302

ORIGINAL
Plasma Cystatin C Level is a Prognostic Marker of Morbidity
and Mortality in Hospitalized Decompensated Cirrhotic
Patients
Natsuda Aumpan1, Tanabute Limprukkasem1, Bubpha Pornthisarn1, Ratha-korn Vilaichone1, 2,
Soonthorn Chonprasertsuk1, Patommatat Bhanthumkomol1, Pichaya Tantiyavarong3, and Sith Siramolpiwat1, 2
Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Thammasat University, Pathumthani, Thailand
Department of Medicine, Chulabhorn International College of Medicine (CICM), Thammasat University, Pathumthani, Thailand
3
Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Thammasat University, Pathumthani, Thailand
1

2

Abstract : Introduction : Cystatin C (CysC) is biomarker for early detection of acute kidney injury (AKI). However, there is limited evidence in decompensated cirrhotic patients without AKI at admission. This study aimed
to assess CysC as a predictor of 90-day mortality. Methods : Decompensated cirrhotic patients without AKI were
prospectively enrolled. CysC and creatinine were measured within 24 hours of admission and compared between patients with in-hospital complications (AKI, hepatorenal syndrome (HRS), acute-on-chronic liver failure(ACLF)) vs. those without, and survivors vs. non-survivors. The AUROC and cut-off point of CysC in predicting
90-day mortality were determined. Results : Of 137 decompensated cirrhotic patients, 46 without AKI at admission were included (58.7% male, age 60.8 ± 11.2years, MELD 13.1 ± 5.1, ChildA / B / C 43.5% / 39.1% / 17.4%). The mean
CysC level tended to be higher in patients with ACLF (1.52 ± 0.60 vs. 1.11 ± 0.28, p = 0.05), and significantly higher
in non-survivors than survivors (1.61 ± 0.53 vs. 1.08 ± 0.28, p = 0.013). The 90-day mortality rate was 21.7%. After adjusting with age and bacterial infection on admission, CysC level ≥ 1.25 mg / L was significantly associated with
90-day mortality. The CysC cut-off level  ≥ 1.25 mg / L provided 80% sensitivity and 75% specificity for predicting
90-day mortality. Conclusion : Plasma CysC within 24 hours could be used as a predictor for 90-day mortality anddevelopment of ACLF in decompensated cirrhotic patients. J. Med. Invest. 68 : 302-308, August, 2021
Keywords : Cystatin C, Cirrhosis, Acute kidney injury, Acute-on-chronic liver failure

INTRODUCTION
Acute kidney injury (AKI) is a common complication associated with high morbidity and mortality in decompensated cirrhotic
patients (1, 2). Approximately 20% of hospitalized patients withcirrhosis experience deterioration of renal function predominantly caused by prerenal azotemia and acute tubular necrosis(3). Early diagnosis of AKI in cirrhotic patients is essential toprevent its progression and reduce mortality. Serum creatinine,
an indicator of renal function, is widely used for the diagnosis of
AKI in clinical practice. However, several limitations should betaken into consideration as serum creatinine might overestimate
renal function, especially in cirrhotic patients (4, 5). Falsely
decreased creatinine in cirrhosis can be resulted from 4 main
reasons : diminished creatinine production due to sarcopenia(6) ; dilution effect from increased volume of distribution (7) ; increased renal tubular creatinine excretion (8) ; bilirubin interference in creatinine estimation (9). Therefore, these drawbacks
have inspired researchers to find new biomarkers to provide
more accurate assessment of renal function in cirrhotic patients.
Cystatin C (CysC) is non-glycosylated, low-molecular-weight
List of abbreviations :CysC, Cystatin C ; AKI, acute kidney injury ; ACLF, acute-on-chronic
liver failure ; HRS, hepatorenal syndrome ; MELD ; model for endstage liver disease ; HIV, human immunodeficiency virus ; GFR,
Glomerular filtration rate ; CKD-EPI, chronic kidney disease epidemiology collaboration ; ROC, receiver operating characteristic ; AUROC, area under the ROC curve ; SBP, spontaneous bacterial
peritonitis ; NASH, non-alcoholic steatohepatitis ; PHT, portal hypertension ; WBC, white blood cell ; AST, aspartate transaminase ; ALT,
alanine transaminase; ALP, alkaline phosphatase ; INR, international normalized ratio

