SERUM CYSTATIN C CONCENTRATION IS A POWERFUL PROGNOSTIC INDICATOR IN PATIENTS WITH CIRRHOTIC ASCITES

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1 SERUM CYSTATIN C CONCENTRATION IS A POWERFUL PROGNOSTIC INDICATOR IN PATIENTS WITH CIRRHOTIC ASCITES YEON SEOK SEO, 1 SOO YOUNG PARK, 2 MOON YOUNG KIM, 3 SANG GYUNE KIM, 4 JUN YONG PARK, 5 HYUNG JOON YIM, 1 BYOUNG KUK JANG, 6 SEUNG HA PARK, 7 JI HOON KIM, 1 KI TAE SUK, 8 JIN DONG KIM, 9 TAE YEOB KIM, 10 JUNG SUNG LEE, 7 SEUNG WON JUNG, 4 JAE YOUNG JANG, 4 HYONGGIN AN, 11 WON YOUNG TAK, 2 SOON KOO BAIK, 3 JAE SEOK HWANG, 6 YOUNG SEOK KIM, 4 JOO HYUN SOHN, 10 SOON HO UM 1 * DEPARTMENT OF INTERNAL MEDICINE, KOREA UNIVERSITY COLLEGE OF MEDICINE, SEOUL, KOREA 1 ; DEPARTMENT OF INTERNAL MEDICINE, KYUNGPOOK NATIONAL UNIVERSITY SCHOOL OF MEDICINE, DAEGU, KOREA 2 ; DEPARTMENT OF INTERNAL MEDICINE, YONSEI UNIVERSITY WONJU COLLEGE OF MEDICINE, WONJU, KOREA 3 ; DEPARTMENT OF INTERNAL MEDICINE, SOONCHUNHYANG UNIVERSITY COLLEGE OF MEDICINE, ASAN, KOREA 4 ; DEPARTMENT OF INTERNAL MEDICINE, YONSEI UNIVERSITY COLLEGE OF MEDICINE, SEOUL, KOREA 5 ; DEPARTMENT OF INTERNAL MEDICINE, KEIMYUNG UNIVERSITY COLLEGE OF MEDICINE, DAEGU, KOREA 6 ; DEPARTMENT OF INTERNAL MEDICINE, INJE UNIVERSITY COLLEGE OF MEDICINE, PUSAN, KOREA 7 ; DEPARTMENT OF INTERNAL MEDICINE, HALLYM UNIVERSITY COLLEGE OF MEDICINE, CHUNCHEON, KOREA 8 ; DEPARTMENT OF INTERNAL MEDICINE, CHEJU HALLA GENERAL HOSPITAL, JEJU, KOREA 9 ; DEPARTMENT OF INTERNAL MEDICINE, HANYANG UNIVERSITY COLLEGE OF MEDICINE, SEOUL, KOREA 10 ; DEPARTMENT OF BIOSTATISTICS, KOREA UNIVERSITY COLLEGE OF MEDICINE, SEOUL 11

2 ACKNOWLEDGEMENT This study was supported by the research fund of the Korean Association for the Study of the Liver.

3 BACKGROUND Renal dysfunction - poor prognosis in patients with chronic liver disease - the leading cause of death in patients with cirrhosis : accurate assessment of renal function is very important most commonly used indirect markers of GFR serum creatinine (Cr) level & Cr-based calculation of GFR.

4 BACKGROUND Cr in patients with cirrhosis - malnutrition, reduced muscle mass - increased tubular Cr secretion - elevated serum bilirubin interfere with Cr measurement using the Jaffe method reduce serum Cr level overestimate GFR serum creatinine shows marked increases only at severely reduced creatinine clearance values

5 BACKGROUND Cystatin C - cationic 13-kDa protein - a member of the cystatin superfamily of cysteine protease inhibitors - produced by all nucleated cells at a constant rate - reflect GFR independent of age, height, muscle mass, or inflammatory conditions - Several reports suggested that cystatin C had a higher sensitivity for detecting reduced GFR in patients with cirrhosis compared with serum Cr level

6 CYSTATIN C IN PTS WITH CIRRHOTIC ASCITES 89 patients with cirrhotic ascites and normal serum Cr level GFR was measured by 99m Tc-DTPA renal scan Conclusion: Serum cystatin C is a useful marker for detecting significant renal dysfunction in patients with cirrhotic ascites with normal serum Cr level. ROC curve for predicting significant renal impairment (GFR <60 ml/min) Kim DJ, Seo YS, et al. Korean J Hepatol 2011;17:

7 CYSTATIN C IN PTS WITH CIRRHOTIC ASCITES 78 patients with cirrhotic ascites and normal serum Cr level HRS developed in 14 pts and 23 pts died during the F/U of days Conclusion: Serum cystatin C level is a good marker for predicting HRS and survival in patients with cirrhotic ascites and a normal Cr level. Seo YS, et al. Liver Int 2009;29:

8 AIMS To evaluate the prognostic efficacy of cystatin C in patients with cirrhotic ascites

9 PARTICIPATING CENTERS Korea Univ. Guro Hospital Inje Univ. Ilsan Paik Hospital Soonchunhyang Univ. Bucheon Hospital Yonsei Univ. Severance Hospital Hanyang Univ. Guri Hospital Hallym Univ. Sacred Heart Hospital Cheju Halla General Hospital Korea Univ. Anam Hospital Soonchunhyang Univ. Seoul Hospital Korea Univ. Ansan Hospital Yonsei Univ. Wonju Severance Christian Hospital Kyungpook National Univ. Hospital Keimyung Univ. Dongsan Medical Center Inje Univ. Haeundae Paik Hospital

