Preoperative plasma growth-differentiation factor-15 for prediction of acute kidney injury in patients undergoing cardiac surgery

Abstract

Background: Growth-differentiation factor-15 (GDF-15) is an emerging humoral marker for risk stratification in cardiovascular disease. Cardiac-surgery-associated acute kidney injury (CSA-AKI), an important complication in patients undergoing cardiac surgery, is associated with poor prognosis. The present secondary analysis of an observational cohort study aimed to determine the role of GDF-15 in predicting CSA-AKI compared with the Cleveland-Clinic Acute Renal Failure (CC-ARF) score and a logistic regression model including variables associated with renal dysfunction.

Methods: Preoperative plasma GDF-15 was determined in 1176 consecutive patients undergoing elective cardiac surgery. Patients with chronic kidney disease stage 5 were excluded. AKI was defined according to Kidney-Disease-Improving-Global-Outcomes (KDIGO) - creatinine criteria. The following variables were screened for association with development of postoperative AKI: age, gender, additive Euroscore, serum creatinine, duration of cardiopulmonary bypass, duration of surgery, type of surgery, total circulatory arrest, preoperative hemoglobin, preoperative oxygen-supplemented cerebral oxygen saturation, diabetes mellitus, hemofiltration during ECC, plasma GDF-15, high sensitivity troponin T (hsTNT), and N-terminal prohormone of B-type natriuretic peptide (NTproBNP).

Results: There were 258 patients (21.9 %) with AKI (AKI stage 1 (AKI-1), n = 175 (14.9 %); AKI-2, n = 6 (0.5 %); AKI-3, n = 77 (6.5 %)). The incidence of AKI-1 and AKI-3 increased significantly from the lowest to the highest tertiles of GDF-15. In logistic regression, preoperative GDF-15, additive Euroscore, age, plasma creatinine, diabetes mellitus, and duration of cardiopulmonary bypass were independently associated with AKI. Inclusion of GDF-15 in a logistic regression model comprising these variables significantly increased the area under the curve (AUC 0.738 without and 0.750 with GDF-15 included) and the net reclassification ability to predict AKI. Comparably, in receiver operating characteristic analysis the predictive capacity of the CC-ARF score (AUC 0.628) was improved by adding GDF-15 (AUC 0.684) but this score also had lower predictability than the logistic regression model. In random forest analyses the predictive capacity of GDF-15 was especially pronounced in patients with normal plasma creatinine.

Conclusion: This suggests that preoperative plasma GDF-15 independently predicts postoperative AKI in patients undergoing elective cardiac surgery and is particularly helpful for risk stratification in patients with normal creatinine.

Trial registration: NCT01166360 on July 20, 2010.

Keywords: Acute kidney injury; Biomarkers; Cardiac surgery; Cleveland Clinic Acute Renal Failure score; Euroscore; Growth-differentiation factor-15.

Fig. 1

Plasma growth-differentiation factor-15 (GDF-15) in patients without acute kidney injury (AKI) and in patients with AKI grade 1 (AKI-1) and grade 3: *analysis of variance; p < 0.001). Preoperative plasma GDF-15 was significantly higher in relation to the severity of AKI in comparison with patients without this complication (no AKI vs. Grade 1, p < 0.001; Grade 1 vs Grade 3, p < 0.001)

Fig. 2

Probability of a prototypical patient aged 65 years with an additive Euroscore of 5.15, and a duration of cardiopulmonary bypass of 123 minutes for a range of creatinine values (x-axis) and the 5 and 95 % quantiles of growth-differentiation factor-15 (GDF-15) (0.467 and 2.770, respectively) as derived from the multivariate model. AKI acute kidney injury, CC-ARF Cleveland Clinic Acute Renal Failure (score)

Fig. 3

Receiver operator characteristics of the Cleveland clinic acute renal failure (CC-ARF) score [13] and nested logistic regression models on the development of cardiac-surgery-associated acute kidney injury (CSA-AKI) with and without taking into account preoperative plasma levels of growth-differentiation factor-15 (GDF). a Analyses for any stage of AKI (i.e., AKI-1 to AKI-3). b Analysis restricted AKI-3 only. The inclusion of GDF in the models led to statistically significant (analysis of variance; p < 0.001) predictive ability (either CC-ARF or a model based on additive Euroscore, age, plasma creatinine, diabetes mellitus, and duration of cardiopulmonary bypass). AUC area under the curve

Fig. 4

Receiver operator characteristics of nested logistic regression models on the development of cardiac-surgery-associated acute kidney injury (CSA-AKI) with and without (w/o) taking into account preoperative plasma levels of growth-differentiation factor-15 (GDF) for acute kidney injury (AKI) grade 1 and 3. While the inclusion of GDF led to a statistically significant increase in the area under curve (AUC) for AKI grade 3, this was not the case for AKI grade 1

Fig. 5

Recursive partitioning using conditional inference trees. Starting from the top, important variables and their respective cutoffs are presented leading (bottom) to the percentage of patients (within each population partition) developing cardiac-surgery-associated acute kidney injury (CSA-AKI). For example, from the group of patients with additive Euroscore <5 and growth-differentiation factor-15 (GDF-15) <1.271 ng/ml, 10 % developed CSA-AKI (Node 3), whereas from the group of patients with additive Euroscore <5 and GDF-15 > 1.271 ng/ml, 20 % of patients developed CSA-AKI (Node 4). CPB cardiopulmonary bypass