How Do We Deal With Subclinical Rejection?

Dr. Namita Singh is the lead nephrologist for the transition of kidney transplant recipients and CKD patients from pediatrics to adult care, and is Associate Professor in the Division of Nephrology at the University of New Mexico.? She is board-certified in internal medicine and nephrology and has participated in research related to home dialysis therapies, renal transplant outcomes, and dialysis outcomes.

In partnership with Eurofins and Transplant Genomics, Dr. Singh recently presented a webinar discussing the incident of subclinical rejection in kidney transplant patients, how to monitor for these outcomes, and the importance of integrating monitoring tools with proactive treatment to support patient and allograft health.??

Observed Incidence of Subclinical Rejection

Dr. Singh began her presentation with a brief overview of some of the bigger studies regarding subclinical rejection over the years. The studies are summarized in the table below.

In discussing these studies, Dr. Singh pointed out that the historical Banff context is important.[1] She notes that the original paper published in 1991, which outlines the criteria for subclinical rejection, set a baseline that has evolved substantially throughout the intervening years. In 1997, for example, the presence of interstitial inflammation lesions was required to have a borderline rejection diagnosis, and by 2005, isolated tubulitis could indicate borderline rejection. Dr. Singh pointed out that the criteria changed again in 2019, and now Banff requirements are that interstitial inflammation and tubulitis are present as a minimal threshold for calling it borderline acute rejection.?

"That's the reason I refrain from going backward to older studies," Singh said. "Because this is a big change."?

However, even given the changing definition of subclinical rejection, you can see in the data above that it remains a concern for clinical teams and post-transplant patients. Even in the 2021 and 2022 studies, which were published after the change in 2019 that Dr. Singh referenced, subclinical rejection rates remained approximately 1 in 5. Those data points are critical to understanding how to support patient and allograft health because, as Dr. Singh said, "Repeated peaks of subclinical acute rejection as well as clinical acute rejection over time do lead to chronic injury...including chronic fibrosis, allograft failure or other poor outcomes."

Understanding Subclinical Rejection

Subclinical rejection refers to negative outcomes that aren't surface-level symptomatic but that, if left untreated, can lead to poor outcomes for the kidney transplant.

Not every bump along the road to transplant recovery is subclinical rejection, however, and evolving criteria for histology means the definition has changed. The application of increasingly advanced technologies in the clinical sphere likely means these definitions will continue to evolve, but what remains the same is that early identification of subclinical rejection is critical to supporting proactive treatment approaches to save allograft health and enhance patient outcomes.

Monitoring Subclinical Rejection

How teams monitor for subclinical rejection has also evolved—and continues to evolve with new technology and treatment methods.

Originally, the only way to monitor subclinical rejection was via biopsy. Teams conducted either protocol or indication biopsies. Protocol biopsies are periodic biopsies to check allograft health while indication biopsies are done because symptoms or other concerns have indicated a reason for one. Dr. Singh said examples of reasons for indication biopsies?include, "the patient has new onset severe acute kidney injury or severe high-grade proteinuria, hematuria, or high BK PCR in the serum."

Biopsies are somewhat invasive and time consuming and expensive for clinical facilities and patients, though. You might still perform a protocol biopsy at the one-year mark, but no one is really doing these tests every few months.?

"The goal," said Dr. Singh, "Is to find a non-invasive testing protocol that can help us make a more informed, educated and better decision about biopsy.”

TruGraf/TRAC supports this goal, especially within a strong Rejection Monitoring Protocol. Dr. Singh highlighted a recommended Rejection Monitoring Protocol that clinicians can implement at their post-transplant treatment centers:

• Every 1 to 3 months following transplant, evaluate the patient. If there is a cause for an indication biopsy, such as the examples provided above by Dr. Singh, continue with the biopsy. If there is no cause for an indication biopsy, check TruGraf/TRAC results. These non-invasive biomarkers have strong negative prediction values — in short, if the biomarker indicates nothing is wrong, there's a high chance no subclinical rejection is present. Clinicians can use the markers to help decide whether a biopsy is needed.
• At the 1-year mark, consider whether a surveillance biopsy is needed. The same protocols above can be used.?
• Given the outcome of the 1-year surveillance, clinicians can adjust the monitoring plan for the next year. Dr. Singh notes in her presentation that it's a good idea to continue with at least 3-month monitoring and use of biomarkers into the second year.
• After the second year, teams can tailor monitoring protocols to the needs of each patient given risks associated with matching, prior rejection, and outcomes demonstrated throughout monitoring in the previous 2 years.

