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Hepatorenal Syndrome-Pathophysiologic Basis of Therapy And Current Management PowerPoint Presentation

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Description : Check out this medical PowerPoint presentation titled "Hepatorenal syndrome-Pathophysiologic basis of therapy and current management” by Geeta Gyamlani, MD.

This medical PowerPoint presentation is about hepatorenal syndrome (HRS), a serious complication that can occur in individuals with advanced liver disease. It is characterized by a rapid deterioration in kidney function, leading to renal failure.

The exact cause of HRS is not fully understood, but it is believed to be related to changes in blood flow within the liver and kidneys. The liver plays a crucial role in filtering toxins from the blood, and when it is damaged or diseased, blood flow can become impaired. This can lead to decreased blood flow to the kidneys, which can then cause kidney damage.

Symptoms of HRS may include decreased urine output, swelling in the legs or abdomen, confusion, and fatigue. If left untreated, HRS can be life-threatening.

Treatment for HRS typically involves addressing the underlying liver disease, such as with medications or liver transplantation. Additionally, medications such as vasopressin analogs and albumin infusions may be used to improve kidney function and manage symptoms. It is important for individuals with advanced liver disease to be closely monitored for signs of HRS and to receive prompt treatment if it occurs.

Tags : Hepatorenal syndrome, advanced liver disease, kidney function, renal failure, Nephrology, Nephrology PowerPoint presentation

Published on : Jun 07, 2023 | Views : 1200 | Downloads : 0

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Slide 1-

Geeta Gyamlani, MD Hepatorenal syndrome : Pathophysiologic basis of therapy and current management
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Outline HRS defined The pathophysiology of the hepatorenal syndrome Treatment of HRS Prevention of HRS
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How is HRS defined? HRS is a distinct form of acute or subacute renal failure characterized by severe renal vasoconstriction, which usually develops in decompensated cirrhosis or acute liver failure( ALF)
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Revised diagnostic hepatorenal syndrome criteria in liver disease Liver disease with ascites. Serum creatinine >133 μmol/l (1.5 mg/dl). CCl exluded. No improvement of sr cr after at least 2 days with diuretic withdrawal + volume expansion with albumin at 1 g/kg of body weight per day up to a max of 100 g/day.Albumin is preferred plama volume expander. Absence of shock. Ongoing bacterial infection without shock may be HRS. No current or recent treatment with nephrotoxic drugs. *Absence of parenchymal kidney disease as indicated by proteinuria >500 mg/day, microhematuria (>50 red blood cells /HPF) and/or abnormal renal US.
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MINOR CRITERIA Urine volume <500 ml/d Urine sodium <10 mEq/L Urine osmolality greater than plasma osmolality Serum sodium concentration <130 mEq/L Arroyo Vet al. Hepatology 23: 164-176, 1996 Modified at Consensus conference ONLY supportive, NOT required
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Types of HRS Type I Severe and rapidly progressive renal failure Doubling of sCr to  2.5 mg/dL in  2 weeks Usually precipitated by GI hemorrhage, surgery, acute hepatitis etc but can occur spontaneously Occurs in 30 % of patients with SBP despite resolution of infection Poor prognosis: median survival time of 2 weeks after onset Arroyo Vet al consensus statement
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Types of HRS Type 2 Moderate and steady decline in renal function: sCr  2.5 mg/dL Less severe liver failure and hypotension than with Type I HRS Characterized by severe ascites which is diuretic-resistant Often evolves into Type I HRS following insult Prognosis: median survival time of 6 months after onset
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Type 3 HRS Patients with advanced liver disease frequently have coexistent intrinsic renal dysfunction. 85% of end-stage cirrhotics due to Hep C have intrinsic renal disease on renal biopsy. A cirrhotic patient with long-standing nephropathy can develop HRS from a precipitating event or worsening liver failure (due to circulatory derangement). Important because of combined liver-kidney transplant. McGuire B, Julian B, Bynon S, et al. . Ann Intern Med 2006;144:735–41.
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Type 4 HRS Upto 50% of patients with ALF may develop HRS. HRS complicating ALF adds on the already poor prognosis of ALF, especially when acetaminophen-related. Both organ failures can be reversed by urgent liver Tx.
