Clinical use of [TIMP-2]•[IGFBP7] biomarker testing to assess risk of acute kidney injury in critical care: guidance from an expert panel

The expert panel agreed on key candidates for biomarker testing based on their direct experience, with the caveat that this list might not be exhaustive. Proposed target populations are specified in rank order in Table 2. Postoperative cardiac or major vascular surgery was the most strongly supported followed by shock/hemodynamically unstable patients regardless of the cause and sepsis (with or without shock). Further down on the list, but still with strong support, were postoperative non-cardiovascular major surgery, cardiac arrest/extracorporeal membrane oxygenation, and patients with persistent oliguria after resuscitation. Additional populations suggested by the group are shown in Table 2.

In general, [TIMP-2]•[IGFBP7] testing has been ordered for patients when the kidney is under threat for any reason—when something creates a toxic event in the kidney, when there is a question of secondary nephrotoxicity, or at any time a significant change in status has occurred that might result in kidney injury. Most users found that [TIMP-2]•[IGFBP7] testing is particularly useful within the first 72 h of ICU admission. Therefore, [TIMP-2]•[IGFBP7] testing is most often being ordered in patients at risk for AKI, including those who are hemodynamically unstable, in respiratory failure, or exhibiting Stage 1 AKI (Fig. 3). Specific clinical scenarios (e.g., cardiac surgery, sepsis) were identified where appropriate testing might differ.

The FDA has approved the cutoff threshold of > 0.3, which ensures that > 92% of all stages 2/3 AKI events over the following 12 h are predicted [3‐5]. A low risk for AKI is defined as a test result ≤ 0.3. Moderate risk is defined as having a result of > 0.3 and ≤ 2.0; high risk is associated with a result > 2.0. Thus, as test results increase, so does the level of kidney stress and the risk of AKI. If the result is > 0.3, there is a “risk” and any potential damage needs to be averted [6, 7]. All of the protocols reviewed used the 0.3 cutoff to separate low from moderate-high risk. A few protocols also specified actions related to the 2.0 cutoff, which generally related to increasing intensity of actions triggered by the 0.3 cutoff (e.g., more frequent monitoring of serum creatinine).

Meeting participants discussed and came to consensus regarding recommended actions (both positive and negative—i.e., things to do as well as things not to do) when the [TIMP-2]•[IGFBP7] test is positive. A complete list of rank-ordered actions after a positive or negative [TIMP-2]•[IGFBP7] test is provided in Table 3. Actions chosen by the group were often found in the KDIGO guideline, as well as in more recent recommendations for prevention of AKI [1, 8]. The highest priority actions fell into two domains, management of nephrotoxins and fluids. Top priority was given to “discontinue all nonessential potential nephrotoxins (e.g., NSAIDs [nonsteroidal anti-inflammatory drugs])”; avoiding vancomycin (or dose adjusting) especially combinations of vancomycin with aminoglycosides or piperacillin tazobactam, and discontinuing angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs) were ranked second and fourth. Goal-directed fluid management (e.g., bedside ultrasound and functional hemodynamic monitoring) was ranked third, and retaining invasive hemodynamic monitoring was ranked seventh. A negative [TIMP-2]•[IGFBP7] test result was seen as just as informative and actionable as a positive test, because low-risk patients may benefit from many of the treatments best avoided in high-risk patients (e.g., NSAIDs). There was strong consensus that patients with a negative test were good candidates for “fast-track” protocols and rapid de-escalation of monitoring (e.g., removal of arterial lines, indwelling urinary catheters). Of note, five authors expressed that they had originally doubted that the information provided by the test would change clinical practice. Only after using the test in several patients were they convinced.

For cardiac surgery patients, most measured [TIMP-2]•[IGFBP7] within 4 h post-surgery. Performing the test at a few different postoperative timepoints is helpful to identify the most appropriate testing time for a particular program given inherent differences in care across institutions. Studies have reported a variety of results in this regard. In several studies [14‐16], [TIMP-2]•[IGFBP7] detected elevations at 4 h; in another study, elevations were not detected until the day after surgery [17]. A recent study [18], with the most granular time-course published to date, shows bimodal elevations of [TIMP-2]•[IGFBP7] with the first peak occurring intraoperatively and the second 6 h after ICU admission in patients who developed stages 2/3 AKI. The authors postulate that the first peak indicates kidney stress caused during the surgery, while the second peak may indicate kidney stress caused during early postoperative care. Measurement at both times resulted in the best predictive ability, as would be expected for two independent episodes of stress.

For patients in shock, [TIMP-2]•[IGFBP7] testing is ordered as early as possible during patient evaluation. Interestingly, there is emerging evidence in septic shock that the post-resuscitation test results may be most predictive [19]. However, it also has been noted that when test results improve (levels decrease) with resuscitation, outcomes are better. There is therefore the hypothesis that [TIMP-2]•[IGFBP7] testing might ultimately be proven useful as a tool to monitor resuscitation efficacy. Establishing clinical utility for this indication will require studies that compare a biomarker-guided approach to a standard approach. Such studies are currently lacking.

Management of potential nephrotoxic medications was the top priority in patients with positive test results. The clinical panel participants agreed that all nonessential nephrotoxic medications should be avoided. The combination of vancomycin and piperacillin-tazobactam, in particular, has been noted to significantly increase risk for AKI [20]. If vancomycin (or an aminoglycoside) is used, it should be dosed strictly by levels, and its duration of use should be as limited as possible. If a pharmacist is not already part of the critical care team, consultation may be appropriate. Likewise, NSAIDs and ACE inhibitors/ARBs should be avoided in the early postoperative period.

