Dr. David Wojciechowski is a transplant nephrologist and Medical Director of the Kidney Transplant Program at UT Southwestern. He previously completed a fellowship in nephrology at Georgetown University and a fellowship in transplant nephrology at the University of California San Francisco. His research focuses on kidney transplantation, including immunosuppression protocols. A major goal of Dr. Wojciechowski work is to support increased positive outcomes and reduced toxicity for post-transplant patients.

In a recent webinar, Dr. Wojciechowski discussed trends in the use of belatacept to reduce transplant rejection. He noted the risks of belatacept-based immunosuppression and the need for monitoring post-transplant.

As care teams move away from automatic reliance on calcineurin inhibitors, a more nuanced understanding of rejection risk in each individual patient is required. The article below, based on Dr. Wojciechowski webinar, explores the role of molecular biomarkers in helping clinicians reach that nuanced understanding. TruGraf and TRAC are presented by Dr. Wojciechowski as complementary tools used in rejection monitoring, immunosuppressive weaning and biopsy reduction — not standalone diagnostics.

Why Belatacept? Addressing the Limits of Calcineurin Inhibitors

Immunosuppressants have significantly lowered rejection rates over the past 2-3 decades, particularly in the first year after transplant. One-year rejection rates for kidney transplants in the 1960s were more than 80%. By the time tacrolimus became commonplace in post-transplant care in the late 1990s, 1-year rejection rates had dropped well below 60.

Today, 1-year rejection rates are lower than 10%, due in part to the use of calcineurin inhibitors like tacrolimus. Dr. Wojciechowski points to the improvement in immunosuppressant treatments through the years. “In the early days of transplants, we had things like radiation, prednisone, and mercaptopurine, and we had very high rejection rates,” he says. As new options were introduced, rejection rates went down.

Dr. Wojciechowski says, “A pivotal point was the introduction of cyclosporine in the mid 1980s…and then, ultimately, with the introduction of tacrolimus…as well as universal antibody induction, you see a significant drop in the overall 1-year acute rejection rate in kidney transplantation.”

By the time belatacept was introduced, rejection rates were already quite low. Even today, tacrolimus remains the backbone of most immune suppression regimens, says Dr. Wojciechowski. SRTR data from a 2023 annual report shows that tacrolimus-based immunosuppression made up more than 80% of treatment regimens annually from 2012 through 2023.

While tacrolimus is certainly responsible for dramatic reductions in 1-year acute rejection rates, these calcineurin inhibitors do come with some side effects and intolerances, including nephrotoxicity, neurotoxicity, hypertension, diabetes, and thrombotic microangiopathy. Dr. Wojciechowski notes that on biopsy, you can find interstitial fibrosis and tubular atrophy as well as vascular changes related to tacrolimus in some patients. Tacrolimus is a very good drug at preventing T-cell rejection, but it’s not as robust at preventing antibody formation and antibody-mediated rejection.

Dr. Wojciechowski also notes that tacrolimus can come with a higher risk for noncompliance, as many patients must take the pill twice a day. There are also concerns about using CNIs in patients with high-risk kidneys.

In short, tacrolimus does a great job in general, but it’s not right for every patient and may not be enough on its own for some. Dr. Wojciechowski says that in cases where CNI regimens don’t work, belatacept can be a viable alternative, as it doesn’t come with the same side effects and concerns. Dr. Wojciechowski notes that they use belatacept fairly often at his center, including for conversion. “We use it for common conversion reasons,” he says. “So, delayed graft function, low eGFR post-transplant, or vascular or CNI toxicity noted on a biopsy.”

Why belatacept over a historical choice like cyclosporine? Dr. Wojciechowski answers the question by looking at data on the probability of patient and graft survival up to 84 months after transplantation. Belatacept demonstrates increased patient and graft survival over cyclosporine. The data is taken from a trial that ultimately resulted in FDA approval for belatacept use in post-kidney transplant care and shows a hazard ratio for death or graft loss of 0.57 for belatacept compared to cyclosporine. Belatacept is also correlated with a higher eGFR than cyclosporine in the same study.

