Mini-review

Hepatorenal Syndrome
Charles KF Ng, Michael HM Chan, Morris HL Tai, *Christopher WK Lam
Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong * For correspondence: Professor Christopher Lam e-mail: waikeilam@cuhk.edu.hk

Abstract Hepatorenal syndrome (HRS) is a serious complication of liver cirrhosis with critically poor prognosis. The pathophysiological hallmark is severe renal vasoconstriction, resulting from complex changes in splanchnic and general circulations as well as systemic and renal vasoconstrictors and vasodilators. Rapid diagnosis and management are important, since recent treatment modalities including vasoconstrictor therapy can improve short-term outcome and buy time for liver transplantation, which can result in complete recovery.

Introduction HRS involves development of renal failure in patients with severe liver disease. It is a life-threatening condition with poor prognosis. The pathophysiology of this syndrome is still not completely understood. However, recent research developments have provided newer treatment modalities with improved prognosis. Now it is possible that a patient developing HRS can survive if it is quickly diagnosed, medical treatment is promptly given to control the renal failure, and liver transplantation is feasible and available for the patient. History and Denition The association between liver disease and renal failure had been known for more than a hundred years. Frerichs, the founder of modern liver pathology, reported the presence of oliguria in patients with ascites in 1877.1 Flint noted that in most cases of renal failure in cirrhosis, there were no signicant histological changes in the kidneys at autopsy.2 In 1956, Hecker and Sherlock described renal failure in nine patients with liver disease characterised by progressive oliguria, very low urinary sodium excretion, hyponatraemia, but no proteinuria.3 It was later established that the renal failure was functional, since the kidneys of these patients could be successfully transplanted to other patients with chronic renal failure, and the renal failure was reversible after liver transplantation.4,5 Using clearance techniques, the hallmark of the HRS was found in 1967 to be severe renal vasoconstriction.6,7 The term hepatorenal syndrome was rst used in 1939 to describe the occurrence of renal failure after biliary surgery

or hepatic trauma.8-10 Later it was extended to other types of acute renal failure in liver diseases. In 1996, the International Ascites Club proposed a new denition and diagnostic criteria for HRS, since then this term has been generally accepted for the functional renal failure that develops in patients with advanced cirrhosis.11 The diagnostic criteria of HRS are listed in the Table. Low glomerular ltration rate (GFR) is a highly specic but not very sensitive marker. For those at risk, the GFR should be monitored frequently to detect progressive reduction. To exclude prerenal failure, renal function should be reevaluated after diuretic withdrawal and expansion of plasma volume with 1.5 L of isotonic saline. Most cases of HRS have urine sodium <10 mmol/L and urine osmolality above plasma osmolality because the tubular function is preserved. However, a minority of patients may have higher urine sodium and low urine osmolality, similar to values found in acute tubular necrosis.12 Conversely, some cirrhotic patients with acute tubular necrosis may have low urine sodium and high urine osmolality.13 So urinary indices are not considered major criteria for the diagnosis of HRS. Other causes of renal failure in cirrhosis include prerenal failure secondary to volume depletion, acute tubular necrosis, drug-induced nephrotoxicity (e.g. aminoglycoside antibiotics, non-steroidal anti-inammatory drugs, and antiviral therapy), renal failure due to radiocontrast agents, obstructive uropathy and glomerulonephritis in patients with hepatitis B or C. Since only about 30% of patients with cirrhosis and renal failure will have HRS and there are no specic clinical ndings,

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Table. International Ascites Clubs Diagnostic Criteria of Hepatorenal Syndrome.(Adapted from reference 11.)

