Hepatorenal syndrome (HRS) is a complication of end stage. Hepatorenal Syndrome. Product Code: SMJ07-10A CME Topic

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1 Product Code: SMJ07-10A CME Topic Hepatorenal Syndrome Deepak Venkat, MD, and K. K. Venkat, MD Abstract: Acute kidney injury (AKI) secondary to hepatorenal syndrome (HRS) is an ominous complication of end-stage liver disease (ESLD). In HRS, splanchnic and peripheral vasodilatation with reduction in effective arterial volume causes activation of mechanisms leading to intense renal vasoconstriction and functional AKI. HRS is a diagnosis of exclusion and all other causes of AKI (especially prerenal azotemia) have to be considered and excluded. Spontaneous bacterial peritonitis (SBP) frequently precipitates HRS and should be ruled out in all ESLD patients presenting with AKI. Prompt therapy of SBP with intravenous antibiotics and albumin lessens the risk of developing HRS. Combined use of intravenous albumin, splanchnic and/or peripheral vasoconstrictors, and renal replacement therapy (RRT) are only bridges to early liver transplantation (or combined liver-kidney transplantation in selected patients). Transplantation is the only definitive way of improving the long-term prognosis. Close collaboration between hospitalists/internists managing HRS patients and hepatology and nephrology consultants is critically important. Key Words: acute kidney injury, end-stage liver disease, hepatorenal syndrome From the Department of Internal Medicine, Ohio State University Medical Center, Columbus, OH; and Division of Nephrology and Hypertension, Henry Ford Hospital, Detroit, MI. Reprint requests to Deepak Venkat, MD, Department of Medicine, Ohio State University Medical Center, 395 W. 12th Avenue, 334B Office Tower, Columbus, OH deepak.venkat@osumc.edu Dr. Deepak Venkat and Dr. K.K. Venkat have no financial disclosures to declare or conflicts of interest to report. Accepted January 11, Copyright 2010 by The Southern Medical Association /0 2000/ Hepatorenal syndrome (HRS) is a complication of end stage liver disease (ESLD) associated with a dismal prognosis for patient survival. It can develop in patients with advanced chronic liver disease (cirrhosis of any etiology) and in patients with acute fulminant hepatic failure of diverse causes. HRS is an entity encountered in the inpatient setting in ESLD patients. This article presents a review of the current concepts regarding HRS for hospitalists, internists, and primary care physicians. HRS is defined as a unique functional form of acute kidney injury (AKI) in patients with advanced cirrhosis (almost always associated with ascites) or in patients with fulminant acute hepatic failure that cannot be explained by the common etiological factors that account for AKI in patients without underlying liver disease. 1 3 HRS is thus a diagnosis of exclusion, requiring ruling out of other causes of AKI. It is a functional disorder because it is caused by intense renal vasoconstriction without structural changes in the kidneys. Prompt reversal of renal dysfunction caused by HRS in the majority of patients is achieved by successful liver transplantation, and prompt restoration of renal function in patients with end-stage renal disease following renal transplantation using a kidney from a donor with HRS proves that HRS is a functional disorder. 4 Table 1 shows the current diagnostic criteria for HRS (proposed originally by the International Ascites Club in 1996 and revised in 2005). 5,6 Two types of HRS are recognized based on the tempo of development of AKI. 3 Type 1 HRS is characterized by rapid Key Points Hepatorenal syndrome (HRS) is a unique form of acute kidney injury (AKI), which develops in patients with advanced chronic (cirrhosis) or acute fulminant liver disease. It is caused by severe renal vasoconstriction without structural changes in the kidneys in the setting of splanchnic and peripheral vasodilatation resulting in a pooling of blood in the vasodilated areas with consequent decreased effective arterial volume and renal hypoperfusion. HRS is a diagnosis of exclusion: all other causes of AKI not unique to patients with advanced liver disease must be ruled out. Management requires combined use of splanchnic and peripheral vasoconstrictors and volume expansion with intravenous albumin, percutaneous transjugular intrahepatic portosystemic shunting (in selected patients), treatment of spontaneous bacterial peritonitis (a common precipitant of HRS), if present, and renal replacement therapy (intermittent or continuous), if indicated. All of the above measures are only bridges to early liver transplantation, which is the only effective way to improve the long-term prognosis of these patients Southern Medical Association