10 METHODS Multicenter prospective observational study Inclusion criteria: patients with cirrhotic ascites (SAAG 1.1) Exclusion criteria taking diuretics within 2 weeks from enrollment parenchymal renal disease (RBC >50/HPF, protein >500 mg/day, abnormal finding in kidney on ultrasound) accompanied by SBP, HCC or other malignancy

11 METHODS History taking: age, sex, alcohol intake, diabetes, hypertension Anthropometric measurement: height, weight Grade of ascites: physical examination and US Laboratory tests: platelet count, INR, ALT, bilirubin, albumin, creatinine, cystatin C, Na Follow-up data: development of HRS, mortality, cause of death

12 BASELINE CHARACTERISTICS N=351 N=351 Age Presence of HE 28 (8.0) Male, n (%) 262 (75.7) Platelet, 10 3 /L BMI, kg/m INR Diabetes, n (%) 81 (23.4) ALT, IU/L Hypertension, n (%) 60 (17.3) Bilirubin, mg/dl Etiology, n (%) Albumin, g/dl Alcohol 195 (55.6) ALP, IU/L Viral 133 (37.9) Glucose, mg/dl Others 23 (6.6) Cr, mg/dl Grade of ascites Na, meq/l Grade 1 83 (24.0) Cystatin C, mg/l Grade (33.5) Child score Grade (42.5) MELD score

13 MORTALITY Duration of follow-up: months (median, 14.0 months) 88 patients died Cause of death HRS-1: 27 (7.7%) Liver failure: 26 (7.4%) Variceal bleeding: 12 (3.4%) Sepsis: 9 (2.6%) HCC progression, 4 (1.1%) Liver-unrelated causes, 8 (2.3%)

14 COX-REGRESSION ANALYSIS FOR MORTALITY P (univariate) P (multivariate) OR (95% CI) Age Gender BMI, kg/m Diabetes Hypertension Etiology Grade of ascites Hepatic encephalopathy Platelet, 10 3 /L INR <0.001 < ( ) ALT, IU/L Bilirubin, mg/dl < Albumin, g/dl Glucose, mg/dl Cr, mg/dl < Na, meq/l <0.001 < ( ) Cystatin C, mg/l <0.001 < ( )

15 DEVELOPMENT OF HRS-1 28 cases of HRS-1 developed during follow-up Cumulative incidence 3.8%, 5.6%, 6.4%, and 7.7% at 3, 6, 9, and 12 months 8.7% at 2 years

16 COX-REGRESSION ANALYSIS FOR HRS-1 P (univariate) P (multivariate) OR (95% CI) Age Gender BMI, kg/m Diabetes Hypertension Etiology Grade of ascites Hepatic encephalopathy Platelet, 10 3 /L INR ALT, IU/L Bilirubin, mg/dl Albumin, g/dl Glucose, mg/dl Cr, mg/dl Na, meq/l <0.001 < ( ) Cystatin C, mg/l <0.001 < ( )

17 1-YEAR MORTALITY 351 patients 89 patients were lost to follow-up within 1 year 262 patients Survival: 212 patients Mortality: 50 patients (19.1%)

18 PREDICTIVE FACTORS FOR 1-YEAR MORTALITY Pts with survival (n=212) Pts with mortality (n=50) P (uni) P (multi) Age Male, n (%) 162 (76.4) 38 (76.0) BMI, kg/m Diabetes, n (%) 46 (21.7) 13 (26.0) Hypertension, n (%) 37 (17.5) 6 (12.0) Etiology, n (%) Alcohol 107 (50.5) 31 (62.0) Viral 95 (44.8) 13 (26.0) Others ) 6 (12.0) Grade of ascites Grade 1 52 (24.5) 11 (22.0) Grade 2 70 (33.0) 17 (34.0) Grade 3 90 (42.5) 22 (44.0) Presence of HE 10 (4.7) 8 (16.0)

19 PREDICTIVE FACTORS FOR 1-YEAR MORTALITY (CONTINUED) Pts with survival (n=212) Pts with mortality (n=50) P (uni) P (multi) Platelet, 10 3 /L INR <0.001 <0.001 ALT, IU/L Bilirubin, mg/dl < Albumin, g/dl ALP, IU/L Glucose, mg/dl Cr, mg/dl Na, meq/l <0.001 <0.001 Cystatin C, mg/l <0.001 <0.001 Child score <0.001 MELD score <0.001

20 CIS INDEX Binary regression analysis for 1-yr mortality Variable Regression Coefficient Regression Coefficient Standard Effort P Cystatin C (log e value) <0.001 INR (log e value) <0.001 Hyponatremia* <0.001 *Serum Na <130 meq/l CIS index: log e (Cystatin C [mg/l]) og e (INR) (Serum Na: 1 if <130 meq/l, 0 otherwise)

21 AUCs FOR PREDICTING 1-YR MORTALITY AUC (95% CI) CIS index ( ) MELD score ( ) Child-Pugh score ( ) CIS index vs. MELD score: P=0.032 CIS index vs. Child-Pugh score: P<0.001

22 AUCs FOR PREDICTING DEVELOPMENT OF HRS TYPE 1 WITHIN 1 YEAR AUC (95% CI) CIS index ( ) MELD score ( ) Child-Pugh score ( ) CIS index vs. MELD score: P=0.028 CIS index vs. Child-Pugh score: P=0.002

23 SURVIVAL ACCORDING TO THE CIS INDEX

24 CONCLUSIONS Serum cystatin C level was one of the independent predictors for mortality and development of type 1 HRS in patients with cirrhotic ascites. CIS index, composed of serum cystatin C level, INR, and serum sodium, was superior to the MELD score for predicting survival in these patients.