Preinterventional Cystatin C: A Highly Prognostic Marker for All-Cause Mortality after Coronarography

Purpose. Glomerular filtration rate <60mL/min/1.73m is associated with increased all-cause mortality. Multiple studies have shown that serum cystatin C is more accurate than serum creatinine for detection of mild to moderate chronic kidney dysfunction. We examined the predictive value of the preinterventional cystatin C for all-cause mortality after contrast media exposition. Methods.The prognostic value of preinterventional cystatin C for all-causemortality was retrospectively analysed in the prospective single-centre “Dialysis-versus-Diuresis” Trial (January 2001–July 2004). Associations during up to 1316 days of followup for all-cause mortality were assessed.The study population consisted of 373 patients (aged 35–89, mean 67 years, 16.4% female). Results. During followup, 65 deaths occurred.Multivariate cox regression confirmed the preinterventional CyC level to be an independent predictor of all-causemortality (odds ratio 2.061, 95% confidence interval 1.054–4.031,P = 0.035).Hazard rate ratio for all-causemortalitywas increased in the third cystatin C quartile (>1.4mg/L) compared with the lowest quartile (<1.1mg/L), 4.12, 95% confidence interval 1.747–9.694 (P = 0.001), in the fourth cystatin C quartile (>1.6mg/L) compared with the lowest quartile, 5.38, 95% confidence interval 2.329–12.427 (P < 0.001). Conclusions. Cystatin C is significantly associated with all-cause mortality after coronarography, regardless of the age, gender, and glomerular filtration rate.


Introduction
Chronic kidney disease (CKD) is an important public health problem worldwide with a prevalence of 13% in the Western world [1,2]. Chronic decreased glomerular filtration rate (GFR) less than 60 mL/min per 1.73 m 2 is associated with an increased risk of developing cardiovascular disease (CVD) [2][3][4][5][6] and strongly associated with increased all-cause mortality [4]. Even mild to moderate renal impairment is associated with an increased risk of mortality [3,4].
Cystatin C (CyC) and serum creatinine (SCr) are used as marker of renal function. A series of studies in the recent years have shown that serum CyC is superior to SCr for detection of mild to moderate renal impairment [7][8][9]. Comparably, CyC was also found to have a higher predictive value than SCr and GFR, based on Modification of Diet in Renal Disease equation for death so far only in selected cohorts such as elderly persons (>65 years) [10][11][12][13].
However, the role of preinterventional CyC in predicting all-cause mortality after contrast media (CM) exposition is not revealed. Our aim was to examine if the preinterventional cystatin C predicts all-cause mortality after coronarography.

Study Design and Methods.
Our report is a retrospective analysis of the cohort of the three hundred and seventy-three patients of the Dialysis-versus-Diuresis (DVD) trial by Reinecke et al. [14] to answer the question if the preinterventional CyC level has a predictive value according to the all-cause mortality of patients after contrast media (CM) exposition.
The DVD trial of Reinecke et al. was a randomized controlled, single-centre study from January 2001 to July 2007, to demonstrate the preventive value of a single haemodialysis, of hydration plus N-acetylcysteine and of hydration only 2 Advances in Nephrology according to the frequency of contrast medium-induced acute kidney injury (CI-AKI).

Patients.
The inclusion criteria of the DVD trial were an elective left heart catheterization between January 1, 2001 and July 6, 2004 and a SCr level between ≥1.3 mg/dL and ≤3.5 mg/dL, initially measured by the Jaffé-method. Patients were excluded if they had an acute or recently suffered myocardial infarction (within 30 days), an advanced chronic heart failure (New York Heart Association class IV), a previous CM exposition within 7 days, or a monoclonal gammopathy.

Measurement of Cystatin C Level, Determination of the Preinterventional Renal Function.
The baseline (preinterventional) serum CyC level was measured by means of a particleenhanced immunonephelometric assay (N Latex Cystatin C, Siemens Healthcare Diagnostics GmbH, Eschborn, Germany) with a nephelometer (BNII, Dade Behring).
The baseline (preinterventional) SCr concentration was measured by the Jaffé-method.
The GFR was estimated based on the preinterventional SCr with the simplified Modification of Diet in Renal Disease equation [15].  A total of 424 were included in the trial [14]. During the trial 12 patients dropped out, because the SCr levels within the planed followup were missing. Finally, for this retrospective report, 39 patients also dropped out because of missing preinterventional CyC levels. Consecutively, this retrospective analysis includes all 373 participants, whom preinterventional serum SCr and CyC levels were measured.