2 CME Topic Table 1. Hepatorenal syndrome: currently recommended diagnostic criteria a,6 Presence of cirrhosis with ascites. b Serum creatinine 1.5 mg/dl (creatinine clearance 40 ml/min no longer included in the criteria). Failure of serum creatinine to improve to 1.5 mg/dl after cessation of all diuretics volume expansion with intravenous albumin 1g/kg body weight/day up to maximum of 100 g/d for at least 48 h. Albumin infusion has replaced normal saline (1.5 L/d) that was included in older diagnostic criteria. HRS can be diagnosed in the presence of infection if shock is absent. No current or recent use of nephrotoxic drugs. No evidence of parenchymal kidney disease: proteinuria 500 mg/d, RBCs in the urine sediment 50/high power field and normal renal ultrasonography. Previously included minor diagnostic criteria (oliguria, low urine sodium level, and high urine osmolality) have been eliminated from current criteria. a HRS, hepatorenal syndrome. b HRS can also complicate acute fulminant liver disease. worsening of renal function (at least a doubling of serum creatinine to 2.5 mg/dl or a 50% drop in creatinine clearance or glomerular filtration rate (GFR) in 2 weeks or less. Renal functional decline is more gradual in type 2 HRS, which is seen mainly in patients with diuretic-refractory ascites. The limitations of defining HRS on the basis of the serum creatinine level, glomerular filtration rate (GFR) estimated from the serum creatinine level (using the Cockroft-Gault or Modification of Diet in Renal Disease formulae), or measured 24 hour urinary creatinine clearance should be recognized. 7 9 ESLD patients have marked muscle wasting and decreased creatinine generation by skeletal muscles. Hepatic synthesis of creatine (the substrate for creatinine synthesis in skeletal muscles) may be impaired. There is also evidence that serum bilirubin levels 10 mg/dl may interfere with colorimetric methods of measuring serum creatinine. 10 These extrarenal factors result in significant overestimation of GFR when the serum creatinine is used as the index of renal function in this population. However, despite its limitations, creatinine is currently the only readily available and easily measured test of renal function. Incidence and Prognostic Significance of HRS In a large cohort of initially nonazotemic cirrhotic patients with ascites at the start of the study, the incidence of HRS was reported as 18% at one year and 39% at 5 years of follow up. 11 The incidence of HRS in acute fulminant liver disease has been reported to be between 20% to 30%. 12 Unless liver transplantation is performed without delay, the development of either type of HRS is associated with very poor patient survival. Type 2 HRS is associated with better patient survival than type 1. However, this is still significantly worse than that in ESLD patients without HRS (Fig.). 3 Fig. One month and six months patient survival without liver transplantation in end-stage liver disease patients with type 1, type 2 or no hepatorenal syndrome (HRS). 3 In addition to high mortality without liver transplantation, patients who are transplanted after developing HRS have significantly decreased survival, increased requirement for early postoperative intermittent or continuous renal replacement therapy (RRT), and increased risk of other posttransplant complications. 13 There may also be incomplete recovery of renal function in some HRS patients following liver transplantation with greater risk of progression eventually to end-stage renal disease. 