Hepatorenal syndrome

1. Description of the problem

What every clinician needs to know

The hepatorenal syndrome (HRS) is a form of volume-unresponsive acute kidney injury, defined as a progressive deterioration of renal function in patients with underlying severe and typically progressive liver failure, in the absence of an identifiable cause, which does not respond to fluid resuscitation.

Clinical features of the condition

• Patients typically have signs of severe progressive liver disease, which may include clubbing, leukonychia, palmar erythema, liver flap, warm peripheries with tachycardia and bounding pulse, normal or low systolic blood pressure, icteric sclera, jaundiced skin color, muscle wasting and loss of limb subcutaneous fat, spider nevi, gynecomastia, ecchymoses, ascites, everted umbilicus, caput medusa of distended veins and peripheral edema. The liver may be enlarged or small and shrunken with splenomegaly. Hepatorenal syndrome may also occur in cases of acute liver failure, following major hepatic resection (small-for-size syndrome) and post liver transplantation associated with delayed or primary graft non-function.
• Typically patients are oliguric (<0.6 ml/kg/h), with a urinary sodium of < 20 mEq/L (mmol/L), with a fractional excretion of sodium (FENa) < 1% and a fractional excretion of urea (FEUrea) < 35%. FENa = (urinary sodium concentration × plasma creatinine concentration × 100)/(plasma sodium × urinary creatinine).The normal FENa is > 1% and FEUrea is > 45%.
• Hypovolemia should be excluded by clinical examination, and patients should not have signs of nail bed delayed capillary refill time, postural hypotension or depressed jugular venous pulse.
• Patients should not have clinical signs of systemic sepsis, including pyrexia, or depressed temperature, or localized infection such as pneumonia.
• Urine dip stick testing should exclude urinary sepsis (leukocyte esterase and nitrite negative) and intrinsic renal disease as the cause of acute kidney injury (<50 rbc per high-power microscope field and proteinuria < 500 mg/l).

Key management points

• Obtain a history to determine whether there has been a precipitating event for either deterioration in liver function (e.g., alcohol binge causing acute alcoholic hepatitis) or renal function (hematemesis, vomiting, diarrhea, change in medications).
• Exclude infection as a precipitant, including spontaneous bacterial peritonitis, which may be occult.
• Exclude hypovolemia as a precipitant and optimize intravascular volume.
• Withdraw diuretics and anti-hypertensives (ACEI, ARBs, calcium channel blockers and vasodilators such as alpha blockers) and other potential nephrotoxins, including nonsteroidal anti-inflammatories.
• Reduce intra-abdominal pressure in patients with tense ascites, with appropriate fluid replacement if large volumes are tapped.
• Arrange renal ultrasound scan to exclude obstruction and intrinsic renal disease (small shrunken kidneys with increased cortical to medullary echogenicity) and estimate resistivity index (ratio of intra-renal arteriole systolic peak flow minus diastolic flow peak, divided by systolic peak flow – ratio > 0.75 in acute kidney injury and hepatorenal syndrome.
• If possible, avoid aminoglycoside antibiotics and consider using MRI or ultrasound examinations to minimize radiocontrast exposure. If radiocontrast studies are required, use isotonic bicarbonate to maintain hydration status and minimize dosage using hypo- or isosmolar radiocontrast agents.
• Monitor renal function daily, and if hepatorenal syndrome is suspected and there is no improvement with conservative supportive management, then consider vasopressor therapy (see specific treatment section).

2. Emergency Management

Overt or covert sepsis is the most common precipitant of hepatorenal syndrome. As such, the emergency management of any patient with acute or chronic liver failure with a deterioration in renal function is as follows:

• Examine the patient for signs of generalized or localized sepsis, take appropriate standard blood and urine cultures, including ascitic fluid (if present) and arrange for chest X-ray. If sepsis is suspected then start empirical broad-spectrum antibiotics (such as 3rd-generation cephalosporins, tazosin or meropenem according to local antimicrobial prescribing guidelines).
• Unless the patient has overt signs of intravascular volume overload, monitor the response to an intravenous volume challenge. Human albumin 1 g/kg (up to a maximum of 100 g) should be given in 100-ml aliquots, observing the response before repeating the next fluid challenge. 20% albumin solutions have an advantage in terms of reducing sodium gain compared to 4.5-5.0% solutions.
• Once volume loaded, if the patient remains hypotensive or has a reduced mean arterial pressure (<65 mmHg), consider vasopressor therapy (see specific management section).
• Once volume loaded, if the patient remains oliguric, consider measuring intra-abdominal pressure and if raised arrange for ascitic drainage.

