Analysis of urinary C–C motif chemokine ligand 14 (CCL14) and first-generation urinary biomarkers for predicting renal recovery from acute kidney injury: a prospective exploratory study

(2023) 11:11 Qian et al. Journal of Intensive Care https://doi.org/10.1186/s40560-023-00659-2 Journal of Intensive Care Open Access RESEARCH Analysis of urinary C–C motif chemokine ligand 14 (CCL14) and first‑generation urinary biomarkers for predicting renal recovery from acute kidney injury: a prospective exploratory study Ben‑Shu Qian1, Hui‑Miao Jia1, Yi‑Bing Weng2, Xin‑Cheng Li1, Chao‑Dong Chen1, Fang‑Xing Guo1, Yu‑Zhen Han1, Li‑Feng Huang1, Yue Zheng1* and Wen‑Xiong Li1*    Abstract Background Acute kidney injury (AKI) is a frequent syndrome in the intensive care unit (ICU). AKI patients with kidney function recovery have better short-term and long-term prognoses compared with those with non-recovery. Numerous studies focus on biomarkers to distinguish them. To better understand the predictive performance of urinary biomarkers of renal recovery in patients with AKI, we evaluated C–C motif chemokine ligand 14 (CCL14) and two first-generation biomarkers (cell cycle arrest biomarkers and neutrophil gelatinase-associated lipocalin) in two ICU settings. Methods We performed a prospective study to analyze urinary biomarkers for predicting renal recovery from AKI. Patients who developed AKI after ICU admission were enrolled and urinary biomarkers including tissue inhibitor of metalloproteinase-2 (TIMP-2), insulin-like growth factor-binding protein 7 (IGFBP7), CCL14, and neutrophil gelatinaseassociated lipocalin (NGAL) were detected on the day of AKI diagnosis. The primary endpoint was non-recovery from AKI within 7 days. The individual discriminative ability of CCL14, [TIMP-2] × [IGFBP7] and NGAL to predict renal nonrecovery were evaluated by the area under receiver operating characteristics curve (AUC). Results Of 164 AKI patients, 64 (39.0%) failed to recover from AKI onset. CCL14 showed a fair prediction ability for renal non-recovery with an AUC of 0.71 (95% CI 0.63–0.77, p < 0.001). [TIMP-2] × [IGFBP7] showed the best prediction for renal non-recovery with an AUC of 0.78 (95% CI 0.71–0.84, p < 0.001). However, NGAL had no use in predicting nonrecovery with an AUC of 0.53 (95% CI 0.45–0.60, p = 0.562). A two-parameter model (non-renal SOFA score and AKI stage) predicted renal non-recovery with an AUC of 0.77 (95% CI 0.77–0.83, p = 0.004). When [TIMP-2] × [IGFBP7] was combined with the clinical factors, the AUC was significantly improved to 0.82 (95% CI 0.74–0.87, p = 0.049). Conclusions Urinary CCL14 and [TIMP-2] × [IGFBP7] were fair predictors of renal non-recovery from AKI. Combing urinary [TIMP-2] × [IGFBP7] with a clinical model consisting of non-renal SOFA score and AKI stage enhanced the *Correspondence: Yue Zheng Wen‑Xiong Li Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Qian et al. Journal of Intensive Care (2023) 11:11 Page 2 of 11 predictive power for renal non-recovery. Urinary CCL14 showed no significant advantage in predicting renal nonrecovery compared to [TIMP-2] × [IGFBP7]. Keywords TIMP-2, IGFBP7, CCL14, NGAL, Acute kidney injury, Renal recovery, Prognosis Background Acute kidney injury (AKI) is a frequent complication of critical illness, resulting in increased short-term and long-term mortality, significant healthcare costs, and higher risks of chronic kidney disease (CKD) and end-stage renal disease [1–4]. Moreover, many studies indicated that the pattern of AKI recovery affected the prognosis and outcomes [5, 6]. Preventing the nonrecovery of renal function should become the therapeutic target of AKI. Therefore, an early biomarker for AKI recovery is needed. Among AKI biomarkers, urine neutrophil gelatinaseassociated lipocalin (NGAL) and the recent combination of urine tissue inhibitor of metalloproteinases-2 and insulin-like growth factor-binding protein 7 ([TIMP-2] × [IGFBP7]) are two first-generation biomarkers that can be used to detect kidney damage and predict AKI before serum creatinine [7–9]. However, only a few studies have assessed the performance of [TIMP-2]*[IGFBP7] as prognosis markers for nonrecovery within 48 h or at discharge in patients following cardiac surgery or patients at surgical ICU [10, 11]. Meanwhile, urine C–C motif chemokine ligand 14 (CCL14) was recently reported to have a good even excellent performance in predicting persistent KDIGO stage 3 AKI, with areas under the receiver operating characteristic curves (AUCs) from 0.81 to 0.93 [12–14]. CCL14 is a kind of chemokine released from tubular epithelial cells after injury. CCL14 binds with the C–C chemokine receptors type 1, C–C chemokine receptors type 5, and C–C chemokine receptors type 3 on monocytes and T cells [12, 15]. Renal monocyte recruitment and activation affected the mechanisms of inflammation and fibrosis in kidney tissue damage [16]. Previous work has shown that CCL14 is one of inflammatory markers mediating the risk of progression to end-stage renal disease in diabetes [17]. Hence, CCL14 as an independent predictor of renal recovery from AKI is biologically plausible. However, no study has explored the predictive role of urine CCL14 for renal non-recovery from AKI. Now, we for the first time report an exploratory comparison of urine CCL14 and first-generation urinary biomarkers in predicting non-recovery in critically ill patients with AKI. Methods Study design and ethics The study is a prospective exploratory study designed to assess the predictive value of urinary biomarkers for renal non-recovery from AKI. The study conformed to the provisions of the Declaration of Helsinki. Ethical approval was obtained from the Human Ethics Committee of Beijing Chao-yang Hospital, Capital Medical University (ethics number 2018-117). Written informed consent was obtained from patients or their delegates. Study design and manuscript preparation followed the Standards for Reporting Diagnostic Accuracy (STARD) statement [18]. Participants The present study was perf (...truncated)