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European Heart Journal Advance Access published online on February 8, 2007
European Heart Journal, doi:10.1093/eurheartj/ehl507
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© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Prognostic value of cystatin C in acute heart failure in relation to other markers of renal function and NT-proBNP

Johan Lassus1,*, Veli-Pekka Harjola2, Reijo Sund3, Krista Siirilä-Waris1, John Melin4, Keijo Peuhkurinen5, Kari Pulkki6, Markku S. Nieminen for the FINN-AKVA Study group1

1 Division of Cardiology, Department of Medicine, Helsinki University Central Hospital, Haartmaninkatu 4, POB 340, 00029 HUS, Helsinki, Finland
2 Division of Emergency Care, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
3 National Research and Development Centre for Welfare and Health (STAKES), Helsinki, Finland
4 Department of Medicine, Central Finland Central Hospital, Jyväskylä, Finland
5 Department of Cardiology, Kuopio University Hospital, Kuopio, Finland
6 Department of Clinical Chemistry, Helsinki University, Helsinki, Finland

Received 31 August 2006; revised 13 December 2006; accepted 12 January 2007.

* Corresponding author. Tel: +358 50 322 4094; fax: +358 9 47174015. E-mail address: johan.lassus{at}fimnet.fi


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusion
 Appendix
 Acknowledgements
 References
 
AIMS: Cystatin C, a novel marker of renal function, has been implicated as a prognostic marker in cardiovascular disease. We investigated the prognostic value of cystatin C in acute heart failure (AHF) in comparison to other markers of renal function and NT-proBNP.

METHODS AND RESULTS: Patients with cystatin C measurements (n = 480) from a prospective multicentre study on AHF were included. All-cause mortality at 12 months was 25.4%. Cystatin C, creatinine, age, gender, and systolic blood pressure on admission were identified as independent prognostic risk factors. Cystatin C above median (1.30 mg/L) was associated with the highest adjusted hazard ratio, 3.2 (95% CI 2.0–5.3), P < 0.0001. Mortality increased significantly with each tertile of cystatin C. Combining tertiles of NT-proBNP and cystatin C improved risk stratification further. Moreover, in patients with normal plasma creatinine, elevated cystatin C was associated with significantly higher mortality at 12 months: 40.4% vs. 12.6% in patients with both markers within normal range, P < 0.0001.

CONCLUSION: Cystatin C is a strong and independent predictor of outcome at 12 months in AHF. Furthermore, cystatin C identifies patients with poor prognosis despite normal plasma creatinine. Cystatin C seems to be a promising risk marker in patients hospitalized for AHF.

Key Words: Cystatin C • Acute heart failure • Prognosis • Renal function • Biomarkers


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusion
 Appendix
 Acknowledgements
 References
 
Understanding of the pathophysiology and modern treatment have improved prognosis of chronic heart failure (CHF) in the last two decades.1,2 Still, heart failure is characterized by repeated hospitalizations and associated with poor long-term prognosis.3,4 The majority of heart failure studies on epidemiology, treatment, and outcome mainly include patients with CHF, however, with only a few describing these issues in the true setting of acute heart failure (AHF). Consequently, more attention has been paid to AHF as one of the most frequent diagnoses in emergency medicine and with 1-year mortality rates exceeding 25–30%.5–7

The association between renal dysfunction and increased mortality has been reported in patients with CHF as well as AHF.6,8–10 Cystatin C, a small 13 kDa cysteine protease inhibitor, has emerged as a novel and interesting marker of renal function. Cystatin C is produced at a constant rate by all functioning cells, and is freely filtrated in the glomerulus. It is subsequently absorbed in the renal tubules where it is fully degraded locally, without re-entering the bloodstream. No active tubular secretion occurs, nor is there any significant extrarenal elimination. Levels of cystatin C in serum are therefore mainly dependent on glomerular filtration rate (GFR). Besides, cystatin C seems not to be affected by gender, age, body mass index (BMI), or diet, leading to the suggestion that it be the preferred endogenous marker of renal function.11–13 Recent studies have revealed that cystatin C has predictive and prognostic value in cardiovascular disease, including CHF.14–17

