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Renal function indices predicting the prognosis of patients with liver cirrhosis
April 2000
AASLDA979
1086
1088
BG9719 (CVT-l24) A illGHLY POTENT ADENOSINE A-I RECEPTOR ANTAGONIST, INITIAL EXPERIENCE IN CIRRHOTIC PATIENTS WITH DIURETIC REFRACTORY ASCITES. James P. O'Beirne, Cathy Bouvier, Donald Bennett, Evan Beckman, David W. Patch, Andrew K. Burroughs, Mark I. Hamilton, Royal Free Hosp, London, United Kingdom; BIOGEN Inc, Cambridge, MA.
RENAL FUNCTION INDICES PREDICTING THE PROGNOSIS OF PATIENTS WITH LIVER CIRRHOSIS, Soon Koo Baik, Seong Jin Park, Hyun Soo Kim, Dong Ki Lee, Sang Ok Kwon, Wonju Coil of Medicine, Wonju, South Korea. Aim : Renal dysfunction commonly develops in patients with established liver disease and the assessment of kidney function is of great clinical importance in patients with cirrhosis and ascites. On the other hand, renal function indices such as glomerular filtration rate and the plasma level of renin, could be better predictors of survivial than the parameters normally used to estimate liver function including Child-Pugh score. Therefore, this study was designed to find whether renal function indices are useful in determining the prognosis concerned with the survival of the patients with liver cirrhosis. Subjects and method : Total of 110 patients were selected with 89 weeks follow-up study, from Dec. 1997 to Sep. 1999. As an index reflecting renal function, creatinine clearance rate, plasma renin activity, aldosterone level and the pulsatility index(PI) and resistive index(RI) using Doppler ultrasonography, were measured. The prognostic values of these indices were determined by comparison and analysis according to survival or death of the patients. For the statistics, univariate and multivariate analysis was done. Results : Data are shown as table. Conclusion: Various renal function indices are closely related to the survival of patients with liver cirrhosis. Especially, creatinine clearance rate and plasma aldosterone level are important prognostic factors, even more Child-Pugh score, for predicting survival of liver cirrhosis.
INTRODUCTION Ascites is a major complication of cirrhosis and portal hypertension. Marked Sodium (Na) retention and afferent renal arteriolar vasoconstriction are consistent features. Activation of Al adenosine receptors causes constriction of the afferent arteriole, reduces glomerular filtration rate (GFR) and mediates Na absorption in the proximal and distal nephron. BG9719, a selective Al-adenosine receptor antagonist inhibits Na reabsorption, whilst maintaining GFR in healthy volunteers and patients with congestive heart failure AIMS To examine the safety, efficacy and tolerability of a single IV dose of BG9719 in patients with diuretic refractory ascites. PATIENTS 6 patients with biopsy proven cirrhosis were enrolled in the study. All gave informed consent as approved by local ethics committee. 5 had Childs C cirrhosis and 1 Childs B. All patients were taking maximally tolerated doses of spironolactone and were dependent on paracentesis to control ascites. METHODS Patients had received stable doses of spironolactone, 2litre fluid restriction and 45 mEq Na restriction for both study days. On baseline day patients collected urine for 24 hours in 2 aliquots of 6 and 18 hrs. 3 patients received 0.3 mg/kg and 3 patients received Img/kg BG9719 IV on dosing day in addition to their usual diuretic medication. Urine collections were then repeated. RESULTS There were statistically significant increases in urine Na excretion and fractional Na excretion at 6 hours and an increase in utine volume at 24 hours (p< 0.05 paired t-test) There were no significant changes in serum Na, creatinine or creatinine clearance (see table). CONCLUSION BG9719 was well tolerated and demonstrated a significant natriuretic effect. These results suggest further investigation may indicate a role for BG9719 in the management of diuretic refractory ascites