Major criteria Chronic or acute liver disease with advanced hepatic failure and portal hypertension Low GFR: serum creatinine >133 mol/L or 24h creatinine clearance <40 mL/min Absence of shock, ongoing bacterial infection or treatment with nephrotoxic drug Absence of gastrointestinal or renal uid losses No sustained improvement in renal function following diuretic withdrawal and expansion of plasma volume with 1.5 L of isotonic saline Proteinuria <0.5 g/d and no ultrasonographic evidence of obstructive uropathy or parenchymal renal disease Additional criteria Urine volume <0.5 L/d Urine sodium <10 mmol/L Urine osmolality > plasma osmolality Urine red blood cells <50 high power eld Serum sodium concentration <130 mmol/L

it is important to exclude other causes, e.g. by abdominal ultrasound. Clinically HRS can be divided into types 1 and 2.11 Type 1 HRS is characterised by a rapid and progressive impairment of renal function as dened by a doubling of the initial serum creatinine to a level higher than 221 mol/L in less than 2 weeks. The GFR is usually below 20 mL/min. The median survival time is less than 2 weeks and practically all patients die within 8-10 weeks after the onset of renal failure. Type 2 HRS is characterised by a subtler course with initial serum creatinine levels less than 221 mol/L. The main clinical consequence of type 2 HRS is diuretic-resistant ascites. Patients have a longer median survival time of approximately 6 months. Epidemiology and Clinical Manifestations HRS occurs in about 4% of patients admitted with decompensated cirrhosis, with a cumulative probability of 18% at 1 year and 39% at 5 years.14 Patients with spontaneous bacterial peritonitis will have a one-in-three chance of developing HRS.15 Mostly HRS develops in patients with advanced cirrhosis so they will usually have jaundice and other stigmata of chronic liver disease such as nger clubbing, palmar erythema and spider naevi. Other clinical features include splenomegaly, bleeding tendency, hepatic encephalopathy, oedema and ascites. Patients will usually have low arterial blood pressure, wider pulse pressure and bounding pulses. The urine output will be drastically reduced, particularly in type 1 HRS. Only
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rarely will HRS occur in patients with early well-compensated disease. Patients with refractory ascites, dened as a lack of response to high doses of diuretics (400 mg of spironolactone per day plus 160 mg of furosemide per day) will have an increased risk of HRS.11 Pathophysiology The pathophysiology of HRS is complex and not completely understood. There are recent reviews with detailed descriptions on various physiological aspects of HRS.16,17 The hallmark of HRS is renal vasoconstriction. In contrast, there is severe arterial underlling in the systemic circulation due to pronounced arterial vasodilatation in the splanchnic circulation, which is related to the portal hypertension. The following postulates contribute to the pathogenesis of HRS as schematically represented in the Figure. Hepatorenal Reex In dogs, increases in intrahepatic pressure resulted in increased renal sympathoadrenal activity with decreases in renal blood ow and GFR, and increases in tubular reabsorption of sodium and water.18 In another experiment, hepatic denervation postponed sodium and water retention and ascites formation in dogs.19 These studies support the existence of a hepatorenal reex, which may be activated via adenosine receptors as in animals, and administration of an adenosine receptor antagonist prevented an increase in sodium and water retention following a reduction in portal venous blood ow.20 However, it is still debatable whether hepatorenal reex is present in humans.

Hepatorenal Syndrome

Arterial Vasodilatation Theory The pathophysiology that best ts with the observed changes in renal and circulatory function in HRS is arterial vasodilatation.21 It is postulated that HRS is the result of the action of vasoconstrictor systems on the renal circulation activated as a homeostatic response to improve the extreme underlling of the arterial circulation. As a result of this increased activity of the vasoconstrictor systems, renal perfusion and GFR are greatly reduced but tubular function is preserved. Activation of the vasoconstrictor systems leads to the retention of sodium (renin-angiotensin-aldosterone system and sympathetic nervous system) and free water (arginine vasopressin) that occurs in advanced cirrhosis.22 Most available data suggest that the arterial underlling is due to vasodilatation of the splanchnic circulation related to increased splanchnic production of various vasodilator substances with nitric oxide being the most studied.23 Renal excretion of nitrates and nitrites is increased in cirrhotic rats

and acute nitric oxide synthase activity inhibition improves their excretory functions. Chronic inhibition of nitric oxide synthase activity also improves sodium and water excretion. Other vasodilators included tumour necrosis factor (TNF), calcitonin gene-related peptide, plasma substance P, adrenomedullin and endocannabinoids.24-29 The HRS patients are also noted to have decreased cardiac output in the settings of severe arterial dilation.30 Renal Vasoconstriction In the early phases of decompensated cirrhosis, renal perfusion is maintained within the normal range because of increased synthesis of vasodilating factors (mainly prostaglandins).31-33 In the later phases, renal perfusion cannot be maintained because the extreme arterial underlling causes maximum activation of vasoconstrictor systems together with decreased production of renal vasodilator factors, and HRS develops. The splanchnic area escapes the effect of vasoconstrictors probably because of the greatly increased local production of vasodilators.

