The Consumer’s Guide to Vasopressin Receptor Antagonists for ADPKD

In April 2018 the FDA approved tolvaptan (Jynarque) as a treatment to help slow kidney function decline in adults who are at risk of rapidly progressing ADPKD. It is the first VRA to be approved for ADPKD, although different VRAs are approved to treat other conditions.

Tolvaptan is a V2 receptor antagonist, meaning it targets vasopressin receptors that are found mainly in the kidneys. “There are also vasopressin 1 receptors throughout the body, in arteries, that are important for vasoconstriction,” or blood vessel constriction, explains Ken Hallows, MD, PhD, chief of the division of nephrology and hypertension at Keck School of Medicine of USC in Los Angeles.

Tolvaptan targets vasopressin receptors only in your kidneys, not in your blood vessels, which helps prevent unwanted and potentially dangerous effects in your body.

Lower doses of tolvaptan, along with another V2 receptor antagonist not studied for ADPKD, are also sometimes used to address low blood sodium levels.

Tolvaptan is not only the first VRA to be approved for ADPKD, but also the first treatment option for ADPKD that’s been shown to slow the loss of kidney function. And it’s likely not going to be the last.

One of the biggest benefits of tolvaptan’s FDA approval is showing that progress in ADPKD treatment is achievable, says Shuchi Anand, MD, a nephrologist and the director of the center for tubulointerstitial kidney disease at Stanford University in Palo Alto, California. “It’s great that we have a tool to delay the inevitable progression of kidney disease. It’s also a great model for us to continue to emulate, to continue to strive for more therapies [for ADPKD] that are based on the mechanism of the disease,” she says.

For some patients, Dr. Anand notes, tolvaptan’s example helps give them hope and motivation to enroll in clinical trials for other potential ADPKD therapies.

In the first major study of tolvaptan for ADPKD, researchers found that over about 3 years, participants who took a placebo experienced a 46 percent greater loss of kidney function each year than those who took tolvaptan. Participants who took tolvaptan also experienced fewer ADPKD-related adverse events, such as episodes of kidney pain.

The second major study focused on people with later-stage ADPKD. Results showed that over a year, participants who took a placebo lost 54 percent more kidney function compared with those who took tolvaptan.

A review of both of these clinical trials determined that taking tolvaptan may delay the onset of kidney failure by 1.5 to 7.3 years in people with ADPKD, depending on the level of kidney function at the time the drug is started.

“Not that tolvaptan completely erases the possibility of kidney failure, but it gives people some control over their diagnosis,” says Anand. “It gives them an option to at least delay dialysis or a kidney transplant.”

“We don’t use tolvaptan in everyone with polycystic kidney disease,” notes Anand. Even though the treatment has been shown to help slow cyst growth and preserve kidney function, it isn’t recommended for everyone with ADPKD, due to potential side effects and safety concerns. So, who’s a good candidate? Anand says that someone with ADPKD who has very enlarged kidneys and is younger than 55 may benefit from tolvaptan, as would someone with a high likelihood of developing kidney failure, based on widely used risk assessment scores and family history.

“We’re trying to identify people who are at risk for fast progression,” she adds. “We can do that by looking at their prior kidney function change over time. If someone is losing kidney function at a reasonably fast clip, then we definitely want to slow that down.”

Some of the more serious side effects of tolvaptan to be aware of include:

Increased thirst and frequent urination In people who take tolvaptan, the kidneys have a greater tendency to excrete water in urine and cannot direct water back into the bloodstream. “It basically forces them to drink water all the time,” says Anand. “That feeling of thirst, drinking water, and having to use the bathroom sometimes every hour can be disruptive.”

For people who find the thirst and frequent urination too disruptive, reducing the dose can sometimes help, says Anand. It may also be possible to stop taking the medication for periods, such as while on a cross-country road trip or hiking trip.

Issues with liver function Because tolvaptan can reduce liver function in some people, regular liver function tests are needed. “If a patient develops liver [changes] above a certain level, it’s indicated to stop the drug at that point,” says Dr. Hallows. “Usually, it’s not causing any long-term damage to the liver, so you could cautiously restart the drug,” he notes, but potentially at a lower dose.

For some people with ADPKD who try tolvaptan, liver function changes are so severe that continuing the drug simply isn’t an option. Anand estimates that this is the case for 1 to 2 percent of her patients who initially take the drug, adding that liver function returns once they stop taking it. In clinical trials, about 4 to 5 percent of participants experienced significant liver function changes, she says.

People with ADPKD who take tolvaptan are required to enroll in what’s known as an REMS (risk evaluation and mitigation strategy) program through the FDA — as are their doctors. “Patients acknowledge they know the risks, and they only get enough tablets to last until their next lab draw is due,” Anand explains. “Only when they’ve completed the lab draw, and their liver function has been evaluated, do they get their next bottle.”

REMS programs are administered only through approved pharmacies, so you probably can’t fill your tolvaptan prescription at your corner drugstore.

Tolvaptan is an expensive drug, but it should be covered by your health insurance plan’s prescription benefits. “Generally, insurance should cover it, because it’s FDA approved and is considered the standard of care in populations that should benefit from it,” says Hallows.

You may still be responsible for a copay, though. If you’re concerned about being able to afford tolvaptan, talk to your doctor about prescription drug assistance programs you may qualify for, or sign up for a savings program through the drug’s manufacturer.

Following a generally healthy, active lifestyle — and drinking enough fluids, especially — is still important if you take tolvaptan, to help slow ADPKD progression. “It may be beneficial to drink more fluids in general, because by doing so, you will naturally reduce your body’s own secretion of vasopressin, which may be part of what’s driving cyst growth,” Hallows explains.

Taking tolvaptan is often compatible with a normal, active lifestyle, Anand says. “Many people do fine on tolvaptan, but others have a change in their quality of life,” she notes.