- Hepatorenal syndrome
Name = Hepatorenal syndrome
DiseasesDB = 5810
ICD10 = ICD10|K|76|7|k|70
ICD9 = ICD9|572.4
MedlinePlus = 000489
eMedicineSubj = med
eMedicineTopic = 1001
MeshID = D006530
Hepatorenal syndrome (HRS) refers to
acute renal failurethat occurs in the setting of cirrhosisor fulminant liver failure, sometimes also associated with portal hypertension, usually in the absence of other disease of the kidney.cite journal |author=Arroyo V, Ginès P, Gerbes AL, "et al" |title=Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club |journal=Hepatology |volume=23 |issue=1 |pages=164–76 |year=1996 |pmid=8550036 |doi=10.1002/hep.510230122 |url=] cite journal |author=Wong F, Blendis L |title=New challenge of hepatorenal syndrome: prevention and treatment |journal=Hepatology |volume=34 |issue=6 |pages=1242–51 |year=2001 |pmid=11732014 |doi=10.1053/jhep.2001.29200 |url=] The pathology involved in the development of hepatorenal syndrome is thought to be an alteration in blood flow and blood vessel tone in the circulation that supplies the intestines (the " splanchnic circulation") and the circulation that supplies the kidney.cite journal |author=Arroyo V, Guevara M, Ginès P |title=Hepatorenal syndrome in cirrhosis: pathogenesis and treatment |journal=Gastroenterology |volume=122 |issue=6 |pages=1658–76 |year=2002 |pmid=12016430 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0016508502090066] It is usually indicative of an end-stage of perfusion, or blood flow to the kidney, due to deteriorating liverfunction. Patients with hepatorenal syndrome are very ill, and, if untreated, the condition is usually fatal. Treatment usually involves medical therapy or TIPS as a bridge to liver transplantation. Interestingly, kidneys from patients with the hepatorenal syndrome have been used successfully for renal transplant.
Definition and diagnosis
The hepatorenal syndrome is defined as renal failure that occurs in the setting of liver disease as follows:
Type I HRS
Type I HRS is characterized by rapidly progressive renal failure with a doubling of serum
creatinineto a level greater than 221 μmol/L (2.5 mg/dL) or a halving of the creatinine clearanceto less than 20 mL/min over a period of less than 2 weeks. Type I HRS carries a very poor prognosis, usually with less than 50% survival at one month. Patients with type I hepatorenal syndrome are usually ill, may have low blood pressures, and may require therapy with inotropes, or intravenous drugs to maintain blood pressure. [http://www.emedicine.com/med/topic1001.htm Hepatorenal syndrome] - emedicine.com article]
Type II HRS
Type II HRS is characterized by a slowly progressive:
*increase in serum
creatininelevel to greater than 133 μmol/L (1.5 mg/dL) or a creatinine clearance of less than 40 mL/min
* urine sodium < 10 meq/dlcite journal |author=Ginés P, Arroyo V, Quintero E, "et al" |title=Comparison of paracentesis and diuretics in the treatment of cirrhotics with tense ascites. Results of a randomized study |journal=Gastroenterology |volume=93 |issue=2 |pages=234–41 |year=1987 |pmid=3297907 |doi=]
It is typically associated with
ascitesthat is unresponsive to diureticmedications, and also carries a poor, if somewhat longer (median survival ~6 months) outlook, [cite journal |author=Blendis L, Wong F |title=The natural history and management of hepatorenal disorders: from pre-ascites to hepatorenal syndrome |journal=Clin Med |volume=3 |issue=2 |pages=154–9 |year=2003 |pmid=12737373 |doi= |url=http://openurl.ingenta.com/content/nlm?genre=article&issn=1470-2118&volume=3&issue=2&spage=154&aulast=Blendis] unless the patient undergoes liver transplantation.
It can be challenging to distinguish hepatorenal syndrome from other entities that cause renal failure in the setting of advanced liver disease. As a result, additional major and minor criteria have been proposed to assist in the
diagnosisof the hepatorenal syndrome.
The "major" criteria include liver disease in the setting of
portal hypertension; renal failure; the absence of shock, infection, recent treatment with medications that affect the kidney's function ( nephrotoxins), and fluid losses; the absence of sustained improvement in renal function despite treatment with 1.5 litres of intravenous normal saline; the absence of proteinuria, or proteinin the urine; and, the absence of renal disease or obstruction of renal outflow as seen on ultrasound.