Checklist

Assess patient

Is there a precipitating event? Does this require specific management (e.g., terlipressin for variceal hemorrhage)?

Physical examination

• Is the patient hypovolemic?
• Does the patient have systemic or localized sepsis? If so, start empiricial antibiotics.
• Culture blood, urine and ascitic fluid, and review chest X-ray to exclude lower respiratory tract infection.
• Fluid resuscitate unless patient has signs of intravascular fluid overload.
• Boluses of 100 ml 20% albumin; reassess response, give 1 g/kg up to a maximum 100 g.
• If systolic blood pressure is low and there is no response to volume expansion (less than 110 mmHg or MAP less than 65 mmHg):
• Consider vasopressor support (use caution if patient has a history of ischemic heart disease or cerebro or peripheral vascular disease), with terlipressin or norepinephrine.
• Is ascites present?
• If tense, then arrange for drainage with appropriate fluid replacement.

3. Diagnosis

The hepatorenal syndrome is defined as a progressive deterioration in kidney function that does not respond to fluid resuscitation and is not due to intrinsic renal disease (glomerulonephritis or interstitial nephritis) or obstruction, in patients with established severe progressive liver failure, which may be acute or chronic.

The diagnosis of hepatorenal syndrome is one of exclusion of other causes of acute kidney injury in patients with established progressive liver failure.

Diagnostic criteria

• Severe progressive liver failure: established cirrhosis with ascites, acute liver failure, ACLF, post liver transplant/major hepatic resection.
• Serum creatinine greater than 1.5 mg/dl (133 umol/l).
• Absence of shock.
• Absence of hypovolemia as defined by no sustained improvement of renal function (creatinine decreasing to less than 1.5 mg/dl or 133 umol/l) following at least 2 days of diuretic withdrawal (if prescribed diuretics), and volume expansion with albumin at 1 g/kg (up to a maximum of 100g/day).
• No current or recent treatment with nephrotoxic drugs.
• Absence of parenchymal renal disease as defined by proteinuria less than 500 mg/day, no microhematuria (less than 50 rbc per high-power field) and normal renal ultrasonography.
• Urine biochemistry is not diagnostic, but the usual findings would be a reduced urine sodium concentration (less than 20 mEq/l or mmol/l), with a fractional sodium excretion of less than 1%, where fractional excretion of sodium= 100 x ([urine sodium/serum creatinine]/[serum sodium x urine creatinine]), and a fractional urea excretion of less than 35%.
• Hyponatremia typically occurs in liver failure due to increasing antidiuretic hormone secretion, and the risk of developing hepatorenal failure increases with progressive hyponatremia and is more likely with a serum sodium less than 132 mEq/l or mmol/l.

Hepatorenal syndrome is traditionally subdivided into type I and type II. Type 1 HRS is characterized by a rapid and progressive impairment in renal function (increase in serum creatinine of equal to or greater than 100% compared to baseline to a level higher than 2.5 mg/dl (223 umol/l) in fewer than 2 weeks (Figure 1), and is now most often observed with ACLF, in the setting of multiple organ dysfunction. Type II HRS is characterized by a stable or less progressive impairment in renal function.

Figure 1.

