Dr. John Friedewald, MD, is a transplant nephrologist and internal medicine doctor who focuses on the care of kidney transplant patients. His research focuses on improving organ allocation and donation policy, transplant genomics and biomarker development, and related areas. He is a Fellow of the American Society of Transplantation, American Society of Nephrology and the American College of Physicians. Dr. Friedewald holds numerous other leadership positions in the transplant medicine community and currently leads clinical trials and research efforts related to kidney transplants and biomarker use.

Dr. Friedewald recently presented a webinar on the topic of dealing with subclinical rejection and the use of molecular biomarkers within this context.

Observed Incidence of Subclinical Rejection

Historically, subclinical rejection has been a threat to the health of kidney transplants. Dr. Friedewald presented a summary of literature reviews and studies from the past 25 years that demonstrates a consistent incidence of subclinical rejection of around 20% or more.

Date of publication	Observed incidence of SubAR
1998	23.5%
2008	Between 12 and 17.3%
2008	Between 12 and 48%
2015	27.4%
2018	42.3%
2021	19.9%
2022	19.4%

Some of the variation in this data has to do with the fact that the criteria for and definition of subclinical rejection has changed as medical research learns more about allograft function in various conditions and pathologic criteria for rejection evolve. The measures across studies were also not completely aligned. Some studies based data on 3-month post transplant protocol biopsies, for instance, while others looked at metrics such as biopsies or other indicators 1 year post transplant or 6 months post transplant.

Variations aside, the general historical trend with regard to subclinical rejection does appear to be positive. In short, as researchers develop new approaches to the care of transplant recipients and post-transplant treatment, allograft failure and other critical outcomes may be declining. Still, with a sustained 20% of patients experiencing some subclinical rejection, there is certainly work to be done in this space.

Understanding Subclinical Rejection

Subclinical rejection is defined as rejection that shows up on a biopsy in the setting of stable kidney function—meaning that the rejection only shows up in a surveillance biopsy, not a for-cause biopsy. This is significant in kidney transplantation as potential rejection can be identified before enough kidney damage is done to cause a change in kidney function which typically prompts a for-cause biopsy. Thiscreates space for proactive approaches to detect and treat subclinical rejection and improve allograft health.

The evolving criteria for histology and the changing definition of subclinical rejection have made some of this a moving target, creating challenges around biopsy and treatment decisions. The first Banff meeting and publication regarding this specific topic dates to 1991, and the 1997 Banff Classification set criteria for acute T-cell mediated rejection (TCMR) that have not changed.^[1] However, the considerations and other criteria have evolved, with some critical changes including:

1997: Interstitial inflammation was mandatory to define borderline rejection.
2005: Isolated tubulitis was added as an indicator of borderline rejection.
2009: The concept of subclinical antibody-mediated rejection was added.
2019: The minimal threshold for borderline rejection was amended to include required i1t1 scores.

Upcoming Banff evolutions are likely to integrate the use of artificial intelligence, digital pathology, and other new technologies to continue to improve the community’s understanding of subclinical rejection and ability to measure it. The goal for clinicians remains the same, however: to benchmark what they see on biopsies, biomarkers, and other tests and relate it to clinical outcomes.

Monitoring Subclinical Rejection

Dr. Friedewald uses a Rejection Monitoring Protocol, and he recommends it for other centers. Because subclinical rejection is not uncommon and has strong associations with poor clinical outcomes—as evidenced by thousands of patients and related data points—taking a proactive approach to monitoring can help identify these issues and ensure patients receive the right treatment individualized for their situations.

According to Dr. Friedewald, this monitoring should begin 1 to 3 months post transplant, and he recommends the following process to limit unnecessary invasive procedures while ensuring optimal insight into allograft health so that you can personalize treatment.

Evaluate the patient. Consider whether noninvasive markers are appropriate at this time or whether there are factors that call for a kidney biopsy. Examples of factors requiring a biopsy include hematuria, proteinuria, BK virus, or other issues unique to the patient.
Check TruGraf/TRAC. If factors don’t exist that would necessitate a biopsy, run TruGraf and TRAC tests. If these noninvasive biomarkers are negative, the combined high negative predictive value allow confidence in skipping a surveillance biopsy. If either or both tests are positive, consider a biopsy for additional information.
Create a surveillance plan. For the next year, continue surveillance as appropriate for the patient given risk factors and other data—typically every 1 to 3 months.
Repeat the process at 1 year. Consider whether you need to do a biopsy or can first check TruGraf and TRAC results to determine if a biopsy might be necessary.
Continue surveillance. Test every 3 months for the second year.
Create a tailored surveillance plan going forward. Consider patient risk factors, the findings of the past 2 years, and any other relevant factors to create a protocol to continue monitoring the patient in the future at a rate and level that is appropriate for the individual.

