or her life and ultimately stop functioning. After the release of the results of a clinical trial earlier this month, there is now for the first time a treatment that’s been proven to slow the growth of those cysts.
How that came to happen is a tale that largely begins in the early 1970s, when Jared Grantham first made PKD the focus of his research at KUMC, researchers there said.
“The story of this research is very much a Kansas story,” said Grantham, now a University Distinguished Professor at the medical center.
PKD is passed on from parent to child, Grantham says, and it takes action while the child is still in the mother’s womb. But its effects are slow. Over time, it causes the hundreds of thousands of tubules that make up the kidney — normally about the size of a human hair — to develop what look like blisters.
But slowly over many years, all those cysts can cause the kidney, normally a fist-sized organ with a smooth surface, to grow to the size of a football or larger and resemble a bunch of grapes — the “grapes” being the fluid-filled cysts that define the disease.
By the time a person is 50 or 60, that can cause kidney failure requiring a transplant or possibly leading to death. The disease progresses at different rates in different people, though, Grantham said.
The enlarged kidneys can cause bleeding, hemorrhaging, kidney stones or intense pain along the way. They can cause people’s stomachs to protrude so much that they resemble that of a woman nine months pregnant.
“It’s not a nice disease,” Grantham said. “Let’s put it that way.”
The good news that emerged this month was a Nov. 3 article in the New England Journal of Medicine about a trial that found a previously existing drug called tolvaptan (currently marketed under the name Samsca as a treatment for people who have too much water in their systems) successfully slowed the growth of cyst-filled kidneys while also slowing the resulting loss of kidney function. The article reported on a 3-year worldwide clinical trial of nearly 1,500 people with PKD in places including Japan, Russia and Europe, plus about 15 patients who participated at KUMC.
“We’ve shown for the first time that you can actually treat this disease,” Grantham said.
The lead author on this month’s article was Vincent Torres of the Mayo Clinic, who Grantham said is a longtime friend and colleague. Grantham is also listed as an author.
But Grantham led a study, the results of which were released in 2006, that made the clinical trial possible in the first place. He found that it was possible to use MRI to measure the changing volume of the kidneys of a person with PKD.
Before that, Grantham said, the only measurable marker of the disease was when a patient’s kidneys actually failed. It was impossible to test the effectiveness of a treatment if there was nothing to measure.
But even before that, it was KU PKD researchers who pinpointed the root cause of PKD patients’ kidney cysts that is targeted by the drug, said fellow longtime KUMC researchers Darren Wallace, an associate professor of medicine, and James Calvet, a professor of biochemistry and molecular biology.
“That validates what we’ve done,” Calvet said of the clinical trial.
KU’s team of PKD researchers found that the “bad guy,” as Calvet put it, was a compound called cyclic AMP, which usually signals to a person’s kidney cells when to absorb more or less water, based on the person’s level of hydration.
But in a person with PKD, cyclic AMP instead sparks kidney cells to proliferate and secrete the fluid that fills the resulting cysts. Tolvaptan blocks the production of cyclic AMP.
Wallace’s research lab has focused on examining cells from polycystic kidneys — removed from patients — and comparing them with normal cells to see what’s causing the abnormality. Calvet has explored the genetic roots of the disease, using mice as models.
The PKD research at KU, and really everywhere, can be traced back to Grantham’s first efforts to study the disease back in the early 1970s, Wallace said.
“Dr. Grantham is kind of considered the grandfather of PKD research,” Wallace said.
Thirty years ago, Grantham co-founded the PKD Foundation in Kansas City, Mo., which seeks funding for PKD research.
His interest in the disease has roots in his childhood, when he discovered that a friend had PKD, along with his mother and grandmother.
“It’s been a long, long slog for me,” Grantham said.
About one in every 500 to 1,000 people has PKD, he said, and he guessed that about 3,000 Kansans are probably among that group.
“You probably have met somebody who has it,” Grantham said.
People who have PKD often don’t talk much about it, he said, and it hasn’t drawn as much attention as some other conditions that affect far fewer people — cystic fibrosis and muscular dystrophy among them — because its effects generally don’t show up until adulthood, and sick children often tug more at people’s heartstrings.
This new potential treatment for these people still must be approved by the FDA, he said, which could take months or years.
But the proven success of one treatment for the disease is a huge hurdle, he said. A pharmaceutical company had to spend hundreds of millions of dollars to test the drug, even though it’s already been approved for another purpose. Now that it’s been proved that it is possible to treat PKD, he said, other drug companies may now be willing to take on the risk of developing more treatments.
“The first drug that you get is probably OK, but it’s not going to be as good as the second, the third or the fourth drug that you get after it,” Grantham said.
Eventually, he said, he does believe that the disease can be cured — perhaps with a combination of drugs that attack it from different angles.
And if that happens, he says, the world will be able to thank, in large part, the state of Kansas.