Normal lab values

In patients with progressive liver failure the diagnosis of hepatorenal syndrome is based on the following:

• Serum creatinine greater than 1.5 mg/dl or 133 umol/l (normal less than 0.9 mg/dl or 120 umol/l). However, creatinine is made from creatine, which is synthesized in the liver and then non-enzymatically converted to creatinine in muscle. So, in liver failure creatine generation rates are reduced which reduces creatinine production, and this is further exacerbated by reduced muscle mass and protein energy malnutrition. Thus, what may appear to be small changes in serum creatinine and levels only marginally above the normal reference range represent a much larger reduction in kidney function than otherwise expected. The standard laboratory assay for creatinine is based on a color change (Jaffe picric acid method), and so creatinine measurements are affected by bilirubin (reduce creatinine value) and drugs, including trimethoprim and 3rd-generation cephalosporins (increase creatinine value). Enzymatic assays of creatinine are less affected by bilirubin.
• Other markers of kidney function. Creatinine clearance overestimates true renal function due to a combination of a relatively reduced serum creatinine and a relatively increased urinary creatinine, as the amount of creatinine secreted into the renal tubule increases compared to that filtered by the glomerulus. Cystatin C, which is filtered by the glomerulus, has recently been shown to been equally inaccurate as serum creatinine in over-estimating renal function in patients with established cirrhosis, as cystatin C is increased many inflammatory conditions.
• Isotopic methods using a single bolus injection determine renal function by measuring the area under the decay curve. This method overestimates renal function in patients who are volume overloaded (peripheral edema) and particularly those with ascites (initial distribution into the ascites and redistribution from the ascites). As such, renal function can only reliably be measured using prolonged continuous infusion techniques, which have allowed time for equilibration with the ascitic compartment, or alternatively, single bolus injection techniques, with delayed sampling at 24 hours. Thus, serum creatinine remains the current marker of renal function in everyday clinical practice, but it should be recognized that creatinine overestimates renal function.
• As the majority of cases of hepatorenal syndrome are precipitated by an acute event, typically sepsis and urinary biomarkers that measure the general inflammatory response (neutrophil gelatinase-associated lipocalpin, liver type fatty acid-binding protein), and those that reflect renal damage (kidney injury molecule 1, cytokines – IL-18, and urinary enzymes – alpha 1 microglobulin, alpha 1 acid glycoprotein, N-acetyl-beta-D-glucosaminidase, gamma glutamyltranspeptidase and alkaline phosphatase, and albumin) are currently unable to differentiate hepatorenal syndrome from other causes of acute kidney injury particularly when there is a concomitant urinary tract infection or hepatorenal syndrome has been triggered by sepsis.

Exclusion of other causes of acute kidney injury:

Normal-sized unobstructed kidneys on ultrasound examination

Normal urine microscopy (less than 50 RBCs per high-power field)

No red cell casts on urinary microscopy/cytology

less than 500 mg/24 hr proteinuria

How do I know this is what the patient has?

The patient has hepatorenal syndrome because:

• Deteriorating renal function with serum creatinine greater than 1.5 mg/dl (133 umol/l) in a patient with progressive liver disease.
• Exclusion of other causes of acute kidney injury.
• Exclusion of hypovolemia.
• Exclusion of active sepsis.
• Normal-sized unobstructed kidneys on ultrasound examination.
• Normal urine microscopy (less than 50 RBCs per high-power field).
• No red cell casts on urinary microscopy/cytology.
• Less than 500 mg/24 hr proteinuria.

What else could it be?

The majority of patients admitted to the hospital with severe progressive liver failure who develop acute kidney injury do not have hepatorenal syndrome. Patients are more likely to have: volume-unresponsive acute kidney injury or volume-responsive acute kidney injury.

The majority of patients with cirrhosis and ascites admitted to the hospital with a sudden deterioration in liver function have sepsis as a precipitating factor. In patients with severe liver disease, splanchnic vasodilatation leads to compensatory activation of the visceral and renal sympathetic nervous systems, and increased neuro-hormonal response (increased renin, aldosterone, norepinephrine and vasopressin, and visceral sympathetic nervous system activation). This alters the normal renal autoregulation curve (Figure 2), and as such these patients are much more susceptible to acute ischemic renal injury due to a fall in the effective intravascular volume associated with sepsis and hypovolemia.

Figure 2.

In addition, ascites increases intra-abdominal pressure, which leads to an increase in renal venous pressure, resulting in increased renal interstitial pressure (Figure 3) and intra-renal endothelin, causing further glomerular ischemia and ischemic kidney injury. If the precipitating event is volume depletion without inflammation, such as acute variceal hemorrhage, excess diarrheal losses due to lactulose or over-diuresis, patients may have volume-responsive acute kidney injury.