Na excretion (mEq) Fractional Na (%) Creatinine clearance (mUmin)
0·6 hrspredose
0-6 hrspost dose
28.55+1·12.7 0.77+1-0.42 87.66 +/- 11.62
6243+1-17.78' 1.80 +/-0.64' 86.49 +/- 14.0 NS
Results ofprognostic value byunivariate and multivariate analysis
Variables
Univariate Analysis log·Rank test p.value
Child·Pugh score : 10~ CCR (mUmln) : <80 Aldosterone (ng/dl) : ~15 Renin (nglmUhr) : ~8 Renal RI : ~_0.7 Renal PI: ~1.15
19.71 14.92 20.83 5.06 608 4.08
Multivariate Analysis Odds rallo 95% CI
0000 0.000 0.000 0025 0014 0.043
2.89 5.37 3.65 1.65 090 1.02
0.97-8.60 209-13.82 109-12.18 050-541 022-367 0.25-4.22
CCR : Creatnine Clearance Rate RI : Resistive Index PI : PUlsatility Index
Mean +/- S.E.M. NS = Non significant '= p<0.05
1089 1087 CAVEOLIN·1 IN NORMAL AND CIRRHOTIC HUMAN LIVER. Rajaa Chatila, N. Theise, V. Shah, A.B. West, W. Sessa, R. 1. Groszmann, VA Med CenterlYale Univ, New Haven, CT; New York Univ Med Ctr, New York, NY; Mayo Clin, Rochester, MN; New York Univ Med Ctr, NY, NY; Yale Univ Sch of Medicine, New Haven, CT; Yale University! VAMC, New Haven, CT. Background: Experimental cirrhosis is characterized by nitric oxide (NO) deficiency in the hepatic microcirculation which has been attributed to decreased eNOS catalytic activity that seems to be mediated, at least in part, by an excess amount of caveolin-I, a plasma membrane protein that tonically inhibits eNOS activity and that have recently been reported by us to be increased in experimental cirrhotic livers. Aims of this study are to determine 1) the localization of caveolin-I in human livers, 2) whether the changes noted in caveolin-I expression in liver cirrhosis are similar to what we have found in experimental cirrhosis, and 3) whether caveolin-I expression varies according to the etiology of cirrhosis. Methods: Immunohistochemical staining with Caveolin-I monoclonal antibody was performed on 22 biopsy specimens: histologically normal (n=4), HCV (stage 0: n=4, cirrhosis: n=5), PBC (cirrhosis, n=5). Two blinded, independent observers examined the cases applying a semi-quantitative scoring system to assess distribution and intensity of caveolin-I immuno-reactivity in the various areas assessed. The areas examined include: sinusoidal endothelium, blood vessels, hepatocytes, bile ducts, inflammatory cells and fibrous tissue in portal triads and septa. Results: Normal and Stage 0 HCV had similar pattern of caveolin-I immunoreactivity. Uniform, mild staining was noted in the sinusoidal endothelium. The hepatic arteries, portal and central veins also expressed caveolin-l immunoreactivity; this was of mild intensity and involved both the endothelial lining as well as occasionally, the sub-endothelial stroma. The staining was localized to the cellular cytoplasm. No staining was seen in the hepatocytes, bile ducts or inflammatory infiltrates when present. Both HCV and PBC cirrhosis showed significantly higher levels of caveolin-l expression compared to controls (normal and stage 0 HCV). However, PBC cirrhosis had the most intense and impressive staining pattern. Whereas caveolin-I immunoreactivity was absent in connective tissue of portal triads, remarkable staining was seen in new connective tissue seen in the creeping fibrosis and septa. Significant intense immunoreactivity was also noted in the proliferating bile ductules and vessels. Conclusions: As seen in experimental cirrhosis, in human liver cirrhosis of different etiologies, caveolin-I expression is increased. This suggests that the catalitic eNOS activity in human cirrhotic livers is also decreased.
