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Hyponatremia in cirrhosis and end-stage liver disease: treatment with the vasopressin V₂-receptor antagonist tolvaptan.

Gaglio P, Marfo K, Chiodo J - Dig. Dis. Sci. (2012)

Bottom Line: Hyponatremia is common in patients with cirrhosis and portal hypertension, and is characterized by excessive renal retention of water relative to sodium due to reduced solute-free water clearance.The primary cause is increased release of arginine vasopressin.Hyponatremia is also associated with numerous complications in liver disease patients, including severe ascites, hepatic encephalopathy, infectious complications, renal impairment, increased severity of liver disease in cirrhosis, and increased hospital stay and neurologic/infectious complications posttransplant.

View Article: PubMed Central - PubMed

Affiliation: Division of Hepatology, Montefiore Medical Center and Albert Einstein College of Medicine, 111 East 210th Street, Rosenthal 2 Red Zone, Bronx, NY 10467, USA. eric.justice@bioscicom.net

ABSTRACT
Hyponatremia is common in patients with cirrhosis and portal hypertension, and is characterized by excessive renal retention of water relative to sodium due to reduced solute-free water clearance. The primary cause is increased release of arginine vasopressin. Hyponatremia is associated with increased mortality in cirrhotic patients, those with end-stage liver disease (ESLD) on transplant waiting lists, and, in some studies, posttransplantation patients. Clinical evidence suggests that adding serum sodium to model for ESLD (MELD) scoring identifies patients in greatest need of liver transplantation by improving waiting list mortality prediction. Hyponatremia is also associated with numerous complications in liver disease patients, including severe ascites, hepatic encephalopathy, infectious complications, renal impairment, increased severity of liver disease in cirrhosis, and increased hospital stay and neurologic/infectious complications posttransplant. Vasopressin receptor antagonists, which act to increase free water excretion (aquaresis) and thereby increase serum sodium concentration, have been evaluated in patients with hypervolemic hyponatremia (including cirrhosis and heart failure) and euvolemic hyponatremia (SIADH). Tolvaptan, a selective vasopressin V(2)-receptor antagonist, is the only oral agent in this class approved for raising sodium levels in hypervolemic and euvolemic hyponatremia. The SALT trials showed that tolvaptan treatment rapidly and effectively resolved hyponatremia in these settings, including cirrhosis, and it has been shown that this agent can be safely and effectively used in long-term treatment. Fluid restriction should be avoided during the first 24 h of treatment to prevent overly rapid correction of hyponatremia, and tolvaptan should not be used in patients who cannot sense/respond to thirst, anuric patients, hypovolemic patients, and/or those requiring urgent intervention to raise serum sodium acutely.

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Observed serum sodium concentration throughout the study treatment period (days 1–30) and 7 days after stopping (day 37) in patients receiving tolvaptan or placebo. Error bars are ±SE (standard error of the mean). *P < 0.001, tolvaptan versus placebo; †P < 0.01, tolvaptan versus placebo; ‡P < 0.05, tolvaptan versus placebo [49]
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Fig5: Observed serum sodium concentration throughout the study treatment period (days 1–30) and 7 days after stopping (day 37) in patients receiving tolvaptan or placebo. Error bars are ±SE (standard error of the mean). *P < 0.001, tolvaptan versus placebo; †P < 0.01, tolvaptan versus placebo; ‡P < 0.05, tolvaptan versus placebo [49]

Mentions: The SALT trials included 63 tolvaptan-treated patients and 57 placebo patients with cirrhosis [49]. The mean age for these patients (52 and 55 years, respectively) was younger than that for patients with heart failure or SIADH/other conditions (67 and 63, respectively) (data on file, Otsuka America Pharmaceutical, Inc., Rockville, MD). At baseline, 44 % had mild hyponatremia (serum sodium 130–134 mEq/L), 56 % had marked hyponatremia (serum sodium < 130 mEq/L), 85 % had cirrhosis due to alcohol and/or hepatitis B/C, and 80 % were Child-Pugh class B/C. Changes in average daily serum sodium AUC for the SALT patients with cirrhosis were 3.5 mEq/L for tolvaptan versus 0.3 mEq/L for placebo at day 4 and 4.2 mEq/L versus 1.2 mEq/L at day 30 (both P < 0.0001). Patients receiving tolvaptan had significantly greater increases in serum sodium (P < 0.05) as early as 8 h after the first dose and at days 2, 3, 4, 11, 18, and 25 (Fig. 5). The proportion of patients with normalized serum sodium was significantly greater with tolvaptan at day 4 (41 vs. 11 %, P = 0.0002) and numerically greater at day 30 (33 vs. 19 %, P = 0.08). Mean mental component summary scores of the Medical Outcomes Study 12-item Short Form General Health Survey (SF-12) improved from baseline to day 30 in the tolvaptan group but not the placebo group (4.68 vs. 0.08, P = 0.02). Before the study began, 98 % of the tolvaptan group were taking diuretics (with the majority on a moderate dose: spironolactone < 200 mg/day or furosemide < 80 mg/day); only 6 % discontinued diuretic use during the trials. Diuretic use did not appear to have an impact on treatment with tolvaptan [49]; however, the data from this limited analysis need to be confirmed in larger clinical trials.Fig. 5


Hyponatremia in cirrhosis and end-stage liver disease: treatment with the vasopressin V₂-receptor antagonist tolvaptan.