protein produced by all nucleated cells at a constant rate. Since
1994, CysC has been introduced as a surrogate marker for determining glomerular filtration rate (10). CysC is freely filteredby glomerulus, completely reabsorbed, and metabolized by proximal tubular cells. In contrast to creatinine, CysC is not affectedby demographic factors and muscle mass (11). These properties
make CysC a good candidate for estimating renal function in cirrhotic patients. Previous studies suggested that CysC might be a
predictor of early renal dysfunction in cirrhotic patients (12-16).
Moreover, the CysC level of more than 1.5 mg / L could predict
90-day mortality in decompensated cirrhotic patients with sensitivity and specificity of 73.3% and 52.5%, respectively (12). Thechanges in CysC level also demonstrated stronger association
with dialysis or mortality than serum creatinine in cirrhotic
patients with AKI (16).
Until now, there have been limited data regarding prognostic
ability of plasma CysC in hospitalized decompensated cirrhotic
patients. This study aimed to determine the efficacy of plasma
CysC as a predictor of morbidity and mortality in acutely decompensated cirrhotic patients who had no AKI on the day ofadmission.
Received for publication January 18, 2021 ; accepted May 31, 2021.
Address correspondence and reprint requests to Sith Siramolpiwat,
MD., Chulabhorn International College of Medicine and Division of
Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Thammasat University, Pathumthani, Thailand and Fax : +66(2)926-9793.

The Journal of Medical Investigation Vol. 68 2021

The Journal of Medical Investigation Vol. 68 August 2021
MATERIALS AND METHODS
Study design and population

This prospective observational study was conducted at
Thammasat University Hospital between October 1, 2017 andNovember 30, 2019. The inclusion criteria were hospitalized
patients diagnosed with acute decompensated cirrhosis aged
between 18 and 80 years old. The exclusion criteria were thepresence of AKI on the day of admission, chronic kidney disease(CKD), pregnancy, hypothyroidism or hyperthyroidism, historyof steroid use, previous liver or kidney transplantation, hepatocellular carcinoma, HIV infection, receiving immunosuppressive
drugs for any disease except severe alcoholic hepatitis, or refusal
to participate in the study.
This study received ethical approval by the Human Research
Ethics Committee of Thammasat University, Thailand and was
conducted according to the good clinical practice guideline, as
well as the Declaration of Helsinki. Written informed consent
was obtained from all participants. The patient’s relative could
provide written informed consent instead of the patient himself
in case of being diagnosed with hepatic encephalopathy. The
informed consent was then requested from the patient after
the resolution of hepatic encephalopathy for continuation in the
study.

Study protocol
All patients were included in this study within 24 hours ofadmission. Demographic data, etiologies of cirrhosis, underlying
medical conditions, history of present illness, physical examination, and treatment outcomes were recorded. Laboratory results
including a complete blood count, a comprehensive metabolic
panel, coagulation tests, hemoculture, ascitic fluid analysis andculture, urinalysis and urine culture were recorded. The ChildPugh score, the model for end-stage liver disease (MELD) score,and MELD-Na score were calculated to assess severity of liver
impairment. Blood samples for determining plasma CysC andserum creatinine were collected from each patient at the sametime within 24 hours of admission. At least 1-ml plasma sample
was obtained by centrifugation and then stored at -20°C until
CysC analysis was performed by using nephelometry (13). All patients received standard treatment for acute decompensated cirrhosis. The 90-day mortality rate was prospectively evaluated.
The primary aim was to determine the efficacy of plasma
CysC as a predictor of 90-day mortality in acutely decompensated cirrhotic patients without AKI on the day of admission. The
secondary aim was to evaluate the efficacy of plasma CysC as apredictor of in-hospital AKI, hepatorenal syndrome (HRS) andacute-on-chronic liver failure (ACLF) in acutely decompensatedcirrhotic patients.