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The pathophysiology of the hepatorenal syndrome
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Pathophysiologic mechanisms of hepatorenal syndrome (HRS). ©2006 by American Society of Nephrology Wadei H M et al. CJASN 2006;1:1066-1079
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Arroyo et al, Annals of Hepatology 10,Supp 1, 2011 S6-14
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66 pts with cirrhosis, ascites and normal renal fx. 27 pts with HRS had systemic +hepatic hemodynamics measured @ baseline+ at diagnosis of HRS. 12 pts had Type 1 and 15 had Type 2 HRS PRA and C.O were the only independent predictors of HRS HRS associated with significant reduction in MAP, C.O, increasein PRA, N.E and hepatic venous pressure gradient. L. Ruiz-del-Arbol, A. Monescillo, C. Arocena, P. Valer, P. Gines and V. Moreira et al., Circulatory function and hepatorenal syndrome in cirrhosis, Hepatology 42 (2005), pp. 439–447. Role of Cardiac dysfx in HRS
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Mediators of Vasodilation NO  in cirrhosis Stimulated by endotoxemia and increased shear steress in the systemic and splanchic circulation. Renders splanchnic circulation resistant to vasopressors Glucagon Desensitizes splanchnic circulation to catecholamines and AII Direct Vasodilator cAMP levels thereby  NO synthesis
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Role of a precipitating factor in HRS. ©2006 by American Society of Nephrology Wadei H M et al. CJASN 2006;1:1066-1079 Role of a precipitating factor in HRS
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Gines P and Schrier R. N Engl J Med 2009;361:1279-1290 Potential Role of Bacterial Translocation and Cytokine Overproduction on Splanchnic Arterial Vasodilatation Factors, such as intestinal bacterial overgrowth, impaired intestinal motility, alterations in gut permeability, and disturbances in local immune systems leads to translocation
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Actuarial probability to survive Alessandria et al, Hepatology 2005 Jun;41(6):1282-9.
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Treatment of the Hepatorenal syndrome Volume expanders and vasoconstrictors Transjugular Intrahepatic Portocaval Shunt (TIPS) Liver transplantation Molecular adsorbent recycling system (MARS)
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General Measures Diuretics and nephrotoxic agents stopped Rx infection and GI bleeding Especially in type 1 HRS, adrenal function should be tested with ACTH stim test and treated with steroids if indicated Assess intravascular volume status Massive ascites may impair renal vein outflow, if tense ascites is present, check bladder pressures and paracentesis with albumin replacement is performed
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Albumin is important in cirrhosis Improves circulatory dysfunction in cirrhosis by expanding central blood volume and increasing cardiac output Albumin has a domain with ability to stabilize free radicals Albumin alleviates splanchnic arterial vasodilation thereby increasing BP probably attributable to the ability of albumin to bind vasodilators
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Albumin vs Hydroxyethyl starch in SBP Fernández et al, Hepatology , 42,Sep 2005, 627-634
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Role of albumin in HRS
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Indications for albumin Large Volume Paracentesis ( >5L)- Albumin 8-10gms/L SBP HRS 1-With terlipressin Diagnosis of HRS 1-1.5 g/kg of 20% albumin Mattos et al, Annals of Hepatology 10, 2011,S15-20
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How do vasoconstrictors help? Vasoconstrictors rely on the assumption that interrupting the splanchnic vasodilation will subsequently releive the renal vasoconstriction resulting in improvement of the circulatory dysfunction. Redistribution of the blood volume to the central compartment will lead to the inhibition of the SNS and RAAS, thereby shifting the autoregulatory curve to the left and making RBF and GFR more responsive to BP changes.