Figure 3.

Occasionally patients may have an acute interstitial nephritis associated with drug reaction; this is more commonly found with penicillin and cephalosporin antibiotics, but can occur secondary to diuretics, nonsteroidal anti-inflammatories, proton pump inhibitors, and other drugs. In addition, toxic renal tubular injury can occur with acetaminophen self-poisoning and ingestion of animal, plant and chemical toxins that also cause liver damage. Patients with HIV taking anti-retrovirals that affect mitochondrial function are much more prone to renal tubular ischemia and volume-unresponsive acute kidney injury.

Glomerulonephritis causing acute kidney injury is less common in patients with severe liver failure but can occur in cases of cryoglobulinemia associated with hepatitis C, and polyarteritis nodosa due to underlying hepatitis B. Very occasionally, patients with IgA nephropathy develop macroscopic hematuria, which results in intra-tubular obstruction and AKI, or patients with decompensated Wilson’s disease have marked hemolysis and developed heme pigment nephropathy.

Patients with acute and chronic liver failure may have established comorbidities, such as diabetes mellitus, hypertension and polycystic kidney disease, which would make them more susceptible to acute kidney injury due to pre-existing chronic kidney disease. In these latter cases and also IgA nephropathy, patients may have established proteinuria and hematuria, and as such, urine testing wiil be abnormal, but this does not necessarily exclude an additional diagnosis of hepatorenal syndrome.

What confirmatory tests should be performed?

There are no specific confirmatory tests that you should perform. The diagnosis is one of exclusion of other causes of acute kidney injury in patients with severe progressive liver failure.

Tests of exclusion include:

Exclusion of active sepsis blood, urine and ascitic cultures, chest X-ray.

Renal ultrasound examination to confirm normal-sized unobstructed kidneys.

Urine microscopy (should be normal, less than 50 RBCs per high-power field).

No red cell casts on urinary microscopy/cytology.

Urine dip stick or quantification to exclude proteinuria (should be less than 500 mg/24 hr proteinuria).

4. Specific Treatment

If there has been a precipitating event in cases of ACLF, such as sepsis or variceal hemorrhage, special treatment is required. Otherwise management centers around two key objectives (Figure 4):

Figure 4.

• Plasma volume expansion.
• Increase in renal perfusion pressure.

Plasma volume expansion

Unless the patient has clinical signs of intravascular volume overload, plasma volume expansion is recommended.

1st day: 1 g/kg albumin (up to a maximum of 100 g), then repeat albumin infusion 40 g/day.

Pharmacological management

Terlipressin, a vasopressin analogue, is currently the vasoconstrictor of choice, as it preferentially causes splanchnic vasoconstriction. However, as it is a potent vasoconstrictor, careful consideration and care should be used in patients with symptoms or signs of myocardial ischemia, peripheral vascular disease or cerebrovascular disease.

It has been recommended that prior to commencing terlipressin therapy patients should have a baseline ECG, and this should be repeated if clinically indicated during treatment. Ideally these patients should have continuous cardiac monitoring in a high-dependency bed.

Terlipressin is usually started at a dose of 0.5-1 mg q4-6h and increased steadily to a maximum of 2 mg q4-6h, given as either a subcutaneous injection or as an infusion over 2-4 hours, if there is no reduction in serum creatinine of at least 25% compared to the baseline value at day 3 of therapy, then terlipressin is unlikely to be effective and the patient most likely has volume unresponsive AKI (formerly termed acute tubular necrosis). Treatment appears equally effective with either subcutaneous injections or continuous infusion, and should then be continued until the serum creatinine has decreased below 1.5 mg/dl, usually to around 1-1.2 mg/dl.

Response to therapy with terlipressin is generally characterized by a slow progressive reduction in serum creatinine in combination with an increase in arterial pressure, urine volume and serum sodium concentration. Median time to response is around 14 days and usually depends on pre-treatment serum creatinine; it is shorter in patients with lower baseline serum creatinine values and longer in those with higher starting creatinine values.