The role of cystatin C in AHF has not been evaluated before. We wanted to assess the prognostic impact of cystatin C in a representative population of patients with AHF in comparison to other contemporary risk markers, especially the conventional markers of renal function plasma creatinine and creatinine clearance (CrCl). Furthermore, we hypothesized that in patients with normal plasma creatinine, elevated cystatin C would be associated with an increased risk of mortality.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusion
 Appendix
 Acknowledgements
 References
 
Study population and laboratory procedures
FINN-AKVA is a prospective, observational, multicentre study on AHF conducted in 14 hospitals, representing both academic centres as well as regional hospitals, in Finland. All patients presenting with symptoms, signs, and diagnostic findings of AHF, according to current European Society of Cardiology (ESC) guidelines,18 and requiring hospitalization were eligible. The diagnosis of heart failure had to be confirmed during hospital stay. Consecutive patients were enrolled between 2 February and 30 May 2004, and 620 patients hospitalized for AHF entered the study. Both patients with new onset (i.e. no previous history) of heart failure and with acute decompensation of CHF were included. The patients were systematically characterized and clinical data on admission recorded in detail.5 Analyses of cystatin C, creatinine, and NT-proBNP were performed in a central laboratory from blood samples taken 48 h post admission. Vital status follow-up was completed for all patients up to 12 months through the national Population Register Centre. The endpoint of interest was death from any cause and the time of death was obtained from the register. Written informed consent was obtained from all patients. The national Ethics Committee approved our multicentre study.

Blood samples were obtained on admission and again ~48 h from hospitalization. Of the 574 patients enrolled in the 13 hospitals attending blood sampling, 6 patients died during the first 48 h and another 16 were discharged before this time point. Some patients had only admission samples drawn (n = 37), and a few patients had neither blood sample taken (2%). Written consent to blood sampling was not given by 24 patients. Consequently, 480 patients had blood samples taken at 48 h and were included in the present study. Patients with and without blood samples at 48 h did not differ in age or gender distribution and had similar co-morbidities (data not shown).

Cystatin C was measured using the Dako Cytomation immunoturbidimetric assay, with an intra-assay coefficient of variation (CV) of 2.0% and inter-assay CV of 4.1% at 0.7 mg/L. For normal renal function, the upper limit of the reference interval recommended by the manufacturer was used: cystatin C <1.2 mg/L for young healthy individuals and <1.4 mg/L for subjects aged over 50 years. Plasma creatinine (enzymatic method CREA Plus Roche Diagnostics, upper limit of reference interval 90 µmol/L for women and 100 µmol/L for men) and NT-proBNP (Roche Diagnostics Elecsys®) were analysed using commercially available kits. We evaluated admission samples, analysed locally with standard methods, for prognostic evaluation of haemoglobin and sodium levels to avoid bias from any corrective measures (i.e. blood transfusion or diuretic therapy) after hospitalization. CrCl was calculated from creatinine values using the Cockcroft–Gault formula.19 Impaired renal function was defined as plasma creatinine >120 µmol/L (1.35 mg/dL) and CrCl <60 mL/min.

Statistical analysis
We calculated hazard ratios (HR) derived from the Cox proportional hazard model to identify predictors of all-cause mortality during 12-month follow-up. We tested several variables, including clinical characteristics such as age, gender, history of CHF, coronary artery disease (CAD), previous myocardial infarction, hypertension, cerebrovascular disease, chronic kidney disease, diabetes, and smoking status as well as acute coronary syndrome (ACS) on admission. Biochemical variables included were markers of renal function (serum cystatin C, plasma creatinine, CrCl), anaemia (WHO definition: blood haemoglobin <130 g/L for men and <120 g/L for women), hyponatraemia (plasma sodium <135 mmol/L), and NT-proBNP. We also included systolic (SBP) and diastolic (DBP) blood pressures on admission as well as left ventricular ejection fraction (LVEF≤40%) in our analyses. For multivariable Cox regression analyses, we retained all variables with P < 0.1 in the univariate analysis. Cystatin C, creatinine, and CrCl were first entered individually in the multivariable model. Subsequently, the other markers of renal function, creatinine and CrCl, were adjusted for cystatin C in separate multivariable analyses. The proportional hazards assumption was tested and confirmed using the weighted residuals score test.

