Donor-derived Cell–free DNA May Confirm Real-time Response to Treatment of Acute Rejection in Renal Transplant Recipients

This is the authors' abstract. We don't add key points for this paper.

Confirmatory biopsy after treatment for acute rejection is uncommon. Serum creatinine (SCr) and random urine albumin to urine creatinine (Ur alb:Ur Cr) ratios are used to monitor resolution of rejection. Donor-derived cell–free DNA (dd-cfDNA) (AlloSure; CareDX, Brisbane, CA) levels >1% detect active renal allograft injury.1 Given the short half-life of dd-cfDNA (approximately 30 minutes), we believed that if patients with acute rejection were treated appropriately, then dd-cfDNA levels could verify resolution of rejection as early as the final days of treatment.2 We treated 3 patients for biopsy-proven renal allograft rejection, and dd-cfDNA declined <1% upon completion of therapy. The first patient received a deceased-donor kidney transplant (DDKT) with alemtuzumab induction followed by steroid-sparing immunosuppression with tacrolimus (TAC) and mycophenolate mofetil (MMF). Nine months after transplant, she experienced a gradual rise in SCr and Ur Alb:Ur Cr, prompting us to obtain a dd-cfDNA level of 1.3%. Luminex single antigen bead immunoassay was negative for donor-specific antibody (DSA), and a radiographically directed, percutaneous biopsy revealed Banff IA plasma cell–rich, mild acute T-cell–mediated rejection (TCMR).3 On the final day of pulse-dose intravenous methylprednisolone treatment, repeat dd-cfDNA was 0.42%. SCr and Ur Alb:Ur Cr returned to a new baseline, and weekly dd-cfDNA samples remained <1%, confirming resolution of plasma cell–rich, mild acute TCMR. Our second patient received a DDKT with rabbit antithymocyte globulin induction plus maintenance TAC + MMF + prednisone until he presented 11 months posttransplant with an elevated SCr and de novo BK viremia (for which we stopped MMF and administered intravenous immunoglobulin-proline). He developed de novo class I DSA, an increased SCr, an increased Ur Alb:Ur Cr, and a dd-cfDNA level of 3.5%, prompting an allograft biopsy that revealed early, borderline TCMR.3 Two days after completion of pulse-dose intravenous methylprednisolone treatment, repeat dd-cfDNA was 0.49%. SCr returned to baseline, BK viremia decreased, class I DSA cleared completely, and serial dd-cfDNA tests remained <1%, confirming resolution of early, borderline TCMR. A third patient received a DDKT with rabbit antithymocyte globulin induction, followed by maintenance of TAC + MMF + prednisone. Twenty-eight months posttransplant, the patient presented with an elevated SCr, elevated Ur Alb:Ur Cr, de novo class I and II DSA, and 2.6% dd-cfDNA, prompting a biopsy that revealed C4d-positive antibody-mediated rejection.3 The patient received pulse-dose steroids and 5 sessions of alternating day therapeutic plasma exchange with intravenous immunoglobulin-proline. We reasoned that dd-cfDNA would likely be removed with therapeutic plasma exchange and decided to wait 1 day after his final session to repeat dd-cfDNA that was 0.67%. SCr and Ur Alb:Ur Cr returned to baseline, class I and II DSAs decreased, and repeat dd-cfDNA levels remained <1%, suggesting resolution of C4d-positive antibody-mediated rejection. We believe this is the first report of monitoring dd-cfDNA trends before and upon completion of acute rejection treatment; large-scale studies are needed to formally explore our findings and investigate the accuracy of dd-cfDNA as a potential biomarker for real-time monitoring of response to therapy.