USE OF MULTISTIX® LEUKOCYTE ESTERASE DIPSTICK TESTING FOR ASCITIC FLUID INFECTION, Raj C. Butani, Richard T. Shaffer, Ronald D. Szyjkowski, Barbara E. Weeks, Linda G. Speights, Shailesh C. Kadakia, SAUSHEClBrooke Army Med Ctr, San Antonio, TX. Introduction: Ascitic fluid infection (AFI) is presumptively diagnosed when the fluid polymorphonuclear (PMN) concentration exceeds 250 cells! uL, and is confirmed by fluid culture. The leukocyte esterase (LE) test has been shown to be a good predictor of the presence of PMNs and bacteria in urine and other body fluids including amniotic fluid, vaginal secretions, and otitis media effusions. LE testing of ascitic fluid has not been reported and may prove valuable in the diagnosis of AFI. This study examines the value of using the Multistix" 10 SG (Bayer Diagnostics) LE dipstick test for the rapid detection of AFI. Methods: All ascitic fluid samples were submitted for LE testing, PMN count and culture. For each sample, the LE dipstick result was recorded, along with the corresponding PMN count and culture result. Based on the degree of color change in the reagent strip, the LE results were scored as NEGATIVE (dipstick negative or trace) or POSITIVE (smafl, moderate or large on dipstick testing). The LE results were then compared to the actual PMN counts and culture results of the samples. Results: Results are summarized in Table I. A positive LE test predicted ascitic fluid PMN >250/uL in 8 of 9 samples (sensitivity & PPV-89%). A negative LE test correlated with PMN <250!uL in 80 of 81 samples (specifity & NPV-99%). There was no clear relationship between LE test and culture results. Conclusions: The Multistix'" LE test may be useful in the rapid detection of an elevated ascitic fluid PMN count, facilitating early diagnosis of AFI. TABLE 1:Comparison ofascitic fluid lE test toPMN count and culture results. lETEST NEGATIVE POSITIVE TOTAL
lE TEST NEGATIVE POSITIVE TOTAL
PMN > 2501 ul
TOTAL
80
1
81
1 81
8
s
90
Culture Negative
Culture Positive
TOTAL
75 5
6
81
4
80
10
9 90
PMN <2501 ul
s
AASLDA979
1086
1088
BG9719 (CVT-l24) A illGHLY POTENT ADENOSINE A-I RECEPTOR ANTAGONIST, INITIAL EXPERIENCE IN CIRRHOTIC PATIENTS WITH DIURETIC REFRACTORY ASCITES. James P. O'Beirne, Cathy Bouvier, Donald Bennett, Evan Beckman, David W. Patch, Andrew K. Burroughs, Mark I. Hamilton, Royal Free Hosp, London, United Kingdom; BIOGEN Inc, Cambridge, MA.
RENAL FUNCTION INDICES PREDICTING THE PROGNOSIS OF PATIENTS WITH LIVER CIRRHOSIS, Soon Koo Baik, Seong Jin Park, Hyun Soo Kim, Dong Ki Lee, Sang Ok Kwon, Wonju Coil of Medicine, Wonju, South Korea. Aim : Renal dysfunction commonly develops in patients with established liver disease and the assessment of kidney function is of great clinical importance in patients with cirrhosis and ascites. On the other hand, renal function indices such as glomerular filtration rate and the plasma level of renin, could be better predictors of survivial than the parameters normally used to estimate liver function including Child-Pugh score. Therefore, this study was designed to find whether renal function indices are useful in determining the prognosis concerned with the survival of the patients with liver cirrhosis. Subjects and method : Total of 110 patients were selected with 89 weeks follow-up study, from Dec. 1997 to Sep. 1999. As an index reflecting renal function, creatinine clearance rate, plasma renin activity, aldosterone level and the pulsatility index(PI) and resistive index(RI) using Doppler ultrasonography, were measured. The prognostic values of these indices were determined by comparison and analysis according to survival or death of the patients. For the statistics, univariate and multivariate analysis was done. Results : Data are shown as table. Conclusion: Various renal function indices are closely related to the survival of patients with liver cirrhosis. Especially, creatinine clearance rate and plasma aldosterone level are important prognostic factors, even more Child-Pugh score, for predicting survival of liver cirrhosis.