+ Portal hypertension

Cirrhosis

Splanchnic vasodilators (e.g. nitric oxide)

Splanchnic Vasodilation + Arterial underlling

Hepatorenal reex (? in human)

Vasoconstrictors activation (e.g. reninangiotensin - aldosterone, endothelin)

Renal Vasoconstriction

Vasoconstriction Renal Vasodilators (e.g. prostaglandins)

HRS

Figure. Pathogenesis of HRS (adapted from References 16 and 17).

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Endothelins Endothelins are a group of three related peptides of 21 amino acids with two receptor subtypes, ETA and ETB. In vascular smooth muscle both receptor subtypes are expressed which mediate vasoconstriction. ETB receptors are also found on endothelial cells where they cause vasodilatation through a nitric oxide dependent mechanism.34 Endothelin 1 (ET-1) was rst isolated from porcine endothelial cells.35 Increased circulating ET-1 concentrations and hepatic release have been found in cirrhosis with highest levels in patients with ascites and HRS, and ET-1 may mediate renal vasoconstriction.36,37 However, the mechanisms leading to increased ET-1 synthesis in HRS are still unknown. Management Until recently, HRS, particularly type 1, has been considered a rapid and fatal complication of end-stage liver disease unless liver transplantation can be immediately performed. Fortunately with increased knowledge in pathogenesis, new pharmacological treatments have been devised to improve short-term outcome and enhance the feasibility of performing liver transplantation for patients with HRS. General Management Usually type 1 HRS develops in patients with advanced chronic liver disease but it can also occur in patients with acute liver failure. Frequent monitorings of uid intake, blood chemistries and urine output are needed. In case of dilutional hyponatraemia, uid restriction of 1 L per day is recommended.38 The use of diuretics in HRS requires very careful consideration due to the potential of worsening electrolytes (hyperkalaemia and hyponatraemia) and resistance to their actions. Patients with type 2 HRS are usually less sick and can be managed in an outpatient setting. Other causes which precipitate HRS should be excluded, e.g. diagnostic paracentesis for spontaneous bacterial peritonitis. Vasoconstrictor Therapy Many pharmacological interventions have been tried for treating HRS. Use of renal vasodilators (dopamine and prostaglandin analogues) was abandoned due to side effects and lack of adequate data conrming the benets.39 Systemic vasoconstrictors with plasma expansion are now the best therapy since several uncontrolled studies have conrmed a benecial role in HRS. They were rst used in 1998 and their actions are to suppress the arterial splanchnic vasodilation and endogenous vasoconstrictor system activation with improvement of renal function. 40 In most studies, vasoconstrictors were given in combination with albumin, with improved efcacy. Vasopressin analogues (ornipressin and terlipressin) have been used in the management

