Hepatorenal syndrome
| Hepatorenal syndrome | |
| ICD-10 | K76.7 |
|---|---|
| ICD-9 | 572.4 |
| DiseasesDB | 5810 |
| MedlinePlus | 000489 |
| MeSH | D006530 |
For patient information click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Heyd syndrome; HRS
Overview
Hepatorenal syndrome (HRS) refers to acute renal failure that occurs in the setting of cirrhosis or fulminant liver failure associated with portal hypertension, usually in the absence of other disease of the kidney.[1][2]
Historical Perspective
Historically, the hepatorenal syndrome was first defined as acute renal failure that occurred in the setting of biliary surgery.[3] The syndrome was soon associated with advanced liver disease.[2] It was determined that kidneys transplanted from patients with hepatorenal syndrome were functional,[4] leading to the hypothesis that hepatorenal syndrome was a systemic as opposed to renal disease.
Classification
The hepatorenal syndrome is defined as renal failure that occurs in the setting of liver disease as follows [1]:
Type I HRS
Type I HRS is characterized by rapidly progressive renal failure with a doubling of serum creatinine to a level greater than 221 μmol/L (2.5 mg/dL) or a halving of the creatinine clearance to less than 20 mL/min over a period of less than 2 weeks.
Type II HRS
Type II HRS is characterized by a slowly progressive:
- Increase in serum creatinine level to greater than 133 μmol/L (1.5 mg/dL) or a creatinine clearance of less than 40 mL/min
- Urine sodium < 10 meq/dl[5]
Pathophysiology
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.[6] It is usually indicative of an end-stage of perfusion, or blood flow to the kidney, due to deteriorating liver function. Patients with hepatorenal syndrome are very ill, and, if untreated, the condition is usually fatal.
The renal failure in hepatorenal syndrome is believed to arise from abnormalities in blood vessel tone in the splanchnic circulation (which supplies the intestines).[7] It is known that there is an overall decreased systemic vascular resistance in hepatorenal syndrome, but that the measured femoral and renal fractions of cardiac output are respectively increased and reduced, suggesting that splanchnic vasodilation is implicated in the renal failure.[8]
There is activation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system, and profound vasoconstriction of the kidneys.[9] Many vasocontrictor chemicals have been hypothesized as being involved in this pathway, including vasopressin,[10] prostacyclin, thromboxane A2,[11], and endotoxin.[6]
Microscopic Pathology
Differentiating Hepatorenal Syndrome from other Diseases
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 creatinine and the excretion of sodium.[1]
- 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 excretion may stay below 1 percent, due to the gradual worsening of renal ischaemia.
- Other causes may include glomerular disease secondary to Hepatitis B or Hepatitis C,[12] drug toxicity (notably gentamicin) or contrast nephropathy.
Epidemiology and Demographics
It is estimated that 39% of patients with cirrhosis and ascites will develop hepatorenal syndrome within five years of the onset of their disease.[9] The prognosis of these patients is grim with untreated patients having an extremely short survival,[6][9][2] and with the severity of liver disease (as evidenced by the MELD score) now believed to determine outcome.[13] Some patients without cirrhosis develop hepatorenal syndrome, with an incidence of about 20% seen in one study of ill patients with alcoholic hepatitis.[14]
Risk Factors
Risk factors include:
- Blood pressure that falls when a person rises or suddenly changes position (orthostatic hypotension)
- Use of medicines called diuretics ("water pill")
- Gastrointestinal bleeding
- Infection
- Recent abdominal fluid tap (paracentesis)
Natural History, Complications and Prognosis
Complications
- Bleeding
- Damage to, and failure of, many organ systems (multiorgan system failure)
- End-stage kidney disease
- Fluid overload with congestive heart failure or pulmonary edema
- Hepatic coma
- Secondary infections
- Death
Prognosis
- Type I HRS carries a very poor prognosis, usually of less than 50% over one month.[6] 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.[15]
- It is typically associated with ascites that is unresponsive to diuretic medications, and also carries a poor, if somewhat longer (median survival ~6 months) outlook,[16] unless the patient undergoes liver transplantation.
