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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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Algorithm for evaluation and treatment of hypo-osmolar patients. The grey arrow running down the center emphasizes that the presence of central nervous system dysfunction due to hyponatremia should always be assessed immediately, so that appropriate therapy can be started as soon as possible in symptomatic patients, even while the outlined diagnostic evaluation is proceeding. Values for osmolality are in mOsm/kg H2O, and those referring to serum sodium concentration are in mEq/L. Δ change (in concentration), 1° primary, 2° secondary, AVP arginine vasopressin, CNS central nervous system, D/C discontinue, ECF extracellular fluid, N no, NNS normal (isotonic) saline solution, Posm plasma osmolality, Rx treat/treatment, SIADH syndrome of inappropriate antidiuretic hormone secretion, Y yes; (modified from Verbalis (2009) Hyponatremia and hypo-osmolar disorders. This chapter was published in: Greenberg A, Cheung AK, Coffman T, et al., eds. Primer on Kidney Diseases, 5th ed. Philadelphia: Saunders; 52–59)
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Fig4: Algorithm for evaluation and treatment of hypo-osmolar patients. The grey arrow running down the center emphasizes that the presence of central nervous system dysfunction due to hyponatremia should always be assessed immediately, so that appropriate therapy can be started as soon as possible in symptomatic patients, even while the outlined diagnostic evaluation is proceeding. Values for osmolality are in mOsm/kg H2O, and those referring to serum sodium concentration are in mEq/L. Δ change (in concentration), 1° primary, 2° secondary, AVP arginine vasopressin, CNS central nervous system, D/C discontinue, ECF extracellular fluid, N no, NNS normal (isotonic) saline solution, Posm plasma osmolality, Rx treat/treatment, SIADH syndrome of inappropriate antidiuretic hormone secretion, Y yes; (modified from Verbalis (2009) Hyponatremia and hypo-osmolar disorders. This chapter was published in: Greenberg A, Cheung AK, Coffman T, et al., eds. Primer on Kidney Diseases, 5th ed. Philadelphia: Saunders; 52–59)

Mentions: Currently, there are no specific guidelines for the treatment of asymptomatic hyponatremia in cirrhosis. A general algorithm for the assessment and treatment of hyponatremia is presented in Fig. 4. As noted previously, fluid restriction in combination with orally administered aldosterone antagonists and loop diuretics is currently the primary approach to treating hypervolemic hyponatremia in cirrhosis. Fluid restriction typically produces only transient benefits, however, as restriction to 500 mL is generally required for benefits to be maintained [33]. In patients resistant to fluid restriction/diuretic therapy, pharmacologic agents such as demeclocycline—which is relatively contraindicated due to a high incidence of nephrotoxicity—and the vasopressin receptor antagonist tolvaptan (profiled below) may be tried. Two small studies have also suggested that the administration of albumin, which aids the expansion of plasma volume, may improve serum sodium concentration in patients with hypervolemic hyponatremia [34, 35]; however, these data must be replicated in larger studies.Fig. 4


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)

Algorithm for evaluation and treatment of hypo-osmolar patients. The grey arrow running down the center emphasizes that the presence of central nervous system dysfunction due to hyponatremia should always be assessed immediately, so that appropriate therapy can be started as soon as possible in symptomatic patients, even while the outlined diagnostic evaluation is proceeding. Values for osmolality are in mOsm/kg H2O, and those referring to serum sodium concentration are in mEq/L. Δ change (in concentration), 1° primary, 2° secondary, AVP arginine vasopressin, CNS central nervous system, D/C discontinue, ECF extracellular fluid, N no, NNS normal (isotonic) saline solution, Posm plasma osmolality, Rx treat/treatment, SIADH syndrome of inappropriate antidiuretic hormone secretion, Y yes; (modified from Verbalis (2009) Hyponatremia and hypo-osmolar disorders. This chapter was published in: Greenberg A, Cheung AK, Coffman T, et al., eds. Primer on Kidney Diseases, 5th ed. Philadelphia: Saunders; 52–59)
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3472061&req=5

Fig4: Algorithm for evaluation and treatment of hypo-osmolar patients. The grey arrow running down the center emphasizes that the presence of central nervous system dysfunction due to hyponatremia should always be assessed immediately, so that appropriate therapy can be started as soon as possible in symptomatic patients, even while the outlined diagnostic evaluation is proceeding. Values for osmolality are in mOsm/kg H2O, and those referring to serum sodium concentration are in mEq/L. Δ change (in concentration), 1° primary, 2° secondary, AVP arginine vasopressin, CNS central nervous system, D/C discontinue, ECF extracellular fluid, N no, NNS normal (isotonic) saline solution, Posm plasma osmolality, Rx treat/treatment, SIADH syndrome of inappropriate antidiuretic hormone secretion, Y yes; (modified from Verbalis (2009) Hyponatremia and hypo-osmolar disorders. This chapter was published in: Greenberg A, Cheung AK, Coffman T, et al., eds. Primer on Kidney Diseases, 5th ed. Philadelphia: Saunders; 52–59)
Mentions: Currently, there are no specific guidelines for the treatment of asymptomatic hyponatremia in cirrhosis. A general algorithm for the assessment and treatment of hyponatremia is presented in Fig. 4. As noted previously, fluid restriction in combination with orally administered aldosterone antagonists and loop diuretics is currently the primary approach to treating hypervolemic hyponatremia in cirrhosis. Fluid restriction typically produces only transient benefits, however, as restriction to 500 mL is generally required for benefits to be maintained [33]. In patients resistant to fluid restriction/diuretic therapy, pharmacologic agents such as demeclocycline—which is relatively contraindicated due to a high incidence of nephrotoxicity—and the vasopressin receptor antagonist tolvaptan (profiled below) may be tried. Two small studies have also suggested that the administration of albumin, which aids the expansion of plasma volume, may improve serum sodium concentration in patients with hypervolemic hyponatremia [34, 35]; however, these data must be replicated in larger studies.Fig. 4

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