Moderator- Prof. J. Mokta

Hepatorenal Syndrome

• A 32 year-old man with cirrhosis due to alcohol is admitted to the hospital with spontaneous bacterial peritonitis.

• He is hemodynamically stable and is not on any diuretics. • He is treated with broad-spectrum IV antibiotics and IV albumin on

admission. At the time of admission, his serum creatinine is 1.2. • On day 5 of his hospitalization, his serum creatinine is 4.1, and he

is anuric. His urinalysis is normal.

WHAT IS THE LIKELY DIAGNOSIS ? WHAT IS THE PROGNOSIS FOR THIS YOUNG

MAN ? WHAT TREATMENT SHOULD HE BE STARTED

ON ?

Case Vignette

Introduction• Freriches and Flint first reported that oliguria in the absence

of renal histological changes in patients with advanced cirrhosis and ascites in 1861

• The term ‘hepatorenal syndrome’ was used in 1939 to describe the occurrence of renal failure after biliary surgery in patients showing a pathological pattern of acute tubular necrosis or tubular interstitial nephritis

• Koppel et al in 1960s also showed that kidneys from patients who succumbed from Hepato- Renal Syndrome (HRS) were functioned normally when transplanted into patients with chronic uremia

• Renal failure is one of the most severe complications of cirrhosis

• More than 50% of patients with renal failure and cirrhosis die within 1 month after the diagnosis

• Twenty percent of hospitalized patients with cirrhosis and ascites develop acute kidney injury.

Twenty percent of these patients have hepatorenal syndrome (HRS), a condition that occurs mainly in patients with cirrhosis and ascites.

Pathophysiology

Clinical features• HRS occurs almost exclusively in patients with ascites

• The cumulative probability of HRS in patients with cirrhosis and ascites is equal to 18% after 1 year, rising to 39% at 5 years

• The hepatorenal syndrome is characterized by the following features in a patient who has established or clinically evident acute or chronic liver disease :

A progressive rise in serum creatinine An often normal urine sediment No or minimal proteinuria (less than 500 mg per day) A very low rate of sodium excretion (ie, urine sodium

concentration less than 10 meq/L) Oliguria

• HRS has two distinct types of clinical presentations.

• Type 1 HRS is an acute form of HRS and characterized by rapidly progressive renal failure.

It is defined as at least a twofold increase in serum creatinine to a level greater than 2.5 mg/dL during a period of less than two weeks

Type 1 HRS usually develops after a precipitating event such as gastrointestinal bleeding, large volume paracentesis, acute alcoholic hepatitis and spontaneous bacterial peritonitis.

Type 1 HRS is commonly associated with rapid deterioration of extra-renal organ function including the heart, brain, liver, and adrenal glands.

• Type 2 HRS is a chronic form of HRS and characterized with moderate and slow progressive renal failure

It is defined as a slowly progressive rise in serum creatinine to more than 1.5 mg/dl

It is usually associated with diuretics resistant ascites.

• Although there is a clear distinction of two different types of HRS, renal impairment is often progressive and can be regarded as “continuum” instead of two different entities, such as most patients initially represents type 2 HRS and turn into type 1 HRS after several episodes of precipitating events

In 50% cases, the development of HRS is spontaneous,

whereas in other half 1 or more identifiable triggers may be found which include—

• Bacterial infections–Ascitic fluid, respiratory system, urinary tract, GI tract infections and infections of the biliary tract

Precipitating Factors for HRS

Approximately one-third of patients with spontaneous bacterial peritonitis develop HRS at the time of infection or immediately thereafter, in the absence of septic shock.

Patients who develop type 1 HRS as a result of spontaneous bacterial peritonitis have a dismal outcome, with almost 100% hospital mortality if not treated appropriately

• Diarrhoea and vomiting

• Diuretics

• Gastrointestinal bleeding-variceal bleeding

• Large volume paracentesis (LVP)–more than 5 litres without adequate blood volume expansion

Risk factors for developing HRS• Three important and easily recognized risk factors

are low mean arterial blood pressure (< 80 mm Hg), dilutional hyponatremia, and severe urinary sodium retention (urine sodium < 5 mEq/L)

