Hepatorenal Syndrome Norton J. Greenberger, MD [S514 REL Uae LE AOE » Type 1 hepatorenal syndrome—rapid and progressive impairment of renal function defined by doubling of the initial serum creatinine level to > 2.5 mg/d or 50% reduction of the initial 24-hour creatinine clearance to < 20 ml/min in less than 2 weeks. » Iype 2 hepatorenal syndrome—impaimment in renal function leading to serum creatinine level > 1.5 mg/dl that does not meet the criteria for type 1. > Frequent precipitants include gastrointestinal bleeding, sepsis, spontaneous bacterial peritonitis, aggressive diuresis and paracentesis, nonsteroidal anti-inflammatory ‘drugs (NSAIDS), and intravenous contrast agents. >» Intravenous albumin, 1.5 g/kg, should be administered at the time of diagnosis of hepatorenal syndrome. General Considerations ‘Hepatorenal syndrome is characterized by functional kidney failure in patients with end-stage liver disease. It results in intense renal vasoconstriction without any other identifiable kidney pathology. Clinical features of hepatorenal syndrome ‘include oliguria, dilutional hyponatremia, progressive azotemia,, and hypotension. Prequent precipitants include gas testinal bleeding, sepsis, aggressive diuresis, and paracentesis. However, many patients develop hepatorenal syndrome as a ‘consequence of chronic end-stage liver disease without any A. Incidence Hepatorenal syndrome develops in 5% of patients with chronic liver disease who present with upper gastrointesti- nal bleeding, 30% of patients admitted with spontancous bacterial peritonitis, 10% of patients with ascites treated with total paracentesis, and 25% of patients with severe alcoholic hepatitis. The probability of hepatorenal syndrome developing ina patient with cirrhosis and new onset of ascites is 7-10%. “The 5-year probability of hepatorenal syndrome developing in a patient with cirshosis and recurrent ascites is 40%. B. Definition 1. Type 1 hepatorenal syndrome—Type is characterized by rapid and progressive impairment of renal function defined by a doubling the initial serum creatinine toa level higher than 2.5 mg/dL or a 50% reduction of the initial 24- hour creatinine clearance toa level lower than 20 ml/min in less than 2 weeks. 2. Type 2 hepatorenal syndrome—Type 2 is defined as impairment in renal function (serum creatinine > 1.5 mg/dL) that does not meet the criteria for type 1. Prevenal failure isa preischemic state and may lead to ischemic tubular necrosis. Arroyo V, GinésP, Gerbes A, ct al. Definition and diagnostic crite- ria of refractory ascites and hepatorenal syndrome in circhosis. International Ascites Club. Hepatology. 199623:164-176, [PMID: 8550036] Pathogene: In patients with cirrhosis and ascites there is activation of the renin-angiotensin and sympathetic nervous systems, result- ing in elevated levels of renin, aldosterone, and norepineph- rine. If cicrhotic patients undergo diuresis successfully, the levels of renin, aldosterone, norepinephrine, and antidiuretic, hormone all decrease. However, in patients with end-stage liver disease complicated by hepatorenal syndrome, levels of renin, akosterone, antidiuretic hormone, and norepineph- rine are raised and remain persistently elevated despite vig ‘orous attempts at volume expansion. This consequence ‘occurs in part because of decreased systemic vascular resist ance and splanchnic arteriolar vasodilation. ‘The splanchnic ‘vasodilation results from increased nitric oxide synthesis. ‘The combination of decreased systemic vascular resistanceCET CHAPTER 46 and arterial underfilling leads to the stimulation of systemic vasoconstrictors whic, in turn, causes renal vasoconstriction In the early stages of cirrhosis, increased systemic and local vasodilators may act to preserve renal function. The vasodila- tors include prostacyclin, prostaglandin Ey nitric oxide, atrial natriuretic peptide, and the kallikrein-kinin system. ‘Vasoconstrictors include angiotensin Il, norepinephrine, neu- ropeptide Y, endothelin-1, adenosine, thromboxane Ay. cy5- teinyl leukotrienes, nd F,-isoprostanes. With the development ‘of hepatorenal syndrome, there is decreased production of local vasodilators and increased production of vasoconstric- tors. The net result is intense renal vasoconstriction aifecting primarily the renal cortex. NSAIDS, and aspirin, by virtue of ‘their inhibition of prostaglandin synthesis, may actually inter- {ere withthe production of local vasodilators in the kidney and can trigger or precipitate an episode of hepatorenal syndrome in cierhotic patients with marginal renal function, Planas R, Montoliu S, BallestéB, etal, Natural history of patients hospitalized for ‘management of cirthotic ascites. Clin Gastroenterol Hepatol. 