What’s your risk of kidney disease, heart attack, or diabetes? A single molecule can tell | Science

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What’s your risk of kidney disease, heart attack, or diabetes? A single molecule can tell | Science

Nate Henry (right), Nick’s identical twin, is healthy. Nick’s high levels of a molecule called suPAR may explain his illness.

Kevin Beasley

Nick Henry first experienced the symptoms of kidney disease in 2004, shortly after the 19-year-old had a severe reaction to a spider bite. “I woke up one morning, and I was just swollen from head to toe,” he recalls. But doctors managed Henry’s disease, allowing him to return to his unusually active lifestyle—including baseball, softball, basketball, flag football, golf, and fishing—in his northeast Louisiana hometown of West Monroe. Shortly after he witnessed the death of his mother in a motor scooter accident in 2012, however, Henry’s renal health took a dramatic turn for the worse. “It’s almost as if my body went into shock,” he says. “Within a couple months, boom, I started swelling up again.”

That swelling was a sign that his kidneys were no longer working normally. A biopsy confirmed that he had focal segmental glomerulosclerosis (FSGS), a severe form of kidney disease. In FSGS, the kidney’s glomeruli—the microscopic filtration units that sieve excess fluid and waste products from the blood—become overly leaky; essential proteins such as albumin seep out, disrupting blood chemistry and causing fluid to leak from the blood vessels into tissues throughout the body. Henry’s condition deteriorated so rapidly that by July 2014, his doctors in Shreveport, Louisiana, decided to remove both diseased kidneys. The next month, Henry received a transplanted kidney from his identical twin, Nate, who was healthy, even though FSGS can be genetic in origin.

Within a day of the transplant, however, Henry felt like the swelling was coming back. At first, his doctors reassured him that he was doing fine. “Once they checked my urine, saw me spilling a bunch of protein again,” he says, “they realized [FSGS] was attacking the new kidney.” Three days after the surgery, Henry’s doctors conceded that the newly transplanted kidney had already become diseased. His transplant doctor, Neeraj Singh of Louisiana State University in Shreveport, says the recurrence was “one of the most dramatic cases I’ve seen.”

The sudden failure of Henry’s new kidney is a recent chapter in a long-running medical mystery, dating to when kidney transplants became routine in the 1970s. Up to 30% of transplanted kidneys fail in FSGS patients—not because of immune rejection by the body, as doctors first suspected, but because the new organ immediately begins succumbing to the same disease process that ravaged the original ones. As he struggled to cope with that devastating turn of events (and relied on dialysis to stay alive), Henry traveled to Chicago, Illinois, to consult with Jochen Reiser, a kidney disease specialist who is chairperson of internal medicine at Rush University Medical Center there.

Ever since he learned about such transplant failures 2 decades earlier, Reiser has been convinced that “there is something in the blood circulating that attacks the kidney. And we were out to catch that.” What he and colleagues claim to have “caught,” in an elegant but still unfolding story of molecular detective work over the past 10 years, is a protein known as soluble urokinase plasminogen activator receptor (suPAR). When Reiser analyzed blood samples from the Henry twins, the results aligned with the message he has been preaching with evangelical fervor for years. Nate, the healthy brother, had relatively low levels of suPAR; Nick’s were high—a driving force, Reiser believes, of his kidney failure.

Nick Henry had a kidney transplant, but his new organ quickly deteriorated, and he spends his nights on dialysis.

Kevin Beasley

Chronic kidney disease affects 14% of the U.S. population, with estimates suggesting nearly 600 million people affected worldwide. The disease steadily erodes the kidneys’ ability to filter the blood, often leading to cardiovascular disease and premature death. Kidney disease—which can directly attack the filtration process, as in FSGS, or damage the kidney’s support structure—is particularly insidious because by the time the first diagnostic signs appear, patients have irreversibly “burned off” much of their kidney function. Historically, the leading risk factors have been high blood pressure, diabetes, and African-American ancestry. (Several mutations associated with increased risk are more common in African-Americans.)