of acute variceal bleeding in cirrhotic patients since they have a marked vasoconstrictor effect in the splanchnic circulation. Use of ornipressin was abandoned since it caused signicant ischaemic side effects.40 Terlipressin has been shown to have the most successful outcomes of the vasoconstrictors studied.41-44 Administration of terlipressin (0.52 mg/4-6h intravenously) is associated with an improvement in renal function in about 60% of the patients and the incidence of ischaemic side-effects is about 10%. The recurrence of HRS after treatment withdrawal is about 50%, and retreatment of recurrence is effective. Somatostatin analogues (octreotide), and alpha-adrenergic agonists (midodrine and noradrenaline) have also been used.45-47 Midodrine (7.5-12.5 mg/8 hr orally) is found to be effective and is often used as a rst-line treatment since the cost of terlipressin is high and it may not be available in some countries. Transjugular Intrahepatic Portosystemic Shunt (TIPS) This is a non-surgical method of portal decompression previously used as an alternative therapy for cirrhotic patients bleeding from oesophageal or gastric varices who do not respond to endoscopic and medical treatment. An interventional radiologist will place a side-to-side portacaval shunt that connects the portal and hepatic veins within the hepatic parenchyma. TIPS reduces portal pressure and returns some of the volume of blood pooled in the splanchnic circulation to the systemic circulation. This suppresses the renin-angiotensin-aldosterone and sympathetic nervous systems activities and decreases their vasoconstrictor effect on the renal circulation.46,48 However there are also many complications associated with TIPS including transcapsular puncture, shunt dysfunction and encephalopathy, and it is contraindicated for patients with advanced Child C cirrhosis.46 Dialysis Small uncontrolled studies using haemodialysis and peritoneal dialysis suggest that both are ineffective mainly due to a high incidence of severe side effects, including arterial hypotension, coagulopathy and gastrointestinal bleeding. However, haemodialysis may be useful in suitable liver transplant candidates as a bridge to transplantation when there is no response to vasoconstrictors or TIPS or patients develop severe volume overload, metabolic acidosis or refractory hyperkalemia. The benecial effect of an extracorporeal albumin dialysis system was reported in patients with Child C cirrhosis and type 1 HRS.49 Liver transplantation This is the denitive treatment for HRS. However, transplantation for type 1 HRS is limited by the fact that many patients die before the operation because they have a short

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survival against a prolonged waiting time in most centres. If liver transplantation can be performed, the 3-year survival probability after transplantation for HRS patients treated with terlipressin and albumin is similar to that of cirrhotic patients without HRS.50 Prevention In patients with spontaneous bacterial peritonitis, the administration of albumin can prevent the circulatory dysfunction and subsequent development of HRS.51 The rationale is that it can prevent arterial underlling and subsequent activation of vasoconstrictor systems during the infection. In patients with acute alcoholic hepatitis, the use of pentoxifylline, an inhibitor of TNF, had been shown to reduce the incidence of HRS and mortality compared to the control group.52 Concluding Remarks HRS is a life threatening complication of liver cirrhosis. With increased knowledge regarding liver cirrhosis, portal hypertension, ascites as well as HRS, new pharmacological treatments such as administration of terlipressin and albumin have proven useful in improving the short-term outcome of HRS. Other medical treatments using different pharmacological principles such as endothelin antagonists, adenosinereceptor antagonists and N-acetylcysteine may also help in reducing renal vasoconstriction and improving renal function.53-55 The future treatment of HRS will likely target the multiple aspects in the pathophysiological process. Competing Interests: None declared. References 1. Frerichs FT. Tratado practico de las Enfermedades del Hgado, de los Vasos Hepaticos y de las Vias Biliares. Madrid: Libreria Extranjera y Nacional, cientifca y Literaria, 1877. 2. Flint A. Clinical report on hydro-peritoneum based on an analysis of forty-six cases. Am J Med Sci 1863;45:30639. 3. Hecker R, Sherlock S. Electrolyte and circulatory changes in terminal liver failure. Lancet 1956;2:12215. 4. Koppel MH, Coburn JN, Mims MM, Goldstein H, Boyle JD, Rubini ME. Transplantation of cadaveric kidneys from patients with hepatorenal syndrome. Evidence for the functional nature of renal failure in advanced liver disease. N Engl J Med 1969;280:1367-71. 5. Iwatsuki S, Popovtzer MM, Corman JL, et al. Recovery from hepatorenal syndrome after orthotopic liver transplantation. N Engl J Med 1973;289:1155-9. 6. Schroeder ET, Shear L, Sancetta SM, Gabuzda GJ. Renal failure in patients with cirrhosis of the liver.

7.

8. 9.