2006;4:1385-1394, [PMID: 17081806] Clinical Findings ‘The major and minor criteria for diagnosis of hepatore- nal syndrome are summarized in lable 46~1, Hepatorenal syndrome is characterized by oliguria (< 500 mL/24 hh), an Table 46-1. Diagnostic criteria for hepatorenal syndrome? Major 1. Conic or acute hepatic disease with advanced hepatic ale and oat hypertension 2. Low glomerua fitvaton rat indicated by serum eatinine > 15 mg/dl or 24 creatinine ceacnce < 40 mi/inin 3. No shock, ongoing bacterial infection sepsis, spontaneous bacterial esti, rena ud losses (uretis, ongoing breathing problems, 4 weatment for tric rugs (NSAIDS, ASA, aminoglycosides) 4. No improvement in eal function i, deceased Serum creatinine to values « 15 mi/dl) ltr dmetc withdrawal and expansion of plasma volume wit 1.5 Lof plasma expander 5. reeinura< 500 mg for 24, and normal renal utrasound (le, no evidence ofobstucive uropathy ox parenchymal renal disease) minor 1. teria frequently present: + Urine volume < 500 mi/ay + tine sodium < 10 mg/L + Wine osmoaty greater han serum osmoaty 2. Serum sodium < 130 mEq/L 235A, amnosalcye a, NSAID, nonseroal anata dog ‘as developed by the itemationalasates Cub Reproduced wth pemisson, fom AmoyoV, Ginés®Garbes A, eta. Definition and dagwsic cia of refactory aces and hepatarenal syndrome in cits Intemational Ascites Club. Hepatatogy. 1996; 2316176 ‘unremarkable urinary sediment, a low rate of sodium secre- tion (< 10 mEq/L}, a low urine output in the absence of livretics, and a progressive rise of plasma creatinine. ‘The onset of renal failure is typically insidious but can be precipitated by acute insults such as gastrointestinal bleed- ing, sepsis, spontancous peritonitis, and overly rapid diure- sis, especially in patients who have marked ascites but no peripheral edema. Although diuretics can cause azotemia and appear to trigger an episode of hepatorenal syndrome, the syndrome usually progresses even after diuretics have been discontinued and expansion has occurred with infusion of plasma expanders. Differential Diagnosis “The differential diagnosis of hepatorenal syndrome includes acute tubular necrosis and other forms of renal disease such as glomerulonephnitis and vasculitis. Patients with cirrhosis and ascites may develop acute tubular necrosis after a course ‘of aminoglycoside therapy, the administration ofa radiocon- ‘rast agent, or an episode of sepsis or bleeding. A fractional excretion of sodium above 2% and granular and epithelial «ell casts in the urine sediment point to a diagnosis of acute tubular necrosis. Farly in the course of hepatorenal syn- drome, fractional excretion of sodium is usually below 1% and the urinary sediment is benign, It has been suggested ‘that persistent hepatorenal syndrome with survival between 2-4 weeks or longer can result in sufficiently persistent severe renal ischemia and acute tubular necrosis, and the resultant changes in the fractional excretion of sodium. Treatment A, Preventive Measures [tis important to recognize incipient hepatorenal syndrome and take preventive measures. Hepatorenal syndrome devel- ‘ops in patients with systemic bacterial infections (ie, sponta- neous bacterial peritonitis or severe alcoholic: hepatitis, or both), and itis important to provide prophylactic treatment to guard against its development. This includes the admi tration of intravenous albumin (1.5 g/kg) at the time of diag- nosis of spontaneous bacterial peritonitis or sepsis, and another dose of albumin (1.0 g/kg) after 48 hours of antibi- otic treatment. Improvement in underlying liver disease has been documented in patients with hepatorenal syndrome and severe alcoholic hepatitis who have received pentoxi- fylline (400 mg three times daily for 28 days) It is well established that norfloxacin is highly effective in preventing recurrent spontaneous bacterial peritonitis in Cirrhosis. A recent study by Ferndndez and colleagues demonstrated that primary prophylaxis with norfloxacin not only reduces the incidence of spontaneous bacterial peri- tonitis, but, importantly, also