• Interestingly, patients with advanced liver disease, defined by a high Child-Pugh score or worsening parameters of liver function, such as albumin, bilirubin, and prothrombin levels, are NOT at higher risk of developing HRS

• Other risk factors High plasma renin activity Increased plasma norepinephrine Low plasma osmolality High urine osmolality High serum potassium Previous episodes of ascites Absence of hepatomegaly Presence of esophageal varices Poor nutritional status

Moderately increased serum urea (>30 mg/dL) Moderately increased serum creatinine (>1.5

mg/dL) Moderately reduced GFR (< 50 mL/min)

Definition and diagnosis

• Although hepatorenal syndrome (HRS) is the most often cited diagnosis whenever renal dysfunction is diagnosed in patients with cirrhosis, HRS is actually a diagnosis of exclusion with a defined set of diagnostic criteria; it is diagnosed when all other causes of renal failure have been ruled out.

The International Ascites Club initially defined HRS in 1996 and then revised in 2007

RIFLE and AKIN criteria for AKI

ICA- ADQI 2011

KDIGO 2012

the latest is----------ICA 2015

Investigations

• The role of biomarkers• The most frequently studied biomarker of renal

dysfunction in cirrhosis is urinary neutrophil gelatinase-associated lipocalin (NGAL), which is a marker of renal tubular damage. In several studies, urinary NGAL levels, could differentiate between functional and structural causes of renal dysfunction in patients with cirrhosis.

• In the future, biomarkers might become specialized for identifying AKI susceptibility, establishing mechanisms of injury, tracking progression of AKI, so that the clinician’s task of initial diagnosis, staging, differential diagnosis and prognosis will be made easier.

• In cirrhotic patients with ascites, the most common causes of acute renal failure are: pre-renal (around 37%), acute tubular necrosis (around 42%), and post-renal failure (0.3%);

HRS is around 20%

Differential Diagnosis

• Martin-Llahi et al. prospectively evaluated 562 patients with cirrhosis and AKI and adjudicated patients into the somewhat unconventional diagnoses of “renal failure because of parenchymal nephropathy”, “hypovolemia related renal failure”, and “hepatorenal syndrome”

• Outcomes differed significantly by etiology with three

month mortality for patients with AKI due to parenchymal injury, hypovolemia, and HRS of 27%, 54%, and 85%, respectively, and etiology was independently associated with mortality

Martin-Llahi M, Guevara M, Torre A, et al. Prognostic importance of the cause of renal failure in patients with cirrhosis. Gastroenterology. 2010; [PubMed: 20682324]

Diagnostic Approach to AKI in Cirrhotics

AKI in a pt with cirrhosis

ECF fluid losses;rapid/excessive diureticsVomiting,diarrhoea,hemorrhage,recentLVP /hemodynamic changes due to use of NSAIDS (or)ACEI

NO

YEShold diuretics/offending medicationsTrial of intravascular volume expander (albumin) if renal function ↑ses with trial,Diagnosis of prerenal failure is made

Recent use of nephrotoxic medications Hypotension(sepsis,hemorrhage)

Glomerular proteinuria&hematuriai.e.,dysmorphic RBCs and RBC cast

Toxic or ischemic renal injury

YES

Glomerular diseaseDepending upon clinical scenarioFurther workup may include Cryoglobulins C3,C4 and renal biopsy

YES NO

NO

Imaging (USG,CT scan)shows Hydronephrosis,urinary retention SuggestObstructive uropathy

Unless long standiing relief of obstructionShould lead to improvement in renalfunction

YES

Patient has evidence of Portal Hypertension & fulfills HRS-AKI diagnostic criteria

Diagnosis of HRS can be made

NOYES

YES

YES

YES

YES

NO

NO

NO

NO

Management of HRS• General Measures

The general management of patients with cirrhosis and HRS depends on the severity of kidney failure and associated complications

Patients with type 1 HRS who are waiting for a liver transplant are managed appropriately in an intensive care setting

Considering the high mortality rate of type 1 HRS, decisions about the management of patients who are not candidates for transplant or who have important comorbid conditions should be made on an individual basis

Patients with type 2 HRS without associated complications are managed as outpatients