14 HRS: Pathogenesis HRS is a functional form of AKI without irreversible structural renal damage. Severe renal vasoconstriction in the setting of generalized vasodilatation, especially in the splanchnic circulation, with blood pooling in areas of vasodilatation and consequent reduction of effective arterial volume (EAV) is the pathophysiologic basis of HRS. 15 Splanchnic vasodilatation is mediated by the production of potent vasodilator substances, in particular nitric oxide. 16 Increased nitric oxide synthesis in the splanchnic vasculature is believed to result from high endothelial shear stress as a result of portal hypertension complicating cirrhosis. There is also experimental evidence showing that the intestinal mucosal barrier is defective in the setting of advanced liver disease and portal hypertension. This permits increased bacterial migration from the intestinal lumen to mesenteric lymph nodes and leads to increased production of vasoactive cytokines, endotoxins, etc, which further increases nitric oxide production, thereby aggravating splanchnic vasodilatation. 17 In ESLD, vasodilatation and decreased EAV antedate the development of HRS. Increased cardiac output initially offsets the decreased EAV and maintains renal blood flow. 18 Decreased EAV also activates a variety of other compensatory mechanisms (the renin-angiotensin system (RAS), sympathetic nervous system, and increased release of antidiuretic hormone (ADH), endothelin, etc), which tend to cause renal vascoconstriction. 18,19 Increased intrarenal synthesis of vasodilators such as prostaglandins initially counters the renal Southern Medical Journal Volume 103, Number 7, July

3 Venkat and Venkat Hepatorenal Syndrome vasoconstriction. HRS eventually develops when increased cardiac output and intrarenal vasodilators are no longer able to counter the decreased EAV and renal vasoconstriction, respectively, with resultant AKI due to decreased renal blood flow. 18 Intense renal vasoconstriction also results in avid renal tubular retention of sodium and water. This sodium retention further aggravates ascites and edema. 18 In fact, HRS almost never develops in the cirrhotic patient who does not have ascites. Nonosmotic ADH release secondary to decreased EAV results in renal water retention and explains the common association of hyponatremia with HRS. 18 Bacterial infection, especially spontaneous bacterial peritonitis (SBP), is a common precipitating factor for HRS. 3 SBP and other infections augment the production of vasoactive cytokines and other factors which further increase nitric oxide synthesis thereby aggravating splanchnic vasodilatation. 20 Reductions in EAV resulting from overdiuresis, vomiting, variceal hemorrhage, diarrhea (aggravated by lactulose use), large volume paracentesis without concomitant albumin administration, etc may also precipitate HRS. Use of nonsteroidal anti-inflammatory agents (NSAIDs) may contribute to the development of HRS by inhibiting renal vasodilatory prostaglandin synthesis. 18 Clinical Presentation of HRS HRS may present as de novo AKI in patients with previously good kidney function or as AKI superimposed on preexisting chronic renal dysfunction. By definition, AKI progresses more rapidly in type 1 compared to type 2 HRS. 3 In both types of HRS, serum creatinine may increase progressively to a level which necessitates RRT. In other HRS patients, serum creatinine, after initially increasing steadily, may stabilize at a level not requiring immediate RRT. In general, type 1 HRS patients are more severely ill than those with type 2 HRS. Uremic encephalopathy secondary to HRS superimposed on preexisting hepatic encephalopathy may result in marked deterioration of mental status. HRS may occur spontaneously. However, the importance of SBP as a precipitating factor cannot be overemphasized: approximately one third of patients with SBP will develop HRS. 21,22 HRS: Diagnostic Approach As previously stated, the diagnosis of HRS is one of exclusion: all causes of AKI that are not unique to ESLD patients have to be considered in the differential diagnosis (Table 2). HRS is unlikely to be the cause of AKI if ascites, features of advanced parenchymal liver dysfunction, oliguria, hypotension, and hyponatremia, are lacking. 3 Typically, urine examination in a patient with HRS reveals high specific gravity/osmolality, low urine sodium concentration, and low fractional excretion of sodium without significant proteinuria, hematuria, or sediment abnormalities. 