HEPATORENAL SYNDROME (HRS)

Hepatorenal syndrome (HRS) is common, with a reported incidence of 10% among hospitalized patients with cirrhosis and ascites.⁽¹⁾ In decompensated cirrhotics, the probability of developing HRS with ascites ranges between 8-20% per year and increases to 40% at 5 years. An estimated 35-40% of patients with end-stage liver disease (ESLD) and ascites will develop HRS.⁽²⁾

According to the study conducted in Pakistan, 15.09% of patients with cirrhosis were found to have HRS.⁽³⁾ Another study found the frequency of hepatorenal syndrome was 19.9% in liver cirrhotic patients.⁽⁴⁾

The hallmark of HRS is renal vasoconstriction, although the pathogenesis is not fully understood. Multiple mechanisms are probably involved and include interplay between disturbances in systemic hemodynamics, activation of vasoconstrictor systems, and a reduction in activity of the vasodilator systems. The hemodynamic pattern of patients with HRS is characterized by increased cardiac output, low arterial pressure, and reduced systemic vascular resistance. Renal vasoconstriction occurs in the absence of reduced cardiac output and blood volume, which is in contrast to most clinical conditions associated with renal hypoperfusion.^(2,6,7)

Although the pattern of increased renal vascular resistance and decreased peripheral resistance is characteristic of HRS, it also occurs in other conditions, such as anaphylaxis and sepsis. Doppler studies of the brachial, middle cerebral, and femoral arteries suggest that extrarenal resistance is increased in patients with HRS, while the splanchnic circulation is responsible for arterial vasodilatation and reduced total systemic vascular resistance.

The RAAS and SNS are the predominant systems responsible for renal vasoconstriction. The activity of both systems is increased in patients with cirrhosis and ascites, and this effect is magnified in HRS. In contrast, an inverse relationship exists between the activity of these 2 systems and renal plasma flow (RPF) and the glomerular filtration rate (GFR). Endothelin is another renal vasoconstrictor present in increased concentration in HRS, although its role in the pathogenesis of this syndrome has yet to be identified.⁽⁸⁾ Adenosine is well known for its vasodilator properties, although it acts as a vasoconstrictor in the lungs and kidneys. Elevated levels of adenosine are more common in patients with heightened activity of the RAAS and may work synergistically with angiotensin II to produce renal vasoconstriction in HRS. This effect has also been described with the powerful renal vasoconstrictor, leukotriene E4.

The vasoconstricting effect of these various systems is antagonized by local renal vasodilatory factors, the most important of which are the PGs. Perhaps the strongest evidence supporting their role in renal perfusion is the marked decrease in RPF and the GFR when nonsteroidals, medications known to sharply reduce PG levels, are administered.

Nitric oxide (NO) is another vasodilator believed to play an important role in renal perfusion. Preliminary studies, predominantly from animal experiments, demonstrate that NO production is increased in people with cirrhosis, although NO inhibition does not result in renal vasoconstriction due to a compensatory increase in PG synthesis. However, when both NO and PG production are inhibited, marked renal vasoconstriction develops.

These findings demonstrate that renal vasodilators play a critical role in maintaining renal perfusion, particularly in the presence of overactivity of renal vasoconstrictors. However, whether vasoconstrictor activity becomes the predominant system in HRS and whether reduction in activity of the vasodilatory system contributes to this have yet to be proven.

Various theories have been proposed to explain the development of HRS in cirrhosis. The 2 main theories are the arterial vasodilation theory and the hepatorenal reflex theory. The former theory not only describes sodium and water retention in cirrhosis, but also may be the most rational hypothesis for the development of HRS. Splanchnic arteriolar vasodilatation in patients with compensated cirrhosis and portal hypertension may be mediated by several factors, the most important of which is probably NO. In the early phases of portal hypertension and compensated cirrhosis, this underfilling of the arterial bed causes a decrease in the effective arterial blood volume and results in homeostatic/reflex activation of the endogenous vasoconstrictor systems.

Activation of the RAAS and SNS occurs early with antidiuretic hormone secretion, a later event when a more marked derangement in circulatory function is present. This results in vasoconstriction not only of the renal vessels, but also in vascular beds of the brain, muscle, spleen, and extremities. The splanchnic circulation is resistant to these effects because of the continuous production of local vasodilators such as NO.

