A Composite of Urinary Biomarkers to Differentiate between Tubulointersttial Inflammation and Fibrosis in Kidney Allografts


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Abstract

BackgroundA composite of urinary biomarkers may be more helpful to monitor kidney allograft pathology compared with a single biomarker.MethodsAs a cross-sectional cohort study, we collected 210 urine samples from living or deceased donor kidney transplant (KT) recipients. Among them, 123 recipients had an indication biopsy and we sampled their urine before the biopsy. After excluding 7 recipients with BK virus nephropathy, the levels of several biomarkers in 116 with an indication biopsy were compared with those in 87 with stable allograft function and in 50 living kidney donors just before donor nephrectomy. The level of transglutaminase 2 (TG2), syndecan 4 (SDC4), alpha 1 microglobulin (A1M), interferon-inducible protein 10 (IP-10), interleukin 6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1) were measured in each urine sample.ResultsThere was a significant increase of log10TG2/Cr (0.63±0.88 vs −0.15±0.58 vs −0.36±0.34, p<0.001), log10A1M/Cr (2.86±0.55 vs 2.41±0.61 vs 2.01±0.51, p<0.001), log10IL-6/Cr (1.79±0.82 vs 1.36±0.85 vs 1.44±0.60, p<0.001), and log10MCP-1/Cr (0.40±0.49 vs −0.03±0.54 vs 0.05±0.34, p<0.001) in the indication biopsy group compared with the other groups. In the indication biopsy group, the higher IFTA score (ct+ci) recipients had, the higher the level of log10TG2/Cr was. Log10TG2/Cr (0.74±0.88 vs 0.01±0.61, p<0.001) and log10SDC4/Cr (0.07±0.36 vs −0.17±0.31, p=0.013) were significantly higher in those with biopsy-proven acute rejection (BPAR) compared with those without BPAR. When the data were adjusted with age, sex, body mass index (BMI), diabetes, hypertension, cardiovascular disease, and the interval between KT and biopsy, TG2 and the interval were significantly correlated variables with interstitial fibrosis and tubular atrophy (IFTA. In regard of tubulointerstitial inflammation (i+t), BMI, TG2, SDC4, and IP-10 were positively correlated variables while the interval and MCP-1 were negatively correlated.ConclusionsPost-transplant urinary TG2 is a potent biomarker for tubulointerstitial inflammation and fibrosis. In addition to TG2, several candidates such as SDC4, MCP-1 and IP-10 are involved in tubulointerstitial inflammation.This research was performed with the grant support from Ministry of Education (2014R1A1A2A16055405) and Ministry of Science & ICT (2016M3A9E8941330) in Republic of Korea.

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