Now, more than six decades later, research led by Aditi Gupta, M.D., an associate professor in the Department of Internal Medicine at the University of Kansas Medical Center, has culminated in the first study demonstrating that these transplants can also reverse some of the brain abnormalities that commonly accompany advanced kidney disease.

Although their cognitive issues frequently go undiagnosed, people with chronic kidney disease (CKD) often struggle with concentration and memory. The more severe the disease, the more likely it is that a patient will experience cognitive problems; up to 87% of patients with end stage kidney disease on hemodialysis have challenges thinking clearly and remembering. They may also have structural brain changes that are common in people with cognitive decline caused by other illnesses and conditions such as Alzheimer’s disease and dementia.

Meanwhile, the prevalence of kidney disease is rising, especially in the United States where 15% of all adults over the age of 18 and close to 40% over age 65 have CKD. Fueling the increase in CKD diagnoses is the skyrocketing rate of type 2 diabetes, a leading cause of kidney disease. Roughly 100,000 Americans are currently on a list waiting for a kidney transplant, and the average wait time for a kidney transplant is three to five years, according to the National Kidney Foundation. And as more people live longer and the population skews older and thus more susceptible to kidney disease and dementia, the KU research will become even more relevant.

“There are changes in the brain with kidney disease, and our research found that those changes are reversible,” said Gupta, who is also a transplant nephrologist and a member of the Jared Grantham Kidney Institute at KU Medical Center. “The damage to the brain caused by CKD is not permanent ― and that finding, to me, is remarkable.”

MORE THAN ONE PATHWAY TO DEMENTIA

Recognition of the connection between kidney disease and brain dysfunction dates as far as back as 1930, when scientists in France first postulated a kidney-related form of encephalopathy (a change in the way the brain works). Nonetheless, the intersection between nephrology and neurology has been under-studied, noted Jeffrey Burns, M.D., co-director of the University of Kansas Alzheimer’s Disease Center, who is an advisor on Gupta’s research.

For Burns, the research is important not just to learn more about that specific connection, but to gain a better understanding of brain health in general.

“We tend to think of one pathway to dementia, and that's Alzheimer's,” he said. “But the truth is, there are many pathways, and to get more precise in our understanding of brain health, the connection to kidney function is one of things we need to understand better.”

Gupta never imagined that she would be one of the few health care professionals to study kidney function and its relationship to dementia and the brain. In fact, when she finished her training to be a physician, she had no plans to conduct research at all. She also hadn’t been taught much about how kidney disease affects the brain because so little was known at the time.

Instead, Gupta’s interest in exploring the connection between kidney disease and cognition happened when she began practicing medicine and witnessed what was happening with her patients who had kidney disease.

“At first, patients did well cognitively, but over time, they started to forget things and had trouble concentrating,” remembered Gupta. “And after transplantation, they would say, ‘I used to have this brain fog, and now it's gone.’ I would tell them that the cognitive improvement could be due to the medications (steroids) they receive with the surgery, and that this effect might not last long. But they would come back in the clinic weeks and months later and tell me that they could still think more clearly.”

Gupta was intrigued. For one thing, these patients had been on dialysis, which takes over the job of kidneys and removes toxins from the blood, yet it appeared that it was the kidney transplant that improved brain function. In addition to her anecdotal evidence, Gupta found a couple of studies showing that cognition may improve after transplantation, but the literature was sparse. She decided she needed to talk to a neurologist ― so she approached Burns.

Gupta didn’t know Burns well at the time, but she thought that he might be interested in the relationship between the kidney and the brain. He had published a paper on the subject with another nephrologist in 2011.

“I suggested to him that we needed to delve deeper into this,” Gupta remembered. “When Dr. Burns suggested I apply for a grant, I reminded him that I didn’t do research. But this area was so interesting that it compelled me to work on this study, and that’s how this all started.”

STUDYING AN UNDER-STUDIED PROBLEM

In 2013, Gupta received a pilot award from KU Medical Center’s Kidney Institute in collaboration with Burns and William Brooks, Ph.D., director of the Hoglund Biomedical Imaging Center at KU Medical Center, to design studies and collect data on the effects of kidney disease on the brain. She also began a critical collaboration with Rebecca Lepping, Ph.D., senior scientist at Hoglund. Lepping is an expert in conducting and interpreting the neuroimaging necessary to evaluate changes in the brain.

That first grant marked Gupta’s transition to becoming a funded clinician-researcher. Developing her research skills, she began studying the prevalence of cognitive impairment in kidney disease, methods to screen for and measure cognitive changes in kidney patients, and the impact of exercise on cognitive impairment in patients with end stage renal disease.

