Hepatorenal Syndrome


Article Author:
Indika Ranasinghe
Bashar Sharma


Article Editor:
Khalid Bashir


Editors In Chief:
Stephen Leslie
Karim Hamawy


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
7/22/2019 2:20:40 PM

Introduction

Hepatorenal syndrome (HRS) is a multiorgan condition affecting the kidneys and the liver. It is a cause of acute kidney injury that can be seen in those with acute or chronic liver disease. The first association of renal failure in cirrhosis was observed in the late 1800s. In the mid to late 1900s, further research revealed that renal failure in liver cirrhosis was functional. This was demonstrated in patients with hepatorenal syndrome with normal kidney histology in addition to the absence of proteinuria. This was further demonstrated clinically when kidneys from patients with HRS were transplanted into those with chronic kidney disease as well as the improvement of renal function in liver cirrhosis patients who underwent a liver transplant. Further research investigating renal clearance established the association of renal vasoconstriction in HRS.[1]

Etiology

Viral hepatitis is the most common cause of liver failure, thus hepatorenal-syndrome, in developing countries. Most commonly, it is caused by Hepatitis B or, less commonly, Hepatitis C. In the developed world, the most common causes are drugs/medications; most commonly acetaminophen, chronic alcoholism or any drugs that induce cytochrome p450; and non-alcoholic steatohepatitis (NASH). Less common causes of liver failure leading to HRS include viruses such as CMV, HHV6, and Parvovirus B19. Alternatively, vascular phenomenon like hepatic/portal vein thrombosis and metabolic causes such as nonalcoholic fatty liver disease.[2]

Epidemiology

The incidence of hepatorenal syndrome in patients with decompensated liver disease is approximately 4%. Most of these patients have portal hypertension from alcoholic hepatitis, cirrhosis, or metastatic cancers. The cumulative probability of developing HRS at 1 year is 18% and at 5 years is 39% in patients with decompensated liver disease. The highest risk patients were those with hyponatremia and high plasma renin activity. One third of patients that have spontenous bacterial pertionitis can go on to develop HRS. [3]

Pathophysiology

Cirrhosis and portal hypertension can trigger the neurohormonal cascade which leads to the development of HRS. This, in turn, causes the production and release of vasodilators and cytokines like nitric oxide and prostaglandins which cause splanchnic and systemic vasodilation. The systemic drop in circulating pressure triggers the carotid and aortic arch baroreceptors to activate three separate compensatory mechanisms. These include the renin-angiotensin-aldosterone system, vasopressin release, and activation of the sympathetic nervous system (SNS). The progression of the cirrhosis causes the fall in cardiac output and the fall in systemic vascular resistance in a cycle that induces further renal vasoconstriction.[3] This leads to further renal hypoperfusion, worsened by renal vasoconstriction with the end point of renal failure.

The most common precipitating factors of HRS are spontaneous bacterial peritonitis, large volume paracentesis of ascites without plasma expansion and gastrointestinal bleeding.[4]

Toxicokinetics

Any form of sepsis can cause HRS in patients with liver cirrhosis, as it can trigger the systemic release of sepsis-related vasoactive mediators, similar to those released in portal hypertension.[5]

History and Physical

Patients with hepatorenal syndrome present with signs and symptoms of severe liver failure. These patients initially can present with fatigue and lethargy which can be multifactorial. This may be contributed to by loss of appetite due to increasing nausea. Over time, patients become increasingly more jaundiced, originating in the sclera and then spreading from head-to-toe. The liver's synthetic function becomes affected, and patients become coagulopathic and more likely to bleed. As all this occurs, there is a very slow, gradual build-up of ascitic fluid in the peritoneum due to the intravascular loss of albumin. Confusion due to hepatic encephalopathy is likely the last and most severe stage of the liver disease as a result of the liver failing to break down toxic metabolites. Most importantly these patients notice they urinate less frequently in smaller and smaller volumes as they become oliguric.  [6]

Evaluation

Hepatorenal syndrome has two types and is a diagnosis of exclusion. Type 1 is characterized by rapid and progressive decline in renal function defined by doubling of the serum creatinine to at least greater than 2.5 or a decrease in the creatinine clearance by half or more over a two week period. This is usually associated with a urine output of less than 500mL/day, a normal urine sediment and a low urinary sodium excretion. Type 2 typically involves less severe kidney injury, and patients ordinarily present with diuretic-resistant ascites. Other apparent causes of acute kidney injury need to be excluded, including pre-renal, nephrotoxic drugs, obstructive nephropathy, and renal parenchymal disease.[7]

