Ascites is one of the main complications of cirrhosis and a major cause of hospitalization in cirrhotic patients. The occurrence of fluid retention in cirrhotic patients is an important marker in their disease history. 2006 study by Planas et al. showed that patients with ascites had a 1-year mortality rate of 15% and a 5-year mortality rate of 44%, so preventing and controlling the occurrence and development of ascites is the key to improving the prognosis of cirrhotic patients.
Current treatment of ascites
Current means of ascites treatment are inadequate. The 2012 Update of the US Guidelines for Adult Cirrhosis with Ascites recommends third-line therapy for patients with ascites, but a closer look at these recommendations shows that most of them are “discontinued” and that the only drugs recommended for the treatment of ascites are spironolactone and furosemide, in combination, once daily. The latest European guideline for the treatment of ascites remains the 2010 edition of the Clinical Practice Guidelines for Cirrhotic Ascites, Spontaneous Peritonitis and Hepatorenal Syndrome. The European guidelines devote space to the debate on mono- versus co-administration, which is judged to be ineffective in the treatment of ascites by a weight loss of less than 2 kg per week. Although furosemide is a strong diuretic, spironolactone is more effective in patients with ascites because the main cause of ascites is increased secretion of aldosterone and the use of aldosterone receptor antagonists is a reasonable choice. At the same time, European guidelines consider that the effect of aldosterone is very slow, so the dose of spironolactone, an aldosterone antagonist, should be adjusted every 7 days. In China, patients with ascites like those encountered in the author’s hospital are often not new and have more opportunities for combined medications.
The dose of the drug is adjusted mainly according to the degree of weight loss of the patient. The dose of diuretics should not be increased arbitrarily because the diuretics currently used can lead to a series of complications such as renal failure, hepatic encephalopathy, electrolyte disturbances (low potassium, high potassium, low sodium), gynecomastia, muscle cramps, etc. Moreover, the current treatment is basically helpless for ascites with hyponatremia (close to 50% incidence), which only makes hyponatremia worse.
Mechanism of ascites
Ascites in patients with cirrhosis is often combined with other comorbidities such as hyponatremia and renal impairment and is interrelated and develops continuously. These complications have a common pathological basis: cirrhosis → portal hypertension → dilated visceral arteries → insufficient effective arterial volume → activation of vasoconstrictor systems including the renin-angiotensin-aldosterone system (RASS), sympathetic nervous system, and vasopressin (antidiuretic hormone system). Activation of these systems eventually leads to ascites, hyponatremia, and hepatorenal syndrome. Florence Wong, a professor of medicine at the University of Hong Kong, has described the effects of the activation of these systems on the liver and kidney. Florence Wong has given a good diagrammatic explanation of the natural course of cirrhosis. Two important events in the progression of cirrhosis are the onset of ascites, which marks the patient’s transition from compensated to decompensated, and hyponatremia. Hyponatremia in cirrhosis is an independent predictor of poor prognosis, and the degree of hyponatremia occurs and worsens with the progression of cirrhosis. Patients with intractable ascites are often associated with hyponatremia, while most patients with hepatorenal syndrome already have low blood sodium levels.
Vasopressin plays an important role in the development of this pathology. Vasopressin, also known as arginine vasopressin (AVP) or antidiuretic hormone (ADH), is the only hormone that primarily affects water metabolism. In liver cirrhosis, vasopressin secretion increases; there are three types of receptors for its action, and type II receptors distributed in the renal collecting duct are mainly responsible for water metabolism. When vasopressin binds to V2 receptors on the basolateral membrane of renal collecting duct cells, it activates aqueous channel protein (APQ2) to increase the reabsorption of water, especially free water, which can lead to increased blood volume and dilutional hyponatremia. Although vasopressin primarily regulates water metabolism, it is not without effect on sodium. When vasopressin binds to the collecting duct V2 receptor, it also activates epidermal sodium channels and promotes sodium reabsorption.
Since vasopressin has an important role in the formation of ascites in cirrhosis, it should be a reasonable choice to select vasopressin receptor antagonists for the treatment of ascites. Currently the only such product in China is tolvaptan, and the effects of tolvaptan on cirrhotic ascites are discussed in detail below.
New vasopressin receptor antagonist tolvaptan
Mechanism of action and advantages
The mechanism of action of tolvaptan is completely different from that of currently used diuretics. Current diuretics depend on sodium excretion and are also called sodium excretion diuretics, whereas tolvaptan does not depend on electrolyte excretion and is also called a drainage diuretic, so tolvaptan does not cause electrolyte disturbances. The sodium-draining effect of tolvaptan is correlated with baseline blood sodium values; when blood sodium is below 132 mEq/L, sodium drainage is not significant; whereas when basal blood sodium is above 132 mEq/L, sodium drainage is significant.
