Urinary MicroRNA-21-5p as Potential Biomarker of Interstitial Fibrosis and Tubular Atrophy (IFTA) in Kidney Transplant Recipients

Abstract

Chronic renal allograft dysfunction (CAD) is a major limiting factor of long-term graft survival. The hallmarks of progressive CAD are interstitial fibrosis and tubular atrophy (IFTA). MicroRNAs are small, regulatory RNAs involved in many immunological processes. In particular, microRNA-21-5p (miR-21) is considered to be strongly associated with pathogenesis regarding tubulointerstitium. The aim of this study was to assess urinary miR-21 expression levels in the kidney transplant recipients and determine their application in the evaluation of IFTA and kidney allograft function. The expression levels of miR-21 were quantified in the urine of 31 kidney transplant recipients with biopsy-assessed IFTA (IFTA 0 + I: n = 17; IFTA II + III: n = 14) by real-time quantitative PCR. Urine samples were collected at the time of protocolar biopsies performed 1 or 2 years after kidney transplantation. MicroRNA-191-5p was used as reference gene. MiR-21 was significantly up-regulated in IFTA II + III group compared to IFTA 0 + I group (p = 0.003). MiR-21 correlated significantly with serum concentration of creatinine (r = 0.52, p = 0.003) and eGFR (r = −0.45; p = 0.01). ROC analysis determined the diagnostic value of miR-21 with an area under curve (AUC) of 0.80 (p = 0.0002), sensitivity of 0.86 and specificity of 0.71. miR-21 is associated with renal allograft dysfunction and IFTA. Therefore, it could be considered as a potential diagnostic, non-invasive biomarker for monitoring renal graft function.

METTL3/N6‐methyladenosine/ miR‐21‐5p promotes obstructive renal fibrosis by regulating inflammation through SPRY1/ERK/NF‐κB pathway activation

“…It has been well documented that miR‐21 is involved in fibrosis of the kidneys and other organs, including the heart, 21 liver 22 and lungs 23 . According to previously published studies, 24,25 the miR‐21 level is increased in renal fibrosis tissue and serves as an important biomarker of fibrosis in plasma 26 and urinary tissue 27 . Ample evidence supports miR‐21 as a promoting factor during renal fibrosis, and targeting miR‐21 likely has a therapeutic effect and attenuates renal fibrosis development 28,29 .…”

“… 23 According to previously published studies, 24 , 25 the miR‐21 level is increased in renal fibrosis tissue and serves as an important biomarker of fibrosis in plasma 26 and urinary tissue. 27 Ample evidence supports miR‐21 as a promoting factor during renal fibrosis, and targeting miR‐21 likely has a therapeutic effect and attenuates renal fibrosis development. 28 , 29 In our study, after ligation of the left ureter for 7 and 14 days, the morphology of obstructed kidneys changed dramatically.…”

Urinary Extracellular Vesicles Are a Novel Tool to Monitor Allograft Function in Kidney Transplantation: A Systematic Review

“…In 2018, another miRNome study of uEV from donors reported that the profile of miRNA did not discriminate between living donors and deceased donors before transplantation [ 62 ]. The role of miRNA in uEV after kidney transplantation is not yet fully explored as currently most diagnostic findings of miRNA are based on human kidney disease before transplantation [ 59 ], cultured kidney cell [ 30 , 63 ], animal model [ 63 , 64 ], or urine sample only with no uEV isolation or detection [ 57 , 65 , 66 , 67 , 68 ], rather than on uEV from KTR after transplantation.…”

“…However, uEV-miRNA might be a major localization/derivation of total urinary miRNA [ 57 ], where urinary miR-21 is especially highlighted during kidney transplantation. Compared to a group with normal function, KTR with IFTA showed upregulated urinary miR-21 [ 65 ], which corresponded to elevated uEV-miR-21 during chronic kidney disease [ 63 ]. Khalid et al reported that elevated urinary miR-21 could predict DGF with an AUC between 0.75 to 0.94 [ 66 ].…”

Kidney microRNA-21 Expression and Kidney Function in IgA Nephropathy

“…Other studies have reported that urinary miR-21 level may have prognostic value in hypertensive kidney injury 9 , 39 and kidney allograft recipients. 40 , 41 …”