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

Hinojosa, Randall J., PharmD1; Chaffin, Kim, RN1; Gillespie, Matthew, PharmD2; Villarreal, V. Herman Jr, MD1,3

doi: 10.1097/TP.0000000000002579
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1 CHRISTUS Transplant Institute, San Antonio, TX.

2 CareDx, Inc., Brisbane, CA.

3 Renal Associates, P.A., San Antonio, TX.

Received 18 November 2018. Revision received 6 December 2018.

Accepted 11 December 2018.

The authors declare no funding or conflicts of interest.

These data were exempt from approval by institutional review, and humans involved in this study were treated in a manner in accordance with the Declaration of Helsinki and the Declaration of Istanbul.

R.J.H. participated in research design, writing of the paper, performance of the research, and data analysis. K.C. participated in the performance of the research and data analysis. M.G. participated in the writing of the paper and data analysis. V.H.V. participated in the performance of the research and data analysis.

Correspondence: Randall J. Hinojosa, PharmD, Department of Pharmacy, University Hospital, 4502 Medical Dr, San Antonio, TX 78229. (randyjessh@utexas.edu).

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.

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REFERENCES

1. Bloom RD, Bromberg JS, Poggio ED, et al. Cell-free DNA and active rejection in kidney allografts. J Am Soc Nephrol. 2017;28:2221–2232.
2. Yu SC, Lee SW, Jiang P, et al. High-resolution profiling of fetal DNA clearance from maternal plasma by massively parallel sequencing. Clin Chem. 2013;59:1228–1237.
3. Haas M, Loupy A, Lefaucheur C, et al. The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials. Am J Transplant. 2018;18:293–307.
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