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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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a Correlation of MELD score and MELD-Na score calculated by Biggins et al. showing change in transplant allocation priority. The bisecting lines represent 121 transplantations performed within 6 months of listing. The 33 patients in the upper left quadrant would have been favored by MELD-Na scoring over those in the lower right quadrant, who are favored by use of MELD alone. From Biggins et al. [23] reproduced with permission. b Distribution of MELD scores and Meld-Na scores calculated by Kim et al. for 477 patients who died on the transplant waiting list. Dark shaded cells indicate patients with similar MELD and MELD-Na scores. Light shaded cells represent patients with MELD-Na scores that were higher than their MELD scores and in a range that may have resulted in their selection for transplantation. The probabilities of receiving a transplant were 18.5 % for MELD scores of 10–19, 58.4 % for scores of 20–29, and 70.4 % for scores of 30–39. According to these percentages, 32 more patients may have received transplants if MELD-Na scoring had been used, potentially preventing death in 7 % of those who died on the waiting list. From Kim et al. [4] reproduced with permission
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Fig3: a Correlation of MELD score and MELD-Na score calculated by Biggins et al. showing change in transplant allocation priority. The bisecting lines represent 121 transplantations performed within 6 months of listing. The 33 patients in the upper left quadrant would have been favored by MELD-Na scoring over those in the lower right quadrant, who are favored by use of MELD alone. From Biggins et al. [23] reproduced with permission. b Distribution of MELD scores and Meld-Na scores calculated by Kim et al. for 477 patients who died on the transplant waiting list. Dark shaded cells indicate patients with similar MELD and MELD-Na scores. Light shaded cells represent patients with MELD-Na scores that were higher than their MELD scores and in a range that may have resulted in their selection for transplantation. The probabilities of receiving a transplant were 18.5 % for MELD scores of 10–19, 58.4 % for scores of 20–29, and 70.4 % for scores of 30–39. According to these percentages, 32 more patients may have received transplants if MELD-Na scoring had been used, potentially preventing death in 7 % of those who died on the waiting list. From Kim et al. [4] reproduced with permission

Mentions: Considerable evidence suggests that addition of serum sodium level to MELD scoring better identifies patients in greatest need of liver transplantation by improving the prediction of waiting list mortality. Biggins et al. [23] developed a new scoring system to adjust MELD based on serum sodium (MELD-Na score: MELD + 1.59 (135 − serum sodium) for maximum and minimum sodium concentrations of 135 and 120 mEq/L, respectively). MELD-Na scores of 20, 30, and 40 were associated with a 6-month risk of death of 6, 16, and 37 %, respectively. It was estimated this scoring system would alter allocation of 27 % of grafts to patients who would have otherwise continued to wait to be transplanted (Fig. 3a). Similarly, in a study of 266 cirrhotic patients on the liver transplantation waiting list, MELD plus hyponatremia (≤130 mEq/L) predicted mortality significantly better than MELD alone (P = 0.006) [24]. Risk of death across all MELD scores was greater for patients with, versus without hyponatremia. In their study of patients awaiting transplantation, Kim et al. [4] found a significant difference in the c-statistic for ranking patients according to risk for death for a MELD-Na index (MELD − serum sodium − [0.025 × MELD × (140-sodium)] + 140, for sodium level between 125 and 140 mEq/L) versus the standard MELD index (0.883 vs. 0.868, P < 0.001). Comparison of use of the MELD-Na index and the MELD index among 477 patients who died within 90 days of transplant registration in 2006 showed that scores were similar using the two indices for 363 patients, and that differences between scores were sufficiently large for 110 (23 %) such that use of the MELD-Na score might have altered prioritization for graft allocation. With use of the MELD-Na score, it was estimated that 7 % of the deaths during this period might have been prevented (Fig. 3b).Fig. 3


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)

a Correlation of MELD score and MELD-Na score calculated by Biggins et al. showing change in transplant allocation priority. The bisecting lines represent 121 transplantations performed within 6 months of listing. The 33 patients in the upper left quadrant would have been favored by MELD-Na scoring over those in the lower right quadrant, who are favored by use of MELD alone. From Biggins et al. [23] reproduced with permission. b Distribution of MELD scores and Meld-Na scores calculated by Kim et al. for 477 patients who died on the transplant waiting list. Dark shaded cells indicate patients with similar MELD and MELD-Na scores. Light shaded cells represent patients with MELD-Na scores that were higher than their MELD scores and in a range that may have resulted in their selection for transplantation. The probabilities of receiving a transplant were 18.5 % for MELD scores of 10–19, 58.4 % for scores of 20–29, and 70.4 % for scores of 30–39. According to these percentages, 32 more patients may have received transplants if MELD-Na scoring had been used, potentially preventing death in 7 % of those who died on the waiting list. From Kim et al. [4] reproduced with permission
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Related In: Results  -  Collection

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Fig3: a Correlation of MELD score and MELD-Na score calculated by Biggins et al. showing change in transplant allocation priority. The bisecting lines represent 121 transplantations performed within 6 months of listing. The 33 patients in the upper left quadrant would have been favored by MELD-Na scoring over those in the lower right quadrant, who are favored by use of MELD alone. From Biggins et al. [23] reproduced with permission. b Distribution of MELD scores and Meld-Na scores calculated by Kim et al. for 477 patients who died on the transplant waiting list. Dark shaded cells indicate patients with similar MELD and MELD-Na scores. Light shaded cells represent patients with MELD-Na scores that were higher than their MELD scores and in a range that may have resulted in their selection for transplantation. The probabilities of receiving a transplant were 18.5 % for MELD scores of 10–19, 58.4 % for scores of 20–29, and 70.4 % for scores of 30–39. According to these percentages, 32 more patients may have received transplants if MELD-Na scoring had been used, potentially preventing death in 7 % of those who died on the waiting list. From Kim et al. [4] reproduced with permission
Mentions: Considerable evidence suggests that addition of serum sodium level to MELD scoring better identifies patients in greatest need of liver transplantation by improving the prediction of waiting list mortality. Biggins et al. [23] developed a new scoring system to adjust MELD based on serum sodium (MELD-Na score: MELD + 1.59 (135 − serum sodium) for maximum and minimum sodium concentrations of 135 and 120 mEq/L, respectively). MELD-Na scores of 20, 30, and 40 were associated with a 6-month risk of death of 6, 16, and 37 %, respectively. It was estimated this scoring system would alter allocation of 27 % of grafts to patients who would have otherwise continued to wait to be transplanted (Fig. 3a). Similarly, in a study of 266 cirrhotic patients on the liver transplantation waiting list, MELD plus hyponatremia (≤130 mEq/L) predicted mortality significantly better than MELD alone (P = 0.006) [24]. Risk of death across all MELD scores was greater for patients with, versus without hyponatremia. In their study of patients awaiting transplantation, Kim et al. [4] found a significant difference in the c-statistic for ranking patients according to risk for death for a MELD-Na index (MELD − serum sodium − [0.025 × MELD × (140-sodium)] + 140, for sodium level between 125 and 140 mEq/L) versus the standard MELD index (0.883 vs. 0.868, P < 0.001). Comparison of use of the MELD-Na index and the MELD index among 477 patients who died within 90 days of transplant registration in 2006 showed that scores were similar using the two indices for 363 patients, and that differences between scores were sufficiently large for 110 (23 %) such that use of the MELD-Na score might have altered prioritization for graft allocation. With use of the MELD-Na score, it was estimated that 7 % of the deaths during this period might have been prevented (Fig. 3b).Fig. 3

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