Recognizing the Risk Profile of Belatacept

As with any immunosuppression option, belatacept has some risks.

Benefits of belatacept	Risks associated with belatacept-based regimens
Non-nephrotoxicNon-diabetogenic and better glycemic controlPotential improved complianceLess de novo DSA formationHigher estimated GFR	Concerns for T-cell mediated rejectionA known risk for PTLD developmentRisk for atypical CMV infections

The risks of belatacept-based immunosuppression post-transplant are well-confirmed via multiple trials. Out of 11 trials comparing belatacept to CNI regimens, nine associated belatacept with higher rates of rejection. Outcomes of such trials indicate:

A higher risk of rejection with belatacept compared to tacrolimus, particularly within the first year — note that these are mostly T-cell mediated rejections
A higher risk of CMV disease with belatacept — particularly much later in the post-transplant timeline

Dr. Wojciechowski points out that when CMV disease presents in patients managed with belatacept, it can be fairly aggressive and frequent. There’s also less of a correlation between patients with traditional risk factors and CMV disease presentation, so clinicians must be watchful in all cases.

One study looked at 2,905 patients between January 1998 and January 2019. Of those, 223 patients were treated with belatacept. The study took a subset of each group — those treated with belatacept and those who were not — with available Banff scores and who met a 1:1 propensity score matching for variables. That left 181 in each group. Around 17.7% of the belatacept-treated group tested positive for CMV, while only 2.8% of the control group did.

Another unique risk with belatacept is an increased risk of developing PTLD. Because of this, patients who don’t have an immunity to EBV (EBV-seronegative recipients) are not good candidates for this immunosuppressive. Clinicians may also want to play it safe and avoid belatacept if possible if serostatus is unknown.

Because belatacept does have numerous pros and may be a better choice for patients who can’t tolerate CNI regimens, the answer to these risks is not to avoid belatacept entirely. Instead, the risks justify a more sensitive and structured monitoring protocol.

A Shift in Monitoring: Why Molecular Diagnostics Matter

Creating a monitoring guardrail is important for any post-transplant situation, but it’s especially imperative when dealing with the known risks that come with belatacept. Traditional markers like creatinine and proteinuria continue to be useful amid a holistic approach to monitoring, but they may not detect subclinical rejection early enough for clinical teams to prevent graft damage. Molecular biomarkers like TruGraf and TRAC allow clinicians to detect immune activation and tissue injury earlier.

TruGraf: A gene expression profile designed to surveil subclinical rejection and intended as a rule-out tool
TRAC ID: A donor-derived cell-free DNA assessment with additional detection of select viral loads, including CMV, ESB, BKV, and TTV

These tools provide noninvasive insight into patient status, making them a valuable support tool for clinical decision-making. They don’t replace at-cause biopsies, but they can help reduce unnecessary surveillance biopsies and provide added peace of mind for patients and providers.

In the context of belatacept-based immunosuppression, the viral load assessment TRAC ID provides may be of special interest. Obviously, any viral load is of interest in monitoring and balancing immunosuppression, but given the specific risk factors associated with belatacept, Dr. Wojciechowski notes that the extra insight into CMV and EBV can be valuable.

How TruGraf and TRAC Offer Complementary Insights

According to Dr. Wojciechowski, these two molecular biomarkers have “a predilection for different rejection types, offering different advantages in monitoring potential.”

As a gene expression test, TruGraf is very good at picking up subclinical acute cellular rejection. TRAC, which is a dd-cfDNA assay, primarily picks up subclinical acute antibody-mediated rejection. When you combine the tests, the predictive power for rejection is even higher.

Dr. Wojciechowski presents a cohort where both tests were used, and TruGraf picked up 42.1% of T-cell mediated rejections that dd-cfDNA missed. At the same time, TRAC ID provides subclinical AMR data that TruGraf might miss as well as the extra viral load data. Even when the results are discordant, clinicians can gain valuable information to help shape their treatment plans.