• Monitoring Patients with type 1 HRS should be monitored

carefully Parameters to be monitored include urine output,

fluid balance, and arterial pressure and standard vital signs

Ideally central venous pressure should be monitored to help with the management of fluid balance and prevent volume overload

• Volume Resuscitation Excessive administration of fluids should be avoided to

prevent volume overload All diuretics should be stopped in patients at the initial

evaluation and diagnosis of HRS There are no data to support the use of furosemide in

patients with ongoing type 1 HRS. Nevertheless furosemide may be useful to maintain urine output and treat central volume overload if present

Spironolactone is contraindicated because of high risk of life-threatening hyperkalaemia

Patients with HRS should be optimally resuscitated, with intravenous administration of albumin (initially 1 g of albumin/kg of body weight for 2 days up to a maximum of 100 g, followed by 20-40 g/day) in combination with vasopressor therapy, for up to 14 days

• Screening for Sepsis Bacterial infection should be identified early, by blood, urine

and ascitic fluid cultures, and treated with antibiotics. Patients who do not have signs of infection should continue

taking prophylactic antibiotics, if previously prescribed.

• Use of Paracentesis There are few data on the use of paracentesis in patients

with type 1 HRS. Nevertheless, if patients have tense ascites, large volume

paracentesis with albumin may be useful. <<Administration of albumin 8 g/litre of fluid aspirated

(specially if the aspiration is more than or equal to 5 litres)>>

Pharmacologic therapy• Administration of vasoconstrictor drugs currently is

considered the best therapy for managing type 1 HRS

• Vasopressin analogues, such as terlipressin which has a preferential effect on V1 receptors, which are densely located in the splanchnic bed. The improvement in renal perfusion is attributed to splanchnic vasoconstriction, rise in the effective circulating volume, mean arterial pressure, and decrease in the plasma renin and aldosterone and overall improvement in renal perfusion pressure.

Terlipressin is not yet approved by the Food and Drug Administration (FDA) in the USA for use in HRS, though it is commonly used in Europe and Asia.

Results from randomized controlled studies and systematic reviews show that treatment with the combination of terlipressin and albumin is associated with reversal of HRS in 40%-50% of patients, making this approach the preferred initial therapy

The ADQI recommends that patients with Type 1 HRS should be optimally resuscitated with albumin in combination with a vasoconstrictor, preferentially terlipressin

The terlipressin treatment protocol comprises an initial dose of 0.5-1 mg terlipressin intravenous injection every 4-6 h

The therapy is aimed to improve renal function and to decrease serum creatinine to less than 1.5 mg/dl (complete response)

If serum creatinine does not decrease at least 25% of its base value after 3 days, the dose of terlipressin should be increased in a stepwise manner up to a maximum of 2 mg/4 hour

• Therapy should be discontinued after 14 days in non-responders and only continued thereafter in partial responders while awaiting the outcome of salvage techniques

• After withdrawal of therapy, HRS recurs in 15% of patients, and in these cases, a second treatment with terlipressin usually is effective.

• The incidence of side effects (usually ischemic) that mandate discontinuation of treatment is 12%

• Contraindications to terlipressin therapy include a history of coronary artery disease, cardiomyopathies, cardiac arrhythmias, and obliterative arterial disease of the lower limbs

• Patients on terlipressin should be carefully monitored for development of cardiac arrhythmias or signs of splanchnic or digital ischaemia, and treatment modified or stopped accordingly.

• Predictors of response include pretreatment bilirubin < 10 mg/dL and increase of MAP ≥ 5mmHg at day three of therapy

• It is unlikely that vasoconstrictor drugs improve survival beyond the short term

• A multicentre randomised controlled trial comparing terlipressin and albumin to albumin alone in 46 patients with HRS showed improved renal function in the former group (43.5% versus 8.7%, = 0.017), but no survival 𝑃advantage in either group at three months (27% versus 19%, = 0.7).𝑃

• Norepinephrine is less expensive than terlipressin; it increases the mean arterial pressure by its α1 –mediated effect on systemic vascular resistance and its β1-mediated inotropic activity.

• Initial dose: 0.1 mg/kg/min intravenous infusion• If no increase in mean arterial pressure by 10 mm Hg: increase dose by 0.05 mg/kg/min

every 4 h up to a maximum dose of 0.7 mg/kg/min

It is recommended by ADQI as an alternative to terlipressin along with albumin for the treatment of HRS.

