Abstract
Predicting immediate and subsequent graft function is important in clinical decision-making around kidney transplantation, but is difficult using available approaches. Here we have evaluated urinary microRNAs as biomarkers in this context. Profiling of 377 microRNAs in the first urine passed post-transplantation identified 6 microRNAs, confirmed to be upregulated by RT-qPCR in an expanded cohort (miR-9, -10a, -21, -29a, -221, and -429, n = 33, P < 0.05 for each). Receiver operating characteristic analysis showed Area Under the Curve 0.94 for this panel. To establish whether this early signal was sustained, miR-21 was measured daily for 5 days post-transplant, and was consistently elevated in those developing Delayed Graft Function (n = 165 samples from 33 patients, p < 0.05). The biomarker panel was then evaluated in an independent cohort, sampled at varying times in the first week post-transplantation in a separate transplant center. When considered individually, all miRs in the panel showed a trend to increase or a significant increase in those developing delayed Graft Function (miR-9: P = 0.068, mIR-10a: P = 0.397, miR-21: P = 0.003, miR-29a: P = 0.019, miR-221: P = 0.1, and miR-429: P = 0.013, n = 47) with Area Under the Curve 0.75 for the panel. In conclusion, combined measurement of six microRNAs had predictive value for delayed graft function following kidney transplantation.
Highlights
Kidney transplantation is the treatment of choice for many patients with end stage renal failure
In order to determine whether urinary microRNAs are more generally useful as a biomarker of DGF in clinical practice, we evaluated urinary expression profile of miR-21 in this cohort for the 5 consecutive days after kidney transplantation. miR-21 in urine was significantly up-regulated in the ‘Cadaveric donor kidney transplant with DGF (CD-DGF)’ group compared with both the ‘No DGF’ groups during the first five days post-transplantation (p < 0.05) (Fig. 5)
We have used unbiased profiling to identify microRNAs in the urine that are predictive of DGF following kidney transplantation and subsequently confirmed these findings using measurement of specific microRNAs by RTqPCR
Summary
Kidney transplantation is the treatment of choice for many patients with end stage renal failure. Due to the increasing number of patients on the waiting list, new ways have been identified to increase the organ donor pool[3,4] These have included the use of ‘marginal’ and ‘extended criteria’ donors (defined by the United Network for Organ Sharing (UNOS) as donors older than 60 years, or donors between age 50–59 with two or more criteria from higher terminal Creatinine >1.5 mg/dl, hypertension and death due to CVA)[5,6]. Identifying a non-invasive biomarker of the extent of IRI and DGF, would improve prediction of outcome and tailored management for transplant patients Development of such a biomarker would facilitate testing of new approaches to attenuate IRI and reduce the risk of DGF. MicroRNAs have emerged as essential post-transcriptional regulators of gene expression[11,12,13] These small non-coding RNAs regulate various physiological and pathophysiological processes, and have an important role in acute kidney injury[14]. The resultant signature predictive of DGF was validated in a second cohort of 47 patients transplanted at an independent center
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