delays the development of hepatorenal syndrome and improves survival. Sixty-eightHEPATORENAL SYNDROME Table 46-2. Fffectiveness of norfloxacin in preventing spontaneous bacterial peritonitis (SBP). Placebo Norfloxacin (W=33) (N35) Probability of 9BP at 1 year ™ 6M Hepatoenal syndrome a 2% Probability of survival, 3 months om 9m 1 year 48% 60m *Patients were randomized To receive norfloxacin (400 mayday) oF placebo. Main end points of the tial were: 3-month and year protatlty of survival Secondary end points were 1-year proba iy of developing SBP and nepatorenal syndrome Data fom Femnde J, Navasa m,Planas Ret al. Primary prop laxs of spontaneous bacterial peitonts delays hepalorenal sy rome and improves survival in cithoss. Gastroenterology 2007;33:818-824, patients who met the inclusion criteria were randomized to receive either norfloxacin (400 mg/day) or placebo. The results are shown in Table 46-2, Note the decreased proba- bility of spontaneous bacterial peritonitis at 1 year, decreased, incidence of hepatorenal syndrome, and survival in nor- floxacin recipients compared with patients receiving placebo. Fernandez J, Navasa M, Planas R, ct al. Primary prophylaxis of ‘spontancous bacterial peritonitis delays hepatorenal syndrome tnd improves survival in cirrhosis. Gastroenterology 2007533 818-824, [PMID: 17854593] B, Vasopressor Therapy ‘Accumulating data suggest that combination therapy with, midodrine and octreotide may be effective and safe. The rationale for such therapy is that midodrine is a systemic ‘vasoconstrictor and addresses the question of inappropriate vasodilation, and octreotide is an inhibitor of endogenous ‘vasodilators. ‘The use of terlipressin, a vasopressin, Mas also been studied Some general considerations with regard to the use of midodrine and octreotide follow. These drugs should be used for at least 7-14 days because the improvement in renal fanction usually occurs slowly. Therapy should be aimed at reducing the serum creatinine level to below 1.5 mg/dl (130 UmoV/L). The effective doses of these drugs have varied in several studies. The recommended dosage for midodrine is usually 7.5 mg subcutaneously three times daily, and for ‘octreotide, 200 mcg subcutaneously three times daily. 487 Terlipressin dosage is 1.0 mg intravenously every 6 hours and is doubled on day 4 if serum creatinine has not decreased 30% from baseline. The concomitant administration of albumin (1.5 g/kg on the first day, followed by 2040 g/day) as a plasma expander appears to be necessary for the vasoconstrictor drugs to have a beneficial effect. The recurrence of hepatorenal syndrome after discontinuation of therapy in patients whose serum cre- atinine level normalizes is uncommon. In one study of 13 patients with hepatorenal syndrome reported by Wong and colleagues, five patients were given midodrine (7512.5 mg three times daily) and octreotide (100-200 meg subcutaneously three times daily). The dose of midodrine was increased until a mean arterial pressure of at least 15 mm Hg was achieved. Esrailian and colleagues compared the survival of patients with hepatorenal syndrome who received octreotide ‘and midodrine treatment with a concurrent control group of hhepatorenal syndrome patients who did not receive this treatment. Of the 81 patients, 60 were treated with octreotide plus midodrine, and 21 were controls. Mortality was significantly lower in the treatment group (43%) than in the controls (7196) (P < 005). Furthermore, 24 study patients (4096) had a sustained reduction of serum creati- nine compared with only 2 controls (10%). This retrospec- tive strongly suggests that octreotide plus midodrine treatment may improve 30-day survival. As the authors emphasize, a randomized controlled trial is needed to eval- uate this treatment modality. ‘wo recent studies have demonstrated that terlipressin is an effective treatment to improve renal function in type 1 hepatorenal syndrome. Sanyal and colleagues studied 112 patients with type | hepatorenal syndrome, as defined by a doubling of serum creatinine to greater than 2.5 mgldl. in less than 2 weeks despite plasma volume expansion. Patients were randomized to receive either telipressin (1 mg intra- venously every 6 hours) plus albumin (100 g on day Land 25 g daily until end of treatment) or placebo plus albumin. The terlipressin dose was doubled on day 4 if serum creatinine hhad not