3 However, in two other functional forms of AKI that may occur in the ESLD patient, Table 2. Acute kidney injury in the patient with liver disease: diagnostic approach a Careful history and physical examination: Vomiting, diarrhea, gastrointestinal bleeding, marked recent weight loss and rapid decrease in ascites and edema: suspect prerenal azotemia due to gastrointestinal losses or overdiuresis. Recent exposure to nephrotoxic agents such as nonsteroidal antiinflammatory agents, aminoglycosides, sulfa-trimethoprim, iodinated radiocontrast, etc: suspect nephrotoxic AKI. If features of advanced liver disease (especially ascites) are not present, hepatorenal syndrome (HRS) is unlikely. Urinalysis looking for proteinuria, hematuria, and other sediment abnormalities; random urine protein/creatinine ratio or 24 h urine collection to quantitate proteinuria; urine sodium/osmolality/fractional excretion of sodium. Differentiating prerenal azotemia from HRS: discontinuation of diuretics and any nephrotoxic medications, and trial of volume expansion with intravenous albumin for at least 48 h. Rule out abdominal compartment syndrome (if tense ascites are present) by large volume paracentesis intravenous albumin. Rule out spontaneous bacterial peritonitis by diagnostic paracentesis for ascitic fluid cell count, gram stain, and culture. Renal ultrasonography to rule out hydronephrosis/obstructive uropathy. Monitor blood urea nitrogen, serum creatinine, electrolytes, and liver function tests daily to assess evolution of renal and hepatic status. Early hepatology and nephrology consultations. a AKI, acute kidney injury; HRS, hepatorenal syndrome. prerenal azotemia 3 and abdominal compartment syndrome (ACS), 23 urinary findings are the same as in HRS. Prerenal azotemia is caused by EAV depletion, hypotension, and/or low cardiac output. The difference between prerenal azotemia and HRS is that only in the former, volume repletion, correction of hypotension, and/or improvement of cardiac output rapidly improves renal function. This is the basis for recommending diuretic withdrawal and volume expansion with intravenous albumin for at least 48 hours to rule out prerenal azotemia before diagnosing HRS (Table 1). 6 Abdominal compartment syndrome (ACS), defined as increased intraabdominal pressure (IAP) of 20 mm Hg of any etiology, may lead to AKI by increasing renal venous pressure and causing renal arterial vasoconstriction. 23 Intratravesical pressure (measured by placing a Foley catheter connected to a manometer) is used as the surrogate for IAP. ACS (due to tense ascites), although rare, has been reported to cause AKI in ESLD patients. 24 Renal function may improve dramatically in cirrhotics when tense ascites are relieved by large volume therapeutic paracentesis with concomitant intravenous albumin administration. Even if ACS is unlikely, all patients with HRS must have at least a diagnostic paracentesis to rule out SBP, a common precipitating factor for HRS. 21,22 The presence of significant proteinuria, hematuria, and sediment abnormalities in an ESLD patient with AKI suggests diagnoses other than HRS. 7 Heavy proteinuria and RBC casts suggest glomerular disease. Common glomerular dis Southern Medical Association

4 CME Topic eases in patients with liver disease include cryoglobulinemic glomerulonephritis in patients with hepatitis C or hepatitis B and glomerulopathy in association with IgA deposits. Numerous granular casts suggest ischemic or nephrotoxic acute tubular necrosis. Tubular cell and/or white blood count casts suggest acute interstitial nephritis. However, it should be remembered that the development of HRS in a patient with preexisting kidney disease, proteinuria, hematuria, and/or sediment abnormalities secondary to the antecedent renal disorder can present a diagnostic difficulty. Therefore, it is important to review any available past test results to rule out preexisting urinary abnormalities. Renal ultrasonography should be performed to rule out hydronephrosis/obstructive uropathy as the cause of AKI. Since the differential diagnosis of AKI in patients with ESLD is extensive and complex, early nephrology consultation is appropriate. A renal biopsy may be required if the cause of AKI is unclear. Patients with significant chronic, irreversible changes (glomerulosclerosis and/or tubular atrophy/interstitial fibrosis) on renal biopsy may require combined liver-kidney transplantation. 