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Research news tip sheet: Story ideas from Johns Hopkins Medicine

Johns Hopkins Medicine

Research News

PROGRESSIVE KIDNEY DISEASE MAY BE PREDICTED BY PROTEINS IN URINE

Media Contact:
Michael E. Newman,
mnewma25@jhmi.edu

In a study of people who were diagnosed during hospitalization with the short term but serious disorder called acute kidney injury (AKI), Johns Hopkins Medicine researchers showed that the levels of three proteins isolated from the urine of these patients could serve as biomarkers to predict the likelihood of progression to chronic kidney disease (CKD), kidney failure -- also called end stage renal disease (ESRD) -- or death.

The findings are reported in the Feb. 1, 2021, issue of The Journal of Clinical Investigation.

AKI, as described by the National Kidney Foundation, is a "sudden episode of kidney failure or kidney damage that happens within a few hours or a few days." It causes waste products to build up in the blood, making it hard for the kidneys to maintain the correct balance of fluids in the body.

Symptoms of AKI differ depending on the cause and may include: too little urine leaving the body; swelling in the legs and ankles, and around the eyes; fatigue; shortness of breath; confusion; nausea; chest pain; and in severe cases, seizures or coma. The disorder is most commonly seen in patients in the hospital whose kidneys are affected by medical and surgical stress and complications.

"Although many studies have investigated biomarkers to detect AKI in its early stages and forecast the short-term outcomes of the condition, little research has been devoted to examining biomarkers for their ability to predict long-term kidney function," says Chirag Parikh, Ph.D., director of the Division of Nephrology at the Johns Hopkins University School of Medicine and the study's senior author. "We looked at three proteins easily measured from urine -- and known to be altered in response to kidney inflammation or damage -- to see if they could be effective in making those predictions."

The three proteins evaluated were monocyte chemoattractant protein 1 (MCP-1), also known as C-C motif chemokine ligand 2 (CCL2); uromodulin (UMOD) and YKL-40, also known as chitinase 3-like 1 (CHI3L1). Their levels in urine were measured for each of 1,538 study participants -- half of whom were diagnosed with AKI during their hospitalizations -- at three months after release from the hospital. Following this baseline measurement, the patients were followed for an extended period of time (median: 4.3 years) to see how many progressed to CKD or ESRD. Throughout the monitoring period, the researchers assessed the relationship between the baseline biomarker levels for each patient with changes in estimated glomerular filtration rate (eGFR), a measure of kidney function (a low number indicates poor performance); the development of CKD or ESRD; or death from kidney failure.

The relationship between baseline biomarker levels and composite kidney outcome (development of CKD or ESRD) was defined using a statistical model that produces a hazard ratio -- a measure over time of how often specific events (in this case, declining kidney performance) happen in a study group (the patients with AKI during their hospitalizations) compared with their frequency in a control group (the patients without AKI during their hospitalizations). In this study, a hazard ratio of 1 suggests no difference between the groups, and a ratio greater than 1 indicates a greater likelihood of a poor composite kidney outcome. Likewise, a ratio less than 1 shows a decreased chance.

The researchers found that higher MCP-1 and YKL-40 levels in patients with AKI during hospitalization were associated with increased progression of the acute condition to CKD or ESRD. The hazard ratio for MCP-1 was 1.32 while the ratio for YKL-40 was 1.15. Both baseline protein measures also were associated with progressively declining eGFR during the observation period.

The opposite was observed for those whose baseline urine samples had higher UMOD levels, with a hazard ratio of 0.85 for CKD or ESRD development. Higher UMOD also predicted less chance of declining renal function over time.

To confirm their results, Parikh and his colleagues studied mice in which AKI was followed by either renal atrophy (shrinking of the kidney, which models progressive kidney decline) or repair. In the mice with atrophy, the researchers observed more activity by the genes that produce MCP-1 and YKL-40. In the repair mice, there was more production of UMOD. This, the researchers say, suggests that MCP-1 and YKL-40 may hinder the ability of kidneys to repair damage caused by AKI, setting the stage for progression to more serious kidney disease. On the other hand, they say UMOD production may enhance recovery.

