Urinary TIMP-2 and IGFBP7 for the prediction of acute kidney injury following cardiac surgery

Acute kidney injury (AKI) is a global health concern associated with increased morbidity and mortality [1‐3]. Patients undergoing cardiac surgery, especially with cardiopulmonary bypass, are at high risk for AKI. A recent meta-analysis estimated the global incidence of AKI following cardiac surgery to be approximately 22% [4]. Development of AKI following cardiac surgery increases hospital and ICU length of stage, short and long term mortality, and risk of long-term renal dysfunction [4‐6].

Despite the adverse consequences associated with AKI, missed or delayed diagnosis of AKI is common [7, 8]. Early diagnosis of AKI requires close monitoring of changes in serum creatinine and urine output, which may not be practical for all patients. Additionally, changes in these markers of renal function often lag injury [9]. Risk assessment for AKI is recommended by clinical practice guidelines to facilitate early detection of AKI and potentially prevent AKI in some cases [10]. Yet, few tools for early risk assessment are available beyond clinical evaluation.

Recently, a biomarker-based test for AKI risk assessment has become available for clinical use in Europe and the United States [11]. The test measures two urinary proteins involved in cell-cycle arrest: tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7). These urinary cell cycle arrest markers are believed to be indicators of renal tubule cell stress involved in the earliest phases of acute kidney injury [12]. The combination of these biomarkers ([TIMP-2]•[IGFBP7]) has been shown to be predictive of AKI in large diverse cohorts of critically ill patients in the Sapphire, Opal and Topaz studies [12‐14].

Studies in Germany have investigated the performance of urinary [TIMP-2]•[IGFBP7] in cardiac surgery patients [15‐18]. Post-operative urinary [TIMP-2]•[IGFBP7] was predictive of AKI with an area under the receiver operating characteristic (ROC) curve as high as 0.9. Moreover, urinary [TIMP-2]•[IGFBP7] outperformed serum creatinine and urinary NGAL. In a subgroup analysis of the Sapphire and Topaz studies (conducted in Europe and the United States), urinary [TIMP-2]•[IGFBP7] predicted AKI with an AUC of 0.84 in patients who had cardiac surgery [19]. However, to our knowledge, urinary [TIMP-2]•[IGFBP7] has not been investigated in hospitals in Asia. In our study, we investigated the use of [TIMP-2]•[IGFBP7] for prediction of AKI in a cohort of adults undergoing cardiac surgery in China.

Our study is the first known investigation of the performance of [TIMP-2]•[IGFBP7] in a Chinese population of patients undergoing cardiac surgery. The cell cycle arrest biomarkers TIMP-2 and IGFBP7 are released in the earliest stages of injury by renal tubule cells that have become stressed from kidney exposures that can lead to AKI [12, 20]. Elevated urinary [TIMP-2]•[IGFBP7] levels thus indicate renal tubule cell stress that precedes AKI, and this is believed to be the reason that [TIMP-2]•[IGFBP7] levels correspond to risk for AKI [12, 14, 20, 21]. Major surgery including cardiac surgery, complications such as hypotension or infection following surgery, and nephrotoxic drugs commonly prescribed in surgical patients are potential kidney exposures that can stress renal tubule cells and thus cause AKI [10], making cardiac surgery patients an appropriate at-risk population for risk stratification with the [TIMP-2]•[IGFBP7] test.

We chose to evaluate the [TIMP-2]•[IGFBP7] test 4 h after ICU admission for several reasons. First, this time is similar to that evaluated in prior studies of non-Asian cardiac surgery patients [15, 18]. Second, patients should be starting to stabilize at this time, and it is therefore a good time to evaluate which patients may be experiencing increased renal tubule cell stress, putting them at risk for developing a serious post-operative AKI complication. Such patients are good candidates to receive preventive measures that have been outlined in the KDIGO guideline [10] and elsewhere [20] for high-risk patients.

In our study, [TIMP-2]•[IGFBP7] measured in urine collected 4 h after ICU admission was predictive of both any stage of AKI and stage 2–3 AKI. The sensitivity at the previously validated 0.3 cutoff was 75% for any AKI and 100% for stage 2–3 AKI, and the specificity at the previously validated 2.0 cutoff was 100% for any AKI and 96% for stage 2–3 AKI.