In the early phases of portal hypertension, renal perfusion is maintained within normal or near-normal limits as the vasodilatory systems antagonize the renal effects of the vasoconstrictor systems. However, as liver disease progresses in severity, a critical level of vascular underfilling is achieved. Renal vasodilatory systems are unable to counteract the maximal activation of the endogenous vasoconstrictors and/or intrarenal vasoconstrictors, which leads to uncontrolled renal vasoconstriction. Support for this hypothesis is provided by studies in which the administration of splanchnic vasoconstrictors in combination with volume expanders results in improvement in arterial pressure, RPF, and the GFR.

The alternative theory proposes that renal vasoconstriction in HRS is unrelated to systemic hemodynamics but is due to either a deficiency in the synthesis of a vasodilatory factor or a hepatorenal reflex that leads to renal vasoconstriction. Evidence points to the vasodilation theory as a more tangible explanation for the development of HRS.

In cirrhosis, the natural history of hepatorenal disorders starts with a pre-ascitic stage and is followed by the development of ascites; hepatorenal syndrome (HRS) begins with compensated renal sodium retention, or preascites. In pre-ascites, the renal sodium retaining tendency leads to ‘overfilling’ of total blood volume, with increased glomerular filtration rates (GFR), overcoming the renal sodium retaining tendency possibly due to renal accumulation of angiotensin II. As peripheral vasodilatation increases, the vascular capacity (in effect the arterial blood volume) becomes inadequately filled, GFR falls, compensatory vasoconstrictors rise, and the resulting renal sodium retention results in diuretic-responsive ascites formation. Increasing proximal reabsorption of sodium results in ascites refractory to diuretic therapy. Repeated abdominal paracentesis will not prevent insidious progression to HRS type II, nor to the precipitation of HRS type I. In contrast, liver transplantation, or transjugular intrahepatic hepatoportal stent shunt (TIPS) in refractory ascites, may prevent the onset of, or reverse, HRS. However, recent non-controlled studies indicate exciting possibilities of medical therapy reversing HRS.

Most individuals with cirrhosis who develop hepatorenal syndrome (HRS) have nonspecific symptoms, such as fatigue, malaise, or dysgeusia. Development of HRS is usually noticed when patients observe decreased urine output and when blood test results show a decline in renal function.

Physical Examination

The following list of physical findings is not all-inclusive, and these findings are not present in all patients with chronic liver disease.

The hands may exhibit the following:

• Palmar erythema
• Leuconychia (white nails)
• Muscle wasting
• Asterixis (flapping tremors)
• Clubbing

Head, ears, nose, throat examination may reveal the following:

• Scleral icterus
• Spider nevi (usually confined to the drainage area of the superior vena cava)
• Fetor hepaticus
• Xanthelasma

Chest findings may include gynecomastia.

Abdominal findings may include the following:

• Caput medusae
• Hepatosplenomegaly
• Ascites
• Paraumbilical hernia
• Bruits

The genitalia may show loss of pubic hair/secondary sexual characteristics in men and/or atrophic testes.

The extremities may exhibit muscle wasting, peripheral edema, and/or clubbing.

Guidelines by the the British Society of Gastroenterology, the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD) recommend the use of abdominal ultrasonography, diagnostic paracentesis, and ascitic fluid cultures in the workup of patients with suspected hepatorenal syndrome (HRS).⁽¹⁰⁾

The diagnosis of HRS is one of exclusion⁽²⁾ and depends mainly on serum creatinine level, as no specific tests establish the diagnosis of HRS. Although serum creatinine level is a poor marker of renal function in patients with cirrhosis, no other validated and reliable noninvasive markers exist for monitoring renal function in these patients.⁽¹¹⁾

Diagnosis of HRS is based on the presence of a reduced glomerular filtration rate (GFR) in the absence of other causes of renal failure in patients with chronic liver disease. The following criteria, as proposed by the International Ascites Club in 1996, help diagnose HRS:

Major criteria include the following (All major criteria are required to diagnose HRS.):

• Low GFR, indicated by a serum creatinine level higher than 1.5 mg/dL or 24-hour creatinine clearance lower than 40 mL/min
• Absence of shock, ongoing bacterial infection and fluid losses, and current treatment with nephrotoxic medications
• No sustained improvement in renal function (decrease in serum creatinine to <1.5 mg/dL or increase in creatinine clearance to >40 mL/min) after diuretic withdrawal and expansion of plasma volume with 1.5 L of plasma expander
• Proteinuria less than 500 mg/d and no ultrasonographic evidence of obstructive uropathy or intrinsic parenchymal disease