Diagnosis
Criteria
Major:
- Liver disease in the setting of portal hypertension
- Renal failure
- Absence of shock
- Infection
- Recent treatment with medications that affect the function of the kidney (nephrotoxins), and fluid losses
- Absence of sustained improvement in renal function despite treatment with 1.5 litres of intravenous normal saline
- Absence of proteinuria, or protein in the urine
- Absence of renal disease or obstruction of renal outflow as seen on ultrasound.[1]
Minor:
- Low urine volume (less than 500 mL per day)
- Low sodium concentration in the urine (less than 10 mEq/L)
- Urine osmolality that is greater than that in the blood
- Absence of red blood cells in the urine (less than 50 per high-power field)
- Serum sodium concentration of less than 130 mmol/L.[1]
Symptoms
- Abdominal swelling
- Change in mental status
- Coarse muscle movements, jerking
- Dark-colored urine
- Decreased urine production - oliguria
- Nausea and vomiting
- Weight gain
- Bleeding easily
Physical Examination
Skin
Abdomen
- Abdominal distension
- Shfting dullness: Dull sound in the belly area when tapped with the tips of the fingers - indicates presence of fluid
Genitals
- Small testicles
Extremities
Neurologic
- Abnormal reflexes
- Confusion on neurologic testing
Laboratory Findings
- Complete blood count and differential count - elevated leukocytes due to infection
- Serum electrolytes and renal function - low blood sodium
- Liver function tests - elevated liver parameters (e.g bilirubin, alkaline phosphatase)
- Urinalysis
- Significant proteinuria or hematuria may be present
- Increased urine specific gravity and osmolality
- Urine electrolytes - urine creatinine and sodium. Patients with low urine sodium excretions (< 5 mEq/L) are at a greater risk of developing HRS
- Prothrombin time (PT) - prolonged
- Blood ammonia levels - elevated
- Serum creatinine - elevated
- Blood cultures
- Alpha-fetoprotein
- Blood albumin - decreased
Imaging
Chest X-ray
- Enlarged heart - heart failure
- Pulmonary edema
Ultrasound
Findings include:
- Fluid in the abdomen
- Shrunken liver in cirrhosis
Treatment
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 infection and hemorrhage, and avoidance of other toxins that can affect both the liver and kidney.[6] [15]
The definitive treatment for hepatorenal syndrome is liver transplantation, and all other therapies can best be described as bridges to transplantation.[2] These treatment strategies include the following:
Albumin
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 [17] [18] One regimen is 1 gm albumin per kg of body weight intravenously on day one followed by followed by 20-40 grams daily.[19]
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.[20] 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.[21] 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".[22]
Vasopressin analogues
The vasopressin analogue ornipressin was found in a number of studies to be useful in improvement of renal function in patients with hepatorenal syndrome,[17] [23] but has been limited by ischemic complications [17]. Terlipressin is 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.[18] 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.[24] [25]
Liver dialysis
Liver dialysis involves 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.[26]
Hemodialysis
Renal replacement therapy may be required to 'bridge' the patient to liver transplantation, although the condition of the patient may dictate the modality used.[27]
Other medications
Other agents used in treatment include
Prevention
Intravenous albumin
A randomized controlled trial found that intravenous albumin on the day of admission and on hospital day 3 can reduce renal impairment.[30]
References
- ↑ 1.0 1.1 1.2 1.3 1.4 Arroyo V, Gines P, Gerbes AL, Dudley FJ, Gentilini P, Laffi G, Reynolds TB, Ring-Larsen H, Scholmerich J. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club. Hepatology. 1996 Jan;23(1):164-76. PMID 8550036
- ↑ 2.0 2.1 2.2 2.3 Wong F, Blendis L. New challenge of hepatorenal syndrome: prevention and treatment. Hepatology 2001 Dec;34(6):1242-51. PMID 11732014
- ↑ Helwig FC, Schutz CB. A liver kidney syndrome. Clinical pathological and experimental studies. Surg Gynecol Obstet 1932;55:570-580.
- ↑ Koppel MH, Coburn JW, Mims MM, Goldstein H, Boyle JD, Rubini ME. Transplantation of cadaveric kidneys from patients with hepatorenal syndrome. Evidence for the functional nature of renal failure in advanced liver disease. N Engl J Med. 1969 Jun 19;280(25):1367-71. PMID 4890476
- ↑ Ginés P, Arroyo V, Quintero E; et al. (1987). "Comparison of paracentesis and diuretics in the treatment of cirrhotics with tense ascites. Results of a randomized study". Gastroenterology. 93 (2): 234–41. PMID 3297907.
- ↑ 6.0 6.1 6.2 6.3 6.4 Arroyo V, Guevara M, Gines P. Hepatorenal syndrome in cirrhosis: pathogenesis and treatment. Gastroenterology 2002 May;122(6):1658-76. PMID 12016430.
- ↑ Gines P, Arroyo V. Hepatorenal syndrome. J Am Soc Nephrol 1999 Aug;10(8):1833-9. PMID 10446954
- ↑ Fernandez-Seara J, Prieto J, Quiroga J, Zozaya JM, Cobos MA, Rodriguez-Eire JL, Garcia-Plaza A, Leal J. Systemic and regional hemodynamics in patients with liver cirrhosis and ascites with and without functional renal failure. Gastroenterology 1989 Nov;97(5):1304-12. PMID 2676683
- ↑ 9.0 9.1 9.2 Gines A, Escorsell A, Gines P, et al. Incidence, predictive factors, and prognosis of the hepatorenal syndrome in cirrhosis with ascites. Gastroenterology 1993 Jul;105(1):229-36. PMID 8514039.