Treatment / Management

First and foremost, HRS involves establishing euvolemia while stopping all nephrotoxic agents. The active medical treatment of HRS is directed at splanchnic vasoconstriction which results in increased systemic vascular resistance and mean arterial pressure. This via counter-regulatory mechanism suppresses the renin-angiotensin-aldosterone system (RAAS) and the SNS. In turn, this reduces renal vasoconstriction and improves renal blood flow. This is achieved with several different combinations of medical therapy. In Europe, a combination of terlipressin and albumin improves renal perfusion in patients with HRS Type 1 and can work in some patients with HRS Type 2.[8] In North America, noradrenaline and midodrine or octreotide are used for the same purpose as terlipressin.[9]

When medical management fails, surgical/interventional management involves placement of a transjugular intrahepatic portosystemic shunt (TIPS). This type of surgical treatment is established with the insertion of an intrahepatic stent to connect the portal vein to the hepatic vein. The shunt redirects portal blood into the systemic circulation, reducing portal pressure and increasing systemic venous return. This reduces the arterial hypoperfusion and thereby downregulates stimulation of the RAAS and SNS.[7]

Definitive treatment for HRS is established through liver transplantation and provides the best long-term survival benefit.

Other experimental techniques such as molecular adsorbent recirculating system, a modified dialysis technique aimed at removing substances causing vasodilation like nitric oxide, tumor necrosis factor, and cytokines have not been shown to improve overall survival. Renal replacement therapy has been tried in patients that do not respond to the vasoconstrictors above or are poor candidates for TIPS. However, both these therapies may be considered more appropriate as a bridge to transplant.[10]

Patients with spontaneous bacterial peritonitis should be treated promptly and remain on long-term antibiotic therapy to prevent the development of HRS. Those with sepsis from other sources should also be treated promptly to limit the release of sepsis-related vasoactive mediators.

Prognosis

Prognosis for Type 1 HRS is poor, with an average survival of just less than 2 weeks. Type 2 HRS survival is dependent on the severity of the Child-Pugh class of liver disease, but generally more chronic and median survial was 6 to 12 months without treatment. [11]

Complications

Renal failure and death.[12]

Deterrence and Patient Education

New thereapeutic appoaches have demonstrated an improvement in survival for patients with HRS Type 1, but these treatment modalities were less clear in HRS Type 2. In patients with HRS Type 1, paracentesis with albumin replacement had demonstrated a median survival of slightly over 1 year. Furthermore, in patients recieving TIPS mendian suvival was shown to be extended to almost 20 months. The overall 2 year suvival in the patient reciveving paracentesis was 30-32% and in the TIPS group was 30-58%.[11]

Enhancing Healthcare Team Outcomes

Coordination of risk assessment and management must occur between the nurses, nurse practitioner, physician, and specialists to optimize care in these patients. [Level V]


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Hepatorenal Syndrome - Questions

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Which is not usually associated with hepatorenal syndrome?



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Which is true regarding prognosis in hepatorenal syndrome?



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Which is an inappropriate action in the treatment of the patient with hepatorenal syndrome?



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65-year-old female patient with nonalcoholic steatohepatitis (NASH) cirrhosis is admitted with hepatorenal syndrome and is clinically significant ascites. She has a background of severe COPD with mild cor pulmonale. Which of the following is not appropriate for management?



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Which of the following is not seen in hepatorenal syndrome?



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A 65-year-old male with a history of alcoholic cirrhosis presents to the hospital with abdominal pain. His physical exam is significant for ascites. He also reports a decrease in his urine output for the past 4-5 days. His vitals reveal a blood pressure of 94/62 mmHg and pulse 89/min. Labs are significant for serum creatinine 2.7 mg/dL (from normal baseline one week ago). Urine analysis is negative for casts or proteinuria. Renal ultrasound is negative for hydronephrosis. Paracentesis is suggestive of spontaneous bacterial peritonitis, and he is started on ceftriaxone. He receives 2 L of normal saline and over 200 g of albumin in the next 48 hours without improvement of his serum creatinine or urine output. What is the most likely etiology of his kidney injury?



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A 54-year-old female with a history of cirrhosis secondary to nonalcoholic steatohepatitis presents to the hospital with abdominal pain. Her physical exam is significant for ascites. Her vital signs reveal a blood pressure of 91/59 mmHg and pulse 78/min. Labs are significant for serum creatinine 1.8 mg/dL (from a normal baseline one week ago). Urine analysis was negative for casts or proteinuria. Renal ultrasound is negative for hydronephrosis. Paracentesis is suggestive of spontaneous bacterial peritonitis, and she is started on appropriate treatment. She receives 1g/kg of albumin in the next 48 hours without improvement of her serum creatinine. What is the most likely pathophysiology of her kidney injury?