INTRODUCTION Ascites is a major complication of cirrhosis and portal hypertension. Marked Sodium (Na) retention and afferent renal arteriolar vasoconstriction are consistent features. Activation of Al adenosine receptors causes constriction of the afferent arteriole, reduces glomerular filtration rate (GFR) and mediates Na absorption in the proximal and distal nephron. BG9719, a selective Al-adenosine receptor antagonist inhibits Na reabsorption, whilst maintaining GFR in healthy volunteers and patients with congestive heart failure AIMS To examine the safety, efficacy and tolerability of a single IV dose of BG9719 in patients with diuretic refractory ascites. PATIENTS 6 patients with biopsy proven cirrhosis were enrolled in the study. All gave informed consent as approved by local ethics committee. 5 had Childs C cirrhosis and 1 Childs B. All patients were taking maximally tolerated doses of spironolactone and were dependent on paracentesis to control ascites. METHODS Patients had received stable doses of spironolactone, 2litre fluid restriction and 45 mEq Na restriction for both study days. On baseline day patients collected urine for 24 hours in 2 aliquots of 6 and 18 hrs. 3 patients received 0.3 mg/kg and 3 patients received Img/kg BG9719 IV on dosing day in addition to their usual diuretic medication. Urine collections were then repeated. RESULTS There were statistically significant increases in urine Na excretion and fractional Na excretion at 6 hours and an increase in utine volume at 24 hours (p< 0.05 paired t-test) There were no significant changes in serum Na, creatinine or creatinine clearance (see table). CONCLUSION BG9719 was well tolerated and demonstrated a significant natriuretic effect. These results suggest further investigation may indicate a role for BG9719 in the management of diuretic refractory ascites
Na excretion (mEq) Fractional Na (%) Creatinine clearance (mUmin)
0·6 hrspredose
0-6 hrspost dose
28.55+1·12.7 0.77+1-0.42 87.66 +/- 11.62
6243+1-17.78' 1.80 +/-0.64' 86.49 +/- 14.0 NS
Results ofprognostic value byunivariate and multivariate analysis
Variables
Univariate Analysis log·Rank test p.value
Child·Pugh score : 10~ CCR (mUmln) : <80 Aldosterone (ng/dl) : ~15 Renin (nglmUhr) : ~8 Renal RI : ~_0.7 Renal PI: ~1.15
19.71 14.92 20.83 5.06 608 4.08
Multivariate Analysis Odds rallo 95% CI
0000 0.000 0.000 0025 0014 0.043
2.89 5.37 3.65 1.65 090 1.02
0.97-8.60 209-13.82 109-12.18 050-541 022-367 0.25-4.22
CCR : Creatnine Clearance Rate RI : Resistive Index PI : PUlsatility Index
Mean +/- S.E.M. NS = Non significant '= p<0.05
1089 1087 CAVEOLIN·1 IN NORMAL AND CIRRHOTIC HUMAN LIVER. Rajaa Chatila, N. Theise, V. Shah, A.B. West, W. Sessa, R. 1. Groszmann, VA Med CenterlYale Univ, New Haven, CT; New York Univ Med Ctr, New York, NY; Mayo Clin, Rochester, MN; New York Univ Med Ctr, NY, NY; Yale Univ Sch of Medicine, New Haven, CT; Yale University! VAMC, New Haven, CT. Background: Experimental cirrhosis is characterized by nitric oxide (NO) deficiency in the hepatic microcirculation which has been attributed to decreased eNOS catalytic activity that seems to be mediated, at least in part, by an excess amount of caveolin-I, a plasma membrane protein that tonically inhibits eNOS activity and that have recently been reported by us to be increased in experimental cirrhotic livers. Aims of this study are to determine 1) the localization of caveolin-I in human livers, 2) whether the changes noted in caveolin-I expression in liver cirrhosis are similar to what we have found in experimental cirrhosis, and 3) whether caveolin-I expression varies according to the etiology of cirrhosis. Methods: Immunohistochemical staining with Caveolin-I monoclonal antibody was performed