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Vasoconstrictors Terlipressin Midodrine/ Octreotide Norepinephrine
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Terlipressin This synthetic vasopressin derivative has a much greater effect on vascular receptors (V1) than renal vasopressin receptors (V2). Prospective RDBPCT with type 1 HRS were randomized to terlipressin (1 mg intravenously every 6 hours) or placebo +plus albumin in both groups. The dose was doubled on day 4 if SCr level did not decrease by 30% of baseline. 56 pts randomized to each arm Treatment was continued X 14 days unless treatment success, death, dialysis, or transplantation occurred. Treatment success was defined by a decrease in SCr level to ≤1.5 mg/dL for at least 48 hours by day 14 without dialysis, death, or relapse of HRS type 1. Sanyal et al, Gastroenterology 2008:134:1360-1368
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Cumulative incidence of HRS reversal Sanyal et al, Gastroenterology 2008:134:1360-1368 34% 12.5%
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Overall survival Overall survival for HRS reversal vs no HRS reversal Sanyal et al, Gastroenterology 2008:134:1360-1368 43% vs 37%, NS 50% vs 35% ,p<0.05
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Use of Terlipressin Metanalysis included 10 clinical trials (154 patients); 2 were rct. The pooled rate of HRS reversal after terlipressin therapy was 0.52 (95% CI, 0.42- 0.61). The pooled frequency of recurrence after terlipressin withdrawal was 0.55 (95% CI, 0.40- 0.69). The pooled rate of patients who showed side-effects to terlipressin therapy was 0.29 (95% CI, 0.17- 0.42). The pooled OR for mortality rate in HRS patients who were not responders to terlipressin vs. responder was 5.746 (95% CI, 1.5 - 21.9). Fabrizi F., et al. Aliment Pharmacol Ther 24. 935-944.2006;
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How important is albumin with terlipressin?Ginés P, Hepatology 2001;34:186A Prospective observational study. 13 Type I HRS patients treated with terlipressin +albumin 8 Type I HRS patients treated with terlipressin alone 10/13 (77%) in the Terlipressin+albumin vs 2/8 (25%) receiving Terlipressin alone achieved a complete response. Albumin administration was the only predictive factor of complete response 1 month survival without transplant was 87% (7/8) in the Terlipressin+Albumin group vs 13% (1/8) in the Terlipressin(p = 0.01)
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Day 0 End of tx p sCr (mg/dL) Terlipressin+Albumin 3.50.5 1.50.1 <0.05 Terlipressin 3.60.3 3.40.7 NS PRA (ng/ml/h) Terlipressin+Albumin 18.08 4.01 <0.05 Terlipressin 25.08 14.03 NS MAP (mmHg) Terlipressin+Albumin 702 79 3 <0.05 Terlipressin 663 655 NS Ginés P, Hepatology 2001;34:186A
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Midodrine and Octreotide Use of midodrine alone an alpha adrenergic agonist , does not work in improving systemic hemodynamics and renal effects in HRS. Arterial vasodilation and reduced response to vasoconstrictors is related to increased level of endothelial( NO) and non endothelial( glucagon) vasodilators. Midodrine is a direct vasoconstrictor, whereas octreotide inhibits endogenous vasodilators, glucagon and vasoactive intestinal peptide.
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Midodrine + Octreotide Angeli P, et al. Hepatology 1999;29:1690–1697 5 patients with Type-I HRS received midodrine /octreotide Midodrine dose (7.5 - 12.5 mg p.o. TID) titrated to achieve an increase in MAP of  15 mmHg with 100 µg SQ tid titrated to 200 µg SQ tid + albumin(20-40gms/day) Controls: 8 Type 1 HRS treated with IV albumin plus dopamine 2–4 µg · kg–1 ·min–1 Angeli P et al. Hepatology 1999;29:1690–1697
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Dopamine O+M
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survival Angeli P et al. Hepatology 1999;29:1690–1697
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Octreotide and Midodrine Retrospective study (81 patients) 60 were treated with octreotide/midodrine (no albumin) and 21 were controls. Reduction of creatinine 24/60 (40%) VS 2/21 (10%) p 0.01 30 day survival 57% Vs 29% P < 0.05 Baseline predominantly Hispanic (70%), 30% alcoholic hepatitis. The effect of midodrine plus octreotide in type 2 HRS has not been studied. Esrailian et al. Dig Dis Sci 52. 742-748.2007
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Norepinephrine vs Terlipressin PR unblinded pilot study,22 pts with HRS (9 - HRS type 1; 13- HRS type 2) Patients were randomly assigned to be treated with noradrenaline (0.1–0.7 μg/kg/min) and albumin (10 patients) or with terlipressin (1–2 mg/4 h) and albumin (12 patients). Treatment was administered until HRS reversal or for a maximum of two weeks. Patients were followed-up until liver transplantation or death. Reversal of HRS was observed 70% treated with noradrenalin vs (83%) treated with terlipressin, p = ns. No patient developed signs of myocardial ischemia. Mean cost 1536 ± 40 euros (terl)Vs 107 ± 31 euros (NA) per patient p < 0.0001. . C Alessandria et al , J of hepatology, Volume 47, Issue 4,October 2007, 499-505
