The Korean Journal of Hepatology 2010;16:301-307 DOI: 10.3350/kjhep.2010.16.3.301
Original Article
Diagnostic value of cystatin C for predicting acute kidney injury in patients with liver cirrhosis Mi Yeon Chung1, Dae Won Jun2, Su Ah Sung1 1
Department of Internal Medicine, Eulji University School of Medicine, Seoul, Korea 2Department of Internal Medicine, Hanyang University School of Medicine, Seoul, Korea Background/Aims: The present study aimed to determine the role of cystatin C as a prognostic factor for acute kidney injury and survival in cirrhotic patients. Methods: The study investigated 53 liver cirrhosis patients. The renal function was evaluated by serum creatinine, serum and urine cystatin C, and 24-hour creatinine clearance on admission. Acute kidney injury was defined as a serum creatinine level exceeding the normal range (>1.2 mg/dl) and an increase of at least 50% from the baseline value. Multivariate analysis, receiver operating characteristic curve, and survival analysis were used to investigate prognostic factors for acute kidney injury and survival. Results: Nine of the 53 cirrhotic patients (17.0%) developed acute kidney injury within 3 months. Both serum creatinine and cystatin C were predictive factors for acute kidney injury in univariate analysis, with a diagnostic accuracy of 0.735 (95% confidence interval (CI), 0.525-0.945; p=0.028) for serum cystatin C and 0.698 (95% CI, 0.495-0.901, p=0.063) for creatinine. In multivariate analysis, only serum cystatin C was an independent risk factor for acute kidney injury. The sensitivity and specificity of a serum cystatin C level of >1.23 mg/L to acute kidney injury were 66% and 86%, respectively. Serum cystatin C was positively correlated with the Model for End-Stage Liver Disease (MELD) and MELD-Na scores (r=0.346 and p=0.011, and r=0.427 and p=0.001, respectively). Comparison of the survival rates over the observation period revealed that a serum cystatin C level of >1.23 mg/L was a useful marker for short-term mortality (p1.23 mg/L than for the serum creatinine concentration in patients with cirrhosis. (Korean J Hepatol 2010;16:301-307) Keywords: Cystatin C; Liver cirrhosis; Acute kidney injury
INTRODUCTION
The most frequently used clinical markers of renal failure include serum creatinine, creatinine clearance, and glomerular
Acute kidney injury is frequently observed in patients with
filtration rate (GFR) measured by dynamic methods.3,4 Unfor-
liver cirrhosis, and is associated with infection, the use of
tunately, in cirrhotic patients, serum creatinine measurements
diuretics, reduced effective circulating volume and hepatorenal
must be interpreted with caution because they can be detected
1 syndrome. In cirrhotic patients, acute kidney injury is
within normal ranges by poor dietary intake, loss of muscle mass,
particularly dangerous because it poses an obstacle to treatment
5 and renal tubular secretion. Acute kidney injury is not accompanied
and has a direct correlation to mortality. In the case of an
by increase in serum creatinine simultaneously in patients with
early-stage decline in renal function, it is possible to achieve
liver cirrhosis and ascites.6,7 Several early markers of renal
recovery, or at least delay the deterioration of renal disease, with
dysfunction have been proposed, including urine neutrophil
active treatment. However, advanced renal failure results in a very
gelatinase-associated lipocalin, kidney injury molecule-1, and
1,2
high mortality rate. Therefore, recognizing renal injury during
interleukin-18.8-10 However, these markers require complicated test
its early stage and beginning aggressive treatment is likely to
procedures, as well as additional research regarding their efficacy.11
delay the deterioration of renal function and improve prognosis.
Cystatin C is known to be a superior marker of renal function
Received May 28, 2010; Revised August 11, 2010; Accepted August 18, 2010 Abbreviations: GFR, glomerular filtration rate; MELD, Model for End-Stage Liver Disease; MDRD, Modification of Diet in Renal Disease Corresponding author: Dae Won Jun, M.D. Department of Internal Medicine, Hanyang University School of Medicine, Haengdang 1-dong, Sungdong-gu, Seoul 133-792, Korea. Tel: +82-2-2290-8338, Fax: +82-2-972-0068, E-mail:
[email protected] Copyrights Ⓒ 2010 by The Korean Association for the Study of the Liver The Korean Journal of Hepatology∙pISSN: 1738-222X eISSN: 2093-8047
302 The Korean Journal of Hepatology Vol. 16. No. 3, September 2010
than creatinine, especially for cirrhotic patients whose muscle
Disease (MELD), and MELD-Na scores. The Child-Pugh score
mass tends to be smaller, because it is produced not just in muscle
was assigned as a number between 5 and 15 according to serum
2,12
cells but in all nucleated cells.
