Dr. Peev is a transplant nephrologist at Rush University Medical Center in Chicago, having served on the faculty for the last eight years. Prior to joining Rush, he did his fellowship in nephrology at the University of Miami. This article is based on an interview conducted with Dr. Peev in May 2022 that has been edited for clarity.
Vasil Peev (VP): Graft injury detection is very important for kidney transplant recipients. We know that when injury is detected in the early stages and treated adequately, it results in much better outcomes for kidney transplant recipients compared to cases where injuries are picked up in advanced stages. One of the hallmarks of injury is perpetual fibrosis that takes place within the graft as a result of ongoing rejection. We know that once fibrosis has progressed, this usually leads to a progressive decline of the graft function and ultimately failure of the graft.
With that in mind, the timely detection of rejection within the graft of kidney transplant recipients is of utmost importance because it has a direct impact on the overall graft survival and longevity of these grafts and clearly impacts the quality of the life that graft recipient has.
VP: Serum creatinine testing, along with other markers developed many years ago as tools to surveil the well-being of kidney allografts have proven themselves to be poor markers of graft health. We know that injury that happens within the graft happens much, much earlier than the elevation of the serum creatinine. We know that these early changes that occur within the graft are not picked up by serum creatinine yet they lead to irreversible damage within the graft, something that will thereafter lead to graft loss and return of the patients to dialysis.
In brief, I think that serum creatinine, along with other markers, including donor specific antibodies, have been vastly outperformed by the development of novel markers like donor-derived cell-free DNA, which can much earlier detect injury of the graft inclusive of rejection. AlloSure® was commercially released in 2017 following its approval by the Center for Medicare and Medicaid Services (“CMS”). Around the same time, a study was published in the Journal of the American Society of Nephrology demonstrating the clinical validation of the assay to evaluate patients for underlining rejection. After we started using AlloSure in our clinical practice, we came to see very quickly that this assay outperforms other commercial tests and tools that we had available to evaluate the grafts for injury inclusive of rejection.
As we acquired more experience with it, we started using it more broadly. And now, not only us, but more than 160 transplant centers the United States have adopted AlloSure as an assay of choice to evaluate the kidney allograft recipients for ongoing rejection.
VP: AlloSure is different from the other commercially available cfDNA tests. One of the things that really distinguishes AlloSure is its fast turnaround time. As a transplant nephrologist, it is very important to diagnose rejection early, so the turnaround time of two days is very important for us as transplant providers because this gives us an ability to treat the patient in a timely manner.
A second thing that distinguishes AlloSure from other cfDNA assays is the volume of data validating its clinical use. No other test has been backed by more robust science – AlloSure is a has been analytically and clinically validated in multiple studies. And this is something that stands out compared to the other tests.
VP: I think that not only transplant nephrologists but also community nephrologists would benefit from incorporating AlloSure into their practice for several reasons. Number one, we know that there is a broad trend of transferring patients’ care from transplant centers to community nephrologists. This is a practice that has been adopted throughout the country and will likely continue to happen. Unlike transplant centers that have the luxury of being able to perform kidney transplant biopsies, as well as have the aid of a transplant pathologist that can aid in the diagnosis of rejection, community nephrologists have fewer resources available. Therefore, a noninvasive assay like AlloSure could have a significant impact in aiding in the diagnosis of rejection.
One of the major advantages of AlloSure is the high negative predictive value of the assay – its ability to rule out rejection very reliably and as such, empower community nephrologists to keep the patients within their practice that remain stable. And on the other hand, triage the patients and send those patients back to the transplant centers where they have identified certain problems within the graft, which may be secondary to ongoing rejection. The transplant centers obviously are much more accustomed to treating patients with rejection, and this is one of the main reasons why AlloSure should be adopted among community nephrologists.
VP: Taking care of patients that suffer from renal disease or chronic kidney disease, we have come to understand that we do not look at absolute changes in serum creatinine; we look at relative changes between longitudinal serum creatinine results. So you can think about relative change values of AlloSure in a similar fashion. It has been proven that there is a fluctuation of about 150% within what is considered to be a baseline dd-cfDNA value, which is still a normal fluctuation. So this is a physiological fluctuation of the dd-cfDNA value. And so knowing this, it is important to establish a baseline AlloSure value in order to compare with future values. If the baseline value is considered to be normal, then a relative change of above 150% from this baseline value could be abnormal. Hence the need for longitudinal dd-cfDNA or AlloSure measurements.
VP: It is very helpful when transplant nephrologists can establish a trajectory of dd-cfDNA measurements, even when patients have left our practice and they have been transitioned to the care of the community nephrologists. The trajectory of change of dd-cfDNA, in my view, is much more reliable in terms of predicting the trajectory of survival or decline of the graft than the trajectory that is used based on serum creatinine.
As already mentioned, AlloSure dd-cfDNA is much more reliable marker of injury to the graft compared to other older markers that that are commercially available. And so with that in mind, when patients transition their care to outside community nephrologists, deviations from what is considered to be a relative change value can shed light on ongoing injury to the graft and a reason for that patient to be referred back to the transplant in order to be evaluated either with a kidney biopsy or with additional testing that can aid in the diagnosis of rejection.
VP: AlloSure testing has benefited my patients in many ways. One is by decreasing the number of unnecessary biopsies. We have seen a tremendous decline in unnecessary biopsies among kidney transplant recipients through the adoption of AlloSure.
As a specific example of patient benefit from my practice, last week I saw a patient with otherwise stable renal function and no other abnormality on routine testing but who exhibited sudden elevation of AlloSure to 1.2%. This was above the well-defined threshold of 1%. Based on the AlloSure result, I decided to perform a kidney biopsy and the patient was this week diagnosed with early humoral rejection that will be treated and his outcomes will likely be favorable. Things may have been very different if the injury had gone undetected – potentially progressive injury, fibrosis of the graft and ultimately failure.
VP: AlloSure testing has benefited my center in a number of ways. We have seen a significant decrease in the number of unnecessary kidney biopsies. We know biopsies are costly, and they cause both discomfort and morbidity for patients. Through the adoption of AlloSure, we have been able to spare numerous patients unnecessary biopsies and on the other hand define the subset of patients that would benefit from a biopsy to aid in the diagnosis of injury or rejection. In this way it has been an invaluable tool that has changed the lives of the patients and brought them greater peace of mind. At the same time, the very high negative predictive value of the assay, as well as the meaningful positive predictive value of the assay, especially when coupled with donor-specific antibodies, has given greater confidence to our providers.
VP: I think that the reluctance of some community nephrologists to using AlloSure primarily originates from their lack of exposure to the assay. Once they use it in clinical practice and get to see its advantages and its accuracy in comparison to the current standards of serum creatinine, proteinuria and GFR, they will very quickly come to the conclusion that AlloSure far outperforms these other tests and offers clear benefits to both their patients and their practices.
I’ll also add that the literature shows that AlloSure is not only an early marker of injury, but has been associated with a greater than threefold increase in the risk of developing donor-specific antibodies. Development of donor-specific antibodies in kidney transplant recipients is correlated with a worse prognosis for these patients. We know that the type of rejection that is associated with the formation of these donor-specific antibodies is hard to treat, but it is treatable when diagnosed early. I think that AlloSure testing should empower the nephrologist to leverage the test’s high negative predictive value and with that, to bring peace of mind to their patients, but also peace of mind for their own practice.
Disclaimer: Dr. Peev was compensated by CareDx for the time required to conduct this interview. He has also served on CareDx advisory boards.