Additional criteria include the following (Additional criteria are not necessary for the diagnosis but provide supportive evidence.):

• Urine volume less than 500 mL/d
• Urine sodium level less than 10 mEq/L
• Urine osmolality greater than plasma osmolality
• Urine red blood cell count of less than 50 per high-power field
• Serum sodium concentration less than 130 mEq/L

Complete blood cell count with differential

This may indicate the presence of underlying infection such as spontaneous bacterial peritonitis (SBP) if leukocytosis or bands are present, a condition known to present with reversible impairment in renal function. However, many patients with SBP do not have a serum leukocytosis. Because shock from gastrointestinal bleeding may cause acute tubular necrosis, checking the hematocrit level and platelet count is helpful.

Serum electrolytes and renal function

These are essential investigations to obtain data for diagnosing HRS.

Liver function tests with prothrombin time

Although the degree of liver failure does not correlate with the development of HRS, these investigations are necessary to assess patients’ Child-Pugh scores.⁽¹²⁾

Alpha-fetoprotein levels

Although few studies demonstrate a relationship between hepatoma and development of HRS, this test should be performed when patients with cirrhosis decompensate.

Blood cultures

Infections place patients at risk for decompensation, and looking for bacteremia, particularly if no precipitant is identified, is prudent. Occasionally, patients may present with culture-negative SBP (20%), and performing blood cultures is wise under these circumstances.

Cryoglobulins

Measuring these may be helpful in patients with hepatitis B and/or C, who can develop renal failure from cryoglobulinemia. Treatment and eradication of the underlying disease, if performed early in the course of the disease process, can reverse renal failure.

Urinalysis and urine electrolytes

Significant proteinuria or hematuria may provide a clue that an organic cause may be responsible for patients’ renal failure. Similarly, urinary tract infection may be detected, and this usually is readily treatable.

Measuring urine sodium and creatinine levels is used as a screening test to assess the degree of sodium retention. Patients with low urine sodium excretions (<5 mEq/L) are at a greater risk of developing HRS. Urine sodium and creatinine levels are also used to calculate the fractional excretion of sodium, which is helpful in differentiating HRS and prerenal azotemia from intrinsic renal disease.

Imaging studies

Abdominal ultrasonography: This is a useful noninvasive test to help exclude hydronephrosis and intrinsic renal disease, which may be characterized by bilateral small kidneys. When combined with Doppler studies, valuable information may be provided on renal vascular flow.

Echocardiography: This study may be helpful for evaluating right ventricular preload, ventricular filling pressures, and cardiac performance in response to fluid replacement.

Procedures

Paracentesis: Spontaneous bacterial peritonitis (SBP) can present with reversible impairment of renal function, and performing diagnostic paracentesis is strongly recommended in all patients. The role of therapeutic paracentesis/large-volume paracentesis (LVP) in hepatorenal syndrome (HRS) is more controversial in the absence of tense ascites. Concerns exist that further volume depletion may aggravate renal function, due to third spacing in a patient with a known underlying systemic circulatory disturbance. Albumin replacement is recommended in these patients when LVP is performed. Ten grams of albumin is administered for every liter of ascites drained, to a maximum of 50 g of albumin.

Bladder catheterization: Catheterization may be helpful to exclude urinary retention as a potential cause of acute renal failure in these patients. However, long-term indwelling urinary catheters are not recommended (because of the risk of acquiring urinary tract infection) unless patients are incontinent and are at risk of developing skin breakdown or unless strict recording of urinary output is mandatory.

Central line and Swan-Ganz line placement: Measurement of central venous pressure and pulmonary capillary wedge pressure may be helpful in patients who do not respond to an adequate trial of plasma expansion. Hemodynamic findings in HRS include increased cardiac output, reduced mean arterial pressure (range of 60-80 mm Hg), and reduced total systemic vascular resistance. These findings, although characteristic of patients with cirrhosis, can also be observed in other conditions, such as anaphylaxis and sepsis. Invasive hemodynamic monitoring, aside from the risk of procedure-related complications, also has limitations for assessing volume status in patients.

Histologic findings: The kidneys are histologically normal because HRS is a functional disorder.

Patients with HRS should be evaluated for liver transplantation, at a liver transplant center if possible. This may be more applicable for patients with type 2 HRS, who have a longer survival time, as opposed to patients with type 1 HRS, whose survival is extremely short and who may require alternative therapeutic methods (e.g. TIPS, vasoconstrictors) as a bridge to transplantation.