But research by Reiser and others has dramatically challenged that traditional picture of risk. If suPAR levels are low, people with the high-risk genes are no more likely to develop kidney disease than people without those gene variants, Reiser says. If suPAR levels are high, people are at greater risk of developing the disease regardless of whether they have the mutations.

Molecular studies in animals as well as a growing number of analyses of large human populations associating suPAR with kidney disease have bolstered his confidence—and convinced him the disease could be treated by suppressing suPAR. Some other researchers aren’t convinced, noting that several clinical studies found no clear association between suPAR levels and FSGS. But on both sides of the debate there is widespread fascination with suPAR, a ubiquitous, Zelig-like bystander molecule that, at elevated levels in the blood, seems to presage many health calamities, such as heart attacks, diabetes, and premature death. Whatever suPAR’s precise role in kidney disease, the molecule appears to be a potent signal broadcast by an immune system under siege. It is exquisitely sensitive to inflammation, an accelerant for many diseases.

“What is inflammation?” asks biochemist Jesper Eugen-Olsen of the University of Copenhagen, a pioneer in suPAR research. “It’s the language of cells. It’s how cells communicate with each other. When something is going wrong, the immune system is activated. It produces suPAR … and suPAR is a voice that just shouts, ‘Get on with it! Something is going on!’”

A brash style

In neither background nor appearance does Reiser conform with the public image of the director of a major metropolitan medical center. His 10th floor office at Rush sits just behind a corridor lined with photographs of hospital administrators going back to the 19th century—stern-faced, all-knowing medical patriarchs. Inside, Reiser, 46, sports a stylish striped blue suit, fashionably stubby beard, red socks, and slick dark hair. Known among colleagues as ambitious and scientifically gregarious, he has been eager to collaborate with anyone interested in exploring suPAR biology, and his brash, full-on style extends to the conspicuous display of large-format books celebrating the history of Aston Martins (he owns one) and Porsches on the coffee table in his office. Describing the speed of data collection for a paper that several years ago ended up in The New England Journal of Medicine (NEJM), he says, “It was like going from zero to 200 in no time,” adding sheepishly, “Car analogy.”

Born and raised in the small German village of Remchingen, on the eastern edge of the Black Forest, Reiser got his medical degree and Ph.D. from Heidelberg University and did an overseas residency at Albert Einstein College of Medicine in New York City. Specializing in kidney disease, he went on to conduct research at Harvard Medical School in Boston and became chief of nephrology at the University of Miami Leonard M. Miller School of Medicine in Florida before being hired by Rush in 2012.

Reiser’s arrival in the United States in 1999 coincided with renewed interest in solving the mystery of why up to 30% of FSGS patients who receive transplants see the disease recur in the new kidney. Just 3 years earlier, a group headed by Flavio Vincenti, a transplant specialist at the University of California, San Francisco (UCSF), and Virginia Savin, at the Medical College of Wisconsin in Milwaukee, announced a major clue. They reported in NEJM that they had amassed evidence for an FSGS-promoting factor in the blood of transplant recipients who’d experienced recurrences; they couldn’t isolate the exact protein, but when colleagues later injected an extract of such patients’ blood into rodents, the animals’ kidneys became permeable and spilled protein in the urine. That mysterious “permeability factor” became “the holy grail” of the field, according to Sanja Sever, a molecular biologist who studies kidney disease at Massachusetts General Hospital in Boston.

While still in Germany, Reiser had trained his research efforts on a unique renal cell called the podocyte (so named because of its amoebic, faintly footlike extensions). That choice turned out to be fortunate. The kidney has about 1 million glomeruli, and in each one, hundreds of podocytes bridge the gap between the bloodstream and the urinary system. Their footlike extensions wrap around capillaries snaking through the kidneys and, along with two other layers of tissue, form a physical mesh of cells, like a three-ply screen door, that allows only small molecules—sodium ions, potassium ions, and metabolic wastes—to pass into the urinary tract. When the podocytes become damaged, however, they essentially lose their architectural integrity. The kidney filters then become leaky, allowing larger essential proteins such as albumin to escape from the blood and pass into the urine.

