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Research Highlights

Issa, Fadi1

doi: 10.1097/TP.0000000000002935
In View: Research Highlights

1 Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

Received 9 August 2019.

Accepted 9 August 2019.

The author declares no funding or conflicts of interest.

Correspondence: Fadi Issa, Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom. (

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A Peripheral Blood Gene Expression Signature to Diagnose Subclinical Acute Rejection

Zhang W, Yi Z, Keung KL, et al. J Am Soc Nephrol. 2019;30:1481–1494.

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Development and Validation of a Peripheral Blood mRNA Assay for the Assessment of Antibody-mediated Kidney Allograft Rejection: A Multicentre, Prospective Study

Van Loon E, Gazut S, Yazdani S, et al. EBioMedicine. 2019;46:463–472.

The early and accurate diagnosis of renal allograft rejection is critical to ensuring continued function and survival of the transplanted organ. Regular monitoring of transplant recipients is therefore an integral part of their management post transplantation. The challenge, however, is the delivery of personalized therapy under conditions in which current monitoring techniques are imprecise and, in the case of renal biopsy, subject to sampling error and procedural complications. The current strategy of most centers is to monitor serum creatinine according to Kidney Disease Improving Global Outcomes (KDIGO) guidelines, as well as protein excretion and viral screening. Due to its nonspecific nature, a rise in serum creatinine normally triggers a biopsy, which is then assessed according to the Banff classification of allograft rejection. In many units, surveillance biopsies are also performed which often demonstrate features that may be consistent with rejection in the absence of a rise in serum creatinine. The significance of this “subclinical rejection” is uncertain and indicates that either our current diagnostic tests are not sensitive enough to detect rejection, or that the biopsy findings lack specificity. While the Banff classification offers standardization of rejection criteria, there remains interobserver variability between pathologists. HLA alloantibody screening post transplantation is also part of the armamentarium, yet there are often cases in which there are clinical features of antibody-mediated rejection but no significant serum donor-specific antibody.

Overall, the situation results in a degree of clinical uncertainty and a lack of diagnostic accuracy to help guide treatment with precision. There is therefore a need to develop noninvasive assays that can accurately evaluate renal function and alloimmune status. Three broad classes of biomarkers have been defined: prognostic, predictive, and surrogate end point biomarkers.1 There have been a number of incremental steps in the development of such biomarkers, with some tests coming to market, such as AlloSure’s donor-derived cell-free DNA assay, which may assist in the discrimination of rejection from other causes of raised creatinine such as BK nephropathy, thus obviating the need for a biopsy.2 Other examples include the Clinical Trials in Organ Transplantation (CTOT) study, which initially demonstrated an association between urinary CXCL9 levels or IFNγ ELISPOT with acute cellular rejection within the first year (CTOT-01), although the association of these markers with 5-year outcomes was less informative (CTOT-17).3

With the recent advent of accessible advanced transcriptomic analysis including RNA sequencing, a number of groups have examined peripheral blood mRNA to provide further insight into the alloimmune status.4 In the two studies highlighted this month, transcriptomic analyses have been used to help address the challenges in the diagnosis of subclinical and antibody-mediated rejection, producing gene sets with predictive and occasionally prognostic value.

In the study from Zhang et al,5 RNA sequencing was performed on 88 patients at the time of a 3-month surveillance biopsy to examine for transcriptomic changes associated with rejection at that time point. Of these, 22 patients had a diagnosis of acute cellular rejection at the time of transcriptomic analysis. A 17-gene set was identified as being associated with acute cellular rejection and then validated on a training set of patients, demonstrating a statistically significant ability to identify patients at higher risk of acute rejection and future graft loss.

In the study from Van Loon et al,6 a transcriptomic analysis on peripheral blood was performed in an effort to detect antibody-mediated rejection. Here, the authors used discovery (117 blood samples and 95 biopsies from 117 patients) and derivation (183 patients) cohorts to develop an 8-gene set with the ability to diagnose antibody-mediated rejection on a test cohort of patients. In contrast to the previous study, here RNA was analyzed by microarray rather than sequencing. Importantly, while the gene set correlated with histologic markers of antibody-mediated rejection (such as glomerulitis and peritubular capillaritis), there was no correlation with features of T-cell–mediated rejection in biopsies.

Both studies highlight the utility that advanced analysis techniques are bringing to the biomarker discovery field and have successfully produced gene panels with real potential for clinical implementation. The advantage will ultimately be a reduced reliance on biopsies without a loss of diagnostic accuracy, as well as enhanced guidance on immunosuppression management without the troublesome clinical uncertainty.

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1. Biomarkers Definitions Working GroupBiomarkers and surrogate endpoints: preferred definitions and conceptual framework.Clin Pharmacol Ther20016989–95
2. Singh N, Samant H, Hawxby A, et al. Biomarkers of rejection in kidney transplantation.Curr Opin Organ Transplant201924103–110
3. Faddoul G, Nadkarni GN, Bridges ND, et al. Analysis of biomarkers within the initial 2 years posttransplant and 5-year kidney transplant outcomes: results from clinical trials in organ transplantation-17.Transplantation2018102673–680
4. Eikmans M, Gielis EM, Ledeganck KJ, et al. Non-invasive biomarkers of acute rejection in kidney transplantation: novel targets and strategies.Front Med (Lausanne)20185358
5. Zhang W, Yi Z, Keung KL, et al. A peripheral blood gene expression signature to diagnose subclinical acute rejection.J Am Soc Nephrol2019301481–1494
6. Van Loon E, Gazut S, Yazdani S, et al. Development and validation of a peripheral blood mRNA assay for the assessment of antibody-mediated kidney allograft rejection: A multicentre, prospective study.EBioMedicine201946463–472
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