Definitions
Acute decompensation was defined as an acute development of one or more of the following complications : ascites,
hepatic encephalopathy, gastrointestinal bleeding, or bacterial
infection in a patient with cirrhosis (17).
Acute-on-chronic liver failure (ACLF) was defined according to the diagnostic criteria established in the CANONIC
study (17).
Acute kidney injury (AKI) was defined as an increase inserum creatinine of ≥ 0.3 mg / dL within 48 hours ; or a percentage increase in serum creatinine of ≥ 50% from baseline which
is known or presumed to have occurred within the previous 7
days (9).
Hepatorenal syndrome (HRS) was defined as the diagnosis of cirrhosis and ascites in concurrent with the diagnosis of
AKI. In addition, the diagnostic criteria included no response of303

AKI after 2 consecutive days of diuretic withdrawal and plasma
volume expansion with 1 gram of albumin per kilogram of bodyweight, absence of shock, no current or recent use of nephrotoxic
drugs, and no macroscopic signs of structural kidney injury (9).
Glomerular filtration rate (GFR) was calculated by using
the chronic kidney disease epidemiology collaboration (CKDEPI) equation based on serum creatinine, or CysC (18).
Chronic kidney disease (CKD) was defined as either structural or functional renal abnormalities. The presence of either
one of markers for kidney damage (e.g., albuminuria, urine sediment abnormalities) or decreased GFR < 60 ml / min / 1.73 m2 for> 3 months is considered as CKD (19).

Statistical analysis
All statistical analyses were performed by using STATA software version 12.0 (Stata Corp, Texas, USA). The demographic
data and clinical characteristics were analyzed by Fisher’s exact
test, or Chi-square test where appropriate. Laboratory results
were compared between 90-day survivors and non-survivors
using Student’s t-test. Plasma CysC level was presented as meanand standard deviation and evaluated for association with thedevelopment of in-hospital complications (AKI, HRS, ACLF),
and 90-day mortality. The receiver operating characteristic(ROC) curve analysis of CysC for predicting 90-day mortality
was performed, and the optimal cut-off point which yielded thehighest sensitivity and specificity was selected. The area under
the ROC curve (AUROC) of CysC and MELD score for predicting 90-day mortality was compared. Statistical significance wasdefined as p-value of less than 0.05.
Sample size for two-sample comparison of means was calculated in order to achieve 90% power using a two-sided test withan alpha level of 0.05. The means of plasma CysC used in thecalculation were from the previous study in which patients who
survived had a mean plasma CysC of 1.5 ± 0.23 mg / L, whereas
patients who died within 90 days had a mean of 1.9 ± 0.33 mg / L(12). The estimated total sample size was at least 42.

RESULTS

Patient characteristics
Of 137 decompensated cirrhotic patients admitted during thestudy period, 91 patients (27 with AKI, 59 with chronic kidneydisease, and 5 with hepatocellular carcinoma) were excluded
from the study. A total of 46 patients were prospectively enrolled(27 men and 19 women) with a mean age of 60.8 ± 11.2 (range 4080) years. All patients were diagnosed with acute decompensated cirrhosis without AKI on the day of admission. The average
serum creatinine within the previous 3 months before the study
entry of all patients was 0.8 ± 0.2 mg / dl, meanwhile the previous
urinary examination (available in 32 / 46 patients) showed nosignificant abnormalities (e.g., albuminuria, urine sediments).
The most common causes of cirrhosis were alcohol (50%), chronic
hepatitis B infection (17.4%) and non-alcoholic steatohepatitis(17.4%). There were 20 (43.5%), 18 (39.1%), and 8 (17.4%) patientsclassified as Child-Pugh class A, B, and C, respectively. The
mean MELD and MELD-Na score were 13.1 ± 5.1 and 15.1 ± 5.4,
respectively. The most common comorbidities were diabetes(39.1%), hypertension (34.8%), and dyslipidemia (17.4%), whereas 18 (39.1%) patients had no comorbidity. Majority of patients
had bacterial infection (37%), and portal hypertension-related
gastrointestinal bleeding (34.8%) as presenting symptoms ofdecompensation. Baseline characteristics of all patients were
demonstrated in the Table 1.
Laboratory results at baseline including complete blood count,renal and liver function test were demonstrated in the Table 2.

N. Aumpan, et al. Plasma Cystatin C in decompensated cirrhosis304

The mean serum creatinine was 0.85 ± 0.17 mg / dL, and mean
plasma CysC was 1.20 ± 0.41 mg / L. The means of GFR estimated by serum creatinine and plasma CysC were 86.3 and 68.3
ml / min, respectively. There was no significant difference of themean CysC level according to Child-Pugh classes (1.09 ± 0.27
mg / L for Child-Pugh A vs. 1.22 ± 0.33 mg / L for Child-Pugh B vs.
1.41 ± 0.72 mg / L for Child-Pugh C, p = 0.164).