18 Prevention of HRS The following measures are effective in decreasing the incidence of HRS. Long-term, once a week, oral quinolone antibiotic suppression for the prevention of SBP which is recommended in selected cirrhotics with ascites (patients with low protein ascitic fluid, Child-Pugh scores 9, early renal dysfunction, history of variceal bleeding, prior history of SBP, etc) also decreases the incidence of HRS. 25 In patients with SBP, two doses of intravenous albumin (1.5 gm/kg body weight upon diagnosis and 1.0 gm/kg 48 hours later) have been shown in a randomized controlled study to significantly reduce the incidence of HRS to 10% compared to 33% in patients not given albumin (both groups treated with cefotaxime). 22 Minimizing EAV depletion by judicious use of diuretics to avoid excessive weight loss, prompt replacement of gastrointestinal fluid or blood loss, and concomitant administration of intravenous albumin (6 to 8 gm/liter of ascitic fluid removed) when performing large volume paracentesis for refractory ascites, may also decrease the risk of developing HRS. 26 It is also judicious to avoid the use of potentially nephrotoxic medications such as nonsteroidal anti-inflammatory drugs and aminoglycoside antibiotics in cirrhotics with ascites. Treatment of Established HRS In established HRS, therapy is aimed at correcting the causative hemodynamic abnormalities. Various direct renal vasodilators ( low-dose or renal dose intravenous dopamine, RAS blocking drugs, oral [misoprostol] or intravenous prostaglandin-e, endothelin antagonists, etc) have been evaluated in the treatment of HRS with uniformly negative results Renal vasodilator therapy is not currently recommended in patients with HRS. Reversing splanchnic and peripheral vasodilatation combined with expansion of EAV with albumin infusion is currently the cornerstone of the treatment of HRS Agents used include octreotide 31 (available in the United States) or the arginine-vasopressin analog terlipressin 32,35 (not yet approved in the United States) as splanchnic vasoconstrictors and oral midodrine 33 or intravenous norepinephrine 34 as peripheral vasoconstrictors. The combination regimens that have been used in clinical trials of HRS are shown in Table 3. In these trials, reversal of HRS has been reported in 25% to 83% of patients treated with pressor agents plus albumin compared to 8.7% to 12.5% of patients treated with albumin alone However, long-term patient survival without liver transplantation did not improve in these trials. The typical duration of vasoconstrictor therapy is 14 days. If HRS recurs, retreatment with the same regimen may again be successful. It should be noted that the use of intravenous albumin and splanchnic and/or peripheral vasoconstrictors has not been shown to be effective in hepatorenal syndrome complicating acute liver disease with fulminant hepatic failure. Liver-dialysis/hemofiltration, which combines dialysis technology with absorbents (albumin or charcoal) and/or hepatocytes ( bioartificial liver ) in the extracorporeal circuit to remove putative toxins resulting from liver failure, has been used in this setting in Europe but is currently unavailable in the United States If SBP is documented, antibiotic therapy with an intravenous third generation cephalosporin or fluoroquinolone should be continued for days followed by indefinite weekly oral fluoroquinolone suppressive therapy. 