Several mechanisms mediating a perioperative decrease in renal function have been identified within recent years and several biomarkers have been proposed to facilitate early detection of AKI, i.e., neutrophil-gelatinase-associated lipocalin (NGAL), kidney-injury molecule -1 (KIM-1), liver-type fatty acid binding protein (L-FABP), interleukin-18 (IL-18), insulin-like growth factor-binding protein 7 (IGFBP7), and tissue inhibitor of metalloproteinase (TIMP-2) [17]. However, these biomarkers are intended for the early detection of AKI after a renal insult has occurred and not for preoperative risk stratification.
Extending the observations of two recent pilot studies in patients undergoing CABG [8, 9], the findings of the present study again show that preoperative plasma GDF-15 is an independent predictor of postoperative renal dysfunction in a heterogeneous population of patients undergoing elective cardiac surgery.
GDF-15, also entitled macrophage inhibitory cytokine-1 (MIC-1) is a cytokine expressed in many tissues, including myocardium, lung, kidney, brain, liver, and the intestine, upon various stimuli, including myocardial stretch, volume overload, experimental cardiomyopathy and oxidative stress, other inflammatory cytokines, and ischemia/reperfusion (for a detailed overview see [18]). However, the physiological role of this peptide in the cardiovascular system still remains to be defined.
Our group has recently shown that preoperative plasma GDF-15 is an independent predictor of postoperative mortality and morbidity in patients undergoing cardiac surgery and can further stratify patients beyond the established risk scores such as the Euroscore, and other cardiovascular risk markers such as NTproBNP or hsTNT [10]. The present analysis extends these findings to the prediction of CSA-AKI, an important complication in patients undergoing cardiac surgery, which is associated with poor short-term and long-term prognosis [1].
Employing logistic regression modeling of variables with an established (age, gender, additive Euroscore, serum creatinine, duration of CPB, duration of surgery, type of surgery, total circulatory arrest, preoperative hemoglobin, and diabetes mellitus) or putative (ScO2, hemofiltration during ECC, plasma GDF-15, hsTNT, and NTproBNP) role as risk factors for CSA-AKI, we observed that GDF-15 is an independent predictor of CSA-AKI and confirmed this finding using multiple statistical methods. It is of note that in random forest analysis the ability of GDF-15 to predict CSA-AKI was especially pronounced in patients with normal plasma creatinine; one explanation why this hormone had superior predictive ability in comparison with a conventional risk score like the additive Euroscore in our previous study [10]. Additionally, the observation that NTproBNP and hsTNT – despite being widely accepted biomarkers of cardiopulmonary dysfunction – did not predict AKI, further supports the powerful potential of GDF-15 for risk stratification in this regard. It is of note that the risk prediction potential of GDF-15 was primarily related to the ability to predict AKI-3. Whether this may be related to the physiology or pathophysiology of GDF-15 or that AKI-1 events are very difficult to predict remains speculative.
Various clinical scores for the prediction of renal dysfunction after cardiac surgery have been developed within recent years and these have highly variable predictive ability [7]. We tested the CC-ARF score as one of the most popular scores [13]. As expected, the predictive ability of this score, which was primarily developed to predict postoperative need of dialysis (that renders patients AKI stage 3), was rather poor if used to predict any type of AKI. However, when combined with GDF-15, the predictive ability was markedly improved for any kind of AKI and especially for AKI-3, as the most severe stage of postoperative renal dysfunction. This may have clinical relevance, because the CC-ARF score – in contrast to our model – has been externally validated and is widely used [13].
Very recently, Bignami and coworkers [19] reported that the preoperative plasma level of the endogeneous hormone ouabain is an independent predictor of AKI in a derivation and a validation cohort of patients undergoing cardiac surgery, and that it improves the predictive ability of a clinical risk score for AKI. It is of note that ouabain and GDF-15 both reflect circulatory stress [20, 21], supporting the role of this factor as a trigger of AKI in this setting. But there are also relevant discrepancies between the two peptides. First of all, Bignami et al. provided experimental data for a pathophysiological link between increased circulating levels of ouabain and decreased renal function (i.e., decreased creatinine clearance, increased urinary protein excretion, and reduced podocyte nephrin) [19], whereas a direct detrimental effect of increased GDF-15 levels on renal function has not been shown so far. In contrast, some lines of evidence point to a protective role of GDF-15 in diabetic nephropathy [22].
Additionally, Bignami et al. [19] employed a more rigorous definition of AKI (AKI grade 2 and 3) than we did. However, restricting our analyses to AKI-3 we also observed a numerically almost comparable and relevant increase in the AUC in ROC analysis by adding GDF-15 to our logistic regression model. Future studies need to determine which of these peptides has the better power to predict for all stages and the most severe forms of AKI.