Elevated Urinary IL-18 Levels at the Time of ICU Admission Predict Adverse Clinical Outcomes

Discussion

Although the critically ill are at high risk for developing AKI (23,24), the timing and origin of kidney injury in this setting is heterogeneous, which challenges biologic markers aiming to provide early diagnostic and prognostic information. uIL-18 measured within 48 h of AKI development did not alone reliably predict nor add to the ability of uNGAL to predict the subsequent development of AKI using changes in SCr. These results do not support the routine assessment of uIL-18 for this purpose in a mixed critically ill population. However, uIL-18 levels were independently associated with the risk of adverse clinical outcomes within 28 days and could provide important prognostic information.

uIL-18 has been studied in several settings to detect AKI and predict subsequent renal outcomes. While results have varied, early detection of AKI has proven more robust in settings of discrete ischemia-reperfusion injury such as cardiopulmonary bypass in children and after kidney transplantation (11,12,25). In contrast, prediction of AKI among co-morbid adults undergoing cardiopulmonary bypass (6,26), critically ill patients including children requiring mechanical ventilation (13), or patients with ARDS has been less robust. This observation may, in part, be explained by the association of the marker with inflammation (27). Kidney ischemia-reperfusion results in a localized inflammatory-mediated injury with important contributions from the pleiotropic effects of IL-18 on both innate and cognate immunity (28). However, in addition to renal tubular cells, expression has been observed within other cell lineages including macrophages, lymphocytes, intestinal epithelia, and fibroblasts raising the possibility of systemic production confounding the association between uIL-18 and AKI during acute illness or inflammatory conditions (27). Nevertheless, the amount of overlap observed in the distribution of uIL-18 levels between those who developed AKI and those who did not develop AKI may therefore limit its use for predicting subsequent rises in SCr in these settings.

Similarly, a relative lack of systemic production may also partially explain the apparent improved performance of this biomarker in the setting of relatively isolated ischemia-reperfusion injury in children (11), during transplantation of relatively “normal” kidneys (12), or in contrast nephropathy (29). Our examination of the interaction between uIL-18 and sepsis also suggested improved performance in nonseptic patients, though this did not reach statistical significance. As septic patients are at higher risk for developing AKI, it can be argued that a higher proportion were at risk for pre-existing AKI at the time of enrollment, which may have contributed to the observed lack of difference in uIL-18 levels within this group. However, our results are consistent with Washburn et al. (13), who recently demonstrated in a cohort of pediatric patients with established baseline kidney function requiring mechanical ventilation that a more robust association between uIL-18 and AKI development occurred only after the exclusion of septic patients. Whether using urine/plasma ratios of IL-18 in systemically ill patients would increase specificity for “kidney-specific” IL-18 production in AKI in such settings remains to be determined. Nevertheless, these observations highlight the challenges of validating candidate markers in settings such as critical illness where AKI phenotyping is more difficult to accomplish relative to those where the injury type is known or otherwise similar to the model in which the biomarker was initially characterized (e.g., ischemia-reperfusion).

Similar to the investigation of biomarkers for the diagnosis of other complex acute diseases such as ALI/ARDS (30), a single biomarker is unlikely to be sensitive to the multiple pathways (e.g., inflammatory, ischemic, nephrotoxic, coagulation cascade abnormalities, oxidative stress) involved in the generation of AKI in a broadly-selected patient population with acute illness. Consequently, we investigated the use of multiple markers to improve our ability to detect AKI early by examining the relative contribution of uIL-18 to uNGAL. When assessed by ROC curve, uIL-18 did not add substantially to the early discriminative or predictive power of uNGAL for the detection of AKI. In addition to the modest performance of uIL-18 alone, another reason may be the high degree of colinearity observed between these biomarkers. As a result, the incremental value of adding uIL-18 in AKI detection may be marginal because it is measuring information already captured by uNGAL. The failure of correlated biomarkers to provide substantial independent value has been illustrated in other disease states and underscores the importance of panels including “orthogonal” biomarkers that target distinct pathophysiologic mechanisms (31).

As SCr is commonly used but an imperfect gold standard to which novel candidate markers are being compared, extending analyses to the prediction of less ambiguous clinical endpoints remains an important area to be explored for all putative AKI biomarkers. Several mortality prediction models have been previously developed in AKI patients (32–35), although variations in case-mix, clinical data collection, and care processes between settings have often led to a lack of external validity (36). The use of more specific biologic indicators of renal injury may enhance the performance of these models in predicting renal-relevant outcomes between patient populations. Recent studies have suggested that uIL-18 may provide substantial prognostic information in different settings. Our results indicate that uIL-18 independently predicts the composite outcome of death or dialysis in critically ill patients even after adjustment for known clinical predictors. This finding is likely largely driven by death, which was the predominant event in this composite outcome, suggesting utility for uIL-18 as a marker of prognosis in critical illness. Sensitivity analyses in the small subgroup of patients requiring dialysis suggest that uNGAL may be a more specific predictor of AKI severity than uIL-18, a hypothesis further supported by its relatively superior performance for AKI prediction. Furthermore, we have previously demonstrated that uNGAL independently predicts the need for dialysis when death was treated as a competing risk (14). These findings need to be validated in larger cohorts and in those with AKI captured at the earliest stages of AKI diagnosis.

While a major strength of this study is the use of a large and diverse ICU-population, it remains a single-center study in need of external validation. Additional limitations include the use of a single time-point assessment of uIL-18 rather than serial measurements. Previous studies have demonstrated a transient peak in uIL-18 levels after a discrete ischemic event and thus, multiple urine samples may have increased the likelihood of observing a difference. However, it can be argued that for a biomarker to be useful in a setting where the type and timing of contributing insults is more variable, sustained expression following injury will be a requisite feature. Urine was also collected from the proximal urinary catheter reservoir and may have been subject to degradation after remaining at room temperature for up to an hour. However, data from our laboratory (CR Parikh, personal communication) suggest that urinary IL-18 is stable in a variety of storage and shipping conditions. Finally, while the higher enrollment SCr values in patients subsequently developing AKI versus controls were at least partially due to the higher underlying CKD rate in this group (27% versus 9%, P < 0.001), some subjects may have already developed AKI at the time of enrollment, thereby limiting the prediction of de novo injury. However, sensitivity analyses using more severe injury criteria (i.e., AKIN stages II and III) or restricting examination to those with preserved and similar eGFR between AKI and non-AKI groups at enrollment only modestly improved uIL-18 performance for early detection. Furthermore, these results are consistent with two recently published studies where baseline function was largely known (13,26) as well as a more selective case-control analysis by Parikh et al. in ARDS indicating only modest utility in this regard (6).

In summary, we found that uIL-18 measured within 24 hours of ICU admission modestly predicted subsequent AKI development in a heterogeneous critically ill adult population, although not independently of previously measured uNGAL levels. uIL-18 was independently associated with adverse clinical outcomes and may have a role in defining further risk-stratification in this patient population. As AKI remains a complex disease unlikely to be described completely by any single marker, the utility of uIL-18 in determining the prognosis of patients early in course of AKI and in combination with other biomarkers reflecting separate biologic pathways remains an important area for further study.