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Vasoconstrictors take home message Vasoconstrictors and albumin are recommended as the first line of treatment for type‐1 HRS. Terlipressin is the most widely used vasoconstrictor. Midodrine+octreotide and NE are possible alternatives requiring further clinical evaluation. With the use of terlipressin (2–12 mg/day) and albumin (20–40 g/day after 1 g/kg on the first day), about 60% of renal failure cases recover. Reversal of HRS improves survival and increases chance of liver transplantation
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TIPSTransjugular intrahepatic portosystemic shunts A low-resistance channel between hepatic vein and the intrahepatic portion of the portal vein (usually the right branch) using angiography Tract kept patent by deployment of an expandable metal stent Returns blood to systemic circulation and reduces portal hypertension
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TIPS Brensing KA. Gut 2000;47:288–295 Long-term efficacy of TIPS in non-transplantable cirrhotics with HRS Patient population: HRS1 21 HRS II 20 TIPS+: Type 1 HRS 14 Type II HRS 17 7/14 Type I HRS on HD
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Creatinine clearance ml/min Time after treatment (weeks) * * * * * p < 0.01 Brensing KA. Gut 2000;47:288–295
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TIPS TIPS markedly reduced the portal pressure gradient (21 ±5 - 13 ±4 mm Hg p<0.001) with one procedure related death (3.2%). Renal function improved (p<0.001) within two weeks after TIPS (CCl 18 ± 15 - 48 ±42 ml/min). 4/7 patients came off HD: all survived > 10 months Following TIPS, 3,6, 12, and 18 month survival rates were 81%, 71%, 48%, and 35%, respectively. 10% of non-shunted patients survived three months Type II had significantly better chance of survival than Type I: log rank 5.04; p = 0.025
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TIPS take home message No randomized trials comparing TIPS to pharmacological treatments Recurrence of HRS was rare, provided that there was no shunt malfunction Hepatic encephalopathy seen frequently as complication of TIPS but can be managed medically TIPS almost always induced a reduction of ascites volume Resolution of type‐1 HRS by TIPS can improve survival Although TIPS may improve renal function and refractory ascites in patients with type‐2 HRS, its effect on survival is still undefined
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Extracorporeal albumin dialysis(ECAD)Molecular adsorbent recycling system (MARS) Cell free, modified dialysis technique using albumin enriched dialysate and CRRT. Extracorporeal liver support system designed to remove albumin-bound substances Hypothesis: Removal of albumin bound and water soluble substances substances will stabilize liver and renal function NO transported primarily bound to serum albumin as an S-nitrosthiol
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Mitzner S, et al. Liver transplantation 2000:6; 277-286 Activated charcoal adsorber Cholestyramine anion exchanger
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Mitzner S, et al. Liver transplantation 2000:6; 277-286
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MARS and HRS Prospective randomized controlled trial of 13 patients with Type I HRS and cirrhosis 8 pts –MARS+HDF x 6-8 hours QD 5 pts HDF x 6-8 hours/day Gambro high-flux P5S membrane BFR = 150-250 mL/min Primary end-point = 30 day survival Mitzner S, et al. Liver transplantation 2000:6; 277-286
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p < 0.05 p < 0.01 Serum creatinine (mg/dL) MARS HDF Mitzner S, et al. Liver transplantation 2000:6; 277-286 Baseline End of study Baseline End of study
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*P < 0.05
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Days cumulative survival HDF MARS p = 0.012 Mitzner S, et al. Liver transplantation 2000:6; 277-286
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Still investigational While toxin elimination is proven to be effective, little data on hard clinical end points No long term survival benefit compared with standard medical therapy Start and timing of treatment, mode, intensity and duration unknown Group with the highest benefit still undefined Although 30 day survival improved , no difference in mortality by 3 months.