decreased 30% from baseline. Treatment was co ‘ued until day 14 unless treatment success, death, dia transplantation occurred, Treatment success was defined bya decrease in serum creatinine to 1.5 mg/dl. or less for atleast 48 hours without dialysis, death, or relapse of hepatorenal syndrome. Treatment success at day 14 was noted in 14 of 56 terlipressin recipients (259%) versus 7 of 56 placebo recipients (12.5%). However, 6-month survival was only marginally better in the terlipressin recipients compared with those who received placebo (42.9% vs 37.59%, respectively), Martin-Llahi and colleagues studied 46 patients with type I hepatorenal syndrome. Improvement in renal function ‘occurred in 10 of 23 patients (43.5%) who received terli- pressin plus albumin versus 2 of 23 patients (87%) who received albumin alone. Survival at 3 months was only mar- ginally better in the terlipressin recipients compared with the placebo-treated group (27% vs 19%, respectively)ret] CHAPTER 46 Angeli P, Volpin R, Gerunda G, et al. Reversal of type 1 hepatore- ‘hal syndrome with administration of midedrine and octreotide. “Hepatology. 1999;29:1690-1697. [PMAD: 10347103], ‘Eszilian E, Pantangeo ER, Kyulo NL, et al Octreotide/Midodrine therapy significantly improves renal function and 30-day sur- ‘vival in patents with type 1 hepatorenal syndrome. Dig Dis Sci. 2007582:742-748. [PMID: 17235705] ‘Martin-Llahi M, Pépin MN, Guevara M, etal. Telipresin and ‘albumin vs albumin in patients with cirehosis and hepatorenal syndrome: a randomized study. Gastroenterology. 2008;134: 1252-1359. [PMID: 18471512], ‘Moreau R, Durand F, Poynard, tal Terlipressn inpatients with, cirthosis and type 1 hepatorenal syndrome: A retrospective tlticenter study. Gastroenterology 20023122:923-930. [PMID: 11910344), ‘Sanyal AT, Boyer T, Garcia Thao G, etal. A randomized, prospec- tive double-blind, placebo- controlled trial of terlpressin fortype 1 al syndrome. Gastroenterology. 2008;134:1 360-1368. [PMID: #471513] C. Transjugular Intrahepatic Shunt (TIPS) ‘Wong and colleagues studied efficacy of TIPS as a treatment for type 1 hepatorenal syndrome in ascitic cirrhotic patients following improvement in systemic hemodynamics with a combination of midodrine, octreotide, and albumin. In this study, 14 ascitic cirrhotic patients with type 1 hepatorenal syndrome received medical therapy until their serum creati- nine decreased to less than 1.5 mg/l, for at least 3 days fol- lowed by TIPS if there were no contraindications. Patients were assessed at 1 week and at 1, 3, 6, and 12 months post- TIPS with serial measurements. All patients received oral midodrine (2.5 mg/dl), intravenous octreotide (25 mcg/h), and intravenous albumin (50 g/day). The medical therapy with midodrine and octreotide led to improvement in 10 of the 14 patients as evidenced by a fall in serum creatinine from 2.6 mg/dl. to 0.84 mg/dl. post-medical treatment. The authors concluded that TIPS was an effective treatment for type 1 hepatorenal syndrome in patients with cirrhosis and ascites, following improvement of renal function with com- bination treatment of midodrine, octreotide, and albumin. There is scattered additional information on the use of ‘TIPS in patients who fulfil the criteria of hepatorenal syn- drome. In two reports, one describing 16 such patients and another describing 7 patients, improvement in serum creati- rnine was noted over a 16-weck period. However most of the patients died within 6 weeks or 6 months of the procedure. Brensing KA, Testor J, Strunk H, etal. Tansjugular intrahepatic pportosystemic stent-shunt for hepatorenal syndrome. Lancet. 1997;349:697~698, [PMID: 9078203], ‘Guevara M, Gines P, Bandi JC eal. Tansjugular intrahepatic por- tosystemic shunt for hepatorenal syndrome: effects on renal function and vasoactive systems. Hepatology 1998;28:416422. [PMID: $696006), ‘Wong F, Pantea L, Sniderman K. Midodrine, octreotide, albumin, ‘and TIPS in sclected patients with cirthosis and type I hepatore” nal syndrome. Hepatology. 200440:55-64. [PMILY: 15239086] D. Dialysis Patients with hepatorenal syndrome can be treated with dial- yysiss this is most frequently done when a patient is waiting for liver transplantation. Although evidence suggests that provement in liver function may result, most patients hhepatorenal syndrome who undergo dialysis do not survive in the absence of liver transplantation.