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Creatinine (mg/dL)

CLINICAL TYPES OF HEPATORENAL SYNDROME (HRS). Type-2 HRS. Type-1 HRS. 6. 5. Cefotaxime. 4. Therapeutic paracentesis. 3. Creatinine (mg/dL). Encephalopathy Jaundice. 2. 1. 0. -6. -4. -2. 0. 1. 2. 3. Months. Weeks. DIFFERENCES BETWEEN TYPE-1 AND TYPE-2 HRS. Type-2. Type-1.

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Creatinine (mg/dL)

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  1. CLINICAL TYPES OF HEPATORENAL SYNDROME (HRS) Type-2 HRS Type-1 HRS 6 5 Cefotaxime 4 Therapeutic paracentesis 3 Creatinine (mg/dL) Encephalopathy Jaundice 2 1 0 -6 -4 -2 0 1 2 3 Months Weeks

  2. DIFFERENCES BETWEEN TYPE-1 AND TYPE-2 HRS Type-2 Type-1 Renal failure Moderate and steady Severe and progressive Setting Non-azotemic cirrhosis Type-2 HRS Onset Spontaneous Precipitated Consequence Refractory ascites Terminal hepatorenal failure Survival Months Days

  3. HRS. SURVIVAL 1.0 Median survival 0.8 Type-1 15 days Type-2 150 days 0.6 Probability Type-2 0.4 p<0.0001 0.2 Type-1 0.0 0 100 200 300 400 500 600 Days

  4. TIME-COURSE OF THE CIRCULATORY, NEUROHORMONAL AND RENAL FUNCTION ABNORMALITIES IN CIRRHOSIS No Ascites Ascites Degree of splanchnic arterial vasodilation Time Hyperdinamic circulation  RAAS, SNS and sodium retention ADH and hyponatremia HRS

  5. CARDIOVASCULAR HEMODYNAMICS IN 8 PATIENTS DEVELOPING TYPE-1 HRS AFTER SBP At SBP diagnosis SBP-HRS MAP (mmHg) 83±7 73±8* PRA (ng/mL.h) 18±11 28±12* SVR (dyn.s/cm-5) 1137±220 1268±320 CO (L/min) 5.7±0.9 4.6±0.7* * p<0.02 Ruiz del Arbol et al., Hepatology 2002

  6. CARDIOVASCULAR HEMODYNAMICS IN 12 PATIENTS DEVELOPING TYPE-1 HRS* Baseline Type-1 HRS p MAP (mmHg) 84±2.6 70±2.3 <0.001 PRA (ng/mL.h) 12.9±2.6 25.8±3.4 <0.01 NE (pg/mL) 735±69 1385±99 <0.001 SVR (dyn.s/cm-5) 1099±81 1211±97 NS CO (L/min) 5.8±0.2 4.6±0.3 <0.01 RAP (mmHg) 7±0.8 5±0.5 <0.01 PCP (mmHg) 8.7±1 6.5±1 <0.01 HR (bpm) 86±5 84±4 NS * baseline measurements: 9±1 months prior HRS Ruiz del Arbol et al., Hepatology 2005

  7. REGIONAL CIRCULATORY CHANGES IN CIRRHOSIS 80 0.9 * p<0.05 p<0.001 0.8 60 0.7 Resistive index middle cerebral artery Brachial blood flow (mL/min) 40 * 0.6 * 0.5 20 0.4 0 H NA A HRS H NA A Maroto et al., Hepatology 1993 Guevara et al., Hepatology 1998 Healthy subjects (H), cirrhotic patients without ascites (NA), with ascites (A) and with hepatorenal syndrome (HRS)

  8. CHANGES IN HEPATIC HEMODYNAMICS ASSOCIATED WITH TYPE-1 HRS HVPG IN PATIENTS DEVELOPING TYPE-1 HRS AFTER SBP HBF IN PATIENTS DEVELOPING TYPE-1 HRS 30 1000 p<0.05 25 800 HVPG (mmHg) Hepatic blood flow (mL/min) 20 600 15 400 At SBP diagnosis After SBP resolution Baseline Type-1 HRS Baseline measurements: 9±1 months prior HRS Ruiz del Arbol et al., Hepatology 2002 Ruiz del Arbol et al., Hepatology 2005

  9. INCIDENCE OF RELATIVE ADRENAL INSUFFICIENCY* IN CIRRHOTIC PATIENTS (n=20) WITH SEPTIC SHOCK Non-cirrhotic patients 10-40% Cirrhotics Child B 25% Cirrhotics Child C 75% * Diagnostic criteria: - baseline cortisol <9 mg/dL - increase in cortisol after ACTH <9 mg/dL - peak cortisol <20 mg/dL Fernández et al. (unpublished)

