Transplant Trial Watch

Circulating cell-free nucleosomes as biomarker for kidney transplant rejection: a pilot study.

Verhoeven, J., et al.

Clin Epigenetics 2021; 13(1): 32.

This study aimed to determine whether circulating cell-free nucleosomes (CCFN) could serve as a biomarker for detecting acute rejection in kidney transplant patients who participated in a randomised controlled trial comparing belatacept with tacrolimus following kidney transplantation.

Participants in the original trial were randomised to either the belatacept group or the tacrolimus group.

40 de novo kidney transplant recipients.

The main outcome of interest was the measurement of CCFN values during acute rejection compared to no acute rejection.

180 days post-transplant.

CET Conclusions
This paper reports an analysis based on the results from a previously published trial. The previous paper, published by De Graav et al in 2017, compared rejection rates between tacrolimus and belatacept in de novo renal transplant recipients. (A Randomized Controlled Clinical Trial Comparing Belatacept With Tacrolimus After De Novo Kidney Transplantation. de Graav et al; Transplantation. 2017;11:11). This study demonstrated a very high rejection rate in the belatacept arm (55%) and less in the tacrolimus arm (10%). The current paper assesses whether or not circulating cell-free nucleosomes (CCFN) are useful biomarkers for acute rejection, particularly with specified modifications, such as citrulline. The authors monitored serum CCFN at several time points up to 180 days after transplantation (Days: -1, 3,4,5,6, 30 and 180). For all of the variations of CCFN they generally followed the same pattern, with a rise in circulating levels after transplantation and then a fall to baseline at day 30. During episodes of acute rejection the overall levels of CCFN + H3 Citrulline rose significantly, by about 50%, compared to samples without rejection. When assessing the performance of CCFN (H3) with ROC curves it showed moderate sensitivity and specificity for acute rejection (69% and 71% respectively). The positive predictive value was poor (15%) but the negative predictive value was relatively good (93%). The low positive predictive value of high CCFN (H3) is related to the fact that circulating levels are higher in many diseases. It may therefore be a better tool for excluding rejection rather than diagnosing rejection. However, on the basis of this study I do not think that it yet can be used to spare renal transplant recipients the risk of transplant biopsy either.

Trial registration
Dutch national trial registry - NTR4242

Funding source
Non-industry funded