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Antibody-mediated rejection (AMR) is a major cause of graft failure limiting long-term graft survival after kidney transplantation. Current diagnostic strategy to detect AMR is suboptimal and requires further improvement. Previously suggested treatment regimens for AMR could not demonstrate efficacy, however novel therapeutic agents are currently under investigation. Donor-derived cell-free DNA (dd-cfDNA) is a novel noninvasive biomarker for allograft injury, that has been mainly studied in the context of rejection. Its short-half-life in circulation and injury-dependent release are its key advantages that contribute to its superior diagnostic accuracy, compared to traditional biomarkers. Moreover, previous studies showed that dd-cfDNA-release is well-linked to histological and molecular features of AMR, and thus able to reflect real-time injury. Further observations suggest that dd-cfDNA can be used as a suitable screening tool for early detection of AMR in patients with donor-specific-anti-HLA-antibodies (DSA), as well as for monitoring AMR activity after anti-rejection treatment. The weight of evidence suggests that the integration of dd-cfDNA in the graft surveillance of patients with AMR, or those suspicious of AMR (e.g., due to the presence of donor-specific anti-HLA-antibodies) has an added value and might have a positive impact on outcomes in this specific cohort. [ABSTRACT FROM AUTHOR]

Antibody-mediated rejection (AMR) is among the most frequent causes for graft loss after kidney transplantation. While there are no approved therapies, several case reports with daratumumab and the very recent phase 2 trial of felzartamab in AMR have indicated the potential efficacy of therapeutic interventions targeting CD38. Donor-derived cell-free DNA (ddcfDNA) is an emerging biomarker with injury-specific release and a short half-life, which could facilitate early diagnosis of AMR andmonitoring of treatment response. We describe two cases of patients with chronic active AMR, who were treated with monthly daratumumab infusions, and in whom donor-derived cell-free DNA (dd-cfDNA) was measured longitudinally to monitor treatment response. In both patients, daratumumab treatment led to stabilization of kidney function parameters, a strong decline of dd-cfDNA below the previously established threshold for rejection, and partial or complete histologic resolution of AMR activity. Our case series suggests that dd-cfDNA may be a useful companion biomarker for longitudinal monitoring of anti-CD38 treatment in patients with AMR. [ABSTRACT FROM AUTHOR]

Background De novo donor-specific antibodies (dnDSAs) may cause antibody-mediated rejection and graft dysfunction. Little is known about the clinical course after first detection of dnDSAs during screening in asymptomatic patients. We aimed to assess the value of estimated glomerular filtration rate (eGFR) and proteinuria to predict graft failure in patients with dnDSAs and their potential utility as surrogate endpoints. Methods All 400 kidney transplant recipients with dnDSAs at our centre (1 March 2000–31 May 2021) were included in this retrospective study. The dates of graft loss, rejection, doubling of creatinine, ≥30% eGFR decline, proteinuria ≥500 mg/g and ≥1000 mg/g were registered from the first dnDSA appearance. Results During 8.3 years of follow-up, graft failure occurred in 33.3% of patients. Baseline eGFR and proteinuria correlated with 5-year graft loss (area under the receiver operating characteristics curve 0.75 and 0.80, P  < .001). Creatinine doubled after a median of 2.8 years [interquartile range (IQR) 1.5–5.0] from dnDSA and the time from doubling creatinine to graft failure was 1.0 year (IQR 0.4–2.9). Analysing eGFR reduction ≥30% as a surrogate endpoint (148/400), the time from dnDSA to this event was 2.0 years (IQR 0.6–4.2), with a positive predictive value (PPV) of 45.9% to predict graft loss, which occurred after 2.0 years (IQR 0.8–3.2). The median time from proteinuria ≥500 mg/g and ≥1000 mg/g to graft failure was identical, 1.8 years, with a PPV of 43.8% and 49.0%, respectively. Composite endpoints did not improve PPV. Multivariable analysis showed that rejection was the most important independent risk factor for all renal endpoints and graft loss. Conclusions Renal function, proteinuria and rejection are strongly associated with graft failure in patients with dnDSA and may serve as surrogate endpoints. [ABSTRACT FROM AUTHOR]

Background and Hypothesis: Donor-derived cell-free DNA (dd-cfDNA) shows good diagnostic performance for the detection of antibody-mediated rejection (AMR) in kidney transplant recipients (KTR). However, the clinical benefits of dd-cfDNA monitoring need to be established. Early diagnosis of AMR at potentially reversible stages may be increasingly important due to emerging treatment options for AMR.We hypothesized that monitoring dd-cfDNA in KTR with de novo donor-specific anti-HLA antibodies (dnDSA) and performing kidney biopsy in case of increased dd-cfDNA may reduce time to AMR diagnosis in comparison to clinical indication biopsy., Methods: In this diagnostic, single-center, open-label, randomized clinical trial, we assigned 40 KTR with prevalent dnDSA and estimated glomerular filtration rate ≥20 mL/min/1.73m2, but without previous biopsy-proven AMR, to either dd-cfDNA-guided biopsy (intervention group) or clinician-guided biopsy (control group) over a 12-months period. In both groups, dd-cfDNA was assessed at inclusion and 1, 3, 6, 9, and 12 months. In the intervention group, dd-cfDNA > 50cp/mL indicated a biopsy. Biopsies for clinical indication could be performed at any point during the study period in both groups. A protocol biopsy was scheduled after 12 months for patients without dd-cfDNA-guided biopsy or clinical indication biopsy until study completion. The primary endpoint was time from study inclusion to diagnosis of active or chronic active AMR., Results: 39/40 patients had functioning grafts at study completion. From these, 26 patients underwent biopsy, 13 in each group. AMR was diagnosed earlier in the intervention group than in the control group (median 2.8 months, IQR 1.7-5.3 vs. median 14.5 months, IQR 13.3-16.7, p = 0.003). Longitudinal dd-cfDNA monitoring had 77% positive predictive value and 85% negative predictive value for AMR., Conclusions: Dd-cfDNA-guided biopsy in KTR with prevalent dnDSA can reduce the time to AMR diagnosis and hereby expedite therapy initiation. (NCT04897438)., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)