The 90-day mortality
There were 10 patients (21.7%) who died within 90 days. Six
deaths were due to sepsis with multiorgan failure, two frommassive gastrointestinal hemorrhage, and another two fromACLF with progressive liver deterioration. All 5 patients whodeveloped in-hospital AKI died within 90 days, 4 of whom diedduring admission, while the other one survived and subsequently died 41 days after being discharged from hospital due to sepsis
with multiorgan failure. Baseline characteristics along withlaboratory results were compared between 90-day survivors andnon-survivors as demonstrated in the Table 1 and 2. The mean
age of non-survivors was significantly higher than survivors(70.1 ± 8.4 vs. 58.2 ± 10.5, p = 0.002). Alcoholic cirrhosis was moreprevalent in survivors, whereas cirrhosis due to unidentified
causes was more common in non-survivors. Non-survivors had
significantly higher MELD-Na score than survivors (18.9 ± 6.6
vs. 14.1 ± 4.6, p = 0.010). Meanwhile the MELD score was higher
in non-survivor (15.2 ± 6.5 vs. 12.5 ± 4.6), however no statisticalsignificance was reached (p = 0.136). The diagnosis of bacterial
infection (70% vs. 27.8%, p = 0.025), and spontaneous bacterial
peritonitis (SBP) (50% vs. 8.3%, p = 0.007) on current admission
were more prevalent in non-survivors than survivors. In addition, the mean CysC level was 1.39 ± 0.42 mg / L in the groupwith bacterial infection compared to 1.08 ± 0.36 mg / L in thegroup without (p = 0.012). The average length of hospital stay
was 8 ± 7 days. Non-survivors had slightly longer average lengthof hospital stay than survivors (9.9 ± 9.5 days vs. 7.9 ± 6.7 days,
p = 0.459).

Table 1. Baseline and clinical characteristics of included patients and comparison between 90-day survivors and non-survivors
Factors

Total(N = 46)

Survivors(N = 36)

Non-survivors(N = 10)

P-value*

4 (40%)

0.277

Male (%)

27 (58.7%)

23 (63.9%)

Mean age

60.8 ± 11.2

58.2 ± 10.5

70.1 ± 8.4

0.002

Body mass index (kg / m2)

23.7 ± 4.2

23.6 ± 4.0

23.9 ± 5.1

0.855

Diabetes mellitus

18 (39.1%)

14 (38.9%)

4 (40%)

1.000

Hypertension

16 (34.8%)

10 (27.8%)

6 (60%)

0.074

Dyslipidemia

8 (17.4%)

4 (11.1%)

4 (40%)

0.055

Cardiovascular disease

4 (8.7%)2 (5.6%)

2 (20%)

0.201

None

18 (39.1%)

15 (41.7%)

3 (30%)

0.717

Alcohol

23 (50.0%)

22 (61.1%)

1 (10%)

0.004

Chronic hepatitis B

8 (17.4%)

7 (19.4%)

1 (10%)

0.664

Chronic hepatitis C

6 (13.0%)

3 (8.3%)3 (30%)

0.107

Comorbidities

Underlying liver diseases
Cirrhosis etiology

NASH

8 (17.4%)

5 (13.9%)

3 (30%)

0.344

Cryptogenic

4 (8.7%)

1 (2.8%)3 (30%)

0.028

A

20 (43.5%)

17 (47.2%)

3 (30%)

B

18 (39.1%)

13 (36.1%)

5 (50%)

Child-Pugh class

C

0.616

8 (17.4%)

6 (16.7%)

2 (20%)MELD (Mean ± SD)

13.1 ± 5.1

12.5 ± 4.6

15.2 ± 6.5

0.136

MELD-Na (Mean ± SD)

15.1 ± 5.4

14.1 ± 4.6

18.9 ± 6.6

0.010

22 (61.1%)

6 (60%)

1.000

Previous decompensation

28 (60.9%)

Acute decompensation present on current admission
Bacterial infection

17 (37%)10 (27.8%)

7 (70%)

0.025

SBP

8 (17.4%)

3 (8.3%)5 (50%)