"Based on our findings, the three proteins we studied show great promise as biomarkers for predicting the risk of CKD or ESRD following AKI, and with more research to prove their abilities, they may become valuable screening tools for physicians in the future," says Parikh.

Parikh is available for interviews.

PEOPLE WITH SERIOUS MENTAL ILLNESS NOT LIKELY TO RECEIVE ADDICTION TREATMENT

Media Contact:
Marisol Martinez,
mmart150@jhmi.edu

In an analysis of records from two Baltimore community mental health centers, Johns Hopkins Medicine researchers found that people with serious mental illnesses such as schizophrenia or severe bipolar disorder were 20 times more likely to use heroin than the general population. The researchers also discovered that only one in seven of these patients received medication for opioid addiction. The researchers note that this may be in part because addiction treatment programs weren't designed with serious mental illness in mind.

In their study published in the February 2021 issue of Psychiatry Research, the investigators note that specialized treatment programs and greater awareness among addiction treatment providers of underlying mental health conditions may be required to meet this underserved population's needs. More aggressive treatment of the mental disorders also may be necessary to reduce the disparity.

Evidence-based programs for treating substance use disorders employ medications such as buprenorphine or methadone, as well as services such as group therapy, doctor appointments and drug testing.

"People with serious mental disorders don't do well in this type of structured treatment setting. They may not be organized enough or may seem distracted, they may feel uncomfortable in groups or they may make other people uncomfortable," says study senior author Stanislav Spivak, M.D., assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. "Similarly, the negative symptoms that accompany serious mental disorders such as apathy, ambivalence or social withdrawal, can decrease these patients' ability to fully participate in treatment."

"Providers who treat substance use disorders need to be made aware of these symptoms as potentially being related to an underlying mental illness, and they shouldn't dismiss these patients as disinterested or intentionally trying to be difficult," he explains.

After reviewing the records of 271 patients with severe mental illness, researchers found that 32% said they used heroin compared with 1.6% of the general population reporting heroin use. Of those patients with a history of drug use, 15% were treated with medications typically prescribed to treat substance abuse. About 59% of these patients were taking at least one anti-psychotic medication, and those people were four times more likely to also be treated for addiction. Patients that scored high on questionnaires measuring social avoidance symptoms were less likely to be treated for their substance abuse.

"There are likely many factors as to why drug use is so much higher in people with severe mental illness," says study lead author (and senior author Spivak's wife) Amethyst Spivak, J.D., who started out as a researcher at the Johns Hopkins University and is now a board member of the National Trafficking Shelter Alliance. "Some of it may be due to self-medication. However, much of the issue lies in that this is a vulnerable group of people. They may have poor coping skills, are more likely to be exposed to drugs and may be less likely to push back when offered drugs."

She adds that exposure to drugs is greater in low income neighborhoods and, unfortunately, people with serious mental illness are more likely to be impoverished.

Because this was a small study focused on one city, the researchers say they now need to see if these trends are representative of people with mental illness across the nation.

The researchers note that this research was only possible after a large gift from an anonymous donor.

Spivak is available for interviews.

STUDY SUGGESTS ALTRUISM COORELATED WITH PATIENTS CHOOSING CHEAPER TREATMENTS

Media Contact:
Rachel Butch;
rbutch1@jhmi.edu

In a medical record review of 189 patients seen for vascular retinal eye diseases at the Johns Hopkins Medicine Wilmer Eye Institute, researchers found that patients who exhibited a marker for altruism were more likely to choose a less expensive, potentially less effective drug to treat their eye condition. The full reasons behind this choice are unknown, but the researchers say this small study could inform how physicians present treatment options to their patients.

The study was published Feb. 22, 2021, in the Journal of the American Medical Association Network Open.

In this study, patients were asked to choose one of two therapies: bevacizumab (Avastin) or aflibercept (Eylea). The former is a chemotherapy used to treat cancer -- but not approved by the U.S. Food and Drug Administration (FDA) to treat ocular vascular disease -- that costs approximately $100 per dose. The latter is an FDA-approved drug for treatment of numerous eye diseases that costs about $2,000 per dose. Some studies have shown that aflibercept may be more effective than bevacizumab for treating eye disease.