  10. TYPE-I HRS AS A PART OF A MULTIORGAN FAILURE Spontaneous bacterial peritonitis or other precipitating event Adrenal dysfunction Increase in arterial vasodilation Decrease in cardiac output A-II, NE, ADH ­ resistance to portal venous flow Regional arterial vasoconstriction Kidneys HRS Aggravation of portal hypertension Brain Encephalopathy Liver Liver failure

  11. EFFECT OF VASOCONSTRICTORS (Ornipressin and Terlipressin) PLUS I.V. ALBUMIN IN TYPE-1 HRS Baseline (n=15) Day 7 (n=9) Day 14 (n=7) MAP (mmHg) 70±8 77±9 79±12 PRA (ng/mL.h) 15±15 2±3 1±1 NE (pg/mL) 1257±938 550±410 316±161 Creatinine (mg/dL) 3±1 2±1 1±1 GFR (mL/min) 9±1 25±2.5 41±1.5 Guevara et al., Hepatology 1998; Uriz et al., J Hepatol 2000

  12. SERUM CREATININE BEFORE AND AFTER TREATMENT OF TYPE-1 HRS (11 cases) WITH TERLIPRESSIN PLUS ALBUMIN 5 4 3 Serum creatinine (mg/dL) 2 1 0 1 day 1 month Baseline After treatment Ortega et al., Hepatology 2002

  13. TREATMENT OF HRS WITH VASOCONSTRICTORS AND ALBUMIN (Group 1) AND STANDARD MEDICAL THERAPY (Group 2). REVIEW OF 18 STUDIES Group 1 (n=154) Group 2 (n=137) MCFS* (n=99) Reversal of HRS 61.7% 2.9% 58% HRS recurrence 20% - - Survival 1 month 41.6% 3% 40% Survival 3 months 30% 0% 22% Liver transplantation 12.3% - 13% * Multicenter French Study

  14. TREATMENT OF TYPE-1 HRS WITH TERLIPRESSIN PLUS I.V. ALBUMIN vs TERLIPRESSIN Terlipressin + albumin (n=13) Terlipressin (n=8) Complete response 10 2 Survival >1 month 12 2 OLT 5 0 Ortega et al., Hepatology 2002

  15. TIPS IMPROVES CIRCULATORY AND RENAL FUNCTION IN TYPE-1 HRS (7 patients) After treatment Baseline Day 7 Day 30 Renin (ng/mL/h) 18±5 6±2 3±1 NE (pg/mL) 1257±187 853±102 612±197 Creatinine (mg/dL) 5.0±0.8 3.7±1.0 1.8±0.4 GFR (mL/min) 9±4 11±5 27±7 Guevara et al., Hepatology 1998

  16. CIRCULATORY SUPPORT WITH I.V. ALBUMIN IN PATIENTS WITH SBP. EFFECT ON ARTERIAL BLOOD VOLUME * * 9 * 8 * p<0.05 7 6 5 PRA (ng/mL.h) 4 3 2 1 0 1 3 6 9 Days Cefotaxime + albumin Cefotaxime Sort et al., N Engl J Med 1999

  17. CIRCULATORY SUPPORT WITH I.V. ALBUMIN IN PATIENTS WITH SBP. EFFECT ON HRS DEVELOPMENT AND HOSPITAL MORTALITY Cefotaxime (n=63) Cefotaxime + albumin (n=63) Resolution of infection 57 (93%) 59 (98%) HRS 20 (32%) 6 (10%)* Hospital mortality 17 (27%) 6 (10%)* * p<0.001 Sort et al., N Engl J Med 1999

  18. EFFECTS OF HYDROXYETHYL STARCH (HES) AND ALBUMIN (ALB) ON EFFECTIVE BLOOD VOLUME IN SBP Baseline At resolution p HES 80±15 81±8 NS MAP (mmHg) ALB 76±9 85±13 0.01 HES 8.5±7.3 16.8±24.6 NS PRA (ng.mL/h) ALB 5.7±4.7 3.1±3.4 0.04 Fernandez et al., Hepatology 2005

  19. EFFECTS OF HYDROXYETHYL STARCH (HES) AND ALBUMIN (ALB) ON PERIPHERAL ARTERIAL CIRCULATION IN SBP Baseline At resolution p HES 777±239 778±290 NS SVR (dyn/cm5) ALB 668±134 803±197 0.03 HES 39±13 63±32 0.03 NO (nmol/mL) ALB 61±30 78±55 NS HES 297±44 278±47 NS vWF:Ag (U/dL)* ALB 331±35 257±65 0.01 * vWF:Ag Von Willebrand-related antigen factor Fernandez et al., Hepatology 2005

  20. EFFECT OF I.V. ALBUMIN ON SYSTEMIC HEMODYNAMICS IN CIRRHOSIS Albumin infusion Intravascular volume expansion Inhibition of endothelial activation Increased cardiac preload Decreased NO synthesis Improvement in left ventricular function Increased systemic vascular resistance IMPROVEMENT OF CIRCULATORY DYSFUNCTION

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