Hepatorenal Syndrome

Introduction Initial reports by Frerichs (1861) and Flint (1863) [1], who had noted an association between advanced liver disease with ascites and acute oliguric renal failure in the absence of significant histological changes in the kidneys, led Heyd [2], and later Helwig and Schutz [3], to introduce the concept of the hepatorenal syndrome (HRS) to explain the increased frequency of acute renal failure after biliary surgery. However, because HRS could not be reproduced in animal models, pathophysiological concepts remained speculative and its clinical entity was not generally accepted. During the 1950s, HRS was more specifically characterised as a functional renal failure in patients with advanced liver disease, electrolyte disturbances and low urinary sodium concentrations [4]. Hecker and Sherlock [5] showed its temporal reversibility by norepinephrine administration. Over the next few decades, haemodynamic and perfusion studies by Epstein and other investigators [6] identified splanchnic and systemic vasodilatation and active renal vasoconstriction as the pathophysiological hallmarks of HRS. Improved models of ascites and circulatory dysfunction contributed to therapeutic advances, including the introduction of large-volume paracentesis, vasopressin analogues, and transjugular intrahepatic stent-shunt (TIPS), which in turn have led to an improved pathophysiological understanding of HRS [7]. Definition HRS is defined as the development of renal failure in patients with severe liver disease (acute or chronic) in the absence of any other identifiable cause of renal pathology. It is diagnosed following the exclusion of other causes of renal failure in patients with liver disease, such as hypovolaemia, drug nephrotoxicity, sepsis or glomerulonephritis. A similar syndrome can also occur in the setting of acute liver failure [8]. In the kidney there is marked renal vasoconstriction, resulting in a low glomerular filtration rate (GFR). In the extrarenal circulation arterial vasodilatation predominates, resulting in reduction of the total systemic vascular resistance and arterial hypotension [9]. Diagnostic Criteria The International Ascites Club (1996) group has defined the diagnostic criteria for HRS, and these are listed in Table 1 [8]. 10 J. Besso, C. Pru, J. Padron, J. Plaz Table 1. International Ascites Club’s criteria for diagnosis of hepatorenal syndrome Major criteria Chronic or acute liver disease with advanced hepatic failure and portal hypertension Low GFR, as indicated by serum creatinine > 1.5 mg/dl or 24-h creatinine clearance < 40 ml/min Absence of shock, ongoing bacterial infection, fluid loss, and current or recent treatment with nephrotoxic drugs Absence of gastrointestinal fluid losses (repeated vomiting or intense diarrhoea) or renal fluid losses (weight loss > 500 g/d for several days in patients with ascites without peripheral oedema or > 1000 ml in patients with peripheral oedema) No sustained improvement in renal function (decrease of serum creatinine to 1.5 mg/dl or less or increase in 24 h creatinine clearance to 40 ml/min or more) after withdrawal of diuretics and expansion of plasma volume with 1.5 l of isotonic saline Proteinuria < 500mg/d and no ultrasonographic evidence of obstructive uropathy or parenchymal renal disease Additional criteria Urine sodium < 10 meq/l Urine volume < 500 ml/d Urine osmolality > plasma osmolality Urine red blood cells < 50 per high-power field Serum sodium concentration < 130 meq/l GFR, glomerular filtration rate Two patterns of HRS are observed in clinical practice and have also been defined by the International Ascites Club [10]: – Type 1 HRS is an acute form in which renal failure occurs spontaneously in patients with severe liver disease and is rapidly progressive. It is characterised by marked reduction of renal function, as defined by doubling of the initial serum creatinine to a level greater than 2.5 mg/dl, or a 50% reduction in initial 24-h creatinine clearance to < 20 ml/min within 2 weeks. Type 1 HRS has a poor prognosis, with 80% mortality at 2 weeks. Renal function can recover spontaneously following improvement in liver function. This is most frequently observed in acute liver failure or alcoholic hepatitis, or following acute decompensation against a background of cirrhosis. These patients are usually jaundiced and have significant coagulopathy. Death often results from a combination of hepatic and renal failure or from variceal bleeding. – Type 2 HRS usually occurs in patients