0.007

PHT-related
gastrointestinal bleeding

16 (34.8%)

15 (41.7%)

1 (10%)

0.130

Hepatic encephalopathy

6 (13.0%)

5 (13.9%)

1 (10%)

1.000

Ascites2 (4.3%)2 (5.6%)0 (0%)

1.000*The p-value of < 0.05 represents significant difference between survivors and non-survivors.
Abbreviations : NASH = non-alcoholic steatohepatitis, MELD = model for end-stage liver disease, SBP = spontaneous bacterial peritonitis PHT = portal hypertension

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The Journal of Medical Investigation Vol. 68 August 2021
Table 2. Laboratory findings of included patients and comparison between 90-day survivors and non-survivors
Factors

Total(N = 46)

Survivors(N = 36)

Non-survivors(N = 10)

P-value*

Complete blood countHemoglobin (g / dL)

9.4 ± 2.2

9.6 ± 2.3

8.6 ± 2.5

0.205

WBC count (x109 / L)

8.4 ± 4.3

8.8 ± 4.6

7.2 ± 2.6

0.297

Platelet count (x109 / L)

109 ± 47

115 ± 48

89 ± 43

0.136

Serum creatinine (mg / dL)

0.85 ± 0.17

0.82 ± 0.16

0.97 ± 0.14

0.010

Plasma cystatin C (mg / L)

1.20 ± 0.41

1.08 ± 0.28

1.61 ± 0.53

0.013

CKD-EPI Cr (ml / min)86.3 ± 18.3

91.3 ± 16.1

68.3 ± 14.2

< 0.001CKD-EPI CysC (ml / min)68.3 ± 26.2

75.1 ± 24.0

43.8 ± 18.4

< 0.001

Renal function test

Glomerular filtration rate

Liver function test
Total protein (g / dl)

6.8 ± 1.0

6.8 ± 1.0

6.7 ± 1.1

0.779

Serum albumin (g / dl)

2.4 ± 0.6

2.5 ± 0.6

2.1 ± 0.5

0.114

Total bilirubin (mg / dl)

3.2 ± 3.7

2.9 ± 3.4

4.3 ± 4.5

0.307

Direct bilirubin (mg / dl)

1.9 ± 2.7

1.6 ± 2.5

2.8 ± 3.5

0.209

AST (U/L)

86 ± 89

93 ± 98

61 ± 410.324

ALT (U/L)

49 ± 8153 ± 91

34 ± 110.520

ALP (U/L)

157 ± 105152 ± 72173 ± 187

0.580

1.52 ± 0.42

1.42 ± 0.31

1.90 ± 0.55

0.024

6.8 ± 2.3

6.7 ± 2.6

6.9 ± 2.4

0.68

Coagulation test
INR
Other
Uric acid (mg / dl)*The p-value of < 0.05 represents significant difference between survivors and non-survivors.
Abbreviations : CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration, Cr = creatinine, CysC = cystatin C, WBC = white blood cell, AST = aspartate transaminase, ALT = alanine transaminase, ALP = alkaline
phosphatase, INR = international normalized ratio

All renal function parameters on the first day of admission
in non-survivors were worse than survivors. Serum creatinine(0.97 ± 0.14 vs. 0.82 ± 0.16, p = 0.01) and plasma CysC (1.61 ± 0.53
vs. 1.08 ± 0.28, p = 0.013) in non-survivors were significantly
higher than survivors, while creatinine- and CysC-based glomerular filtration rate (GFR) were lower. International normalized ratio (INR) was also higher in patients who died (1.90 ± 0.55
vs. 1.42 ± 0.31, p = 0.024). Other laboratory results including
complete blood count and liver function test were not significantly different between 2 groups.

Development of AKI, HRS, and ACLF
Five patients (10.9%) developed AKI during admission. The
causes of AKI were prerenal azotemia (60%) and hepatorenal
syndrome (40%). The mean of plasma CysC tended to be higher in patients who developed AKI (1.82 ± 0.71 vs. 1.12 ± 0.29
mg / L, p = 0.093), whereas there was no significant differenceof baseline serum creatinine between 2 groups (0.94 ± 0.15 vs.
0.84 ± 0.17 mg / dL, p = 0.214). Of the 5 patients with in-hospital
AKI, all had normal serum creatinine, whereas 4 patients (80%)
had elevated plasma CysC on the first day of admission. Twopatients who developed HRS during admission had higher meanof plasma CysC than those without, however no statistical significance was reached (2.03 ± 1.00 vs. 1.16 ± 0.34 mg / L, p = 0.434).
On the contrary, there was no significant difference of baseline
serum creatinine between patients who developed HRS andthose who did not (0.87 ± 0.21 vs. 0.85 ± 0.17 mg / dL, p = 0.892).