• Midodrine, an α-1 agonist causes vascular smooth muscle constriction

The availability of an oral preparation makes administration of this drug on an outpatient basis feasible.

Studies have shown that it is the combination of thrice daily midodrine (7.5- 12.5 mg) with octreotide (100- 200 µg subcutaneously) and albumin, which improves renal plasma flow, GFR, urinary sodium excretion along with a reduction in renin, vasopressin and glucagon after 3 weeks of treatment.

• Low-dose dopamine (2-5 mcg/kg/min) is frequently prescribed to patients with renal failure in the hope that its vasodilatory properties may improve renal blood flow. Little evidence exists to support this practice.

Five studies have evaluated the role of dopamine in HRS, and none have reported significant changes in RPF, GFR, or urine output.

• Misoprostol is a synthetic analogue of PG E1, whose use in HRS was based on the observation that these patients had low urinary levels of vasodilatory PGs. None of the studies demonstrated an improvement in the GFR, sodium excretion, or renal function in patients with HRS.

Transjugular Intrahepatic Portosystemic Shunt (TIPS)

• TIPS involves the insertion of an intrahepatic stent that connects the portal vein to the hepatic vein. This shunts portal blood into the systemic circulation, which reduces the portal pressure and increases the systemic venous return. In turn, this treats the arterial underfilling and the overactivity of the RAAS and SNS.

• Unfortunately, most patients with HRS are ineligible for TIPS due to contraindications (e.g., INR > 2, serum bilirubin > 5mg/dL, CP score > 11, and cardiopulmonary disease).

• Furthermore, TIPS can aggravate the liver failure and precipitate encephalopathy.

• The ADQI work group recommends that (i) TIPS should not be used as the first line treatment for type 1 HRS due to insufficient data and (ii) TIPS may be used in patients with type 2 HRS and refractory ascites

• RRT may be used to treat specific complications of renal impairment such as metabolic acidosis, hyperkalaemia, volume overload, and uraemic symptoms

• The ADQI work group recommends that RRT should be avoided in type 1 HRS patients unless there is an acute reversible component or an intention to pursue liver transplantation

Renal replacement therapy

• Molecular adsorbent recirculating system (MARS) is a modified dialysis technique for extracting albumin bound and water-soluble substances from the blood. This removes vasodilator substances such as nitric oxide, tumour necrosis factor, and cytokines, which are implicated in the pathogenesis of HRS.

Recently, a large randomised controlled trial (RELIEF) involving 19 European centres comparing MARS with standard therapy in patients with acute-on-chronic liver failure reported that while MARS provided temporary organ benefit (liver, kidney, and brain), it did not improve overall survival

Artificial Liver Support Systems

• Prometheus is an extracorporeal technique involving fractional plasma separation and adsorption with haemodialysis for removing water-soluble and albumin bound substances.

• Given the lack of a definitive survival benefit and high costs, the ADQI work group suggests that extracorporeal support systems should be limited to research protocols

• Liver transplantation is the definitive treatment for HRS

• The five-year survival for HRS is 60% for patients that underwent liver transplantation compared with 0% for patients that did not undergo liver transplantation

• Patients with HRS have worse post transplant outcomes than patients without HRS. This includes reduced short- and long-term survival, increased risk of bleeding and infection, and longer hospital stay .

Liver Transplantation

• Restuccia et al suggested that reversal of the renal dysfunction prior to transplantation improves posttransplant outcomes

The study found that HRS patients treated with

vasopressin analogues before transplantation had similar outcomes to controls with normal renal function. Both groups had comparable survival (three-year survival 100% in HRS-treated group versus 83%in controls, = 0.15), frequency of 𝑃posttransplant renal dysfunction, and length of hospital stay.

• Between 58 and 94% of patients with HRS demonstrate recovery of renal function after liver transplantation .

• Factors associated with a failure of renal recovery include the time interval between onset of HRS and transplantation (≥ 4–6 weeks),

dialysis for ≥ 8 weeks, and a serum creatinine of ≥ 2mg/dL . Such patients may benefit from simultaneous

liver and kidney transplantation.