Gaglio P, Marfo K, Chiodo J - Dig. Dis. Sci. (2012)

Observed serum sodium concentration throughout the study treatment period (days 1–30) and 7 days after stopping (day 37) in patients receiving tolvaptan or placebo. Error bars are ±SE (standard error of the mean). *P < 0.001, tolvaptan versus placebo; †P < 0.01, tolvaptan versus placebo; ‡P < 0.05, tolvaptan versus placebo [49]
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3472061&req=5

Fig5: Observed serum sodium concentration throughout the study treatment period (days 1–30) and 7 days after stopping (day 37) in patients receiving tolvaptan or placebo. Error bars are ±SE (standard error of the mean). *P < 0.001, tolvaptan versus placebo; †P < 0.01, tolvaptan versus placebo; ‡P < 0.05, tolvaptan versus placebo [49]
Mentions: The SALT trials included 63 tolvaptan-treated patients and 57 placebo patients with cirrhosis [49]. The mean age for these patients (52 and 55 years, respectively) was younger than that for patients with heart failure or SIADH/other conditions (67 and 63, respectively) (data on file, Otsuka America Pharmaceutical, Inc., Rockville, MD). At baseline, 44 % had mild hyponatremia (serum sodium 130–134 mEq/L), 56 % had marked hyponatremia (serum sodium < 130 mEq/L), 85 % had cirrhosis due to alcohol and/or hepatitis B/C, and 80 % were Child-Pugh class B/C. Changes in average daily serum sodium AUC for the SALT patients with cirrhosis were 3.5 mEq/L for tolvaptan versus 0.3 mEq/L for placebo at day 4 and 4.2 mEq/L versus 1.2 mEq/L at day 30 (both P < 0.0001). Patients receiving tolvaptan had significantly greater increases in serum sodium (P < 0.05) as early as 8 h after the first dose and at days 2, 3, 4, 11, 18, and 25 (Fig. 5). The proportion of patients with normalized serum sodium was significantly greater with tolvaptan at day 4 (41 vs. 11 %, P = 0.0002) and numerically greater at day 30 (33 vs. 19 %, P = 0.08). Mean mental component summary scores of the Medical Outcomes Study 12-item Short Form General Health Survey (SF-12) improved from baseline to day 30 in the tolvaptan group but not the placebo group (4.68 vs. 0.08, P = 0.02). Before the study began, 98 % of the tolvaptan group were taking diuretics (with the majority on a moderate dose: spironolactone < 200 mg/day or furosemide < 80 mg/day); only 6 % discontinued diuretic use during the trials. Diuretic use did not appear to have an impact on treatment with tolvaptan [49]; however, the data from this limited analysis need to be confirmed in larger clinical trials.Fig. 5

Bottom Line: Hyponatremia is common in patients with cirrhosis and portal hypertension, and is characterized by excessive renal retention of water relative to sodium due to reduced solute-free water clearance.The primary cause is increased release of arginine vasopressin.Hyponatremia is also associated with numerous complications in liver disease patients, including severe ascites, hepatic encephalopathy, infectious complications, renal impairment, increased severity of liver disease in cirrhosis, and increased hospital stay and neurologic/infectious complications posttransplant.

View Article: PubMed Central - PubMed

Affiliation: Division of Hepatology, Montefiore Medical Center and Albert Einstein College of Medicine, 111 East 210th Street, Rosenthal 2 Red Zone, Bronx, NY 10467, USA. eric.justice@bioscicom.net

ABSTRACT
Hyponatremia is common in patients with cirrhosis and portal hypertension, and is characterized by excessive renal retention of water relative to sodium due to reduced solute-free water clearance. The primary cause is increased release of arginine vasopressin. Hyponatremia is associated with increased mortality in cirrhotic patients, those with end-stage liver disease (ESLD) on transplant waiting lists, and, in some studies, posttransplantation patients. Clinical evidence suggests that adding serum sodium to model for ESLD (MELD) scoring identifies patients in greatest need of liver transplantation by improving waiting list mortality prediction. Hyponatremia is also associated with numerous complications in liver disease patients, including severe ascites, hepatic encephalopathy, infectious complications, renal impairment, increased severity of liver disease in cirrhosis, and increased hospital stay and neurologic/infectious complications posttransplant. Vasopressin receptor antagonists, which act to increase free water excretion (aquaresis) and thereby increase serum sodium concentration, have been evaluated in patients with hypervolemic hyponatremia (including cirrhosis and heart failure) and euvolemic hyponatremia (SIADH). Tolvaptan, a selective vasopressin V(2)-receptor antagonist, is the only oral agent in this class approved for raising sodium levels in hypervolemic and euvolemic hyponatremia. The SALT trials showed that tolvaptan treatment rapidly and effectively resolved hyponatremia in these settings, including cirrhosis, and it has been shown that this agent can be safely and effectively used in long-term treatment. Fluid restriction should be avoided during the first 24 h of treatment to prevent overly rapid correction of hyponatremia, and tolvaptan should not be used in patients who cannot sense/respond to thirst, anuric patients, hypovolemic patients, and/or those requiring urgent intervention to raise serum sodium acutely.

Show MeSH
Related in: MedlinePlus