Early postoperative serum cystatin C predicts severe acute kidney injury following cardiac surgery: a post-hoc analysis of a randomized controlled trial

Particularly in the case of pre-existing renal disease and complex surgical procedures, acute kidney injury (AKI) is a frequently observed complication of heart surgery (5-10%) [1–3]. AKI is associated with increased mortality and ventilation time and longer stays in the ICU and hospital [2]. Criteria for diagnosing AKI are based on the relative or absolute serum creatinine fluctuations [4] and urine excretion. The disadvantage of these non-specific markers is their delayed appearance in particular. Serum creatinine is also affected by non-renal factors such as muscle mass, distribution volume and tubular secretion [4].

A series of new, alternative markers which are said to detect renal function as well as the appearance of acute insufficiency earlier and more accurately has been published. One of these new markers is cystatin C (CysC), a 13-kD cysteine protease inhibitor protein which is formed in all cells with a cell nucleus. In contrast to creatinine, it does not undergo tubular filtration but instead glomerular filtration and it is not subject to any significant protein binding. CysC has shown that it can accurately indicate even small changes in the glomerular filtration rate. However, various extrarenal factors can distort and affect cystatinC values. These include for example the thyroid function or the administration of glucocorticosteroids,. The mean reference serum cystatin C level is 0.84 mg/L in non-Hispanic adolescents and normal renal function [5]. It is not known how ultrafiltration during extracorporeal circulation affects serum CysC levels [6].

Studies were able to demonstrate that CysC is a good prognostic factor for the duration and severity of AKI following aortic valve replacement, coronary angiography and complex cardiac-surgery procedures [7–9]. The question of at what point postoperatively increases in CysC are predictive in nature is unclear. From this we formulated the main question of the study: from when and with which RIFLE definition [10] can CysC levels predict AKI in patients with cardiopulmonary bypass (CPB) (with and without intraoperative ultrafiltration).

Following cardiac-surgery procedures, serially measured serum CysC concentrations are positively associated with the onset of postoperative renal failure. CysC values measured immediately at the end of the operation provide an early indication of the possible onset of AKI. However, the predictive value depends on the AKI definition, according to whether renal replacement therapy or the increase in creatinine (AKIN 1) is used for this purpose. This may also explain the weakness of CysC, namely that it is not possible to predict before surgery whether the patient will develop AKI postoperatively.

Our results are comparable with those of other studies which confirm the reliability of CysC as a marker of renal function [13, 14], particularly when an CPB is used [15–17]. Our data support the expanded indication of CysC as a marker of glomerular filtration as well as of chronic and acute renal insufficiency. CysC is an attractive marker for assessing GFR [17]. CysC is synthesized by all nucleated cells and, in contrast to creatinine, which is produced by muscle cells, CysC is not affected by the interindividual differences and intraindividual changes in the muscle mass. In addition, CysC is filtered at glomerular level and metabolised without undergoing tubular secretion or reabsorption. It is noteworthy that CysC concentrations differ in patients with and without AKI at all time points. The decrease during CPB can be explained by haemodilution [18] and for the immediate postoperative increase there is a correlation between CysC and C-reactive protein as a direct marker of CPB-induced inflammation [19].

Current studies remain unclear with regard to the benefit of CysC, however. Our finding regarding a limited benefit of CysC as an early marker of AKI is identical to the observations of Koyner et al. [20]. The CysC values of 70 patients with CPB were determined upon arrival in the ICU. With an AUC for the development of AKI (defined as a serum creatinine increase of 50% as compared to the baseline value) of 0.62 (95% CI, 0.48 to 0.75), there is a slight CysC-AKI association. This can be explained by the work of Rosner et al. and Moran [2, 21], who see CPB-associated AKI as being mediated by damage to the renal tubules, whereas CysC is a marker of glomerular filtration. As a result of tubular damage, upstream glomerular filtration can be impacted due to congestion and can explain an increase in CysC.

However, other studies support the utility of CysC as an early predictor of AKI. In a cohort of critically ill patients, serum cystatin C demonstrated the occurrence of a creatinine-based AKI 1 to 2 days earlier than an established marker [22]. In a recently published study of 100 patients with CPB, the predictive capacity of plasma CysC upon arrival at the ICU was excellent (AUC 0.83, 95% CI, 0.68 to 0.98) [23]. The reasons for the discrepancy are not entirely clear. On the one hand, the perfusion techniques may differ with regard to haemodilution and post-filtration. On the other hand, the definition of AKI remains very variable and, finally, the CysC measurement times are different. A meta-analysis by Zhang et al. [23] was able to identify 15 studies which investigated the predictive value of CysC. A high OR of 23.5/95% CI, 14.2-38.9 = for serum CysC was found across all different study endpoints. Five studies were performed in a cardiac-surgery population. The pooled AUC was 0.96 (95%0.95.0.97), which corresponds to a very good correlation with AKI. In this review, Zhang concluded that serum CysC is an outstanding predictor of the onset of AKI, irrespective of the population investigated (sepsis, cardiac surgery). The superiority to serum creatinine is the non-dependence on age, sex, muscle mass and earlier onset. In a multicentre, prospective study of the Tribe-AKI (Translational Research Investigating Biomarker endpoints for Acute Kidney Injury) consortium [24] published in July 2012, it was found, in contrast to Zhang [25], that in the case of creatinine-defined AKI (cardiac surgery), sensitivity and specificity were lower for CysC than for serum creatinine. However, the sampling times differ from our results. Spahillari et al. [24] did not collect blood samples until 24 h after the operation but concluded that there were no advantages of CysC over CREA. The limitations of the study are, firstly, patient selection. Due to the post-hoc sub-analysis, no urgent and complex procedures (e.g. triple valves, aortic surgery, redo’s) were included in the evaluation. On the other hand, blood sampling times in a narrower postoperative interval would have been of use. AKI was only defined by creatinine increase and not by the second criteria of a decreasing urine output. Patients who develop AKI have higher rates of mortality and resource utilization, with the worst values seen in dialyzed patients. Emerging evidence suggests that even small changes in creatinine after cardiac surgery are associated with significant effects on mortality. Whether AKI directly causes adverse outcomes is not entirely clear; however, an increase in infection and new-onset sepsis, congestive heart failure, and fluid overload may be contributory [1]. Traditional biomarkers of AKI (creatinine and urea) increase slowly in response to renal injury, are insensitive to mild degrees of AKI, and are influenced by nonrenal factors. There is considerable interest in novel biomarkers of AKI such as cystatine c that increase rapidly after renal injury, detect mild degrees of AKI, and are less subject to nonrenal factors. It has been postulated that the early diagnosis of cardiac surgery-associated AKI using novel biomarkers will result in improved outcomes. However, there is little evidence that interventions started early in the course of evolving AKI enhance renal recovery. Until effective therapies are developed that significantly improve the outcome from AKI, there is little benefit from early diagnosis using novel biomarkers [25, 26].

In summary, we were able to calculate a subanalysis of the connection between CysC and AKI in our prospective study. The early predictive value can only be evaluated when AKI is defined as renal replacement therapy. By contrast, in the case of an AKIN 1 stage (increase in creatinine >50% baseline value), no good statistical connections can be detected. Cystatin can be determined as an additional parameter in cardiac-surgery procedures; however, the cost-effective and simple determination of the serum creatinine value continues to be the routine recommendation. A prospective, randomised study with prophylactic dialysis as an indication in one study arm may potentially provide a new starting point for the validity of CysC in clinical use.