ACLF were diagnosed in 10 patients (21.7%), 4 of whom diedduring admission. Half of all ACLF patients had renal failure as
one of organ failure. The mean of plasma CysC tended to be higher in patients who developed ACLF (1.52 ± 0.60 vs. 1.11 ± 0.28
mg / L, p = 0.05), whereas there was no significant difference
in baseline serum creatinine between 2 groups (0.93 ± 0.16 vs.
0.83 ± 0.17 mg / dL, p = 0.102).

Predictors of AKI, HRS, ACLF, and 90-day mortality
The ROC curve analysis showed that the AUROC of plasma CysC in predicting 90-day mortality was 0.85 (95% CI
0.71-0.97), which was marginally superior to the MELD score(AUROC 0.64, 95% CI 0.43-0.84, p = 0.04). The best cut-off
value of plasma CysC for predicting 90-day mortality was ≥ 1.25
mg / L, which yielded sensitivity and specificity of 80% and 75%,
respectively. Patients with CysC of ≥ 1.25 mg / L demonstrated
significant association with 90-day mortality (OR 12 ; 95%CI
2.14-67.24, p = 0.005).
In terms of in-hospital AKI, the AUROC curve of plasma
CysC in predicting in-hospital AKI was 0.79 (95% CI 0.39-1.0).
The cut-off value of plasma CysC ≥ 1.25 mg / L for predicting
in-hospital AKI provided sensitivity and specificity of 80%
and 68%, respectively. The AUROC curve of plasma CysC in
predicting in-hospital ACLF was 0.75 (95% CI 0.56-0.93). The
cut-off value of plasma CysC ≥ 1.25 mg / L for predicting in-hospital ACLF yielded sensitivity and specificity of 70% and 72%,
respectively. Patients with CysC of ≥ 1.25 mg / L demonstrated

N. Aumpan, et al. Plasma Cystatin C in decompensated cirrhosis

306

a significant association with the development of ACLF (OR6.07 ; 95%CI 1.31-28.20, p = 0.021). Plasma CysC as a predictor
for development of in-hospital AKI, HRS, ACLF, and 90-day
mortality was demonstrated in the Table 3.
Table 4 shows univariate logistic regression analysis of factors
associated with 90-day mortality. Baseline demographic data
including severity of liver cirrhosis, type of decompensation,and initial laboratory parameters were included in the analysis. By univariate logistic regression analysis, age, MELD-Na
score, bacterial infection on admission, SBP on admission, andplasma CysC level ≥ 1.25 mg / L were significantly associatedwith 90-day mortality. Taking into account that the number of
event in this study was low, we therefore decided to include only
3 factors in the multivariate regression model : age, bacterial
infection, and plasma CysC level ≥ 1.25 mg / L. The MELD-Na
score was excluded because it may collinear with plasma Cys C
level given that both factors were based on the patients’ kidney
function. Similarly, SBP was excluded because of its collinearity
with bacterial infection. As shown, after adjusting with age
and bacterial infection, plasma CysC level ≥ 1.25 mg / L was independently associated with 90-day mortality with an adjusted
OR of 6.70 (95%CI 1.05-42.73), however the statistical significant
was borderline (p = 0.044).