A serum bilirubin less than 10 mg/dl before treatment and an increase in mean arterial pressure greater than 5 mmHg by day 3 of treatment are associated with a high probability of response to therapy. Treatment is effective in 40-50% of patients and is most successful when used in combination with daily albumin infusions. Once the serum creatinine has fallen to less than 1.5 mg/dl, withdraw terlipressin rather than decreasing the dose, as recurrence after withdrawal of therapy is uncommon.

If terlipressin is unavailable, then norepinephrine (0.5-3.0 mg/h) may be a suitable alternative in the intensive care setting. In the ward setting the combination of oral midodrine and subcutaneous octreotide has had some success, albeit less effective than terlipressin. Midodrine is typically started at 2.5 mg pot id, and increased up to 15 mg pot id, and octreotide 50 ug sc tid increased up to 200 ug sc tid.

If the precipitating factor is alcohol ingestion: in patients with alcohol-induced cirrhosis, oxypentifylline 200 mg pg tid was previously recommended, although more recent trials have not shown any benefit.

If the patient is not responding to terlipressin therapy by day 5, review the patient and reassess intravascular volume status. If volume depleted, then increase the volume of albumin administered.

Assess ascites

If the patient has tense ascites, arrange for drainage with appropriate fluid replacement. If in doubt, measure intra-abdominal pressure via bladder catheter and consider draining ascites if intra-abdominal pressure is more than 18 mmHg.

Patients with hepatorenal syndrome precipitated by sepsis may have a reduced adrenal response. Thus, in refractory cases, check cortisol response to synacthen, and if sub-optimal then give hydrocortisone.

As cortisol is bound to cortisol binding globulin (CBG), then total cortisol concentrations may appear low to due to reduced CBG synthesis, and if free cortisol assay is not available then salivary cortisol may be equivalent to free cortisol.

If no response, then discontinue terlipressin on day 10 and consider alternative therapies.

Transjugular intrahepatic portosystemic shunting (TIPS) has been reported to improve renal function in patients with type 1 hepatorenal syndrome. However, many patients with hepatorenal syndrome will have contraindications to TIPS, including severe liver failure and hepatic encephalopathy, and plasma ammonia should be checked prior to a TIPS procedure, as ammonia levels will increase post TIPS.

Renal replacement therapy (RRT) in the form of peritoneal dialysis, intermittent hemodialysis and continuous forms of hemodialysis and hemofiltration have been used in selected cases of hepatorenal syndrome. RRT is indicated for life-threatening hyperkalemia, severe metabolic acidosis and volume overload. However, patients with severe acute or chronic progressive liver failure are prone to infection, hypotension and bleeding, which may make RRT problematic.

As RRT has not been shown to improve outcomes in patients with hepatorenal syndrome, RRT should only be considered as a short-term bridging treatment for life-threatening emergencies, or short-term supportive therapy for patients predicted to have recovery of liver failure, or those considered for liver transplantation.

As RRT only effectively removes small water-soluble toxins, a number of extracorporeal devices have been developed that can remove lipid-soluble and protein-bound toxins. The MARS system uses an albumin dialysate, which is regenerated by two sorbent columns, whereas the Prometheus device has a high-permeability filter and the ultrafiltrate passes through two sorbent columns.

As these sorbents become saturated these are intermittent treatments of 4-6 hours. In addition, some centers use single-pass albumin dialysis (SPAD) as a continuous treatment. Although initial single-center trials suggested encouraging results for MARS and Prometheus treatments for patients with hepatorenal syndrome, later prospective controlled multicenter trials showed no survival benefit.

Liver transplantation is the definitive treatment of choice for both type 1 and type 2 HRS. Treatment of hepatorenal syndrome before transplantation with terlipressin may decrease early complications after transplantation and the need for post-transplantation RRT and reduce mortality in these patients.

Patients with hepatorenal syndrome who respond to vasopressor therapy should be treated by liver transplantation alone.

Similarly, patients with hepatorenal syndrome who do not respond to vasopressor therapy, and who require renal support, should be offered liver transplantation alone, as the majority will recovery renal function after liver transplantation.

There is, however, a subgroup of patients who require prolonged renal support (more than 12 weeks), and these patients should therefore be considered for combined liver and kidney transplantation.