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Liver Transplantation
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79.8 65.7 87.2 76.6 Gonwa TA et al. Transplantation 1991: 51; 428-430
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Gonwa TA et al. Transplantation 1991: 51; 428-430
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Gonwa TA et al. Transplantation 1991: 51; 428-430
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Survival after transplantation of patients with HRS treated with vasopressin analogues before transplantation vs patients without renal failure Restuccia et al, J Hepatol Volume 40, 1January 2004, Pages 140-146 Rxed HRS-100% No HRS-83%
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Probability of developing renal failure during the first 6 months after transplantation in patients with HRS treated with vasopressin analogues before transplantation vs patients without renal failure Restuccia et al, J Hepatol Volume 40, 1,January 2004, Pages 140-146
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Effects on MELD Score Patients with HRS who received vasoconstrictors therapy and improvement seen in MELD score, reduce the chances of receiving a liver transplantation, particularly for type 1 HRS patients. ?? Whether improvement of HRS induced by vasopressor therapy is better than liver transplantation is debatable. HRS often recurs after discontinuation of vasoconstrictor therapy and then has a high mortality. These patients should be maintained at a high level on the waiting list, despite their reduced MELD score
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Liver Transplantation Patients with types 1, 2, or 4 HRS should undergo evaluation for liver transplantation. Patients with type 1 HRS are on priority for transplant and despite this, not transplanted because of underlying precipitating factor, or MSOF Liver transplantation is more practical and successful in type 2 HRS, because of an absence of precipitating events and relatively less severe renal failure Patients with type 3 HRS should be evaluated for combined liver-kidney transplantation
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Consideration for combined L-K transplant in patients with renal failure and cirrhosis ESRD with cirrhosis and symptomatic portal hypertension or hepatic venous pressure gradient of ≥ 10 mm Hg. CKD with GFR < 30 or > 30% glomerulosclerosis or fibrosis in renal biopsy with Liver failure. AKI or HRS with Cr > 2 and treatment with dialysis for > than 8 weeks. Eason et al. Transplant 2008,8:2243-51
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TJRB 39 TJRB procedures on 39 patients. The procedure was technically successful in (97%). 63% had a platelet count of less than or equal to 75 × 109/L, 29% had an elevated INR of more than 1.4, and seven received therapeutic anticoagulation. Patients with a platelet count of less than or equal to 75 × 109/L or those with an elevated INR of more than 1.4 after transfusion were not at increased risk of hematoma formation (P = NS). The renal tissue was sufficient for diagnosis in 92% of patients. Major complications occurred 1 pt,(2.6%) and minor complications—primarily renal hematoma—occurred in 52% of the patients. Contrast medium–induced nephropathy occurred in three patients (7.8%), two of whom also had renal hematomas. Misra , Gyamlani et al:Journal of Vascular and Interventional Radiology Volume 19, issue 4,Pages 546-551, April 2008
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Liver Tx take home message Gold-standard therapy for ESLD and GFR improves post-transplant in patients with HRS Reversal of HRS by pharmacological Rx prior to Rx may improve survival after Tx. Improvement in GFR and MELD score should not alter the decision to perform liver Tx since prognosis after recovering from HRS-1 very poor History of HRS portends: worse post-transplant renal function greater need for post-op HD worse survival than patients without HRS
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Prevention of HRS
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Why does SBP lead to HRS? SBP is usually due to gram negative organisms which are capable of releasing endotoxin Endotoxin induces production of IL-1, IL-6, and TNF- IL-1, IL-6, and TNF- stimulate endothelial cells to produce nitric oxide Nitric oxide may then lead to splanchnic vasodilation and HRS
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pg/ml Plasma TNF- Ascitic fluid TNF- Diagnosis 48 hr Resolution Diagnosis 48 hr Resolution Resolution Resolution 48 hr 48 hr Diagnosis Diagnosis Plasma IL-6 Ascitic fluid IL-6 pg/ml pg/ml pg/ml * * * * * p < 0.05 Follo A, et al. Hepatology 1998;27:1227-1232
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Prevention of HRS Sort P, et al. NEJM 1999:341;403-409 126 patients with cirrhosis and SBP randomized to receive: Cefotaxime alone vs Cefotaxime and albumin 1.5g/kgbw at diagnosis and 1g/kg 48hrs later. Primary end points: development of renal failure mortality
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Sort P, et al. NEJM 1999:341;403-409
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Plasma Renin Activity (ng/ml/hr) Day * * † † p= 0.005, * = p < 0.001 Sort P, et al. NEJM 1999:341;403-409
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Prevention of HRS RCT aimed at comparing norfloxacin vs placebo in primary prophylaxis of SBP 35/68 received norfloxacin Inclusion criteria were cirrhotics with ascitic fluid total protein <1.5 g/dL who fulfilled either of the following criteria Child-Pugh score >9 points and serum bili >3 mg/dL OR Serum creatinine >1.2 mg/dL , BUN >25 mg/dL or serum sodium <130 meq/L. End pts:Survival,1yr probability of developing HRS and SBP. Fernandez et al,Gastroenterology, Volume 133,3 September 2007, Pages 818-824
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Decreased one-year probability of SBP (7 vs 61 %) Decreased one-year probability of HRS (28 vs 41 %) Improved survival @ 3 months ( 94 vs 62%)and 1 yr (60 vs 48%)
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Summary HRS is a functional renal failure caused by intrarenal vasoconstriction seen in patients with ESLD/ALF and circulatory dysfunction. Circulatory dysfunction is characterized by vasodilatation in the splanchnic bed , low CO and stimulation of renal SNS . HRS may occur spontaneously with worsening liver function, or secondary to a precipitating event such as bacterial infection (eg, SBP). HRS Type 1 has rapid and progressive course and high mortality. HRS Type 2 has slow but progressive course, Type 3 with CKD, Type 4 with ALF Prevention: SBP prophylaxis, Pentoxifylline, Variceal hemorrhage Albumin infusion may prevent HRS in patients with SBP.