25 Table 3. Combination therapy regimens used in hepatorenal syndrome a,31 35 Intravenous terlipressin (not yet approved for use in the United States) initial dose mg every 4 to 6 h, increased on day 4 to 2 mg intravenously every 4 6 h, if serum creatinine has not decreased by 30% from baseline intravenous albumin (initial dose 1 g/kg followed by 20 to 40 g/d). Oral midodrine (initial dose 7.5 mg orally TID with an increase to 12.5 to 15 mg TID as needed to increase mean arterial pressure by 15 mm Hg) octreotide b SQ 100 g TID, titrated 200 g TID on day 2, if renal function has not improved intravenous albumin (initial dose 1 g/kg followed by 20 to 40 g/d). Intravenous norepinephrine ( mg/h as continuous intravenous infusion adjusted to increase mean arterial pressure by 10 mm Hg even in the absence of hypotension or shock) intravenous albumin (initial dose 1 g/kg followed by 20 to 40 g/d). This combination can be used as initial therapy or alternative therapy for those who do not respond to midodrine octreotide. a Above measures have not been shown to be effective in hepatorenal syndrome complicating acute liver disease with fulminant hepatic failure. b Use of octreotide alone without midodrine has not been shown to be effective. When using vasoconstrictor drugs such as midodrine, norepinephrine or terlipressin, the patient must be monitored closely for coronary, cerebrovascular, mesenteric, and/or digital ischemic complications. Southern Medical Journal Volume 103, Number 7, July

5 Venkat and Venkat Hepatorenal Syndrome Transjugular intrahepatic portosystemic shunt (TIPS) placement ameliorates portal hypertension. TIPS has improved renal function in carefully selected patients with HRS. 36 TIPS may, however, increase the risk of hepatic encephalopathy. The decision to use TIPS will have to be made in conjunction with the hepatologist who should be consulted early in the care of HRS patients. In patients who are candidates for liver transplantation, if AKI progresses despite the above therapies, intermittent or continuous RRT will have to be initiated. RRT is futile in patients who are not candidates for liver transplantation, given the dismal prognosis of refractory HRS without transplantation. It should be remembered that all of the above treatments are only temporizing measures. The only definitive way of improving the long term survival of HRS patients is liver transplantation. 11 The development of HRS is an urgent indication for liver ( / kidney) transplant evaluation or for expediting transplantation in patients already on the transplant waiting list. Conclusion HRS is a serious complication of chronic or acute ESLD. It is a functional form of AKI caused by intense renal vasoconstriction in the setting of splanchnic and peripheral vasodilatation with pooling of blood in the vasodilated areas with consequent reduction in EAV. All other causes of AKI will have to be ruled out before diagnosing HRS. SBP, a common precipitant of HRS, will have to be excluded by ascitic fluid studies. Use of splanchnic and peripheral vasoconstrictors in combination with intravenous albumin may improve renal function in HRS. However, these regimens and RRT (if indicated) are only bridges to liver ( / kidney) transplantation which is the only definitive way of improving long term outcomes. References 1. Wadei HM, Mai ML, Ahsan N, et al. Hepatorenal syndrome: pathophysiology and management. Clin J Am Soc Nephrol 2006;1: Ginès P, Guevara M, Arroyo V, et al. Hepatorenal syndrome. Lancet 2003;362: Arroyo V, Terra C, Ginès P. Advances in the pathogenesis and treatment of type-1 and type-2 hepatorenal syndrome. J Hepatol 2007;46: Koppel M, Coburn JW, Mims MM, et al. Transplantation of cadaveric kidneys from patients with hepatorenal syndrome: evidence for functional nature of renal failure in advanced liver disease. N Engl J Med 1969;280: Arroyo V, Ginès P, Gerbes AL, et al. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club. Hepatology 1996;23: Salerno F, Gerbes A, Ginès P, et al. Diagnosis, prevention and treatment of hepatorenal syndrome with cirrhosis. Gut 2007;56: Mackelaite L, Alsauskas ZC, Ranganna K. Renal failure in patients with cirrhosis. Med Clin North Am 2009;93: , viii. 8. MacAulay J, Thompson K, Kiberd BA, et al. Serum creatinine in patients with advanced liver disease is of limited value for identification of moderate renal dysfunction: are the equations for estimating renal function better? Can J Gastroenterol 2006;20: Proulx NL, Akbari A, Garg AX, et al. Measured creatinine clearance from timed urine collections substantially overestimates glomerular filtration rate in patients with liver cirrhosis: a systematic review and individual patient meta-analysis. Nephrol Dial Transplant 2005;20: Daugherty NA, Hammond KB, Osberg IM. Bilirubin interference with the kinetic Jaffé method for serum creatinine. Clin