It’s like a coffee filter, Sever says. “If there are holes in your filter, then you get some coffee grounds in your urine.” Podocyte damage can be reversed early in kidney disease. But, she says, “If you keep losing them, there’s a point of no return. … You are basically walking toward end-stage renal disease.”

An organ under attack

In one scenario for a severe form of kidney disease, a blood-borne molecule called soluble urokinase plasminogen activator receptor (suPAR) disrupts the organ’s filtration units, or glomeruli, which remove waste and fluid from the bloodstream. Other molecules may intensify this attack.

A dangerous immune responseAnimal models suggest immature immune cells in the bone marrow release more suPAR when an organism is under attack. The molecule, an all-purpose marker of ill health, may be directly toxic to the kidney.A HEALTHY FILTERIn each glomerulus, the footlike extensions of cells called podocytes wrap around capillaries, fitting together tightly to create narrow “slit diaphragms.” The slits form a fine mesh that allows only small molecules to escape from the bloodstream into the urine.KIDNEY DISEASEKidneyGlomerulusFunctional unit of kidneyPodocyteGlomerular basement membraneEndothelial cellsuPARsuPARMonocyteImmature myeloid cellNeutrophilPodocyte lost to urinary spaceSlit diaphragmCapillary Albumin leakageBone marrow

What causes such damage? Reiser suspected that the mysterious blood-borne factor disrupts podocytes through receptor molecules on their cell surface. He focused on one: β3-integrin, a molecule whose activation perturbs the shape and motility of cells. When he looked for the molecular key that turned the lock of the integrin receptor, he discovered that oncologists had already been working on one such protein, urokinase PAR (uPAR), a cell surface receptor that plays a role in cancer metastasis. Reiser became even more intrigued when he learned that uPAR can be cleaved from cell surfaces and circulate in the blood—at which point it becomes a soluble cousin known as suPAR. Maybe suPAR was the mysterious kidney-destroying factor.

In 2011, Reiser and colleagues reported in Nature Medicine that in cell culture, suPAR damaged human podocytes through the integrin pathway. The researchers supplemented that evidence with three mouse models showing that rodents with elevated levels of suPAR suffered kidney damage, although sometimes more slowly than in FSGS. With human clinical data suggesting that elevated suPAR levels correlated with the recurrence of FSGS in patients, a picture emerged in which the protein triggers a pathogenic process that ultimately produces holes in the coffee filter, leading to kidney disease.

The findings both electrified and polarized the nephrology community. In a commentary for Nature Medicine, Martin Pollak of Harvard Medical School, who studies the genetics of kidney disease, and nephrologist Stuart Shankland of the University of Washington in Seattle described the findings as “paradigm shifting for our understanding of the pathogenesis of FSGS.”

But some groups could not find the same clinical association between suPAR levels and recurrent disease in FSGS patients, and other groups questioned the protocol and interpretation of the animal models. And regardless of whether suPAR actually destroys the kidney, many nephrologists thought its levels were not very informative—by the time those specialists saw patients with kidney disease, suPAR levels were already high and offered no prognostic value. With Reiser claiming to have found the “holy grail” even as several groups were reporting discordant results, says one source, “People felt very emotional.”

An omen of ill-health

By that point, another key strand of the suPAR story had emerged in Europe. There, the focus was on the molecule as a potential biomarker for a range of diseases.

The first clues came from AIDS patients. In Copenhagen, Eugen-Olsen and others examined blood collected from more than 300 HIV patients in the early 1990s, before life-saving antiretroviral therapies became available. All those patients had died, but a retrospective analysis showed their suPAR levels eerily correlated with disease progression: Higher levels were associated with an earlier death. Eugen-Olsen then spent several years collaborating with a hospital in the West African nation of Guinea-Bissau, testing suPAR levels in patients suspected of being HIV-infected. Again, higher suPAR levels predicted a quicker death among the infected. Surprisingly, however, suPAR also predicted mortality in patients who didn’t have AIDS; many turned out to have tuberculosis. That finding led him to hypothesize that suPAR might be a more general biomarker for chronic inflammation.

