AKI remains a common and serious clinical syndrome in critically ill patients. It is well recognized an episode of AKI may have persistent impairment in renal function, with the potential to progress to CKD, use of RRT and end-stage kidney disease (ESKD) with dialysis dependence, which is in turn strongly associated with increased short- and long-term mortality [3, 4]. Therefore, renal recovery after an episode of AKI is necessary. Urinary [TIMP-2]*[IGFBP7] was identified to be used for risk stratification in high-risk patients for AKI [8]. The current study evaluated the ability of urinary [TIMP-2]*[IGFBP7] for predicting failure to recover after AKI development. The main findings were: 1) all of urinary [TIMP-2]*[IGFBP7], TIMP-2 and IGFBP7 on day 0 showed useful values for predict non-recovery from AKI, but urinary [TIMP-2]*[IGFBP7] was superior to TIMP-2 and IGFBP7 alone; 2) urinary [TIMP-2]*[IGFBP7], TIMP-2 and IGFBP7 on day 1 performed poorly for predicting AKI recovery; 3) urinary [TIMP-2]*[IGFBP7] was validated to be able to help clinicians recognize the patients who failed to recover early at the time diagnosing AKI, with the sensitivity and specificity of 82.3 % and 76.9 %, respectively; 4) when adding urinary [TIMP-2]*[IGFBP7] on day 0 to clinical risk prediction model 1, the predictive value was greatly improved to 0.852. The utility of ([TIMP-2]*[IGFBP7] day 0) - clinical risk prediction model 1 was confirmed in the diverse critically ill patients, with the sensitivity and specificity of 88.8 % and 92.6 %, respectively. 5) non-recovery patients had worse short-term prognosis compared with recovery patients.
Two novel biomarkers, urine TIMP-2 and IGFBP7, are inducers of the G1 cell cycle arrest found in renal tubular cells. Study by Kashani K, et al [8] firstly identified their ability to predict the development of KDIGO stage 2 or 3 AKI within 12 hours in high-risk patients. Many other studies subsequently confirmed the effectively predictive value for detection of AKI. And our meta-analysis showed the same conclusion [19]. AKI is associated with the mechanisms of inflammation, oxidative stress, and apoptosis in cellular and molecular pathways [20, 21], and AKI may occur following ischemic or toxic insults. TIMP-2 and IGFBP7 participate in these mechanisms and reflect early damage of the kidney [22]. Most studies evaluated the prediction for AKI development, only few estimated the prognostic value in AKI patients.
In study by Pilarczyk K, et al [18] patients with AKI 2 or 3 showed significantly higher values for [TIMP-2]*[IGFBP7] than patients with AKI 0–1. And another study showed higher median values of [TIMP-2]*[IGFBP7] were associated with an increased degree of renal injury, and patients requiring RRT had the highest median [TIMP-2]*[IGFBP7] test results, which illustrated that the degree of early cellular damage was associated with the severity of the functional impairment [23]. The study further assessed the value of [TIMP-2]*[IGFBP7] for RRT and 28-day death, and the result showed the AUC for use of RRT was 0.83 and for 28-day mortality was 0.77 [23]. Study by Dewitte A, et al [24] enrolled 57 consecutive patients presenting with AKI within the first 24 hours after admission. They found urinary [TIMP-2]*[IGFBP7] had a useful prediction for renal recovery within 48 hours after AKI. Recently, Cho WY, et al [7] conducted a single-center study prospectively enrolling 124 patients diagnosed with AKI. The results showed urine TIMP-2/IGFBP7 could serve as a biomarker for predicting renal recovery. We enlarged population including consecutive AKI patients in two Chinese ICUs and conducted two cohorts to derivate and validate the utility of urinary [TIMP-2]*[IGFBP7] for predicting patients who failed to recover within 7 days. Urinary [TIMP-2]*[IGFBP7] on day 0 showed a useful predictive value for non-recovery. When it was added to clinical risk prediction model 1 consisting of AKI diagnosed by UO criteria, AKI stage 2–3 and nonrenal SOFA score, the performance for predicting nonrecovery improved to be good.
In previous study, many risk factors could contribute to non-recovery after AKI, such as age,
comorbidity, more severe AKI, The severity of extrarenal organ dysfunction and so on [5, 13, 24]. Our study did not show the difference of age and comorbidity between patients with and without recovery, but more severe AKI and higher nonrenal SOFA score were observed in non-recovery patients.
Notably, the variable of AKI diagnosed by UO criteria played an important role in the prediction model for non-recovery of AKI. In this study, 129 (34.0 %) patients showed oliguria (reaching UO criteria for AKI diagnosis) and were diagnosed AKI by UO. Oliguria was of the oldest “biomarkers” of AKI, which may occur following a normal physiological response or reflecting an underlying pathological process [25]. Many different pathophysiological pathways may cause oliguria, such as the neuro-hormonal pathway, absolute (hypovolemia), and relative (hemodynamic perturbations) reductions in effective blood volume [26]. Moreover, renal blood flow (RBF) may be preserved or even be increased in sepsis-associated AKI. In this situation, abnormal distribution of intra-renal blood flow may be more influential than global RBF [27]. Besides circulatory changes, immunologic and inflammatory mechanisms may participate in renal endothelial injury and microvascular dysfunction, which may lead to oliguria [27]. In study by Federspiel CK, et al [28], a UO < 0.5 ml/kg/h was associated with lower rates of resolving AKI (Hazard Ratio 0.31; 95% CI 0.20–0.47). This was also found in another study that enrolled 264 patients with severe cardiac surgery-associated AKI (CS-AKI) requiring RRT. The result showed significantly fewer patients with oliguria recovered renal function [29]. Therefore, including the clinical factor of AKI diagnosed by UO criteria for prediction of renal recovery was reasonable. In general, urinary [TIMP-2]*[IGFBP7] combining with the easily available clinical factors of AKI diagnosed by UO criteria, AKI stage 2–3 and nonrenal SOFA score performed well to distinguish the patients who would fail to recover from AKI at an early time, which would be feasible and helpful in clinic.
Despite several meaningful findings, our study has several limitations. We did not distinguish AKI causes before detecting urinary [TIMP-2]*[IGFBP7] and predicting non-recovery in this study. AKI with different causes has different mechanisms for renal injury. It would be more accurate if the predictive value of urinary [TIMP-2]*[IGFBP7] was tested in AKI following the same mechanism of development. Furthermore, we assessed the short-term prognosis, but did not explore long-term prognosis. It would also be helpful for clinic to explore the association between urinary [TIMP-2]*[IGFBP7] with long-term prognosis of AKI.