Separate from this choice, patients were asked if they wanted to participate in a clinical trial to identify future treatments for their eye disease. The patients were not compensated for participation in the clinical study. Because participation required an invasive procedure that would benefit the research community but not the individual patient, the researchers used it as an indication that the volunteers were motivated by altruism. A total of 125 patients (approximately 66%) of the 189 who were studied volunteered for the trial.

Controlling for factors, such as age, race, economic status and health insurance, the researchers found that altruistic patients were 24% more likely to choose bevacizumab. These results suggest that for some patients, altruism may be a driving factor in the decision to select a potentially less clinically effective, but more cost-effective medicine for their own health care.

"It raises ethical questions for how or when to ask patients to make these decisions if a certain segment of the population is willing to make a potential sacrifice for the greater good," says Akrit Sodhi, M.D., Ph.D., the Branna and Irving Sisenwein Professor in Ophthalmology at the Johns Hopkins University School of Medicine.

Overall, personality traits like altruism are flexible and can change situation-to-situation. Sodhi and his colleagues say more research is needed to determine how altruism may influence health care decisions.

Sodhi is available for interviews.

RESEARCHERS LEARN HOW EXERCISE DAMAGES HEART TISSUE IN GENETIC CONDITION

Media Contact:
Brian Waters,
bwaters3@jhmi.edu

Although exercise can lead to sudden death in people with genetic heart rhythm disorders, the cellular and molecular mechanisms behind the process haven't been pinned down. Now, using mice with one of these heart rhythm disorders, Johns Hopkins Medicine researchers and their colleagues have teased out the intricate biological steps leading to heart cell death during exercise. These steps, they report, can create a buildup of scar tissue in the heart that interrupts the electrical waves propagating heart beats.

In their study published Feb. 17, 2021, in Science Translational Medicine, the researchers used a synthetic peptide -- a laboratory-produced fragment of a protein -- to prevent heart cells from dying in simulated exercise. The results of their findings suggest that researchers one day may develop therapies that enable people with genetic heart diseases to work out and participate in other physical activities.

"We've always thought that exercise promotes more arrhythmias, or irregular heartbeats, in people with these genetic heart rhythm disorders, but now we've demonstrated why exercise is bad for them on a cellular level," says Stephen Chelko, Ph.D., an adjunct assistant professor of medicine at the Johns Hopkins University School of Medicine and assistant professor of biomedical sciences at Florida State University.

Using a mouse with the second most common mutation for arrhythmogenic cardiomyopathy -- one of the genetic heart rhythm disorders -- the researchers first showed that when these mice swam for exercise, it caused heart cells to accumulate calcium ions. This pushed the cells into a programmed death or suicide, known as apoptosis (a natural process to remove old or damaged cells). They found that exercise activates the protein calpain, which upon moving to the mitochondria in a cell -- traditionally known as the cell's power factory -- triggers another protein: apoptosis-inducing factor (AIF). A normal component of the mitochondria, AIF ultimately causes heart muscle cell death. However, when it's clipped by calpain, AIF migrates outside of the mitochondria and docks to the cell nucleus. There, it induces the DNA inside the nucleus to break apart and cause cell death.

"We believe that this mechanism is not something specific to this particular disease, but may be at the core of other cardiomyopathies and, very likely, many other heart diseases," says Nazareno Paolocci, M.D., Ph.D., associate professor of medicine at the Johns Hopkins University School of Medicine. "We think that understanding how this works in great detail will enable us to develop therapeutics to treat these type of genetic heart diseases."

To gain this insight, the researchers collaborated with Fabio Di Lisa, M.D., of the University of Padua and Nunzianna Doti, Ph.D., and Menotti Ruvo, Ph.D., at the National Research Council of Italy. The team developed a protein fragment made to look like a portion of AIF and put it inside mouse heart cells grown in the laboratory. After treating the cells with calcium ions and hormones from the adrenal glands to simulate conditions during exercise, the researchers observed that the mimic protein fragment blocked the activator and prevented the heart cell suicide from occurring.