A second category of high-priority actions involved fluid management. Participants noted that patients with a positive test result are at risk for fluid overload but also might be volume depleted. There was strong consensus therefore that a “goal-directed” approach to fluid/diuretic management was essential. Two examples of such an approach were published, one in 2017 in cardiac surgery patients [7] and one in 2018 in non-cardiac surgery patients [11]. In the first study, biomarker-positive patients were randomized to receive a care bundle that included a hemodynamic management algorithm based on mean arterial pressure and stroke volume variation. AKI was significantly reduced with the intervention compared to controls (55.1 vs. 71.7%; ARR 16.6% (95% CI 5.5–27.9%); p = 0.004). Rates of moderate to severe AKI were also significantly reduced by the intervention compared to controls (41/138 (29.7%) vs 62/138 (44.9%); p = 0.009; OR, 0.518 (95% CI, 0.316–0.851); ARR, 15.2% (95% CI, 4.0–26.5%)). The intervention resulted in significantly improved hemodynamics (p < 0.05) as well as less hyperglycemia (p < 0.001) and use of ACEi/ARBs (p < 0.001) compared to controls. The total administered volume was not different between the two groups, but the distribution of fluid was different, with patients in the intervention group receiving significantly less volume during the last 3 h of the intervention period (p = 0.024). However, there were no differences in rates of renal replacement therapy between intervention and control either within 72 h (7.2% vs. 5.1%, p = 0.45), during hospitalization (10.1% vs. 6.5%, p = 0.28), or at 30 days (3.1% vs. 2.3%. p = 0.72). Neither were there differences in mortality or persistent renal dysfunction at 30, 60, or 90 days.

In the second study [11], a similar care bundle including early optimization of fluid status and maintenance of perfusion pressure, was applied to non-cardiac major surgery patients after testing positive for the biomarker. Overall AKI rates were not statistically different between groups (19/60 (31.7%) in the intervention group vs. 29/61 (47.5%) in the standard care group, p = 0.076). However, rates of moderate and severe AKI, a secondary endpoint, were reduced with the intervention (4/60 (6.7%) vs. 12/61 (19.7%), p = 0.04), as were lengths of ICU stay (median difference 1 day, p = 0.035) and hospital stay (median difference 5 days, p = 0.04). There were no significant differences regarding renal replacement therapy, in-hospital mortality, or major kidney events at hospital discharge. Interestingly, 48-h cumulative balance was not statistically different (2567 ml (1617–3706) vs. 3207 ml (2015–4486), p = 0.085) but favored lower volumes in the intervention group. This last finding brings to attention the fact that “optimization” of fluid status for AKI patients does not mean “give fluid” and frequently results in less fluid.

As with any new technology, there are potential barriers to adoption. The value proposition for new technology involves both potential benefits as well as costs. Although a cost-effectiveness analysis for the test is beyond the scope of this report, it is notable that AKI is extremely expensive—estimates put the cost at more than 19,000 USD [21] to as much as 39,000 USD per case [22]. By comparison, the test itself retails for approximately 100 USD per determination. However, the test will not be useful in all patients, and protocols should define appropriate lines of communication to ensure that the [TIMP-2]•[IGFBP7] test is ordered for the appropriate patients. Given that [TIMP-2]•[IGFBP7] provides an early warning of kidney stress, the test results are most valuable when reported promptly. Therefore, the [TIMP-2]•[IGFBP7] should be ordered as a “stat” (i.e., as soon as possible) test so that results are available as quickly as possible. Most participants reported a 1-h turn around by their clinical lab. By instituting an AKI biomarker protocol, hospitals have the opportunity to develop and test metrics that can enhance quality improvement initiatives.

As part of [TIMP-2]•[IGFBP7] test protocol integration, the inclusion of information technology and the electronic health record (EHR)/electronic medical record (EMR) system is imperative to ensure that test reporting is online, and the test is used consistently. The test may become a part of cardiopulmonary bypass protocols and can be added as an EHR order. It is helpful to provide sample protocols and data to demonstrate what is needed. If [TIMP-2]•[IGFBP7] testing is effectively integrated into these systems, it also may be beneficial to expand testing into other hospital systems and networks. For example, [TIMP-2]•[IGFBP7] testing could work well in other ICUs, for all patients admitted with shock, the emergency department, and/or trauma unit, as well as operating rooms.

Despite its brief history, dozens of studies have evaluated the diagnostic value of [TIMP-2]•[IGFBP7] for AKI, in various settings (e.g., cardiac surgery, ICU, emergency department/trauma), different patient populations (e.g., KDIGO criteria, elderly, high-risk surgeries), and measurement criteria (e.g., thresholds, sampling times). Detailed discussion of these studies is beyond the scope of this report, but several systematic reviews are available [23‐27]. Overall, [TIMP-2]•[IGFBP7] is accurate in identifying patients at risk for AKI. However, to our knowledge, only two studies, thus far, have attempted to evaluate whether use of the test alters the clinical course of AKI [7, 11]. Thus, future research is warranted to better understand how treatment protocols based on [TIMP-2]•[IGFBP7] results can improve outcomes.