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Vasoconstrictors and albumin are recommended as the first line of treatment for HRS. With the use of terlipressin (2–12 mg/day) and albumin (20–40 g/day after 1 g/kg on the first day), about 60% of renal failure cases recover. The improvement of survival using only vasoconstrictors and albumin seems rather limited.
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TIPS is an alternative treatment in suitable patients, especially in those who do not show a complete response to vasoconstrictors. Liver transplantation is the only treatment that assures long‐term survival. Pharmacological treatment and TIPS can bridge the time to liver transplantation and improve post‐transplant survival. ECAD/MARS are still considered investigational
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THANK YOU
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HRS and Pentoxifylline Evangelos A, et al. Gastroenterology 2000; 119:1637-1648 Elevated TNF found in sera and liver tissue specimens from patients with alcoholic hepatitis Pentoxifylline inhibits TNF synthesis 101 patients with severe alcoholic hepatitis randomized to receive oral Pentoxifylline (PTX, 400 mg TID) or placebo x 4 weeks Endpoints: survival and development of HRS
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HRS and Pentoxifylline HRS PTX 8% (4/49) Placebo 35% (18/52) p < 0.005 Mortality (during hospitalization): PTX 24.5% (12/49) Placebo 46.1% (24/52) p<0.03 Withdrawals due to adverse effects PTX (diarrhea, epigastric pain) 7 (14%) Placebo 1 (2%) Variables independently associated with survival Age, sCr at randomization and treatment with PTX Evangelos A, et al. Gastroenterology 2000; 119:1637-1648
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Evangelos A, et al. Gastroenterology 2000; 119:1637-1648 *p=0.002 *
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Gines P and Schrier R. N Engl J Med 2009;361:1279-1290 Pathogenesis of Circulatory Abnormalities and Renal Failure in Cirrhosis
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Albumin in liver disease (Gines et al :Gastroenterology 111:1002-1006,1996
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Albumin in liver disease (Gines et al :Gastroenterology 111:1002-1006,1996
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Vasoconstrictor agents in type-1 HRS: response to treatment and outcome.
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Albumin improves the circulatory function, prevents hepatorenal syndrome, and reduces hospital mortality in patients with cirrhosis and spontaneous bacterial peritonitis as compared with plasma expander hyroxyethyl starch. 10 pts randomized to albumin and 10 to hydroxyethyl starch Albumin treatment was associated with a improvement in circulatory function Significant increase in arterial pressure and SVR Suppression of plasma renin activity. Serum nitrates and nitrites increased in patients treated with hydroxyethyl starch but not in those treated with albumin.
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Reversal of HRS-1 with Midodrine and octreotide control Midodrine + ocreotide Angeli P et al. Hepatology 1999;29:1690–1697
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Bacterial Translocation Passage of bacteria from the intestinal lumen to the mesenteric l.n play an important role in impairing circulatory function in advanced cirrhosis. Bacterial translocation elicits an inflammatory response  inc production of TNF α and IL-6 and vasodilator factors (NO) in the splanchnic area. Rasaratnam B et al Ann Intern Med 2003;139:186-193
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Peripheral Arterial Vasodilation portal hypertension splanchnic arterial vasodilation decreased effective arterial blood volume and arterial hypotension high pressure baroreceptor mediated activation of the RAAS, SNS and ADH vasoconstriction in renal circulation and non-splanchnic beds impaired free water excretion sodium and water retention Schrier RW et al. Hepatology 1988;8:1151-1157 TIPS Splanchnic vasoconstrictors