Furthermore, we compared the three markers of renal function in their ability to predict mortality at different time points. Adjusted odds ratios (OR) for in-hospital, 30-day, and 12-month mortality were calculated using multivariable logistic regression analysis. We entered the same variables used in the Cox proportional hazard model, but using continuous parameters. The approach based on fractional polynomials was used to address the linearity assumption in the analysis of continuous risk variables. Goodness-of-fit was assessed by the Hosmer–Lemeshow test.

In risk stratification analysis, we divided patients into tertiles of cystatin C. Differences between tertiles were assessed, and Kaplan–Meier survival curves generated for each tertile. We also tested the hypothesis that patients with creatinine within the normal range but with elevated cystatin C values would have a higher risk of mortality compared with study subjects with normal renal function as assessed by both markers. We assessed group differences by log rank, {chi}2, or t-test as appropriate. Results are shown as means (SD), median [interquartile range (IQR)], numbers (percentages), and HR with 95% confidence intervals (CI). Tests were two-sided and P-values <0.05 regarded statistically significant. We used statistical software packages SPSS 12.0.1, Survo MM, and Stata 8.0 to perform the analyses.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusion
 Appendix
 Acknowledgements
 References
 
Population demographics and all-cause mortality
Patients were on average 74.8 (SD 10.4) years old (range 39–98). Half of them were female and 52% had a previous history of heart failure. Co-morbidities and heart failure medication on admission are listed in Table 1. Of the patients studied, 30% had ACS as the precipitating factor, out of which two-thirds had an acute myocardial infarction. At presentation, 72% of patients were in clinical New York Heart Association (NYHA) class III or IV. Ejection fraction (EF) was reported in two-thirds (n = 317) of the patients, of which 52% had preserved LVEF ≥45%. Median in-hospital length of stay (LOS) was 7 (IQR 5–12) days. During the index hospitalization, 24 patients died (5.0%). All-cause mortality at 30 days, 6, and 12 months after admission was 7.5, 18.3, and 25.4%, respectively.


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  		Table 1 Baseline demographic characteristics of population by vital status at 12 months

 
Effect of cystatin C on mortality
The median cystatin C level for all subjects was 1.30 mg/L (IQR 1.04–1.70 mg/L). Even though only 7.9% were reported as having chronic kidney disease on admission, 20% of patients had creatinine values over 120 µmol/L (1.35 mg/dL) and 42% had CrCl <60 mL/min. The Pearson correlation coefficient between logarithmic values of cystatin C and creatinine was 0.74 (P < 0.0001) and between (log) cystatin C and (log) CrCl –0.67 (P < 0.0001). As expected in a population with AHF, NT-proBNP levels were elevated, with a median value of 3916 ng/L (IQR 1981–8431 ng/L). A small but significant difference in LOS was observed between patients with cystatin C above median (LOS 8 days, IQR 6–13) and patients with cystatin C below median (LOS 7 days, IQR 5–10), log rank P = 0.005.