with diuretic resistance ascites. Renal failure has a slow course, with deterioration over months in some cases. It is also associated with a poor prognosis, although the survival time is longer than that of patients with type 1 HRS. Application of these diagnostic criteria has become widely accepted as an important precondition of successful multicentre trials in HRS. Use of the term ‘pseudohepatorenal syndrome’ to summarise other forms of renal failure in the setting of liver disease is not recommended [11]. Pathophysiology The hallmark of HRS is renal vasoconstriction, although the pathogenesis is not fully understood.Multiple mechanisms are probably involved and include interplay between disturbances in systemic haemodynamics, activation of vasoconstrictor systems and a reduction in activity of the vasodilator systems [16–19]. The haemodynamic pattern of patients with HRS is characterised by increased cardiac output, low arterial pressure and reduced systemic vascular resistance. Renal vasoconstriction occurs in the absence of reduced cardiac output and blood volume, which is a point of contrast to most clinical conditions associated with renal hypoperfusion. Although the pattern of increased renal vascular resistance and decreased peripheral resistance is characteristic of HRS, it also occurs in other conditions, such as anaphylaxis and sepsis. Doppler studies of the brachial, middle cerebral and femoral arteries suggest that extrarenal resistance is increased in patients with HRS, while the splanchnic circulation is responsible for arterial vasodilatation and reduced total systemic vascular resistance. The renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS) are the predominant systems responsible for renal vasoconstriction [20]. The activity of both systems is increased in patients with cirrhosis and ascites, and this effect is magnified in HRS. In contrast, an inverse relationship exists between the activity of these two systems and renal plasma flow (RPF) and the glomerular filtration rate (GFR). Endothelin is another renal vasoconstrictor that is present in increased concentration in HRS, although its role in the pathogenesis of this syndrome has yet to be identified. Adenosine is well known for its vasodilator properties, although it acts as a vasoconstrictor in the lungs and kidneys. Elevated levels of adenosine are more common in patients with heightened activity of the RAAS and may work synergistically with angiotensin II to produce renal vasoconstriction in HRS. This effect has also been described with the powerful renal vasoconstrictor, leukotriene E4. The vasoconstricting effect of these various systems is antagonised by local renal vasodilatory factors, the most important of which are the prostaglandins. Perhaps the strongest evidence supporting their role in renal perfusion is the marked decrease in RPF and the GFR when nonsteroidal medications known to bring about a sharp reduction in PG levels are administered. Nitrous oxide (NO) is another vasodilator that is believed to play an important part in renal perfusion. Preliminary studies, predominantly based on animal experiments, have demonstrated that NO production is increased in the presence of cirrhosis, although NO inhibition does not result in renal vasoconstriction owing to a compensatory increase in PG synthesis.However, Hepatorenal Syndrome 13 when both NO and PG production are inhibited, marked renal vasoconstriction develops. These findings demonstrate that renal vasodilators have a critical role in maintaining renal perfusion, particularly in the presence of overactivity of renal vasoconstrictors. However, we do not yet know for certain whether vasoconstrictor activity becomes the predominant system in HRS and whether a reduction in the activity of the vasodilator system contributes to this [21–29].Various theories have been proposed to explain the development of HRS in cirrhosis. The two main ones are the arterial vasodilatation theory and the hepatorenal reflex theory. The first not only describes sodium and water retention in cirrhosis, but may also be the most rational hypothesis for the development of HRS. Splanchnic arteriolar vasodilatation in patients with compensated cirrhosis and portal hypertension may be mediated by several factors, the most important of which is probably NO. In the early phases of portal hypertension and compensated cirrhosis, this underfilling of the arterial bed causes a decrease in the effective arterial blood volume and results in homeostatic reflex