10. 11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

III Evaluation of intrarenal blood ow by paraaminohippurate extraction and response to angiotensin. Am J Med 1967;43:887-96. Epstein M, Berk DP, Hollenberg NK, et al. Renal failure in the patient with cirrhosis. The role of active vasoconstriction. Am J Med 1970;49:175-85. Nonnenbruch W. Das hepatorenale Syndrom. Verh Dtsch Ges Inn Med 1939;51:341-58. Wilensky AO. Occurrence, distribution and pathogenesis of so called liver death and/or hepatorenal syndrome. Arch Surg 1939;38:625-91. Orr TG, Helwig FC. Liver trauma and the hepatorenal syndrome. Ann Surg 1939;110:683-92. Arroyo V, Gines P, Gerbes A, et al. Denition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. Hepatology 1996;23:164-76. Dudley FJ, Kanel GC, Wood LJ, Reynolds TB. Hepatorenal syndrome without avid sodium retention. Hepatology 1986;6:248-51. Cabrera J, Arroyo V, Ballesta AM, et al. Aminoglycoside nephrotoxicity in cirrhosis. Value of urinary beta2-microglobulin to discriminate functional renal failure from acute tubular damage. Gastroenterology 1982;82:97-105. Gines A, Escorsell A, Gines P, et al. Incidence, predictive factors, and prognosis of hepatorenal syndrome in cirrhosis. Gastroenterology 1993;105:229-36. Gines P, Martin P-Y, Niederberger M. Prognostic signicance of renal dysfunction in cirrhosis. Kidney Int Suppl 1997;61:S77-S82. Arroyo V, Guevara M, Gines P. Hepatorenal syndrome in cirrhosis: pathogenesis and treatment. Gastroenterology 2002;122:1658-76. Moller S, Bendtsen F, Henriksen JH. Pathophysiological basis of pharmacotherapy in the hepatorenal syndrome. Scand J Gastroenterol 2005;40:491-500. Kostreva DR, Pontus SP. Hepatic vein, hepatic parenchymal, and inferior vena caval mechanoreceptors with phrenic afferents. Am J Physiol 1993;28:G15-20. Levy M, Wexler MJ. Hepatic denervation alters rstphase urinary sodium excretion in dogs with cirrhosis. Am J Physiol 1987;253:F664-71. Ming Z, Smyth DD, Lautt WW. Decreases in portal ow trigger a hepatorenal reex to inhibit renal sodium and water excretion in rats: role of adenosine. Hepatology 2002;35:167-75. Schrier RW, Arroyo V, Bernardi M, Epstein M, Henriksen JH, Rodes J. Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology 1988;8:1151-7. Schrier RW, Niederberger M, Weigert A, Gines P. Peripheral arterial vasodilation: determinant of functional spectrum of cirrhosis. Semin Liver Dis 1994;14:14-22.
Clin Biochem Rev Vol 28 February 2007 I 15

Georgiou Siah C et A Petersen al. Ng et M PH& Westbrook J Peakeal. & Whiting M

23.

24.

25.

26.

27.

28.

29.

30.

31. 32.

33.

34.

35.

36. 37. 38.

Martin PY, Gines P, Schrier RW. Nitric oxide as mediator of hemodynamic abnormalities and sodium and water retention in cirrhosis. N Engl J Med 1998;339:533-41. Navasa M, Follo A, Jimenez W, et al. Tumor necrosis factor and interleukin-6 in spontaneous bacterial peritonitis in cirrhosis: relationship with the development of renal impairment and mortality. Hepatology 1998;27:1227-32. Wiest R, Groszmann RJ. Nitric oxide and portal hypertension: its role in the regulation of intrahepatic and splanchnic vascular resistance. Semin Liver Dis 1999;19:411-26. Moller S, Bendtsen F, Schifter S, Henriksen JH. Relation of calcitonin gene-related peptide to systemic vasodilatation and central hypovolaemia in cirrhosis. Scand J Gastroenterol 1996;31:928-33. Lee FY, Lin HC, Tsai YT, et al. Plasma substance P levels in patients with liver cirrhosis: relationship to systemic and portal hemodynamics. Am J Gastroenterol 1997;92:2080-4. Guevara M, Gines P, Jimenez W, et al. Increased adrenomedullin levels in cirrhosis: relationship with hemodynamic abnormalities and vasoconstrictor systems. Gastroenterology 1998;114:336-43. Batkai S, Jarai Z, Wagner JA, et al. Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis. Nat Med 2001;7:82732. Ruiz-del-Arbol L, Monescillo A, Arocena C, et al. Circulatory function and hepatorenal syndrome in cirrhosis. Hepatology 2005;42:439-47. Epstein M. Renal prostaglandins and the control of renal function in liver disease. Am J Med 1986;80:46-61. Guarner C, Colina I, Guarner F, et al. Renal prostaglandins in cirrhosis of the liver. Clin Sci (Lond). 1986;70:47784. Laf G, La Villa G, Pinzani M, et al. Altered renal and platelet arachidonic acid metabolism in cirrhosis. Gastroenterology 1986;90:274-82. La M, Reid JJ. Endothelin-1 and the regulation of vascular tone. Clin Exp Pharmacol Physiol 1995;22:31523. Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988;332:411-5. Moller S, Henriksen JH. Endothelins in chronic liver disease. Scand J Clin Lab Invest 1996;56:481-90. Moore K. Endothelin and vascular function in liver disease. Gut 2004;53:159-61. Cardenas A, Gines P. Pathogenesis and treatment of dilutional hyponatraemia in cirrhosis. In: Arroyo V, Forns X, Garcia-Pagan JC, Rodes J, editors. Progress in the treatment of liver diseases. Barcelona: Ars Medica,