5. Disease monitoring, follow-up and disposition

Although treatment with terlipressin combined with albumin is effective in 40-50% of patients, the long-term outlook for patients with hepatorenal syndrome without liver transplantation remains poor, with an average median survival time of only approximately 3 months.

It is currently unclear whether patients who do not respond to the combination of terlipressin and albumin have hepatorenal syndrome or ischemic acute kidney injury. However, patients who have failed to respond to vasopressors and volume expansion after 5 days of therapy should be reassessed and the diagnosis of hepatorenal syndrome reviewed.

Patients discharged from the hospital should be assessed for their suitability for liver transplantation by specialist hepatologists.

Pathophysiology

There are five major factors generally recognized in the development of hepatorenal syndrome:

• The development of arterial vasodilatation, predominantly affecting the splanchnic bed, leading to a reduction in the effective arterial blood volume with a decrease in mean systemic arterial blood pressure. The splanchnic vasodilatation is predominantly driven by increased local nitric oxide production.
• Activation of the sympathetic nervous system and the renin-angiotensin-aldosterone axis, which causes renal vasoconstriction and shifting the renal auto-regulatory curve, making renal blood flow much more sensitive to changes in mean arterial pressure.
• Impairment of cardiac function, due to the development of cirrhotic cardiomyopathy, which leads to a relative reduction in the compensatory increase in cardiac output secondary to splanchnic and systemic vasodilatation, so that the effective cardiac output is reduced for the individual patient.
• The increased synthesis of several vasoactive mediators, both systemically and locally within the kidney affect renal blood flow and intra-glomerular microcirculatory hemodynamics. These include adenosine, cysteinyl leukotrienes, endothelin-1, F2-isoprostanes, thromboxane A2, and others which remain to be determined.
• Intra-abdominal hypertension due to a combination of ascites and increased right ventricular systolic pressure due to cirrhotic cardiomyopathy result in raised renal venous pressure and increased intra-renal endothelin, leading to glomerular vascular and mesangial vasoconstriction.

More recently it has been recognized that patients with a greater systemic inflammatory response (SIRS) are at increased risk of developing hepatorenal syndrome. Increasing inflammation results in reduced ability for albumin to act as a detoxifying molecule, as binding site capacity falls, and structural modifications of albumin reduce its ability to take up further toxins. So called ischemia modified albumin.

Prevention of hepatorenal syndrome

Long-term norfloxacin (400 mg/day) has been shown to decrease the risk of developing hepatorenal syndrome and to improve survival in patients with advanced cirrhosis, hyponatremia and those with low protein concentration in their ascitic fluid.

Patients presenting with spontaneous bacterial peritonitis should be treated with intravenous albumin, as this has been shown to decrease the incidence of hepatorenal syndrome and improve survival.

There are limited data to suggest that pentoxifylline decreases the incidence of hepatorenal syndrome in patients with severe alcoholic hepatitis.

Epidemiology

The probability of developing hepatorenal syndrome in patients presenting with cirrhosis and ascites increases from 18% in the first year to approximately 40% at 5 years.

Risk factors originally identified in “stable” patients for the development of hepatorenal syndrome include the presence of hyponatremia, decreased solute-free water clearance, poor nutritional status, absence of hepatomegaly, arterial hypotension, and elevated plasma renin activity or norepinephrine concentrations.

Patients with established cirrhosis should be regularly monitored by medical review as patients will generally develop progressive liver disease over time.

Prognosis

The long-term outlook for patients with hepatorenal syndrome without liver transplantation remains poor, with an average median survival time of approximately only 3 months. Liver transplantation is the treatment of choice for both type 1 and type 2 hepatorenal syndrome, with survival rates of approximately 65% in type 1 hepatorenal syndrome.

The lower survival rate compared to patients with cirrhosis without hepatorenal syndrome is due to the fact that renal failure is a major predictor of poor outcome after transplantation. Moreover, patients with type 1 hepatorenal syndrome have an increased mortality while on the waiting list for liver transplantation.

Special considerations for nursing and allied health professionals

Patients should be managed in a high-dependency level 2 facility.

What’s the evidence?