• The median survival of patients with type 1 HRS is only 10% at 90 days, whereas for type 2 HRS it is 6 months without treatment

Prognosis is however improved with treatment with the 3 month survival of 20 and 40% respectively for type 1 and 2 HRS

• The survival in these groups of patients is dictated by the deterioration in liver function, and the response to pharmacological treatment.

If there is no improvement with treatment of vasoconstrictors for 10-14 days, it indicates a poor prognosis.

Prognosis

Prevention of HRS

• With better understanding of the pathophysiology of HRS, certain specific strategies have been identified to prevent HRS in specific clinical situations

• A systematic literature review was conducted by acute dialysis quality initiative (ADQI) in 2010, where the experts developed a consensus recommendation for standardised care of cirrhotics with HRS.

Careful assessment, close monitoring and prevention of precipitating factors in cirrhotics with ascites

Drugs which reduce renal perfusion and those causing nephrotoxicity have been reported to precipitate HRS, should be avoided

Antibiotic prophylaxis has shown to reduce spontaneous bacterial peritonitis (SBP). Studies using norfloxacin have reported not only a reduction in SBP (7 versus 61%) but also a reduction in the incidence of HRS (28 versus 41%)

Albumin infusions have been reported to decrease the incidence of HRS in patients with SBP

Prophylactic pentoxifylline, a tumour necrosis factor-α antagonist, reduces complications in patients with advanced cirrhosis including renal dysfunction

Large volume paracentesis (LVP) may induce paracentesis induced circulatory dysfunction (PICD) leading to development or exacerbation of AKI and HRS. Administration of albumin 8 g/litre of fluid aspirated (specially if the aspiration is more than or equal to 5 litres) leads to the prevention of PICD

Case Vignettes

• A 54-year-old male was hospitalized 3 days ago following a self-limited episode of hematemesis. He is now being evaluated for 24 hours of oliguria. He is a K/C/O cirrhosis due to chronic hepatitis C infection.

The patient’s temperature is 36.9 C, BP is 110/65 mmHg, PR is 75/min, and respiratory rate is 18 /min. Physical examination reveals severe ascites and abdominal tenderness to

palpation. He has 2+ pitting edema in both lower extremities. Serum creatinine is 5.14 mg/dL.

Urine sodium is 6mEq/L. Urine analysis is normal. A challenge with 60gm of albumin over several hours fails to improve urine

output.

• Which of the following is the most likely diagnosis?

a. Acute tubular necrosis

b. HRS

d. Prerenal azotemia

• A 55-year old man with decompensated cirrhosis admitted with SBP is noted to have a low urine output and increasing creatinine after resolution of the infection.

He has jaundice, tense ascites and peripheral edema. Laboratory data reveal a serum creatinine 3.1 mg/dL (4 weeks prior:

0.8 mg/dL, at time of SBP 2.0 mg/dL), BUN 52 mg/dL, serum sodium 123 mEq/L

• All of the following management options is are appropriate at the present time EXCEPT?

A. Obtain urinalysis, urine sodium measurement, and urine sediment B. Obtain renal ultrasound C. Expand intravascular volume with albumin D. Start IV furosemide

• A 32 year-old man with cirrhosis due to alcohol is admitted to the hospital with spontaneous bacterial peritonitis. He is hemodynamically stable and is not on any diuretics.

He is treated with broad-spectrum IV antibiotics, and IV albumin on admission. At the time of admission, his serum creatinine is 1.2. On day 5 of his

hospitalization, his serum creatinine is 4.1, and he is anuric. He is diagnosed with hepatorenal syndrome.

• Which of the following is TRUE?

A. He has type II hepatorenal syndrome and should be evaluated for a combined liver/kidney transplant. B. He has type I hepatorenal syndrome, and should be treated with daily IV albumin and

terlipressin, as a bridge to a liver transplant. C. After a liver transplant, his renal function is unlikely to fully recover. D. Pharmaceutical management involves vasodilator therapy, with the goal of improving

renal perfusion.

Thank you

A new algorithm for the management of AKI in cirrhosis

• According to the new ICA-AKI diagnostic criteria for AKI, a new algorithm for the management of AKI in patients with cirrhosis is proposed.

• The algorithm is based on the new staging of AKI.