activation of the endogenous vasoconstrictor systems. Activation of the RAAS and SNS occurs early with antidiuretic hormone secretion, a later event when a more marked derangement in circulatory function is present. This results in vasoconstriction not only of the renal vessels, but also in the vascular beds of the brain,muscle, spleen and extremities. The splanchnic circulation is resistant to these effects because of the continuous production of local vasodilators, such as NO. In the early phases of portal hypertension, renal perfusion is maintained within normal or near-normal limits as the vasodilatory systems antagonise the renal effects of the vasoconstrictor systems. However, as liver disease progress in severity, a critical level of vascular underfilling is achieved; renal vasodilatory systems are unable to counteract the maximal activation of the endogenous vasoconstrictors and/or intrarenal vasoconstrictors, which leads to uncontrolled renal vasoconstriction. Support for this hypothesis is provided by studies in which the administration of splanchnic vasoconstrictors in combination with volume expanders results in improvement in arterial pressure, RPF and GFR [30–34]. The alternative theory proposes that renal vasoconstriction in HRS is not related to systemic haemodynamics but is due either to a deficiency in the synthesis of a vasodilator factor or to a hepatorenal reflex that leads to renal vasoconstriction. Evidence points to the vasodilatation theory as a more tangible explanation for the development of HRS. References 1. Flint A (1863) Clinical report on hydro-peritoneum, based on analysis of forty-six cases. Am J Med Sci 45:306–339 2. Heyd CG (1924) The liver and its relation to chronic abdominal infection. Ann Surg 79:55–77 3. Helwig FC, Schutz CB (1932) A liver-kidney syndrome: Clinical, pathologic and experimental studies. Surg Gynecol Obstet 55:570–580 4. Papper S, Belsky JL, Bleifer KH (1932) Renal failure in Laennec’s cirrhosis of the liver. I. Clinical and laboratory features. Ann Intern Med 57:759–773 22 J. Besso, C. Pru, J. Padron, J. Plaz 5. Hecker R, Sherlock S (1956) Electrolyte and circulatory changes in terminal liver failure. Lancet 2:1121–1125 6. Epstein M, Berk DP,Hollenberg NK et al (1970) Renal failure in the patient with cirrhosis. The role of active vasoconstriction. Am J Med 49:175–185 7. Arroyo V, Bataller R (1999) Historical notes on ascites in cirrhosis. In: Arroyo V, Gines P, Rodes J et al (eds) Ascites and renal dysfunction in liver disease. Blackwell Science, Oxford, pp 3–13 8. Arroyo V, Gines P, Gerbes AL et al (1996) Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. Hepatology 23:164–176 9. Arroyo V, Gines P, Jimenez V et al (1999) Renal dysfunction in cirrhosis. In: Bircher J, Benhamou J-P, McIntyre N et al (eds) Oxford textbook of clinical hepatology. Oxford University Press, Oxford, pp 733–761 10. Arroyo V, Gines P, Gerbes AL et al (1996) Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club Hepatology 23:164–176 11. Conn HO (1973) A rational approach to the hepatorenal syndrome. Gastroenterology 65:321–340 12. Gines A, Escorsell A, Gines P et al (1993) Incidence, predictive factors, and prognosis of the hepatorenal syndrome in cirrhosis with ascites. Gastroenterology 105:229–236 13. Gines P, Martin P-Y, Niederberger M (1997) Prognostic significance of renal dysfunction in cirrhosis. Kidney Int Suppl 51:S77–S82 14. Kramer L, Horl WH (2002) Hepatorenal syndrome. Semin Nephrol 22:290–301 15. Hampel H, Bynum GD, Zamora E et al (2001) Risk factors for the development of renal dysfunction in hospitalized patients with cirrhosis. Am J Gastroenterol 96:2206–2210 16. Cardenas A, Gines P, Uriz J et al (2001) Renal failure after upper gastrointestinal bleeding in cirrhosis: incidence, clinical course, predictive factors, and short-term prognosis. Hepatology 34:671–676 17. Schrier RW,Arroyo V, Bernardi M et al (1988) Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology 8:1151–1157 18. Fernandez-Seara J, Prieto J, Quiroga J et al (1989) Systemic and regional hemodynamics in patients with liver cirrhosis and ascites with and without functional renal failure. Gastroenterology 97:1304–1312 19. Koyama S, Kanai K, Aibiki M et al (1988) Reflex increase in renal nerve activity during acutely altered portal venous pressure. J Auton Nerv Syst 23:55–62 20. Ming Z, Smyth DD, Lautt WW (2002) Decreases in portal flow trigger a hepatorenal reflex to inhibit renal sodium and water excretion in rats: role of adenosine. Hepatology 