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kidney transplant

Nephrology

Desensitization Brings Hope to Children Waiting for a Kidney

Dr. Michael E. Seifert is the medical director of the Pediatric Kidney Transplant Program at Children’s of Alabama.

A new protocol at Children’s of Alabama is giving sensitized children who need a new kidney a brighter glimmer of hope for successful donor match and transplant.

Children who need a kidney transplant typically wait about a year or two for an organ. But if they’ve been exposed to external blood products, been pregnant or had a previous organ transplant, they could find themselves waiting up to five times longer. That’s because they’ve become sensitized to certain proteins that are foreign to their immune system, which results in high antibody levels that react to foreign tissues. “That makes finding a compatible transplant for them really, really problematic,” pediatric nephrologist Michael E. Seifert, M.D., said. Plus, those antibodies significantly increase the risk of an immediate rejection or graft failure.

Historically, finding a compatible kidney donor for sensitized patients has been challenging, but thanks to a process called desensitization, that’s changing for some. It involves using a combination of immunosuppressive therapies to try to reduce the immune reaction to potential donor organs. Although it’s been used in adults for years, pediatric centers like Children’s have only recently introduced their own protocols. “With these immunomodulatory therapies, we try to turn down the volume on their sensitization,” Seifert said. “You can’t get rid of it altogether. Once a patient is sensitized, they’re always sensitized to some extent.”

The desensitization protocol is a combination of plasmapheresis—a kind of dialysis for blood that removes some of the problematic antibodies and immune proteins—and IV and oral immunosuppressants to prevent the antibodies from returning. Together, Seifert said, “this creates a more potent and widespread ratcheting-down of the immune response that allows some transplants to be done safely.”

The process requires close collaboration between clinicians and the immunology, or HLA, laboratory to choose the right cocktail of immunosuppressants and the right time for transplant. While it’s still challenging to find compatible organs, Seifert says the therapies can help shorten the time on the waitlist for some patients and give them access to more donors.

The team has used the protocol on several children so far, one of whom was able to receive a transplant. “So far, the patients are doing really, really well on it,” Seifert said. “And it’s been a success. But it’s a more challenging transplant because they are still much more likely to reject this kidney than a straightforward kidney transplant. We balance that risk against the risks of remaining on the kidney transplant waitlist for several years, waiting for a compatible donor.”

The children also need more attention post-transplant to keep their immune system at bay without triggering complications like infections, and they’ll have to maintain that throughout their lives, Seifert said. They will also always have a higher risk of rejection and premature graft loss. Yet if the transplant fails, subsequent transplants become more challenging, given greater sensitization.

“It’s a Catch-22,” Seifert said, “in that we achieve our goal, which is getting them a transplant, but it’s a lot more work for us to keep that transplant going.”

January 17, 2023 by childrensal

Nephrology

Children’s Nephrologists Hope to Use Biomarkers to Better Identify Kidney Transplant Rejection

Dr. Michael E. Seifert is leading a study to evaluate biomarkers for their potential to predict kidney transplant rejection.

A new study at Children’s of Alabama aims to establish a new, non-invasive way to predict kidney rejection through the blood or urine with better accuracy than the current standard.

The study, Biomarkers from Multiple Platforms to Enhance Diagnosis of Rejection in Children and Young Adults after Renal Transplantation (BuMPER-CAR), is led by pediatric nephrologist Michael E. Seifert, M.D. He and the Children’s nephrology team are conducting it using a large biorepository of patients’ blood, urine and kidney biopsy tissue. With this, they’re evaluating individual biomarkers for their potential to predict rejection. They’re also trying to identify a panel of several biomarkers that may be more accurate and may provide results quickly.

“The idea with this study is, hopefully, we can not only find the patients that are having trouble but confirm the patients who are stable, so we can feel confident that we’re not missing something clinically by avoiding a biopsy in that patient.” The results, he said, could be transformative.

An estimated 1,000 children in the U.S. receive a kidney transplant each year—about 15 to 20 of them at Children’s of Alabama. While the procedure is usually successful, 10-15% of patients experience acute rejection each year, and most transplants fail after about 10-15 years. The standard for assessing the health of a transplant has been to measure creatinine blood levels and urine protein levels. If either is elevated, patients must undergo an invasive biopsy, which carries risks of complications—a heavy cost when only about 1 in 5 biopsies show signs of rejection, meaning most are unnecessary.

According to Seifert, one reason for the poor correlation between rejection and creatinine and protein levels is that the tests are “notoriously bad indicators” of transplant health. By the time the creatinine levels signal a problem, the kidney has often already suffered significant injury.

“On the flip side, there are lots of reasons why somebody’s creatinine might become abnormal, or they might start spilling protein in the urine that has nothing to do with rejection. But we must do biopsies to figure that out,” Seifert said. “So, we need better markers to tell us when the creatinine is a problem, so we can make better assessments.”