Reasons for transferring patients to a liver transplant center include the following:

• Assessment of candidacy for liver transplantation
• Lack of facilities for performing dialysis at local/referring hospital
• Entrance into study/treatment protocol for HRS at referral center

If patients are not candidates for liver transplantation, they have a poor prognosis and outpatient care will only be palliative in nature.

The ideal treatment of HRS is liver transplantation; however, because of the long waiting lists in the majority of transplant centers, most patients die before transplantation. An urgent need exists for effective alternative therapies to increase survival chances for patients with HRS until transplantation can be performed. This is reinforced by a study that reported that patients successfully treated medically for HRS before liver transplantation had posttransplantation outcome and survival comparable to that of patients who underwent transplantation without being treated for HRS. Interventions that have shown some promise are drugs with vasoconstrictor effects in the splanchnic circulation and use of the transjugular intrahepatic portosystemic shunt (TIPS).

Pharmacotherapy

Numerous medications have been used to treat HRS with little, if any, effect. The pharmacologic approach has shifted, however, with greater attention now focused on the role of vasoconstrictors as opposed to the initial predominant use of vasodilators. The rationale for this change is that the initial event in HRS is vasodilatation of the splanchnic circulation and the use of a vasoconstrictor may thus prevent homeostatic activation of endogenous vasoconstrictors.

Dopamine: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.

Misoprostol: 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.

Renal vasoconstrictor antagonists: Saralasin, an antagonist of angiotensin II receptors, was used first in 1979 in an attempt to reverse renal vasoconstriction. Because this drug inhibited the homeostatic response to hypotension commonly observed in patients with cirrhosis, it led to worsening hypotension and deterioration in renal function. Poor results were also observed with phentolamine, an alpha-adrenergic antagonist, highlighting the importance of the SNS in maintaining renal hemodynamics in patients with HRS.

Systemic vasoconstrictors: These medications have shown promise for the treatment of HRS; they include vasopressin analogues (ornipressin, terlipressin), somatostatin analogues (octreotide), and alpha-adrenergic agonists (midodrine).

Dietary considerations

Institute a low-salt (2 g) diet. Do not restrict protein intake unless patient has severe encephalopathy.

Surgical Care

Peritoneovenous shunting: Peritoneovenous shunting (PVS) seems attractive in theory because it leads to plasma volume expansion and improvement of circulatory function. However, very few studies evaluating the role of PVS in this area have been performed because PVS has been used predominantly for treating refractory ascites.
This may be important for patients with type 2 hepatorenal syndrome (HRS), who often develop refractory ascites, are not candidates for orthotopic liver transplantation, and do not tolerate frequent LVPs.

PVS has no role in type 1 HRS.

Surgical shunts: No description on the treatment of HRS is complete without a brief review of the role of portacaval shunts, particularly with the introduction of TIPS.

Despite the theoretical benefit of improving portal hypertension and thus HRS with a portosystemic shunt, only a few scattered case reports have shown some benefit.

Currently, no indication exists for portacaval shunts in this setting.

Liver transplantation: Liver transplantation is the ideal treatment of HRS,⁽²⁾ but it is limited by the availability of donors.
Long-term survival rates are excellent, with the survival rate at 3 years approaching approximately 60%. This is only slightly lower than the 70-80% survival rate of transplant recipients without HRS and is markedly better than the survival rate of patients with HRS not receiving transplants, which is virtually 0% at 3 years.
Medication Summary

The pharmacological approach to the treatment of HRS continues to evolve, with several possible effective treatments. However, readers should be aware that none of these medications (including the addition of albumin) has been validated in randomized controlled trials. A brief review of only the most promising (but yet unproven) medications will be described.

Vasopressin analogues

Improve circulatory dysfunction secondary to splanchnic vasodilatation. Also improve RPF, the GFR, and urine output.

Ornipressin (POR-8): Synthetic vasopressin analogue with a short half-life that requires continuous IV administration. V1 vasopressin receptors are abundantly expressed in the mesenteric arteries as compared with other vascular areas. Has been used in conjunction with albumin to treat HRS but is associated with ischemic complications.