In 2001, Eugen-Olsen founded the company ViroGates, which began to manufacture a relatively inexpensive test to measure suPAR levels in the blood. With the test in hand, he and colleagues in Copenhagen began to look at collections of blood samples banked in large-cohort prospective studies. In one called MONICA, which monitored healthy members of the Danish population for about 13 years, elevated levels of suPAR were associated with a higher risk of cardiovascular disease, type 2 diabetes, cancer, and premature death. Two other large European populations, enrolled in the Malmo Diet and Cancer Study and the Danish Inter99 Study, showed similar associations.

The findings caught the attention of researchers at Emory University School of Medicine in Atlanta who had been looking for new and better biomarkers to predict risk of adverse cardiac events in people with heart disease. The researchers had built the Emory Cardiovascular Biobank with serum from several thousand patients. “We draw blood, and we follow them for years,” says Salim Hayek, a physician and research fellow at Emory. When two of Hayek’s colleagues, Danny Eapen and Arshed Quyyumi, delved into the biobank, they found that higher suPAR levels predicted heart attacks and death, as they reported in the Journal of the American Heart Association in 2014. (At the annual meeting of the American College of Cardiology last month, Hayek presented further evidence from the Emory group, suggesting that suPAR is a better predictor of cardiac events including heart attacks and death than any other biomarker in widespread clinical use.)

Jochen Reiser has spent years amassing evidence that suPAR mounts a powerful assault on the kidney.

Rush Production Group

In addition to serving as an omen of ill health, suPAR seems to be a remarkably sensitive indicator of lifestyle insults. Studies have shown that the protein’s blood levels typically rise with obesity and with smoking. (Eugen-Olsen, an inveterate smoker, confesses that he quits when his suPAR levels rise and resumes when they subside again.) “Just looking at the data,” Hayek says, “clearly the environment is a much larger contributor to suPAR than genetics.”

With its links to multiple diseases and environmental stresses, suPAR appears to sit at the nexus of immune signaling, chronic inflammation, and tissue damage. Among the protein’s normal sources are fat cells, immune cells, and endothelial cells, which produce low baseline levels. But a team led by Reiser and David Scadden of the Harvard Stem Cell Institute showed in 2017 that in mice, immature “stemlike” cells in the bone marrow can release a pulse of suPAR when the immune system detects an attack.

Reiser believes suPAR is an ancient and unspecific way for the immune system to send urgent signals to the major organ systems when an organism faces a severe challenge from disease or the environment. Kidney damage, he says, is the long-term cost of that vital signaling mechanism. “As one example,” he says, “you get infected, you release more suPAR, you open your kidneys up, and you can dump the big molecules out into the urine. Almost like a primitive coupling of the immune system to vital organs.” In an acute infection, he says, the body urgently needs to flush out bacterial toxins, relatively big molecules. But if that inflammatory signaling becomes chronic, it takes its toll on kidney function—a trade-off that may have been acceptable earlier in human history, Reiser suggests, but is less so now. “If you live 40 years long, you can burn off the kidney this way, no problem,” he says. “If you live to be 80, 90, 100, you might burn off your kidneys too soon.”

For Reiser, the Emory cardiac biobank offered a chance to put to rest the notion that high levels of suPAR are simply a nonspecific sign of failing kidneys, not a cause. When he saw the 2014 heart risk paper from the Emory group, he had the obvious question: Could the large databank show whether suPAR levels predicted the onset of kidney disease years later? He immediately fired off an email to Hayek.

The Emory-based group quickly agreed to conduct follow-up renal examinations in more than 1300 patients who had no evidence of kidney dysfunction when they enrolled. The team found a strong link between high suPAR levels and the later development of kidney disease. For patients with the highest levels of suPAR, the risk was three times that of patients in the lowest group, and suPAR levels could predict kidney disease up to 5 years before the first symptoms appeared. “The effect was huge,” Hayek recalls.