35:167–175 21. Arroyo V, Bosch J, Rivera F et al (1979) The renin angiotensin system in cirrhosis. Its relation to functional renal failure. In: Bartoli E, Chiandussi L (eds) Hepatorenal syndrome. Piccin Medical Books, Padua, pp 201–29 22. Schriern RW, Arroyo V, Bernardi M et al (1988) Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology 8:1151–1157 23. Colle I,Moreau R, Pessione F et al (2001) Relationship between haemodynamic alterations and the development of ascites or refractory ascites in patients with cirrhosis. Eur J Gastroenterol Hepatol 13:251–256 24. Platt JF,Ellis JH,Rubin JM et al (1994) Renal duplex Doppler ultrasonography: a non Hepatorenal Syndrome 23 invasive predictor of kidney dysfunction and hepatorenal failure in liver disease. Hepatology 20:362–369 25. Epstein M (1986) Renal prostaglandins and the control of renal function in liver disease. Am J Med 80:46–55 26. Vallance P, Moncada S (1991) Hyperdynamic circulation in cirrhosis: a role for nitric oxide? Lancet 337:776–778 27. Sogni P, Garnier P, Gadano A et al (1995) Endogenous pulmonary nitric oxide production measured from exhaled air is increased in patients with severe cirrhosis. J Hepatol 23:471–473 28. Moncada S, Higgs A (1991) The L-arginine-nitric oxide pathway. N Engl J Med 329:2002–2012 29. Genesca J, Gonzalez A, Segura R et al (1999) Interleukin-6, nitric oxide, and the clinical and hemodynamic alterations of patients with liver cirrhosis. Am J Gastroenterol 94:169–177 30. Pateron D, Tazi KA, Sogni P et al (2000) Role of aortic nitric oxide synthase in the systemic vasodilation of portal hypertension. Gastroenterology 119:196–200 31. Rockey DC, Chung JJ (1998) Reduced nitric oxide production by endothelial cells in cirrhotic rat liver: endothelial dysfunction in portal hypertension. Gastroenterology 114:344–351 32. Song D, Liu H, Sharkey KA et al (2002) Hyperdynamic circulation in portal-hypertensive rats is dependent on central c-fos gene expression. Hepatology 35:159–166 33. Gadano A,Moreau R,Heller J et al (1999) Relation between severity of liver disease and renal oxygen consumption in patients with cirrhosis. Gut 45:117–121 34. Helmy A, Jalan R,Newby DE et al (2000) Role of angiotensin II in regulation of basal and sympathetically stimulated vascular tone in early and advanced cirrhosis. Gastroenterology 118:565–572 35. Gerbes AL, Gülberg V, Bilzer M (1998) Endothelin and other mediators in the pathophysiology of portal hypertension. Digestion 59 [Suppl 2]:8–10 36. Lhotta K (2002) Beyond hepatorenal syndrome-glomerulonephritis in patients with liver disease. Semin Nephrol 22:302–308 37. Rector WG Jr, Kanel GC, Rakela J et al (1985) Tubular dysfunction in the deeply jaundiced patient with hepatorenal syndrome. Hepatology 5:321–326 38. Heyman SN,Darmon D, Goldfarb M et al (2000) Endotoxin-induced renal failure. I. A role for altered renal microcirculation. Exp Nephrol 8:266–274 39. Mandal AK, Lansing M, Fahmy A (1982) Acute tubular necrosis in hepatorenal syndrome: an electron microscopy study. Am J Kidney Dis 2:363–374 40. Eckardt KU, Frei U (2000) Reversibility of hepatorenal syndrome in an anuric patient with Child C cirrhosis requiring haemodialysis for 7 weeks. Nephrol Dial Transplant 15:1063–1065 41. Gines P, Rimola A, Planas R et al (1990) Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double blind, placebo-controlled trial. Hepatology 12:716–724 42. Follo A, Llovet JM, Navasa M et al (1994) Renal impairment after spontaneous bacterial peritonitis in cirrhosis: predictive factors of infection resolution and survival in patients with cefotaxime. Hepatology 20:1495–1501 43. Sort P, Navasa M, Arroyo V et al (1999) Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 341:403–409 44. Gines P, Tito L, Arroyo V et al (1988) Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis. Gastroenterology 84:1493–1502 24 J. Besso, C. Pru, J. Padron, J. Plaz 45. Gines P, Fernandez-Esparrach G, Monescillo A et al (1996) Randomized trial comparing albumin, dextran 70, and polygeline in cirrhotic patients with ascites treated by paracentesis. Gastroenterology 111:1002–1010 46. Gines P, Arroyo V (2000) Is there still a need for albumin infusions to treat patients with liver disease? Gut 46:588–590 47. Cabrera J, Arroyo V, Ballesta AM et al (1982) Aminoglycoside toxicity in cirrhosis. Value of urinary beta-2 microglobulin to discriminate functional renal failure from acute tubular damage. Gastroenterology 82:97–105 48. Hadengue A,Moreau R, Gaudin C et al (1992) Total effective vascular