Terlipressin: Nonselective V1 vasopressin agonist that has similar vasoconstrictor potency to ornipressin but a lower incidence of ischemic complications. Inactive by itself but is transformed into a biologically active form (lysine-vasopressin) by the action of tissue endopeptidases and exopeptidases. Due to its longer half-life (2-10 h) compared to ornipressin, may be administered as a bolus. Has lower incidence of adverse ischemic effects, with < 5% of cases reported in a series of 1258 patients receiving it for variceal bleeding.

Sympathomimetic agents

Improve renal artery perfusion.

Dopamine: Stimulates both adrenergic and dopaminergic receptors. Hemodynamic effect is dependent on dose. Lower doses predominantly stimulate dopaminergic receptors, which, in turn, produce renal and mesenteric vasodilation. Cardiac stimulation and renal vasodilation are produced by higher doses. Described for its historical interest because it has no role in monotherapy for HRS. However, reversal of HRS has been described when used at low doses in conjunction with ornipressin.

Somatostatin analogs

Improvement in splanchnic circulation may improve renal hemodynamics.

Octreotide: Synthetic derivative of somatostatin. Potent physiological inhibitor of several gastrointestinal functions, one of which is a reduction in intestinal blood flow by splanchnic vasoconstriction.

Antioxidants

Experimental evidence demonstrates improvement of renal function in acute cholestasis and renal failure.

N-acetylcysteine: Traditionally used to treat acetaminophen overdose. Replenishes low hepatic glutathione stores to prevent synthesis of toxic epoxide intermediates. Does not have a role in the treatment of non–acetaminophen-related liver failure. Exact mechanism of action in HRS remains unclear.

Antibiotics

Only indicated in the treatment of HRS if renal dysfunction is precipitated by an infection. Prophylactic antibiotics may play a role in preventing spontaneous bacterial peritonitis (SBP), which, in turn, is also a risk factor for the development of type 1 HRS in patients with type 2 HRS. The efficacy and safety of prophylactic antibiotics remains to be established because of reports of emergent resistant bacteria. May play an important role in selected patients, such as those awaiting liver transplantation, although the duration (long-term vs cyclic) remains to be determined.

Cefotaxime: Because the most common cause of type 1 HRS is SBP, IV cefotaxime is the DOC.

Ciprofloxacin: Fluoroquinolone with activity against pseudomonads, streptococci, MRSA, Staphylococcus epidermidis, and most gram-negative organisms, but no activity against anaerobes. Inhibits bacterial DNA synthesis and, consequently, growth.

Norfloxacin: Fluoroquinolone with activity against pseudomonads, streptococci, MRSA, S epidermidis, and most gram-negative organisms, but no activity against anaerobes. Inhibits bacterial DNA synthesis and, consequently, growth.

Sulfamethoxazole and trimethoprim: Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid.

Plasma volume expanders

Indicated for the correction of abnormal hemodynamic parameters.
Albumin: Useful for plasma volume expansion and maintenance of cardiac output.

The goal of medical therapy or TIPS in patients with hepatorenal syndrome is reversal of the acute kidney injury. In addition, when patients are treated with norepinephrine, terlipressin, or midodrine plus octreotide, an immediate goal of therapy is to raise the mean arterial pressure by approximately 10 to 15 mmHg to a level of >82 mmHg.

To review EASL guidelines on EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis

http://www.easl.eu/medias/cpg/issue4/English-report.pdf

Nephrologist

The importance of a nephrologist in the multidisciplinary management of patients with hepatorenal syndrome (HRS) cannot be overemphasized. Nephrologists play a critical role in assisting hepatologists and liver transplant surgeons in the management of these critically ill patients.

No controlled studies evaluating the role of dialysis in this setting have been performed, but most centers dialyze patients with HRS who are on a waiting list. Continuous arteriovenous or venovenous hemofiltration has also been used, but the efficacy of these 2 measures has yet to be determined.

Interventional radiologist

The use of TIPS in the treatment of HRS has yet to be established. Due to its ability to reduce portal hypertension in patients with variceal bleeding and refractory ascites, its role in HRS initially seemed logical, particularly in view of isolated reports of renal function improvement following surgical shunts in the 1970s. However, TIPS quickly fell out of favor because of high morbidity and mortality rates.

Patients who have cirrhosis with ascites must be informed that they are at risk of developing HRS and they must be informed about the dismal prognosis this carries in the absence of liver transplantation. They should be very cautious when new medications are prescribed by physicians not familiar with their care and must avoid known nephrotoxic agents such as nonsteroidals and aminoglycosides. Any deterioration in their clinical condition should result in a prompt call to their physician to determine if they have developed HRS.

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