All-cause mortality at 12 months was 39% in patients with cystatin C above median, as compared with 12% in patients with cystatin C levels below the median (log rank P < 0.0001). Cystatin C above median was associated with higher adjusted HR, 3.2 (95% CI 2.0–5.3) P < 0.0001, than creatinine >120 µmol/L or CrCl <60 mL/min (Table 2). Other statistically significant predictors of mortality in Cox multivariable regression analysis were older age, male gender, and lower SBP on admission. NT-proBNP above median was associated with an adjusted HR of 1.5 (95% CI 1.0–2.3), P = 0.06. When both creatinine and cystatin C were entered together in the same multivariable model, the prognostic power of creatinine (HR 1.6; 95% CI 1.0–2.5, P = 0.04) was clearly attenuated compared with cystatin C (HR 2.8; 95% CI 1.7–4.7, P = 0.0001). Likewise, direct comparison to CrCl (HR 1.0; 95% CI 0.6–1.7, P = 0.98) did not diminish the prognostic power of cystatin C (HR 3.1; 95% CI 1.7–5.5, P = 0.0001). Finally, we compared the prognostic impact of the markers of renal function at different time points of follow-up. We found that each standard deviation increase of cystatin C was associated with a higher risk of in-hospital mortality as well as mortality at 30 days and at 12 months compared with creatinine or CrCl (Table 3).


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  		Table 2 Predictors of 12-month all-cause mortality in AHF

 

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  		Table 3 Markers of renal function and adjusted OR for mortality at different time points

 
Mortality risk stratification of patients with AHF
In patients with normal creatinine values (n = 290), we found that as many as 52 patients (18%) had elevated cystatin C levels. Of these, 21 died during follow-up, compared to 30 out of 238 patients with both renal markers in the reference range (log rank P < 0.0001) (Figure 1). Likewise, in patients with CrCl≥90 mL/min (n = 108) elevated cystatin C was associated with a mortality of 50% as compared with 3% in patients with both CrCl and Cystatin C within the normal range (log rank P < 0.0001).


Figure 5071
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  		Figure 1 Effect on survival of elevated cystatin C in patients with normal creatinine. Kaplan–Meier curves for patients with normal creatinine and normal cystatin C level (upper line) and patients with normal creatinine but elevated cystatin C level (lower line). Mortality at 1 year 12.6 vs. 40.4%. Log rank P < 0.0001.

 
Categorizing patients in tertiles of cystatin C yielded three separate risk groups with low, medium, and high 1-year mortality (Figure 2). Compared with the first tertile, risk of death increased significantly with each tertile. Moreover, after combining tertiles of cystatin C and NT-proBNP, even more comprehensive risk stratification was possible, with all-cause mortality at 12 months ranging from 5% in patients in the lowest tertile of both biomarkers to 49% in patients in the highest (Figure 3).


Figure 5072
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  		Figure 2 One year survival by tertiles of cystatin C. All-cause mortality at 12 months: 9.9% for first tertile (upper line, cystatin C <1.13 mg/L), 24.8% for second tertile (middle line, cystatin C 1.13–1.55 mg/L) and 41.8% for third tertile (lower line cystatin C >1.55 mg/L). P-values (log rank) for difference between tertiles: first vs. second P < 0.001, second vs. third P < 0.01, first vs. third P < 0.0001.

 

Figure 5073
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  		Figure 3 Risk stratification in AHF by combining tertiles of cystatin C and NT-proBNP. Increase in mortality at 1 year from 5.2% in patients in the first tertile of both biomarkers (n = 77) to 48.7% in patients in the third tertile (n = 76) of cystatin C and NT-proBNP.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusion
 Appendix
 Acknowledgements
 References
 
In this study, we describe for the first time cystatin C as a strong predictor of outcome in patients hospitalized for AHF. In multivariable analysis, cystatin C above median was associated with an approximately three-fold increase in 1-year mortality risk. Higher cystatin C levels were associated with increased risk of death both in short- and long-term follow-up. Furthermore, in patients with normal creatinine, elevated cystatin C levels were associated with greatly increased risk of death compared with those with both cystatin C and creatinine in the normal range. Mortality increased significantly with every tertile of cystatin C. Consequently, cystatin C enables stratification of patients with AHF according to risk of death, and may help in directing intensified treatment efforts to high-risk groups.