compliance in patients with cirrhosis: a study of the response to acute blood volume expansion. Hepatology 15:809–815 49. Guevara M, Gines P, Fernandez-Esparrach G et al (1998) Reversibility of hepatorenal syndrome by prolonged administration of ornipressin and plasma volume expansion. Hepatology 27:35–41 50. Uriz J, Cardenas A, Sort P et al (2000) Telipressin plus albumin infusion: an effective and safe therapy of hepatorenal syndrome. J Hepatol 33:43–48 51. Gentilini P (1999) Hepatorenal syndrome and ascites -an introduction. Liver 19 [Suppl]:5–14 52. Bacq Y, Gaudin C,Hadengue A et al (1991) Systemic, splanchnic and renal hemodynamic effects of a dopaminergic dose of dopamine in patients with cirrhosis. Hepatology 14:483–487 53. Barnardo DE, Baldus WP,Maher FT (1970) Effects of dopamine on renal function in patients with cirrhosis. Gastroenterology 58:524–531 54. Bellomo R, Chapman M, Finfer S et al (2000) Low-dose dopamine in patients with early renal dysfunction: a placebo–controlled randomised trial.Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet 356:2139–2143 55. Dagher L, Patch D,Marley R et al (2000) Pharmacological treatment of the hepatorenal syndrome in cirrhotic patients (review article). Aliment Pharmacol Ther 14:515–521 56. Fevery J,Van Cutsem E, Nevens F et al (1990) Reversal of hepatorenal syndrome in four patients by peroral misoprostol (prostaglandin E1 analogue) and albumin administration. J Hepatol 11:153–158 57. Holt S,Marley R, Fernando B et al (1999) Improvement of renal function in hepatorenal syndrome with N-acetyl cysteine. Lancet 353:294 58. Moore K,Wendon J, Frazer M et al (1992) Plasma endothelin immunoreactivity in liver disease and the hepatorenal syndrome. N Engl J Med 327:1774–1778 59. Soper CP, Latif AB, Bending MR (1996) Amelioration of hepatorenal syndrome with selective endothelin-A antagonist. Lancet 347:1842–1843 60. Lenz K,Hornatgl H, Druml W et al (1989) Beneficial effect of 8-ornithine vasopressin on renal dysfunction in decompensated cirrhosis. Gut 30:90–96 61. Lenz K, Druml W, Kleinberger G et al (1985) Enhancement of renal function with ornipressin in a patient with decompensated cirrhosis. Gut 26:1385–1386 62. Gulberg V, Bilzer M, Gerbes AL (1999) Long-term therapy and retreatment of hepatorenal syndrome type 1 with omipressin and dopamine. Hepatology 30:870–875 63. Hadengue A, Gadano A,Moreau R et al (1998) Beneficial effects of the 2-day administration of terlipressin in patients with cirrhosis and hepatorenal syndrome. J Hepatol 29:565–570 64. Kaffy F,Borderie C, Chagneau C et al (1999) Octreotide in the treatment of the hepatorenal syndrome in cirrhotic patients. J Hepatol 30:174 Hepatorenal Syndrome 25 65. Angeli P,Volpin R, Gerunda G et al (1999) Reversal of type 1 hepatorenal syndrome with the administration of midodrine and octreotide. Hepatology 29:1690–1697 66. Rösch J, Keller FS (2001) Transjugular intrahepatic portosystemic shunt: Present status, comparison with endoscopic therapy and shunt surgery, and future perspectives. World J Surg 25:337–345 67. Rössle M, Haag K, Ochs A et al (1994) The transjugular intrahepatic portosystemic stent-shunt procedure for variceal bleeding. N Engl J Med 330:165–171 68. Brensing KA, Textor J, Perz J et al (2000) Long term outcome after transjugular intrahepatic portosystemic stent-shunt in non transplant cirrhotics with hepatorenal syndrome: a phase II study. Gut 47:288–295 69. Colombato LA, Spahr L, Martinet JP et al (1996) Haemodynamic adaptation two months after transjugular intrahepatic portosystemic shunt (TPS) in cirrhotic patients. Gut 39:600–604 70. Kramer L, Gendo A,Madl C et al (2000) Biocompatibility of a cuprophane charcoalbased detoxification device in cirrhotic patients with hepatic encephalopathy. Am J Kidney Dis 36:1193–1200 71. Wilkinson SP,Weston MJ, Parsons V et al (1977) Dialysis in the treatment of renal failure in patients with liver disease. Clin Nephrol 8:287–292 72. Mitzner SR, Stange J, Klammt S et al (2000) Improvement of hepatorenal syndrome with extracorporeal albumin dialysis MARS: result of a prospective, randomized, controlled clinical trial. Liver Transplant 6:277–286 73. Gonwa TA, Klintmalm GB, Levy M et al (1995) Impact of pretransplant renal function on survival after liver transplantation. Transplantation 59:361–365 74. Gonwa TA, Mai ML, Melton LB et al (2001) End-stage renal disease (ESRD) after orthotopic liver transplantation (OLTX) using calcineurin-based immunotherapy:risk of development and treatment. Transplantation 72:1934–1939