Chem 1978;24: Ginés A, Escorsell A, Ginés P, et al. Incidence, predictive factors, and prognosis of the hepatorenal syndrome in cirrhosis with ascites. Gastroenterology 1993;105: Akriviadis E, Botla R, Briggs W, et al. Pentoxifylline improves shortterm survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial. Gastroenterology 2000;119: Nair S, Verma S, Thuluvath PJ. Pretransplant renal function predicts survival in patients undergoing orthotopic liver transplantation. Hepatology 2002;35: Gonwa TA, Morris CA, Goldstein RM, et al. Long-term survival and renal function following liver transplantation in patients with and without hepatorenal syndrome experience in 300 patients. Transplantation 1991;51: Arroyo V, Fernandez J, Ginés P. Pathogenesis and treatment of hepatorenal syndrome. Semin Liver Dis 2008;28: Niederberger M, Martin PY, Ginès P, et al. Normalization of nitric oxide production corrects arterial vasodilation and hyperdynamic circulation in cirrhotic rats. Gastroenterology 1995;109: Wiest R, Garcia-Tsao G. Bacterial translocation (BT) in cirrhosis. Hepatology 2005;41: Ginés P, Schrier RW. Renal failure in cirrhosis. N Engl J Med 2009; 361: Asbert M, Ginés A, Ginés P, et al. Circulating levels of endothelin in cirrhosis. Gastroenterology 1993;104: Bories PN, Campillo B, Azaou L, et al. Long-lasting NO overproduction in cirrhotic patients with spontaneous bacterial peritonitis. Hepatology 1997;25: Follo A, Llovet JM, Navasa M, et al. Renal impairment after spontaneous bacterial peritonitis in cirrhosis: incidence, clinical course, predictive factors and prognosis. Hepatology 1994;20: 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;341: Bailey J, Shapiro MJ. Abdominal compartment syndrome. Crit Care 2000;4: de Cleva R, Silva FP, Zilberstein B, et al. Acute renal failure due to abdominal compartment syndrome: report on four cases and literature review. Rev Hosp Clin Fac Med Sao Paulo 2001;56: Fernández J, Navasa M, Planas R, et al. Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology 2007;133: Sandhu BS, Sanyal AJ. Management of ascites in cirrhosis. Clin Liver Dis 2005;9: , viii. 27. Ginés A, Salmeron JM, Ginés P, et al. Oral misoprostol or intravenous prostaglandin E2 do not improve renal function in patients with cirrhosis and ascites with hyponatremia or renal failure. J Hepatol 1993;17: Wong F, Moore K, Dingemanse J, et al. Lack of renal improvement with nonselective endothelin antagonism with tezosentan in type-2 hepatorenal syndrome. Hepatology 2008;47: Southern Medical Association

6 CME Topic 29. Saló J, Ginés A, Quer JC, et al. Renal and neurohormonal changes following simultaneous administration of systemic vasoconstrictors and dopamine or prostacyclin in cirrhotic patients with hepatorenal syndrome. J Hepatol 1996;25: Fernández J, Monteagudo J, Bargallo X, et al. A randomized unblinded pilot study comparing albumin versus hydroxyethyl starch in spontaneous bacterial peritonitis. Hepatology 2005;42: Pomier-Layrargues G, Paquin SC, Hassoun Z, et al. Octreotide in hepatorenal syndrome: a randomized, double-blind, placebo-controlled, crossover study. Hepatology 2003;38: Sanyal AJ, Boyer T, Garcia-Tsao G, et al. A randomized, prospective, double-blind, placebo-controlled trial of terlipressin for type 1 hepatorenal syndrome. Gastroenterology 2008;134: Angeli P, Volpin R, Gerunda G, et al. Reversal of type 1 hepatorenal syndrome with the administration of midodrine and octreotide. Hepatology 1999;29: Sharma P, Kumar A, Sharma BC, et al. An open label, pilot, randomized controlled trial of noradrenaline versus terlipressin in the treatment of type 1 hepatorenal syndrome and predictors of response. Am J Gastrenterol 2008;103: Martín-Llahí M, Pépin MN, Guevara M, et al; TAHRS Investigators. Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study. Gastroenterology 2008;134: Brensing KA, Textor J, Perz J, et al. Long term outcome after transjugular intrahepatic portosystemic stent-shunt in non-transplant cirrhotics with hepatorenal syndrome: a phase II study. Gut 2000;47: Southern Medical Journal Volume 103, Number 7, July

