Young Nephrologists Asking BIG QUESTIONS About Kidney Diseases

A trio of early-career researchers have wide-ranging projects that aim to improve kidney health around the world.

From left: Drs. Shuchi AnandColin Lenihan,  and Michelle O’Shaughnessy are addressing some of nephrology's toughest challenges. 

Your kidneys, nestled in your lower back on either side of your spine, are the kind of organ system you don’t think about much until something goes wrong with them. If you’re healthy, your kidneys filter your blood to keep it clean, removing waste and producing urine. But if both kidneys stop doing this job, then you either need a new kidney—a transplant—or something else to mechanically filter your blood—dialysis.

The rate of kidney diseases in the United States and the rest of the developed world is on the rise, so research into how to prevent and treat these diseases is needed more than ever. At Stanford, a trio of early-career researchers exemplify the breadth of current nephrology research, and the energy and creativity needed to tackle some tough questions.

A Medical Mystery

Halfway around the world, in rural Sri Lanka, a mysterious kidney disease is killing farm workers. In the last decade, more than 20,000 deaths have been blamed on the disease, which is called chronic kidney disease of unknown etiology, or CKDu. Here in Palo Alto, nephrologist Shuchi Anand, MD, is on the hunt to find out what’s causing it and help spearhead new ways to screen and manage the thousands of patients who need ongoing care.

“The concern is that it’s a single toxin that’s causing the disease,” says Anand, who completed her fellowship in nephrology at Stanford in 2012 before joining the faculty as a nephrology instructor. “But at this point, we still don’t know.”

In the United States and developing countries, most cases of chronic kidney disease (CKD) are seen in older individuals with risk factors like diabetes, high blood pressure, and cardiovascular disease. But in Sri Lanka—as well as small regions of southern India, Nicaragua, and El Salvador—the disease has been appearing in young, otherwise healthy, adults.

A similar outbreak of kidney diseases occurred in the 1950s and 1960s in the Balkans. Years later, researchers discovered that an herb growing in nearby fields was causing the cluster of cases. That historical case is why today’s scientists have a hunch that a toxin—in the groundwater, soil, or plants—may play a role in the current outbreaks.

Anand, who has traveled to affected areas in Sri Lanka, is working on setting up a study to analyze what CKDu patients in Sri Lanka have been exposed to. So far, she and her colleagues have collected kidney biopsy data on about a hundred patients, with the goal of testing for infections, pesticides in their bodies, and other chemical levels.

“In the past, there’s been a lot of single-hypothesis research on CKDu,” says Anand. “There’s this new momentum toward creating collaborations that guide a more systematic approach, and Stanford has been a leading part of that effort.”

The results of their effort are still forthcoming, and the group hopes to eventually collect data on a total of 300 patients. Somewhere in the molecules contained in blood samples, they hope, is an answer.

Putting Numbers on a Disease

There are different ways that the kidneys can stop working. The blood vessels leading into the organs can become damaged, cysts can grow, stones can block the flow of urine, or the immune system can attack the kidneys. One subset of these diseases is dubbed glomerular diseases: They affect the tiny filters, called glomeruli, that help the kidneys function. But not all glomerular diseases are the same, and they have diverse causes—patients can develop them due to an autoimmune disease like lupus, after contracting an infection or taking certain drugs, or because of a genetic disease.

Michelle O’Shaughnessy, MD, an assistant professor of nephrology who moved to Stanford from Ireland in 2013, wants to sort out the differences between each type of glomerular disease, by quantifying the patients who contract them, how they contract them, and which treatments work.

“We see a huge spectrum of outcomes with glomerular disease,” says O’Shaughnessy. “Some patients do really well, while others do very poorly, and lots are in a spectrum between those two extremes.”

The challenge in figuring out which patients have which outcomes, she says, stems from the fact that there’s no national—or worldwide—registry of glomerular disease patients. As a result, studies tend to be small, focused only on patients within an individual hospital system. O’Shaughnessy is working on ways to mine large health record databases for information on patients with glomerular disease.

In 2017, O’Shaughnessy published the results of a large epidemiological study of more than 21,000 glomerular disease patients referred to the University of North Carolina, Chapel Hill, over a 30-year time span. She and collaborators found the rate of diabetes-related kidney disease to increase dramatically—accounting for nearly a fifth of all biopsy-proven glomerular disease by 2015.

“That’s really concerning because having diabetes and kidney disease portends a much poorer prognosis than having diabetes alone,” says O’Shaughnessy. “From a public health perspective, we as physicians need to be aware that this is increasing.”

Her next steps are to assemble a larger study of glomerular disease patients, following the course of disease beginning at diagnosis and including people who aren’t typically included in small controlled trials—those with other chronic diseases, and elderly people, for instance.

Targeting Transplants

Whether patients have glomerular disease or CKDu, they may need a kidney transplant if their kidney function deteriorates enough. Today, more than 100,000 people in the United States are on the waiting list for a kidney, yet only around 17,000 transplants are performed each year. While much of this lag is due to a shortage of organs, matching donors with recipients can also be a problem because patients can have antibodies that make them reject an organ. These antibodies react to proteins on the donor kidney called human leukocyte antigens, or HLAs.

“Our tissues are covered in these HLA proteins, and they’re kind of like a fingerprint,” explains Colin Lenihan, MD, an assistant professor of nephrology who—like O’Shaughnessy—hails from Ireland. If you’re exposed to these HLA molecules from someone else’s body—through pregnancy, blood transfusion, or a previous transplant—you can develop anti-HLA antibodies, a process called sensitization. However, some patients are sensitized but have no history of pregnancy, transfusion, or transplant, and it’s not clear why they have developed anti-HLA antibodies.

“Sensitization is a big problem,” Lenihan says. “Highly sensitized patients are less likely to find a compatible donor, and they also don’t tend to do as well after the transplant.” Some 20 percent of people waiting for a deceased donor kidney transplant, he says, are sensitized to more than 80 percent of all HLA types, limiting the organs they can receive.

Lenihan is studying whether the flu vaccine may play a role—he and his colleagues are testing levels of HLA antibodies in patients on the transplant waiting list at Stanford before and after they get a routine flu shot.

“The flu vaccine is really beneficial and saves lives, but there may be a subset of people who develop unwanted anti-HLA antibody after they get vaccinated,” Lenihan says. Of course, he admits, the study could also show no effect on HLAs from the flu vaccine, so it’s too early to make any changes to vaccine policies.