We found that cystatin C, a novel marker of renal function, was a stronger predictor of mortality than creatinine or CrCl. This finding was consistent across gender and age groups, irrespective of aetiology (including ACS and coronary heart disease), and remained significant even after adjustment for other prognostic factors. In ambulatory CHF patients, renal dysfunction is one of the strongest risk factors for mortality, being at least as significant as most clinical variables.8,10 In patients hospitalized for decompensated heart failure, impaired renal function on admission and/or worsening renal function during hospitalization is associated with a significantly increased length of hospital stay, increased risk of mortality as well as higher rehospitalization rates.5,20–22

Reliable identification of renal dysfunction is a key issue in identifying patients at risk of death. Cystatin C performs well as an endogenous marker of true renal function over a wide range of GFR. It also allows detection of minor changes in renal function.12,23 We find it most important that, even in patients with normal creatinine and CrCl values, elevated cystatin C levels have a powerful impact on prognosis. It shows that cystatin C identifies a markedly increased mortality risk in patients with normal renal function as assessed by commonly used markers. It is likely that cystatin C reflects actual GFR better than creatinine or CrCl and that even minor impairment of renal function is associated with poor outcome in AHF. Our results indicate that the impact of the cardiorenal syndrome on heart failure prognosis, although recognized, may still be underestimated.

Increased mortality associated with higher cystatin C levels has been reported in both CHF15 and ACS.16 Cystatin C levels in these studies were somewhat lower than in our population with AHF. However, the immunoturbidimetric (PETIA) method used for the determination of cystatin C levels in our study has been found to give slightly higher results than the nephelometric assay (PENIA).11 Even though the cystatin C values are not directly comparable between different populations, all the studies found that increasing levels of cystatin C were associated with worse outcomes. Identification of AHF patients at high risk of death requires studies in a representative population, in particular since findings from CHF studies are not directly applicable in the setting of AHF.4,18 We studied an unselected population with AHF, and patient characteristics and mortality at 12 months in the present study are well in line with the recent literature on AHF.5,6,9,24 The validity of our results is therefore good, and would apply to the majority of patients with AHF.

We did not use a direct method of measuring GFR as reference to cystatin C and other markers of renal function. In clinical practice, however, assessment of renal function is dependent on readily available methods. The relationship between creatinine and GFR is non-linear and creatinine is an insensitive measure for detecting small decreases in GFR. Creatinine concentrations are also affected by factors such as age, gender, muscle mass, and diet. In moderate and severe renal insufficiency, creatinine is actively secreted by the tubules, and serum creatinine-based GFR calculations overestimate renal function.25 Creatinine-based formulas that take into account age, gender, and weight in estimating GFR try to overcome some of these limitations. The most widely used are the Cockcroft–Gault19 and Modification of Diet in Renal Disease (MDRD)26 equations. However, oedema and volume overload typical for AHF may affect the accuracy of equations incorporating body weight. The MDRD equation has been validated in one small study in advanced heart failure,27 but did not provide any advantages over creatinine or the Cockcroft–Gault equation in our study on AHF (data not shown). As a sensitive marker of renal function, cystatin C probably overcomes many of the shortcomings of the more commonly used measures of renal function in the setting of AHF. Consequently, we suggest that the preferred marker of renal function with the strongest prognostic value for patients hospitalized with AHF is cystatin C.

We acknowledge that increased mortality with higher levels of cystatin C largely reflects the association with renal dysfunction. Whether the independent prognostic value of cystatin C is solely due to its superior ability to estimate the true renal function and detect small changes in GFR is not clear. We consider cystatin C a possible marker of impaired renal perfusion that reflects early end organ failure in patients with AHF. However, we cannot exclude that cystatin C affects prognosis by mechanisms unrelated to renal function. Further studies are needed to increase knowledge about the independent effect on mortality in heart failure and possible underlying mechanisms.