- ↑ Lenz K, Hortnagl H, Druml W, Reither H, Schmid R, Schneeweiss B, Laggner A, Grimm Gm Gerbes AL. Ornipressin in the treatment of functional renal failure in decompensated liver cirrhosis. Effects on renal hemodynamics and atrial natriuretic factor. Gastroenterology 1991 Oct;101(4):1060-7. PMID 1832407
- ↑ Moore K, Ward PS, Taylor GW, Williams R. Systemic and renal production of thromboxane A2 and prostacyclin in decompensated liver disease and hepatorenal syndrome. Gastroenterology 1991 Apr;100(4):1069-77. PMID 2001805
- ↑ Han SH. Extrahepatic manifestations of chronic hepatitis B. Clin Liver Dis. 2004 May;8(2):403-18. PMID 15481347
- ↑ Alessandria C, Ozdogan O, Guevara M, Restuccia T, Jimenez W, Arroyo V, Rodes J, Gines P. MELD score and clinical type predict prognosis in hepatorenal syndrome: Relevance to liver transplantation. Hepatology 2005 Jun;41(6):1282-9. PMID 15834937
- ↑ 14.0 14.1 Akriviadis E, Botla R, Briggs W, Han S, Reynolds T, Shakil O. Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial. Gastroenterology 2000 Dec;119(6):1637-48. PMID 11113085.
- ↑ 15.0 15.1 Hepatorenal syndrome - emedicine.com article
- ↑ Blendis L, Wong F. The natural history and management of hepatorenal disorders: from pre-ascites to hepatorenal syndrome. Clin Med 2003 Mar-Apr;3(2):154-9. PMID 12737373
- ↑ 17.0 17.1 17.2 Guevara M, Gines P, Fernandez-Esparrach G, Sort P, Salmeron JM, Jimenez W, Arroyo V, Rodes J. Reversibility of hepatorenal syndrome by prolonged administration of ornipressin and plasma volume expansion. Hepatology 1998 Jan;27(1):35-41. PMID 9425914
- ↑ 18.0 18.1 Ortega R, Gines P, Uriz J, Cardenas A, Calahorra B, De Las Heras D, Guevara M, Bataller R, Jimenez W, Arroyo V, Rodes J. Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: results of a prospective, nonrandomized study. Hepatology 2002 Oct;36 (4 Pt 1):941-8. PMID 12297842
- ↑ Ginès P, Cárdenas A, Arroyo V, Rodés J (2004). "Management of cirrhosis and ascites". N. Engl. J. Med. 350 (16): 1646–54. doi:10.1056/NEJMra035021. PMID 15084697.
- ↑ Pomier-Layrargues G, Paquin SC, Hassoun Z, Lafortune M, Tran A. Octreotide in hepatorenal syndrome: a randomized, double-blind, placebo-controlled, crossover study. Hepatology 2003 Jul;38(1):238-43.
- ↑ Angeli P, Volpin R, Gerunda G, Craighero R, Roner P, Merenda R, Amodio P, Sticca A, Caregaro L, Maffei-Faccioli A, Gatta A. Reversal of type 1 hepatorenal syndrome with the administration of midodrine and octreotide. Hepatology 1999 Jun;29(6):1690-7. PMID 10347109
- ↑ Esrailian E, Pantangco ER, Kyulo NL, Hu KQ, Runyon BA (2007). "Octreotide/Midodrine therapy significantly improves renal function and 30-day survival in patients with type 1 hepatorenal syndrome". Dig. Dis. Sci. 52 (3): 742–8. doi:10.1007/s10620-006-9312-0. PMID 17235705.
- ↑ Gulberg V, Bilzer M, Gerbes AL. Long-term therapy and retreatment of hepatorenal syndrome type 1 with ornipressin and dopamine. Hepatology 1999 Oct;30(4):870-5. PMID 10498636
- ↑ Wong F, Pantea L, Sniderman K. Midodrine, octreotide, albumin, and TIPS in selected patients with cirrhosis and type 1 hepatorenal syndrome. Hepatology. 2004 Jul;40(1):55-64. PMID 15239086.
- ↑ Guevara M, Rodes J. Hepatorenal syndrome. Int J Biochem Cell Biol. 2005 Jan;37(1):22-6. PMID 15381144.
- ↑ Mitzner SR, Stange J, Klammt S, Risler T, Erley CM, Bader BD, Berger ED, Lauchart W, Peszynski P, Freytag J, Hickstein H, Loock J, Lohr JM, Liebe S, Emmrich J, Korten G, Schmidt R. Improvement of hepatorenal syndrome with extracorporeal albumin dialysis MARS: results of a prospective, randomized, controlled clinical trial. Liver Transpl. 2000 May;6(3):277-86. PMID 10827226.
- ↑ Witzke O, Baumann M, Patschan D, Patschan S, Mitchell A, Treichel U, Gerken G, Philipp T, Kribben A. Which patients benefit from hemodialysis therapy in hepatorenal syndrome? J Gastroenterol Hepatol. 2004 Dec;19(12):1369-73. PMID 15610310
- ↑ Holt S, Goodier D, Marley R, Patch D, Burroughs A, Fernando B, Harry D, Moore K. Improvement in renal function in hepatorenal syndrome with N-acetylcysteine. Lancet. 1999 Jan 23;353(9149):294-5. PMID 9929029
- ↑ Clewell JD, Walker-Renard P. Prostaglandins for the treatment of hepatorenal syndrome. Ann Pharmacother. 1994 Jan;28(1):54-5. PMID 8123962
- ↑ 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 (6): 403–9. PMID 10432325.