Predictive and pathogenetic value of plasma biomarkers for acute kidney injury in patients with acute lung injury

Abstract

Objective: To identify biological and clinical predictors of acute kidney injury in subjects with acute lung injury.

Design: Secondary data analysis from a multicenter, randomized clinical trial.

Setting: Intensive care units in ten university medical centers.

Patients: A total of 876 patients enrolled in the first National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Clinical Network trial.

Interventions: Study subjects were randomized to receive a low tidal volume ventilation strategy and pharmacologic therapy with ketoconazole or lisofylline in a factorial design.

Measurements and main results: We tested the association of baseline levels of interleukin-6, interleukin-8, interleukin-10, von Willebrand factor, tumor necrosis factor-[alpha], type I and II soluble tumor necrosis factor receptors (sTNFR-I and -II), protein C, plasminogen activator inhibitor-1 (PAI-1), surfactant protein-A, surfactant protein-D, and intracellular adhesion molecule-1 with subsequent acute kidney injury. Of 876 study participants who did not have end-stage renal disease, 209 (24%) developed acute kidney injury, defined as a rise in serum creatinine of >50% from baseline over the first four study days. The 180-day mortality rate for subjects with acute kidney injury was 58%, compared with 28% in those without acute kidney injury (p < .001). Interleukin-6, sTNFR-I, sTNFR-II, and PAI-1 levels were independently associated with acute kidney injury after adjustment for demographics, interventions, and severity of illness. A combination of clinical and biological predictors had the best area under the receiver operating characteristic curve, and the contribution of sTNFR-I and PAI-1 to this model was highly significant (p = .0003).

Conclusions: Elevations in PAI-1, interleukin-6, and the sTNFRs in subjects with acute kidney injury suggest that disordered coagulation, inflammation, and neutrophil-endothelial interactions play important roles in the pathogenesis of acute kidney injury. The combination of these biological and clinical risk factors may have important and additive value in predictive models for acute kidney injury.

Figure 1

Box-plot summaries of plasminogen activator inhibitor-1 (PAI-1), soluble tumor necrosis factor receptors (sTNFR-I and -II), and interleukin-6 (IL-6) levels in those with and without acute kidney injury (AKI). The horizontal line represents the median, box encompasses the 25th through 75th percentiles, and whiskers encompass the 10th through 90th percentiles. In all four cases, the p value for the Wilcoxon’s rank-sum test comparing biomarker levels in those with and without AKI was <.0001.

Figure 2

Receiver operating characteristic (ROC) curves for predictive models for acute kidney injury. Left, comparison of ROC curves based on a predictive model using clinical risk factors only (dotted line) to a model containing clinical risk factors and biomarker levels (soluble tumor necrosis factor receptor-1 and plasminogen activator inhibitor-1; solid line) for acute kidney injury during the first 4 days of the study. The areas under the ROC curve are 0.66 (95% confidence level [CI], 0.60–0.71) and 0.70 (95% CI, 0.65–0.75), respectively, p = .0003. In all three cases, the Hosmer-Lemeshow goodness-of-fit p value was >.30. Right, comparison of ROC curves based on a predictive model using clinical risk factors only (dotted line) to a model containing clinical risk factors and biomarker levels (soluble tumor necrosis factor receptor-1 and plasminogen activator inhibitor-1; solid line) for acute kidney injury during the first day of the study. The areas under the ROC curve are 0.72 (95% CI, 0.65–0.79) and 0.77 (95% CI, 0.71–83), respectively, p = .006 for difference in areas under the ROC curve. In all three cases, the Hosmer-Lemeshow goodness of fit p > .30.