Multiple studies in Germany have investigated urinary [TIMP-2]•[IGFBP7] for prediction of AKI following cardiac surgery in adults [15, 17, 18]. These studies either specifically enrolled patients undergoing coronary artery bypass graft (CABG) surgery or enrolled cardiac surgery patients deemed to be high risk for AKI as defined by a Cleveland Clinic Foundation Score [22] ≥ 6. Unlike in these studies, we did not restrict our enrolled cohort by type of cardiac surgery or pre-surgery risk. Yet, our results are strikingly similar to those of these other studies. In the CABG study, for which the endpoint was stage 2–3 AKI, the AUC (95% CI) of urinary [TIMP-2]•[IGFBP7] at 4 h after surgery was 0.86 (0.72–1.00) as compared to 0.83 (0.69–0.96) at 4 h after ICU admission for the same endpoint in our study.

Addition of urinary [TIMP-2]•[IGFBP7] to a clinical risk model significantly improved model performance, demonstrating that [TIMP-2]•[IGFBP7] provides critical information about AKI risk that is not obtainable from clinical risk factors alone. Our study also found that preoperative serum creatinine was significantly higher in AKI group and it is a risk factor for the prediction of AKI after cardiac surgery similar to previous studies in which subjects with higher serum creatinine developed acute or chronic kidney dysfunction after surgery [22, 23]. Of course the combination of creatinine and biomarkers is the future of AKI prediction. It is important to note that clinical risk prediction models derived from small data sets such as ours are “over-trained” and their performance thus overestimated. Therefore, although the AUCs for our clinical models (0.83 for clinical variables alone and 0.94 for clinical variables plus [TIMP-2]•[IGFBP7]) are high, clinicians should not rely on our clinical model for risk assessment. Nevertheless, the results are important because they show that [TIMP-2]•[IGFBP7] provides valuable information about AKI risk even when clinical risk factors are considered.

In our study, average urinary [TIMP-2]•[IGFBP7] levels appeared to be on the rise at the time of ICU admission and reached maximum levels 2–6 h after ICU admission in patients who developed AKI. In contrast, in patients who did not develop AKI, average urinary [TIMP-2]•[IGFBP7] levels appeared to slowly decrease after ICU admission. Most prior studies of cardiac surgery patients [15, 17, 18] have shown significant elevations of [TIMP-2]•[IGFBP7] 4 h after the end of cardiopulmonary bypass (CPB) in patients who developed AKI, similar to the measurement time in our study. However, two prior studies [17, 24] have shown maximum predictive ability the morning after surgery. Although it is usually assumed that the earliest injury in cardiac surgery associated AKI occurs during the surgery, it is possible in some patients that significant post-operative kidney exposures such as episodes of hypotension, developing infections or nephrotoxic drugs cause kidney stress and AKI to start developing during the post-operative period. This may explain why the maximum predictive ability of [TIMP-2]•[IGFBP7] occurred early after surgery in some studies (including ours) and later in other studies. This hypothesis requires additional investigation, but suggests that repeated testing might be appropriate in cases in which significant post-operative exposures might exist. Indeed, one study [15] found that use of three measurements (4, 12 and 24 h after CPB) had greater predictive value (AUC = 0.90) than a single measurement 4 h after CBP (AUC = 0.81).

Although all patients experiencing significant kidney exposures are at increased risk of AKI, only a small fraction (about 10% in our study) will develop the severest forms of AKI (stage 2–3). The [TIMP-2]•[IGFBP7] test provides a quantitative indication of risk (renal tubule cell stress) for each particular patient, with higher test values indicating higher stress and thus higher risk. Two well-established cutoffs, one at 0.3 that is highly sensitive and one at 2.0 that is highly specific provide risk stratification that allows the physician to apply preventative measures such as enhanced hemodynamic monitoring and modified drug dosing commensurate with the risk level [20]. Our study for the first time verifies these cutoffs in a Chinese population. Therefore, we can expect that protocols developed in other countries for using the test to help manage patients at risk for AKI will be relevant to patients undergoing cardiac surgery in China.

The prediction performance of urine [TIMP-2]•[IGFBP7] in a Chinese cardiac surgery population is good for all of the AKI patients, not just stage 2–3 AKI. It is even better than that reported previously in non-Asian populations.