Collateral diuretics such as furosemide require organic anion transport proteins (OAT-1, OAT-4) to be secreted from the vascular surface to the luminal surface in the proximal tubule and then transported with the filtrate to the thick segment of the ascending branch of Henry’s collaterals to act. V2 receptors are mainly distributed in the vascular surface of the renal collecting duct, so tolvaptan is less affected by the factors and can still work well in hypoproteinemia and poor renal function.
Tolvaptan also has a great advantage at the microcirculatory level. Tolvaptan excretes more free water, which increases the plasma osmolality after the water is excreted, while the hydrostatic pressure inside the blood vessels decreases. The combined effect of the two can move the extravascular solution to the intravascular level, which can facilitate both the decongestion of organs, while maintaining intravascular volume and blood flow without activating neurohormones. In patients with low blood pressure (systolic <105 mmHg, >90 mmHg), tolvaptan remains effective and does not lower blood pressure.
Key clinical evidence for tolvaptan in cirrhotic ascites
Phase III data on tolvaptan cirrhosis showed that the addition of tolvaptan 7.5 mg/d in patients with cirrhotic ascites who were not well treated with conventional diuretics (aldosterone + furosemide) resulted in further weight loss, decreased ascites volume, and improved edema. Basal blood sodium values were normal in all patients in this study [(135.7±4.1) mEq/L in the conventional treatment group and (135.3±4.5) mEq/L in the tolvaptan group], and blood sodium decreased significantly in the conventional treatment group over the course of treatment (P=0,006), suggesting that current conventional treatment triggers and exacerbates hyponatremia, which is an independent predictor of poor prognosis in cirrhosis. Blood sodium was significantly higher in the tolvaptan group compared to baseline (P=0.0002), but no hyponatremia occurred, suggesting that the addition of tolvaptan to cirrhotic ascites prevents the development of hyponatremia. In cirrhotic ascites where hyponatremia has already occurred, the advantages of tolvaptan are even more pronounced, not only in effectively correcting hyponatremia, but also in reducing hyponatremia-induced cerebral edema, improving cognition, and improving quality of life.
Clinical practice in the treatment of cirrhotic ascites with tolvaptan is currently up to 6 months. This study showed that after 6 months a lower weight than before the drug was maintained, liver and kidney function and electrolytes were not affected, and no hyponatremia occurred. Bioelectrical impedance analyzer measurements demonstrated that the weight loss was primarily extracellular water.
Observational studies with tolvaptan have shown that tolvaptan remains highly effective in patients with cirrhotic ascites with hepatocellular carcinoma and hepatorenal syndrome; tolvaptan treatment of hepatic ascites significantly reduces additional treatment events such as laparotomy and hospitalization compared to laparotomy treatment (p=0.01).
Safety data
The clinical safety profile of tolvaptan is good, with thirst and urinary frequency being the main adverse effects and the remaining adverse effects not significantly different compared to placebo. The safety of tolvaptan in patients with cirrhosis was of concern because of the risk of liver injury shown in clinical trials in polycystic kidneys (doses of 60-120 mg/d for 3 years). However, recent analyses have shown that tolvaptan liver injury is disease-specific and currently occurs only in patients with polycystic kidney; other patients, including those with cirrhosis, heart failure, and hyponatremia, have no propensity to develop liver injury with tolvaptan.
Summary
Prevention and control of the development and progression of ascites is key to improving the prognosis of patients with cirrhosis, and drugs play a major central role in the treatment of ascites. Current US and European guidelines recommend the use of drugs for the treatment of ascites, mainly aldosterone receptor antagonists such as spironolactone and collaterals diuretics such as furosemide, with spironolactone taking precedence over furosemide in the treatment of ascites.
The new vasopressin receptor antagonist, tolvaptan, is a new drainage diuretic that further reduces the amount of ascites and improves the associated edema in patients with cirrhosis and remains effective in patients with low plasma albumin, concomitant hepatorenal syndrome and hepatocellular carcinoma. In patients with hyponatremia, tolvaptan is effective in correcting blood sodium and reducing cerebral edema due to hyponatremia in cirrhosis, which in turn improves cognition and quality of life; in patients with normal blood sodium, tolvaptan does not cause hypernatremia. Compared with laparotomy, tolvaptan reduces the incidence of events; compared with conventional diuretics, tolvaptan does not cause electrolyte disturbances, renal impairment, or neurohormonal activation. In conclusion, on the basis of current data, tolvaptan is a new effective and safe treatment option for patients with ascites.