on 22 biopsy specimens: histologically normal (n=4), HCV (stage 0: n=4, cirrhosis: n=5), PBC (cirrhosis, n=5). Two blinded, independent observers examined the cases applying a semi-quantitative scoring system to assess distribution and intensity of caveolin-I immuno-reactivity in the various areas assessed. The areas examined include: sinusoidal endothelium, blood vessels, hepatocytes, bile ducts, inflammatory cells and fibrous tissue in portal triads and septa. Results: Normal and Stage 0 HCV had similar pattern of caveolin-I immunoreactivity. Uniform, mild staining was noted in the sinusoidal endothelium. The hepatic arteries, portal and central veins also expressed caveolin-l immunoreactivity; this was of mild intensity and involved both the endothelial lining as well as occasionally, the sub-endothelial stroma. The staining was localized to the cellular cytoplasm. No staining was seen in the hepatocytes, bile ducts or inflammatory infiltrates when present. Both HCV and PBC cirrhosis showed significantly higher levels of caveolin-l expression compared to controls (normal and stage 0 HCV). However, PBC cirrhosis had the most intense and impressive staining pattern. Whereas caveolin-I immunoreactivity was absent in connective tissue of portal triads, remarkable staining was seen in new connective tissue seen in the creeping fibrosis and septa. Significant intense immunoreactivity was also noted in the proliferating bile ductules and vessels. Conclusions: As seen in experimental cirrhosis, in human liver cirrhosis of different etiologies, caveolin-I expression is increased. This suggests that the catalitic eNOS activity in human cirrhotic livers is also decreased.
USE OF MULTISTIX® LEUKOCYTE ESTERASE DIPSTICK TESTING FOR ASCITIC FLUID INFECTION, Raj C. Butani, Richard T. Shaffer, Ronald D. Szyjkowski, Barbara E. Weeks, Linda G. Speights, Shailesh C. Kadakia, SAUSHEClBrooke Army Med Ctr, San Antonio, TX. Introduction: Ascitic fluid infection (AFI) is presumptively diagnosed when the fluid polymorphonuclear (PMN) concentration exceeds 250 cells! uL, and is confirmed by fluid culture. The leukocyte esterase (LE) test has been shown to be a good predictor of the presence of PMNs and bacteria in urine and other body fluids including amniotic fluid, vaginal secretions, and otitis media effusions. LE testing of ascitic fluid has not been reported and may prove valuable in the diagnosis of AFI. This study examines the value of using the Multistix" 10 SG (Bayer Diagnostics) LE dipstick test for the rapid detection of AFI. Methods: All ascitic fluid samples were submitted for LE testing, PMN count and culture. For each sample, the LE dipstick result was recorded, along with the corresponding PMN count and culture result. Based on the degree of color change in the reagent strip, the LE results were scored as NEGATIVE (dipstick negative or trace) or POSITIVE (smafl, moderate or large on dipstick testing). The LE results were then compared to the actual PMN counts and culture results of the samples. Results: Results are summarized in Table I. A positive LE test predicted ascitic fluid PMN >250/uL in 8 of 9 samples (sensitivity & PPV-89%). A negative LE test correlated with PMN <250!uL in 80 of 81 samples (specifity & NPV-99%). There was no clear relationship between LE test and culture results. Conclusions: The Multistix'" LE test may be useful in the rapid detection of an elevated ascitic fluid PMN count, facilitating early diagnosis of AFI. TABLE 1:Comparison ofascitic fluid lE test toPMN count and culture results. lETEST NEGATIVE POSITIVE TOTAL
lE TEST NEGATIVE POSITIVE TOTAL
PMN > 2501 ul
TOTAL
80
1
81
1 81
8
s
90
Culture Negative
Culture Positive
TOTAL
75 5
6
81
4
80
10
9 90
PMN <2501 ul
s