DISCUSSION
This is a prospective observational study investigating the
prognostic ability of plasma CysC in predicting in-hospitalcomplications and 90-day mortality in acutely decompensatedcirrhotic patients without AKI at admission. The data suggested
that plasma CysC level within 24 hours after admission was significantly higher in 90-day non-survivors, and it could be used asa reliable marker for prediction of in-hospital ACLF, and 90-day

mortality in these patients. In addition, by multivariate analysis,
plasma CysC ≥ 1.25 mg / L was an independent predictor of 90day mortality.
Acute kidney injury frequently occurs as a complication leading to grave prognosis in decompensated cirrhosis (1, 2). Thesepatients are generally susceptible to intravascular volume depletion resulted from many conditions such as gastrointestinal
bleeding, diarrhea, or sepsis-induced microvascular leakage (3).
These precipitating events cause a decrease in effective arterial
blood volume which can activate neurohormonal system, subsequently induce renal vasoconstriction, and contribute to AKI (3).
Apart from precipitating factors, the severity of cirrhosis itself
can provoke AKI through the mechanism of reduced renal bloodflow due to portal hypertension in HRS (20). Our study demonstrated a lower number of patients who developed in-hospital
AKI compared with other study (10.9% vs. 53%) (21). This could
be explained by the fact that our study mainly comprised ChildPugh A cirrhosis with relatively low MELD score resulting in alower rate of complications and mortality (22). However, anotherstudy revealed a comparable number of hospitalized decompensated cirrhotic patients who later developed renal dysfunction(14%) during admission using different criteria for renal dysfunction (serum creatinine ≥ 1.5 mg / dL) (12). It should be notedthat the demographic factors including age and male preponderance of our cohort were almost similar to the previous study (12).
Cystatin C has been recognized as a promising biomarker
to evaluate renal function for several years (10). Studies havereported that it could overcome limitations of serum creatinineand facilitate early detection of AKI in cirrhotic patients (12-16).
So far, few studies have evaluated the role of plasma CysC in
hospitalized cirrhosis with acute decompensation (12, 15). The
recent prospective study in hospitalized cirrhotic patients using
CANONIC database has found that higher plasma CysC level
was associated with the development of renal dysfunction, ACLF

Table 3. Plasma cystatin C as a predictor for development of in-hospital AKI, HRS, ACLF, and 90-day mortality
Cystatin < 1.25 mg / L(N = 29)

Cystatin ≥ 1.25 mg / L(N = 17)

Odds ratio (95% CI)

AKI

1 (3.4%)4 (23.5%)

8.62 (0.87-84.9)

0.065

HRS

0

2 (11.8%)

-

0.131

ACLF

3 (10.3%)

7 (41.2%)

6.07 (1.31-28.20)

0.021

Death within 90 days

2 (6.9%)8 (47.1%)

12 (2.14-67.24)

0.005

OutcomeP-value

Abbreviations : AKI = acute kidney injury, HRS = hepatorenal syndrome, ACLF = acute-on chronic liver failur

Table 4. Univariate and multivariate analysis of factors associated with 90-day mortality
Variables

Univariate analysis

Multivariate analysis

OR (95% CI)

P-value

OR (95% CI)

P-value

1.11 (1.03-1.20)

0.006

1.07 (0.98-1.17)

0.133Child-Pugh class A

1-

Child-Pugh class B

2.18 (0.44-10.83)

0.341Child-Pugh class C

1.89 (0.25-14.19)

0.537

MELD-Na

1.18 (1.02-1.37)

0.022

Bacterial infection

6.07 (1.31-28.2)

0.021

1.99 (0.29-13. 41)

0.477

SBP on admission

11 (1.98-61)

0.006

Plasma cystatin C ≥ 1.25 mg / L

12 (2.14-67.24)

0.005

6.70 (1.05-42.73)

0.044

Age

Abbreviations : MELD = model for end-stage liver disease, SBP = spontaneous bacterial peritonitis