The "minor" criteria are
laboratoryin nature, and include a low urine volume (less than 500 cc per day), low sodiumconcentration in the urine, a urine osmolalitythat is greater than that in the blood, the absence of red blood cellsin the urine, and a serum sodium concentration of less than 130 mmol/L.
Many other diseases of the kidney are associated with liver disease and must be excluded before making a diagnosis of hepatorenal syndrome. They include the following:
*Pre-renal failure: Pre-renal failure usually responds to treatment with intravenous fluids, resulting in reduction in serum
creatinineand the excretion of sodium.
Acute tubular necrosis(ATN): This can be difficult to confidently diagnose. It may be an inability to concentrate the urine, if any is being produced. The urine sediment should be bland, microscopy may show hyaline casts. ATN may recover with supportive treatment only or progress to end-stage renal failure. In cirrhosis, urinary sodium is not a reliable guide to the development of ATN, as fractional sodium excretionmay stay below 1 percent, due to the gradual worsening of renal ischaemia.
*Other causes may include glomerular disease secondary to
Hepatitis Bor Hepatitis C, [cite journal |author=Han SH |title=Extrahepatic manifestations of chronic hepatitis B |journal=Clin Liver Dis |volume=8 |issue=2 |pages=403–18 |year=2004 |pmid=15481347 |doi= |url=] drug toxicity (notably gentamicin) or contrast nephropathy.
renal failurein hepatorenal syndrome is believed to arise from abnormalities in blood vesseltone in the splanchnic circulation(which supplies the intestines). [cite journal |author=Ginès P, Arroyo V |title=Hepatorenal syndrome |journal=J. Am. Soc. Nephrol. |volume=10 |issue=8 |pages=1833–9 |year=1999 |pmid=10446954 |doi= |url=http://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=10446954] It is known that there is an overall decreased systemic vascular resistancein hepatorenal syndrome, but that the measured femoral and renal fractions of cardiac outputare respectively increased and reduced, suggesting that splanchnic vasodilationis implicated in the renal failure. [cite journal |author=Fernandez-Seara J, Prieto J, Quiroga J, "et al" |title=Systemic and regional hemodynamics in patients with liver cirrhosis and ascites with and without functional renal failure |journal=Gastroenterology |volume=97 |issue=5 |pages=1304–12 |year=1989 |pmid=2676683 |doi= |url=]
There is activation of the
renin-angiotensin-aldosterone system(RAAS) and the sympathetic nervous system, and profound vasoconstrictionof the kidneys.cite journal |author=Ginès A, Escorsell A, Ginès P, "et al" |title=Incidence, predictive factors, and prognosis of the hepatorenal syndrome in cirrhosis with ascites |journal=Gastroenterology |volume=105 |issue=1 |pages=229–36 |year=1993 |pmid=8514039 |doi= |url=] Many vasocontrictorchemicals have been hypothesized as being involved in this pathway, including vasopressin, [cite journal |author=Lenz K, Hörtnagl H, Druml W, "et al" |title=Ornipressin in the treatment of functional renal failure in decompensated liver cirrhosis. Effects on renal hemodynamics and atrial natriuretic factor |journal=Gastroenterology |volume=101 |issue=4 |pages=1060–7 |year=1991 |pmid=1832407 |doi= |url=] prostacyclin, thromboxaneA2, [cite journal |author=Moore K, Ward PS, Taylor GW, Williams R |title=Systemic and renal production of thromboxane A2 and prostacyclin in decompensated liver disease and hepatorenal syndrome |journal=Gastroenterology |volume=100 |issue=4 |pages=1069–77 |year=1991 |pmid=2001805 |doi= |url=] and endotoxin.
It is estimated that 39% of patients with
cirrhosisand asciteswill develop hepatorenal syndrome within five years of the onset of their disease. The prognosis of these patients is grim with untreated patients having an extremely short survival, and with the severity of liver disease (as evidenced by the MELD score) now believed to determine outcome. [cite journal |author=Alessandria C, Ozdogan O, Guevara M, "et al" |title=MELD score and clinical type predict prognosis in hepatorenal syndrome: relevance to liver transplantation |journal=Hepatology |volume=41 |issue=6 |pages=1282–9 |year=2005 |pmid=15834937 |doi=10.1002/hep.20687 |url= ] Some patients without cirrhosis develop hepatorenal syndrome, with an incidence of about 20% seen in one study of ill patients with alcoholic hepatitis.cite journal |author=Akriviadis E, Botla R, Briggs W, Han S, Reynolds T, Shakil O |title=Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial |journal=Gastroenterology |volume=119 |issue=6 |pages=1637–48 |year=2000 |pmid=11113085 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0016508500511834]
Because of the high mortality associated with hepatorenal syndrome, emphasis is on prevention in patients who are at risk for the condition. Strategies for avoiding hepatorenal syndrome include appropriate and non-aggressive use of diuretics, identification and early treatment of
infectionand hemorrhage, and avoidance of other toxins that can affect both the liver and kidney.