The study’s genesis came from a nephrology fellow who wanted to do a research project around biomarkers of kidney transplant diseases. A literature search revealed a plethora of “favorite” biomarkers to predict transplant rejection, but Seifert said there was no consensus on which biomarker worked best. “I think that’s part of the reason why, despite having really good data to support their clinical use, a lot of biomarkers remain on the outskirts of clinical medicine and aren’t being integrated into clinical practice,” he said.

The BuMPER-CAR study is funded in part by Natera, a molecular diagnostics company that manufactures a blood test that detects a form of DNA from the donor kidney, called donor-derived, cell-free DNA (dd-cfDNA), that can be a sign of kidney damage. However, the test is approved only for adults and has not been validated in children. One goal of the study is to set baseline levels for children.

The study also assesses other biomarkers, including new ones in development at Natera and others developed in Seifert’s lab. Researchers hope to see if a panel of any of these biomarkers would perform better than any individual biomarker. They also want to know if the biomarkers can predict the type of rejection, which could help guide management.

January 16, 2023 by childrensal

Inside Pediatrics, Nephrology

Researchers Get One Step Closer to Non-invasive Test for Kidney Rejection

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Monitoring kidney transplant rejection in children is akin to sticking your hand into five pots of water, four of which could burn you. The only surefire way to know if a child is rejecting the organ is with a biopsy. The procedure is invasive, requires anesthesia, carries risks of complications and is expensive. In other words, it’s very hot water.

Yet every kidney transplant patient at Children’s of Alabama receives a routine biopsy six months after transplant. Only about one 1 in 5, however, actually show signs of rejection, meaning most of those biopsies were unnecessary. Now imagine there was a simple blood or urine test to tell which children were likely to reject the kidney and need a biopsy. That could mean going from 1 in 5 biopsies positive for rejection to 4 in 5 or 5 in 5, sparing hundreds of children from a painful procedure they don’t need.

Pediatric nephrologist Michael E. Seifert, MD, and his team have been working for years on developing such a test, using a large biorepository of patients’ blood, urine and kidney biopsy tissue collected throughout and after the transplant process.

Their work involves investigating gene expression in the tissue samples to find signals of rejection. But while they are good at identifying abnormalities from a piece of biopsy tissue, the process still has room for improvement. With the way tissue is processed, it’s difficult to determine if the abnormal signals are coming from cells that are relevant for rejection—such as immune cells—or from cells that don’t play a role in rejection.

Now, Seifert and his lab are using a novel technique called spatial transcriptomics, or spatial gene expression assays, which enable them to “see” the signals in the context of their natural habitat without destroying the underlying tissues.

“Spatial transcriptomics allows you to develop non-invasive biomarkers that are more reflective of the underlying biology of the disease you’re interested in, such as rejection,” Seifert said. And those more precise biomarkers could narrow down the number of patients who require biopsies. “This will help us understand the mechanisms of kidney transplant injury and rejection with much higher precision,” he said.

Before this technique, they used one of two methods to study gene expression in the tissue. One is to take the tissue, grind it up, see which genes are high and which are low, then develop a test based on the findings. The other is to separate a piece of biopsy tissue into its component cells and individually examine their gene expression. That’s more precise than the bulk gene expression or grinding method, Seifert said, but you lose any spatial context as to where in the tissue the cell came from.

One way to think about it is having all your furniture jammed into a pod in the front yard, taking a chair into the house, and hoping it’s the right piece for that spot by the window. But without the rest of the furniture in the room, it’s hard to know. With spatial transcriptomics, he said, you’re viewing the chair in context with the rest of the furniture.

“The spatial platform is a really incredible tool in that it allows you to be so precise in the areas of the kidney that you’re studying,” Seifert said. He can also isolate cells he’s interested in from the rest of the tissue without disturbing the tissue itself. “Being able to keep the tissue intact enables you to assign geographic locations for the different signals you’re getting when you test the tissue,” he said.

“We’re just beginning to learn all the ways we can apply it to kidney transplant diseases.”

He and his team presented their first paper on their findings using the new platform at the American Transplant Congress in Boston in June.

September 5, 2022 by childrensal

Inside Pediatrics, Nephrology

Tracking Kidney Transplant Rejection in the Blood and Urine

Michael Seifert, M.D., is a pediatric nephrologist at Children’s of Alabama and an associate professor in the Division of Nephrology in the University of Alabama at Birmingham Department of Pediatrics.

Children who receive kidney transplants at Children’s of Alabama undergo a routine biopsy six months after the procedure to look for signs of rejection. In about 20 percent of patients, those signs are there, even if their blood and urine tests look normal. “On the flip side,” said Children’s pediatric nephrologist Michael E. Seifert, M.D., “that means about 80 percent of our patients are getting biopsies that are normal.”

The holy grail, then, would be a non-invasive biomarker test using blood or urine that can identify kidney transplant injury without needing a biopsy — which is exactly what Dr. Seifert and his lab are working on. Their research relies on a biorepository of patients’ blood, urine, and kidney biopsy tissue collected throughout and after the transplant process.