The Journal of Medical Investigation Vol. 68 August 2021
and 90-day mortality (12). However, it should be noted that morethan one-third of the included patients in the previous study had
impaired renal function during the inclusion period. This factpotentially limits the clinical application of plasma CysC as an
early marker of kidney injury in decompensated cirrhosis if one
already had impaired renal function at baseline. Therefore, ourstudy aimed to explore the predictive ability of plasma CysC indecompensated cirrhosis who had no AKI at admission. In thepresent study, we found that the mean plasma CysC was higher
in patients who died within 90 days compared with those who
were alive. Moreover, patients who developed in-hospital AKI,HRS and ACLF tended to have higher CysC level than patients
without these conditions. The mean CysC values of patients who
had in-hospital AKI and HRS (1.82 and 2.03 mg / L, respectively)
were quite comparable to what have been reported in the earlier study (1.6 and 2.1 mg / L, respectively) (12). In addition, we
demonstrated that the cut-off value of plasma CysC level ≥ 1.25
mg / L yielded the best sensitivity for prediction of 90-day mortality. The cut-off point was slightly lower than previously reported,which could be possibly attributed to variability of patients included and ethnic diversity(12).
Most of patients (80%) who developed in-hospital AKI in thisstudy had elevated plasma CysC but normal serum creatininelevel on the first day of admission. This suggested that elevatedbaseline plasma CysC level could predict AKI earlier than a risein serum creatinine in hospitalized decompensated cirrhotic
patients. In addition to renal outcomes, this study disclosed an
association between higher CysC level and the development of
ACLF. This information is clinically relevant as ACLF patients
carry an exceptionally high morbidity and mortality rates (17).
Therefore, an early identification of ACLF by a simple and reliable biomarker should be encouraged. Supporting this idea, in
the present study, all ACLF patients died within 90 days indicating an ominous prognosis especially when renal failure was oneof end organ damage.
Mortality rate has long been a primary focus in cirrhosis
research field. Patients with compensated cirrhosis has remarkably longer median survival time than the decompensatedones ( > 12 vs. 2 years, respectively) (23). The transition fromcompensated to decompensated cirrhosis can be accelerated bycomplications at any time during the disease course. Our study
revealed a slightly lower 90-day mortality rate than prior studies, which might be caused by a higher number of patients withearly cirrhosis included in the present study (12, 24). Regarding
causes of death, sepsis with multiorgan failure was the mostfrequent cause, which was similar to what has been previously
reported (23). In the present study, we have demonstrated that,in the multivariate regression analysis, after adjusting with age
and bacterial infection on admission, plasma CysC level was significantly associated with 90-day mortality. This finding emphasizes a potential advantage of plasma CysC level as a predictor
for short-term mortality. However, taking into consideration thatthe statistical significance level was marginal, more data areneeded to clarify this issue.
Another point worth mentioning in the present study was thatbacterial infection and SBP were significantly associated with
90-day mortality in the univariate analysis. It is well known
that bacterial infection is very common among hospitalized
cirrhotic patients, and is associated with an increase risk ofmortality (25). From the pathophysiological standpoint, bacterial
infection is distinct from other decompensations given that it cancause an exaggerated systemic inflammation that is responsible
for organ failure in patients with cirrhosis (26). Of note, a recent
global scale study has demonstrated that 48% of ACLF patientswere documented with bacterial infection, of which the majority
were SBP, pneumonia, and infections caused by multidrug-resis-

307

tant organisms (27).
There were some limitations in this study. First, our study
had a relatively small sample size, however, the number of participants exceeded the minimum number determined by sample
size calculation. Second, AKI was diagnosed by International
Club of Ascites definitions based on serum creatinine, which
could underestimate renal dysfunction in cirrhotic patients.
However, serum creatinine is the most widely used biomarker
of kidney function in clinical practice. Third, our study lacked
validation cohort. Therefore, our results including the optimal
cut-off point of plasma CysC need to be redetermined in the
future study. Finally, the result of the ROC analysis showingthat plasma CysC was superior to the MELD score for 90-day
mortality prediction should be interpreted with caution because
the sample size and the event rate in the present may be too
small for the ROC analysis, as well as the significance level was
considerably borderline.
In conclusion, plasma cystatin C within 24 hours after admission can be used as a renal biomarker for prognostic predictionof 90-day mortality, and the development of in-hospital ACLF in
hospitalized decompensated cirrhotic patients who have no AKI
at admission. This information could facilitate early identification and raise awareness of ACLF in these patients.

FUNDING
This work was partially supported the Gastrointestinal Association of Thailand.

COMPLIANCE WITH ETHICAL STANDARDSCONFLICT OF INTERESTS

Natsuda Aumpan, Tanabute Limprukkasem, Bubpha
Pornthisarn, Ratha-korn Vilaichone, Soonthorn Chonprasertsuk,
Patommatat Bhanthumkomol, and Pichaya Tantiyavarong haveno conflicts of interest to declare. Sith Siramolpiwat has served aspeaker for Ferring Pharmaceuticals Thailand.

ETHICAL APPROVAL
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and / or national research committee and with the 1964
Helsinki declaration and its later amendments or comparable
ethical standards.

INFORMED CONSENT
Informed consent was obtained from all individual participants included in the study.

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