The definitive treatment for hepatorenal syndrome is
liver transplantation, and all other therapies can best be described as bridges to transplantation. These treatment strategies include the following:
All major studies showing improvement in renal function in patients with hepatorenal syndrome have involved expansion of the volume of the plasma with albumin given intravenously One regimen is 1 gm albumin per kg of body weight intravenously on day one followed by 20-40 grams daily.cite journal |author=Ginès P, Cárdenas A, Arroyo V, Rodés J |title=Management of cirrhosis and ascites |journal=N. Engl. J. Med. |volume=350 |issue=16 |pages=1646–54 |year=2004 |pmid=15084697 |doi=10.1056/NEJMra035021]
Midodrine and octreotide
Midodrine is an alpha-agonist and octreotide is an analogue of
somatostatin. The medications are respectively systemic vasoconstrictors and inhibitors of vasodilators, and were not found to be useful when used individually in treatment of hepatorenal syndrome. [cite journal |author=Pomier-Layrargues G, Paquin SC, Hassoun Z, Lafortune M, Tran A |title=Octreotide in hepatorenal syndrome: a randomized, double-blind, placebo-controlled, crossover study |journal=Hepatology |volume=38 |issue=1 |pages=238–43 |year=2003 |pmid=12830007 |doi=10.1053/jhep.2003.50276 |url= ] However, one study of 13 patients with hepatorenal syndrome showed significant improvement when the two were used together (with midodrine given orally, octreotide given subcutaneously and both dosed according to blood pressure), with three patients surviving to discharge.cite journal |author=Angeli P, Volpin R, Gerunda G, "et al" |title=Reversal of type 1 hepatorenal syndrome with the administration of midodrine and octreotide |journal=Hepatology |volume=29 |issue=6 |pages=1690–7 |year=1999 |pmid=10347109 |doi=10.1002/hep.510290629 |url= ] A nonrandomized, observational study used "100 μg subcutaneously TID, with the goal to increase the dose to 200 μg subcutaneous TID" and "midodrine administration started at 5, 7.5, or 10 mg TID orally, with the goal to increase the dose to 12.5 or 15 mg if necessary" and found that "octreotide/midodrine treatment appears to improve 30-day survival".cite journal |author=Esrailian E, Pantangco ER, Kyulo NL, Hu KQ, Runyon BA |title=Octreotide/Midodrine therapy significantly improves renal function and 30-day survival in patients with type 1 hepatorenal syndrome |journal=Dig. Dis. Sci. |volume=52 |issue=3 |pages=742–8 |year=2007 |pmid=17235705 |doi=10.1007/s10620-006-9312-0]
The vasopressin analogue
ornipressinwas found in a number of studies to be useful in improvement of renal function in patients with hepatorenal syndrome,cite journal |author=Guevara M, Ginès P, Fernández-Esparrach G, "et al" |title=Reversibility of hepatorenal syndrome by prolonged administration of ornipressin and plasma volume expansion |journal=Hepatology |volume=27 |issue=1 |pages=35–41 |year=1998 |pmid=9425914 |doi=10.1002/hep.510270107 |url= ] [cite journal |author=Gülberg V, Bilzer M, Gerbes AL |title=Long-term therapy and retreatment of hepatorenal syndrome type 1 with ornipressin and dopamine |journal=Hepatology |volume=30 |issue=4 |pages=870–5 |year=1999 |pmid=10498636 |doi=10.1002/hep.510300430 |url= ] but has been limited by ischemic complications. Terlipressinis a vasopressin analogue that has been found in one study to be useful for improving renal function in patients with hepatorenal syndrome with a lesser incidence of ischemia.cite journal |author=Ortega R, Ginès P, Uriz J, "et al" |title=Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: results of a prospective, nonrandomized study |journal=Hepatology |volume=36 |issue=4 Pt 1 |pages=941–8 |year=2002 |pmid=12297842 |doi=10.1053/jhep.2002.35819 |url= ] Neither medication is available for use in North America.
