Identification of molecular biomarkers in blood and urine samples has the potential to revolutionize post transplantation management. Such biomarkers could help risk stratify patients and reduce the need for invasive testing with biopsies to diagnose acute rejection (AR). Furthermore, changes at molecular level are likely to precede both histological findings and graft dysfunction, allowing earlier diagnosis and treatment to limit graft damage.

Aim To identify and characterize biomarkers that can diagnose and predict AR in renal transplant recipients.

Methods Blood and urine samples are collected from recipients before transplant and over the first year post-transplant at 26 time-points and during episodes of graft dysfunction. RNA is extracted from blood collected into Tempus Blood RNA tubes and from urine sediment cells. Quantitative RT-PCR was done for 20(blood) or 23(urine) target and 4 control genes.

Results A pilot study consisting of 10 biopsy proven acute rejection (BPAR) and 18 stable patients revealed a significant over- expression of 5 genes in blood (SEMA7A, PF4, TGFB1, ITGAM, C6orf25) at week 2 after transplantation in the BPAR group, thereby predicting the subsequent development of rejection episodes occurring up to one year post-transplantation (Wilcoxon test, p<0.05, false discovery rate <5%). Using the expression of these 5 genes in a multivariate prediction model returned a probability score that predicted BPAR with a sensitivity of 0.7, specificity of 0.95, and an AUC of 0.80.

For urine, the difference of gene expression 1-2 weeks and 3-4 weeks pre-biopsy was analysed in 7 BPAR and 7 stable samples. Preliminary analysis suggests that differences in expression for perforin and FasL were detected between these groups. This suggests that it might be possible to use a urine test to predict a rejection episode with high specificity and sensitivity up to 4 weeks before it occurs.

Conclusions Our pilot study suggests that mRNA levels in blood and urine could help risk-stratify patients for AR before rejection allowing potential individualisation of anti-rejection therapy. Validation of these findings in a larger cohort is clearly needed.

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