Dr. Singh did note that she doesn't think biomarkers like TruGraf and TRAC replace biopsies yet. "Right now, we don't have enough evidence that we can substitute or replace biopsy with biomarkers," she said. But she noted that biomarkers are very helpful and should be used whenever possible as a tool to make better decisions about biopsies.?

Special Use Scenarios for Rejection Monitoring

TruGraf and TRAC are also useful in special rejection monitoring scenarios outside of the standard protocol described above, including:

• Balancing immunosuppression.?If the patient has a viral infection such as BK, CMV,, or COVID, said Dr. Singh, it may be necessary to bring down their immunosuppression level to allow their body to fight off the infection. However, clinicians walk a fine line in supporting overall body health and protecting allograft health. Biomarkers help clinicians keep a watchful eye on allograft health so they can proactively raise immunosuppression at the first signs of potential subclinical rejection.
• Converting medications.?Clinicians may convert immunosuppression medications for any number of reasons. Dr. Singh notes that some side effects of these medications include GI intolerance that can lead to vomiting, nausea, and other issues. In these?cases, teams might work to reduce medications while watching the outcomes with help from biomarkers.?
• Patient compliance.?Dr. Singh specializes in pediatric to adult transitions, which means she often works with teenagers and young adults in post-transplant scenarios. "Young adults are at a high risk for noncompliance, and they're also very smart," said Dr. Singh. She discussed how biomarkers help her track allograft health in patients that might attempt to "game" the outcomes of other tests to demonstrate they are compliant with medication regimes when they aren't.

Treating Subclinical Rejection

If subclinical rejection is found via biomarkers and biopsies, treatments must be tailored to the needs and history of the patient. "If?we get subclinical rejection and treat it with a one-time pulse of steroids without changing maintenance immunosuppression, we're not paying attention to how we got there in the first place," said Dr. Singh.

TruGraf results can be especially helpful here, as they allow clinicians to tweak medication doses and other treatments while getting feedback about potential allograft health. Dr. Singh notes that clinicians know that seeing an unexplained rise in creatine or other such display of potential graft dysfunction means it may be too late to stop actual damage to the transplanted organ, which makes biomarkers especially important in overall monitoring and treatment protocols.?

Monitoring Response to Treatment

According to Dr. Singh, "TruGraf is the only approved surveillance test at this time, and it's really gene expression profiling that basically tells us whether our immune system is quiescent versus nonquiescent, which would indicate a risk of subclinical rejection."

The strong negative prediction value of TruGraf makes it a helpful tool in monitoring subclinical rejection and the response to treatment after rejection. If the TruGraf results are negative, there is an 80 to 90% chance there is no subclinical rejection. Positive prediction values aren't currently quite as strong, but they are strong enough to provide an impetus for potential biopsy or more frequent testing.?

For example, if clinicians are treating someone for subclinical rejection after a biopsy, they may use biomarkers to test the outcome at the 1-month mark. If the biomarker result is positive for potential subclinical rejection, the clinician might make some changes to medications or other protocols and test again in a month. But if the biomarker is negative, the clinician might stay the course with protocols and test again in 3 months, all depending on the patient's risk factors and history of treatment.?

Dealing With Subclinical Rejection Efficiently

Identifying and managing subclinical rejection is essential to improving outcomes for transplant patients. Effective use of biomarkers and the ability to tailor medication and other treatments to specific patient needs are just one step in addressing subclinical rejection. As these technologies are adopted and other innovations occur in the space, the hope is that the number of people facing subclinical rejection during their post-transplant journey continues to decrease and that when subAR does occur, it is met swiftly with proactive treatments that support positive outcomes.?

Transplant Genomics aims to improve transplant outcomes for recipients through non-invasive treatment options. Learn more today.

Bibliography

1. Becker JU, Seron D, Rabant M, Roufosse C, Naesens M. Evolution of the definition of rejection in kidney transplantation and its use as an endpoint in clinical trials. Transplant International. 2022;35. doi:10.3389/ti.2022.10141. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9163319/