Dr. Friedewald notes that consistent implementation of this type of monitoring process and the use of TruGraf and TRAC can substantially reduce unnecessary surveillance biopsies. Negative TruGraf results provide a high degree of confidence in stable kidney transplant patients that biopsies would also be normal, and Dr. Friedewald estimates that his suggested monitoring program can eliminate the need for roughly 60% of surveillance biopsies in stable patients.

Special Use Scenarios for Rejection Monitoring

The noninvasive tools Dr. Friedewald recommends in regular post-transplant monitoring are also relevant to special use scenarios, especially with regard to understanding whether patients are appropriately immunosuppressed.

For example, when patients on post-transplant protocols have an infection, immunosuppressive drug doses are typically reduced, allowing the patient’s immune response to increase so the body can help fight off the infection. But the clinician must find a balance between immunosuppression that supports allograft health and an appropriate level that reduces infection risks. Invasive biopsies are not a practical measure of success during what may be an evolving drug protocol. However, noninvasive TruGraf testing can provide insight that helps clinicians strike the right balance with each unique patient. Dr. Friedewald notes, “I typically get baseline testing at the ‘new lower level’ of immunosuppression then monitor going forward based on risk.”

Another special use case involves immunosuppression conversions. Dr. Friedewald recommends monthly testing during early conversion and then moving to testing every 3 months once the patient is on a stable dose. He also notes, “Most rejections on Belatacept are T cell mediated—monitoring with TruGraf may be advantageous given its ability to preferentially detect early TCMR.”

Treating Subclinical Rejection

The monitoring protocols laid out by Dr. Friedewald can lead to the discovery of subclinical rejection. Whether you discover it via noninvasive biomarkers or biopsy, the next step is responding with a treatment. Dr. Friedewald notes that possible approaches to treatment can include adding prednisone back into the mix, increasing dosages of maintenance immunosuppression drugs, or adding new medications.

It’s important to, as Dr. Friedewald says, “Make the punishment fit the crime.” It’s also critical to avoid responding with a one-time pulse of steroids or other medication without reviewing maintenance protocols that address the situation that caused the issue in the first place. Creating a tailored treatment based on patient history and the severity of rejection is also key to supporting higher chances of successful outcomes, and biomarker tests can help you do this.

Monitoring Response to Treatment

Clinical responsibility certainly doesn’t end after identifying and treating T cell rejection. Dr. Friedewald notes that the transplant community is still not great at treating rejection.

Consider data from a meta analysis of studies that looked at whether rejection was still present even after treatment. This was confirmed by a post-treatment biopsy.

Study	Proportion of cases with rejection present post-treatment
Bouatou 2019	0.22
Nankivell 2019	0.26
Hoffman 2019	0.32
Chandran 2021	0.44
Seifert 2019	0.46
Friedewald 2019	0.58
Hoffmann 2021	0.61
Naumnik 2017	0.67
Zhu 2018	1.00

Obviously, these results indicate that there is work to be done in developing more effective treatment protocols for subclinical rejection. However, it also underscores the importance of ongoing monitoring after treatment. Dr. Friedewald’s 2019 study indicates a negative predictive value of 78%-88% for noninvasive biomarker testing, making it a good monitoring tool even after treatment for subAR.^[2]

Enhancing Transplant Outcomes Through Innovation

Dr. Friedewald’s work, along with research from others in the kidney transplant community, shows that continued innovation in transplant genomics is important. Clinicians and their patients continue to engage in an ongoing balancing act between rejection and other issues, such as infection, malignancy, cardiovascular disease, or other poor outcomes. Having the right tools like noninvasive biomarkers to guide them is critical to improving successful outcomes.

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

Bibliography

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/
Friedewald JJ, Kurian SM, Heilman RL, et al. Development and clinical validity of a novel blood-based molecular biomarker for subclinical acute rejection following kidney transplant. American Journal of Transplantation. 2019;19(1):98-109. doi:10.1111/ajt.15011. https://pubmed.ncbi.nlm.nih.gov/29985559/