Noninvasive detection of acute renal allograft rejection by measurement of soluble Tim-3 in urine

摘要

The purpose of the present study was to assess whether urinary soluble T-cell immunoglobulin and mucin domain-containing protein 3 (sTim-3) could be adopted as a novel non-invasive biomarker for acute rejection (AR) following renal transplantation. A total of 156 patients were enrolled between January 2006 and December 2009, comprising 49 patients with biopsy-proven AR, 58 patients with stable grafts and no abnormal histological findings (NO-AR), 10 patients with subclinical rejection (SCR) in protocol biopsies, 10 patients with acute tubular necrosis (ATN) and 29 patients with chronic allograft nephropathy (CAN). Additionally, urine samples from 40 healthy individuals were also collected as controls. The urinary concentration of sTim-3 was determined by ELISA in the 156 renal allograft recipients and 40 healthy controls. Compared with NO-AR and healthy controls, patients with AR excreted urinary sTim-3 at a significantly higher level (4,356+/-440.4, 95% CI: 3,473-5,242 ng/mmol creatinine). Likewise, patients with ATN exhibited a significantly lower level of urinary sTim-3 (2,060+/-217, 95% CI: 1,679-2,680 ng/mmol creatinine) than patients with AR. The discriminatory value was measured by the area under the receiver operating characteristic curve (ROC), which had a value of 0.88 (95% CI: 0.809-0.951), demonstrating that sTim-3 was a suitable marker for the diagnosis of AR. At a cut-off point of 1,836 ng/mmol creatinine, the sensitivity was 89.8% and the specificity was 82.8% (P< 0.001). Amongst the patients with AR, patients with steroid-resistant acute rejection (n=31) had significantly higher urinary sTim-3 concentrations than patients with steroid-sensitive acute rejection (n=18; 5,548+/-613.5, 95% CI: 4,287-6,809 ng/mmol creatinine vs. 2,653+/-391.7, 95% CI: 1,830-3,476 ng/mmol creatinine; P=0.0002). No significant difference in urinary sTim-3 was found between patients with AR and CAN (3,920+/-543.5, 95% CI: 3,473-5,242 ng/mmol creatinine), and a significantly higher level of Tim-3 was excreted by patients with CAN compared with patients with NO-AR and healthy controls (P< 0.001). The present study, therefore, suggests that urinary sTim-3 may be used as a valuable non-invasive biomarker for the detection of AR. In addition, urinary sTim-3 levels were demonstrated to be associated with the response to anti-rejection therapy. The results of the present study may provide support future research into the screening of novel immune suppressants.