Causes of Renal Allograft Injury in Recipients With Normal Donor-derived Cell-free DNA

BACKGROUND. Donor-derived cell-free DNA (dd-cfDNA) is a noninvasive biomarker for the early detection of organ transplant rejection and other causes of graft injury. For nonrejection renal injuries, there is little information about the performance characteristics of this biomarker. We highlight some of the possible causes of kidney injury that may arise in patients with normal dd-cfDNA levels. METHODS. We performed a retrospective analysis of solitary renal transplant cases between January 2017 and November 2019. Those who had an abnormal laboratory or pathological finding within 1 mo of a normal dd-cfDNA test were selected. Subgroups were stratified for those who had normal or abnormal/rising serum creatinine, and differences between the groups were analyzed. RESULTS. Of 414 individuals who received a kidney transplant, 24 (7.5%) had a total of 41 normal dd-cfDNA values and 51 abnormal laboratory tests or histologic findings. The most common graft-injuring event was BK virus viremia (24 of 51). Other abnormal findings included urinary traction infections (n = 4), CMV viremia (n = 4), and biopsies demonstrating antibody-mediated rejection (AMR) (n = 2), T cell–mediated rejection (n = 1), focal segmental glomerulosclerosis (n = 2), nondonor-specific antibody chronic AMR (n = 1), and interstitial fibrosis and tubular atrophy (n = 7). Subgroup analysis of those with normal dd-cfDNA and normal/stable versus abnormal/rising creatinine showed that BK virus viremia was the most common abnormal finding in both groups at 53% and 38% respectively. On biopsy, 1 case of acute T cell–mediated rejection (1B and 2B) was seen with normal/stable creatinine, whereas 1 of nonspecific C4d focally positive and 1 of nondonor-specific antibody AMR were seen with abnormal/rising creatinine. CONCLUSIONS. Low levels of serum dd-cfDNA do not preclude detection of active graft-injuring events and that subclinical injuries may be developing. Context is important in the interpretation of dd-cfDNA, so renal biopsy remains a part of the diagnostic pathway for allograft dysfunction and maintenance of allograft health.