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A 66-year-old male with a history of decompensated cirrhosis secondary to hepatitis B infection on furosemide and spironolactone presents with a 2-day history of hematemesis. His physical exam is significant for ascites. He also reports a decrease in his urine output for the past two days. His vitals reveal blood pressure 89/56 mmHg and pulse 95/min. Labs are significant for serum creatinine 3.8 mg/dL (from normal baseline two weeks ago) and serum potassium 4 mEq/L. Urine analysis is negative for casts or proteinuria. Renal ultrasound is negative for hydronephrosis. What is the best next step in the management of this patient?



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A 55-year-old male with a history of decompensated cirrhosis secondary to cryptogenic cirrhosis and recurrent ascites on furosemide and spironolactone presents with a worsening abdominal distention and diffuse abdominal pain. He also reports a decrease in urine output over the past week. His physical exam is significant for ascites and mild abdominal tenderness. His vitals reveal a blood pressure of 93/59 mmHg and pulse 85/min. Labs are significant for serum creatinine 2 mg/dL (from normal baseline one month ago) and potassium 3.9 mEq/L. Urine analysis is negative for casts or proteinuria. Renal ultrasound is negative for hydronephrosis. Paracentesis is suggestive of spontaneous bacterial peritonitis, and he is started on ceftriaxone. For his kidney injury, he is resuscitated with IV albumin 1g/kg for two days without improvement in his urine output or his kidney function. What is the next best step in the management of this patient?



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Hepatorenal Syndrome - References

References

Evolving Indications for Tips., Smith M,Durham J,, Techniques in vascular and interventional radiology, 2016 Mar     [PubMed]
Human albumin solution for patients with cirrhosis and acute on chronic liver failure: Beyond simple volume expansion., Valerio C,Theocharidou E,Davenport A,Agarwal B,, World journal of hepatology, 2016 Mar 8     [PubMed]
Evidence-Based Therapeutic Options for Hepatorenal Syndrome., Glass L,Sharma P,, Gastroenterology, 2016 Apr     [PubMed]
Amin AA,Alabsawy EI,Jalan R,Davenport A, Epidemiology, Pathophysiology, and Management of Hepatorenal Syndrome. Seminars in nephrology. 2019 Jan;     [PubMed]
Sivanathan V,Kittner JM,Sprinzl MF,Weinmann A,Koch S,Wiltink J,Nguyen-Tat M,Marquardt JU,Wörns MA,Zimmermann T,Lang H,Galle PR,Schattenberg JM, [Etiology and complications of liver cirrhosis: data from a German centre]. Deutsche medizinische Wochenschrift (1946). 2014 Sep;     [PubMed]
Egerod Israelsen M,Gluud LL,Krag A, Acute kidney injury and hepatorenal syndrome in cirrhosis. Journal of gastroenterology and hepatology. 2015 Feb;     [PubMed]
Angeli P,Tonon M,Pilutti C,Morando F,Piano S, Sepsis-induced acute kidney injury in patients with cirrhosis. Hepatology international. 2016 Jan;     [PubMed]
Ng CK,Chan MH,Tai MH,Lam CW, Hepatorenal syndrome. The Clinical biochemist. Reviews. 2007 Feb;     [PubMed]
Terra C,Mattos ÂZ,Pereira G,Farias AQ,Kondo M,Mattos AA,Medeiros Filho JEM,Strauss E,Dutra FRD,Mazza M,Lopes EP,Pereira TS,Schiavon LL,Carvalho Filho RJ,Fagundes C,Bittencourt PL, RECOMMENDATIONS OF THE BRAZILIAN SOCIETY OF HEPATOLOGY FOR THE MANAGEMENT OF ACUTE KIDNEY INJURY IN PATIENTS WITH CIRRHOSIS. Arquivos de gastroenterologia. 2018 Jul-Sep;     [PubMed]
Arroyo V,Moreau R,Jalan R,Ginès P, Acute-on-chronic liver failure: A new syndrome that will re-classify cirrhosis. Journal of hepatology. 2015 Apr;     [PubMed]
Angeli P, Review article: prognosis of hepatorenal syndrome--has it changed with current practice? Alimentary pharmacology     [PubMed]
Mansour D,McPherson S, Management of decompensated cirrhosis. Clinical medicine (London, England). 2018 Apr 1     [PubMed]

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