Kidney biopsy remains the gold standard for diagnosing acute rejection of transplanted kidneys, but it is an invasive procedure that carries risks, and it is subject to potential sampling errors that could result in misleading findings. Noninvasive tests, such as those that measure donor-derived cell-free DNA (dd-cfDNA) and genomic blood assays, have come on the market in recent years that can alert physicians to kidney allograft problems before they become clinically apparent. While these can improve management of kidney transplant recipients (KTRs) and potentially help them avoid kidney biopsies, investigators continue to look for other noninvasive approaches to early detection of acute rejection of kidney transplants.
Presentations at the 2022 American Transplant Congress in Boston, Massachusetts, provide a glimpse of their progress. Chen Dong, MS, of Olaris, Inc., a precision medicine company based in Framingham, Massachusetts, reported that the company’s investigational urine test myOLARIS-KTdx is highly accurate in distinguishing patients with immune-mediated graft rejection from those with polyomavirus-associated nephropathy (PVAN), a complication of over-immunosuppression that occurs in 10% of patients after kidney transplantation. The assay also identified patients who retained stable graft function for 2 years with no infection or rejection events.
The assay is designed to detect a novel urinary metabolite-based signature indicative of over-immunosuppression, the identification of which is challenging as no clinically validated biomarkers exist. Dong reported findings from an analysis of metabolites in 371 longitudinal urine samples from 115 KTRs. They correlated their findings with pathology results from kidney biopsies.
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“The myOLARIS-KTdx score could potentially offer a noninvasive urine-based analysis to diagnose PVAN, differentiate PVAN from rejection, and identify KTRs with stable graft function,” Dong told attendees. “This would avoid invasive, potentially dangerous, and costly biopsies while still providing clinicians with confidence that the immunosuppressant dose is correct for a given patient or to confidently alter the dose according to graft rejection or infection.”
During another presentation, Amber Carrier, MD, PhD, and colleagues at the University of Maryland in Baltimore reported encouraging findings from their study of the novel use of both donor-derived cell-free DNA and gene-expression profiling in conjunction with serum creatinine measurements and urinalysis. The study included 41 patients enrolled in the Outcomes of Kidneycare on Renal Allografts (OKRA) study. Among 27 patients who had at least 1 abnormal dd-cfDNA test or gene-expression profile, 25 had elevated serum creatinine levels. An abnormal dd-cfDNA test or gene-expression profile successfully identified 19 patients who were confirmed on for-cause and surveillance kidney biopsies to have a combination of allograft rejection (8 patients), BK viremia (4 patients), tacrolimus toxicity (6 patients), and/or recurrent focal segmental glomerulosclerosis (FSGS, 2 patients), according to Dr Carrier’s team.
“The novel use of both dd-cfDNA and gene-expression profiling in conjunction with serum creatinine and urinalysis can improve early detection of significant graft injury, including rejection, BK viremia, tacrolimus toxicity, and recurrent FSGS, through non-invasive means,” the investigators concluded in a poster presentation.
In addition, Hitoshi Iwamoto, MD, of Tokyo Medical University in Japan, and colleagues reported promising results using metabolomics technologies to identify substances in samples of blood, urine, and saliva. Their study population included 9 healthy kidney donors, 19 kidney transplant recipients with normal kidney function, and 32 patients with impaired kidney function following kidney transplantation. In patients with impaired kidney function after kidney transplantation, 8 substances in blood, 3 in urine, and 7 in saliva differed significantly from those in the other groups. The investigators concluded that the salivary test, which can be performed frequently because it is noninvasive, has significant advantages over blood-based tests.
“The goal of the field is to move to have better and more sensitive tools to detect graft injury than relying on serum creatinine and ultimately a biopsy,” said Roslyn B. Mannon, MD, a professor in the Division of Nephrology of the University of Nebraska Medical Center in Omaha and past president of the American Society of Transplantation. “These noninvasive tools really are an opportunity to be able to monitor for subclinical injury and to personalize immunosuppressive therapy in a proactive fashion rather than the current reactive fashion we have relied on for decades.”
Acute rejection often occurs without pain or fever, and the graft may not appear enlarged, Dr Mannon explained. It typically manifests by a rise in serum creatinine, with many physicians using a threshold of a 15% to 20% increase from baseline to order a biopsy. A rise in serum creatinine might first prompt clinicians to look for other potential causes that could be managed noninvasively, such as urinary tract infection, tacrolimus toxicity, polyomavirus infection, heart failure that had been overlooked, and ACE inhibitor and nonsteroidal anti-inflammatory agent use, she said.
For now, she said, none of the available noninvasive assays can predict which patients will experience kidney rejection. Rather, the assays are intended to monitor for early rejection and to inform clinical decision-making. In her own experience, the assays may indicate subclinical rejection but kidney biopsy fails to confirm it, Dr Mannon said. These assays are more useful in ruling out rejection in patients with elevated serum creatinine so that physicians would know to look for other causes of the elevation.
References
Raghavendra Rao S, Honrao C, Rodrigues L, et al. Non-invasive metabolite-based urine signature detects over-immunosuppression in renal transplant recipients. Presented at: ATC 2022, June 4-7, 2022, Boston, Massachusetts. Presentation 5035.
Carrier AN, Crane A, Pinedo M, et al. Donor-derived cell-free DNA and gene expression profiling for surveillance of renal allograft injury and rejection. Presented at: ATC 2022, June 4-7, 2022, Boston, Massachusetts. Abstract 1590.
Iwamoto H, Konno O, Kihara Y, et al. Diagnosis of acute graft rejection after kidney transplantation using metabolome analysis by liquid biopsy approach. Presented at: ATC 2022, June 4-7, 2022, Boston, Massachusetts. Abstract 1590.
