Clinical outcomes from the Assessing Donor-derived cell-free DNA Monitoring Insights of kidney Allografts with Longitudinal surveillance (ADMIRAL) study.

The use of routine monitoring of donor-derived cell-free DNA (dd-cfDNA) after kidney transplant may allow clinicians to identify subclinical allograft injury and intervene prior to development of clinically evident graft injury. To evaluate this, data from 1092 kidney transplant recipients monitored for dd-cfDNA over a three-year period was analyzed to assess the association of dd-cfDNA with histologic evidence of allograft rejection. Elevation of dd-cfDNA (0.5% or more) was significantly correlated with clinical and subclinical allograft rejection. dd-cfDNA values of 0.5% or more were associated with a nearly three-fold increase in risk development of de novo donor-specific antibodies (hazard ratio 2.71) and were determined to be elevated a median of 91 days (interquartile range of 30-125 days) ahead of donor specific antibody identification. Persistently elevated dd-cfDNA (more than one result above the 0.5% threshold) predicted over a 25% decline in the estimated glomerular filtration rate over three years (hazard ratio 1.97). Therefore, routine monitoring of dd-cfDNA allowed early identification of clinically important graft injury. Biomarker monitoring complemented histology and traditional laboratory surveillance strategies as a prognostic marker and risk-stratification tool post-transplant. Thus, persistently low dd-cfDNA levels may accurately identify allograft quiescence or absence of injury, paving the way for personalization of immunosuppression trials.

Dynamic Response of Donor-Derived Cell-Free DNA Following Treatment of Acute Rejection in Kidney Allografts.

Background: The quantification of rejection treatment efficacy has been insufficient using traditional markers due, in part, to the lagging response of serum creatinine and histologic alterations on biopsy specimens. Donor-derived cell-free DNA (dd-cfDNA) is a molecular marker of injury that may assess allograft injury after rejection. Methods: Retrospective review of the DART study identified 70 patients who had a clinically indicated biopsy, simultaneous dd-cfDNA measurement, and at least one follow-up dd-cfDNA within 3 months post-treatment. Thirty-five patients had no biopsy-proven rejection and no rejection treatment (NR), 16 patients had no biopsy-proven rejection but did receive rejection treatment (CR), 9 patients had diagnosis of ABMR/mixed rejection on biopsy and received rejection treatment (ABMR), and 10 patients had diagnosis of TCMR and received rejection treatment (TCMR). The CR, ABMR, and TCMR groups combined to form a rejection (R) group. Results: In the R group, median dd-cfDNA values at baseline and 1 month were 0.62% and 0.35% (n=21 pairs, p=0.34), and at baseline and 2-3 months were 0.77% and 0.21% (n=23 pairs, p=0.002). In TCMR, median dd-cfDNA values at baseline and 1 month were 1.13% and 0.37% (n=5 pairs, p=0.63), and at baseline and 2-3 months were 0.25% and 0.12% (n=9 pairs, p=0.004). In ABMR, median dd-cfDNA values at baseline and 1 month were 1.61% and 1.2 % (n=6 pairs, p>0.99), and at baseline and 2-3 months were 3.85% and 1.32% (n=6 pairs, p=0.09). In CR, median dd-cfDNA values at baseline and 1 month were 0.31% and 0.29% (n=10 pairs, p=0.38), and at baseline and 2-3 months were 0.38% and 0.17% (n=8 pairs, p=0.31). Lastly, in NR, median dd-cfDNA values at baseline and 1 month were 0.23% and 0.18% (n=21 pairs, p=0.10), and at baseline and 2-3 months were 0.33% and 0.17% (n=26 pairs, p=0.003). Changes in serum creatinine across 1 month and 2-3 months following rejection were similar. Conclusions: dd-cfDNA may be a useful dynamic biomarker to assess the health of the kidney allograft following rejection treatment.

Gene expression profiling scores in dual organ transplant patients are similar to those in heart-only recipients.

BACKGROUND: Serial gene expression profiling (GEP) may reduce the need for endomyocardial biopsies for detecting acute cellular rejection (ACR) after transplantation, but its performance in dual organ transplant recipients is currently unknown. METHODS: We analyzed 18 months of follow-up in a national cohort of 27 dual organ recipients (18 heart-kidney, 8 heart-liver, 1 heart-lung) matched to 54 heart-only recipients for gender, age, and time to first GEP (AlloMap®) test. ACR, antibody-mediated rejection (AMR), cytomegalovirus infections, biopsies, and longitudinal GEP scores were evaluated. RESULTS: During the first 90 days post-transplant, the mean GEP score for dual organ recipients was 25.2 ±â€¯9.1, vs. 23.5 ±â€¯7.7 for heart-only recipients (P = 0.48), with final GEP scores being 29.1 ±â€¯6.1 and 32.3 ±â€¯3.4, respectively (P = 0.34). GEP scores increased over time (P < 0.001) at a similar rate (P = 0.33) for both groups. One heart-only recipient had treated ACR (GEP score = 17). Fourteen subjects had cytomegalovirus infection, 8 of whom were dual-organ. During follow-up, mean GEP score among patients with cytomegalovirus infection was 32.3, compared to 26.7 (p < 0.001) in patients without cytomegalovirus. Only 4 (2%) of 233 biopsies were positive for mild AMR; all occurring in 2 heart-only recipients (GEP scores = 18-33). CONCLUSIONS: This largest cohort to date suggests that dual organ transplantation alone should not be reason to omit GEP testing from post-transplant medical management, as the two groups' scores did not differ significantly. Confirming that GEP scores increase over time for heart-only and dual organ recipients and in the presence of cytomegalovirus infection, our work shows promise for the use of serial GEP testing in dual organ recipients.