albumin, bilirubin, prothrombin time extension, ascites, and
Gerbes et al. found that serum cystatin C is more effective for detecting kidney injury in advanced cirrhotic patients than serum
hepatic encephalopathy, then divided into three classes: A (5-6), 16
B (7-9), and C (10-15).
creatinine.2 There is also a study that reported the efficacy of
The renal function of cirrhotic patients was evaluated by
cystatin C as an early biomarker for predicting the occurrence of
testing for serum creatinine, serum and urine cystatin C (Human
13
acute kidney injury. Others have proposed the possibility of
Cystatin C ELISA kits; BioVendor LLC, Candler, NC, USA),
using serum cystatin C in patients with diabetes or heart failure as
and 24-hour creatinine clearance. Serum sample was obtained at
a prognostic factor enabling the early detection of mild renal
admission time. Urine sample was collected for 24 hours, from
14,15
dysfunction and the prediction of mortality.
However, there
the second hospital day to the next day. Samples were assayed
are only a limited number of studies that examine the possibility
immediately or stored at -20℃. Cystatin C assay employed the
of using cystatin C as an early marker for predicting acute kidney
quantitative sandwich enzyme immunoassay technique. Cystatin
injury and survival in patients with liver cirrhosis.
C kits microplates were precoted with monoclonal antibody
Therefore, this study observed the changes in renal function in
specific for cystatin C. Dilution buffer was used to dilute samples.
patients with liver cirrhosis to evaluate the role of cystatin C as a
Modification of Diet in Renal Disease (MDRD) equation was
prognostic factor for acute kidney injury. It also examined the
used to calculate the estimated GFR (e-GFR) using the following
efficacy of cystatin C measurements in predicting patient survival
formula: e-GFRMDRD (mL/min/1.73m2)=186×(serum creatinine)-1.154×
rates.
(age)-0.203×(0.742 if female).
PATIENTS AND METHODS The following three formulae were used to calculate the
1. Patients This study was conducted by retrospective review on consecutive
estimated GFRs (e-GFRs) using serum cystatin C: e-GFRHoek (mL/min)=80.35/serum cystatin C-4.32.17
cirrhotic patients who were hospitalized in Department of
e-GFRLansson (mL/min)=99.43×serum cystatin C-1.5837.18
Gastroenterology from June to December 2007. The diagnosis of
e-GFRLesley (mL/min)=177.6×serum creatinine-0.65×cystatin
liver cirrhosis was defined as the combination of a physical
C-0.57×age-0.20×(0.82 if female).4
examination showing ascites, an endoscopy showing the existence of varices, and an abdominal ultrasonography or computed
Acute kidney injury was defined as a serum creatinine level
tomography indicating cirrhosis of the liver. At the time of
was detected over normal range (>1.2 mg/dL) at follow-up
admission, patients with acute infection, gastrointestinal bleeding,
sample and showed increase of 50% or more from the baseline
or acute renal failure, as well as those undergoing hemodialysis
value. Instances suggesting obvious prerenal or intrinsic-renal
or peritoneal dialysis due to chronic kidney disease, were
injury caused by dehydration, bleeding, septicemia, drug etc.
excluded from the study. Follow-ups were performed every three
were excluded from analysis.
months for patients with compensated liver cirrhosis, and every 1-2 months for those with decompensated liver cirrhosis. This
3. Statistical analysis
study was approved by institutional review board (IRB) in Eulji
All statistical analysis was performed using spss version 12.0
University Hospital.
k (SPSS Inc., Chicago, IL, USA). Data were presented as mean± SD or n (%). The chi-square test and Mann-Whitney U-test were
2. Methods
used to compare variables for renal and hepatic functions
To evaluate the liver function of cirrhotic patients, a range of
between different patient groups. The results of comparing the
tests consisting of serum albumin, bilirubin, prothrombin time,
correlation between two continuous variables were indicated by
electrolytes, physical examination, and ultrasonography were
the correlation coefficient (r) using correlation analysis. The
performed to obtain the Child-Pugh, Model for End-Stage Liver
reference values for creatinine and serum cystatin C were
Mi Yeon Chung, et al. Cystatin C in cirrhosis 303
expressed using a receiver operating characteristic (ROC) curve.
The MELD score was 14.11±6.22, and the MELD-Na score was
Reference values were defined the maximum sum of sensitivity
16.41±7.48. The mean duration of follow-up was 13±8.9 months
and specificity with over 0.6 of each value. Cross tabulation
(average±standard deviation). The baseline characteristics were
analysis was used to derive the sensitivity, specificity, positive
shown in Table 1.
predictive value, and negative predictive value of the reference values. Survival analysis was used to compare the cumulative incidence of acute kidney injury and mortality rate during the
2. Serum and urine cystatin C in patients with liver cirrhosis
observation period. Logistic regression test was performed to
Creatinine clearance and the e-GFRMDRD showed a negative
identify independent factors impacting acute kidney injury and
correlation with serum cystatin C [r=-0.532 (p