Based on this finding, the researchers next plan to see if the mimic protein fragment can protect heart cells during exercise in live mice bred with the mutation for genetic heart disease.

Chelko and Paolocci are available for interviews.

IMMUNE PROTEIN MAY LINK CHRONIC INFLAMMATION AND FRAILTY IN OLDER ADULTS

Media Contact:
Waun'Shae Blount,
wblount1@jhmi.edu

Chronic inflammation in people age 65 and older may be marked by frequent infections, pain, injuries and slow healing wounds. To make matters worse, the negative impact of chronic inflammation on older adults is often compounded by frailty -- the state of aging characterized by weakness, weight loss, poor balance and other symptoms that makes older adults among the most vulnerable for accidents, mobility issues, poor outcomes following illnesses, and death.

In recent years, medical researchers have proposed that the dangerous connection between chronic inflammation and frailty may be due to a protein called interleukin-6 (IL-6). IL-6 is a cytokine, a molecule produced by immune system cells to help regulate the body's response to injury or infection. It is one of the main stimulators of inflammation and fever, two of the mechanisms the immune system uses to restore health.

What isn't known is how IL-6 contributes to the loss of physical ability commonly associated with increasing frailty during aging. To better understand this role, a Johns Hopkins Medicine research team genetically engineered a new mouse model that develops chronic inflammation but lacks IL-6. The model can be used to determine if the absence of IL-6 during uncontrollable chronic inflammation is enough to protect against the physical and functional decline observed with age.

The team's findings were published in the February 2021 issue of The Journals of Gerontology, Series A.

To characterize their new mouse model, the researchers used a state-of-the-art metabolomic profiling assay that enabled them to define the unique chemical fingerprints involved in the development of chronic inflammation without IL-6.

They also used an advanced dynamic positron emission tomography-computed tomography (PET-CT) system to determine how the absence of IL-6 (with presence of inflammation) impacts energy production by mitochondria (the cell's "energy factory") in the hearts of the mice. Decline in energy production during aging is considered a major contributor to many age-related illnesses including heart failure and Alzheimer's disease.

What the researchers found in frail mice lacking IL-6 were increases in circulating fat compounds -- lysolecithins -- that are important in maintaining healthy mitochondria function and decrease with age in humans. The frail mice lacking IL-6 also had increased heart energy production compared to the frail mice that produced IL-6. Together, these findings show that improvements in mitochondrial function occurred in frail mice when IL-6 was not present.

To determine if the enhancements in mitochondrial function translated to improvements in physical performance, the researchers used functional assessment tools commonly reserved for humans, such as running on a treadmill and grip strength. Treadmill running was chosen because of its similarity to human cardiac stress tests and because it assesses several systems at once: cardiovascular, skeletal muscle and pulmonary.

"Frail mice without IL-6 had short term improvements in running and fewer falls off the treadmill, but this improvement disappeared after three days," says study senior author Peter Abadir, M.D., associate professor of medicine at the Johns Hopkins University School of Medicine. "Surprisingly, and perhaps counterintuitively, we observed dramatically higher mortality in these mice in the presence of chronic inflammation -- as high as a fourfold increase compared with nonmodified mice and with mice that developed chronic inflammation but could still produce IL-6."

The researchers say these results suggest multiple impacts for IL-6. While the deletion or absence of IL-6 may improve some molecular and physical functions, its absence in the context of stress or chronic inflammation also may precipitate a quick decline in health and eventually, death.

Hints of similar effects can be gleaned from clinical studies of human patients with autoimmune disorders who were taking treatments with antibodies against TNF alpha, a cytokine similar to IL-6. When these patients develop fever or signs of infection, clinicians often withhold their medication to allow the body to mount an immune response.

The researchers say their findings in frail mice suggest a delicate balance exists between aging and chronic inflammation, and that IL-6 may be needed to maintain long-term exercise ability and prevent premature death. Therefore, they caution physicians to keep this balance in mind when prescribing drugs to reverse age-related increases in IL-6 levels.

Abadir is available for interviews.

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