In 2017, Gupta was awarded a K award, a career development grant by the National Institutes of Health (NIH), to expand her researcher further.

“The pilot grants enabled us to get started and working together, but then she decided to really make a jump into the research arena, which takes a big commitment. You can't do it as a hobby and succeed,” said Burns. “She ended up getting a K award from the NIH to study an area that not many people are studying, becoming one of a few scientists who are really beginning to connect the kidneys and brain.”

Unlike much research that focuses on why something in the body is going wrong, Gupta is exploring why something is going right: why those kidney transplant patients report better cognitive function.

“We started the study because there were these signs of improvement in cognition after transplantation,” said Gupta. “So the question was, does the brain also show changes after kidney transplantation? Or is it possible that the patient is simply feeling better and is less depressed, and that’s why we are observing an improvement in cognition?”

REVERSAL OF FUNCTION

To answer those questions, Gupta’s team focused on three types of brain abnormalities associated with CKD, none of which are corrected by dialysis. Each of these abnormalities is also associated with cognitive decline in people with other conditions and illnesses such as Alzheimer’s disease and traumatic brain injuries. These abnormalities include alterations in cerebral blood flow (blood circulating to and through the brain); concentrations of cerebral neurochemicals; and the integrity of the brain’s white matter, the fat-coated cells that connect different brain regions and enable neurons to talk to each other.

For the latest study, they followed patients with end stage kidney disease ranging in age from 30 to 70 years. The researchers took different types of magnetic resonance imaging (MRI) measurements before transplantation―and then at 3 and 12 months after. They compared these measurements to those of a control group of healthy people of similar ages.

Gupta and her collaborators measured cerebral blood flow by using a method called arterial spin labeling, which shows where the blood is being delivered. To gauge the white matter integrity, they used diffusion tensor imaging to assess how and where water is diffusing in the brain, which an indirect way to measure cerebral edema.

“When you get water pooling in the brain where it shouldn't be, that can put pressure on the neurons and cause the brain not to function very well,” explained Lepping.

To assess changes in neurochemical concentrations, the researchers used magnetic resonance spectroscopy to measure N-acetylaspartate, choline, glutamate, glutamine, myo-Inositol and total creatine.

The results? Cerebral blood flow, which was higher in the pre-transplant patients than in the controls, dropped after transplantation. Concentration levels of two of the brain neurochemicals that were higher in the transplant patients than they were in the controls ― choline and myo-Inositol ― also normalized after transplantation. In addition, white matter integrity improved after the transplant.

Moreover, they found that this normalization persisted one year after transplantation, which means that it cannot be solely attributed to the initial after-effects of the transplant surgery or to the medications, including steroids, that patients take after transplantation to keep them from rejecting the new organ.

The researchers also devised a testing battery to measure changes in cognition before and after the transplant. That data, which came from a larger group of patients than the ones who also underwent the MRIs, will be published separately, but Gupta said that they expect to see improvement in cognition based on the preliminary results and the fact that patients report that they can think more clearly after transplantation.

It’s not every day that medical researchers identify a way to repair brain damage.

“With the majority of diseases associated with cognitive impairment such as Alzheimer's disease or traumatic brain injury, there's not a lot of improvement in cognition,” said Lepping, who was the lead author on the study. “With kidney transplant, we found out that there might be something that's happening during the disease state and that when we correct it, we can actually see reversible change. That’s big.”

SO MUCH STILL TO BE DONE

While the results are promising, they also raise many questions. Gupta wants to explore further the reasons why transplantation does a better job in restoring cognition than dialysis. She noted that dialysis replaces the filtration function of the kidney but does not remove the toxins secreted in the kidney tubules, the tiny tubes that return needed substances to the blood.

“There are some toxins we are not able to remove properly with dialysis, and we want to determine if they are the ones causing some of the changes in cognition and in the brain,” she said.

Moreover, what the researchers are learning about the biology of CKD and the effect of transplants on cognition could also be used to develop earlier, less drastic ways to improve brain function and health of people with CKD. They could also be used to understand the mechanisms underlying other types of dementia.

“We know that what’s good for the heart is good for the brain, and now I think Dr. Gupta and Dr. Lepping have shown that what's good for the kidneys is also good for the brain,” said Burns. “We need to start to expand our view of how to promote brain health. And it's not just preventing Alzheimer's, it's also about other things like diet, exercise and preserving kidney function.”

The results could also be used to help those kidney patients who might not be eligible for a transplant.

“Maybe this will help us come up with treatment strategies other than transplantation to reverse the brain changes,” said Gupta. “Our life expectancy is improving, we will be living longer and we have to be able to offer a better quality of life. There's so much work to be done in this area.”