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

2003. p. 31-42. Arroyo V, Bataller R, Guevara M. Treatment of hepatorenal syndrome in cirrhosis. In: Arroyo V, Gines P, Rodes J, Schrier RW, editors. Ascites and renal dysfunction in liver disease. Pathogenesis, diagnosis, and treatment. Malden (MA): Blackwell Science, 1999. p. 492-510. Guevara M, Gines P, Fernandez-Esparrach G, et al. Reversibility of hepatorenal syndrome by prolonged administration of ornipressin and plasma volume expansion. Hepatology 1998;27:35-41. Moreau R, Durand F, Poynard T, et al. Terlipressin in patients with cirrhosis and type 1 hepatorenal syndrome: a retrospective multicenter study. Gastroenterology 2002;122:923-30. Ortega R, Gines P, Uriz J, et al. Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: results of a prospective, non-randomized study. Hepatology 2002;36:941-8. Colle I, Durand F, Pessione F, et al. Clinical course, predictive factors and prognosis in patients with cirrhosis and type 1 hepatorenal syndrome treated with Terlipressin: a retrospective analysis. J Gastroenterol Hepatol 2002;17:882-8. Solanki P, Chawla A, Garg R, et al. Benecial effects of terlipressin in hepatorenal syndrome: a prospective, randomized placebo-controlled clinical trial. J Gastroenterol Hepatol 2003;18:152-6. Angeli P, Volpin R, Gerunda G, et al. Reversal of type 1 hepatorenal syndrome with administration of midodrine and octreotide. Hepatology 1999;29:1690-7. Wong F, Pantea L, Sniderman K. Mitodrine, octreotide, albumin, and TIPS in selected patients with cirrhosis and type 1 hepatorenal syndrome. Hepatology 2004;40:5564. Duvoux C, Zanditenas D, Hezode C, et al. Effects of noradrenaline and albumin patients with type 1 hepatorenal syndrome: a pilot study. Hepatology 2002;36:374-80. Boyer TD. Transjugular intrahepatic portosystemic shunt: current status. Gastroenterology 2003;124;170010. Mitzner SR, Stange J, Klammt S, et al. Improvement of hepatorenal syndrome with extracorporeal albumin dialysis MARS: results of a prospective, randomized, controlled clinical trial. Liver Transpl 2000;6:277-86. Restuccia T, Ortega R, Guevara M, et al. Effects of treatment of hepatorenal syndrome before transplantation on post-transplantation outcome. A case-control study. J Hepatol 2004;40:140-6. Sort P, Navasa M, Arroyo V, et al. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 1999;5:403-9.

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52.

53.

Akriviadis E, Botla R, Briggs W, et al. Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: A double-blind, placebo-controlled trial. Gastroenterology 2000;119:1637-48. Soper CP, Latif AB, Bending MR. Amelioration of hepatorenal syndrome with selective endothelin-A antagonist. Lancet 1996;347:1842-3.

54.

55.

Stanley AJ, Forrest EH, Dabos K, Bouchier IA, Hayes PC. Natriuretic effect of an adenosine-1 receptor antagonist in cirrhotic patients with ascites. Gastroenterology 1998;115:406-11. Holt S, Goodier D, Marley R, et al. Improvement in renal function in hepatorenal syndrome with N-acetylcysteine. Lancet 1999;353:294-5.

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