Real-World Application: Monitoring Protocol at UT Southwestern

At UT Southwestern, the team uses what Dr. Wojciechowski refers to as “quite a bit of belatacept,” as previously mentioned. In addition to using it de novo, they use it for conversion. Regardless of immunologic risk, all kidney transplant patients at UT Southwestern are part of a universal monitoring protocol.

Dr. Wojciechowski describes the protocol as follows:

TRAC is tested monthly for the first 6 months post-initiation
TRAC is tested every other month from months 7 to 12
TRAC is tested quarterly after 1 year

UT Southwestern actually started with a selective protocol, only monitoring patients who met certain risk factors. However, the team found that they had much better compliance with monitoring and greater staff efficiency when making universal monitoring part of the order set for all patients.

Dr. Wojciechowski says the team adds a TruGraf test when creatinine is unstable but cell-free DNA is stable or elevated. These are potential indications of T-cell mediated rejection, and the TruGraf test better monitors for that.

TRAC ID is a relatively new tool, and Dr. Wojciechowski says the clinical team at UT Southwestern is currently discussing incorporating it as the cfDNA monitoring tool, as the ID component adds valuable clinical knowledge about viral loads.

Investigating Molecular Monitoring in Clinical Research

Dr. Wojciechowski team is conducting a clinical trial to evaluate whether biomarker-guided monitoring can support belatacept monotherapy in stable transplant recipients. The patients included in the trial are treated with belatacept — some de novo and some were converted to belatacept.

The study uses traditional biomarkers, including creatinine, DSA, and urine protein, as well as novel molecular diagnostics like dd-cfDNA and gene expression profiling to support clinicians in establishing and maintaining immune quiescence in belatacept-treated patients. The goal of the study is to determine whether patients can be weaned off other medications to arrive at a mono-belatacept therapy environment via a structured approach.

The team recruited 25 patients to be monitored for 27 total months. That includes a 3-month lead to establish a quiescent state and 2 years of follow-up to wean immunosuppression.

Dr. Wojciechowski reports that the first patient in the trial is almost through the final period, and there should be data coming soon about whether biomarker-guided therapy may enable safe weaning from adjunctive immunosuppression while supporting graft stability.

An Interpretive Framework for Molecular Results

When TruGraf and TRAC results are used together, they let clinicians categorize findings into four categories for better decision-making:

Double negative: TruGraf result is TX and TRAC result is <0.7. The biomarkers don’t indicate subclinical rejection or organ injury. Clinical teams should continue to assess and monitor at an appropriate frequency for their protocol.
Positive/negative: TruGraf result is Not-TX and TRAC result is <.0.7. The tests don’t indicate organ injury but do suggest potential subclinical immune activation. Clinical teams should investigate immunosuppression, repeat the test if warranted, or move on to biopsy if there are other points of concern.
Negative/positive: TruGraf Result is TX and TRAC result is >/=0.7. The tests don’t indicate subclinical rejection, but elevated dd-cfDNA suggests potential for organ injury. Clinical teams should investigate immunosuppression, repeat the test if warranted, or move on to biopsy if there are other points of concern.
Positive/positive: TruGraf is Not-TX and TRAC result is >/=0.7. When both tests are positive, there is a high likelihood for organ rejection, and clinical teams should consider a for-cause biopsy.

Note that discordance of the tests is an opportunity for further investigation, not a diagnostic failure. The fact that each test focuses on a specific mechanism of rejection means that discordant results can actually tell clinicians more, not less.

Bringing Precision to Post-Transplant Monitoring

Belatacept offers some meaningful long-term advantages for kidney transplant recipients. However, as with all post-transplant regimens, it comes with risks. TruGraf and TRAC help clinical teams identify potential immune activation and tissue injury early, providing them with time to act to save graft health and patients regardless of what immunosuppression is used.

Transplant Genomics is committed to providing clinicians with the tools and data they need to make confident, patient-centered decisions in post-transplant care.

Watch the full webinar here