One of the blood tests they’re working on uses technology originally developed to screen maternal blood for signs of fetal abnormalities. The test looks for cell-free DNA, or cfDNA, which comes from the fetus and differs from maternal DNA. Since transplanted kidneys also have DNA different from the patient’s own kidney, “you can look in the bloodstream for the proportion of the DNA coming from the transplant versus the normal background from the recipient’s non-transplant cells,” Dr. Seifert said. High levels of cfDNA is a sign of acute kidney injury that could be due to rejection.

Studies in adults validate this as a good method to detect rejection. “But the problem is, those are done in adults whose native kidneys would be roughly similar in size to the transplant they’re carrying,” Dr. Seifert said. Children often have a much larger, adult-sized transplant compared to the size of their native kidneys, so the cutoff levels used for diagnosing rejection in adults may not work in children. “We’re trying to make these existing diagnostic tests more pediatric specific,” he said.

The story is different for urinary biomarkers. It’s been known for years that the kidney releases certain proteins when it’s injured. Tests to detect those proteins, however, can take days. But a new device called SimplePlex, currently available only in the research setting, can measure several of these proteins at one time in a single sample in less than an hour.

“We’re looking at ways to get this technology closer to the clinic, so you’re not just profiling kidney transplant patients’ risk for injury based on their standard blood tests like creatinine, but you’re also adding these additional biomarkers that can tell you more information about what’s happening inside the organ,” Dr. Seifert said.

Being able to determine via blood and urine tests who needs a biopsy and who doesn’t would have a huge impact for pediatrics, particularly at Children’s, where these biopsies are done on a universal basis, he said. Ideally, the tests could also provide information on the underlying cause of the rejection. For instance, the cfDNA test is good at picking up antibody-mediated rejection, but not as good at recognizing cell-mediated rejection. The urine biomarkers are good at identifying both rejection types, but not at identifying rejection related to viral infections.

“Once we understand more about the clinical scenarios in which the biomarkers perform well,” said Dr. Seifert, “we’ll be able to design interventional trials to treat the patient based on the biomarker changes rather than just the standard clinical tests such as creatinine.”

February 15, 2022 by childrensal

Nephrology

Continual Performance Improvement in Pediatric Kidney Transplantation

The renal transplant team at Children’s of Alabama has performed more than 500 kidney transplants since 1968. To this day, continuous improvement remains at the heart of everything it does.

The hospital is part of the Improving Renal Outcomes Collaborative (IROC), a learning health system of 32 pediatric kidney transplant centers in the U.S. that share data and best practices in an effort to improve transplant outcomes.

“We know we can achieve better things more efficiently together than if we’re working individually,” said Children’s pediatric nephrologist Michael E. Seifert, M.D.

Improvement Projects

One recent project involved improving blood pressure assessments. “We know that if we control blood pressure we get better patient outcomes and the transplant does better,” Seifert said. Yet an analysis of 17 IROC transplant centers found that blood pressure was being measured appropriately based on current guidelines at just 12% of transplant clinic visits.

Each IROC center had the freedom to design custom tools to fit its needs for improving blood pressure measurement. The answer at Children’s was paper-based tracking logs and regular meetings to review progress. The team also educated all staff on the importance of measuring blood pressure and how to measure it according to the most recent guidelines. “It was pretty simple things that, when applied systematically and consistently, led to prolonged improvement,” Seifert said. Today, at least 85% of clinic visits include an appropriately measured blood pressure and the team is working to improve that number.

The next project is to improve adherence to immunosuppressive drugs, a major risk factor for rejection and loss of the kidney transplant. The team is developing a questionnaire for parents and patients so they can identify the barriers to adherence and develop targeted interventions. “We have to get away from an accusatory approach to a partnership and ask, ‘How can we work with you to make it easier to take your medications?’” Seifert said.

Children’s is also a national leader in studying surveillance biopsies to help reduce acute rejection rates. Most pediatric transplant centers do not perform early surveillance biopsies at pre-specified time points because of their invasive nature, but Seifert and his team demonstrated that surveillance biopsies in the first six months after transplant can detect subclinical inflammation, which is associated with a nearly threefold increased risk of acute rejection and allograft failure. Treating patients who demonstrated such inflammation, they recently reported, significantly reduces that risk. Importantly, they also demonstrated that the surveillance biopsy procedure was safe for pediatric patients, with extremely low rates of mild adverse events.

Bringing the Bench and the Clinic Closer

The transplant team also runs a robust translational research program, with half of transplant patients enrolled in at least one research study. One is a biorepository study in which patients’ blood, urine and kidney biopsy tissue is collected throughout and after the transplant process. “Then we can develop biomarkers of kidney transplant diseases that impact the survival of the transplant,” Seifert said.

The second study will identify determinants of cardiovascular health in pediatric and young adult kidney transplant recipients who have a high burden of cardiovascular risk. “Transplantation improves but doesn’t eliminate this risk,” Seifert said. “This study is

designed to understand certain unique cardiovascular risk factors, such as the impact of

early life stress, on cardiovascular and renal outcomes.”

The Transplant Experts

Learn more about kidney transplantation at Children’s of Alabama.

August 20, 2019 by childrensal