We show the ability of cystatin C to distinguish patients with AHF having low, medium, and high risk of death. The difference in mortality between each tertile of cystatin C is marked and statistically highly significant. This finding provides clinicians with a simple tool in risk stratification, which is essential in the management of heart failure patients. The prognostic value of the natriuretic peptides has recently been described.28–30 In fact, by combining tertiles of two prognostic biomarkers in AHF, cystatin C and NT-proBNP, we were able to further improve the identification of patients with very low mortality risk. Patients in the first dual biomarker tertile had a 95% survival rate at 1 year. Worst prognosis, with a nearly 10-fold increase in mortality risk, was observed in patients belonging to the highest dual biomarker tertile.

Study limitations
It has been reported that factors other than renal function, such as glucocorticoid use, inflammation, and thyroid function, might influence cystatin C levels.25,31 However, other studies and metaanalyses have not identified such associations.11,14,32 It is also noteworthy that one study comparing cystatin C levels with direct GFR measurements did not detect any association between cystatin C and inflammation or steroid therapy.13 Nevertheless, these issues were beyond the scope of our study. We analysed cystatin C levels from samples taken at 48 h from admission. During hospitalization, changes in renal function due to clinical condition or administered medication may occur.


   Conclusion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
Appendix
 Acknowledgements
 References
 
In our study, we found that cystatin C is a strong predictor of mortality in patients hospitalized for AHF, both in-hospital and during follow-up. The prognostic effect seems to be independent of other renal function markers, i.e. plasma creatinine and estimated CrCl. Elevated cystatin C also identifies patients at high risk of death despite normal creatinine and normal CrCl. There is a significant increase in mortality for each tertile of cystatin C. Combining cystatin C and NT-proBNP gives a new possibility to categorize patients into a wider spectrum of risk profiles with patients at very low risk of death at one end and cumulatively high risk at the other. In conclusion, cystatin C seems to be a promising new risk marker and a new clinical tool for risk stratification of patients with AHF. Further studies are needed to assess the applicability of cystatin C in directing in-hospital treatment and as a risk marker during follow-up.


   Appendix
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Appendix
Acknowledgements
 References
 
FINN-AKVA Study group: V.-P.H., K.S.-W., M.S.N., Helsinki University Central Hospital, Helsinki, Finland; J.M., Central Finland Central Hospital, Finland; K.P., Kuopio University Hospital, Finland; M. Halkosaari, Keski-Pohjanmaa Central Hospital, Finland; K. Hänninen, Kymenlaakso Central Hospital, Finland; T. Ilva, T. Talvensaari, Kanta-Häme Central Hospital; H. Kervinen, Hyvinkää Hospital, Finland; K. Kiilavuori, Jorvi Hospital, Finland; K. Majamaa-Voltti, Oulu University Hospital, Finland; H. Mäkynen, V. Virtanen, Tampere University Hospital, Finland; T. Salmela-Mattila, Rauma Hospital, Finland; K. Soininen, Kuusankoski Hospital, Finland; M. Strandberg, H. Ukkonen, Turku University Hospital, Finland; I. Vehmanen, Turku Hospital, Finland; E.-P. Sandell, Orion Pharma, Espoo, Finland. Study nurses: K. Hautakoski, Keski-Pohjanmaa Central Hospital, Finland; J. Lamminen, Hyvinkää Hospital, Finland; M.-L. Niskanen, Kuopio University Hospital, Finland; M. Pietilä, Helsinki University Central Hospital, Finland; O. Surakka, Central Finland Central Hospital, Finland.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Appendix
 Acknowledgements
References
 
The study was supported by grants from the Finnish Foundation for Cardiovascular Research, Paulo Foundation, and an unrestricted grant from Orion Pharma. Roche Diagnostics kindly provided kits for the analysis of NT-proBNP and a grant for the study of sample logistics. J.L. was supported by personal grants from Aarne Koskelo Foundation and Perkléns Foundation. We are thankful to Mervi Pietilä for technical assistance and Pirjo Tanner and Aija Helin for laboratory analysis.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Appendix
 Acknowledgements
 References
 

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