By Erin Allday

Dr. Alan Pao had a patient years ago with recurring, debilitating kidney stones that due to their chemical makeup were essentially unpreventable. He recalled telling the man once that he was sorry, but there were no options that wouldn’t make his condition worse.

“There are some things someone could try,” Pao told the man, thinking of patients he’d seen over the years at the Stanford Kidney Stone Clinic and ideas that had tickled the back of his mind as possible options for treating them. And the man said, well, why shouldn’t Pao be the one to try?

And thus launched Pao’s efforts to find a new drug to treat and prevent some types of kidney stones. His research at Stanford is focused on a particular type of kidney stone, but he hopes his work will help scientists across the field better understand the mechanics and chemistry of kidney stones and how to harness that information to stop them.

Kidney stones are an incredibly painful inconvenience and potentially harmful condition for many adults, typically people in their 40s and 50s but sometimes younger. One in 10 people will suffer from kidney stones in their lifetime, and for some, including those with a rare kidney condition, they are a recurring and devastating problem.

“There is a dearth of medicines that have been targeted to prevent stones,” said Pao, who is head of the Stanford stone clinic that he started in 2014. “There are so many other new drugs being developed for cancer and heart diseases — I think stones need something as well.

“It’s a tough disease and it causes a lot of pain and anxiety.”

What are kidney stones?

Garrett Farwell, now 42, got his first and so far only kidney stone on his birthday a few years ago. The pain was excruciating, he said. At first he felt a strong urge to urinate but found he couldn’t, and before long he had pain radiating along his back and left flank. He ended up in the Stanford emergency room, and was discharged after a few hours to pass the stone at his home in Lafayette.

“I’ve been really, really lucky and fairly diligent with my diet and I haven’t had another kidney stone, thank God,” said Farwell, who eventually ended up in Pao’s care. “I cannot even fathom having them regularly.”

Kidney stones are hard mineral deposits that form in and around the organ over time due to concentrated urine — if there is too much of certain minerals and not enough water in the urine, the minerals can clump into stones. The exact chemical makeup of the stones depends on the individual and factors like their diet, lifestyle and genetics.

The most common types are formed by too much calcium, oxalate, uric acid, cystine or phosphate in the urine. One stone isn’t necessarily worse than the other, but some are harder to treat or prevent. In some cases, treating the cause of one type of stone can increase the risk of developing a different type of stone — that’s Pao’s field of research.

“The kidneys are responsible for filtering waste from our body. But unfortunately if there’s a lot of, let’s say, oxalate present, it can combine with calcium in the urine and form these hard rocks or pebbles in the kidney and be there for years,” said Dr. Matthew Breeggemann, medical director of the kidney stone prevention center at UCSF, which he started in 2023.

“The stone gets bigger and bigger, and for reasons we don’t really know it breaks off,” he said.

The stones aren’t necessarily a problem until they enter the ureter, a muscular tube that moves urine from the kidney to the bladder. The ureter is narrow, and when a kidney stone — which can range in size from a grain of sand to a small pebble — becomes lodged in there and stops the urine flow, the tube contracts painfully.

The pain can be severe — every year about half a million Americans end up in the emergency room for kidney stones, according to the National Kidney Foundation. And the pain can last for days, until the stone passes or is removed by surgery. Symptoms of stones include severe pain in the lower back or side and blood in the urine, plus general stomach pain or nausea.

Many people have recurring stones, sometimes getting them once a year or even more frequently. Once someone has one stone, the risk of developing a second is about 50-50, or higher depending on age and the type of stone.

“We have patients who have had 200 stones in their lifetime,” Breeggemann said. “They’re feeling like they’re having stones every other week, so they’re frustrated, they’re scared. They’re just looking to do anything they can to prevent more stones.”