Transjugular intrahepatic portosystemic shunt
Transjugular intrahepatic portosystemic shunts (TIPS) involve decompression of the high pressures in the portal circulation by placing a small stent between a portal and hepatic vein. They have also been shown to improve renal function in patients with hepatorenal syndrome. [cite journal |author=Wong F, Pantea L, Sniderman K |title=Midodrine, octreotide, albumin, and TIPS in selected patients with cirrhosis and type 1 hepatorenal syndrome |journal=Hepatology |volume=40 |issue=1 |pages=55–64 |year=2004 |pmid=15239086 |doi=10.1002/hep.20262 |url= ] [cite journal |author=Guevara M, Rodés J |title=Hepatorenal syndrome |journal=Int. J. Biochem. Cell Biol. |volume=37 |issue=1 |pages=22–6 |year=2005 |pmid=15381144 |doi=10.1016/j.biocel.2004.06.007 |url=http://linkinghub.elsevier.com/retrieve/pii/S1357272504002444]
Liver dialysisinvolves extracorporeal dialysis to remove toxins from the circulation. The molecular adsorbents recirculation system (MARS) has shown some utility as a bridge to transplantation in patients with hepatorenal syndrome. [cite journal |author=Mitzner SR, Stange J, Klammt S, "et al" |title=Improvement of hepatorenal syndrome with extracorporeal albumin dialysis MARS: results of a prospective, randomized, controlled clinical trial |journal=Liver Transpl. |volume=6 |issue=3 |pages=277–86 |year=2000 |pmid=10827226 |doi=10.1002/lt.500060326 |url= |doi_brokendate=2008-07-17 ]
Renal replacement therapymay be required to 'bridge' the patient to liver transplantation, although the condition of the patient may dictate the modality used. [cite journal |author=Witzke O, Baumann M, Patschan D, "et al" |title=Which patients benefit from hemodialysis therapy in hepatorenal syndrome? |journal=J. Gastroenterol. Hepatol. |volume=19 |issue=12 |pages=1369–73 |year=2004 |pmid=15610310 |doi=10.1111/j.1440-1746.2004.03471.x |url=http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0815-9319&date=2004&volume=19&issue=12&spage=1369]
Other agents used in treatment include
pentoxifylline, acetylcysteine, [cite journal |author=Holt S, Goodier D, Marley R, "et al" |title=Improvement in renal function in hepatorenal syndrome with N-acetylcysteine |journal=Lancet |volume=353 |issue=9149 |pages=294–5 |year=1999 |pmid=9929029 |doi= |url=] and misoprostol. [cite journal |author=Clewell JD, Walker-Renard P |title=Prostaglandins for the treatment of hepatorenal syndrome |journal=Ann Pharmacother |volume=28 |issue=1 |pages=54–5 |year=1994 |pmid=8123962 |doi= |url=]
Historically, the hepatorenal syndrome was first defined as acute renal failure that occurred in the setting of biliary surgery. [Helwig FC, Schutz CB. A liver kidney syndrome. Clinical pathological and experimental studies. "Surg Gynecol Obstet" 1932;55:570-580.] The syndrome was soon associated with advanced liver disease. It was determined that kidneys transplanted from patients with hepatorenal syndrome were functional, [cite journal |author=Koppel MH, Coburn JW, Mims MM, Goldstein H, Boyle JD, Rubini ME |title=Transplantation of cadaveric kidneys from patients with hepatorenal syndrome. Evidence for the functionalnature of renal failure in advanced liver disease |journal=N. Engl. J. Med. |volume=280 |issue=25 |pages=1367–71 |year=1969 |pmid=4890476 |doi= |url=cite journal |author=Koppel MH, Coburn JW, Mims MM, Goldstein H, Boyle JD, Rubini ME |title=Transplantation of cadaveric kidneys from patients with hepatorenal syndrome. Evidence for the functionalnature of renal failure in advanced liver disease |journal=N. Engl. J. Med. |volume=280 |issue=25 |pages=1367–71 |year=1969 |pmid=4890476 |doi= |url=] leading to the hypothesis that hepatorenal syndrome was a systemic as opposed to renal disease.
randomized controlled trialfound that intravenous albumin on the day of admission and on hospital day 3 can reduce renal impairment.cite journal |author=Sort P, Navasa M, Arroyo V, "et al" |title=Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis |journal=N. Engl. J. Med. |volume=341 |issue=6 |pages=403–9 |year=1999 |pmid=10432325 |doi=]
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