25% of patients with stable renal function are experiencing “silent” subclinical acute rejection that could lead to worse outcomes.
“Silent” subclinical acute rejection (subAR) occurs in advance of any clinical signs of graft damage, such as a rise in serum creatinine or donor-derived cell-free DNA. SubAR affects ~35% of kidney transplant recipients in the first two (2) years post-transplant and has significant implications for long-term graft survival. Before TruGraf, subAR could only be detected by surveillance biopsies.
TruGraf is a clinically validated, blood-based gene expression assay with a negative predictive value of 89-91% — meaning that patients who would have displayed normal histology following surveillance biopsy have a ~90% chance of receiving a negative TruGraf test, making it a highly effective “rule out” test for routine surveillance of patients with stable renal function.
A negative TruGraf result, which is reported as “TX” (for Transplant eXcellence), has been demonstrated to be correct 94% of the time in studies involving testing of blood samples from patients with stable renal function who had simultaneous surveillance biopsies confirming normal histology. Transplant programs that employ a serial testing strategy using TruGraf in stable patients have the potential to dramatically reduce the number of surveillance biopsies performed.
A serial testing strategy relying on TruGraf provides an attractive alternative for programs that do not routinely perform protocol biopsies, enabling them to stratify their stable patient population into those likely to be adequately immunosuppressed or not, without waiting for onset of clinical symptoms to guide therapy.
TruGraf: the Alternative to Biopsies for the Earliest Detection of Silent Rejection
TruGraf is the first non-invasive blood test that offers clinicians the earliest possible guidance of whether their patients are adequately immunosuppressed, prior to a rise in their serum creatinine — when damage to the kidney has already occurred — without having to perform a risky and invasive biopsy.
TruGraf measures differentially-expressed genes in the blood of renal transplant recipients to identify patients who are likely to be adequately immunosuppressed, and in doing so rule out subclinical acute rejection.
TruGraf uses RNA microarray technology to determine whether a patient’s blood gene expression profile is more similar to that obtained from a reference population classified by simultaneous histological analysis of a biopsy as Transplant eXcellence (TX), and likely adequately immunosuppressed, or Not-TX, and likely to be inadequately immunosuppressed.
Key benefits of serial testing with TruGraf include:
- patients benefit by avoiding painful, risky, invasive procedures that are negative 75% of the time
- patients and their caregivers benefit from the knowledge that they don’t harbor silent subclinical rejection without having to undergo an invasive procedure
- transplant clinicians benefit by stratifying patients into those who may benefit from surveillance biopsy and those who likely won’t, allowing them to eliminate a large percentage of surveillance biopsies that would likely have been negative if performed
What Makes TruGraf a Good Biomarker to Rule Out Subclinical Acute Rejection?
- 107 genes (mRNA) related to inflammation pathways
- 91% Negative Predictive Value (NPV)
- 94% concordance with biopsy
- risk stratification of patient population to provide comfort to those in whom silent rejection is confidently ruled out, and enable clinicians to focus on those that likely need closer attention
Indications & Contraindications for Use
The TruGraf test is intended for use in kidney transplant recipients with stable renal function as an alternative to surveillance biopsies.
Patients who meet all of the following criteria are eligible for TruGraf testing:
- Males or females of at least 18 years of age.
- Recipient of a primary or subsequent deceased-donor or living-donor kidney transplantation.
- Stable serum creatinine (current serum creatinine <2.3 mg/dl, <20% increase compared to the average of the previous 3 serum creatinine levels)
- Kidney transplant patients who are more than 90 days post-transplant
TruGraf has not yet been evaluated in patients who are:
- Recipients of a combined organ transplantation with an extra-renal organ and/or islet cell transplant.
- Recipients of previous non-renal solid organ and/or islet cell transplantation.
- Infected with HIV.
- Patients with BK nephropathy.
- Patients that have nephrotic proteinuria (urine protein >3 gm/day).
- The performance and clinical utility of TruGraf have been established in a cross sectional study (i.e., single point in time) at transplant centers utilizing surveillance biopsies. Clinical utility of TruGraf at centers not utilizing surveillance biopsies is currently being investigated.
- A TruGraf test result of TX does not guarantee adequate immunosuppression. Patients with a TX TruGraf test result should be advised to continue monitoring as per their local standard of care and clinical assessment.
- TruGraf may produce false negative or false positive results. A false positive result occurs when TruGraf produces a not-TX result, even though a biopsy will not find evidence of immune activation. A false negative result occurs when TruGraf produces a TX result, even though a biopsy will identify evidence of immune activation.
Non-invasive blood or urine based biomarkers for renal graft rejection have been investigated for many years. To date, only TruGraf has been validated and is reimbursable by CMS as having clinical utility for surveillance of kidney transplant recipients with stable renal function, providing a non-invasive means of assessing whether such a patient is adequately immunosuppressed, without the potential harm and cost of performing biopsies.
An external clinical validation from seven transplant centers defined the key clinical performance parameters for this assay, as summarized in Figure 1 and Table 1. In this study, the high negative predictive value (NPV) of TruGraf was demonstrated in clinical use, making it a strong rule-out test. Over 90% of stable patients who received a “TX” (“Transplant eXcellence”; negative) result were confirmed to have an immune quiescent phenotype, meaning that a physician can have a high degree of confidence that a patient who tests as “TX” does not harbor silent subclinical rejection. Importantly, this study also found that up to 65% of surveillance biopsies could be avoided in the cohort tested.
Unpublished data involving analysis of an additional 129 biopsy-confirmed blood samples provided by Northwestern University (originally used for the CTOT-08 study) revealed identical performance metrics for TruGraf (NPV of 90%).
A fourth publication described the impact of TruGraf results on physician decision making for clinical decisions. This study highlighted the high degree of confidence physicians place on the ability of TruGraf to provide valuable, added information that could lead to avoidance of unnecessary surveillance biopsies as summarized in Table 2.
TruGraf Clinical Evidence Figure 1
TruGraf Clinical Evidence Table 1
TruGraf Clinical Evidence Table 2
- Friedwald JJ, et al., Development and clinical validity of a novel blood-based molecular biomarker for subclinical acute rejection following kidney transplant, American Journal of Transplantation, July 2019, 98-109. DOI: 10.1111/ajt.15011
- Primary research study by CLINICevAL Solutions, LLC, 2019
- First MR, Pierry D, McNulty M, Kurian SM, Rose S, Whisenant T, et al. Analytical performance validation of a molecular diagnostic signature in kidney transplant recipients. J Transplant Technol Res 2017;7:176. DOI: 10.4172/2161-0991.1000176
- First MR, Peddi VR, Mannon R, et al. Investigator Assessment of the Utility of the TruGraf Molecular Diagnostic Test in Clinical Practice. Transplantation Proceedings, 2019, 51, 729-733. DOI: 10.1016/j.transproceed.2018.10.024.
- Marsh C, Kurian SM, Rice J, et al. Application of TruGraf® v1: A Novel Molecular Biomarker for Managing Kidney Transplant Recipients with Stable Renal Function. Transplantation Proceedings. April 2019. DOI: 10.1016/j.transproceed.2019.01.054
- Local Coverage Determination MolDX: TruGraf Blood Gene Expression Test (DL38039). Effective Date of Reimbursement: 25, November, 2019 from cms.gov.