Donor-Derived Cell-Free DNA for Kidney Allograft Surveillance after Conversion to Belatacept: Prospective Pilot Study

Abstract

Donor-derived cell-free DNA (dd-cfDNA) is used as a biomarker for detection of antibody-mediated rejection (ABMR) and other forms of graft injury. Another potential indication is guidance of immunosuppressive therapy when no therapeutic drug monitoring is available. In such situations, detection of patients with overt or subclinical graft injury is important to personalize immunosuppression. We prospectively measured dd-cfDNA in 22 kidney transplant recipients (KTR) over a period of 6 months after conversion to belatacept for clinical indication and assessed routine clinical parameters. Patient and graft survival was 100% after 6 months, and eGFR remained stable (28.7 vs. 31.1 mL/min/1.73 m2, p = 0.60). Out of 22 patients, 2 (9%) developed biopsy-proven rejection—one episode of low-grade TCMR IA and one episode of caABMR. While both episodes were detected by increase in creatinine, the caABMR episode led to increase in absolute dd-cfDNA (168 copies/mL) above the cut-off of 50 copies/mL, while the TCMR episode did show slightly increased relative dd-cfDNA (0.85%) despite normal absolute dd-cfDNA (22 copies/mL). Dd-cfDNA did not differ before and after conversion in a subgroup of 12 KTR with previous calcineurin inhibitor therapy and no rejection (12.5 vs. 25.3 copies/mL, p = 0.34). In this subgroup, 3/12 (25%) patients showed increase of absolute dd-cfDNA above the prespecified cut-off (50 copies/mL) despite improving eGFR. Increase in dd-cfDNA after conversion to belatacept is common and could point towards subclinical allograft injury. To detect subclinical TCMR changes without vascular lesions, additional biomarkers or urinary dd-cfDNA should complement plasma dd-cfDNA. Resolving CNI toxicity is unlikely to be detected by decreased dd-cfDNA levels. In summary, the sole determination of dd-cfDNA has limited utility in the guidance of patients after late conversion to belatacept. Further studies should focus on patients undergoing early conversion and include protocol biopsies at least for patients with increased dd-cfDNA.

Dd-cfDNA in liver transplantation: The future of non-invasive liver graft evaluation

“…Moreover, dd-cfDNA has been used for the personalization of dosage and monitoring of patients receiving tocilizumab and belatacept in kidney transplant recipients, with possible application to liver transplant recipients as well. [81,82]. The success of tocilizumab treatment is evaluated with the decrease of levels of dd-cfDNA (%), with a decrease of 47% being reported after 12 months of treatment [81].…”

Costimulatory Blockade and Solid Organ Transplantation: The Past, Present, and Future

“… 66 Though promising, these subsets require further clinical validation and have yet to be implemented clinically for prospective use to guide belatacept usage. Other emerging technologies such as cell-free donor-derived DNA 67 , 68 and eplet HLA mismatching 69 may also ultimately prove useful in risk-stratifying patients for de novo or conversion use of belatacept, although further studies are certainly needed to validate these biomarkers in patients receiving belatacept therapy. Interestingly, an examination of predicted indirectly recognizable HLA epitopes (PIRCHE-II) by our group suggests that belatacept may modify the immune event risk for acute rejection, DSA and AMR based on risk PIRCHE-II scores that could serve to guide immunosuppression management (unpublished data).…”

“…For protocol conversions or those that require less urgent discontinuation of CNI, we dose belatacept monthly and wean CNI over at least 3 months or until at least 6 months posttransplant. Emerging evidence is also suggesting that serial immune monitoring with biomarkers such as urinary chemokine CXCL9 117 or donor-derived cell-free DNA 68 may help facilitate the safe transition from CNI to belatacept by identifying patients at higher risk of ACR on belatacept, although the results of these pilot studies remain to be validated in larger patient cohorts.…”