**Koen E. Groeneweg, Jacques M.G.J. Duijs, Barend W. Florijn, Cees van Kooten, Johan W. de Fijter, Anton Jan van Zonneveld, Marlies E.J. Reinders and Roel Bijkerk \***

Department of Internal Medicine (Nephrology) and the Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, Zuid Holland, The Netherlands; k.e.groeneweg@lumc.nl (K.E.G.); J.M.G.J.Duijs@lumc.nl (J.M.G.J.D.); b.w.florijn@lumc.nl (B.W.F.); C.van\_Kooten@lumc.nl (C.v.K.); J.W.de\_Fijter@lumc.nl (J.W.d.F.); A.J.van\_Zonneveld@lumc.nl (A.J.v.Z.); M.E.J.Reinders@lumc.nl (M.E.J.R.)

**\*** Correspondence: R.Bijkerk@lumc.nl

Received: 29 June 2020; Accepted: 3 August 2020; Published: 5 August 2020

**Abstract:** Acute rejection (AR) of a kidney graft in renal transplant recipients is associated with microvascular injury in graft dysfunction and, ultimately, graft failure. Circulating long noncoding RNAs (lncRNAs) may be suitable markers for vascular injury in the context of AR. Here, we first investigated the effect of AR after kidney transplantation on local vascular integrity and demonstrated that the capillary density markedly decreased in AR kidney biopsies compared to pre-transplant biopsies. Subsequently, we assessed the circulating levels of four lncRNAs (LNC-RPS24, LNC-EPHA6, MALAT1, and LIPCAR), that were previously demonstrated to associate with vascular injury in a cohort of kidney recipients with a stable kidney transplant function (*n* = 32) and recipients with AR (*n* = 15). The latter were followed longitudinally six and 12 months after rejection. We found higher levels of circulating LNC-EPHA6 during rejection, compared with renal recipients with a stable kidney function (*p* = 0.017), that normalized one year after AR. In addition, LNC-RPS24, LNC-EPHA6, and LIPCAR levels correlated significantly with the vascular injury marker soluble thrombomodulin. We conclude that AR and microvascular injury are associated with higher levels of circulating LNC-EPHA6, which emphasizes the potential role of lncRNAs as biomarker in the context of AR.

**Keywords:** long noncoding RNA; kidney transplantation; rejection; microvascular injury