Description of the problem

Ginès, P, Quintero, E, Arroyo, V. “Compensated cirrhosis: natural history and prognostic factors”. Hepatology. vol. 7. 1987. pp. 122-8. (Outlines problems of patients with severe liver disease.)

Cazzaniga, M, Dionigi, E, Gobbo, G, Fioretti, A, Monti, V, Salerno, F. “The systemic inflammatory response syndrome in cirrhotic patients: relationship with their in-hospital outcome”. J Hepatol. vol. 51. 2009 Sep. pp. 475-82. (Study showing that patients who are admitted with or develop sepsis during inpatient stay have worse outcomes.)

Alessandria, C, Ozdogan, O, Guevara, M, Restuccia, T, Jiménez, W, Arroyo, V. “MELD score and clinical type predict prognosis in hepatorenal syndrome: relevance to liver transplantation”. Hepatology.. vol. 41. 2005. pp. 1282-9.

Etiology

Arroyo, V, García-Martinez, R, Salvatella, X. “Human serum albumin, systemic inflammation, and cirrhosis”. J Hepatol.. vol. pii. 2014 Apr 18. pp. S0168-8278. (Role of albumin as a detoxifying molecule in cirrhosis.)

Cavasi, A, Cavasi, E, Grigorescu, M, Sitar-Taut, A. “Relationship between NT-proBNP and cardio-renal dysfunction in patients with advanced liver cirrhosis”. J Gastrointestin Liver Dis. vol. 23. 2014 Mar. pp. 51-6. (Patients with more severe liver disease have higher NTporBNP.)

Møller, S, Krag, A, Bendtsen, F. “Kidney injury in cirrhosis: pathophysiological and therapeutic aspects of hepatorenal syndromes”. Liver Int.. 2014 Mar 26. (Recent overview of hepatorenal syndrome.)

Emergency management

Guevara, M, Cárdenas, A, Uriz, J, Ginès, P, Ginès, P, Arroyo, V, Rodés, J, Schrier, RW. “Prognosis in patients with cirrhosis and ascites”. Ascites and renal dysfunction in liver disease: pathogenesis, diagnosis and treatment. 2005. pp. 260-70. (Good review of underlying pathophysiology of hepatorenal syndrome.)

Arroyo, V, Terra, C, Gines, P. “Advances in the pathogenesis and treatment of type-1 and type-2 hepatorenal syndrome”. J Hepatol. vol. 46. 2007. pp. 935-46. (Review of vasopressor support for hepatorenal syndrome.)

Fernández, J, Escorsell, A, Zabalza, M, Felipe, V, Navasa, M, Mas, A. “Adrenal insufficiency in patients with cirrhosis and septic shock: Effect of treatment with hydrocortisone on survival”. Hepatology. vol. 44. 2006. pp. 1288-95. (Adrenal insufficiency in patients with hepatorenal syndrome.)

Diagnosis

Arroyo, V, Ginès, P, Gerbes, AL, Dudley, FJ. “Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis”. Hepatology. vol. 23. 1996. pp. 164-76. (Original definition of hepatorenal syndrome by the Ascites Club.)

Salerno, F, Gerbes, A, Ginès, P, Wong, F, Arroyo, V. “Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis”. Gut. vol. 56. 2007. pp. 1310-8. (Revised definition of hepatorenal syndrome by the Ascites Club.)

Arroyo, V, Moreau, R, Jalan, R, Ginès, P. “EASL-CLIF Consortium CANONIC Study. Acute-on-chronic liver failure: A new syndrome that will re-classify cirrhosis”. J Hepatol.. vol. 62. 2015 Apr. pp. S131-43. (Revised definition of cirrhosis and how hepatorenal syndrome fits into an acute deterioration of liver function.)

Nadim, MK, Kellum, JA, Davenport, A, Wong, F. “ADQI Workgroup. Hepatorenal syndrome: the 8th International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group”. Crit Care.. vol. 16. 2012 Feb 9. pp. R23(Definition of acute kidney injury in patients with cirrhosis and how hepatorenal syndrome fits into an acute deterioration in renal function.)

