Abstract
Urine has been regarded as a good resource based on the assumption that urine can directly reflect the state of the allograft or ongoing injury in kidney transplantation. Previous studies, suggesting the usefulness of urinary mRNA as a biomarker of acute rejection, imply that urinary mRNA mirrors the transcriptional activity of the kidneys. We selected 14 data-driven candidate genes through a meta-analysis and measured the candidate genes using quantitative PCR without pre-amplification in the cross-sectional specimens from Korean kidney transplant patients. Expression of 9/14 genes (CXCL9, CD3ϵ, IP-10, LCK, C1QB, PSMB9, Tim-3, Foxp3, and FAM26F) was significantly different between acute rejection and stable graft function with normal pathology and long-term graft survival in 103 training samples. CXCL9 was also distinctly expressed in allografts with acute rejection in in situ hybridization analysis. This result, consistent with the qPCR result, implies that urinary mRNA could reflect the magnitude of allograft injury. We developed an AR prediction model with the urinary mRNAs by a binary logistic regression and the AUC of the model was 0.89 in the training set. The model was validated in 391 independent samples, and the AUC value yielded 0.84 with a fixed manner. In addition, the decision curve analysis indicated a range of reasonable threshold probabilities for biopsy. Therefore, we suggest the urine mRNA signature could be used as a non-invasive monitoring tool of acute rejection for clinical application and could help determine whether to perform a biopsy in a recipient with increased creatinine.
Highlights
Kidney transplantation (KTx) provides better quality of life in patients with end-stage renal disease (ESRD), but KTx patients often experience allograft failure due to acute rejection (AR)
The expression of AR-specific mRNAs in urinary cell pellets for monitoring the immune status of kidney transplant patients has been studied by many investigators in the last decade
Absolute quantification with preamplification, which was developed by Suthanthiran et al, has been regarded as the standard method for biomarker research using urinary mRNA quantification in kidney transplantation [16]
Summary
Kidney transplantation (KTx) provides better quality of life in patients with end-stage renal disease (ESRD), but KTx patients often experience allograft failure due to acute rejection (AR). Various tests such as ATP assay, immune cell analysis, and determination of cytokines in blood and urine have been introduced [3,4,5,6,7], but the usefulness of these tools for monitoring kidney graft status is yet to be evaluated in clinical trials. Urine samples have been considered a good source of factors to monitor allograft status by biomarker researchers in the urine of KTx patients [8], because the cells contained in urine comprise various molecules that reflect the biological processes of allograft or ongoing kidney injury and because urine can be sampled for serial monitoring of the kidney allograft by a truly noninvasive manner in the clinical setting. We conducted a meta-analysis from public datasets of biopsy transcriptome to select proper candidates for diagnosing AR in KTx patients
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