7 Product Code: SMJ07-10A Hepatorenal Syndrome July 2010 CME Questions 1. Which of the following features distinguishes prerenal azotemia from hepatorenal syndrome? A. Random urine sodium level 10 meq/l B. Random urine osmolality 500 mosm/l C. Prompt improvement in renal function following intravenous albumin D. Random urine protein/creatinine ratio 500 mg/gram E. Unremarkable urine sediment 2. Which of the following hemodynamic patterns is typical of hepatorenal syndrome? A. Splanchnic vasoconstriction, renal vasodilatation and increased effective arterial volume B. Splanchnic and renal vasoconstriction and decreased effective arterial volume C. Splanchnic, peripheral and renal vasodilatation with increased effective arterial volume D. Splanchnic and peripheral vasodilatation, renal vasoconstriction and decreased effective arterial volume 3. Which of the following measures have been reported to improve renal function in patients with hepatorenal syndrome? a. Direct renal vasodilatation using low-dose dopamine infusion b. Combination therapy with octreotide (or terlipressin), midodrine (or norepinephrine infusion) and intravenous albumin c. Renal vasodilatation using a combination of drugs blocking the renin-angiotensin system and endothelin antagonists d. Combination therapy with octreotide (or terlipressin) and low-dose dopamine infusion Online CME Request Form SMA Southern Medical Association Advocacy, Leadership, Quality and Professional Identity 2010 Southern Medical Association All Rights Reserved W. Lakeshore Drive Birmingham July 2010 CME Questions - Answer Key 1. C, 2. D, 3. B

8 Southern Medical Journal s CME/CE Activity Date of Original Release: July 5, 2010 Expiration: July 5, 2011 Estimated Time of Completion: 1 hour Product Code: SMJ07-10A Check box(es) below to document your participation in this Journal CME/CE activity I attest that I have read the article and completed the self-assessment test as directed. Time spent: hours minutes. Maximum award is 1 AMA PRA Category 1 Credit TM per article. Completion Date: Name Degree(s) Nursing License # Mailing Address City State Zip Phone Fax Specialty Cost for nonmembers: $15.00 SMA member # (SMJ CME/CE activity is free for SMA members) Credit Card Information Master Card Credit Card # Expiration Date Security code Visa American Express Discover Signature Check payable to SMA Billing address (if different from above) Directions: Read the designated article(s), including a review of tables, illustrations, photographs, etc.; complete the selfassessment test(s) to test your knowledge, and evaluate each article below. To request a CME/CE certificate, complete all sections of this form and return with payment as directed. Target Audience: This CME activity was designed for physicians in all specialties and healthcare professionals. Accreditation/Credit Designation: The Southern Medical Association (SMA) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The SMA designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit per article. Participants should only claim credit commensurate with the extent of their participation in the activities. Nurse CE Contact Hours: The SMA is an approved provider of continuing nursing education by the Alabama State Nurses Association, an accredited approver by the American Nurses Credentialing Center's Commission on Accreditation; Southern Medical Association provider # Each activity qualifies for up to 1 contact hour. Hepatorenal Syndrome Objective: Upon completion, participants should be able to recognize the diagnostic criteria for hepatorenal syndrome, outline the pathophysiologic changes responsible for this disease, workup renal failure in cirrhotic patients and initiate appropriate therapy. Evaluate these statements as they relate to this article. Agree Neutral Disagree Presented objective, balanced, scientifically rigorous, evidence-based content Achieved stated objectives Satisfied my educational need Will improve my practice/professional outcomes How many patients with this condition do you currently treat? (circle) 0, 1-5, 6-10, 11-20, over 20 patients Outcomes: What changes, if any, do you plan to make in your practice as a result of reading this article? Needs Assessment: Clinical topic/experience that most needs to be addressed in future SMJ articles: Please mail completed form to SMA, Attn: SMJ CME, 35 W. Lakeshore Drive, Birmingham, AL , or fax to (205)