What causes stones

Stones are caused by a buildup of certain minerals, and in many cases it can be traced to an individual’s diet. One of the most common sources of mineral buildup is a diet high in salt and meat products. But even eating too much spinach can lead to certain types of stones. In Farwell’s case, peanut butter was the primary culprit — it’s high in oxalate, one of the minerals that can crystallize in the kidneys, and he was eating it daily.

Certain medical conditions, including diabetes and inflammatory bowel disease, also increase the risk of developing stones. A genetic kidney condition called primary hyperoxaluria can cause repeated stone episodes starting in childhood; Breegemann’s clinic at UCSF specializes in treating that disease.

The type of stone mostly matters for prevention. Depending on the chemical makeup, the prevention plan may include medication plus changes in diet, though not all stones can be treated with drugs. Dietary recommendations often include drinking more water and limiting salt.

To prevent future stones, doctors generally will analyze the chemical makeup of a first stone and take a close look at the patient’s urine. Often, patients will be directed to collect their urine for 24 hours at home, then send a sample to their doctor for analyses. If they pass a stone at home, they should try to collect it and give that to their doctor too.

For example, analyses could find that patients have low levels of citrate, a chemical that can bind to calcium and help it dissolve instead of forming hard deposits, in their urine; increasing citrate through diet or medication could prevent future stones. Or some patients, like Farwell, may have too much oxalate in their urine, which can come from overindulging on peanut butter plus spinach and some other nuts and leafy green vegetables.

Aside from lowering salt intake and drinking more water, doctors don’t advise that people make major dietary changes in response to kidney stones — they’re better off getting an analysis first to fine-tune their prevention plan.

“Drinking plenty of water is going to be helpful for everyone. And lowering salt,” said Dr. Alex Wu, chief of urology at Kaiser Permanente South San Francisco. “For stone formers, or people who are concerned about forming stones, drinking about two liters of water each day would be good.”

The future

Though kidney stones have been recorded in historical figures dating back thousands of years, they’ve become a worsening problem for humans in recent decades.

As recently as the 1970s, only about 5% of people would get kidney stones in their lifetime; now that’s more like 10%, and somewhat higher for men than for women, according to the kidney foundation. Some providers expect those rates to get worse with climate change, as the planet gets hotter and dehydration becomes more prevalent.

“When you’re affected by heat you get more dehydrated, and if you produce a chronically concentrated urine, that will probably cause more stones over time,” Pao said.

Doctors who study the condition say one of the main reasons for the increase in stones over the decades is changes in diet, with more reliance on processed foods and meat. It’s increasingly seen as a potential metabolic disorder, with people who are obese also at much higher risk of developing stones.

Pao’s work focuses on the most common type of kidney stone, calcium oxalate, which generally is treated with citrate to reduce the calcium. But for some patients with alkaline urine, including many women, citrate can actually increase their risk of developing a different kind of stone, called calcium phosphate. Those are the patients for whom Pao often doesn’t have a good solution for preventing future stones.

“For a subset of patients, you’re stuck,” he said. His lab at Stanford is currently looking for new drugs that could help those patients. “The best case scenario would be to find a new compound and a new drug to prevent kidney stones.”

Pao and others noted that for a long time kidney stones have been ignored, or perhaps not taken as seriously as they should, by health care providers, in part because they’re generally not life-threatening, though they can cause kidney damage over time and with repeated incidents.

But for some people kidney stones can have dramatic effects on their lives with regular recurrences. The pain can last for weeks, and some patients experience major stress between episodes, waiting for the next stone.

“It’s not cancer or dementia, but it’s really painful for a lot of people and it can really be a lifestyle challenge,” Farwell said. For a full year after his kidney stone, he said he was so wary of a recurrence that he wouldn’t travel far — an avid outdoorsman, he was afraid he’d have a stone while camping or backpacking.

“There was a really big mental side to the kidney stone, like, what happens if I get another one? I was afraid to be away from proper emergency care,” Farwell said. “You have this thing that could potentially be sitting in your body ready to strike you. There’s this whole mental anxiety side that I don’t think anybody talks about.”