Results
For analyses regarding the role of CyC for evaluating the risk of all-cause mortality the patients were divided into four groups: CyC quartiles 1-4.
Indications for invasive imaging of these patients were characterization of structural heart disease in patients with dilatative or ischaemic cardiomyopathy, valvular defects, tachyarrhythmias, or congenital heart disease.

Preinterventional Cystatin C as a Predictor of All-Cause
Mortality after Contrast Media Exposition. The median duration of long-term followup was 553 days (range 63 to 1316 days).
A total of 65 (17.4%) patients died during followup. The preinterventional serum CyC concentration was significantly associated with all-cause mortality in the followup.
All factors, which were found to be significant ( < 0.05) associated with all-cause mortality in univariate analyses (Table 2), were entered into a multivariate cox regression model (Table 4). These were baseline CyC, baseline SCr, baseline GFR, age, hyperlipidemia, hypertension, ejection fraction ≤35%, and the haemoglobin level. Even after adjustment of these covariates, the baseline CyC turned out to be a significant independent predictor of all-cause mortality (odds ratio 2.061, 95% confidence interval 1.054-4.031, = 0.035, Table 4). Hyperlipidemia, hypertension, and ejection fraction ≤35% also turned out to be independent predictors for allcause mortality ( Table 4). The cox regression model of longterm survival of the patients after contrast media exposure  depending on the preinterventional CyC quartiles is shown in Figure 1. The frequency of all-cause mortality depending on the CyC quartiles is shown in Figure 2 and demonstrates a stepwise and significant association.

Discussion
This study aimed to investigate whether the preinterventional cystatin C concentration in blood predicts an elevated risk of all-cause mortality. We found that the preinterventional CyC level in the blood flow is an independent predictor for allcause mortality after CM exposition, with a higher predictive value than SCr and GFR, based on Modification of Diet in Renal Disease equation. CyC is used as marker of renal function and also superior to SCr for detection of mild to moderate chronic kidney dysfunction [7][8][9]. CyC is produced at a constant rate by all nucleated cells [17], is not significantly binded to protein in the blood [18]. CyC is completely filtered by the glomeruli and undergoes complete tubular reabsorption and catabolism, without any secretion [19]. Hence it is not related to the muscle mass [20]. However, it seems that some factors like inflammation, thyroid dysfunction, and corticosteroids alter serum CyC levels independent of GFR [21].
The study population was divided into four groups according to their CyC concentrations. The risk of death was found to increase with increasing CyC level in the study group: mortality was the highest in the highest quartile of CyC concentrations (28%, with 7%, 12%, and 22% in the first, second, and third quartile, resp.).  In our study most patients had a mild or moderate renal impairment. In this area SCr tends to overestimate the GFR [22]. Consequently it is not surprising that in our cohort the SCr and the GFR, based on Modification of Diet in Renal Disease equation, appeared after adjustment to the other non-and biomarker baseline variables not to be independent predictors of all-cause mortality. This is in line with Shlipak et al., who reported 2006 that SCr was not associated with increased mortality. Their cohort had mainly a mild to moderate renal impairment [23]. In another study Shlipak et al. found that CyC had a much stronger association with mortality risk than SCr or creatinine-based estimates of GFR [11]. Stevens and Levey even suggested that CyC is linked to mortality risk independently of kidney function in the elderly [24]. Similar assumptions have been anticipated by Shlipak et al. [10,11].

Advances in Nephrology
So we can assume that CyC has a higher predictive value than SCr and the GFR for mortality in mild to moderate chronic kidney dysfunction.
We do not find any significant difference between men and women, whether related to the CyC levels or all-cause mortality. This is in line with previous CyC studies like Dharnidharka et al., 2002 [25].
Although we found across the CyC quartiles an association with older age, increasing frequency of diabetes mellitus, and decreasing haemoglobin levels in both men and women, which is in accordance with the well-known fact that renal function declines with age and higher frequency of diabetes [26,27].
Contrary to former studies, we could not witness a significant association between CyC levels and adipositas, hyperlipidemia, and hypertension [28]. We found a significant independent association between hyperlipidemia, hypertension, ejection fraction ≤35%, and all-cause mortality. In this study we found no significant association between PAD or CHD and a higher risk of all-cause mortality.
Our study is limited by its retrospective, single-center design. Other important limitations are the fact that we cannot be certain whether the strong association of CyC with the all-cause mortality based due solely to its correlation with renal function. We cannot exclude the possibility of confounding due to potential associations between CyC with diseases that are independent of its correlation with renal function.
Shlipak et al. reported that CyC is an independent predictor of all-cause mortality in adults who were 65 years of age or older. We could expand these findings and conclude that CyC is a promising predictor of outcome in clinical patients after coronarography. CyC remained an independent predictor of death, regardless of the age, gender, and GFR.