An Exosomal mRNA Urine Test for Detection and Risk Stratification of Human Kidney Transplant Rejection

IF 5.7 2区医学 Q1 UROLOGY & NEPHROLOGY

Kidney International Reports Pub Date : 2025-04-01 DOI:10.1016/j.ekir.2025.01.036

Rania El Fekih , Kurt Franzen , James Hurley , Brian C. Haynes , Tamara Merhej , Areej Alghamdi , Elliot Hallmark , Shuran Xing , Sonia Kumar , John Choi , Zhabiz Solhjou , Christa Deban , Anis Saad , Ahmad Halawi , Nour Younis , Katherine Cashman , Maribel Dagher , Siawosh K. Eskandari , Soltan Al Chaar , Helmut Rennke , Jamil R. Azzi

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引用次数: 0

Abstract

Introduction

We recently discovered 2 urinary exosomal mRNA signatures to identify and differentiate T-cell–mediated rejection (TCMR) from antibody-mediated rejection (ABMR) in kidney transplant recipients. Here, we developed Exosome Transplant Rejection Urine (ExoTRU), a urinetest based on a 4-gene signature from the previous discovery cohort, showed its clinical utility in a new cohort of kidney transplant recipients undergoing clinically indicated biopsies, and validated it through a separate laboratory in an independent-cohort of patients.

Methods

A workflow suited for clinical laboratories was developed, allowing for smaller urine volumes and widely standardized qPCR instrumentation. A total of 226 urine samples from 214 patients were paired with clinically indicated biopsies. Urinary exosomal mRNAs levels were evaluated for previously defined targets.

Results

Four mRNAs (IL32, B2M, CXCL11, and PGK1) performed well in distinguishing biopsies with rejection or significant inflammation from those without inflammation, achieving 94% sensitivity, 62% positive predictive value, and 52% specificity. Patients who tested positive by the signature but negative by biopsy were nearly twice as likely to experience adverse outcomes in the 5-year follow-up period, including subsequent rejection, thereby showing the limitations of kidney biopsies and the prognostic potential of molecular signatures. The evaluation of an independent validation cohort showed similar performance, achieving an area under the curve (AUC) of 0.838. Another 6-gene signature distinguished TCMR from ABMR, with an AUC of 0.756.

Conclusion

Exosomal mRNA gene signatures identified patients with different stages and classes of rejection, including early stage and significant inflammation, enabling improved decision-making and patient management and reducing unnecessary biopsies by 45%. This represents a potential tool for risk stratification based on poor outcomes in patients with positive signatures.

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来源期刊

Kidney International Reports Medicine-Nephrology

CiteScore

7.70

自引率

3.30%

发文量

1578

审稿时长

8 weeks

期刊介绍： Kidney International Reports, an official journal of the International Society of Nephrology, is a peer-reviewed, open access journal devoted to the publication of leading research and developments related to kidney disease. With the primary aim of contributing to improved care of patients with kidney disease, the journal will publish original clinical and select translational articles and educational content related to the pathogenesis, evaluation and management of acute and chronic kidney disease, end stage renal disease (including transplantation), acid-base, fluid and electrolyte disturbances and hypertension. Of particular interest are submissions related to clinical trials, epidemiology, systematic reviews (including meta-analyses) and outcomes research. The journal will also provide a platform for wider dissemination of national and regional guidelines as well as consensus meeting reports.