The association was so robust, he says, that when the group first submitted its findings for publication, “the first response we got from [NEJM] was: ‘How is that association so strong? Is that real? Something is wrong with your cohort.’” But after Hayek and Reiser found the same association in a second, unrelated cohort—the Women’s Interagency HIV Study—NEJM published their findings in 2015. “In that paper,” Reiser says, “we could show that suPAR is the strongest risk factor known in healthy people for new chronic kidney disease. Even stronger than hypertension, diabetes, black race—all of these risk factors that are known to be strong. When you adjust for those, suPAR had the strongest risk.”

In the latest piece of evidence, published last summer in Nature Medicine, Reiser collaborated with researchers at the African American Study of Kidney Disease and Hypertension, based at Johns Hopkins University School of Medicine in Baltimore, Maryland, to compare the influence of suPAR and two gene mutations known to predispose African-Americans to kidney disease. A study of about 600 participants revealed that if suPAR levels remain low, “no notable differences” in kidney dysfunction were apparent between people who had the high-risk “disease genes” and people who did not. Conversely, high levels of suPAR strongly predicted kidney disease in African-Americans, regardless of whether the individual had the genetic variants.

The proof is the cure

Yet nephrologists are still divided about whether suPAR actually attacks the kidneys—and if so, how aggressively. Doubters point to the conflicting clinical results and the slow progress of kidney damage in Reiser’s mice with elevated suPAR levels. The original 2011 animal and clinical data are “as complete as you can get,” Vincenti says. “But at some point, there has to be independent duplication of that data.”

Several unresolved issues might explain the discrepancies. Different forms of suPAR can circulate in the blood, and some variants might be more pathogenic than whole suPAR. And a team led by Minnie Sarwal of UCSF, Dany Anglicheau of Necker Hospital in Paris, and Reiser has shown that in FSGS, a second blood-borne factor, an anti-CD40 autoantibody, works with suPAR to attack podocytes. “Everyone agrees it’s more complicated” than the initial findings in 2011 suggested, Reiser concedes. “But meanwhile, the data gets stronger and stronger that suPAR is the worst toxin you can have for the kidneys.”

The data gets stronger and stronger that suPAR is the worst toxin you can have for the kidneys.

Jochen Reiser, Rush University Medical Center

The controversy may not be resolved to everyone’s satisfaction until a human trial indisputably shows that removing suPAR cures or slows the progression of kidney disease. Several groups are trying to develop a monoclonal antibody drug that would remove suPAR from the blood. One such group is Trisaq, a company Reiser and Sever founded in 2011. Vincenti said his group also has developed monoclonal antibodies to suPAR for clinical testing. “I was excited to try it in patients,” he says. “But we could not demonstrate, at least in our samples, that suPAR was a biomarker for either FSGS or recurrent FSGS. [That’s] held it back.”

The first human proof may come not from a drug, but from a medical device. Miltenyi Biotec, a company in Bergisch Gladbach, Germany, makes apheresis devices, which remove substances from plasma, and it is developing a technology that would selectively scrub suPAR out of patients’ blood. “The key question,” notes CEO Stefan Miltenyi, “is if suPAR is the cause [of] renal diseases or just a bystander molecule.” Miltenyi hopes to launch a clinical trial in 2019.

For FSGS patients such as Henry, who relies on 8-hour overnight sessions of dialysis to stay alive, a breakthrough therapy can’t come soon enough. But suPAR is already beginning to influence clinical decisions. Singh, Henry’s transplant physician, has used suPAR levels to manage the care of several kidney patients. And since 2013, every patient arriving at the emergency department at Copenhagen University Hospital Hvidovre has undergone suPAR testing to help physicians make triage and discharge decisions.

Reiser often likens suPAR to cholesterol—a key marker and disease-associated molecule that can be monitored and, perhaps, ultimately controlled. But the main lesson of suPAR, he believes, is cautionary in an age of genomics and personalized medicine. Although a huge amount of attention (and government coin) has been devoted to identifying genes associated with disease, the environment can sometimes trump them. “I think that the gene adds to the risk profile—it’s part of the picture,” he concedes. “But the environment is a way-underestimated modifier that becomes way more important, quite frankly, than the underlying gene event. And this is … a beautiful illustration of exactly that principle.”

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