Specific treatment

Sort, P, Navasa, M, Arroyo, V, Aldeguer, X, Planas, R, Ruiz del Arbol, L. “Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis”. N Engl J Med. vol. 341. 1999. pp. 403-40. (Study showing the importance of albumin in reducing incidence of hepatorenal syndrome.)

Moreau, R, Durand, F, Poynard, T, Duhamel, C, Cervoni, JP, Ichaï, P. “Terlipressin in patients with cirrhosis and type 1 hepatorenal syndrome: a retrospective multicenter study”. Gastroenterology. vol. 122. 2002. pp. 923-30. (Multicenter French retrospective study on the use of terlipressin in hepatorenal syndrome.)

Ortega, R, Ginès, P, Uriz, J, Cárdenas, A, Calahorra, B, De Las Heras, D. “Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: results of a prospective, nonrandomized study”. Hepatology. vol. 36. 2002. pp. 941-8. (Study showing importance of the combination of albumin infusions with terlipressin.)

Cade, R, Wagemaker, H, Vogel, S, Mars, D, Hood-Lewis, D, Privette, M. “Hepatorenal syndrome. Studies of the effect of vascular volume and intraperitoneal pressure on renal and hepatic function”. Am J Med. vol. 82. 1987 Mar. pp. 427-38. (Study reporting on the effect of ascites on renal function.)

Umgelter, A, Reindl, W, Franzen, M, Lenhardt, C, Huber, W, Schmid, RM. “Renal resistive index and renal function before and after paracentesis in patients with hepatorenal syndrome and tense ascites”. Intensive Care Med. vol. 35. 2009. pp. 152-6. (Study reporting reduced intra-renal pressure and improved perfusion following ascitic drainage.)

Thursz, MR, Forrest, EH, Ryder, S. “STOPAH investigators. Prednisolone or Pentoxifylline for Alcoholic Hepatitis”. N Engl J Med.. vol. 373. 2015 Jul 16. pp. 282-3. (Trial reporting no benefit for oxypentifylline and only short-term benefits for steroids in the treatment of acute alcoholic hepatitis.)

Disease monitoring, follow-up, and disposition

Alessandria, C, Ozdogan, O, Guevara, M, Restuccia, T, Jiménez, W, Arroyo, V. “MELD score and clinical type predict prognosis in hepatorenal syndrome: relevance to liver transplantation”. Hepatology.. vol. 41. 2005. pp. 1282-9. (Prognosis and MELD score.)

Barreto, R, Elia, C, Solà, E, Moreira, R, Ariza, X, Rodríguez, E, Graupera, I, Alfaro, I, Morales-Ruiz, M, Poch, E, Guevara, M, Fernández, J, Jiménez, W, Arroyo, V, Ginès, P. “Urinary neutrophil gelatinase-associated lipocalin predicts kidney outcome and death in patients with cirrhosis and bacterial infections”. J Hepatol.. vol. pii. 2014 Mar 5. pp. S0168-8278. (Importance of infection both as a precipitant but also risk of mortality.)

Fernández, J, Navasa, M, Planas, R, Montoliu, S, Monfort, D, Soriano, G. “Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis”. Gastroenterology. vol. 133. 2007. pp. 818-24. (Prophylactic antibiotics reduce risk of developing hepatorenal syndrome.)

Gonwa, TA, Morris, CA, Goldstein, RM. “Long-term survival and renal function following liver transplantation in patients with and without hepatorenal syndrome – experience in 300 patients”. Transplantation. vol. 51. 1991. pp. 428-30. (Study showing patients with hepatorenal failure have lower survival.)

Jeyarajah, DR, Gonwa, TA, McBride, M. “Hepatorenal syndrome: combined liver kidney transplants versus isolated liver transplant”. Transplantation. vol. 64. 1997. pp. 1760-5. (Discussion of whether patients with hepatorenal syndrome require combined liver and kidney transplantation.)

Restuccia, T, Ortega, R, Guevara, M, Ginès, P, Alessandria, C, Ozdogan, O, Navasa, M, Rimola, A, Garcia-Valdecasas, JC, Arroyo, V, Rodés, J. “Effects of treatment of hepatorenal syndrome before transplantation on posttransplantation outcome. A case-control study”. J Hepatol.. vol. 40. 2004. pp. 140-5.

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